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Library of Congress Cataloging-in-Publication Data

Hastings, Caroline, 1960-

Handbook of pediatric hematology and oncology : Children’s Hospital &

Research Center Oakland / Caroline A. Hastings, Joseph Torkildson, Anurag

Kishor Agrawal. - 2nd ed.

p. ; cm.

Rev. ed. of: The Children’s Hospital Oakland hematology/oncology handbook /

Caroline Hastings. 1st ed. c2002.

Includes bibliographical references and index.

ISBN 978-0-470-67088-0 (pbk. : alk. paper)

Torkildson, Joseph. II. Agrawal, Anurag Kishor. III. Hastings, Caroline,

1960- Children’s Hospital Oakland hematology/oncology handbook. IV. Children’s

Hospital Medical Center (Oakland, Calif.) V. Title.

[DNLM: 1. Child. 2. Hematologic Diseases-Handbooks.

3. Neoplasms-Handbooks. WS 39]

618.97⁰6994-dc23

2011048154

A catalog record for this book is available from the British Library.

Set in 10/12.5 pt Minon by Thomson Digital, Noida, India

2011

Preface

The pace of change in the field of pediatric

never mentioned in the large studies or

hematology and oncology is staggering.

case reports.

Molecular biology, genomics, and bio-

This handbook represents the work of my

chemistry have accelerated the accumula-

colleagues at Children’s Hospital & Research

tion of knowledge and understanding of

Center Oakland toward this endeavor. The

disease states. Yet the application of this

guidelines offered here have been used to

new knowledge to the individual child

train medical students, pediatric residents,

before you, the work of the physician, is

and pediatric hematology/oncology fellows

often overwhelming, even for the most

for over 20 years. This handbook will give you

experienced practitioner. The course and

clinical approaches for common problems in

prognosis for the child is often determined

pediatric hematology and oncology, the

by the rapidity of disease onset, diagnosis,

knowledge to organize and to evaluate the

and initial treatment. What is needed is

care of your patients, and a framework to

a practical, tested approach to these

incorporate ever-expanding psychosocial

problems that ensures timely evaluation,

needs, clinical studies, medical treatments,

competent early care, and avoidance of

and science. All of these are essential com-

pitfalls that might prejudice future treat-

ponents that make up the care of the child

ment options. This practical approach is

with cancer or a blood disease.

clearly brought by spending time with

the patients and their families, and

Caroline Hastings, M.D.

observing the myriad variations that are

March 2012

Approach to the

Anemic Child

Anemia is the condition in which the con-

age (Table 1.1). The blood smear and red

centration of hemoglobin or the red cell

cell indices are very helpful in the diagnosis

mass is reduced below normal. Anemia

and classification of anemia. It allows for

results in a physiological decrease in the

classification by the cell size (MCV, mean

oxygen-carrying capacity of the blood and

corpuscular volume), gives the distribution

reduced oxygen supply to the tissues. Causes

of cell size

(RDW, red cell distribution

of anemia are increased loss or destruction

width), and may give important diagnostic

of red blood cells (RBCs) or a significant

clues if specific morphological abnormali-

decreased rate of production. When evalu-

ties are present (e.g., sickle cells, target cells,

ating a child with anemia, it is important to

and spherocytes). The MCV, RDW, and

determine if the problem is isolated to one

reticulocyte count are helpful in the differ-

cell line (e.g., RBCs) or multiple cell lines

ential diagnosis of anemia. A high RDW, or

(i.e., RBCs, white blood cells [WBCs], or

anisocytosis, is seen in stress erythropoiesis

platelets). When two or three cell lines are

and is often suggestive of iron deficiency or

affected, it may indicate bone marrow

hemolysis. A normal or low reticulocyte

involvement (leukemia, metastatic disease,

count is an inappropriate response to ane-

and aplastic anemia), sequestration

(i.e.,

mia and suggests impaired red cell produc-

hypersplenism), immune deficiency, or an

tion. An elevated reticulocyte count suggests

immune-mediated process (e.g., hemolytic

blood loss, hemolysis, or sequestration.

anemia and immune thrombocytopenic

The investigation of anemia requires

purpura).

the following steps:

1. The medical history of the anemic child

(Table 1.2), as certain historical points may

Evaluation of anemia

provide clues as to the etiology of the

anemia.

The evaluation of anemia includes a com-

2. Detailed physical examination (Table 1.3),

plete medical history, family history, physical

with particular attention to acute and chronic

examination, and laboratory assessment. See

effects of anemia.

Figure 1.1.

3. Evaluation of the complete blood count

The diagnosis of anemia is made after

(CBC), RBC indices, and peripheral blood

reference to established normal controls for

smear, with classification by MCV,

Handbook of Pediatric Hematology and Oncology: Children’s Hospital & Research Center Oakland,

Second Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.

2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

Chapter 1

History

Physical examination

Complete blood count

Reticulocyte count

Peripheral blood smear examination

Microcytic*

Normocytic*

Macrocytic*

Iron deficiency

Early iron deficiency

Normal newborn

Dietary

Acute blood loss

Reticulocytosis

Chronic blood loss

Hemolysis

Post splenectomy

Thalassemia, α or β

Red cell enzyme deficiency

Liver disease

Hemoglobin E

Red cell membrane defects

Aplastic anemia

Lead toxicity

Red cell aplasia

Bone marrow failure

Chronic disease/Infection

Aplastic anemia

syndromes

Severe malnutrition

DBA, TEC

Hypothyroidism

Sideroblastic anemia

Malignancy

Down syndrome

Infection

Preleukemia

Syndromes with elevated Hgb F

Renal failure

Megaloblastic anemia

Hypersplenism

Folic acid deficiency

Drugs

Malabsorption, drugs

Vitamin B12 deficiency

Evaluations

Dietary

To Consider

Pernicious anemia

Iron Studies

Red cell enzyme panel

Liver function tests

RDW, FEP, ferritin,

G6PD, Pyruvate kinase

Thyroid function tests

transferrin saturation, TIBC

Osmotic fragility/Ektacytometry

Hemoglobin electrophoresis

Coombs test (DAT)

Folic acid level

Lead level

Hemoglobin electrophoresis

Red cell

Family studies

Bone marrow aspirate

Serum

Check newborn screen

Vitamin B12 level

Oral iron challenge

Bone marrow aspirate

Figure 1.1 Diagnostic approach to the child with anemia. (Abbreviations: DBA, Diamond-Blackfan

anemia; TEC, transient erythroblastopenia of childhood; RDW, red cell distribution width; FEP, free

erythrocyte protoporphyrin; TIBC, total iron binding capacity; G6PD, glucose-6-phosphate dehy-

drogenase deficiency; DAT, direct antiglobulin test).

Refer to Table 1.1 for age-based normal values.

reticulocyte count, and RBC morphology.

Interventions

Consideration should also be given to the

WBC and platelet counts as well as their

Oral iron challenge

respective morphology.

An oral iron challenge may be indicated

4. Determination of an etiology of the

in the patient with significant iron deple-

anemia by additional studies as needed

tion, as documented by moderate-to-severe

(see Figures 1.1, 1.2, and 1.3).

anemia and deficiencies in circulating

Approach to the Anemic Child

Table 1.1 Red blood cell values at various ages.*

Age

Hemoglobin (g/dL)

MCV (fL)

Mean

2 SD

Mean

2 SD

Birth (cord blood)

16.5

13.5

108

1-3 d (capillary)

18.5

14.5

108

1 wk

17.5

13.5

107

2 wk

16.5

12.5

105

1 mo

14.0

10.0

104

2 mo

11.5

9.0

3-6 m

11.5

9.5

0.5-2 y

12.0

11.0

2-6 y

12.5

11.5

6-12 y

13.5

11.5

12-18 y female

14.0

12.0

12-18 y male

14.5

13.0

18-49 y female

14.0

12.0

18-49 y male

15.5

13.5

Compiled from the following sources: Dutcher TF. Lab Med 2:32-35, 1971; Koerper

MA, et al. J Pediatr 89:580-583, 1976; Marner T. Acta Paediatr Scand 58:363-368, 1969; Matoth Y,

et al. Acta Paediatr Scand 60:317-323, 1971; Moe PJ. Acta Paediatr Scand 54:69-80, 1965; Okuno

T. J Clin Pathol 2:599-602, 1972; Oski F, Naiman J. Hematological Problems in the Newborn, 2nd

ed., Philadelphia: WB Saunders, 1972, p. 11; Penttila I, et al. Suomen Laakarilehti 26:2173, 1973;

and Viteri FE, et al. Br J Haematol 23:189-204, 1972. Cited in: Rudolph AM (ed). Rudolph’s

Pediatrics, 16th ed., Norwalk, CT: Appleton & Lange, 1977.

Abbreviation: MCV, mean corpuscular volume.

and storage iron forms

(such as total

elemental iron) orally; third, draw another

iron-binding capacity [TIBC], serum iron,

serum iron level 30 to 60 minutes later.

transferrin saturation, and ferritin). Iron

The serum level is expected to increase by

absorption is impaired in certain chronic

at least

100 mcg/dL if absorption is ade-

disorders

(autoimmune diseases such as

quate. The oral iron challenge is a quick

lupus, peptic ulcer disease, ulcerative

and easy method to assess appropriateness

colitis, and Crohn’s disease), by certain

of oral iron to treat iron deficiency—a safer,

medications

(antacids and histamine-2

cheaper yet equally efficacious method of

blockers), and by environmental factors

treatment as parenteral iron.

such as lead toxicity.

Indications for an oral iron challenge

Parenteral iron therapy

include any condition in which a poor

Due to the potential risks of older parenteral

response to oral iron is being questioned,

iron preparations (specifically high molec-

such as in: noncompliance, severe anemia

ular weight iron dextran), a reluctance

secondary to dietary insufficiency (exces-

remains to use the newer and much safer

sive milk intake), and ongoing blood loss.

formulations. The majority of safety data

Administration of an oral iron challenge

exists with low molecular weight (LMW)

is quite simple: first, draw a serum iron level;

iron dextran although many practitioners

second, administer a dose of iron (3 mg/kg

have moved to newer (and perceived safer)

Chapter 1

Table 1.2 The medical history of the anemic child.

History of

Consider

Prematurity

Anemia of prematurity (EPO responsive)

Perinatal risk factors

Maternal illness (autoimmune)

Hemolytic anemia

Drug ingestion

Impaired production

Infections (TORCH [e.g., rubella, CMV],

hepatitis)

Perinatal problems

Acute blood loss

Fetal-maternal hemorrhage

Iron deficiency due to above or maternal iron

deficiency

Ethnicity

African-American

Hgb S, C; a- and b-thalassemia; G6PD deficiency

Mediterranean

a- and b-thalassemia; G6PD deficiency

Southeast Asian

a- and b-thalassemia; Hgb E

Family history

Gallstones, cholecystectomy

Inherited hemolytic anemia, spherocytosis,

elliptocytosis

Splenectomy, jaundice at birth or

Inherited enzymopathy, G6PD, pyruvate kinase

with illness

deficiencies

Isoimmunization (Rh or ABO)

Hemolytic disease of newborn (predisposed to

iron deficiency)

Sex

Male

X-linked enzymopathies (G6PD deficiency)

Early jaundice (<24 h of age)

Isoimmune, infectious

Persistent jaundice

Suggests hemolytic anemia

Diet (Usually > 6 mo)

Pica (ice, dirt)

Lead toxicity, iron deficiency

Excessive milk intake

Iron deficiency

Macrobiotic diets

Vitamin B₁₂ deficiency

Goat’s milk

Folic acid deficiency

Drugs

Sulfa drugs, anticonvulsants

Hemolytic anemia (G6PD deficiency)

Chloramphenicol

Hypoplastic anemia

Low socioeconomic status

Pica

Lead toxicity, iron deficiency

Malnutrition

Malabsorption

Anemia of chronic disease

Environmental

Iron, vitamin B₁₂, or folate deficiency, vitamin E

or K deficiency

Liver disease

Shortened red cell survival

Heinz bodies

Renal disease

Shortened red cell survival

Decreased red cell production (#EPO)

Infectious diseases

Mild viral infection (acute gastroenteritis,

Transient mild decreased Hgb

otitis media, pharyngitis)

Sepsis (bacterial, viral, mycoplasma)

Hemolytic anemia

Parvovirus

Anemia with reticulocytopenia (TEC)

Abbreviations: EPO, erythropoietin; TORCH, toxoplasmosis, other, rubella, cytomegalovirus,

herpes simplex virus; G6PD, glucose-6-phosphate dehydrogenase deficiency; TEC, transient

erythroblastopenia of childhood.

Approach to the Anemic Child

Table 1.3

Physical examination of the anemic child.

System

Clinical sign or symptom

Potential underlying disorder

Skin

Pallor

Severe anemia

Jaundice

Hemolytic anemia, acute and chronic

hepatitis, aplastic anemia

Petechiae, purpura

Autoimmune hemolytic anemia with

thrombocytopenia, hemolytic uremic

syndrome, bone marrow aplasia or

infiltration

Cavernous hemangioma

Microangiopathic hemolytic anemia

HEENT

Frontal bossing, prominent

Extramedullary hematopoiesis (thalassemia

malar and maxillary bones

major, congenital hemolytic anemia)

Icteric sclerae

Congenital hemolytic anemia and hyper-

hemolytic crises associated with infection

(red cell enzyme deficiencies, red cell

membrane defects, thalassemias,

hemoglobinopathies)

Angular stomatitis

Iron deficiency

Glossitis

Vitamin B₁₂ or iron deficiency

Chest

Rales, gallop rhythm,

Congestive heart failure, acute or severe

tachycardia

anemia

Spleen

Splenomegaly

Congenital hemolytic anemia, infection,

hematological malignancies, portal

hypertension, resultant hypersplenism

Extremities

Radial limb dysplasia

Fanconi anemia

Spoon nails

Iron deficiency

Triphalangeal thumbs

Red cell aplasia

formulations including ferric gluconate and

Dosage ðmLÞ ¼ 0:0442

LBW ðkgÞ

iron sucrose. Three additional compounds

ðHgb_n Hgb_oÞ

have been approved recently, 2 in Europe

þ ½0:26

LBW ðkgÞ ;

(ferric carboxymaltose and iron isomalto-

where

side) and 1 in the United States (ferumox-

LBW ¼ lean body weight

ytol). These newer agents have the potential

benefit of total dose replacement in a very

males: 50 kg þ 2:3 kg for every

short and single infusion as compared to

inch over 5 ft in height

ferric gluconate and iron sucrose which

females: 45:5 kg þ 2:3 kg for

require multiple doses. LMW iron dextran

every inch over 5 ft in height

is approved as a total dose infusion for

Hgb_n ¼ desired hemoglobin ðg=dLÞ ¼ 12

adults in Europe but not the United States.

Due to the smaller dose generally required

< 15 kg or 14:8 if > 15 kg

in pediatric patients, total iron replacement

Hgb_o ¼ measured hemoglobin ðg=dLÞ

is feasible in

1 to 2 doses of LMW iron

dextran. Calculation of the necessary dose is

The maximum adult dose is 2 mL and

as follows:

each milliliter of iron dextran contains 50 mg

Chapter 1

Assess degree of anemia

Mild

Moderate

Severe

(Hemoglobin > 10 g/dL)

(Hemoglobin 7-10 g/dL)

(Hemoglobin < 7 g/dL)

History and physical exam

compatible with iron deficiency

History, physical,

iron studies, consider

hemoglobin electrophoresis

and family studies

Trial of oral iron

Iron Studies

4-6 mg/kg/day

FEP

Consider

Dietary counseling

Iron, TIBC, % iron

Reticulocyte count

Deficient

saturation

Review smear

Hospitalization

at 1 week

Reticulocyte count

Transfusion

Stool guaiac

IV or oral iron

(if indicated)

Not Deficient

Continue oral iron

Hemoglobinopathy/Thalassemia

3-6 months

Consider

Hgb electrophoresis

Family studies

Blood Loss

Lead toxicity

Consider

Urinalysis

Stool guaiac

Meckel’s scan

Severe iron deficiency

Hemolysis

Red cell aplasia

Coombs test (DAT)

Malignancies

Peripheral smear

Infections

Hemoglobinopathy/Thalassemia

Hemolytic anemia with

Hemoglobin electrophoresis

illness/infection

Family studies

Thalassemia

Lead poisoning

Hgb H disease

Iron malabsorption

β-thalassemia major

Iron studies

Hemoglobinopathy

Oral iron challenge

Sickle cell disease

Consider parenteral iron

Bowel disease (Crohn’s, IBD)

Inflammatory disorder (lupus)

Figure 1.2 Evaluation of the child with microcytic anemia. (Abbreviations: FEP, free erythrocyte

protoporphyrin; TIBC, total iron binding capacity; DAT, direct antiglobulin test; IBD, inflammatory

bowel disease).

of elemental iron. Add 10 mg elemental iron/

utilized. A test dose (10 to 25mg) should be

kg to replenish iron stores (chronic anemia

given prior to the first dose with observation

states). Replacement may be given in a single

of the patient for 30 to 60 minutes prior to

dose, depending on the dose required. See

administering the remainder of the dose. A

the formulary for further information.

common side effect is mild to moderate

Severe allergic reactions can occur

arthralgias the day after drug administration,

with iron dextran and the low molecular

especially in patients with autoimmune

weight product should be preferentially

disease.

Acetaminophen

frequently

Approach to the Anemic Child

Low hemoglobin concentration

Low

Elevated or normal

reticulocyte

reticulocyte count

count

Infection

TORCH

Congenital hypoplastic anemia

Coombs test (DAT)

Transcobalamin II deficiency

Immune hemolytic anemia

Positive

ABO incompatibility

Rh incompatibility

Minor blood group incompatibility

Negative

Microcytic

α-thalassemia syndrome

Normocytic

Chronic intrauterine blood loss

Macrocytic

Iron deficiency

Blood loss

Peripheral smear

Iatrogenic

Traumatic delivery

Internal hemorrhage

Normal

Twin-twin transfusion

Fetal-maternal transfusion

Abnormal

Infection

TORCH

Membrane defect

Hereditary spherocytosis

Hereditary elliptocytosis

Red cell enzyme deficiency

G6PD

Pyruvate kinase

Figure 1.3 Approach to the full-term newborn with anemia. (Abbreviations: DAT, direct antiglobulin

test; G6PD, glucose-6-phosphatase deficiency; TORCH, toxoplasmosis, other, rubella, cytomegalo-

virus, herpes simplex virus).

alleviates the arthralgias. Iron dextran is

doses are more convenient and feasible than

contraindicated in patients with rheuma-

the outpatient setting. With continued

toid arthritis.

usage and safety data, ferumoxytol will

Iron sucrose or ferric gluconate can be

likely replace the currently used products

considered in inpatients in which multiple due to the much larger maximum dose that

Chapter 1

can be given, lack of need for a test dose, and

transfusions to children with cardiovascular

excellent side effect profile.

compromise (i.e., gallop rhythm, pulmo-

nary edema, excessive tachycardia, and poor

Erythropoietin

perfusion) while being monitored in an ICU

Recombinant human erythropoietin

setting. Transfusions are given in multiple

(EPO) stimulates proliferation and differ-

small volumes, sometimes separated by sev-

entiation of erythroid precursors, with an

eral hours, with careful monitoring of the

increase in heme synthesis. This increased

vitals and fluid balance. For those children

proliferation creates an increased demand

who have gradual onset of severe anemia,

in iron availability and can result in a

without cardiovascular compromise, con-

functional iron deficiency if not given with

tinuous transfusion of 2 mL/kg/h has been

iron therapy.

shown to be safe and result in an increase in

Indications for EPO include end-stage

the hematocrit of 1% for each 1 mL/kg of

renal disease, anemia of prematurity,

transfused packed RBCs (based on RBC

anemia of chronic disease, anemia associ-

storage method). The hemoglobin should

ated with treatment for AIDS, and autolo-

be increased to a normal value to avoid

gous blood donation. EPO use for the

further cardiac compromise

(i.e., Hgb

treatment of chemotherapy-induced ane-

to 12 g/dL). Again, the final endpoint may

mia remains controversial and is not rou-

be dependent on several factors including

tinely recommended in pediatric patients

nature of anemia, ongoing blood loss or lack

(see Chapter 25).

of production, baseline hemoglobin, and

The most common side effect of EPO

volume to be transfused. Care should be

administration is hypertension, which may

taken to avoid unnecessary exposure to

be somewhat alleviated with changes in the

multiple blood donors by maximal use of

dose and duration of administration.

the unit of blood, proper division of units in

Typical starting dose of EPO is 150 U/kg

the blood bank, and avoidance of opening

three times a week (IV) or subcutaneous

extra units for small quantities to meet a

(SC). CBCs and reticulocyte counts are

total volume. See Chapter 5 for product

checked weekly. Higher doses, and more

preparation, ordering, and premedication.

frequent dosing, may be necessary. Response

A posttransfusion hemoglobin can be

is usually seen within 1 to 2 weeks. Adequate

checked if necessary at any point after the

iron intake (3 mg/kg/d orally or intermittent

transfusion has been completed. Waiting

parenteral therapy) should be provided to

for “reequilibration” is anecdotal and un-

optimize effectiveness and prevent iron

necessary.

deficiency.

Transfusion therapy

Case study for review

Children with very severe anemia (Hgb < 5

g/dL) may require treatment with red cell

You are seeing a one year old for their well

transfusion, depending on the underlying

child check in clinic. As part of routine

disease and baseline hemoglobin status,

screening, a fingerstick hemoglobin is

duration of anemia, rapidity of onset, and

recommended.

hemodynamic stability. The pediatric liter-

ature is scarce as to the best method of

1. What questions in the history might help

transfusing such patients. However, it

screen for anemia?

appears to be common practice to give slow

2. What about the physical examination?

Approach to the Anemic Child

Multiple questions in the history can be

disease, or a suggestive newborn screen, an

helpful. Dietary screening for excessive milk

empiric trial of oral iron supplementation

intake is important in addition to asking

should not be performed. Similarly, if there

about intake of iron-rich foods such as

are signs that are consistent with a hemolytic

green leafy vegetables and red meat. One

process or a significant underlying disorder,

should also ask about pica behavior such as

further workup should be done. In these

eating dirt or ice and include questions

cases, it would be correct to next perform

regarding the age of the house to help screen

a CBC. If there are concerns for sickle cell

for lead paint exposure and ingestion. Any

disease or thalassemia, it would be reason-

sources of blood loss should also be

able to also perform hemoglobin electro-

explored including blood in the urine or

phoresis. If there are concerns for hemoly-

stool as well as frequent gum or nose bleed-

sis, labs including reticulocyte count, total

ing (more likely in an older child). Finally,

bilirubin, lactate dehydrogenase, and a

family history should be explored regarding

direct Coombs should be performed.

anemia during pregnancy, previous history

Finally, if there is concern for a systemic

of iron deficiency in siblings, and history of

illness such as leukemia, a manual differ-

hemoglobinopathies.

ential should be requested. Further workup

Physical examination to search for ane-

for iron deficiency

(ferritin and TIBC)

mia should be focused. Pallor, especially

as well as lead toxicity could be included

subconjunctival, perioral, and periungual

or deferred until the anemia is better

should be checked. Tachycardia, if present,

characterized utilizing the MCV and RDW

would be more consistent with acute anemia

on the CBC.

rather than well-compensated chronic ane-

mia. Splenomegaly, sclera icterus, and jaun-

dice may point to an acute or chronic

Suggested Reading

hemolytic picture.

Auerbach M, Ballard H. Clinical use of intrave-

You do the fingerstick hemoglobin in

nous iron: administration, efficacy, and safety.

clinic and it is 10.2 g/dL. The history is not

Hematology Am Soc Hematol Educ Program

suggestive of iron deficiency and the exam is

338-347, 2010.

unremarkable.

Bizzarro MJ, Colson E, Ehrenkranz RA. Differ-

ential diagnosis and management of anemia

3. What are the reasonable next steps?

in the newborn. Pediatr Clin North Am

Depending on the prevalence of iron

51:1087-1107, 2004.

deficiency in your population, it would be

Hermiston ML, Mentzer WC. A practical

reasonable at this point to give a 1 month

approach to the evaluation of the anemic

child. Pediatr Clin North Am 49:877-891,

trial of oral iron therapy. The family should

2002.

be counseled that oral iron tastes bad and

Janus J, Moerschel SK. Evaluation of anemia in

should be given with vitamin C (i.e., orange

children. Am Fam Physician 81:1462-1471,

juice) and not milk to improve absorption.

2010.

If there is a low likelihood of iron deficiency,

Richardon M. Microcytic anemia. Pediatr Rev

a family history of thalassemia or sickle cell

28:5-14, 2007.

Hemolytic Anemia

Red blood cells (RBCs) normally live for

has intermittent jaundice, and hemolytic or

about 100 to 120 days in the circulation.

red cell aplastic episodes associated with

Hemolytic anemia results from a reduced red

viral infection, splenomegaly, and choleli-

cell survival due to increased destruction. To

thiasis. However, the clinical presentation is

compensate for a reduced RBC life span, the

quite variable, with most severe cases pre-

bone marrow increases its output of red cells,

senting in the newborn period or early

a response mediated by erythropoietin.

childhood and milder cases presenting in

Destruction of red cells can be intravascular

adulthood.

(within the circulation) or extravascular (by

Several membrane protein defects are

phagocytic cells of the bone marrow, liver,

responsible for HS. Most result in the insta-

or spleen). Red cell injury or destruction is

bility of spectrin, one of the major red cell

associated with a transformation to a rigid

skeletal membrane proteins. Structural

or abnormal form. Altered cell deformability

changes that result as a consequence of pro-

then leads to decreased survival. Hemolytic

tein deficiency lead to membrane instability,

anemia may be inherited

(thalassemias,

loss of surface area, abnormal membrane

hemoglobinopathies, red cell enzyme defi-

permeability, and decreased red cell deform-

ciencies, or membrane defects) or acquired

ability. Metabolic depletion accentuates the

(immune-mediated, associated with infec-

defect in HS cells, which accounts for an

tion, or medication related). It can be chronic

increase in osmotic fragility after a 24-hour

or acute. Some types of low-grade chronic

incubation of whole blood at 37

C. The

hemolytic anemias can have acute exacerba-

splenic sinusoids prevent passage of nonde-

tions, such as a child with glucose-6-

formable spherocytic red cells. This explains

phosphate dehydrogenase (G6PD) deficiency

the occurrence of splenomegaly in HS and

with an exposure to fava beans or

the therapeutic effect of splenectomy.

naphthalene.

Patients with HS have a mild-to-moderate

chronic hemolytic anemia. Red cell indices

reveal a normal to low mean corpuscular

Red cell membrane disorders

volume (MCV) depending on the number

of microspherocytes. Cellular dehydration

Hereditary spherocytosis (HS) is the most

increases the mean corpuscular hemoglobin

common congenital red blood cell mem-

concentration

(characteristically

>36%).

brane disorder. The usual patient with HS

The red cell distribution width (RDW) is

Handbook of Pediatric Hematology and Oncology: Children’s Hospital & Research Center Oakland,

Second Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.

2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

Hemolytic Anemia

elevated because of the variable presence

peripheral blood after splenectomy and

of microspherocytes and reticulocytes in

the osmotic fragility is more abnormal, the

proportion to the degree of hemolysis. The

hemoglobin value is normal. Platelet

peripheral blood smear can be diagnostic

counts frequently increase to more than

with the presence of spherocytes, although

1000

10⁹/L immediately after splenec-

this can be a normal finding in the patient

tomy but return to normal levels over

with severe anemia and a resultant reticulo-

several weeks. No therapeutic interventions

cytosis. Osmotic fragility tests and ektacyto-

are required for postsplenectomy thrombo-

metry studies are characteristic for HS,

cytosis in patients with HS.

with increased fragility in hypotonic

To minimize the risk of sepsis due to

environments.

Haemophilus influenza and Streptococcus

As with other hemolytic anemias,

pneumoniae, the splenectomy procedure

affected individuals are susceptible to hypo-

(when necessary) is often postponed until

plastic crises during viral infections. Human

after the child’s fifth or sixth birthday.

parvovirus B19, a frequent pathogen and the

Patients should be immunized against these

organism responsible for erythema infectio-

organisms in addition to Neisseria meningi-

sum (fifth disease), selectively invades ery-

ditis prior to splenectomy and receive pen-

throid progenitor cells and may result in a

icillin prophylaxis following the procedure.

transient arrest in red cell proliferation.

The increase in penicillin-resistant strains of

Recovery begins within 7 to 10 days after

S. pneumoniae has raised questions regard-

infection and is usually completed by 4 to 6

ing the use of prophylactic penicillin. No

weeks. If the initial presentation of a patient

studies have determined the frequency of

with HS is during an aplastic crisis, a diag-

this problem in children receiving prophy-

nosis of HS might not be considered because

lactic penicillin after splenectomy.

the reticulocyte count will be low and the

peripheral blood smear may be nondiagnos-

tic. The family history of HS should be

Red cell enzyme deficiencies

explored; if it is positive, the patient should

be evaluated for HS after recovery from the

Glucose is the primary metabolic substrate

aplastic episode.

for the red cell. Because the mature red cell

Splenectomy is often considered for

does not contain mitochondria, it can

patients who have had severe hemolysis

metabolize glucose only by anaerobic

requiring transfusions or repeated hospital-

mechanisms. The two major metabolic

ization. In patients with mild hemolysis, the

pathways within the red cell are the

decision to perform splenectomy should be

Embden-Meyerhof pathway (EMP) and the

delayed; in many cases, it is not required.

hexose monophosphate shunt.

For pediatric patients who have excessive

Red cell morphological changes are

splenic size, an additional consideration for

minimal in patients with red cell enzyme

splenectomy is to diminish the risk of trau-

deficiency involving the EMP. Red cell

matic splenic rupture. The risks of splenec-

indices are usually normocytic and normo-

tomy must be considered before any clinical

chromic. The reticulocyte count is elevated

decision is made regarding the procedure.

in proportion to the extent of hemolysis.

Red cell survival returns to normal

Because many enzyme activities are

values after splenectomy unless an accessory

normally increased in young red cells, a

spleen develops. Although an increased

mild deficiency in one of the enzymes may

number of spherocytes can be seen in the

be obscured by the reticulocytosis.

Chapter 2

Pyruvate kinase (PK) deficiency is the

Mediterraneans, American Indians, South-

most common enzyme deficiency in the

east Asians, and Sephardic Jews are also

EMP. The inheritance pattern of this disor-

affected. In African-Americans, 12% of the

der is autosomal recessive. Homozygotes

male population has the deficiency, 18% of

usually have hemolytic anemia with spleno-

the female population is heterozygous, and

megaly, whereas heterozygotes are usually

2% of the female population is homozy-

asymptomatic. The disorder is found world-

gous. In Southeast Asians, G6PD deficiency

wide, although it is most common in Cau-

is found in approximately 6% of the male

casians of northern European descent. The

population. Most likely, the prevalence of

range of clinical expression is variable, from

this enzyme abnormality confers resistance

severe neonatal jaundice to a fully compen-

to malaria, thus its geographic distribution.

sated hemolytic anemia. Anemia is usually

Many variants of G6PD deficiency are

normochromic and normocytic, but macro-

known and have been characterized at the

cytes may be present shortly after a hemo-

biochemical and molecular levels. A variant

lytic crisis, reflecting erythroid hyperplasia

found in Mediterraneans is associated with

and early release of immature red cells. The

chronic hemolytic anemia. Other variants

osmotic fragility of red cells is normal to

are associated with an unstable enzyme that

slightly reduced. Diagnosis is confirmed by a

has normal levels in young red cells. These

quantitative assay for pyruvate kinase, by

result in hemolysis only in association with

the measurement of enzyme kinetics and

an oxidant challenge (as found in African-

glycolytic intermediates, and by family

Americans). In some cases of G6PD defi-

studies.

ciency, hemolysis may be triggered by the

Splenectomy is a therapeutic option for

oxidant intermediates generated during

PK-deficient patients. As with HS, the deci-

viral or bacterial infections or after ingestion

sion should be made on the basis of the

of oxidant compounds. Shortly after expo-

patient’s clinical course. Unlike HS patients,

sure to the oxidant, hemoglobin is oxidized

PK-deficient patients, although they

to methemoglobin and eventually dena-

improve after splenectomy, do not have

tured, forming intracellular inclusions

complete correction of their hemolytic ane-

called Heinz bodies that attach to the red

mia. As with all hemolytic anemias, these

cell membrane. This portion of the mem-

patients should have dietary supplementa-

brane may be removed by reticuloendothe-

tion with folic acid (1 mg/day) to prevent

lial cells resulting in a “bite” cell that has a

megaloblastic complications associated with

shortened survival owing to its loss of mem-

relative folate deficiency. Immunization

brane components. To compensate for

against H. influenza, S. pneumonia, and N.

hemolysis, red cell production is increased

meningiditis should be given, as well as

and thus the reticulocyte count is increased.

lifelong penicillin prophylaxis in the sple-

Individuals with the Mediterranean or

nectomized patient.

Asian forms of G6PD deficiency, in addition

Glucose-6-phosphate dehydrogenase

to being sensitive to infections and certain

(G6PD) deficiency is the most common

drugs, often have a chronic, moderately

X-linked red cell enzyme deficiency, with

severe anemia, with nonspherocytic red

partial expression in the female population

cells and jaundice. Hemolysis usually starts

and full expression in the affected male

in early childhood. Reticulocytosis is pres-

population. The distribution of G6PD defi-

ent and can increase the MCV.

ciency is worldwide, with the highest inci-

When a hemolytic crisis occurs in G6PD

dence in Africans and African-Americans.

deficiency (or favism), pallor, scleral icterus,

Hemolytic Anemia

hemoglobinemia, hemoglobinuria, and

jaundice, scleral icterus, elevated bilirubin,

splenomegaly may be noted. Plasma hapto-

and anemia with reticulocytosis). Fortu-

globin and hemopexin concentrations are

nately, the majority of pediatric cases of

low with a concomitant rise in plasma-free

autoimmune hemolytic anemia (AIHA) are

hemoglobin. The peripheral smear shows

acute and self-limited.

the fragmented bite cells and polychromato-

In the DAT, the patient’s erythrocytes

philic cells. Red cell indices may be normal.

are washed and then incubated with specific

Special stains can detect Heinz bodies in the

antiglobulin antisera (usually anti-IgG and

cells during the first few days of hemolysis.

anti-C3d). Agglutination indicates a posi-

A diagnosis of G6PD deficiency should be

tive test. In patients with severe immune-

based on family history, ethnicity, laboratory

mediated hemolytic anemia, the DAT is

features, physical findings, and clinical sus-

often strongly positive, although the

picion suggested by a recent exposure to

strength of the reaction does not always

oxidants with resultant acute hemolysis. The

correlate to the severity of the disease. Sim-

diagnosis is confirmed by a quantitative

ilarly, up to 80% of patients will have anti-

enzyme assay or by molecular analysis of the

bodies in the serum as well, measured by the

gene. Since reticulocytes may have a normal

indirect Coombs (indirect antiglobulin test,

level of G6PD enzyme activity, screening tests

IAT). In the IAT, donor erythrocytes are

during acute hemolysis may be falsely ele-

incubated with test serum, washed, and then

vated; therefore, it is important to test once

incubated with specific antiglobulin anti-

the hemolytic crisis has ended and the patient

sera. Agglutination again indicates a posi-

again has mature red blood cells. Treatment is

tive test. Of note, patients without symp-

directed toward supportive care during the

toms of hemolysis may have a positive DAT

acute event and counseling regarding pre-

and/or IAT; therefore, screening is only

vention of future hemolytic crises. In patients

recommended in the setting of clinical and

with chronic hemolysis, dietary supplemen-

laboratory signs of hemolysis. In approxi-

tation with folic acid (1 mg/day) is recom-

mately 5% to 10% of cases, patients may

mended. Use of vitamin E, 500 mg/day, may

have an AIHA with a negative DAT.

improve red cell survival in patients with

The initiation of autoimmunity is poorly

chronic hemolysis.

understood. Viral syndromes are often pro-

posed as a culprit, although causation has

been hard to prove. A majority of cases of

Autoimmune hemolytic anemia

AIHA in pediatrics are due to “warm” anti-

bodies, so named because they react at

In addition to intrinsic causes of hemolytic

37 C. These are often secondary to a viral

anemia, patients may also develop an auto-

syndrome, although patients with an under-

antibody and/or alloantibody toward their

lying autoimmune disease or oncological

red blood cells. The underlying cause for

process can also present with a warm AIHA.

this antibody formation is often idiopathic

The formation of IgG antibodies leads

or due to a secondary condition including

to extravascular hemolysis in which pieces

drugs, infectious syndromes, autoimmune

of the red cell membrane are sequentially

diseases, or an oncological process. A pos-

removed during passages through the

itive direct antiglobulin test (DAT, direct

spleen. Patients may also develop direct

Coombs) is pathognomonic for immune-

Coombs positive hemolytic anemia and

mediated hemolysis with the appropriate

immune-mediated

thrombocytopenia

clinical and laboratory findings

(i.e.,

(Evans syndrome).

Chapter 2

Hemolytic disease of the

damaged by the formation of an intravas-

newborn

cular fibrin mesh due to hypercoagulability,

leading to fragmentation (e.g., schistocytes)

Intrinsic causes of hemolytic anemia can

and intravascular hemolysis.

present as jaundice in the newborn period.

These syndromes must be differentiated

Evaluation

from hemolytic disease of the newborn in

which alloimmunization in the mother

The evaluation of hemolytic anemia includes

occurs due to foreign RBC antigens from

a thorough history assessing for evidence of

the fetus. RBC antigens can either be major

chronic hemolytic anemia and possible pre-

(ABO) or minor (Rh, Kell, Duffy, etc.). For

cipitants of an acute event (see Figure 2.1).

ABO hemolytic disease, typically the mother

The family history is equally important

is type O and the fetus is type A; anti-A

and questions to ask include:

antibodies subsequently produced by the

mother then traverse the placenta leading

History of newborn jaundice

to hemolytic anemia in the fetus.

Gallstones

RhoGAM (Rho[D] Immune Globulin) has

Splenomegaly or splenectomy

virtually eliminated hemolytic disease in the

Episodes of dark urine and/or yellow skin/

Rh-negative

(D-negative) mother with a

sclerae

Rh-positive (D-positive) fetus although is

Anemia unresponsive to iron

still possible in the mother not receiving

supplementation

prenatal care. Many cases of hemolytic dis-

Medications

ease of the newborn are now due to other

Environmental exposures

minor RBC antigens with varying levels of

Ethnicity

clinical severity. AIHA in the mother can

Dietary history

also lead to hemolytic disease of the new-

born. In this case, maternal antibodies tra-

The physical exam should be complete, but

verse the placenta and are transferred to the

focused on:

fetus. If the mother is DAT positive but does

Skin color

(pallor, jaundice, and icteric

not have clinical signs of hemolytic anemia,

sclerae)

there is usually no risk to the fetus.

Facial bone changes

(extramedullary

hematopoiesis)

Abdominal fullness and splenomegaly

Microangiopathic hemolytic

anemia

The laboratory evaluation includes:

Complete blood count, RBC indices, and

Microangiopathic hemolytic anemias are

reticulocyte count (")

due to extracorpuscular abnormalities and

Peripheral blood smear (assess for fragmen-

are not associated with antibody formation.

ted forms or evidence of inherited ane-

Causes include disseminated intravascular

mia with specific morphological

coagulation, thrombotic thrombocytopenic

abnormalities)

purpura/hemolytic uremic syndrome, pre-

Bilirubin (")

eclampsia, malignant hypertension, valvular

Coombs test, direct and indirect (to exclude

abnormalities, and march hemoglobinuria.

antibody-mediated red cell destruction)

In these cases, red blood cells travel through

Urinalysis (for heme, bili)

damaged blood vessels or heart valves or are

Free plasma hemoglobin (")

Hemolytic Anemia

History

Physical examination

Low hemoglobin

Increased reticulocyte count

Peripheral smear

Morphologic characteristics

Coombs test (DAT)

Immune mediated

Coagulation studies

ANA

Identification of antibody

Red cell

Spherocytes

Target cells

Normal

fragmentation

Elliptocytes

Sickle cells

Nonspecific

abnormalities

Consider

RBC enzyme studies

Ceruloplasmin

DIC

Coagulation

Family studies

Hemoglobin

Enzyme deficiency

screen

Osmotic fragility or

electrophoresis

PK deficiency

(fibrinogen,

ektacytometry

PT, PTT, FDP)

G6PD deficiency

Platelet count

Wilson disease

Blood cultures

Antibiotics

HUS

Blood pressure

Hereditary spherocytosis

Hgb SS

BUN, Cr

Hereditary elliptocytosis

Hgb SC

Urinalysis

Hypersplenism

Hgb CC

Platelet count

Coombs (DAT) negative

Hgb S/ β-thalassemia

Cardiac prosthesis

autoimmune hemolysis

Figure 2.1 Diagnostic approach to the child with hemolytic anemia. (Abbreviations: DAT, direct

antiglobulin test; ANA, anti-nuclear antibody; DIC, disseminated intravascular coagulation;

PT, prothrombin time; PTT, partial thromboplastin time; FDP, fibrin degradation products;

HUS, hemolytic uremic syndrome; BUN, blood urea nitrogen; Cr, creatinine; PK, pyruvate kinase;

G6PD, glucose-6-phosphate dehydrogenase).

Specific tests for diagnosis may include:

cells is increased when the surface area to

Osmotic fragility

volume ratio of the red cells is decreased, as

Ektacytometry

in hereditary spherocytosis, in which mem-

Red cell enzyme defects (G6PD and PK)

brane instability results in membrane loss

Red cell membrane defects (HS)

and decreased surface area. Conversely,

osmotic fragility is decreased in liver disease

The osmotic fragility test is used to measure

as the ratio of the red cell surface area to

the osmotic resistance of red cells. Red cells

volume is increased. Ektacytometry mea-

are incubated under hypotonic conditions,

sures the deformability of red cells subjected

and their ability to swell before lysis is

simultaneously to shear stress and osmotic

determined. The osmotic fragility of red

stress.

Chapter 2

Treatment

fatigued over the last few days with a red

color to the urine. Fingerstick hemoglobin

Therapy depends on the underlying cause

at the pediatrician’s office reveals a hemo-

of the anemia and the degree of acute

globin of 5 g/dL prior to transfer to the ED.

hemolysis. In chronic hemolysis, such as

On the basis of this history and hemoglobin,

that associated with hereditary spherocyto-

it appears that the child is suffering from a

sis, splenectomy is often recommended to

hemolytic anemia.

decrease the degree of splenic destruction

1. What initial lab studies will help confirm

and level of anemia and to decrease the

the diagnosis and also help with the initial

incidence of bilirubin gallstones. This

treatment plan?

therapy must be now weighed against the

potential long-term complications of sple-

Initial lab studies should include a com-

nectomy including risk for infection,

plete blood count with reticulocyte count.

thrombosis, and pulmonary hypertension.

The reticulocyte count is an important first

In other forms of inherited anemias in

step to confirm that the patient is undergoing

which the hemolysis is more significant and

hemolysis, which should present with a low

even life-threatening, such as thalassemia or

hemoglobin and a resultant increase in the

some forms of enzymopathies, chronic

reticulocyte count. A low reticulocyte count

transfusion therapy is recommended. Other

in this setting should lead to consideration of

general measures include folic acid replace-

alternative diagnoses such as viral suppres-

ment due to high cell turnover, avoidance of

sion (although one would not expect hemo-

oxidant chemicals and drugs, and iron che-

lysis). A complete metabolic panel as well as

lation therapy as indicated for transfusion-

lactate dehydrogenase (LDH) should be done

related iron overload.

to ensure that the patient is actually suffering

Immune hemolytic anemias can require

from jaundice (elevated total bilirubin) and

more immediate and aggressive therapy.

hemolysis (elevated LDH and AST). A direct

The underlying disease, if present and

and indirect Coombs

(DAT/IAT) is an

identifiable, warrants treatment. Addition-

important first step to determine if the

ally, the use of corticosteroids in high doses

is frequently necessary. Splenectomy and

patient is undergoing an immune or nonim-

immunosuppressive drugs have also

mune hemolytic anemia.

been successful. Microangiopathic hemo-

The patient is noted to have a hemoglobin

lytic anemias can also be severe and life-

of 4.6 g/dL with 12.6% reticulocytes. One

threatening. Treatment should again first be

should first determine if the patient is having

directed toward the primary disorder to

an appropriate bone marrow response to

remove the cause of trauma, if possible.

anemia by calculating the reticulocyte index

Transfusions are frequently necessary and

(RI):

splenectomy may be needed in some

patients with severe hypersplenism.

RI ¼ Reticulocyte count ð%Þ

current hemoglobin

expected hemoglobin

Case study for review

In this case, the RI is 12.6%

(4.6/13) ¼ 4.5.

You are seeing a 6-year-old child in the

An RI

3.0 is consistent with an appro-

emergency department. The family notes

priate bone marrow response to anemia, and

that the child has been jaundiced and

therefore helps to rule out bone marrow

Hemolytic Anemia

dysfunction in this case. Modern blood cell

of symptomatic anemia and congestive heart

analyzers have the ability to calculate the

failure.

absolute reticulocyte count and the fraction

4. How should your treatment change at

of “immature” reticulocytes directly. Patients

this point?

who are demonstrating an appropriate

response to hemolysis will have an elevated

Since the patient has a falling hemoglobin

absolute reticulocyte count and immature

with clinical signs of cardiac instability and

reticulocyte fraction; these will be low or

volume overload, the patient should be

normal in patients with an inadequate

transfused. The term

“least incompatible

response.

unit” has been used in the past but is a

Other labs include a total bilirubin of

misnomer if phenotypically matched blood

6.7 mg/dL, LDH of 936 U/L (reference range

is given. The patient may not have a normal

313 to 618 U/L), and AST of 161 U/L. DAT is

increase in hemoglobin with transfusion

noted to be positive for IgG and C3d.

due to continued hemolysis and the poten-

2. What is the likely diagnosis?

tial for increased, bystander hemolysis with

transfusion. Because of the cardiac instabil-

With the positive DAT to IgG and com-

ity, it is advisable to give the transfusion

plement and clinical and laboratory signs of

slowly and monitor for worsening cardiac

hemolysis, warm antibody-mediated AIHA

function. Finally, a change in therapy would

is the likely diagnosis. It should be noted

be advisable at this point with either intra-

that a positive DAT without clinical and

venous immunoglobulin or a different

laboratory signs of hemolysis is not suffi-

immunosuppressant such as cyclosporine,

cient for the diagnosis of AIHA.

cyclophosphamide, or rituximab (monoclo-

3. What should be the initial treatment plan?

nal antibody to CD20).

The patient is started on steroid therapy,

IV methylprednisolone 1 mg/kg BID. After a

couple of days, the hemoglobin has contin-

Suggested Reading

ued to decrease to 3 g/dL even though the

methylprednisolone has been increased to

Garratty G. Immune hemolytic anemia—a

4 mg/kg BID and the patient is showing signs

primer. Semin Hematol 42:119-121, 2005.

Sickle Cell Disease

Sickle cell disease refers to a group of genetic

it is not possible to predict the severity of

disorders that share a common feature:

disease in advance of severe complications.

hemoglobin S (Hgb S) alone or in combi-

Generally, children who have vaso-occlusion

nation with another abnormal hemoglobin.

and other complications have a more severe

The sickle cell diseases are inherited in

course. Increased leukocyte count, decreased

an autosomal codominant manner. The

hemoglobin with concomitant increased

molecular defect in Hgb S is due to the

reticulocytosis, as well as frequency and

substitution of valine for glutamic acid at

severity of vaso-occlusive episodes (VOEs)

the sixth position of the b-globin chain.

are associated with increased morbidity and

The change of location of this substitution

mortality.

results in polymerization of the hemoglobin

Alpha-thalassemia (frequency 1% to 3%

and causes the red cells to transform from

in African-Americans) may be coinherited

deformable biconcave discs into rigid,

with sickle cell trait or disease. Individuals

sickle-shape cells. Hypoxia, acidosis, and

who have both a-thalassemia and sickle cell

hypertonicity facilitate polymer formation.

anemia are less anemic than those who have

The most common combinations of

sickle cell anemia alone due to a more

abnormal hemoglobins are

(1) Hgb SS,

similar concentration of a- and b-globulins.

(2) Hgb SC, and (3) Hgb S with a beta-

However, a-thalassemia trait does not

thalassemia, either Sb^þ or Sb⁰. The most

appear to prevent frequency or severity of

severely affected individuals have either Hgb

vaso-occlusive complications, resulting in

SS or Sb⁰ (no normal beta-globin produc-

eventual end-organ damage.

tion). Individuals with Hgb Sb^þ have

Sickle cell disease is not uncommon and

decreased beta-globin production and less

has developed due to protection from

severe disease, whereas children who have

malaria in those with sickle cell trait. In

Hgb SC have intermediate severity of dis-

African-Americans, the frequency of genetic

ease. There is phenotypic overlap between

alteration is quite high: 8% have the Hgb S

Hgb SS and Hgb SC; some children with

gene,

4% the Hgb C gene, and 1% the

Hgb SC are more symptomatic than chil-

b-thalassemia gene. Approximately

dren with Hgb SS. There are many variables

600 African-American infants has sickle cell

to expression of this hemoglobinopathy

anemia. Sickle cell disease also occurs in

including haplotypes, Hgb F concentration,

children from the Middle East, India, Cen-

and other yet to be delineated factors. As yet,

tral and South America, and the Caribbean.

Handbook of Pediatric Hematology and Oncology: Children’s Hospital & Research Center Oakland,

Second Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.

2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

Sickle Cell Disease

All children who have sickle cell hemo-

Most children with sickle cell disease are

globinopathies have a variable degree of

identified at birth, started on prophylactic

hemolytic anemia and vaso-occlusive tis-

penicillin by age 2 months, and aggressively

sue ischemia resulting in numerous clinical

monitored and treated for signs of infection.

complications. Organs most sensitive to

However, with the increasing concern for

the ischemic-hypoxic injury of red cell

bacterial antibiotic resistance, health care

sickling are the lungs, spleen, kidneys,

providers need to be vigilant when con-

bone marrow, eyes, brain, and the heads

fronted with an infant or a child who has

of the humeri and femurs. Sickling has

fever (

38.3

C) and/or appears ill. Overall,

both acute and long-term implications for

Streptococcus pneumoniae is responsible for

organ function. Cerebral vascular disease

>80% of the morbidity of infection. In

can be subtle, causing only abnormal

some areas of the United States, up to

neuropsychological testing or it can be

50% of pneumococcal isolates are penicillin

catastrophic, resulting in hemiparesis,

resistant. Infections can precipitate vaso-

coma, or death; acute pulmonary sickling

occlusive episodes and other complications

causes lung injury leading to restrictive

of sickle cell anemia and, in this population,

lung disease and eventually pulmonary

can quickly become fulminant. Although

hypertension; osteonecrosis of the femoral

the American Academy of Pediatrics guide-

head can be debilitating, resulting in the

lines recommend the discontinuation of

need for hip replacement; untreated reti-

penicillin prophylaxis after 6 years of age,

nopathy can lead to blindness; and, sickle

our institutional practice is to continue it

cell nephropathy can cause asymptomatic

as long as possible

(until compliance

proteinuria, an early sign of the risk of

becomes an issue) due to the high risk of

eventual renal failure.

S. pneumoniae infection.

Now that newborn hemoglobinopathy

Additional bacteria that cause morbidity

testing is mandatory in most states, chil-

and mortality include Haemophilus influen-

dren are diagnosed early and receive

zae, Neisseria meningitidis, Mycoplasma

appropriate care before they are at risk for

pneumoniae, Staphylococcus aureus, Salmo-

complications. All infants who have an

nella species, Escherichia coli, and Strepto-

electrophoretic pattern of Hgb FS at

coccus pyogenes. The S. pneumoniae and

birth will have some form of sickle cell

H. influenzae vaccines have importantly

disease.

resulted in a lowered case rate of sepsis from

these organisms. Viral infections, particu-

larly parvovirus B19, can cause severe aplas-

Fever and infection in sickle cell

tic crises as well as acute chest syndrome

disease

(ACS).

Infants, young children, and any patient

Susceptibility to infection is increased not

who has a central venous catheter with a

only because of loss of splenic function due

fever

(

38.3

C) should have a complete

to infarction but also because of other

evaluation and laboratories including CBC

acquired immunologic abnormalities.

with differential, reticulocyte count, blood

This can result in life-threatening episodes

culture, urinalysis, and urine culture (see

of sepsis. Recognition of this susceptibility

Figure 3.1). A chest radiograph should also

and aggressive medical management have

be obtained. Meningitis can occur in chil-

resulted in an increased life span for most

dren with sickle cell disease but routine

patients.

lumbar puncture without physical signs of

Chapter 3

Rapid assessment

history & physical

Infant, child less than

Septic appearing child

2-3 years of age:

nontoxic appearing

Rapid assessment

History (last dose of penicillin):

for degree of respiratory and

Cardiovascular and respiratory status,

cardiovascular compromise;

splenomegaly, jaundice, pain;

meningismus;

neurologic screen for weakness and

cardiovascular monitoring and

altered mental status

pulse oximetry

IV access

* Respiratory distress or

IV access

Blood culture, CBC with

pulse oximetry saturation

Blood culture, CBC with

differential and reticulocyte count

< 90%

differential and reticulocyte count

Catherized urine culture

Oxygen

Catherized urine culture

Consider LP

Chest X-ray

Consider LP

Type and cross match

ABG

Chest X-ray

Antibiotics

Fluid bolus to

Antibiotics

Ceftriaxone 50 mg/kg IV push

maintain blood pressure

Ceftriaxone 50 mg/kg

or rapid infusion

Note: fluid overload can lead

(plus azithromycin if CXR findings

to ACS

concerning for atypical

pneumonia)

Evaluate intervention;

if stable complete physical exam

*Respiratory distress: It is preferred to

and history and

obtain an ABG on room air; in a critically ill

review labs

child oxygen should be given first, and

oxygenation status assessed after stabilization

Figure 3.1 Fever in a child with sickle cell disease.

(Abbreviations: IV, intravenous; CBC, complete

blood count; LP, lumbar puncture; ABG, arterial blood gas; CXR, chest x-ray; ACS, acute chest

syndrome).

meningitis is not warranted. Urosepsis is

practitioners would recommend complete

common in sickle cell patients of all ages.

evaluation in all patients with a fever.

All infants (up to 2 to 3 years of age) should

Children with a documented fever

be admitted and cultures followed for 48 to

should have the same workup as infants,

72 hours. These patients should not be

although admission is not required if they

discharged during this time even if they

are well appearing, with reassuring labs and

appear well and are afebrile. Some

chest radiograph, and follow-up can be

Sickle Cell Disease

reasonably guaranteed. Acute chest syn-

occur and eventually lead to collapse of the

drome should be high on the differential

vertebral plates and compression. The clas-

in all children with fever. While physical

sic radiographic appearance is of

“fish

examination is essential, 60% of pulmonary

mouth” disc spaces and the “step” sign (a

infiltrates in children with sickle cell disease

depression in the central part of the verte-

and fever will be missed on exam alone,

bral body). Back pain is a common symp-

therefore chest radiography is essential. If

tom in sickle cell disease, likely as a result of

there is another possible source of infection,

recurrent infarction and vertebral compres-

appropriate cultures should be obtained. If a

sion. Infarction in the long bones can cause

child appears to be ill, has a temperature of

swelling and edema in the overlying soft

38.3

C or higher, or has an elevated WBC

tissues. It may be difficult to differentiate

with a left shift, treatment should be imme-

VOE from acute osteomyelitis. Although

diate with parenteral antibiotics and close

uncommon, infection should be consid-

monitoring, preferably in a hospital setting.

ered. Osteomyelitis may be ruled out by

Of note, studies have shown that the higher

close clinical observation, blood cultures,

the temperature, the more likely the risk for

and occasionally, aspiration of the affected

bacterial sepsis. If there is difficulty with

area. Plain radiographs are not helpful in

intravenous

(IV) access, ceftriaxone can

the early stages of infection and bone

be given intramuscular (IM) while access

scans may not differentiate a simple infarct

is being obtained.

from osteomyelitis.

Children who do not appear septic, in

Dactylitis, or hand-foot syndrome,

whom there is a low index of suspicion, and

refers to painful swelling of the hands and

who are older than 2 to 3 years of age (per

feet. This is seen exclusively in infants and

institutional preference), can be treated as

children (<5 years of age). It presents with

outpatients with IV/IM ceftriaxone while

pain, low-grade fever, and diffuse nonpit-

awaiting culture results, only if close mon-

ting edema of the dorsum of the hands and

itoring can be assured (parents can be con-

feet, which extends to the fingers. One or

tacted by telephone and daily evaluation is

more extremities may be affected at one

easily done while still febrile). If all cultures

time. Radiographic changes (periostitis and

are negative after 2 to 3 days and the child is

subperiosteal new bone formation with

afebrile without clinical symptoms, the anti-

periosteal elevation) may appear

1 week

biotics and follow-up can be discontinued.

or more after the clinical presentation.

All patients who appear ill should be

Therapy is analgesics, hydration, and paren-

hospitalized and treated for presumed infec-

tal reassurance. Although the swelling or

tion. Many children will develop increasing

radiographic changes may persist for weeks,

symptoms after being evaluated and hospi-

the syndrome is almost always self-limited.

talized. Acute chest syndrome commonly

Transfusions and antibiotics are not neces-

occurs after hydration and is frequently pre-

sary, unless there is concern for infection or

cipitated by a vaso-occlusive pain episode.

the medical condition worsens.

Occasionally, there is a precipitating

event such as hypoxia (obstructive sleep

Vaso-occlusive episodes

apnea), fever, viral illness, or dehydration

that leads to the vaso-occlusive episode. Few

The bones and joints are the major sites

children have frequent pain episodes; it

of pain in sickle cell disease. In trabecular

should not be taken for granted that each

bones, such as the vertebrae, infarction can

of these episodes is similar, and a source for

Chapter 3

each painful event should be sought. If the

High-risk factors for complications

pain changes or is very persistent, the child

other than VOE in children with pain:

should be reevaluated. If a young child has a

* Fever

101 F

(38.3 C) and signs of

symptom that is interpreted as pain, such as

infection

refusal to walk or a limp, also consider that

* Acute pulmonary symptoms (chest pain,

the cause may be due to an acute CNS event.

hypoxia, abnormal ausculatory exam)

The most common type of pain is mus-

* Persistent vomiting

culoskeletal pain. The pain may be of any

* Pain that is unusual for the patient

configuration: isolated, multifocal, symmet-

* Severe abdominal pain

ric, migratory, or associated with erythema

* Extremity weakness or loss of function

or swelling. There can be low-grade fevers,

* Any neurological symptoms

possibly associated with other clinical symp-

* Severe headache

toms. It can sometimes be difficult to dis-

* Acute joint swelling

tinguish pain from an infection, synovitis,

or other pathological process.

Children are frequently seen with

Pain management

abdominal pain. A surgical abdominal

problem needs to be considered. Children

Following are the recommendations for the

who have sickle cell anemia have a high

management of vaso-occlusive events. How-

incidence of cholecystitis. Also consider

ever, many children and adolescents need

pancreatitis, urinary tract infection, pelvic

individualized care plans for their routine

inflammatory disease, and pneumonia

treatment.

presenting as abdominal pain. Ileus and

acute chest syndrome are frequent com-

Outpatient

plications of abdominal vaso-occlusive

Mild pain

episodes.

* Increase fluids to 1 to 1.25

maintenance.

Vaso-occlusive episodes can last for

Water, fruit juice, and fruit drinks as well as

many days. Do not assume that the episode

decaffeinated soda are recommended.

is controlled when the acute administration of

* Acetaminophen without codeine (15 mg/

analgesia is effective. Children with these

kg q4 to 6 hours) orally should be tried prior

symptoms may have a medical problem that

to using acetaminophen with codeine

needs aggressive treatment beyond therapy

(1.0 mg codeine/kg q4

6 hours). For

for their pain. A vaso-occlusive episode is a

many children, acetaminophen alone is not

diagnosis of exclusion. The pain needs to be

sufficient for vaso-occlusive pain.

treated while there is a workup for potential

* Ibuprofen (10 mg/kg q6 to 8 hours) orally

other causes of pain beyond the vaso-occlu-

should be used routinely, every 8 hours even

sive episode itself.

if pain is temporarily controlled.

A reliable tool should be used to assess a

* Rest and heat to the area of pain.

child’s level of pain. The assessment should

* Relaxation and biofeedback exercises,

be modified depending on the age and

such as positive visualization and meditation.

developmental level of the child, and the

pain tool should be able to rate both sub-

Severe pain

jective and objective aspects of the child’s

* IV hydration: bolus to correct fluid losses,

pain. Physicians should be familiar with

then IV with D5W 1/2 NS at 1 to 1.25

their use and refer to them when assessing

maintenance (IV þ PO). Use caution not

children and adolescents with pain.

to overhydrate, especially if there are any

Sickle Cell Disease

pulmonary symptoms (overhydration can

days (10 to

15 doses). There should be

lead to pulmonary edema and precipitate

follow-up within 72 hours. If this regimen

acute chest syndrome). Note that if the

is not successful, if other symptoms develop

patient does not appear volume depleted,

with hydration, or a fever develops, the

an IV fluid bolus is not routinely required.

patient should be admitted and observed.

* Analgesics

(IV): Morphine:

0.1

0.15 mg/kg/dose q3 to 4 hours. In children

Inpatient

<2 years who have not been exposed to

As noted above, the administration of nar-

narcotic analgesics, 0.05 to 0.1 mg/kg should

cotics to acutely ill patients requires careful

be used. The pharmacokinetics of morphine

monitoring. A plan for pain management is

differs between individual children and

defined on admission and followed for the

doses must be titrated for individual

duration of hospitalization. In addition to

patients. Both underdosing and overdosing

whirlpool therapy, warm packs, and bio-

need to be avoided. Careful management

feedback therapy (as available), routine care

is required! Previous medication history is

includes:

often a good starting place.

* Ketorolac: (child) IV: 1 mg/kg/load, then

Management

0.5 mg/kg q6 hours (max 30 mg); (adult) IV:

* Correct acute losses due to dehydration.

30 to 60 mg/load, then 15 to 30 mg/kg q6

Do not overhydrate children who have pul-

hours. GI bleeding has been reported, and

monary symptoms.

an H2 blocker such as ranitidine is required

* Total fluid intake (IV þ PO) should be 1

if ketorolac is given IV. Morphine and

to 1.25

daily maintenance fluids; do not

ketorolac can be given simultaneously or

overhydrate.

in succession for the initial treatment of

* Monitor daily weight, record strict intake

pain in children. Added to narcotic therapy,

and output (l&O), and observe for signs of

ketorolac increases analgesia and has a nar-

fluid overload.

cotic sparing effect. Ketorolac is very useful

* Encourage ambulation, sitting up in bed,

in pain control, but should not be used for

and taking deep breaths.

more than 5 days. There are numerous

* Incentive spirometry, 10 times an hour,

other analgesic medications that have been

every hour while awake.

used to treat sickle cell pain.

Analgesics

Upon presentation to the clinic or emer-

* Pain medication should be administered

gency room, the child or adolescent should

on a fixed-time schedule, with an interval

be rapidly assessed and treated for pain.

that does not extend beyond the duration of

Initially, both morphine and ketorolac

the analgesic effect. Do not give narcotics on

should be given at the maximum recom-

a PRN basis except for when the patient is

mended doses. If the pain returns, repeat the

ready for discharge.

parenteral narcotic dose; it is unlikely that

* Titration schedules

(requires a written

oral analgesics will be successful if this reg-

plan, close observation, and a flow sheet

imen is not effective. If pain relief can be

to monitor effectiveness; sedation and

achieved and maintained for

hours,

hypoventilation can lead to hypoxia and

administer an oral narcotic and observe for

increased sickling and pain).

1 hour. If this regimen is successful, give a

* Patient-controlled analgesia (PCA). This

prescription of narcotic and nonsteroidal

is the method of choice for controlling pain

anti-inflammatory medications for several

in children who are

7 years of age or older.

Chapter 3

PCA protocols may be hospital specific.

Drug addiction is extremely rare and

Generally, there is an initial bolus

should not be a primary concern. The goal

(0.1 mg/kg morphine), and an on-demand

should be to provide patients with ade-

dose (0.01 to 0.04 mg/kg morphine) with a

quate relief by understanding the pharma-

10 to 20 minute lock out, and a 1 hour

cology of the medications, drug tolerance,

maximum of 0.1 to 0.15 mg/kg of mor-

and physical dependence. Drug tolerance

phine. At night, there may be a need for a

is common, and withdrawal symptoms

continuous low-dose infusion

(0.01

after hospitalization are probably under-

0.02 mg/kg/h morphine) without changing

reported by the patients. All patients

the 1 hour lock out.

should start a narcotic taper while in the

hospital and complete this as an outpa-

Side effects of narcotics include respiratory

tient. On average, patients admitted for the

depression, nausea, vomiting, pruritus,

management of VOE require 3 to 7 days of

hypotension, constipation, inappropriate

inpatient care.

secretion of anti-diuretic hormone, and

change in seizure threshold. Low-dose nal-

oxone drip has been used for severe pruritus

Acute chest syndrome/

and urinary retention due to morphine. The

pneumonia

most common side effects of nausea, vomit-

ing, and pruritus resolve over time. IV or

Acute chest syndrome (ACS) is defined as

PO diphenhydramine may be used safely in

the development of a new pulmonary infil-

this setting and can have a synergistic pos-

trate in the presence of fever or respiratory

itive effect with morphine. Meperidine

symptoms. As chest radiograph changes may

should not be substituted for morphine.

be delayed, the diagnosis may not be appar-

The metabolites of meperidine can accumu-

ent at presentation. Approximately 50% of

late and cause seizures, especially if used

children with sickle cell disease will have

over a longer period at high doses. A plan

acute chest syndrome. ACS is frequently

for withdrawal should be a part of discharge

caused by community-acquired pathogens

planning; clonidine hydrochloride has been

such as chlamydia, mycoplasma, and other

used successfully in this setting, but should

bacterial or viral organisms. In older chil-

be carefully monitored.

dren, adolescents, and young adults, ACS

All patients who are hospitalized for pain

may be more commonly associated with

should have an incentive spirometer at the

vaso-occlusion, infarction, fat embolism, or

bedside. Ensure that the patient has been

in situ sickling. These episodes are charac-

instructed on its usage and can demonstrate

terized by chest pain, fever, hypoxia, and

it appropriately.

pulmonary infiltrates. Although ACS usually

Alternative methods of pain control

improves with medical management, it can

(behavior modification, relaxation, visuali-

present with or progress rapidly to respira-

zation, self-hypnosis, and transcutaneous

tory failure (acute respiratory distress syn-

electrical nerve stimulation) are helpful

drome), requiring mechanical ventilation

adjuvants in the outpatient and inpatient

and emergent exchange transfusion.

setting but should not replace standard

Sixty percent of children who have pneu-

therapy. Children should have access to a

monia on X-ray will be missed by physical

psychologist who is experienced in the man-

exam alone. In addition, many children with

agement of sickle cell pain.

a negative chest film on admission will

Sickle Cell Disease

Child presents with respiratory

distress, cough, and/or chest pain,

with or without fever

Physical exam:

Evidence of respiratory distress: abnormal or absent breath sounds,

egophony, tachypnea, splinting

(60% of children with infiltrate will have a normal examination)

Pulse oximetry and chest radiography

CBC, reticulocyte count, blood culture

Dyspnea and tachypnea

Extensive or progressive infiltrate

Infiltrate without

ABG PaO₂ < 70 mmHg on room air

respiratory distress and

Evidence of right heart failure or

stable pulse oximetry > 89%

pulmonary hypertension

Antibiotics:

Ceftriaxone and azithromycin

Intensive care unit

Incentive spirometry

Emergent transfusion:

Maintain fluid balance

straight or exchange

Lasix for fluid retention (I > O)

(exchange if severe ACS,

Analgesics per pain protocol

high hematocrit, or clinically

Continuous pluse oximetry

worsens or remains hypoxic

Albuterol aerosols

after straight transfusion)

Frequent re-evaluation

Children who have an episode of life threatening acute chest syndrome will need to be on

hydroxyurea therapy or chronically transfused. In addition, they should be followed for

evidence of pulmonary hypertension with cardiac echocardiography

Figure 3.2 Sickle-cell disease with acute pulmonary infiltrate. (Abbreviations: CBC, complete blood

count; ABG, arterial blood gas; ACS, acute chest syndrome).

develop findings after hydration. All chil-

incentive spirometry are helpful adjuncts

dren who have symptoms of pulmonary

in treatment and prevention of worsening

disease, such as fever, shortness of breath,

ACS. If there is an infiltrate, the patient

tachypnea, chest pain, cough, wheezing,

should be closely observed for hypoxia

rales, or dullness to percussion, should

and progression of pulmonary infiltrates,

have an assessment of oxygen saturation,

with repeat chest radiographs. Overhydra-

a chest radiograph, receive parenteral anti-

tion can lead to pulmonary edema and

biotics, and be admitted to the hospital

exacerbate acute chest syndrome. Over-

(see Figure

3.2). Bronchodilators and sedation with narcotics can also lead to

Chapter 3

hypoventilation, increasing the risk for ACS.

Hgb SC disease have relatively more fat

Narcotics should be used with caution in

in their marrow and resultantly can have

this setting.

more severe pulmonary fat emboli when

Acute chest syndrome can develop in a

their course is complicated by acute chest

matter of hours and is associated with

syndrome.

a high rate of morbidity and mortality.

Stroke and other central nervous sys-

Children should have oxygen saturation

tem events are more common in children

monitored and, if indicated, arterial

with ACS in the 2 week period after the

blood gases also. Oxygen therapy should

event.

be used only for significant hypoxia (O₂

saturation

92%). Supplemental oxygen

can decrease erythropoietin production

Laboratory evaluation of acute

and lead to more severe anemia. Pulmo-

chest syndrome

nary infections should be treated aggres-

* CBC with differential and reticulocyte

sively, and these children watched closely.

count.

If there is no improvement, and/or wors-

* Type and hold for possible blood trans-

ening anemia, a red blood cell transfusion

fusion (phenotypically matched, sickledex

(straight or exchange, dependent upon

negative).

the severity of the hypoxia, anemia, and

* Chest radiograph, as often as clinically

clinical status of the patient) may help to

indicated to monitor progression of

correct the anemia, decrease the percent

disease.

Hgb S, and improve oxygen-carrying

* Continuous pulse oximetry and baseline

capacity to aid in reversing the pulmo-

arterial blood gas (on room air if possible).

nary sickling and improve the clinical

* Blood culture for fever.

course. Transfusions are more effective

when administered early in the course

of ACS, rather than as a life-saving mea-

Management

sure in a critically ill child.

All patients with evidence of acute pulmo-

There is a distinct difference between

nary pathology should be admitted to the

the etiology of acute chest syndrome in

hospital. If fever is present or if an infec-

children and that of adolescents and

tious process is suspected, antibiotic ther-

adults. In children, the incidence of acute

apy should be started immediately. See

chest syndrome is seasonal, lower in the

Fever and Infection section, and Figures 3.1

summer months with increasing rates in

and 3.2.

the winter when viral infections are prev-

* Oxygen

alent. In adults and adolescents, ACS is

Hypoxemic patients

(P_aO₂

frequently a complication of an episode of

80 mmHg, O₂ saturation

92%): 2 L/min

vaso-occlusion

(without fever) due to

per nasal cannula.

pulmonary fat embolism. This event will

Reevaluate arterial blood gas on oxygen.

progress to include chest pain, fever, and a

* Antibiotics

pulmonary infiltrate (usually basilar with

Initiate broad spectrum antibiotic: cef-

pleural effusion). Adults and adolescents

triaxone

50 mg/kg/d IV every

hours

more frequently need transfusions and

after blood cultures obtained

(maximum

less frequently have a viral or bacterial

2 g/dose).

infection associated with their episode

Due to the frequency of atypical organ-

of acute chest syndrome. Individuals with

isms (e.g., chlamydia and mycoplasma), a

Sickle Cell Disease

macrolide or quinolone antibiotic should

Priapism

be included: azithromycin 10 mg/kg on day

1, followed by

5 mg/kg on days 2 to 5

Forty percent of men who are homozygous

(maximum 500 mg on day 1, 250 mg on

for Hgb S report having priapism in their

days 2 to 5).

adolescence and early adulthood. Priapism

* Analgesics

has a second peak at 21 to 29 years. Priapism

As indicated for vaso-occlusive pain man-

is defined as a painful erection that lasts for

agement, administration must be moni-

more than 30 minutes. It frequently results

tored to provide the maximum pain control

in interference with the urinary stream.

and prevent hypoventilation or atelectasis

Priapism can be precipitated by prolonged

from splinting or narcotization.

intercourse or masturbation, frequently

* Hydration

occurs at night, and can be differentiated

PO and IV hydration (D5W 1/2 NS) at a

from a nocturnal erection by its duration

maximum of 1.25

maintenance. Caution

and pain. Children will occasionally com-

should be used in patients with potential

plain of dysuria as the first complaint of

acute chest syndrome to avoid fluid over-

priapism. Prognosis is poorer in adolescents

load. Monitor Is & Os, daily weight.

and adults who have recurrent prolonged

* Other supportive measures

priapism, and if aggressive treatment has

Continuous pulse oximetry.

not been successful, impotence may result.

Incentive spirometry, 10 times an hour,

Children who have priapism generally have

every hour while awake

(prevention of

a better prognosis than adolescents and

hypoventilation and atelectasis).

adults and usually do not have prolonged

Albuterol aerosols q4

hours

(airway

episodes requiring aggressive therapy. Pria-

hyperreactivity common in ACS).

pism can occur with vaso-occlusive episodes

* Physical therapy

as well as with fever and sepsis.

Warm packs.

Priapism can last for hours, days, or

Ambulation as tolerated, sitting up in bed.

weeks with moderate-to-severe pain, or it

* Transfusion

can occur as a pattern of painful erections

Straight transfusion.

that recur over a period of days to several

Exchange transfusion (for patients with

weeks (stuttering priapism). Chronic non-

hematocrit > 30% or moderate-to-severe

painful priapism can also occur.

ACS to more efficiently reduce Hgb S%).

Since priapism can lead to impotence,

early medical management is indicated. A

Transfusion decreases the proportion of

urologist familiar with priapism in sickle cell

sickling red cells and increases blood oxygen

disease should be consulted. Treatment

affinity. The main indication is worsening

includes hydration, pain management, intra-

respiratory function, as documented by

cavernous injection of alpha-adrenergic

hypoxemia (p_aO₂ <70 mmHg on room air),

agents, exchange transfusion, and shunting

worsening chest pain, evolving clinical

surgery. Oral alpha-adrenergics (e.g., pseu-

examination, or worsening infiltrates on

doephedrine hydrochloride 30 mg BID) have

chest radiography. For patients with chronic

been used successfully to treat stuttering

hypoxemia, a drop of >10% from baseline

priapism. Chronic transfusion therapy has

is a reasonable level at which to transfuse.

been used in patients with recurrent priapism

Delays in instituting transfusion therapy,

(maintenance of Hgb S below 30% to 40%),

particularly in rapidly deteriorating patients,

although no controlled trials have been per-

should be avoided.

formed proving the efficacy of this therapy.

Chapter 3

Stroke (cerebrovascular

during an exchange transfusion realizing

accident)

that, relative to the normal population,

children with sickle cell disease are hypo-

Stroke is a common event in children

tensive. The diagnosis of stroke in children

homozygous for Hgb S. Between 10% and

should initially be made based on clinical

15% of children with sickle cell disease

findings and treated emergently. Children

suffer from overt strokes. In children,

should be monitored until they are stable

strokes are more frequently the result of

and the hemoglobin electrophoresis is

cerebral vascular stenosis and infarction.

documented. Those who have had a stroke

The mean age of occurrence of clinically

require chronic transfusion therapy for an

evident stroke is 7 to 8 years with the highest

undetermined length of time.

risk occurring between 2 and 9 years. Hem-

Children with sickle cell disease have

orrhage and infarct may occur together.

more frequent and more severe headaches

Strokes in children who have sickle cell

than other children; these may be manifes-

disease involve stenosis and occlusion of the

tations of cerebral hypoxia and vasodilation.

major anterior arteries of the brain, includ-

Children who have severe headaches accom-

ing the carotids. The presenting symptoms

panied by vomiting need extensive evalua-

of stroke can be dramatic and acute, such as

tion with imaging as well as neurologic and

coma, seizure, hemiparesis, hemianesthesia,

neuropsychological testing.

visual field deficits, aphasia, or cranial nerve

Transcranial Doppler (TCD) has been

palsies. Subtle limb weakness (without pain)

shown to predict increased risk of stroke in

is often mistaken for an acute vaso-occlusive

children who have increased flow velocity in

episode but can be due to stroke. By defi-

major cerebral arteries. Unsuspected cere-

nition, the symptoms must persist for at

bral vascular damage was detected by CT

least 24 hours to be classified as a stroke. The

and MRI in 25% to 30% of children in the

presentation of severe headache and vomit-

Cooperative Study of Sickle Cell Disease. No

ing with no other neurological findings can

clinical factors, with the exception of tran-

be symptoms of an intracranial hemorrhage.

scranial Doppler, predicted the occurrence

Initially, a CT scan without contrast will

of stroke. In this study, there was a corre-

be normal for up to 6 hours after a stroke

lation between first stroke and transient

but will rule out intracerebral hemorrhage,

ischemic attack, acute chest syndrome, ele-

abscess, tumor, or other pathology that

vated systolic blood pressure, and severe

would explain the neurological symptoms.

anemia. All children who can cooperate

Magnetic resonance imaging

(MRI) and

with transcranial Doppler (usually by 2 years

magnetic resonance angiography (MRA) are

of age) should have an annual evaluation

much more sensitive methods to determine

if the study is available locally. Normal

intracranial infarct but can remain normal

middle cerebral artery velocity in children

for 2 to 4 hours after an event. All cata-

with sickle cell disease is approximately

strophic neurological events should first be

120 cm/s. Children who have velocities of

evaluated with CT since it is generally more

170 to 199 cm/s are considered at high risk

available and will rule out acute pathology.

and those with velocities

200 cm/s are at

With clinical concern prior to definitive

highest risk. The STOP trial

(Stroke

diagnosis by MRI/MRA imaging, children

Prevention Trial in Sickle Cell Anemia)

are exchange transfused to achieve a con-

showed that transfusion greatly reduces the

centration of Hgb S of less than 30%. Blood

risk of first stroke in children who have

pressure should be continually monitored

abnormally high TCD velocity (

200 cm/s).

Sickle Cell Disease

Prophylactic chronic transfusion should be

6 months to 3 years of age when the spleen

strongly considered if there are two studies

becomes fibrotic due to multiple infarc-

at least 2 weeks apart with velocities

200

tions. These crises can occur in older chil-

cm/s. Compliance issues and risks of

dren who have Hgb SC or Sb^þ thalassemia

chronic transfusions must also be consid-

but are usually not as severe; still, fatal

ered when deciding on this therapy.

events have been recorded for these chil-

Transient ischemic attacks are defined

dren. The incidence is between 10% and

as focal neurological deficits with a vascular

30% and the recurrence rate is 50%. Mild

distribution persisting for less than

events can indicate the possibility of life-

hours, although they typically last less than

threatening sequestration events. Chronic

an hour. Patients with transient ischemic

sequestration can also be a sequelae with

attacks are treated in a similar manner to

chronic anemia and thrombocytopenia.

those who have an infarct. The diagnosis is

The clinical presentation is usually rapid

made in retrospect when the follow-up MRI

in onset; the child will typically have sudden

is negative for a persistent lesion that would

weakness, pallor of the lips and mucous

explain the neurological symptoms.

membranes, breathlessness, rapid pulse,

Intracerebral hemorrhage or subarach-

faintness, and abdominal fullness. Evalua-

noid hemorrhage may present without

tion of the CBC will frequently show a

focal neurologic symptoms. Exchange

precipitous drop from the baseline

transfusion should be carried out immedi-

hemoglobin.

ately. Arteriography is used to identify the

The treatment for splenic sequestration

arterial bleed and the patient may need

is transfusion to restore circulating blood

emergent surgical intervention. Mortality

volume, usually with phenotypically mat-

is very high during the acute event (

50%).

ched blood (unless there is a life-threatening

situation). As the shock is reversed and

the transfused blood decreases the percentage

Acute anemia

of Hgb S, the splenomegaly regresses and

much of the blood is remobilized with a

There are two common causes of acute life-

rapid rise in the child’s hemoglobin.

threatening anemia in sickle cell disease:

Splenectomy should be strongly consid-

splenic sequestration and aplastic crisis.

ered in all children who have a splenic

sequestration crisis. Transfusions can

Splenic sequestration

prevent recurrence until surgery can be

Infants and young children who have Hgb

arranged. Some children who have Hgb

SS and Sb⁰ thalassemia and older children

SS and older children who have other S

(over 10 years) who have Hgb SC or Sb^þ

hemoglobinopathies can have massive

thalassemia syndromes can have intrasple-

splenomegaly with hypersplenism after an

nic pooling of large amounts of blood and

episode of splenic sequestration. If hypers-

platelets. This can lead to anemia, throm-

plenism (with resultant anemia, neutrope-

bocytopenia, hypovolemia, cardiovascular

nia, or thrombocytopenia) is persistent

collapse, and sudden death within hours

and severe, splenectomy is indicated.

of the onset of sequestration. The syndrome

Prior to splenectomy, younger children

has been reported in infants as young as 2

should have an evaluation of splenic func-

months of age. Classically, however, it

tion with a pit count and a spleen scan. In

occurs in children with Hgb SS after the

normally eusplenic persons, fewer than 1%

disappearance of Hgb F from approximately

of the circulating red cells are pitted; values

Chapter 3

2% to 12% may represent decreased

last for weeks. Avascular necrosis (osteone-

splenic function. If they still have a func-

crosis) causes pain that can sometimes be

tional spleen, usually under 2 years of age, a

confused with a bone infarct. Symptoms of

partial splenectomy can be performed. Chil-

avascular necrosis, such as limping, can

dren should have appropriate immuniza-

sometimes be confused with stroke. Limp-

tions, including pneumococcal and menin-

ing with weakness but without pain is

gococcal vaccinations, prior to splenectomy.

stroke not avascular necrosis.

Penicillin prophylaxis is continued indefi-

Avascular necrosis is common in all age

nitely in all children who have been

groups but is more frequently diagnosed in

splenectomized.

the adolescent and usually involves the

humeral and femoral heads. It is more

Aplastic crisis

common in individuals who have Hgb

Severe anemia can develop over several days

Sb⁰ thalassemia and Hgb SS with alpha-

due to shortened red cell survival without

thalassemia. It is also seen, though with a

compensatory reticulocytosis. Reticulocyto-

lower frequency, in those who have Hgb

penia can last 7 to 10 days. The primary

Sb^þ thalassemia. Individuals who have Hgb

cause of transient red cell aplasia is parvo-

SS are more frequently affected than those

virus B19, though it can follow other viral

with Hgb SC.

infections as well. Parvovirus B19, the most

Avascular necrosis is a result of an infarct

common cause of aplasia in children with

in the cancellous trabeculae in the head of

hemoglobinopathies, can also cause neutro-

either the femur or the humerus. The pro-

penia. While many patients recover spon-

cess of necrosis and repair can be progres-

taneously, the anemia can be profound. Red

sive, leading to collapse of the head or arrest

cell transfusion is indicated for those who

with varying degrees of disability and scle-

become symptomatic from anemia or if the

rosis. Below is a method of describing the

hemoglobin falls 2 g/dL or more from base-

progression of avascular necrosis:

line. Symptoms occurring with aplastic cri-

Stage 0: no evidence of disease

sis include nausea and vomiting, myalgias,

Stage 1: X-ray normal, bone scan abnormal,

and arthralgias. Splenic and hepatic seques-

MRI abnormal

tration have also been reported with aplastic

Stage 2: X-ray: sclerosis and cystic changes

crises. If the ability to follow-up is of con-

without collapse

cern, the child should be hospitalized for

Stage

3: Subchondral collapse

(crescent

observation. The patient should be isolated

sign) without collapse

from other patients with chronic hemolytic

Stage 4: Collapse and flattening of the fem-

anemias (sickle cell disease or thalassemia)

oral head without acetabular involve-

or red cell aplasia and should not have

ment, normal joint space

pregnant caregivers. If the child is mildly

Stage 5: Joint narrowing and/or acetabular

anemic and asymptomatic, outpatient mon-

involvement

itoring is reasonable.

Stage 6: Increased joint narrowing and/or

acetabular involvement

Avascular necrosis

Treatment for avascular necrosis of the

femur includes bed rest with crutch walking

Bone pain is common in sickle cell disease.

for 6 weeks, nonsteroidal anti-inflammatory

Marrow infarcts can cause pain that can

drugs (NSAIDs), and core decompression

Sickle Cell Disease

surgery for stages 1 or 2. Extensive physical

occurs most commonly in individuals who

therapy has been found to be beneficial but

have Hgb SC.

is often difficult to perform. Decompression

Treatment of sickle cell retinopathy

surgery is relatively simple; a core is

requires recognition. The damaged periph-

removed from the head of the femur.

eral vessels are not generally appreciated by

The coring begins approximately

2 cm

direct ophthalmic examination and require

below the trochanteric ridge extending

the use of indirect binocular stereoscopic

through the neck and into the head of the

ophthalmoscopy. Sea fanning, vitreous

femur. Acutely this procedure provides

hemorrhage, and retinal detachment can

relief of pain and is thought to arrest the

be observed by direct ophthalmoscopy.

progression of avascular necrosis; however,

Annual ophthalmic evaluations should

this has not been confirmed in a prospective

begin at age 10 for all children with sickle

trial. Higher stage avascular necrosis

cell disease. Treatment of early neovascular-

requires joint replacement.

ization requires laser photocoagulation.

Surgical approaches are required for

advanced lesions.

Retinopathy/Hyphema

Hyphema is a medical emergency in

sickle cell disease. It requires immediate

The eye is particularly sensitive to hypoxia.

ophthalmic evaluation and transfusion

Vaso-occlusion of retinal vessels and hyp-

(exchange or straight) to reduce sickling

oxia of the retina cause permanent retinal

and improve oxygenation. If a conservative

damage. Blood in the anterior chamber of

approach is not successful, anterior cham-

the eye (hyphema) becomes rapidly deoxy-

ber paracentesis is performed to relieve

genated and permanently sickled, obstruct-

intraocular pressure and remove the

ing the outflow from the aqueous humor.

hyphema.

The accumulation of aqueous humor in the

anterior chamber increases intraocular pres-

sure leading to decreased blood flow to the

Hyperbilirubinemia /Gallstones

retina until the perfusion pressure of the

globe is reached. This leads to sudden vas-

Bilirubin gallstones can eventually be

cular stasis and blindness. The events occur-

detected in most patients with chronic

ring in hyphema can also occur in children

hemolytic anemia. In sickle cell disease,

who have sickle cell trait.

gallstones occur in children as young as 3

Retinal vascular occlusion initially occurs

to 4 years of age, and are eventually found in

in peripheral retinal vessels without signifi-

approximately 70% of patients. It may be

cant sequelae. It eventually leads to neovas-

difficult to differentiate between gallbladder

cularization from the retina into the vitreous

disease and abdominal vaso-occlusive crisis

(sea fans). These abnormal vessels are fragile

in patients with recurrent abdominal pain.

and can bleed into the vitreous causing

Cholecystectomy may be necessary for

“floaters” or blindness if the hemorrhage is

patients with fat intolerance, presence of

sufficient. If bleeds do not obscure vision and

gallstones, and recurrent abdominal pain.

are unnoticed, they can cause collapse of the

Hepatomegaly and liver dysfunction

vitreous, traction on the retina, and eventu-

may be caused by a combination of intra-

ally cause retinal detachment. Retinal disease

hepatic trapping of sickled cells,

of the eye is common in sickle cell disease. It

transfusion-acquired

infection,

Chapter 3

transfusional hemosiderosis. The combina-

study obtained prior to any transfusion.

tion of hemolysis, liver dysfunction, and

Sickle cell patients should receive pheno-

renal tubular defects can result in very high

typically matched blood to decrease the

bilirubin levels. Benign cholestasis of sickle

risk of alloimmunization. In addition, all

cell disease results in severe asymptomatic

blood should be sickledex negative and

hyperbilirubinemia without fever, pain, leu-

leukodepleted. The following transfusion

kocytosis, or hepatic failure.

guidelines are recommended. See also

Chapter 5.

a. Patients with Hgb SS or Sb⁰ disease

who are undergoing any procedure other

Perioperative management of

than myringotomy tube placement

sickle cell patients

should have a simple transfusion to

achieve a hemoglobin of 10 to 12 g/dL.

Following are guidelines for the manage-

Do not exceed 12 g/dL due to the risk of

ment of sickle cell patients who have sur-

stasis/sludging.

gical procedures or require anesthesia for

b. Patients with Hgb SC disease or Sb^þ

other purposes. General anesthesia results

who have baseline hemoglobin below

in atelectasis and hypoxia, which is poorly

10 g/dL may need transfusions to achieve

tolerated by the patient with sickle cell

a hemoglobin of 10 to 12 g/dL. However,

disease; therefore, special precautions must

do not transfuse these patients prior to

be taken perioperatively to decrease mor-

consulting the hematologist. Many fac-

bidity and mortality associated with even

tors may affect this decision including a

minor surgical procedures. Other risk fac-

history of significant complications of

tors include the presence of chronic organ

their sickle cell disease (i.e., pneumonia,

damage in some patients, the effects of asple-

vaso-occlusive episodes, priapism, and

nia, and the propensity for sickling and

aseptic necrosis).

obstruction of microvasculature with even

c. Consult the hematologist if there is

mild hypoxia. The guidelines suggested

confusion regarding individual patients.

below are extrapolated from a multicenter

7. Patients with central venous catheters or

randomized trial of transfusion (exchange vs

those undergoing dental procedures should

straight) in the perioperative period.

receive antibiotic prophylaxis prior to

surgery.

Preoperative care

1. Admission to the hospital the afternoon

prior to scheduled surgery.

Postoperative care

2. Hydration at 1.25

maintenance (IV þ

1. Adequate pain management to prevent

PO) the evening and night prior to surgery.

splinting and atelectasis, with care to pre-

3. Pulse oximetry on room air

(spot

vent narcosis.

checks).

2. Pulse oximetry for at least the first 12 to

4. Incentive spirometry at least 10 times per

24 hours postoperatively.

hour while awake.

3. Incentive spirometry at least 10 times per

5. Lab work: CBC with differential and

hour while awake. Be aggressive!

reticulocyte count, urinalysis, type and

4. Ambulation as early as possible, taking

cross, chemistry panel.

into account the specific surgical procedure.

6. Transfusion: All sickle cell patients

5. Lab work: CBC with reticulocyte count

should have a red cell phenotype

daily.

Sickle Cell Disease

6. Follow-up in clinic approximately

cell pheresis is recommended. Studies sug-

1 week post-hospital discharge or sooner

gest early transfusion may prevent progres-

if there are ongoing problems.

sion of acute pulmonary disease.

The efficacy of transfusion in the man-

Transfusion therapy

agement of acute stroke has not been well

studied, though anecdotal reports indicate

Red blood cell transfusion increases oxygen-

that early exchange transfusion may limit

carrying capacity and improves microvas-

neuronal damage by improving local oxy-

cular perfusion by decreasing the propor-

genation and perfusion. Chronic transfu-

tion of sickle red cells (Hgb S%). Transfu-

sion therapy reduces the rate of recurrence

sions are given to patients with sickle cell

and is indicated in all patients after a first

disease to stabilize or reverse an acute med-

stroke.

ical complication, or as part of chronic

therapy in certain situations to prevent

Perioperative transfusion

future complications.

Patients with sickle cell anemia undergoing

major surgery should be prepared in

Indications

advance by transfusion to a hemoglobin

Acute illnesses

of approximately 10 g/dL and a decrease

Splenic sequestration

in Hgb S% to approximately 60%. While

Transient red cell aplasia

standard practice guidelines have not

Hyperhemolysis (infection, ACS)

been developed for Hgb SS patients under-

going minor procedures or those with Hgb

Patients should be transfused if there is

SC, it is generally acceptable to not trans-

evidence of cardiovascular compromise

fuse these patients, assuming they are med-

(heart failure, dyspnea, hypertension, or

ically stable.

marked fatigue). Generally, transfusion is

indicated if the hemoglobin falls below 5 g/

Chronic transfusion therapy

dL or drops greater than 2 g/dL from the

Chronic transfusions are indicated in

steady state.

several conditions in which the potential

medical complications warrant the risks

Sudden severe illness

of alloimmunization, infection, and trans-

Acute chest syndrome

fusional iron overload. Transfusions are

Stroke

given every 3 to 4 weeks, with a goal to

Sepsis

maintain the Hgb S% at 30% to 50%. While

Acute multiorgan failure

straight transfusions are acceptable, red cell

pheresis or exchange transfusions may be

These life-threatening illnesses are often

preferred to decrease the rate of iron

accompanied by a falling hemoglobin.

overload.

Transfusion therapy has become standard

medical practice in the management of

Indications

these illnesses. When ACS is associated with

1. Primary stroke prevention

hypoxia and a falling hemoglobin, transfu-

2. Pulmonary hypertension/chronic lung

sion is indicated. Many patients can be

disease

treated with straight transfusion, though

3. Frequent ACS

in severe cases, exchange transfusion or red

4. Chronic debilitating pain

Chapter 3

Other indications for transfusions:

prophylaxis in more patients. Some would

Transfusions are sometimes suggested for

argue that all patients with hemoglobin SS

a number of conditions in which efficacy is

and Sb⁰ thalassemia should be on HU ther-

unproven,butmaybeconsideredundersevere

apy; this may become the standard of care in

circumstances. Such circumstances include:

the near future.

Acute priapism

HU therapy begins at 20 mg/kg/d and

Pregnancy (frequent complications)

should be titrated based on beneficial incre-

“Silent” cerebral infarcts

ment in Hgb F% and resultant increase in

Leg ulcers

hemoglobin and MCV. Potential toxicities

with HU therapy that should be monitored

closely include neutropenia, leukopenia, and

Hydroxyurea therapy

anemia. Elevation in ALT and thrombocyto-

penia can also occur, though less commonly.

Hydroxyurea (HU) was originally utilized as

an antineoplastic agent, but due to its effects

on increasing fetal hemoglobin (Hgb F), it

Hematopoietic stem cell trans-

has gained favor in the treatment of patients

plantion in sickle cell disease

with sickle cell disease. Hydroxyurea’s

mechanism of action is not clearly under-

Hematopoietic stem cell transplantion is

stood; however, it is thought that inhibition

curative for patients with sickle cell disease

of ribonucleotide reductase leads to down-

and should be considered in young patients

stream cytotoxicity of erythroid progenitors

with hemoglobin SS and Sb⁰ thalassemia

leading to upregulation of fetal hemoglobin

and a matched sibling donor.

production. In addition, hydroxyurea’s

Patients with severe manifestations of

cytotoxic effects lead to leukopenia and

sickle cell disease including multiple pain

neutropenia, beneficial in sickle cell disease

episodes, recurrent ACS, stroke, and end-

secondary to the viscous properties of these

organ damage should be considered for

cells during vaso-occlusion.

unrelated bone marrow or umbilical cord

Long-term adult studies have shown no

blood transplantation when a matched sib-

significant complications of HU usage and it

ling donor is not available.

is being used more commonly in pediatric

patients with sickle cell disease. Current

Case study for review

recommendations for HU usage include the

following:

You are a primary care physician taking care

* Frequent episodes of VOE including

of a 2-year-old with known sickle cell disease

dactylitis

(Hgb SS). You are counseling the family on

* Acute chest syndrome

* Chronic hypoxia

particular risks for the patient at this age.

* Low hemoglobin and Hgb F

1. What are some of the main areas of

* Signs of increased hemolysis (increased

discussion?

LDH and total bilirubin)

* Abnormal TCD or history of stroke with

In evaluating the patient as a whole, one

refusal for chronic transfusion therapy

must first discuss growth and development

and the risks of low hemoglobin on brain

As experience grows with HU therapy,

development. Assuming the patient has had

practitioners are recommending HU as

previous laboratory studies, past hemoglobin

Sickle Cell Disease

values can help objectively guide this discus-

to walk, decreased appetite, as well as local-

sion as phenotypic disease is related to level

ized swelling and/or tenderness. A pain plan

of anemia and concomitant reticulocytosis,

should be established with the family which

amount of leukocytosis, as well as evidence

should include the availability of oral med-

of hemolysis (total bilirubin and LDH levels).

ications at home (e.g., acetaminophen, ibu-

In this discussion, newer treatment modali-

profen, Tylenol with codeine, and/or Lortab

ties including hydroxyurea therapy and the

elixir) as well as adjuvant strategies such as

potential for hematopoietic stem cell trans-

warm bath and heating pads.

plantation should be discussed.

Finally, the practitioner should discuss

Fortunately, this child has had a relatively

other potential acute complications such as

benign course to date.

splenic sequestration. If the child has a pal-

pable spleen, the family should be advised on

2. What are some of the potential acute

the current size and to monitor for changes

risks that should again be discussed with

in size if the patient appears to be pale or

the family?

weak. In addition, if the child does appear

The major risks to the child include severe

to have these symptoms without a change

infection, pain including dactylitis, and

in the size of the spleen or does not have a

splenic sequestration. These risks should all

palpable spleen, the family should be advised

be discussed in detail with the family.

that these symptoms should again lead to

In terms of severe infection, the family

prompt evaluation as they could be signs of

should be aware that they should monitor

splenic sequestration or an aplastic crisis.

the child closely if the child appears ill and

check the temperature before administering

Suggested Reading

antipyretics, even if given for pain alone. In

addition, they should be aware that if the

Adams RJ, McKie VC, Hsu L, et al. Prevention of

child appears ill, they should immediately call

a first stroke by transfusion in children with

the on-call physician and will likely require

sickle cell anemia and abnormal results on

immediate evaluation including blood work,

transcranial Doppler ultrasonography. N Engl

chest radiography, parenteral antibiotics, and

J Med 339:5-11, 1998.

Ballas SK. Current issues in sickle cell pain and its

hospital admission and observation. You

management. Hematology Am Soc Hematol

should again reinforce the need for the child

Educ Program 97-105, 2007.

to be on penicillin prophylaxis. Finally, one

Claster S, Vichinsky EP. Managing sickle cell

should review the child’s vaccinations to

disease. BMJ 327:1151-1155, 2003.

ensure they are up to date, especially for

Rees DC, Olujohungbe AD, Parker NE, et al.

encapsulated bacteria including S. pneumo-

Guidelines for the management of the

niae, H. influenzae, and N. meningitidis.

acute painful crisis in sickle cell disease. Br

J Haematol 120:744-752, 2003.

Regarding episodes of pain, although it is

Vichinsky EP, Neumayr LD, Earles AN, et al.

reassuring the child has had a relatively unre-

Causes and outcomes of the acute chest syn-

markable course to date, VOE can start at any

drome in sickle cell disease. National Acute

age. At 2 years of age, the child is still at risk

Chest Syndrome Group. N Engl J Med

for developing episodes of dactylitis. The

342:1855-1865, 2000.

family should be advised on the signs and

Ware RE. How I use hydroxyurea to treat young

symptoms to monitor for pain in a young

patients with sickle cell anemia. Blood

115:5300-5311, 2010.

child which may present as irritability, refusal

Thalassemia

The thalassemias are a diverse group of

An excess of alpha-globin chains (beta-

genetic diseases characterized by absent or

thalassemia) leads to the formation of

decreased production of normal hemoglo-

alpha-globin tetramers that accumulate in

bin, resulting in a microcytic anemia. The

the erythroblast. These aggregates are very

alpha-thalassemias are concentrated in

insoluble and precipitation of these aggre-

Southeast Asia, Malaysia, and southern

gates interferes with erythropoiesis, cell

China. The beta-thalassemias are seen pri-

maturation, and cell membrane function

marily in the Mediterranean, Africa, and in

leading to ineffective erythropoiesis and

Southeast Asia. Due to global migration

anemia.

patterns, there is an increase in the incidence

An excess of beta-globin chains (alpha-

of thalassemia in North America, primarily

thalassemia) leads to tetramers of beta-

because of immigration from Southeast

globin, Hgb H. These tetramers are more

Asia. Like with sickle cell anemia, develop-

stable and soluble, but as the red cell ages in

ment of thalassemia is directly related to

the circulation and, under conditions of

evolutionary pressure secondary to malaria.

oxidant stress, Hgb H precipitates and inter-

Normally,

95% of adult hemoglobin

feres with cell membrane function leading

found on electrophoresis is Hgb A (a₂b₂).

to an increase in hemolysis.

Two minor hemoglobins occur: 2% to 3.5%

is Hgb A2 (a₂d₂) and

2% is Hgb F (a₂g₂).

A mutation affecting globin chain produc-

Alpha-thalassemia

tion or deletion of one of the globin chains

leads to a decreased production of that

The alpha-thalassemias are caused by a

chain and an abnormal globin ratio. The

decrease in the production of alpha-globin

globin that is produced in normal amounts

due to a deletion or mutation of one or more

is in excess and forms aggregates or inclu-

of the four alpha-globin genes located on

sions within the red cells. These aggregates

chromosome

16. Alpha-gene mapping

become oxidized and damage the cell mem-

can be obtained to determine the specific

brane leading to ineffective erythropoiesis,

mutation. The alpha-thalassemias are cate-

hemolysis, or both. The quantity and prop-

gorized as: silent carrier, alpha-thalassemia

erties of these globin chain aggregates deter-

trait, hemoglobin H disease, hemoglobin

mine the phenotypic characteristics of the

H-constant spring, and alpha-thalassemia

thalassemia.

major. Frequently, the diagnosis of

Handbook of Pediatric Hematology and Oncology: Children’s Hospital & Research Center Oakland,

Second Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.

2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

Thalassemia

alpha-thalassemia trait in a parent is discov-

Hemoglobin H (

/ a) should be con-

ered after the birth of an affected child.

sidered in the case of a neonate in whom all

Silent carrier status is characterized by

of the red blood cells are very hypochromic.

three functional genes for a-globin:

Neonates who have Hgb H will also have a

( a/aa). Outside the newborn period, it

high percentage of Hgb Bart’s on their

is not possible to make this diagnosis by

newborn screen (

20%). In children, this

conventional methods. There is overlap

hemoglobinopathy is characterized by mod-

between the red blood cell indices of these

erate anemia with a hemoglobin in the 8 to

individuals and normals, although the MCV

10 g/dL range, hypochromia, microcytosis,

may be slightly lower. This state is deduced

red cell fragmentation, and a fast migrating

when a “normal” individual has a child with

hemoglobin (Hgb H) on electrophoresis.

Hgb H disease or with microcytic anemia

Hemoglobin H does not function as a

consistent with alpha-thalassemia trait. An

normal hemoglobin, and has a high oxygen

unusual case of the silent carrier state is the

affinity, so the measured hemoglobin in these

individual who carries the hemoglobin con-

children is misleading. Individuals who have

stant spring mutation (a_csa/aa or aa_cs/aa).

Hgb H generally have a persistent stable

This is an elongated a-globin due to a

state of anemia that may be accentuated by

termination codon mutation. Individuals

increased hemolysis during viral infections

who have this mutation have normal red

and by exposure to oxidant medications,

blood cell indices, but can have children

chemicals, and foods such as sulfa-drugs,

who have Hgb H-constant spring if the

benzene, and Fava beans, similar to indivi-

other parent has alpha-thalassemia trait

duals who have G6PD deficiency. As the red

(aa/

). Generally, these children are more

cells mature, they lose their ability to with-

affected clinically than other children who

stand oxidant stress and Hgb H precipitates,

have Hgb H.

leading to hemolysis. Therapy for individuals

Individuals who have alpha-thalassemia

who have Hgb H disease includes folate,

trait ( a/-a) or (aa/

) are identified by

avoidance of oxidant drugs and foods,

microcytosis, erythrocytosis, hypochromia,

genetic counseling, education, and frequent

and mild anemia. The diagnosis is made

medical care. Uncommon occurrences in a

by genetic studies, ruling out both iron-

child with Hgb H would be severe anemia,

deficiency anemia and beta-thalassemia

cholelithiasis, skin ulceration, and spleno-

trait. In the neonatal period, when hemo-

megaly requiring splenectomy. Unlike indi-

globin Bart’s

(g₄) is present

(

5% on

viduals who have beta-thalassemia, hemosi-

newborn screen), the diagnosis can be sus-

derosis is rare in Hgb H disease.

pected. In children, there are no markers

Children with hemoglobin H-constant

such as elevated Hgb A₂ and Hgb F (as seen

spring (

/a_csa or a_cs-/a-) have a more

in beta-thalassemia trait) to make the diag-

severe course than children who have Hgb

nosis. The diagnosis is one of exclusion and

H. They have a more severe anemia, with a

is often mistaken for iron-deficiency anemia

steady-state hemoglobin ranging between 7

secondary to the microcytosis. Clues for the

and

8 g/dL. They more frequently have

diagnosis include a normal RDW and an

splenomegaly and severe anemia with febrile

increase in red blood cells for the level of

illnesses and viral infections, often requiring

hemoglobin. During pregnancy, the micro-

transfusion. If anemia is chronically severe

cytic anemia can be mistaken for anemia of

and the child has splenomegaly, a splenec-

pregnancy, and may be a clue for a family

tomy may be performed. If splenectomy is

history of alpha-thalassemia trait.

anticipated, a complication can be severe

Chapter 4

postsplenectomy thrombocytosis with

unique mutations. Individuals with beta-

hypercoagulability leading to thrombosis

thalassemia major are usually homozygous

of the splenic vein or hepatic veins. This

for one of the common mutations (as well as

complication has also been reported as

having one of the geographically unique

recurrent pulmonary emboli and clotting

mutations) that lead to the absence of

diathesis. Children who are scheduled to

beta-chain production.

have surgery are treated with low-molecular-

The beta-thalassemia syndromes are

weight heparin, followed by low-dose aspi-

much more diverse than the alpha-thalassemia

rin, continued indefinitely.

syndromes due to the diversity of the

The most severe form of alpha-thalasse-

mutations that produce the defects in the

mia is alpha-thalassemia major

(

beta-globin gene. Unlike the deletions that

This diagnosis is frequently made in the last

constitute most of the alpha-thalassemia

months of pregnancy when fetal ultrasound

syndromes, beta-thalassemias are caused

indicates a hydropic fetus. The mother fre-

by mutations on chromosome 11 that affect

quently exhibits toxemia and can develop

all aspects of beta-globin production: tran-

severe postpartum hemorrhage. These

scription, translation, and the stability of the

infants are usually stillborn. There can be

beta-globin product. Most hematologists

other congenital anomalies, though none

feel there are three general categories of

are pathognomonic for alpha-thalassemia

beta-thalassemia: beta-thalassemia trait,

major. Because of in utero hypoxia, the

beta-thalassemia intermedia, and beta-

hemoglobins found in these infants are Hgb

thalassemia major. However, with the lack

Portland (z₂g₂), Hgb H (b₄), and Hgb Bart’s

of genotypic differentiation, there remains

(g₄), and no Hgb A or A₂. These babies can

phenotypic overlap between these three

have other complications associated with

general categories.

hydrops such as heart failure and pulmo-

Splice site mutations also occur and are

nary edema.

of clinical consequence when combined

If the diagnosis is made early, intrauter-

with a thalassemia mutation. Three splice

ine transfusions can be performed. There

site mutations occur in exon 1 of the beta-

are reports of survival with chronic trans-

globin gene. These mutations result in three

fusion in these infants, now more recently

different abnormal hemoglobins: Malay, E,

replaced by curative hematopoietic stem cell

and Knossos. Hemoglobin E is a very com-

transplantation. Undoubtedly, more of

mon abnormal hemoglobin in the Southeast

these infants could be saved if the diagnosis

Asian population and when paired with a

was anticipated by prenatal diagnosis and

b₀-thalassemia, mutation can produce

the treatment provided.

severe transfusion-dependent thalassemia.

Hemoglobin E is described in the section

on newborn screening.

Beta-thalassemia

Individuals who have beta-thalassemia

trait have microcytosis and hypochromia;

Beta-thalassemia is caused by mutations in

there may be targeting and elliptocytosis,

the beta-globin gene. Although there have

though some individuals have an almost

been hundreds of mutations identified

normal smear. These hematologic features

within the beta-globin gene locus, about

can be accentuated in women with trait who

20 different alleles make up about 80% of

are pregnant and individuals who are folate

the mutations found worldwide. Within

or iron deficient. If iron deficiency is con-

each geographic population, there are

current with beta-thalassemia trait, there

Thalassemia

may be a normal Hgb A₂. Iron deficiency

Problems can still arise if both alpha- and

causes decreased hemoglobin production

beta-thalassemia coexist since the changes in

and folate or vitamin B₁₂ deficiency can

Hgb A₂ and F will not be apparent as noted

lead to megaloblastic anemia with increased

above. Family studies and DNA analysis can

Hgb A₂. Both of these deficiencies need to be

be used to make a definitive diagnosis.

treated prior to evaluation for thalassemia

Children who are diagnosed with thalas-

trait. In iron-, B₁₂-, and folate-replete indi-

semia intermedia have a homozygous or

viduals, the Hgb A₂ can be as high as 3.5% to

heterozygous beta-globin mutation that

8% and the Hgb F as high as 2% to 5%.

causes a greater decrease in beta-chain pro-

Generally, beta-thalassemia trait is milder in

duction than seen in thalassemia minor, but

African-Americans (who frequently have a

not to the degree for which chronic transfu-

promoter gene mutation) but has a similar

sion therapy is required. The phenotype can

presentation in individuals of Chinese,

also occur in children who have a mutation

Southeast Asian, Greek, Italian, and Middle

that increases production of a-globin, in

Eastern heritage.

children who have coinherited alpha- and

Infants born in most states in the United

beta-thalassemia, and in other rarer muta-

States are screened for hemoglobinopathies.

tions. Children who have thalassemia

In states without newborn screening for

intermedia are able to maintain a hemoglo-

hemoglobinopathies and in recent immi-

bin of 7 g/dL or slightly higher with a greatly

grants to this country, affected children are

expanded erythron and may manifest bony

frequently found later than the newborn

deformities, pathological fractures, and

period, and the evaluation of their micro-

growth retardation. Children who have thal-

cytic anemia includes differentiation bet-

assemia intermedia can also have delayed

ween iron deficiency and beta-thalassemia

pubescence, exercise intolerance, leg ulcers,

trait. The red blood cell indices can be

inflammatory arthritis, and extramedullary

helpful in this differentiation as the hemo-

hematopoiesis causing spinal cord compres-

globin concentration and the red cell count

sion—a medical emergency requiring radia-

will generally be lower in iron deficiency.

tion therapy and transfusion. They can also

The distinguishing finding in beta-thalasse-

have iron overload due to increased absorp-

mia is a hemoglobin electrophoresis with an

tion of iron from the gastrointestinal tract

elevated Hgb A₂

and F. Both will be

and intermittent transfusion. They are at risk

increased in beta-thalassemia trait without

for the cardiac and endocrine complications

iron deficiency, and will be normal or

of hemosiderosis, but usually at an older age

decreased in alpha-thalassemia and isolated

than chronically transfused children. Chela-

iron-deficiency anemia. There are several

tion therapy is indicated for increasing fer-

formulas to help in office screening, but

ritin and elevated liver iron.

they are also based on the assumption that

Children who cannot maintain a hemo-

the child is not iron deficient. Usually, iron

globin between 6 and 7 g/dL should have an

deficiency can be ruled out using free

alternative diagnosis considered. If thalas-

erythrocyte protoporphyrin, transferrin sat-

semia is the cause of the anemia, transfusion

uration, or ferritin as a screening test in

and/or splenectomy should be considered.

children who have a hypochromic microcytic

Frequently, adolescents and adults are

anemia. The least expensive test is a trial of

unable to tolerate the degree of anemia

iron and a repeat hemogram after a month. A

that is seen in thalassemia intermedia.

lead level should be obtained if there is an

Hypersplenism, splenic pain, congestive

index of suspicion for lead toxicity.

heart failure, severe exercise intolerance,

Chapter 4

thrombocytopenia, and leukopenia should

ratio as g, rather than b, globin is present in

be considered indications for transfusion

Hgb F). These children have little or no Hgb

and splenectomy.

A₂ and a low reticulocyte count. The diag-

Appropriate clinical management of

nosis can be made with certainty by dem-

thalassemia intermedia patients may be

onstrating thalassemia trait in both parents,

more difficult than patients with thalasse-

by globin biosynthetic ratios, or by

mia major requiring chronic transfusion

beta-gene screening. Beta-gene screening

due to phenotypic heterogeneity. Patients

identifies the most common and some

with clinically mild disease still may have

uncommon mutations, but not all muta-

serious long-term complications as

tions. An electrophoresis showing only Hgb

described above due to ineffective erythro-

F, a complete blood count, and a peripheral

poiesis as well as chronic hemolysis, leading

blood smear will generally be diagnostic. In

to pulmonary hypertension with resultant

most states, these children will be discovered

congestive heart failure and thrombosis in

by newborn screening or occasionally by the

addition to cholelithiasis. Currently, trans-

obstetrician who makes a diagnosis of thal-

fusion therapy is limited to patients with

assemia trait in the mother and obtains a

symptomatic anemia or in children with

family history of thalassemia or anemia in

delayed growth and development and is

both parents prior to the birth of the baby.

generally tailored to the individual patient.

Children who have untreated thalasse-

Hydroxyurea has been utilized as in sickle

mia die in the first decade of life from

cell anemia, increasing Hgb F and obviating

anemia, septicemia, and pathologic frac-

some of the need for transfusion. Splenec-

tures. When palliative transfusions are

tomy has been utilized but now is thought to

introduced, children live into their late teens

be at least partly responsible for the devel-

eventually succumbing to heart failure due

opment of pulmonary hypertension and

to iron overload.

thrombosis secondary to chronic hemolysis.

With the introduction of frequent

Some argue that transfusion therapy is

chronic transfusion therapy with regular

underutilized in thalassemia intermedia and

iron chelation, children are now surviving

improved risk stratification is needed.

into adulthood, adding to the complexity of

Thalassemia major was first described

the disease. The longevity of patients who

by a Detroit pediatrician, Thomas Cooley,

are compliant with their chelation therapy,

in 1925. The clinical picture he described is

or in those who have received bone marrow

prevalent today in countries without the

transplantation, is not yet known.

necessary resources to provide patients with

chronic transfusions and iron chelation

therapy. Children who have untreated thal-

Neonatal screening for

assemia major have ineffective erythropoi-

hemoglobinopathies

esis, decreased red cell deformability, and

enhanced clearance of defective red cells by

Newborn screening identifies patients with

macrophages. The result is a very hypermet-

beta-thalassemia major, hemoglobin H, and

abolic bone marrow with thrombocytosis,

sickle cell disease. Patients with beta-

leukocytosis, and microcytic anemia in the

thalassemia major and sickle cell disease will

young child prior to the enlargement of

be asymptomatic at birth due to high fetal

their spleen. At presentation, they have

hemoglobin levels but will become symp-

almost 100% Hgb F (these cells have a

tomatic over the next 2 to 3 months as

longer life span due to a balanced globin

normal production of Hgb F wanes. Patients

Thalassemia

Table 4.1 Classification of the alpha-thalassemias.

Diagnosis

Genetic finding

Symptoms

Barts (%)

Silent carrier

a-/aa

Hematologically normal

1-3

a-thalassemia trait

a-/a- or aa/—

Mild anemia with microcytosis

3-6

and hypochromia

Hemoglobin H disease

a-/-

Moderately severe hemolytic

5-20

OR Hemoglobin

aa_CS/— or a-/a_CS-

anemia

H-constant spring

Icterus and splenomegaly

a-thalassemia major

-/-

Severe anemia not compatible

100

with life; hydrops fetalis

without intrauterine

transfusion

with significant Bart’s hemoglobin

(see

hemoglobin A and A2 in the normal patient.

Table 4.1) should be considered to have

The pattern FA is normal and should not be

hemoglobin H and require alpha-gene

interpreted as beta-thalassemia trait. This is

screening to detect the possibility of Hgb

a diagnosis made by the practitioner when

H-constant spring.

microcytic anemia is seen during routine

The presence of Hgb F only on the

childhood screening and an investigation

newborn screening will be interpreted as

for thalassemia confirms the diagnosis.

beta-thalassemia major (see Table 4.2). This

Hgb FE will be presumed to be Hgb E-

diagnosis must be confirmed with parental

beta-thalassemia until that diagnosis is inves-

electrophoresis and repeat testing of the

tigated and confirmed, or ruled out by repeat

infant at 2 to 3 months after fetal hemoglo-

electrophoresis and family studies. Hemoglo-

bin wanes with concomitant increase in

bin E is the most common abnormal

Table 4.2 Interpretation of common newborn screening results.

Result

Diagnostic possibilities

Action required

Normal

None

b-thalassemia trait

Genetic counseling

b-thalassemia major

Referral to hematologist

FAS

Sickle cell trait

Genetic counseling

Sickle cell disease (Hgb SS)

Repeat testing at 2-3 months

Hgb S/b₀-thalassemia

Family studies

Referral to hematologist

FSA

Hgb S/b_þ -thalassemia

Referral to hematologist

FSC

Sickle cell disease (Hgb SC)

Referral to hematologist

FAC

Hemoglobin C trait

Genetic counseling

Hgb E/b-thalassemia

Repeat testing at 2-3 months

Hgb EE

Family studies

FAE

Hgb E trait

Genetic counseling

Order of results is listed from highest to lowest frequency (i.e., in FA, higher percentage of

Hgb F than Hgb A).

Chapter 4

hemoglobin discovered in the state of Cali-

MCV, and reticulocyte count would be helpful

fornia on newborn screening. It is common in

to narrow the differential. Iron deficiency is

Laos, Cambodia, and Thailand. Hemoglobin

unlikely before 6 months of age due to mater-

E results from a mutation in an exon (exon 1,

nal iron stores unless the baby was born

codon 26: GAG to AAG) that creates an

prematurely (and would have been routinely

alternate splice site competing with the nor-

put on iron therapy) or if the mother had

mal splice site. This results in abnormal

severe anemia during pregnancy or if there

hemoglobin production and mild microcytic

was acute or occult blood loss. Viral suppres-

anemia (Hgb

10 g/dL) in the homozygous

sion or aplasia from infections such as par-

state. Electrophoresis reveals about 90% Hgb

vovirus is possible, but less likely without

E with varying amounts of Hgb F. The het-

any history of recent infection or fever.

erozygote has a hemoglobin of about 12 g/dL

Beta-thalassemia as well as sickle cell anemia

with microcytosis and an electrophoretic

should be high in the differential as fetal

pattern consistent with Hgb E plus Hgb A.

hemoglobin lives 60 to 90 days and therefore

When combined with other more severe

by 4 months of age the infant will be produc-

beta-thalassemias, Hgb E-beta-thalassemia can

ing little fetal hemoglobin (a₂g₂) and should

produce an anemia that is profound requiring

have moved to almost solely hemoglobin A

chronic transfusion therapy. All children who

(a₂b₂) unless there is a problem with the

have Hgb E and Hgb F on their state screen

b-globin chain. Additional possibilities

require scrutiny for the emergence of a severe

include a hemolytic anemia, transient ery-

thalassemia syndrome. Individuals who are

throblastopenia of childhood (though rarely

homozygous for Hgb E should not have a

seen at this young of an age), infant leuke-

significant anemia and do not require special

mia, and folate and vitamin B₁₂ deficiency if

care. Like patients with alpha-thalassemia, they

the baby is being fed goat’s milk or the

should not be treated with iron for their micro-

mother is vegan, respectively.

cytic anemia unless they are proven to have

concomitant iron deficiency.

2. What additional piece of information

may be helpful in this young child?

Case study for review

In addition to asking about a family history

of sickle cell anemia and thalassemias, the

You are seeing an infant that has been fol-

provider should look for the results of new-

lowing in your clinic since the newborn

born screen which could be very helpful in

period. The baby was born full-term without

this case. If the patient has a newborn screen

any significant issues. You are now seeing the

that is FA, sickle cell anemia and b-thalas-

baby back at 4 months for the well-child

semia major can be ruled out. More con-

check and their secondary vaccinations. The

cerning newborn screening results would

parents note that the baby has been more

include F (b-thalassemia major), FS (Hgb

listless, not eating as well, and looking paler.

SS disease or Hgb S/b⁰-thalassemia), and

There are no recent infections or fevers.

FSA

(Hgb S/b^þ -thalassemia). b⁰- and

b^þ -thalassemia are differentiated based

1. Assuming this baby is anemic, what would

on the presence (b^þ ) or absence (b⁰) of

your differential diagnosis be at this point?

hemoglobin A, although phenotypically

the patient can have an extremely vari-

Causes of anemia are quite broad at this point.

able clinical presentation, in part due to

Complete blood count with differential,

the persistence of fetal hemoglobin. If the

Thalassemia

patient had sickle cell trait, their newborn

would be FA. As adults, after fetal hemo-

screen result would be FAS as the percentage

globin production has decreased, they

of hemoglobin A should be greater than

would have increased amounts of both A2

the percentage of hemoglobin S. If neces-

(>3.5%) and F (>2%) in addition to hemo-

sary, results can be confirmed at

globin A.

6 months of age after fetal hemoglobin

levels should be significantly decreased or,

5. What other clinical signs might be appar-

if possible, the parents can be tested. In

ent in the infant?

this case, the newborn screen results are F

only.

One would expect to see increasing signs of

extramedullary hematopoiesis with increas-

3. How might repeat hemoglobin electro-

ing age and decreasing fetal hemoglobin

phoresis be different at this age?

production. Some of the early signs could

be frontal bossing as well as maxillary and

The patient that has no hemoglobin A will

mandibular prominence. The infant may

be on the extreme end of the clinical spec-

have failure to thrive as well as the devel-

trum with definitive b-thalassemia major.

opment of hepatosplenomegaly.

For those patients with some b-

globin production, the clinical severity of

Suggested Reading

disease at this point cannot be determined

on a molecular level. Patients who are solely

Aessopos A, Kati M, Meletis J. Thalassemia inter-

fetal hemoglobin (a₂g₂) on newborn screen

media today: should patients regularly receive

transfusions? Transfusion 47:792-800, 2007.

will likely continue to make some amount of

Olivieri NF. The beta-thalassemias. N Engl J Med

fetal hemoglobin in addition to hemoglobin

341:99-109, 1999.

A2 (a₂d₂). Their repeat hemoglobin electro-

Singer ST, Kim HY, Olivieri NF, et al. Hemoglo-

phoresis will represent this with variable

bin H-constant spring in North America: an

amounts of hemoglobin A2 and F and no

alpha-thalassemia with frequent complica-

hemoglobin A.

tions. Am J Hematol 84:759-761, 2009.

Taher AT, Musallam KM, Karimi M, et al. Over-

4. What would you expect the parents’

view on practices in thalassemia intermedia

hemoglobin electrophoresis to show?

management aiming for lowering compli-

cation rates across a region of endemicity:

the OPTIMAL CARE study. Blood

115:

The parents likely both have b-thalassemia

1886-1892, 2010.

trait. If they were tested as newborns, they

Transfusion Medicine

Transfusion of blood products continues

patients to eliminate the risk of clerical

to be an important and necessary part of

error.

therapy in children with hematologic and

Directed donation from first-degree

oncologic diagnoses. Many complications

relatives

(especially maternal) should be

can result from transfusion, both infectious

discouraged for patients who may be can-

and noninfectious. With continued

didates for an allogeneic bone marrow

improvements in donor screening, and

transplant due to the possibility of antigen

better testing techniques, infections from

sensitization. If it cannot be avoided, the

known entities have become a rarity. How-

blood should be irradiated to prevent graft-

ever, as long as blood component therapy is

versus-host disease (GVHD). Studies have

derived from human blood donation, the

shown that blood from directed donation is

risk will persist. Donor selection criteria are

not safer than the general donation pool due

designed to screen out potential donors with

to current sophisticated screening and

increased risk of infection with HIV-1/2,

testing methods.

HTLV-I/II, and hepatitis B and C, as well

These risks must be carefully considered

as other infectious pathogens. Despite rig-

and weighed against expected benefit

orous screening and testing for these infec-

each time a transfusion is contemplated.

tions, the risk of transmitting these viruses is

Informed consent should be obtained prior

not totally eliminated.

to every nonemergent transfusion. In

Clerical errors and misidentification are

California, the Gann Act must be renewed

major risks for transfusion and can result in

on a yearly basis for those patients under-

serious consequences, including death. It is

going frequent transfusion due to an

essential that all blood samples drawn for a

underlying hematologic or oncologic

type and cross-match be clearly labeled with

condition.

the patient’s identification. Before adminis-

tration of the blood product, the order

should be checked, patient identification

Packed red blood cell transfusion

reviewed

(patient’s identification band),

and blood type verified. Many institutions

Transfusion decisions are made on the basis

have moved toward testing two separate

of clinical context, rather than the level of

blood type specimens for nonemergent

hemoglobin alone (see Figure 5.1). Prior to

transfusion in previously untransfused

transfusion, it is necessary to assess the

Handbook of Pediatric Hematology and Oncology: Children’s Hospital & Research Center Oakland,

Second Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.

2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

Chapter 5

mechanism responsible for anemia (bone

related risks including risk of infection,

marrow infiltration, ineffective erythropoi-

febrile nonhemolytic transfusion reactions

esis of chronic disease, occult or obvious

(FNHTRs), and alloimmunization from

blood loss, transfusion or drug-related sup-

PRBC transfusion. Although not universal

pression of normal hematopoiesis, and

as yet in the United States, leukoreduction is

nutritional deficiency), the severity of the

becoming standard of care and is universal

signs and symptoms, and the likelihood of

in Canada and much of Europe.

resumption of normal hematopoiesis.

Irradiation of blood products should be

Whole blood is rarely, if ever, utilized in

utilized for all patients who are immuno com-

standard practice, though may occasionally

promised in order to prevent transfusion-

be utilized for massive transfusion after

associated graft-versus-host disease

(TA-

military trauma. Packed red blood cells

GVHD). This should include all oncology

(PRBCs) are depleted of the majority of

patients as well as neonates.

platelets and white blood cells and need

Cytomegalovirus (CMV)-negative blood

to be ABO and RhD compatible, at the

should be considered in patients in the

minimum. Phenotypically, and now more

peritransplant period who are noted to be

recently genotypically, matched blood for

CMV seronegative in addition to neonates

minor antigens should be utilized for

born to CMV-negative mothers and patients

patients undergoing chronic transfusion

with immunodeficiencies. Institutional

(e.g., sickle cell disease). One unit of PRBCs

guidelines vary and should be consulted in

is approximately

250

350 mL with a

determining the need for CMV-negative

hematocrit of 55% to 60% when prepared

blood secondary to the limited supply of

with adsol. Based on the hematocrit of the

this product.

stored PRBCs, one can calculate the pre-

Finally, washing of PRBCs is rarely indi-

sumed rate of rise from blood transfusion.

cated and decreases the red cell mass by

For adsol-preserved units, the transfusion

approximately 20%. Washing is indicated

factor is approximately

(assuming no

for severe allergic transfusion reactions,

hemolysis of transfused blood or blood

hyperkalemia, large-volume transfusions,

loss). The estimated hemoglobin

(Hgb)

and selective IgA deficiency.

increase can be derived utilizing this trans-

fusion factor:

Indications for PRBC transfusion

Estimated hemoglobin rise ðg=dLÞ

Neonates

Guidelines for transfusion in neonates and

¼VolumeofPRBCtransfusionðmL=kgÞ

Transfusion factor

infants vary widely in the literature. Clinical

correlation is required in addition to the

For example, for a transfusion of 15 mL/kg,

following basic guidelines:

the estimated hemoglobin increase should

* Transfusion of leukopoor, irradiated

3 g/dL. Of note, waiting a certain

blood in premature infants and low-birth

period of time for a posttransfusion

weight neonates

(CMV-negative if CMV

“reequilibration” prior to rechecking the

status of mother is negative or unknown)

hemoglobin is not necessary.

* High oxygen requirement or severe car-

Removal of the vast majority of remain-

diac disease, keep Hgb 11 to 15 g/dL

ing white blood cells, or leukoreduction, is

* Mild-to-moderate respiratory distress or

an important step in reducing transfusion-

perioperative care, keep Hgb 10 g/dL

Transfusion Medicine

Stable infants who become symptomatic

Oncology patients

from anemia, keep Hgb > 7 to 8 g/dL (based

In general, a hemoglobin of 7 g/dL is used as

on degree of symptoms)

the threshold for transfusion in pediatric

oncology patients. This may be altered in

Acute blood loss and nonimmune

cases where the patient is asymptomatic

hemolytic anemia

with imminent recovery of red blood cells

Unlike chronic conditions that result in a

(often heralded by increase in platelet

slow drop in hemoglobin and time for

count). Infants with effects on growth and

compensation, patients with acute blood

development due to anemia should be

loss or nonimmune hemolytic anemia may

maintained at higher hemoglobins; simi-

be symptomatic at much higher hemoglo-

larly, adolescents may complain of headache

bin levels and should be transfused accord-

and fatigue and be less symptomatic with

ingly. In situations of continuing blood loss,

hemoglobins in the

8 to

10 g/dL range.

patients should be transfused to achieve an

Those with cardiopulmonary dysfunction

expected hemoglobin level in addition to

and those requiring procedural sedation

receiving blood to compensate for ongoing

with anticipated blood loss should be kept

losses. In an emergent situation, transfusion

in the 8 to 10 g/dL range as well.

consent is not required, and if there is no

time for a cross-match, O-negative blood

Autoimmune hemolytic anemia

should be given.

In patients with an autoimmune hemolytic

anemia, immunosuppressive therapy is usu-

Severe chronic anemia

ally sufficient to abate the underlying pro-

In pediatric patients, iron-deficiency ane-

cess. In those patients who are symptomatic

mia is the most likely cause of severe

with a continuing drop in hemoglobin and/

chronic anemia

(i.e., Hgb < 5 g/dL), in

or resultant significant cardiopulmonary

addition to viral suppression, transient

dysfunction, phenotypically matched blood

erythroblastopenia of childhood, aplastic

may be given with close observation know-

anemia, and newly diagnosed leukemia.

ing that hemolysis is likely to continue and

Pediatric patients can present with an

may even be augmented.

extremely low hemoglobin (e.g., 2 to 3 g/

dL) and yet be relatively well compensated.

Chronically transfused patients

Patients should be assessed closely for sub-

Patients with b-thalassemia major as well as

tle signs of congestive heart failure (cardi-

some with b-thalassemia intermedia, Hgb

omegaly on chest radiograph, increased

SS, and Hgb S/b⁰-thalassemia require

diastolic blood pressures, hepatomegaly,

chronic transfusion therapy, as outlined in

oliguria, and periorbital edema) prior to

previous chapters. These patients should

transfusion. Slow transfusion (e.g.,

1 mL/

have a red cell phenotype prior to initiating

kg/h) has been recommended in the past,

transfusions and based on institutional

although studies have shown that

practice will usually receive phenotypically

3 mL/kg/h is safe in patients with normal

matched blood to a small panel of antigens

underlying cardiopulmonary function.

(at our institution, other Rh antigens

Those with signs of cardiopulmonary dys-

including C/c and E/e as well as Kell). If

function should be transfused slowly with

the patient develops antibodies to other

judicious usage of diuretics, and exchange

minor red cell antigens (e.g., MNS, Duffy

transfusion should be considered in those

[Fy^a/Fy^b], Kidd [Jk^a/Jk^b], and Lewis [Le^a/

with heart failure.

Le^b]), more extensive phenotype matching

Chapter 5

is performed in order to decrease the con-

sickle cell events, hyperbilirubinemia, or in

tinued risk for alloimmunization. Genotyp-

an anemic patient treated with severe fluid

ing for a wider range of antigens is becoming

restriction (increased ICP). In sickle cell dis-

more universally available and will likely

ease, exchange transfusion quickly reduces

become the future standard of care. Sickle

the concentration of sickle cells without

cell patients in addition should receive sick-

increasing the hematocrit or whole blood

ledex-negative blood as blood donors are

viscosity. In addition, red cell exchange

not screened for sickle cell trait. Transfusion

transfusion reduces iron accumulation since

is given on a regular basis (i.e., every 3 to 4

an equal volume of red cells and iron are

weeks) in order to suppress ineffective

removed as infused. Therefore, for sickle cell

erythropoiesis.

disease, erythrocytopheresis is preferred over

straight transfusion in patients requiring

chronic transfusion in addition to those

Dosing of PRBC transfusion

patients with acute events. Automated ery-

throcytopheresis can be done rapidly and

The desired incremental increase in hemo-

safely in most situations. Limitations of this

globin should be considered when deter-

technique include increased red cell utiliza-

mining the amount of blood to be trans-

tion, venous access, and increased cost.

fused. In general, 10 to 20 mL/kg over 4

hours is given in order to increase the

hemoglobin by 2 to 4 g/dL. Care should

Platelets

be taken to not waste blood; therefore,

orders should be rounded to the nearest

Platelet transfusions are indicated for throm-

unit or half unit, as feasible. Remaining

bocytopenic patients with bleeding due to

blood may be sterilely aliquoted and used

severely decreased platelet production or for

later in the same patient in order to decrease

patients with bleeding secondary to function-

exposure to multiple donors. Slow transfu-

ally abnormal platelets. Transfusion is not

sion should be given in patients with signs of

indicated for those with rapid destruction

volume overload or cardiopulmonary dys-

(e.g., immune thrombocytopenic purpura

function. Patients with frank heart failure

and neonatal alloimmune thrombocytope-

should be exchange transfused. Care should

nia) unless there is life-threatening hemor-

be taken to not increase the hemoglobin

rhage; however, transfusion may be useful in

above 12 g/dL in patients with sickle cell

the bleeding patient with rapid consumption

disease secondary to hyperviscosity and

(e.g., disseminated intravascular coagula-

increased risk of CNS events. Similarly, in

tion [DIC]) or dilutional thrombocytopenia

leukemic patients with hyperleukocytosis at

(massive transfusion or exchange). Platelets

diagnosis(whitebloodcellcount>100

10⁹/

are frequently needed in the patient receiving

L), the hemoglobin should preferably be kept

chemotherapy or one thrombocytopenic

below 10 g/dL and transfusion avoided if

secondary to a marrow infiltrative process.

possible due to the same risks of increasing

viscosity and the propensity for leukostasis.

Indications for platelet

Exchange transfusion

transfusion

Exchange transfusion or erythrocytopher-

1. Premature or sick infants

esis may be indicated in the severely anemic

a. Stable infant with platelet count

patient with congestive heart failure, acute

<50

10⁹/L

Transfusion Medicine

b. Distressed infant with platelet count

g. Intramuscular injection

(i.e., PEG-

<100

10⁹/L

asparaginase) with platelet count

2. Children

<20

10⁹/L

a. Platelet count <10

10⁹/L; higher if

Dosing of platelet transfusion

febrile, septic, or with active bleeding

One unit of random platelets (

40 mL) per

b. Platelet count <20 to 50

10⁹/L with

10 kg will increase the platelet count by 40 to

a minor invasive procedure such as:

10⁹/L if there is no active consumptive

i. Lumbar puncture

process (e.g., fever, immune thrombocyto-

ii. ECMO or CV bypass

penic purpura, sepsis, alloimmunization, or

iii. Other minor procedures such as

DIC) or sequestration. This is equivalent to

central line placement

an increment in platelet count of 10

10⁹/L

c. Invasive procedure in a patient with a

per mL/kg of transfused platelets (i.e., in a

qualitative platelet defect

10 kg child, 10 mL/kg or 100 mL of trans-

d. More invasive procedures will require

fused plates should raise the platelet count

discussion with the surgical team regarding

by 100

10⁹/L). The platelet count should

platelet transfusion threshold, although

be checked 1 to 2 hours after infusion to

recommendations are generally not evi-

identify refractory patients. A patient is

dence based

refractory if

1 hour after transfusion the

3. Patients

undergoing therapy for

platelet increment is less than

malignancy

10⁹/L per unit transfused for two sep-

a. Platelet count <10

10⁹/L; higher if

arate transfusions.

febrile, septic, or with active bleeding

A patient may have platelet refractori-

b. Induction chemotherapy:

ness secondary to alloantibodies (immune

i. ALL <10

10⁹/L

mediated). Nonimmune causes of platelet

ii. AML <10 to 20

10⁹/L

refractoriness are common and include

c. Children undergoing intensive ther-

splenomegaly, fever, infection, DIC, and use

apy with active mucositis should have

of amphotericin B.

their platelet count maintained at 30 to

For refractory patients, a trial of cross-

10⁹/L (i.e., Head Start protocol for

matched platelets should be given. Other

brain tumors)

possibilities for treatment should this fail

d. Lumbar puncture with platelet count

include leukocyte-depleted, human leuko-

<20 to 50

10⁹/L; potentially <50 to 100

cyte antigen

(HLA)-matched platelets,

10⁹/L with diagnostic lumbar puncture

intravenous immunoglobulin (IVIG) with

e. Bleeding patient with normal coagu-

HLA-matched platelets, or massive trans-

lation studies, platelets

<50

10⁹/L;

fusion with random donor platelets

(to

with abnormal coagulation studies,

overwhelm the antibody).

platelet count <100

10⁹/L

Most institutions now utilize pheresed

f. Patient requiring a moderately inva-

platelets that are harvested from a single

sive surgical procedure, with a platelet

donor and generally contain greater than

count

<50 to 100

10⁹/L

(requiring

10⁹/L of platelets, equivalent to

discussion with surgical team secondary

approximately 6 to 8 units of random plate-

to lack of evidence-based guidelines).

lets. The volume is usually 250 to 350 mL.

Most surgeons would like platelet count

Secondary to the apheresis, these platelet

to remain >50 to 75

10⁹/L for 48 to

products are considered to be leukoreduced.

72 hours after the surgical procedure

In addition, although controversial, most

Chapter 5

believe that apheresis is sufficient to reduce

concentration of plasma antibodies, FFP is

the risk of CMV transmission. Plasma ABO

often the cause in cases of transfusion-asso-

compatibility should generally be utilized,

ciated acute lung injury (TRALI) and there-

especially with increasing volume of trans-

fore should be used judiciously. The direct

fusion. Type-specific platelets can be given

antiglobulin test (DAT; Coombs test) may

in cases of refractoriness and should be

also be positive for this reason.

given to patients in the peritransplant

period to eliminate the production of any

Indications for FFP

potential red blood cell antibodies. As with

* Bleeding or invasive procedure with

PRBC transfusion, platelet irradiation is

documented clotting factor deficiency and

required in oncology patients, premature

appropriate factor not available

or low birth weight newborns, and patients

* Treatment of protein C or S deficiency,

with immunodeficiencies.

factor XI deficiency (hemophilia C)

Dosage of platelet transfusion is gener-

* Bleeding during massive transfusion, not

ally 10 to 15 mL/kg and can be given over 30

from thrombocytopenia

minutes to 1 hour. Due to the expected

increase in platelet count and short life-

Dosing of FFP

span of platelets, 1 unit of pheresed platelets

The usual dosage of FFP is 10 to 15 mL/kg

is usually sufficient for transfusion in

over 1 hour, which is expected to increase

patients over 30 kg. As with PRBCs, pher-

the concentration of coagulation factors by

esed platelet units should be rounded to

25% to

50%. Due to the presence of

the nearest half and full units as feasible

isohemagglutinins, FFP should be ABO

to decrease waste and may be sterilely

matched. White blood cells are killed or

aliquoted as needed.

made nonfunctional during the freezing

process; therefore, leukoreduction and irra-

diation are unnecessary.

Fresh frozen plasma

Fresh frozen plasma (FFP) is a source of

Cryoprecipitate

plasma proteins, including nonlabile clotting

factors, such as fibrinogen. It is used for the

Cryoprecipitate is prepared by thawing FFP

treatment of stable clotting factor deficiencies

and recovering the cold precipitate. Each

in which no concentrate is available (not for

bag contains >80 U factor VIII coagulant

factor VIII or IX). By definition, each milliliter

activity and >150 mg fibrinogen in approx-

of undiluted plasma contains 1 international

imately 15 mL of plasma. In addition, cryo-

unit (IU) of each coagulation factor.

precipitate contains factor XIII and von

Plasma consists of the anticoagulated

Willebrand factor. Bags must usually be

clear portion of blood separated by centri-

pooled to achieve an adequate dose.

fugation. FFP is collected from single

donors, with each unit being removed from

Indications for cryoprecipitate

a unit of whole blood and frozen within 6 to

* Bleeding or invasive procedure with

8 hours of collection. FFP should not be

factor VIII deficiency or von Willebrand

used when the coagulopathy can be cor-

disease and factor concentrate not available

rected more effectively with specific treat-

* Bleeding or invasive procedure with

ment such as vitamin K, cryoprecipitate, or

hypofibrinogenemia or factor XIII

factor concentrate. Due to the high

deficiency

Transfusion Medicine

Dosing of cryoprecipitate

increased granulocyte yields, and therefore

The usual dosage for cryoprecipitate is

the therapeutic benefit of transfusion, as

1 unit/5 kg. Obtain a fibrinogen level at

the dose of granulocytes is the most impor-

30 minutes postinfusion. For hypofibrino-

tant factor in success of this treatment

genemia with coagulopathy, the goal is to

modality.

maintain fibrinogen >100 mg/dL Specific

Granulocytes migrate toward, phago-

factor or coagulation protein levels need

cytize, and kill bacteria. When given a gran-

to be determined in addition to assessing

ulocyte transfusion, the cells migrate to the

clinical status to decide on frequency of

foci of infection, though there is rarely a

transfusion. As with FFP, cryoprecipitate

measurable increase in the peripheral

is preferably ABO compatible and leukor-

granulocyte count. This is likely from

eduction and irradiation are not required.

sequestration at the site of infection, prior

immunization to leukocyte antigens, or a

consumptive process secondary to the infec-

Antithrombin III

tion. Side effects of granulocyte transfusion

include the risk of CMV infection, TA-

Antithrombin III

(ATIII) concentrate is

GVHD, respiratory distress with pulmonary

available for use in patients with inherited

infiltrates (TRALI, concurrent administra-

or acquired ATIII deficiency

(sepsis,

tion of amphotericin B, or secondary to

thrombosis, and medication induced). It

granulocyte

sequestration),

and

may also be needed in patients receiving

alloimmunization.

heparin therapy who have a low ATIII

level. Patients with thrombosis after aspar-

Preparation of granulocyte

aginase therapy should have an ATIII

concentrates

level checked and repletion as necessary.

Donor mobilization is recommended with

ATIII replacement should also be consid-

G-CSF at 5 mcg/kg (maximum 300 mcg IV/

ered in patients with veno-occlusive disease

SC) and dexamethasone 12 hours prior to

(sinusoidal obstructive syndrome) after

col-lection. Granulocytes are then collected

hematopoietic stem cell transplantation.

by apheresis and ideally should be transfused

Dosing of ATIII is based on the baseline

within 8 to 12 hours of collection. RBC

and desired level.

contamination requires ABO compatibility.

Due to risks of TA-GVHD and CMV infec-

tion, irradiation and CMV seronegativity

Granulocyte transfusion

are required

(in those that are CMV-

negative), respectively. Amphotericin B and

Patients with profound and prolonged neu-

concomitant granulocyte transfusion is

tropenia are at increased risk for serious life-

potentially associated with severe pulmo-

threatening fungal and bacterial infections.

nary reactions, although the evidence is

The beneficial effect of granulocyte trans-

controversial; however, it is reasonable to

fusion in this population, with known

space these therapies apart by at least

persistent infection, especially with Gram-

hours. HLA-matched granulocytes

negative organisms and fungus, is yet to be

should be given in patients with known

proven by randomized controlled trials,

alloimmunization. Since granulocyte half-

although observational studies are available.

life is only

7 hours, daily collection and

Donor mobilization with granulocyte

transfusion for several days are likely

colony-stimulating factor

(G-CSF) has

required for benefit.

Chapter 5

Indications for granulocyte

clerical error resulting in the transfusion of

transfusion

an ABO incompatible unit. AHTRs classi-

With a lack of randomized controlled trials,

cally present with fever, chills, nausea, and

there are no evidence-based guidelines for

vomiting in addition to dyspnea, hypo-

granulocyte transfusion. Limited data in

tension, shock, hemoglobinuria, and DIC.

neonates with sepsis has failed to show a

Bacterial contamination must be considered

significant benefit. After weighing the

in the differential for an AHTR. Delayed

potential risks and benefits, as well as deter-

hemolytic transfusion reactions (DHTRs)

mining the daily availability of an eligible

present 2 to 14 days after transfusion with

donor and collection site, granulocyte trans-

milder symptoms including low-grade

fusion can be considered in severely neu-

fever, jaundice, and a posttransfusion

tropenic patients with a refractory or pro-

hemoglobin increment less than expected

gressive bacterial or fungal infection on

due to minor antigen incompatibility

appropriate, aggressive therapy with neu-

(alloimmunization) from prior transfusion.

tropenia that is expected to continue for, at

Evaluation of a potential AHTR should

the least, several days.

include work-up of all recently transfused

blood products (see Figure 5.2). A bedside

check of labeling should occur followed by

Transfusion reactions

laboratory evaluation including repeat

cross-matching and a DAT (Coombs test).

Approximately 4% of transfusions are asso-

The DAT may not always be positive if all

ciated with some form of adverse reaction,

the antibodies have been destroyed during

ranging from brief episodes of fever to life-

the hemolytic crisis. Other labs that should

threatening episodes of hemolysis and

be sent to rule out intravascular hemolysis

shock. Fortunately, the majority of reactions

include indirect bilirubin, LDH, plasma-

are short-term, specifically FNHTRs and

free hemoglobin (and/or haptoglobin), and

allergic reactions, and easily managed.

urinalysis for hemoglobinuria.

Life-threatening reactions are nearly always

DHTRs lead to extravascular hemolysis

due to clerical error resulting in transfusion

and should be evaluated in a patient with

of an ABO incompatible unit. The challenge

clinical or laboratory symptoms after the

for the clinician is to promptly recognize

first

24 hours. Labs to follow include a

potential serious complications that may

posttransfusion hemoglobin level and retic-

present with common symptoms such as

ulocyte count, indirect bilirubin, LDH, and

fever. For any transfusion reaction, a bed-

DAT.

side check of all labels, forms, and patient

If an AHTR is suspected, emergent man-

identification should be done, in addition to

agement is vital. The transfusion should be

notifying the blood bank. Transfusion reac-

immediately stopped and IV fluid resusci-

tions are summarized below and include

tation commenced. Inotropic support may

FNHTRs, allergic reactions, immune-

be required for hypotension and shock.

mediated hemolysis, TRALI, transfusion-

Renal perfusion and urine output should

associated circulatory overload

(TACO),

be followed closely and additional blood

TA-GVHD, and acute infection.

product support may be required. DHTRs

usually do not require intervention

Hemolytic transfusion reactions

although may rarely cause profound

Hemolytic transfusion reactions can either

anemia.

be acute or delayed. Acute hemolytic trans-

FNHTRs were significantly more com-

fusion reactions (AHTRs) are usually due to

mon prior to near universal leukoreduction

Transfusion Medicine

Fever (≥38.0ºC or 100.4ºF)

during blood transfusion

Any concerning clinical signs including:

Signs of sepsis (hypotension, delayed capillary refill, mental status changes)

Signs of hemolysis (hemoglobinuria, dyspnea, hypotension)

Yes

Stop transfusion

≥1ºC (1.8ºF) ↑ in temperature

Initiate supportive care (IVF,

over last 24 hours?

antibiotics)

Contact Intensive Care

Yes

Continue transfusion

Stop transfusion

Monitor clinical exam

closely

Contact Blood Bank

Bedside check of all forms, labels, and patient identification

Blood culture from patient and remaining blood product

Repeat crossmatch on remaining blood product

STAT labs: CBC, indirect bili, LDH, UA, DAT, plasma free hgb

Consider CXR if respiratory symptoms or new hypoxia

Positive work-up?

Yes

Provide appropriate care based on

Restart transfusion

likely diagnosis and clinical symptoms

Monitor clinical exam closely

*See text for more detail

Complete in allotted time as possible

Figure 5.2 Approach to fever during blood transfusion. (Abbreviations: CBC, complete blood

count; LDH, lactate dehydrogenase; UA, urinalysis; DAT, direct antiglobulin test,

(Coombs);

CXR, chest X-ray).

and occur due to pyrogenic cytokines

discontinued until an AHTR can be ruled

released by leukocytes during blood com-

out (see Figure 5.2). Fever due to FNHTR is

ponent storage. FNHTR is defined as a

usually self-limited and resolves with anti-

temperature increase of 1

C (1.8

F) with-

pyretic usage and stopping the transfusion.

out any other attributable cause. More seri-

Chills, rigors, and discomfort can occur,

ous causes of fever including AHTR and

mimicking an AHTR. Transfusion can

bacterial contamination must be ruled out

potentially be restarted after AHTR has been

prior to the diagnosis of FNHTR being

ruled out based on the clinical status of the

made. Transfusion must therefore be

patient and urgency of the transfusion.

Chapter 5

Although patients with a history of FNHTR

transfusion with plasma-containing blood

oftenreceive premedicationwith acetamin-

components. Signs and symptoms include

ophen with future transfusions, this prac-

hypoxia, chest infiltrates (without volume

tice is not evidence based. Antipyretics

overload), dyspnea/tachypnea, fever, and

should be considered for the patient with

hypotension. TRALI generally should

multiple FNHTRs; if acetaminophen is not

occur within 6 hours of transfusion com-

effective, a trial of washed blood compo-

pletion. A majority of patients with TRALI

nents can be considered. Of note, transfu-

will recover in a

2- to

4-day period,

sion can be given to the febrile patient if

although respiratory support, and in some

urgently necessary, as the criteria for work-

cases mechanical ventilation, is often

up (beyond a close and continued clinical

required.

assessment) is an increase of 1

C in fever

compared to the fever curve from the

Transfusion-associated

previous 24 hours.

circulatory overload

TACO also is becoming more widely rec-

Allergic transfusion reactions

ognized but is likely rare in the pediatric

Allergic reactions are typically type I hyper-

population. TACO occurs due to cardio-

sensitivity reactions to plasma in blood

genic edema from too rapid or too large a

components. Allergic reactions are com-

volume of transfusion. Clinical signs such as

mon, occurring in 1% to 5% of transfusions,

dyspnea/tachypnea and hypoxia may be

and usually with mild symptoms such as

confused with TRALI. Differentiating fea-

urticaria, although anaphylaxis can occur.

tures include hypertension rather than

For the majority of allergic reactions, an

hypotension due to pulmonary overcircula-

antihistamine such as diphenhydramine is

tion with a positive fluid balance. Chest

sufficient to alleviate symptoms and the

radiograph should be more consistent with

transfusion can likely be completed in the

pulmonary edema/effusion rather than

allotted time. For more severe symptoms,

infiltrates. Aggressive diuresis should be

the transfusion should be stopped. Steroids,

utilized.

an H2 blocker (e.g., ranitidine), epineph-

rine, volume expansion, b2 agonists (e.g.,

albuterol), and oxygen may be required.

Transfusion-associated

Patients with a severe allergic reaction

graft-versus-host disease

should be tested for IgA deficiency. As with

TA-GVHD can occur in immunocompro-

FNHTRs, premedication (with an antihis-

mised patients who receive nonirradiated

tamine) remains controversial in patients

blood or platelet transfusion due to donor

with a history of a reaction. Patients with

T-lymphocytes that cannot be rejected by

multiple episodes may benefit from preme-

the host. TA-GVHD has also been reported

dication with an antihistamine and, if not

in immunologically normal patients with an

effective, potentially corticosteroids. If aller-

HLA-compatible donor such as in homo-

gic reactions continue, washed blood pro-

geneous populations or in cases where the

ducts should be utilized.

donor is a close relative (directed donation).

Clinical symptoms are equivalent to those

Transfusion related acute lung

with transplant GVHD including fever,

injury

anorexia, vomiting/diarrhea, and skin rash.

TRALI is becoming increasingly recognized

Hepatic dysfunction and pancytopenia can

as an important cause of morbidity after

similarly manifest.

Transfusion Medicine

Bacterial infections

2. What amount of PRBCs should be given?

Blood components may be contaminated

3. Are there any special considerations for

with bacteria at the time of collection or

the type of blood product required?

during processing. Infection rates are higher

4. What are some specific risks with this

after platelet transfusion since platelets are

patient presentation?

stored at room temperature, although clin-

First, the patient should be given PRBCs,

ical signs and symptoms are often more

pheresed platelets

(if possible), and FFP.

severe after transfusion of contaminated

Cryoprecipitate may or may not be required

PRBCs. Infection is associated with a rapid

dependent on the increase in fibrinogen

onset of symptoms and a high rate of

with FFP. If the patient is clinically wors-

morbidity and mortality, especially from

ening (e.g., problems oxygenating, drop-

Gram-negative organisms. The patient may

ping blood pressures), consideration should

present acutely septic with fever/chills,

be given to transfusing O-negative PRBCs

hypotension, tachycardia, and shock. If

while awaiting cross-matching.

bacterial contamination is suspected, the

Second, one can utilize the transfusion

transfusion should be stopped immediately.

Aggressive supportive treatment including

factor to estimate the increment in hemo-

globin with transfusion. In this case, the

IV fluid resuscitation, initiation of broad-

spectrum antibiotics, and potential therapy

transfusion factor will likely overestimate

the bump as the patient is actively septic

for renal failure, shock, and/or DIC should

and therefore hemolyzing PRBCs and con-

be started emergently.

suming platelets. Still, estimating will help

determine a reasonable plan. Assuming the

Case study for review

decision is made to give 15 mL/kg (3 units),

one would expect at most an increase in

You are following a 12-year-old, 60-kg boy

hemoglobin of 3 g/dL:

admitted to the pediatric intensive care unit

Transfusion amount

(mL/kg)/transfusion

with septic shock. He is secondarily found to

factor ¼ Hgb increase (g/dL)

be anemic and thrombocytopenic with coa-

Therefore, in this case (15 mL/kg)/5 ¼ 3 g/

gulopathy and hypofibrinogenemia in DIC.

After initial stabilization of the patient

with IVF, antibiotics, mechanical ventila-

In general, platelet and FFP transfusion will

tion, and pressors, the PICU team is deter-

also be 10 to 15 mL/kg. Platelet transfusion

mining their transfusion plan. Current

should initially be a maximum of one pher-

hemoglobin is

7.0 g/dL, platelets are

esed unit (approximately 250 to 350 mL).

10⁹/L, PT is

27.2 seconds, PTT is

Posttransfusion hemoglobin, platelets, and

74.6 seconds, and fibrinogen is 76 mg/dL.

coagulation studies can help determine the

There is no noted active bleeding. 1:1 mix-

need for additional transfusion as well as the

ing studies correct both the PT and PTT,

likely frequency of necessary transfusion

implying a factor deficiency rather than an

(directly dependent on the clinical status

antibody. The patient does appear to have

of the patient). Time for

“equilibration”

some amount of hemolysis with an elevated

after the completion of transfusion is

indirect bilirubin and LDH but has a neg-

unnecessary.

ative direct Coombs test.

Third, in this case, no significant special

1. What blood products should be

arrangements need to initially be made in

transfused?

regards to the transfusions. The patient does

Chapter 5

not need sickledex-negative blood unless

transfusion-associated

microchimerism.

they have concomitant sickle cell disease.

Microchimerism is the presence of donor

Also, phenotypically matched blood is

lymphocytes in the recipient’s circulation.

unnecessary. As the patient does not

The significance of transfusion-associated

have a known underlying reason to be

microchimerism is unknown. Patients

immunocompromised, irradiated blood

receiving large amounts of plasma are at

and platelets are not required. Similarly,

risk for developing TRALI that must be

CMV-negative blood is unnecessary.

considered with worsening respiratory

Finally, specific risks exist for this patient

symptoms.

and must be considered during transfusion.

Due to the likelihood of continued transfu-

sions as well as the presence of sepsis, the

Suggested Reading

patient may develop volume overload and

potentially TACO; therefore, the judicious

Eder AF, Chambers LA. Noninfectious complica-

use of diuretics with transfusion should be

tions of blood transfusion. Arch Pathol Lab

Med 131:708-718, 2007.

considered. In addition, a significant vol-

Fasano R, Luban NL. Blood component therapy.

ume of PRBC transfusion can have a dilu-

Pediatr Clin N Am 55:421-445, 2008.

tional effect on platelets and coagulation

Klein HG, Spahn DR, Carson JL. Red blood cell

factors, thus increasing transfusion require-

transfusion in clinical practice. Lancet

ments for these blood products. The patient

370:415-426, 2007.

is also at risk for hyperkalemia with increas-

Roseff SD, Luban NL, Manno CS. Guidelines for

ing PRBC transfusion. If hyperkalemia

assessing appropriateness of pediatric trans-

begins to occur, washed PRBCs should

fusion. Transfusion 42:1398-1413, 2002.

be given. Massive PRBC or whole blood

Stroncek DF, Rebulla P. Platelet transfusions.

transfusion has been shown to induce

Lancet 370:427-438, 2007.

Chelation Therapy

Transfusional iron overload

routine use. Currently, R2

MRI (proton

magnetic resonance imaging) is becoming

Iron overload may occur in any patient

more widely utilized as an accurate and

receiving intermittent transfusions for acute

noninvasive measure of organ iron content,

illness

(e.g., sickle cell disease), chronic

and T2

MRI is becoming the new standard

transfusion therapy (thalassemia, sickle cell

for measuring cardiac iron stores. Further

disease, red cell aplasia, bone marrow failure

study is required for these new techniques to

syndromes), or in those having received

become uniformly calibrated methods.

an intensive period of frequent transfusion

Institution of chelation therapy relative to

(myelosuppressive chemotherapy/radiation

transfusion frequency is based on institu-

for treatment of malignancy and after

tional practice. Patients that will require

hematopoietic stem cell transplant). Each

chronic transfusion therapy should be che-

milliliter of blood contains 1 mg of iron and

lated before their liver iron reaches a high

normal iron stores are approximately 3 g,

level, measured by liver biopsy, MRI quan-

with 2 g in the blood and 1 g in the liver.

tification, or based on the number of trans-

Therefore, patients receiving frequent trans-

fusions received (i.e., chelation initiated after

fusion likely will have received a large

receiving 10 to 20 transfusions, or approxi-

amount of transfused iron and should be

mately 3 to 6 g of transfusional iron in a

monitored for evidence of iron accumulation.

30 kg patient). Thalassemia patients tend to

There is no simple test for quantifying

have a higher iron burden than sickle cell

total iron burden. Serial serum ferritin levels

patients as the chronic inflammatory state in

are helpful in determining hepatic iron

sickle cell disease limits gastrointestinal iron

stores, but values are altered in states of

absorption. Thalassemia patients should be

inflammation. Liver biopsy remains the

counseled to be on a low-iron diet.

gold standard for quantification of total

Patients receiving intermittent transfu-

body iron but is an invasive procedure. Liver

sion or those receiving frequent transfusion

iron levels

7 mg/g dry weight liver are

therapy in a short period of time (e.g., with

indicative of iron overload. The supercon-

intensive leukemia therapies) may have a

ducting quantum interference device

more insidious development of iron overload.

(SQUID) is accepted as a noninvasive

Patients with leukemia should have serum

method to quantitate total body iron, but

ferritin levels checked at the end of therapy.

its limited availability does not allow for

Those with ferritin levels

> 1000 ng/mL

Handbook of Pediatric Hematology and Oncology: Children’s Hospital & Research Center Oakland,

Second Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.

2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

Chapter 6

should have serial checks every 3 months; if

effective in all patients, which must be

ferritin remains above this threshold after 6 to

weighed against the risks of noncompliance

12 months, the patient should undergo liver

with Desferal. Deferiprone

(Ferriprox or

biopsy or R2 MRI for more accurate iron

Kelfer) was approved by the Food and Drug

quantification. These patients, especially

Administration

(FDA) in October

2011.

male adolescents, may benefit from monthly

Usage of two agents concomitantly is cur-

phlebotomy which can be discontinued when

rently undergoing clinical trials and may have

the ferritin and liver iron concentration reach

particular benefit in chelation of cardiac iron.

normal levels (i.e., 1.6 mg/g dry liver weight).

Concomitant administration of ascorbic

Younger children and menstruating females

acid (vitamin C) increases the excretion of

have been shown to have reversible iron

iron when given with chelation. Iron che-

overload in most such cases.

lators should not be administered when

Current treatment strategies for iron

there is concern for a bacterial infection.

overload and potential side effects of iron

By mobilizing free iron, chelators promote

chelators are summarized in Table 6.1. Des-

bacterial growth, in particular Yersinia

feroxamine (Desferal) has the longest treat-

enterocolitica. For febrile patients on chela-

ment record but requires parenteral admin-

tor therapy, chelation should be stopped

istration and has been widely replaced by

until blood cultures are definitively nega-

deferasirox (Exjade) due to the convenience

tive. Broad-spectrum antibiotic prophylaxis

of oral intake and therefore presumed

should be initiated and include coverage for

increased compliance. Exjade may not be

this unusual organism.

Table 6.1 Iron chelators.

Name

Desferoxamine (Desferal)

Deferasirox

Deferiprone (Ferriprox/

(Exjade)

Kelfer/L1)

Dose (mg/kg/d)

25-50

20-40

75-100

Administration

SC/IV, given as continuous

PO, daily

PO, TID

infusion over 8-24 hours,

5-7 d/wk

Side effects

Irritation at infusion site,

GI disturbance,

Agranulocytosis, neutro-

ototoxicity (tinnitus,

rash, renal and

penia, GI disturbance,

transient hearing loss),

hepatic

transaminitis,

ocular disturbance

impairment,

arthropathy, progres-

(decreased night vision),

GI hemorrhage

sion of hepatic fibrosis

allergic reactions, growth

failure, skeletal distur-

bance, pulmonary

hypersensitivity

Potential thera-

Highly effective but compli-

Long-term data

Recently approved for

peutic issues

ance may be an issue due

lacking; may

use by the FDA; long-

to route of administration

not be effective

term data lacking

in all patients

Abbreviations: SC, subcutaneous; IV, intravenous; GI, gastrointestinal; FDA, Food and Drug

Administration.

Chelation Therapy

Lead toxicity

minimal amounts

(3%) detected in the

plasma. The half-life in the blood is approx-

Lead poisoning is an environmental disease

imately 21 to 30 days. Excretion is primarily

that has undergone a major evolution in the

through the kidneys, with small amounts

past few decades. Recognition of the devas-

deposited in the hair, nails, and bile. The

tating neurologic effects of high lead levels

lead that remains in the body accumulates

and knowledge of the causes have led to

mostly in the bone (65% to 90%). Lead can

universal efforts to decrease environmental

enter any cell and toxicity may occur in any

lead contamination, with a resultant

tissue or organ. Classically, in severe lead

decrease in measured blood lead levels in

intoxication, gastrointestinal and central

children over the past

decades.

nervous system toxicities are the most clin-

Sources of lead have included gasoline addi-

ically apparent. Gastrointestinal symptoms

tives, food can soldering, lead-based paints,

include anorexia, nausea, vomiting, abdom-

ceramic glazes, certain toys, drinking water

inal pain, and constipation. The blood lead

systems (lead pipes), and folk remedies. The

level is typically 50 mcg/dL or greater when

use of these products has been markedly

these symptoms are present. Lead poisoning

reduced as the result of federal guidelines

was a lethal disease in the United States

and the development of cost-effective alter-

decades ago, primarily related to neurotoxic

natives. Lead in gasoline and paint is at

effects. At levels above 100 mcg/dL, children

extremely low levels and has been elimi-

may show evidence of encephalopathy,

nated altogether from food can soldering.

including a marked change in mentation

Housing built prior to 1960 is likely to have

or activity, ataxia, seizures, and coma.

been painted with high-content lead-based

Increased intracranial pressure may be pres-

paint, and since lead isotopes are very stable,

ent on examination. These effects are usu-

environmental exposure presents an on-

ally permanent with long-term sequelae of

going risk. High risk populations have a

retardation, palsies, and growth failure.

greater likelihood of living in older housing,

Most children who have elevated blood

which has not had lead abatement. Risk

lead levels have subclinical disease. Fewer

factors for excessive lead exposure include

than

5% of children present with overt

poverty, age younger than 6 years, African-

symptoms of lead toxicity. An elevated

American ethnicity, and urban housing.

blood lead level, suggesting excessive envi-

Lead may enter the body through direct

ronmental exposure, is defined as 10 mcg/dL.

ingestion, inhalation, or via skin absorption.

Many studies have shown associations

The most common pathway among young

between blood lead levels and impaired neu-

children is through the mouth. Lead absorp-

rocognitive function. These results have pro-

tion is enhanced in the presence of other

vided the primary impetus for current public

dietary mineral deficiencies, such as calcium

health efforts. Of note, no lead level is normal

and iron, due to competitive biochemical

and even lead levels below 10 mcg/dL are

pathways. Pica behavior enhances the like-

thought to lead to subtle neurocognitive

lihood of direct ingestion. Toddlers in par-

dysfunction.

ticular are at risk due to normal develop-

mental behaviors such as putting objects

Screening for lead toxicity

and toys in the mouth and chewing on

Prevention and treatment of lead toxicity

unusual surfaces (e.g., window sills).

remains a major public health concern, and

Lead entering the intravascular space

efforts for screening have primarily focused

rapidly attaches to the red blood cell, with

on high risk populations. All children

Chapter 6

Table 6.2 Recommendations for the treatment of lead toxicity.

Blood lead

Recommendations

level (mcg/dL)

<10

Environmental assessment, risk reduction, nutritional guidance, retest in 3 mo if

concern for exposure

10-14.9

Environmental assessment, risk reduction, nutritional guidance, report to public

health department, confirm result with venous sample

15-19.9

As above, if no improvement on retest, aggressive environmental assessment,

abdominal radiographs if ingestion suspected

20-44.9

Aggressive environmental intervention, abdominal radiographs if ingestion is

suspected. If blood lead levels persist on retest, chelation with oral succimer

(DMSA) should be considered although does not have proven efficacy in

reducing blood lead levels at these concentrations and therefore impacting

neurocognitive outcomes

45-69.9

Chelation therapy with oral succimer (DMSA) 10 mg/kg TID

5 d followed by

10 mg/kg BID

14 d. Abdominal radiograph to assess for enteral lead. If with

CNS symptoms, should treat as if lead level >70 mcg/dL. May require

hospitalization to monitor for adverse effects, institute environmental

abatement, and ensure compliance. Consider alternative regimen of CaNa₂

EDTA 25 mg/kg/d for 5 d as IV infusion (continuous or intermittent) with

required inpatient administration for hydration and monitoring electrolytes.

Ensure calcium salt is given

>70

Dimercaprol (BAL) 25 mg/kg/d IM, divided Q4 hours for minimum 72 h; after

the second dose of BAL, immediately follow with CaNa₂ EDTA 50 mg/kg/d

continuous IV for 5 d. Urine should be alkalinized with BAL therapy. In

addition, can cause hemolysis with G6PD deficiency and is dissolved in

peanut oil. Multiple potential side effects. BAL and EDTA cause renal

dysfunction, EDTA may also cause hypokalemia. Must give adequate

hydration and monitor electrolytes. After the initial treatment, subsequent

courses may be BAL and CaNa₂ EDTA or CaNa₂ EDTA alone based on repeat

lead level. Ensure calcium salt is given

Abbreviations:

CNS, central nervous system; EDTA, ethylenediaminetetraacetic acid; IV,

intravenous; IM, intramuscular.

should have a screen of potential environ-

years of age. Venous blood samples should

mental exposures by their primary health

be used to assess blood lead levels as capil-

care provider starting at 1 year of age, and

lary samples may give falsely low results. If

repeated when the child is mobile and

the screening test confirms an elevated

attains hand-to-mouth behavior. The Cen-

blood lead level, specific management

ters for Disease Control

(CDC) and the

guidelines have been developed by the CDC

American Academy of Pediatrics

(AAP)

and AAP and are summarized in Table 6.2.

recommend venous blood lead sampling for

The vast majority of children with elevated

children identified to be at high risk (living

lead levels are not candidates for chelation

in housing built prior to 1960, indigent,

therapy with currently available drugs. Chil-

urban, and minority children) at 1 and 2

dren with low levels

(<20 mcg/dL) are

Chelation Therapy

asymptomatic and unlikely to have signifi-

3. Ensuring adequate nutrition, especially

cant increase in lead excretion with chela-

minerals, to limit lead absorption, including

tion. These children benefit primarily from

evaluation for concomitant iron deficiency.

decreased exposure.

4. Administering medications

(chelators)

Blood lead levels measure the blood con-

in children with very high lead levels to

centration at a point in time and may not be

increase lead excretion.

able to accurately predict bone stores. Bone

lead content may be assessed noninvasively

After chelation therapy, a period of reequili-

using a radiographic technique called X-ray

bration for 10 to 14 days should be allowed,

fluorescence. Measurement of the heme pre-

prior to repeat assessment of the blood lead

cursor, free erythrocyte protoporphyrin

concentration.

Subsequent treatments

(FEP), may also provide a useful clue about

should be based on these levels, using the

the duration of exposure and the degree of

same criteria specified in Table 6.2. Ongoing

lead accumulation. Excessively high FEP

efforts should be made to provide the family

levels classically are seen with severe lead

with education in order to prevent exposure

toxicity. Other causes of elevated FEP levels

in the child’s environment in addition to

include iron deficiency, inflammatory disor-

assuring adequate nutrition. Family mem-

ders

(due to decreased iron absorption),

bers and siblings should be screened as well.

increased fetal hemoglobin, and rarely,

porphyria.

Suggested Reading

Management of lead toxicity

Bellinger DC. Very low lead exposures and chil-

The primary aims of management are pre-

dren’s neurodevelopment. Curr Opin Pediatr

20:172-177, 2008.

vention of future lead exposure and resul-

Brittenham GM. Iron-chelating therapy for

tant absorption as well as enhancement of

transfusional iron overload. N Engl J Med

excretion. The steps to accomplish these

364:146-156, 2011.

goals include:

Chandra L, Cataldo R. Lead poisoning: basics and

1. Assessment of the environment to elimi-

new developments. Pediatr Rev 31:399-406,

nate the sources of exposure or removal of the

2010.

child from the contaminated environment.

Neufeld EJ. Update on iron chelators in thalas-

2. Modifying the child’s behavior to decrease

semia. Hematology Am Soc Hematol Educ

hand-to-mouth activity.

Program. 451-455, 2010.

Approach to the

Bleeding Child

Hemostasis is a critical protective response

ecchymoses. Typical manifestations are pro-

of the body to reverse a loss of vascular

longed oozing from minor wounds or abra-

integrity and prevent excessive blood loss.

sions, or abnormal intraoperative bleeding.

It requires a coordinated interaction

Aberrations in secondary hemostasis are

between platelets, vascular endothelial cells,

characterized by bleeding from large vessels

and plasma clotting factors. The first and

with subcutaneous, palpable hematomas,

primary stage of hemostasis is the formation

hemarthroses, or intramuscular hemato-

of a platelet plug that involves a complex

mas. The hemophilias are examples of dis-

interaction between circulating platelets and

orders in this category.

the exposed vascular subendothelial layer.

The steps in the process include platelet

adhesion, mediated by an interaction

Evaluation of the bleeding child

between von Willebrand factor (VWF) and

platelet surface glycoprotein (Gp) Ib, and

There are three critical questions that must

platelet activation, mediated by platelet sur-

be addressed when faced with a child who is

face Gp IIb/IIIa and leading to release of

actively bleeding or has experienced a major

platelet contents. Gp IIb/IIIa interacts with

hemorrhage in the past. The first two ques-

VWF and fibrinogen, leading to platelet

tions are,

“is the patient continuing to

aggregation and enlargement of the platelet

bleed?” and “is the patient hemodynami-

plug. This lays the foundation for the for-

cally stable?” These questions should be

mation of a fibrin clot, the secondary stage

answered quickly and simultaneously.

of hemostasis caused by activation of the

Patients who are actively bleeding but are

coagulation cascade.

hemodynamically stable should have efforts

Clinical disorders associated with abnor-

directed at controlling the bleeding. While

malities of primary hemostasis include vas-

therapies that are specific for a particular

cular abnormalities, qualitative platelet

bleeding disorder should not be provided

abnormalities, quantitative platelet abnor-

before a diagnosis is made, more general

malities, and von Willebrand disease. These

strategies such as ice, pressure, and elevation

aberrations in primary hemostasis are

can be used. Patients who do not appear to

characterized by bleeding of the mucous

be actively bleeding but are hemodynami-

membranes, epistaxis, and superficial

cally unstable require rapid initiation of

Handbook of Pediatric Hematology and Oncology: Children’s Hospital & Research Center Oakland,

Second Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.

2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

Approach to the Bleeding Child

vascular reexpansion and a search for occult

A family history and pedigree are crucial,

bleeding.

as many bleeding disorders are hereditary.

Once the patient is stabilized and bleed-

The history should also address the use of

ing is controlled, the third critical question

over-the-counter and prescription drugs

is whether the child presenting with bleed-

that can induce bleeding. The most com-

ing warrants an evaluation for a bleeding

mon offenders are aspirin, ibuprofen, and

disorder. Examples of excessive bleeding

naproxen. It is important to ask the patient

include epistaxis lasting more than 15 min-

specifically about the use of medications

utes despite the appropriate application of

for colds, sinus trouble, muscle aches, or

pressure to the side of the nose, significant

headaches, which may contain these medi-

blood loss following a dental procedure

cations. Some antibiotics, penicillins in

lasting more than 24 hours or requiring

particular, can affect platelet function or

blood transfusion, bruising that seems

be associated with specific inhibitors of

excessive following trauma, or menorrhagia

clotting. Anticonvulsants can cause thrombo-

(heavy menstrual bleeding lasting for 7 days

cytopenia, and procainamide has been asso-

or more, or loss of more than 80 mL of

ciated with an acquired lupus anticoagulant.

blood per cycle). When evaluating a child

for

“excessive bruising,” it is essential to

Physical examination

determine whether the bruising could be the

In addition to the routine examination, the

result of nonaccidental trauma. Bruising

skin should be scrutinized carefully for pete-

involving the scalp, back, or chest, or having

chiae, purpura, and venous telangiectasias.

a pattern suggestive of common instruments

The joints should be examined for swelling

of abuse such as belts, cords, or wire should

or chronic changes such as contractures or

be reported. Excessive bruising caused by

distorted appearance with asymmetry rela-

underlying bleeding disorders occurs on

ted to repeated bleeding episodes. Mucosal

areas more commonly involved in falls or

surfaces such as the gingiva and nares

trauma such as shins and bony prominences.

should be examined for bleeding.

History

Initial laboratory evaluation

Assessment of the child with a suspected or

The purpose of the initial laboratory eval-

known bleeding diathesis begins with a

uation is to screen for the presence of a

complete history. The nature of the bleeding

bleeding disorder, hopefully categorize the

should be explored with particular attention

disorder as primary or secondary, and direct

to location, duration, frequency, and the

further evaluation. Appropriate screening

measures necessary to stop it. The time of

tests include a complete blood count (CBC),

the patient’s first episode of bleeding should

peripheral blood smear, prothrombin time

be documented and a careful history of

(PT), and partial thromboplastin time

bruising during the toddler age is impor-

(PTT). In certain circumstances, this list

tant. A previous history of bleeding asso-

will also include a fibrinogen and a throm-

ciated with trauma or surgery, dental

bin time (TT).

extraction, circumcision, or tonsillectomy

The CBC provides several pieces of use-

is also important, as is a history of petechial

ful information. It provides the platelet

rash, arthritis with hemarthroses, or blood

count, identifying in most cases the presence

transfusion. In females, the duration and

or absence of thrombocytopenia. However,

severity of menstrual bleeding should be

it is important to review the peripheral

documented.

blood smear, as a small number of patients

Chapter 7

with a low measured platelet count will have

some coagulation proteins. A normal value

pseudothrombocytopenia, a condition

is 1.00 to 1.10. The INR is used to evaluate

caused by platelet clumping in the presence

the adequacy of oral anticoagulant therapy;

of the anticoagulant EDTA. It provides the

the PT should be used to look for the

hemoglobin and mean corpuscular volume

presence of a clotting factor deficiency.

(MCV), which can provide clues regarding

The PTT assesses the integrity of the

the duration and severity of the patient’s

intrinsic system of coagulation. Depending

bleeding. The presence of anemia indicates a

on the laboratory methods, the PTT will be

clinically significant bleeding disorder; the

normal when the activity of all measured

concomitant presence of microcytosis sug-

coagulation factors is at least 30% of nor-

gests the bleeding has been prolonged and

mal. It is prolonged in patients with hemo-

has led to iron deficiency. A normocytic

philia, and in some patients with VWD due

anemia suggests that the bleeding has been

to the decreased concentration of factor VIII

more recent and likely more severe, as the

in the plasma. However, the PTT is much

blood loss has likely been more significant.

more susceptible than the PT to spurious

Abnormalities in more than one cell line

abnormalities caused by errors in collection

(anemia, thrombocytopenia, and/or neutro-

or processing of the specimen. These are

penia) suggest the presence of a bone marrow

outlined in Table 7.1.

failure state such as aplastic anemia or

The most commonly encountered inhi-

marrow infiltration as is seen in leukemia.

bitors of coagulation detected in children

Many analyzers provide a measure of the

are so-called lupus anticoagulants. These are

mean platelet volume which can be useful

IgG antibodies directed against phospholi-

in evaluating the thrombocytopenic patient.

pids, and while they are commonly identi-

Large platelets are often seen in consumptive

fied in adults with autoimmune disease,

thrombocytopenia such as immune throm-

they occur frequently in children as a post-

bocytopenic purpura

(ITP), normal-sized

infectious phenomenon that is short-lived.

platelets in hypoproliferative thrombocyto-

As phospholipid is an essential cofactor in the

penia, and small platelets in inherited con-

PTT assay, antiphospholipid antibodies will

ditions such as Wiskott-Aldrich syndrome.

commonly cause prolongation of the test.

The PT evaluates the extrinsic system of

Addition of normal plasma (with additional

coagulation. Factor VII is the only coagu-

phospholipid) as is done in mixing studies

lation factor measured by the PT that is not

will often at least partially normalize the test,

measured by the PTT. Thus, in isolated

but it will most often remain abnormal.

factor VII deficiency, the PT is prolonged

These antibodies have no effect on clotting

with a normal PTT. Factor VII is vitamin K

in vivo, and patients with lupus anticoagu-

dependent and has a very short half-life, so

lants do not have clinical bleeding; in fact,

the PT is one of the most sensitive measures

their most common coagulation problem is

of oral anticoagulant therapy with vitamin

thrombophilia rather than bleeding.

K antagonists such as warfarin. Most labo-

The TT is useful in evaluating the ter-

ratories now report an international nor-

minal steps of coagulation and identifying

malized ratio (INR) along with the PT. The

anticoagulants present in plasma. The TT is

INR is calculated as the patient PT/control

abnormal when the plasma concentration of

PT to the power of the international sensi-

fibrinogen is decreased

(hypofibrino-

tivity index. This index corrects for the large

genemia or afibrinogenemia), when the

variation in the sensitivity of thromboplas-

fibrinogen present is dysfunctional (dysfi-

tin reagents to low plasma concentrations of

brinogenemia), or when there are

Approach to the Bleeding Child

Table 7.1 Factors affecting the validity of the partial thromboplastin time (PTT) test.

Aspect

Problem

Remarks

Sample

Clots

Clots caused by slow blood flow or delay in transferring

collection

sample will cause abnormal results

Plasma volume

Volume of anticoagulant must be corrected for plasma

volume. If tube is not completely filled, or patient is

extremely anemic or polycythemic, sample will not

be appropriately anticoagulated

Heparin contamination

Very small amounts of heparin will cause the PTT to be

abnormal

Interpretation

Age-dependent normal

Mild prolongation is normal in the newborn period

values

(immaturity of the coagulation system)

Inhibitor vs. factor

A number of agents can interfere with the PTT assay

deficiency

and cause a factitious prolongation of the test. If the

concentration is high they can lead to a mild pro-

longation of the PT as well. These are diagnosed by

mixing the patient’s plasma and normal plasma in a

1:1 ratio and repeating the test. If the PTT is

prolonged due to factor deficiency, this maneuver

will increase the level of all coagulation factors to at

least 50% and normalize the test. If the prolongation

is due to an inhibitor, it may improve but will

remain prolonged. See the discussion of inhibitors

Abbreviations: PTT, partial thromboplatin time; PT, prothrombin time.

circulating anticoagulants

(heparin) or

chapters. Two exceptions are management

fibrin degradation products. As dysfibrino-

of epistaxis and menorrhagia. These types

genemia is most often asymptomatic, a

of bleeding can be caused by a variety of

prolonged TT in the face of a normal fibrin-

different conditions; yet in most situations,

ogen level is almost always associated with

the following management plans will be

heparin or an inhibitor.

effective. See also Figure 7.1.

Abnormalities in one or more of the

above screening tests will be noted with

Management of epistaxis

most bleeding disorders. An approach to

1. Place patient in a sitting position to

identifying the most likely coagulation dis-

decrease venous pressure, or if the patient

orders given the results of these tests is

is recumbent in bed, turn head to the side.

presented in Table 7.2.

Keep the head higher than the level of the

heart. Do not allow patient to lie flat.

2. Flex neck anteriorly, with the chin touch-

Management

ing the chest.

3. With the thumb and index finger, pinch

Once the diagnosis is made, specific treat-

the soft parts of the nose. Hold pressure

ment can be provided based on the recom-

firmly over the lower half of the nose. Avoid

mendations outlined in the following

compressing the upper half of the nose.

Chapter 7

Table 7.2 Interpretation of screening coagulation tests.

Test results

Differential diagnosis

Follow-up laboratory studies

PT normal

Von Willebrand Disease

PFA-100

PTT normal

Platelet function disorder

Von Willebrand studies

Platelet count

Factor XIII deficiency

Platelet aggregation studies

normal

Fibrinolytic defect

Urea clot lysis test

Euglobulin clot lysis

Factor XIII assay

Alpha-2-antiplasmin, PAI-1, and TPA

PT normal

PTT inhibitor

PTT mixing study

PTT prolonged

Von Willebrand disease

Factor assays (VIII, IX, and XI)

Platelet count

Hemophilia A or

Von Willebrand studies

normal

Hemophilia B

TT/reptilase time

Heparin contamination

PT prolonged

PT inhibitor

PT mixing study

PTT normal

Vitamin K deficiency

Factor assays (II, VII, IX, and X)

Platelet count

Warfarin

normal

Factor VII deficiency

PT prolonged

Circulating inhibitor

PT/PTT mixing studies

PTT prolonged

Liver dysfunction

TT/reptilase time

Platelet count

Vitamin K deficiency

Fibrinogen

normal

Factor deficiency (II, V, X,

Factor assays

or fibrinogen)

Dysfibrinogenemia

PT prolonged

DIC

PTT prolonged

Liver disease

Fibrinogen

Platelet count low

Kasabach-Merritt syndrome

Factor assays

D-dimers

PT normal

Acute ITP

None

PTT normal

Chronic ITP

Antinuclear antibodies

Platelet count low

Collagen vascular disease

Anticardiolipin antibodies

Early bone marrow failure

Direct antiglobulin test (Coombs)

syndrome

Serum immunoglobulin levels

Serum complement levels

HIV and hepatitis C antibody testing

Bone marrow aspirate

Marrow chromosomal analysis

Abbreviations: PT,

prothrombin time; PTT, partial

thromboplastin time; PFA-100, platelet

function analyzer-100; PAI-1, plasminogen activator

inibitor-1; TPA, tissue plasminogen

activator; TT, thrombin time; DIC, disseminated intravascular coagulation; ITP, immune

thrombocytopenic purpura.

Approach to the Bleeding Child

Menorrhagia : >80 mL blood loss/cycle or heavy, regular periods >7 days duration with pad/tampon use

>1 per hour or passing >1 inch wide clots

and

Diagnosis or suspicion of von Willebrand disease or other bleeding disorder: type and severity may influence

nature of bleeding and intervention

Assessment:

1. History: categorize bleeding pattern by duration, regularity, quantification of bleeding

2. Medication History: evaluate for drugs associated with bleeding including warfarin, heparin,

salicylates, non-steroidal anti-inflammatory drugs, phenytoin, antipsychotics (SSRIs) and tricyclic anti-

depressants, prolonged antibiotic use (low vitamin K), herbal supplements

3. Physical: evidence of bleeding disorder or gynecologic problem

4. Laboratory: assess for degree of anemia and red cell indices with CBC, urine βHCG for pregnancy

screen, consider STI (gonorrhea, chlamydia with bleeding and use of OCPs)

5. Imaging: assess for anatomic etiology with pelvic ultrasound to look for fibroids, polyps,

endometriosis, pregnancy complications, ovarian cysts, endometrial cancer

Management

Active, heavy bleeding and anemia

Routine Management (listed in order of preference,

1. Avoid D&C, may worsen bleeding

patients may require 1 or more interventions):

2. Treat with high dose estrogen PO or IV,

1. OCP*: combined oral contraceptive, minimum

e.g., estrogen 30 mcg/norgestrel 0.3 mg

3 month trial (synthetic estrogen + progestin);

(LoOvral):

1 pill QID x 4 days, then

consider no withdrawal week for 1-3 months;

TID x 3 days, then BID x 2 days, then

consider increase in dose if breakthrough

daily for 3 weeks

bleeding or persistence of menorrhagia after

3. Consider desmopressin or factor

3 months

concentrate

2. Desmopressin: intranasal at initiation of

4. If controlled, follow routine

menses, could give second dose at 24 hours

management

3. Antifibrinolytic therapy with initiation of

menses: tranexamic acid or aminocaproic acid

4. Intrauterine device impregnated with

progestin (Mirena), may cause bleeding with

*Estrogen containing therapies may not be safe

insertion and require preventive intervention

for women who smoke or have known

5. Avoid medications that may cause or

thrombophilia; may increase coagulation proteins

exacerbate bleeding

Figure 7.1 Menorrhagia in young women with bleeding diathesis: clinical assessment and manage-

ment strategies. Abbreviations: SSRI, selective serotonin reuptake inhibitors; CBC, complete blood

count; STI, sexually transmitted infection; OCP, oral contraceptive pill, D&C, dilatation and curettage.

4. Hold pressure for 20 minutes with the

clot(s) can be visualized, remove clot(s) and

head in a flexed position. If manual pressure

reapply digital pressure for 20 minutes.

is stopped momentarily to examine or

5. Advise patient not to blow nose for at

change dressings, the

minute digital

least 12 hours to avoid dislodging the clot.

pressure will likely need to start again. Pres-

6. Nasal packing may be indicated if the

sure and time allow for clot formation to

source of bleeding is not well visualized or

occur. If bleeding continues, reassess loca-

bleeding is profuse. Types of packing include

tion of digital pressure and reapply. If bleed-

compressed sponge, Vaseline gauze packing,

ing stops and recurs, repeat manual pressure

gelfoam, or topical thrombin packing. Com-

for 20 minutes. If bleeding continues and

pressed sponges are compressed when dry and

Chapter 7

expand when wet. The expansion produces

predicting menstrual blood loss of >80 mL

active and passive absorption and places gen-

include the passing of clots >1 inch in diam-

tle pressure on the mucosa. The nasal sponge

eter, a low serum ferritin, or changing a pad

should fit snugly through the nare and be

or tampon more often than hourly.

placed along the floor of the nasal cavity.

2. The most effective management of men-

Sponges are easy to insert and can be removed

orrhagia is prevention. This can often be

with little discomfort. Neosporin can be

accomplished with hormonal therapy. The

applied to the sponge for ease of insertion

most common approach is the use of com-

and to act as an antimicrobial agent. Topical

bination estrogen-progestin oral contracep-

thrombin powder (a vasoconstrictor) applied

tive pills (COCP), both cyclic and extended

to the inserted end of the sponge can provide

cycle use. Regular COCPs can been prescribed

additional hemostasis. Anterior packs may be

in an extended cycle pattern, with the patient

left in place for 1 to 5 days, though should be

taking 63 to 84 days of active pills before

removed within 24 hours in an immunocom-

stopping for

7 days to allow withdrawal

promised patient due to the risk of infection.

bleeding. Young women often prefer this

Humidification and nasal saline spray can help

approach despite the occasional breakthrough

prevent drying and crusting of the oral

bleeding that may occur. Table 7.3 lists COCP

mucous membranes as a result of mouth

preparations that have been used successfully

bleeding. Broad-spectrum antibiotics, to

in managing menorrhagia in women with

cover skin flora as well, should be considered

bleeding disorders. There are no data that

in patients who are immunosuppressed with a

indicate that any of these agents are superior

nasal pack in place. Vaseline gauze packing,

to the others in controlling bleeding.

when placed correctly and snugly, is a reliable

3. Other hormonal approaches to prevent

means of packing. Packing may be soaked in

menorrhagia include the levonorgestrel

4% topical cocaine or a solution of 4% lido-

intrauterine system (Mirena), oral progesto-

caine and topical epinephrine (1:1000) to

gens, and injected progestogens. Mirena has

provide local anesthesia and vasoconstriction.

been shown to be as efficacious as endome-

trial ablation in decreasing the incidence and

Management of menorrhagia

severity of menorrhagia. It has also been

1. The American College of Obstetricians

shown in one small study to be well tolerated

and Gynecologists and the American Acad-

by nulliparous adolescent females. Oral

emy of Pediatrics issued a committee con-

progestin-only OCPs (Micronor, Nor-QD)

sensus report in 2006 in which they defined

contain norethindrone as the active agent.

normal menstruation. This report stated that

The progestin implant (Implanon) contains

normal menstruation begins at 11 to 14 years

etonogestrel. Depo-Provera is an injectable

of age, the normal cycle interval is 21 to 45

progestin only contraceptive containing

days, and the normal length of menstrual

medroxyprogesterone as the active agent.

flow is 7 days or less with product use no

4. Young women presenting with the acute

more than three to six pads or tampons per

complaint of menorrhagia should have a

day. Based on this, menorrhagia has been

pregnancy test performed to ensure that

defined as heavy menstrual bleeding lasting

they are not having a miscarriage. They

for more than 7 days or resulting in the loss of

should also be carefully evaluated to rule

more than 80 mL per menstrual cycle. How-

out the presence of severe anemia or hypo-

ever, attempts to quantify menstrual blood

volemia. If they are hemodynamically stable,

loss in clinical practice can be quite difficult.

have no prior personal or family history of

Variables that have been identified as

abnormal bleeding, and are not allergic to

Approach to the Bleeding Child

Table 7.3 Preparations of combination oral contraceptive pills used to treat menorrhagia in women

with bleeding disorders.

Hormone content

Brand name

150 mcg desorgestrel/30 mcg ethinyl estradiol

Apri

Cyclessa

Desogen

Ortho-Cept

Reclipsen

Velievet

150 mcg levonorgestrel/30 mcg ethinyl estradiol

Enpresse

Jolessa

Levora

Lutera

Nordette

Portia

Quansense

250 mcg norgestimate/35 mcg ethinyl estradiol

MonoNessa

Ortho-Cyclen

Previfem

Sprintec

3 mg drospirenone/30 mcg ethinyl estradiol

Ocella

Yasmin

nonsteroidal anti-inflammatory drugs

treat menorrhagia in women both with and

(NSAIDs), ibuprofen 200 mg every 4 to 6

without coagulopathies.

hours can be tried. NSAIDs have been

7. Women with inherited coagulopathies

shown to decrease the amount of menstrual

(Type 1 VWD, hemophilia carriers, platelet

flow by 25% to 30% by altering the endo-

function disorders) should ideally be tested for

metrial prostaglandin balance. However,

responsiveness to DDAVP prior to menarche.

they are contraindicated in women with

If they are responsive, this should be used as

known or suspected coagulopathy.

first-line therapy for menorrhagia. It can be

“Double-dose” COCPs can be used to

given IV at a dose of 0.3 mcg/kg in 50 mL

treat young women presenting with acute

normal saline over 30 minutes. A concentrated

menorrhagia as well. Any of the COCPs in

nasal preparation is also available (Stimate)

Table 7.3 containing 35 mcg of ethinyl estra-

containing 150 mcg/spray; it is given at a dose

diol/tablet can be prescribed twice a day for

of one spray in each nostril once daily. Either

up to 7 days until the bleeding stops, after

preparation can be repeated daily for up to 3 to

which the remainder of the pack is com-

4 days during the heaviest menstrual flow. It

pleted on a once daily schedule.

should be used in conjunction with tranexa-

6. If these steps are not effective or the

mic acid if the bleeding is heavy. Side effects

bleeding is more significant, tranexamic

include flushing, headache, nausea, fluid

acid can be added to any of these treatments

retention, and rarely, hyponatremia.

at a dose of 1300 mg (two tablets) three

8. Women with persistent bleeding despite

times daily for up to 5 days. This antifibri-

these therapies should be hospitalized for

nolytic agent has been successfully used to

more aggressive therapy, including

Chapter 7

intravenous estrogen. Consultation with a

The presence of petechiae and increased

gynecologist or adolescent medicine physi-

superficial bruising suggests a disorder of

cian well versed in the management of this

primary hemostasis. The lack of a previous

disorder is recommended.

history and a negative family history suggest

this is more likely to be an acute problem

rather than a congenital one, although this

Case study for review

is not certain. Acquired problems of primary

hemostasis include acquired (often immune-

A 4-year-old girl presents to the emergency

mediated) thrombocytopenia or acquired

department with a 3 day history of easy

(often drug-induced) platelet function

bruising and “rash.” She denies any other

abnormalities. This presentation could also

bleeding including epistaxis, oral bleeding,

result from a vasculitis, although most

hematuria, or hematochezia. She has oth-

patients with such a problem would likely

erwise been well except for an upper respi-

appear more ill. The best next steps would be

ratory infection 2 weeks ago.

to obtain a CBC and coagulation studies to

see if you can identify where an abnormality

1. What other information would be help-

might be. The CBC reveals a hemoglobin of

ful in evaluating this child?

12.3 g/dL, a WBC count of 6.5

10⁹/L with

The girl’s parents deny any previous history

a normal differential, and a platelet count

of easy bruising, hemarthroses, or muscle

of 6

10⁹/L. The PT is 12.2 seconds (refer-

bleeding in the past. The family history is

ence range, 12.6 to 13.5 s) and the PTT is

significant for two older brothers who have

30 seconds (range, 26 to 33 s).

never had any bleeding abnormalities. There

4. What do you think now, and what is

is no history of epistaxis, gingival bleeding,

your next step?

menorrhagia, or excessive bleeding with sur-

gery or trauma in any other family members.

The patient has isolated thrombocytopenia

There is no family history of malignancy or

with a normal hemoglobin and platelet

autoimmune disorders. The patient has not

count, and no evidence of a clotting factor

been taking any medications recently.

deficiency. The recent history of a viral

illness is very consistent with ITP. The

2. What will you be looking for on physical

absence of any clinically significant bleeding

examination?

at this point means that no immediate inter-

The vital signs are normal, and the patient is

vention is necessary. The management of

at the 50th percentile for height and weight.

ITP is discussed more fully in Chapter 12.

She appears completely healthy. There are

no signs of oral bleeding or purpura. Her

Suggested Reading

heart and lung exam are normal, and she has

no tenderness, masses, or hepatosplenome-

Allen GA, Glader B. Approach to the bleeding

galy on abdominal exam. You note a diffuse

child. Pediatr Clin N Am 49:1239-1256, 2002.

petechial rash over her entire body, with

Hayward CP. Diagnostic approach to platelet

several ecchymoses on her shins and arms,

function disorders. Trans Apheresis Sci

with a few on her back. Her neurological

38:65-76, 2008

exam is completely normal.

Ahuja SP, Hertweck SP. Overview of bleeding

disorders in adolescent females with menor-

3. What are your first thoughts, and what

rhagia. J Pediatr Adolesc Gynecol 23:S15-S21,

would you like to do next?

2010.

Von Willebrand

Disease

Von Willebrand disease (VWD) is the most

plasma. This accounts for the prolonged

common inherited bleeding disorder,

partial thromboplastin time (PTT) seen in

affecting as much as

1% of the general

some patients.

population, and equally affects both genders

VWD is classified into three types:

as well as all races and ethnicities. The actual

Type 1, found in 70% to 80% of cases, is

prevalence is difficult to determine, as many

characterized by partial deficiency of nor-

affected individuals are either asymptomatic

mally functioning VWF. Type 2 is charac-

or have such mild symptoms that they do

terized by functional defects in VWF. It is

not seek medical attention. While most

divided into four subtypes. Type 2A is char-

patients with VWD have the inherited form,

acterized by a decreased number of high-

an acquired form also occurs. The three

molecular-weight multimers and a concom-

characteristic clinical features of the inher-

itant decrease in platelet adhesion. The

ited form are excessive mucocutaneous

measured amount of VWF:Ag (antigen) is

bleeding, abnormal von Willebrand factor

normal or only slightly decreased, but the

(VWF) laboratory studies, and a family

VWF:RCo (ristocetin cofactor), a measure

history of abnormal bleeding.

of VWF activity, is much lower. Type 2B is

VWF is a large multimeric glycoprotein

caused by mutations that pathologically

that is synthesized in megakaryocytes and

increase platelet-VWF binding, which leads

endothelial cells. VWD is usually inherited

to the proteolytic degradation and depletion

in an autosomal dominant manner, but a

of large, functional VWF multimers. Circu-

rare autosomal recessive form and an X-

lating platelets are also coated with mutant

linked recessive form have also been

VWF, which may prevent the platelets from

described. VWD results from either a defi-

adhering at sites of injury. The VWF-coated

ciency or a defect in the VWF protein. This

platelets often become sequestered in the

protein plays two critical roles in hemosta-

microcirculation, leading to thrombo-

sis: the large multimers bind to platelet

cytopenia. Type

2M is characterized by

glycoprotein Ib (GPIb) causing platelet acti-

decreased interaction between VWF and

vation and adherence to damaged endothe-

platelet GPIb on connective tissue. The ratio

lium, and it is the carrier protein for factor

of VWF:RCo to VWF:Ag is low as in Type 2A,

VIII (FVIII), stabilizing it and protecting

but the multimer panel appears normal.

it from degradation and clearance from

Type 2N is marked by decreased binding

Handbook of Pediatric Hematology and Oncology: Children’s Hospital & Research Center Oakland,

Second Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.

2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

Chapter 8

between VWF and FVIII, resulting in a phe-

themselves with a safety razor) can be more

notype of autosomal recessive hemophilia.

informative. Often, the child is diagnosed

Type 3, a rare condition, is characterized by

with VWD and then a parent or sibling is

the almost complete absence of VWF.

found to have the disorder after screening.

The majority of affected patients expe-

In patients with mild VWD, the stress

rience mucocutaneous bleeding such as epi-

associated with serious operations or child-

staxis, easy bruising, and menorrhagia in

birth may prevent symptoms. VWF is an

women. They may also experience posttrau-

acute phase reactant and the level will fre-

matic or postsurgical bleeding. Patients with

quently increase into the normal range fol-

severe VWD may experience bleeding into

lowing surgery, in pregnancy, or in patients

muscles and joints as well. VWD should be

with active liver disease or collagen vascular

suspected in the patient with platelet-type

disease. It can be reduced in hypothyroid-

bleeding and a family history of a bleeding

ism. Even the stress of phlebotomy can

diathesis.

increase the level of VWF, which can

make it difficult to confirm the diagnosis

even with repeat testing. Neonates have

Clinical presentation

elevated VWF levels following vaginal deliv-

ery, making it difficult to diagnose in the

The clinical features of VWD can be quite

neonatal period. VWF levels can be up to

variable. In most cases of VWD, the bleed-

25% lower in individuals who are blood

ing is mild. Mucosal bleeding, such as epi-

type O, increasing the difficulty in distin-

staxis, gingival bleeding with tooth brush-

guishing between VWD and normal indivi-

ing, ecchymoses, or menorrhagia, are clas-

duals with a low VWF level.

sic. The initial presentation, however, may

be postoperative bleeding, such as following

a tonsillectomy and adenoidectomy or den-

Diagnosis

tal extraction. In retrospect, the child who

was thought to have normal childhood

Screening tests are of little value in making

complaints (bruising and epistaxis) is real-

the diagnosis of VWD. The complete blood

ized to actually have a bleeding disorder.

count (CBC) may demonstrate iron defi-

Recurrent or severe epistaxis, particularly in

ciency anemia if the patient’s blood loss has

the older child or adult, is unusual and

been significant, but it is nonspecific. The

warrants investigation. It is important to

rare patient with Type 2B VWD may have

obtain a thorough medical history of bleed-

mild thrombocytopenia. If the level of VWF

ing from the family as this may provide

is sufficiently low, the PTT may be prolonged

clues. Since other affected family members

due to decreased concentration of FVIII, but

are often unaware that they have the condi-

this is neither sensitive nor specific. The

tion, simply inquiring about a history of

PFA-100 platelet function analyzer is a more

bleeding problems often yields negative

useful screening test for VWD. It measures

results. Specific questions such as “Have any

the time required for blood, drawn through a

women in the family had hysterectomies

fine capillary, to block a membrane coated

during their child-bearing years because of

with collagen and epinephrine or collagen

intractable uterine bleeding?” or “Do any

and ADP. Its sensitivity in identifying

men in the family insist on shaving with

patients with VWD is fairly high, but its

an electric razor?” (because of the prolonged

specificity is low. Four specific tests are used

oozing they experience if they nick

to diagnose VWD:

Von Willebrand Disease

1. Factor VIII coagulant (FVIIIc): func-

VWD. The National Heart, Lung, and Blood

tional measurement of FVIII coagulant

Institute (NHLBI) of the National Institutes

activity, which is carried in the circulation

of Health published an algorithm, presented

by VWF.

in Figure 8.1, to assist in identifying affected

2. Von Willebrand factor antigen (VWF:

individuals while at the same time avoiding

Ag): VWF protein as measured by protein

overdiagnosis. Except for patients with

assays; does not imply functional ability.

clearly abnormal VWF levels (<30%), the

Immunologic quantitation of VWF by

diagnosis should be made after consultation

either the quantitative immunoelectropho-

with a hematologist.

retic assay (Laurell assay) or the enzyme-

linked immunosorbent assay.

3. Von Willebrand factor activity (VWF:

Treatment

RCo): ristocetin induces the binding of

VWF to the GPIb receptor on formalin-

The goal of treatment in VWD is to control

fixed platelets. The slope of the platelet

or prevent serious or life-threatening bleed-

agglutination curve correlates with the level

ing. There are no effective therapies to limit

of plasma VWF.

the chronic bruising that many active chil-

4. Multimeric analysis: an agarose gel elec-

dren experience, and parents need to be

trophoretic study used to identify quantita-

given assistance to accept that reality. Many

tive or qualitative multimer abnormalities.

children and adults with Type

1 VWD,

The most common type of VWD (Type 1)

especially males, never require therapy.

has a normal multimeric analysis.

Individuals with Type 2 or Type 3 VWD

are much more likely to need treatment at

The classification of patients with VWD

various times throughout life.

based on the results of these tests is pre-

Three strategies are used to treat patients

sented in Table 8.1.

with VWD: increase the plasma concentra-

Even with these test results, it can be

tion of VWF by releasing endogenous VWF

difficult to determine whether a child has

stores through stimulation of endothelial

VWD or not, especially in mild cases. Unlike

cells with desmopressin, replace VWF by

hemophilia, there are not clearly defined

using human plasma-derived, viral-inacti-

levels of VWF antigen or activity that sep-

vated concentrates, and use agents that pro-

arate normal patients from those with

mote hemostasis and wound healing but do

Table 8.1 Classification of von Willebrand disease.

VWD subtype VWF:Ag VWF:RCo FVIII:C RCo:Ag ratio (%) Multimer pattern

# or N

>60

Normal

# or N

<60

Abnormal

# or N

<60

Abnormal

# or N

<60

Normal

# or N

10-40%

>60

Normal

###

<10%

Abbreviations: VWD, von Willebrand disease; VWF:Ag, von Willebrand factor antigen; VWF:

RCo, von Willebrand factor ristocetin cofactor activity; FVIII:C, Factor VIII coagulant; N, normal.

Von Willebrand Disease

not substantially alter the plasma concen-

other measures. Given its high cost and

tration of VWF. These strategies are not

relatively short shelf life (6 months after

mutually exclusive; different bleeding epi-

the bottle is opened), it is less suitable for

sodes may require a combination of two or

individuals with very infrequent bleeding

even all three of these strategies to be

episodes. Although effective, there is some

effective.

variability in response due to inconsistent

Desmopressin (DDAVP) is the treat-

absorption. Therefore, patients should be

ment of choice in mild Type

1 disease

tested for responsiveness prior to prescrib-

(65% to 80% of all cases) and may be of

ing. The dose for children weighing less

benefit with some of the other variants. It

than 50 kg is one spray (150 mcg) once

stimulates endogenous release of VWF from

daily. The effective dose in adolescents and

endothelial cells, with most patients

adults is one spray in each nostril (total

experiencing a two- to fourfold increase

dose of

300 mcg) once daily. The peak

in their plasma VWF and FVIII levels within

effect is observed 60 to 90 minutes after

minutes of the infusion. The

administration.

approximate half-life of these released fac-

Patients undergoing surgical procedures

tors is 8 to 10 hours. Occasionally, patients

such as tonsillectomy or dental extractions

do not respond to this therapy (especially

may need extended therapy to maintain

children younger than 18 months of age).

increased levels of VWF and FVIII until

The peak effect is observed in 30 to 60

healing has occurred. Studies have demon-

minutes. A therapeutic trial of DDAVP

strated that DDAVP can be repeated daily

should be given to determine individual

for up to 4 days with little loss of efficacy as

responsiveness to this therapy with mea-

measured by VWF levels or PFA-100. Pre-

surement of FVIII and VWF levels before

and postinfusion measurements of VWF:Ag

and after administration. After baseline

or VWF:RCo can be done to establish con-

levels are obtained, a standard dose of

tinued clinical responsiveness. However, it

0.3 mcg/kg is administered intravenously

may be difficult to obtain the results of these

in 30 to 50 mL of normal saline over 15

tests quickly.

to 30 minutes, and levels are measured again

Patients with Type 1 VWD who have

60 minutes after completion of the infusion.

severe bleeding manifestations unrespon-

A positive trial is defined as at least a twofold

sive to DDAVP or those patients with

increase in the VWF:Ag and VWF:RCo

desmopressin-unresponsive Type

activity. Ninety percent of patients with

disease require treatment with exogenous

Type

VWD demonstrate a positive

VWF. Unlike FVIII replacement products,

response to intravenous (IV) DDAVP.

there are no recombinant VWF products yet

A unique intranasal form of DDAVP

in clinical use, although one product is being

(Stimate, 1500 mcg/mL) is also available to

evaluated in animal models. The FDA has

treat bleeding in VWD. A more dilute form

approved three plasma-derived FVIII/VWF

of DDAVP (100 mcg/mL) is approved for

products, Humate-P, Wilate, and Alphanate

use in patients with diabetes insipidus but

for the treatment of VWD. A fourth plasma-

should not be prescribed for VWD, as it is

derived product, Koate DVI, is licensed in

impossible to deliver an adequate dose with

the United States for the treatment of hemo-

this preparation. Stimate is most useful for

philia and is used off-label to treat VWD.

individuals with more frequent episodes of

These agents are not identical, and have

bleeding requiring therapy, such as women

differing ratios of FVIII to VWF, so should

with menorrhagia not controlled using

not be considered interchangeable.

Chapter 8

Humate-P contains 50 to 100 IU/mL VWF:

amount of endometrial development that

RCo activity and 20 to

40 IU/mL FVIII

takes place. Minor surgical procedures such

activity. It has the highest ratio of VWF:

as laceration repairs or dental extractions

RCo to FVIII activity and the highest con-

can frequently be managed with a single

centration of high-molecular-weight multi-

treatment of desmopressin or factor con-

mers. Alphanate contains 40 to 180 IU/mL

centrate followed by antifibrinolytic therapy

FVIII activity and at least 16 IU/mL VWF:

for 7 to 10 days. Two antifibrinolytic agents

RCo activity. The FDA approved Wilate, the

are available, epsilon aminocaproic acid

most recently licensed product, in 2010. It

(Amicar) and tranexamic acid; Amicar is

was approved specifically for use in VWD,

the more widely used agent. The oral dose of

and has essentially equal amounts of VWF:

aminocaproic acid is

100

200 mg/kg

RCo and FVIII activity. It has demonstrated

(maximum dose, 10 g) as the initial dose,

both safety and efficacy in patients with

followed by

100 mg/kg (maximum dose,

VWD. There are no head-to-head studies

5 g) every 6 hours. To maintain effective-

comparing the efficacy of any of these pro-

ness, families must be instructed to adhere

ducts. Wilate’s packaging promotes more

to the every 6 hour schedule. The dose of

frequent dosing with lower doses of prod-

tranexamic acid is 25 mg/kg/dose every 6 to

uct, which the company states is more

8 hours. Both drugs are available in oral and

physiological and more cost-effective.

intravenous forms. These drugs are partic-

The goal of factor replacement therapy is

ularly effective in minimizing bleeding from

to reach a therapeutic level of VWF:RCo

mucosal surfaces due to the increased level

100 IU/mL and nadir of

>50 IU/mL.

of fibrinolytic activity present in these areas.

Recommended starting doses are

Patients with Type 3 VWD have plasma

60 IU/kg of VWF:RCo activity, followed

VWF and FVIII levels that are extremely

by 20 to 40 IU/kg every 8 to 24 hours as

low (typically less than 5 IU/dL). Desmo-

needed to maintain desired levels. Major

pressin is usually ineffective in these cases,

surgical procedures should only be per-

but a therapeutic trial of desmopressin may

formed at centers that have the capability

be given, as occasionally patients will

of measuring VWF activity levels in-house

respondappropriately.These patients often

on a daily basis. To decrease the risk of

have significant bleeding including pro-

thrombotic events, VWF:RCo levels should

found epistaxis or hemarthroses similar

be <200 IU/mL, and FVIII levels should be

to that seen in patients with hemophilia

<250 to 300 IU/mL.

due to their low levels of both FVIII and

Other adjuvant therapies are available

VWF. With bleeding, such patients should

that are often helpful in managing bleeding

be managed similarly to patients with

in patients with VWD. Direct pressure is

hemophilia, using the previously men-

very effective in managing epistaxis and

tioned FVIII concentrates that contain

bleeding from tooth sockets or lacerations.

adequate levels of VWF and FVIII.

Family members must be taught to main-

Patients with Type 2A VWD have abnor-

tain continuous pressure “without peeking”

mally small VWF multimers, and desmo-

for at least 20 minutes for best results. If the

pressin, though frequently effective, often

bleeding remains uncontrolled, a single dose

has only a transient effect. Serious bleeding

of desmopressin is usually effective to stop

should be treated with plasma-derived

bleeding in patients who have shown

FVIII/VWF concentrates. These patients

responsiveness. Low-estrogen oral contra-

may do well with desmopressin for the

ceptives have been very helpful in control-

treatment of minor bleeds or dental

ling menorrhagia as they minimize the

extractions.

Von Willebrand Disease

Type 2B VWD is often associated with

thrombocytopenic purpura (ITP), lympho-

mild thrombocytopenia due to excessive

proliferative diseases, systemic lupus erythe-

platelet binding to an abnormal VWF

matosus, other autoimmune disorders, and

molecule and rapid clearance. Stress can

some cancers, most commonly Wilms

exacerbate the thrombocytopenia. Desmo-

tumor. Pathologic increases in fluid shear

pressin is usually contraindicated due to

stress can occur with cardiovascular lesions

the potential for worsening thrombocyto-

such as ventricular septal defect and aortic

penia and failure to demonstrate a thera-

stenosis, or with primary pulmonary hyper-

peutic response. However, in mild bleeding,

tension. This leads to increased destruction

desmopressin may be effective. For internal

of VWF, particularly the larger multimers;

bleeding or surgery, patients should receive

the multimer panel often resembles that seen

FVIII/VWF concentrate. If profound throm-

in Type 2A VWD. Its occurrence in Wilms

bocytopenia exists, concomitant administra-

tumor and other malignancies is believed to

tion of platelets may be necessary.

be due to expression of platelet GPIb on the

Patients with 2M VWD will demonstrate

tumor cell surface, leading to binding of

an increase in VWF:Ag but not in VWF:RCo

VWF to the tumor with subsequent degra-

in response to DDAVP, due to the defective

dation. Hyaluronic acid secretion by nephro-

binding of their VWF to GPIb. These

blastoma cells is another potential mecha-

patients routinely require replacement with

nism in Wilms tumor patients leading to

FVIII/VWF concentrates for bleeding epi-

decreased efficacy of VWF. Patients may

sodes or for surgery. Patients with Type 2N

present with classic signs and symptoms of

VWD similarly require factor replacement;

VWD and their levels of VWF, VWF:Ag, and

although they produce normal amounts of

FVIII are typically quite low.

FVIII, it is destroyed prematurely due to the

Desmopressin may induce a transient rise

inability of their VWF to bind to the FVIII

in VWF in AVWS. One small study demon-

molecule and protect it. Replacement with

strated that intravenous immunoglobulin

functional VWF will typically normalize their

(IVIG) at a dose of 1 g/kg/d for 2 days was

FVIII levels even if the relative concentration

beneficial in improving VWF levels and

of FVIII in the product is low since they are

decreasing clinical bleeding, but this is only

able to produce normal amounts.

beneficial in immune-mediated AVWS. Plas-

mapheresis, corticosteroids, and immuno-

suppressive agents have also been successful

Acquired von Willebrand

in these patients. For serious bleeding, treat-

syndrome

ment with factor concentrate (high VWF

content) should be given. The antibodies

Acquired von Willebrand syndrome

typically disappear with control or resolution

(AVWS) refers to defects in VWF concen-

of the underlying disease.

tration, structure, or function that are not

inherited directly but are consequences of

other medical disorders. It is usually caused

Other considerations

by one of three mechanisms: autoimmune

clearance or inhibition of VWF, increased

As a general precaution, all children with

shear-induced proteolysis of VWF, or

bleeding disorders should be immunized with

increased binding of VWF to platelets or

the hepatitis B vaccine, with boosters given at

other cell surfaces. Autoimmune causes of

appropriate time intervals, since these chil-

AVWS in children include postviral anti-

dren have a lifelong potential for receiving

body production similar to immune

blood products. Patients and families should

Hemophilia

Hemophilia is defined as an inherited bleed-

50%). The frequency of bleeding symptoms

ing disorder caused by low levels, or

generally correlates well with the measured

absence, of a blood protein that is essential

residual factor activity. Boys with severe

for clotting. The congenital hemophilias are

hemophilia bleed with minimal trauma and

uncommon disorders, with a total incidence

bleeding symptoms are usually apparent by

of 10 to 20 per 100,000 births. The most

the time the infant begins to crawl or walk,

common form is factor VIII (FVIII) defi-

whereas those with mild hemophilia usually

ciency

(hemophilia A or classic hemo-

bleed only with significant trauma or surgery

philia), with an estimated incidence of 1

and may have a delayed diagnosis.

in 5000 males. The second most common

Several other congenital factor deficien-

form is factor IX (FIX) deficiency (hemo-

cies have been described as well, but are all

philia B), with an incidence of approxi-

very uncommon. They are described in

mately 1 in 25,000 males. Both the FVIII

Table 9.1.

and FIX genes are carried on the X chro-

Afibrinogenemia is associated with fre-

mosome; thus, both hemophilia A and B are

quent and serious bleeding. Spontaneous

X-linked recessive disorders. Approximately

bleeding is rare if the fibrinogen level is

80% of hemophilia patients have hemo-

>50 mg/dL. The thrombin time (TT) is the

philia A and 20% have hemophilia B. Both

most sensitive test to diagnose this disorder.

disorders are found throughout the world

Hypoprothrombinemia is an autosomal

and do not appear to have any ethnic or

recessive disorder associated with mild bleed-

racial predisposition.

ing. All patients have some prothrombin

Hemophilia A and B are clinically indis-

activity. Prothrombin deficiency also occurs

tinguishable since both FVIII and FIX are

in patients with vitamin K deficiency, liver

essential factors in the intrinsic clotting

disease, and warfarin use. Factor V (FV)

pathway for activating factor X (FX). Factor

deficiency is often characterized by bleeding

levels are measured in comparison to a

from mucous membranes including epi-

reference standard that is assumed to have

staxis, menorrhagia, and bleeding after dental

a factor level of 100% (1.0 IU/mL). In the

procedures. Congenital deficiency of both FV

normal individual, FVIII and FIX levels range

and FVIII can occur as a result of a mutation

from 50% to 200% (0.50 to 2.0 IU/mL).

in the ERGIC-53 gene, which acts as a chap-

Disease severity is defined as severe (<1%),

erone for intracellular transport of these

moderate (1% to 5%), and mild (6% to

factors through the endoplasmic reticulum.

Handbook of Pediatric Hematology and Oncology: Children’s Hospital & Research Center Oakland,

Second Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.

2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

Chapter 9

Table 9.1 Rare coagulation factor deficiencies.

Deficiency

Estimated

Source of

Biological

Gene on

prevalence

replacement

half-life

chromosome

Fibrinogen

1/1,000,000

Cryoprecipitate

90 h

Prothrombin

1/2,000,000

Activated PCCs

60 h

Factor V

1/1,000,000

FFP

12 h

Factor VII

1/500,000

rFVIIa

2-6 h

Factor X

1/1,000,000

Activated PCCs

24 h

Factor XI

1/1,000,000

FFP

40 h

Factor XIII

1/2,000,000

FFP

3-5 days

1 and 6

Abbreviations: PCC, prothrombin complex concentrate; FFP, fresh frozen plasma; rFVIIa,

recombinant factor VII.

Patients with factor VII deficiency who have

effectively inhibit plasmin, and therefore lyse

levels less than 1% have bleeding symptoms

clots abnormally quickly leading to abnormal

similar to that of classic hemophilia with

bleeding. As clots are formed normally, all the

hemarthrosis, intramuscular hemorrhage,

usual screening coagulation tests are normal

and intracranial hemorrhage

(ICH).

except for the euglobulin and urea clot lysis

Heterozygotes are typically asymptomatic.

tests. Factor XII (FXII) deficiency, prekal-

Two-thirds of patients with factor X (FX)

likrein deficiency, and high-molecular-

deficiency have hemarthroses and hemato-

weight kininogen deficiency all cause pro-

mas. The proportion of patients with FX

longation of the PTT but are not associated

deficiency who require treatment is higher

with clinical hemorrhage.

than that of the other rare coagulation

deficiencies. Factor XI (FXI) deficiency is

characterized by mucocutaneous and geni-

Clinical presentation

tourinary tract bleeding; the likelihood of

bleeding does not correlate well with mea-

Boys with hemophilia may develop symp-

sured FXI levels. Only individuals with factor

toms very early in life, experiencing a

XIII

(FXIII) deficiency whose levels are

hemorrhage after circumcision or with sep-

<1% are symptomatic. Bleeding manifesta-

aration of the umbilical cord. However, up

tions include soft-tissue hemorrhages,

to 50% of affected male infants have no

hemarthroses, and hematomas, and patients

difficulty during the neonatal period, and

undergoing surgery or trauma may experi-

a negative history of bleeding after circum-

ence poor wound healing.

cision does not rule out the diagnosis of

Alpha2-antiplasmin deficiency, factor XII

hemophilia. Mild hemophilia may go

deficiency, prekallikrein

(Fletcher’s factor)

unsuspected for years until the patient

deficiency, and high-molecular-weight kini-

experiences trauma or has a surgical proce-

nogen (Fitzgerald’s factor) deficiency have

dure. Conversely, patients with severe

also been identified using appropriate clot-

hemophilia often experience spontaneous

ting measurements. Alpha2-antiplasmin is

hemorrhages, both externally and inter-

the primary inhibitor of plasmin, a key com-

nally, into the head, joints, muscles, and

ponent of the fibrinolytic pathway. Patients

retroperitoneum. Bleeding from the mouth

with a2-antiplasmin deficiency are unable to

or frenulum often occurs during infancy,

Hemophilia

and minimal lacerations may cause very

treatment of an acute hemarthrosis is

prolonged bleeding. Intramuscular injec-

recommended to relieve symptoms and

tions (as with immunizations) often result

hopefully prevent recurrent bleeding into

in large hematomas. Joint hematomas

the same joint, setting up the situation of

(hemarthroses) can result in secondary joint

a “target” joint.

degeneration. Life-threatening blood loss

Bleeding into muscle is characterized by

can occur with intramuscular bleeds. ICH

pain and limitation of mobility. They can be

occurs in 2% to 14% of hemophilia patients

difficult to evaluate, particularly if they

and is associated with an 18% mortality.

occur in deep muscles such as the iliopsoas

Although ICH is much more common in

muscle (see below). They can result in long-

severe hemophilia, it has been reported in

term complications such as permanent

patients with mild hemophilia as well.

muscle contractures. It is important to

ICH is the most serious complication in

exclude any potential neurovascular com-

hemophilia. A history of trauma is elicited

promise that can result from compression of

in only 20% to 25% of patients with central

adjacent nerves.

nervous system (CNS) hemorrhages, and

An iliopsoas hemorrhage can be quite

there may be a delay of days or weeks before

devastating due both to the long-term con-

symptoms develop. Bleeding can be intra-

sequences and to the large volume of blood

cerebral, subdural, subarachnoid, or epidu-

loss that can occur acutely into this large

ral. Patients who survive these episodes

muscle bed and into the retroperitoneal

frequently experience complications such

space. The presenting signs of groin or lower

as mental retardation, seizure disorders,

abdominal/upper thigh pain can be difficult

or motor impairment. Any history of head

to differentiate from a hip bleed. With an

trauma should be considered emergent. A

iliopsoas bleed, examination reveals inabil-

nonfocal neurologic examination does not

ity to extend the hip, with normal internal

exclude a diagnosis of an intracranial bleed.

and external hip rotation. Radiologic con-

Any suspicion of a significant intracranial

firmation by CT scan is recommended.

injury should prompt a head CT and close

Soft tissue hemorrhages occur very

neurological observation. Immediate treat-

commonly and do not require therapy

ment to achieve a factor level of 80% to

unless their location is near vital structures.

100% should be provided and maintained

For instance, a retropharyngeal bleed with

until an intracranial bleed can be fully

potential airway compromise should be

excluded. An intraspinal hemorrhage

aggressively treated. Vigorous examination

should be excluded with any back trauma

of the oropharynx with a tongue blade or

or symptoms of a peripheral neuropathy. A

other manipulations should be avoided to

lumbar puncture should never be per-

prevent injury with subsequent hemor-

formed in a hemophilia patient without

rhage. A “straddle” injury resulting in a

factor therapy to avoid this complication.

hematoma of the perineal/perirectal area

Hemarthroses appear in young children

should be closely evaluated for neurologic

as they become mobile. The elbows are often

compromise as evidenced by either bladder

first affected as the infant begins crawling,

or bowel dysfunction.

followed by shoulders, wrists, hips, knees,

About 70% of hemophilia patients will

and ankles. The hands and spine are rarely

have at least one episode of hematuria.

involved. The initial signs of a hemarthrosis

Usually, these episodes are painless, thus

are vague and difficult to detect, especially

if there is severe pain associated with hema-

in the nonverbal infant. Early, aggressive

turia, a thrombosis in the renal pelvis

Chapter 9

should be excluded. Increased fluid intake

Newborn males with a possible or con-

and bed rest is recommended. Factor

firmed diagnosis of hemophilia should be

replacement may be warranted with per-

carefully evaluated for an intracranial hem-

sistent symptoms. Treatment with antifi-

orrhage, especially if delivered via assisted

brinolytic drugs is contraindicated given

vaginal delivery

(vacuum extraction or

the risk of upper urinary tract obstruction

forceps). However, infants delivered via

caused by clot.

cesarean section are also at risk for severe

Epistaxis occurs in hemophilia patients,

bleeding. The initial PTT can be performed

most commonly in those with severe dis-

on cord blood, but it must be remembered

ease. Gastrointestinal bleeding can also

that the upper limit of normal for newborns

occur but is atypical; an underlying gastro-

is longer than for adults. The normal range

intestinal lesion should be excluded. Intra-

for FVIII levels in the newborn is the same as

mural bleeding into the bowel wall can

for adults, but FIX levels are lower until the

occur, with signs of severe pain and possible

concentrations of factors produced by the

intestinal obstruction. Appropriate therapy

liver mature to adult levels (approximately 6

may avoid an unnecessary laparotomy.

months of age). Therefore, the diagnosis of

Prolonged gingival oozing is common

hemophilia B may be more difficult initially.

after shedding of deciduous teeth, eruption

Confirmatory studies should be performed

of new teeth, or instrumentation. Treatment

on a sample obtained by venipuncture if a

with an antifibrinolytic medication is

cord blood sample was initially obtained.

recommended for prolonged symptoms.

Arterial as well as femoral or jugular venous

Routine dental care is particularly important

sites to obtain plasma samples should be

in the patient with a bleeding disorder to

avoided if possible. Prenatal testing for both

prevent the need for restorative care in the

conditions is available to pregnant women

future where extensive factor replacement

who are known carriers.

therapy is often indicated. Regional block

anesthesia is discouraged, even with factor

coverage, given the risk of hemorrhage that

Treatment

can lead to nerve damage and extension into

the neck causing airway compromise.

After the newborn period, affected infants

rarely require treatment until they become

more mobile with increasing age. Treatment

Diagnosis

recommendations for the hemophilia

patient depend on several factors: the type

The diagnosis of FVIII deficiency should be

and severity of disease (mild, moderate, or

suspected in males presenting with a char-

severe; FVIII or FIX deficiency); the site of

acteristic bleeding history, especially if there

the bleed

(proximity to vital structures)

is a family history of males with abnormal

with consideration of long-term debilitating

bleeding. However, 30% of patients with

consequences; and therapy response (factor

hemophilia A and B have spontaneous

recovery/survival and inhibitor status).

mutations and no family history of abnor-

Treatment of patients with hemophilia

mal bleeding. A prolonged PTT in conjunc-

and bleeding is by replacement of factor in a

tion with a normal PT and platelet count is

concentrated form. Many high-purity

suggestive of the diagnosis; this can be

plasma-derived preparations are currently

confirmed by specifically measuring levels

available, as are recombinant FVIII and FIX

of FVIII and FIX.

products. Most experts feel that hemophilia

Hemophilia

patients who have not been previously trea-

the calculated target dose. Doses are calcu-

ted with plasma-derived products should be

lated using the following formula:

treated with only recombinant products.

There are two treatment strategies cur-

Dose ðunits of FVIIIÞ ¼ Weight ðkgÞ

rently used for patients with hemophilia.

desired % rise of FVIII level

0:5

Episodic or on-demand treatment involves

providing treatment at the time a bleeding

For FIX, multiply result by 2, for recom-

episode occurs. Prophylactic therapy is the

binant FIX, multiply by 2.4.

periodic infusion of factor replacement to

Round up to the whole vial since factor is

prevent such bleeding episodes. A number

expensive and not uniformly dispersed in

of single institutional case series have dem-

suspension. Table 9.2 outlines the dose and

onstrated the superiority of prophylaxis

duration of therapy for commonly encoun-

regimens in the prevention of joint disease,

tered bleeding episodes in hemophilia

but widespread adoption of this strategy for

patients. More serious bleeding episodes

all patients has been limited by the high cost

should be treated using doses at the higher

of factor replacement therapy and the chal-

end of the range.

lenge of adequate vascular access, particu-

Other important interventions for a

larly in young patients.

hemarthrosis include initial immobilization

When providing on-demand therapy,

and application of ice to the area or use of a

the duration, frequency, and doses of factor

cryocuff. For particularly critical joints such

provided depend on the severity of the

as the shoulder or hip, where long-term

hemophilia and bleeding episode. Factor

consequences of pressure-induced avascular

vials vary in the number of units of

necrosis can be debilitating, a longer treat-

factor activity they contain. The required

ment course is recommended. Iliopsoas

factor dose should be calculated, and vials

bleeds should be treated as retroperitoneal

should then be selected that come closest to

rather than as muscle bleeds.

Table 9.2 Guidelines for factor replacement in hemophilia A and B.

Site of hemorrhage

Optimal factor

Dose (units/kg body

Minimum duration of

level (%)

weight)

treatment (days)

Factor VIII Factor IX

Muscle

30-50

20-30

30-40

1-2

Joint

50-80

25-40

50-80

1-2

Gastrointestinal tract

40-60

30-40

40-60

10-14

Oral mucosa

30-50

20-30

30-40

2-3

Epistaxis

30-50

20-30

30-50

2-3

Hematuria

30-100

25-50

70-100

1-2

Retroperitoneal

80-100

100

7-10

Central nervous system

80-100

100

Trauma or surgery

80-100

100

Recombinant FIX should be dosed 1.2 times higher.

Chapter 9

Inhibitors

Other considerations

The development of an inhibitor, an anti-

In addition to aggressive factor replacement

body that inactivates the coagulant func-

when bleeding has occurred and the use of

tion of replacement factor, is one of the

physical therapy programs to prevent or min-

most serious complications of hemophilia

imize chronic joint disease, comprehensive

treatment. FVIII inhibitors develop in 20%

medical care must be provided to all patients

to 30% of boys with severe hemophilia A,

with hemophilia. All immunizations includ-

whereas FIX inhibitors develop in 3% to

ing hepatitis B vaccine should be given on

5% with severe hemophilia B. These usu-

schedule. Regular dental care is essential to

ally develop within the first 50 exposures to

prevent excessive decay and gingival disease

factor replacement. Risk factors for inhib-

that may predispose to complications. Psy-

itor development include the nature of the

chological support is essential to assist patients

underlying mutation, with those leading

and families cope with the emotional and

to substantial loss of coding information

social burden imposed by the disease. A com-

representing greater risk, high-intensity

prehensive program of patient and family

product exposure, CNS bleeding, and Afri-

education will prevent complications caused

can-American race. Inhibitors are quanti-

by failure to recognize or understand warning

tated by Bethesda titers: one Bethesda unit

signs of hemorrhage as well as empower

(BU) is the amount of inhibitor that inac-

family members and eventually the patient

tivates 50% of FVIII function in a one-stage

to take an active role in the management of the

clotting assay. Low-titer inhibitors

(<5

disease. Education in home treatment is vital,

BU) can be managed by using larger doses

and should be used whenever possible, as

of factor replacement; higher titer inhibi-

speed in the treatment of bleeding, especially

tors require the use of alternative hemostatic

hemarthroses, is directly related to minimizing

agents. Alternative agents include prothrom-

long-term complications of the disease.

bin complex concentrates (PCCs), activated

Suggested Reading

PCCs (aPCCs), and recombinant factor VIIa

(rFVIIa). Immune tolerance induction with

Kessler CM. New perspectives in hemophilia

high, frequent doses of FVIII or FIX has also

treatment. Hematology Am Soc Hematol

been successful. Management of patients

Educ Prog 429-435, 2005.

with inhibitors is difficult and complex and

Manco-Johnson MJ. Advances in the care and

should be performed only by experienced

treatment of children with hemophilia. Adv

hematologists.

Pediatr 57:287-294, 2010.

The Child with

Thrombosis

Virchow’s triad describes risk factors for

Evaluation of thrombosis

thrombus (blood clot) formation: (1) venous

stasis, (2) endothelial injury, and (3) hyper-

Pediatric patients may have both congenital

coagulability. Hypercoagulability, also called

and acquired risk factors underlying throm-

thrombophilia or a prothrombotic state, is

bus formation. The single most common

defined as a propensity to develop throm-

acquired risk factor for venous thromboem-

bosis secondary to aberrations in the coag-

bolism is the presence of a central venous

ulation system. Thrombophilia is becoming

catheter

(e.g., endothelial injury). Other

increasingly recognized in pediatric patients

acquired risk factors include trauma, surgery,

and can refer to multiple potential condi-

infection, nephrotic syndrome, inflammatory

tions: (1) spontaneous thrombus formation,

syndromes, diabetes, complex congenital

(2) recurrent thrombosis, (3) thrombosis out

heart disease, liver disease, and malignancy

of proportion to the underlying risk factor,

(e.g., acute lymphoblastic leukemia in asso-

and (4) thrombosis at a young age.

ciation with the use of asparaginase or solid

Optimal prevention and treatment in

tumors with tumor thrombus). Asymptom-

pediatric patients with thrombosis differs

atic patients may be found to have an

from adult patients for several reasons.

incidental clot on imaging, or the patient

These include physiologic age-dependent

may be symptomatic, most often with swell-

differences in the hemostatic system that

ing, pain, or erythema in an extremity.

influence the risk for venous thromboem-

Venous ultrasonography with Doppler flow

bolism, differing underlying etiologies and

remains the cornerstone of evaluation for

location of clots, and differing responses to

thrombosis, as in adults. Lack of venous

antithrombotic agents. Little evidence exists

compression or Doppler flow is diagnostic

as how best to manage pediatric patients

for thrombus. This imaging modality is

with thrombosis, both from a diagnostic

limited to the extremities, neck, distal sub-

and from a treatment standpoint. Much

clavian veins, and potentially, distal iliac

of the currently utilized data is based on

veins. Echocardiography can be utilized to

adult studies, and here we summarize the

evaluate for atrial clots and the proximal

generally accepted recommendations in lieu

superior and inferior vena cava. Imaging of

of evidence-based pediatric guidelines (see

the abdomen and pelvis as well as the upper

Figure 10.1).

venous system requires CT or magnetic

Handbook of Pediatric Hematology and Oncology: Children’s Hospital & Research Center Oakland,

Second Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.

2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

Chapter 10

Initial evaluation

Physical examination

History (medications, family history)

Laboratory (PT, PTT, fibrinogen, CBC)

Diagnostic imaging confirming VTE

Assessment of risk

Unusual site without underlying risk factor (e.g., portal vein, renal vein)

Life threatening without underlying risk factor (pulmonary embolus,

CNS event)

Recurrent

Laboratory assessment of primary

Family history of VTE

thrombophilia traits

Yes

Adolescent on OCPs

Factor V Leiden mutation

Neonatal stroke

Prothrombin gene mutation

ATIII deficiency

Protein C deficiency

Protein S deficiency

Hyperhomocysteinuria

Elevated lipoprotein (a)

Antiphopholipid antibodies

Further assessment of risk factors:

Elevated factor VIII

Venous catheter

Trauma, surgery, immobilization

Prematurity

Congenital heart disease

Nephrotic syndrome

Inflammatory bowel disease

No multitrait

Malignancy (ALL)

thrombophilia

Collagen vascular disease

Multitrait (≥ 3)

Yes

thrombophilia

High risk for recurrence

Moderate risk for recurrence

Minimal risk for recurrence

Long-term anticoagulation

Consideration for long-term

Long-term anticoagulation

anticoagulation while with

not required

continued risk factors

Figure 10.1 Evaluation of the child with venous thromboembolism (VTE). (Abbreviations: PT,

prothrombin time; PTT, partial thromboplastin time; CBC, complete blood count; CNS, central

nervous system; OCP, oral contraceptive pill; ATIII, antithrombin III; ALL, acute lymphoblastic

leukemia).

resonance venography

(MRV). Similarly,

underlying hypercoagulable state. In the

sinus venous thrombosis must be eva-

patient with a known acquired risk factor

luated by magnetic resonance imaging/

and secondary thrombosis, it is unclear that

arteriography

(MRI/MRA). Pulmonary

testing for thrombophilia will aid in the

emboli or thrombosis can be identified with

management of the patient (e.g., asymptom-

a helical CT scan.

atic catheter-related thrombosis). Patients

might have a single-trait thrombophilia on

Testing for thrombophilia

testing, but this alone may not contribute

Although often undertaken, clear guidelines

significantly to thrombus development.

are lacking as to the utility of testing for an

Patients with a consumptive process (e.g.,

The Child with Thrombosis

disseminated intravascular coagulation and

asymptomatic patient with a positive family

sepsis) and secondary thrombosis such as

history, the decision to test for thrombophi-

with deficiencies in protein C and S and

lia must be made on an individual basis after

antithrombin III could benefit from testing

appropriate family counseling. The family

and factor replacement if found to be defi-

must be advised that a positive screen for a

cient. For patients with spontaneous throm-

single thrombophilia trait will not result in a

bosis, often found in adolescents

(e.g.,

change in management and may lead to

adolescent female starting oral contracep-

unnecessary anxiety. Similarly, negative test-

tives) and in neonates (secondary to stroke

ing may give false reassurance and does not

or sinus venous thrombosis), testing should

completely abrogate the potential for throm-

be considered. For patients with a symptom-

bosis. The primary thrombophilia traits are

atic catheter-related thrombosis or for an

listed in Table 10.1.

Table 10.1 Primary thrombophilia traits.

Thrombophilia trait

Description

Factor V Leiden

G1691A polymorphism, present in

5% of Caucasian popula-

tion, leads to inherited activated protein C resistance

Prothrombin gene mutation

PT G20210A polymorphism, present in

2% of Caucasian

population, leads to elevated prothrombin levels

Antithrombin III deficiency

Can be seen in consumptive process (sepsis, DIC, active clot),

liver disease, heparin therapy, complex congenital heart dis-

ease, asparaginase use in acute lymphoblastic leukemia

Protein C deficiency

Can be seen in consumptive process (sepsis, DIC, active clot),

liver disease, warfarin therapy, nephrotic syndrome, complex

congenital heart disease

Protein S deficiency

Can be seen in consumptive process (sepsis, DIC, active clot),

liver disease, warfarin therapy, nephrotic syndrome, complex

congenital heart disease

Hyperhomocysteinemia

Check fasting homocysteine, can be secondary to underlying

MTHFR mutation

Elevated lipoprotein (a)

Poorly understood, competes with plasminogen, thus decreasing

fibrinolysis, also activates PAI-1 decreasing fibrinolysis and

potentially leading to increased thrombogenesis

Antiphospholipid antibodies

Antibodies against cell membrane phospholipid, called lupus

anticoagulant, paradoxically leads to elevated PTT without

correction on 1:1 mix. Secondary confirmatory testing

includes anticardiolipin antibodies and b2 glycoprotein, must

be confirmed on two separate occasions 12 weeks apart as can

be seen transiently with infection

Elevated factor VIII

An acute phase reactant, can be constitutively elevated

Abbreviations: DIC, disseminated intravascular coagulation; MTHFR, methylenetetrahydrofolate

reductase; PAI-1, plasminogen activator inhibitor-1; PT, prothrombin time; PTT, partial

thromboplastin time.

Chapter 10

Management of thrombosis

first-pass liver metabolism, although this is

mitigated with the use of systemic TPA as it is

Management of pediatric thrombosis is again

expected that much of the TPA will bypass

based on adult studies and expert guidelines.

the obstruction through collateral circulation.

Removal of the precipitating agent should be

Patients receiving systemic low-dose TPA

done as possible in cases with an acquired risk

therapy should have close monitoring of

factor. Treatment of thrombosis is under-

coagulation studies

(prothrombin time

taken to prevent clot propagation, pulmo-

[PT], partial thromboplastin time [PTT], and

nary embolus, and the postthrombotic syn-

fibrinogen), platelets, and plasminogen to

drome (PTS). Although reported frequently

ensure hemostatic and fibrinolytic potential

in adults, PTS is poorly understood in chil-

and the need for potential repletion with fresh

dren but can potentially lead to chronic pain,

frozen plasma (FFP).

swelling, skin changes, and collateral venous

formation. The decision to initially utilize a

Anticoagulation

thrombolytic (tissue plasminogen activator,

If TPA is thought to pose significant risk, or

TPA) versus an anticoagulant (unfractio-

if the patient has a nonocclusive thrombus

nated heparin, UH or low-molecular-weight

or transient risk factors, UH or LMWH may

heparin, LMWH) must be made in consul-

be started. UH is a natural anticoagulant

tation with a pediatric hematologist. In some

and works by complexing to the physiologic

cases, thrombectomy or thrombolysis by

inhibitor antithrombin III (ATIII), acceler-

intervention radiology should be considered.

ating the inhibition of thrombin and other

coagulant proteins. It is therefore important

Thrombolysis

to ensure adequate levels of ATIII when

In general, a thrombolytic should be con-

administering heparin. Many potential

sidered in patients with an occlusive throm-

issues are present with UH usage in chil-

bus without significant risk factors for

dren:

(1) rapid clearance,

(2) low ATIII

bleeding

(recent surgery, central nervous

levels in the first few months of life,

system hemorrhage). Patients with a long-

(3) greater variability in dosing compared

standing occlusive thrombus (i.e., >14 days)

to adults, and (4) lack of evidence assessing

or without evidence of improvement on

the optimal target PTT range for the preven-

imaging studies after 24 to 48 hours of

tion and treatment of venous thromboem-

TPA therapy may benefit from thrombect-

bolism. The patient must also be monitored

omy or thrombolysis by interventional

for the development of heparin antibodies

radiology. Although not evidence based,

that can most notably lead to heparin-

we typically treat with low-dose systemic

induced thrombocytopenia

(HIT). Long-

TPA as suggested by Manco-Johnson

term usage can also lead to osteoporosis.

(see suggested further reading) at a dose

LMWH is more widely utilized now due

of 0.03 to 0.06 mg/kg/h with a maximum

to a more narrow dosing range and wide

of 2 mg/h for 24 to 48 hours to decrease

therapeutic window secondary to direct

the risk of significant hemorrhage that is

targeting of Factor Xa as well as reduced

seen with bolus TPA, unless there is a life-

incidence of HIT and osteoporosis.

threatening clot (e.g., massive pulmonary

In general, we utilize LMWH unless

embolism). Arterial clots may benefit from

there is potential need for immediate rever-

a higher systemic dose for a shorter time

sal of anticoagulation. Although protamine

period. Also if possible, TPA should be

can be utilized with LMWH, the reversal

instilled distal to the clot in order to decrease

effect is not complete (thought to be about

The Child with Thrombosis

two-thirds effective) and therefore a risk of

marker elevation may be confounded by

bleeding can still be present if, for instance,

continuing inflammation.

surgical intervention is required emergently.

In these cases, UH should be utilized due to

Duration of therapy

its short half-life and ability to be fully

Duration of therapy depends on multiple

reversed. UH is generally given at a loading

factors including the time to removal of

dose of 75 U/kg followed by a maintenance

inciting agents such as central venous cathe-

dose of 20 U/kg/h with a goal PTT of 2 to

ters, presence of thrombophilia traits,

the upper limit of the reference range or,

and time to clot resolution. Patients initially

preferably, anti-Xa levels of 0.3 to 0.7 U/mL,

treated with TPA or UH therapy should be

if available in a timely manner. Currently,

transitioned to LMWH or warfarin therapy

the only LMWH approved by the FDA for

for long-term maintenance. Because of the

pediatric patients is enoxaparin, with a half-

time required to reach an appropriate ther-

life of 4 hours and subcutaneous dosing. For

apeutic level, warfarin therapy should begin

treatment of thrombosis, enoxaparin must

at least 48 hours prior to discontinuation of

be given every 12 hours, usually starting at

heparin therapy. Maintenance with LMWH

1.0

1.25 mg/kg

(see Formulary and

is frequently used due to the difficulty in

Manco-Johnson for more specific dosing

maintaining a therapeutic international nor-

guidelines). Treatment effectiveness is fol-

malized ratio (INR) with warfarin therapy.

lowed by anti-Xa levels, with goal levels of

For patients with clot resolution, antic-

0.5 to 1.0 U/mL (checked 4 hours after the

oagulation should be continued at prophy-

second or subsequent dose). For prophy-

lactic dosing for 6 weeks to 3 months after

laxis, 0.5 mg/kg is typically given twice daily.

removal of the inciting agent (e.g., central

Anti-Xa levels do not need to be checked

venous catheter) due to the likelihood of

with prophylactic dosing. In practice, some

continued endothelial injury. For patients

hematologists utilize 1 mg/kg once daily for

without clot resolution (potentially after inef-

prophylaxis, although available data suggest

fective interventional thrombectomy and/or

this may undertreat a group of patients,

thrombolysis), anticoagulation should be

especially those <5 years of age.

continued for 6 to 12 months to potentially

Concomitant use of TPA and UH or

decrease or resolve the clot and prevent the

LMWH may also be beneficial in clot lysis

development of PTS. Patients that had a

without significantly increasing hemorrhagic

spontaneous or recurrent thrombus and were

risk, although again this recommendation is

found to have multitrait thrombophilia (

not evidence-based in pediatric patients and

traits) or antiphospholipid syndrome should

must be determined on a per patient basis in

continue life-long anticoagulation.

consultation with a pediatric hematologist,

weighing the potential risks of hemorrhage

New agents

and potential benefits of clot lysis. Therapeu-

Multiple new agents will be available in the

tic efficacy can simply be followed with repeat

near future for pediatric patients and are

imaging, although this can be difficult with

summarized in Table 10.2.

central venous clots that may require multi-

ple CT or MRI with resultant increased radi-

ation exposure and cost, respectively. Other

Case study for review

potential markers to follow for clot lysis

include d-dimers or fibrin-split products

You are seeing a 17-year-old female in clinic

which should increase with lysis, although

who is deciding on whether to start oral

Chapter 10

Table 10.2 Novel anticoagulants.

Name

Comments

Factor Xa inhibitors

Fondaparinux

Selective factor Xa inhibitor, mediates its effects through ATIII,

decreased HIT, half-life 17 hours, once daily SC dosing

Idraparinux

Hypermethylated analogue of fondaparinux, 80-hour half-life

(once weekly SC dosing)

Rivaroxaban

Oral factor Xa inhibitor, once daily dosing in adults for

thromboprophylaxis, has shown noninferiority to warfarin

Direct thrombin inhibitors

Argatroban

Approved in adult patients with HIT, narrow therapeutic

window and short-acting IV formulation

Dabigatran

Oral formulation, approved in adult patients, has shown

noninferiority to warfarin, currently approved in the United

States for stroke prevention in patients with atrial fibrilla-

tion, in the United Kingdom as an alternative to warfarin for

thromboprophylaxis

Abbreviations: ATIII, antithrombin III; HIT, heparin-induced thrombocytopenia; SC,

subcutaneous; IV, intravenous.

contraceptive pills (OCPs). She has an aunt

incidence is also highest in the first year of

that had a “blood clot” when she was in her

OCP usage.

fifties. Your patient does not know any

Thrombophilia testing can be considered

further details about the incident but does

on an individual basis for the patient wish-

know about the potential increased risk of

ing to start OCPs who has a family member

blood clots with oral contraceptive pills.

with a known thrombophilia. Additionally,

the patient should be offered alternative

1. What advice would you give the patient?

lower risk forms of contraception. In this

2. She asks about testing for clotting risk

case, the practitioner should try to get

factors, what do you advise her?

more information regarding the episode

of thromboembolism in the aunt. Were

All patients who are starting OCPs should

there acquired risk factors such as trauma,

be made aware of the increased risk of blood

surgery, or immobility? Was the clot

clots with estrogen-containing contracep-

thought to be spontaneous? If so, was the

tives (about a three times increased risk).

aunt tested for thrombophilia?

This risk is thought to be about 2 to 3 per

Current recommendations would not

10,000 per year on OCPs, or about 0.02% to

advise testing your patient without further

0.03% incidence per year

(baseline risk

information. If the aunt had a spontaneous

being approximately

0.008% per year).

thrombus, one could advise that she

Single-trait thrombophilias, most com-

should be tested for thrombophilia, and if

monly Factor V Leiden mutation, increase

found to be positive your patient could be

this risk significantly. Specifically for Factor

tested as well. If it was determined that

V Leiden, the risk for a heterozygous carrier

there was an underlying risk factor in the

increases the risk approximately 30 times to

aunt’s thromboembolism, testing her and/

a yearly incidence of 0.6% to 0.9%. This

or your patient would not be advised. In the

The Child with Thrombosis

situation where thrombophilia testing of

Goldenberg NA. Thrombophilia states and mar-

your patient is not advisable (the most likely

kers of coagulation activation in the predic-

tion of pediatric venous thromboembolic

scenario in general), you should counsel

outcomes: a comparative analysis with respect

your patient closely on the risks and benefits

to adult evidence. Am Soc Hematol Educ Prog

of OCPs and the potential lower risk alter-

236-244, 2008.

native therapies such as progesterone-only

Manco-Johnson MJ. How I treat venous throm-

preparations (e.g., Depo-Provera).

boembolism in children. Blood 107:21-29,

2006.

Raffini L. Thrombophilia in children: who to test,

Suggested Reading

how, when, and why? Am Soc Hematol Educ

Prog 228-235, 2008.

Bounameaux H, Perrier A. Duration of anticoa-

Rosendaal FR. Venous thrombosis: the role of

gulation therapy for venous thromboembolism.

genes, environment, and behavior. Am Soc

Am Soc Hematol Educ Prog 252-258, 2008.

Hematol Educ Prog 1-12, 2005.

The Neutropenic Child

Neutrophils are a key component in the

determining the individual’s risk for infec-

defense against infection. They contain toxic

tion and the urgency of medical interven-

cytoplasmic granules that, following inges-

tion. However, this definition fails to take

tion of infecting bacteria and fungi, are

into account important variations in nor-

released into the phagocytic vacuole and

mal neutrophil number related to age and

destroy them. Once released from the bone

ethnicity. Up to

25% of young African-

marrow, they circulate in the blood for a

American children will have an ANC

brief time (4 to 6 hours) before leaving the

between 1.0 and 1.5

10⁹/L, and this level

circulation and entering the tissue where, in

should be considered normal in this group.

response to the presence of infection, they

Also, the normal range for ANC extends

act to control the infection while sending

down to 1.0

10⁹/L in infants between 2

chemotactic signals to recruit additional

weeks and 6 months of age, and should not

neutrophils to the area and stimulate the

be considered abnormal if less than this.

accelerated production of neutrophils in the

bone marrow. While the presence of ade-

quate neutrophil numbers in the tissue is the

Risk assessment

best predictor of the patient’s ability to fight

infection, there is no easy clinical method to

The first question when evaluating a child

determine the number of tissue neutrophils,

with neutropenia is:

“What is the risk

so the number present in the blood is used

that this patient has or will develop a life-

as a surrogate marker.

threatening infection?” This is particularly

Neutropenia has traditionally been de-

pertinent if the patient presents with fever.

fined as a decrease in the absolute neutro-

The susceptibility to bacterial infection in

phil count

(ANC) to <1.5

10⁹/L. The

neutropenic patients is quite variable and

ANC is calculated by multiplying the white

depends on a number of factors. The first

blood cell count by the total percentage of

is the severity of neutropenia, as described

segmented

(mature) neutrophils plus

above. Patients with mild neutropenia have

bands. Mild neutropenia is defined as an

minimal to no increased risk of infection,

ANC of 1.0 to 1.5

10⁹/L, moderate neu-

those with moderate neutropenia have a

tropenia is an ANC of 0.5 to 1.0

10⁹/L,

mildly increased risk of frequent or severe

and severe neutropenia is an ANC below

infections, and those with severe neutropenia

0.5

10⁹/L. This division is useful for

are highly susceptible to bacterial infection.

Handbook of Pediatric Hematology and Oncology: Children’s Hospital & Research Center Oakland,

Second Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.

2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

The Neutropenic Child

However, patients who are neutropenic as a

Etiology of neutropenia

result of cytotoxic therapy (e.g., chemother-

apy and radiation) may be at an increased

A large variety of conditions can lead to

risk of infection because of the rate of decline

neutropenia in childhood. They can be clas-

of the neutrophil count or other immuno-

sified as being either acquired causes or

suppressive effects of chemotherapy, even

inherited causes. Of these, acquired causes

before the ANC falls below

0.5

10⁹/L.

are much more frequent. These are pre-

Another factor is the cause of the neutrope-

sented in Table 11.1.

nia, if known. Patients with neutropenia

Viral infection is the most common

caused by intrinsic bone marrow failure or

cause of mild-to-moderate neutropenia.

hypoplasia have a greater risk of infection

Transient marrow suppression is seen in

than those whose neutropenia is due to

children with Epstein-Barr virus

(EBV),

factors extrinsic to the bone marrow such

respiratory syncytial virus, influenza A and

as excessive neutrophil destruction or

B, hepatitis, human herpesvirus-6 (HHV6),

sequestration

(immune neutropenia and

varicella, rubella, and rubeola. This typically

splenomegaly, respectively). While patients

lasts for 3 to 8 days. Neutropenia can also be

with extrinsic neutropenia may have a low

seen in the setting of overwhelming bacte-

circulating neutrophil count, their tissue

rial infection as well as with typhoid fever,

counts are near normal and they are more

Rocky Mountain spotted fever, and tuber-

protected from infection. A third factor is the

culosis. Phagocytosis of microbes leads to

presence or absence of other phagocytic cells.

release of toxic metabolites, which then

Many patients with chronic neutropenia

activate the complement system, inducing

have an elevated circulating monocyte count,

neutrophil aggregation and adherence of

which provides some additional protection

leukocytes to the pulmonary capillary bed.

against pyogenic organisms. Conversely,

Tumor necrosis factor and interleukin-1,

patients being treated with steroids or other

released by macrophages, likely accelerate

immunosuppressive therapy will have treat-

this process. Activated granulocytes seques-

ment-related abnormalities in cell-mediated,

tered in the lungs may cause acute cardio-

humoral, and macrophage-monocyte immu-

pulmonary complications. Neonates have a

nity and may be at increased risk of invasive

limited granulocyte pool in their bone mar-

infection even with a normal neutrophil

row, which can be exhausted rapidly during

count. Patients with a history of splenectomy

overwhelming bacterial sepsis.

have an increased risk of overwhelming infec-

Replacement of the bone marrow (as

tion caused by encapsulated bacteria regard-

occurs with hematologic malignancies, gly-

less of their neutrophil count.

cogen storage diseases, granulomas associated

The age at presentation with neutropenia

with infection, and fibrosis related to chemical

is an important factor in risk assessment.

or radiation injury or osteoporosis) results in

The younger the child is at the time of

neutropenia. Frequently, the erythroid and

diagnosis, the greater the concern that the

megakaryocytic lines are also affected.

patient could have a severe form of chronic

Medications are a common cause of neu-

neutropenia, whereas children who are

tropenia. Neutropenia is a common and

found to be neutropenic later in life and

expected side effect of anticancer therapy.

who do not have a history of frequent

Many chemotherapeutic agents have a direct

bacterial infections or chronic illness are

toxic effect on the early marrow stem cells.

more likely to have a more benign form

The severity and duration of the neutropenia

of neutropenia.

depend on the particular medication and

Chapter 11

Table 11.1 Acquired causes of neutropenia.

Condition

Pathogenesis

Occurrence

Associated findings

Infection

Viral marrow suppression,

Common

EBV, parvovirus, HHV6,

viral-induced immune

other viruses

neutropenia

Bacterial sepsis-endotoxin

Less common

Severe infection

suppression

Bone marrow

Infiltration of marrow with

Uncommon

Vary depending on

replacement

malignant cells, fibrosis,

underlying cause

granulomas

Drug-induced

Direct marrow suppression

Common

Underlying condition

Immune destruction

Less common

Autoimmune

Primary (molecular

Common

Monocytosis common

mimicry)

Secondary (SLE, Evans

syndrome)

Newborn

Alloimmune-maternal

Rare

Antigen difference in

immune

sensitization

newborn and mother

Due to maternal autoim-

Maternal neutropenia

mune neutropenia

Chronic

Ineffective or decreased

Common

Consider also familial

idiopathic

production

benign neutropenia

Often asymptomatic

Sequestration

Hypersplenism

Common if

Mild neutropenia

spleen is

Enlarged spleen—

enlarged

many causes

Nutritional

Vitamin B₁₂ or folate

Rare in children

Hypersegmented

deficiency

neutrophils

Copper deficiency

Zinc excess

Impaired DNA processing

Abbreviations:

EBV, Epstein-Barr virus; HHV6, human herpesvirus-6; SLE, systemic lupus

erythematosus.

dosage as well as the patient’s underlying

immune-mediated destruction, toxic effect

disease, state of nutrition, and general health.

of the drug or metabolites on the marrow

Many other medications can induce neutro-

stem cells, and toxic effects on the marrow

penia, including antibiotics (chlorampheni-

microenvironment. After withdrawal of the

col, cephalosporins, penicillins, and sulfona-

drug, the marrow can repopulate with early

mides), anticonvulsants

(phenytoin and

myeloid forms within 3 to 4 days and appear

valproic acid), anti-inflammatory agents,

morphologically normal by 1 to 2 weeks.

cardiovascular agents, tranquilizers, and

The duration of neutropenia is likely related

hypoglycemic agents. The severity and dura-

to the underlying mechanism; some chronic

tion of drug-induced neutropenia are vari-

idiosyncratic drug reactions can last from

able. The underlying mechanism is not

months to years.

known, although studies with certain drugs

Autoimmune neutropenia is another

have led to various hypotheses including common cause of neutropenia following a

The Neutropenic Child

viral infection, and may be difficult to dis-

neutrophils caused by impaired neutrophil

tinguish from virus-associated marrow sup-

nuclear maturation is a clue to this condition.

pression due to the difficulty in identifying

Similarly, copper deficiency is a rare cause of

antineutrophil antibodies. Unlike viral sup-

neutropenia often secondary to an underlying

pression, autoimmune neutropenia can per-

malabsorptive process or due to zinc excess.

sist for 7 to 24 months, and affected children

These patients usually present with concom-

occasionally suffer from infections of the

itant anemia and thrombocytopenia.

ear, lung, skin, or other sites.

A number of inherited conditions have

Neonatal alloimmune neutropenia is

neutropenia as one of their characteristic

analogous to Rh-related hemolytic disease

features. The more common of these con-

of the newborn; mothers generate IgG anti-

ditions are presented in Table 11.2.

bodies against paternal neutrophil antigens

Children with severe congenital neutro-

expressed on fetal neutrophils. These anti-

penia (SCN) often present in early infancy

bodies cross the placenta and cause neutro-

with umbilical infection, skin infections, oral

penia in the fetus and newborn.

ulcers, pneumonia, or perineal infections.

“Chronic idiopathic” neutropenia, also

There are two forms: an autosomal recessive

known as chronic benign neutropenia of

form (Kostmann syndrome) involving muta-

childhood, is likely caused by a variety of

tions in the HAX1 gene that is involved in

disorders without a unifying etiology. It is

signal transduction and an autosomal dom-

likely that many of these children in fact

inant form involving mutations in the neu-

have autoimmune neutropenia or familial

trophil elastase gene (ELA2) or, more rarely,

benign neutropenia. They often have mild-

in the GFI1 gene that targets ELA2. Bone

to-moderate neutropenia; the susceptibility

marrow aspiration reveals a maturational

to infection is roughly proportionate to the

arrest at the promyelocyte stage. In addition

degree of neutropenia. The blood neutro-

to the risk of death due to overwhelming

phil count remains stable over years, and

infection, patients with either of these con-

becomes elevated in response to an infection

ditions have an increased risk of developing

in a subset of children. Spontaneous remis-

myelodysplastic syndrome (MDS) or acute

sions at

2 to

4 years of age have been

myelogenous leukemia (AML).

reported. Affected individuals have normal

Cyclic neutropenia is characterized by

life expectancies. Evaluation of the bone

approximately 21-day cycles of changing

marrow shows decreased myelopoiesis

neutrophil counts, with frank neutropenia

(often with monocytosis), and there is con-

developing at regular intervals and lasting 3

siderable variability in the stage at which

to 6 days. Fever and oral ulcerations usually

maturation is arrested. These patients are at

are seen during the nadir, as well as gingi-

low risk for the development of serious

vitis, pharyngitis, and skin infections. Diag-

infections, and no treatment is required

nosis is often delayed because the neutrophil

except during infectious episodes.

count may have improved by the time

Splenomegaly from any cause including

the patient seeks medical attention. These

chronic hemolytic anemia, portal hyperten-

patients also demonstrate mutations in the

sion, liver disease, and storage disorders can

ELA2 gene, but at different locations than in

cause mild neutropenia, as well as anemia

those with SCN. They do not have the same

and thrombocytopenia. If severe, splenec-

risk of developing MDS or AML. Diagnosis

tomy may be necessary.

is made by obtaining serial complete blood

Deficiencies of folate and B₁₂ are rare in

counts (CBCs) 2 to 3 times/week over 4 to

children; the presence of hypersegmented

6 weeks to demonstrate the periodicity of

Chapter 11

the cycle. Granulocyte colony-stimulating

have very short germ line telomeres, and

factor (G-CSF) has been used in patients

approximately half have mutations in one

who develop recurrent infections during

of six genes encoding proteins that maintain

their nadir.

telomere function. Affected patients rarely

Shwachman-Diamond syndrome in-

present with hematologic abnormalities dur-

cludes exocrine pancreatic insufficiency,

ing childhood.

short stature, metaphyseal dysplasia, and

Diamond-Blackfan anemia is a congen-

bone marrow failure with typically mild-to-

ital anemia that presents in infancy. There

moderate neutropenia. Affected patients

is typically a failure of erythropoiesis with

also have an increased risk of MDS and

preservation of myeloid and platelet

AML. Intestinal malabsorption with failure

production. Only 20% to 25% of cases are

to thrive commonly occurs, especially in

inherited; the rest are sporadic. Approxi-

infancy and early childhood.

mately 50% of affected persons have devel-

Benign familial neutropenia is charac-

opmental abnormalities including growth

terized by moderate neutropenia with min-

retardation and craniofacial, upper limb/

imal risk of invasive bacterial infections. It

hand, cardiac, and genitourinary malforma-

has been postulated that the underlying

tions. Neutropenia is seen in 25% to 40%

cause is a defect in neutrophil mobilization

of affected children. Patients also have an

from the bone marrow, but the etiology is as

increased risk of MDS, AML, and osteogenic

yet unknown. It occurs more commonly in

sarcoma. Genetic studies have identified

individuals of African, Arabic, and Yeme-

heterozygous mutations in at least one of

nite Jewish descent. Periodontal disease is

eight ribosomal protein genes in up to 50%

the most frequent complication.

of cases. Mutations in ribosomal protein L5

Fanconi anemia is characterized by a

(RPL5) are associated with multiple physi-

defect in DNA repair leading to extensive

cal abnormalities including cleft lip/palate,

chromosomal breakage. Affected patients

thumb, and heart anomalies. The diagnosis

have mutations within the FANC family of

is often difficult due to incomplete pheno-

genes, including FANC A, C, and G. It pre-

types and a wide variability of clinical

sents most commonly during the early school

expression. Up to 80% of patients respond

age years; patients with the characteristic

to a course of steroids with improvement in

physical findings may be diagnosed sooner.

their cytopenias.

Thrombocytopenia is often the presenting

The etiology of neutropenia in glycogen

hematologic abnormality, with anemia and

storage disease 1b is not definitively known,

neutropenia developing later. Up to 10% of

but appears to be related to increased

patients ultimately develop MDS or AML.

neutrophil apoptosis caused by an excess

Bone marrow transplantation is curative, but

of reactive oxygen species due to a defect in

challenging to complete successfully given

neutrophil energy metabolism.

the underlying chromosomal fragility.

Almost one-third of patients with selec-

Dyskeratosis congenita (DKC) is char-

tive IgA deficiency have evidence of

acterized clinically by the triad of abnormal

autoimmune disease; neutropenia in this

nails, reticular skin pigmentation, and oral

condition is felt most likely related to the

leukoplakia. Bone marrow failure occurs

presence of antineutrophil antibodies.

during early adulthood and is associated with

Patients with a mild form of Wiskott-

a high risk of developing aplastic anemia,

Aldrich syndrome

(WAS) known as

MDS, leukemia, and solid tumors. Patients

X-linked neutropenia have a unique “gain

The Neutropenic Child

of function” mutation in the GTPase-binding

include antineutrophil antibodies, assess-

domain of the WAS protein (WASp) that

ment of cellular and serum immune status,

leads to increased actin polymerization in

and careful review of the peripheral smear

neutrophils, causing defective mitosis and cell

for morphologic abnormalities of the white

movement and ultimately severe neutropenia.

cells. If severe congenital neutropenia or

Kostmann syndrome is suspected, assess-

ment for ELA2

and HAX1

mutations

Initial evaluation of the child with

should be made. A bone marrow aspirate

neutropenia

and biopsy may be necessary to identify

granulocyte precursors and to search for

Evaluation of the child with neutropenia

defects in myeloid maturation. In addition,

begins with a thorough history and physical

the bone marrow aspirate and biopsy can be

examination. It is critical to know whether

used to exclude hematologic malignancies,

the child has had recent or recurrent bac-

marrow infiltration, or fibrosis.

terial infections, and whether there is a

family history of neutropenia or recurrent

bacterial infections. On examination, atten-

Management of the child with

tion should be paid to any phenotypic

neutropenia and fever

abnormalities, adenopathy, splenomegaly,

evidence of a chronic or underlying disease,

Children identified with neutropenia but who

and meticulous evaluation of the skin and

are free of fever or other signs of infection

mucous membranes (particularly in the oral

should be evaluated as outlined above, but

and perirectal areas). A CBC must be done

require no other therapy at that time. Man-

to determine if the patient has isolated

aging the child with neutropenia and fever is

neutropenia or neutropenia associated with

more complex and depends on many factors

anemia and/or thrombocytopenia. The

including the nature of the neutropenia

approach to a child with bi- or trilineage

(acute or chronic), its severity, and the asso-

abnormalities is different than that in a child

ciation with immune defects, underlying

with isolated neutropenia; multiple abnor-

illnesses, or malignancies. Patients with

mal lineages increase the likelihood of a

acquired neutropenia arising from malig-

more generalized marrow failure state such

nancy or chemotherapeutic drugs have a

as aplastic anemia or a marrow infiltrative

diminished inflammatory capability and have

process such as leukemia. It is valuable to

a greater susceptibility to sepsis. Fever may be

repeat the CBC at least once, especially if the

the earliest and only warning sign. Sepsis

child appears well, to avoid proceeding with

related to chemotherapy-induced neutrope-

a major evaluation due to a laboratory error.

nia remains a leading cause of mortality in

Well-appearing children with mild-to-

these patients. Aggressive management of the

moderate neutropenia can typically be

febrile, neutropenic cancer patient in the

observed over the next 2 to 3 weeks with

hospital has markedly reduced morbidity and

serial CBCs. Children with persistent or

mortality due to infection. For management

worsening neutropenia require further eval-

of oncology patients with fever and neutro-

uation. Patients with recurrent neutropenia

penia, see Chapter 27.

should have blood counts checked 2 to 3

The management of the febrile child who

times per week for

6 weeks to evaluate

is discovered to be neutropenic depends on

for cyclic neutropenia. Additional studies

several factors. Patients with fever and mild

100

Chapter 11

or moderate neutropenia and signs and

antibiotic choices are appropriate and

symptoms suggestive of a viral illness that

depend on local practice.

otherwise look well may be managed sup-

* Careful physical evaluation, paying

portively without antibiotics, although in

meticulous attention to potential sites of

most cases they will receive a long-acting

occult infection (e.g., the oral cavity and

cephalosporin such as ceftriaxone prior to

perineum).

discharge from the clinic or emergency

* Laboratory studies: CBC with differential,

department. Their parents should be

blood cultures, urinalysis and urine culture,

instructed to bring them back in 24 hours

and cultures from sites of suspected infec-

for further evaluation, or sooner if they

tion such as the skin, throat, and stool.

develop additional symptoms or begin to

* Chest radiograph if any pulmonary

appear unwell. If they become afebrile, their

symptoms are present.

neutropenia should be evaluated as outlined

* Daily blood cultures and a CBC with

above. Patients with fever and mild or mod-

differential every 24 hours in the persistently

erate neutropenia who have evidence of

febrile patient to help determine further

localized bacterial disease

(otitis media,

management.

sinusitis, or local skin infections) may be

* CT scan of the chest (þ / sinuses, abdo-

treated with appropriate oral antibiotics in

men, and pelvis) looking for evidence of

the outpatient setting. Patients with mild

occult infection in any patient remaining

neutropenia and evidence of bacterial pneu-

febrile for

>96 hours without a specific

monia, GU tract infections, lymphadenitis,

cause being identified. They should be

or systemic symptoms should have cultures

started on empiric antifungal coverage due

of the infection site and of the blood. They

to the increased risk of invasive fungal

may be treated with appropriate oral anti-

infection in this patient population.

biotics if their appearance is not concerning,

but should be seen back for reevaluation

Prophylactic antibiotics have been used in

within 24 hours. Similar patients with mod-

the past in an attempt to decrease the fre-

erate neutropenia can also be treated in the

quency of serious infections in patients with

outpatient setting if they appear totally well.

severe neutropenia. However, this has gen-

Febrile patients with moderate or severe

erally fallen out of favor. Exceptions include

neutropenia who appear in any way unwell

the use of prophylactic penicillin or amox-

require emergent medical assessment and

icillin in patients following splenectomy and

initiation of therapy, as do children who

the use of trimethoprim-sulfamethoxazole

are known to have severe forms of neutro-

prophylaxis to prevent Pneumocystis jiroveci

penia such as severe congenital neutrope-

(previously known as Pneumocystis carinii)

nia or Kostmann syndrome. These children

pneumonia in patients with T-cell dysfunc-

require:

tion in addition to neutropenia.

* Hospital admission.

The use of cytokines, particularly G-CSF,

* Coverage with broad-spectrum antibio-

has become increasingly popular in the

tics due to their increased risk of mortality

management of symptomatic neutropenia.

due to sepsis. These should provide cover-

It is particularly useful in patients with

age for Gram-negative and Gram-positive

symptomatic cyclic neutropenia or in the

organisms. A combination of an aminogly-

neutropenia-accompanying disorders such

coside and a b-lactam antibiotic provides

as glycogen storage disease

1b, as these

initial broad coverage and is synergistic for

patients typically respond well to low dose

Pseudomonas species, but several different

therapy (1 to 2 mcg/kg/dose) on a daily or

The Neutropenic Child

101

alternate day schedule with a goal of main-

she was discharged from the nursery at

taining an ANC between

1.0

and 1.5

24 hours of life. She is an only child. There

10⁹/L. It is also used frequently in patients

is no family history of recurrent fevers, or

with severe chronic neutropenia. However,

severe or unusual infections. Her parents are

the doses required to raise the ANC into the

unaware of any “blood problems” in other

desired range vary significantly between

family members.

patients. A typical starting dose is

5 mcg/kg/day, and the dose is increased

2. What additional studies would you like

slowly until the desired ANC is achieved.

to obtain?

Patients with severe neutropenia who fail

to respond to doses as high as

Given her age and degree of fever, a sepsis

100 mcg/kg/day are considered poor respon-

workup is indicated. A CBC reveals a

ders. These patients are candidates for bone

WBC count of 12.4

10⁹/L, a hemoglobin

marrow transplantation given their high like-

11.7 g/dL, and a platelet count of

lihood of mortality due to infection as well as

423

10⁹/L. The differential reveals

an up to 30% chance of developing myeloid

neutrophils,

73% lymphocytes, and 27%

malignancy.

monocytes. A urinalysis is normal. Because

of her severe neutropenia she is admitted to

the hospital and started on broad-spectrum

Case study for review

antibiotics. A blood culture is performed

and is negative. The vulvar lesion is cultured

A 7-week-old girl presents to your clinic for

and grows Pseudomonas aeruginosa. The

evaluation of a fever to 38.6

C. She had

lesion resolves with intravenous antibiotics.

been seen 4 weeks earlier for a well child visit

A bone marrow aspiration is performed

and was noted to have a small ulcer on her

and reveals an adequately cellular specimen

vulva. This was treated with oral antibiotics

with normal megakaryocytes and erythroid

and resolved. Her parents report that the

precursors. The myeloid lineage shows a

vulvar lesion had recurred 24 hours before

maturational arrest at the myelocyte stage,

she developed the fever. She had no blood

however.

work performed at the previous visit. Her

physical examination reveals her to be alert

3. What are you thinking now? What would

and nontoxic appearing. A 6-mm shallow

you do next?

ulceration is present on her vulva with

minimal surrounding erythema, drainage,

The isolated neutropenia in the face of a

or induration. It is mildly tender, however.

normal hemoglobin and platelet count

Her physical examination is otherwise

makes congenital aplastic anemia unlikely.

normal.

The young age at presentation, the signifi-

cant degree of neutropenia, and the unusual

1. What additional information would you

organism identified raise concern that this

like?

child may have a severe form of congenital

neutropenia. Once her active infection has

The patient was born at term via spontaneous

resolved and she is afebrile she can be dis-

vaginal delivery after an uncomplicated preg-

charged from the hospital, but should have

nancy. Her weight, height, and head circum-

regular follow-up to determine what her

ference were appropriate for gestational age.

neutrophil count does over time. More

Her nursery course was unremarkable, and

importantly, her parents need to understand

102

Chapter 11

the importance of bringing her immediately

family history, the autosomal recessive form

to you or to the emergency room if she

(Kostmann syndrome) would be more likely,

develops another fever.

although she may have a new ELA2 muta-

Twice weekly CBCs are performed over

tion. Genetic testing for HAX1 and ELA2

the next 6 weeks and reveal a consistent

mutations can be sent for confirmation.

pattern of severe neutropenia, with ANCs

A trial of G-CSF can also be initiated to see

ranging from 0 to 170. Serum immunoglo-

if it will result in an increase in the ANC.

bulins are measured and are normal, as are

T-cell subset studies. Over that time period,

Suggested Reading

she has several episodes of oral mucosal

ulcers.

Berliner N, Horwitz M, Loughran TP. Congenital

and acquired neutropenia. Hematol Am Soc

4. What would be your next step?

Hematol Educ Prog 63-79, 2004.

James RM, Kinsey SE. The investigation and

The persistent, noncyclic nature of her neu-

management of chronic neutropenia in chil-

tropenia provides further evidence that this

dren. Arch Dis Child 91:852-858, 2006.

infant is suffering from a form of severe

Klein C. Congenital neutropenia. Hematol Am

congenital neutropenia. Given the lack of a

Soc Hematol Educ Prog 344-350, 2009.

Thrombocytopenia

Thrombocytopenia, or low platelets, can

low platelet count and symptoms of muco-

occur as an isolated finding or in conjunc-

cutaneous bleeding. Most cases are consid-

tion with a multitude of underlying clinical

ered idiopathic whereas others are second-

conditions. Normal platelet counts range

ary to coexisting conditions. The diagnosis

from 150 to 400

10⁹/L and thrombocyto-

of ITP is one of exclusion (see Table 12.1,

penia is generally defined as a platelet count

Figures 12.1, 12.2, and 12.3).

of less than 100

10⁹/L. Thrombocytopenia

The most common cause of destructive

may further be defined as mild

(50

thrombocytopenia is autoimmunity. Short-

100

10⁹/L), moderate (20 to 50

10⁹/L),

ened platelet survival is due to platelet auto-

and severe

(<20

10⁹/L). Other sources

antibody production (usually IgG), often

define thrombocytopenia as a platelet

stimulated by infection or drug exposure.

count of <150

10⁹/L or in patients with

IgM antibodies and complement activation

a drop of >50% from their baseline platelet

are less frequently found but can also be seen

counts (if known). Thrombocytopenia is

in childhood ITP. It is an acute, self-limited

typically subdivided into immune and

disease of isolated thrombocytopenia that

nonimmune causes. Immune causes gener-

usually occurs in children aged 2 to 5 years

ally cause increased platelet destruction.

(though may occur at any age from infancy

Nonimmune causes may cause increased

to adolescence), typically resolving in more

destruction or decreased bone marrow

than 80% of children within 6 weeks to 6

production. In patients with splenomegaly,

months. When ITP occurs in the child over

platelet sequestration may also lead to

10 years of age, especially females, the course

thrombocytopenia.

may be chronic and associated with an

autoimmune disorder. The otherwise

healthy child presents with sudden onset

Acute immune thrombocytope-

of severe thrombocytopenia (usually < 20

nic purpura

10⁹/L), manifested by petechiae and

purpura and less frequently mucosal bleed-

Immune thrombocytopenic purpura (ITP;

ing such as epistaxis, menorrhagia, hema-

also referred to as immune thrombocyto-

turia, and hematochezia. There is a history

penia or idiopathic thrombocytopenic pur-

of an antecedent viral illness within the past

pura) is an acquired, isolated disorder in

1 to 3 weeks in up to 60% to 70% of

which the patient typically presents with a

children. It may also follow vaccination with

Handbook of Pediatric Hematology and Oncology: Children’s Hospital & Research Center Oakland,

Second Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.

2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

104

Chapter 12

Table 12.1 Differential diagnosis of thrombocytopenia.

Destructive thrombocytopenias

Immunologic

ITP

Drug-induced (valproic acid, amphotericin B, digoxin)

Infection-induced (HIV, CMV, EBV, parvovirus B19)

Postvaccination (MMR, Varivax)

Posttransfusion purpura

Autoimmune disease (SLE, JIA)

Evans syndrome (AIHA/ITP)

Posttransplant

Hyperthyroidism

Lymphoproliferative disorders (ALPS)

Nonimmunologic

Microangiopathic disease

Cyclic thrombocytopenia

Hemolytic uremic syndrome

Thrombotic thrombocytopenic purpura

Platelet consumption/

Sepsis/DIC

destruction

Giant hemangioma (Kasabach-Merritt syndrome)

Cardiac (prosthetic heart valves, repair of

intracardiac defects)

Malignant hypertension

Neonatal problems

Neonatal alloimmune (NAIT)

Neonatal autoimmune (maternal ITP)

Pulmonary hypertension

Polycythemia

RDS

Infection (viral, bacterial, protozoal, spirochetal)

Sepsis/DIC

Prematurity

Meconium aspiration

Erythroblastosis fetalis (Rh incompatibility)

Maternal hypothyroidism

Impaired production

Congenital and

TAR syndrome

hereditary disorders

Fanconi anemia

Bernard-Soulier syndrome

Wiskott-Aldrich syndrome

Glanzmann thrombasthenia

MYH9 disorders (May-Hegglin anomaly)

CAMT

Rubella syndrome

Von Willebrand disease, type II

ATRUS

Dyskeratosis congenita

Agenesis of the corpus callosum

Associated with

Trisomy 13 or 18

chromosomal defect

Thrombocytopenia

105

Table 12.1 (Continued)

Metabolic disorders

Marrow infiltration

Malignancies (leukemia, neuroblastoma, metastatic

solid tumors)

Storage disease

Myelofibrosis

Acquired processes

Aplastic anemia

Liver disease/failure

Drug-induced

Radiation-induced

Severe iron deficiency

Sequestration

Hypersplenism (portal hypertension, neoplastic,

infectious, glycogen storage disease, cyanotic

heart disease)

Hypothermia

Abbreviations: ITP, immune thrombocytopenic purpura; SLE, systemic lupus erythematosis; JIA,

juvenile idiopathic arthritis; AIHA, autoimmune hemolytic anemia; ALPS, autoimmune

lymphoproliferative syndrome; DIC, disseminated intravascular coagulation; NAIT, neonatal

alloimmune thrombocytopenia; CAMT, congenital amegakaryocytic thrombocytopenia; TAR,

thrombocytopenia absent radii; ATRUS, amegakaryocytic thrombocytopenia radio-ulnar

synostosis; RDS, respiratory distress syndrome.

MMR or Varivax (live virus vaccines).

be associated with trauma. Bleeding into

Severe bleeding such as protracted epistaxis,

joints

(hemarthroses) should lead one to

hemoptysis, or gastrointestinal bleeding

consider an alternative bleeding disorder

leading to severe anemia and need for trans-

(e.g., congenital or acquired factor defi-

fusion is rare. Intracranial hemorrhage

ciency such as hemophilia). There should

(ICH) is the most feared complication with

be no history of unexplained fevers, bone

an estimated incidence of 0.1% to 0.5%;

pain, or weight loss which would be con-

more than 50% of patients with ICH present

cerning for an underlying malignancy or

with this finding at diagnosis or within

chronic infection. A medication history is

1 week of diagnosis. More than

75% of

critical as many drugs have been implicated

patients with ITP and ICH survive. It has

in inducing drug-mediated immune throm-

yet to be defined what risk factors predis-

bocytopenia. Implicated drugs include hep-

pose children with ITP to sustain this rare

arin, aspirin, aspirin-containing cold med-

but extremely serious complication.

ications, nonsteroidal anti-inflammatory

drugs (NSAIDs), and seizure medications

Evaluation

such as valproic acid. Chronic infections

The initial evaluation of the child with

with HIV, CMV, and hepatitis C may cause

suspected ITP begins with a complete his-

a low platelet count and appropriate screen-

tory and physical examination. Other than a

ing should be done. Helicobacter pylori has

possible antecedent illness and the acute

been implicated in adults with ITP and there

onset of minor bleeding and bruising, the

are some reports of this association in chil-

child should be otherwise clinically well

dren as well. Family history should include

appearing. More significant bleeding may

an assessment for autoimmune diseases,

106

Chapter 12

History, physical examination,

CBC, differential, platelet count,

peripheral smear evaluation

Thrombocytopenia with

neutropenia or pancytopenia

Consider

Marrow infiltration

Marrow failure

Hypersplenism

Assess

Bone marrow aspirate

Imaging for splenomegaly

(ultrasound/CT/MRI)

DDx:

Aplastic anemia

Fanconi anemia

Malignancy

Storage disease

Hypersplenism

Figure 12.1 Approach to the child with thrombocytopenia and additional cytopenias. Abbreviations:

CBC, complete blood count; DDx, differential diagnosis.

immune deficiency, or congenital syndromes

neutrophil count may be altered due to

associated with thrombocytopenia

(see

a recent infection, and the hemoglobin

Table 12.1). The physical exam should assess

may be low due to bleeding. Coagulation

for lymphadenopathy, hepatosplenomegaly,

screening tests including PT, PTT, and

short stature, dysmorphic features, or the

fibrinogen and the complete metabolic

presence of congenital anomalies

(e.g.,

panel should be normal. Therefore, no

radius, thumb, and fingers).

studies other than a CBC truly need to

The laboratory features of ITP include

be done if the diagnosis of ITP is strongly

a low platelet count in the face of an

suspected. The platelet count should be

otherwise normal complete blood count

confirmed to be low on a second evalua-

(CBC). However, the hemoglobin, white

tion if the physical findings do not corre-

blood cell count, and/or absolute

late with the laboratory value.

Thrombocytopenia

107

History, physical examination,

CBC, differential, platelet count,

peripheral smear evaluation

Isolated thrombocytopenia

Assess platelet morphology

Normal

Abnormal

Large platelets

Assess for splenomegaly

Negative

Congenital

and/or lymphadenopathy

anomalies

Bernard-Soulier syndrome

MYH9 disorders (May-Hegglin)

Jacobsen syndrome

Positive

Platelet-type von Willebrand

disease

Benign Mediterranean

macrothrombocytopenia

Bone marrow aspirate

Normal exam

Gray platelet syndrome

Small platelets

Wiskott-Aldrich syndrome

DDx:

ITP (see Table 12.1)

Viral-induced

DDx:

Drug-induced

Malignancy

HIV

Skeletal

Infection

Autoimmune disease

Fanconi anemia

HIV, EBV, CMV

Infant

TAR, ATRUS

Storage disease

Alloimmune (NAIT)

Cyanotic heart disease

Gaucher disease

Eczema

Autoimmune (maternal Ab transfer)

Hypersplenism

Hemangioma (may be visceral)

Wiskott-Aldrich syndrome

Aplastic anemia

Hemangiomas

Kasabach-Merritt syndrome

Fanconi anemia

Congenital amegakaryocytic

thrombocytopenia (CAMT)

Figure 12.2 Approach to the child with isolated thrombocytopenia. Abbreviations: CBC, complete

blood count; DDx, differential diagnosis; ITP, immune thrombocytopenia purpura; HIV, human

immunodeficiency virus; EBV, Epstein-Barr virus; CMV, cytomegalovirus; NAIT, neonatal alloim-

mune thrombocytopenia; Ab, antibody; TAR, thrombocytopenia absent radius; ATRUS, amegakar-

yocytic thrombocytopenia radio-ulnar synostosis.

If two cytopenias are present with any

megakaryocytes in normal or increased num-

findings on the history or physical suggestive

bers with normal erythroid and myeloid

of another diagnosis, consideration should

lineages. By convention, a BMA is done on

be given to performing a bone marrow aspi-

individuals with suspected ITP only if ster-

ration

(BMA). However, a bone marrow

oids are to be part of the treatment plan due

evaluation is rarely necessary to confirm

to the small chance the thrombocytopenia

the diagnosis. BMA in ITP typically demon-

may be an early manifestation of leukemia.

strates

the presence of immature However, even this practice is controversial.

108

Chapter 12

History, physical examination,

CBC, differential, platelet count,

peripheral smear evaluation

Thrombocytopenia with anemia

DAT test

Assess for intravascular

yes

(Coombs)

Microangiopathic

hemolysis, red cell

process

fragments

Consumption

negative

positive

DDx:

Reticulocyte

Evans syndrome

count

Autoimmune disease

Drug-induced

DDx:

DIC, sepsis

HUS

TTP

high

normal or low

CHD

Assess physical:

Bone marrow aspirate:

see Figure 12.2

see Figure 12.1

Figure 12.3 Approach to the child with thrombocytopenia and anemia. Abbreviations: CBC, complete

blood count; DAT, direct antiglobin test (Coombs); DDx, differential diagnosis; DIC, disseminated

intravascular coagulation; HUS, hemolytic uremic syndrome; TTP, thrombotic thrombocytopenic

purpura; CHD, congenital heart disease.

Additional laboratory evaluations may

Review of the peripheral blood smear

be required for specific clinical indications

confirms a low platelet count, and the few

(e.g., screening for autoimmune or thyroid

remaining platelets typically are large. If

disease, viral testing for HIV, hepatitis C,

platelet size is determined by an automated

CMV, or parvovirus B19; direct antiglobu-

cell counter (Coulter), it is usually elevated,

lin testing [DAT; Coombs] and reticulocyte

consistent with young platelet age (due to

count if concern for autoimmune hemolytic

early marrow release associated with rapid

anemia; and immunoglobulin levels and T/

peripheral platelet destruction). Oftentimes

B cell numbers if concern for underlying

the platelet count is underestimated as very

immunodeficiency syndrome). Antiplatelet

large immature platelets

(megakaryocytic

antibody tests are not sensitive or specific

fragments) are not counted by the Coulter.

and not required for diagnosis or for routine

This may in part explain the relative lack of

clinical management.

bleeding symptoms in children with very

Thrombocytopenia

109

low platelet counts. The erythrocyte and

and general anticipatory guidance such as

leukocyte counts and morphology should

the use of protective gear (helmets) and seat

be normal and there should be no evidence

belts. Intramuscular injections should be

of hemolysis or microangiopathic disease

withheld until platelet counts increase. Spe-

(e.g., schistocytes and/or burr cells).

cific medications that interfere with platelet

False values for platelet counts can result

function (such as NSAIDs, SSRIs [selective

from aggregation of platelets in the syringe

serotonin reuptake inhibitors], anticonvul-

or collection tube, counting of small non-

sants, and aspirin) should not be given.

platelet particles (fragmented red or white

The use of a bleeding score as the frame-

cells) by automated cell counters, and pseu-

work for a consistent treatment strategy is

dothrombocytopenia due to in vitro platelet

gaining in popularity and several scoring

agglutination by anticoagulant-dependent

systems have been published to date.

ethylenediaminetetraacetic acid

(EDTA)

Patients are categorized by the presence of

antibodies. Review of the blood film should

clinical signs and symptoms of bleeding;

assess for clumps of agglutinated platelets at

more than 80% present with mild clinical

the periphery of the slide.

bleeding (manifested by bruising, petechiae,

mild epistaxis, and no anemia). Moderate

Treatment

clinical bleeding is characterized by more

The natural history of acute ITP is com-

significant mucosal bleeding such as more

plete resolution in the majority of children.

severe epistaxis or menorrhagia and severe

Despite the relatively benign course experi-

bleeding

(usually

< 5% of patients) is

enced by most children with ITP, the sud-

marked by unusual or severe bleeding

den onset, concern for a possible serious

requiring hospitalization for control and/

condition such as leukemia or aplastic ane-

or blood transfusion support with symp-

mia, and concern for life-threatening bleed-

toms seriously interfering with quality of

ing often guide the initial treatment decision

life. All patients may present with very low

making. Parents often bring their child to

platelet counts (e.g., 1 to 20

10⁹/L) though

see the primary care or emergency physi-

those with severe symptoms tend to have

cian, many of whom are not accustomed to

initial platelet counts < 10

10⁹/L.

encountering such severe thrombocytope-

Utilizing the bleeding score, many

nia. Risk factors for the rare life-threatening

patients with clinically mild or moderate

hemorrhage have yet to be elucidated and

bleeding can be effectively managed with

dogma has been to treat the patient according

observation. The anxiety of patients,

to platelet count rather than being guided by

families, and other caregivers can often be

the degree of clinical symptoms. This clinical

alleviated with education on the pathophys-

scenario has led to significant controversy

iology and natural history of ITP in addition

as to whether intervention is warranted,

to general preventive measures and periodic

when it is warranted, and with what treat-

clinical and laboratory assessments. Platelet

ment. Contemporary therapies have not been

counts do not need to be checked more

shown to alter the course or outcome of

often than every 1 to 2 weeks (or even less

children with acute ITP. As such, the concept

often in the clinically stable child). Disrup-

of nontreatment in ITP is increasingly

tion of school or work is not necessary,

becoming the standard of care in most pedi-

though participation in contact sports or

atric hematology/oncology centers.

other situations that could lead to head or

All patients and families should be coun-

abdominal injury should be avoided until

seled regarding rough play, contact sports,

the platelet count is known to have returned

110

Chapter 12

to a safe levels (typically >50

10⁹/L). With

premedication with acetaminophen is

observation, the majority of patients with

advisable. Rare side effects include anaphy-

ITP will have resolution of symptoms and

laxis in an IgA-deficient patient, aseptic

the underlying thrombocytopenia while

meningitis, acute renal failure, pulmonary

avoiding unnecessary costs and side effects

insufficiency, and thrombosis. Although

of medications and hospitalization.

IVIG is a pooled blood product, it is thought

Pharmacological treatments to raise

to be safe with regard to viral transmission

the platelet count in children with moder-

and does not require consent as with blood

ate-to-severe bleeding include two first-line

product administration. Subsequent dosing

therapies: intravenous immune globulin

with IVIG may be indicated depending on

(IVIG) and RhoGAM (anti-Rh [anti-D]

clinical symptomatology and continued

immune globulin, also Rhophylac). IVIG

thrombocytopenia.

is thought to function by saturating the

RhoGAM is a less-expensive alternative

Fc receptors on the reticuloendothelial cells

therapy to IVIG. The dose is 75 mg/kg IV

in the spleen and liver, thereby decreasing

over 20 to 30 minutes. Response rate and

the clearance of opsonized platelets. These

time to onset are similar to IVIG. Anti-D

treatments typically provide a quick yet

works by binding the RhD antigen expressed

transient increase in the platelet count, often

on the surface of red blood cells, leading to

sustained 2 to 4 weeks. More than 80% of

their recognition by Fc receptors on cells of

patients respond with an increase in the

the reticuloendothelial system. The coated

platelet count, which is sufficient to decrease

red cells are thought to compete with the

or eliminate bleeding symptoms. Patients

antiplatelet-antibody coated platelets for the

and families should be counseled as to the

activated Fc receptor sites, thereby slowing

transitory effect of IVIG treatment due to

platelet clearance. Side effects include fever

the misconception that a subsequent

and chills, intravascular hemolysis, head-

decrease in platelet count is indicative of

ache, emesis, and rarely anaphylaxis. Preme-

increased disease severity. The dose of IVIG

dication with acetaminophen and diphen-

is 0.8 to 1 g/kg over 4 to 6 hours. If neces-

hydramine may prevent these adverse effects

sary, IVIG may be repeated two to three

with subsequent infusions. A response is

times for a total dose of 2 to 3 g/kg; doses

typically seen within 24 to 48 hours. Patients

should be given at least 24 hours apart to

must be Rh positive, have a functional spleen

allow sufficient time to determine response.

(at least not known to be splenectomized

A rise in the platelet count is usually seen

or asplenic), and not be anemic (i.e., > 2 to

within 24 to 72 hours and peaks at approx-

4 g/dL below expected hemoglobin for age).

imately 9 days. A good initial response is an

RhoGAM does cause transient hemolysis

increase in platelet count by 20 to 50

10⁹/L.

and a decrease in hemoglobin of

Side effects of IVIG are usually immediate,

2 g/dL over the ensuing 3 to 4 days should

relate to the rate of infusion, and include

be expected. The hemoglobin should subse-

nausea, lightheadedness, and headache. At

quently recover within 10 days. Though rare,

times, onset of a severe headache can

the U.S. Food and Drug Administration

prompt an emergent head CT to assess for

currently mandates that patients be moni-

potential intracranial hemorrhage. These

tored for 8 hours with serial urinalysis after

symptoms can be alleviated by slowing the

administration of anti-D due to cases of

rate of infusion and premedicating with

severe, life-threatening hemolysis.

diphenhydramine if further doses are

Amicar (e-aminocaproic acid) may be

needed. Fever may also occur, and

utilized in patients with prolonged

Thrombocytopenia

111

thrombocytopenia and persistent mucosal

Dexamethasone has also been used with

bleeding without anemia (mild bleeding).

efficacy in refractory patients.

Reports of efficacy with minimal side effects

make low-dose therapy a good option

Emergency therapy

(10 mg/kg/dose every 6 to 8 hours). Another

Patients with known or suspected life-

option is low-dose prednisone which may

threatening hemorrhage such as central

benefit the patient with a long course of ITP

nervous system hemorrhage from ITP (usu-

who secondarily develops alteration in vas-

ally with concomitant platelet count < 10

cular integrity. Low-dose steroids would not

10⁹/L) should be treated emergently with

be expected to raise the platelet count; how-

combination therapy including IVIG 1 g/kg

ever, they would have minimal side effects.

daily for 2 to 3 days and intravenous high-

Corticosteroids may be used in the ini-

dose methylprednisolone 30 mg/kg/day (up

tial medical management of ITP, though

1 g/day) for

1 to 3 days. Active life-

typically are considered a second-line ther-

threatening hemorrhage with refractory

apy in pediatrics. Response is slower than

thrombocytopenia is one of the only current

with IVIG or RhoGAM and is usually within

indications for emergency splenectomy.

3 to 4 days. The first steroid prescribed is

Continuous infusion of platelets should be

prednisone,

2 mg/kg/day for

considered in an emergent situation and

weeks, tapering the dose post-platelet

during surgery or childbirth in a severely

response

(i.e., >100

10⁹/L) over several

thrombocytopenic patient, in conjunction

weeks. The initial response rate is 70% to

with other therapies. Off-label recombinant

90%. An immune rebound may occur with a

factor VIIa (rFVIIa) may also be considered.

taper that is too rapid and patients will often

require prolonged steroid therapy to main-

Chronic immune thrombocytope-

tain the desired platelet count. There are

nic purpura

several mechanisms by which steroids affect

Acute and chronic ITP are defined based on

the platelet count: inhibition of phagocyto-

disease duration, with chronic ITP defined

sis of the antibody-coated platelets leading

as persisting for > 6 months. Approximately

to prolonged platelet survival; inhibition of

10% to 20% of children with acute ITP that

antibody production by B-lymphocytes;

persists will go on to have chronic ITP. The

improvement of capillary integrity reducing

child with chronic ITP is still likely to have

clinical bleeding; and an increase in platelet

complete resolution within

6 months to

production. Many patients respond to this

2 years or may have an associated auto-

treatment, although side effects may occur

immune disease or underlying immunod-

with repeated treatment or chronic use such

eficiency state. Some practitioners define

as gastritis, fluid retention, weight gain,

chronic ITP as that lasting beyond a 1 year

mood lability, acne, striae, high blood pres-

period. Most patients with chronic ITP do

sure, and elevated serum glucose. An alter-

not need treatment as the platelet count is

native to oral steroids is high-dose pulse

often above 20

10⁹/L and bleeding is min-

infusion of intravenous methylpredniso-

imal. Platelet count alone does not correlate

lone. Some patients become thrombo-

with the risk of hemorrhage as platelets are

cytopenic again after therapy and require

large due to a healthy marrow response to

retreatment. A relapse may be managed

peripheral thrombocytopenia and, as a con-

safely by observation and restriction of

sequence, have greater than normal procoa-

activity and medications, or with inter-

gulant activity. In the rare patient with

mittent IVIG and/or pulse steroids.

chronic, refractory ITP who has clinical

112

Chapter 12

hemorrhage or cannot tolerate the living

decrement in humoral response, although

restrictions imposed by the thrombocytope-

decreased total IgG immunoglobulin levels

nia, intervention with medical or surgical

and increased infections have not been fre-

therapies should be considered.

quently reported. For the treatment of ITP

ITP may be the initial manifestation of

without an underlying immunodeficiency,

aplastic anemia including Fanconi anemia

it remains unclear if increased infection is a

before progression to pancytopenia, Evans

risk in pediatric patients after rituximab.

syndrome (association of ITP with autoim-

Although considered a T-cell-dependent

mune hemolytic anemia), systemic lupus

infection, B-cell depletion may lead to an

erythematosis (SLE), or autoimmune lym-

increased risk of PCP (Pneumocystis jiroveci

phoproliferative syndrome. HIV infection

pneumonia) and cotrixomazole prophylaxis

should be considered in all patients with

should be considered. Hepatitis B reactiva-

isolated thrombocytopenia as this is fre-

tion and progressive multifocal leukoence-

quently the first manifestation of disease

phalopathy secondary to JC virus are rare

in children. ITP may also be present in

considerations in this population.

children years before the diagnosis of

Splenectomy may be considered for

immunodeficiency (i.e., common variable

patients with chronic ITP with bleeding

immunodeficiency) is evident.

and/or limitation in activities negatively

Therapies utilized in the treatment of

impacting quality of life. Splenectomy is suc-

acute ITP may be utilized for chronic ITP,

cessful in 60% to 85% of patients; however,

though continued administration, cost, and

relapse of ITP may occur due to immune-

side effects frequently limit their use. Other

mediated platelet destruction in other organs,

considerations include additional medical

especially the liver. Patients should ideally

and surgical approaches.

receive appropriate immunization several

Rituximab is a chimeric human-mouse

weeks prior to surgery due to the risk of

monoclonal antibody directed against the

infection with encapsulated organisms

transmembrane CD20 antigen present on B

(pneumococcus, haemophilus influenza, or

cells, leading to apoptosis and antibody-

meningococcus). Lifelong penicillin prophy-

dependent cellular cytotoxicity. Children

laxis is recommended postsplenectomy.

with chronic ITP may have a 30% to 50%

Vinca alkaloids (vincristine and vinblas-

response rate with rituximab. The standard

tine), danazol (a virilizing androgen), and

dosage is

375 mg/m² IV weekly infusion

immunosuppressive agents such as azathio-

(over

4 to

6 hours) for

4 weeks. Most

prine and cyclophosphamide have also been

patients start to show a response by the

used with some success. Ascorbic acid, cyclo-

second week, though delayed responses sev-

sporine, and interferon a-2b are other agents

eral weeks later may occur. Responses may

that have also been investigated for use in

be short-lived or last for years. Acute tox-

chronic ITP. Long-term management of

icity is minimal though patients may expe-

chronic ITP includes periodic assessments

rience fever and chills (often abates with

for development of other manifestations of

subsequent infusions), serum sickness,

immunodeficiency or autoimmune disease,

headache, nausea, emesis, and mucocutane-

counseling regarding activities and medica-

ous reactions (continuum from hives and

tions, and periodic assessments of the platelet

dermatitis to rarely reported Stevens-John-

count to assess for continuation or resolution

son syndrome and toxic epidermal necro-

of the underlying process.

lysis). B-cell depletion lasts for approxi-

The thrombopoietin

(TPO) mimetics

mately

months with a significant

are currently under investigation for the

Thrombocytopenia

113

treatment of childhood chronic ITP, follow-

with an HPA-1a-positive fetus). HPA-1a

ing successful clinical trials in adults. As ITP

resides on the GP IIb/IIIa complex that is

is likely the result of impaired production in

responsible for fibrinogen receptor activity

addition to peripheral immune-mediated

and thus important in aggregation and

destruction, these drugs may have some role

platelet-plug formation. Therefore, devel-

in treatment to stimulate increased produc-

opment of anti-HPA-1a antibodies may

tion, even in patients with normal throm-

interfere with normal platelet aggregation

bopoietin levels. Drugs currently under

in addition to decreasing platelet number,

investigation are romiplostim

(Nplate

)

resulting in a qualitative platelet defect as

and eltrombopag (Promacta

). Concerning

well as in addition to a quantitative one.

toxicities include marrow reticulin fibrosis

This may in part explain the high incidence

and thromboembolism. It is likely that

of serious bleeding in these infants as com-

these drugs or subsequent generations will

pared with those born to mothers with ITP

provide potential new therapeutic options

with alloantibodies directed against alter-

in the future.

nate antigens. HPA-1a is common in the

Caucasian population in addition to HPA-

5b. HPA-4 incompatibility is more common

Neonatal alloimmune

in Asian populations.

thrombocytopenia

The infant with NAIT typically presents

with moderate-to-severe thrombocytopenia

Neonatal alloimmune thrombocytopenia

(<20

10⁹/L) and may rapidly

(NAIT) is caused by the transplacental pas-

develop petechiae, purpura, and bleeding.

sage of maternal alloantibodies directed

ICH is common, occurring in 10% to 20%

against fetal platelets, similar in pathophys-

of neonates and may occur prenatally or

iology to hemolytic disease of the newborn.

antenatally. Therefore, head ultrasound

Unlike hemolytic disease of the newborn,

should always be part of the initial diagnos-

NAIT often affects the first-born offspring.

tic workup. Complications of early central

Although rare, NAIT is the most common

nervous system hemorrhage include hydro-

cause of severe thrombocytopenia in the

cephalus, porencephaly, seizures, and fetal

first few days of life. Alloantibodies are

loss. Early jaundice occurs in 20% of cases

secondary to human leukocyte antigen

owing to resolution of intracranial or

incompatibility as fetal platelet antigens are

intraorgan hemorrhage. The infant should

inherited from the father. Immunization in

otherwise be generally healthy without other

the mother against fetal platelet antigens can

perinatal complications and the mother

occur during the current or a previous

should have an unremarkable hematologic

pregnancy or secondary to a previous plate-

history. For a mother with a previous low

let transfusion and may lead to severe

platelet count, the differential diagnosis

thrombocytopenia in the fetal-newborn

should include maternal idiopathic, auto-

period, with a high risk of fatal hemorrhage.

immune, and drug-dependent thrombocy-

Thrombocytopenia leading to fetal loss and

topenias, infection, and preeclampsia.

hemorrhage has been reported as early as 16

Infants may also be thrombocytopenic

to 24 weeks of gestation. Although several

secondary to birth asphyxia, infection,

platelet antigens have been implicated, the

congenital bone marrow hypoplasia, or

large majority of cases can be related to

from prematurity. The presence of hepatos-

human platelet antigen

(HPA-1a)

plenomegaly, intrauterine growth retarda-

incompatibility

(HPA-1a-negative mother

tion, and/or intracranial calcifications with

114

Chapter 12

thrombocytopenia should suggest a congen-

every 6 to 8 hours, with IVIG is frequently

ital viral infection. However, if a secondary

effective. Regular head ultrasounds should

diagnosis is not clearly delineated, it is

be done while the infant remains severely

important to exclude alloimmune throm-

thrombocytopenic (<50

10⁹/L). If intra-

bocytopenia by appropriate immunologic

cranial bleeding is present, platelets should

testing as future-affected pregnancies tend

be kept at

100

10⁹/L. Head MRI is nec-

to be more severe and require close ante-

essary to further define the hemorrhage.

natal monitoring.

Ultrasound should be repeated at 1 month

Early platelet alloantigen evaluation of

in children with ICH to identify early

the newborn and parents is important, both

hydrocephalus. Resolution of thrombocyto-

in offering the affected infant appropriate

penia typically occurs within 2 to 6 weeks.

treatment and in order to minimize the risk

Mothers with an affected infant should

of devastating complications with future

be counseled on the need for aggressive

pregnancies. Evaluation includes platelet

monitoring with future pregnancies due

typing on the mother and father, specifically

to the risk of increasingly severe NAIT. Fetal

looking for antigens responsible for alloim-

platelet counts should be obtained starting

munization such as HPA-1a. Serum from

around 20 weeks of gestation, with ultra-

the mother and infant is screened for anti-

sound monitoring for hemorrhage. Mater-

platelet antibodies against either the infant’s

nal antiplatelet titers cannot be used to

or the father’s platelets. We send blood for

accurately predict affected fetuses. IVIG

the NAIT workup to the Blood Center of

1 g/kg/week given to the mother from

Wisconsin

mid-gestation until near term has been

Several treatment options are available

shown to effectively increase fetal platelet

for the infant with neonatal alloimmuniza-

counts in the majority of cases. Delivery

tion. Transfusion with antigen-negative pla-

should be planned near term with an elec-

telets has been the mainstay of treatment,

tive cesarean section or planned induced

when available. Since HPA-1a-negative pla-

vaginal delivery after documented increase

telets are present in only 2% of the Cauca-

in fetal platelet count following administra-

sian population, the most available source

tion of maternal IVIG. Antigen-negative

of platelets is from the mother. Random

platelets, which can be obtained from the

platelet transfusions (10 to 20 mL/kg) may

mother by apheresis, should be obtained

provide a transient increase, lasting 1 to 2

and prepared prior to delivery in the event

days, and should be used in cases of serious

of extreme thrombocytopenia or hemor-

hemorrhage, while antigen-negative plate-

rhage. The infant’s platelet count should

lets are being obtained and prepared. If

be checked at birth and every 6 to 12 hours

random donor platelets are ineffective, then

for 1 to 2 days and be kept

10⁹/L.

cross-matched donor platelets or washed

Frequency of monitoring can be decreased

maternal platelets may be used if available.

depending on the stability of the platelet

An excellent alternative treatment is IVIG.

count and the clinical status of the infant.

The recommended dose is 1 g/kg/24 hours

for 1 to 2 doses (until the platelet count is

10⁹/L). Platelet transfusion may still

Neonatal autoimmune

be necessary with IVIG if immediate cor-

thrombocytopenia

rection of the thrombocytopenia is needed.

Corticosteroids can be effective in reducing

Neonatal autoimmune thrombocytopenia

platelet destruction and increasing vascular

occurs due to the passive transfer of auto-

integrity. Methylprednisolone, 1 mg/kg IV

antibodies from mothers with ITP and may

Thrombocytopenia

115

be idiopathic, caused by other disorders

illness, organomegaly and sequestration,

including autoimmune diseases such as sys-

development of alloimmunization, sepsis,

temic lupus erythematosis, hypothyroidism,

and other medications. Other potential

and lymphoproliferative states, or second-

offending drugs include anticonvulsants

ary to medications. Unlike NAIT, these

such as valproic acid, chlorothiazides, estro-

antibodies recognize both maternal and

genic hormones, ethanol, ristocetin, and

fetal platelet antigens. Maternal ITP should

protamine sulfate.

be distinguished from gestational thrombo-

Heparin-induced thrombocytopenia

cytopenia that tends to occur late in preg-

(HIT) is caused by antibody formation to

nancy and leads to mild thrombocytopenia

complexes of heparin and platelet factor 4

in the mother

(e.g.,

100

10⁹/L)

leading to platelet activation, often resulting

without the development of antibodies.

in severely low counts as well as risk for

Therefore, the infant is not at risk for

thrombosis. It is much less common in

thrombocytopenia. Maternal platelet counts

children than adults. HIT should be sus-

return to normal shortly after birth. The

pected in the child receiving heparin (usu-

degree of thrombocytopenia seen in neo-

ally secondary to unfractionated but can

nates born to mothers with ITP is less severe

also occur with low molecular weight) who

than with NAIT, with only 10% to 15%

develops unexplained thrombocytopenia of

having platelet counts <50

10⁹/L. Bleed-

any degree within 5 to 10 days of exposure,

ing is minimal and ICH is rare (<1% to

often defined as a decrease of

50% from

2%). The platelet count may be normal at

baseline (even if still in the normal range).

birth but falls within 1 to 3 days of delivery.

Testing for heparin-induced antibodies is

Platelet counts should be monitored closely

not very specific as many patients without

and a head ultrasound obtained to exclude

HIT will have circulating antibody. If sus-

ICH. Treatment should be initiated if the

pected, based on clinical scoring that defines

platelet count falls below 30 to 50

10⁹/L

likelihood, functional studies of platelet

with the same treatment regimen as for

activation under the presence of heparin

NAIT: IVIG, IV methylprednisolone, and

can be done by specialized laboratories.

random donor platelet transfusion if neces-

These tests include the serotonin release

sary for hemorrhage. The duration of

assay and heparin-induced platelet aggrega-

thrombocytopenia is usually 3 to 6 weeks.

tion assay. Heparin should be discontinued

and replaced by an anticoagulant that does

not lead to antibody formation such as

Drug-induced thrombocytopenia

argatroban. Warfarin should not be utilized

immediately due to associated protein C

In addition to immune-mediated mechan-

deficiency with risk of microthrombosis

isms induced by drugs, many bone marrow

leading to skin necrosis and gangrene.

suppressive agents such as chemotherapy

cause thrombocytopenia, though usually

in the face of pancytopenia. Management

Nonimmune thrombocytopenia

is usually with platelet transfusion, to pre-

vent or treat bleeding. The bone marrow

Many nonimmune-mediated processes lead

effects of these agents often define their

to increased platelet consumption. Gener-

dose-limiting toxicity, and thrombocytope-

alized platelet activation with trapping of

nia is a common effect. Patients usually

microaggregates in the small vasculature

respond well to platelet transfusion but can

contributes to microangiopathic hemolytic

become refractory because of the underlying

anemia (MAHA) occurring in congenital

116

Chapter 12

heart disease, hemolytic uremic syndrome

in the microvasculature that can also be seen

(HUS), and thrombotic thrombocytopenic

in the lymph nodes and spleen. Classic signs

purpura (TTP). HUS is primarily associ-

and symptoms include fever, malaise,

ated with a prothombotic state induced by

nausea and vomiting, abdominal and chest

exposure to shiga-toxin producing Escher-

pain, arthralgia and myalgia, pallor, jaun-

ichia coli

(usually O157:H7), particularly

dice, purpura, progressive renal failure, and

affecting the renal vasculature and leading

fluctuating neurologic signs and symptoms.

to the triad of MAHA, platelet consump-

Laboratory features include thrombocyto-

tion, and renal failure. HUS is the most

penia and MAHA. The peripheral blood

common cause of acute renal failure in

smear will show polychromasia, basophilic

children. Patients may present with abdom-

stippling, schistocytes, microspherocytes,

inal pain and bloody diarrhea and are trea-

and nucleated red cells. The DAT (Coombs)

ted with supportive care (i.e., red cell trans-

should be negative as TTP is not an auto-

fusions, dialysis as necessary). Platelet trans-

immune hemolytic anemia. The LDH and

fusion may worsen the clinical status and

unconjugated bilirubin will be elevated and

should be used with caution.

haptoglobin reduced due to the MAHA,

Idiopathic TTP is a rare disease in chil-

with associated hemoglobinuria. Without

dren, characterized by the pentad of throm-

treatment, mortality is >90%. Plasmaphe-

bocytopenia, hemolytic anemia, renal

resis is the mainstay of therapy in the

impairment, neurologic symptoms, and

acquired form. Fresh frozen plasma is usu-

fever, although few patients present with

ally sufficient to treat the congenital form.

the full gamut of symptoms. Idiopathic TTP

Patients may also benefit from rituximab

is often clinically indistinguishable from

and other immunosuppressive drugs

diarrhea-negative HUS. There is also a rare

including steroids, cyclosporine, cyclophos-

congenital form in which affected neonates

phamide, vincristine, and azathioprine.

present with jaundice and thrombocytope-

Increased utilization of platelets may

nia, although patients may not have an

occur in active bleeding, infection, or sepsis.

episode of overt TTP for years until triggered

In disseminated intravascular coagulation

by infection, pregnancy, or stress. Patients

(DIC), there is an imbalance between intra-

with congenital TTP have low levels of

vascular thrombosis and fibrinolysis, with

ADAMTS13, a protein that cleaves unusually

increased platelet consumption, depletion

large multimers of von Willebrand factor

of plasma clotting factors, and formation

into a biologically less-active form. Absence

of fibrin. DIC can be initiated by many

of ADAMTS13 inhibits cleavage of these

events, including sepsis due to bacteria,

large multimers allowing spontaneous plate-

viruses, or fungi; malignancy, particularly

let adhesion and aggregation.

acute promyelocytic leukemia and neuro-

Patients with acquired TTP, which is

blastoma; hemolytic transfusion reactions;

often idiopathic, commonly demonstrate

and trauma. Therapy is aimed at treating

antibodies to the protein, unlike the con-

the underlying etiologic process. Supportive

genital form in which there is a constitutive

care consists of platelet transfusion to

deficiency. Affected individuals are more

maintain platelet counts >50

10⁹/L and

commonly female, of African descent, and

plasma protein replenishment to correct

diagnosis can be associated with pregnancy,

coagulopathies and maintain fibrinogen

autoimmune disease, infection, or trans-

>100 mg/dL.

plantation. The hallmark of disease is the

Thrombocytopenia can occur in the sick

presence of segmental hyalin microthrombi

newborn for many reasons, most

Thrombocytopenia

117

commonly with infection, prematurity,

Interferon a-2a has been shown to be ben-

asphyxia, respiratory distress syndrome,

eficial in correcting the platelet count and

pulmonary hypertension, or meconium

shrinking the lesion. Recent fortuitous dis-

aspiration. These infants appear to have

covery of propanolol as a treatment for

normal to increased platelet production, but

hemangiomas has now made it first-line

a decreased platelet life span for reasons that

therapy; although not clearly delineated, the

are unclear. Thrombocytopenia is a fre-

mechanism of action is likely related to the

quent occurrence in congenital cyanotic

inhibition of angiogenesis. Supportive

heart disease associated with compensatory

transfusion therapy is indicated with active

polycythemia. Therapeutic phlebotomy

bleeding due to thrombocytopenia. Platelet

may lessen the thrombocytopenia.

transfusion as well as infusion of coagula-

The association of thrombocytopenia

tion factors (fresh frozen plasma, cryopre-

and giant hemangiomas occurs in the

cipitate, and antifibrinolytic drugs) may be

infant with Kasabach-Merritt syndrome

helpful but usually are of only transitory

and represents a form of localized intravas-

benefit. Antiplatelet medications

(aspirin

cular coagulation. The hemangiomas may

and dipyridamole) have been used in the

be multiple and may involve only viscera.

past to interfere with platelet trapping

Therefore, in an infant with unexplained

within the hemangioma but carry the risk

thrombocytopenia, imaging studies should

of causing platelet dysfunction in addition

be done to look for a vascular anomaly.

to the existing thrombocytopenia.

Hemangiomas are proliferative lesions that

A variety of conditions that result in

grow rapidly for several months and then

splenomegaly are associated with throm-

regress spontaneously. Platelet thrombi may

bocytopenia. The large spleen sequesters

develop in these lesions and platelet life span

and destroys circulating platelets. Anemia,

may be decreased. These infants may also

leukopenia, and neutropenia may also be

have a consumptive coagulopathy with low

present. Megakaryocytic production in the

fibrinogen levels and elevated concentra-

marrow is normal, and may be accelerated

tions of fibrin degradation products. The

in response to a decrease in the circulation.

lesions are also prone to necrosis and infec-

Storage diseases, early portal hyperten-

tion. A particular hemangioma’s size or

sion, hemolytic conditions (red cell mem-

location cannot predict whether it will lead

brane defects), infections such as with

to platelet trapping and thrombocytopenia.

HIV, EBV, and CMV, and malignancies

These infants should be managed by close

are frequently associated with splenomeg-

observation and hematologic monitoring

aly and may result in hypersplenism

while waiting for regression to occur. How-

(increased splenic activity and resultant

ever, the lesions may become large enough

red cell destruction).

to compromise the infant by impinging on

the airway or vital organs, leading to com-

partment syndrome, and resulting in serious

Decreased platelet production

illness or death. External compression of

hemangiomas by firm bandaging, when

Thrombocytopenia due to decreased produc-

possible due to location, may reduce blood

tion may be a result of an acquired or inher-

flow and platelet trapping. Corticosteroid

ited disease process. Decreased production

treatment at a dose of 1 to 2 mg/kg/day may

may be a direct effect of marrow crowding

bring about regression of the lesion and

due to malignancy (leukemia or metastatic

normalization of the platelet count.

solid

tumors such as lymphoma,

118

Chapter 12

neuroblastoma, medulloblastoma, and

difficult to appreciate small platelets in the

rhabdomyosarcoma) or storage diseases

newborn and the mean platelet volume

(Gaucher, Neimann-Pick, etc.). Drugs may

reported on the CBC is unreliable in the

be implicated in decreased production. The

face of thrombocytopenia.

liver is the site of TPO production and liver

Patients with inherited thrombocytope-

disease is associated with chronic severe

nia may have normally sized platelets in

thrombocytopenia. Severe iron deficiency

certain conditions including congenital ame-

can result in decreased production, though

gakaryocytic thrombocytopenia

(CAMT),

early iron deficiency states are associated with

thrombocytopenia with absent radii (TAR),

an elevated platelet count likely due to mar-

familial platelet disorder and predisposition

row stress. Diseases affecting the marrow

to AML (acute myelogenous leukemia), ame-

matrix (aplastic anemia and myelofibrosis)

gakaryocytic thrombocytopenia with radio-

cannot support stem cell growth and matu-

ulnar synostosis (ATRUS), and autosomal

ration with resultant thrombocytopenia.

dominant thrombocytopenia. CAMT, a rare

Thrombocytopenia related to an inher-

cause of neonatal thrombocytopenia, is a

ited condition is frequently distinguished

bone marrow failure syndrome inherited in

by characteristic clinical features, early

an autosomal recessive manner due to defi-

presentation and chronic course, family

ciency in the TPO receptor c-mpl. Bleeding

history, platelet morphology, and lack of

symptoms lead to diagnosis in infancy

response to classic treatments for ITP. A

although CAMT is often initially confused

number of these conditions are associated

with other more common neonatal causes of

with macrothrombocytes and mild-to-

thrombocytopenia such as alloimmune- and

moderate thrombocytopenia including

autoimmune-mediated processes. However,

Bernard-Soulier syndrome, MYH9-related

unlike these other conditions, the thrombo-

disorders

(May-Hegglin anomaly with

cytopenia does not resolve with time. There

bluish cytoplasmic inclusions including

are no classic physical features. Diagnosis is

Sebastian, Fechtner, Epstein, and Alport-

based on markedly reduced megakaryocytic

like syndromes), platelet-type von Willeb-

precursors in the bone marrow with normal

rand disease, gray platelet syndrome (stor-

erythroid and myeloid lineages with elevated

age pool disease), benign Mediterranean

TPO levels. Current treatment is supportive

macrothrombocytopenia, Paris-Trousseau

care, platelet transfusion as needed, and con-

type thrombocytopenia, and more poorly

sideration for curative hematopoietic stem

defined syndromes such as Montreal plate-

cell transplantation. Gene therapy is being

let syndrome. Microthrombocytes are seen

developed.

in Wiskott-Aldrich syndrome, an X-linked

Children with ATRUS present similarly

disorder resulting from a mutation on the

to CAMT with severe thrombocytopenia at

WAS gene. Wiskott-Aldrich syndrome is

birth, but with the addition of associated

characterized by thrombocytopenia, recur-

skeletal anomalies and sensorineural hear-

rent bacterial and viral infections secondary

ing loss. Skeletal abnormalities are fusion of

to T-cell dysfunction, chronic eczema, and a

the radius and ulna at the elbow, often

propensity to develop autoimmune disor-

associated with minor clinodactyly. The

ders. Patients with defects in the WAS gene

disease may progress to aplastic anemia

may also have a milder syndrome called

or leukemia. TAR syndrome is also thought

X-linked thrombocytopenia with small

to be secondary to a defective response to

platelets and immune dysregulation which

TPO with variable thrombocytopenia and

may develop over time. Of note, it is

normal erythroid and myeloid lineages.

Thrombocytopenia

119

Mostcasesarediagnosedatbirthorinutero

3. What findings do you look for on exam-

due to bilateral absence of the radii man-

ination to either confirm or dispute your

ifested as a shortening of the forearms

suspected diagnosis?

and flexion at the elbows. The thumbs are

present, which distinguish TAR from the

Obviously, the first concern is to try to stop

skeletal anomaly associated with Fanconi

the bleeding and treat him for acute, symp-

anemia. Patients may have additional plate-

tomatic hemorrhage. You suspect a bleeding

let dysfunction and are at risk for significant

disorder and see this is an otherwise healthy

bleeding episodes. Typically, the thrombocy-

child with no known inherited bleeding

topenia improves through childhood. Asso-

diathesis. Although ITP presents with acute

ciated clinical features include additional

massive bleeding in fewer than 5% of cases,

skeletal limb defects, renal and cardiac anom-

you are appropriately concerned that he has

alies, facial capillary hemangiomas, and cow’s

mucosal type bleeding associated with either

milk intolerance. Fanconi anemia is an in-

an acquired or inherited platelet problem,

herited disorder characterized by chromo-

which may be qualitative or quantitative.

somal instability with skeletal anomalies

You order a STAT CBC to determine both

and hypoproductive thrombocytopenia,

platelet and hemoglobin levels and initiate

although other cell lines are eventually

fluid resuscitation awaiting the results.

affected. These patients have an increased

Additional historical points to elicit

susceptibility to develop leukemia and may

include recent illness, medication exposure,

benefit from early hematopoietic stem cell

underlying disease, and prior symptoms.

transplantation if a suitable donor is available.

You are contemplating other diagnoses such

as von Willebrand disease and acute leuke-

mia and ask questions related to these pos-

sibilities. In this case, the mother states that

Case study for review

he has been healthy, with no prior medica-

tions, illnesses, hospitalizations, or other

A 9-year-old previously well Hispanic boy

comorbidities. There is no family history

presents to the emergency department

of a diagnosed bleeding disorder (though

with a 2-hour history of profuse epistaxis.

you make a mental note to pursue these

On presentation he is noted to be well-

questions later as family members may not

developed and well-nourished, frightened,

have been evaluated for symptoms sugges-

fatigued, and pale, with numerous ecchy-

tive of von Willebrand disease). The mother

moses and blood pouring from both

states that he on awakening this morning

nares. He is emergently triaged and has

had unexplained bruises over his torso and

bilateral nasal packing placed. He con-

extremities and blood blisters in his mouth.

tinues to have massive bleeding and has

He complained of feeling sick to his stom-

repeated emesis of digested and bright red

ach and began to have simultaneous emesis

blood. His vitals are T 37.2 C, HR 156, RR

and nose bleeding, which led to her calling

30, and BP 62/38.

an ambulance as she could not stop it.

1. What are your immediate thoughts

On examination, you note he is alert and

regarding possible diagnosis? How do you

oriented, though frightened to see so much

confirm this and what steps do you take in

blood and expresses to you he thinks he is

treatment and stabilization of your patient?

going to die. You provide reassurance and

2. What pertinent history should you

quickly note his oral and skin findings of

obtain?

diffuse petechiae and purpura. Purpuric

120

Chapter 12

lesions on the torso are very unusual and

(1 pheresed unit every 2 to 3 hours), FFP

frequently not associated with trauma, reflect-

infusion, further doses of methylpredniso-

ing more spontaneous bleeding. He has no

lone, and a second dose of IVIG. On day 3,

adenopathy, organomegaly, other skin rashes,

the hemoglobin drops to 4.6 g/dL and the

and no pain on palpation of the extremities

decision is made to perform an emergent

and abdomen with full range of motion of all

splenectomy. The family is counseled that he

joints, and in general appears well developed

may not survive this procedure. Fortunately,

and appropriate for age. All these findings are

however, he does very well and is supported

supportive of a diagnosis of ITP.

with transfusions without a worsened clinical

Your patient’s CBC comes back with a

course. Unfortunately, there is no immediate

platelet count of 2

10⁹/L, hemoglobin 6.2 g/

response to splenectomy. Typically, in

dL, and white blood cell count of 7.4

10⁹/L

patients that do respond there is an imme-

with a normal differential. You explain the

diate increase in postoperative platelet count,

anemia as secondary to massive epistaxis.

often to above normal levels due to an exag-

Your patient now has evidence of gross

gerated marrow response that persists after

hematuria and melena, with a further drop

the source of peripheral destruction or

in blood pressure despite having received a

sequestration has been removed. Splenec-

unit of packed red blood cells and volume

tomy is not successful in

30% of cases and

support. The complete metabolic panel and

it cannot be predicted who will respond. Our

coagulation studies are normal.

patient continues to receive massive blood

product support for one week, then starts to

4. What is your next thought for treatment?

stabilize with an increase in hemoglobin to

5. How do you counsel the family?

8 g/dL and platelet count of 54

10⁹/L. He

continues on a course of steroids, eventually

As you are now certain that this is acute ITP

transitioning to oral prednisone, and taper-

and your patient is experiencing life-threat-

ing off by 6 weeks. By this time his platelet

ening hemorrhage, you initiate therapy

count normalizes, and several years later he

with IVIG 1 g/kg IV over 4 hours, methyl-

continues to have a normal platelet count.

prednisolone 1 mg/kg IV every 8 hours,

Of interest, the patient re-presents with

continuous infusion of packed red blood

moderate epistaxis, no anemia, and a nor-

cells, and fluid support with Lactated

mal platelet count 1 year later. Further diag-

Ringer’s or normal saline. Consideration

nostic workup reveals a diagnosis of type 1

should also be given to continuous infusion

von Willebrand disease.

of platelets. Consultation with an ENT

surgeon should be obtained for nasal pack-

6. How would the knowledge of this

ing and control of the bleeding in the

comorbidity have influenced your manage-

posterior pharynx.

ment of the patient with the initial presen-

The prognosis of ITP, even in the face of

tation of ITP and massive epistaxis?

such a dramatic presentation, is excellent.

However, this situation is tenuous due to

Knowledge of this disease may have led

lack of therapies that could cause an imme-

to the use of additional therapies such

diate rise in the platelet count. At this time,

as DDAVP to stimulate release of von

his prognosis is guarded.

Willebrand factor, and Humate-P, a

Your patient is hospitalized in the PICU

Factor VIII concentrate that also contains

and continues to received red cell trans-

von Willebrand factor and is used for von

fusions, continuous platelet transfusion

Willebrand factor replacement. It is

Thrombocytopenia

121

unknown whether such additional therapies

Israels SJ. Diagnostic evaluation of platelet func-

may have impacted the clinical course.

tion disorders in neonates and children: an

update. Semin Thromb Hemost 35:181-188,

2009.

Neunert CE, Buchanan GR, Imbach P, et al.

Suggested Reading

Severe hemorrhage in children with newly

diagnosed immune thrombocytopenic pur-

Buchanan GR. Bleeding signs in children with

pura. Blood 112:4003-4008, 2008.

idiopathic thrombocytopenic purpura. J

Neunert C, Lim W, Crowther M, et al. The

Pediatr Hematol Oncol 25:S42-S46, 2003.

American Society of Hematology 2011 evi-

Bussel JB, Sola-Visner M. Current approaches to

dence-based practice guidelines for immune

the evaluation and management of the fetus

thrombocytopenia. Blood

117:4190-4207,

and neonate with immune thrombocytope-

2011.

nia. Semin Perinatol 301:35-42, 2009.

Segel GB, Feig SA. Controversies in the diagnosis

Cines DB, Bussel JB, Liebman HA, Luning Prak

and management of childhood acute immune

ET. The ITP syndrome: pathogenic and clin-

thrombocytopenic purpura. Pediatr Blood

ical diversity. Blood 113:6511-6521, 2009.

Cancer 53:318-324, 2009.

Evaluation of the Child

with a Suspected

Malignancy

Each year approximately 15,000 children

The history is the first step in the diag-

and adolescents under 20 years of age are

nostic process, with the chief complaint

diagnosed with cancer in the United States.

providing the most important clue. Most

The likelihood of a young adult having a

of the symptoms of childhood cancer are

history of childhood cancer is approxi-

either due to a mass and its effect on the

mately 1 in 300. Although cancer remains

surrounding tissues, invasion of the mar-

the leading cause of death in children except

row, or secretion of a substance by the

for accidents, survival continues to steadily

tumor that disturbs normal function. A

increase. In adolescents, cancer deaths are

careful family history should be elicited and

less common than those caused by acci-

include familial cancers. Certain conditions

dents, homicide, and suicide. More than

can predispose to malignancy such as

80% of children diagnosed with cancer are

genetic diseases

(e.g., Down syndrome,

now expected to be cured of their disease.

Beckwith-Wiedemann syndrome, neurofi-

That being said, cancer remains a devastat-

bromatosis), prior history of a malignancy,

ing diagnosis. The initial approach to the

or radiation therapy. Environmental and

child and family must be with a heightened

genetic factors have been associated with

sensitivity to the emotional impact. Once a

the development of malignancy; genetic

diagnosis of cancer is suspected, an imme-

factors are known to play a significant role

diate and thorough evaluation should

in the development of pediatric cancer,

proceed.

whereas environmental factors are postu-

Initial symptoms of cancer may be some-

lated to play a role in the increasing inci-

what elusive, given the subtle and overlap-

dence of certain cancers.

ping symptoms and signs that may be pres-

Timely diagnosis is critical though can be

ent in both malignant and nonmalignant

difficult due to the nonspecific symptoms

disease. Many pediatricians and clinicians

and rarity of the diseases. Though highly

may only see a new case of childhood cancer

curable in many circumstances, earlier diag-

every 5 to 7 years, and each case may be so

nosis may play a factor in improved prog-

unique as to not allow for the increased

nosis. Consideration should be given to the

awareness of this possibility.

nature of the complaint by the child and

Handbook of Pediatric Hematology and Oncology: Children’s Hospital & Research Center Oakland,

Second Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.

2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

Evaluation of the Child with a Suspected Malignancy

123

Table 13.1 Presenting signs and symptoms of some common pediatric cancers and their

differential diagnoses.

Presenting signs or

Common diagnoses

Potential malignancy

symptoms

(nonmalignant conditions)

Headache, morning

Migraine, sinusitis

Brain tumor

vomiting

Lymphadenopathy

Infection

Lymphoma, leukemia

Bone pain/limping

Infection, trauma, growing pains

Bone tumor, leukemia,

neuroblastoma

Abdominal mass

Constipation, kidney cyst, full

Wilms tumor, neuroblastoma

bladder

Extremity mass

Cyst, infection, trauma

Bone tumor, soft tissue sarcoma

Mediastinal mass

Infection, cyst

Lymphoma, leukemia

Pancytopenia

Infection

Leukemia

Bleeding

Coagulation disorders, platelet

Leukemia (APL), neuroblastoma

disorders, ITP

Back pain

Trauma

Leukemia, lymphoma, CNS

tumor, extension of abdomi-

nal tumor into spinal cord

Chronic ear drainage

Otitis media/externa

Langerhans cell histiocytosis

Feminizing/masculinizing

Precocious puberty

Adrenocortical carcinoma, brain

symptoms

tumor, germ cell tumor

Abbreviations: APL, acute promyelocytic leukemia (AML M3); ITP, immune

thrombocytopenic purpura; CNS, central nervous system.

family, potential explanations for the com-

changes in the quality, frequency, and pat-

plaint (or lack thereof), persistence of symp-

tern of the headaches. Associated neurologic

toms, and lack of response to common

symptoms or signs should warrant an emer-

interventions (see Table 13.1).

gent evaluation for a tumor in the central

Headache is one of the most common

nervous system. These include, but are not

complaints in the pediatric population, the

limited to, localizing symptoms such as

majority of which are attributable to non-

focal weakness, cranial nerve palsies, ataxia,

malignant conditions. Although few head-

failure to thrive, and developmental delays

aches are caused by intracranial masses,

or regression. A thorough neurologic

primary brain tumors or metastases must

examination, including evaluation for

be ruled out when dealing with a patient

papilledema, should precede radiographic

with repeated or persistent headaches.

imaging. Other important historical points

Headaches are often the first symptom of

include an assessment of changes in visual

a brain tumor and, dependent on location,

acuity, behavior, and academic perfor-

are frequently accompanied by more subtle

mance. MRI is recommended to evaluate

findings on neurologic examination. His-

for the presence of an intracranial mass in

tory should include questions to character-

children with symptoms suggestive of a

ize the headache including worrisome signs

brain tumor. CT may be appropriate as

such as recurrent morning headache, head-

an initial test in certain settings depending

ache that awakens the child, intense inca-

on the availability of MRI. CT is a good,

pacitating headache, associated vomiting, or

rapid tool for the assessment of acute

124

Chapter 13

Table 13.2 Conditions suggesting need for

concerning for malignancy as is a unilateral

brain imaging in children with headache.

location. Nodes that are hard, nonmobile,

and nontender are worrisome for malig-

Presence or onset of neurologic abnormality

nancy. Nodes associated with fluctuance,

Ocular findings such as papilledema,

tenderness, warmth, or overlying erythema

decreased visual acuity, or loss of vision

are more consistent with infection. How-

Vomiting that is persistent, increasing in

frequency, or preceded by recurrent

ever, these are only generalizations as rap-

headaches

idly growing malignant nodes may be ten-

Change in character of headache such as

der and infectious nodes may be quite firm

increased severity and frequency

and nonmobile.

Recurrent morning headaches or headaches

Important historical points to elicit

that repeatedly awaken child from sleep

include:

Short stature or deceleration of linear growth

* Duration of lymphadenopathy or local-

Precocious puberty

ized mass

Diabetes insipidus

* Presence of a recent infectious illness

Age 3 years or less

* Skin lesions, cuts, or abrasions (and rela-

Neurofibromatosis

History of acute lymphoblastic leukemia with

tionship to nodal drainage patterns)

irradiation of central nervous system

* Recent immunizations

* Medications

* Animal contact (e.g., cat scratch, rodent

hemorrhage or increased intracranial pres-

bite, tick bite)

sure (see Table 13.2).

* Recent transfusion

Lymphadenopathy is a common finding

* Travel

on examination in children. Enlarged lymph

* Possible sexually transmitted infection

nodes are a frequent presenting sign in

* Presence of symptoms such as arthralgias,

association with malignancies or infection,

weight loss, and night sweats

and differentiation requires a meticulous

and systematic approach. Lymph nodes

The differential diagnosis of lymphadenop-

become large in response to infection or

athy includes infectious etiologies (viral, bac-

infiltration. Generally, a lymph node is con-

terial, spirochetal, and protozoan), connec-

sidered enlarged if it measures greater than

tive tissue disease, hypersensitivity states,

10 mm, although inguinal nodes may be

lymphoproliferative disorders, immunodefi-

15 mm or greater before being considered

ciency states, storage diseases, and malig-

worrisome and epitrochlear nodes are con-

nancy. In infants, the differential diagnosis

cerning once greater than 5 mm. In addition

of head and neck lumps includes lymphade-

to size, other factors to consider in establish-

nopathy and congenital malformations such

ing a differential between infection and

as cystic hygroma, thyroglossal duct cyst,

malignancy include persistence or rate of

branchial cleft cyst, epidermoid cyst, and

growth, quality of the node, location and

neonatal torticollis. Localized adenopathy

distribution

(e.g., adenopathy that is

may be infectious in origin including bacte-

symmetric, localized, regional, or dissemi-

rial causes such as Staphylococcus aureus,

nated), and presence of other signs or symp-

beta-hemolytic strep, cat-scratch disease

toms of infection. Adenopathy in the supra-

(Bartonella henselae), and tuberculous and

clavicular, axillary, or epitrochlear areas is

nontuberculous mycobacteria, in addition to

considered an abnormal finding. Adenopa-

nonbacterial causes such as HIV, EBV, cyto-

thy that persists longer than

6 weeks is

megalovirus (CMV), and toxoplasmosis.

Evaluation of the Child with a Suspected Malignancy

125

The physical examination of the child

as indicated by history and examination. A

with lymphadenopathy includes an assess-

biopsy should be done on enlarging or

ment of the size, location, and quality of the

persistently large nodes or if adenopathy

node(s). A full examination should include

is also seen on chest radiography. It is

assessment of the skin and mucocutaneous

recommended that excisional biopsies

tissues draining to the particular node in

(i.e., removal of intact node) be performed

question, and evidence of other signs related

when malignancy is suspected to evaluate

to an underlying disease process such as

the architecture of the node in addition to

hepatomegaly and splenomegaly. Nodes

the cellular infiltrate. The largest node

should be measured in largest diameter, the

should be biopsied when possible, with

quality should be assessed as to mobility,

avoidance of the upper cervical and ingui-

firmness, tenderness, and overlying skin

nal areas. Studies to be performed on the

changes, and these findings should be docu-

tissue include Gram stain and culture (bac-

mented. Children with mildly enlarged

terial, mycobacterial, viral, and/or fungal);

nodes should be monitored with frequent

histology and immunohistochemistry

examinations, and when not associated with

for suspected malignancy; and if malig-

malignancy, most of these nodes will revert

nancy is confirmed, flow cytometry and

to normal size.

specific cytogenetic testing for further

If infection is considered the cause of

classification.

the adenopathy, as in localized cervical

Splenomegaly is the finding of a palpa-

adenitis, it is reasonable to treat the patient

ble spleen edge on examination. A 1 to 2 cm

with a 2 week course of antibiotics. Depen-

splenic tip is found in 30% of full-term

dent on the history, physical, and clinical

neonates and in as many as 10% of healthy

suspicion, a particular antibiotic regimen

children. Approximately

3% of healthy

can be chosen in addition to sending serol-

college students have palpable spleens.

ogy or further testing for likely organisms.

Therefore, this finding on a routine physical

A baseline complete blood count (CBC)

examination of an otherwise healthy child

with differential and peripheral blood

should not create great concern. Children

smear should be done if there is any con-

with other signs of systemic disease,

cern for a diagnosis other than infection.

however, should have their splenomegaly

The patient should be seen again following

evaluated.

completion of the antibiotics and if the

Splenomegaly is associated with many

node has not changed or has increased in

disease states, both congenital and acquired:

size, consideration should then be given to

* Hemolytic anemia: hereditary spherocy-

biopsy. Many cases of infection-related

tosis, thalassemia, splenic sequestration in

adenopathy resolve spontaneously in 2 to

sickle cell disease, and autoimmunity

6 weeks or as a result of antibiotic treat-

* Immunological disease: common variable

ment (see Figure 13.1).

immune deficiency, connective tissue dis-

For the large node (i.e., >2.5 cm in size)

orders, and autoimmune lymphoprolifera-

or in the patient without response to anti-

tive disease

biotics, further evaluation is required.

* Infection: viral (EBV, CMV, HIV, hepa-

Additional studies should include a PPD

titis), bacterial (tularemia, abscesses, tuber-

(or quantiferon gold), chest radiograph,

culosis, infective endocarditis), spirochetal,

CBC with differential (if not already done),

protozoan, and fungal

chemistries including lactate dehydroge-

* Storage disease: Gaucher, Neimann-Pick,

nase (LDH) and uric acid, and serologies

and mucopolysaccharidoses

126

Chapter 13

Initial evaluation

Physical examination

Size, location, character of nodes

Presence of organomegaly

Other signs/symptoms concerning for malignancy

Evaluation for source of infection

History

Duration

Concurrent symptoms, recent skin abrasions/lesions

Animal contact

Travel

Laboratory evaluation

CBC, differential, peripheral blood smear assessment

ESR or CRP

LDH, uric acid for suspected malignancy

CMV, EBV, and other titers as indicated (HIV, B. henselae, toxoplasmosis, etc.)

Place PPD or send quantiferon gold

Consider CXR for large, unexplained nodes

Cytopenias

Hilar adenopathy

Suspicious cells on smear

Consider Hodgkin lymphoma, tuberculosis

Lymph node excisional biopsy

Imaging with CT chest/abdomen/pelvis

Uncertain diagnosis

Nodes in suspicious locations

Bone marrow aspirate

(axillary, supraclavicular, epitrochlear) or

Duration 6 weeks or longer or

Infection confirmed or likely

Growing in size or

Node ≥ 2.5 cm or

Node < 2.5 cm

Empiric antibiotic therapy

Hard, nonmobile or

No infectious signs/symptoms

Consider other titers (STI,

non-tuberculous mycobacterium,

histoplasmosis, etc.) as necessary

No diagnosis

Excisional node biopsy

No resolution with antibiotics, within 2-6 weeks

Figure 13.1 Evaluation of the child with adenopathy. (Abbreviations: CBC, complete blood count;

ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; LDH, lactate dehydrogenase; CMV,

cytomegalovirus; EBV, Epstein-Barr virus; CXR, chest X-ray; CT, computed tomography; STI, sexually

transmitted infection).

Malignancy: leukemias as well as Hodgkin

bleeding or bruising (malignancy), travel

and non-Hodgkin lymphoma

to endemic areas (malaria), trauma (splenic

hematoma), and family history (hemoglo-

A detailed history should be obtained to

binopathies, thalassemia, and hereditary

gain clues as to the etiology of the enlarged

spherocytosis with prior splenectomy or

spleen. The patient should be questioned

cholescystectomy). The physical examina-

regarding current or recent infectious symp-

tion should include a measurement of the

toms, fevers or rigors

(e.g., in subacute

spleen size (centimeters below the midcostal

bacterial endocarditis, infectious mononu-

margin), consistency, and presence of ten-

cleosis, and malaria), jaundice (with hemo-

derness (which suggests rapid increase in

lytic anemia or liver disease), abnormal

size) in addition to the presence of

Evaluation of the Child with a Suspected Malignancy

127

adenopathy or hepatomegaly. The vitals

* Connective tissue disease: ESR, comple-

should be reviewed for evidence of fever

ment (C3, C4, CH50), antinuclear antibody,

or hypotension and the skin assessed for

and rheumatoid factor

cutaneous bleeding. Other considerations

* Infiltrative diseases: bone marrow aspirate

include evaluation for stigmata of specific

and biopsy

(looking for blasts, storage

disease states including jaundice, cardiac

cells) and enzyme study for Gaucher

murmurs, arthritis, as well as specific find-

(glucocerebrosidase)

ings of endocarditis including Roth spots

* Lymph node biopsy: can be done if per-

(retinal hemorrhages), Janeway lesions

formed with coexistent lymphadenopathy

(nontender hemorrhagic lesions on the

* Imaging: volumetric and heterogeneity

palms/soles), and Osler nodes

(tender

assessment with ultrasound, CT, or MRI;

microemboli on the fingers and toes).

liver-spleen scan with^99mTc-sulfur colloid

The laboratory and imaging assessment

for functional analysis; can also send pit

is determined based on suspicion of the

count for pitted red blood cells.

underlying etiology of splenomegaly.

Consideration should also be given to a

Bone pain is unusual in children and ado-

secondary effect of hypersplenism in which

lescents except when associated with trauma.

the child may have cytopenias due to a large

Growing pains are a common complaint and

spleen. Persistent splenomegaly should be

consist of bilateral

(80% of cases) lower

fully investigated as follows:

extremity pain occurring in the afternoon,

* CBC: evaluate red cell indices, reticulo-

evening, or night, affect children between 3

cyte count, platelet count, white blood

and 14 years of age, occur most commonly on

cell count, and review peripheral blood

a weekly or monthly basis and much less

smear (all to help rule out hematologic

frequently daily, and are relieved with mas-

disorders such as hemolytic anemia;

sage in the majority of cases. Children pre-

membrane disorders with spherocytes or

senting with this complaint have an excellent

elliptocytes; increased red cell indices and

prognosis. Pain is otherwise usually due to

anemia in thalassemia; atypical lympho-

bone, bone marrow, or nerve infiltration.

cytes as in EBV; leukemic blasts; and

Back pain in young people is pathologic and

cytopenias secondary to leukemia or

may be due to a tumor in the spinal cord or

hypersplenism)

one causing external compression such as

* Infection: blood culture, viral studies,

neuroblastoma, rhabdomyosarcoma, or a

PPD (or quantiferon gold), thick and thin

leukemic chloroma. This finding should

smear, and serologies to rule out EBV,

prompt an MRI of the spine, as these con-

CMV, HIV, histoplasmosis, tuberculosis,

ditions typically result in no abnormalities on

and malaria

plain film.

* Hemolytic evaluation: CBC, reticulocyte

Patients with primary bone tumors

count, direct antiglobulin test (Coombs),

often present with localized pain, fre-

haptoglobin, serum bilirubin, LDH, red cell

quently in association with a growing mass.

enzyme assays (G6PD, pyruvate kinase defi-

Pain may be attributed to recent mild

ciency), osmotic fragility testing or ektacy-

trauma or growing pains. In some cases,

tometry, and urinalysis

patients sustain a pathological fracture after

* Liver disease: complete metabolic panel,

seemingly mild trauma due to infiltration

coagulation studies, hepatitis panel, a-1

of the periosteum and weakening of the

antitrypsin, ceruloplasmin

(Wilson dis-

bone. Bone pain is typically a presenting

ease), and 24-hour urine copper

symptom in patients with osteogenic

128

Chapter 13

sarcoma and Ewing sarcoma. Langerhans

for a marrow infiltrative process, primarily

cell histiocytosis very often involves bone

leukemia. Isolated anemia, leukopenia, or

and may present with localized bone pain

thrombocytopenia can occur in leukemia

anywhere in the body, often with overlying

but much more commonly the patient will

soft tissue swelling.

present with bi- or pancytopenia. Pancyto-

Diffuse or multifocal bone pain is a

penia may also indicate the lack of blood cell

common presenting symptom in acute

production as in aplastic anemia, or is

leukemia. It is reported in more than

caused by the proliferation of malignant

25% of patients diagnosed with acute lym-

cells in the marrow with resultant crowding.

phoblastic leukemia (ALL), but is seen less

The anemia is frequently characterized as

commonly in acute myelogenous leukemia

one of chronic diseases (i.e., normochromic

(AML). It is due to marrow crowding with

and low reticulocyte count). Leukocyte

leukemic cells. Patients will often com-

counts are variable at presentation in acute

plain of back or leg pain that is persistent

leukemia and may be normal, decreased, or

and increasing in intensity and very young

elevated. The cell differential, however, is

children may become irritable and refuse

likely to show neutropenia and the periph-

to walk or participate in normal activities.

eral blood smear will likely, though not

Musculoskeletal pain in children is often

always, demonstrate blasts or immature

diagnosed as arthritis or bone or joint

cells. Unless metastasis to the marrow has

infection. Pain may be asymmetric and

occurred, leukopenia and thrombocytope-

often children present with a limp with

nia are rarely associated with extramedul-

pain seemingly disproportionate to the

lary malignancies (see Table 13.3).

findings on examination. In contrast to

Patients with bi- and pancytopenia

children with arthritis, children with leuke-

require bone marrow aspiration and possi-

mia will have worsened pain at night, severe

bly biopsy for suspected diagnosis of a

pain that may shift to other locations, no

marrow infiltrative process, most likely

morning stiffness or swelling, and may have

acute leukemia. The situation can be more

associated constitutional symptoms such as

complex in the case of a single depressed

weight loss and night sweats. Associated

lineage. Children with persistent or wors-

laboratory findings that may suggest malig-

ening normocytic, normochromic anemia

nancy include an elevated erythrocyte sed-

without manifestations of hemolysis, clini-

imentation rate, elevated serum LDH, ane-

cal suspicion of transient erythroblastopenia

mia, thrombocytopenia, neutropenia, and/

of childhood, or renal disease with low

or leukopenia. Any of these findings should

erythropoietin production should have

prompt an examination of the bone

diagnostic bone marrow studies performed.

marrow.

Those with isolated severe thrombocytope-

Bone pain may also be a direct result

nia suspected of having immune thrombo-

of bony metastatic disease or marrow

cytopenic purpura (ITP) with no clinical

infiltration secondary to other tumors

signs or symptoms of malignancy should be

including neuroblastoma, rhabdomyosar-

followed closely and, if with the develop-

coma, Ewing sarcoma, and non-Hodgkin

ment of additional cytopenias or the need

lymphoma. Localized bone pain warrants

to start corticosteroids as part of their treat-

radiographic evaluation

(two-view plain

ment for ITP, should also have a bone

radiographs) for the assessment of a lesion

marrow examination. The necessity of bone

or leukemic changes.

marrow examination prior to the initiation

Cytopenias and/or abnormalities on

of steroids for the treatment of ITP is

the peripheral blood smear are suspicious

controversial.

Evaluation of the Child with a Suspected Malignancy

129

Table 13.3 Evaluation of the child with suspected leukemia.

History and physical examination

Assess life-threatening conditions including severe anemia, thrombocytopenia, DIC, infection,

compression of vital organs, hyperleukocytosis, and metabolic derangements

Laboratory studies

CBC with manual differential, reticulocyte count, examination of peripheral blood smear

Metabolic panel with electrolytes, BUN, creatinine, uric acid, LDH, AST, ALT, alkaline phos-

phatase, total bilirubin, magnesium, calcium, and phosphorus

Serologies: varicella, CMV, HSV, hepatitis A, B, and C (obtain prior to transfusion if possible)

Coagulation studies (PT, PTT, fibrinogen, FDP, or D-dimers) in suspected AML (especially APL)

Type and screen for red cell transfusion, if necessary

If febrile or ill-appearing: blood and urine cultures

Radiographic studies

Chest radiograph (assess for mediastinal mass)

Plain bone films of sites of bone pain (assess for pathological fractures)

Diagnostic studies

Bone marrow aspiration

Specimens for morphology, immunophenotyping, and karyotype

Extra “pulls” as per protocol for biological studies (Children’s Oncology Group or local

institutional studies)

For “dry” tap, obtain bone marrow biopsy for diagnostic studies

Lumbar puncture (platelet count

50-100

10⁹/L per institutional protocol)

Cytology, chamber count (WBC, RBC, protein, and glucose), and CSF culture if patient is febrile

Initial procedure should be done by an experienced clinician, after careful evaluation for elevated

ICP

Abbreviations: DIC, disseminated intravascular coagulation; CBC, complete blood count; BUN,

blood urea nitrogen; LDH, lactate dehydrogenase; PT, prothrombin time; PTT, partial throm-

boplastin time; AML, acute myelogenous leukemia; APL, acute promyelocytic leukemia (AML

M3); WBC, white blood cell; RBC, red blood cell; CSF, cerebrospinal fluid; ICP, intracranial

pressure; FDP, fibrin degradation products; CMV, cytomegalovirus; HSV, herpes simpex virus.

Bone marrow examination with aspi-

leukemia. Manifestations typically involve

rate and/or biopsy is indicated in the fol-

mucocutaneous tissues with clinical signs

lowing situations:

including petechiae, purpura, epistaxis, and

* Significant depression of one or more

menorrhagia. Patients with acute promye-

peripheral blood lineages (white cells, red

locytic leukemia (APL; AML M3) are at risk

cells, and platelets) without an obvious

for severe bleeding at presentation due to

explanation

underlying coagulation abnormalities and

* Presence of circulating blasts on the

disseminated intravascular coagulation

peripheral blood smear

(DIC), whereas Wilms tumor patients may

* Any cytopenias associated with unex-

have acquired von Willebrand disease at

plained lymphadenopathy, splenomegaly,

presentation increasing bleeding risk.

hepatomegaly, anterior mediastinal mass,

Patients with extensive marrow involvement

or bone pain.

such as advanced stage neuroblastoma may

also present with significant purpura.

Bleeding as a presenting sign in cancer is

Mediastinal masses may lead to com-

usually related to severe thrombocytopenia

pression of respiratory, vascular, or other

and occurs commonly in children with acute

structures and can range from an

130

Chapter 13

asymptomatic incidental finding to signifi-

stool, intussusception, abdominal aorta, a

cant compromise and an emergent situa-

distended bladder, hydronephrotic kidneys,

tion. Most mediastinal masses in children

and pregnancy.

are malignant. Imaging with chest radio-

The age of the child can provide a clue to

graphy and chest CT yields information

diagnosis. In the newborn, an abdominal

with respect to location in the mediastinum

mass is most likely to be a congenital abnor-

and potential for compromise.

mality of renal origin. The most common

Anterior mediastinal masses are more

malignant tumors in young children are

typically seen in older children and adoles-

neuroblastoma and Wilms tumor. Children

cents and frequently are associated with lym-

with Wilms tumor most often present well

phomas, T-cell leukemia, thymic tumors,

appearing and the mass is an incidental

thyroid tumors, and some benign tumors

finding by a family member or during a

(teratomas, lipomas, and angiomas). Malig-

well-child check. Unlike Wilms tumor, neu-

nant tumors, especially lymphomas and

roblastoma will often present with evidence

leukemia, may have rapid growth rates and

of spread and systemic symptoms including

quickly lead to compromise with presenta-

weight loss, fever, and bone pain. In older

tion of superior vena cava syndrome, airway

patients, the mass may be related to leuke-

obstruction, dysphagia, and symptoms of

mia or lymphoma with enlargement of the

increased intracranial pressure due to

spleen and liver. The most common lym-

decreased cerebral venous return. The mass

phoma in children is Burkitt lymphoma

may cause a pericardial effusion or directly

that may present as a rapidly enlarging

obstruct cardiac outflow leading to cardiac

abdominal mass leading to pain and

compromise. See Chapter 14 for assessment

obstructive symptoms (gastrointestinal and

and management.

urinary tracts) in association with metabolic

Middle mediastinal masses are also

derangements from tumor lysis. Burkitt and

more likely malignant. Infections should

other lymphomas, as well as primary gas-

be in the differential diagnosis and one

trointestinal tumors, may also occur in the

should consider tuberculosis or histoplas-

ileocecal area and serve as a lead point for

mosis in addition to pericardial cysts, bron-

intussusception.

chogenic cysts, esophageal lesions, or direct

The history is important to determine if

extension of an abdominal mass. Malignant

thesymptomsarerelatedtothemass.Acareful

tumors common in this location include

genitourinary history should be obtained to

Hodgkin lymphoma and nodal masses of

determine if the mass may be of renal origin.

neuroblastoma, rhabdomyosarcoma, and

Historical points may provide suspicion of

germ cell tumors.

catecholamine production such as flushing,

Posterior mediastinal masses are gen-

palpitations, diarrhea, and sweating

(very

erally neurogenic in origin and include

rare). Constitutional symptoms such as fail-

benign and malignant tumors. These

ure to thrive, fever, night sweats, and sudden

include ganglioneuroma, neurofibroma,

weight loss should lead one to suspect a

and neuroblastoma. Most of these lesions

disseminated process such as neuroblastoma

are asymptomatic, but may present with

in young children or lymphoma in older

symptoms of spinal cord compression such

children and adolescents.

as pain or focal neurological signs.

A meticulous and careful physical exam-

A palpable abdominal mass is one of

ination of the child should be done by first

the most common presenting findings of a

attempting to have the child relax. When

malignant solid tumor in children. Non-

examining the abdomen, keep in mind the

malignant etiologies include impacted

normal structures that may be present such

Evaluation of the Child with a Suspected Malignancy

131

as the liver or spleen edges, kidneys, aorta,

and genitourinary abnormalities have been

sigmoid colon, stool, or spine. A rectal exam-

reported in association with Wilms tumor.

ination and pelvic/vaginal examination may

Subcutaneous nodules

(typically bluish),

be indicated but should be performed only

periorbital ecchymoses, opsoclonus-myoc-

by an experienced practitioner and after

lonus, and presence of organomegaly are

obtaining laboratory studies

(should not

seen with neuroblastoma. Signs of preco-

be neutropenic for a rectal examination).

cious puberty may be seen with tumors

Care should be taken to palpate the mass

involving the liver, adrenal glands, or

gently and limit the number of examiners.

gonads (i.e., germ cell tumors). The neu-

Imaging will also help determine size and

rological examination may show evidence

location. A careful general physical exami-

of a Horner’s syndrome with apical tumors

nation is vital as many tumors may have

(often neuroblastoma) or spine compres-

associated signs and symptoms or underly-

sion with large abdominal masses. See

ing syndromes. Aniridia, hemihypertrophy,

Table 13.4 for the workup of a child with

Table 13.4 Evaluation of the child with an abdominal mass.

History and physical examination

Radiological studies

First steps

Flat plate and upright views of the abdomen

Abdominal ultrasound

Further assessment as needed

Abdominal/pelvis CT or MRI

Chest CT if with abdominal primary to assess extent of local disease and presence of metastatic

disease

Bone scan in suspected neuroblastoma, rhabdomyosarcoma, clear cell or rhabdoid tumor of the

kidney

MRI and plain radiography of the spine in tumors with neurologic impairment or other

radiographic suggestion of spinal invasion

MIBG scan for neuroblastoma

Laboratory studies

First steps

CBC with differential, reticulocyte count (bleeding into mass may cause iron deficiency anemia;

tumor may also involve the bone marrow and cause cytopenias), and review of peripheral

smear

Electrolytes, calcium, phosphorus, uric acid, LDH, BUN, creatinine, and liver transaminases

Urinalysis

As indicated by history/examination/imaging:

Urine for tumor markers: catecholamines (VMA and HVA)

Serum markers: neuron-specific enolase, a-fetoprotein, b-HCG, ESR, copper, and ferritin

Bone marrow aspirate/biopsy; if neuroblastoma, lymphoma, or rhabdomyosarcoma suspected

or confirmed

Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging; MIBG, metaio-

dobenzylguanidine; CBC, complete blood count; LDH, lactate dehydrogenase; BUN, blood urea

nitrogen; VMA, vanillylmandelic acid; HVA, homovanillic acid; HCG, human chorionic

gonadotrophin; ESR, erythrocyte sedimentation rate.

Oncologic

Emergencies

The prognosis for children diagnosed with

Valsalva maneuver. The physical examina-

cancer has steadily improved over the past

tion often reveals a plethoric, edematous

50 years, and it is now estimated that more

face and neck, jugular venous distension,

than 80% of children newly diagnosed with

papilledema, and pulsus paradoxus. Blood

cancer will ultimately be cured of their

pressure changes, pallor, and even cardiac

disease. Given this positive outlook, it

arrest can result from postural changes.

becomes even more important that life-

Superior mediastinal syndrome is the com-

threatening complications arising either as

bination of SVCS and tracheal compression

a result of the patient’s cancer diagnosis or

that leads to symptoms of cough, dyspnea,

the treatment being provided be promptly

air hunger, and wheezing. Examination

recognized and appropriately treated.

often reveals decreased breath sounds,

Oncologic emergencies can be catego-

wheezing, stridor, or cyanosis. Affected chil-

rized based on their pathogenesis, including

dren are often incredibly anxious as well.

emergencies caused by space-occupying

Malignant tumors are the most common

lesions, those caused by abnormalities of

primary cause of SVCS. The most common

blood and blood vessels, and metabolic

cause is non-Hodgkin lymphoma (NHL;

emergencies.

usually lymphoblastic lymphoma or diffuse

large B-cell lymphoma). Other malignant

causes include Hodgkin lymphoma, T-cell

Emergencies caused by

acute lymphoblastic leukemia

(T-ALL),

space-occupying lesions

malignant teratoma, thymoma, neuroblas-

toma, rhabdomyosarcoma, or Ewing sar-

Superior vena cava syndrome and

coma. A secondary cause can be thrombosis

superior mediastinal syndrome

of the major vessels caused by the presence

Superior vena cava syndrome (SVCS) refers

of a central venous catheter. Nonmalignant

to the signs and symptoms resulting from

causes include mediastinal granulomas

the compression or obstruction of the SVC

(histoplasmosis), aortic aneurysms, vascular

caused by an anterior mediastinal mass.

thrombosis complicating cardiovascular

These include orthopnea, headache, facial

surgery for congenital heart disease, shunting

swelling, dizziness or fainting, sudden pal-

for hydrocephalus, catheterizations, and

lor, and exacerbation of symptoms with the

infections (e.g., tuberculosis and syphilis).

Handbook of Pediatric Hematology and Oncology: Children’s Hospital & Research Center Oakland,

Second Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.

2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

134

Chapter 14

The SVC is a thin-walled vessel with low

General anesthesia may cause cardio-

intraluminal pressure, prone to thrombosis,

vascular and/or respiratory compromise

and surrounded by thymus and nodes that

by increasing abdominal tone and decreas-

drain the right side and lower left side of

ing respiratory muscle tone and lung vol-

the chest. Part of the SVC is also in the

ume. Sedatives can also decrease venous

pericardial reflection. Lymph nodes, thy-

return and should be used cautiously.

mus, and the pericardium may become

5. Bone marrow aspiration under local anes-

enlarged from infection or tumor involve-

thesia. If the bone marrow is involved, this

ment and compress the SVC. Adjacent cor-

test will allow the diagnosis to be made

onary and collateral vessels can become clot-

without a biopsy of the mass itself.

ted. Compression, clotting, and edema lead

6. Examination of pleural fluid/pericardial

to diminished air flow and blood flow. Addi-

fluid/ascitic fluid. In addition to relieving

tionally, the trachea and right mainstem

distress, removal of fluid and subsequent

bronchus are less rigid in children as com-

cytological examination may allow a defin-

pared to adults.

itive diagnosis to be made, especially in the

case of NHL.

Evaluation

7. Echocardiography. This is necessary to

1. History and physical examination. The

look for pericardial effusion and cardiac tam-

history is nonspecific, with a typically short

ponade and to evaluate myocardial function.

period of progressively worsening symptoms.

8. Pulmonary function tests. The patient’s

Patients with ALL may have a short history of

peak expiratory flow rate and the shape of

fever, bone pain, bruising, petechiae, or other

the flow volume loop can reliably predict

signs of marrow dysfunction. Presenting

the patient’s ability to tolerate various diag-

symptoms and signs include cough and dys-

nostic and therapeutic procedures.

pnea (commonest), closely followed by dys-

9. Measurement of b-HCG (b-subunit of

phagia, orthopnea, hoarseness, chest pain,

human chorionic gonadotrophin) and AFP

facial edema, wheezing, pleural effusion,

(a-fetoprotein). Elevations in these markers

pericardial effusion, features of carbon diox-

are diagnostic of a malignant germ cell

ide retention like anxiety, confusion, leth-

tumor, but they are generally not available

argy, headache, distorted vision, and syn-

urgently.

cope, and occasionally other symptoms like

conjunctival suffusion and cyanosis.

Management

2. Chest radiography including a lateral

1. Children should be under close observa-

view. This usually shows mediastinal wid-

tion in the intensive care unit with elevation

ening, tracheal deviation or compression,

of the head, continuous cardiovascular and

and possibly pleural effusions.

respiratory monitoring, and pulse oximetry.

3. CT scan of the chest. This helps delineate

2. Children with impending or actual air-

distortion of normal anatomy, identify tra-

way obstruction should receive emergent

cheal compression, and allow assessment of

radiation therapy, given in 1 to 2 Gy frac-

mediastinal mass width. This may be done

tions for 1 to 4 days. A small area of the

in the prone position if the patient is unable

tumor should be shielded to prevent radi-

to lie supine.

ation-induced changes if a biopsy still needs

4. Tissue diagnosis with least invasive proce-

to be performed to establish the diagnosis.

dures, with no sedation, and local anesthesia

The surgeon and radiation oncologist

only. A biopsy is essential for diagnosis,

should communicate to ensure that the

but must be able to be performed safely.

most easily accessible area is shielded.

Oncologic Emergencies

135

Tracheal swelling and further airway com-

compression, more commonly from an intra-

promise can occur as a result of the

medullary location.

radiation.

Evaluation

3. Empiric therapy for suspected malig-

1. Localized back pain or radicular pain

nancy may need to be initiated due to the

extending down the leg occurs in up to

life-threatening situation. Steroids, cyclo-

80% of children with cord compression.

phosphamide, vincristine, or anthracyclines

The duration is variable but generally short;

have been given in this situation to children

one series reported a range of 5 days to

with suspected leukemia or lymphoma.

4 weeks. Characteristically, straight leg rais-

Prednisone is commonly used as most of

ing, neck flexion, or the Valsalva maneuver

these children are ultimately diagnosed with

aggravates the pain. Pain is almost always

lymphoma or leukemia, especially if other

the first presenting symptom, with weak-

clues to the diagnosis are apparent (e.g.,

ness and bowel or bladder dysfunction

organomegaly, generalized adenopathy,

occurring later. Sensory loss may occur but

evidence of tumor lysis syndrome [TLS],

is often difficult to identify, especially in

elevated WBC

[white blood cell] counts).

young children. Any objective neurological

Intravenous methylprednisolone is started

deficit requires further evaluation.

at a dose of

50 mg/m²/day divided BD.

2. Plain radiographs are generally not help-

Hydration should be given and the child

ful in identifying abnormalities in children,

monitored for tumor lysis syndrome that

as cord compression typically occurs via

may be exacerbated by the initiation of

extension of tumor through the interverte-

therapy and is discussed later.

bral foramina without bony erosion or

injury. MRI is the best study for demon-

strating intraspinous extension, but is not

Spinal cord compression

always immediate available. While CT is less

Acute spinal cord compression occurs in

sensitive in identifying extension of disease

about 5% of children with cancer. Prolonged

into the spinal canal, it will effectively iden-

cord compression leads to irreversible neu-

tify paraspinous disease.

rological injury with paralysis, sensory loss,

3. Examination of the cerebrospinal fluid

and loss of bowel and bladder control. Once a

(CSF) is rarely helpful, and patients may

neurological deficit occurs, it often progresses

experience rapid neurological deterioration

to paraplegia within days or even hours. The

following a lumbar puncture (spinal coning).

most frequent cause of cord compression is

external compression caused by extension of a

Management

paravertebral tumor through an interverte-

1. Patients with rapidly progressing spinal

bral foramen into the epidural space. The

cord dysfunction require immediate inter-

tumor compresses the vertebral venous

vention. Dexamethasone 1 mg/kg should be

plexus leading to cord edema, venous hem-

given IV even before imaging is performed,

orrhage, myelopathy, and ischemia. The most

and an MRI should be obtained immedi-

common tumors leading to spinal cord com-

ately. Patients with suspicious findings who

pression include neuroblastoma, Ewing

are stable should be started on a lower dose

sarcoma, NHL, and Hodgkin lymphoma.

of oral dexamethasone (0.25 to 0.5 mg/kg

Intraspinous chloromas in patients with acute

every

6 hours) with imaging performed

myelogenous leukemia (AML) are a less com-

within 24 hours.

mon cause. Spinal cord astrocytomas and

2. If imaging reveals a tumor with spinal

ependymomas can also cause cord

cord compression, this must be promptly

136

Chapter 14

relieved. Surgical decompression with a

at first, and then becomes more frequent

laminectomy quickly relieves pressure and

and severe. It characteristically occurs in

allows tumor to be removed for diagnosis. It

the morning, and is often but not always

should be performed if the diagnosis is

accompanied by vomiting without diar-

unknown. If the diagnosis is known and

rhea. Other signs and symptoms include

the tumor is radiosensitive, emergent radi-

diplopia, ataxia, hemiparesis, speech dis-

ation therapy should be promptly initiated.

turbance, neck stiffness, dizziness, lethargy,

Chemotherapy is an alternative for chemo-

and coma.

therapy-responsive tumors such as neuro-

Some tumors may also cause focal neu-

blastoma, Ewing sarcoma, Hodgkin lym-

rological changes. Cerebellar astrocytomas

phoma, and NHL; the onset of action in

may lead to ipsilateral weakness, hypotonia,

these tumors is similar to radiation therapy.

and ataxia. Herniation of a cerebellar tonsil

often causes head tilt and neck stiffness.

The prognosis for recovery of function is

Tumors near the third ventricle (cranio-

directly related to the degree of disability at

pharyngiomas, germ cell tumors, optic gli-

diagnosis. This is associated with the dura-

omas, and hypothalamic and pituitary

tion of symptoms and the length of time

tumors) may cause visual loss, increased

required to make the diagnosis. Patients

intracranial pressure, and hydrocephalus.

who are ambulatory at diagnosis typically

A pineal tumor may lead to Parinaud’s

remain ambulatory; approximately 50% of

syndrome

(impairment of upward gaze,

children who are nonambulatory at diagno-

convergence nystagmus, and alterations in

sis regain the ability to ambulate.

pupillary response).

Increased intracranial pressure

Evaluation

and brain herniation

1. Assessment of vital signs is critical.

Brain tumors are the most common solid

Increased ICP will often result in Cushing’s

tumor in childhood, and the majority of

triad: bradycardia, hypertension, and apnea.

patients present with signs and symptoms

2. A careful physical examination looking

of increased intracranial pressure (ICP). For-

for signs of increased ICP or impending

tunately, few of these patients progress to

herniation must be done quickly. In addition

actual brain herniation. Most pediatric brain

to the findings mentioned above, impending

tumors are infratentorial and cause increased

brain herniation may cause changes in respi-

ICP by obstructing the third or fourth ven-

ratory pattern, pupil size and reactivity,

tricle with resultant obstructive hydroceph-

extraocular movements, spontaneous motor

alus. They can also cause increased ICP sim-

function, and responsiveness to verbal and

ply by mass effect. This most commonly

physical stimuli.

occurs with astrocytomas, as well as with

primitive neuroectodermal tumors includ-

Management

ing medulloblastoma.

If increased ICP or impending brain herni-

The presentation can vary significantly

ation is suspected, appropriate management

depending on patient age. Common symp-

must be initiated prior to more definitive

toms in infants include vomiting, lethargy,

testing to hopefully avoid death or perma-

personality changes, loss of developmental

nent neurological injury. The following

milestones, and increased head circumfer-

steps should be initiated:

ence. Older children commonly complain

1. Fluid intake should be limited to no

of headache. This is frequently intermittent

more than 75% maintenance.

Oncologic Emergencies

137

2. A loading dose of dexamethasone 0.5 to

urine output and azotemia), or dissemi-

1 mg/kg should be given IV followed by 0.25

nated intravascular coagulation.

to 0.5 mg/kg every 6 hours.

2. A biopsy and staging evaluation including

3. An emergent CT scan of the head should

CT scan of the chest, abdomen, and pelvis,

be performed. A noncontrast scan will effec-

bone scan, bilateral bone marrow aspiration

tively identify bleeding, most tumors, cere-

and biopsy, and other imaging such as MRI

bral edema, and hydrocephalus.

of the brain and spine should be performed

4. If the diagnosis of increased ICP is con-

quickly if the patient is able to tolerate these

firmed, the patient should be admitted to

procedures. This will allow prompt initiation

the ICU. Neurosurgical consultation should

of appropriate therapy.

be immediately obtained if a tumor is iden-

tified or the patient has hydrocephalus.

Treatment

5. Acetazolamide 5 mg/kg/dose every 6 hours

1. If the patient is stable and does not exhibit

can be given to decrease CSF production.

any of the findings above, careful observation

6. Intubation and hyperventilation to

and supportive care should be provided.

decrease the pCO₂ to 20 to 25 mmHg will

2. If the patient is unstable, treatment with

decrease cerebral perfusion. Care must be

chemotherapy or radiation therapy should

taken not to cause cerebral ischemia.

be considered. Cyclophosphamide 5 mg/kg/

7. Surgical options

(external ventricular

day for 5 days has been shown to be effec-

drainage, third ventriculostomy) should

tive, as has radiation therapy at a dose of

be considered.

150 cGy/day

3 days.

8. Prophylaxis with antiseizure medication

should also be considered.

9. Intracranial pressure monitoring may be

Emergencies caused by

beneficial.

abnormalities of blood and

10. An MRI should be obtained as soon as

blood vessels

possible to look for or confirm the presence

of a tumor.

Hyperleukocytosis

Hyperleukocytosis is defined as a peripheral

WBC count exceeding 100

10⁹/L. It is

Massive hepatomegaly

most commonly seen at presentation or

Massive hepatomegaly is the most emergent

relapse of AML, ALL, or chronic myeloge-

complication of stage 4S neuroblastoma in

nous leukemia (CML). Using this defini-

infants, especially those under 4 weeks of

tion, the incidence of hyperleukocytosis at

age. While 4S neuroblastoma often regresses

presentation is 9% to 13% of children with

spontaneously, when it occurs during early

ALL, 5% to 22% with AML, and almost all

infancy the resulting hepatomegaly can

children in chronic phase of CML. How-

cause death due to respiratory insufficiency

ever, clinically significant hyperleukocytosis

or hepatic failure.

occurs with WBC counts >200

10⁹/L in

AML and >300

10⁹/L in ALL and CML.

Evaluation

Using these criteria, the incidence is lower.

1. The patient should be examined for evi-

The most common complication of hyper-

dence of gastrointestinal dysfunction, respi-

leukocytosis in AML and CML is stroke,

ratory compromise (respiratory rate >60/

whereas in ALL it is TLS. It is more common

min or oxygen requirement), poor venous

in infantile ALL and AML, T-cell ALL, and

return (leg edema), renal dysfunction (poor

in any phase of CML.

138

Chapter 14

Hyperleukocytosis leads to occlusion of

magnesium, liver function studies, and

small veins in the brain, lung, and other

LDH at presentation, and then follow the

organs through the formation of WBC

electrolytes, BUN, creatinine, calcium,

aggregates (white thrombi). The excessive

phosphorus, and uric acid frequently to

leukocytes also cause local hypoxia by com-

assess response to therapy.

peting for available oxygen, leading to blood

vessel damage and bleeding. The degree of

Treatment

obstruction is related to the whole blood

1. Therapeutic intervention should

viscosity, which is related to the deform-

immediate.

ability of the cells present and the sum of the

2. If the child is being transported, these

packed erythrocyte and packed leukocyte

simple measures should be initiated prior

volumes. As myeloblasts and monoblasts

to transport. The mainstay of therapy is

are less deformable than lymphoblasts or

aggressive hydration, typically two to three

granulocytes, leukostasis is more likely to

times maintenance intravenous fluids. The

occur in AML than in ALL or CML. Other

fluids should be alkalinized to promote

factors that can increase the risk of leukos-

excretion of uric acid by converting it to a

tasis include dehydration and an elevated

more soluble urate salt. A fluid such as D₅W

hemoglobin level.

1/4NS with 40 mEq/L NaHCO₃ is quite suit-

Poor perfusion and anaerobic metabo-

able. Allopurinol or urate oxidase (rasburi-

lism in the microcirculation lead to lactic

case) should also be started to prevent or

acidosis. When the WBC count is >300

decrease the severity of hyperuricemia. If

10⁹/L, local proliferation of cells occurs

urate oxidase is given, alkalinization is not

within the cerebral vasculature and brain and

required as the uric acid level falls precipi-

vessel damage occurs, leading to secondary

tously and uric acid solubility is no longer an

hemorrhage. Vessel damage can occur any-

issue. This topic is discussed more fully in the

where in the body, though the most clinically

section on TLS.

significant is in the brain and lungs.

3. If aggressive hydration does not bring the

WBC count down quickly to

100

Evaluation

200

10⁹/L or the WBC count is rapidly

1. Signs and symptoms of leukemia are

rising due to rapid tumor growth, cytore-

usually present (pallor, fatigue, fever, bleed-

duction may be necessary. Two techniques

ing, bone pain, adenopathy, organomegaly,

that have been used previously to acutely

anemia, thrombocytopenia).

decrease the number of circulating WBCs

2. Possible signs and symptoms of leukos-

are leukapheresis and exchange transfu-

tasis in the lungs or brain include hypoxia,

sion. Because of the infectious disease

acidosis, dyspnea, cyanosis, blurred vision,

concerns with exchange transfusion, leuka-

papilledema, stupor, coma, or ataxia. Pria-

pheresis is used almost exclusively where it

pism may also occur in this setting.

is available and technically feasible. The

3. The laboratory assessment should

purpose of leukapheresis is to decrease

include frequent monitoring (q6 to 8 hours)

tumor bulk, decrease the risk of TLS, and

of the WBC count to follow the rate of rise

correct the anemia and hyperviscosity (goal

or the response to therapy. Metabolic stud-

of >30% leukocyte reduction with leuka-

ies also need close monitoring as the child

pheresis). If used, single volume exchange

may have evidence of tumor lysis and renal

transfusion should be performed with

dysfunction. Evaluate electrolytes, BUN,

repeat laboratory analysis to determine

creatinine, uric acid, calcium, phosphorus,

effectiveness. Further exchanges can be

Oncologic Emergencies

139

performed to reach the goal of a total WBC

2. Several authors of textbooks on pediatric

count <200

10⁹/L.

oncology recommend that children with

4. Therapy for the underlying malignancy

profound anemia

(hemoglobin

<5 g/dL)

should begin as soon as possible and is the

that has developed over an extended period

only permanent therapy for hyperleukocy-

of time be transfused more slowly (1 vs.

tosis. In general, it is safer from a metabolic

3 mL/kg/h) to avoid causing congestive

viewpoint to initiate chemotherapy with a

heart failure. This concern is based on an

lower WBC.

extrapolation of the Starling law of cardiac

5. Emergency cranial radiation therapy has

physiology, but there are few data support-

not been demonstrated to improve outcome

ing this concern. Two published studies as

and is not recommended.

well as experience in our own institution

6. Platelet transfusions can be given safely

suggest that this practice is unnecessary,

in small volumes, as platelets have not been

especially if these children are being cared

shown to increase viscosity or worsen leu-

for in the ICU where more careful moni-

kostasis. Platelets should be given if the child

toring is being performed. This can avoid

is bleeding or the platelet count is

<20

potentially exposing patients to additional

10⁹/L. Red cell transfusions should be

donor units unnecessarily.

given with extreme caution due to the

3. All blood products given to known or

potential to increase total blood viscosity

potential oncology patients should be

and worsen leukostasis. The only indication

irradiated to prevent transfusion-associated

is cardiovascular compromise caused by

graft-versus-host disease (TA-GVHD). They

anemia. The hemoglobin level should be

should also be leukoreduced to decrease

kept below 10 g/dL.

the risk of CMV transmission.

4. Erythropoietin is not used in children at

this time to increase the hemoglobin and

Anemia

decrease the need for transfusion due to data

Anemia is a common finding in children

from adult studies that suggest patients

presenting with malignancy. Up to 80% of

receiving erythropoietin have inferior out-

children presenting with ALL will be anemic

comes compared to those who do not.

at diagnosis. This can result from bleeding,

inflammation, or marrow infiltration by

tumor. It is rarely an emergency; children

Leukopenia

can tolerate a hemoglobin level as low as 2 to

Leukopenia is commonly found in newly

3 g/dL if it develops slowly from decreased

diagnosed oncology patients as well as during

production. Conversely, levels as low as 5 g/

therapy. This predisposes them to a variety of

dL can be life threatening if they occur as a

infections with bacteria, viruses, fungi, and

result of sudden hemorrhage.

protozoa. The evaluation and management

of this is discussed in Chapter 27.

Treatment

1. Anemia in this situation is treated with

Coagulopathy

packed red blood cell (PRBC) transfusions.

Coagulopathy in children with cancer

As a general rule, 10 mL/kg of PRBCs will

results from a variety of mechanisms. The

increase the hemoglobin level by 2 to 3 g/dL.

most common is thrombocytopenia, which

In practice, children with acute anemia due

can result from decreased platelet produc-

to blood loss may need 15 to 20 mL/kg to

tion (marrow infiltration or adverse effect

reach this level.

of therapy) or from increased consumption

140

Chapter 14

(infection/DIC, splenomegaly, and sinu-

count is less predictable than the increase

soidal obstruction syndrome). Abnormal

in hemoglobin following PRBC transfusion.

platelet function is seen in patients with

3. As with PRBCs, platelets should be

uremia. Reduced levels of coagulation fac-

irradiated and leukoreduced to decrease the

tors are seen in patients with liver disease or

risk of TA-GVHD and CMV transmission,

in DIC when coagulation factors are abnor-

respectively.

mally consumed. It is important to remem-

4. Patients with bleeding and an abnormal

ber that consumption can deplete anticoag-

PT/PTT should receive fresh frozen plasma

ulant proteins as well, potentially making

(FFP) at a dose of

10 mL/kg. This will

the patient hypercoagulable.

correct most clotting factor deficiencies

with the exception of Factor VIII and fib-

Evaluation

rinogen. Patients with a fibrinogen level

1. The CBC will reveal thrombocytopenia,

<100 mg/dL or a persistently prolonged

and the prothrombin time

(PT), partial

PTT despite FFP replacement should

thromboplastin time (PTT), fibrinogen, and

receive cryoprecipitate at a dose of 5 mL/

D-dimers will provide evidence of a clotting

kg; a typical unit of cryoprecipitate has a

disorder.

volume of 20 to 50 mL. FFP and cryopre-

2. Patients presenting with a stroke-like

cipitate do not need to be irradiated or

syndrome should have measurements of

leukoreduced as they are acellular products

protein C, protein S, and antithrombin III,

and have no risk of causing TA-GVHD or

especially if they have recently received

transmitting CMV.

asparaginase therapy.

3. A patient with an alteration in con-

sciousness or neurological abnormalities

Metabolic emergencies

associated with symptoms or signs sugges-

tive of a coagulopathy should have a non-

Tumor lysis syndrome

contrast CT scan of the brain performed

TLS is a pattern of specific metabolic abnor-

emergently looking for evidence of bleeding

malities that occurs as a result of extremely

or thrombosis.

rapid cellular turnover. It is almost always

encountered in the context of malignant

Management

tumors that either have a rapid rate of

1. The short-term therapy for thrombocyto-

apoptosis or after initiation of therapy in

penia is platelet transfusion. Patients who are

bulky tumors that are exquisitely sensitive

ill or unstable should be transfused to keep

to the therapy being provided. The rapid

their platelet count

>20

10⁹/L. Patients

lysis of tumor cells in either situation causes

who are actively bleeding should be trans-

large amounts of potassium, phosphate,

fused if their platelet count is <50

10⁹/L in

and nucleic acids to be released into the

case they have a component of platelet dys-

circulation, resulting in hyperuricemia,

function. Patients undergoing invasive pro-

hyperphosphatemia, and hyperkalemia.

cedures (intubation, central venous catheter

When the uric acid concentration in the

placement, or biopsy) should be transfused

renal tubule exceeds its solubility coeffi-

to a platelet count of

50 to

100

10⁹/L

cient, urate crystals form in the tubule

depending on the procedure.

causing obstruction. Lactic acidosis, sec-

2. One pheresed unit of platelets/m² will

ondary to poor tissue oxygenation in

typically increase the platelet count by 50 to

patients with high WBC counts, may con-

10⁹/L, although the increase in platelet

tribute to uric acid deposition. In addition,

Oncologic Emergencies

141

phosphates are released when tumor cells

3. Carefully monitor vital signs, intake and

lyse. When the calcium- phosphorus prod-

output for evidence of renal insufficiency,

uct exceeds 60, precipitation occurs in the

and possible symptoms of hypocalcemia

microvasculature, particularly in an alka-

(anorexia, vomiting, cramps, spasms, tet-

line environment, further obstructing the

any, and seizures). A renal ultrasound may

renal tubules and resulting in hypocalce-

be indicated in suspected renal dysfunction.

mia. Lymphoblasts are particularly rich in

phosphate, containing up to four times the

Therapy

amount found in normal lymphocytes.

1. Aggressive hydration should be provided

Potassium is also released from tumor cells,

at a rate of two to three times maintenance.

is secondarily elevated in poor renal func-

If alkalinization of serum and urine is

tion, and can lead to fatal arrhythmia. The

desired, an appropriate starting fluid is

complete syndrome includes all these com-

D₅W 1/4NSþ

40 mEq/L NaHCO₃. The

ponents, with progressively worsening

bicarbonate should then be titrated to keep

renal failure. Tumor infiltration of the kid-

the urine pH between 7 and 7.5, which will

ney and dehydration can further impair

optimize the excretion of both uric acid and

renal function and accelerate the develop-

calcium phosphate.

ment of TLS.

2. An agent to prevent or reverse hyper-

In children, TLS develops most

uricemia should also be initiated immedi-

frequently in association with Burkitt

ately. Allopurinol is the most commonly

lymphoma or T-ALL. These malignancies

used agent for this purpose, and it can be

typically present with a large tumor

given at presentation and as needed during

mass, short doubling time

(38

116

the early phase of therapy for the preven-

hours in Burkitt lymphoma), poor urine

tion or treatment of TLS. The urine is

output, and elevated uric acid and LDH.

typically alkalinized when allopurinol is

TLS has also been reported in children

used, as it often does not cause a significant

with hepatoblastoma and advanced stage

decrease in the uric acid level until the rate

neuroblastoma.

of tumor lysis slows. It is given at a dose of

300 mg/m²/day divided every

hours

Evaluation

(800 mg/day maximum). Another agent,

1. Evaluate for signs and symptoms of

rasburicase (urate oxidase), is a recombi-

metabolic abnormalities. These include

nant enzyme that acts as a catalyst in the

lethargy, nausea, vomiting, hypotension,

degradation of uric acid into allantoin, a

muscle spasm, and cardiac dysrhythmia.

highly soluble product compared with uric

2. Perform a metabolic panel in all chil-

acid. It works quickly (within 30 minutes

dren with suspected malignancy to assess

of IV infusion) and keeps the uric acid level

for TLS. Frequent reassessments should be

low for 12 to 24 hours or longer, depend-

performed early in therapy as well, par-

ing on the underlying rate of cell turnover.

ticularly in patients with high tumor

Rasburicase has been studied in children

burdens and those expected to respond

with cancer who have hyperuricemia as a

rapidly to treatment. The timing of this

result of tumor lysis and has been found to

will depend on the underlying disease,

be safe and effective. However, it is quite

evidence of preexisting renal dysfunction,

expensive compared to allopurinol. Many

timing of initiation of therapy, and the

hospital pharmacies have practice guide-

risk of TLS.

lines that specify the conditions where

142

Chapter 14

rasburicase should be prescribed to avoid

phosphate from the circulation. Persistent

overuse. It is given at a dose of 0.15 to

hyperphosphatemia may require dialysis.

0.2 mg/kg/day in 50 mL preservative-free

normal saline IV over 30 minutes. While

Hypercalcemia

the package insert states that this dose

Malignancy-associated

hypercalcemia

should be repeated daily for up to 5 days,

(MAH) is a rare complication of childhood

in practice a single dose will often keep the

cancer, occurring in 0.4% to 1.3% of newly

uric acid level low for 48 hours or more,

diagnosed cases. It is seen most frequently in

and may be sufficient to prevent TLS for

ALL and alveolar rhabdomyosarcoma, but has

the entire course. Patients treated with

also been reported in children diagnosed with

rasburicase do not require alkalinization,

rhabdoid tumor, hepatoblastoma, Hodgkin

which is an advantage when managing

lymphoma, NHL, AML, brain tumors, and

other electrolyte abnormalities. It will

neuroblastoma. The cause of MAH can be

precipitate hemolysis in patients with

increasedboneresorptionfromskeletalmetas-

G6PD deficiency and has caused methe-

tases or production of calcium-mobilizing

moglobinemia in susceptible individuals.

substances such as parathyroid hormone

Routine screening for G6PD deficiency is

(PTH)-related peptide or osteoclast-activat-

not recommended before use, but families

ing factor by the tumor. MAH in turn

should be asked about this possibility. It

adversely affects the ability of the kidney to

also has rarely caused anaphylaxis.

concentrate the urine, leading to dehydration,

3. Potassium should not be added to IV

decreased glomerular filtration rate (GFR), a

fluids until it is clear that the potassium is

further reduction in calcium excretion, and

stable and not increasing due to TLS or renal

worsening hypercalcemia.

insufficiency.

4. The patient’s intake and output must be

Evaluation

closely monitored to ensure it remains

1. Symptoms of mild hypercalcemia (12 to

balanced, taking into account insensible

15 mg/dL) include generalized weakness,

losses.

poor appetite, nausea, vomiting, constipa-

5. Careful metabolic monitoring should be

tion, abdominal or back pain, polyuria,

performed.

and drowsiness. More severe hypercalcemia

6. An ECG should be obtained if the

(>15 mg/dL) results in profound muscle

potassium is 7 mEq/L or higher. This may

weakness, severe nausea and vomiting, coma,

show widened QRS complexes and peaked

and bradydysrhythmias with broad T waves

T waves in hyperkalemia. Symptomatic

and prolonged PR interval on the ECG.

hyperkalemia requires immediate therapy

2. Patients exhibiting any of these symp-

with calcium gluconate, albuterol, and

toms should have a serum Ca2þ level

glucose and insulin, along with kayexalate

measured immediately. Measurement of

to remove excess potassium from the body.

an ionized Ca2þ should be done if there

If this is ineffective, continuous renal

is any question about the validity of the total

replacement therapy or dialysis may be

calcium measurement or to rule out

required.

primary hyperparathyroidism or pseudohy-

7. If hyperphosphatemia is present, treat-

percalcemia due to increased plasma pro-

ment is forced saline diuresis with furo-

tein binding capacity.

semide and dietary phosphate restriction.

3. Measurement of the intact parathy-

Oral phosphate binders are typically not

roid hormone

(PTH) level should be

effective, as they do nothing to remove

performed to exclude concomitant

Oncologic Emergencies

143

hyperparathyroidism. PTH levels are usu-

3. If the patient is hypophosphatemic,

ally low, normal, or suppressed in MAH.

phosphate replacement at a dose of

The serum concentration of calcitriol

10 mg/kg/dose 2 to 3 times/day may inhibit

should be measured when the hypercalce-

osteoclastic activity and promote calcium

mia is suspected to be due to Hodgkin

deposition into bone.

lymphoma or NHL, as it has been impli-

4. Bisphosphonates have become the

cated as a key mediator of hypercalcemia in

treatment of choice for adults with MAH,

almost all cases of Hodgkin lymphoma and

but these have not been widely studied in

30% to 40% of cases of NHL.

children. The most published experience is

with pamidronate at a dose of 0.5 to 2 mg/

kg given IV over 2 to 24 hours. This has

Treatment

been highly successful in correcting MAH

1. The goals of treatment are to increase

within 1 to 4 days of treatment. When

renal clearance of calcium and decrease

MAH is associated with ALL, rapid initi-

bone resorption.

ation of induction therapy has been shown

2. Aggressive hydration will help increase

to be very important in reversing the

renal excretion of calcium. Forced diuresis

hypercalcemia.

with normal saline at two to three times

maintenance and furosemide 2 to 3 mg/kg

every 2 hours was previously recommended.

Suggested Reading

Furosemide blocks calcium reabsorption by

the kidney, and can decrease the calcium

Coiffier B, Altman A, Pui CH, et al. Guidelines for

level in 24 to 48 hours. However, a recent

the management of pediatric and adult tumor

meta-analysis suggests the data to support

lysis syndrome: an evidence based review.

this approach are limited, and it can also

J Clin Oncol 26:2767-2778, 2008.

cause severe loss of sodium, potassium, and

Kelly KM, Lang B. Oncologic emergencies.

magnesium. At present, the use of furose-

Pediatr Clin N Am 44:809-830, 1997.

mide is recommended only for patients

Seth R, Bhat AS. Management of common

experiencing fluid overload following

oncologic emergencies. Indian J Pediatr 78:

709-717, 2011.

aggressive saline diuresis.

Acute Leukemias

Acute leukemia is the most common type

developing leukemia (e.g., Down syndrome

of malignancy in children, accounting for

[DS], Fanconi anemia, Bloom syndrome,

approximately

25% of newly diagnosed

ataxia telangiectasia). Siblings, in particular

cancers in patients less than 15 years of age.

identical twins, have an increased risk of

Approximately 2500 to 3000 new cases are

developing leukemia as children. Most cases

diagnosed each year in the United States.

of leukemia stem from somatic genetic

The peak incidence is between 2 and 5 years

alterations, as opposed to an inherited

of age. Acute lymphoblastic leukemia (ALL)

genetic predisposition. Though unclear at

accounts for

75% of cases of leukemia,

this time, inciting events in the development

followed by acute myelogenous leukemia

of leukemia in children and adolescents

(AML) in 20%, with the remainder being

involve complex relationships between host

other, rarer forms. The acute leukemias are

genetic polymorphisms, environmental

biologically classified by blast morphology,

exposures, and infections.

surface proteins, cytogenetic abnormalities,

and cytochemical staining. This informa-

tion, in addition to clinical features, is uti-

Acute lymphoblastic leukemia

lized for risk stratification into treatment

groups. Risk-based therapy optimizes cura-

The majority of ALL cases arise from B-cell

tive potential while minimizing risks and

committed progenitors. T-cell ALL repre-

side effects.

sents approximately

15% of ALL cases.

A number of hypotheses regarding the

Cytogenetic abnormalities are common and

etiology and pathogenesis of acute leukemia

provide important prognostic information.

have been described, including Knudson’s

Hyperdiploidy (an excess of chromosomes;

two-hit hypothesis that entails an initial

e.g.,

>50) is seen in approximately one-

early event (possibly prior to birth), fol-

third of children with B-precursor ALL, and

lowed by a second, environmentally-medi-

the TEL-AML translocation t(12;21)(p13;

ated

(possibly infectious) event. Ionizing

q22) is present in another 25% of cases.

radiation and exposure to benzene have

Both of these cytogenetic findings are asso-

been associated with an increased risk of

ciated with a favorable outcome, whereas

developing leukemia. Certain syndromes

hypodiploidy (

44 chromosomes), and the

and chromosomal abnormalities have also

presence of certain translocations such

been associated with a high incidence of

as the Philadelphia chromosome t(9;22)

Handbook of Pediatric Hematology and Oncology: Children’s Hospital & Research Center Oakland,

Second Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.

2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

Acute Leukemias

145

and the mixed lineage leukemia

(MLL)

such as fatigue, irritability, and anorexia

rearrangement t(4;11) or t(1;19) have tra-

as well as clinical signs such as pallor, tachy-

ditionally been associated with poorer out-

cardia, and more rarely evidence of conges-

comes. The addition of tyrosine kinase inhi-

tive heart failure. Low-grade fever of

bitors in therapy may be significantly alter-

unknown etiology may be a presenting

ing the outcome of patients with the Phila-

manifestation due to presumed cytokine

delphia chromosome translocation. It is

release or may be related to infection

important to note that conventional cyto-

secondary to neutropenia and immunosup-

genetics may not detect these common

pression. Bleeding secondary to thrombo-

translocations seen in ALL and therefore

cytopenia is usually mild and manifests as

FISH (fluorescent in situ hybridization) is

petechiae, bruising, gingival oozing, and/or

necessary for detection.

epistaxis. Life-threatening hemorrhage may

occur, but is very rare. Bone pain (typically

Clinical presentation

long bones) is common and may result in

The clinical manifestations of leukemia are a

refusal to walk or irritability in young chil-

direct result of marrow invasion with resul-

dren. This may result from direct leukemic

tant cytopenias

(anemia, thrombocytope-

infiltration of the periosteum or expansion

nia, leukopenia, and/or neutropenia) and

of the marrow cavity by leukemic cells.

rarely extramedullary involvement

(see

Pathologic fractures may also be present

Table 15.1). Children typically present with

at diagnosis and cause significant pain (see

nonspecific symptoms related to anemia

Table 15.2). Patients with T-cell ALL present

Table 15.1 Common clinical and laboratory features of acute lymphoblastic

leukemia (ALL) at presentation.

Finding

Percentage of patients (%)

Fever

Pallor

Bleeding

Bone pain

Lymphadenopathy

Splenomegaly

Hepatosplenomegaly

White blood cell count (

10⁹/L)

<10

10-49

Hemoglobin (g/dL)

<7.0

7.0-11.0

>11.0

Platelet count (

10⁹/L)

<20

20-99

100

146

Chapter 15

Table 15.2 Radiographic changes of the

spinal cord or CNS hemorrhage (related to

bones in leukemia.

leukostasis and coagulopathy) are rare and

more likely to be associated with AML.

Osteolytic lesions involving the medullary

Leukemic involvement of the testes

cavity or cortex

occurs in 2% to 5% of boys at diagnosis

Subperiosteal new bone formation;

and presents as painless enlargement, either

pathologic fracture

Transverse metaphyseal radiolucent bands

unilaterally or bilaterally. Early testicular

Transverse metaphyseal lines of increased

involvement is also associated with T-cell

density (growth arrest lines)

disease, elevated WBC count, and lympho-

matous features.

Diagnostic evaluation

with some distinctive features. It more fre-

Children presenting with more than one

quently occurs in males, and the incidence of

cytopenia and clinical symptomatology sug-

central nervous system (CNS) leukemia at

gestive of bone marrow infiltration should

diagnosis is higher than for B-cell ALL (10%

undergo a diagnostic evaluation to investi-

to 15% vs. 2% to 5%). Patients are more

gate for the possibility of acute leukemia.

likely to present with a mediastinal mass

Laboratory and imaging studies indi-

(nearly 50%) or a white blood cell (WBC)

cated are:

count above 100

10⁹/L (30% to 50%). The

* Complete blood count (CBC), differen-

presence of an anterior mediastinal mass

tial, review of peripheral blood smear by an

may cause airway or cardiovascular compro-

experienced individual

mise (see Chapter 14).

* Bone marrow aspirate (consider biopsy

Frequently seen laboratory abnormali-

for dry tap or inadequate specimen) for

ties include elevated liver enzymes and lac-

morphology, blast count, immunopheno-

tate dehydrogenase

(LDH). Evidence of

typing, cytogenetics, cytochemistry

tumor lysis related to a large tumor burden

* Metabolic panel, to include liver function

and rapid cell turnover may result in hyper-

studies, electrolytes, lactate dehydrogenase

uricemia, hyperkalemia, and hyperpho-

(LDH), uric acid, phosphorus, calcium,

sphatemia (with resultant hypocalcemia due

blood urea nitrogen, and creatinine

to precipitation of calcium phosphate).

* Blood culture if febrile; cultures of other

CNS involvement occurs in less than 5%

suspected sites of infection

of children at presentation, but is more

* Chest radiography to evaluate for the

common in children with T-cell disease. It

presence of a mediastinal mass

is usually detected in an asymptomatic child

* Plain films of the long bones for patients

with analysis of the cerebrospinal fluid

presenting with pain to evaluate for patho-

(CSF). Rarely, a patient may present with

logic fracture or evidence of leukemic

signs or symptoms of increased intracranial

changes

pressure (e.g., cranial nerve VI palsy with

resultant esotropia and diplopia, papille-

Typically the bone marrow is 80% to 100%

dema, visual changes, morning headache,

replaced with lymphoblasts at diagnosis. At

vomiting, lethargy, irritability, possible sei-

times, due to the packed condition of the

zures) or evidence of parenchymal involve-

marrow, it may be difficult to aspirate a

ment, hypothalamic syndrome, or diabetes

sample (dry tap) and a bone marrow biopsy

insipidus. Other rare complications such

may provide diagnostic samples. The diag-

as chloromas causing compression of the

nosis of acute leukemia requires the

Acute Leukemias

147

presence of 25% or more blasts (M3 bone

puncture is done to assess possible involve-

marrow); however, the diagnosis is sus-

ment of the CSF and to assist with

pected when the marrow contains 5% to

therapeutic decision-making and risk strat-

25% blasts (M2 bone marrow with M1

ification. Many patients require a platelet

being a normal bone marrow with <5%

transfusion prior to the initial lumbar punc-

blasts) (Table 15.3). Lymphoblasts have a

ture, which should be performed by an

typical morphology with a high nuclear to

experienced clinician to decrease the chance

cytoplasmic ratio, fine nuclear chromatin,

of a traumatic tap. There is some evidence

and the presence of nucleoli. In addition,

that a platelet count of

100

10⁹/L is

the cells tend to have a uniform size and

desired to decrease this risk. In addition,

appearance. Immunophenotyping and

evidence exists that a traumatic tap at diag-

cytochemistry are used to differentiate ALL

nosis (with peripheral blasts) can theoreti-

and AML and identify T- and B-cell ALL.

cally seed the CSF space increasing the risk

Lymphoid malignancies should lack mye-

of later CNS relapse. Subsequent procedures

loid cell surface markers (CD13 and CD33;

may be done with platelet counts of 20 to

CD [cluster of differentiation]). B-cell ALL

10⁹/L, per institutional and provider

should have B-cell surface markers such as

preference. A cell count and cytocentrifuge

CD10, CD19, kappa, and lambda, whereas

examination for cell morphology is done on

T-cell ALL should have T-cell surface mar-

the fresh CSF. The diagnosis of CNS leuke-

kers including CD2, CD5, and CD7. T-cell

mia requires the presence of 5 or more

ALL cells should also stain for terminal

WBCs/mL and identification of blasts on the

deoxynucleotidyl transferase, an immature

CSF cytocentrifuge examination. CNS leu-

lymphoid marker.

kemia is classified as follows:

After the diagnosis is confirmed, evalu-

* CNS1: no detectable blasts

ation of the CSF should be done prior to

* CNS2: <5 WBCs/mL, blasts present

therapy (this is frequently done at the time

* CNS3:

5 WBCs/mL and blasts present or

of the diagnostic bone marrow aspirate if

signs of CNS leukemia (i.e., facial nerve

the clinical suspicion is high). A lumbar

palsy, hypothalamic syndrome, or brain/eye

involvement)

Table 15.3 Differential diagnosis of acute

lymphoblastic leukemia (ALL).

A traumatic lumbar puncture is defined as

the presence of

10 red blood cells/mL.

Nonmalignant disorders

Formulas are available to assist with inter-

Aplastic anemia

pretation of CNS status in the event of

Immune thrombocytopenia

traumatic initial taps with blasts on cytospin

Infections: EBV, CMV, pertussis,

(Steinherz/Bleyer algorithm).

parapertussis

Malignant disorders (round blue cell

Other assessments prior to

tumors with marrow involvement)

Lymphoma

initiation of therapy

Neuroblastoma

An echocardiogram and electrocardiogram

Retinoblastoma

are done as baseline studies in all patients

Medulloblastoma

who will be receiving anthracyclines. These

Rhabdomyosarcoma

drugs are frequently given in induction for

high risk patients and in the delayed inten-

Abbreviations: EBV, Epstein-Barr virus;

sification phase for all patients. Acute and

CMV, cytomegalovirus.

delayed cardiotoxicity may occur, though

148

Chapter 15

late complications are more often related to

approximately two-thirds of pre-B and

high cumulative doses (i.e., >300 mg/m²)

one-third of T-cell ALL patients are classified

given at a young age (<4 years) and asso-

as SR. Better outcomes are observed in youn-

ciated with other risk factors for cardiac

ger children, B-cell phenotype, those with

disease such as mediastinal radiation, obe-

more favorable cytogenetic features, and

sity, family history of early cardiovascular

females.

disease, and abnormal lipid profiles.

Further stratification into treatment

Viral serologies for hepatitis B and C,

groups is done within the first few weeks

cytomegalovirus

(CMV), herpes simplex

of therapy based on early morphologic

virus (HSV), and varicella zoster virus (VZV)

response to therapy (as measured by day

are obtained as baseline information (see

7and/or day 14 bone marrow aspirate),

Chapter 25). This aids in determining if later

cytogenetic abnormalities identified on the

infection with one of these viral agents could

diagnostic marrow, and remission status

be related to transfusion (potentially in the

at the end of induction (morphologic and

case of hepatitis B and C), and whether

as measured by minimal residual disease

the infection is primary or reactivation (in

[MRD] detection). Other considerations

the case of CMV, HSV, and VZV). Baseline

include presence of extramedullary disease

knowledge of previous exposure may impact

such as testicular or CNS disease. Infants

later treatment choices.

have a special category as they are a partic-

ularly high risk group, especially the very

Risk group classification

young.

The concept of risk stratification allows

patients at comparatively high risk of

Treatment

relapse to be treated with more intensive

Treatment of childhood leukemia is one of

and potentially more toxic therapies,

the success stories in pediatric oncology,

whereas patients at lower risk of relapse are

though much remains to be accomplished.

given lower intensity regimens that main-

Remarkable advances have occurred by the

tain the same low risk of recurrence while

identification of more effective drug com-

minimizing exposure to unnecessary agents

binations, recognition of drug sanctuary

and decreasing toxicity. Classification into

sites and routine presymptomatic CNS

risk groups is generally based on clinically

directed therapy, intensification of therapy

apparent prognostic factors identified by

in early phases, and identification of clinical

retrospective analysis and then verified

and biologic variables predictive of outcome

by prospective studies. Many risk factors

for use in risk stratification.

have been utilized in risk classification for

Most children with cancer in the United

acute leukemia, but only age, WBC, and

States are treated at pediatric oncology cen-

immunophenotype (i.e., AML vs. ALL, T-

ters and have access to participation in clin-

vs. B-cell ALL) at diagnosis continue to be

ical trials. These studies have accelerated the

the most significant factors for initial

advances made in the diagnosis and treat-

classification.

ment of pediatric cancer and clearly are a

The commonly used National Cancer

major reason for many of the successes. The

Institute criteria classify standard risk (SR)

Children’s Oncology Group is a national

ALL as children 1 to 10 years of age with a

collaborative group of professionals involved

WBC <50

10⁹/L and high risk (HR) ALL

in the treatment of children with cancer.

as children with age

10 years or WBC

Most pediatric cancer centers register

10⁹/L. Utilizing these criteria,

patients on these trials. Families are asked

Acute Leukemias

149

to give informed consent to participate in

cytarabine

(Ara-C) and methotrexate.

these trials, which may include clinical and

Patients with HR ALL also receive daunoru-

biologic questions. For families not wishing

bicin. Consolidation for HR patients incor-

to participate, the standard of care is offered

porates cyclophosphamide, cytarabine,

(best published clinical regimen). Many

asparaginase, 6-mercaptopurine, and inten-

centers may also participate in smaller pilot

sified therapy directed toward the CNS (either

studies or have their own clinical protocols.

intrathecal methotrexate alone or with radi-

The purpose of therapy in ALL is to

ation for patients with CNS disease). SR

induce a permanent biologic and clinical

patients receive intensified CNS therapy with

remission (no evidence of disease on labo-

minimal systemic chemotherapy. The delayed

ratory and physical assessment). Overall,

intensification (DI) phase has led to signifi-

approximately 85% of children with ALL will

cantly improved outcomes as has further

be cured of their disease. Treatment regimens

intensification of the interim maintenance

are classically divided into phases of therapy:

phase (intensified vincristine and methotrex-

* Induction: refers to the first 28 to 35 days

ate compared to standard maintenance). DI

of therapy, after which the child should be in

is a concept in which reintensification of

a morphologic remission. Remission induc-

therapy following attainment of remission

tion rate in SR ALL is 98%.

can be achieved with some alteration in drugs

* Consolidation: further systemic chemo-

utilized previously in the induction and con-

therapy is given, in addition to a focus on

solidation phases. Maintenance classically

CNS prophylaxis.

consists of pulses of steroid (prednisone or

* Interim Maintenance: similar drugs as

dexamethasone) and vincristine in addition

maintenance, but in a more intensified

to oral methotrexate and 6-mercaptopurine.

manner.

Individualized drug dosing is required to

* Delayed Intensification: refers to rein-

maintain certain hematologic levels and dif-

duction and reconsolidation; may be given

ferences in metabolism and tolerability are

once or twice, depending on the protocol.

likely related to individual polymorphisms.

* Maintenance: continuation of therapy;

This aspect of management in addition to

this phase lasts 2 to 3 years (longer in males

the length of maintenance makes it a unique

due to theoretical increased risk for testic-

cancer therapy for children.

ular relapse).

CNS prophylaxis continues with peri-

* CNS directed therapy: intrathecal meth-

odic intrathecal methotrexate throughout

otrexate; cranial radiation in select groups

therapy. Children with CNS3 disease receive

(CNS3, T-cell).

augmented therapy with 1800 cGy cranial

radiation, in addition to intrathecal meth-

Open clinical trials will likely alter some

otrexate. Treatment of children with CNS2

aspect of therapy for certain risk groups

disease is controversial although recent

in an attempt to improve outcomes and

Children’s Oncology Group studies have

diminish acute and late toxicity. Some

showed no difference between CNS1 and

examples may include adding a new agent

CNS2 patients receiving equivalent therapy.

in certain phases, altering chemotherapy

This is due to the addition of medications

dosing or timing in specific phases, or pos-

with improved penetration through the

sibly asking a radiation-related question.

blood-brain barrier, including dexametha-

Conventional induction therapy includes

sone instead of prednisone and high-dose

prednisone or dexamethasone, asparaginase,

methotrexate. Without CNS prophylaxis, it

and vincristine in addition to intrathecal

is estimated that 60% to 70% of children

150

Chapter 15

would relapse in the CNS (based on histor-

on to have a long-term remission with inten-

ical data). T-cell patients are at higher risk

sified therapy. Due to the frequency of ALL as

for CNS relapse and augmented CNS-

compared to other pediatric malignancies,

directed therapy is given to all patients (even

relapsed ALL is the fourth most common

without overt CNS involvement) with pro-

oncologic diagnosis in children. Timing and

phylactic 1200 cGy cranial radiation.

site of relapse are prognostic and important

determinants for future therapy. Sites of

Complications of therapy

relapse include the bone marrow or an extra-

Because of the myelosuppressive nature of

medullary site, such as the CNS or testes, or

therapy and the underlying disease state,

some combination of sites. Early relapse

children undergoing chemotherapy and/or

(<18 months since therapy initiation) is

radiation may expect to experience compli-

associated with a particularly grim prognosis.

cations during the course of their treatment.

Concepts of therapy include systemic retreat-

Many of these complications can be antici-

ment and radiation therapy to sites of extra-

pated and prevented (see Chapter 25). Most

medullary relapse. Allogeneic hematopoietic

patients will require transfusion support with

stem cell transplantation

(HSCT) may

packed red blood cells and/or platelets (see

improve the outcome of patients with mar-

Chapter 5). Children with neutropenia are

row or combined relapse. Overall survival

instructed to take special precautions to

after relapse is also impacted by cumulative

decrease the risk of infection exposure. Any

toxicity from prior therapy and high infec-

child receiving chemotherapy who develops a

tion rates due to the increased intensity of

fever should have emergent medical atten-

therapy. In general, children with late, iso-

tion, especially during phases of anticipated

lated extramedullary relapse fare better.

neutropenia (i.e., induction, consolidation,

delayed intensification; see Chapter

27).

New agents

Certain therapies are associated with specific

New agents are currently under investigation

toxicities: anthracyclines with cardiotoxicity,

to improve outcomes for high-risk and

vincristine with peripheral neurotoxicity,

relapsed patients. Such agents include the

intrathecal methotrexate with central neuro-

tyrosine kinase inhibitors (imatinib, dasati-

toxicity, steroids (especially dexamethasone)

nib) in Philadelphia chromosome positive

with avascular necrosis of bone, and radiation

ALL and nelarabine in T-cell disease. Finding

with acute and late effects (see Chapter 30).

agents with favorable toxicity profiles for use

These anticipated side effects should also be

in highly treated relapse patients is a

discussed in detail with the patient and family

challenge. Monoclonal antibodies such as

to help with earlier recognition and support-

inotuzumab and epratuzumab (anti-CD22

ive care should be initiated as needed. Poten-

antibodies) may be part of the solution.

tial late toxicities are monitored throughout

Clofarabine, a new generation nucleoside

the course of treatment and in the off-therapy

analog that inhibits DNA synthesis, is

phase of follow-up.

currently being investigated in relapsed and

refractory ALL. Other drugs are being

Relapse

explored utilizing newly acquired knowledge

Despite the dramatic improvements in our

of novel signaling pathways such as mTOR

knowledge about the biology of ALL, prog-

inhibitors. It is anticipated that the next

nostic factors, and more tailored therapy,

generation of clinical trials will be utilizing

20% of children with ALL will relapse, with

a combination of conventional chemother-

only about one-third of those patients going

apy and immunomodulator therapy.

Acute Leukemias

151

Acute myelogenous leukemia

by 4 to 6 weeks of age. However, these

children have a 20% to 30% risk of devel-

Approximately 20% of acute childhood leu-

oping AML before 3 years of age. Children

kemia is myelogenous. Unlike ALL, AML

with transient myeloproliferative disorder

does not have a peak incidence in children

or presumed congenital AML who do not

as there are only subtle increases in inci-

display phenotypic features of DS should

dence from infancy to adolescence. On the

have a karyotype performed to look for

other hand, there appears to be a steady

possible trisomy 21 mosaicism.

increase with age in adults, in whom the

Patients with inherited bone marrow

incidence of AML is approximately four

failure syndromes such as Fanconi anemia,

times that of ALL. AML is associated with

Kostmann syndrome, Bloom syndrome,

a poorer prognosis than ALL, with long-

dyskeratosis

congenita,

Shwachman-

term survival expected to be 50% to 60%.

Diamond syndrome, congenital amegakar-

Additionally, therapy for AML, which

yocytic thrombocytopenia, and Diamond-

includes multiagent chemotherapy and

Blackfan anemia have a predisposition to

HSCT, is one of the most toxic therapies

malignancy, including AML. Other condi-

in childhood cancer. Hispanic children are

tions such as Li-Fraumeni syndrome,

noted to have a higher incidence of AML,

Noonan syndrome, acquired paroxysmal

mostly accounted for by the acute promye-

nocturnal hemoglobinuria, and myelodys-

locytic leukemia subtype (APL; M3). The

plastic syndrome confer an increased risk.

incidence of secondary AML following

Twins and siblings of AML patients have an

treatment of childhood cancer is rising, due

increased risk of AML, though this is much

in part to increased survival after primary

more significant in monozygotic twins

malignancy as well as increased use of agents

within 6 years of initial diagnosis. Exposure

that cause direct DNA damage (e.g., alka-

to ionizing radiation has also been convinc-

lytors

[cyclophosphamide, ifosfamide],

ingly implicated, especially following the

anthracyclines

[doxorubicin, daunorubi-

atomic bombs in World War II.

cin], radiation therapy), and those that

inhibit topoisomerase II (e.g., epidophyllo-

Clinical presentation

toxins [etoposide] and anthracyclines).

AML and ALL are indistinguishable at pre-

The etiology of AML is likely sporadic

sentation, with the majority of signs and

although several inherited and acquired risk

symptoms being related to infiltration of the

factors may predispose to this disease. The

marrow and other body organs. Dependent

most common inherited predisposition to

on the number of circulating myeloblasts

develop leukemia is DS. Children with DS

and total WBC, some of the presenting

have a

10- to

20-fold increased risk of

manifestations may be life threatening.

developing acute leukemia compared to

Children with extreme leukocytosis (WBC

other children. In early life, children with

> 200

10⁹/L) may present with metabolic

DS have a particularly high risk of the

abnormalities and tumor lysis syndrome

megakaryoblastic subtype of AML (AMKL;

(see Chapter 14). Clinically, they are at risk

M7). Overall, children with DS constitute

for hypoxia in the small vessels of the brain

approximately 10% of children with AML.

and lungs as a result of increased blood

In addition, approximately 10% of neonates

viscosity related to the rheology of the mye-

with DS may develop a transient myelopro-

loblasts (large, adherent, and nondeform-

liferative disorder that mimics congenital

able cells). This may translate to sludging

AML but typically improves spontaneously

in the small vasculature of the retinal,

152

Chapter 15

pulmonary, and central nervous systems

thromboplastin from cytoplasmic granules

with resultant decreased oxygen delivery,

in the promyelocytic blasts.

hypoxia, and stroke.

Children with AML and hyperleukocyto-

Patients typically present with signs and

sis (WBC >100

10⁹/L) are at risk for tumor

symptoms related to pancytopenia with pal-

lysis syndrome at presentation and with the

lor, fatigue, anorexia, and bleeding. Fever is

initiation of therapy. Risk factors include the

very common at presentation, often with no

presence of bulky disease with lymphadenop-

apparent infectious etiology. Bone pain is

athy and/or hepatosplenomegaly as well as a

also common, though not typically associ-

rapidly escalating WBC count suggesting a

ated with fractures. Some unique and sug-

high mitotic index (see Table 15.4).

gestive features of AML at presentation

include leukemia cutis in infants (blueberry

Diagnostic evaluation

muffin rash thought secondary to extrame-

The same studies suggested for the evalua-

dullary hematopoiesis) and chloromas

tion of ALL should be obtained in the

(extramedullary collections of myeloblasts).

evaluation of the child with suspected AML.

Chloromas may occur in up to 10% of

It is common to see severe anemia and

children with AML and present most com-

thrombocytopenia in association with an

monly in the bones, skin, soft tissues, and

elevated total WBC count. The definitive

lymph nodes, but may occur anywhere in

diagnosis is made with the evaluation of the

the body. Gingival hypertrophy is a unique

bone marrow, with at least 25% to 30% of

finding in AML secondary to chloroma of

the cellular elements identified as myelo-

the gums. A particularly rare yet important

blasts based on immunophenotyping and

presentation is spinal cord compression

cytochemistry. Morphologic review may

from a chloroma in the paraspinal/epidural

also reveal Auer rods (clumps of azurophilic

region.

granules shaped into elongated needles and

Life-threatening bleeding is another

located in the cytoplasm), classically only

complication somewhat unique to AML.

seen in some subtypes of AML (i.e., M2 and

Although the majority of patients will be

M3). A lumbar puncture should be done as

thrombocytopenic secondary to marrow

up to 5% of children will have overt CNS

infiltration with myeloblasts, patients with

involvement at presentation. A coagulation

concomitant coagulopathy due to dissemi-

evaluation should be performed in these

nated intravascular coagulation are at partic-

patients including PT, INR, PTT, fibrino-

ularly high risk, a finding seen most com-

gen, and D-dimers to evaluate for the

monly in APL (M3 AML). This association is

possibility of disseminated intravascular

thought to be secondary to the release of

coagulation (most typically seen in M3).

Table 15.4 Clinical manifestations of hyperleukocytosis in acute myelogenous leukemia (AML).

Organ at risk

Consequence

Lungs

Hypoxia, respiratory distress, pulmonary infiltrates

CNS

Alteration of mental status, stroke, intracranial bleeding

Eyes

Decreased visual acuity

Kidneys

Renal insufficiency (exacerbated by tumor lysis syndrome)

Abbreviation: CNS, central nervous system.

Acute Leukemias

153

Several morphologic classification sys-

prognosis. Finally, chromosomal aberra-

tems are available for AML, including the

tions including monosomy 7 or 7q deletion,

classic French-American-British (FAB) clas-

monosomy 5 or 5q deletion, and complex

sification of M0

to M7 and the World

abnormalities

(

or more unrelated

Health Organization (WHO) categorization

changes) all impart a worse prognosis.

into four major subgroups (Table 15.5).

Monosomy 5 and 7 are also highly associ-

Additionally, chromosome analyses are per-

ated with cases of secondary myeloprolifer-

formed to obtain important diagnostic and

ative disorders and AML that develop after

prognostic markers. Approximately 60% of

chemotherapy for a primary malignancy.

children with primary AML demonstrate

See Other assessments prior to initiation of

clonal abnormalities in the blast lineage

therapy in the ALL section for further

prior to therapy initiation. The t(8;21)

information.

translocation is the most common chromo-

some translocation and is associated with

Risk group classification

the M2 subgroup and a more favorable

Historically AML has been classified utiliz-

prognosis. The t(15;17) translocation is

ing the FAB morphologic classification sys-

classically seen in APL (AML M3). Inversion

tem (Table 15.5). The WHO classification

of chromosome 16 (inv(16)) is associated

system was subsequently developed to also

with acute myelomonoblastic leukemia

include cytogenetics, disease biology, and

(AML M4) and also portends a favorable

clinical history. Host factors such as age,

Table 15.5 Morphologic classification for acute myelogenous leukemia (AML).

AML Subtype

Clinical/biologic features

Undifferentiated leukemia

Similar to ALL, requires CD13, CD33, CD117,

and absence of lymphoid markers

Acute myeloblastic leukemia

MPO þ by special stains/flow cytometry

without differentiation

Acute myeloblastic leukemia with

Auer rods, t(8;21) common, chloromas,

differentiation

good prognosis

Acute promyeloblastic leukemia

Auer rods, DIC/bleeding, t(15;17), good

prognosis with ATRA therapy

Acute myelomonoblastic leukemia

Mixed myeloblasts (20%) and monoblasts,

peripheral monocytosis

Acute monocytic leukemia

80% marrow nonerythroid cells are

monocytic, MLL (11q23) rearrangements

in infants, CNS disease more common,

chloromas (e.g., gingival hyperplasia)

Erythroleukemia

Rare in children

Acute megakaryoblastic leukemia

Classically seen in Down syndrome with

GATA1 mutation, good prognosis; rare

in non-DS with t(1;22), poor prognosis

Abbreviations: ALL, acute lymphoblastic leukemia; MPO, myeloperoxidase; DIC, disseminated

intravascular coagulation; ATRA, all-trans retinoic acid; MLL, mixed lineage leukemia; CNS,

central nervous system; DS, Down syndrome.

154

Chapter 15

gender, race, and constitutional abnormal-

have shown no added benefit for a mainte-

ities all have some prognostic influence on

nance phase following intensification. Allo-

outcome. Females do slightly better than

geneic HSCT is recommended for patients

males, older children do better than infants

with high risk cytogenetics (i.e., monosomy

(though outcomes in infants are improving

7, FLT3/ITD [internal tandem duplication],

with current therapies), and Caucasians fare

monosomy 5, or 5q-) or those who have not

better than non-white patents. Children

attained a remission following two courses

with DS, particularly those under the age

of induction therapy. Patients with favor-

of 4 years at diagnosis, have an improved

able risk cytogenetics and good early

outcome with less intensive therapy (overall

responses to induction therapy receive allo-

survival 80%) but also show increased tox-

geneic HSCT only in the case of relapse and

icity with therapy. Children with an initial

if a second remission has been achieved. It

WBC < 20

10⁹/L have an improved out-

remains unclear if HSCT has benefit for

come and those with hyperleukocytosis

those AML patients with intermediate risk

(WBC >100

10⁹/L) have a worse out-

features (usually defined as neither high risk

come. A number of recurring cytogenetic

features nor low risk features) and decisions

abnormalities are associated with AML and

must be made on an individual basis asses-

confer prognostic significance. Overall,

sing the clinical status of the patient, avail-

poor risk features include WBC count >100

ability of an appropriate match, and family

10⁹/L, monosomy 7, and secondary AML.

preference.

Good risk features include certain FAB sub-

The morphologic subtypes of AML with

types (M1/M2 with Auer rods, M3, M4 with

highest involvement of the CNS are FAB M4

eosinophilia), rapid response to initial ther-

and M5. Overall, the frequency of CNS

apy, and favorable chromosomal features

involvement is between 15% and 20% at

such as t(8;21), t(15;17), and inversion 16.

diagnosis. All patients receive CNS conso-

As with ALL, assessment of MRD is becom-

lidative therapy with intrathecal cytarabine

ing an important marker of outcome with

in addition to high-dose cytarabine, which

chemotherapy and transplant.

has good CSF penetration. AML patients

with myeloblasts in the CNS can usually be

Treatment

cleared with intrathecal cytarabine. Cranial

As with ALL, the goal of induction therapy is

irradiation is reserved for those children

to induce a clinical and biologic remission

with refractory CNS involvement. Children

by rapidly reducing the number of malig-

with Down syndrome rarely have CNS

nant cells. Approximately 80% of children

involvement, and due to their increased

achieve remission with induction therapy.

risk of toxicity, CNS prophylaxis has been

The most effective induction regimens use a

greatly reduced without negative conse-

combination of cytarabine and an anthra-

quence in these patients.

cycline, typically daunorubicin. Individual

APL is distinctly different from the other

trials have built upon this backbone with

AML subtypes and has a particularly good

changes in dosing and timing, alternative

prognosis due to the development of tar-

anthracyclines, or introduction of new sup-

geted therapies. Approximately

3% of

portive care strategies to better manage

patients with APL die in the early phases

potential adverse effects of therapy. Other

of therapy as a result of the unique hemor-

agents utilized in continuation therapy

rhagic complications of this disease.

include etoposide, dexamethasone, 6-thio-

Patients receive treatment with differentiat-

guanine, and asparaginase. Prior studies

ing agents such as all-trans retinoic acid

Acute Leukemias

155

(ATRA) and arsenic trioxide (ATO). The

Complications of therapy

t(15;17) translocation is present in the

Given the intensity of therapy for AML,

majority of cases and leads to the produc-

children can expect to experience a number

tion of a fusion protein involving the reti-

of complications that include cytopenias

noic acid receptor alpha and promyelocyte

requiring frequent blood product support,

gene leading to arrest of differentiation at

mucositis, liver toxicity, need for parenteral

the promyelocyte stage. ATRA induces the

hyperalimentation, and severe, prolonged

differentiation of immature promyelocytes

marrow suppression. Infection is common

into mature granulocytes, followed by res-

and should be anticipated. Once neutrope-

toration of normal hematopoiesis. ATRA

nic, these children are at particularly high

does not cross the blood-brain barrier

risk for the development of sepsis with

and is therefore ineffective in treating CNS

Gram-negative organisms in addition to

involvement with APL. A WBC

10⁹/L

invasive fungal disease. Routine antifungal

is associated with a higher risk of relapse.

prophylaxis with fluconazole is recom-

Higher WBC count is also associated with

mended in addition to PCP prophylaxis.

the microgranular variant (M3v), presence

Streptococcus viridans sepsis is associated

of the FLT3/ITD mutation, and the bcr3

with the use of high-dose cytarabine and

isoform. Treatment includes induction with

resultant altered integrity of the gastroin-

ATRA and anthracycline therapy (i.e., idar-

testinal mucosa. Sepsis with this organism

ubicin or daunorubicin) followed by anthra-

can be rapidly fatal. Empiric therapy for

cycline consolidation and maintenance with

fever and neutropenia should include cov-

intermittent ATRA and low dose 6-mercap-

erage for S. viridans and be started imme-

topurine. The use of arsenic trioxide in the

diately with the first fever. Prolonged hos-

initial treatment of patients with APL

pitalization is expected during the course of

remains controversial and is currently under

treatment for AML and these patients

investigation. Similarly, the length and use

should be in protective environments.

of a consolidation phase as well as the need

Coagulopathy at diagnosis is not uncom-

for intrathecal chemotherapy are yet to be

mon, especially in the child with APL. Coag-

answered questions. Patients can expect an

ulation studies should be done routinely. In

event-free overall survival of 70% to 80%.

general, platelet counts should be maintained

Toxicities with ATRA may be significant;

above 10

10⁹/L (>50

10⁹/L for the APL

specifically, ATRA may lead to a differenti-

patient at diagnosis). The use of fresh frozen

ation syndrome in 2% to 6% of patients and

plasma, cryoprecipitate, and platelets are

present with fever, respiratory distress,

important supportive care measures due to

weight gain, edema, and, importantly,

the frequently observed coagulopathy, hypo-

hyperleukocytosis. The incidence of ATRA

fibrinogenemia (fibrinogen <150 mg/dL),

syndrome has decreased due to the addition

and thrombocytopenia, respectively. This

of anthracycline therapy in induction and

will help prevent bleeding complications,

can be treated with IV dexamethasone.

especially in the APL patient (in addition

ATRA may cause other side effects including

to the early initiation of ATRA therapy).

dryness of the lips and mucosa, fever, trans-

aminitis, and headache associated with

Relapse

pseudotumor cerebri. Due to the rarity of

Even with current intensive therapies, only

APL in pediatric patients, the role of arsenic

about half of children diagnosed with AML

trioxide and transplant after relapse is still

are expected to be long-term survivors. As

poorly defined.

mentioned, patients with DS and APL have

156

Chapter 15

an improved prognosis. Some patients suc-

nucleoside analogues (clofarabine), farnesyl-

cumb to early mortality related to progressive

transferase inhibitors

(tipifarnib), histone

disease, infection, bleeding, and other com-

deacetylase inhibitors

(vorinostat), protea-

plications of therapy. After relapse, chemo-

some inhibitors (bortezomib), and demethy-

therapy alone results in <10% 1-year disease-

lating agents (decitabine and azacitidine).

free survival (DFS). For those patients that

can again obtain a morphologic remission

after reinduction chemotherapy, HSCT

Suggested Reading

improves survival to 30% to 50%. MRD after

reinduction therapy for AML relapse has

Pui CH, Carroll WL, Meshinchi S, Arceci RJ.

been shown to be a vital prognostic factor

Biology, risk stratification, and treatment of

in DFS after HSCT. Newer modalities of

pediatric acute leukemias: an update. J Clin

therapy are needed and are under investiga-

Oncol 29:551-565, 2011.

tion. These include targeted immunotherapy

Seibel NL. Treatment of acute lymphoblastic

(gemtuzumab targeted against CD33), tyro-

leukemia in children and adolescents: peaks

sine kinase inhibitors (lestaurtinib and sor-

and pitfalls. Am Soc Hematol Educ Prog

afenib for patients with FLT3 mutations),

374-380, 2008.

Central Nervous

System Tumors

Central nervous system (CNS) tumors are the

criteria useful in grading of tumors include

most common cancer diagnosed in children

cellular pleomorphism, mitotic rate, degree

after leukemia, accounting for 20% of all

of anaplasia, and presence or absence of

pediatric malignancies. The most common

necrosis. A growing number of chromo-

location is infratentorial in children up to 14

somal abnormalities and specific genomic

years of age, while supratentorial tumors are

signatures have been identified in pediatric

more common in adolescents. Spinal cord

brain tumors, and the use of these is becom-

tumors are also more common in adolescents

ing increasingly important for accurate

than in younger children (9% vs. 3%).

pathologic classification.

The cause of most pediatric CNS tumors

is unknown. The majority of them are

sporadic, although a small percentage is

Clinical presentation

associated with genetic disorders such as

neurofibromatosis, tuberous sclerosis, von

It is often difficult to make the diagnosis of

Hippel-Lindau syndrome, and Li-Fraumeni

a CNS tumor in a child. The presenting

syndrome (germ line mutation of p53, a

symptoms of CNS tumors can be quite

suppressor oncogene). Radiation therapy

variable, depending on the location of the

is the most frequently identified cause of

tumor, its rate of growth, and the age of the

pediatric CNS tumors; these occur as second

child. Additionally, most of the symptoms

malignancies in children who have previ-

are nonspecific, and occur more commonly

ously received radiation therapy for the

in children with a variety of benign condi-

treatment of leukemia or primary CNS

tions. Prompt diagnosis of a CNS tumor

tumors.

requires an appropriate index of suspicion

In general, brain tumor classification is

and a good understanding of the duration of

based on embryonic derivation and histo-

symptoms that is expected with other dis-

logic cell of origin, and occasionally on

orders. Due to the frequent association of

tumor location. The World Health Organi-

hydrocephalus with infratentorial tumors,

zation Classification System for brain

50% of children with brain tumors will

tumors contains more than

100 entries,

present with signs of increased intracranial

making it difficult for pathologists to agree

pressure (ICP), including lethargy, vomit-

on a diagnosis in specific cases. Microscopic

ing, and irritability. These symptoms may

Handbook of Pediatric Hematology and Oncology: Children’s Hospital & Research Center Oakland,

Second Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.

2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

158

Chapter 16

be less prominent in infants because the

Seizures are relatively rare in younger

cranial sutures remain open and the skull

children but occur twice as often in adoles-

can accommodate the increase in ventric-

cents (13% vs. 25%). They can be focal or

ular size. For this reason, accurate mea-

generalized. When focal they may provide a

surement of the head size should be part of

clue as to the location of the tumor. An

every well-baby examination. Headache is

often-overlooked symptom in school-age

a presenting symptom in 70% of children

children is deterioration in school perfor-

with posterior fossa tumors and 50% of

mance and behavioral changes. It is not

central tumors. Features that are helpful in

uncommon for these children to be referred

distinguishing tumor-related headache

by a psychologist or psychiatrist after many

from a primary headache syndrome

months of unsuccessful therapy for these

include nausea and vomiting (particularly

symptoms.

in the morning), increasing frequency and/

Symptoms of spinal cord tumors are

or severity over a few weeks, and abnor-

caused by compression of the spinal cord

malities on neurologic examination.

or nerve roots by the mass. The most com-

Neurologic deficits such as ataxia, visual

mon symptom in children with spinal cord

changes, and hemiparesis occur in about

tumors is back pain. Unlike adults, the

25% of cases. Weakness is sometimes sub-

complaint of back pain is very rare in child-

tle, but parents often relate a loss of phys-

hood. “Benign” causes of back pain include

ical function or developmental milestones.

trauma, medical conditions such as sickle

Visual changes include diplopia caused by

cell disease, or involvement in aggressive

cranial nerve dysfunction and loss of visual

sports such as football, gymnastics, skate-

acuity caused by optic nerve involvement

boarding, or motocross bicycling. In the

or papilledema.

absence of such a history, there should be

Two specific clinical syndromes are fre-

concern that a tumor might be the cause.

quently associated with childhood brain

Tumor-related pain is often described as

tumors. Parinaud’s syndrome consists of

being worse in the supine position or with

paralysis of upward gaze, accommodative

Valsalva’s maneuver. Other symptoms asso-

paresis, nystagmus during attempts at

ciated with spinal cord tumors include sci-

upward gaze, eyelid retraction

(Collier’s

atica, weakness, numbness, problems with

sign), and

“setting-sun sign”

(conjugate

or loss of bowel and/or bladder control, and

downward gaze). It is most commonly asso-

spinal deformity.

ciated with pineal region tumors, but can also

Tumors within the spinal canal are either

be caused by obstructive hydrocephalus from

intramedullary (within the spinal cord or

any cause, posterior fossa tumors, or a num-

nerve roots) or extramedullary. Intramedul-

ber of infectious or vascular abnormalities

lary spinal cord tumors are almost always glial

leading to ischemia or damage to the dorsal

in origin, the most common histologies being

midbrain. Diencephalic syndrome is a rare

astrocytoma, myxopapillary ependymoma,

cause of failure to thrive in infants and young

and oligodendroglioma. Extramedullary tu-

children. Characteristic features include pro-

mors are either intradural or extradural.

found emaciation with normal caloric intake,

Extramedullary intradural tumors are most

absence of subcutaneous fat, locomotor

commonly neurofibromas, Schwannomas, or

hyperactivity, euphoria, and alertness. It is

more rarely meningiomas. Extradural tumors

almost always associated with hypothalamic/

are usually not CNS tumors at all, but

suprasellar tumors, most commonly optic

metastatic tumors from other locations such

pathway gliomas.

as neuroblastoma, lymphoma, or Ewing

Central Nervous System Tumors

159

sarcoma. Tumors within the vertebral bodies

for identification of tumor within areas of

such as primary bone tumors, tumors met-

surrounding edema, detects focal areas of

astatic to bone, and histiocytosis can also

blood-brain barrier (BBB) breakdown, and

extend into the spinal canal and cause the

improves delineation of cysts from solid

above symptoms.

tumor.

Recent advances include MR spectros-

copy, tractography, and functional MRI

scanning. MR spectroscopy allows the

Diagnostic evaluation

determination of the chemical makeup of

tissue within a predefined region of interest.

Imaging studies

Different types of tumors have characteristic

The first step in evaluating a child with a

spectroscopic signatures, allowing the iden-

suspected CNS tumor is neuroimaging. A

tification of the most likely tumor type

variety of imaging techniques can be useful

before surgery takes place. Tractography is

in this assessment.

a software technique that allows identifica-

tion of the location of white matter tracts

Computerized tomography

and their associated nuclei. This has become

Computerized tomography (CT) was the

very useful as a preoperative planning tool

first imaging modality to revolutionize the

that allows the neurosurgeon to avoid dis-

diagnosis of CNS tumors both in children

ruption of eloquent nuclei and fiber tracts

and in adults. It is often still the first imaging

during surgery. Functional MRI is another

study obtained when evaluating patients

technique that precisely identifies specific

suspected of having a tumor. However,

motor regions, speech and language centers,

magnetic resonance imaging

(MRI) has

and other eloquent areas for preoperative

largely replaced it as the definitive neuro-

planning purposes.

imaging study. Advantages of CT include

widespread availability, rapid acquisition

Positron emission tomography

time, superior resolution of bone and vas-

Positron emission tomography (PET) imag-

cular structures including lesions of the

ing is a relatively new modality for evalu-

skull base, and utility in patients with con-

ating a variety of tumors including those of

traindications to MRI (e.g., ferrous metal

the CNS. It detects the relatively higher rate

implants). Its limitations include inferior

of metabolism present in many neoplasms

resolution of the brain itself, particularly

by measuring the rate of metabolism of

within the posterior fossa, and significant

one of a growing number of radioactively

radiation exposure, especially with regular

labeled compounds. It has been used to

monitoring.

distinguish between recurrent tumor and

necrotic tissue, scar, or edema, each of

Magnetic resonance imaging

which can develop following the treatment

An MRI with and without gadolinium

of a malignant brain tumor. It is used to

enhancement is the single best study for

determine the most appropriate site for a

evaluating the majority of tumors within

biopsy. Its utility in young children is lim-

the brain and spine. It provides greater

ited due to the need for a 30- to 60-minute

sensitivity in areas that may be obscured

period of limited mental activity between

by proximity to bone, such as the temporal

injection and scanning to optimize the dis-

lobe and posterior fossa. It also provides

tinction between normal and abnormal

multiplanar images. Contrast MRI allows

structures.

160

Chapter 16

Single-photon emission C T

Bone marrow aspiration

Single-photon emission CT is a three-

In the past it was recommended that patients

dimensional imaging technique introduced

with medulloblastoma undergo a bone mar-

in the early 1980s for the investigation of

row aspiration at the time of diagnosis to rule

regional cerebral blood flow that often cor-

out metastatic disease prior to starting ther-

relates with tumor metabolic activity. In this

apy. However, more recent studies have

technique, radioactive thallium and radiola-

indicated that fewer than 3% of patients

beled tyrosine have been used to localize

diagnosed with medulloblastoma have extra-

brain tumors as well as distinguish viable

neural metastases at diagnosis, with fewer

tumor from radiation necrosis. It is much

than 25% of these having disease in the

less expensive than PET scanning, but the

marrow. Therefore, recent clinical trials have

resolution is less and the 20- to 30-minute

no longer recommended routine examina-

acquisition times needed for high-quality

tion of the bone marrow, but have instead

pictures again limit the utility in young

recommended this only for patients with

children.

unexplained cytopenias. Extraneural metas-

tases are almost unheard of in other types of

pediatric CNS tumors, making bone marrow

Other studies

aspiration at diagnosis unnecessary.

Lumbar puncture

Bone scan

Certain primary CNS tumors such as

While 90% of extraneural metastases in

medulloblastoma, primitive neuroectoder-

patients with medulloblastoma are to bone,

mal tumor (PNET), ependymoma, malig-

this remains an unlikely presenting finding

nant germ cell tumors (GCTs), and, to a

since, as mentioned above, fewer than 3%

lesser extent, malignant gliomas have a pro-

of patients have extraneural metastases at

pensity to metastasize throughout the sub-

diagnosis. Therefore, bone scan should be

arachnoid space. As with other malignant

reserved for brain tumor patients who pres-

tumors, the presence of metastatic disease

ent with bone pain with the underlying

alters both treatment and prognosis. For

diagnosis of medulloblastoma.

this reason, a lumbar puncture (LP) is a

routine part of the diagnostic workup of

these patients. Spinal fluid is collected and

Treatment

sent for cell count and differential, glucose,

protein, and cytological examination to

Children with CNS tumors are typically

look for malignant cells. Measurements of

a-fetoprotein (AFP) and the beta subunit of

treated with some combination of neuro-

surgery, radiation therapy, and chemother-

human chorionic gonadotropin (b-HCG)

should also be performed on patients with

apy. The specific treatment chosen is depen-

suprasellar and pineal region tumors to

dent on the histology, location, resectability,

identify malignant germ cell tumors. These

and prognosis of the patient’s tumor.

markers can, if present, also be used to

measure response to therapy. The diagnostic

Neurosurgery

LP should be delayed for at least 7 days

Initial neurosurgical intervention is indi-

following tumor resection to allow any

cated in the majority of patients. Exceptions

nonviable tumor cells present in the CSF

include diffuse intrinsic pontine gliomas

as a result of the surgery itself to be cleared.

due to the infiltrative nature of the tumor

Central Nervous System Tumors

161

throughout the pons and tumors that are

6 years of age can be expected to suffer

radiographically consistent with germ cell

significant impairment of intellectual and

tumors and present with elevation of both

physical development as a result of this

AFP and b-HCG. This combination con-

therapy. A group of young Canadian chil-

firms the diagnosis of nongermanomatous

dren with medulloblastoma who received

germ cell tumor

(NGGCT) without a

“curative” doses of radiation therapy were

biopsy, and aggressive surgery at diagnosis

followed longitudinally into adulthood;

has not been shown to improve survival.

none of the survivors were capable of inde-

The role of surgery in children with func-

pendent living. Another concern is the

tioning pituitary adenomas is also limited.

development of secondary malignancies in

The goals of neurosurgical intervention

the radiation field. Children receiving pro-

are to achieve the maximum tumor removal

phylactic craniospinal radiation for leuke-

possible while minimizing morbidity and

mia have been shown to have a >20-fold

mortality and to obtain tissue for a histo-

increase in the risk of secondary CNS

logic diagnosis. In the case of medulloblas-

tumors; more than 80% of these tumors

toma, PNET, ependymoma, and high-grade

occurred in children who were radiated

gliomas, extent of surgical resection is one of

before 5 years of age. Children with standard

the major predictors of outcome.

risk medulloblastoma who survive >5 years

Children with increased ICP caused by

following conventional treatment including

obstructive hydrocephalus will likely have a

radiation without a relapse are more likely

CSF diversion procedure performed as well,

to die from a secondary radiation-induced

either before their definitive surgery if they

cancer than from a recurrence of their pri-

are unstable or at the time of resection. An

mary tumor.

external ventricular drain will often be placed

A variety of innovations in radiation

initially and will be clamped at some point

therapy delivery have been developed

after surgery to determine if normal CSF flow

recently to minimize the side effects of

has been restored. Children who redevelop

radiation. These include

3D conformal

symptoms of increased ICP will likely require

planning techniques and intensity-modu-

placement of a permanent shunt.

lated radiation therapy, which minimize the

dose of radiation delivered to adjacent nor-

Radiation therapy

mal tissue. Another innovation is proton

Radiation therapy has played a pivotal role

beam therapy, which takes advantage of the

in the management of children with malig-

shorter decay path of high-energy protons

nant brain tumors for decades. It has been

compared with gamma rays (photons). This

used to destroy remaining tumor in cases of

minimizes the exit dose delivered beyond

incomplete surgical resection and to treat

the site of the tumor. These innovations

microscopic residual disease and metastatic

have proven very valuable in decreasing the

disease in children who have malignant

radiation exposure to heart, lung, bowel,

tumors with a high likelihood of tumor

and reproductive organs in children receiv-

regrowth. The dose of radiation used is

ing whole spine radiation. Nevertheless, the

dependent on the type of tumor and the

use of radiation therapy continues to carry

location and volume to be irradiated.

the risk of significant morbidity. Work con-

Unfortunately, the use of radiation ther-

tinues to develop novel strategies that will

apy is associated with significant adverse late

allow the avoidance of radiation therapy

effects, particularly in young children.

completely in children with CNS tumors,

Those children receiving radiation before

or at least to delay it in very young children.

162

Chapter 16

Chemotherapy

Medulloblastoma is the most common

The utility of chemotherapy in the treat-

malignant CNS tumor in children, account-

ment of CNS tumors was recognized more

ing for up to 20% of all childhood brain

recently than in other tumors. It was initially

tumors. Supratentorial PNET is much less

felt that the BBB would prevent the delivery

common, comprising about 2.5% of cases

of effective concentrations of chemothera-

when pinealoblastoma is included. It has a

peutic agents to the tumor. However, it

propensity to metastasize early; in up to

became apparent that many drugs do ade-

40% of cases, widespread seeding of the

quately cross the BBB, or that this barrier is

subarachnoid space is present. Extraneural

abnormally permeable in many malignant

spread is unusual at diagnosis, but may

brain tumors. Other factors such as tumor

develop later if tumor recurrence occurs.

heterogeneity, cell kinetics, drug distribu-

The initial mode of therapy is surgery,

tion, and drug excretion may also have a

and extent of surgical resection directly

significant impact on effectiveness of

affects prognosis and treatment. Patients

chemotherapy. Lower grade tumors are

with <1.5 cm³ of residual tumor after sur-

characterized by a low mitotic index and

gery and no evidence of metastatic disease

relatively slow growth rate; it was long felt

are defined as standard risk, while patients

that these tumors would be less sensitive to

with >1.5 cm³ of residual disease or meta-

chemotherapy, while more malignant

static disease are considered high risk. Once

tumors would be more sensitive. However,

the diagnosis is confirmed, patients should

several studies over the last two decades

be staged with an MRI of the spine and an

have demonstrated that many low-grade

LP for cell count, glucose, protein, and

tumors are sensitive to chemotherapy.

cytology. Additional studies looking for

Commonly used drugs for the treatment

extraneural metastases are no longer con-

of brain tumors include vincristine, meth-

sidered necessary.

otrexate, temozolomide, procarbazine,

PNETs including medulloblastoma are

lomustine (CCNU), cisplatin, carboplatin,

very sensitive to radiation therapy, and as a

cyclophosphamide, and etoposide.

result this has traditionally been considered

the mainstay of postsurgical therapy. Due to

the high likelihood of metastases through-

Specific tumor types

out the CNS, it has been considered neces-

sary to deliver a dose of radiation to the

Primitive neuroectodermal tumor

entire brain and spine (craniospinal irradi-

PNETs are the most common malignant

ation; CSI) to these patients, with a higher

brain tumors in children. They are comprised

(boost) dose delivered to the region of their

primarily of small cells with hypochromatic

tumor. As the long-term consequences of

nuclei and can occur throughout the CNS.

radiation have become more apparent,

There has been controversy regarding

especially for young children, strategies to

whether these tumors should be classified

delay or avoid radiation in young children

as a single entity or divided by location.

have become more widely used and

The WHO has chosen the latter approach,

attempts have been made to decrease the

and divided these tumors into medullo-

doses of radiation given to older children.

blastoma

(occurring in the cerebellum),

The value of chemotherapy both in

pinealoblastoma

(occurring in the pineal

improving survival among patients with

gland), and supratentorial PNET (occurring

PNETs and in allowing a reduction in the

elsewhere in the supratentorial region).

dose of radiation therapy required for cure

Central Nervous System Tumors

163

has become increasingly evident over the

multimodality therapy is >80%. Children

past three decades. For the past several years

with high risk medulloblastoma and supra-

a combination of cisplatin, vincristine,

tentorial PNET do less well; the most

CCNU, and cyclophosphamide has been

recently published

5-year EFS rates are

used following completion of radiation

50% to 60%.

therapy with good effect. Vincristine is also

used during radiation therapy, and the

Gliomas

Children’s Oncology Group is evaluating

Gliomas account for just over 50% of all

whether the addition of carboplatin during

CNS tumors in childhood. They are a het-

radiation therapy will improve outcomes

erogeneous collection of tumors including

further in children with high risk disease.

astrocytoma (60%), ependymoma (15%),

Due to the devastating effects that CSI

oligodendroglioma (15%), mixed gliomas

can have in children less than 6 years of age

(5%), and other unspecified glial tumors

at the time of treatment, an alternative

(5%). They can occur anywhere in the CNS,

strategy was developed in the early 1990s

although certain subtypes have a propensity

that substituted very intensive chemother-

to occur in specific locations.

apy followed by consolidative myeloablative

Gliomas are classified histologically into

chemotherapy and hematopoietic stem cell

grades 1 to 4 based on cellular pleomor-

rescue without radiation therapy for these

phism, cell density, mitotic index, and

young children. Known as the Head Start

necrosis. Grade 1 and 2 tumors are defined

regimen, this strategy proved fairly effective

as low grade gliomas (LGG); they are con-

for children with standard risk embryonal

sidered by some to be “benign,” but many

tumors, but results were suboptimal for

neuro-oncologists disagree with this defini-

patients with high risk medulloblastoma

tion. Grade 3 and 4 gliomas are defined as

or supratentorial PNET, including pinealo-

high grade gliomas (HGG) and are clearly

blastoma. In 1995, the second Head Start

malignant. For most gliomas, the histologic

study added high-dose methotrexate to the

classification is the most important factor in

existing chemotherapy; results from this

choosing therapy and predicting long-term

modification were very encouraging.

outcome.

Patients with standard risk medulloblas-

Surgical resection is a key component of

toma had 5-year event-free survival (EFS)

therapy for most gliomas that are amenable

rates of 50% and overall survival rates of

to this approach. This includes cerebellar

75%. Children who relapsed following che-

gliomas and supratentorial gliomas that are

motherapy alone were effectively salvaged

not centrally located or within the optic

with reoperation and radiation therapy in

pathway. Gliomas occurring in the tectal

half of the cases. This strategy led to more

region of the midbrain are an exception

than 70% of children with standard risk

to this rule; these are very indolent tumors

disease treated on Head Start II being cured

that typically require no intervention. LGG

without radiation therapy. The Children’s

that are completely resected do not require

Oncology Group is investigating a similar

adjuvant therapy and are simply observed. If

strategy for children <3 years of age with

they recur, re-resection is generally curative.

high risk medulloblastoma and supraten-

Surgery should be used judiciously, how-

torial PNET.

ever. Most LGG can be controlled success-

The outlook for children >3 years of

fully with chemotherapy, so surgery that

age with standard risk medulloblastoma is

leaves the patient with significant postop-

quite good;

5-year EFS with current

erative morbidity should be avoided. HGG

164

Chapter 16

always require adjuvant therapy, but the

therapy has been estimated to prolong sur-

likelihood of cure is related to the degree

vival for a median of 2 months; since the

of surgical resection.

therapy takes 6 weeks to deliver, the impact

Radiation therapy was a key part of the

of this treatment on improving quality of

treatment of all gliomas for many years, but

life may be minimal, especially for children

it is used very rarely now to treat children

requiring anesthesia for their radiation.

with LGG due to the frequency of long-term

Many trials have been conducted over the

consequences of this therapy and the real-

past 25 years trying to improve the survival

ization that these tumors can be managed

of children with this tumor, all with disap-

successfully with chemotherapy. It remains

pointing results.

an essential component of therapy for HGG,

Although ependymomas are traditionally

however. Since these tumors metastasize

classified with other glial tumors, their behav-

much less frequently than PNETs, children

ior and management is quite different. They

do not require CSI, but they do require

represent about 5% to 10% of childhood

doses of 50 to 60 Gy to their tumor sites

primary brain tumors. About 60% of intra-

to achieve local control.

cranial ependymomas occur in the posterior

The value of chemotherapy in the man-

fossa and 40% are supratentorial. Grade 1

agement of children with LGG has become

ependymomas are rare and almost never

increasingly apparent over the past ten years.

occur in the brain, although Grade 1 (myx-

This is especially true for children with neu-

opapillary) ependymomas of the spine com-

rofibromatosis-associated LGG, as the fre-

prise about 10% of childhood ependymomas.

quency of secondary malignant tumors in

Grade 4 ependymoma does not exist.

these children after treatment with radiation

The extent of surgical resection is the

therapy is alarmingly high. The goal of ther-

most important prognostic factor in chil-

apy in this situation is different than with

dren with ependymoma. The 5-year EFS

other tumors. Chemotherapy rarely leads to

for patients having a complete resection is

total disappearance of the tumor, but rather

80%, versus 40% for those patients having a

produces a state of stable disease that is

near-total or subtotal resection. Unfortu-

hopefully maintained after therapy is discon-

nately, ependymomas are often difficult to

tinued. In this regard, management of

completely resect, especially in the posterior

incompletely resected LGG is similar to man-

fossa due to their predilection to surround

aging a chronic illness like asthma, with

cranial nerves and other vital structures. It

periods of stability, occasional flares of dis-

remains unclear that postoperative chemo-

ease, and a hope that the child will eventually

therapy improves survival in patients with

“grow out” of their condition.

ependymoma, but it may improve outcome

Gliomas arising in the brain stem deserve

when given before second look surgery to

special mention. These comprise about 15%

improve the likelihood that a complete

of brain tumors in children. About 70% of

resection can be achieved. Radiation ther-

these arise in the pons and are diffusely

apy remains an important component of

infiltrative, and are termed diffuse intrinsic

therapy for this tumor; the doses required

pontine gliomas. These are the most deadly

are similar to those needed to achieve local

of all childhood brain tumors; median sur-

control of other glial tumors. Ependymo-

vival of children with this diagnosis is 8 to 9

mas are more likely to metastasize within

months, and 90% of affected children are

the CNS than other gliomas, especially if

dead within 2 years of diagnosis regardless

they originate in the posterior fossa or are

of the treatment provided. Radiation

Grade 3. Assessment of the spinal fluid

Central Nervous System Tumors

165

postoperatively is important, although neg-

management quite challenging. The best

ative spinal fluid cytology does not reliably

outcomes for these children occur when

identify patients less likely to recur away

they are diagnosed early and treated at a

from their primary tumor site.

center with a multidisciplinary neuro-

oncology program. Therefore, every effort

Germ cell tumors

should be made to ensure that potential

CNS GCTs are relatively uncommon. Their

signs of a brain tumor are not missed and

management shares many similarities with

that early referral to such a multidisciplinary

GCTs occurring outside the CNS. They are

center occurs.

discussed in Chapter 21.

Suggested Reading

Summary

Robertson PL. Advances in treatment of pediatric

In summary, although brain tumors occur

brain tumors. NeuroRx 3:276-291, 2006.

relatively commonly in children, the varia-

Wen PY, Schiff D, Kesari S, et al. Medical man-

tions in histologic appearance, presentation,

agement of patients with brain tumors. J

treatment, and prognosis make their

Neurooncol 80:313-332, 2006.

Hodgkin and Non-

Hodgkin Lymphoma

Hodgkin and non-Hodgkin lymphoma

B-cells. In both forms of the disease, the

together account for approximately 10% to

tumor cells comprise only 0.1% to 10% of

12% of malignancies in children; they are

the cells within the tumor.

third in relative frequency after acute leuke-

Epidemiologic studies suggest that two

mias and brain tumors. Non-Hodgkin lym-

different forms of pediatric HL exist: child-

phoma

(NHL) comprises approximately

hood and adolescent/young adult (AYA).

60% of all lymphomas.

The childhood form is defined as occurring

in those

14 years of age, and is character-

ized by a male predominance and a histo-

Hodgkin lymphoma

logic subtype that is more likely to be mixed

cellularity (30% to 35%) or nodular lym-

Hodgkin lymphoma (HL) is rare among

phocyte predominant (10% to 20%). An

children <5 years of age and relatively rare

increased proportion of childhood HL is

in the adult population, but is the most

associated with Epstein-Barr virus (EBV)

commonly diagnosed cancer among adoles-

infection, and studies suggest that early

cents aged 15 to 19. HL is classified into two

exposure to EBV is a risk factor for devel-

general groups: classical HL (95% of cases)

oping HL in childhood. AYA HL occurs in

and nodular lymphocyte predominant HL

patients between 15 and 35 years of age.

(NLPHL, 5% of cases). Classical HL is further

There is no gender predilection. The most

subdivided into nodular sclerosis, mixed

common histologic subtype is nodular

cellularity, lymphocyte-depleted, and lym-

sclerosis

(70% to

80%). EBV infection

phocyte-rich forms. The tumor cells in clas-

appears to play a role in AYA HL also. Other

sical HL are designated Hodgkin and Reed-

infectious agents that have been associated

Sternberg (HRS) cells, whereas in NLPHL

with HL include human herpesvirus 6 and

they are designated lymphocyte-predomi-

cytomegalovirus. There is clearly an associ-

nant (LP) cells. HRS cells are now felt to

ation between HL and alterations in immune

derive from germinal center B-cells that have

function. HL is seen more commonly in

acquired unfavorable immunoglobulin V

patients with HIV disease, acquired immu-

gene mutations and that normally would

nodeficiency (e.g., hematopoietic stem cell or

have undergone apoptosis, whereas LP cells

solid organ transplant), and autoimmune

derive from antigen-selected germinal center

disease.

Handbook of Pediatric Hematology and Oncology: Children’s Hospital & Research Center Oakland,

Second Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.

2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

Hodgkin and Non-Hodgkin Lymphoma

167

Clinical presentation

should be identified, as patients with HL

The most common presentation of HL is

can present with a variety of paraneoplastic

painless cervical or supraclavicular adeno-

syndromes. All superficial nodal groups

pathy. The nodes are typically described as

should be carefully examined, and the size

rubbery or firm and nontender, although

of any enlarged nodes and their character

may be sensitive to touch with rapid growth.

should be documented.

As the disease progresses, the nodes enlarge

2. The laboratory evaluation should

and often aggregate into larger masses that

include a complete blood count (CBC) with

may become fixed to the underlying tissue.

differential, erythrocyte sedimentation rate

As children often have reactive or infectious

(ESR), C-reactive protein (CRP), complete

adenopathy, it is common to have received

metabolic panel (including transaminases,

treatment with several courses of antibiotics

lactate dehydrogenase [LDH], and alkaline

before ultimately coming to biopsy. This is

phosphatase), serum copper, and serum

more common with cervical than with

ferritin. One or more of these nonspecific

supraclavicular adenopathy, as the latter is

inflammatory markers may be elevated and

less frequently associated with infection or

thus be useful initially to monitor response

inflammation and leads more quickly to

to therapy and later to identify possible

referral for possible malignancy. At least

recurrence.

two-thirds of patients with cervical or

3. A posterior-anterior

(PA) and lateral

supraclavicular adenopathy have mediasti-

chest radiograph will identify bulky medi-

nal involvement as well. This is frequently

astinal disease, if present. This is important,

asymptomatic, but may be associated with

as it will influence the approach used to

cough (usually nonproductive), shortness of

obtain diagnostic material since patients

breath, chest pain, or superior vena cava

with bulky mediastinal disease are more

syndrome. HL limited to infradiaphrag-

likely to experience complications with gen-

matic sites occurs in <5% of pediatric cases,

eral anesthesia. Other important imaging

occurring most commonly in femoral,

studies include a CT scan of the neck, chest,

superficial iliac, or inguinal nodes.

abdomen, and pelvis. The radiologist should

Constitutional symptoms commonly

be reminded to include the Waldeyer ring in

occur in patients with HL. They are caused

the scan as this nodal area can be involved

by cytokines produced by the HRS cells

with disease as well, especially in patients

within the tumor. Certain specific symp-

with upper cervical node involvement. Oral

toms known as “B symptoms” have been

and intravenous contrast are required for

demonstrated to have a negative prognostic

accurate identification of intra-abdominal

significance. These are unplanned weight

adenopathy. Splenic involvement occurs in

loss of >10% of body weight over the 6

30% to

40% of children at diagnosis.

months preceding diagnosis, drenching

Positron emission tomography

(PET)-CT

night sweats, or fever >38 C for at least

is now commonly used at diagnosis as a very

three consecutive days. Other common con-

sensitive tool for identifying sites of involve-

stitutional symptoms include generalized

ment, when it is available. A gallium scan

pruritus and alcohol-induced pain.

should be performed if PET is not available.

4. Bone marrow involvement at initial pre-

Evaluation

sentation of pediatric HL is uncommon and

1. A careful history and physical examina-

rarely occurs as an isolated site of extranodal

tion is imperative. The presence of B symp-

disease. However, it is seen more commonly

toms and any other unusual symptoms

in patients with advanced stage (stage III

168

Chapter 17

or IV) disease or patients with B symptoms.

therapy (RT). While this approach was fairly

These patients should undergo bone mar-

effective in curing the disease in low risk

row aspiration and biopsy from at least two

patients, it resulted in unacceptable muscu-

sites as part of their diagnostic evaluation.

loskeletal hypoplasia, cardiovascular and

All patients experiencing a recurrence of

pulmonary dysfunction, and the develop-

their disease should have their bone marrow

ment of subsequent secondary cancers. This

examined.

led to the development of combined modal-

5. Skeletal metastases are also rare at diag-

ity therapy with the goal of improving

nosis, and bone scans have typically been

event-free and overall survival, especially

performed only in patients with bone pain,

in higher risk patients, and decreasing the

unexplained elevations in the alkaline phos-

long-term adverse effects of a radiation

phatase, or other sites of extranodal disease.

only approach. Current research efforts in

PET-CT is a sensitive test for identifying

HL treatment seek to maintain the excellent

bone metastases and ultimately may replace

survival rates presently achieved while con-

bone scanning all together. It is important

tinuing to decrease the frequency of later

to remember that typical PET-CT imaging

adverse events. Today, patients with favor-

stops at the knee; patients with distal lower

able disease presentations receive fewer

extremity pain will need to have the exam

cycles of multiagent chemotherapy than

carried further or have alternative imaging

those with advanced and unfavorable clin-

of these areas.

ical presentations, either alone or combined

with low-dose, involved-field radiation.

Staging

With current therapy, more than 80% of

The most widely used staging system for

children diagnosed with classical HL are

pediatric HL is the Ann Arbor staging

expected to be long-term disease-free survi-

system. This system divides lymph node

vors, regardless of stage at diagnosis.

regions into nodal sites (e.g., neck, axilla,

For treatment purposes, patients with

and mediastinum), and the number of

HL are typically divided into low, inter-

involved sites then determines the stage.

mediate, and high risk disease groups.

Stage I disease involves only a single nodal

These groups are defined by clinical stage,

site, whereas stage II involves two or more

presence of bulky disease, and presence

sites that lie together on one side of the

of B symptoms. The current approach to

diaphragm. Stage III disease spans the dia-

therapy also includes the adaptation of

phragm and stage IV is disseminated sys-

treatment based on the patient’s response

temic disease. Additional modifiers include

to early therapy, a so-called response-based

A or B, to describe the absence or presence

approach.

of systemic symptoms respectively, and E,

A variety of chemotherapy agents have

involvement of a single extranodal site that

been shown to be effective in treating

is contiguous or proximal to a known nodal

HL. However, many early regimens such

site. The presence of bulky mediastinal

as nitrogen mustard, vincristine, procar-

disease, described as greater than one-third

bazine, and prednisone (MOPP) resulted

of the intrathoracic diameter, is also

in a very high rate of secondary malig-

considered.

nancy. Newer regimens have replaced

nitrogen mustard with cyclophosphamide

Treatment

(COPP) and added other agents such as

The first successful treatment strategy for

doxorubicin, bleomycin, vinblastine, and

HL was based solely on the use of radiation

etoposide.

Hodgkin and Non-Hodgkin Lymphoma

169

Classical HL—low risk disease

node can be successfully treated with surgery

A number of studies have attempted to elim-

alone. Stage I patients with more than one

inate the use of RT completely in children

involved node and stage II patients, which

with low risk disease. This approach has

represent more than 80% of patients with

resulted in an increased rate of relapse in

NLPHL, are successfully treated with similar

patients not receiving RT, but many of these

protocols used in low risk classical HL

patients were successfully salvaged with com-

patients. Current studies are investigating

bination chemotherapy and RT, thus long-

whether therapy can be reduced even further

term survival was not affected. The most

in this group of very low risk patients.

recent Children’s Oncology Group study

treated patients with three cycles of doxoru-

Complications of treatment

bicin, vincristine, prednisone, and cyclophos-

Short term

phamide. Those having a complete response

The chemotherapy regimens used for the

by PET-CT or gallium scan were observed;

treatment of HL are moderately emetogenic.

those having a partial response received

The nausea and vomiting can usually be

involved-field radiation therapy (IFRT).

controlled with serotonin receptor antago-

nist antiemetics such as ondansetron. It is

Classical HL—intermediate and

not uncommon for patients to develop

high risk disease

anticipatory nausea and vomiting with

The majority of patients with intermediate

repeated cycles; this can be managed with

risk disease either have stage I/II disease with

benzodiazepines such as lorazepam. Myelo-

one or more unfavorable features (B symp-

suppression occurs very commonly, espe-

toms, lymph node bulk, hilar lymph node

cially with the more intensive regimens, and

involvement, involvement of three or more

patients occasionally require hospitalization

lymph node regions, and extranodal exten-

for fever and neutropenia. Varicella zoster

sion to contiguous structures) or have

occurs frequently both during and after ther-

stage IIIA disease. High risk patients typically

apy, with a frequency that correlates with the

include those with stage IIIB or IV disease.

intensity of therapy. Appropriate preventive

Due to their more advanced stage, these

and therapeutic steps should be taken

patients are treated with more aggressive

quickly in the event of exposure or infection

chemotherapy followed by IFRT. Current

(see Chapter 25). Peripheral neuropathy can

therapy includes doxorubicin, bleomycin,

result from vincristine and vinblastine ther-

vincristine, etoposide, prednisone, and

apy, as can constipation. Pulmonary toxicity

cyclophosphamide (ABVE-PC); slow respon-

can result from bleomycin, with develop-

ders may also receive additional chemother-

ment of restrictive lung disease and reduc-

apy. The role of IFRT continues to be

tions in diffusion capacity. Anthracycline-

investigated in the treatment of intermediate

induced cardiac toxicity is unusual with the

risk patients, whereas high risk patients all

decreased doses used in current regimens,

receive consolidation with IFRT.

but is more common when combined with

mediastinal RT.

Nodular lymphocyte

predominant HL

Long term

Several studies have demonstrated that

The most significant long-term complica-

patients with NLPHL who present with

tion of HL therapy is the development of a

stage I disease and a single involved lymph

second malignant neoplasm. The frequency

170

Chapter 17

has decreased with recent modifications in

and has been linked to several subtypes of

chemotherapy and reductions in RT dose

NHL in the developed world. Other identi-

and volume, but it remains a concern dur-

fied risk factors include Helicobacter pylori

ing long-term follow-up. One specific issue

infection, tobacco exposure, and chemical or

is the risk of development of early breast

other environmental exposures. It is likely

cancer in female patients treated during

that there is not a single etiology responsible

adolescence, especially those treated with

for the development of all cases of NHL.

mediastinal radiation. Other potential

The histologic classification of NHL

long-term consequences of therapy include

has changed frequently over time and has

sterility/infertility (most common in males

become more precise as our understand-

treated with alkylating agents), secondary

ing of the development of lymphoma has

acute myelogenous leukemia

(etoposide,

improved and better diagnostic tools

alkylating agents), pulmonary fibrosis

(immunophenotyping, cytogenetics, molec-

(bleomycin), and atherosclerotic heart dis-

ular biology, and gene profiling) have been

ease (anthracyclines þ RT). Comprehen-

developed. The current World Health Orga-

sive long-term follow-up is essential for

nization classification is now widely used.

survivors of HL due to their increased risk

There are four major histologic subtypes of

of late complications of therapy.

NHL that occur commonly in children (in

order of frequency): diffuse, large B-cell

lymphoma (DLBCL), lymphoblastic lym-

Non-Hodgkin lymphoma

phoma (LL), BL, and anaplastic large cell

lymphoma (ALCL).

NHL is about 1.5 times as common as

DLBCL and ALCL tend to be heteroge-

Hodgkin lymphoma. The incidence is low

neous immunologically. Most are B-cell

in children less than 5 year of age, but from

derived, although some are T-cell derived

that point it increases steadily with age

or arise from the macrophage-histiocyte

throughout life. In all age groups, there is

lineage. Burkitt and Burkitt-like subtypes

a significant male predominance, particu-

are virtually all B-cell tumors, distinguished

larly among patients with Burkitt lym-

only by the amount of cellular heterogene-

phoma (BL). During childhood, the disease

ity. The most common site of occurrence of

is more common among non-Hispanic

LL is the mediastinum, and these tumors are

whites and Asians/Pacific Islanders; after

virtually all of T-cell origin. Less commonly

age twenty, it occurs more commonly in

LL occurs in bone or subcutaneously; these

African-Americans. The incidence of differ-

tumors are typically of B-cell origin. All of

ent histologic subtypes is very different in

these subtypes can invade the bone marrow

children and adults.

and undergo leukemic transformation.

Children with congenital or acquired

immune system dysfunction have a high risk

Clinical presentation

of developing lymphoma. Congenital condi-

The clinical presentation of NHL varies and

tions include ataxia-telangiectasia, as well

depends on the primary site of disease,

as Bloom, Wiskott-Aldrich, and Chediak-

histologic subtype, and extent of disease.

Higashi syndromes; acquired conditions

NHL can arise anywhere in the body, but

include HIV and prolonged immunosup-

occurs most frequently in the lymph nodes,

pressive therapy following bone marrow or

thymus, Waldeyer’s ring, Peyer’s patches,

solid organ transplant. EBV is clearly asso-

and bone marrow. In the United States,

ciated with BL in underdeveloped countries,

BL typically presents in the intestine,

Hodgkin and Non-Hodgkin Lymphoma

171

resulting in obstruction. These children

* A CBC with differential and review of the

usually present with nausea, vomiting, and

peripheral smear to assess for possible bone

abdominal distention. It is not unusual for

marrow involvement or leukemia.

NHL to be confused with a surgical abdo-

* Serum chemistries to include liver trans-

men, such as appendicitis. BL also presents

aminases, blood urea nitrogen, creatinine,

in Waldeyer’s ring or in the facial bones.

LDH, uric acid, electrolytes, calcium, and

T-cell LL most commonly arises from the

phosphorus. Lymphomas, particularly LL

thymus; these children typically present

and BL, can present with overt tumor lysis

with respiratory symptoms, cervical or

syndrome (TLS) and/or renal dysfunction.

supraclavicular adenopathy, or superior

The LDH can be useful prognostically, espe-

vena cava syndrome. Children may have

cially in patients with advanced stage

very limited disease affecting the tonsils,

disease.

nasopharynx, or Waldeyer’s ring, and the

* Bilateral bone marrow aspirations and

diagnosis has resulted from the pathologic

biopsies as the child may actually have leu-

examination following a tonsillectomy and

kemia, defined as a marrow with >25%

adenoidectomy. Lymphomas arising in less

replacement by lymphoblasts.

common sites such as superficial lymph

* A lumbar puncture to assess the cerebro-

nodes, bone, skin, thyroid, orbit, eyelid,

spinal fluid for involvement by NHL.

kidney, and the epidural space can be

caused by any subtype of lymphoma.

Radiologic procedures that should be per-

formed will vary depending on the location

Diagnostic evaluation

of the mass and associated symptoms, but

It is not unusual to begin with a surgical

should include:

procedure for excision or biopsy of a

* ApromptPAandlateralchestradiograph

node or laparotomy in the case of an acute

to evaluate for mediastinal involvement.

abdominal presentation. Many times the

* CT scan of the neck, chest, abdomen, and

diagnosis is not suspected prior to these

pelvis if the patient is sufficiently stable.

procedures. In any event, histologic confir-

* MRI of the brain for patients with immu-

mation is necessary for diagnosis. The diag-

nodeficiency-related NHL as these patients

nosis of NHL is usually made using biopsy

more commonly present with parenchymal

material but it can also be confirmed by

brain disease.

cytological examination of effusion fluids or

* MRI of the brain and spine for patients

review of bone marrow smears. In this way,

with focal neurologic symptoms.

major surgical procedures can often be

* PET-CT to include all identified sites of

avoided in patients presenting with BL and

disease. Ideally, this should be performed

LL, who are frequently unstable at presen-

following the diagnostic procedure, as these

tation. If possible, sufficient material should

patients frequently have residual abnormal-

be obtained for immunologic and cyto-

ities in their surgical bed on plain CT that

genetic or molecular biology studies. Many

are discovered on PET-CT to not represent

therapeutic trials now have requirements for

active disease.

submission of material for central pathology

review or biology studies; these require-

ments should be taken into consideration

Staging

when planning a diagnostic procedure.

NHL is staged using the St. Jude (Murphy)

The laboratory studies that should be

staging system that is presented in

obtained include:

Table 17.1.

172

Chapter 17

Table 17.1 St. Jude staging system for non-Hodgkin lymphoma.

Stage

Description

A single tumor (extranodal) or single anatomic area (nodal), excluding

mediastinum or abdomen

A single tumor (extranodal) with regional node involvement

On same side of diaphragm:

* Two or more nodal areas

* Two single (extranodal) tumors regional node involvement

* A primary gastrointestinal tract tumor (usually ileocecal) with or without

associated mesenteric node involvement, grossly completely resected

III

On both sides of the diaphragm:

* Two single tumors (extranodal)

* Two or more nodal areas

All primary intrathoracic tumors (mediastinal, pleural, thymic)

All extensive primary intra-abdominal disease; unresectable

All primary paraspinal or epidural tumors regardless of other sites

Any of the above with central nervous system or bone marrow involvement

(<25%) at diagnosis

Treatment

regimens for patients with B-cell lym-

Therapy is based on clinical staging, local-

phoma, although clear evidence that it sig-

ized versus disseminated disease, and histo-

nificantly improves pediatric outcomes is

logic subtype. In general, children with

lacking. Patients with LL have superior out-

localized NHL have an excellent prognosis,

comes with longer acute lymphoblastic

with a 90% long-term survival. Therapy

leukemia-type therapy. CNS prophylaxis

may begin with surgical resection in the

in either type is indicated in advanced stages

case of primary gastrointestinal tumors that

and in those patients with parameningeal or

are amenable to complete resection, but this

overt CNS disease at diagnosis. The optimal

is not a necessary part of therapy for treat-

treatment of ALCL is not yet well defined.

ment of other sites (unless a life-threatening

Patients with stage I and II disease do well

complication is present).

with brief, multiagent intensive chemother-

These tumors are exquisitely sensitive to

apy and CNS prophylaxis. Patients with

chemotherapy, and multidrug regimens,

advanced stage disease who express the

similar to those used for leukemia, are fre-

fusion protein generated by the anaplastic

quently recommended. Radiotherapy is

lymphoma kinase (ALK) gene have superior

generally reserved for some patients with

outcomes compared to patients who are

CNSþ lymphoblastic lymphoma, relapsed

ALK negative. The latter patients typically

patients, or oncologic emergencies due to

require a more intensive, anthracycline-

tumor compression. In general, B-cell lym-

containing regimen.

phomas require intensive short-course ther-

With the initiation of therapy, the

apy ranging from 2 to 8 months in duration

child must be closely monitored for the

depending on initial tumor burden. Ritux-

development of TLS and resultant meta-

imab is now frequently added to treatment

bolic abnormalities. Some therapeutic

Wilms Tumor

Wilms tumor is the second most common

identified in two syndromes associated with

retroperitoneal tumor in children, account-

Wilms tumor: WAGR syndrome (Wilms

ing for approximately

6% of childhood

tumor, Aniridia, GU anomalies, and mental

malignancies. A tumor of the developing

Retardation) and Denys-Drash syndrome

kidney, it typically occurs in young children

(Wilms tumor, nephropathy, and GU

between the ages of 1 and 5 years, with equal

anomalies including pseudohermaphrodit-

incidence among boys and girls (though

ism). Beckwith-Wiedemann syndrome

interestingly occurs at earlier ages in boys).

(macroglossia, omphalocele, viscerome-

Most cases of Wilms tumor are sporadic,

galy, with or without hemihypertrophy)

with approximately 1% being familial and

is associated with imprinting defects at

2% to 4% associated with rare congenital

several genes at chromosome 11p15.5, a

syndromes. Familial cases are more likely to

locus referred to as the WT2 gene. Patients

present with bilateral tumors and occur at a

with this syndrome have a genetic predis-

younger age.

position to develop Wilms tumor, with an

incidence as high as 5% to 10%.

Genetics

Clinical presentation

Congenital anomalies occur in 12% to 15%

of cases, the most common being hemihy-

Most children with Wilms tumor are gen-

pertrophy, aniridia, and genitourinary tract

erally in good health at presentation and

(GU) anomalies such as cryptorchidism,

come to medical attention due to abdom-

hypospadias, horseshoe kidney, ureteral

inal enlargement or when a family member

duplication, and polycystic kidney. Most

has felt a mass. Associated signs and symp-

children with Wilms tumor have a normal

toms include abdominal pain, malaise,

karyotype; however, a chromosomal dele-

fever, hypertension, and microscopic

tion in the short arm of chromosome 11

hematuria. Bleeding within the tumor may

(11p13 deletion) is seen in association with

occur and result in anemia, pallor, and

congenital aniridia. The Wilms tumor 1

fatigue. Tumor thrombus may extend into

(WT1) gene encodes a transcription factor

the vena cava, causing partial obstruction,

important in normal kidney development.

hypertension, and distention of abdominal

Mutations within the WT1 gene have been

veins. Polycythemia may be seen in Wilms

Handbook of Pediatric Hematology and Oncology: Children’s Hospital & Research Center Oakland,

Second Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.

2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

Wilms Tumor

175

tumor and may or may not be related to

patients with Wilms tumor with lung or

elevated erythropoietin levels. Acquired

liver metastatic disease and bony

von Willebrand disease with reduced von

symptoms

Willebrand factor (VWF), factor VIII coag-

^* MRI of the brain for metastases if the

ulant, and ristocetin cofactor levels has

tumor is a rhabdoid tumor or clear cell

been reported in approximately

8% of

sarcoma

patients newly diagnosed with Wilms

^* Echocardiogram for detecting tumor

tumor and typically resolves with therapy

extension from the IVC to the right

initiation. Its occurrence in Wilms tumor is

atrium and also indicated in the child

thought secondary to binding of VWF to

receiving anthracycline chemotherapy

the tumor with subsequent degradation as

well as hyaluronic acid secretion by nephro-

Pathologic diagnosis

blastoma cells leading to decreased efficacy

Children with suspected Wilms tumor

of VWF.

should have an immediate consultation

with a pediatric surgeon. Surgical removal

Evaluation of suspected Wilms

of the involved kidney and intact tumor is

tumor

indicated at diagnosis if possible. Cases

* History: include family history of malig-

with tumor in the renal pelvis and IVC

nancies, congenital anomalies, or syndromes

require a detailed imaging assessment to

* Physical examination: assess gently for

guide the surgeon. In some cases, complete

abdominal/flank mass (usually distinct and

removal of the primary tumor at diagnosis

not crossing the midline), congenital anom-

may not be possible. In these cases, open

alies (hemihypertrophy, GU malformations,

biopsy is indicated for pathologic confir-

aniridia), hypertension, abdominal venous

mation and determination of histology.

distention, and liver enlargement

Tumor pathology is critical in diagnosis

* Laboratory studies: urinalysis with

as well as helping to determine the staging

microscopic evaluation, complete blood

and therefore subsequent treatment.

count (polycythemia and anemia), serum

Classic Wilms tumor presents with three

chemistries

(hypercalcemia in rhabdoid

types of nephroblastoma tissue elements:

tumor or congenital mesoblastic nephroma),

blastema, stroma (mesenchyme), and epi-

and coagulation studies including von Will-

thelium. Additional assessment includes

ebrand panel

determination of histology as either favor-

* Diagnostic imaging studies:

able

(well-differentiated components) or

^* Doppler abdominal ultrasound to eval-

unfavorable

(presence of anaplasia with

uate the tumor, possible vena cava

poor differentiation and a worse prognosis).

involvement, blood flow, and contralat-

Other malignant tumors of the kidney need

eral kidney

to be considered and ruled out including

^* Abdominal CT or MRI with special

rhabdoid tumor of the kidney, clear cell

attention to evidence of bilateral involve-

sarcoma of the kidney, and renal cell carci-

ment, vessel involvement or extension to

noma. Chromosome analysis is performed

the inferior vena cava (IVC), lymph node

on the tumor and may prove to be especially

involvement, and liver metastases

useful in association with congenital anom-

^* Chest radiography and chest CT to assess

alies and familial cases. Loss of heterozygos-

for lung metastases (most common site)

ity (LOH) of chromosomes 1p and 16q has

^* Bone scan to assess for metastases if the

also recently been confirmed to be a nega-

tumor is a clear cell sarcoma and for all

tive prognostic indicator.

176

Chapter 18

Staging

Treatment

Staging is done postoperatively and is deter-

The prognosis of Wilms tumor is excellent,

mined based on the extent of disease, ability

with more than 85% of children being cured

to perform a total resection, and the path-

of their disease. Histology is more prognos-

ologic findings. Patients unable to undergo

tic for outcome than staging; for example,

a radical nephrectomy at diagnosis due to

patients with stage IV disease but with

excessive risk receive preliminary staging

favorable histology still have a 4-year sur-

and preoperative chemotherapy with

vival of more than 85%, compared to chil-

delayed resection. A careful pathologic eval-

dren with diffuse anaplasia and advanced

uation at the time of excision should be

disease who have very poor outcomes. Chil-

performed regardless of whether this occurs

dren with stage I and II favorable histology

at diagnosis or later following preoperative

tumors have an event-free survival rate

chemotherapy, as the histology may be dif-

exceeding 95%.

ferent than that seen on initial biopsy. This

Many tumors are low stage at presenta-

evaluation includes identifying tumor his-

tion and are able to be fully resected.

tology and looking for extension of disease

Additionally, these tumors are very sensitive

outside the kidney, including penetrance of

to chemotherapy and radiation. Based on

the tumor through the renal capsule into the

the exceedingly good outcomes, contempo-

renal pelvis and vessels and presence of

rary studies have looked to decrease therapy

nodal involvement.

in the lower risk stratum. This includes the

Clinicopathologic staging is as follows:

elimination of chemotherapy in patients

* Stage I: tumor limited to the kidney and

younger than 2 years with stage I disease

completed excised without tumor rupture

and tumor mass of <550 g without LOH at

or biopsy prior to resection

1p and 16q. For patients receiving chemo-

* Stage II: tumor extends through the renal

therapy, the backbone of therapy is based on

capsule, has been biopsied, or ruptured

previous studies by the National Wilms

prior to excision with spillage confined to

Tumor Study Group and includes vincris-

the flank; tumor may involve the perirenal

tine, doxorubicin, and dactinomycin.

soft tissue and/or infiltrate vessels outside

Higher stage patients may require radiation

the kidney but is completely excised

therapy in addition to this chemotherapeu-

* Stage III: residual nonhematogenous dis-

tic backbone. Patients with stage IV disease

semination of tumor confined to the abdo-

or patients with advanced stage and LOH at

men; tumor may extend beyond surgical

1p and 16q receive more aggressive therapy

margin at resection, may involve local

with the addition of cyclophosphamide and

lymph nodes, or have tumor spillage with

etoposide. In general, patients with pulmo-

peritoneal implants

nary metastasis will require lung irradiation

* Stage IV: hematogenous dissemination

although newer protocols are studying

of tumor to lungs, liver, bone, brain, or

whether this can be eliminated in patients

distant lymph nodes

with a rapid response to chemotherapy and

* Stage V: bilateral renal involvement

no additional risk factors. Finally, patients

with higher stage anaplastic disease as well

Patients with bilateral involvement of tumor

as patients with rhabdoid tumor of the

(stage V) should have each side indepen-

kidney or metastatic clear cell sarcoma

dently staged with treatment based on the

receive a similar regimen with the addition

side with the highest stage.

of carboplatin.

Wilms Tumor

177

Relapse is uncommon in Wilms tumor;

patients with right-sided tumors who

patients may be salvaged with aggressive

receive flank irradiation and those receiving

multiagent chemotherapy, radiation if pre-

whole abdomen irradiation have an

viously not given, and possibly may benefit

increased risk of developing a secondary

from high-dose chemotherapy with autol-

liver cancer. These potential issues must all

ogous stem cell rescue. As survival is excel-

be taken into account in the patient’s long-

lent, much attention has focused on late

term follow-up plan.

effects related to therapy and limiting

potential toxicities. Patients are at risk for

Suggested Reading

hypertension and renal insufficiency, as

most children will have a solitary remaining

Davidoff AM. Wilms tumor. Curr Opin Pediatr

kidney. Patients with bilateral disease,

21:357-364, 2009.

partial resection, and radiation exposure are

Nakamura L, Ritchey M. Current management of

particularly at risk for developing protein-

Wilms tumor. Curr Urol Rep 11:58-65, 2010.

uria and renal compromise in addition to

Pritchard-Jones K. Nephrectomy only for Wilms

hypertension. Cardiac complications may

tumor: negotiating the tangled web requires

be seen in those patients who receive anthra-

multiprofessional input. Pediatr Blood Can-

cyclines and lung irradiation. Additionally,

cer 54:865-866, 2010.

Neuroblastoma

Neuroblastoma is a neoplasm of the sym-

commonly, amplification of the oncogene

pathetic nervous system and the most com-

N-myc in tumor tissue has been found to

mon solid tumor of early childhood, with a

have a profound negative impact on prog-

peak incidence around 2 years of age. Neu-

nosis. Similarly, a near diploid (low DNA

roblastoma is a disease of developing neural

index, DNA index ¼ 1) chromosome num-

crest tissue and has an extremely heteroge-

ber in the tumor has also been found to be a

neous prognosis based on multiple factors

negative prognostic indicator as compared

such as the age of the patient, differentiation

to patients with a DNA index >1. Based on

and biology of the tumor, and extent of

these factors, in addition to age, stage, and

disease spread. Screening in the Japanese

histology (favorable or unfavorable based

infant population found a high incidence

on mitosis-karyorrhexis index and maturity

of neuroblastoma, although the majority of

of the tumor), a complicated risk-stratified

these cases matured or involuted spontane-

treatment regimen has been created.

ously, again implying the heterogeneous

prognosis based on patient age. Although

survival rates for neuroblastoma have

Clinical presentation

improved over the last 30 years, the majority

of these gains have been observed in patients

As neuroblastoma originates from primor-

with lower risk disease. Recent break-

dial neural crest cells that normally give rise

throughs hold promise to increase survival

to the adrenal medulla and the sympathetic

in those with high risk disease as well.

ganglia, tumors present in the abdomen and

Familial cases of neuroblastoma are

along the sympathetic neural pathway. The

quite rare. However, genetic risk factors for

most common presentation is an abdomi-

neuroblastoma have been identified includ-

nal mass with primary tumor in the adrenal

ing the anaplastic lymphoma kinase 1 and

gland, often with metastatic disease via lym-

PHOX2B homeobox genes. Patients with

phatic and hematogenous spread. Tumors

Hirschsprung’s disease, neurofibromatosis

are often seen along the paraspinal ganglion

type I, and congenital hypoventilation syn-

and may be found in the neck, thorax, and

drome may have genetic alterations in

pelvis. Infants are more likely to have tho-

PHOX2B and an increased risk of develop-

racic and cervical tumors. Common sites of

ing neuroblastoma, although clear genetic

metastasis are the lymph nodes, bone mar-

links have not as yet been identified. More

row, bone, liver, and skin.

Handbook of Pediatric Hematology and Oncology: Children’s Hospital & Research Center Oakland,

Second Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.

2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

Neuroblastoma

179

The signs and symptoms at presentation

be carefully evaluated for the presence of

depend on the site of the tumor, size, and

an occult neuroblastoma. Children with

the degree of spread. Patients with locore-

OMAS tend to have a low-stage, highly

gional disease may be relatively asymptom-

curable neuroblastoma. Unfortunately, this

atic, whereas patients with widely metastatic

cure often has little impact on the OMAS,

disease are often ill-appearing with fever,

and these children are frequently left with

pain, weight loss, and irritability. Abdomi-

severe, chronic neurologic deficits. The

nal tumors are usually palpable, hard, fixed

pathophysiology of this syndrome is not

masses. The liver may be enlarged, leading

well defined but is likely due to formation

to respiratory compromise, especially in the

of an antibody directed against the neuro-

infant. There may be evidence of anemia

blastoma cells also targeting cerebellar neu-

(pallor, weakness, and fatigue), coagulopa-

rons. In addition to treatment of the neu-

thy (bruising and bleeding), and bone pain

roblastoma, these children may benefit

or limping with bone or bone marrow

from immunosuppressive therapy with

involvement. Thoracic masses are usually

agents such as dexamethasone, cyclophos-

picked up in the posterior mediastinum

phamide, intravenous immune globulin

incidentally by imaging studies done for

(IVIG), and adrenocorticotropic hormone

other reasons. Cervical masses may initially

(ACTH). Neuroblastoma patients may also

be treated as cervical adenopathy related to

present with hypersecretory diarrhea sec-

infection. The presence of Horner’s syn-

ondary to hypersecretion of vasoactive

drome (miosis [contracted pupil], ptosis,

intestinal peptide

(VIP) from the neuro-

enophthalmos

[posterior eye displace-

blastoma cells. In most cases, treatment of

ment], and anhidrosis) or heterochromia

the underlying disease will eliminate the

iridis should prompt an evaluation for cer-

VIP hypersecretion.

vicothoracic neuroblastoma. Pelvic masses

may cause bowel or bladder symptoms and

tumors along the sympathetic ganglia may

Diagnostic evaluation

cause spinal cord compression. Skin lesions

tend to be limited to infants and appear as

History

bluish, nontender subcutaneous nodules.

Assess for constitutional symptoms, abdom-

Sphenoid or retro-orbital bone involvement

inal pain, bowel or bladder control problems,

may occur and appear clinically as “raccoon

bleeding, bone pain, and limping.

eyes” secondary to periorbital hemorrhage.

In addition to Horner’s syndrome, the

Physical examination

clinician should be aware of potential para-

Assess vital signs (fever and hypertension)

neoplastic syndromes with neuroblastoma.

and evaluate for abdominal mass, spinal

One unusual presentation is opsoclonus-

cord compression, unusual signs/symptoms

myoclonus-ataxia syndrome (OMAS), also

associated with neuroblastoma

(hetero-

referred to as “dancing eyes/dancing feet.”

chromia, raccoon eyes, Horner’s syn-

These children have cerebellar and truncal

drome), subcutaneous nodules in infants,

ataxia as well as myoclonus (muscle jerks)

enlarged liver or lymph nodes, and evidence

and opsoclonus (rapid, involuntary, unco-

of anemia or coagulopathy.

ordinated eye movements). Developmental

delay, language deficits, and behavioral

Laboratory studies

abnormalities

(e.g., irritability) may also

Obtain complete blood count with differ-

be present. Children with OMAS should

ential, serum chemistries

(liver function

180

Chapter 19

studies and lactate dehydrogenase), ferritin

* Bone scan (technetium-99m).

(may be a tumor marker and elevated in

* MIBG (metaiodobenzylguanidine) scan

neuroblastoma, though also an acute-phase

(123I-MIBG scan preferred over131I-MIBG

reactant), and urine for catecholamines

due to decreased risk to thyroid function).

including homovanillic acid

(HVA) and

Prior to MIBG scanning, the patient must

vanillylmandelic acid (VMA). These urine

receive thyroid protection with potassium

metabolites are elevated in more than 90%

iodide

(SSKI) drops and should have

of children with neuroblastoma, especially

baseline thyroid function

(FT4/TSH)

in the higher stages of disease. In patients

checked. MIBG, a functional analog of

with clinical suspicion for neuroblastoma

norepinephrine, is taken up by sympathetic

and negative urine markers, urine dopa-

neurons and is a sensitive test for neuro-

mine can be measured in addition to

blastoma cells. It is also positive in

24-hour urine collections for HVA and

pheochromocytoma.

VMA. Neuron-specific enolase

(NSE), a

* Due to the high radiation doses with both

serum marker specific to the sympathetic

bone scan and MIBG scanning, patients can

nervous system, is relatively specific to neu-

be followed solely with MIBG if results of

roblastoma although it can be elevated after

baseline imaging are concordant.

brain injury and seizures.

Localized tumors should be surgically

Diagnostic studies

removed if it deemed safe and feasible.

Patients with confirmed neuroblastoma

Many tumors are initially unresectable.

should have bilateral bone marrow aspira-

These tumors should be surgically biopsied,

tion and biopsy performed to assess for

with sampling of local lymph nodes. Diag-

bone marrow involvement. Special stains

nosis is generally established by pathologic

(S100, synaptophysin, and NSE) are used

assessment of the resected or biopsied mass

to differentiate this tumor from other small,

and can be confirmed by diagnostic features

round blue cell tumors of childhood such as

such as bone marrow involvement with

rhabdomyosarcoma, Ewing sarcoma, lym-

appropriate immunohistochemical mar-

phoma, and primitive neuroectodermal

kers, MIBG avidity, and positive urine cate-

tumor. Lumbar puncture should be avoided

cholamines and serum NSE.

as this procedure may increase the incidence

of central nervous system metastases.

Imaging studies should include:

Staging

* CT or MRI of the primary site (MRI is

preferred due to the radiation exposure

The International Neuroblastoma Staging

associated with repeated CT imaging). Cal-

System as shown in Table 19.1 was most

cifications and hemorrhage are commonly

recently revised in 1993 and provides a basic

seen, especially in large abdominal masses.

prognostic model that has been more

The tumors tend to be large and displace

recently complemented by biologic and

adjacent organs; however, the tumor can

pathologic assessments including N-myc

wrap around major structures, causing

amplication, DNA ploidy, and histology.

obstruction and dysfunction. If there is

A new risk-stratified staging system by the

suspicion of paraspinal or intraspinal

International Neuroblastoma Risk Group is

involvement, MRI and plain films of the

currently being prospectively evaluated in

spine should be done.

clinical trials.

Neuroblastoma

181

Table 19.1 International Neuroblastoma Staging System.

Stage I

Localized tumor confined to the area of origin; complete gross resection, with or

without microscopic residual disease; negative lymph nodes

Stage IIA

Unilateral tumor with incomplete gross resection; negative lymph nodes

Stage IIB

Unilateral tumor with complete or incomplete gross resection; positive ipsilateral

lymph nodes, negative contralateral lymph nodes

Stage III

Tumor infiltrating across midline with or without regional lymph node involve-

ment, unilateral tumor with contralateral lymph node involvement, or midline

tumor with bilateral regional lymph node involvement

Stage IV

Tumor disseminated to distant lymph nodes, bone, bone marrow, liver, or other

organs (except as defined by stage IVS)

Stage IVS

Localized primary tumor as defined for stage I or II with dissemination limited to

liver, skin, and/or bone marrow (under 1 year of age and <10% bone marrow

involvement)

Treatment

of age with unfavorable histology and/or

DNA ploidy ¼ 1

and all patients

>18

Risk stratification divides patients into mul-

months of age

tiple potential treatment categories that are

4. Stage IVS patients with N-myc nonam-

continually evaluated through clinical stud-

plification who have unfavorable histology

ies. For simplicity, we divide treatment

and/or DNA ploidy ¼ 1

strategies into three main groups: (1) obser-

vation, (2) chemotherapy, and (3) high-dose

High-dose chemotherapy with

chemotherapy with autologous stem cell res-

autologous transplant

cue and adjuvant therapy with immunomo-

* Stage III, IV, and IVS patients not

dulators (described below).

included above and all patients >12 years

of age with stage III or greater disease

Observation

1. All Stage I patients

(after surgical

As mentioned, clinical studies are ongoing

resection)

to refine treatment groups. Specifically,

2. Stage IIA/B patients with >60% tumor

attempts are being made to reduce treat-

resection and N-myc nonamplification

ment in some of the lower risk subgroups

3. Stage IVS patients with N-myc nonam-

that still require therapy but have an excel-

plification, favorable histology, and DNA

lent overall prognosis

(>90% survival).

ploidy >1

Novel therapeutic agents are being utilized

in addition to the current backbone of

Chemotherapy

therapy that includes drugs such as carbo-

1. Stage IIA/B patients with

<60%

platin, cyclophosphamide, doxorubicin,

resection

and etoposide. The majority of work is

2. Stage III patients with N-myc nonampli-

centered on high risk patients who continue

fication, not including patients >18 months

to have an extremely poor prognosis (30%

of age with unfavorable histology

to 40% survival). Multiple efforts are cur-

3. Stage IV patients with N-myc nonampli-

rently being evaluated in clinical trials

fication, not including patients >12 months

including the benefit of myeloablative

182

Chapter 19

chemotherapy with autologous stem cell

patients, potentially increasing survival in

rescue as well as tandem transplantation.

this population to as high as 60%.

Therapy with isotretinoin

(cis-retinoic

acid; cis-RA) has been shown beneficial as

amaturing agent in neuroblastoma patients

Suggested Reading

after cytotoxic therapy with minimal

residual disease and is being evaluated in

Maris JM. Recent advances in neuroblastoma.

combination with monoclonal antibodies

N Engl J Med 362:2202-2211, 2010.

directed at neuroblastoma-specific anti-

Park JR, Eggert A, Caron H. Neuroblastoma:

gens, specifically gangliosidase

(GD2).

biology, prognosis, and treatment. Hematol

Pilot studies with anti-GD2 antibodies and

Oncol Clin N Am 24:65-86, 2010.

concomitant use of cis-RA and cytokine

Yu AL, Gilman AL, Ozkaynak MF, et al. Anti-

therapy (interleukin-2 and GM-CSF) have

GD2 antibody with GM-CSF, interleukin-2,

shown promising results in the high risk,

and isotretinoin for neuroblastoma. N Engl J

poor prognosis subgroup of neuroblastoma

Med 363:1324-1334, 2010.

Sarcomas of the Soft

Tissues and Bone

Sarcomas comprise a heterogeneous group

Osteosarcoma is believed to arise from

of malignant tumors that arise in the soft

osteoblasts and has a bimodal age distribu-

tissues or bone. Soft tissue sarcomas (STS)

tion with an initial peak in the second

are derived from primitive mesenchymal

decade of life and a second peak in older

cells such as muscle, connective tissue (ten-

adulthood. Ewing sarcoma is thought to

dons and synovial tissue), supportive tissue

derive from neural crest and is also most

(fat and nerves), and vascular tissue (lymph

frequently diagnosed in the second decade

and blood vessels). Rhabdomyosarcoma

of life.

(RMS) is the most common STS in younger

children, comprising more than half of these

tumors in children up to 9 years of age.

Genetics

Other nonrhabdomyomatous soft tissue

sarcomas

(NRSTS) include synovial sar-

The majority of soft tissue and bone sarco-

coma, liposarcoma, fibrosarcoma, alveolar

mas develop without a predisposing genetic

soft part sarcoma, leiomyosarcoma, and

risk factor, although there have been mul-

malignant peripheral nerve sheath tumor.

tiple reported associations: RMS in patients

STS account for approximately 6% of can-

with neurofibromatosis type 1, Beckwith-

cer cases in those less than 19 years of age

Wiedemann syndrome, Costello syndrome,

(annual incidence 11 cases per million in the

Li-Fraumeni familial cancer syndrome, and

United States). The relative incidence of

cardio-facial-cutaneous syndrome. There

various STS varies by age, gender, and race.

has also been an association with maternal

For instance, NRSTS such as fibrosarcoma

use of marijuana and cocaine as well as first-

and malignant hemangiopericytoma are

trimester exposure to radiation, including

more common in infants (less than 1 year

diagnostic radiographs. Children with

of age). NRSTS also account for the major-

hereditary retinoblastoma (who harbor the

ity of STS in patients over 10 years of age.

Rb germ line mutation) are at increased risk

The most common bone sarcomas in

of developing sarcoma. Alveolar RMS

children are osteosarcoma and Ewing sar-

(ARMS) has a characteristic translocation

coma (annual incidence 8.7 per million).

of the FKHR gene at 13q14 with PAX3 at

Approximately two-thirds of cases are oste-

2q35 or less commonly PAX7 at 1p36, lead-

osarcoma and one-third Ewing sarcoma.

ing to a fusion transcription factor that is

Handbook of Pediatric Hematology and Oncology: Children’s Hospital & Research Center Oakland,

Second Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.

2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

184

Chapter 20

thought to inappropriately activate gene

bone turnover. Soft tissue and bone sarco-

transcription. Embryonal RMS (ERMS) dis-

mas also occur as secondary malignancies.

plays a loss of heterozygosity in the short

arm of chromosome 11, especially at 11p15.

The allelic loss of 11p15 has also been seen in

Soft tissue sarcoma

translocation negative, histologic ARMS. In

general, patients with ERMS have a better

Clinical presentation

prognosis than patients with ARMS, in large

STS may occur anywhere in the body and

part due to the increased risk of metastatic

are not limited to muscle or connective

disease at presentation with ARMS. DNA

tissues. The most common sites for RMS

content or ploidy has also been implicated

are head and neck (35%), genitourinary

in prognosis with hyperdiploid tumors

system

(26%), and extremities

(20%).

(

51 chromosomes) having a better out-

Younger children less than 10 years of age

come. NRSTS can occur in sites of prior

tend to develop ERMS in head and neck or

radiation, and children with human immu-

genitourinary locations, whereas adoles-

nodeficiency virus may develop leiomyosar-

cents tend to develop extremity, truncal,

coma (often in association with Epstein-

or paratesticular ARMS. The majority of

Barr virus). Interestingly, family members

RMS are localized, and, of the

15% to

of children affected with Ewing sarcoma

20% of cases with metastatic disease at

family of tumors (ESFT; also referred to

presentation, most involve the lungs, bone

as primitive neuroectodermal tumors) have

marrow, lymph nodes, or bone.

an increased risk of neuroectodermal and

As RMS can arise from anywhere in the

stomach malignancies. The translocation

body, the presenting symptoms are highly

t(11;22)(q24;q12) occurs in greater than

variable. Typically, RMS presents as a pain-

95% of ESFT and some consider this finding

less growing mass. Depending on location,

to be pathognomonic and sufficient to con-

adjacent structures may be compressed and

firm the diagnosis. This translocation results

lead to symptoms such as airway obstruc-

in the EWS-FLI1 fusion transcript that acts

tion or cranial nerve findings with nasopha-

as an aberrant transcription factor altering

ryngeal tumors, proptosis with orbital

tumor suppressor gene pathways.

tumors, and urinary obstruction with blad-

Osteosarcoma is characterized by com-

der or prostate tumors.

plex unbalanced karyotypes with alterations

in the Rb and p53 tumor suppressor path-

Diagnostic evaluation

ways, linking this tumor to retinoblastoma

Patients presenting with an enlarging mass

and Li-Fraumeni syndrome, respectively.

suspected to be malignancy should have an

Osteosarcoma has long been thought to

open surgical biopsy for confirmation of

be associated with adolescent growth spurts

diagnosis. Sufficient tissue should be

and the higher incidence in large dog breeds

obtained for pathologic evaluation and

and taller people support this correlation.

staining in addition to cytogenetic and

Girls have a peak incidence younger than

molecular biologic studies. Patients may

boys (12 vs. 16 years) correlating with the

be eligible to participate in a clinical ther-

different average age for pubertal develop-

apeutic or biologic trial that also mandates

ment. Well-documented risk factors include

submission of tissue. A complete assessment

radiation exposure, Paget’s disease, and

of extent of disease with meticulous atten-

other disorders associated with increased

tion to sites of metastatic disease is

Sarcomas of the Soft Tissues and Bone

185

mandated prior to initiating definitive ther-

essential to tailoring of therapy to maximize

apy. Some protocols also mandate biopsy of

outcome. A unique aspect of the RMS stag-

regional nodes or a sentinel node in patients

ing is the postoperative clinical grouping

with primary extremity tumors. These eva-

system that is based on extent of surgical

luations include:

resection and results of the lymph node

* Complete history and physical examina-

evaluation. Risk group classification is then

tion with careful assessment of the mass,

based on pretreatment stage, postoperative

adjacent structures, and regional lymph

clinical group, and histology. Favorable sites

nodes.

include the orbit, genitourinary (nonbladder

* Laboratory studies including complete

nonprostate), and nonparameningeal head

blood count, complete metabolic panel with

and neck locations. Unfavorable sites are

renal and liver function studies, coagulation

bladder/prostate, extremity, cranial parame-

testing, and urinalysis.

ningeal, trunk, and retroperitoneum.

* Radiographic studies including mag-

Low risk group: patients with nonmeta-

netic resonance imaging

(MRI) and/or

static favorable site ERMS (stage I, regard-

computed tomography (CT) scan of the

less of degree of initial resection) and

primary lesion, depending on the location.

completely resected (groups I and II) non-

Chest CT and radioisotope bone scan

metastatic unfavorable site ERMS

should also be conducted to evaluate for

Intermediate risk group: patients with

potential lung metastases and bone metas-

any nonmetastatic ARMS and all ERMS

tases, respectively. Site-dependent studies

with unfavorable sites (stages 2 or 3) that

may include: brain MRI for parameningeal

have been incompletely resected (group III)

head and neck tumors, ultrasound and

High risk group: patients with meta-

cystourethroscopy in bladder or prostate

static tumors, both ARMS and ERMS

tumors, and spine MRI in patients with

NRSTS are generally staged using the

evidence of medullary compression. Fluo-

same criteria above. The major determi-

rine-18-fluorodeoxyglucose positron emis-

nants of outcome include tumor grade, size,

sion tomography (FDG-PET) imaging may

extent of initial resection, and presence of

be helpful to determine initial extent of

metastatic disease. Extent of resection is

disease and to monitor response to therapy.

strongly correlated with treatment stratifi-

* Bilateral bone marrow aspirate and

cation and prognosis.

biopsy should be performed, especially in

patients with metastatic disease or alveolar

histologic subtype of RMS.

Pathologic diagnosis and

* Lumbar puncture in patients with para-

treatment

meningeal head and neck primary lesions.

RMS is classified pathologically as embryo-

nal (ERMS) with botryoid and spindle cell

Staging and classification

variants or alveolar (ARMS). Investigation

RMS are stratified into groups based on

for particular translocations (see Genetics

prognostic factors. The principal determi-

section) should be done to assist with defin-

nants of prognosis are primary site, tumor

itive tissue diagnosis in combination with

size, histologic subtype, degree of regional

histochemical studies.

spread and nodal involvement, distant met-

A multidisciplinary approach to the

astatic disease, and extent of prechemother-

treatment of STS is crucial. Basic principles

apy tumor resection. Risk stratification is

of therapy include systemic treatment of

186

Chapter 20

micrometastatic disease with adjuvant che-

Recent trials have not been able to show

motherapy and aggressive local control with

improvement in survival in patients with

definitive surgery and addition of radiation

metastatic rhabdomyosarcoma and new

as necessary.

drug therapies are being investigated. Such

Local control is achieved with either

therapies include irinotecan, temozolomide,

complete surgical resection (with negative

bevacizumab

(anti-vascular endothelial

margins) or surgery and radiation (if micro-

growth factor monoclonal antibody), tem-

scopic or gross residual disease remains after

sirolimus

(mTOR inhibitor), vinorelbine

surgical intervention). Primary re-excision

(vinca alkaloid), and cixutumumab (mono-

may be indicated prior to initiation of che-

clonal antibody to the insulin-like growth

motherapy in certain situations such as: if

factor-1 receptor). High-dose chemother-

the diagnosis was not suspected and only a

apy with hematopoietic stem cell rescue has

biopsy was performed; gross or microscopic

not shown benefit in patients with high risk

residual disease is amenable to wide exci-

and metastatic disease.

sion; or if there is uncertainty about residual

disease or margins. Aggressive surgical

Prognosis

debulking that would result in significant

Overall, survival without relapse is greater

loss of function is not recommended. RMS

than 70% in children and adolescents 5 years

often arise in sites in which complete or

from diagnosis. Low risk groups, represent-

wide resection is not feasible (e.g., orbit,

ing approximately 30% of RMS, can be

most genitourinary and parameningeal

expected to have an excellent outcome with

sites). STS are moderately sensitive to radi-

long-term survival greater than

90%. Of

ation therapy, and this treatment modality

the 55% of patients with intermediate risk

is critical for tumors that cannot be fully

disease, 5-year overall survival is approxi-

excised surgically with negative margins.

mately 55% to 65%. In patients with met-

Radiation is typically delayed until the com-

astatic alveolar disease (15% to 20% of the

pletion of 10 to 20 weeks of systemic che-

population), survival is poor, at less than

motherapy, but may be indicated earlier in

30%. Several caveats are present that help

patients with intracranial primary tumors

determine prognosis:

or in those with compromise of function

* Site of the primary tumor has a major

that may be debilitating or life threatening.

impact on survival and is associated with

Current studies are evaluating the optimal

pathologic subtypes, ease of surgical resect-

timing of irradiation.

ability, timing to presentation, and involve-

Chemotherapy provides the backbone

ment of regional nodes.

of treatment for patients with RMS and

* Extent of disease is the most significant

is initiated following the initial surgical

predictive factor for survival. Children with

procedure. After definitive local control

localized, completely resected disease do

surgery and/or radiation, chemotherapy

better than those with widespread or dis-

continues due to the risk of microscopic

seminated disease.

residual or metastatic disease. The most

* Patients with smaller tumors

(<5 cm)

active drugs in the treatment of RMS are

have improved survival compared to chil-

vincristine, dactinomycin, and cyclo-

dren with tumors >5 cm.

phosphamide

(VAC), doxorubicin, and

* The alveolar subtype of RMS has an

ifosfamide and etoposide

(IE). VAC is

adverse prognosis and is often associated

considered the standard of therapy in all

with an aggressive clinical course and met-

risk groups.

astatic disease at diagnosis and relapse.

Sarcomas of the Soft Tissues and Bone

187

Patients between 1 and 9 years of age

this group of patients. Patients with meta-

have a better prognosis compared to infants

static NRSTS have a dismal long-term prog-

and older children.

nosis and fewer than 20% survive 5 years

from diagnosis. Neoadjuvant chemora-

Children with recurrent RMS have a dismal

diotherapy is being explored in this group

prognosis with long-term survival of less

but there continues to be a paucity of new

than 15%, particularly if the disease recurs

potential therapeutic agents.

in a metastatic site or area of prior irradi-

ation. The majority of relapses occur within

3 years of therapy completion. Metastatic

Bone sarcomas

recurrence is essentially incurable, though

treatment may offer palliation. Treatment

Primary malignant bone tumors in children

with surgical resection and adjuvant mul-

are the sixth most common malignant neo-

tiagent chemotherapy is recommended with

plasm in children and the third most com-

new drug combinations such as ifosfamide/

mon malignancy in adolescents and young

carboplatin/etoposide, docetaxel/gemcita-

adults. They constitute approximately 6% of

bine, and irinotecan in combination with

all childhood malignancies. The two most

temozolomide or vinorelbine. Durable

common bone tumors are osteosarcoma

remissions for several years may be obtained

and Ewing sarcoma. Other malignant bone

with aggressive local retreatment and sys-

tumors include chondrosarcoma and non-

temic therapy. High-dose chemotherapy

Hodgkin lymphoma of bone. Bone lesions

followed by hematopoietic stem cell rescue

may also represent Langerhans cell histio-

has not been shown to be advantageous in

cytosis, benign tumors, or metastatic dis-

this group.

ease. Osteosarcoma is classified into three

major subtypes: osteoblastic, chondroblas-

tic, and fibroblastic, reflecting the predom-

Nonrhabdomyomatous soft

inant type of matrix in the tumor. Histo-

tissue sarcomas

logic variants include telangiectatic, small

cell, periosteal, and parosteal.

Few clinical trials and prospective studies

have been conducted in this population of

Clinical presentation

children. Surgery is the mainstay of effective

Patients typically present with a mass in the

therapy and every effort should be made to

involved area and pain, with symptoms pre-

completely excise the tumor with clear

ceding diagnosis often by several months.

tumor margins. Patients with completely

Patients frequently attribute the pain to a

excised low-grade tumors or high-grade

minor trauma and indeed may present with a

tumors <5 cm have a favorable outcome

pathologic fracture in the affected bone. A

with survival exceeding 85%. Patients with

palpable mass or swelling of the involved site

high-grade NRSTS larger than 5 cm and

typically arises after the onset of pain. Sys-

those with unresectable, localized disease

temic symptoms such as weight loss or short-

have an intermediate prognosis with

ness of breath may be late sequelae and

approximately 50% survival. Patients with

secondary to metastatic disease. Fever is a

high-grade tumors and positive tumor

common symptom of ESFT and may lead to

resection margins typically receive adjuvant

confusion with osteomyelitis and a longer

irradiation. It is not clear if adjuvant che-

period of time from development of symp-

motherapy confers a survival advantage in

toms to diagnosis.

188

Chapter 20

Diagnostic evaluation

and confirm suspicion of a malignant

Osteosarcoma may occur in any bone but

tumor. Osteosarcoma usually produces

primarily occurs in the metaphyses of the

dense sclerosis in the metaphyses of long

most rapidly growing bones. The most com-

bones with soft tissue extension seen in 75%

mon primary sites are the distal femur,

of tumors, radiating calcifications (sunburst

proximal tibia, and proximal humerus with

pattern) in 60% of tumors, osteosclerotic

approximately 50% of tumors originating

lesions in 45% of cases, lytic lesions in 30%

around the knee. Approximately 10% of

of cases, and mixed lesions in 25% of cases.

patients have primary tumors in the axial

A triangular area of periosteal calcification

skeleton including the pelvis, and 15% to

in the border region of the tumor and

20% present with metastatic disease (lung,

healthy tissue is known as a Codman trian-

bone, lymph nodes, and rarely brain).

gle. ESFT are described as lytic with an

Most ESFT occur in bones and their loca-

“onion peel” periosteal reaction and typi-

tions tend to differ from that of osteosarcoma.

cally occur in the diaphysis. Patients with

Flat bones of the axial skeleton are more

soft tissue ESFT only may have normal

commonly affected; in long bones, the diaphy-

radiographs. Additional assessment of the

seal portion is usually involved. The most

primary tumor site with MRI should be

common primary locations include the pelvic

undertaken to view the soft tissue compo-

bones, the long bones of the lower extremities,

nent, surrounding structures, vessels and

and the bones of the chest wall. Metastatic

nerves, and the intramedullary extension

disease is present in 25% of patients at diag-

to assist with surgical planning. MRI should

nosis and is primarily located in the lungs,

include the entire involved bone and neigh-

bones, or bone marrow. Site of primary disease

boring joints to evaluate for skip lesions.

is related to the incidence of metastases at

Metastatic disease is typically in the lungs or

diagnosis; central primaries are associated

bone and therefore imaging with chest CT

more frequently with distant disease (40%),

and technetium-99m bone scan is essential

whereas distal primary lesions have the lowest

in the initial workup for staging. FDG-PET

incidence (15%).

imaging is a sensitive screening tool for the

The requisite elements of evaluation

detection of bone metastases in ESFT but its

include:

role in evaluation of osteosarcoma has yet to

* A complete history and physical

be determined.

examination.

* Bilateral bone marrow aspirate and biopsy

* Routine laboratory studies include a com-

should be performed in patients with ESFT.

plete blood count, complete metabolic panel

* Baseline audiogram and echocardiogram

with renal and liver function tests, serum

should be obtained prior to initiation of

creatinine, creatinine clearance, and urinal-

ototoxic and cardiotoxic chemotherapy,

ysis. A measured or calculated glomerular

respectively.

filtration rate should be obtained prior to

initiation of nephrotoxic chemotherapy. The

Pathologic diagnosis

alkaline phosphatase may be elevated and has

Patients presenting with a bone mass sus-

been associated with an inferior outcome in

picious for malignancy should undergo a

osteosarcoma. The serum lactate dehydroge-

diagnostic incisional or core biopsy. It is

nase may also be elevated and may correlate

strongly recommended that an experienced

with tumor burden.

oncologic orthopedic surgeon who will also

* Imaging studies should begin with plain

be performing the definitive procedure per-

radiographs to visualize osseous changes

form the biopsy so that the biopsy tract can

Sarcomas of the Soft Tissues and Bone

189

be excised en bloc with the planned surgical

techniques in younger children. Tumors of

resection. Sufficient tissue should be

the pelvis or axial skeleton present a difficult

obtained for diagnostic histopathology as

situation, as resection with adequate mar-

well as for any submissions required for

gins may not be possible. Outcome is related

participation in a clinical trial. Biopsy may

to degree of resection and these patients as a

be taken from an extraosseous component,

group have inferior outcomes compared to

if present, to prevent pathologic fracture.

patients with extremity tumors.

As the histologic and immunophenoty-

Radiation therapy has limited utility in

pic features of ESFT overlap to some degree

patients with osteosarcoma, but is indicated

with many other small, round blue cell

for those unable to undergo complete resec-

tumors of childhood, an expanded immu-

tion. The most active chemotherapeutic

nohistochemical panel should include

agents are cisplatin, doxorubicin, high-dose

assessment for CD99 (a cell surface glyco-

methotrexate, ifosfamide, and etoposide.

protein with strong expression in ESFT) as

Patients can expect to be treated for approx-

well as markers for neuroblastoma (neuron-

imately

1 year, with a definitive surgical

specific enolase and S100), synovial sarcoma

procedure performed at approximately

(Leu-7), and rhabdomyosarcoma (vimen-

week 12, followed by continuation of mul-

tin, desmin, and myogenin). Molecular

tiagent chemotherapy.

genetic studies using fluorescent in situ

Patients presenting with metastatic dis-

hybridization or reverse transcriptase-

ease undergo the same therapeutic approach

polymerase chain reaction are valuable in

with systemic chemotherapy and definitive

diagnosis, specifically for the detection of

surgery of the primary site in addition to

characteristic translocations that allow for

surgery of metastatic sites, as feasible.

definitive diagnosis of ESFT, RMS, and

Approximately one-third of osteosarcoma

synovial cell sarcoma.

patients with pulmonary metastases will

have additional microscopic pulmonary

Treatment

nodules not visible on the current, highest

Systemic multiagent chemotherapy prior to

resolution CT imaging. It is recommended

and following definitive radical surgery is

that pulmonary nodules identified on CT

the standard of care for treatment of oste-

imaging be surgically resected by open tho-

osarcoma. Complete resection of all disease

racotomy that will allow intraoperative lung

sites including metastatic lesions is critical

palpation to potentially identify additional

to long-term survival. An assessment of

sites of metastatic disease. Patients with

histologic response to initial induction che-

unilateral lung metastases on imaging

motherapy at the time of definitive surgery

should undergo bilateral thoracotomies for

may guide subsequent treatment and helps

this reason.

define prognosis. The orthopedic oncologic

As with osteosarcoma, cure in ESFT

surgeon determines the type of surgical

can be achieved only with a multimodal

procedure performed and factors used in

approach, using surgery and/or radiation

this determination include the location and

therapy for local control of the primary

size of the tumor, patient age and skeletal

lesion and chemotherapy for eradication

maturity, presence of metastatic disease,

of subclinical micrometastases. Definitive

and patient lifestyle choices. Limb sparing

surgery follows a period of induction

procedures are feasible in the majority of

chemotherapy and many patients are

patients and the development of expandable

candidates for complete surgical resection

endoprostheses has allowed the use of these

with limb salvage procedures. Induction

190

Chapter 20

chemotherapy may also render initially

estimated at 2 years as 10% to 30%. The

unresectable tumors resectable. ESFT are

degree of tumor necrosis following neoad-

radiation responsive, although typically this

juvant

(presurgery) chemotherapy is an

therapeutic modality is reserved for surgi-

independent predictor of event-free and

cally unresectable tumors or in tumors with

overall survival, presumably reflecting

positive margins after resection. Patients

tumor sensitivity to chemotherapy. Specif-

who receive radiation therapy as the only

ically, osteosarcoma patients with a good

local control modality have an inferior

response, defined as greater than

95%

outcome. Frequently, these patients have

tumor necrosis at the time of surgery, have

other adverse features including large tumor

a superior survival. A similar cutoff is yet to

size, unfavorable locations (e.g., vertebral

be defined for ESFT. To date, intensified

tumors), or both. Radiation is also utilized

treatment for those with less favorable

in the treatment of metastatic disease.

tumor necrosis has not improved outcome.

Debulking procedures have not been shown

The prognosis for patients with recur-

to improve outcome and should not be part

rence is quite poor. Most local recurrence is

of local control therapy.

associated with concomitant distant disease.

Active chemotherapy agents in ESFT

Time to relapse and tumor burden correlate

include vincristine, dactinomycin, cyclo-

with postrelapse outcome. Late recurrence

phosphamide, doxorubicin, ifosfamide, and

(e.g., >5 to 10 years) has been reported in

etoposide (similar to RMS). As with osteo-

bone sarcoma. Surgical resection remains

sarcoma, the length of systemic therapy is

the mainstay of therapy for curative second-

approximately one year. The current stan-

line therapy. Patients with osteosarcoma

dard of care for localized pediatric ESFT is

who develop pulmonary lesions after com-

alternating cycles of vincristine, doxorubi-

pletion of therapy can be cured with surgery

cin, and cyclophosphamide

(VDC) with

alone. The role of adjuvant chemotherapy in

ifosfamide and etoposide (IE) given in a

relapse is controversial, though patients are

compressed, every 2-week schedule. This

often offered such treatments including

increased time-dose intensity schedule has

cyclophosphamide/topotecan, irinotecan/

shown benefit in pediatric patients though

temozolomide, and gemcitabine/taxotere.

not for adults. Although still being investi-

Radiation has a role in the treatment of

gated, high-dose chemotherapy with autol-

patients with ESFT who develop new met-

ogous stem cell rescue has not as yet shown

astatic sites and for palliation and pain

benefit in the treatment of bone sarcoma.

control in either osteosarcoma or ESFT.

Targeted and biologically based thera-

Prognosis

pies are being investigated in patients with

Most patients with bone sarcomas have

poor response to initial chemotherapy,

micrometastatic disease at diagnosis since,

those with metastatic disease, and those

in the past, 80% to 90% developed lung

with recurrent disease. Novel agents with

metastases following local control therapy

potential therapeutic benefit include mono-

(i.e., surgery and/or radiation) alone. There-

clonal antibodies to insulin growth factor-1

fore, prior to the use of systemic chemo-

receptor, tyrosine kinase inhibitors, mTOR

therapy, survival rates at 2 years were 15%

inhibitors, and monoclonal antibodies to

to 20%. Currently, patients with localized

vascular endothelial growth factor. Specific

disease can expect a long-term survival of

novel therapies for osteosarcoma include

greater than

70%. Survival in patients

bisphosphonates (e.g., zoledronic acid) and

with metastatic disease remains dismal,

RANK inhibitors

(e.g., denosumab); for

Sarcomas of the Soft Tissues and Bone

191

ESFT, transcription inhibition of the EWS-

Case study for review

FLI1 translocation is being studied.

A 9-year-old boy presents with a nontender

Late effects

4 cm mass in the right inguinal region.

Site and extent of disease, as well as thera-

He denies fever, weight loss, or pain else-

peutic interventions with chemotherapy,

where. The mass has been present and

radiation, and surgery all contribute to late

growing for several weeks.

sequelae in sarcoma patients. A majority of

first-line protocols utilize high cumulative

1. What key elements should you obtain in

doses of anthracyclines (i.e., doxorubicin)

the history?

resulting in a lifelong risk of developing

2. What are you looking for on the physical

cardiomyopathy. Thus, lifelong cardiac

examination?

monitoring with serial echocardiograms

3. What is your differential diagnosis for

and periodic functional assessments is

this boy?

recommended. Alkylator therapy (e.g., ifos-

4. How do you approach a diagnostic eval-

famide) can lead to gonadal toxicity (pri-

uation and staging?

marily in males) and increased risk of

5. What do you tell the child and his family?

secondary malignancy. Second malignant

6. Assuming you find out this is a localized

neoplasms occur in approximately 3% of

undifferentiated sarcoma, what is the child’s

patients within 10 years of therapy comple-

prognosis and what is the general treatment

tion, likely related to both a genetic predis-

plan?

position and treatment with mutagenic

therapies. Platinum therapy (e.g., cisplatin)

Key elements in the history include length of

can lead to long-term oto- and nephrotox-

symptoms, possible relationship to infec-

icity. High-frequency hearing loss is com-

tion (could this be a lymph node?), animal

mon and some patients will require hearing

exposures and bites, travel, cuts or injuries

aids. Renal dysfunction is rare but could

to the affected leg, systemic symptoms such

result in chronic electrolyte wasting due to

as malaise, fevers, unexplained weight loss,

proximal tubular damage (see Chapter 30

or discomfort that limits activities or neces-

for more details).

sitates medication.

For osteosarcoma patients, contempo-

The physical examination should be

rary orthopedic surgery techniques are

complete, head to toe. The mass should

aimed at preservation of function and

be measured and characterized for mobility,

improved limb salvage without compromis-

tenderness, warmth, and erythema. The

ing survival. Amputation may result in

mass may be hard and nontender if malig-

superior limb function in some cases. In a

nant disease is present. If the mass is sus-

skeletally immature child, expandable pros-

pected to be a node, it may be enlarged as a

theses may require subsequent revisions

result of disease spread and therefore the

though some may benefit from newer

distal extremity must be carefully examined.

self-expanding prostheses. Late prosthetic

All other lymph node chains as well as the

failures or infection can occur, requiring

liver and spleen should also be carefully

surgical revision or delayed amputation.

assessed.

Radiation therapy can lead to local effects

The differential diagnosis of a mass in the

including growth impairment, muscle

inguinal area consists of lymphadenopathy

fibrosis, and increased risk of secondary

secondary to an infectious or malignant

malignancy, in a dose-dependent manner.

etiology. Infections may be bacterial,

192

Chapter 20

protozoal, fungal, or viral and may be the

aggressive local control (complete surgical

result of introduction by a cut (which may

excision and focal radiation) can expect to

have since healed), animal bite, or scratch.

have approximately a 70% event-free sur-

A mass that is hard, nontender, and non-

vival. This is in stark contrast to patients

mobile, without signs and symptoms of

with metastatic disease in which case sur-

infection, is concerning for malignancy.

vival is less than

20% despite aggressive

Malignancies that can lead to regional

therapy. Those patients with regional

spread in an extremity include sarcomas

spread, similar to this case, have an inter-

(bone and soft tissue).

mediate prognosis. Such cases would be

Assuming you could find no lump or

treated with aggressive multiagent chemo-

tender area on the extremity exam, it is

therapy in addition to aggressive local con-

prudent to begin a detailed investigation

trol. Future therapies may include novel

with imaging and biopsy. Imaging should

biologic or targeted agents. In this child,

consist of MRI of the inguinal area and leg

local control would involve treatment of the

(to the tips of the toes), bone scan, and plain

toe and the inguinal mass. One should also

films. An excisional biopsy should be per-

consider treatment (i.e., radiation therapy)

formed as well given the concern for malig-

of the lymph nodes in between these regions

nancy

(and to prevent potential tumor

in addition to nearby pelvic nodes.

tracking which can occur with an incisional

biopsy). Once the mass is a biopsy-proven

Suggested Reading

malignancy, further staging should evaluate

for distant disease and include CT of the

Caudill JS, Arndt CA. Diagnosis and manage-

chest, abdomen, and pelvis.

ment of bone malignancy in adolescence.

Prior to initiation of the biopsy and

Adolesc Med State Art Rev 18:62-78, 2007.

imaging, it is best to be straightforward with

Hayes-Jordan A, Andrassy R. Rhabdomyosar-

the family and let them know your concern

coma in children. Curr Opin Pediatr

that this mass likely represents a malignancy.

21:373-378, 2009.

As the mass is in the inguinal area, it could

Loeb DM, Thornton K, Shokek O. Pediatric soft

represent regional spread of a distant tumor.

tissue sarcomas. Surg Clin North Am

In this case, the child had a nonpalpable

88:615-627, 2008.

mass in the fifth distal toe found on MRI.

McCarville MB. The child with bone pain: malig-

nancies and mimickers. Cancer Imaging 9:

The pathologic diagnosis of undifferenti-

S115-S121, 2009.

ated sarcoma was made on excisional biopsy

Spunt SL, Skapek SX, Coffin CM. Pediatric non-

of the inguinal mass. No other evidence of

rhabdomyosarcoma soft tissue sarcomas.

distant tumor was found on further imag-

Oncologist 13:668-678, 2008.

ing. Prognosis for undifferentiated sarcoma

Subbiah V, Anderson P, Lazar AJ, et al. Ewing’s

is generally similar to alveolar rhabdomyo-

sarcoma: standard and experimental treat-

sarcoma, and patients with localized disease

ment options. Curr Treat Options Oncol

who receive systemic chemotherapy and

10:126-140, 2009.

Germ Cell Tumors

Germ cell tumors (GCT) arise from primor-

more frequent in males. Testicular GCT

dial cells involved in gametogenesis and

have several known risk factors including

occur primarily in the testes and ovaries.

infertility/testicular atrophy as well as crypt-

These tumors represent approximately 4%

orchidism. Males with cryptorchidism have

of pediatric cancers. Primordial germ cells

a higher incidence of testicular cancer in

(PGCs) are thought to originate in the yolk

both the undescended testis and the nor-

sac endoderm and migrate along the genital

mally descended contralateral testis despite

ridge and thus may also present in midline

surgical correction, hormonal therapy, or

extragonadal sites such as the sacrococcygeal

spontaneous descent. However, early cor-

region, midline of the brain, mediastinum,

rection may partially ameliorate this risk.

and retroperitoneum. Due to the pluripoten-

The incidence of testicular GCT in the

tiality of PGCs, GCT are an array of different

Caucasian population is increasing at a rate

histologic subtypes, adding to the complexity

of 3% to 6% per year. Perinatal and envi-

of the disease. In addition, GCT can occur

ronmental risk factors are thought to play a

due to tumorigenesis or as part of normal

role although these are yet to be clearly

embryonal development, in part explaining

elucidated. Young parental age at birth, low

the pediatric bimodal age of distribution (2

birth order, low birth weight, and breech

and 20 years). In addition, age of presenta-

birth have all been noted to be statistically

tion and histologic subtype varies signifi-

significant risk factors in multiple studies.

cantly between males and females. This is

Maternal exposure to pesticides or hor-

thought to be due in part to the differential

mones, parental smoking, and alcohol con-

timing of male and female development;

sumption may also be factors. Genetic risk

female germ cells enter meiosis at 11 to 12

factors also play a role, specifically in tes-

weeks of gestation while male germ cells

ticular GCT, as a family history of cancer,

begin meiosis with the onset of puberty.

especially at a young age, has been associ-

ated with increased risk in pediatric

patients. Additionally, there is a higher inci-

Epidemiology

dence in monozygotic twins and some

familial clusters have been reported. A num-

Due to the differential timing of germ cell

ber of congenital genitourinary anomalies

maturation, GCT are more common in

such as retrocaval ureter, bladder divertic-

females until adolescence and then become

ulum, and inguinal hernia have been

Handbook of Pediatric Hematology and Oncology: Children’s Hospital & Research Center Oakland,

Second Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.

2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

194

Chapter 21

associated with increased risk, emphasizing

develop malignant components (i.e., squa-

that abnormalities in development likely

mous cell carcinoma) and therefore are

play a role. Similarly, disorders of sexual

treated with complete surgical resection.

development, especially in cases with excess

Immature teratomas are tumors of inter-

Y chromosome material (e.g., gonadal dys-

mediate malignant potential with less dif-

genesis), pose an increased risk in both

ferentiated tissues.

males and females. Children with Down

Germinomas may be of pure histology or

syndrome, who generally have a decreased

mixed. Syncytiotrophoblastic cells occur in

risk of solid tumors, are at a predisposition

about 5% of germinomas and secrete the

to develop testicular GCT, whereas patients

beta subunit of human chorionic gonado-

with Klinefelter syndrome have an increased

tropin (b-HCG). Embryonal carcinoma is

risk of mediastinal GCT. Gain of chromo-

most often found as a component of testic-

some 12p is also seen in the majority of

ular mixed GCT and is thought to be the

testicular and malignant ovarian GCT.

driver for the development of other histo-

Approximately half of all pediatric GCT are

logic subtypes including teratoma, yolk sac

extragonadal in origin, with about 15% of

tumor, and choriocarcinoma. Yolk sac

these being malignant.

tumor is generally found as a part of testicular

mixed GCT but can also be seen as a pure

histologic variant in young children. Yolk sac

Pathology and serum tumor

tumor secretes a-fetoprotein (AFP).

markers

Choriocarcinoma contains syncytiotro-

phoblastic cells and therefore also secretes

The main histologic variants of GCT include

b-HCG. Ovarian cases should be distin-

germinomas (dysgerminoma in the ovary

guished from metastatic gestational

and seminoma in the testis), embryonal

choriocarcinoma.

carcinoma, yolk sac tumor

(endodermal

In the ovary and testis, GCT should be

sinus tumor), choriocarcinoma, and tera-

distinguished from sex cord stromal

toma (mature and immature). Mixed GCT

tumors, which arise from the nongermina-

are composed of two or more histologies.

tive components of gonadal tissue and

Teratomas contain tissues from all three

include tumors involving the Sertoli-Leydig

germ layers

(ectoderm, endoderm, and

cells of the testis and granulosa cells of the

mesoderm). Mature teratomas contain no

ovary. Sarcoma as well as gonadal infiltra-

malignant germ cell elements and are most

tion by leukemia and non-Hodgkin lym-

commonly located in the ovary or sacro-

phoma should also be considered in the

coccygeal region. The vast majority of

differential diagnosis of gonadal tumors.

female GCT are teratomas. Teratomas in

Due to the specific histologies that

the prepubertal male are benign, whereas

secrete AFP and b-HCG, these tumor mar-

those occurring during or after the onset of

kers can be quite helpful in distinguishing

puberty are always malignant, as they arise

tumor type as well as following disease.

from other forms of testicular germ cell

Mature teratomas secrete neither marker;

tumor (specifically embryonal carcinoma).

therefore, if a serum marker is present in the

Therefore, teratomatous elements in the

patient diagnosed with a mature teratoma,

testis largely occur as a component of a

one must consider that the tumor contains

mixed GCT. In the female or prepubertal

one or more foci of yolk sac tumor if the

male, these tumors are thought to derive

AFP is positive, choriocarcinoma or germi-

from a benign germ cell but may rarely

noma if the b-HCG is positive, and that the

Germ Cell Tumors

195

patient in fact has a mixed malignant germ

pain due to testicular torsion. The differen-

cell tumor. Due to physiologic changes in the

tial diagnosis of a testicular mass includes

secretion of fetal AFP, this marker can be

hydrocele, hematocele, varicocele, inguinal

difficult to utilize in young infants. AFP is

hernia, and torsion of a normal testis. Girls

made in the fetal liver and does not decline to

most frequently present with abdominal

adult levels until approximately

pain, distention, and weight gain. Torsion

months of age. Age appropriate levels can

of an involved ovary, hemorrhage, or tumor

be obtained from published tables. AFP can

rupture may occur and present as an acute

also be secreted by regenerating liver post-

surgical abdomen. Secretion of b-HCG may

injury or by certain liver tumors such as

lead to isosexual precocity. Occasionally, the

hepatoblastoma. Degree of AFP elevation

increasing abdominal girth and elevated

may be related to tumor volume. b-HCG

urine and serum b-HCG have been con-

is elevated in pregnancy and can also be seen

fused with pregnancy.

in association with childhood hepatic tumors

The most common site of extragonadal

and other cancers involving the breast, stom-

tumors is the sacrococcygeal region.

ach, and pancreas in adults. Nonspecific

Although usually benign, patients can have

markers of GCT include lactate dehydroge-

malignant tumors of higher stage. Older age

nase isoenzyme 1, neuron-specific enolase,

at diagnosis is associated with a greater risk

and placental alkaline phosphatase.

of malignancy. Sacrococcygeal tumors are

classified as four anatomic variants: type I

(predominantly outside the body), type II

Clinical presentation

(equally inside and outside the body),

type III

(largely intra-abdominal), and

GCT should be considered in children who

type IV (completely within the body). More

present with a pelvic, ovarian, or testicular

than 90% of tumors present with some

mass, or a midline mass in the sacrococcy-

component of an externally visible mass.

geal region, retroperitoneum, mediastinum,

These tumors are often detected in utero

or pineal or suprasellar regions of the brain.

with prenatal ultrasonography. They may

GCT present with signs and symptoms

also present later in children with constipa-

related to the site and size of the primary

tion, urinary obstruction, urgency or fre-

tumor. Compression of internal structures

quency, lower back or pelvic pain, lower

can lead to pain, constipation, and urinary

extremity weakness, or sensory changes, all

obstruction. Large ovarian tumors can addi-

signs and symptoms due to compression of

tionally lead to decreased lung volumes and

normal structures by tumor.

respiratory distress. GCT can metastasize,

Approximately

20% of children with

most commonly to the lungs, but patients

GCT will present with metastatic disease,

rarely present with clinical symptoms refer-

most commonly to the lung, liver, or lymph

able to these metastases. Occasionally,

nodes, and rarely to the central nervous

patients may present with hormonal man-

system, bone, or bone marrow. Regional

ifestations secondary to secretion of

spread resulting in surgically unresectable

b-HCG. Specifically, peripheral conversion

tumors occurs in approximately 25% of

of androgen to estrogen can lead to gyneco-

patients at presentation. Tumor dissemina-

mastia or uterine bleeding.

tion occurs by local extension, intracavitary

Boys with gonadal GCT typically present

seeding, or hematogenous spread. Intraca-

with a slowly enlarging testicular mass,

vitary seeding may involve the omentum,

occasionally complicated by acute severe

bowel, spleen, diaphragm, or pelvic organs.

196

Chapter 21

Rarely, bone involvement can occur by

sperm banking should be discussed with the

direct extension.

patient and family prior to radical inguinal

orchiectomy.

Diagnostic evaluation and risk

Treatment and prognosis

stratification

Staging is done postoperatively and is based

The following studies should be performed

on pathologic degree of tumor invasion,

in a child with a suspected or confirmed

presence of lymph node involvement, con-

GCT:

tinued positivity of tumor markers, positive

* Complete history

peritoneal washings (in ovarian tumors),

* Physical examination

and presence of residual or metastatic dis-

* Baseline laboratory studies consisting of a

ease. Factors known to affect prognosis

complete blood count, transaminases, blood

include extreme tumor marker elevation

urea nitrogen, creatinine, and electrolytes

and failure of these markers to appropriately

* Baseline tumor markers including AFP,

decline following tumor resection, based on

b-HCG, and lactate dehydrogenase (LDH)

the appropriate half-life for each marker. Site

* Imaging studies to evaluate the extent of

of tumor is prognostic, with mediastinal

the mass and potential metastatic sites:

tumors fairing more poorly. Histology is also

ultrasound, CT, or MRI of the primary mass

important as pure germinomas are generally

(testicular ultrasound in males, abdominal

very chemotherapy sensitive and have a high

and pelvic ultrasound, CT, or MRI in

response rate. Patients with higher stage,

females); abdominal and pelvic MRI or

metastatic disease also fair more poorly.

CT as well as baseline chest radiography

In the patient with suspected GCT,

with or without CT of the chest to evaluate

every effort should be made to perform a

for metastatic disease (all CTs should be

complete resection with negative margins.

done with contrast)

In situations where the patient presents

emergently with torsion, there may not

Determination of the extent of disease at

be time to wait for a definitive diagnosis

diagnosis allows proper decision making

prior to surgery; every effort should be

regarding the safest and most reasonable

made in these cases to perform a gross

place to biopsy. Localized tumors of the

total resection (GTR), assuming there is

ovary or testis should be completely

low operative risk, after sending the appro-

removed. Resection of ovarian tumors

priate tumor markers. In the case of a large,

should include abdominal exploration and

invasive tumor, biopsy should be done

peritoneal washings for cytologic assess-

followed by administration of chemother-

ment. Risks and benefits of lymph node

apy and delayed surgical resection. Due to

sampling and biopsy of the contralateral

the location of some extragonadal tumors,

testis or ovary should be discussed with the

especially those in the mediastinum and

surgeon, patient, and family.

retroperitoneum, neoadjuvant chemother-

GCT are known to grow rapidly and

apy is often required prior to surgery in

metastasize frequently. Diagnostic studies

order to help facilitate the chance of a

should be done expeditiously to allow ini-

safe GTR.

tiation of therapy. Due to the potential

Depending on tumor location and his-

underlying risk of contralateral testicular

tology, some GCT can be observed after

atrophy, infertility, or carcinoma in situ,

GTR without additional therapy. Young

Germ Cell Tumors

197

patients with extragonadal tumors and a

retroperitoneal lymph node dissection may

GTR can generally be observed after surgery,

also be recommended in patients with exten-

as these tumors rarely have malignant ele-

sive disease at presentation. Patients with a

ments. Sacrococcygeal tumors must be

poor response to therapy or recurrent disease

removed with the coccyx in order to

may benefit from second-line therapies such

decrease the risk of local recurrence. Young

as paclitaxel

(Taxol), ifosfamide, cisplatin

patients are more likely to present with pure

(TIP); vinblastine, ifosfamide, cisplatin

yolk sac tumors, and these patients can also

(VeIP); or gemcitabine/oxaliplatin. GCT are

be observed after GTR. Gonadal tumors that

also quite radiosensitive, although the high

are histologically consistent with mature

cure rates seen with chemotherapy alone

teratoma similarly require only observation

have obviated the need for radiation in most

after GTR. Localized testicular seminoma

cases. Radiation may be considered in refrac-

can be observed, although patients with

tory or recurrent disease, or for palliation.

continued elevation of tumor markers

Additionally, high-dose chemotherapy with

should undergo adjuvant radiotherapy.

autologous stem cell rescue may be benefi-

Patients with this pure histology are very

cial in a subset of refractory patients.

chemotherapy sensitive and easily salvaged

Patients treated with high-dose platinum

in the event of relapse. In general, patients

agents may develop high-frequency hearing

with localized testicular mixed GCT can also

loss and require hearing assistive devices.

be observed assuming that tumor markers

Additionally, these drugs may lead to tran-

normalize after surgery, again due to the

sient proximal tubule renal dysfunction and

high rate of salvage with potential relapse.

resultant electrolyte wasting. Patients who

Due to this risk of relapse, which is directly

receive alkylator therapy (e.g., ifosfamide)

related to the amount of vascular tumor

are at risk for secondary malignancy and

invasion, size of the primary tumor, and

infertility (especially in males). Topoisom-

percent embryonal carcinoma, patients

erase II inhibitors (etoposide) also increase

should be presented the options of obser-

risk for secondary neoplasms. Bleomycin

vation versus chemotherapy. Due to the

may lead to pulmonary fibrosis, although

rarity of malignant ovarian GCT, recom-

the risk is poorly quantified.

mendations for chemotherapy versus obser-

vation generally follow those presented for

testicular tumors.

Germ cell tumors of the central

Higher stage, nonlocalized GCT are trea-

nervous system

ted with chemotherapy and are generally

very chemotherapy sensitive. Patients are

Intracranial GCT comprise approximately

treated with bleomycin, etoposide, and

3% of primary childhood brain tumors with

cisplatin (BEP) regimens for 3 to 4 cycles.

a peak incidence between the second and

These tumors exhibit a steep dose-response

third decade of life. The majority of these

curve to platinum compounds, though the

tumors are germinomas, which account for

risk of toxicity (oto- and nephrotoxicity)

50% to 70% of cases. Nongerminomatous

must be considered. Due to the potential

germ cell tumors (NGGCT) account for the

risk of long-term pulmonary fibrosis from

remaining third and consist of multiple

bleomycin, etoposide/cisplatin

(EP) and

histologies including endodermal sinus

etoposide (VP-16), ifosfamide, and cisplatin

(yolk sac) tumors, choriocarcinoma, mature

(VIP) regimens have been developed as

and immature teratoma, and embryonal

alternative therapies to BEP. Bilateral

carcinoma. Most NGGCT are of mixed

198

Chapter 21

histology and may contain germinomatous

surgical GTR, as safely feasible. In other

elements but will not have this as a pure

tumor types, the value of a surgical resection

histology. Mature and immature teratomas

has not been clearly delineated and is

predominate in the neonatal period. Patients

recommended only in specific situations

typically present with symptoms depending

(i.e., persistence of tumor following induc-

on the location and size of the tumor,

tion chemotherapy). Pure germinomatous

further influenced by the extent of pituitary

tumors are highly sensitive to both radio-

dysfunction and the presence or absence of

and chemotherapy. In the past, radiother-

hydrocephalus. Midline pineal tumors are

apy was the modality of choice for these

often associated with symptoms related to

tumors due to the high cure rate

increased intracranial pressure due to

(5-year survival >80%). Due to the recog-

obstruction of the cerebral aqueduct and

nized long-term risks from this therapy

Parinaud’s syndrome (paralysis of upward

(neuropsychological and endocrine), adju-

gaze) due to involvement of the tectal plate.

vant chemotherapy is now being used to

Tumors in the suprasellar area often lead to

allow a reduction in the dose and extent of

endocrinopathies such as diabetes insipidus

radiotherapy without increasing relapse

(DI) and visual field defects. Occasionally

rate. Chemotherapeutic agents are similar

DI is related to occult involvement of the

to those used for systemic GCT and include

infundibulum. In children with clinical

platinum agents (cisplatin and carboplatin),

symptoms of DI and consistent MRI find-

alkylators

(cyclophosphamide and ifosfa-

ings (i.e., absence of a posterior pituitary

mide), and topoisomerase II inhibitors (eto-

bright spot, possibly in association with

poside). Of note, patients with DI should be

thickening of the pituitary stalk), the differ-

carefully monitored in an ICU setting while

ential diagnosis should include GCT and

receiving alkylators or platinum therapy due

Langerhans cell histiocytosis. The presence

to the increased risk of nephrotoxicity.

or absence of CSF tumor markers may assist

Management during this therapy can be

with this diagnostic dilemma.

simplified by the use of IV vasopressin

Children with midline brain tumors

administered as a continuous infusion.

should be assessed for a GCT. CSF should

Patients with NGGCT have had a poorer

be obtained for routine studies (glucose,

outcome in the past as these tumors are

protein, chamber count, and cytology) in

generally less radiosensitive than pure

addition to assessment of tumor markers

germinoma. Outcome is related to tumor

(AFP and b-HCG). Patients with classic

histology as those patients with pure embry-

findings on MRI and elevated AFP with

onal carcinoma, endodermal sinus tumor,

or without a significantly elevated b-HCG

and choriocarcinoma fair much more

do not require a biopsy for diagnosis as they

poorly than those with mixed histology,

have chemical evidence of NGGCT. Patients

especially those with a high proportion of

with negative markers or a modest elevation

teratoma or germinoma. Neoadjuvant plat-

in b-HCG only should have a biopsy per-

inum-based chemotherapeutic regimens

formed. Central nervous system GCT often

have shown benefit in patients with NGGCT

spread along the CSF pathways; thus, MRI

prior to radiation therapy. Second-look sur-

of the spine should be obtained in addition

gery is beneficial in those patients with an

to head imaging for diagnostic and staging

incomplete radiologic response or persis-

purposes.

tently elevated tumor markers following

Patients with benign tumors such as

induction chemotherapy, prior to radiation

mature teratoma should have a curative

therapy. High-dose chemotherapy with

Germ Cell Tumors

199

autologous stem cell rescue has been shown

though may benefit from additional chemo-

to be of benefit in patients with residual

therapy, surgery, radiation, and/or high-

malignant disease after chemotherapy and

dose chemotherapy with stem cell rescue.

surgery.

Patients with recurrent disease may be

successfully treated, depending on initial

Suggested Reading

therapy. Patients with pure germinoma

treated solely with chemotherapy may ben-

Echevarria ME, Fangusaro J, Goldman S. Pedi-

efit from additional chemotherapy followed

atric central nervous system germ cell tumors:

by radiation therapy. Those that have pre-

a review. Oncologist; 13:690-699, 2008.

viously received radiation may benefit from

Horton Z, Schlatter M, Schultz S. Pediatric germ

high-dose chemotherapy with autologous

cell tumors. Surg Oncol 16:205-213, 2007.

stem cell rescue. Patients with recurrent

Horwich A, Shipley J, Huddart R. Testicular

NGGCT have a much more dismal outcome

germ-cell cancer. Lancet 367:754-765, 2006.

Rare Tumors of

Childhood

The rarer tumors of childhood collectively

utmost importance in affected families due

comprise fewer than 20% of all pediatric

to the risk of tumors in siblings as well as

cancers. The more frequently seen of these

offspring of survivors, especially in those with

include retinoblastoma (2% to 3%), liver

bilateral retinoblastoma.

tumors (1%), and epithelial tumors of the

The RB1 gene is a tumor suppressor gene

adrenal or thyroid gland (2% to 3%), which

and individuals with loss of function of both

are discussed herein. Many other rare pedi-

allelic copies are predisposed to malignancy.

atric malignancies also exist that are beyond

Germline de novo mutations of the RB1 gene

the scope of this chapter.

largely occur during spermatogenesis. Sec-

ondary mutations may then be germline or

somatic depending on the timing of events.

Retinoblastoma

Those mutations that are germline are her-

itable for future generations.

Retinoblastoma is the most common

Retinoblastoma arises from the photo-

malignant ocular tumor in childhood,

receptor cells of the innermost layer of the

affecting 200 to 300 children per year in

retina. The tumor frequently extends into

the United States. Retinoblastoma is rarely

the vitreous cavity, presenting with a fleshy

diagnosed after 5 years of age. This unique

nodular mass visible on ophthalmologic

neoplasm has a strong genetic component

examination. Large tumors may occupy

related to mutation in the RB1 gene located

most of the posterior chamber. Less fre-

on chromosome 13. It was the model for the

quently, tumors may extend externally

development of Knudson’s two-hit hypoth-

resulting in retinal detachment. The tumor

esis after observation that children with

tends to outgrow its blood supply and may

bilateral retinoblastoma developed disease

develop areas of necrosis and calcification.

at an earlier age compared to those with

Due to the large mass or retinal detach-

unilateral disease. The genetic form of the

ment, the normal papillary red reflex is

disease is inherited in an autosomal domi-

replaced by leukocoria (white papillary dis-

nant manner yet only 15% to 25% of children

coloration) and is often first noticed by the

have a family history, suggesting the acqui-

family. Strabismus is the second most com-

sition of a new germ line or somatic mutation

mon presenting sign and is due to visual

in the majority. Genetic counseling is of

impairment from the tumor. Other less

Handbook of Pediatric Hematology and Oncology: Children’s Hospital & Research Center Oakland,

Second Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.

2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

Rare Tumors of Childhood

201

common presenting signs include hetero-

to radiation that increases the likelihood of

chromia, inflammatory changes, hyphema,

secondary malignancy. MRI is most useful

and glaucoma. Familial cases are often

for identification of extraocular extension

detected early when the family is appropri-

and trilateral retinoblastoma. MRI of the

ately advised on the need for frequent and

spine and lumbar puncture for cerebrospi-

careful screening with ophthalmologic

nal fluid cytology should be done in patients

examinations under anesthesia. The differ-

with intracranial spread, involvement of the

ential diagnosis of leukocoria includes a

optic nerve, or evidence of tumor invasion

number of rare nonmalignant conditions

beyond the lamina cribrosa on pathology

such as Coats disease, congenital cataracts,

after eye enucleation. In patients with delay

toxocariasis, retinopathy of prematurity,

in diagnosis and concern for metastatic

and persistent hyperplastic primary vitre-

disease, bone marrow studies and bone scan

ous. Careful retinal examination by an

should be performed.

ocular oncologist can rule out these other

Treatment for retinoblastoma is individ-

diseases and obviate the need for tissue

ualized and dependent on multiple factors

biopsy. Patients with advanced disease may

including unilaterality or bilaterality of dis-

present with proptosis and swelling depend-

ease, potential for preserving vision, and

ing on the degree of extraocular invasion.

extent of intraocular and extraocular dis-

Metastatic spread can occur through infil-

ease. Enucleation performed by an experi-

tration of the optic nerve, dissemination

enced ophthalmologist is indicated for

into the subarachnoid space, invasion into

large tumors filling the vitreous and in

the choroid plexus, and anteriorly into the

those with little or no likelihood of vision

conjunctiva. Invasion through the optic

preservation. Enucleation is often indicated

nerve and subarachnoid can lead to involve-

for unilateral localized retinoblastoma, and

ment of the brain and spinal cord, invasion

alone is effective therapy in these children.

of the vascular choroid plexus can lead to

The eye must be removed intact to avoid

vascular spread, and anterior invasion can

seeding and care must be taken to resect

lead to regional lymph node involvement.

enough optic nerve to ensure negative mar-

Patients with bilateral retinoblastoma

gins. After enucleation, patients are fitted

may present with a concurrent intracranial

with a prosthetic implant.

neuroblastic tumor, referred to as trilateral

Focal treatments such as laser photoco-

retinoblastoma. These patients tend to have

agulation, cryotherapy, and thermotherapy

a poor prognosis and usually present with a

may be utilized for very small tumors. Che-

pinealoblastoma, although they may have a

motherapy (usually vincristine, etoposide,

neuroblastic tumor in the suprasellar region

and carboplatin) can be utilized for local-

as well. The intracranial tumor may present

ized tumors in order to facilitate focal treat-

at the same time as the retinoblastomas, or

ment for tumor eradication and prevent the

after the identification and treatment of the

need for enucleation.

original tumors, emphasizing the need for

Patients with bilateral disease may

close follow up after initial treatment.

require enucleation of the more affected

Ultrasound, CT, and MRI are typically

eye, but fortunately bilateral enucleation is

used in addition to ophthalmologic exam-

rarely indicated. As with localized unilateral

ination to further characterize the tumor.

retinoblastoma, chemotherapy may be uti-

CT is the most useful test as it effectively

lized prior to focal therapy to avoid enucle-

demonstrates intraocular calcifications that

ation in either eye or in the less-affected eye.

confirm the diagnosis, but it creates risk due

External beam radiation therapy is generally

202

Chapter 22

reserved for patients with refractory or

Hepatoblastoma is the most common,

recurrent disease after these other treatment

representing more than

60% of hepatic

modalities have been exhausted due to the

tumors, and occurs almost exclusively

high incidence of side effects including risk

during infancy and young childhood. The

of secondary malignancy.

incidence of hepatoblastoma is increasing,

Patients with regional extraocular disease

possibly due to increased survival in very

and metastatic disease have historically faired

low birth weight infants. Hepatocellular

very poorly. Newer studies have shown the

carcinoma (HCC), approximately 20% to

potential benefit of chemotherapy (or high-

25% of childhood primary liver tumors, is

dose chemotherapy with autologous stem

seen most often in children above 10 years of

cell rescue in those with metastatic disease)

age. Although chronic hepatitis B infection

with external beam radiation therapy.

is the leading cause of HCC in Asia, few

Children treated for retinoblastoma are

American children with HCC have an

at high risk for cosmetic and functional

apparent etiology. Benign hepatic tumors,

impairment related to either enucleation

such as hemangioendothelioma, hamartoma,

or radiation. Patients with a heritable muta-

mature teratoma, angiolipoma, and ade-

tion in the RB1 gene have an especially high

noma, also occur in childhood and

rate of secondary malignancy after radiation

account for up to 20% of liver tumors in this

therapy. Reported second malignancies

age group. Other extremely rare malignant

include head and neck cancers, osteosar-

hepatic tumors include cholangiocarcinoma,

coma, soft tissue sarcoma, and melanoma.

rhabdoid tumor, yolk sac tumor, rhabdomyo-

Adult tumors also have an increased inci-

sarcoma, undifferentiated sarcoma, angiosar-

dence in those with germline RB1 muta-

coma, leiomyosarcoma, and lymphoma.

tions, especially epithelial tumors such as

Malignant hepatic tumors of childhood

lung cancer. Radiation therapy also may

have been associated with a number of

lead to decreased visual acuity, eye irrita-

genetic syndromes and environmental risk

tion, and dry eye as well as growth abnor-

factors. Hepatoblastoma has been reported

malities in the orbital bones. After therapy,

in children with Beckwith-Wiedemann syn-

patients should be followed closely due to

drome, familial adenomatous polyposis

the risk of recurrent disease. Patients with

(which includes Gardner syndrome), and

bilateral retinoblastoma and those diag-

isolated hemihypertrophy. The strongest

nosed with unilateral retinoblastoma at a

association has been reported in infants

young age (i.e., <1 year of age) should be

born at less than 1500 g. Additional associa-

observed for the development of an intra-

tions may include maternal smoking (inde-

cranial mass and, in the case of unilateral

pendent of birth weight), use of infertility

disease, a contralateral retinal mass. Recur-

treatment, fetal alcohol syndrome, use of

rence or new disease rarely occurs after 5

oral contraceptives during pregnancy, and

years of age, although an ophthalmologist

occupational exposure to metals, petro-

should examine these patients annually.

leum, paints, and pigments. HCC is seen

in association with hereditary tyrosinemia,

biliary cirrhosis, glycogen storage diseases,

Liver tumors

hemochromatosis, ataxia telangiectasia, and

a₁-antitrypsin deficiency. Infection with

Primary hepatic tumors in childhood and

hepatitis B or C has been identified as a

adolescence account for just more than 1%

risk factor for HCC as have exposure to

of malignancies in these age groups.

alcohol, anabolic steroids, aflatoxin, and

Rare Tumors of Childhood

203

certain carcinogens such as pesticides and

more accurate reporting. Those with HCC

vinyl chloride.

may also have elevation in AFP but not to

the same magnitude as hepatoblastoma.

Clinical presentation

b-HCG may be elevated in patients with

The most common presenting signs of a

carcinoma of the biliary tract. Of note,

malignant hepatic tumor in childhood are

carcinoembryonic antigen (CEA) and vita-

generalized abdominal enlargement or an

min B₁₂ binding capacity may be elevated in

asymptomatic abdominal mass palpated by

some cases of HCC. Imaging studies should

the family or physician. Patients with HCC

begin with abdominal and specifically liver

may present with constitutional symptoms

ultrasound with Doppler flow to character-

including weight loss, anorexia, emesis, and

ize the tumor as well as the relationship

abdominal pain. Rarely, children may pres-

between tumor and hepatic vessels. CT or

ent with jaundice in HCC or in cases with

MRI should also be obtained prior to sur-

biliary tree involvement. Occasionally, males

gical intervention. Angiography may be

with hepatoblastoma present with signs of

required to help with surgical planning, but

isosexual precocious puberty due to excessive

is rarely needed now due to the excellent

production of the beta subunit of human

resolution of current generation CT and

chorionic gonadotropin

(b-HCG) that is

MRI. Evaluation for metastatic disease

converted to testosterone. Lung metastases

should include chest CT.

(typically asymptomatic) may occur at

AFP is the most sensitive marker for

presentation in up to 20% to 30% of children

disease, especially in hepatoblastoma.

with hepatoblastoma and HCC. Extrahepatic

Patients with small-cell undifferentiated his-

extension may include peritoneal implants as

tology have a poorer prognosis and tend to

well as spread to regional and distant lymph

have low serum AFP, which is a poor

nodes, bone, bone marrow, and rarely the

prognostic marker. Decline in AFP levels with

central nervous system. Liver tumors may

courses of treatment is prognostic and AFP

also invade into adjacent intra-abdominal

should be followed for normalization after

structures.

surgical resection and as a marker for poten-

tial disease recurrence. Of note, serum AFP

Diagnosis and staging

levels vary with age in infancy, declining to

Work up of a suspected hepatic mass should

adult levels by around 6 to 8 months of age.

include laboratory measurement of liver

In addition, AFP has a long serum half-life

function with coagulation studies in addi-

of 5 to 6 days and therefore may take several

tion to transaminases, total bilirubin, and

weeks to normalize in cases with an extremely

alkaline phosphatase. Patients should have a

high level at presentation.

baseline complete blood count (CBC) in

In cases where clinical presentation, imag-

addition to metabolic studies as patients

ing, and tumor markers are highly suggestive

may present with thrombocytosis and/or

of hepatoblastoma, patients should undergo

leukocytosis. Patients with suspected hepa-

a primary resection if it is deemed safe and

toblastoma should have elevation of a-feto-

feasible. In cases where a complete resection

protein

(AFP) and, less commonly, of

is not feasible or the diagnosis is uncertain,

b-HCG. In certain cases with an extremely

the patient should first undergo biopsy. A

high AFP, the value reported out may be

current Children’s Oncology Group clinical

falsely low due to overwhelming of the assay

trial hopes to determine whether patients

(hook effect). When the index of suspicion

who undergo a complete resection with a

is high, serial dilution of serum can allow for

favorable histology (i.e., pure fetal histology)

204

Chapter 22

can be safely observed without adjuvant che-

hepatic artery chemoembolization, per-

motherapy. Patients who cannot obtain a

cutaneous radiofrequency ablation, and

complete resection or have a less favorable

percutaneous ethanol injection may be

histology will receive chemotherapy. In the

beneficial in patients with localized yet unre-

past, chemotherapy for hepatoblastoma has

sectable HCC.

consisted of cisplatin, 5-FU (fluorouracil),

and vincristine

(C5V). For patients with

higher risk disease (i.e., small-cell undiffer-

Adrenocortical carcinoma

entiated histology or higher stage), the addi-

tion of other chemotherapeutic agents such

Adrenocortical carcinoma (ACC) is a rare

as doxorubicin and irinotecan is being

malignancy in childhood and adolescence

explored. Patients should receive chemother-

with peaks in both the first and fourth dec-

apy in order to facilitate total resection when

ades of life. The incidence varies worldwide

feasible, and if not feasible, prior to ortho-

with an interestingly high incidence in south-

topic liver transplantation. Consolidative

ern Brazil. ACC has been reported in asso-

chemotherapy is given after resection to treat

ciation with specific genetic syndromes such

any residual microscopic metastatic disease.

as Beckwith-Wiedemann syndrome, isolated

Patients with gross metastatic disease at pre-

hemihypertrophy, Li-Fraumeni syndrome,

sentation have a poor prognosis, as do

and in association with congenital adrenal

patients with recurrent disease.

hyperplasia and multiple endocrine neopla-

In general, HCC has a poor prognosis

sia type

(MEN-1 syndrome). Germline

and often presents with multifocal liver and

mutations in the p53 tumor suppressor gene

metastatic disease. Previous studies treated

have been implicated in the majority of pedi-

pediatric patients with a similar chemother-

atric cases in the United States and Brazil.

apeutic regimen as hepatoblastoma

(i.e.,

ACC may be functionally inactive or

C5V) with disappointing results. Gross total

secrete hormones such as glucocorticoids,

surgical resection remains the mainstay of

sex steroids and their precursors, and miner-

cure for HCC. In cases where resection is

alocorticoids. Benign adrenocortical tumors

not safe or feasible at presentation, neoad-

are more common and must be carefully

juvant chemotherapy may be of benefit and

differentiated from ACC. Patients frequently

allow for a later total resection or for ortho-

present with clinical signs and symptoms of

topic liver transplantation.

excessive cortisol production

(Cushing’s

A distinct pathologic variant, fibrolamel-

syndrome) or excessive androgen produc-

lar HCC, has been associated with a higher

tion (virilization). Other less common symp-

resection rate and improved survival com-

toms include abdominal pain and weight

pared to other forms of HCC. Novel tar-

loss. The diagnosis is made based on the

geted agents have shown a modest benefit at

presence of elevated concentrations of adre-

best, but may have promise when used as

nocortical hormones and their intermediates

part of multimodal therapy.

in the serum or urine. Baseline studies

Radiation therapy has not been proven to

should include a 24-hour free cortisol, dexa-

be effective in the treatment of hepatoblas-

methasone suppression test, basal cortisol,

toma and HCC, but it may have a role in

and adrenocorticotropic hormone (ACTH)

palliation of lung metastases. Similarly,

to measure glucocorticoid secretion; testos-

high-dose chemotherapy with autologous

terone, estradiol, androstenedione, dehydro-

stem cell rescue has not as yet been

epiandrosterone sulfate

(DHEA-S), and

found beneficial. Local therapies including

17-OH-progesterone to measure sex steroids

Rare Tumors of Childhood

205

and their precursors; and aldosterone and

a subset of patients with invasive, meta-

renin in patients with hypertension or hypo-

static, or recurrent disease. Mitotane may

kalemia to rule out mineralocorticoid excess.

have benefit in patients with localized, fully

Pheochromocytoma can be ruled out by

resected disease, although this question has

checking catecholamines and metane-

not been clearly answered. Mitotane levels

phrines. Imaging with CT or MRI of the

greater than 14 mg/L seem to be most ben-

abdomen confirms the presence of a supra-

eficial. As mitotane is an adrenocorticolytic

renal mass. FDG-PET may be utilized in

agent, replacement with hydrocortisone and

equivocal cases or if CT/MRI are negative

fludrocortisone is necessary to prevent adre-

with positive hormone markers. FDG-PET is

nal insufficiency. For patients that progress

negative in benign adrenocortical tumors.

on mitotane or have side effects that limit its

Many patients present with large primary

usage, chemotherapy with cisplatin, etopo-

tumors and evidence of metastatic disease

side, and doxorubicin may be beneficial.

involving the lungs, liver, or bones. CT of the

ACC is considered radioresistant, so this

chest, abdomen, and pelvis in addition to

is not a therapeutic option.

bone scan should be done for staging

purposes prior to surgical resection. ACC

are locally aggressive tumors with a thin

Thyroid tumors

pseudocapsule; an open adrenalectomy

should be performed to prevent extensive

The incidence of malignant thyroid carci-

hemorrhage or tumor rupture. Surgical

noma in children is very low, comprising

resection is the only known curative therapy

less than 2% of pediatric cancers. The peak

for ACC, both for primary and metastatic

incidence is in the older adolescent age

sites. Surgery is also indicated in recurrent

group, 15 to 19 years of age, with a prepon-

disease to prolong survival.

derance in females. Childhood thyroid

Due to the poor response to chemother-

carcinomas are clinically and biologically

apy, patients with advanced disease have a

distinct from those seen in adults. The

very poor prognosis. A tumor weight <

majority of thyroid carcinomas are papillary

200 g (<5 cm in diameter in adults) is a

or follicular variants of papillary carcinoma.

good prognostic factor. Patients with local-

Exposure to head and neck irradiation is

ized disease should undergo aggressive gross

associated with an increased risk of thyroid

total surgical resection. Patients with large

carcinoma, particularly the papillary vari-

tumors (>200 g) without metastatic disease

ant. An increased incidence has been seen in

may also benefit from radical retroperito-

children receiving therapeutic radiation

neal lymph node dissection

(RPLND).

with a median latency of 13 years and has

Patients with advanced disease

(invasive

also been observed in survivors following the

or metastatic) should be treated with aggres-

Chernobyl nuclear accident. Genetics plays

sive surgical resection of the primary tumor,

a major role in patients with medullary

RPLND, and resection of metastatic lesions

carcinoma with many children having a

in addition to chemotherapy. If resection

positive family history. Inherited medullary

of metastases is not feasible, resection of

carcinoma is also seen in association with

the primary tumor may not be of benefit.

MEN types 2A and 2B or as part of familal

Mitotane, a synthetic derivative of the insec-

medullary carcinoma. MEN types 2A and 2B

ticide

dichlorodiphenyltrichloroethane

are caused by germline mutations in the RET

(DDT), has a specific cytotoxic effect on

(rearranged during transfection) proto-

adrenocortical cells. It has shown benefit in

oncogene. Patients with MEN type

206

Chapter 22

develop medullary thyroid carcinoma, pheo-

obtain tissue diagnosis. Surgical removal

chromocytoma, and parathyroid tumors.

may be considered in higher risk patients

Patients with MEN type 2B may develop

with suspicious features on imaging, posi-

medullary carcinoma or pheochromocytoma

tive family history, or past history of irra-

and are associated with a marfanoid body

diation. When a thyroid carcinoma is diag-

habitus, mucosal neuromas, and ganglio-

nosed, staging is completed with a neck

neuromatosis. A high incidence of papillary

ultrasound, CT, or MRI to evaluate lymph

carcinoma of the thyroid is seen in familial

nodes, chest CT to evaluate for metastasis,

adenomatous polyposis coli and Cowden

and possibly a neck MRI to assess for degree

disease.

of local invasion.

Patients typically present with a painless

Surgical resection is key to curative ther-

solitary thyroid nodule (approximately 70%

apy in thyroid carcinoma. Patients should

to 75%) and up to 35% to 40% present with

undergo a total or subtotal thyroidectomy.

palpable cervical adenopathy. If the tumor

No specific recommendations are currently

has invaded locally, patients may present with

available in children with regard to lymph

dysphagia or dysphonia. Children are more

node dissection. When lymph node involve-

likely than adults to present with advanced or

ment is confirmed on imaging or by biopsy,

metastatic disease (primarily lungs). Pulmo-

a modified lateral neck dissection is recom-

nary metastases classically appear as miliary

mended. Following surgery, a diagnostic

lesions. Staging in children is based on the

whole body scan with I¹²³ or I¹³¹ is recom-

presence or absence of metastases. Younger

mended to define areas of residual disease.

children may have an increased risk of recur-

Radioiodine ablation is then recommended

rence. Presence of metastatic disease, age, size

and has been shown to reduce the incidence

of tumor, and degree of extrathyroid invasion

of locoregional recurrence. Lifetime thyroid

are predictive of outcome.

replacement is required after surgery and

The initial evaluation of the child with a

radioablation.

thyroid nodule should include thyroid

ultrasound as well as measurement of free

Suggested Reading

thyroxine

(FT4) and thyroid-stimulating

hormone (TSH). Up to 20% of thyroid

Khara L, Silverman A, Bethel C, et al. Thyroid

nodules in children will be malignant, and

papillary carcinoma in a 3-year-old American

younger age, past history of irradiation, and

boy with a family history of thyroid cancer: a

family history are all highly predictive of

case report and literature review. J Pediatr

malignant disease. Ultrasound characteris-

Hematol Oncol 23:e118-e121, 2010.

tics may guide the clinician in the diagnosis

Litten JB, Tomlinson GE. Liver tumors in chil-

as malignant tumors are more likely to have

dren. Oncologist 13:812-820, 2008.

indistinct margins, vascularity, an absence

Lohmann D. Retinoblastoma. Adv Exp Med Biol

685:220-227, 2010.

of an echogenic halo around the nodule,

Ribeiro RC, Pinto EM, Zambetti GP. Familial

and presence of calcifications. Nuclear

predisposition to adrenocortical tumors: clin-

medicine thyroid scintigraphy

(usually

ical and biologic features and management

with I¹²³) can be utilized but is not diag-

strategies. Best Pract Res Clin Endocrinol

nostic and delivers quite a bit of radiation.

Metab 24:477-490, 2010.

The majority of thyroid nodules are cold on

Sinnott B, Ron E, Schneider AB. Exposing the

thyroid scan but most of these are benign

thyroid to radiation: a review of its current

follicular adenomas. Image-guided fine

extent, risks, and implications. Endocr Rev

needle aspiration is recommended to

31:756-773, 2010.

Histiocytic Disorders

Histiocytes

(composed of dendritic cells

Langerhans cell histiocytosis

and monocytes/macrophages; also called

tissue macrophages) are cells of the mono-

LCH is now the accepted umbrella term

nuclear phagocytic system that fight infec-

for a wide variety of other conditions pre-

tion and clear debris. Histiocytic disorders

viously described, including histiocytosis X,

occur due to abnormal proliferation or

eosinophilic granuloma, Hand-Schuller-

activity of these cells and have a wide variety

Christian syndrome, Letterer-Siwe disease,

of clinical presentations, from the localized

Hashimoto-Pritzker syndrome, self-healing

and mild to the generalized and severe.

histiocytosis, pure cutaneous histiocytosis,

The classification of these conditions can

Langerhans cell granulomatosis, Langerhans

be as confusing as the conditions themselves.

cell

(eosinophilic) granulomatosis, type II

The most recent World Health Organization

histiocytosis, and nonlipid reticuloendothe-

(WHO) classification was developed in 1997

liosis. The pathogenesis of LCH is poorly

and is presented in Table 23.1. While most of

understood. Immune dysregulation likely

the histiocytic disorders are considered non-

plays a role and may be reactive, occurring

malignant conditions, many are treated sim-

secondary to trauma and infection, especially

ilarly to malignant disease, and the mortality

in those patients with remitting disease. A

of several conditions is quite high. The eti-

neoplastic process may also be possible in

ology of most types is unknown, but appears

cases that are systemic and widely dissemi-

secondary to poorly understood pathophys-

nated. LCH is a misnomer as the Langerhans

iological mechanisms. This chapter focuses

cell, an epidermal dendritic cell, is not the

on the more common presentations of dis-

sole culprit; rather, like other histiocytic

ease, specifically Langerhans cell histiocytosis

disorders, LCH is due to abnormalities in

(LCH) and hemophagocytic lymphohistio-

the mononuclear phagocytic system. Diag-

cytosis

(HLH). Less common disorders

nosis is based on histologic features of these

include juvenile xanthogranuloma (includ-

Langerhans cells (characterized by Birbeck

ing Erdheim-Chester disease) and sinus his-

granules on electron microscopy) in addition

tiocytosis with massive lymphadenopathy

to specific immunophenotypic markers

(Rosai-Dorfman disease).

(CD1a and CD207).

Handbook of Pediatric Hematology and Oncology: Children’s Hospital & Research Center Oakland,

Second Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.

2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

208

Chapter 23

Table 23.1 Classification of histiocytic disorders.

Group

Cell of origin

Condition

Disorders of varied

Dendritic cell

Langerhans cell histiocytosis

biological behavior

Secondary dendritic cell processes

“Excludes disorders

Juvenile xanthogranuloma and related disorders

that are considered

Solitary histiocytomas of various dendritic cell

to be malignant

phenotypes

while recognizing a

Macrophage

Hemophagocytic lymphohistiocytosis

wide scope of

(familial and sporadic; commonly elicited by

severity ranging

viral infections)

from self-limited to

Secondary hemophagocytic syndromes

lethal disease”

Infection-associated

Malignancy-associated

Other

Rosai-Dorfman disease (sinus histiocytosis with

massive lymphadenopathy)

Solitary histiocytoma with macrophage phenotype

Malignant disorders

Monocyte

Leukemias (FAB and revised FAB classifications)

Monocytic leukemia (M5A and B)

Acute myelomonocytic leukemia (M4)

Chronic myelomonocytic leukemia

Extramedullary monocytic tumor or sarcoma

(monocytic counterpart of granulocytic

sarcoma)

Dendritic cell

Dendritic cell-related histiocytic sarcoma (localized

or disseminated)

Specify phenotype; follicular dendritic cell,

interdigitating dendritic cell, etc.

Macrophage

Macrophage-related histiocytic sarcoma (localized

or disseminated)

Abbreviations: FAB, French-American-British.

LCH most often presents in the bone as a

underlying immune reaction. Observation is

solitary or as multifocal lesions and may also

generally favored in this situation, with certain

be localized to the skin or lymph nodes. Bone

caveats:

lesions may be painful or painless. On plain

1. Vertebral lesions have an inherent risk of

film, lesions appear lytic, often with a

causing vertebral compression

(vertebra

“punched out,” beveled appearance and may

plana) or spinal cord compression if signif-

have an associated periosteal reaction with

icant soft tissue swelling exists, therefore

soft tissue swelling. Skin lesions are scaly,

radiation therapy should be considered.

erythematous papules often involving the

2. Large or symptomatic solitary lesions

scalp. Localized disease in these areas portends

may benefit from surgical curettage or resec-

a good prognosis with chance for spontane-

tion, intralesional steroid injection, or radi-

ous remission due to “burning out” of the

ation therapy.

Histiocytic Disorders

209

3. For solitary bone lesions, the recom-

This condition presents with prolonged

mendation for observation excludes

and excessive activation of macrophages,

sites that put the patient at increased

histiocytes, and cytotoxic T-lymphocytes

risk for the development of diabetes insi-

(CTL). Natural killer (NK) cells, vital to

pidus

(facial bones and anterior/middle

antigen recognition and killing as well

cranial fossa). For these

“special sites,”

as contraction of the immune response

and for multifocal bone, skin, or lymph

from T-cells and histiocytes, often have

node involvement, chemotherapy with

decreased activity, in part allowing for this

12 months of prednisone and vinblastine

hyperproliferative immune response. Viral

is recommended.

infection by Epstein-Barr virus is the most

common known acquired cause, although

Systemic disease, which involves multiple

multiple other viruses have been implicated,

organs including the bone marrow, liver,

and often the pathogen is not identified.

spleen, or lungs, has a much worse progno-

Familial HLH can occur secondary to mul-

sis, especially in those patients without an

tiple known genetic causes that lead to NK

early response to therapy. Poor responders

and CTL dysfunction. The familial causes

likely will require more intensive therapy

are outlined in Table 23.2. An underlying

including, potentially, hematopoietic stem

genetic predisposition may still require a

cell transplantation.

“second hit,” such as a viral infection, to

develop HLH.

Clinical findings are secondary to the

Hemophagocytic

chronic inflammatory state and most

lymphohistiocytosis

notably include fever, splenomegaly,

cytopenias, and hepatitis. Diagnostic cri-

Like other histiocytic disorders, immune

teria for HLH are summarized in

dysregulation is the key feature in HLH.

Table

23.3. For the patient with high

Table 23.2 Genetic mutations associated with HLH.

Gene

Pathophysiology

Perforin 1 (PRF1)

Synthesized in natural killer and cytotoxic

T-cells, permeabilizes target membrane

allowing granzyme B to initiate apoptotic

pathways

MUNC 13-4 (UNC13D)

Important for cytolytic granule fusion to

target membrane

RAB27A (Griscelli syndrome)

Docking of secretory granules

Syntaxin (STX11/STXBP2)

Failure of degranulation when encountering

susceptible targets

LYST (Chediak-Higashi syndrome)

Involved in maturation of cytolytic enzyme

granules

AP3B1 (Hermansky-Pudlak syndrome type II)

Polarization/intracellular movement of

cytolytic granules

SH2D1A (X-linked lymphoproliferative

Polarization/intracellular movement of

syndrome)

cytolytic granules

210

Chapter 23

Table 23.3 Diagnostic criteria for hemophagocytic lymphohistiocytosis.

Diagnosis by molecular criteria (summarized in Table 23.2)

Five of the following eight criteria:

Fever

Splenomegaly

Bicytopenia (i.e., hemoglobin <9 g/dL, platelets < 100

10⁹/L, neutrophils < 1

10⁹/L)

Hemophagocytosis in bone marrow, spleen, lymph nodes, or central nervous system

Fasting hypertriglyceridemia (

265 mg/dL) and/or hypofibrinogenemia (

150 mg/dL)

Low or absent natural killer activity

Ferritin

500 mcg/L

CD25 (soluble IL-2 receptor) >2400 U/mL (based on reference level)

clinical suspicion for HLH, treatment

to the underlying inflammatory state, but

should be initiated promptly even while

these levels will trend down with the

pending pertinent laboratory evaluation.

development of MAS. Fevers may become

Current therapy includes dexamethasone,

nonremitting, and due to worsening liver

etoposide, and cyclosporine. For patients

dysfunction, there may be a paradoxical

that have a complete response after

improvement in inflammatory markers

weeks, treatment can be stopped. For

such as the erythrocyte sedimentation rate

those that have not responded completely

(ESR) and fibrinogen with a resultant

or relapse after stopping therapy, hemato-

improvement in inflammatory symptoms

poietic stem cell transplantation is the

such as arthritis. Treatment for MAS

treatment of choice.

includes pulse steroids and cyclosporine.

Excessive activation of macrophages and

Duration of therapy is dependent on clinical

T-lymphocytes may also lead to a secondary

response; patients that do not respond or

or reactive HLH known as macrophage

relapse may benefit from primary HLH

activation syndrome (MAS). Clinical crite-

therapy although outcomes are poor.

ria for MAS are similar to HLH and the

underlying pathogenesis is due to an auto-

immune condition, most commonly sys-

Case study for review

temic onset juvenile idiopathic arthritis

(adult Still’s disease). Multiple other auto-

You are seeing a 6-year-old child that pre-

immune diseases have been reported to

sents to the emergency department with 3

cause MAS. NK cells are vital in the pre-

weeks of an erythematous and painful dif-

vention of autoimmunity; decreased NK

fuse and spreading rash. Fever began soon

activity could result in both the develop-

after the rash with associated weakness,

ment of an autoimmune disease and sec-

malaise, and anorexia. Initial laboratory

ondary HLH. Often it is difficult to separate

tests include the following:

the symptoms of MAS from the underlying

Complete blood count:

autoimmune disease or primary HLH.

12.5

Patients may have leukocytosis, thrombo-

19.8

150

cytosis, and hyperfibrinogenemia secondary

Histiocytic Disorders

211

Differential: 35% segs, 44% bands, 6%

A ferritin is sent and is very elevated

lymphs, and 12% monos

68,300 mcg/L. Fasting triglycerides are

253 mg/dL.

ESR: 47 mm/h

CRP: 6.3 mg/dL

Complete metabolic panel:

2. How do these lab values help with the

131

103

differential?

222

3.7

0.7

Total protein 5.2 g/dL

The patient continues to have signs of an

Albumin 2.1 g/dL

underlying inflammatory picture and

AST 146 U/L

hypercytokinemia. Sepsis should still be

ALT 44 U/L

considered on the differential with the

Total bili 0.3 mg/dL

continued elevated ESR, CRP, and fibrin-

ogen. The worsening bicytopenia though

On examination, the patient is alert and

should make HLH and MAS higher on the

interactive, but seems somewhat uncom-

differential. The extremely elevated ferri-

fortable from the rash. There is mild spleno-

tin is relatively specific for HLH and MAS,

megaly and no hepatomegaly. The patient is

and a level this high is concerning for

started on antibiotics for presumed sepsis/

MAS. The decreasing ESR and fibrinogen

toxic shock with initial resolution of fever.

also raise the concern that the patient is

Cultures are all normal. Due to worsening

moving for symptoms of an underlying

labs and rash, as well as no source of infec-

autoimmune disorder to frank MAS.

tion, the differential diagnosis is revisited.

Finally, the elevated white blood cell count

The patient again becomes febrile.

with neutrophilia makes MAS much more

likely than HLH.

1. What findings in the initial laboratory

tests suggest sepsis as well as HLH and MAS?

The patient has elevated inflammatory markers

Suggested Reading

(CRP and ESR). Hyponatremia and hypoalbu-

minemia are often seen with an underlying

Arceci RJ. When T cell and macrophages do not

talk: the hemophagocytic syndromes. Curr

inflammatory condition. There are no signifi-

Opin Hematol 15:359-367, 2008.

cant cytopenias, making HLH less likely. In

Filipovich AH. Hemophagocytic lymphohistio-

addition, the high CRP makes HLH less likely.

cytosis (HLH) and related disorders. Hema-

You review the lab trends:

tol Am Soc Hematol Educ Prog 127-131,

2009.

Hemoglobin: 12.5 ! 10.3 ! 8.9

Filipovich A, McClain K, Grom A. Histio-

Platelets: 150 ! 98 ! 67

cytic disorders: recent insights into patho-

White blood cell count: 18.4 ! 28.7 ! 39.7

physiology and practical guidelines. Biol

(continued left shift)

Blood Marrow Transplant

16:S82-S89,

ESR: 50 ! 47

2010.

CRP 6.3 ! 12.9 ! 18.1

Fibrinogen: 441 ! 387 mg/dL

Hematopoietic Stem

Cell Transplantation

Hematopoietic stem cell transplantation

allogeneic transplantation is generally

(HSCT) has become increasingly accepted

recommended for hematologic malignan-

as a therapeutic modality for a variety of

cies due to the underlying bone marrow

malignant and nonmalignant conditions.

involvement (Table 24.1). In addition to

HSCT involves the ablation of the reci-

the effectiveness of high-dose chemotherapy

pient’s bone marrow with high doses of

in tumor killing, there is benefit of a “graft-

chemotherapy as well as, in some cases,

versus-leukemia” (or lymphoma) effect in

radiation therapy in order to allow engraft-

allogeneic transplant in which the immu-

ment of the donor’s stem cells. Collected

nosensitized donor T-cells can theoretically

stem cells can either be allogeneic (from a

kill residual malignant cells. In contrast,

separate donor) or autologous (from the

autologous transplant is generally reserved

patient). The rationale for HSCT is based

for patients with solid tumors and no evi-

on the logarithmic dose-response curve

dence of bone marrow involvement after

for many chemotherapeutic agents: a much

failure of standard chemotherapeutic regi-

higher dose effectively increases tumor kill-

mens (Table 24.2). Recommendations for

ing at the cost of profound myelosuppres-

allogeneic HSCT in nonmalignant condi-

sion. Secondarily, multidrug therapy is

tions are summarized in Table 24.3.

required to overcome resistance and

heterogeneity within the malignant cell

population.

Types of transplantation

Stem cells for allogeneic transplantation are

Transplantable conditions

collected from bone marrow, peripheral

blood, or umbilical cord blood

(UCB),

Diseases treated using HSCT can be divided

whereas stem cells for autologous transplan-

into malignant and nonmalignant condi-

tation are collected most commonly from

tions. Recommendations for malignant

peripheral blood. Collection of stem cells

conditions are continually being updated

from peripheral blood occurs after mobili-

due to changes in the effectiveness of

zation with granulocyte colony-stimulating

standard chemotherapy and the risks and

factor (G-CSF). The usual volume of bone

benefits of HSCT. In pediatric patients,

marrow required to ensure successful

Handbook of Pediatric Hematology and Oncology: Children’s Hospital & Research Center Oakland,

Second Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.

2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

Hematopoietic Stem Cell Transplantation

213

Table 24.1 Malignant conditions potentially

transplantation and highest after peripheral

benefiting from allogeneic transplant.

blood stem cell transplant (PBSCT). En-

graftment of donor cells occurs earliest after

Acute lymphoblastic leukemia (ALL) in first

PBSCT. Availability of allogeneic stem cells

remission and high risk for relapse

is often limited by the lack of an eligible

Relapsed ALL in second remission

donor.

Acute myelogenous leukemia (AML)

Juvenile myelomonocytic leukemia (JMML)

Hodgkin or non-Hodgkin lymphoma in

second or subsequent partial or complete

Donor matching in allogeneic

remission

transplantation

Myelodysplastic syndromes (MDS)

Relapsed, refractory, or familial hemopha-

The major histocompatibility complex

gocytic lymphohistiocytosis

(MHC) is a large genomic region on chro-

mosome 6 that encodes the human leuko-

cyte antigen (HLA) system. MHC is vital for

engraftment of donor cells is 10 to 20 mL/kg

the immune system to recognize self versus

of recipient body weight. Younger donors

nonself and varies greatly between indivi-

have a higher proportion of marrow

duals. MHC is divided into two major

repopulating cells. Peripheral blood stem

classes, class I and class II. MHC class I

cells are collected via apheresis and identi-

molecules are found on nucleated cells and

fied by the presence of a cell surface marker,

present the MHC to cytotoxic T-cells and

CD34 (cluster of differentiation). In general,

natural killer cells. MHC class I includes

10⁶

CD34^þ cells/kg are required to

HLA-A, HLA-B, and HLA-C. MHC class II

ensure engraftment. For allogeneic trans-

molecules are located on antigen-presenting

plant, the physician must balance the risks,

cells (B-cells and macrophages) and present

benefits, and availability of cells derived

the MHC to T helper cells. MHC class II

from bone marrow, peripheral blood, and

includes HLA-DP, HLA-DQ, and HLA-DR.

UCB. Peripheral blood has the highest yield

Many other minor histocompatibility

of CD34^þ cells (with G-CSF mobilization),

complexes are important in the immune

whereas UCB has the lowest (due to the

response; however, current donor matching

volume of UCB). The risk of graft-versus-

for HSCT is limited to class I and II

host disease (GVHD) is lowest after UCB

molecules.

Identification of a suitable donor

Table 24.2 Malignant conditions potentially

requires matching the recipient’s MHC

benefiting from autologous transplant.

class I and II antigens with those of the

donor. Greater disparity between donor and

High risk neuroblastoma

recipient leads to increasing risk of rejection

High risk brain tumors (medulloblastoma/

of the donor cells and, if engraftment

PNET)

Metastatic retinoblastoma

occurs, GVHD. Matched family member

Recurrent high risk germ cell tumors

donor grafts have been found to be the least

Relapsed Hodgkin or non-Hodgkin

immunogenic. Unfortunately, 60% to 70%

lymphoma

of patients will not have a matched family

Relapsed Wilms tumor

donor. In these cases, unrelated volunteer

donors can be found through bone marrow

Abbreviation: PNET, primitive neuroecto-

donor registries, such as the National Mar-

dermal tumor.

row Donor Program in the United States

214

Chapter 24

Table 24.3 Nonmalignant conditions benefiting from allogeneic transplant.

Congenital syndromes

Immunodeficiency syndromes

SCID, congenital agammaglobulinemia (Bruton’s),

DiGeorge syndrome, Wiskott-Aldrich syndrome,

chronic mucocutaneous candidiasis,

lymphoproliferative syndromes

Hematologic disorders

Sickle cell disease, b-thalassemia, Fanconi anemia,

Shwachman-Diamond syndrome, Diamond-Blackfan

anemia, dyskeratosis congenita, chronic granulomatous

disease, Chediak-Higashi syndrome, leukocyte

adhesion deficiency

Metabolic disorders

Storage diseases, lysosomal diseases, mucolipidosis,

mucopolysaccharidoses

Acquired syndromes

Severe aplastic anemia

Paroxysmal nocturnal hemoglobinuria

Abbreviation: SCID, severe combined immunodeficiency syndrome.

and Bone Marrow Donors Worldwide that

alloreactivity of these immature cells. Ulti-

coordinates multiple worldwide registries.

mately, the physician must balance the avail-

Due to the unavailability of a matched

ability of a matched donor with other factors

donor in many cases, partially matched

such as the patient’s disease stage, remission

donors must be used with increasing risk

status, and general condition. In most cases,

of immune reactions.

disease stage has a greater impact on survival

Currently, HLA matching is limited to

than the level of HLA mismatch.

HLA-A, HLA-B, HLA-C, HLA-DR, and

HLA-DQ. National Marrow Donor

Pretransplant preparative

Program retrospective reviews on HLA

regimens

matching in unrelated donor bone marrow

transplantation have shown that mismatches

High-dose chemotherapy, with or without

at MHC class I (HLA-A, HLA -B, and HLA

radiation, is administered in order to max-

-C) and MHC class II DR (specifically HLA-

imize tumor killing and, in patients under-

DRB1) each had a separate, significant effect

going allogeneic transplant, to affect a suf-

on survival and risk of GVHD. Additionally,

ficient amount of immunosuppression to

an increasing number of mismatches led to

overcome recipient rejection of the HSCT.

decreasing survival. HLA-DQB1 was also

Commonly used conditioning agents, their

found to have an additive negative effect in

mode of action, and potential side effects are

patients with other mismatches. UCB trans-

summarized in Table 24.4.

plantation has been shown to not require the

same level of HLA matching, and matching is

Engraftment and graft failure

limited to HLA-A, HLA-B, and HLA-DR.

UCB transplantation is thought to be less

Evidence of donor replacement of the reci-

immunogenic secondary to the decreased

pient’s bone marrow begins with increasing

Hematopoietic Stem Cell Transplantation

215

Table 24.4 Common agents used in pretransplant preparative regimens.

Agent

Mode of action

Common potential risks

Antithymocyte globulin

Alteration of function and

Fever and chills, pruritus, anaphy-

elimination of T-cells

laxis, serum sickness

BCNU (Carmustine)

Alkylation leading to DNA

Nausea and vomiting, pulmonary

damage

infiltrates and fibrosis, transami-

nitis, nephrotoxicity

Busulfan

Alkylating agent

Nausea and vomiting, electrolyte

abnormalities, seizures, mucosi-

tis, alopecia, hyperpigmentation,

sterility

Carboplatin

Inhibits DNA synthesis by

Nausea and vomiting, type I

forming DNA cross-links

hypersensitivity, renal

impairment and electrolyte

wasting, ototoxicity

Cyclophosphamide

Alkylating agent, elimination

Fluid retention (SIADH), hemor-

of T regulatory cells,

rhagic cystitis, nausea, vomiting,

immunosuppressant

and anorexia, cardiomyopathy,

sterility

Etoposide

Inhibits topoisomerase II

Hypotension, nausea, skin blisters or

causing DNA strand

erythema, nephropathy, hemor-

breakage

rhagic cystitis, alopecia, stomati-

tis, transaminitis

Fludarabine

Purine analog inhibiting

Nausea, vomiting, and anorexia,

DNA synthesis,

mucositis, hemolytic anemia

immunosuppressant

Melphalan

Alkylating agent

Nausea and vomiting, mucositis

Thiotepa

Alkylating agent

Nausea, vomiting, and anorexia,

sterility, excretion through the

skin

Topotecan

Inhibits topoisomerase I

Nausea, vomiting, and anorexia,

causing DNA strand

diarrhea, mucositis, peripheral

breakage

neuropathy

Total body irradiation

Antitumor activity,

Fever, myelosuppression, mucositis,

immunosuppressant

alopecia, diarrhea, skin reactions

and hyperpigmentation, parotitis,

pancreatitis, multiple late effects

including risk of secondary

malignancy

Abbreviation: SIADH, syndrome of inappropriate antidiuretic hormone. See Chapter 30

and Formulary for more information.

white blood cell counts and decreasing trans-

neutrophil count (ANC) > 0.5

10⁹/L. Due

fusion dependency. Engraftment is defined to

to the volume of CD34^þ stem cells, engraft-

occur when the transplant recipient achieves

ment of donor cells occurs earliest after

three consecutive days of an absolute

PBSCT and latest after UCB transplantation.

216

Chapter 24

Engraftment syndrome, characterized by

patients at high risk for infection with a

fever, rash, as well as pulmonary symptoms

variety of organisms. Finally, immunogenic

and weight gain (secondary to capillary leak),

donor T-cells can lead to GVHD due to the

may take place during the initial rapid rise in

recognition of host alloantigens as foreign.

the white blood cell count. After infection has

Multiple late sequelae of HSCT must also be

been ruled out, a short course of intravenous

considered.

steroid therapy can alleviate symptoms.

Primary graft failure is defined as a lack

Infections

of engraftment within 6 weeks after trans-

Practitioners must be cognizant of the many

plant. Chimerism studies, either of the

potential infectious complications in the

peripheral blood or bone marrow, measure

HSCT patient. Infection prophylaxis is an

percentage of donor and recipient cells and

important aspect of supportive care and is

thus also help determine marrow engraft-

outlined in more detail below

(text and

ment or primary graft failure. Factors in

Table 24.12). The duration of severe neutro-

graft failure include: a nonmyeloablative

penia

(ANC < 0.5

10⁹/L) and time to

preparative regimen, insufficient volume

engraftment are significant risk factors, as the

of stem cells

(i.e., UCB transplant),

large majority of patients will have a docu-

increased immunogenicity due to mis-

mented infection after 4 to 5 weeks of neu-

matched HSCT, and the use of myelosup-

tropenia. Even though the white blood cell

pressive agents

(i.e., medications for

count recovers in weeks after transplant,

GVHD). Secondary graft failure (graft rejec-

immune reconstitution takes months to

tion) occurs after the initial wave of engraft-

years depending on the type of transplant

ment secondary to the continued presence

(autologous vs. allogeneic) as well as

of recipient cytotoxic T-cells. Chimerism

the continued use of immunosuppressive

studies must again be utilized to show that

agents to prevent or treat GVHD. The

the majority of cells are of host origin. Other

presence of a central venous catheter is a

causes of graft failure including infection

secondary risk factor. Infections tend to

and recurrence of an underlying hemato-

occur at different times after transplant as

logical malignancy should be ruled out.

outlined in Table 24.5. Work up of fever in

the posttransplant period is outlined in

Table 24.6. Engraftment syndrome, GVHD,

Complications of hematopoietic

and medications such as G-CSF can all be

stem cell transplantation

causes of fever in the posttransplant period

but are diagnoses of exclusion. Clostridium

HSCT recipients have a unique set of poten-

difficile should be considered in the patient

tial complications that must be well under-

with associated symptoms such as fever,

stood when caring for these patients. The

abdominal pain, and diarrhea.

pretransplant preparative regimen can lead

to a number of posttransplant complica-

Veno-occlusive disease/sinusoidal

tions as outlined in Table 24.4. A common

obstructive syndrome

complication is veno-occlusive disease

Veno-occlusive disease (VOD), also called

(VOD) of the liver, also known as sinusoidal

sinusoidal obstructive syndrome

(SOS),

obstructive syndrome (SOS). The profound

results from hepatic injury caused by

immunosuppression that occurs both

high-dose chemotherapy or total body irra-

before and after engraftment puts HSCT

diation leading to fibrosis of small hepatic

Hematopoietic Stem Cell Transplantation

217

Table 24.5 Common infections seen at different time points following hematopoietic stem cell

transplantation.

First 30 days

Bacterial

Gram-negative aerobes and anaerobes

Staphylococcus epidermidis

Fungal

Aspergillus species

Candida

Viral

Herpes simplex type I reactivation

30-120 days

Fungal

Candida albicans and C. tropicalis

Aspergillus

Other Candida sp., Trichosporon sp., Fusarium sp.

Pneumocystis jiroveci

Viral

Cytomegalovirus (CMV)

Adenovirus

Epstein-Barr virus (EBV)

Human herpesvirus 6 (HHV-6)

Protozoal

Toxoplasma sp.

Formerly Pneumocystis carinii, generally considered to be a fungal organism.

vessels. VOD/SOS typically occurs in the

Supportive care in transplant

first

days after allogeneic transplant

patients

and presents with worsening weight gain,

jaundice, and hepatomegaly. Treatment of

Routine care for the HSCT patient is a

VOD/SOS is supportive; general guidelines

unique and vital aspect of preventing

are outlined in Table 24.7.

infections and a multitude of other

potential complications including bleeding,

Graft-versus-host disease

transfusion-associated GVHD, and CMV

GVHD occurs due to the proliferation of

reactivation, as well as ABO incompatibility

donor T-cells that recognize host antigen

between recipient and donor.

as foreign. Direct effects of the T-lympho-

cytes and cytokine response lead to the signs

Infection prophylaxis

and symptoms of GVHD. Acute GVHD can

Due to profound immunosuppression,

begin within weeks of transplantation;

HSCT patients are at risk for reactivation

chronic GVHD is defined as GVHD lasting

of latent viral infections in addition to fun-

beyond 100 days after transplant. Signs and

gal and bacterial infection. Guidelines for

symptoms of acute and chronic GVHD are

infection prophylaxis and surveillance are

summarized in Table 24.8, grading of GVHD

outlined in Table 24.12.

is outlined in Table 24.9, and prophylaxis and

treatment are described in Table

24.10.

Diet

Patients should be checked daily for signs

Due to the pretransplant preparative regi-

and symptoms of acute GVHD while hospi-

men, patients will have an extended period

talized following HSCT.

of anorexia requiring total parenteral

nutrition

(TPN). Triglycerides should be

Late sequelae

followed weekly while on TPN in addition

Multiple late effects must be considered and

to routine monitoring of electrolytes. Trace

are summarized in Table 24.11.

elements should be included in the TPN.

218

Chapter 24

Table 24.6 Evaluation and empiric treatment of fever in the posttransplant period.

Rule out bacterial infection

Daily blood cultures from central catheter (aerobic and anaerobic)

while febrile

Consider noncatheterized urinalysis and culture

Rule out pneumonia

Chest radiography at first fever and then as clinically indicated

Rule out fungal infection

Daily fungal cultures from central catheter while febrile

Careful skin exam; if concern for infection perform skin biopsy

CT of the chest and/or sinuses if with localizing signs or symptoms

Rule out occult infection

Consider CT of the chest ( sinuses, abdomen, pelvis) if

asymptomatic with prolonged fevers (i.e.,

5-7 days) without

a source

Consider galactomannan antigen testing if with persistent fever

Rule out viral infection

CMV serology; consider studies for adenovirus, HHV-6, EBV, BK

virus (urine) if prolonged fever (i.e.,

5-7 days) and consistent

clinical symptoms

Rule out pneumonia or

CT of the chest if with consistent symptoms or CXR equivocal

interstitial pneumonitis

Treatment

If not on empiric antibiotic therapy (see Table 24.12), begin

antipseudomonal cephalosporin (i.e., ceftazidime or cefepime)

aminoglycoside (i.e., tobramycin) or carbapenem (i.e.,

meropenem)

If with prolonged fevers (i.e.,

5-7 days), consider switching

empiric cephalosporin to carbapenem for broader (anaerobic)

coverage. Addition of an echinocandin (i.e., micafungin) for

broader fungal coverage with prolonged fevers (i.e.,

3-7 days)

Consider vancomycin for staphylococcal and streptococcal cov-

erage if patient worsening clinically

Directed antimicrobial coverage or further studies based on

positive work-up

Based on institutional preference.

Abbreviations: CT, computed tomography; CMV, cytomegalovirus; HHV-6, human herpesvirus 6;

EBV, Epstein-Barr virus; CXR, chest radiography.

Once the patient is eating, it is vital that the

packed red blood cell (PRBC) transfusions

patient’s family be aware of the bone

should be CMV negative for HSCT recipi-

marrow transplant low microbial diet of

ents who are identified as CMV seronega-

acceptable foods and appropriate methods

tive during the pretransplant period. CMV

of handling, preparation, and storage in

seronegative platelets are not routinely

order to prevent infection from food-borne

required as leukofiltered platelets are con-

pathogens.

sidered sufficiently leukoreduced to pre-

vent transmission of CMV. In order to

Transfusion guidelines

diminish the risk of spontaneous bleeding,

Due to immunosuppression, all HSCT

platelet level is kept above 20

10⁹/L after

patients should receive irradiated blood

HSCT. This threshold is increased to above

products in order to eliminate the risk of

10⁹/L in certain cases, including

transfusion-associated GVHD. In addition,

patients with sickle cell disease, brain tumor

Hematopoietic Stem Cell Transplantation

219

Table 24.7 Treatments for veno-occlusive disease/sinusoidal obstructive syndrome.

Supportive care

Fluid and sodium restriction

Spironolactone therapy (in lieu of loop diuretics) for sodium and water

diuresis (e.g., aldactone 1-3 mg/kg/day div BID PO)

Antioxidant therapy

N-acetylcysteine. Loading dose of 150 mg/kg IV over 15 min, followed by

50 mg/kg over 4 hours. Maintenance dose of 100-150 mg/kg/day

Vitamin C, vitamin E, selenium (can be added to parenteral nutrition)

Thrombolytic therapy TPA. 0.1 mg/kg/h IV for 4 hours over 4 consecutive days; maximum dose

5.0 mg/h

Heparin. Initial bolus of 20 units/kg IV (max 1000 units), concomitantly

with TPA infusion, then 150 units/kg/day. Dose adjusted to keep PTT

just at or slightly above ULN

Antithrombin III. Loading dose of 50 U/kg IV every 8 h for the initial 24 h

followed by 50 U/kg daily

Defibrotide is an experimental agent with fibrinolytic and antithrombotic

properties that has shown potential benefit for prophylaxis of VOD/

SOS and possible therapeutic benefit in severe disease. Patients must be

off all other thrombolytic therapies. In experimental study given at

25 mg/kg/day div Q6 h IV for at least 21 days

Abbreviations: TPA, tissue plasminogen activator; PTT, partial thromboplastin time; ULN, upper

limit of normal; VOD/SOS, veno-occlusive disease/sinusoidal obstructive syndrome.

Table 24.8 Signs and symptoms of acute and chronic graft-versus-host disease.

Acute GVHD

Skin

Mild maculopapular rash to generalized erythroderma;

can be nonspecific

Secretory diarrhea, nausea, vomiting, anorexia, stomatitis,

hepatic dysfunction

Hematologic

Anemia, thrombocytopenia

Ocular

Photophobia, hemorrhagic conjunctivitis

Pulmonary

Interstitial pneumonitis, alveolar hemorrhage

Chronic GVHD

Skin

Sclerodermatous changes, contractures, alopecia

Xerostomia, oral atrophy with depapillation of tongue,

oral erythema and/or lichenoid lesions, esophagitis,

cholestasis, malabsorption, hepatic dysfunction

Hematologic

Thrombocytopenia

Ocular

Dry eyes, keratoconjunctivitis sicca (conjunctival and/or

corneal inflammation caused by dryness)

Pulmonary

Interstitial pneumonitis, bronchiolitis obliterans

Other

Arthritis, immunologic abnormalities

Abbreviations: GVHD, graft-versus-host disease; GI, gastrointestinal.

220

Chapter 24

Table 24.9 Grading of graft-versus-host disease.

Clinical Skin

Liver (TB,

Diarrhea (children;

Diarrhea (adults;

grade

mg/dL)

<70 kg) (mL/kg/day)

70 kg) (mL/day)

<25% involvement,

1.5-3.0

10-15

500-1000, nausea/

maculopapular

vomiting

25-50% involvement,

3.0-6.0

16-20

1000-1500, nausea/

maculopapular

vomiting

III

>50% involvement,

6.0-15.0

21-25

>1500, nausea/

maculopapular or

vomiting

generalized

erythroderma

Desquamation/bullae

>15

>25, pain/ileus

>2500, pain/ileus

Abbreviation: TB, total bilirubin; adapted from Lanzkowsky P. Hematopoietic stem cell

transplantation. In: Manual of Pediatric Hematology and Oncology, 5th ed. New York:

Elsevier, 2011.

Table 24.10 Agents used for prophylaxis and treatment of graft-versus-host disease.

Agent

Mode of action

Common potential risks

Cyclosporine

Inhibits T-cell activation

Hypomagnesemia, bicarbonate wasting,

renal insufficiency, nausea, vomiting,

hyperglycemia, gingival hypertrophy,

hirsutism, hypertension, seizures,

paresthesias, tremors

Methotrexate

Cell cycle specific; inhibits

Transaminitis, mucositis, renal insuffi-

T-cells as they divide

ciency, effusions, nausea, vomiting,

anorexia, bone marrow suppression

Tacrolimus

Inhibits T-cell activation

Hypomagnesemia, hyperkalemia, renal

insufficiency, hypertension, seizures,

paresthesias, nausea, vomiting,

hyperglycemia

Methylprednisolone

Immunosuppressant;

Hypertension, increased blood sugars,

mechanism not well

increased appetite, insomnia, mood

understood

swings, acne, truncal obesity

Mycophenolate mofetil

Inhibits T-cell proliferative

Nausea, vomiting, anorexia, bone

(MMF)

response

marrow suppression, multiple others

Antithymocyte

Alteration of function and

Fever and chills, pruritus, anaphylaxis,

globulin (ATG)

elimination of T-cells

serum sickness

Etanercept/infliximab

TNF-a inhibitors;

Severe immunosuppression

consideration in

refractory GVHD

Abbreviations: TNF, tumor necrosis factor; GVHD, graft-versus-host disease.

Hematopoietic Stem Cell Transplantation

221

Table 24.11 Late effects of hematopoietic stem cell transplantion.

Late effect

Underlying cause

Endocrine disorders (gonadal failure,

TBI

delayed pubescence, growth hormone

deficiency, hypothyroidism)

Sterility

TBI, busulfan, cyclophosphamide, thiotepa

Secondary malignancy

TBI, busulfan, ATG, cyclophosphamide, etoposide,

genetic factors

Cataracts

TBI

Renal insufficiency

Cyclosporine, other nephrotoxic drugs

Pulmonary disease

Chronic GVHD, BCNU

Cardiomyopathy

Anthracycline therapy, TBI, chronic GVHD

Avascular necrosis

Steroid therapy

Leukoencephalopathy

IT methotrexate

Immunological dysfunction

Chronic GVHD, immunosuppressive therapy

Posttransplant lymphoproliferative

Immunosuppressive therapy

disorder

Poor dentogenesis (in young children)

TBI

Decreased bone mineral density

Multiple factors

Abbreviations: GVHD, graft-versus-host disease; TBI, total body irradiation; ATG, antithymocyte

globulin; IT, intrathecal; adapted from Lanzkowsky P. Hematopoietic stem cell transplantation.

In: Manual of Pediatric Hematology and Oncology, 5th ed. New York: Elsevier, 2011.

patients, and patients with severe mucositis,

recover immune function. Loss of memory

VOD/SOS, or problems with hemostasis (e.

B-lymphocytes due to the pretransplant

g., epistaxis and GI bleeding). A lower thresh-

preparative regimen leads to loss of anti-

old of 10

10⁹/L can be utilized in stable

body secondary to vaccination and lifetime

patients who are out of the immediate post-

environmental exposures. Immune recov-

transplant period. Hemoglobin levels are

ery is variable but generally occurs once the

usually kept above 8 to 9 mg/dL depending

patient is off immunosuppressant therapy,

on institutional practice. Platelet transfu-

and therefore is often earlier in patients

sions should be limited to 1 pheresed unit

undergoing autologous transplantation.

(see Chapter 5). ABO blood types of both the

Once there is sufficient evidence of immune

donor and recipient must be considered

reconstitution, HSCT patients will proceed

when transfusing platelets and PRBCs.

with revaccination. Studies of immune

Appropriate transfusion in ABO-incompat-

reconstitution, which begin once the abso-

ible donor and recipient is summarized in

lute lymphocyte count is >1

10⁹/L and

Table 24.13.

the patient is off immunosuppressive ther-

apy, are summarized in Table 24.14.

Immune reconstitution

Case study for review

Even with the recovery of white blood cell

counts and specifically lymphocyte counts,

A 14-year-old boy is on the bone marrow

HSCT patients take months to years to

transplant unit after receiving an HSCT for

222

Chapter 24

Table 24.12 Routine infection prophylaxis and surveillance in transplant patients.

Prophylaxis for

PCP

TMP-SMX until 2 days prior to transplant, then restarted once ANC

>0.75

10⁹/L for 2-3 consecutive days; for at least six months (until

PRP >1 mcg/mL or per institutional guidelines, see Table 24.14)

HSV

If seropositive, at least 30 days of acyclovir (until off immunosup-

pressive therapy; until HSV blastogenesis present if with recurrent

infection)

VZV

If seropositive, at least 180 days of acyclovir (until VZV blastogenesis

present)

Candida albicans

Fluconazole until immune reconstitution to Candida; hold if

transaminases increased to >2-3

ULN

Bacterial infection

Anti-pseudomonal cephalosporin (i.e., ceftazidime or cefepime)

aminoglycoside (i.e., tobramycin) or carbapenem (i.e., meropenem)*;

start with first fever or once ANC drops to <0.5

10⁹/L if afebrile,

continue until afebrile and ANC > 0.5

10⁹/L for 2 days

Routine surveillance

CMV

Weekly serology

Occult bacterial infection

Weekly to three times weekly blood culture if on steroids and afebrile

(controversial)

Pneumonia

Weekly chest radiograph (controversial)

Deficient IgG

Monthly quantitative IgG; replace with IVIG if IgG < 400 mg/dL

Based on institutional preference.

Abbreviations: PCP, Pneumocystis jiroveci pneumonia; TMP-SMX, trimethoprim-sulfamethoxazole;

PRP, polyribose phosphate; ANC, absolute neutrophil count; HSV, herpes simplex virus; VZV,

varicella zoster virus; ULN, upper limit of normal; CMV, cytomegalovirus; IgG, immunoglobulin

G; IVIG, intravenous immune globulin.

acute myelogenous leukemia

(AML) in

otherwise unremarkable. His medications

remission. His stem cell reinfusion took

include ceftazidime, tobramycin, flucona-

place 14 days ago. He has been having daily

zole, and acyclovir.

fevers up to 39.5

C for 3 days with negative

blood cultures to date. He is not in any

1. What is the differential for fever at this

respiratory distress and his physical exam is

point after HSCT?

unremarkable except for a mild rash. His

laboratory tests are remarkable for a WBC

Differential diagnosis:

count that has been increasing, most

Bacterial infection (Gram-negative rods,

recently

0.2

10⁹/L. He has a double

Staphylococcus epidermidis, Streptococ-

lumen central catheter and is on total

cus viridans species)

parenteral nutrition. He has moderate-

Viral infection (CMV, herpes simplex I)

to-severe mucositis that is improving. His

Fungal infection (Candida, Aspergillus)

weight has been stable and his tests are

Engraftment syndrome

Hematopoietic Stem Cell Transplantation

223

Table 24.13 Transfusion in ABO-incompatible transplantation.

Recipient Donor Transplant

Choice for

Choice for First-choice Second-

type

incompatibility PRBC

plasma

platelets

choice

transfusion

platelets

Minor

A, AB

AB, B, O

Major

A, B, O

Major

A, O

A, AB

A, B, O

Minor

B, AB

AB, A, O

Major

B, A, O

Major

B, O

B, AB

B, A, O

Major

A, AB

AB, B, O

Major

AB, A, O

Major

A, B, O

Minor

A, B, O

Minor

A, O

A, B, O

Minor

B, O

B, A, O

Abbreviation: PRBC, packed red blood cell.

Table 24.14 Immune reconstitution studies following bone marrow transplantation.

Test

Interpretation

Blastogenesis

Viral panel (CMV, HSV, VZV)

Measures response to CMV, HSV, and

VZV and defines length of acyclovir

prophylaxis

Mitogens (Concanavalin A, poke-

Concanavalin A measures T- and B-cell

weed, phytohemagglutinin)

function

Pokeweed measures B-cell function

Phytohemagglutinin measures T-cell

function, must be reactive before

PCP prophylaxis is discontinued

Antigens (tetanus toxoid, Candida

Lack of response to tetanus toxoid

albicans)

indicates need for revaccination

Response to Candida defines length of

fluconazole prophylaxis

PRP

(If done by institution)

Measurement of T- and B-cell function;

indicates need for PCP prophylaxis as

well as ability to respond to conju-

gated vaccines

Abbreviations: CMV, cytomegalovirus; HSV, herpes simplex virus; VZV, varicella zoster virus; PCP,

Pneumocystis jiroveci pneumonia; PRP, polyribose phosphate.

224

Chapter 24

2. What medications would you consider

Viral infection

adding based on the above differential?

Engraftment syndrome

Heart failure

(secondary to infection,

The patient is well covered for Gram-neg-

fluid overload, and previous anthracy-

ative infections with ceftazidime and

cline therapy)

tobramycin. Gram-positive infections

Graft-versus-host disease

usually have a positive blood culture,

although vancomycin should be consid-

At this time point after transplant, with a

ered if the patient is clinically worsening

negative infectious work up, VOD/SOS is

(i.e., respiratory distress or hypotension).

the most likely diagnosis. If the patient is

The patient is at risk for S. epidermidis

having increasing WBC counts with rash

secondary to the central catheter and

and diarrhea, engraftment syndrome is

S. viridans secondary to mucositis, neither

possible but should be a diagnosis of exclu-

of which is covered with ceftazidime and

sion. Although GVHD is a possible cause of

tobramycin. Fungal infection must be

hyperbilirubinemia and weight gain, it is

seriously considered. Fluconazole will

less likely this soon after HSCT. Heart

cover Candida albicans but not other can-

failure is a possibility secondary to toxicity

didal species or Aspergillus. You should

from therapy or an underlying infection

consider discontinuing fluconazole and

and should be ruled out with

starting an antifungal agent with a broader

echocardiogram.

spectrum of activity such as an echinocan-

din (i.e., micafungin). Micafungin has a

4. What would be changes in therapy that

broader spectrum of activity than flucon-

you should institute?

azole, but only has moderate coverage

against Aspergillus and does not cover most

Most patients with VOD/SOS ultimately

mold species. Finally, the addition of

recover with supportive care alone. Fluid and

steroids for engraftment syndrome with

sodium restriction should be initiated in

fever and rash should be a consideration

addition to starting spironolactone therapy.

if infection is relatively well ruled out

An abdominal ultrasound with Doppler flow

after negative blood cultures and chest

should be undertaken to look for hepatic

radiography.

fibrosis and changes in portal venous flow.

After a few days the patient defervesces

Antioxidants including vitamin C, E, and

but has developed an increase in his

selenium should be added to the TPN. If the

bilirubin. The infectious work up has been

patient develops increasing weight gain and

negative to date. On looking at his fluid

liver dysfunction, more aggressive interven-

status for the last 48 hours, you note that he

tions such as antithrombin III therapy or

is 2 L positive and his weight has increased

defibrotide should be instituted.

by 2 kg from the time of his transplant.

3. What is the differential diagnosis for

Suggested Reading

hyperbilirubinemia and weight gain at this

point after transplant?

Copelan EA. Hematopoietic stem-cell trans-

plantation. N Engl J Med

354:1813-1826,

Differential diagnosis:

2006.

Veno-occlusive

disease/sinusoidal

Coppell JA, Richardson PG, Soiffer R, et al.

obstructive syndrome

Hepatic veno-occlusive disease following

Supportive Care of the

Child with Cancer

Much of the dramatic improvement in

they have an increased exposure to nosoco-

outcomes in pediatric oncology over the

mial organisms as well. Many of these chil-

last 50 years can be attributed to the devel-

dren have central venous catheters and may

opment of novel chemotherapeutic agents

intermittently have mucosal breakdown

and an increase in therapeutic intensity.

secondary to chemotherapy, both factors

With this increased intensity, supportive

disrupting the integrity of the body’s phys-

care has become a vital component in

ical defense barriers. Poor nutrition also

preventing, recognizing, and treating the

plays a significant role in host susceptibility.

potential side effects of this therapy.

Certain standards of care are indicated to

The practitioner should be familiar with

minimize the risk of acquiring infection in

the potential risks of chemotherapy as out-

these children. Infection prophylaxis

lined in Chapter 30, guidelines for trans-

remains the cornerstone of supportive care

fusional supportive care as described in

in children with malignancies, decreasing

Chapter 5, and treatment for febrile neu-

morbidity and mortality.

tropenia as discussed in Chapter 27. Here

General measures for the prevention of

we discuss infection prophylaxis, anti-

infection include avoidance of crowded

emetic therapy, and the use of hematopoi-

environments, wearing a mask in public when

etic growth factors. Specific supportive care

severely neutropenic (i.e., absolute neutro-

information for patients after hematopoi-

phil count [ANC] <0.5

10⁹/L), and careful

etic stem cell transplantation

(HSCT) is

hand washing (by the patient and all those

discussed in Chapter 24.

who have direct contact). Good nutrition and

proper dental hygiene cannot be overempha-

sized. Oral hygiene should include daily

Infection prophylaxis

brushing (with a soft brush) and oral rinsing

with tap water or saline solution. Cleanliness

Children receiving chemotherapy for treat-

of the perianal area is important, especially in

ment of their malignancies are susceptible to

the neutropenic state. Constipation should be

acquiring infection from bacterial, viral,

avoided with an age-appropriate diet, and, if

fungal, and protozoal organisms. They are

necessary, a stool softener

(e.g., docusate

chronically immunosuppressed as a direct

sodium) or laxative (e.g., MiraLax). Rectal

result of chemotherapy, and at times

suppositories and rectal temperatures should

severely myelosuppressed. While inpatient

be avoided to decrease the possibility of a

Handbook of Pediatric Hematology and Oncology: Children’s Hospital & Research Center Oakland,

Second Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.

2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

Supportive Care of the Child with Cancer

227

mucosal tear and infection with enteric

Fungal prophylaxis is indicated in

organisms.

severely myelosuppressed patients. Mouth

Trimethoprim/sulfamethoxazole (TMP/

care with brushing and oral rinsing is

SMX) prophylaxis is indicated in immuno-

routinely recommended for the prevention

suppressed children to reduce the risk of

or treatment of mouth sores and yeast. Flu-

acquiring Pneumocystis jiroveci pneumonia

conazole (3 mg/kg/day PO or IV) is indicated

(PCP) due to T-lymphocyte dysfunction

in patients that are at very high risk of

secondary to chemotherapy. Current pro-

developing infection (i.e., acute myelogenous

phylactic dosing is 5 mg/kg/day of the TMP

leukemia [AML], relapsed acute lymphoblas-

component in two divided doses on two to

tic leukemia [ALL] patients). The most com-

three successive days per week. Evidence

mon fungal infections in patients receiving

indicates that this regimen also provides

intensive chemotherapy include candidiasis

good general antibacterial prophylaxis,

and aspergillosis. Efforts to prevent invasive

although probably more effectively in

fungal disease (especially Aspergillus sp., an

patients given daily prophylaxis, which

airborne organism) include respiratory iso-

must be balanced with potential allergy or

lation, laminar air flow rooms, and high-

intolerance to TMP/SMX and especially

efficiency particulate air filters. Patients

secondary to myelosuppression from the

should not have live plants in the room, play

therapy. For patients unable to take TMP/

in dirt or gardens, or be in proximity to

SMX, inhaled pentamidine or oral dapsone

construction work. Some patients may ben-

may be given. Pentamidine is preferred but

efit from the addition of an echinocandin (e.

due to the need for a cooperative patient

g., micafungin

1.5-2 mg/kg IV daily) for

who can appropriately inhale the medica-

broader prophylactic fungal coverage while

tion, is usually limited to children above the

inpatient with prolonged fevers and severe

age of 7 years. The dose is 300 mg inhaled on

neutropenia (see Chapter 27).

a monthly basis. Dapsone is given once

Prophylaxis for subacute bacterial

weekly at 4 mg/kg, with a maximum dose

endocarditis is recommended for patients

of 200 mg. It is dispensed as 25 and 100 mg

with central venous catheters undergoing

tablets. Patients should commence prophy-

invasive procedures that could cause tran-

laxis at the time of diagnosis and continue

sient bacteremia and seeding of the catheter

until 3 months after completion of therapy

or heart valves. Such interventions include

to ensure T-lymphocyte immune reconsti-

dental cleaning or procedures and poten-

tution. Prophylaxis with TMP/SMX should

tially surgery involving the gastrointestinal

be discontinued one day prior to the admin-

or genitourinary tract (controversial). The

istration of high-dose IV methotrexate

standard regimen is the same as recom-

(doses >1 g/m²) and restarted after the

mended by the American Heart Association

serum methotrexate level has fallen to below

for children with congenital heart disease:

10^-7 M due to competitive excretion

amoxicillin 50 mg/kg (maximum 2 g) orally

between TMP/SMX and methotrexate and

1 hour prior to the procedure. Azithromy-

the risk for delayed methotrexate clearance.

cin may be given to penicillin-allergic

Temporary interruption of TMP/SMX or a

patients

(15 mg/kg, max 500 mg, 1 hour

change to an alternative therapy may be

prior to the procedure).

necessary for prolonged marrow suppres-

sion or transaminitis rather than decreasing

Viral prophylaxis and treatment

the dose of maintenance chemotherapy

Common viral infections may be particu-

for children with acute lymphoblastic

larly virulent in immunocompromised chil-

leukemia (ALL).

dren. These viruses include varicella zoster

228

Chapter 25

(VZV), herpes simplex (HSV), cytomegalo-

chemotherapy during the incubation period

virus (CMV), Epstein-Barr virus, hepatitis

should be based on the intensity of expo-

types A and B, respiratory syncytial virus,

sure, condition of the patient, and intensity

and rubeola (measles). Infection with these

of the chemotherapy. If >96 hours have

viruses may result in prolonged viral excre-

passed since exposure, the patient should

tion, increased morbidity, or death. At the

be given acyclovir at 80 mg/kg/day (max

time of diagnosis, an immunization and

dose 800 mg/dose) divided QID PO for 7

infection history should be determined. In

days. In the event of varicella or zoster

addition, serologies for VZV, HSV, and

infection, chemotherapy should be stopped

CMV should be obtained as potential future

and IV acyclovir should be given, 30 mg/kg/

exposure to and infection with these agents

day divided TID for 7 to 10 days, until all

will result in different treatment recommen-

lesions are crusted and no new lesions have

dations depending on the potential for pri-

appeared for 24 to 48 hours. Monitor renal

mary infection versus reactivation. CMV

function and fluid status daily due to poten-

serology should also be known in determin-

tial nephrotoxicity from acyclovir. Of note,

ing whether a potential HSCT patient needs

it is safe for household contacts to receive

CMV-negative blood (see Chapter 5).

varicella vaccination as transmission from

The child exposed to varicella or zoster

healthy recipients rarely occurs. If skin

with known negative varicella immune sta-

lesions occur after vaccination, exposure

tus (negative titers [IgG] and no history of

should be avoided until all lesions have

varicella infection) should receive Varicella

crusted over.

Zoster Immune Globulin (VariZIG) within

Children with a history of recurrent

96 hours of exposure (of note, VariZIG

herpes simplex infections are at an

remains an investigational agent in the

increased risk of reactivation with subse-

United States and requires institutional

quent courses of chemotherapy or during

review board approval and completion of

and after HSCT. Acyclovir administered

an investigational new drug form). Parents

prophylactically can prevent or decrease

should be counseled on the risk of exposure

the severity of recurrent herpes infection;

for the child with negative immune status

the recommended oral dose is 200 mg TID-

and the need for immediate evaluation and

QID for children above 2 years of age.

treatment if exposed. The dosage is one vial

Immunocompromised patients with active

(125 units) per 10 kg, with a minimum dose

HSV infection should receive IV acyclovir

of 125 units and a maximum of 625 units (5

(30 mg/kg/day or 1500 mg/m²/day divided

vials), intramuscularly. Administration of

q8h). HSCT guidelines for HSV and

VariZIG extends the incubation period

VZV prophylaxis are summarized in

from 14 to 28 days and decreases, but does

Chapter 24.

not eliminate, the possibility of clinical

infection with VZV (the incubation period

generally is shortened in the immunocom-

Immunization during

promised patient who does not receive Var-

chemotherapy

iZIG). If VariZIG is not available then

intravenous immune globulin can be given

Patients receiving chemotherapy, or who are

at 400 mg/kg. Myelosuppressive chemother-

otherwise immunocompromised, should not

apy may need to be stopped 7 days after the

receive live virus vaccines (MMR, live atten-

exposure and held until the end of the

uated influenza vaccine [LAIV; FluMist

incubation period. The decision to hold

varicella, rotavirus, and oral polio). Siblings

Supportive Care of the Child with Cancer

229

or household contacts should not receive oral

Catch-up immunizations should occur

polio although MMR, varicella, and rotavirus

after the completion of therapy. Most

are safe as transmission is rare. Limited

sources feel that waiting 3 to 6 months after

information is available regarding risk of

therapy completion will produce sufficient

transmission with LAIV; since an inactivated

immune reconstitution to allow an appro-

form of influenza vaccination is available,

priate response to inactivated vaccines.

this should be the preferred immunization

Patients who had not previously completed

in family members as well as health care

their primary vaccination series should

providers. Although varicella vaccination has

restart from the beginning. Patients who

been shown to be safe in patients with ALL in

previously completed the primary series

maintenance, the benefits and risks of this

can have antibody titers drawn to deter-

immunization should be weighed carefully.

mine what protection they have lost, if

Consideration should be given to the likeli-

any. Children above 5 years of age (not

hood of developing a protective response

including patients with HL) have a small

while still on chemotherapy and the poten-

risk of developing significant disease

tial to develop active infection with admin-

from pneumococcus or Hemophilus in-

istration of a live attenuated vaccine. This

fluenza, but revaccination against these

must be weighed with the significant risks

pathogens should be considered in all

from natural varicella infection in the immu-

patients after therapy. Postvaccination

nocompromised, although the chance of

titers can be considered although the

infection has decreased significantly with

likelihood of an insufficient response is

herd immunity.

minimal in patients who are vaccinated

Inactivated vaccines (e.g., DTaP, Tdap,

6 months after chemotherapy has been

Hepatitis A, Hepatitis B, pneumococcal,

completed. Little evidence exists as to

Hib, IPV, meningococcal, and influenza)

the appropriate and safe timeframe to

can be safely given during therapy, although

receive live vaccinations after chemo-

response will be significantly attenuated

therapy. In general, we recommend waiting

based on the level of immunosuppression.

12 months after therapy completion before

Yearly influenza vaccination is reasonable

reimmunizing with MMR and varicella.

during therapy as the potential benefit of

HSCT guidelines are briefly described in

immunization outweighs the risks, espe-

Chapter 24.

cially for children with ALL in maintenance.

In order to increase the chance of an appro-

priate antibody response, vaccination

Prevention of chemotherapy-

should be spaced out from chemotherapy

induced nausea and vomiting

as much as feasible. Due to potential risks of

pneumococcal and Hib infection in patients

Antiemetics are a vital component of the

with Hodgkin lymphoma

(HL) some

supportive care regimen for patients

experts recommend vaccination against

receiving chemotherapy or radiation.

these pathogens prior to starting therapy.

There are three types of chemotherapy-

Although not immunocompromised, un-

induced nausea and vomiting (CINV): (1)

treated patients with HL have an underlying

anticipatory, (2) acute, and (3) delayed.

B-lymphocyte dysfunction and the benefits

Anticipatory emesis occurs before chemo-

of immunization prior to therapy are often

therapy is administered and may be a

significantly diminished. Evidence is lacking

result of nausea and vomiting experienced

to make firm recommendations.

during previous cycles of therapy. Acute

230

Chapter 25

emesis occurs within the first 24 hours of

based on limited evidence in pediatric

therapy; delayed emesis occurs at least 24

patients and are generally derived from

hours after therapy has been completed.

adult data. Here we summarize general

Poor control of nausea and vomiting may

recommendations for the use of these

prolong, or result in, hospitalization and

agents in pediatric oncology.

lead to dehydration and electrolyte abnor-

malities. The single most important factor

Granulocyte colony-stimulating

in CINV is the emetogenic potential of a

factor

particular chemotherapeutic agent, which,

G-CSF is a lineage specific cytokine that

in pediatric patients, is also dose depen-

stimulates the proliferation of neutrophils

dent for some drugs (Table 25.1).

(granulocytes). As patients may have pro-

Multiple agents are useful for the pre-

longed periods of myelosuppression after

vention and treatment of CINV. Recogni-

chemotherapy, G-CSF is recommended

tion of the chemoreceptor trigger zone and

for adult patients with: (1) the expectation

the importance of the 5-HT₃ receptor have

for prolonged myelosuppression to pre-

been instrumental in better controlling

vent episodes of febrile neutropenia and

CINV. Cytotoxic chemotherapy appears

infection, (2) a history of febrile neutro-

to be associated with release of local

penia, (3) the history of a delay between

mediators such as 5-HT and substance P

chemotherapy cycles, and (4) a diagnosis

from the enterochromaffin cells of the

of febrile neutropenia. Pediatric evidence

small intestine. The release of these local

is minimal compared to adult studies but

mediators subsequently stimulates vagal

supports the use of G-CSF for patients with

afferents that initiate vomiting.

5-HT₃

two of these four scenarios: (1) prevention

receptors and substance P receptors (called

of febrile neutropenia and infection (pri-

neurokinin-1) are located both peripherally

mary prophylaxis), and (2) treatment of

(vagal nerve terminals) and centrally in the

febrile neutropenia. Although infection-

chemoreceptor trigger zone; thus,

5-HT₃

related morbidity has not been shown

and substance P antagonists may have both

to decrease with G-CSF usage in these

peripheral and central effects in inhibiting

scenarios, risk of infection and length of

vomiting.

hospitalization have been shown to be sig-

The major pediatric antiemetics, and

nificantly reduced in meta-analyses, with

their specific mechanisms of action and

potential benefits for quality of life and

dose, are summarized in Table 25.2.

decreased cost from shorter hospitalization.

GM-CSF has shown similar results to G-CSF

but has not been shown to be superior in

Hematopoietic growth factors in

clinical studies. In general, G-CSF is the

children with cancer

colony-stimulating factor of choice in

pediatric patients. Clinical studies have

Several hematopoietic growth factors have

also established that the appropriate dose

been approved for clinical use in children

of G-CSF and GM-CSF are 5 mcg/kg/day

including granulocyte colony-stimulating

and 250 mcg/m²/day respectively, given SC

factor

(G-CSF, filgrastim) granulocyte-

or IV. It should be noted that the IV dose

macrophage colony-stimulating factor

may be less effective than the SC dose. A

(GM-CSF, sargramostim), and erythro-

longer lasting pegylated form of G-CSF

poietin (EPO, epoetin alfa). The indica-

(pegfilgrastim) has been shown to be

tions for each of these growth factors are

equally efficacious in adult studies with

232

Chapter 25

Table 25.2 Common pediatric antiemetic agents.

Agent

Mechanism of action

Dose

Comments

Ondansetron

5-HT₃ receptor

0.15 mg/kg q8h IV/PO

Well tolerated; common

antagonist

(max 32 mg/day)

side effects include

headache, fatigue, con-

stipation, diarrhea. Also

available as orally disin-

tegrating tablet

Lorazepam

Interaction with

0.25-0.5 mg q4-6 h IV/

Used as adjunctive; can be

GABA receptor;

PO, max dose 2 mg

utilized for anticipatory

poorly understood

nausea. At higher doses

antiemetic effects

has more sedation/anxi-

olytic effect than anti-

emetic effect

Diphenhydramine

H1 histamine recep-

0.5-1 mg/kg q6 h IV/

Used as adjunctive; can be

tor antagonist

PO, max dose 50 mg

utilized for anticipatory

nausea. Higher dose used

for prevention of dys-

tonic reaction with

metoclopramide

Metoclopramide

Dopamine antagonist

1 mg/kg q4-6 h IV/PO,

Used as adjunctive; higher

max dose 50 mg

dose required for anti-

emetic effect as com-

pared to prokinetic.

Must be given with

diphenhydramine at

higher dose

Decadron

Poorly understood

5 mg/m² q6 h IV/PO

Used as adjunctive; cannot

be used in malignancies

where steroids are part of

the treatment regimen

Scopolamine

Anticholinergic

Transdermal patch for

Must be changed q72 h;

adolescents/adults

patient must be advised

to not touch patch and

then rub eyes as this will

lead to mydriasis

Dronabinol

Cannabinoid; agonist

5 mg/m² q2-4 h, max

No established pediatric

antiemetic effect

dose 15 mg/m² in

dosing. Teens and young

adults

adults should be advised

to not smoke cannabi-

noids that can contain

impurities or increase the

risk of fungal infection

Aprepitant

Neurokinin-1 recep-

80-125 mg daily PO in

Pediatric dosing not estab-

tor antagonist

adults

lished; insufficient stud-

ies in pediatric patients

to date

Supportive Care of the Child with Cancer

233

less frequent dosing; pediatric randomized

LDH, or alkaline phosphatase. Occasionally

controlled studies are lacking.

G-CSF has been reported to cause fever,

nausea and vomiting, diarrhea, splenomeg-

aly, and erythema at the injection site.

Primary prophylaxis

G-CSF should be given to patients receiving

Recombinant human

multiagent chemotherapy who are expected

erythropoietin

to experience a high incidence of febrile

Erythropoietin induces proliferation and dif-

neutropenia or severe, prolonged neutrope-

ferentiation of red blood cell progenitors. The

nia (i.e., ANC <0.5

10⁹/L for 7 or more

recombinant product erythropoietin alfa

days). G-CSF should not be given on the

(rHuEPO) has been approved in pediatric

same days patients are given myelosuppres-

patients although administration of rHuEPO

sive chemotherapy or radiation therapy.

to oncology patients with chemotherapy-

G-CSF is generally not administered to

induced anemia remains controversial. A sec-

patients with myeloid leukemia due to the

ond recombinant, darbopoietin alfa, which

theoretical risk of stimulating proliferation

has a two- to threefold longer half-life, has

of the leukemic clone.

been approved in adult patients only.

Meta-analysis of adult data has shown

that although rHuEPO decreases transfu-

Treatment of febrile neutropenia

sion requirements in cancer patients, there

Pediatric guidelines are not clear but treat-

is a significant increase in venous throm-

ment should be considered in patients with

boembolism and, potentially, mortality.

profound neutropenia (ANC <0.1

10⁹/L),

Pediatric data are limited but have not to

uncontrolled primary disease, pneumonia,

date shown a significant difference in sur-

hypotension, multiorgan failure, and inva-

vival with the use of rHuEPO, although

sive fungal infection.

quality of life may be improved. In addi-

tion, venous thromboembolism has not

Duration

been seen in pediatric patients. Concern

G-CSF should be started between 1 to 5

remains that the decrease in adult survival

days after the last dose of myelosuppressive

rates with rHuEPO may be secondary to

chemotherapy or radiation. G-CSF should

the ubiquitous expression of the EPO-

be continued until the ANC is greater than

receptor on tumor cells and therefore

1.5

10⁹/L for 1 to 2 days following the

tumor upregulation with rHuEPO usage.

expected neutrophil nadir from chemo-

Conclusive in vivo data are lacking.

therapy. Specific protocols may call for

Pediatric guidelines for rHuEPO therefore

different ANC thresholds.

include the following: (1) use of rHuEPO is

not recommended in pediatric oncology

patients, and (2) rHuEPO should be consid-

Monitoring

ered on a case-by-case basis in special popu-

Once G-CSF is initiated, a complete blood

lations where blood product usage is rela-

count

(CBC) and differential should be

tively contraindicated. Specifically, Jehovah’s

monitored at least weekly.

Witnesses forbid blood product transfusion

and therefore the potential risks and benefits

Adverse effects

of rHuEPO should be discussed with the

The most common side effects of G-CSF

practicing patient and their family. A candid

are bone pain and elevation of uric acid,

discussion should occur between the

Central Venous

Catheters

Indwelling central venous catheters (CVCs)

These catheters are typically made of plastics

have revolutionized the care of children

with flexible silicone rubber tubing. They

with cancer by simplifying the administra-

are surgically placed

(and removed) by

tion of therapy, increasing safety, decreasing

experienced practitioners via a percutane-

pain, and improving quality of life by reduc-

ous or cut down technique. The patient

ing physical and psychological stress.

should be assessed for bleeding risk by

Peripheral venous access can become

having a platelet count and coagulation

increasingly difficult in young children.

studies checked preoperatively. External

Additionally, peripheral administration of

right atrial catheters are typically inserted

certain antineoplastic drugs may cause

into the subclavian, internal jugular, or

injury due to extravasation. CVCs provide

external jugular vein and are tunneled to

a safe, accessible route for infusion of che-

an exit site on the anterior or lateral chest.

motherapy, total parenteral nutrition, blood

Placement in other locations may be neces-

products, antibiotics, pain medications,

sary for patients with a history of throm-

hematopoietic stem cells, and other medi-

bosis, multiple previous CVCs, or in the

cations and infusions. These devices also

patient with compression of the upper

allow for frequent and convenient blood

venous system due to tumor. The location

sampling, which can be taught to home care

of the catheter tip should be confirmed by

providers. CVCs are now an integral aspect

fluoroscopy or chest radiography to be at

of management of cancer or chronic illness

the junction of the superior or inferior vena

in children.

cava and the right atrium prior to the

The optimal type and timing of place-

catheter being used. Ultrasonography or

ment of a CVC are not standardized. Many

angiography may assist the surgeon in

types of CVCs are available and are divided

determining the most accessible vein for

between temporary (peripherally inserted

CVC placement. External CVCs have a

central catheters) and more permanent,

Dacron cuff attached to the catheter wall

tunneled catheters. Tunneled catheters can

that is positioned 1-2 cm from the skin exit

either be entirely under the skin or have an

site. This allows for the growth of fibrous

external portion that allows access. This

tissue (scar) into the cuff, preventing migra-

chapter focuses on the permanent catheters,

tion and loss of the line. Surgeons will

placed to provide access for months to years.

typically place sutures externally as well that

Handbook of Pediatric Hematology and Oncology: Children’s Hospital & Research Center Oakland,

Second Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.

2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

236

Chapter 26

may be removed after healing. Totally

collection early in their course of therapy

implanted catheters (ports) are secured to

may benefit from the placement of a phere-

the deep fascia on the anterior chest wall

sible catheter, such as a Medcomp. These

with sutures. Ports are made of nonimmu-

lines require meticulous maintenance and

nogenic materials and some now allow for

are not repairable, unlike the standard

high-pressure infusion of contrast for radio-

external tunneled catheters. Due to the

graphic imaging. The silicone membrane of

larger lumen size required for a pheresible

the reservoir is accessed by a special non-

catheter and associated risk of thrombosis,

coring needle (Huber) and is self-sealing

these lines are not always feasible for long-

with needle removal. Topical anesthesia is

term access in smaller children. The Bard

typically applied over the reservoir prior to

PowerLine is becoming a popular double

internal catheter access.

lumen pheresible catheter due to the higher

The most frequently used tunneled

flow rates that are possible through them. In

external catheters are Broviac, Hickman,

addition, they can frequently be placed in

and Leonard. Totally implantable catheters

children who are too small to safely receive a

include Medi-Port, Port-a-Cath, BardPort,

conventional double lumen catheter (see

and PowerPort. Single lumen external

Table 26.1).

catheters and ports are used most com-

The decision about the type of CVC to be

monly in children, but double and triple

placed is based on multiple factors including

lumen catheters and ports are available.

length and intensity of therapy; frequency of

Patients that require pheresis for stem cell

lab draws; the need for multiple lumens to

Table 26.1 Common tunneled central venous catheters and related care.

Catheter type Saline flush

Heparin

Site care

Hickman

10 kg: 5 mL/lumen

10 units/mL

Dressing change weekly

Broviac

>10 kg: 10 mL/lumen

2 mL q24 hours

or per institution policy

after access

PRN after catheter

(or when wet, dirty)

access or blood

Type of dressing per

draw

institution (tegaderm,

Mepore, etc.)

Pheresible

10 mL each lumen

100 units/mL

Dressing change weekly or

catheter

q24 hours

>30 kg: 2 mL/lumen

per institution policy

15-30 kg: 1.5 mL/lumen

(or when wet, dirty)

<15 kg: 1 mL/lumen

Do not use iodine or

q24 hours and after

iodine-based disinfectants

access

Mediport

10 mL q24 hours and

10 units/mL

Huber needle changed

PRN when accessed

2 mL q24 hours and

weekly if continuously

Flush 20 mL after

PRN while accessed

accessed; dress securely

blood draw

100 units/mL

when accessed; apply

2 mL with deaccess

topical anesthetic prior to

and monthly

port access

<10 kg, give 2 mL of 10 units/mL.

Central Venous Catheters

237

Table 26.2 Type of central venous catheter to be placed by diagnosis.

CVC type

Number of lumens

Diagnosis

External

Single

ALL, high risk

Solid tumors, not metastatic

Neuroblastoma, low and intermediate risk

Non-Hodgkin lymphoma

External

Double

AML

Neuroblastoma, advanced stage

Brain tumors requiring Head Start/HSCT

Solid tumors, advanced stage

Internal

Single

ALL, standard and high risk

Wilms tumor

Hodgkin and non-Hodgkin lymphoma

Malignant glioma

Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myelogenous leukemia; CVC,

central venous catheter; HSCT, hematopoietic stem cell transplantation.

support simultaneous administration of

potential for introduction of infection. Ulti-

chemotherapy, hydration, pain medication,

mately, in cases where an external catheter is

parenteral nutrition, antibiotics, and other

not essential, the decision on the type of

agents; age; and lifestyle. In general, external

catheter to utilize must include a discussion

and multilumen devices are associated with

with the patient and the family reviewing

greater risk, primarily due to an increased

the pros and cons of each type of device.

incidence of infection and thrombosis.

Table 26.2 summarizes the type of CVC to

Ports are becoming increasingly more pop-

consider based on diagnosis and subsequent

ular, especially with lower intensity thera-

therapy intensity.

pies and in older children and adolescents.

Ports are cosmetically more satisfactory, do

not require routine care, and allow for easy

Maintenance

bathing and swimming. However, ports

may be difficult to place and access in obese

External catheters require daily heparin

or very thin patients. Additionally, the use

flushes and periodic dressing changes

of ports for routine blood draws is limited

(see Table 26.1). Families require detailed

due to their need to be accessed prior to use.

education on the care and potential com-

An external CVC should be used in patients

plications of CVCs. They should be taught

requiring frequent laboratory monitoring.

sterile technique to access the CVC for

External CVCs and ports may be used

blood draws or flushes and to provide exter-

immediately after placement. In the case

nal care. Frequency of dressing changes may

of a port, the surgeon should be asked to

be dependent on institution policy, type of

access the device when it is placed, prior

CVC, and local factors such as a wet, dirty,

to development of postoperative edema.

or loose dressing. At all times, the CVC exit

This allows immediate use, decreasing

site should be kept dry and clean. Patients

patient discomfort and reducing the

are instructed to protect it during bathing

238

Chapter 26

and not immerse the dressing or exit site in a

colonization and consequent seeding of the

bath, hot tub, or pool. Should this occur, the

pathogen into the circulation (see Chapter 27

dressing should be changed immediately

for common pathogens and management of

with careful cleansing of the exit site. Ports

fever in patients with CVCs). Patients with

require less care, and heparin flushes, which

CVCs require constant attention for pre-

are required only monthly, are typically per-

vention and early recognition of infection.

formed by the health care team. No dressing

Despite the meticulous techniques used by

is needed for implantable devices when they

health care providers and caregivers to main-

are not accessed. Each institution has a stan-

tain sterility, many children with CVCs will

dardized approach to the care and mainte-

develop a line infection or bacteremia. Infec-

nance of CVCs that is followed by staff, family

tion is often related to organisms that

members, and home health care agencies.

are ubiquitous but can lead to true infection

in the immunosuppressed patient (such as

gut and skin flora), or be due to organisms

Complications: mechanical

introduced with venous access or with blood

product or medication/fluid administration.

The use of CVCs can result in a number of

Coagulase-negative staphylococci, Staphylo-

short- and long-term complications. Imme-

coccus aureus, aerobic Gram-negative bacilli,

diate complications related to CVC placement

and Candida albicans most commonly cause

include malposition, hemorrhage, pneumo-

catheter-related bloodstream infection. Addi-

thorax, chylothorax, arterial cannulation, car-

tionally, development of a thrombus in the

diac dysrhythmia, and failure to place the line.

catheter may serve as a nidus for infection.

Rarely, complications may occur due to the

Occasionally, despite best efforts and appro-

anesthetic required for surgical placement.

priate antibiotic therapy, the line may be

Long-term complications include mechanical

colonized and need to be removed. Recent

failure, catheter breakage, leakage, and port

techniques for catheter sterilization include

extrusion. Mechanical failures have been

antibiotic and ethanol locks. Additionally,

reported in up to 10% of patients and may

many manufacturers have created antibacte-

result in removal of the CVC. Some types of

rial substances bonded to the catheters.

external CVCs may be repaired if the break is

Risk factors for CVC infection include

distal to the catheter exit site. Children with

the placement of an external catheter, young

implanted ports are at risk for the Huber

patient age, multilumen catheter, early

needle becoming dislodged during infusion,

placement (i.e., within 2 weeks of diagnosis

leading to extravasation with resultant skin

of acute lymphoblastic leukemia

[ALL]),

irritation or breakdown. These require careful

stem cell transplant, solid tumor, lack of

periodic assessment.

perioperative prophylactic antibiotics, high-

intensity protocol, and placement during

periods of neutropenia. These factors must

Complications: infectious

be weighed against the benefits of early line

placement, type of line placed, and number

Infection is the most common complication of

of catheter lumens. The relatively higher

CVCs. Most catheter-related infectionsarise by

infection rate seen with external catheters

one of two mechanisms: (1) infection at the

favors the use of implanted catheters when

exit site with migration of the pathogen along

possible.

the external catheter surface, and (2) contam-

Approximately 50% of catheter-related

ination of the hub, leading to intraluminal

infections occur locally at the exit site, along

Central Venous Catheters

239

the tunneled catheter or as a “pocket” infec-

review meticulous local CVC management

tion around the implanted reservoir. Skin

with the caregivers.

irritation may occur with external CVCs

In addition to site infections, coloniza-

and requires alteration of the prescribed exit

tion of the catheter may occur. In this case,

site care and dressing to avoid repeated

the patient will have repeatedly positive

irritation, skin breakdown, infection, and

cultures with the same organism, often

pain. Patients with local catheter infections

without systemic symptoms of infection.

typically have local signs and symptoms

In cases of colonization, cultures may

with tenderness on palpation, erythema,

become quickly positive and may persist

purulent drainage, lack of healing, swelling,

through appropriate antibiotic therapy. At

and pain. Severely neutropenic patients

times, catheters may be reseeded from dis-

may only have pain and tenderness as these

tant sites of occult infection (e.g., cardiac

symptoms do not require the presence of

vegetations, osteomyelitis, deep abscesses).

neutrophils. If drainage is present, the site

The CVC should always be considered

should be cultured. Tunnel infections are

the source of infection in a patient who

characterized by a spreading cellulitis along

presents with fever until proven otherwise.

the subcutaneous tract of long-term cathe-

Fever, chills, or hypotension temporally

ters. The catheter should be removed if the

related to line flushing increase the likeli-

administration of appropriate parenteral

hood of a line infection. Broad-spectrum

antibiotics does not result in resolution of

empiric antibiotics should be administered

the signs and symptoms within 24 to 48

after drawing cultures from each lumen of

hours. When evaluating a child with fever

the CVC. Persistent bacteremia despite

and a CVC, palpate along the tunnel to

appropriate antibiotic coverage

(>72

assess for tenderness or to express drainage.

hours), signs of sepsis (hypotension, chills,

Pocket abscesses may need to be surgically

persistent fever, cool extremities, delayed

drained and packed and almost always

capillary refill), or infection with fungus

will require removal of the reservoir and

or water-borne bacteria (e.g., pseudomonas,

catheter. Site infections with minor exit site

stenotrophomonas) warrant CVC removal.

erythema and tenderness are treated with

If placement of a new CVC is deemed

topical antibiotics and monitored with care-

necessary, the patient should first complete

ful, daily assessment; systemic antibiotics

an appropriate course of antibiotic therapy

should be added for clinical worsening, lack

allowing for sufficient healing time and

of improvement, or a positive blood culture

decreasing the risk of subsequent reinfection

from the line. Tunnel and pocket infections

of the new CVC.

should be treated with both topical and

CVC infection may be overdiagnosed,

systemic antibiotics, as well as a daily sterile

resulting in either prolonged antibiotic

dressing change. The patient should be

administration or unnecessary removal of

treated systemically with broad-spectrum

the catheter. Differential time to positivity

antibiotics providing good Gram-positive

is a reliable diagnostic technique to differ-

coverage and be monitored for the devel-

entiate a true line infection from bacter-

opment of an abscess requiring surgical

emia. Paired blood samples (aerobic and

drainage. The antibiotic regimen may be

anaerobic) from a peripheral vein and the

altered with culture results, but if the patient

central catheter are obtained and compared

is neutropenic it should include both broad-

with respect to time to positivity. If the

spectrum and directed antibiotic therapy.

culture from the catheter turns positive

Site infections provide an opportunity to

2 or more hours before the peripheral

240

Chapter 26

culture, this is diagnostic of a catheter-

is not currently recommended as standard

related infection. A positive differential

practice; however, it may be warranted in

time to positivity may not change manage-

certain situations with documented

ment, although consideration should be

increased risk.

given to the type and duration of systemic

Thrombosis should be suspected in

antibiotic therapy, utility of an antimicro-

patients whose catheter does not flush or

bial or ethanol lock, and the need for cath-

draw easily or in the event of suggestive

eter removal. Additional factors include

clinical findings (pain or swelling in extrem-

the type of catheter, prior history of infec-

ity, prominent vasculature or swelling on

tion, current neutrophil count, likelihood

side of neck/chest with CVC, inability to

of short term recovery, and current che-

successfully access an implanted port). It

motherapeutic regimen. When a specific

should be noted that a line that does not

pathogen has been identified, antibiotic

draw or flush might be occluded by the vessel

therapy should be targeted, with additional

wall or a valve. Patients suspected of having

broad empiric coverage in the neutropenic

a thrombosis should undergo imaging to

patient (see Chapter 27). The possibility

confirm this and determine the extent

of an infected catheter-related thrombus

(see Figure 26.1). Based on the timing of

should be considered, and treatment may

line dysfunction or symptom development,

also involve thrombolytic agents or

the age of the clot can be approximated.

anticoagulation.

Additionally, pertinent family history of

thrombosis should be sought out to help

guide the necessity of genetic evaluation for

Assessment and management of

thrombophilia

(see Chapter

10). Finally,

catheter-related thrombosis

environmental and medication prothrombo-

tic factors should be considered (e.g., immo-

Venous thromboembolism is another

bilization, steroids, and other medications).

common complication of long-term CVCs.

Treatment of thrombosis may require

The extent of thrombosis may include the

thrombolytic therapy, anticoagulation, or

catheter tip (ball-valve clot), the length of

catheter removal. Below are guidelines for

the catheter (fibrin sheath), or the cathe-

the assessment and treatment of a suspected

terized vessel (e.g., the upper limb with or

CVC-associated thrombus:

without the central vasculature of the

* Examine the catheter for any kinks in the

neck or mediastinum). Catheter-related

tubing.

venous thromboembolism can result in

* Reposition the patient; flush the CVC

significant morbidity, and subclinical

with normal saline (if possible) and again

thrombosis may occur in up to 50% of

attempt to withdraw blood. Have the

patients with CVCs. The risk of thrombosis

patient hold their hands above their head,

is influenced by catheter location, insertion

turn, cough, or hold their breath.

technique, catheter kinking or compres-

* Attempt a tissue plasminogen activator

sion by a mass or other structure, ratio

(TPA) dwell if the catheter can be flushed:

of the catheter size to the intraluminal

* Infants

<3 months receive

0.25 mg

vessel diameter, blood flow rheology,

(0.5 mL) per lumen; older children receive

genetic predisposition, and administration

0.5 mg (1 mL) per lumen. Dwell should be

of prothrombotic medications or infusions

administered for 30 minutes.

(e.g., asparaginase and total parenteral

* After the first dwell, attach an empty 3 mL

nutrition). Primary thromboprophylaxis

syringe and attempt to withdraw blood. If

Central Venous Catheters

241

Ini al evalua on

Physical examina on, including assessment of malfunc oning CVC

History (prothrombo c medica ons, family history)

Laboratory assessment (fibrinogen, PT, PTT, CBC)

Diagnos c imaging for confirma on of TE:

Ultrasound with Doppler and/or

CT with venography and/or

Catheter dye study

Is CVC essen al for care?

yes

Thrombophilia risk assessment (see

Occlusive: ini ate thrombolysis, then

Chapter 10)

an coagula on

Nonocclusive: an coagula on

Occlusive: ini ate thrombolysis up to 48-72 hours; an coagula on

Nonocclusive: consider thrombolysis up to 48-72 hours;

an coagula on

Func onal CVC?

yes

Successful lysis

Residual thrombus

of TE

Con nue therapeu c

Remove CVC

an coagula on

Con nue therapeu c an coagula on

Consider CVC removal

if s ll with residual clot un l clot

dissolu on

Con nue prophylac c an coagula on

Therapeu c an coagula on for 3 months

for 6 weeks to 3 months a er clot

followed by prophylaxis un l CVC

resolu on

removed

Figure 26.1 Evaluation of suspected thromboembolism in patients with tunneled central venous

catheters. Abbreviations: CVC, central venous catheter; PT, prothrombin time; PTT, partial throm-

boplastin time; CBC, complete blood count; TE, thromboembolism; CT, computed tomography.

successful, obtain blood work and flush line

* Obtain further imaging studies

per protocol. If unsuccessful, instill a second

such as a dye study of the line, ultra-

TPA dwell for an additional 30 minutes.

sound with Doppler flow, or CT with

* If the TPA dwell is unsuccessful, further

venography to evaluate for thrombosis

workup is required to determine the extent

location and extent. Assess for sleeve

of thrombus.

thrombus, mechanical failure of the

* Obtain a chest radiograph to confirm

CVC, or migration of the catheter out-

appropriate line position.

side the vessel.

242

Chapter 26

If a thrombus is identified and the time

genetic predisposition to thrombosis based

from symptom onset is <14 days, throm-

on family history or a personal history of

bolytic therapy with low-dose systemic TPA

previous thromboembolism, a thrombophi-

should be attempted if the catheter can be

lia trait workup should be sent (see Chapter

flushed

10 for details). If the patient has multitrait

* Infants < 3 months receive 0.06 mg/kg/

thrombophilia and therefore a higher risk of

h for 6 to 24 hours; older children receive

rethrombosis, every effort should be made to

0.03 mg/kg/h. If no clinical improvement

remove the CVC once the risk of having an

in 24 hours, double the dose to 0.06-

indwelling line outweighs the benefit (i.e.,

0.12 mg/kg/h (max dose 2 mg/h).

maintenance therapy in the ALL patient).

* Systemic TPA can be given for up to

If the patient on prophylactic anticoagula-

96 hours.

tion develops rethrombosis, management

* Monitor the fibrinogen level and main-

should be the same as with the initial clot with

tain above 100 mg/dL with cryoprecipitate.

systemic low-dose TPA followed by therapeu-

* Monitor the patient for signs of sepsis as

tic anticoagulation with LMWH until clot

bacteria can be released into the blood-

dissolution. If the patient is on therapeutic

stream with dissolution of the thrombus.

anticoagulation with clot extension, the CVC

* If the catheter becomes functional after

will need to be removed. In cases where the clot

administration of systemic TPA, obtain a

cannot be dissolved or stabilized and the line

follow-up radiographic study to assess for

needs to be removed, 3 to 5 days of antic-

clot resolution.

oagulation is recommended for clot stabiliza-

* Remove the catheter if the thrombus

tion prior to catheter removal. Special circum-

cannot be cleared after 24 to 48 hours.

stances will warrant disruption in anticoagula-

tion, such as lumbar punctures to administer

If the thrombus dissolves, or is stabilized

intrathecal chemotherapy or other surgical

with normal CVC function, determination

procedures. In general, LMWH should be held

should be made as to the current necessity of

for 24 hours in advance of theseprocedures and

the line and risk for recurrent thrombosis.

resumed 12 to 24 hours after procedure com-

If the CVC can be safely removed, some

pletion, depending on the nature of the pro-

practitioners recommend short-term pro-

cedure and risk of postoperative bleeding.

phylactic anticoagulation to mitigate the

Additionally, LMWH should be held during

risk for rethrombosis (usually 6 weeks to 3

periods of moderate thrombocytopenia (i.e.,

months of low-molecular-weight heparin

<50

10⁹/L) to minimize additional risk

[LMWH]). If the line needs to be maintained

of bleeding. If the CVC is removed and it is

and the clot has resolved, the patient should

necessarytoplaceanewcatheter,consideration

continue on therapeutic LMWH for

should be given to anticoagulation prophylaxis

months and then switch over to prophylactic

to prevent recurrence of thrombosis.

LMWH until the line is removed. For the

patient with a stable clot and a functional

Suggested Reading

CVC, therapeutic anticoagulation with

LMWH should be continued until approx-

Gallieni M, Pittiruti M, Biffi R. Vascular access in

imately 3 months after clot dissolution and

oncology patients. CA Cancer J Clin

then switched to prophylactic anticoagula-

58:323-346, 2008.

tion until line removal (see Chapter 10 and

Hirsh J, Guyatt G, Albers GW, et al. Antithrom-

Formulary for dosing guidelines). Addition-

botic and thrombolytic therapy: American

ally, if the patient is determined to have a

College of Chest Physicians evidence-based

Management

of Fever in the Child

with Cancer

Children with cancer are at an increased

* Defects in cellular immunity such as seen

risk for serious bacterial, viral, and fungal

in patients with T-cell malignancies or those

infections. Many factors contribute to this

receiving steroids or radiation; persistence

susceptibility in immunocompromised

of lymphopenia due to chemotherapy.

children. The two most important deter-

* Colonization from endogenous micro-

minants of susceptibility to bacterial and

flora.

fungal infection are the number of circu-

* Presence of indwelling catheters or shunts.

lating neutrophils

(absolute neutrophil

The ANC is calculated by multiplying the

count; ANC) and the duration of severe

percentage of neutrophils (segmented neu-

neutropenia. Other factors include:

trophils þ bands) by the total white blood

* Underlying disease: leukemia, especially

cell (WBC) count.

acute myelogenous leukemia

(AML),

Example: WBC ¼ 1.0

10⁹/L, segmented

advanced stage lymphoma, or other meta-

neutrophils ¼ 10%, bands ¼ 10%

static solid tumors are at higher risk due to

ANC ¼ 20%

1.0

10⁹/L ¼ 0.2

10⁹/L

increased therapy intensity.

* Remission status: patients not in remis-

ANC<1.5

10⁹/L is defined as neutropenia

sion are at higher risk.

ANC < 1.0

10⁹/L is defined as moderate

* Type of therapy with dose- or time-inten-

neutropenia

sive therapies: administration of high-dose

ANC < 0.5

10⁹/L represents severe neu-

cytarabine and stem cell transplant confer

tropenia

the highest risk.

ANC < 0.1 to 0.2

10⁹/L represents pro-

* Nutritional status: malnutrition adversely

found neutropenia

affects immune function.

* Disruption of protective barriers such as

In general, patients with an ANC of less than

skin, mucocutaneous tissues, gastrointesti-

0.5

10⁹/L or those with dropping counts

nal tract, and exit sites of catheters.

after chemotherapy are considered severely

* Defects in humoral immunity related to

neutropenic. The ANC at time of presenta-

therapy, impaired splenic function, or B-cell

tion with respect to the most recent chemo-

malignancies.

therapy gives important information. For

Handbook of Pediatric Hematology and Oncology: Children’s Hospital & Research Center Oakland,

Second Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.

2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

Management of Fever in the Child with Cancer

245

instance, if a child is neutropenic without

may have fever as their only symptom of

recent myelosuppressive therapy, infection

infection. It should be noted that neutro-

(and less likely relapse of a hematologic

penia will not prevent the patient from

malignancy) should be considered as the

having a temperature spike with infection;

most likely etiology due to marrow suppres-

one exception is the patient on steroids

sion. In general, the expected nadir in ANC

(such as in acute lymphoblastic leukemia

occurs 7 to 14 days from the start of mye-

[ALL] induction) who may not mount a

losuppressive chemotherapy. This timing

fever with an underlying infection. A careful

should be considered when assessing the

clinical examination is critical as the

patient and determining the management

patient’s status may change quickly and

plan. Practitioners may also utilize the abso-

dramatically.

lute phagocyte count (APC), which is the

Septic shock results from overwhelming

summation of the ANC and absolute mono-

infection with microorganisms in the

cyte count, in determining the risk of bac-

blood leading to central vascular dilation

terial infection as monocytes also possess

with resultant circulatory failure and inad-

bacteria-fighting ability. An increasing

equate tissue perfusion. Symptoms of septic

monocyte count is often seen prior to and

shock include hypotension, tachycardia,

often heralds neutrophil recovery.

tachypnea, clammy extremities (although

Fever is defined as a single temperature

can be warm with initial sepsis), decreased

of 38.3 C (101.0 F) or greater, two tem-

urine output, and deterioration of mental

peratures of

38.0

38.2 C

(100.4

status. Although septic shock can be seen

100.9 F) within a

24-hour period, or a

with any organism, the usual culprits with

temperature of 38.0 to 38.2 C (100.4 to

acute and overwhelming sepsis are Gram-

100.9 F) persistently for 1 hour, taken in

negative rods.

the axilla, orally, or by tympanic probe.

The most common organisms causing

Generally, oral and tympanic temperatures

bacteremia and sepsis are:

are preferred since the axillary temperature

* Gram-positive: Staphylococci (coagulase-

can be affected by outside temperature. Oral

negative, Staphylococcus aureus including

temperatures preferably are taken without

methicillin-resistant [MRSA]), streptococci

any recent hot or cold oral intake. Once a

(a-hemolytic) including Streptococcus viri-

fever is documented, it should be consid-

dans and S. mitis

ered as real no matter what the underlying

* Gram-negative: Enterobacteriaceae (E. coli,

circumstances are, even if the patient defer-

Enterobacter, Klebsiella, Serratia), Pseudomo-

vesces without any intervention. Patients

nas aeruginosa, Stenotrophomonas maltophi-

who develop a low-grade fever (38.0 C to

lia, Acinetobacter sp.

38.2 C) should be monitored without anti-

* Anaerobic: Clostridium difficile, Bacter-

pyretics to determine if a fever spike will

oides sp., Proprionobacterium acnes

occur. Rectal temperatures should never be

Other pathogens infecting cancer

taken in potentially neutropenic children.

patients include:

* Fungi: Candida sp., Aspergillus sp., zygo-

mycetes, cryptococci

Fever and neutropenia

* Viruses: Herpes simplex virus

(HSV),

varicella zoster virus (VZV), cytomegalovi-

Every oncology patient who presents with

rus (CMV), Epstein-Barr virus, respiratory

febrile neutropenia (FN) is considered sep-

syncytial virus, adenovirus, influenza, para-

tic until proven otherwise. These children

influenza, human herpesvirus 6

246

Chapter 27

Other: Pneumocystis jiroveci, Toxoplasma

a. Determination of vitals and evalua-

gondii, Strongyloides stercoralis, cryptospo-

tion for shock.

ridium, Bacillus sp., atypical mycobacterium

b. Meticulous physical examination with

particular attention to sites of occult

infection such as the skin, exit sites of

Initial evaluation of febrile

catheters, sites of recent bone marrow

neutropenia

aspiration, oral cavity, and perianal areas.

See Figure 27.1.

Even subtle evidence of inflammation

1. History and physical examination

(faint erythema, tenderness, or minimal

Fever: Temperature 38.3°C x 1 or 38.0°C x 2 at least 1 hour apart

Neutropenia: ANC <0.5 x 10⁹/L or <1.0 x 10⁹/L and falling

Ini al Evalua on

History: Chills, rigors, fever within 1 hour of CVC flush

Recent immunosuppressive therapy

Symptoms of AGE, URI, pain

Physical examina on: Vitals, CVC exit site(s), skin/mucosa, perineum

Laboratory assessment: CBC with differen al

Blood culture from each CVC lumen (peripheral, see text)

Culture from all suspicious sites (throat, skin, stool, catheter site)

Urinalysis and urine culture

Stool culture, C. difficile toxin, rotavirus for diarrhea/abdominal pain

Electrolytes, BUN, crea nine, liver transaminases

Imaging: CXR if signs/symptoms of pulmonary process

CT as necessary per physical findings (sinuses, chest, abdomen, pelvis)

Risk group assessment

High risk

Low risk

Any malignancy not controlled (i.e., relapse, refractory, induc on)

Diagnosis: ALL, NHL, solid tumors in remission

AML, high risk ALL in consolida on or delayed intensifica on

Neutropenia: Dura on <7 days

High dose cytarabine

Nontoxic appearance

Prolonged neutropenia an cipated ≥7 days

No focal infec on, mucosi s, diarrhea

Profound neutropenia <0.1 x 10⁹/L

Toxic appearance: Hypotensive, rigors, shock, tachypnea, hypoxia

Evidence of infec on: Pneumonia, celluli s, abdominal pain and

diarrhea, neurologic (mental status) changes

Known coloniza on with MRSA

Prior history of bacteremia/sepsis

Empiric an bio c therapy; monotherapy

Mucosi s following chemotherapy

Consider outpa ent management

Empiric therapy, broad spectrum, ini ated promptly

Hospitaliza on

Treatment of co-morbidi es as appropriate

Pain management as appropriate

Directed therapy as appropriate:

Vancomycin for recent high dose cytarabine, new fever in AML pa ent

Clindamycin or meropenem for diarrhea/abdominal pain

Figure 27.1

Evaluation and initial management of febrile neutropenia in the child with cancer.

(Abbreviations: CVC, central venous catheter; AGE, acute gastroenteritis; URI, upper respiratory

infection; CBC, complete blood count; BUN, blood urea nitrogen; CXR, chest radiography; CT,

computed tomography; ALL, acute lymphoblastic leukemia; NHL, non-Hodgkin lymphoma; AML,

acute myelogenous leukemia; MRSA, methicillin-resistant Staphylococcus aureus).

Management of Fever in the Child with Cancer

247

discharge) may represent a source of

i. If diarrhea is present, send a stool

infection as neutropenia diminishes clas-

sample for stool culture, rotavirus, and

sic inflammatory changes. Pain, however,

C. difficile antigen.

is always a concerning finding and should

j. In contrast to nononcology patients, a

be considered a potential clue to site and

lumbar puncture (LP) is not routinely

source of infection.

done as part of a serious bacterial infec-

Laboratory evaluation

tion evaluation in patients with FN and

a. Complete blood count (CBC) with

an oncologic diagnosis. If an LP appears

manual differential to determine ANC.

clinically indicated, evaluation for

b. Blood cultures from each lumen of the

increased intracranial pressure with

central venous catheter (CVC); peripheral

appropriate imaging

(i.e., head CT)

culture is necessary if the child does not

should be done and the pediatric oncol-

have a central line or it is unobtainable

ogy attending notified prior to the pro-

from the central line. Controversy still

cedure. An adequate platelet count and

exists as to utility of a peripheral blood

at least near-normal coagulation studies

culture when cultures are taken from the

are also required in advance of the LP.

line as delayed time to positivity between

k. If another implanted device is present

these two sources can help determine the

(e.g., ventriculoperitoneal shunt or

existence of a line infection versus bac-

Ommaya reservoir), do not attempt to

teremia (see Chapter 26). Do not flush

obtain a culture without speaking to

the catheter after labs are obtained in

the appropriate attending physicians.

the patient with a recent history of high

Intervention by a neurosurgeon may

fever, hypotension, chills, or rigors within

be required. It is uncommon for these

1 hour of flushing the catheter, suggestive

devices to be the source of infection if

of a line infection. See below under Initial

it has been more than 2 to 4 weeks since

management.

they were inserted.

c. Serum chemistries to include electro-

lytes, liver, and renal function studies.

Initial management

d. Urinalysis and urine culture (no cath-

Risk stratification models for pediatric

eter sample for neutropenic patients).

oncology patients with FN to determine

e. Chest radiograph only if the patient

which patients are low risk and could poten-

has ausculatory signs or symptoms of

tially be managed as outpatients and which

infection or respiratory compromise.

are higher risk and should be monitored as

f. If the child has tenderness over the

inpatients have yet to be validated and

sinuses, perform diagnostic imaging to

widely accepted. Adult studies suggest that

evaluate for sinusitis (plain radiographs

patients with predicted time of severe neu-

and/or CT).

tropenia of

7 days and no concerning

g. Patients with symptoms of esophagi-

clinical signs including focal infection such

tis should be evaluated for viral or fungal

as pneumonia, new abdominal pain, or

causes with serologies and culture, if

hypotension can be safely managed as out-

possible.

patients. With the lack of data in pediatric

h. Cultures and bacterial Gram stain or

patients, we continue to recommend that

fungal stains from suspicious sites such

parenteral broad-spectrum antibiotics be

as the oropharynx, skin breakdown sites,

started immediately and the patient admit-

and catheter sites.

ted to the hospital. FN is considered an

248

Chapter 27

oncologic emergency and all measures

combination with broad-spectrum coverage

should be taken to ensure prompt evaluation

due to the high risk of S. viridans infec-

and treatment, with a goal of

60 minutes

tion with its accompanying septic shock

between presentation and the initiation of

and acute respiratory distress syndrome.

antibiotics. Antibiotics should be chosen

Cytarabine is known to alter mucosal integ-

based on microbial prevalence and antibi-

rity and allow entry of this organism.

otic sensitivity patterns at each institution.

Patients with S. viridans sepsis have a high

In general, due to the more acute risk from

rate of morbidity and mortality. They

Gram-negative organisms, broad coverage

typically require prolonged hospitalization

for these organisms (including Pseudomo-

following chemotherapy until neutrophil

nas) should be initiated. Many combina-

recovery occurs to allow emergent initiation

tions of antibiotics are effective and accept-

of treatment in the event of fever or other

able regimens include:

signs of impending shock or sepsis. Other

1. Monotherapy:

indications for vancomycin in the empiric

Fourth generation cephalosporin (anti-

regimen include:

pseudomonal b-lactam)

* Presentation with hypotension or other

Cefepime 150 mg/kg/day intravenous

evidence of shock

(IV) divided q8h

* Mucositis due to chemotherapy

Carbapenem

* Patients with prior history of a-hemolytic

Imipenem 50 mg/kg/day IV divided

streptococcus bacteremia

q6-8h

* Catheter site infection or other skin

Meropenem 60 to 120 mg/kg/day IV

breakdown

divided q8h

* Patients colonized with resistant organ-

Piperacillin/Tazobactam

isms treatable only with vancomycin

Zosyn

240

300 mg/kg/day IV

* Vegetations on echocardiogram

divided q8h

2. Dual therapy (antipseudomonal b-lac-

Anaerobic therapy should be considered in

patients who have significant mucosal

tam plus an aminoglycoside):

breakdown, perianal skin breakdown, peri-

Ceftazidime

100 to 150 mg/kg/day IV

toneal signs, or in cases of typhilitis with

divided q8h and

presumed or proven C. difficile infection.

Tobramycin 7.5 mg/kg/day IV divided

For patients on dual therapy with an

q8h or 7-9 mg/kg/dose IV daily

aminoglycoside, trough levels should be

Other antibiotics used in specific circum-

monitored weekly due to the risks of

stances (see below) are:

nephro- and ototoxicity, especially in those

1. Anaerobic drugs:

receiving other nephro- or ototoxic drugs

(e.g., vancomycin, furosemide). For patients

Clindamycin 40 mg/kg/day IV divided

on therapy with vancomycin, trough levels

q6-8h

should be monitored for toxicity as well as

Metronidazole

30 mg/kg/day

(loading

medication effectiveness, with goal trough

dose 15 mg/kg) IV divided q6h

levels of 10 to 15 mcg/mL. Dose increases

2. Vancomycin

60 mg/kg/day IV divided

are often required in pediatric patients to

q8h

reach these levels. Monitor daily electro-

Patients with AML receiving high-dose

lytes, fluid balance, renal function studies,

cytarabine (Ara-C) should have vancomy-

and ensure adequate hydration. Patients

cin as part of their empiric regimen in

with renal dysfunction should receive renal

Management of Fever in the Child with Cancer

249

dosing with more frequent trough levels to

the fever curve, presence of new symptoms or

prevent toxicity.

signs of infection with a meticulous physical

Any patient that presents with hypoten-

examination, and results of prior cultures

sion, chills, rigors, or fever immediately

and diagnostic imaging performed

(see

following, or within

hour, of central

Figure 27.2). The status of catheters should

venous catheter flushing should be seen

be assessed (site, function, and concern for

emergently due to the risk of bacteremia

thrombosis). Daily blood cultures and a CBC

and septic shock. In our practice, we elect

with differential should be done on persis-

not to use the central venous line for IV

tently febrile patients. Determination of the

fluids or medication administration initially

ANC is also important for patients who have

in this situation due to the risk of infusing

defervesced and have negative cultures to

a large amount of bacteria into the blood-

determine the length of appropriate therapy.

stream and worsening the signs of clinical

When the neutropenic child becomes afebrile

sepsis. Patients should have central catheter

(no fever for 24 hours) and cultures are

cultures, placement of a peripheral IV

negative

(obtained daily while febrile),

with peripheral cultures, administration

broad-spectrum coverage should be contin-

of broad-spectrum antibiotics, and a fluid

ued until there is evidence of adequate mar-

bolus (e.g., NS/LR 20 mL/kg), if necessary.

row recovery and an appropriate period of

The central catheter should not be flushed

therapy for any initially positive cultures has

or utilized until the patient improves clin-

been provided. Resolution of neutropenia is

ically with defervescence, resolution of

defined as an ANC of >0.5

10⁹/L and

hypotension, and negative follow-up blood

evidence of bone marrow recovery is an ANC

cultures. If the line cannot be flushed, a TPA

of >0.2

10⁹/L and rising on 2 consecutive

dwell can be attempted; if unsuccessful, the

days. Some practitioners also use an APC of

line will need to be removed (see Chap-

>0.5

10⁹/L as sufficient evidence of recov-

ter 26). It is advisable to give an IV fluid

ery from neutropenia. When the patient no

bolus prior to reusing the catheter in the

longer has fever, has negative blood cultures,

event the patient again develops symptoms

and has signs of neutrophil recovery, the

of bacteremia with hypotension following

antibiotics may be safely discontinued and

the flush. In the event the initial blood

the child discharged, assuming an appropri-

culture from the catheter is positive, the

ate treatment length for any positive cultures

clinician will need to decide whether to

has been provided. Should the child have any

remove the catheter or attempt to reuse it

local evidence of infection such as diarrhea or

depending on the patient’s clinical condi-

skin breakdown, appropriate therapy should

tion and the type of organism that is grow-

continue, but in the outpatient setting.

ing. Patients that have persistent fever and

Modification should be made to the

Gram-negative organisms may do best with

initial broad-spectrum antibiotic regimen

removal of the line; patients that have defer-

if a source of infection is found to explain

vesced and are looking clinically well can

the initial fever, or the fever persists for

generally have their line reused and ulti-

more than 3 to 7 days. If the source of the

mately salvaged.

infection is a catheter site with accompa-

nying signs or symptoms of inflammation

Modification of initial antibiotic

(discharge, palpable tenderness, local

treatment

abscess), vancomycin should be added for

Patients should be assessed daily for changes

Gram-positive coverage. If the source is

in vital signs, persistence of fever or change in

perianal, gingival, or intra-abdominal,

250

Chapter 27

Empiric therapy

Nega ve cultures 48-72 hours, unknown

site of infec on

Blood or site

cultures posi ve or site

organism suspected

Persistent

Afebrile ≥24 hours

fever/neutropenia

Evidence of neutrophil

Broaden coverage:

Con nue empiric

recovery (ANC ≥0.5 or ≥

Staphylococcal species: add vancomycin

therapy:

0.2 x 10⁹/L and rising on

Fungus: add echinocandin and/or triazole

Reassess every

2 consecu ve days)

Mucosi s/perineal breakdown: add clindamycin or

24 hours with PE

Discon nue an bio cs

meropenem

and cultures

Esophagi s: add acyclovir, consider an fungal

Pulmonary infiltrates: add triazole and/or echinocandin

a er BAL/bronchoscopy

Persistent neutropenia:

Catheter associated bacteremia >72 hours or fungemia:

Con nue an bio cs, un l neutrophil

remove CVC

recovery

If fever recurs, reassess with PE and

cultures, broaden an bio cs, and

consider an fungal therapy

Persistent fever 3-5 days with neutropenia:

Imaging for infec on if with expected

con nua on of neutropenia: CT chest, other

areas based on symptoms

Urine cytospin for hyphae, fungal culture

Con nue broad spectrum an bio cs,

broaden as indicated clinically

Ini ate empiric an fungal therapy with

echinocandin or triazole

Figure

27.2

Ongoing management of fever and neutropenia.

(Abbreviations: ANC, absolute

neutrophil count; PE, physical examination; BAL, bronchoalveolar lavage; CVC, central venous

catheter; CT, computed tomography).

anaerobic coverage should be added to the

immunocompromised patient. Finally,

regimen (clindamycin, metronidazole, or

though rarely seen, MRSA should be a

meropenem).

consideration in the very sick patient.

Vancomycin is the most effective anti-

Vancomycin should be used judiciously due

biotic against skin flora such as coagulase

to emerging resistance patterns such as van-

negative staphylococci (i.e., S. epidermidis)

comycin-resistant enterococcus

(VRE).

as well as mouth flora, most commonly

Vancomycin should not be part of the

streptococcal species (S. viridans, Peptostrep-

empiric antibiotic regimen unless the insti-

tococcus). Vancomycin is also effective

tutional experience and susceptibility pat-

against bacillus nonanthracis species that

terns require it or there are special circum-

can be true pathogens in the

stances (see above).

Management of Fever in the Child with Cancer

251

Protracted fever may signify the presence

* In multilumen devices, the antibiotic

of a second or previously untreated infec-

infusion should be rotated among the

tion. Patients should be reassessed daily for

lumens as infection may not be limited to

new signs or symptoms of infection and

one lumen. If one particular lumen has the

appropriate interventions and studies per-

positive blood culture, it is reasonable to

formed. Antibiotic-induced colitis may

run the majority of the antibiotic through

occur after any antibiotic. C. difficile over-

this lumen.

growth may be asymptomatic, lead to mild

* Daily blood cultures while febrile or if

diarrhea, or may have moderate-to-severe

growth is present

(from each lumen of

diarrhea and abdominal pain. The patient

CVC), until afebrile and negative cultures

may also develop pseudomembranous coli-

for 3 days.

tis with peritoneal signs, mucosal erosions,

* Assess cardiac valves for vegetations with

and bloody diarrhea. Since C. difficile is a

an echocardiogram for repeatedly positive

normal bowel inhabitant, the toxin must

cultures with Gram-positive organisms.

be documented to diagnose this condition.

* If bacteremia persists for more than 3

If oral therapy is possible, vancomycin

days of appropriate therapy, the catheter

(40 mg/kg divided q8h) or metronidazole

should be removed.

(30 mg/kg divided q6h) may be given; in the

patient unable to tolerate oral medications,

For patients with a history of multiple

IV metronidazole (same as PO dose) should

positive cultures or a difficult to eradicate

be given. Abdominal pain may also be due

organism, consideration should be made

to infection with aerobic Gram-negative

for the use of ethanol or vancomycin lock

bacteria, enterococcus (which no cephalo-

therapy to possibly prevent the need for line

sporin covers in vivo), or anaerobes.

removal. Ethanol locks should not be used

If the patient is determined to have a

with polyurethane catheters

(PowerLine,

catheter-associated bacteremia with a spe-

MedComp) as ethanol will damage the

cific organism, broad-spectrum antibiotics

catheter material.

should be continued with addition of anti-

biotics as needed to ensure adequate

Duration of therapy

coverage of the identified organism until

When a pathogen has been identified, its

sensitivity patterns are reported. If daily

antibiotic susceptibility pattern must be

cultures are persistently positive with the

determined and appropriate antibiotic cov-

same organism for 72 hours after initiation

erage provided along with broad-spectrum

of appropriate antibiotics, it will be neces-

coverage until the patient is afebrile and has

sary to remove the catheter. In addition,

evidence of bone marrow recovery. Once

several organisms including S. aureus, Pseu-

the child is afebrile and the ANC recovers,

domonas, B. cereus, Corynebacterium, Myco-

antibiotics can be tailored to the specific

bacterium sp., Stenotrophomonas, and fungi

organism for a 10- to 14-day course, with

usually require line removal. General care

day 1 being the day of the first negative

measures are as follows:

culture.

* Hand washing with clean or sterile gloves

Patients that defervesce but do not have

prior to manipulation of CVC.

recovery of the ANC should continue on

* Monitor CVC site on a daily basis; change

broad-spectrum antibiotics to prevent sec-

CVC dressing weekly.

ondary infection. Some practitioners may

* Assess site for skin infection (including

discontinue antibiotics after 14 days if the

tunnel infection) with any fever.

patient continues to be neutropenic but

252

Chapter 27

afebrile, although our general practice is to

fungal nodules. Fungal cultures should be

continue until count recovery.

sent from the blood and urine as well as

any suspicious skin site. In addition, the

Empiric antifungal therapy

patient should have a serum galactoman-

When FN persists for 4 to 7 days, empiric

nan performed to screen for Aspergillus

treatment should be broadened to include

infection. CT imaging of the chest, as well

fungal prophylaxis. The risk of fungal

as imaging of other symptomatic areas,

infection is directly related to the duration

should be performed. It should be noted

of neutropenia, which is secondary to the

that in the severely neutropenic patient,

severity of chemotherapy or radiation

areas of infection may not be appreciated

cytotoxicity. Thus, patients undergoing

on imaging until neutrophil recovery has

more intensive therapy such as for AML,

occurred. In these cases, the patient will

relapsed ALL, and hematopoietic stem cell

generally have continued or new fevers with

transplantation are at highest risk of an

count recovery that should alert the clini-

invasive fungal infection. The major caus-

cian to the need for repeat CT imaging

ative fungi are Aspergillus and Candida,

which should include the sinuses, chest,

with mortality as high as 30% to 60% with

and abdomen.

documented invasive disease. Fungal infec-

Commonly used antifungal agents for

tions can be difficult to detect due to the

empiric therapy in prolonged FN include:

frequent absence of localizing signs or

1. Echinocandins

symptoms and lack of means of detection

Micafungin

by culture. Prompt diagnostic assessment

and initiation of antifungal empiric therapy

Prophylaxis 1 to 2 mg/kg IV daily

Treatment 3 to 4 mg/kg IV daily

are paramount for improving outcomes in

these patients.

Caspofungin

Anidulafungin

Empiric antifungal therapy prevents

fungal overgrowth in patients with pro-

2. Triazoles

longed neutropenia. It also provides early

Voriconazole

treatment of clinically occult infection.

Posaconazole

Clinical trials have found that antifungal

3. Amphotericin B

treatment of children with persistent or

4. Lipid formulations of amphotericin B

recurring fever reduced morbidity and

mortality from invasive fungal disease. This

The echinocandins have replaced ampho-

is especially true in patients with profound

tericin B as the empiric antifungal agent of

neutropenia not receiving antifungal pro-

choice due to their once daily dosing, sig-

phylaxis. The current recommendation is

nificantly decreased side effect profile, and

that high risk groups (i.e., those expected to

broad coverage. Echinocandins are fungi-

have neutropenia >7 days) should receive

cidal to most Candida species and at least

antifungal prophylaxis during episodes of

fungistatic against Aspergillus species. They

prolonged FN.

also have limited activity against Fusarium

A meticulous physical examination,

species and Zygomycetes. The triazoles are

laboratory assessments, and radiographic

derivatives of fluconazole with broad-spec-

studies in search of deep-seated infections

trum antifungal activity and limited side

are also warranted after this 4 to 7 day time

effects. Of note, the triazoles are fungicidal

frame. Particular attention should be paid

against Aspergillus species. In general, we

to the skin examination as it can reveal

utilize the echinocandins as first-line

Management of Fever in the Child with Cancer

253

empiric therapy and consider adjustment in

and mortality. In transplant patients, pri-

patients that are worsening clinically or have

mary infection or reactivation with cyto-

signs consistent with Aspergillus infection.

megalovirus (CMV) is an important cause

Patients on either an echinocandin or tria-

of interstitial pneumonitis, marrow aplasia,

zole should be monitored closely for hepatic

and other infections. Antiviral drugs are

toxicity; voriconazole may also cause visual

available for a limited number of infections

disturbance that is more common in adult

including herpes simplex virus (HSV), var-

patients. Posaconazole may provide better

icella zoster virus (VZV), CMV, and influ-

coverage against Aspergillus species but is

enza and should be utilized in the treatment

only available as an oral medication and

of immunocompromised patients. Other

clinical trial data are limited in pediatric

patients may also be candidates for prophy-

patients.

laxis

(e.g., solid organ transplant patients

Amphotericin B remains the most widely

and patients with a prior history of infection

active antifungal agent but has generally

on therapy).

been replaced due to its significant toxicity

Patients with documented infection

profile, most notably nephrotoxicity and

with HSV should be treated with IV acy-

infusional toxicity. Fever, chills, nausea,

clovir (30 mg/kg/day if <12 years; 15 mg/

metabolic abnormalities, hypokalemia and

kg/day for

12 years divided TID for 7 to 14

other electrolyte disturbances, and hepatic

days). Infection with VZV is potentially life

toxicity can all occur. In order to treat, and

threatening and therefore chemotherapy

possibly prevent, some of these complica-

should be stopped while treating with IV

tions, several measures are taken. Patients

acyclovir (30 mg/kg/day divided TID for 7

with a history of nephrotoxicity may benefit

to 10 days or until all lesions are crusted and

from receiving pre- and postinfusion NS

no new lesions have appeared for 24 to 48

boluses and diuretics. Premedications

hours). It is important to monitor renal

including acetaminophen, diphenhydra-

function and ensure adequate fluid intake

mine, and meperidine may be given to treat

due to potential nephrotoxicity from

or prevent acute symptoms related to the

acyclovir.

infusion

(fever, chills, rigors, nausea).

Patients with symptomatic primary

Hydrocortisone can also be added to

CMV infection or reactivation can be trea-

address infusion-related toxicity. Use of

ted with ganciclovir

(10 mg/kg/day IV

liposomal formulations of amphotericin B

divided q12h for 2 to 4 weeks until resolu-

(Ambisome and Abelcet) results in signifi-

tion of viremia by polymerase chain reac-

cantly fewer adverse events, but they are

tion). Patients with persistent infection

much more expensive than amphotericin B.

may require longer therapy or may have

resistant disease and require alternate

therapy with foscarnet or cidofovir. Of

Viral infection

note, ganciclovir can be myelosuppressive,

whereas foscarnet and cidofovir are quite

Immunosuppressed children are able to tol-

nephrotoxic. Concomitant therapy with

erate many viral infections without diffi-

intravenous immune globulin (IVIG) may

culty. However, defects in cellular immunity

be beneficial especially in the setting of

predispose them to unusually severe infec-

CMV pneumonitis. Data regarding pro-

tions with certain viruses, particularly the

phylactic therapy in this setting is lacking,

herpes family of viruses. Primary varicella

although once daily dosing can be consid-

infection is associated with high morbidity

ered in patients that complete a course of

254

Chapter 27

antiviral therapy and remain neutropenic

component of

15 mg/kg/day IV divided

or severely immunocompromised.

q8h for 14 to 21 days. If the patient fails

Patients who develop influenza while on

to respond to TMP/SMX within 72 hours,

therapy should be treated with neuramini-

or develops this infection while on prior

dase inhibitors (i.e., oseltamivir for children

TMP/SMX prophylaxis with good compli-

1 year of age, twice daily for 5 days) to

ance, initiate therapy with pentamidine,

reduce symptom duration and severity of

4 mg/kg IV daily. In patients with moderate

disease. Oseltamivir may also be given as

or severe proven infection, concomitant

daily prophylaxis for 5 days to patients that

administration of corticosteroids may be

have been exposed to the virus. If given as

beneficial with IV methylprednisolone or

treatment, it is most effective when given

prednisone given 2 to 4 times per day for

within 48 hours of symptom onset.

5 to 7 days, followed by a taper over 1 to 2

weeks.

Pneumocystis jiroveci

pneumonia

New sites of infection

Pneumocystis jiroveci is now considered an

New or persistent fever and neutropenia

atypical fungus and is a ubiquitous organ-

may be associated with the development

ism that may cause severe or fatal pneumo-

of new sites of infection due to continued

nitis in immunocompromised patients

severe immunosuppression. Particular

(most notably patients with HIV and those

symptoms may provide clues to site and

being treated for cancer). Patients typically

potential pathogen.

develop a rapid onset of fever in association

1. Burning retrosternal pain may be esoph-

with tachypnea and other symptoms of

agitis from Candida sp. or HSV. Cytotoxic

respiratory compromise such as nasal flar-

treatment may also cause severe pain due to

ing and intercostal retractions. Lung sounds

mucosal erosions. Empiric micafungin or

may be clear and typically patients do not

acyclovir, or both, may be needed. Esoph-

have rales. Hypoxemia is evident by pulse

agitis may also be bacterial, especially as a

oximetry and arterial blood gas. Chest radi-

result of Gram-positive aerobes.

ography or CT shows an interstitial pattern.

2. Pulmonary infiltrates may be due to

Without appropriate therapy, patients rap-

resistant bacteria, Pneumocystis, fungi, or

idly progress to respiratory failure.

viruses. Neutropenic patients may not show

Diagnosis is made by demonstrating the

evidence of pulmonary infiltrates due to

organism by Gomori methanamine silver

lack of an appropriate local inflammatory

stain on a sample obtained by induced spu-

response. However, with the recovery of the

tum, bronchoalveolar lavage, percutaneous

ANC, these sites of infection may become

needle biopsy, or open lung biopsy. Patients

evident. If FN has been less than 7 days,

who are at risk and present with the classic

pulmonary infiltrates are very likely to be of

signs and symptoms should be treated while

bacterial origin. If the neutropenia persists

awaiting definitive diagnosis, given the

for greater than 7 days, the patient is at

rapidity of clinical deterioration.

particularly high risk for fungal infection.

For documented or highly suspected

Bronchoalveolar lavage or induced sputum

infection with P. jiroveci, trimethoprim/sul-

may identify Pneumocystis, viruses, or fungi.

famethoxazole (TMP/SMX) is the treatment

The risks and benefits of open lung biopsy

of choice, at a dose based on the TMP

and pursuing an aggressive diagnostic

Management of Fever in the Child with Cancer

255

evaluation must be considered. It is impor-

ings should have appropriate diagnostic

tant to remember that the child may rapidly

procedures. Clinical judgment must be uti-

become very ill and this decision must be

lized to determine the risk for the patient

made expeditiously after discussion between

without an obvious source of infection.

the oncologist, surgeon, radiologist, pulmo-

Issues in the social history such as family

nologist, as well as the patient and family.

reliability, compliance, and ability to travel

to the outpatient center must be factored

Other supportive measures

into a decision plan. If the patient has

recently received chemotherapy and is

Granulocyte colony-stimulating factor

expected to reach a nadir in the next few

(G-CSF) may be indicated in the setting

days, consideration should be given to more

of FN; however, there are no specific stan-

frequent assessment or hospital admission.

dards for its use. Therapy with 5 mcg/kg/day

As with the neutropenic patient, blood

subcutaneously is recommended under cer-

cultures should be drawn and empiric anti-

tain conditions in which the clinical course

biotics initiated. The risk for Pseudomonas

is likely to worsen before the anticipated

is significantly decreased in the patient

marrow recovery (see Chapter 25). Patients

without severe neutropenia and therefore

who remain severely neutropenic with life-

ceftriaxone IV/IM at 50 mg/kg (maximum

threatening infections should receive G-

2 g) can be given daily while febrile in the

CSF. Granulocyte transfusions may be con-

outpatient setting in the otherwise well-

sidered in the setting of profound neutro-

appearing child for at least the first

penia and sepsis, especially an invasive bac-

hours, while awaiting results of the blood

terial or fungal infection that is not improv-

culture. Hospitalization may be required

ing on appropriate therapy with expected

in patients who are persistently febrile with

continuation of profound neutropenia (see

a dropping ANC and in those with a pos-

Chapter

5). However, such transfusions

itive blood culture or the development of

are becoming increasingly more difficult

localizing signs.

to obtain.

Suggested Reading

Fever in the nonneutropenic

oncology patient

Donowitz GR, Maki DG, Crnich CJ, et al. Infec-

tions in the neutropenic patient—new views

of an old problems. Hematol Am Soc Hema-

The febrile, nonneutropenic patient

tol Educ Prog 113-139, 2001.

remains susceptible to infection secondary

Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical

to immune dysfunction and often second-

practice guideline for the use of antimicrobial

ary to the presence of a CVC. These patients

agents in neutropenic patients with cancer:

should have a careful assessment with his-

2010 update by the Infectious Disease Society

tory, physical examination, and pertinent

of America. Clin Infect Dis 52:e56-e93, 2011.

laboratory studies as in the febrile neutro-

Pizzo PA. Fever in immunocompromised

penic patient. Patients with localizing find-

patients. N Engl J Med 341:893-900, 1999.

Acute Pain

Management in the

Inpatient Setting

Pain is a common problem for children with

framework that physicians could use when

hematologic or oncologic conditions, as it

developing treatment plans for cancer

can result both from the condition itself and

pain, paving the way for significant im-

from its management. A number of studies

provements in its management. Over the

have demonstrated that effective pain man-

subsequent 25 years, it has undergone much

agement not only increases a patient’s com-

scrutiny and several modifications have

fort level but can also effect long-term

been proposed. A recent adaptation is pre-

changes in a patient’s pain threshold, and,

sented in Figure 28.1.

in critically ill patients, it has been demon-

The cornerstone of the ladder rests on

strated to improve morbidity and mortality.

five simple recommendations that remain

Despite this, other studies have demon-

valid today:

strated that pediatric pain management is

1. The oral form of medication should be

often suboptimal. This results from percep-

chosen whenever possible.

tions on the parts of both parents and care

2. Analgesics should be given at regular

providers that pain is less frequent or less

intervals. It is necessary to respect the dura-

severe than is the case, or from concerns of

tion of the medication’s efficacy and to

causing dependence or addiction.

prescribe doses at specific intervals in accor-

The management of chronic pain is a

dance with the patient’s level of pain. The

frequent challenge for pediatric hematologists

dose should be adjusted until the patient is

and oncologists, but is outside the scope of this

comfortable.

chapter. For pain management at the end of

3. Analgesics should be prescribed accord-

life, see Chapter 29. For pain management in

ing to pain intensity as evaluated by a scale

patients with sickle cell disease, see Chapter 3.

of intensity of pain. The prescription must

be given according to the level of the

The World Health Organization

patient’s pain and not according to the

analgesic ladder

medical staff’s perception of the pain.

4. Dosing of pain medication should be

1986 the World Health Organization

adapted to the individual. The correct dos-

presented the analgesic ladder as a

age is one that will allow adequate relief of

Handbook of Pediatric Hematology and Oncology: Children’s Hospital & Research Center Oakland,

Second Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.

2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

Acute Pain Management in the Inpatient Setting

257

STEP 4

Neurosurgical

procedures

Nerve block

Epidurals

STEP 3

PCA pump

Acute pain

Neuroly c block therapy

Chronic pain without control

Strong opioids

Spinal s mulators

Acute crises of chronic pain

Methadone

STEP 2

Oral administra on

Transdermal patch

Weak opioids

STEP 1

Chronic pain

Non-malignant pain

Nonopioid

Cancer pain

analgesics

NSAIDs

(with or without adjuvants

at each step)

Figure 28.1 Adaptation of the World Health Organization analgesic ladder. Abbreviations: NSAID,

non-steroidal anti-inflammatory drug; PCA, patient-controlled analgesia.

pain. The dosing should be adapted to

on the best method of assessment have

achieve the best balance between the anal-

made its measurement a challenge. As a

gesic effect and the side effects.

result, a variety of pediatric pain assessment

5. Analgesics should be prescribed with a

scales have been developed to assist in this

constant concern for detail. The regularity

process.

of analgesic administration is crucial for the

adequate treatment of pain.

Neonates and infants

The Neonatal Infant Pain Scale

(NIPS),

It is important to remember that these are

developed at the Children’s Hospital of

guidelines and that there are situations

Eastern Ontario, is a widely used method

where a stepwise approach to pain is not

of assessing pain in this patient population.

the best choice for management. For exam-

It evaluates a series of six parameters, with a

ple, management of sickle cell vaso-occlusive

range of scores between 0 and 7. Scores

crises typically involves early introduction of

above 3 are considered indicative of a pain

step 3 medications without waiting for the

level sufficient to require intervention. The

patient to fail step 1 and 2 therapies.

scale is presented in Table 28.1. Its major

limitation is that it may underestimate the

level of pain in infants who are too ill to

Assessment of pain

respond appropriately or are receiving a

paralyzing agent.

The accurate and reproducible assessment

of pain is essential to effective management,

Preverbal/Nonverbal children

allowing the provider to determine when

Pain assessment for children who are unable

intervention is necessary and to more

to describe their pain or use an interactive

objectively measure the response to inter-

pain assessment scale due to young age,

vention. However, the subjective nature of

cognitive dysfunction, injury, or medical

pain and the impact of developmental stage

interventions such as intubation requires

258

Chapter 28

Table 28.1 The Neonatal Infant Pain Scale (NIPS).

Parameter

0 points

1 point

2 points

Facial expression

Relaxed

Contracted/grimacing

Cry

Absent

Mumbling

Vigorous

Breathing patterns

Relaxed

Different than basal

Arms

Relaxed

Flexed/stretched

Legs

Relaxed

Flexed/stretched

State of arousal

Sleeping/calm

Uncomfortable

an alternative similar to the NIPS that allows

School aged and older children

the subjective evaluation of pain-related

Children 5 years of age and older have been

behaviors by another individual. One of the

shown to have the ability to accurately rate

more commonly used assessment tools is

their level of pain using a numerical rating

the Face, Legs, Activity, Cry, Consolability

scale. A commonly used tool is the Wong-

(FLACC) Behavior Scale. Developed at the

Baker FACES scale, presented in Figure 28.2.

University of Michigan as a tool to assess

Developed in the early 1980s, it remains one

postoperative pain, it has been shown to

of the most widely used tools for assessing

reliably measure pain in a variety of clinical

pain in both children and adults.

situations. It is presented in Table 28.2. The

range of possible scores is from 0 to 10,

When pain assessment scales are used

consistent with other commonly used

appropriately they can be very valuable in

numerical rating scales used for older

helping the care team know whether their

children.

pain management interventions are

Table 28.2 The Face, Legs, Activity, Cry, Consolability (FLACC) Scale.

Parameter

0 Points

1 Point

2 Points

Face

No particular expression Occasional grimace, or

Frequent to constant

or smile

frown, withdrawn or

frown, clenched jaw,

disinterested

quivering chin

Legs

Normal position or

Uneasy, restless, or tense Kicking or legs drawn up

relaxed

Activity

Lying quietly, normal

Squirming, shifting back Arched, rigid, or jerking

position, moves easily

and forth, or tense

Cry

No cry

Moans, whimpers, or

Crying steadily, screams

occasional complaint

or sobs, frequent

complaints

Consolability Content, relaxed

Reassured by occasional

Difficult to console or

touching, hugging, or

comfort

being talked to;

distractible

Acute Pain Management in the Inpatient Setting

259

No pain

Li le pain

Mild pain

Moderate pain Severe pain

Worst pain

Figure 28.2 The Wong-Baker FACES Pain Rating Scale.

appropriate or need to be adjusted. How-

age. Hepatic enzymes are initially immature,

ever, there is no “magic number” that indi-

but these mature quickly. Children 2 to 6

cates when interventions need to be initi-

years of age develop a larger relative hepatic

ated. Studies consistently show that there is

size for weight and often metabolize drugs

little correlation between a child’s pain score

more quickly than younger or older chil-

and their perception as to whether or not

dren; this can translate to a need for larger

they need pain medication. Therefore, in

doses of drug given more frequently to

situations where patients are likely to have

achieve adequate analgesia. Variations in

pain, it is essential to question them regu-

age, weight, blood flow, and organ function

larly regarding their need for medication.

can all affect effective drug dosing.

Step 1 therapy: nonopioid

Pain pharmacology

analgesics

Drugs that are commonly used for step 1

Pain can be subdivided into two categories,

therapy of pain in children are presented in

nociceptive and neuropathic. Acute pain in

Table 28.3. These should be first-line therapy

children is most often nociceptive, and a

for pain unless the clinical situation dictates

variety of drugs can be used to treat this pain.

that therapy should begin at a higher step.

Much of the information regarding this ther-

The use of NSAIDs in children with can-

apy is empiric, as there are few formal drug

cer is generally discouraged due to the com-

studies for many of these agents, especially in

mon occurrence of thrombocytopenia in this

children less than

12. Nonsteroidal anti-

population and concern for an increased risk

inflammatory drugs (NSAIDs), opiates, mus-

of bleeding due to an inhibition of platelet

cle relaxants, local anesthetics, and tramadol

function. However, there have been no large,

can be used. Some other adjuvant therapies

controlled trials demonstrating the validity of

can also be utilized, such as psychological

this concern. Several clinical trials have dem-

intervention, distraction, and biofeedback.

onstrated that ibuprofen can safely be used

When treating pain in neonates it is

following dental surgery, tonsillectomy, and

important to remember that several factors

neurosurgery in healthy children and in vitro

can modify their response and clearance of

data suggest that ibuprofen causes no signif-

drugs. They have increased body water con-

icant prolongation of the platelet function

tent and decreased fat, which can alter drug

assay PFA-100.

distribution. A relative increase in blood

flow to the brain and a somewhat “leaky”

Step 2 therapy: weak opioids

blood-brain barrier can cause a prolonga-

Patients whose pain is inadequately con-

tion of drug effect. Renal clearance of drugs

trolled with step 1 therapy or who are being

can be relatively decreased up to 1 year of

weaned from step

therapy require

260

Chapter 28

Table 28.3 Step 1 pain therapy medications.

Drug

Dose

Comments

Ibuprofen

1-3 months: 5 mg/kg 3-4 times daily

* Block conversion of arachi-

3 months-1 year: 50 mg 3 times daily

donic acid into prostaglan-

1-4 years: 100 mg 3 times daily

dins and thromboxanes

4-7 years: 150 mg 3 times daily

* Nonselective; variably impair

7-10 years: 200 mg 3 times daily

platelet function

10-12 years: 300 mg 3 times daily

* Ketorolac can affect renal

12-18 years 300-400 mg 3 times daily

function or bone growth with

Maximum dose 30 mg/kg/day; 2.4 g/day

prolonged use

Naproxen

5 mg/kg/dose 2 times daily

Maximum dose 15 mg/kg/day

Ketorolac

0.5 mg/kg/dose IV/IM every 6 hours

Maximum dose 30 mg

Maximum 20 doses

Acetaminophen

15 mg/kg/dose every 4-6 hours

* Has no antiplatelet effect

Maximum 5 doses/day; maximum 4 g/day

* Can be hepatotoxic

* Avoid rectal dosing in neu-

tropenic patients

* Parenteral form recently

licensed in United States

Abbreviations: IV, intravenous, IM, intramuscular.

treatment with step 2 agents. In the United

Step 3 therapy: strong opioids

States, the most common agents used are

Patients not responding to step 2 therapy or

those that combine acetaminophen with

whose condition indicates the need for

a weak opioid. These include codeine or

stronger pain therapy at the outset are can-

hydrocodone, although there is some dis-

didates for step 3 therapy. All of the med-

agreement about the inclusion of hydroco-

ications in this category are strong opioids.

done in the weak opioid category.

They act by binding to m-receptors in the

Commonly used agents in this category are

spinal cord and central nervous system

presented in Table 28.4.

(CNS). These receptors are also found

It is important to remember that the

throughout the body, and binding to

designation “weak opioid” does not translate

peripheral sites accounts for many of the

to “without side effects.” The use of codeine

side effects seen with opiate therapy.

and hydrocodone can cause the same side

Opioids vary both by their duration of

effects seen with stronger opioids: respiratory

action and by the emotional effect they

depression, hypoxia, nausea, vomiting, pru-

produce. Meperidine and oxycodone typi-

ritus, constipation, physical tolerance, and

cally cause euphoria; conversely, morphine

dependence. Although the Food and Drug

more commonly causes dysphoria. Equiva-

Administration

(FDA) classifies them as

lent doses of the strong opioids and the

Schedule III medications, the risks of abuse

pharmacokinetics of their oral formulations

and diversion still exist.

are presented in Table 28.5.

Acute Pain Management in the Inpatient Setting

261

Table 28.4 Step 2 pain therapy medications.

Drug

Dose

Comments

Codeine

0.5-1 mg/kg q4-6 hour

* Comes as 30 and 60 mg tablets

Max: 60 mg/dose

* Up to 35% of children are

inefficient metabolizers of

codeine to morphine; they

will achieve minimal benefit

from this product

Acetaminophen with

0.5-1.0 mg/kg/dose of codeine

* Tablet: 300 mg/15 mg, 300 mg/

codeine

q4-6 hour

30 mg

Max: 2 tablets/dose; 15 mL/dose

* Liquid: 120 mg/12 mg per 5 mL

* Up to 35% of children are

inefficient metabolizers of

codeine to morphine; they

will achieve minimal benefit

from this product

Acetaminophen with

>2 years: 0.135 mg/kg/dose hydro-

* Tablet: 5 mg/500 mg

hydrocodone

codone

* Liquid: 7.5 mg/500 mg per

<40 kg: do not exceed 5 mg hydro-

15 mL

codone per dose

* Elixir contains 7% alcohol

>40 kg: do not exceed 7.5 mg

hydrocodone per dose

Oral starting doses of step 3 medications

to deal with postchemotherapy mucositis

are presented in Table 28.6. It is important

or sickle cell vaso-occlusive crisis. Rather, it

to remember that patients with severe

refers to long-term, ambulatory PCA pump

chronic pain will often be on doses much

use for severe chronic pain. With the

larger than this due to tolerance. Tactics

increased availability of highly concen-

such as narcotic substitution can be used to

trated oral narcotics and novel delivery

deal with tolerance or with side effects

systems, the use of home PCA therapy has

resulting from large doses. However, these

declined significantly. Additional step

steps should be performed under the guid-

therapies include nerve blocks, epidural

ance of individuals who are well versed in

injections, and other alternative interven-

such measures. Transdermal fentanyl has

tions routinely provided by a specialized

not been included; practitioners familiar

pain service.

with its usage should transition patients

to this agent when deemed necessary.

Nonpharmacologic

Step 4 therapy

approaches to pain

As can be seen in Figure 28.1, step 4 therapy

does not introduce new medications.

The effectiveness of psychological interven-

Patient-controlled analgesia (PCA) pumps

tions to decrease the perception of pain

are listed; this does not refer to short-term

and the anxiety associated with it, and to

PCA pump use such as following surgery or

improve the quality of life in patients

Acute Pain Management in the Inpatient Setting

263

Table 28.6 Step 3 oral pain therapy medications.

Drug

Oral dose

Comments

Oxycodone

* Instant release: 0.05-0.15 mg/kg/

dose up to 5 mg/dose q4-6 hour

* Sustained release: for patient

taking >20 mg/day of oxycodone

can administer 10 mg q12 hour

Morphine

* 0.3-0.6 mg/kg/dose every 12 hours

* Injection (mg/mL): 1, 2, 4, 5, 10

for sustained release

* Injection, preservative free

* 0.2-0.5 mg/kg/dose q4-6 hour prn

(mg/mL): 1, 5

for immediate release tablets or

* Oral solution (mg/mL): 2, 4, 20

solution

* Tablet (IR) (mg): 10, 15, 30

* Tablet (ER) (mg): 15, 30, 60,

100, 200

Hydromorphone

0.03-0.08 mg/kg/dose PO q4-6

hour; max: 5 mg/dose

Methadone

0.03-0.08 mg/kg/dose PO q4-6

hour; max: 5 mg/dose

Abbreviations: IR, immediate release; ER, extended release.

with chronic pain, has been clearly demon-

quality of life in patients with sickle cell

strated in a number of clinical settings.

disease.

These include:

* Minimizing postoperative pain and anx-

It is vital that child-life workers become

iety through the use of preoperative inter-

involved with children admitted with a pos-

ventions before painful procedures. These

sible diagnosis of cancer very shortly after

include the explanation of the event in

admission. Data indicate that psychological

developmentally appropriate terms, mini-

interventions are most effective in decreas-

mizing wait times once the patient arrives in

ing anxiety related to painful procedures

the operating room, child-friendly waiting

when initiated before the first painful expe-

spaces, and cognitive-behavioral therapies

rience. It is also important to obtain input

(CBT) such as directed imagery, deep

from a psychologist early on for children

breathing, and role playing. These interven-

with conditions causing chronic pain so that

tions are typically provided and coordinated

appropriate interventions can be started.

by the child-life program.

* The use of CBT, relaxation therapy, and

biofeedback to decrease the perception of

Suggested Reading

pain among children suffering from chronic

pain caused by cancer, headache, and

Friedrichsdorf SJ, Kang TI. The management of

abdominal pain.

pain in children with life-limited illnesses.

* The use of CBT, relaxation, self-hypno-

Pediatr Clin N Am 54:645-672, 2007.

sis, biofeedback, and social support groups

Verghese ST, Hannallah RS. Acute pain manage-

to decrease painful episodes and improve

ment in children. J Pain Res 3:105-123, 2010.

Palliative Care

The World Health Organization defines

There is a role for palliative care for all

pediatric palliative care as care that “aims

children diagnosed with cancer, even those

to improve the quality of life of patients

whose cancers have an excellent prognosis

facing life-threatening illnesses, and their

with appropriate therapy. It also applies to

families, through the prevention and relief

the large number of children with life-

of suffering by early identification and treat-

threatening nononcologic conditions. The

ment of pain and other problems, whether

definition stresses the importance of “early

physical, psychosocial, or spiritual.” It is the

identification and treatment of pain and

active total care of the child’s body, mind,

other problems.” Palliative care is not syn-

and spirit, and also involves giving support

onymous with “end-of-life” care; palliative

to the family. It begins when illness is diag-

care must begin at the time of diagnosis and

nosed, and continues irrespective of

continue on throughout the period of dis-

whether or not a child receives disease-

ease-directed therapy. It also must include

directed treatment. It requires that health

many resources from throughout the

providers evaluate and alleviate a child’s

patient’s and family’s range of experience:

physical, psychological, and social distress

physicians, nurses, social workers, psychol-

at all times during their treatment. To be

ogists, spiritual counselors, and a variety of

effective, it requires a broad multidiscip-

other support personnel chosen because of

linary approach that includes the family and

each child’s unique situation. During any

makes use of available community

hospitalization, an important responsibility

resources. However, it can be successfully

of the medical team is to ensure that

implemented even if community resources

each child has access to all needed services

are limited. Palliative care can and should be

and is being supported to the greatest

provided in tertiary-care facilities, commu-

extent possible.

nity health centers, and at home.

This definition contains several concepts

that deserve consideration. It contains the

Individualized care planning

broadly defined term “life-threatening” that

and coordination

includes situations in which a cure is pos-

sible, instead of the more limited “life-limit-

At the time of diagnosis, parents and care-

ing” that includes only those conditions for

givers of children with life-threatening ill-

which there is no realistic hope of cure.

ness have two goals: a care-directed goal of

Handbook of Pediatric Hematology and Oncology: Children’s Hospital & Research Center Oakland,

Second Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.

2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

Palliative Care

265

cure and a comfort-directed goal of decreas-

undergoing bone marrow transplantation,

ing suffering. Introducing palliative care

the model is useful in helping to define what

principles early on in the care process is

care options are acceptable to the patient and

respectful and supportive of these goals.

family given the prognosis and goals of treat-

A model developed by the Palliative and

ment. Key concepts in this model include the

End-of-Life Care Task Force at St. Jude

establishment of a close and caring relation-

Children’s Hospital, the Individualized Care

ship with the patient and family, clarifying

Planning and Coordination model is

patient and family values and priorities,

designed to facilitate this introduction

determining the goals of care based on the

(Figure 29.1). Although developed to assist

patient’s and family’s understanding of prog-

in making care decisions for children

nosis, and allowing them to choose from

Eligibility

Step 1 : Rela onship

Understanding

Sharing

illness

Relevant

Experience

Informa on

Needs assessment

Step 2 : Nego a on

Prognosis

Goals

Treatment

op ons

Step 3 : Plan

Medical plan

Life plan

Comperhensive

Care Plan

Ac on

(Care Coordina on)

Figure 29.1 The Individualized Care Planning and Coordination Model.

266

Chapter 29

available goal-directed treatment options.

totally clear. Studies have also demonstrated

From this foundation, the members of the

that significant levels of parental dissatisfac-

care team can coordinate the provision of

tion with hospital staff can arise from

care to ensure the social, psychological, and

confusing, inadequate, or uncaring commu-

emotional needs of the patient and family are

nication regarding treatment and prognosis

addressed at the same time that appropriate

as well as discrepancies between parents

medical care is provided.

and care providers in understanding the

terminal condition. When a language bar-

rier exists between family and staff, these

End of life care

problems are often exacerbated.

Despite the tremendous advances made in

the care of children with cancer over the past

Common symptoms at the end

50 years, at the present time one in five

of life

children diagnosed with cancer will ulti-

mately die of their disease. The death of a

Pain

child affects the physical and psychological

Parents and caregivers report that their

well-being of family members for the rest of

child’s pain is the symptom they fear most.

their lives. Events occurring around the time

A large survey of parents whose children

of death, both positive and negative, play a

died of cancer revealed that 75% of them felt

critical role in defining how family members

their child suffered pain at the end of life,

grieve and ultimately come to terms with

but only 37% felt the pain was successfully

the event. Families who have lost a child

managed.

have identified several needs regarding end-

The principles of pediatric pain manage-

of-life care. These include the need to have

ment are presented in Chapter 28 and pain

complete information honestly communi-

management at the end of life follows these

cated, to have easy access to essential staff

same principles. However, it becomes par-

members who will be supportive, to have

ticularly important to clarify and under-

assistance in coordinating necessary ser-

stand the goals of treatment as elucidated

vices, to have their relationship with their

by the patient and parents. The desire to

child maintained as much as possible, and to

maintain alertness and interaction early in

be allowed to feel that their child’s life and

treatment may give way to a desire to keep

death has meaning.

the patient comfortable, even if it means the

Research studies involving pediatric pal-

patient will be more sedated and less aware.

liative care are limited, but they have iden-

Acceding to the family’s wishes that the

tified several important shortcomings in the

patient not be hooked up to monitors might

level of palliative care provided to children.

outweigh concern that the doses of pain

Several studies have demonstrated a lack of

medications being used could result in

successful management of pain and other

respiratory depression. These decisions

distressing symptoms. Other studies have

often run counter to what physicians see

demonstrated that the majority of children

as their primary goal of care, to prolong life

dying of life-threatening diseases die in the

as long as possible. Working through some

hospital, often in the intensive care unit.

of these difficult philosophical issues with

The impact of this outcome on the appro-

the help of a mentor can be essential to

priateness of care provided and its effect on

working comfortably and effectively in this

the family’s bereavement process are not

type of setting.

Palliative Care

267

Nausea and vomiting

A stepwise approach to the management

Nausea and vomiting at the end of life can be

of nausea and vomiting in the palliative care

triggered by many different stimuli. A variety

setting is outlined in Table

29.1. A key

of toxins such as medications and their

feature of this approach is to ensure that

metabolites, urea resulting from renal failure,

the interventions selected are in keeping

or metabolic byproducts of hepatic failure

with the patient’s and family’s goals of care.

can all stimulate the chemoreceptor trigger

A number of medications can be tried to

zone and cause nausea. Increased intracranial

control nausea and vomiting. The ideal

pressure and a variety of emotional and

agent is one that targets the specific cause

sensory stimuli can mediate nausea and

of the patient’s distress if such an agent can

vomiting through cortical pathways. The

be identified. A list of useful medications is

gastrointestinal (GI) tract can stimulate the

outlined in Table 29.2.

vomiting center in response to local receptor

Opioids frequently cause nausea and

stimulation caused by obstruction, stasis,

vomiting due to a direct effect on the che-

toxins, or drugs. In addition, pharyngeal

motherapy trigger zone or secondarily to

stimulation by mucous or mucosal break-

their effect on GI motility leading to gastro-

down can also trigger the vomiting center.

paresis and constipation.

Table 29.1 Management of nausea and vomiting.

Step

Objective

Intervention

Attempt to identify causes

History (timing, quality, severity of nausea;

description of vomiting)

Physical exam focused on neurological, abdominal

symptoms

Medication history (opioids, chemotherapy, anti-

biotics, NSAIDs, other drugs)

Initiate environmental changes

Small meals

Minimize strong smells

Create a comfortable environment

Provide support for emotional distress

Clarify scope of interventions

Discuss goals of care with patient and family

that will be acceptable to

patient and family

Choose treatment based on

Chemically induced: stop medications if possible,

etiology and goals of care

opioid rotation if felt to be cause; antiemetics

Increased ICP: surgical treatment if possible (shunt

insertion, shunt revision), medical therapy

(steroids, antiemetics)

Obstruction/ileus: surgical management if consis-

tent with goals of care; medical management

(steroids, octreotide, opioids with scopolamine,

haloperidol)

Other/unknown cause: trial of antiemetics

Abbreviations: NSAIDs, nonsteroidal anti-inflammatory drugs; ICP, intracranial pressure.

268

Chapter 29

Table 29.2 Medications for treatment of nausea and vomiting.

Drug

Dose

Metoclopramide (prokinetic/

Prokinetic dose: 0.1 mg/kg/dose IV or orally every 6 hours

dopamine antagonist)

Dopamine antagonist (antiemetic) dose: 0.5-1 mg/kg/dose

IV or orally every 6 hours; use with diphenhydramine to

prevent extrapyramidal symptoms

Ondansetron (serotonin receptor

0.45 mg/kg/day IV or orally; may be dosed once daily or

antagonist)

divided every 8 hours

Scopolamine (anticholinergic)

For children >40 kg: 1.5 mg patch behind ear every

72 hours

Meclizine (antivertigo agent)

For children >12 years of age: 25-75 mg/day orally in up to

3 divided doses

Dexamethasone (anti-

Antiemetic: 10 mg/m² IV or orally daily; maximum dose

inflammatory)

20 mg daily

Increased ICP: increase dosing frequency to 2-4 times

daily, with a maximum dose of 40 mg/day

Octreotide (somatostatin analogue)

5-10 mg/kg/day (continuous 24-hour IV infusion or

divided twice daily subcutaneously)

Dronabinol (cannabinoid)

For children aged 6 years and older; 2.5-5 mg/m²/dose

every 4-6 hours. Not recommended for children who

have clinical depression

Lorazepam (benzodiazepine)

0.025 mg/kg/dose IV or orally every 6 hours

Abbreviations: IV, intravenous; ICP, intracranial pressure.

Constipation

intake of fluids and food, decreased physical

Constipation often causes pain and distress

activity, neurological dysfunction, and intes-

for children at the end of life, both physically

tinal obstruction due to presence of tumor.

and psychologically. Prevention of consti-

Assessment

pation should therefore be a primary goal of

History

end-of-life care.

One of the most common causes of

* Stool frequency, consistency, and associ-

constipation are opioids, which decrease

ated discomfort

GI motility and fluid secretion, leading to

* Abdominal pain, nausea, vomiting, and

hard, dry stools. Unlike other narcotic side

anorexia

* Neurological symptoms: urinary pro-

effects, constipation does not seem to

decrease with ongoing use. Patients and

blems, lower extremity numbness, weak-

ness, and paresthesias

families should be informed ahead of time

about this side effect, as children in severe

* Diarrhea

(sign of encopresis or

pain may not consider regular bowel move-

obstipation?)

ments a priority. Once well established,

* Prior episodes, previously effective

constipation may require quite aggressive

therapies

and unpleasant therapies to correct it.

Other factors that contribute to consti-

Physical Examination

pation in terminal patients include poor oral

* Abdominal palpation

Palliative Care

269

External rectal exam (digital exam rarely

Table 29.3 Appetite stimulants for cancer-

needed and may be dangerous)

associated anorexia.

* Neurologic exam

Drug

Dose

Medications

Cyproheptadine

2-6 year: 2 mg bid

* Stool softeners (docusate): rarely effective

(Periactin)

>6 year: 4mg bid

alone

Megestrol acetate

7.5-10 mg/kg/day in

* Osmotic agents (Miralax

, magnesium

(Megace)

1-4 divided doses

sulfate, and lactulose): effective for long-

Maximum 800 mg/day

or 15 mg/kg/day

term use; Miralax requires 4 to 8 oz. of fluid

Dronabinol

2.5 mg/m²/dose every

which can be a limitation

(Marinol)

4-6 hours

* Stimulants (senna, bisacodyl): often use-

Use with caution in

ful and necessary in the end-of-life setting

children with

when less concern exists regarding develop-

depression; avoid

ment of dependence

in children with

sensitivity to

Anorexia and weight loss

sesame oil

Anorexia or loss of appetite is a familiar

symptom in children with cancer. It can occur

at any point in treatment; institutional studies

Support for emotional distress

indicate that it affects as many as 40% of

Discontinue medications that might be

children with cancer at diagnosis and the pre-

causing anorexia

valence increases to as high as 70% in children

with advanced stage disease. Early in treat-

Step 3: more aggressive therapies

ment it is most often a side effect of chemo-

(if consistent with plan of care)

therapy or radiation, or a result of stomatitis,

Medications

(see Table 29.3)

dysphagia, constipation, pain, or depression.

As the child’s cancer becomes progressive,

Nutritional supplementation

If acceptable to patient and family, enteral

it is often a component of the anorexia/

feeding with a nasogastrostomy (NG) or

cachexia syndrome, a complex set of central

gastrostomy tube is often reasonably well

nervous system (CNS) and metabolic abnor-

tolerated unless the patient has a GI

malities caused by a combination of tumor

obstruction or is chronically nauseated.

byproducts and host cytokine release.

Total parenteral nutrition

(TPN) is

Step 1: assessment

rarely useful in the end-of-life setting except

State of primary disease

for short-term use in the patient with GI

Diet and fluid history

obstruction.

Nausea/vomiting/constipation

Oral lesions (including candidiasis)

Fatigue

The National Comprehensive Cancer Net-

Medication history

work defines cancer-related fatigue as “a dis-

History of prior eating disorder

tressing persistent, subjective sense of physi-

Sense of smell

cal, emotional and/or cognitive tiredness or

Step 2: environmental changes

exhaustion related to cancer or cancer treat-

Small meals

ment that is not proportional to recent activ-

Regular mouth care

ity and interferes with usual functioning.”

Comfortable environment

It is pervasive, multidimensional, and

270

Chapter 29

incapacitating; as such it significantly de-

associate their feelings of fatigue to sleep

creases health-related quality of life in chil-

disturbance or side effects of therapy

dren. While it can exist throughout the entire

whereas parents are more likely to include

period of cancer treatment, fatigue is most

emotions and nutritional status as potential

often seen as significant as the child’s disease

causes. A recent study suggested that pain

progresses. In several studies, parents have

and dyspnea were frequently associated with

identified fatigue as the most significant

fatigue; the authors postulated that opioids

symptom that moderately or severely im-

and benzodiazepines, common therapies for

pacted their child’s well-being toward the end

pain and dyspnea, might have significantly

of life. These same studies have also demon-

contributed to their patients’ fatigue.

strated that it is the symptom most likely to be

In a recent review on the assessment and

missed by care providers; fewer than 50% of

management of fatigue and dyspnea in pedi-

children whose parents described them as

atric palliative care, Dr. Christina Ulrich

suffering highly from fatigue had this docu-

defined a conceptual model for understand-

mented in their medical record.

ing fatigue in this population. This frame-

Cancer-related fatigue is more common

work is outlined in Figure 29.2.

and more severe in children with brain

Data are very limited regarding effective

tumors than in those with other cancers.

treatments for cancer-related fatigue in chil-

Pediatric patients tend more often to

dren, although a number of interventions

Psychosocial factors

• Depression

• Familial stressors

• Anxiety

• Spiritual concerns

• Fear

• Caregiver status

• Boredom

• Prac cal concerns

Sleep disturbance

• Unrelieved symptoms

• Change in environment

Fa gue experience

• Circadian rhythm altera on

• Medica on effect

Physical factors

• Underlying illness

• Metabolic abnormali es

Type, site, stage

• Nutri onal impairment

Disease-directed treatment

Cachexia

• Unrelieved symptoms

Dehydra on

• Side effects of symptom treatment

• Comorbidi es

• Changes in muscle

Anemia

Decondi oning

Infec on

Abnormal muscle structure, func on

Hormone imbalance

Organ dysfunc on

Figure 29.2 A model of fatigue in life-threatening illness.

Palliative Care

271

Table 29.4 Treatments for cancer-related fatigue.

Nonpharmacologic interventions

Pharmacologic interventions

Psychosocial

Stimulants

* Education

* Methylphenidate

* Support groups

* Modafinil

* Individual counseling

Antidepressants

* Coping strategies

* SSRIs

* Stress management training

Paroxetine

* Individualized behavioral intervention

Sertraline

Exercise

* Other antidepressants

Sleep therapy

Bupropion

* Behavioral therapy

Steroids

* Stimulus control

* Sleep restriction

* Sleep hygiene

Acupuncture

Abbreviation: SSRI, selective serotonin reuptake inhibitor.

have been shown to be effective in adults.

treatment is a key component of end-of-

These are outlined in Table 29.4.

life care.

Psychosocial and activity-based inter-

Dyspnea can result from either an

ventions have been shown to be quite effec-

increased metabolic demand or an inability

tive in adults with cancer-related fatigue;

to maintain a normal minute ventilation.

data in children are lacking. Exercise has the

The former can be caused by complications

strongest data regarding its value, but this is

of the disease or its treatment, such as

largely in adult cancer survivors suffering

infection, metabolic acidosis, or increased

from fatigue after the completion of curative

metabolic demands caused by extensive

therapy. Its utility in ameliorating fatigue in

tumor burden. The latter can result from

patients near the end of life is less well

conditions such as decreased lung compli-

established.

ance due to tumor, infection, or fluid, or by

other conditions such as interstitial lung

Dyspnea

disease, anemia, or fatigue.

Dyspnea is the term used to describe the

It follows that treatment of dyspnea

feeling of breathlessness that occurs when

would involve steps to decrease metabolic

the respiratory system fails to meet the

demand or improve the efficiency of respi-

body’s need for oxygen uptake or carbon

ration. However, this can prove to be quite

dioxide removal. It occurs under normal

challenging in practice. It is often difficult to

circumstances such as after brisk exercise,

determine whether the cause of dyspnea is

but in pathological conditions it can cause

in fact respiratory or metabolic, and once

severe distress. It occurs very frequently at

discovered, the unwillingness of the patient

the end of life, as respiratory failure occurs

or family to accept certain interventions can

very commonly as a terminal event. There-

create additional challenges for the treat-

fore, recognition of dyspnea and its effective

ment team.

272

Chapter 29

Appropriate therapies to decrease meta-

Support of respiration

bolic demand depend on the cause of the

When intubation and mechanical ventilation

increased demand. For the patient who

are not appropriate or acceptable to the

becomes dyspneic with activity, it may be

patient and family, noninvasive positive pres-

as simple as recommending that the patient

sure ventilation (NIPPV) can be useful in

use a wheelchair instead of walking or

supporting respiration. However, the use of

decrease physical activity in other ways.

NIPPV in adult patients who have elected to

Increased metabolic demand caused by

forgo intubation or other aggressive respira-

infection or inflammation can be treated

tory support is controversial. Its use in chil-

with aggressive use of antibiotics or anti-

dren with cancer is unstudied; there have been

inflammatory agents, as long as such ther-

a handful of papers published regarding its use

apies are in keeping with the patient’s and

in children with neuromuscular disorders.

family’s wishes.

From the adult literature, it appears clear

Respiratory failure can result from two

that the most important issue when deciding

general causes: lung parenchymal dysfunc-

on the use of NIPPV to support respiration is

tion and respiratory muscle fatigue or fail-

a clear understanding of the goals of therapy

ure. It is important to distinguish between

among all involved. In 2007, the Society of

these, as the treatments are different. An

Critical Care Medicine Palliative Noninva-

algorithm for distinguishing between these

sive Positive Pressure Ventilation Task Force

causes is presented in Table

29.5. It is

published its recommendations on the use

important to note that hypercarbia can be

of NIPPV in the palliative care setting.

a late finding in parenchymal dysfunction

While intended for adults, the concepts can

as well.

be applied to the pediatric care setting as well.

The Task Force proposed a three-category

Treatment

approach to assist in decision making regard-

Treatment for dyspnea can be divided into

ing this technology. An overview of this

three general categories: mechanical sup-

approach is presented in Table 29.6.

port of respiration, support of gas exchange,

The key areas of distinction in this model

and therapies to decrease the sensation of

are goals of care, determination of success,

dyspnea.

appropriate endpoints, and response to

Table 29.5 Classification and features of respiratory failure.

Parenchymal dysfunction

Muscle failure/fatigue

Causes

Airway obstruction

Neuromuscular disease

* Interstitial, bronchial inflammation

* Weak musculature

* Excessive secretions

* Lowered fatigue threshold

External compression

* Prolonged recovery time

* Pleural fluid

Abnormal load on respiratory system

* Pleural-based nodules

Weakness caused by systemic disease

* Infiltration of interstitium by

metastases

Blood gas

Hypoxemia

Hypoxemia, hypercarbia

findings

Palliative Care

275

failure. It is imperative that each member of

as well. The dose that is required is lower

the care team agrees on each of these com-

than what is commonly used for pain; a

ponents to avoid confusion and conflict

morphine dose of 0.025 mg/kg, or an equiv-

later in the course.

alent dose of fentanyl or Dilaudid, is often

effective in the narcotic-na€ıve child, and an

Support of gas exchange

increase in the dose by 25% will often be

NIPPV can also be used to augment gas

effective in the child already receiving mor-

exchange in patients with low lung volumes

phine. The dose should then be titrated to

in whom the surface area for gas exchange is

achieve symptom relief, with no set upper

reduced and the caliber of the airways is

limit. Benzodiazepines can help with the

decreased, increasing the likelihood of

anxiety associated with dyspnea; lorazepam

obstruction. Continuous positive airway

0.05 mg/kg (maximum 2 mg) can be given

pressure and bilevel positive airway pressure

every 4 to 8 hours for this purpose.

are useful in situations in which the pressure

A variety of nonpharmacologic interven-

necessary to maintain airway patency is too

tions have been shown to decrease the dis-

high to allow for efficient exhalation.

tress associated with dyspnea. These

In the setting of respiratory failure with-

include:

out hypercapnia, supplemental oxygen is

1. Cool air blown on the face

the most appropriate intervention to facil-

2. Chest wall percussion

itate gas exchange. It is often better tolerated

3. Relaxation therapy and counseling

than NIPPV devices, especially by young

4. Proper positioning

children, facilitating pulmonary vasculature

5. Limitation of activities

dilatation and inhibiting cerebral artery

6. Cooler room temperature

dilatation, a frequent cause of headaches.

7. Avoidance of respiratory irritants

It is important to remember, however, that

(tobacco smoke and cleaning fluids)

patients with hypercapnic respiratory fail-

ure frequently rely on a “hypoxic drive” to

Most experts agree that these work best as an

maintain respiration. Provision of supple-

adjunct to pharmacologic therapy; they are

mental oxygen to these patients can lead to

rarely effective alone.

hypopnea or apnea.

Therapies to decrease the sensation of

Conclusion

dyspnea

In end-of-life settings respiratory failure is

Unfortunately, many questions remain

often the ultimate cause of death and the

about how to best care for children who are

main goal of therapy is minimizing the

destined to die before they reach adulthood.

distress resulting from the sensation of dys-

These include practical issues such as how to

pnea as this occurs. This goal can be

best manage distressing symptoms such as

achieved with a combination of pharmaco-

those listed above, how to best communicate

logic and nonpharmacologic therapies.

with children about the dying process and

The two most effective classes of drugs

involve them in decisions regarding their

for minimizing the perception of dyspnea

care, and how to avoid aggressive end-of-life

are opioids and benzodiazepines. Morphine

therapies that only delay death and prolong

is the opioid used most often for this pur-

suffering instead of extending life. After the

pose, but fentanyl and hydromorphone

child’s death, families must continue to move

(Dilaudid) have been shown to be effective

forward, raising questions about how best to

276

Chapter 29

help them deal with the bereavement that

Questions

inevitably accompanies such an event. It is

* As Julie’s physician, are you comfortable

fortunate that research into these questions

with her parents’ approach?

has expanded greatly over the past few years,

* Should Julie’s parents prevent her from

and it is likely that answers to these questions

knowing information relevant to her

will soon be available in the medical litera-

disease?

ture. The children we care for, but cannot

* How do you reconcile your responsibility

save, deserve no less.

to be forthright with Julie while simulta-

neously being respectful of her parents’

request?

Case study for review

* If you believe that her parents’ approach

is not in Julie’s best interest, how might you

Julie, a 13-year-old girl with widely meta-

proceed?

static alveolar rhabdomyosarcoma diag-

* Should children with life-limiting ill-

nosed 6 months earlier continues to have

nesses be involved in end-of-life decisions?

extensive bony disease, including possible

new metastatic lung lesions. Julie’s treat-

Understanding familial adaptation toward

ment has been complicated by chronic

the dying process is imperative. As health-

pain and a challenging family situation.

care providers, our goal is to anticipate and

Although Julie lives with her mother, her

identify problems and to assist dying chil-

father oversees her care. Her parents do not

dren and their families as they adjust to and

get along with one another. They frequently

cope with the emotional responses, which

argue and scream in her presence, which

are part of the dying process.

clearly upsets her.

Many children, parents, and physicians

Since diagnosis, her father has adamantly

are hesitant to discuss death and dying so

refused to let caregivers have one-on-one

that opportunities for planning how to cope

conversations with Julie. He insists on

are often missed. Failure to prepare ade-

remaining the only one to relate to Julie

quately for death can deprive families of the

any disease-related information, as he

chance to enjoy what time they have left

knows her best and can gauge how she will

with one another.

react. He has stated that Julie need not know

Each child and family grieve in their own

that she will likely die of her disease and he

unique way, determined by personal experi-

has forbidden the medical team from dis-

ences with death, religious and cultural

cussing issues related to prognosis.

backgrounds, and individual makeup.

Julie is to undergo a CT-guided lung

Dying is a process and all parties need to

biopsy to determine the nature of the lung

learn to live with dying or, as stated by the

lesions. Her parents state that she is already

American Academy of Pediatrics, “the goal

anxious enough and do not want the med-

[of palliative care] is to add life to the

ical team to tell her about the biopsy or the

child’s years, not simply years to the child’s

possibility that her disease has progressed.

life” [1].

Instead, they ask that Julie be told that she is

Parents’ natural tendency to protect

to be sedated only for a “scan.” Moreover,

their children influences the amount of

should she prove to have new disease, they

information children receive and the degree

do not want Julie to be informed and ask

to which they are involved in decision

that her caregivers not discuss end-of-life

making about their care [2]. Some parents

matters with her.

feel that by giving their child a choice their

Palliative Care

277

responsibilities are being usurped, while

important to follow the child’s lead [11].

others perceive including their sick child

In other words, answer what children ask

in decisions as overly burdensome. For

and on their terms. Often, rather than being

many parents, the sicker their child, the

direct, a child’s question or statement may

more they assume decisional priority and

be suggestive of something they are uncom-

attempt to minimize, veto, or even preclude

fortable asking and therefore it is vital to

their child from having a role in decisions at

determine what their underlying intention

all. Seemingly, such an approach is under-

is and not to give too much or too little

standable; however, parents need to be

information or answer the wrong question.

aware of the consequences of not preparing

Finally, failure to inform and involve chil-

their children for medical outcomes that are

dren can lead to feelings of isolation and

inevitable, such as anxiety, stress, and

distress [12].

confusion.

Ideally, discussions should occur early

Children frequently know more about

and routinely and physicians should reassess

their disease than for which they are credited.

how the child and parents understand the

Even when kept in the dark by parents

plan and goals of care. This helps the dying

and providers, children often know that

child and parents make appropriate deci-

the endpoint of a life-threatening illness is

sions. Discussions should be in language

death [3-5]. As children appreciate certain

that parents and children can understand

facts about their diseases and know that they

and be presented gently, accurately, and

are dying, it stands to reason that they should

repeatedly. Doing so will help minimize

be involved in decisions about their care so

misunderstandings and defuse conflicts.

that they can voice their preferences [6,7].

The challenge is to do so in a way that is

Therefore, the question we ask ourselves

both sensitive and respectful of the child’s,

should not be “should I tell,” rather it should

parents’, and providers’ needs, needs that

be “how do I tell?” Increasingly, research

are often in conflict with one another.

supports the need for direct communication

According to the Institute of Medicine

between parents, physicians, and children

(IOM), “conflicts may . . . be productive or

with life-limiting illnesses. This includes dis-

beneficial”

[11]. Confronted with a dis-

cussions relating to prognosis and even

agreement, parties tend to engage in a more

death [1,2,8,9]. Hinds et al. [10] found that

in-depth discussion allowing for a greater

children with life-limiting cancer between

appreciation of each other’s position, and,

ages 10 to 20 years were capable of partici-

in the process, each side may become more

pating in end-of-life decision making.

sensitive to the other’s values and concerns.

Physicians must be aware of the unique

Mack et al. [13] surveyed parents of

barriers to a child’s ability to participate in

children with cancer and found that par-

decision making as it relates to the dying

ents rated the quality of care provided by

process. The first question we must ask is,

physicians more favorably when physicians

“does this child have the ability to understand

communicated directly with children

that he/she is dying and what dying entails.”

(when appropriate). Similarly, in a survey

As children mature, their intellectual and

of more than 400 Swedish parents of chil-

emotional understanding of serious illness

dren who died of cancer, Kreicbergs

and the prospect of death matures too.

et al. [14] found that none of the parents

Discussions about death should be honest

who spoke with their child about death

and take into consideration the child’s

regretted doing so, whereas more than

emotional and developmental level. It is

one-quarter of parents who did not speak

278

Chapter 29

with their child regretted not doing so. The

consider temporary steps that accommo-

latter parent group had higher levels of

date each party’s goals, and (3) periodically

anxiety and depression than parents who

reevaluate each party’s views concerning

did speak to their children.

the goals of care and the options to achieve

Parents are not alone in valuing the

those goals [11].

importance of direct communication

between children and physicians. Recent

research has shown that children with can-

Case resolution

cer consider direct communication

Since Julie’s diagnosis, her father has peri-

between doctors and children more impor-

odically sought the guidance of the unit’s

tant than any other aspect [15]. Nearly 40

social worker. Prior to the lung biopsy,

years ago, following parental approval,

Julie’s father agreed to meet with her

Nitschke et al. [4] began including children

oncologist and the social worker in the

aged 5 years and older who were near death

latter’s office, a place where he is comfort-

from cancer in end-of-life discussions.

able speaking. Following a brief update by

They found that the majority of children

the oncologist of Julie’s current medical

and parents found the child’s inclusion a

status, the social worker asked her father

positive experience. They also reported that

to share his concerns about Julie not being

some children from whom information

included in disease-related discussions. Her

was withheld experienced fear and isolation

father stated that Julie is “just a kid,” and

prior to dying.

that it was “his job to protect, and to decide

what is best for her.” He recounted his

Conclusions and practical

limited parental role in Julie’s life prior to

suggestions

her cancer diagnosis and blamed himself for

Situations like Julie’s do not lend themselves

not being more present in her life, admitting

to easy solutions. Dishonesty, evading the

that Julie’s illness and likely death “terrify”

question at hand, inconsistencies, and white

him and that he is resolute not to abandon

lies are to be avoided at all costs. Deception

her again.

is difficult to maintain. When the truth is

The social worker asked Julie’s father

ultimately discovered, the patient-parent-

what he believes she knows of her disease

physician relationship is often irrevocably

and its prognosis. He replied that Julie

damaged, an unfortunate circumstance in

knows she has cancer and that it is

any situation, but particularly for a child like

“treatable,” and nothing more. She then

Julie who is nearing the end of life. Such

asked if he would allow Julie to join them,

action may lead Julie to withdraw and even

which would permit the oncologist (in his

to experience feelings of isolation and fear,

presence) to answer any questions she may

let alone profoundly disrespect her devel-

have about the “scan” and to clarify what

oping autonomy.

she indeed knows. Hesitant at first, he

By helping to facilitate, clarify, and

ultimately agreed. After greeting and

resolve areas of contention, pediatricians

thanking her for joining them, the oncolo-

can be extremely helpful. As appreciated by

gist asked Julie if she has any questions

the IOM, the following steps may be useful:

about the upcoming CT scan. Julie asked

(1) postpone decisions to allow for time to

why she has to have another CT when

think about concerns and to discuss goals,

reevaluation scans, including a chest CT,

(2) rather than making definitive decisions

were just completed 1 week ago. Directing

that offer no room for compromise,

her words to the oncologist, Julie asked,

Palliative Care

279

“is something wrong?” Before the oncolo-

Freyer DR. Care of the dying adolescent: special

gist or her father could reply, Julie stated,

considerations. Pediatrics 113:381-388, 2004.

Himelstein BP, Hilden JM, Boldt AM, Weissman

“I’ve been online talking to other kids with

D. Pediatric palliative care. N Engl J Med

cancer. A few of them said that the only

350:1752-1762, 2004.

reason to repeat a scan so soon is to see

Kazak AE, Rourke MT, Alderfer MA, et al.

if the disease is back.” Without hesitation

Evidence-based assessment, intervention and

and still speaking to her oncologist, Julie

psychosocial care in pediatric oncology: a

said, “I know that most kids with my kind of

blueprint for comprehensive services across

cancer die.”

treatment. J Pediatr Psychol 32:1099-1110,

The social worker encouraged Julie and

2007.

her father to speak openly and freely. Ten-

Liben S, Papadatou D, Wolfe J. Paediatric palli-

tatively, and with the support of the oncolo-

ative care: challenges and emerging ideas.

Lancet 371:852-864, 2008.

gist and social worker, they began to speak

Wolfe J, Grier HE, Klar N, et al. Symptoms and

to one another and share their respective

suffering at the end of life in children with

concerns and goals. Following their conver-

cancer. N Engl J Med 342:326-333, 2000.

sation, Julie’s father cautiously agreed to

include Julie in future discussions. The

oncologist assured both Julie and her father

References

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on Bioethics and Committee on Hospital

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Hilden JM, Watterson J, Chrastek J. Tell the

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anced and honest perspective, and commu-

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nicate frequently and consistently.

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We would like to acknowledge and thank

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Yoram Unguru, MD, MS, MA, for writing

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this case and instructor guide. Dr. Unguru is

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an attending physician in the Division of

for Infants, Children, and Adolescents: A

Pediatric Hematology/Oncology, The Her-

Practical Handbook. Baltimore: JHU Press,

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2004.

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pediatric palliative care: a foundation for

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Chapter 29

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ical Experience of the Child with a Life-

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et al. Talking about death with children who

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125:e876-e883, 2010.

Chemotherapy Basics

Chemotherapeutic agents have multiple

Erwinia (Erwinase

). Asparaginase is a nat-

mechanisms of action and many potential

urally occurring enzyme produced by many

side effects. In order to be prepared for the

microorganisms. In the L- and PEG-aspar-

potential complications, we discuss the most

aginase forms, the enzyme is produced by

common pediatric agents, their mechanisms

Escherichia coli, whereas the Erwinia form

of action, the types of malignancies for which

is produced by Erwinia chrysanthemi. PEG-

they are utilized, and finally, the most likely

asparaginase is a modified form of L-aspar-

side effects. We discuss how best to monitor

aginase with a much longer half-life resulting

for these adverse events, and how to manage

from its covalent binding to PEG, allowing

them should they occur. Note that side effects

the same therapeutic effect from fewer doses.

from chemotherapy are numerous and we

Intramuscular asparaginase is the current

detail some of the more common ones rather

standard of care due to concerns about severe

than provide a comprehensive list; further

anaphylaxis with intravenous (IV) use; how-

reading may be required in appropriately

ever, two current Children’s Oncology

diagnosing and managing a patient. Emeto-

Group (COG) protocols are investigating the

genic potential of common pediatric agents is

safety and efficacy of IV PEG-asparginase.

included in Chapter 25. The majority of

Less frequent dosing with PEG-asparaginase

agents are dosed depending on the patient’s

is important for patient comfort and con-

body surface area (BSA) rather than weight,

venience until intravenous asparaginase

especially for patients older than 1 year of

becomes more widely accepted. Since Erwi-

age. Multiple formulas exist for the calcula-

nia is produced by a different microorgan-

tion of BSA; we prefer the Mosteller formula:

ism, it is immunologically distinct and can be

utilized in patients that have had a hyper-

rffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffifi

HeightðcmÞ WeightðkgÞ

sensitivity reaction to the E. coli forms.

BSA ¼

3600

Mechanism of action

L-asparagine is a nonessential amino acid

Asparaginase

that cannot be synthesized by malignant cells

of lymphoid and myeloid origin. Asparagi-

Asparaginase comes in three forms: L-

nase depletes L-asparagine from leukemic

asparaginase (Elspar

), polyethylene glycol

cells by catalyzing the conversion of

(PEG)-asparaginase

(Oncaspar

and

L-asparagine to aspartic acid and ammonia.

Handbook of Pediatric Hematology and Oncology: Children’s Hospital & Research Center Oakland,

Second Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.

2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

282

Chapter 30

Utilized in

Acute lymphoblastic leukemia

Germ cell tumors

Acute myelogenous leukemia

Hodgkin lymphoma

Non-Hodgkin lymphoma

Side effects, monitoring, and

treatment

Side effects, monitoring, and

Bleomycin can cause infusional fever and

treatment

chills followed later by mucositis, as well as

The most immediate side effect from aspar-

pruritus and excoriation leading to hyper-

aginase compounds is an allergic reaction

pigmentation. Raynaud’s phenomenon can

that can range from local irritation to ana-

also commonly occur later, especially with

phylaxis. Patients should be monitored

combination chemotherapy. Patients may

closely for at least

hour after Elspar

occasionally complain of rash, dysgeusia,

injection, and 2 hours following Oncaspar

and anorexia. Due to the formation of

injection. Based on the level of allergic

oxygen-free radicals, patients are at risk for

symptoms, treatment can range from an

dose-dependent pneumonitis and rarely

antihistamine such as diphenhydramine to

pulmonary fibrosis and therefore should

treatment of anaphylaxis with steroids, an

be monitored with pulmonary function

antihistamine, an H₂ blocker (i.e., raniti-

testing, especially carbon monoxide-diffus-

dine), and epinephrine. A common later

ing capacity (PFT/DLCO). An anaphylac-

side effect is coagulopathy secondary to

toid-type reaction may also rarely occur.

decreased synthesis of antithrombin III

(ATIII), fibrinogen, and other clotting fac-

tors. Currently, routine monitoring of ATIII

Cisplatin/Carboplatin

and fibrinogen and repletion of low levels

are not recommended without clinical

Cisplatin was the first of the platinum-based

symptoms. Rare side effects that should

chemotherapeutic agents. Carboplatin has

be considered include pancreatitis, throm-

less severe side effects, in particular decreased

bosis, and seizures.

nephrotoxicity and ototoxicity. It is more

myelosuppressive, however.

Bleomycin

Mechanism of action

The platinum agents, like the alkylators,

Bleomycin is obtained as a mixture of

cause interstrand DNA cross-linking. In

antibiotics isolated from Streptomyces

addition, they bind to replicating DNA

verticillus.

causing single-strand breaks.

Mechanism of action

Utilized in

Bleomycin leads to the formation of oxy-

Brain tumors

gen-free radicals that cause single-strand

Germ cell tumors

and double-strand DNA breaks. In addi-

Hepatoblastoma

tion, bleomycin leads to cellular degrada-

Hodgkin lymphoma

tion of cellular RNA. Bleomycin is cell cycle

Neuroblastoma

specific, targeting the G2 and M phases, thus

Osteogenic sarcoma

inhibiting cell growth and division, espe-

Soft tissue sarcomas

cially in rapidly dividing cells.

Wilms tumor

Chemotherapy Basics

283

Side effects, monitoring, and

measurements of the glomerular filtration

treatment

rate and likely platinum dose reduction.

Infusional nausea and vomiting are common

as platinum agents have an extremely high

emetogenic potential. This is followed later

Cyclophosphamide/Ifosfamide

by myelosuppression. Electrolyte abnormal-

ities including hypokalemia, hypomagnese-

Cyclophosphamide (Cytoxan) and ifosfamide

mia, hypocalcemia, and hyponatremia are

are alkylating agents and structural analogues.

common and the patient may develop Fan-

They are related to nitrogen mustard.

coni syndrome (diminished reabsorption of

solutes by the proximal tubule resulting in

hypophosphatemia, metabolic acidosis, and

Mechanism of action

secondary hypokalemia). Nephrotoxicity

Cyclophosphamide and ifosfamide require

and ototoxicity

(high-frequency sensori-

conversion by the hepatic P450 system to

neural hearing loss) occur occasionally with

their active form that ultimately leads to

carboplatin but are more common and

the intracellular release of two compounds,

severe with cisplatin.

acrolein and phosphoramide mustard.

Ototoxicity must be monitored with

Phosphoramide mustard causes interstrand

serial audiograms during therapy. Due to

DNA cross-linking.

the risk of electrolyte abnormalities, chem-

istry panels including magnesium should be

Utilized in

followed daily while receiving platinum-

Acute lymphoblastic leukemia

based therapy. In addition, due to the risk

Acute myelogenous leukemia

of nephrotoxicity, the patient’s intake and

Brain tumors

output should be followed closely and be

Ewing sarcoma

well-matched. If it appears the patient is

Germ cell tumors

developing a negative fluid balance, addi-

Hodgkin and non-Hodgkin lymphoma

tional fluids should be provided. If the

Neuroblastoma

patient develops a positive fluid balance,

Osteogenic sarcoma

mannitol should be used to increase urine

Soft tissue sarcomas

output. Renal function should be moni-

Wilms tumor

tored closely, as a reduction in the glomer-

ular filtration rate will necessitate a dose

reduction. In general, for pediatric patients

Side effects, monitoring, and

with no previous history of nephrotoxicity,

treatment

serum creatinine can serve as a measure of

Cyclophosphamide and ifosfamide com-

renal function utilizing the Cockcroft-Gault

monly cause nausea, vomiting, and anorexia

equation:

with drug infusion. Myelosuppression, im-

munosuppression, and alopecia are common

later adverse effects. Sterility is dose depen-

Estimated creatinine clearance

dent

(greatest with cumulative doses of

Age½years Þ MassðkgÞ

½0:85ðif femaleÞ

¼ð¹⁴⁰

cyclophosphamide >7.5 g/m²) and occurs

serum creatinineðmg=dLÞ

more commonly in pubertal males (though

prepubertal males and females are also at

Decrease in the estimated creatinine

risk). Due to the risk of nephrotoxicity,

clearance should lead to more formal

particularly with ifosfamide, patients should

284

Chapter 30

be well-hydrated prior to and after infusion.

cycle specific, killing cells during synthesis

Though the syndrome of inappropriate

(S phase); it therefore specifically targets

diuretic hormone (SIADH) is rare, patients

rapidly dividing cells.

should be monitored for appropriate urine

output by following their intake and output

Utilized in

as well as urine specific gravity. Electrolytes

Acute lymphoblastic leukemia

are also routinely followed for hyponatremia.

Acute myelogenous leukemia

If there are signs of fluid retention, the patient

Hodgkin and non-Hodgkin lymphoma

should initially be given increased hydration

followed by diuresis with furosemide or

Side effects, monitoring, and

mannitol if hydration is ineffective.

treatment

Excretion of acrolein into the urine can

Cytarabine commonly causes nausea,

cause hemorrhagic cystitis. The addition of

vomiting, and anorexia immediately after

MESNA for bladder protection when the cyclo-

infusion. Later, myelosuppression, stomati-

phosphamide dose exceeds 1.0 g/m²/day has

tis, and alopecia are common. Although not

significantly decreased the frequency of this

common, the patient should be monitored

adverse event. MESNA specifically binds to

for Ara-C syndrome that includes fever,

acrolein and other toxic metabolites in the

myalgias, bone pain, malaise, conjunctivitis,

urine to detoxify them and protect the bladder

maculopapular rash, and occasionally chest

wall. The urine should be monitored for the

pain. High-dose IV cytarabine requires pro-

presence of occult blood during and after in-

phylaxis with dexamethasone eye drops to

fusion and, if positive, should be examined

prevent conjunctivitis. A flu-like syndrome

microscopically. If red blood cells are noted

with fever, chills, and rash occurs occasion-

on microscopy, hydration should be increased.

ally with cytarabine; infection must still be

Of note, MESNA can cause a false positive test

ruled out with bacterial cultures. Streptococ-

for ketones on urine dipstick. Finally, metab-

cus viridans sepsis and acute respiratory

olism of ifosfamide leads to formation of chlor-

distress syndrome are possible after high-

oacetaldehyde, a byproduct thought responsi-

dose cytarabine, therefore the addition of

ble for nephrotoxicity as well as the neurotox-

vancomycin with fever or clinical deterio-

icity seen occasionally with ifosfamide (som-

ration should be strongly considered. Intra-

nolence, depressive psychosis, and confusion).

thecal (IT) cytarabine similarly can cause

Thiamine prophylaxis may have benefit in a

fever, nausea, and vomiting in addition to

patient with prior neurotoxicity.

headache. More serious and immediate side

effects including arachnoiditis, somnolence,

meningismus, convulsions, and paresis are

Cytarabine (Ara-C)

rare but should be considered as clinically

indicated.

Cytarabine, also known as cytosine

arabinoside or Ara-C

(arabinofuranosyl

cytidine), is utilized in the treatment of

hematologic malignancies.

Dactinomycin (Actinomycin-D)

Mechanism of action

Dactinomycin is an antibiotic compound

Cytarabine is an antimetabolite that inhibits

isolated from Streptomyces parvullus, similar

DNA polymerase. In addition, it is cell

to the anthracycline class.

Chemotherapy Basics

285

Mechanism of action

rather than an alcohol. Idarubicin lacks a

Dactinomycin intercalates with DNA, inhi-

methoxy group which increases its lipophi-

biting RNA and DNA synthesis. In addition,

licity as compared with other anthracyclines.

dactinomycin interacts with topoisomerase,

which is required for DNA replication, and

Utilized in

leads to single-strand DNA breaks.

Acute lymphoblastic leukemia

Acute myelogenous leukemia

Utilized in

Hepatoblastoma

Soft tissue sarcomas

Hodgkin and non-Hodgkin lymphoma

Wilms tumor

Neuroblastoma

Osteogenic sarcoma

Soft tissue sarcomas

Side effects, monitoring, and

Wilms tumor

treatment

Infusional nausea and vomiting are com-

mon, followed later by alopecia and mye-

Side effects, monitoring, and

treatment

losuppression. Anorexia, fatigue, diarrhea,

Anthracyclines commonly cause nausea and

and mucositis also occur occasionally.

vomiting with treatment. Due to the color of

Radiation recall can occur in patients who

the infusion, the patient should be warned

previously received radiation therapy.

that urine, saliva, tears, and sweat may all

have a pink or red coloring. After treatment,

Daunorubicin/Doxorubicin/

myelosuppression, alopecia, and mucositis

Idarubicin

commonly occur. Due to the production

of free radicals during electron reduction

Daunorubicin and doxorubicin are both

of anthracyclines, patients are at risk for

anthracycline antibiotics isolated from

dose-dependent cardiotoxicity occurring as

Streptomyces species (S. coeruleorubidus and

a late finding. Echocardiographic monitor-

S. peucetius, respectively). Idarubicin is an

ing is required during and after treatment at

analogue of daunorubicin used less com-

regular intervals based on the total anthra-

monly in pediatric oncology.

cycline dose received as well as concomitant

radiation therapy to the chest. Cardioprotec-

Mechanism of action

tion with continuous versus rapid infusion as

Anthracyclines as a group are cytotoxic to

well as agents such as dexrazoxane remains

malignant cells due to nucleotide base inter-

controversial and is not yet routinely recom-

calation and cell membrane lipid-binding

mended. Dexrazoxane may have benefit

activity. Nucleotide intercalation inhibits

when patients receive high cumulative doses

replication as well as DNA and RNA poly-

of anthracyclines (i.e.,

300 mg/m²). Addi-

merases. The anthracyclines also interact

tionally, anthracyclines provide different

with topoisomerase II, which is vital for

cumulative toxicity, and dose conversion

DNA replication. Cell membrane binding

based on doxorubicin isotoxic dose equiva-

affects a variety of cellular functions. In addi-

lents must be performed as below:

tion, electron reduction of the anthracyclines

Doxorubicin: multiply total dose

produces free radicals leading to DNA dam-

Daunorubicin: multiply total dose

0.833

age and lipid peroxidation. Daunorubicin

Epirubicin: multiply total dose

0.67

differs from doxorubicin structurally as the

Idarubicin: multiply total dose

side chain terminates in a methyl group

Mitoxantrone: multiply total dose

286

Chapter 30

Radiation recall is also a potential rare

Mechanism of action

complication of anthracyclines when given

Imatinib is a selective inhibitor of the tyro-

after radiation therapy.

sine kinase activity of the BCR-ABL fusion

protein, a product of the Philadelphia chro-

mosome (reciprocal translocation of chro-

Etoposide

mosome 9 and 22) seen mainly in chronic

myeloid leukemia and rarely with acute

Etoposide is derived from podophyllotoxin,

lymphoblastic leukemia.

a toxin found in the American mayapple.

Utilized in

Acute lymphoblastic leukemia (Philadelphia

Mechanism of action

chromosome-positive)

Etoposide binds to topoisomerase II, which

Chronic myelogenous leukemia

is vital for DNA replication, leading to DNA

strand breakage. Etoposide is cell cycle spe-

Side effects, monitoring, and

cific and appears to act mainly on the G2

treatment

and S (synthesis) phases, thus targeting

Imatinib has multiple potential side effects.

rapidly dividing cells.

Common immediate effects include fluid

retention, nausea, and diarrhea. Later com-

Utilized in

mon effects include fatigue, muscle cramps,

Acute myelogenous leukemia

rash, arthralgias, and myelosuppression.

Brain tumors

Ewing sarcoma

Germ cell tumors

Irinotecan

Hodgkin and non-Hodgkin lymphoma

Hemophagocytic lymphohistiocytosis

Irinotecan is a semisynthetic analog isolated

Neuroblastoma

from the plant alkaloid Camptotheca

Osteogenic sarcoma

acuminata.

Soft tissue sarcomas

Wilms tumor

Mechanism of action

Irinotecan in its active form is a potent

Side effects, monitoring, and

inhibitor of topoisomerase I which is vital

treatment

for DNA replication. Inhibition of topo-

Infusional nausea and vomiting is common

isomerase inhibits replication and also leads

followed by myelosuppression and alopecia.

to DNA damage.

Although rare, the patient should be mon-

itored closely for hypotension and anaphy-

Utilized in

laxis during the infusion. In addition to

Brain tumors

fluid support, the infusional rate can be

Hepatoblastoma

slowed if the patient develops hypotension.

Soft tissue sarcomas

Side effects, monitoring, and

Imatinib (Gleevec )

treatment

Patients receiving irinotecan can suffer from

Imatinib was the first successful targeted

cholinergic symptoms including intestinal

drug therapy for oncology patients.

hyperperistalsis that can lead to abdominal

Chemotherapy Basics

287

cramping and early diarrhea. Patients should

leukemia and dietary deficiency of folic acid

be monitored closely for early diarrhea; if

could improve leukemia symptoms.

it occurs loperamide should be given prior

to an anticholinergic (e.g., atropine). Other

Mechanism of action

cholinergic symptoms that may occur with

Methotrexate inhibits folic acid by prevent-

drug administration include rhinitis, in-

ing the reduction of folic acid by the enzyme

creased salivation, miosis, lacrimation, dia-

dihydrofolate reductase. This inhibition

phoresis, and flushing. Common later side

subsequently limits the synthesis of purines

effects include diarrhea, alopecia, transami-

and DNA. Some of the methotrexate meta-

nitis,

neutropenia,

mucositis,

and

bolites also lead to DNA damage.

hyperbilirubinemia.

Utilized in

Acute lymphoblastic leukemia

Mercaptopurine (6-MP)

Acute myelogenous leukemia

Brain tumors

Mercaptopurine is a purine analog.

Non-Hodgkin lymphoma

Osteogenic sarcoma

Mechanism of action

Mercaptopurine is converted into several

Side effects, monitoring,

active metabolites that inhibit RNA and DNA

and treatment

synthesis. As a purine analog it can also

Because of significant enterohepatic circula-

interfere with purine biosynthesis. Mercap-

tion of methotrexate, transaminitis is com-

topurine is converted to nucleotide metabo-

mon. Nausea, vomiting, and anorexia may

lites, some of which can lead to DNA toxicity.

also occur; therefore, oral doses are generally

given at bedtime. Many side effects of meth-

Utilized in

otrexate are due to delayed clearance after

Acute lymphoblastic leukemia

high-dose IV treatment. Aggressive hydration

Non-Hodgkin lymphoma

and alkalinization of fluids can improve renal

clearance. Drugs including trimethoprim-

Side effects, monitoring, and

sulfamethoxazole, penicillin, nonsteroidal

treatment

Mercaptopurine is generally well tolerated,

anti-inflammatories (NSAIDs), and proton

pump inhibitors (PPIs) can competitively

although myelosuppression occurs com-

monly. Mercaptopurine is usually adminis-

inhibit renal clearance and must be held

during high-dose therapy. Leucovorin

tered at night as patients may occasionally

complain of anorexia, nausea, and vomit-

(folinic acid) is used to decrease many of the

toxic effects of folic acid antagonists such as

ing. Many foods can decrease absorption

and therefore administration should be

methotrexate. Leucovorin can participate in

metabolic reactions requiring folic acid with-

separated from meals. Diarrhea and an ery-

thematous rash may also occasionally occur.

out the necessity of reduction by dihydrofo-

late reductase which is inhibited by metho-

trexate. This mechanism of action can also

Methotrexate

counteract the therapeutic effect of metho-

trexate; therefore, leucovorin should not be

Methotrexate was the first successful chemo-

started until 18 to 24 hours after the meth-

therapeutic agent utilized in children after

otrexate infusion has been completed. For

the observation that folic acid worsened

this reason, patients should be advised to not

288

Chapter 30

take folic acid supplements during metho-

Mechanism of action

trexate therapy as this may similarly reduce

Steroids have a variety of actions on the

efficacy.

body. Although not completely understood,

Urine pH should be monitored closely

steroids are thought to destroy lympho-

and kept above 7.5 during high-dose ther-

blasts by binding to the cortisol receptor

apy to facilitate renal excretion of metho-

found on lymphoid cells and specifically in

trexate. The patient’s intake and output

large number on lymphoblasts. Steroids are

should also be followed. Methotrexate levels

immunosuppressive and target T-lympho-

are usually drawn starting 24 hours after the

cytes, monocytes, and eosinophils. Steroids

infusion is started. Leukemia protocols pro-

may also function by halting DNA synthesis.

vide a methotrexate nomogram that allows

Dexamethasone has better central nervous

the practitioner to determine if methotrex-

system (CNS) penetration than prednisone

ate levels are declining appropriately or

and has benefit in preventing CNS relapse

are in a toxic range requiring an increase

in ALL.

in hydration and leucovorin frequency or

dose. Rarely, renal failure occurs and can

be managed with carboxypeptidase G2.

Utilized in

Toxicity is typically worse after delayed

Acute lymphoblastic leukemia

clearance and includes severe mucositis and

Hemophagocytic lymphohistiocytosis

myelosuppression. IT methotrexate often

Hodgkin and non-Hodgkin lymphoma

causes nausea and headache. Arachnoiditis

Langerhans cell histiocytosis

occasionally occurs and the patient should

be monitored for symptoms including

fever, vomiting, and meningismus. Long-

Side effects, monitoring, and

term cognitive dysfunction and learning

treatment

disabilities occasionally occur. Leukoence-

Steroid treatment results in a multitude of

phalopathy and progressive cognitive dete-

side effects. Common ones include hyper-

rioration rarely occur, especially in adoles-

phagia, insomnia, personality changes,

cents and adults, with high-dose IV meth-

adrenal suppression, acne, immuno-

otrexate and accentuated by cranial radia-

suppression, and Cushing’s syndrome.

tion therapy. Management of patients with

Occasional side effects include gastritis,

neurotoxicity including seizures, confusion,

hyperglycemia, poor wound healing, facial

ataxia, cranial nerve palsies, speech disor-

erythema, striae, thinning of the skin, mus-

ders, and paraparesis is controversial. Prac-

cle weakness, osteopenia, and cataracts.

titioners may recommend leucovorin rescue

Avascular necrosis of various joints, most

after future IT doses or replacement with IT

commonly hips, knees, and ankles, occurs

cytarabine, with or without hydrocortisone.

rarely. It is more common in adolescents,

Conclusive evidence is lacking on the use of

and females are at higher risk. It appears to

dextromethorphan as a neuroprotectant.

occur more commonly with dexametha-

sone than with prednisone. Hypertension

occurs rarely; blood pressure should be

Steroids

monitored closely in addition to blood

glucose. Patients should be on an H₂

Dexamethasone and prednisone are the

blocker

(i.e., ranitidine) while receiving

steroids used most commonly as chemo-

daily steroids to prevent gastritis and peptic

therapeutic agents.

ulcer disease.

Chemotherapy Basics

289

Temozolomide

Although rare, the patient should be moni-

tored for transaminitis as well as signs of veno-

Temozolomide (Temodar ) is an oral alky-

occlusive disease

(now termed sinusoidal

lating agent.

obstructive syndrome) and hepatic fibrosis.

Mechanism of action

As with other alkylators, temozolomide

Topotecan

leads to DNA interstrand cross-linking.

Like irinotecan, topotecan is a semisynthetic

Utilized in

analog isolated from the plant alkaloid

Brain tumors

C. acuminata.

Side effects, monitoring,

Mechanism of action

and treatment

Topotecan is a potent inhibitor of topo-

Temozolomide commonly causes anorexia,

isomerase I that is vital for DNA replication.

nausea, vomiting, and constipation fol-

Inhibition of topoisomerase inhibits repli-

lowed by myelosuppression. Occasionally,

cation and also leads to DNA damage.

temozolomide may cause abdominal pain,

diarrhea, headache, and mucositis. Contin-

Utilized in

uous low-dose (metronomic) therapy may

Brain tumors

be effective in some patients with a

Neuroblastoma

decreased side effect profile.

Side effects, monitoring,

Thioguanine (6-TG)

and treatment

Topotecan can commonly cause nausea,

Like mercaptopurine, thioguanine is an oral

vomiting, diarrhea or constipation, fever, pain

antimetabolite and purine analog.

and later myelosuppression, fatigue, and alo-

pecia. The patient should also be monitored

for the occasional findings of headache, rash,

Mechanism of action

hypotension, transaminitis, and mucositis.

Metabolites of thioguanine interfere with

purine synthesis and DNA replication. The

intercalation of nucleotide metabolites into

DNA also leads to DNA strand breaks.

Vincristine/Vinblastine

Utilized in

Vincristine and vinblastine are alkaloids

Acute lymphoblastic leukemia

isolated from the Madagascar periwinkle

Acute myelogenous leukemia

plant

(Vinca rosea, now Catharanthus

Non-Hodgkin lymphoma

roseus) and therefore often referred to as

vinca alkaloids. Vincristine and vinblastine

Side effects, monitoring,

are structurally identical except for a single

and treatment

substitution (a formyl group in vincristine is

Thioguanine commonly leads to myelosup-

replaced by a methyl group in vinblastine),

pression and occasionally causes fatigue,

which leads to significant differences in their

nausea, vomiting, diarrhea, and anorexia.

cytotoxic effects.

290

Chapter 30

Mechanism of action

commonly causes neurotoxicity including

The vinca alkaloids bind to microtubules

constipation and loss of deep tendon

especially in the mitotic spindle leading to

reflexes. Both can lead to alopecia. Jaw

metaphase arrest, thus targeting rapidly divid-

pain, peripheral paresthesias, wrist and

ing cells. They have other disruptive cellular

foot drop, and abnormal gait occasionally

functions that may or may not be related to

occur, especially with vincristine. Ptosis,

their effects on tubulin and microtubules.

vocal cord dysfunction, and damage to the

eighth cranial nerve (clinically with dizzi-

Utilized in

ness, nystagmus, vertigo, and hearing loss)

Acute lymphoblastic leukemia

are rare findings. Vinca alkaloids are vesi-

Brain tumors

cants; therefore, extravasation, if it occurs,

Ewing sarcoma

can lead to local ulceration (see Chapter 32

Hepatoblastoma

for management of extravasation).

Hodgkin and non-Hodgkin lymphoma

Langerhans cell histiocytosis

Neuroblastoma

Suggested Reading

Soft tissue sarcomas

Wilms tumor

Committee on Shortening the Time Line for New

Cancer Treatments. National Cancer Policy

Side effects, monitoring,

Board. In: Adamson PC, Weiner SL, Simone

and treatment

JV, Gelband H (eds), Making Better Drugs for

Vinblastine more commonly causes mye-

Children with Cancer. Washington, DC:

losuppression, whereas vincristine more

National Academies Press, 2005.

Guide to Procedures

Patients with suspected or known oncologic

cells, and white blood cells in addition to

or hematologic disease undergo procedures

the supporting matrix to allow for cell growth

to obtain valuable diagnostic information

and maturation. Aspirates are routinely

and receive certain therapies. Traditionally,

obtained for morphologic as well as immu-

tumor biopsies are performed under general

nohistochemical and flow cytometric evalu-

anesthesia by pediatric surgeons, pediatric

ation in patients with suspected leukemia.

orthopedic oncologists, and pediatric inter-

Those with suspected or known solid tumors,

ventional radiologists. Pediatric hematol-

storage diseases, aplastic anemia, or other

ogy/oncology physicians and their trained

marrow failure states require evaluation by

staff perform lumbar punctures (LPs) to

bone marrow biopsy as well. A core section of

look for involvement of the cerebral spinal

the marrow matrix is obtained in order to

fluid (CSF) by malignancy and to adminis-

assess the suitability of the marrow environ-

ter intrathecal (IT) chemotherapy. Intrathe-

ment for growth of normal cellular elements,

cal refers to the administration of a drug

the cellularity of the marrow, and the presence

directly into the subarachnoid space of the

of abnormal cells that may be adherent to the

spinal column. Drugs are administered in

trabeculae. Samples are typically taken from

this manner to bypass the blood-brain bar-

more than one site when looking for evidence

rier and therefore be more available for

of marrow involvement by solid tumors in

central nervous system

(CNS) directed

order to increase the sensitivity of the test.

therapy. Currently, there are only three

Basic principles for performing such

agents licensed for intrathecal chemother-

procedures include: (1) ensuring the proce-

apy: methotrexate, cytarabine (Ara-C), and

dure is indicated for diagnosis, assessment

hydrocortisone. Other common procedures

of response to therapy, or for possible

include bone marrow aspiration (BMA) and

relapse; (2) ensuring the proper medication

biopsy and administration of chemotherapy

is being administered at the proper time;

via a peripheral vein or Ommaya reservoir.

(3) providing a safe and sterile environment;

Bone marrow examination is required for

and, (4) obtaining informed consent with

the diagnosis of leukemia, lymphoma, bone

proper documentation. The patient’s med-

marrow failure states, evaluation of pancyto-

ical record should be carefully reviewed

penia of unknown etiology, suspected storage

prior to the procedure and the purpose and

diseases, and certain cases of anemia. The

nature of the procedure be reviewed with

bone marrow produces the cellular elements

the patient and family. A discussion should

of the blood including platelets, red blood

be held to review anticipated risks and

Handbook of Pediatric Hematology and Oncology: Children’s Hospital & Research Center Oakland,

Second Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.

2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

292

Chapter 31

benefits and documented in the medical

CNS lymphoma (treatment or assessment

record with the signed informed consent.

of relapse), CNS malignancy, and therapy

All procedures should be performed or

complications related to the CNS, specifi-

supervised by practitioners with technical

cally infection or neurotoxicity

(patients

expertise. For patients undergoing anesthe-

with suspected meningitis, encephalitis, or

sia, a skilled caregiver (i.e., anesthesiologist,

change in mental status without evidence of

nurse anesthetist, or critical care physician)

increased intracranial pressure).

should administer the sedation and monitor

the patient. In addition to the practitioners

Pretreatment evaluation

performing the procedure and sedation,

1. Review patient history for use of

another skilled caregiver (i.e., nurse or phy-

anticoagulants

(should be discontinued

sician) should be present to assist with

with appropriate time interval prior to pro-

positioning, sterile transfer of chemother-

cedure), seizures, or other CNS concerns

apy, and general patient care and monitor-

including prior complications with LPs or

ing. Many centers perform all LPs and

intrathecal chemotherapy. Review of sys-

BMAs under deep sedation or anesthesia;

tems to include history of headaches, altered

however, some patients prefer to have these

mental status, fevers, bleeding, back pain, or

procedures performed awake, or possibly

lower extremity weakness.

with mild sedation.

2. Physical examination should be per-

Prior to initiation of the procedure, a

formed prior to the procedure with special

time out should be done to properly identify

attention to a focused neurologic evaluation

the patient

(hospital wrist band, medical

with assessment for papilledema or other

record, and labels on medications) and

evidence of increased intracranial pressure

acknowledge the procedure and informed

such as high blood pressure, widened pulse

consent. All materials and medications

pressure, or altered level of consciousness.

should be brought into the room and

Evaluate vitals and assess for any evidence of

checked by at least two practitioners. If mul-

infection or metabolic abnormalities to

tiple medications are to be administered, care

ensure safety for anesthesia. Evaluate site

should be taken to avoid an error in admin-

of procedure to assure no localized infection

istration by bringing in one drug at a time.

or skin breakdown.

Standardized procedures should be followed

3. Laboratory parameters must be checked

to minimize error. Procedures may be per-

to confirm that the chemotherapy should be

formed in an outpatient or inpatient setting

given (platelet count, absolute neutrophil

by individuals who have been properly

count, and hemoglobin). A current meta-

trained and supervised. Many teaching hos-

bolic panel and coagulation tests should be

pitals will also provide a training opportunity

checked as indicated. Patients with moderate

for procedures and close supervision by an

thrombocytopenia

(platelet count

< 50

experienced practitioner is mandatory.

10⁹/L) may need a platelet transfusion,

although this varies with the skill of the

practitioner and the purpose of the proce-

Lumbar puncture/intrathecal

dure (many practitioners prefer a platelet

chemotherapy

count

100

10⁹/L for a diagnostic LP

in suspected or newly diagnosed leukemia).

Indications

4. The chemotherapy to be administered

Patients with suspected leukemia or lym-

should be checked on the label to ensure

phoma (staging), history of leukemia or

the correct drug, dose, mode of infusion,

Guide to Procedures

293

and patient identification. This should be

4. Prepare the skin surface in a sterile man-

compared to the patient’s medical record

ner with providone iodine solution begin-

and schema sheet to ensure appropriate

ning at the site of puncture, working out-

timing as well.

ward with friction. Repeat for a total of three

scrubs. The skin may then be cleansed with

Materials

alcohol. Place a fenestrated drape over the

1. Standard LP tray, 10 mL sterile syringe for

site and ensure an adequate sterile field with

chemotherapy transfer,

22 g spinal needle

additional drapes as desired.

(1.5 in. for infants, 2.5 in. for older children,

5. Have the assistant transfer the chemo-

longer needles available as needed for larger

therapy in a sterile manner to the sterile

patients), 25 gauge needle for lidocaine injec-

syringe on the tray. Open all CSF collection

tion if needed, providone iodine and alcohol,

tubes.

mask, and sterile gloves. A Quincke needle is

6. Administer local anesthetic with preser-

the standard needle used for an LP; however,

vative-free

1% lidocaine with a 25 gauge

the pencil point Whitacre needle may be

needle, if desired. Awake patients may prefer

indicated in patients with prior history of

application of a topical lidocaine anesthetic

severe spinal headache

(see below under

(LMX or EMLA) or ethyl chloride cold

Post-procedure monitoring).

spray. Local anesthesia is not necessary in

2. Chemotherapy agent(s) to be adminis-

the anesthetized patient.

tered. Errors have occurred in the past with

7. Insert the spinal needle into the midline of

vincristine being inadvertently administered

the interspace with the bevel up, directed at

intrathecally. This is almost uniformly fatal.

a slight (10-20 ) angle toward the umbilicus.

This drug should never be brought into the

Ensure the needle is perpendicular to the

room of a patient undergoing an LP with IT

surface. Advance the needle; if bony resis-

chemotherapy.

tance is noted, draw back and reposition. The

less experienced practitioner should check

Procedure

for CSF flow every 2 to 3 mm by withdrawing

1. Proper positioning is the key to a success-

the stylet and looking at the translucent

ful procedure. The lateral decubitus position

window hub for visualization of CSF. If

may be used for a sedated or small patient.

blood is returned, the needle should be

The patient should be placed on a firm bed,

removed and the procedure be reattempted

head flexed with chin to chest, and legs

one interspace higher. The most experienced

maximally flexed toward the head. Ensure

practitioner should assume responsibility for

the hips and shoulders are aligned and the

subsequent LPs.

back is straight. Alternatively, an awake

8. Once clear CSF return is established,

patient may prefer the sitting position, flexed

rotate the needle

counterclockwise

forward, and supported by the assistant.

(bevel in transverse plane) for patients in

2. Identify the landmark with palpation of

the lateral decubitus position to increase

the interspaces. The L4-5

interspace is

rapidity of CSF flow and allow for easier

located by a perpendicular line at the top

administration of the chemotherapy.

of the iliac crests; either this space or the one

Patients in the sitting forward position

above (L3-4) may be used.

do not usually need repositioning of the

3. Some centers require the person per-

needle. Obtain the desired amount of

forming the procedure to wear a mask to

CSF in 2 or 3 collection tubes. Tradition-

prevent infection. Put on sterile gloves and

ally the volume of CSF withdrawn should

set up the tray.

approximate the volume of medication

294

Chapter 31

administered. CSF should be collected in

Post-procedure monitoring

one tube for a chamber count (red blood

and complications

cell and white blood cell counts) and a

1. Observe the patient for 1 hour or until

second tube for cytology (assessment of

fully recovered from anesthesia with appro-

morphology). Additional tubes may be

priate postanesthesia monitoring. Most cen-

necessary for culture, immunohistochem-

ters direct that patients remain in a supine

istry, or any special studies such as myelin

position (without head pillow, mild Tren-

basic protein, tumor markers, or research

delenburg position) for 1 hour post-proce-

studies. Glucose and protein are checked

dure to minimize spinal headache and assist

initially for all patients, though not rou-

with dilution and flow of chemotherapy in

tinely for leukemia patients receiving

the CSF.

intrathecal chemotherapy.

2. Patients should be monitored for signs of

9. For intrathecal administration of che-

bleeding, pain at site, headache, nausea,

motherapy, attach the chemotherapy

vomiting, or change in neurologic status.

syringe to the spinal needle, ensuring no

In addition to monitoring for post-procedure

advancement or withdrawal of the spinal

complications, the patient’s cardiovascular

needle and a tight fit to avoid leakage. One

and respiratory status should be monitored

can attempt to withdraw CSF to assure

along with frequent vital signs until recovered

proper placement (will see a mix in the

from anesthesia.

syringe) but this may not be possible and

3. Headache occurs following lumbar

is not necessary. Slowly inject the chemo-

puncture in a small percentage of patients,

therapy over 1 to 2 minutes. There should

primarily adolescents and females. Typi-

be no resistance.

cally, onset of headache is within 12 hours

10. Chemotherapy should not be adminis-

to 5 days of the procedure and is due to a

tered when any of the following situations

slow leakage of CSF from the puncture site

exist: the spinal fluid is bloody indicating

(though may not be visible externally).

puncture of a vessel; the patient is moving

Other symptoms include nausea, vomiting,

not allowing for a safe procedure; the che-

dizziness, neck stiffness, light sensitivity,

motherapy does not advance easily and

and diminished hearing or vision. These

when the syringe is removed, the flow of

symptoms may be worse in a standing

CSF has stopped or greatly diminished; the

position.

chemotherapy drug or dose is incorrect; or

a. Patients are instructed to take fluids

the awake patient experiences pain with

liberally in addition to caffeine (highly

injection.

caffeinated sodas or coffee) with onset of

11. Remove the needle. Apply gentle pres-

symptoms and after subsequent LPs.

sure, cleanse as necessary with alcohol, and

b. Patients with severe headache or neu-

place a dry sterile dressing.

rologic symptoms should be evaluated

12. Assess patient for any adverse effect of

immediately. If a postdural puncture

the procedure. Have the patient in the

headache is suspected, treatment is ini-

supine position.

tiated with caffeine, fluids, and narcotics.

13. Label all CSF tubes and send to the lab.

If these steps are ineffective, a dural

14. Document the procedure in the medical

blood patch may be performed by an

record.

anesthesiologist to provide immediate

15. Follow up with the patient and family as

relief.

to the results of the procedure, including

c. Use of a pencil point spinal needle

interpretation of the CSF specimens.

(Whitacre) for subsequent LPs should be

Guide to Procedures

295

considered for these patients. These nee-

management of patients for whom it is dif-

dles are designed to spread the dural

ficult to perform LPs for any reason. They are

fibers and help reduce the frequency and

also used in patients who suffer a CNS relapse

severity of postdural headaches. They

of their leukemia and require frequent

can be more difficult to use and may

administration of intrathecal chemotherapy.

require an introducer to puncture the

Practitioners may opt to administer chemo-

skin and soft tissues.

therapy in reduced dosing compared to stan-

4. Fever may occur following administra-

dard intrathecal dosing (50% to 100% of IT

tion of intrathecal chemotherapy. Some

dosing) or give small daily dosing for up to

drugs (e.g., cytarabine) have been impli-

4 days (based on the concept of concentration

cated in causing fever; however, the patient

time to optimize therapeutic benefit).

should be assessed for presumed infection.

Frequently patients have indwelling central

Pretreatment evaluation

venous catheters and are receiving other

The same principles apply as in Lumbar

immunosuppressive therapy. Evaluation

puncture/intrathecal chemotherapy. Patients

should be comprehensive and may include

are not sedated for this procedure.

hospitalization for observation and admin-

istration of intravenous antibiotics.

Materials

5. Patients may experience pain or bleeding

1. Standard LP tray, two 5 mL sterile syrin-

at the LP site for several days. The patient

ges for chemotherapy transfer and CSF col-

should be evaluated and if experiencing

lection, 25 g butterfly needle, mask, razor,

minor bleeding, be treated with local therapy

antibacterial soap, 4

4 sterile gauze, pro-

(dry sterile bandaging) and pain medication

vidone iodine and alcohol, and two sets of

as needed. Prolonged or heavy bleeding

sterile gloves.

requires immediate evaluation including

2. Chemotherapy agent(s) to be adminis-

physical examination and imaging.

tered. Do not bring vincristine into the room.

6. Neurotoxicity may occur related to the

intrathecal medication or related to nerve

Procedure

damage secondary to the procedure.

1. The patient is placed in a supine or

Patients should be evaluated immediately

sitting position. If needed, the reservoir area

and intervention be taken as appropriate.

is shaved.

2. Topical anesthesia may be achieved with

lidocaine gels (EMLA or LMX) prior to the

Intra-Ommaya reservoir tap and

procedure.

injection of chemotherapy

3. While wearing a mask and sterile gloves,

the LP tray is set up.

Indications

4. Prepare the skin surface overlying the

See Lumbar puncture/intrathecal chemother-

reservoir site by cleansing with sterile gauze

apy. The Ommaya reservoir is an intraven-

moistened with an antibacterial soap in a

tricular catheter with a reservoir implanted

circular fashion, three times. Change gloves.

under the scalp that allows for administration

Continue with a routine sterile prep with

of chemotherapy or other medication directly

three providone iodine scrubs and alcohol

into the ventricular system, in addition to

wipes. Place a fenestrated drape over the site

facilitating sampling the CSF. Although they

and ensure an adequate sterile field with

are placed infrequently, they are useful in the

additional drapes as desired.

296

Chapter 31

5. Have the assistant transfer the chemo-

Bone marrow aspiration

therapy in a sterile manner to the sterile

and biopsy

syringe on the tray. Open all CSF collection

tubes.

Indications

6. Holding the reservoir firmly with one

The purpose of bone marrow aspiration

hand, puncture the reservoir site with a

or biopsy is to obtain tissue for diagnostic

25 g butterfly needle. The CSF is allowed

and staging evaluation of malignancies,

to drip (or is slowly withdrawn) from the

marrow infiltrative diseases, or marrow

butterfly into a sterile tube. The total

failure states.

volume collected should approximate the

total volume of chemotherapy and normal

Pretreatment evaluation

saline flush to be delivered. CSF should be

1. Review of systems including recent ill-

collected in one tube for a chamber count

nesses or back pain.

and a second tube for cytology. Additional

2. Physical examination should be per-

tubes may be necessary for culture, immu-

formed prior to the procedure, with vitals

nohistochemistry, or any special studies

and assessment for any evidence of infection

such as myelin basic protein, tumor mar-

or metabolic abnormalities to assure safety

kers, or research studies. Glucose and

for anesthesia. Evaluate site of procedure

protein are checked initially for all

to assure no localized infection or skin

patients, though not routinely for leuke-

breakdown.

mia patients receiving intra-Ommaya

3. Routine laboratory studies may include a

chemotherapy.

complete blood count, chemistries, and

7. The chemotherapy is injected over 2 to

coagulation studies. No specific platelet

3 minutes. Do not give the chemotherapy if

count is necessary for the procedure. The

the CSF is blood tinged.

anesthesiologist will want to ensure an ade-

8. The needle is removed and firm pressure

quate hemoglobin level and be aware of any

is applied to the site for several minutes. A

metabolic abnormalities.

spot bandage is applied.

4. The technician to assist with the marrow

9. Assess the patient for any adverse effects

slide preparation should be present at the

from the procedure.

start of the procedure with appropriate

10. Label all CSF tubes and send to the

materials.

lab.

11. Follow up with the patient and family as

to the results of the procedure, including

Materials

interpretation of the CSF specimens.

1. Biopsy tray with providone iodine,

alcohol,

gauze,

20 mL syringes

Post-procedure monitoring

4 depending on samples to be col-

and complications

lected),

16 gauge bone marrow aspirate

1. Document in the patient’s chart details

needle, 11 gauge 4 in. or 13 gauge 3.5 in.

of the procedure, chemotherapy adminis-

Jamshidi biopsy needle

(or similar),

tered, specimens collected, and the patient’s

25 gauge needles, sterile gloves, and

status after the procedure.

Elastoplast adhesive or other pressure

2. See Post-procedure monitoring for LP

dressing.

regarding complications such as headache,

2. EDTA and heparin to anticoagulate sam-

fever, bleeding, or neurologic changes.

ples, lidocaine 1% for local anesthesia.

Guide to Procedures

297

Procedure

syringe, constant and strong pressure

1. Position patient in a prone or lateral

should be applied to draw up marrow into

decubitus position with a small lift under

the syringe. If awake, the patient may expe-

the hip to accentuate the posterior iliac

rience a shooting sensation down the legs at

crests. Identify the posterior superior iliac

the time of aspiration. Aspirate approxi-

spine. Have assistant secure patient’s posi-

mately 1 to 2 mL of marrow, detach the

tion. At times, other locations for bone

syringe carefully, and hand the specimen

marrow specimen collection are necessary

immediately to the technician for quick

(infants, children on ventilators, and so on)

visual inspection for marrow tissue

(fat,

and may include the anterior iliac spine,

spicules). Once this has been confirmed,

tibia, sternum, or other sites.

obtain additional marrow as needed with

2. Put on gloves and set up sterile tray.

the other primed syringes. Once complete,

3. Scrub the site with providone iodine,

remove the needle. If marrow is not visible

applying some friction, beginning at the

and the sample is thought to represent

site and moving outward, and repeating

peripheral blood, reposition the needle and

for a total of three scrubs. Repeat procedure

reattempt an aspirate.

with alcohol swabs. Allow to dry and apply

7. A bone marrow biopsy may be obtained

sterile drapes.

from the same side and skin puncture site as

4. Administer local anesthetic with a 22 to

the aspirate. The needle should be inserted

25 gauge needle. This is often done in the

into a fresh spot on the iliac spine (although

sedated patient to minimize post-procedure

should utilize the same skin puncture site).

discomfort. Local anesthesia is achieved

Holding the skin tight, insert the bone

with lidocaine 1% (2 to 3 mL depending

marrow (trephine) biopsy needle (with cut-

on size of the patient) injected down to and

ting trocar in place) holding at an angle

including the periosteum.

until through the skin, then placing perpen-

5. Prepare marrow aspirate and/or biopsy

dicular to the spine and inserting with

needles, ensuring the stylets are freely

strong, controlled pressure until the needle

removable. Prime syringes as per institu-

is firmly anchored into the cortex. Remove

tional protocol with heparin, EDTA, etc.

the trocar and holding the forefinger along

Ensure inner side of syringe is coated with

the needle at the desired depth of the core

anticoagulant, if being used.

biopsy (5 to 20 mm depending on size of the

6. Holding skin taught with outstretched

patient), insert the needle with a firm twist-

fingers, insert the bone marrow aspiration

ing pressure. The needle is then rocked in

needle (with stylet in place) initially at an

four angles (i.e., sideways as well as up and

angle to the skin and then perpendicular to

down) to break off the core marrow biopsy

the iliac spine once through the skin. With

sample at the base and then the needle is

gradual, controlled pressure and a gentle

removed. The provided push rod (no sharp

twisting motion, insert the needle into the

edge) is inserted into the sharp end of the

iliac spine. Once through the cortex, the

needle and the biopsy is pushed out gently

needle will “give” as it enters the marrow

onto sterile gauze. It is then examined to

space and a crunching sound or feeling may

ensure that adequate marrow tissue is pres-

be appreciated. The stylet should then be

ent. If so, it is given to the technician.

removed, and the needle should remain

8. Apply pressure for several minutes,

firmly in place. A 20 mL syringe is then

cleanse the site with alcohol swabs, and

firmly attached to the hub of the aspiration

apply a Band-Aid. If needed, a dry 4

needle. Holding onto both the needle and

folded into quarters may be applied over the

298

Chapter 31

Band-Aid with an elastic tape such as

practitioners, administration of push intra-

Elastoplast.

venous chemotherapy is a safe alternative to

9. Assess the patient for any adverse effect

the use of a CVC. Vincristine is frequently

of the procedure.

administered via peripheral vein in the out-

10. Document procedure(s) in the medical

patient setting during maintenance phases

record.

of treatment for acute lymphoblastic leuke-

11. Follow up with the patient and family to

mia. Peripheral access should not be used

ensure completion of procedure, explana-

routinely for infusional chemotherapy due

tion of any complications, review care of

to the difficulty in monitoring and ensuring

wound, and follow up on results of studies

continued patency of the IV during infu-

done on specimens obtained.

sion. Many chemotherapeutic drugs are

vesicants and may cause significant injury

Post-procedure monitoring

with extravasation (see Chapter 32).

and complications

1. Patients may be discharged from the

Pretreatment evaluation

recovery area after appropriate monitoring

1. Review the patient’s chemotherapy reg-

postanesthesia.

imen to determine what medications are to

2. The pressure dressing, if used, should be

be administered and at what dose. The

removed after 6 hours and the Band-Aid

patient’s height, weight, and total body

after 24 hours. The parents should inspect

surface area are verified with the dosage

the site for evidence of infection, bleeding,

calculations.

or other drainage. If noted, a practitioner

2. Ensure that required laboratory criteria

should be contacted and the site be evalu-

have been met (e.g., absolute neutrophil

ated. Pain medications including acetamin-

count, platelet count, and transaminases)

ophen, acetaminophen with codeine, or

as directed by the treatment protocol.

occasionally an intravenous narcotic may

3. Complete a physical examination on the

be administered for local pain (especially

patient and assess the adequacy of veni-

following biopsy). Patients may feel achy or

puncture sites.

bruised for several days following the pro-

4. Verify the labels on the syringe(s) of the

cedure. Discomfort can also be alleviated

drug(s) against the patient’s chart and

with a warm pack.

orders to ensure accuracy.

3. Patients may resume normal activities as

5. Prepare the patient for the procedure.

desired.

Explain the procedure, taking into account

the patient’s age, developmental status, and

Administration of peripheral

prior experience with the procedure. Elicit

chemotherapy

the patient’s help by encouraging him/her to

hold as still as possible. Enlist the assistance

Indications

of the parent(s) and staff (including child

Intravenous

(IV) chemotherapy may be

life) as needed. Explain each step as you go;

given into a central venous catheter (CVC)

be honest, thorough, and patient. Establish

or by peripheral vein administration in

a routine with each patient; many also like

patients without a CVC. Many patients may

to have the same practitioner if possible

have had their catheters removed due to

(confidence boosting).

infection, thrombosis, or electively in order

6. Patients desiring topical anesthesia

for the patient to resume more normal

should have a topical lidocaine gel (EMLA

activities. In the hands of experienced

or LMX) applied

minutes in

Guide to Procedures

299

advance of the procedure. This may result in

with clean gauze. Insert butterfly needle

vasoconstriction and increase difficulty of

with bevel pointed up. Advance needle until

access in some patients.

blood returns. When blood returns, remove

tourniquet, connect stopcock, and flush

Materials

line with 2 to 3 mL of saline.

1. Chemotherapy (premixed by pharmacy

4. If no sign of infiltration occurs (e.g., pain

in enclosed syringe).

or swelling) and blood return continues,

25 g butterfly needle, stopcock, alcohol

administer chemotherapy slowly via IV

wipes, gauze

2), tourniquet,

10 mL

push, checking intermittently every

5 to

saline flush, bandage, and gloves.

10 seconds for blood return or swelling.

When chemotherapy administration is

Procedure

completed, flush with remaining saline.

1. Assemble equipment; attach butterfly

5. Remove butterfly and apply pressure for

tubing to stopcock, attach chemotherapy

1 to 2 minutes with clean gauze. Apply

syringe to right side of stopcock, attach

bandage.

saline flush syringe to remaining junction

6. Document in the patient’s chart the

of stopcock, and flush stopcock and butter-

indication for and details of the proce-

fly with saline.

dure, medication, dosage, site, and any

2. Select an appropriate vein, preferably on

complications.

the dorsum of the hand or foot. Ask the

child to assume a comfortable position that

Post-procedure monitoring

also allows for easy access to the desired

and complications

vein. Avoid the antecubital fossae or joint

If infiltration has occurred, see Chapter 32.

spaces due to the possibility of deep extrav-

Areas that may have sustained tissue dam-

asation of chemotherapy with resultant

age should not be used for future adminis-

injury.

tration of chemotherapy. At times, subclin-

3. Clean the venipuncture site with alcohol

ical burns and scarring may occur and can

and apply tourniquet. Let air dry or wipe dry

appear as hyperpigmented areas.

Treatment of

Chemotherapy

Extravasations

Extravasation is the leakage of an intrave-

loss of the full thickness of the skin and,

nous (IV) drug into the surrounding tissues.

if severe, underlying structures.

Local reactions from extravasation of a ves-

icant chemotherapy agent can range from

The incidence of vesicant extravasation

mild pain and erythema to tissue necrosis,

injury ranges from 0.5% to 6% in peripheral

ulceration, and damage to tendons and

IV infusions and 0.3% to 4.7% in implanted

nerves. Cytotoxic drugs are classified as irri-

venous access port infusions, although real-

tants or vesicants (causing blisters), depend-

istically the incidence is likely higher as

ing on their potential for local toxicity.

many milder events may not be reported

* Extravasation of an irritant drug may

by patients. Treatment of an extravasation

cause an inflammatory reaction, with pain,

is determined by the particular chemother-

burning, tightness, or phlebitis at the nee-

apy agent involved, although the efficacy of

dle insertion site or along the vein. Clinical

such therapy may be modest. Prevention is

signs include warmth, erythema, and ten-

the key, and every possible measure should

derness in the area of extravasation, but

be taken to avoid such a complication. If it

there is no tissue sloughing or necrosis.

is anticipated that a patient will need fre-

Symptoms are typically of short duration

quent or prolonged infusions of vesicants, it

(days) and there are no long-lasting

is advisable to place a central venous cath-

sequelae. An irritant may cause a soft tissue

eter for safer drug administration. Rarely,

ulcer if a large amount of concentrated

extravasation may occur even with such

drug solution is inadvertently extravasated

a device.

causing an inflammatory reaction; again,

The causes of extravasation are multiple

this will not result in persistent tissue

and largely preventable. Factors that place

damage.

children at risk for peripheral IV extravasa-

* Extravasation of a vesicant drug may

tion include poor vein selection, multiple

cause tissue necrosis with a more severe

venous punctures to establish a patent

or lasting injury. Clinical signs and symp-

IV, obesity, dehydration, inability to report

toms may be similar to extravasated irri-

pain at the injection site, a moving

tants. Vesicant extravasation may result in

patient, and inexperience of the individual

Handbook of Pediatric Hematology and Oncology: Children’s Hospital & Research Center Oakland,

Second edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.

2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

Treatment of Chemotherapy Extravasations

301

administering the chemotherapy. Risk fac-

or cause pain. If this occurs, immediately

tors for extravasation from central venous

stop the infusion and attempt to withdraw

catheters include needle displacement, cath-

any medication in the needle/cannula.

eter migration, or fibrin sheath formation

* After infusing the medication, flush the

and thrombosis. Mechanical occlusions

vein with 3 to 10 mL of the carrier solution.

may be due to thrombus formation, drug

Do not continue to flush if resistance is met

precipitation, and positional catheter occlu-

or a local reaction suggesting a blown vein

sion or kinking of the line. Avoidance of

occurs.

extravasation depends on proper placement

and maintenance of IV access and frequent

Each incident of extravasation should be

monitoring. Recommendations to prevent

documented and reported.

extravasation are:

Although this complication is frequently

* Venipuncture and placement of the can-

encountered with antineoplastic agents, a

nula or other intravenous access performed

number of other drugs can also act as vesi-

by experienced personnel.

cants if extravasated into the surrounding

* Vesicants should be administered in

tissues. These noncytotoxic drugs include

accordance with the manufacturers’ recom-

alcohol, aminophylline, digoxin, nafcillin,

mendations (e.g., proper dilution and spec-

phenytoin, tetracycline, and total parenteral

ified administration time) with proper ver-

nutrition. Among cytotoxic drugs that cause

ification and identification

(patient and

extravasation injury, the anthracyclines are

protocol specific).

among the most important, both because of

* Avoid multiple venipunctures in the same

their widespread use in various chemother-

area. Do not use a vein distal to a recent

apeutic protocols and because of their abil-

venipuncture site as the vesicant may leak

ity to produce severe tissue damage and

from one of these proximal sites.

necrosis. The extent of tissue damage

* Instruct the patient to avoid movement.

depends on the chemotherapeutic agent’s

In young children, this may require addi-

binding capacity to DNA.

tional physical assistance for holding or

DNA-binding agents include anthracy-

coaxing with diversion techniques.

clines, antitumor antibiotics, platinum ana-

* Never use a previously placed IV access

logues, and some alkylating agents. These

device; a new IV cannula should be placed

drugs cause tissue damage by propagating

immediately prior to delivery of the

lethal DNA crosslinking or strand breaks

medication.

caused by free radicals, which lead to cell

* Choose a large, intact visible vein with

apoptosis. As the cells die, the drug is

good blood flow.

released and enters undamaged cells. This

* Use the smallest needle or cannula pos-

further increases the area of damage and

sible for venipuncture. Check the patency of

slows healing. Injuries from doxorubicin

the device by aspirating blood, as well as

may continue for weeks.

patency of the vein by flushing with the

Non-DNA-binding antineoplastics (vinca

carrier solution

(normal saline), before

alkaloids, taxanes, and topoisomerase inhibi-

administering the medication. Obtain a

tors) also function as vesicants by interfering

blood return prior to, and during, vesicant

with mitosis. These agents clear more easily

administration.

from extravasation sites and cause less dam-

* The intravenous infusion should flow

age than the DNA-binding agents. The tissue

freely without pressure. The local area

often resembles a chemical burn and heals

should not swell, become erythematous,

more quickly.

302

Chapter 32

Table 32.1 Extravasation treatment.

Drug

Local care

Pharmacologic treatment

DNA-binding vesicants

Anthracyclines

Cold pack, 20 minutes

Dexrazoxane 1000 mg/m² IV within

Doxorubicin

4 times/day

48-72 hours

6 hour on day 1, repeat day 2;

Daunomycin

Elevate

500 mg/m² day 3 or

DMSO 50% topical 1-2 mL within

10-25 minutes, then q8 hour

7-14 days; allow to dry, then

apply nonocclusive dressing

Do not use Dexrazoxane and DMSO

concurrently

Alkylating agents

Cold pack, 20 minutes

None

Nitrogen mustard

4 times/day

48-72 hours

Elevate

Other

Cold pack, 20 minutes

Sodium thiosulfate

Dactinomycin

4 times/day

48-72 hours

10% 2 mL in 6 mL sterile water for

Mitomycin C

Elevate

IV/SC injection

Dacarbazine

None

DMSO as above

Hydrocortisone 1% cream topically

Non-DNA binding vesicants

Vinca alkaloids

Warm pack, 20 minutes

None

Vinblastine

4 times/day

48-72 hours

Hyaluronidase 150 units in 1 mL

Vincristine

Elevate

injected SC in multiple sites with

Vendesine

small gauge needle

Taxanes

Cold pack, 20 minutes

Hyaluronidase as above

Docetaxel

4 times/day

48-72 hours

Paclitaxel

Elevate

Irritants

Alkylating agents

Carboplatin, cisplatin

Cold pack as above

Hydrocortisone 1% cream topically

Topotecan

Ifosfamide, cyclophosphamide

No local care

None

Melphalan

No local care

None

Antimetabolites

Cytarabine, fludarabine

None

Methotrexate, 5-

Cold pack as above

Hydrocortisone 1% cream topically

fluorouracil

Gemcitabine

None

Other

Bleomycin

None

Etoposide, irinotecan

Cold pack

Hydrocortisone 1% cream topically

Suggested as possible antidote in the literature; lack of prospective studies to currently advocate as

treatment. Abbreviation: SC, subcutaneous.

Treatment of Chemotherapy Extravasations

303

The signs and symptoms of extravasa-

Table 32.1) for which local heat is applied.

tion may be readily apparent with pain and

For other vesicant extravasations, including

erythema although it may take days for the

anthracyclines, initial treatment is geared

full extent of the epithelial damage to be

toward localizing and neutralizing the agent

evident. Discoloration and skin induration

with cold compresses, thus limiting its

may progress with the development of blis-

uptake into cells. The placement of extrav-

ters or necrosis and possibly ulceration or

asation kits that contain syringes and can-

deep tissue injury. Patients may develop

nulas, cold and hot packs, gauze pads, sterile

scarring or permanent hyperpigmentation

and chemoprotective gloves, and medica-

at the site of drug extravasation. These sites

tions to treat extravasation in locations

should not be utilized for subsequent

where chemotherapy is administered will

administration of chemotherapy or place-

facilitate early treatment (see Table 32.1).

ment of an IV device.

In addition to local care and possible phar-

Treatment should begin immediately

macologic antidotes, topical hydrocortisone

with discontinuation of the chemotherapy

1% and pain medications may alleviate local

and cooling or dilution of the site. Initial

discomfort.

treatment includes an attempt to aspirate

the vesicant with a 10 mL syringe. Clinicians

should work quickly to reduce morbidity

Suggested Reading

and avoid further patient harm. Manage-

ment of nonvesicant extravasation includes

Goolsby TV, Lombardo FA. Extravasation of

elevation and cooling and does not usually

chemotherapeutic agents: prevention and

include the use of pharmacologic therapy.

treatment. Semin Oncol 33:139-143, 2006.

An exception to the cooling technique is

Schulmeister L. Extravasation management.

extravasation with vinca alkaloids

(see

Semin Oncol Nurs 23:184-190, 2007.

Formulary

Sample entry:

drug in pregnant women may be acceptable

despite its potential risk.

Generic name

Trade and other names

X. Studies in animals or humans demon-

Drug category

strate fetal abnormalities or adverse reac-

How supplied

tion; reports indicate evidence of fetal risk.

Pregnancy category (see explanation below)

The risk of use in a pregnant woman clearly

Indications

outweighs any possible benefit.

Dosage

Notes, including adverse events, monitor-

ACYCLOVIR

ing, and dose modification

Zovirax

Pregnancy categories:

Antiviral

Capsules: 200 mg

A. Adequate studies in pregnant women

Tablets: 400, 800 mg

have not demonstrated a risk to the fetus

Suspension: 200 mg/5 mL

in the first trimester of pregnancy and there

Injection: 500 mg vial

is no evidence of risk in later trimesters.

B. Animal studies have not demonstrated a

Pregnancy category B

risk to the fetus, but there are no adequate

studies in pregnant women; or animal stud-

Indications:

ies have shown an adverse effect, but ade-

Treatment of initial, and prophylaxis for

quate studies in pregnant women have not

recurrent, mucosal and cutaneous herpes

demonstrated a risk to the fetus during the

simplex virus (HSV-1 and HSV-2) infections,

first trimester of pregnancy, and there is no

herpes simplex encephalitis, herpes zoster

evidence of risk in later trimesters.

infections, and varicella zoster infections.

C. Animal studies have shown an adverse

effect on the fetus, but there are no adequate

Dosage:

studies in humans; or there are no animal

reproduction studies and no adequate stud-

Children and neonates:

ies in humans.

Mucocutaneous HSV:

750 mg/m²/day IV

D. There is evidence of human fetal risk, but

divided q8h or

25 mg/kg/day IV

the potential benefits from the use of the

divided q8h for 5 to 10 days

Handbook of Pediatric Hematology and Oncology: Children’s Hospital & Research Center Oakland,

Second Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.

2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

306

Formulary

HSV encephalitis:

1500 mg/m²/day IV

m²/day IV q8-24h; maximum 600 mg/day,

divided q8h or

50 mg/kg/day IV

300 mg/dose

divided q8h for 10 days

Children >10 years of age to adult:

Neonatal HSV: 1500 mg/m²/day IV divided

600 to 800 mg/day PO q8-12h for the pre-

q8h or 30 to 50 mg/kg/day IV divided q8h

vention of acute uric acid nephropathy;

for 10 to 14 days

maximum 800 mg/day, 300 mg/dose or

200 to 400 mg/m²/day IV divided q8-24h;

Varicella zoster: 1500 mg/m²/day IV divided

maximum 600 mg/day, 300 mg/dose

q8h or 30 to 50 mg/kg/day IV divided q8h

for 7 to 10 days

Notes:

HSV prophylaxis: 750 mg/m²/day IV divided

Reduce dosage in renal impairment; discon-

q8h during risk period or 600 to 1000 mg/

tinue with rash (may be exacerbated with

day divided q6-8h during risk period

ampicillin or amoxicillin). Risk of hyper-

Notes:

sensitivity may be increased in patients

receiving thiazides/angiotensin-converting

Adjust dose in renal impairment. Adequate

enzyme inhibitors. May cause fever, neuri-

hydration and slow IV (1 hour) adminis-

tis, gastrointestinal disturbance, hepatotox-

tration are essential to prevent crystalliza-

icity, bone marrow suppression, and drows-

tion in the renal tubules. Oral absorption is

iness. Avoid concomitant use of amoxicillin,

unpredictable (15% to 30%). Use ideal body

ampicillin, mercaptopurine, cyclophospha-

weight for obese patients when calculating

mide, theophylline derivatives, and vitamin

dosage.

K antagonists.

ALLOPURINOL

ALTEPLASE

Zyloprim, Alloprim

Uric acid lowering agent, xanthine oxidase

Tissue plasminogen activator (TPA)

inhibitor, antigout agent

Activase, Cathflo Activase

Tablets: 100, 300 mg

Thrombolytic

Suspension: 20 mg/mL

Injection:

Injection (Alloprim): 500 mg vial

Cathflo Activase: 2 mg/2 mL vial

Activase: 50 mg (29 million units), 100 mg

Pregnancy category C

(58 million units)

Indications:

Pregnancy category C

Prevention of uric acid nephropathy in

myeloproliferative neoplastic disorders that

Indications:

may occur as a result of tumor lysis syn-

Treatment of recent severe or massive deep

drome (beginning 1 to 2 days prior to

vein thrombosis (DVT) or arterial throm-

initiation of chemotherapy); prevention of

bosis, pulmonary embolus, or occluded cen-

recurrent calcium oxalate calculi; preven-

tral venous catheter (CVC).

tion of gouty arthritis and nephropathy.

Dosage:

Pulmonary embolus, DVT, central venous

Children

10 years of age:

thrombosis, superior vena cava syndrome:

10 mg/kg/day PO divided q6-8h; maxi-

Systemic thrombolytic therapy should be

mum dose 800 mg/day or 200 to 300 mg/

given in consultation with a hematologist.

Formulary

307

Under 3 months of age: 0.06 mg/kg/hour for

AMIFOSTINE

6 to 24 hours

Ethyol

Over 3 months of age: 0.03 mg/kg/hour (max

Antidote for cisplatin, cytoprotective agent

2 mg/hour)

Injection: 500 mg vial

If no clinical improvement in 24 hours,

Pregnancy category C

double the dose to

0.06

0.12 mg/

kg/hour.

Indications:

Systemic TPA can be given for up to 96 hours.

A cytoprotective drug that scavenges free

In the case of a pulmonary embolus, bolus

radicals and binds to reactive drug deriva-

dosing of 1 mg/kg up to a maximum of

tives reducing toxicity of radiation and

50 mg may be given.

platinum-containing and alkylating agents

such as cisplatin, carboplatin, ifosfamide,

Maximum duration of therapy is 96 hours or

carmustine, melphalan, mechlorethamine,

based on the patient’s clinical course.

and cyclophosphamide.

Preferable to infuse thrombolytic agent dis-

tal to (and as close to) the site of thrombus

Dosage:

as possible.

Refer to individual protocol.

Occluded CVC:

Under 3 months of age:

0.25 mg IV (in

Usual dosage is 740 to 910 mg/m² IV daily

0.5 mL)

over 15 minutes prior to the dose of a

Over 3 months of age: 0.5 mg IV (in 1 mL)

platinum or alkylating agent. Infusions over

Instill a dose in each lumen of the central

less than 15 minutes are associated with a

venous catheter; allow to dwell for 30 min-

higher incidence of adverse reactions.

utes. If unsuccessful, repeat dose. If the

catheter remains obstructed, begin systemic

Notes:

thrombolytic therapy as outlined above.

Avoid in hypotension or dehydration. Can

Purpura fulminans:

cause severe nausea and vomiting and usu-

0.5 mg/kg IV infusion over 1 hour, followed

ally requires antiemetic premedication.

by 0.25 mg/kg/hour over 3 hours (total dose

1.25 mg/kg over 4 hours)

AMINOCAPROIC ACID

Amicar

Notes:

Hemostatic agent

Tablet: 500, 1000 mg

Avoid central venous puncture and non-

Syrup: 250 mg/mL

compressible arterial sticks during infusion.

Injection: 250 mg/mL (20 mL)

Avoid use in excessive hypertension, within

10 days of a cerebral vascular accident, with

Pregnancy category C

gastrointestinal bleeding or trauma, within

1 week of surgery, in patients with a bleeding

Indications:

diathesis, or with suspicion of a subarach-

noid hemorrhage. Plasminogen levels

Treatment of bleeding resulting from exces-

should be followed daily and fresh frozen

sive activity of the fibrinolytic system.

plasma be given for replenishment if level

Typically used to treat mucosal-type bleed-

<50%.

ing in patients with bleeding diatheses (von

308

Formulary

Willebrand disease, mild hemophilia,

Rhizopus. Also used empirically to treat sus-

immune thrombocytopenia purpura).

pected invasive fungal disease in immuno-

compromised hosts with prolonged fever and

Dosage:

neutropenia. May be given intrathecally or

via bladder irrigation for localized therapy.

100 to 200 mg/kg IV/PO loading dose (max-

imum 10 g), followed by 50 to 100 mg/kg

Dosage:

q4-6h maintenance dose; maximum 30 g/24

Optional test dose: 0.1 mg/kg to a maximum

hour. Treat until symptoms resolve (1 to

of 1 mg IV over 20 to 60 minutes

14 days).

Initial dose: 0.5 to 1.0 mg/kg/day

Low doses (10 mg/kg) have been reported to

control bleeding in patients with thrombo-

The daily dose is increased by 0.25 mg/kg

cytopenia for long periods of time (weeks to

until the desired daily dose is reached. In

months).

critically ill patients, rapid escalation of

dosing may be needed.

Continuous IV infusion:

Empiric dose is 0.6 mg/kg/day

Loading dose of

100 mg/kg, then

33 mg/kg/hour in

5% dextrose in water

Therapeutic dose for confirmed invasive

(maximum 1.25 g/hour)

fungal infection is 0.6 to 1 mg/kg/day. Daily

infusion is over 2 to 6 hours, depending on

Notes:

the infusion tolerability. Salt loading with

10 to 15 mL/kg of normal saline prior to

May accumulate in patients with decreased

each infusion may prevent hypokalemia

renal function and require decreased dos-

and nephrotoxicity. Premedication is fre-

ing. Avoid in patients with disseminated

quently needed with acetaminophen and/

intravascular coagulation or hematuria.

or diphenhydramine, and if the patient

Increased risk of thrombosis with oral con-

experiences rigors, meperidine hydrochlo-

traceptives, estrogens, and factor IX or

ride may be given. Once therapy has been

prothrombin complex concentrates. May

established, alternate-day dosing may be

cause nausea, diarrhea, malaise, headache,

administered at a dose of 1 to 1.5 mg/kg/

decreased platelet function, and false

every other day.

increase in urinary amino acids.

AMPHOTERICIN B

Notes:

Fungizone, Amphocin

Because of the nephrotoxic potential of this

Polyene antifungal

drug, avoidance of other nephrotoxic med-

Injection: 50 mg vial

ications is advised, if possible. Monitor

daily electrolytes, renal and hepatic studies,

Pregnancy category B

and urine output. Common metabolic

abnormalities include hypokalemia, hypo-

Indications:

magnesemia, and hypocalcemia. Other pro-

Treatment of severe systemic infections and

blems that may occur are thrombocytope-

meningitis caused by susceptible fungi such

nia, hyperglycemia, diarrhea, dyspnea, back

as Candida species, Histoplasma capsulatum,

pain, and increases in transaminases and

Cryptococcus neoformans, Aspergillus species,

bilirubin. Common infusion-related toxici-

Blastomyces dermatitidis, Torulopsis glabrata,

ties are fever, chills, rigors, nausea, vomiting,

Coccidioides immitis, Mucormycoses, and

hypotension, and headache. Imidazole

Formulary

309

derivatives

(e.g., miconazole, fluconazole,

spleen, lung and liver, and therefore may be

and ketoconazole) may antagonize the

more beneficial in the treatment of hepa-

effect and induce fungal resistance to

tosplenic candidiasis. Cerebrospinal fluid

amphotericin.

(CSF) levels may be lower than with ampho-

tericin B or the liposomal compound.

AMPHOTERICIN B CHOLESTERYL

SULFATE

Dosage:

Amphotec

Usual dose is 2.5 to 5 mg/kg IV once daily

Polyene antifungal

over

hours. Rate should not exceed

Injection: 50,100 mg vial

2.5 mg/kg/hour.

Pregnancy category B

Notes:

Indications:

See Amphotericin B.

Treatment of invasive fungal disease in

patients who are refractory to or intolerant

AMPHOTERICIN B, LIPOSOMAL

of conventional amphotericin B.

AmBisome

Polyene antifungal

Dosage:

Injection: 50 mg vial

Start at

3 to 4 mg/kg/day and increase to

Pregnancy category B

6 mg/kg/day if necessary. A test dose of

10 mL of the diluted solution over 15 to

Indications:

30 minutes is recommended. Give first dose

Treatment of systemic or invasive fungal

at 1 mg/kg/hour; if well tolerated, the infusion

infection in patients refractory to or intoler-

time can be gradually decreased to 2 hours.

ant of conventional amphotericin B. Cere-

Notes:

brospinal fluid concentrations are higher

See Amphotericin B.

than with other amphotericin products.

Higher concentrations in the liver and spleen

AMPHOTERICIN B LIPID COMPLEX

than with conventional amphotericin B.

Abelcet

Polyene antifungal

Dosage:

Injection: 5 mg/mL (10, 20 mL)

Systemic fungal infections: 3 to 5 mg/kg/day

Pregnancy category B

IV over 2 hours. Doses as high as 10 mg/kg/

day have been used in patients with Asper-

Indications:

gillus species.

Treatment of aspergillosis or invasive fungal

Empiric therapy for fever and neutropenia:

infection in patients who are refractory to or

3 mg/kg/day

intolerant of conventional amphotericin B

Infusion may be shortened to 1 hour if well

therapy. Patients with acute or preexisting

tolerated.

renal toxicity (serum creatinine level double

that of baseline) should receive this product

Notes:

in lieu of conventional amphotericin B.

Higher concentrations are achieved in the

See Amphotericin B.

310

Formulary

ASPARAGINASE

Dose for Erwinia L-asparaginase is per

L-Asparaginase, (Elspar [native or Escheri-

protocol.

chia coli], Erwinase [Erwinia chrysanthemia])

Maximum 2 mL volume per injection site.

PEG-asparaginase

(polyethylene glycol

Many patients require multiple injections.

asparaginase; Oncaspar)

IM administration results in delayed peak

Antineoplastic, results in asparagine deple-

plasma concentration compared with IV

tion in malignant cells

administration.

Injection: 10,000 unit vial (Elspar)

Patients should be observed in a clinic or

10,000 unit vial (Erwinase)

hospital setting for at least 1 hour after admin-

3,750 unit vial (Oncaspar)

istration to monitor for a hypersensitivity

Pregnancy category C

reaction. Appropriate agents for treatment

of hypersensitivity should be readily available

(oxygen, epinephrine, antihistamines, intra-

Indications:

venous steroids) in addition to resuscitative

Treatment of acute lymphoblastic leukemia

equipment.

(ALL). Current and future trials for ALL treat-

Notes:

ment largely incorporate PEG-asparagase

during induction therapy due to an increased

Do not give to patients with prior significant

rapid early response compared to the native

pancreatitis associated with asparaginase.

form, prolonged half-life, and decreased like-

Hypersensitivity to E. coli or pegylated aspar-

lihood of developing neutralizing antibodies

aginase necessitates a switch to the Erwinia

during later phases of therapy. Due to the

form or omission of future doses. Patients

longer half-life of the pegylated form (5.8 days

who have had a significant hemorrhagic or

in children compared to 1.24 days with native

thrombotic event should have levels of fibrin-

and 0.65 days with Erwinase), longer intervals

ogen and antithrombin III checked and may

for therapy are suggested. Recent studies have

be rechallenged with future doses if with

established safety of the intravenous prepara-

improvement in their symptoms and nor-

tion, thereby decreasing the pain associated

malization of their laboratory parameters.

with intramuscular injection of the drug.

Use with caution in patients with hepatic

Erwinase has traditionally been utilized if

impairment or in those receiving other hep-

hypersensitivity develops to the native or

atotoxic drugs. Use with caution in patients

pegylated forms, although its availability may

receiving anticoagulation or nonsteroidal

be limited.

anti-inflammatory agents (NSAIDs). Aspar-

aginase may cause hyperglycemia, hyperuri-

cemia, hyperammonemia, hypofibrinogen-

Dosage:

emia, thrombosis, hemorrhage, anaphylaxis,

and hemorrhagic cystitis. Dexamethasone

Refer to individual protocol.

may alleviate allergic symptoms.

Usual dose in ALL of PEG-asparagase is

2500 IU/m² IV/IM every

weeks

BEVACIZUMAB

(induction, delayed intensification, and

Avastin

interim maintenance phases).

Angiogenesis inhibitor; monoclonal anti-

Dose for native (E. coli) L-asparaginase is

body to vascular endothelial growth factor

6000 units/m² IM three times a week for

Injection: 25 mg/mL

nine doses. High-dose protocols may give

15,000 to 20,000 IU/m²/dose.

Pregnancy category C

Formulary

311

Indications:

Treatment of Hodgkin and non-Hodgkin

Treatment of metastatic colon cancer, lung

lymphoma, soft tissue sarcoma, renal cell car-

cancer, and glioblastoma multiforme. Cur-

cinoma, and germ cell tumor. Used as a scle-

rently being investigated in pediatric pro-

rosing agent to control malignant effusions.

tocols for the treatment of brain tumors,

refractory or recurrent solid tumors, and

neurofibromatosis.

Dosage:

Refer to individual protocol.

Dosage:

10 to 20 IU/m² IV one to two times per week

Refer to individual protocol.

or once every 2 to 4 weeks.

15 mg/kg q2 weeks in 28-day cycles as a

Test dose recommended for lymphoma

single agent or

patients (1 to 2 units for the first 2 doses;

if well tolerated, give remainder of dose 1

5 to 10 mg/kg q2 weeks in combination

hour later). Administer over at least

regimens.

minutes, not to exceed 1 IU/minute.

May be given as continuous IV infusion 15

Notes:

to 20 IU/m²/day over 24 hours for 3 to 5

Avoid use in patients with recent surgery,

days in some protocols.

hemoptysis, gastrointestinal or central ner-

vous system bleeding, or any other serious

Notes:

bleeding. The interval required between

Do not give to patients with known hyper-

surgery and drug administration to avoid

sensitivity to bleomycin. Premedication

impairment in wound healing has not been

with acetaminophen, hydrocortisone, and

determined. General recommendation is to

antihistamine may decrease infusional tox-

allow 28 days prior to and following major

icity. Dose may need to be modified for

surgery. Use with caution in patients with

renal or pulmonary toxicity. Monitor renal

thrombocytopenia. An increased risk of

function studies and pulmonary function,

thromboembolic events have been reported

including forced expiratory volume in

in combination regimens. May impair fer-

minute, forced vital capacity, and carbon

tility and have adverse effects on fetal devel-

monoxide diffusion in lungs.

opment; adequate contraception must be

used during therapy. May cause infusional

toxicity (discontinue infusion until symp-

BUSULFAN

toms abate) or proteinuria. May potentiate

Myleran, Busulfex

cardiac effects of anthracyclines. Discon-

Antineoplastic

tinue therapy in patients who develop fis-

Tablet: 2 mg

tulas, hypertensive crisis, encephalopathy,

Injection: 6 mg/ml

or nephrotic syndrome.

Pregnancy category D

BLEOMYCIN SULFATE

Indications:

Blenoxane, generic

Treatment of chronic myelogenous leuke-

Antineoplastic antibiotic

mia (CML) and for marrow-ablative con-

Injection: 15 unit vial (1 unit ¼ 1 mg)

ditioning regimens prior to bone marrow

Pregnancy category D

transplant.

312

Formulary

Dosage:

Indications:

Treatment of pediatric brain tumors, neu-

Refer to individual protocol.

roblastoma, testicular tumors, relapsed leu-

For CML induction:

kemia, and solid tumors.

0.06 to 0.12 mg/kg once daily PO (or 1.8

to 4.6 mg/m²/day); titrate dose to maintain

Dosage:

a leukocyte count >40

10⁹/L and discon-

tinue if the leukocyte count drops to

Refer to individual protocol. Many require

10⁹/L.

dose calculation using the modified Calvert

formula to achieve the appropriate area

Hematopoietic stem cell transplant regimen:

under the curve for concentration over time

(dose based on actual body weight; adjust-

rather than dosing by body surface area. IV

ments based on therapeutic drug monitor-

administration over 15 minutes to 1 hour is

ing per protocol)

less toxic than bolus dosing.

12 kg: 1.1 mg/kg/dose q6h for 16 doses

Solid tumors:

over 4 consecutive days

400 to 560 mg/m² every 3 to 4 weeks or per

>12 kg: 0.8 mg/kg/dose q6h for 16 doses

protocol

over 4 consecutive days

Brain tumor protocols:

Notes:

weekly for 4 weeks, then 2 week

175 mg/m²

Do not give to patients with known hyper-

recovery

sensitivity to busulfan; should not be used in

Dose is adjusted based on suppression of

pregnancy or while nursing. May cause

neutrophil and platelet counts or renal

severe bone marrow suppression. Use with

toxicity

caution with other myelosuppressive drugs

or radiation. May cause hemorrhagic cysti-

Bone marrow transplant preparative regimen:

tis. Use with thioguanine may increase

500 mg/m²/day for 3 days

hepatic toxicity. Patients with a known sei-

zure history or those at risk for seizures (e.g.,

Notes:

sickle cell disease) should be placed on a

Do not give to patients with known hyper-

prophylactic antiepileptic drug while receiv-

sensitivitytocarboplatin,cisplatin,orother

ing busulfan.

platinum-containing compounds. Ana-

Metabolism of busulfan may be inhib-

phylaxis may occur within minutes of

ited by antifungal agents (azoles), CYP3A4

administration. May cause hypotension,

inhibitors, dasatinib, and metronidazole

electrolyte abnormalities, nausea, hearing

leading to increased levels and effect.

loss, and peripheral neuropathy. Severe

Busulfan metabolism may be potenti-

marrow suppression or vomiting may

ated by CYP3A4 inducers, deferasirox, and

occur. Reduce dose in impaired renal func-

Echinacea, leading to decreased levels and

tion

(creatinine clearance

<60 mL/min)

effect.

utilizing the modified Calvert formula.

Aminoglycosides may increase serum

CARBOPLATIN

levels/effects of carboplatin and augment

Paraplatin-AQ, generic

ototoxicity and nephrotoxicity; nephro-

Antineoplastic, alkylating agent

toxic drugs may increase renal toxicity of

Injection: 50, 150, and 450 mg vials

carboplatin. Avoid concomitant adminis-

Pregnancy category D

tration of topotecan and taxanes.

Formulary

313

All patients should receive hydration

CASPOFUNGIN

prior to and following administration with

Cancidas

sodium chloride containing solution, with

Antifungal agent, echinocandin

or without mannitol and/or furosemide,

Injection: 50, 70 mg

to ensure good urine output and decrease

risk of nephrotoxicity. Reduce dose for

Pregnancy category C

young children

(<6 months) and with

Indications:

renal impairment. Electrolytes and magne-

sium should be monitored. Acute leukemia

Treatment of invasive aspergillosis in

has been reported as a second malignant

patients refractory or intolerant to ampho-

neoplasm.

tericin B (including lipid formulations) or

itraconzaole; candidemia, candidal intra-

CARMUSTINE

abdominal abscess, or esophageal candidi-

asis; empiric therapy of presumed fungal

BCNU

infection in febrile neutropenic patients.

BiCNU, Gliadel

Antineoplastic, alkylating agent

Dosage:

Injection: 100 mg vial

Preterm neonates to infants

<3 months:

Pregnancy category D

25 mg/m²/dose IV once daily

Indications:

Infants

3 months to adults: 70 mg/m² load-

Treatment of brain tumors and Hodgkin

ing dose IV, followed by 50 mg/m²/dose IV

and non-Hodgkin lymphoma. Wafer

once daily

implant (Gliadel) may be an adjunct to

Patients may benefit from increased daily

surgery and radiation for glioblastoma mul-

dosing to 70 mg/m² once daily dependent

tiforme and high-grade glioma.

on clinical status and response.

Empiric therapy should be given until neu-

Dosage:

tropenia resolves. In neutropenic patients,

Refer to individual protocol.

continue treatment for at least 7 days after

signs and symptoms of infection and neu-

Typical dose may be 200 to 250 mg/m²/dose

tropenia have resolved and at least 14 days

IV every 4 to 6 weeks.

following a positive culture in patients with

Bone marrow transplant conditioning regimen:

documented fungal infection.

300 to 600 mg/m² divided into 1 to 6 doses,

infused over

hours and administered

Notes:

12 hours apart.

Modify dose in patients with hepatic

impairment. Drug interactions exist with

Notes:

cyclosporine, tacrolimus, and rifampin and

Do not give to patients with known hyper-

may require dose modification.

sensitivity tocarmustine.Severe, prolonged

(6 weeks) marrow suppression may neces-

CISPLATIN

sitate change in dosing for subsequent

Platinol, generic

cycles. Toxicity is cumulative and delayed

Antineoplastic, alkylating agent

pulmonary fibrosis may occur in patients

Injection: 50, 100, 150 mg vials

receiving 770 to 1800 mg/m². Cimetidine

potentiates myelosuppressive effects.

Pregnancy category D

314

Formulary

Indications:

and decrease risk of nephrotoxicity. Reduce

Treatment of soft tissue sarcoma, osteosar-

dose for young children (<6 months) and

with renal impairment. Electrolytes and

coma, Hodgkin and non-Hodgkin lym-

phoma, brain tumors, germ cell tumor, and

magnesium should be monitored. Acute

leukemia has been reported as a second

neuroblastoma.

malignant neoplasm.

Dosage:

CLOFARABINE

Refer to individual protocol. Verify any

dosing schedule in which the cisplatin dose

Clolar

exceeds 120 mg/m² per course.

Antineoplastic, antimetabolite

Injection: 1 mg/mL

Intermittent dosing schedule: 37.5 to 100 mg/

m² every 2 to 3 weeks

Pregnancy category D

Daily dosing schedule: 15 to 20 mg/m²/day

for 5 days every 3 to 4 weeks

Indications:

Osteosarcoma and neuroblastoma:

Treatment of relapsed or refractory acute

100 mg/m² once every 3 to 4 weeks

lymphoblastic leukemia, acute myelogenous

leukemia, myelodysplastic syndrome.

Bone marrow transplant: 55 mg/m²/day con-

tinuous infusion for 72 hours (total dose

Dosage:

165 mg/m²)

The rate of intravenous infusion is dose

Children (

1 year) to adults: 40 mg/m²/day

dependent and ranges from a 15- to 20-

for 5 days every 28 days or per protocol

minute infusion to a 6- to 8-hour infusion;

24-hour continuous infusions are also used.

Notes:

Cytokine release may develop into a sys-

Notes:

temic inflammatory response with resultant

Do not give to patients with known hyper-

capillary leak syndrome and organ failure. If

sensitivity to cisplatin or platinum-con-

this occurs, discontinue clofarabine and

taining compounds, preexisting renal

initiate therapy with diuretics, corticoster-

impairment, hearing impairment, and

oids, and albumin. If hypotension resolves

myelosuppression. Increased risk of neph-

without pharmacologic intervention, clo-

rotoxicity when given with other nephro-

farabine may be resumed. The risk for

toxic drugs (aminoglycosides and ampho-

hepatic toxicity and veno-occlusive disease

tericin B). Reduces renal elimination of

is increased in patients who have previously

methotrexate. Cisplatin may increase the

undergone hematopoietic stem cell trans-

levels/effects of aminoglycosides, taxane

plantion. Avoid concomitant use of neph-

derivatives, topotecan, and vinorelbine.

rotoxic and hepatotoxic drugs.

Effects or levels of cisplatin may be

increased with concomitant administration

CYCLOPHOSPHAMIDE

of loop diuretics.

Cytoxan, generic

All patients should receive hydration

Antineoplastic, alkylating agent

prior to and for 24 hours after administra-

Tablets: 25, 50 mg

tion with a sodium chloride containing

Injection: 500 mg, 1 g, 2 g vials

solution (with or without mannitol and/

or furosemide), to ensure good urine output

Pregnancy category D

Formulary

315

Indications:

Treatment of Hodgkin and non-Hodgkin

Used with corticosteroids to prolong organ

lymphoma, acute leukemia, and neuroblas-

and patient survival in kidney, liver, heart,

toma. Conditioning therapy for bone mar-

and bone marrow transplants; treatment of

row transplant. Treatment of nephrotic syn-

aplastic anemia and other bone marrow

drome, systemic lupus erythematosus, and

failure syndromes.

other rheumatic diseases.

Dosage (Sandimmune):

Dosage:

Due to better absorption, lower doses of

Refer to individual protocol.

Neoral and Gengraf may be required com-

Acute lymphoblastic leukemia:

1000

pared to Sandimmune.

1200 mg/m²/dose, in consolidation and

Oral:

delayed intensification phases

Initial: 15 mg/kg single oral dose, beginning

Bone marrow transplant conditioning:

4 to 12 hours pretransplant

50 mg/kg/day IV for 3 to 4 days

Maintenance: 15 mg/kg/day PO for 1 to 2

Nephrotic syndrome: 2 to 3 mg/kg/day orally

weeks posttransplant, decrease by 5% per

for up to 12 weeks

week to 3 to 10 mg/kg/day

Systemic lupus erythematosus: 500 to 750 mg/

Intravenous:

m² IV monthly; maximum dose 1g/m²

Initial: 5 to 6 mg/kg IV single dose, admin-

Juvenile idiopathic arthritis/vasculitis: 10 mg/

istered over 2 to 6 hours, beginning 4 to 12

kg IV every 2 weeks

hours pretransplant. Continue same IV dose

posttransplant until patient able to tolerate

Notes:

oral form.

Do not give to patients with known hyper-

Conversion from IV to PO dose (1:3 ratio):

sensitivity to cyclophosphamide. Dose

Multiply total daily IV dose by 3 and admin-

may need to be adjusted for myelosup-

ister in two divided oral doses per day.

pression or impaired renal function.

Mesna should be given with high-dose

Notes:

therapy (>1 g/m²/day) to reduce potential

Do not give to patients with known hyper-

of hemorrhagic cystitis. Allopurinol may

increase the myelotoxicity of cyclophos-

sensitivity to cyclosporine (castor oil is an

ingredient in the preparation). May cause

phamide by inhibiting its metabolism.

Ensure aggressive hydration with sodium

nephrotoxicity, hepatotoxicity, hypomag-

nesemia, hyperkalemia, hyperuricemia,

chloride containing fluids and frequent

bladder emptying.

hypertension, hursuitism, acne, gastrointes-

tinal symptoms, tremor, leukopenia, head-

CYCLOSPORINE

ache, and gingival hyperplasia. Use with

caution with concomitant administration

Sandimmune, Neoral, Gengraf

of other nephrotoxic drugs (e.g. amphoter-

Immunosuppressant

icin B, aminoglycosides, tacrolimus, acyclo-

Capsules: 25, 50, 100 mg

vir, NSAIDs). Requires close monitoring

Solution: 100 mg/mL

of renal and hepatic function and frequent

Injection: 50 mg/mL

determination of trough levels (drawn just

Pregnancy category C

prior to dose at steady state).

316

Formulary

Cyclosporine is a substrate for the

High-dose cytarabine:

(AML, relapsed or

cytochrome P450

3A4

oxidase system.

refractory ALL, non-Hodgkin lymphoma)

Drug interactions include ketoconazole,

3 g/m²/dose q12h for up to 12 doses

itraconazole, fluconazole, erythromycin,

For central nervous system (CNS) treatment

and methylprednisolone, which increase

and prophylaxis (intrathecal dose): Dosing

the cyclosporine concentration by inhibit-

per age

ing hepatic metabolism. Cimetidine may

Drug may be combined with other intra-

increase cyclosporine concentration. Refer

thecal agents such as hydrocortisone and

to the Physicians’ Desk Reference for more

methotrexate per protocol

extensive drug interaction information.

Children <1 year: 20 mg

CYTARABINE HYDROCHLORIDE

Children 1 to <2 years: 30 mg

Ara-C

Children 2 to <3 years: 50 mg

Cytosar-U, generic

Children

3 years and adults: 70 mg

Antineoplastic, antimetabolite

Injection: 100 and 500 mg, 1 and 2 g vials

Notes:

Pregnancy category D

Do not give to patients with known hyper-

sensitivity to cytarabine. May need to reduce

Indications:

dose with myelosuppression or hepatic dys-

function. Causes significant bone marrow

Treatment of acute lymphoblastic and

suppression. High doses have been associated

myelogenous leukemia (ALL and AML),

with gastrointestinal, CNS, pulmonary, and

refractory non-Hodgkin lymphoma, and

ocular toxicities as well as cardiomyopathy.

may be used in conditioning regimens for

May cause nausea, vomiting, mucositis, fever,

bone marrow transplantation. High doses

headache, somnolence, anorexia, alopecia,

penetrate the blood-brain barrier into the

conjunctivitis, ataxia, diarrhea, hepatic dys-

cerebrospinal fluid.

function, and peripheral neuropathy. Pro-

Dosage:

phylaxis with dexamethasone ophthalmic

drops may decrease effects of conjunctivitis.

Refer to individual protocol.

When prepared for intrathecal use,

Infants under 3 years:

added precautions should be taken when

3.3 mg/kg/day IV/SC for

days

(dose

other medications are also being delivered

reduced in children with Down syndrome)

to ensure appropriate labeling and handling

such that only medications intended for

Children and adults:

administration in the CNS are with the

Remission induction:

patient for the procedure.

200 mg/m²/day for 5 days at 2-week inter-

vals as a single agent; 100 to 200 mg/m²/

DACARBAZINE

day (or 2 to 6 mg/kg/day) for 5 to 10 days

DTIC

or every day until remission (as a part of

Antineoplastic

combination chemotherapy). Give IV con-

Injection: 100, 200 mg

tinuous infusion or every 12 hours.

Pregnancy category C

Maintenance:

1 to 1.5 mg/kg IM/SC as a single dose at 1- to

Indications:

4-week intervals or 70 to 200 mg/m²/day for

Treatment of Hodgkin lymphoma and solid

2 to 5 days at monthly intervals

tumors.

Formulary

317

Dosage:

Notes:

Do not give to patients with known hyper-

Refer to individual protocol.

sensitivity to dactinomycin. Avoid in infants

Solid tumors:

<6 months of age because of increased

200 to 470 mg/m²/day IV over 5 days every

adverse events. Use with caution in patients

3-4 weeks

with hepatobiliary dysfunction or who have

Neuroblastoma:

received radiation (radiation recall effect).

Reduce dosage in patients receiving concur-

800 to 900 mg/m² IV as a single dose on day

rent radiation. Avoid extravasation. May

1 of the cycle every 3 to 4 weeks

cause myelosuppression, anorexia, vomit-

Hodgkin lymphoma:

ing, diarrhea, and stomatitis.

375 mg/m² on days 1 and 15 of each course,

repeated every 28 days

DAPSONE

Generic

Notes:

Antibacterial

Do not give to patients with known hyper-

Tablet: 25, 100 mg

sensitivity to dacarbazine. Dosage reduc-

tion may be necessary in patients with

Pregnancy category C

renal or hepatic insufficiency. Drug extrav-

asation may result in tissue damage and

Indications:

severe pain.

Prevention and treatment of Pneumocystis

jiroveci pneumonia (PCP) in immunocom-

DACTINOMYCIN

promised hosts; treatment of Toxoplasma

Actinomycin D

gondii and Mycobacterium leprae.

Cosmegen

Antineoplastic antibiotic

Dosage:

Injection: 500 mg vial

Children 1 month to <12 years: 2 mg/kg/

Pregnancy category D

day or 4 mg/kg/dose once weekly (maximum

100 mg/dose daily or 200 mg/dose weekly)

Indications:

Children >12 years and adults: 100 mg/day

Treatment of Wilms tumor, rhabdomyosar-

or 200 mg once weekly

coma, Ewing sarcoma, ovarian germ cell

tumor, and gestational trophoblastic

Notes:

neoplasm.

Do not give to patients with known hyper-

sensitivity to dapsone. Dapsone is a strong

Dosage:

oxidizing agent and may cause hemolysis in

susceptible individuals. Screening for glu-

Refer to individual protocol. Note that

cose-6-phosphate dehydrogenase

(G6PD)

medication orders for dactinomycin may

deficiency is suggested in high-risk popula-

be written in micrograms (mcg) or milli-

tions (e.g., Mediterranean) and should not

grams (mg).

be used if positive. May be safe to use in

Children over 6 months to adult:

the African-American variant of G6PD defi-

15 mcg/kg/day or 400 to 600 mcg/m²/day once

ciency though some degree of hemolysis

daily for 5 days; repeat every 3 to 6 weeks.

may occur. May also cause marrow sup-

Higher doses are given in some protocols.

pression or methemoglobinemia. Drug

318

Formulary

interactions occur, primarily with rifampin.

Chapter 30). This may be an acute or late

May be given to immunosuppressed

effect and monitoring with ECHO or

patients who cannot tolerate or are allergic

MUGA and ECG is required per protocol.

to cotrimoxazole.

Secondary leukemia has been reported.

Extravasation may result in severe local

tissue necrosis and require intervention. A

DAUNORUBICIN HYDROCHLORIDE

transient red-orange discoloration of the

Cerubidine

urine, sweat, saliva, and tears may occur for

Antineoplastic antibiotic, anthracycline

up to 48 hours after a dose.

Injection: 20 mg vial

Pregnancy category D

DEFEROXAMINE MESYLATE

Desferal

Indications:

Chelating agent; antidote, iron toxicity

Treatment of acute lymphoblastic and acute

Injection: 500, 2000 mg

myelogenous leukemia (ALL and AML);

Pregnancy category C

used in combination with other chemother-

apeutic agents during ALL and AML induc-

Indications:

tion therapy.

Treatment of acute iron intoxication and

Dosage:

chronic transfusional iron overload.

Refer to individual protocol.

Dosage:

Infants <2 years or <0.5 m²should have dos-

Chronic iron overload:

ing based on body weight:

25 to 60 mg/kg/day SC/IV over 8 to 24

0.67 mg/kg/day IV with frequency depen-

hours; maximum 2 g/24 hours

dent on protocol

Children

2 years:

Notes:

25 to 60 mg/m² IV with frequency depen-

Avoid in severe renal disease, anuria, or

dent on protocol

primary hemochromatosis. Prolonged use

can result in cataracts, decreased visual acu-

Notes:

ity, impaired peripheral, night, and color

Do not give to patients with known hyper-

vision, and neurotoxicity-related auditory

sensitivity to daunorubicin, congestive heart

abnormalities (i.e., high-frequency hearing

failure, arrhythmias, or preexisting bone

loss). Periodic hearing and vision exams

marrow suppression. Reduce dosage in

should be performed. High doses (>60 mg/

patients with hepatic, biliary, or renal

kg) especially in children

3 years have

impairment. May cause myelosuppression,

been associated with growth retardation;

nausea, vomiting, alopecia, stomatitis, and

reduction in dosage may increase growth

pigmentation of nail beds. Irreversible myo-

velocity.

cardial toxicity may occur as the cumulative

Discontinue use in febrile patients

dosage approaches 550 mg/m² (or 400 mg/

because of increased susceptibility to infec-

m² with chest irradiation or concomitant

tion with Yersinia enterocolitica. Avoid rapid

cyclophosphamide administration; based

IV administration as flushing, urticaria,

on anthracycline dose equivalents, see

hypotension, and shock have been reported.

Formulary

319

DEFERASIROX

caution in patients with hepatic disease

Exjade

as well as in patients with concomitant

anticoagulant, NSAID, or corticosteroid

Chelating agent, iron; antidote, iron toxicity

Tablet, for oral suspension: 125, 250, 500 mg

use. Monitor transaminases and liver

function. May cause ocular or auditory

Pregnancy category C

disturbances, skin rash, gastrointestinal

pain, headache, diarrhea, sore throat,

Indications:

nausea, and vomiting. Interruption or

Treatment of chronic iron overload due to

dose modification may be necessary for

blood transfusions.

evidence of renal, hepatic, or gastrointes-

tinal dysfunction.

Dosage:

Children

2 years to adults: 20 to 40 mg/kg

DESMOPRESSION ACETATE

daily (round to nearest whole tablet)

DDAVP, Stimate

Initiate therapy at

20 mg/kg/day. Adjust

Antihemophilic, hemostatic agent

dose every 3 to 6 months based on serum

Injection: 4 mg/mL (1 mL)

ferritin levels or other measurement of iron

Tablets: 0.1, 0.2 mg

overload; increase by

5 to

10 mg/kg/day

Solution: 1500 mcg/mL, 150 mcg/spray (25

(round to nearest whole tablet). Consider

sprays, 2.5 mL) (Stimate)

higher doses for ferritin >2500 ng/mL. Con-

100 mcg/mL, 10 mcg/spray (50 sprays, 5 mL,

sider holding dose or discontinuing for

with rhinal tube) (DDAVP)

ferritin

<500 ng/mL. Maintenance range:

Pregnancy category B

20 to 40 mg/kg/day.

Consider giving daily dose divided BID to

Indications:

patients experiencing abdominal discom-

Intranasal Stimate or IV DDAVP are indi-

fort or nausea and vomiting.

cated for maintenance of hemostasis in

Do not chew or swallow whole tablets. Dis-

patients with mild or moderate hemophilia

perse tablets in water, apple juice, or orange

A during surgery and postoperatively as well

juice

(use

3.5

ounces for doses

<1 g; 7

as treatment of mucosal bleeds in patients

ounces for doses

1 g); stir to form suspen-

with von Willebrand disease and mild

sion and drink entire contents. Rinse

hemophilia A. DDAVP is indicated for the

remaining residue in glass and drink.

treatment of central diabetes insipidus and

Administer at the same time every day, at

primary nocturnal enuresis.

least 30 minutes prior to food ingestion.

Dosage:

Notes:

Von Willebrand disease, hemophilia A, bleed-

Do not give to patients with known

ing diathesis:

hypersensitivity to deferasirox, low platelet

IV: 0.3 mcg/kg, dilute in normal saline (10 mL

counts (<50

10⁹/L), creatinine clearance

for patients <10 kg and 50 mL for

10 kg),

<40 mL/min, or serum creatinine >2

infuse slowly over 15 to 30 minutes

age-appropriate upper limit of normal.

Assess patients for renal impairment and

concurrent nephrotoxic drugs. May cause

Intranasal spray

(Stimate): one puff

intermittent proteinuria. Monitor serum

(150 mcg) for children under 50 kg and 2

electrolytes and urinalysis. Use with

puffs (300 mcg) for children over 50 kg

320

Formulary

Peak effect is 1 to 5 hours with intranasal

A desmopressin challenge to document

route, 1.5 to 3 hours with IV route, and 2 to

responsiveness to these agents is indicated

7 hours with PO route. Duration of effect is

in patients with bleeding disorders to doc-

5 to 24 hours. Tachyphylaxis may occur

ument benefit prior to emergent use.

with repeated dosing within 72 hours.

Note: intranasal forms come in two concen-

Diabetes insipidus:

trations, use as specifically indicated.

Children

12 years: Start with 0.05 mg/dose

BID and titrate to effect (i.e., control of

DEXAMETHASONE

excessive thirst and urination); usual dose

Decadron, generic

range is 0.1 to 0.8 mg/24 hours.

Corticosteroid, anti-inflammatory, imm-

Children >12 years and adults: Start with

unosuppressant

0.05 mg/dose BID and titrate to effect; usual

Tablets: 0.25, 0.5, 0.75, 1.5, 2, 4, 6 mg

dose range is 0.1 to 1.2 mg/24 hours divided

Solution: 1 mg/mL

BID or TID or

Ophthalmic solution: 0.1% (5 mL)

Injection: 4 mg/mL

Children 3 months to 12 years: 5 to 30 mcg/24

hours intranasally divided BID.

Pregnancy category C

Children >12 years and adults: 10 to 40 mcg/

24 hours intranasally divided daily to TID;

Indications:

titrate dose to effect.

Used systemically for chronic inflamma-

Nocturnal enuresis (

6 years):

tion, allergic, hematologic, neoplastic (e.g.,

0.2 mg PO at bedtime, titrate to effect (max-

leukemia), autoimmune disease, cerebral

imum dose 0.6 mg) or

edema and increased intracranial pressure,

20 mcg intranasal at bedtime; divide and

and septic shock. Utilized as an antiemetic

for chemotherapy-induced nausea and

administer 10 mcg in each nostril.

vomiting and as an ophthalmic solution for

Notes:

control of chemical conjunctivitis from con-

Do not give to patients with known hyper-

comitant administrations of agents such as

sensitivity to desmopressin. Avoid in

high-dose cytarabine.

patients with severe type I, type IIB, or

platelet-type von Willebrand disease, hemo-

Dosage:

philia B, and severe hemophilia A (<1%

Antiemetic:

factor VIII activity). Patients with moderate

hemophilia A may not demonstrate an ade-

0.2 mg/kg/dose (5 mg/m²/dose) IV 30 min-

quate response. Use cautiously in patients

utes prior to and every

hours after

with a predisposition to thrombophilia,

chemotherapy

electrolyte imbalance, and hypertensive car-

Brain tumor associated cerebral edema:

diovascular disease. May cause headache,

Loading dose: 1 to 2 mg/kg IV as a single

nausea, emesis, seizures, blood pressure

dose; maintenance: 1 to 2 mg/kg/day IV in 4

changes, hyponatremia, nasal congestion,

to 6 divided doses for 1 to 5 days, or longer;

abdominal cramps, and hypertension.

maximum dose 16 mg/24 hours

Avoid in young children <2 years due to

Spinal cord compression with neurologic

hyponatremia and seizures. Not FDA

abnormalities:

approved in <6 years for treatment of noc-

turnal enuresis.

2 mg/kg/24 hours IV divided q6 hours

Formulary

321

Chemotherapy:

2000 mg; followed by 500 mg/m²/dose on

days 3; maximum dose 1000 mg.

Refer to individual protocol.

Do not use dimethylsulfoxide

(DMSO) in

Doses range from 6 to 20 mg/m²/day for 5 to

patients receiving dexrazoxane for anthracy-

7 days (may be longer in induction therapy

cline-induced extravasation.

for acute lymphoblastic leukemia).

Ophthalmic use:

Notes:

Instill 1 to 2 drops into the conjunctival sac

Limited experience in pediatrics (high risk

bilaterally. May use q1-2 hours as needed to

acute lymphoblastic leukemia). Use only in

prevent and control symptoms.

patients with a cumulative doxorubicin

dose of 300 mg/m² who are continuing to

Notes:

receive anthracyclines or as directed by pro-

tocol. Dose-limiting toxicity is myelosup-

Do not administer during active, untreated

infections with viral, fungal, or bacterial

pression, which may be additive to chemo-

therapy. May chelate heavy metals, leading

organisms. Prolonged use may cause bone

pain, glucose intolerance, hypertension, fat

to increases in calcium, iron, and triglycer-

ides and decreases in sodium and zinc. May

redistribution and striae, and avascular

necrosis of bone.

have antitumor effects.

DIMETHYL SULFOXIDE

DEXRAZOXANE

DMSO

Zinecard, generic

Antidote (anthracycline extravasation)

Antidote, anthracycline; antidote (anthracy-

Topical: 50% solution

cline extravasation)

Injection: 250, 500 mg

Pregnancy category C

Pregnancy category C/D

Indications:

Used after cooling for local control of

Indications:

extravasation of anthracyclines. May also

Reduction of anthracycline-induced cardi-

be indicated for extravasation of ifosfamide,

otoxicity. Treatment for local tissue extrav-

cisplatin, fluorouracil, and carboplatin.

asation of anthracyclines. Currently, FDA

approved in adults only.

Dosage:

Apply 1 to 2 mL within 10 to 25 minutes

to affected area, then every 4 to 8 hours

Refer to individual protocol.

for 7 to 14 days, until resolution. Allow to

Children and adults: 10:1 dose ratio with

dry and apply clean, dry dressing. Vitamin

doxorubicin for acute lymphoblastic leuke-

E or aloe vera have been used topically

mia (ALL; i.e., 300 mg/m² dexrazoxane for

following the first application to alleviate

30 mg/m² doxorubicin). Complete anthra-

local burning or stinging (ensure DMSO

cycline administration within 30 minutes of

has dried).

start of dexrazoxane.

Treatment for extravasation: Adolescents

Notes:

years to adults: 1000 mg/m²/dose within 6

The role of DMSO in the treatment of

hours on days 1 and 2; maximum dose

anthracycline

extravasation

remains

322

Formulary

controversial. Do not use with dexrazoxane.

cadmium poisoning. Use with caution in

Use with local cooling of tissues.

patients with G6PD deficiency (may cause

hemolysis) and peanut sensitivity. Hydrate

DIMERCAPROL

and alkalinize urine to protect the kidneys.

May cause hypertension, tachycardia, gastro-

British anti-Lewisite (BAL)

intestinal disturbance, headache, fever,

Chelating agent (antidote for gold, mercury,

transient neutropenia, and nephrotoxicity.

lead, and arsenic toxicity)

Symptoms may be relieved by antihistamines.

Injection: 100 mg/mL

Ensure calcium salt is given if edetate calcium

Pregnancy category C

disodium is used in conjunction with BAL.

Indications:

DIPHENHYDRAMINE

Antidote to gold, mercury, and arsenic poi-

Benadryl, generic

soning; used in conjunction with edetate cal-

Antihistamine

cium disodium to treat severe lead poisoning.

Capsules/tablets (OTC): 25, 50 mg

Chewable tablets: 12.5 mg

Dosage:

Elixir: 12.5 mg/5 mL

Injection: 50 mg/mL

For severe lead poisoning (lead level

70 mcg/

dL) or encephalopathy:

Pregnancy category B

25 mg/kg/day divided q4h deep IM for a

minimum of 72 hours, may give up to 5

Indications:

days in severely symptomatic patients. Cal-

Treatment of allergic symptoms, anaphy-

cium sodium EDTA should be started at a

laxis, medication and transfusion reactions,

dose of 50 mg/kg/day continuous IV infu-

chemotherapy and other induced nausea

sion immediately after the second dimer-

and vomiting, and motion sickness; used

caprol dose. If symptoms of encephalopathy

as an antitussive or for mild sedation.

persist, a second course of treatment can

Prevents or treats metocloperamide- and

begin after a minimum of 2 days of rest

phenothiazine-induced dystonic reactions.

following the initial 5-day course. Therapy

should be continued until the patient is

Dosage:

clinically stable. Once this occurs, a 10- to

14-day period of equilibration should occur

Antiemetic and antivertigo:

before again measuring the lead level. If the

0.5 to 1 mg/kg/dose q6h PO, IM, or IV

level remains

70 mcg/dL, another course

Pruritus:

of double therapy should be provided.

0.5 to 1 mg/kg/dose q6h PO, IM, or IV

Less severe lead poisoning (45 to <70 mcg/dL):

Treatment with dimercaprol is not recom-

Notes:

mended in this situation due to toxicity;

Do not give to patients with known hyper-

patients should be treated with succimer or

sensitivity to diphenhydramine. Do not

calcium disodium EDTA instead.

use with concurrent MAO inhibitors, in

acute attacks of asthma, or in patients with

Notes:

GI or urinary obstruction. Use with caution

Do not give to patients with hepatic or renal

in patients with glaucoma, peptic ulcer

insufficiency. Do not use in iron, selenium, or

disease, urinary tract obstruction, and

Formulary

323

hyperthyroidism. Avoid alcohol. Note: many

ECHO or MUGA and ECG after every 75

preparations contain alcohol. May cause

to 100 mg/m² of anthracycline given. Car-

sedation, nausea, vomiting, xerostomia,

diac toxicity may be acute or delayed and

blurred vision, and central nervous system

long-term monitoring is essential.

effects. May cause paradoxical activation in

Modify dosage in renal impairment.

children.

May cause severe bone marrow suppres-

sion, alopecia, mucositis, and transient

DOXORUBICIN HYDROCHLORIDE

(48 hour) red-orange discoloration of the

urine, sweat, saliva, and tears. Extravasa-

Adriamycin, Doxil (liposomal formulation)

tion may result in severe local tissue necro-

Antineoplastic antibiotic, anthracycline

sis. May cause photosensitivity reactions

Injection: 10, 50 mg vials (protect from light)

and patients should be instructed to avoid

Pregnancy category D

excessive exposure to sunlight and utilize

sunblock (SPF

15).

Indications:

Treatment of acute lymphoblastic leukemia,

DRONABINOL

acute myelogenous leukemia, lymphoma,

Marinol, tetrahydrocannabinol

Wilms tumor, and sarcoma.

Cannabinoid

Capsules: 2.5, 5, and 10 mg

Dosage:

Pregnancy category C

Refer to individual protocol.

20 to 90 mg/m² IV in repeated doses (may be

Indications:

weekly or monthly or per phase of therapy).

Infusions may be over 15 minutes, several

Treatment of nausea and vomiting associ-

hours, or as a continuous infusion over 24

ated with chemotherapy in patients who

to 48 hours. Although controversial, longer

have failed to respond to conventional

infusions may be more cardioprotective, espe-

antiemetic therapy; treatment of anorexia

cially when high cumulative doses (i.e., >450

associated with weight loss in patients with

mg/m²) are anticipated. Children

<12 kg

human immunodeficiency virus

(HIV).

and infants are dosed based on weight rather

Evidence of benefit in chemotherapy-

than body surface area. The use of cardiopro-

induced anorexia is mixed; no well-con-

tective agents such as dexrazoxane is being

trolled studies have been performed in

studied in pediatric trials.

children.

Notes:

Dosage:

Do not give to patients with known hyper-

Antiemetic:

sensitivity to doxorubicin, severe congestive

5 mg/m²/dose 1 to 3 hours prior to chemo-

heart failure or cardiomyopathy, or preex-

therapy, then q2-4h; maximum 6 doses/24

isting myelosuppression. Use with caution

hour, 15 mg/m²/dose in adults. Titrate dose

in patients who have received very high

to effect.

cumulative doses of anthracyclines

(i.e.,

Appetite stimulant:

550 mg/m² or

400 mg/m² with concom-

itant use of cyclophosphamide or chest

Adult dosing: 2.5 mg BID 1 hour prior to

radiation; based on anthracycline dose

lunch/dinner; if not tolerated, reduce dose to

equivalents, see Chapter

30). Monitor

2.5 mg qhs; maximum dose 20 mg/24 hour.

324

Formulary

Notes:

and frequent monitoring of serum electro-

Do not give to patients with known hyper-

lytes including calcium and phosphorus,

renal function, and urinalyses. Establish

sensitivity to any cannabinoid or sesame oil.

Do not use in patients with history of sub-

urine flow prior to administration and

maintain hydration/urine output through-

stance abuse or mental illness. Use with

out course of therapy. Dose reduction is

caution in heart disease, seizures, and hepatic

recommended for mild renal disease. Mon-

disease. A dose-related “high” (easy laughing,

itor with continuous ECG due to risk for

elation, or heightened awareness) is reported

arrhythmias. Rapid IV infusion can result in

in one-quarter of patients using cannabi-

sudden increase in intracranial pressure in

noids as antiemetics. Other side effects

patients with cerebral edema. May cause

include dizziness, anxiety, difficulty concen-

zinc and copper deficiency. May be admin-

trating, hypotension, and increased appetite.

Psychological and physiologic dependence

istered IM; give with

0.5% prilocaine.

Ensure calcium salt is given.

may occur, but addiction is uncommon. It

is a controlled (Schedule III) substance.

ENOXAPARIN

EDETATE CALCIUM DISODIUM

Lovenox

Anticoagulant, low-molecular-weight hepa-

Calcium EDTA, CaNa₂EDTA

rin (LMWH)

Calcium disodium versenate

Heavy metal antagonist; antidote, lead

Injection

(prefilled syringe):

30 mg/0.3 mL,

40 mg/0.4 mL, 60 mg/0.6 mL, 80 mg/0.8 mL,

toxicity

Injection: 200 mg/L

100 mg/mL

Approximate anti-factor Xa activity:

Pregnancy category B

100 IU/mg

Pregnancy category B

Indications:

Used as an adjunct in the treatment of acute

Indications:

and chronic lead poisoning.

Prophylaxis and treatment of throm-

Dosage:

boembolic disorders such as deep vein

thrombosis

(DVT) following surgery or

For severe lead poisoning (lead level

70 mcg/

trauma and pulmonary embolus.

dL) and/or encephalopathy:

50 mg/kg/day

(continuous IV infusion)

Dosage:

given in combination with dimercaprol

Treatment of DVT or thromboembolus (TE):

(BAL). Give at a separate site starting with

Infants <1 month: 1.625 mg/kg q12h SC

the second dimercaprol dose.

Less severe lead poisoning (45 to <70 mcg/dL):

Infants 1 to 12 months: 1.5 mg/kg q12h SC

Children 1 to 6 years: 1.375 mg/kg q12h SC

25 mg/kg/day as a continuous or intermit-

tent IV infusion

Children 6 to 21 years: 1.25 mg/kg q12h SC

Titrate dose to achieve peak anti-factor Xa

Notes:

levels of 0.5 to 1.0 U/mL. Peak anti-factor Xa

Do not give to patients with severe renal

levels should be drawn 4 hours after admin-

disease or anuria. Requires inpatient admis-

istration of a steady state dose (minimum 2

sion with aggressive intravenous hydration

to 3 prior doses).

Formulary

325

See Chapter 10 for further guidelines. Some

hypochromic anemia, thrombocytopenia,

centers advocate that TPA be given con-

and pain/erythema at the injection site.

comitantly with enoxaparin in high risk

In case of overdose, protamine sulfate

situations

(i.e., large central embolism).

can be given although the reversal is not

Prophylaxis or treatment with enoxaparin

complete as with unfractionated heparin.

may continue for prolonged periods depen-

1 mg of protamine sulfate neutralizes

dent on the underlying risks for thrombo-

approximately 0.6 to 0.7 mg of enoxaparin.

philia and response to therapy. For those

patients that will be maintained with oral

EPOETIN ALFA

anticoagulation (e.g., warfarin), 4 to 5 days

Recombinant human erythropoietin

of overlap with enoxaparin should be given

Epogen, Procrit

in order to achieve a therapeutic interna-

Blood formation

tional normalized ratio (INR).

Injection:

2000,

3000,

4000,

10,000,

DVT/TE prophylaxis:

20,000 U/mL (1 mL)

0.5 mg/kg q12h SC

Pregnancy category C

Anti-factor Xa levels do not need to be

followed in patients on prophylactic dosing.

Indications:

Data is limited but 1 mg/kg once daily dos-

Treatment of anemia associated with

ing can be considered in patients with com-

chronic renal failure, anemia related to

pliance issues and in those with difficulty

therapy with zidovudine (AZT) in HIV-

giving twice daily SC injections. An insuflon

infected patients, and anemia of prematu-

catheter should also be considered.

rity. Usage in cancer patients remains con-

Note: LMWH may be given IV at the same

troversial. May be considered as an adjunct

dose as SC.

for anemia treatment in patients with reli-

gious beliefs against utilization of blood

Notes:

transfusion.

Do not give to patients with known hyper-

sensitivity to enoxaparin or pork products

Dosage:

(derived from porcine intestinal mucosa),

Anemia in chronic renal failure:

active major bleeding, prosthetic heart valves,

acute heparin-induced (or LMWH-induced)

50 to 150 U/kg administered SC/IV three

thrombocytopenia, and recent major surgery

times a week; higher doses may be needed.

or cerebral hemorrhage. Use of the medica-

Dose is individualized to achieve and main-

tion should be discussed in patients with

tain the lowest hemoglobin sufficient to

religious beliefs which prohibit the consump-

avoid transfusion, not to exceed 12 g/dL.

tion of pork products. Do not give to patients

Anemia in AZT-treated HIV patients:

with drug-induced thrombocytopenia. Use

100 U/kg SC three times a week; dose range

with caution in patients with recurrent gas-

50 to 4000 U/kg two to three times per week

trointestinal ulcers, bleeding diathesis, and

severe renal dysfunction; lower initial doses

Anemia in cancer patients:

should be given to patients with renal insuf-

600 U/kg IV once weekly; dose titrated to

ficiency and failure. Do not use with concur-

effect (maximum 40,000 U). Do not initiate

rent spinal or epidural anesthesia or lumbar

therapy at Hgb

10 g/dL; adjust dose to

puncture for chemotherapy. May cause fever,

maintain the lowest Hgb level needed to

confusion, edema, nausea, hemorrhage,

avoid transfusions. Adult dose

150 U/kg

326

Formulary

SC three times a week or 40,000 U SC once

AML remission induction:

weekly.

150 mg/m²/day for 2 to 3 days for 2 to 3

Anemia of prematurity:

cycles in induction, followed by 250 mg/m²/

day for 3 days in consolidation and inten-

No FDA-approved dosing regimen, a vari-

sification courses. Dose per body weight in

ety of different doses and schedules have

infants.

been used. Utility in decreasing need for

transfusion in VLBW and ELBW infants is

Brain tumors:

not well-proven.

150 mg/m²/day for 2 days; may also be given

long term orally (using injection for oral

Notes:

administration); has good central nervous

Do not give to patients with known hyper-

system penetration

sensitivity to albumin, uncontrolled hyper-

Neuroblastoma:

tension, and in newborns with neutropenia.

100 mg/m²/day over 1 hour days 1 to 5 or

Use with caution in patients with porphyria

alternate day for 3 doses q3-4 weeks for 3 to

or a history of seizures. May cause headache

4 courses

and elevated blood pressure. Meta-analyses

have shown that usage leads to a significant

BMT conditioning regimen:

increased risk of death, thrombosis, and

160 mg/m²/day for 4 days

serious cardiovascular events in cancer

patients.

Notes:

Evaluate iron stores (ferritin and total

Do not give to patients with known hyper-

iron binding capacity [TIBC]) before ther-

sensitivity to etoposide. Use with caution and

apy initiation. Iron supplementation is

consider dose reduction in patients with

recommended unless iron stores are already

renal or hepatic impairment. May cause

in excess.

facial flushing, fever, fatigue, nausea, vomit-

ing, bone marrow suppression, and periph-

ETOPOSIDE

eral neuropathy. Associated with second

VP-16

malignant neoplasms, likely dose and fre-

VePesid, Toposar

quency related.

Antineoplastic, mitotic inhibitor

Give IV infusions over at least 1 hour

Capsule, softgel: 50 mg

due to associated hypotension with rapid

Injection: 20 mg/mL

infusion. Infusion should be stopped or

infusion rate be decreased with hypoten-

Pregnancy category D

sion. After fluid resuscitation, the infusion

may be restarted at a slower rate if stopped

Indications:

and the hypotension resolved.

Treatment of germ cell tumors, lymphoma,

brain tumors, acute myelogenous leukemia

EUTECTIC MIXTURE OF LIDOCAINE

(AML), neuroblastoma, rhabdomyosar-

AND PRILOCAINE

coma, histiocytosis, and conditioning for

bone marrow transplantion (BMT).

EMLA, LMX

Local anesthetic, topical anesthetic

Dosage:

Cream: 5, 30 g tubes

Refer to individual protocol.

Pregnancy category B

Formulary

327

Indications:

Prophylaxis:

Used as a topical anesthetic applied to nor-

Premature infant: 2 mg/kg/day, maximum

mal intact skin to provide local anesthesia

dose 15 mg/24 hour

for minor procedures such as venipuncture,

Term infant: 1 to 2 mg/kg/day, maximum

placement of peripheral venous access line,

dose 15 mg/24 hour

lumbar puncture, and minor dermatologic

procedures.

Notes:

Do not give to patients with known hyper-

Dosage:

sensitivity to iron salts, hemochromatosis,

Apply 2.5 g per site to normal intact skin

and transfusional iron overload. Absorption

and cover with occlusive dressing for 30 to

of iron is decreased when given with tetra-

60 minutes prior to procedure.

cycline, antacids, or milk. Less gastrointes-

tinal irritation when given with food. Con-

Notes:

current administration of 200 mg or more

of vitamin C per

30 mg elemental iron

Do not give to patients with known hyper-

increases absorption of oral iron; iron

sensitivity to lidocaine, prilocaine, or

replacement products should be given with

other local anesthetic or methemoglobine-

orange juice. May cause constipation, dark

mia. Do not use in neonates <37 weeks

stools, nausea, and epigastric pain.

gestation or in infants <12 months of age

who are receiving concurrent treatment

FERROUS SULFATE

with methemoglobin producing agents

(e.g., sulfa drugs, dapsone, phenobarbital,

Feosol, Fer-In-Sol

benzocaine).

Iron (20% elemental Fe)

Tablet OTC: 300 mg (60 mg Fe), 324 mg

FERROUS GLUCONATE

(65 mg Fe), 325 mg (65 mg Fe)

Drops (Fer-in-sol) OTC: 75 mg (15 mg Fe)/

Fergon

0.6 mL

Iron (12% elemental Fe)

Elixir OTC: 220 mg (44 mg Fe)/5 mL

Tablets (OTC): 240 mg (29 mg Fe), 300 mg

Oral liquid OTC: 300 mg (60 mg Fe)/5 mL

(36 mg Fe), 325 mg (39 mg Fe)

Pregnancy category A

Indications:

Prevention and treatment of iron deficiency

anemia.

Dosage:

See Ferrous Gluconate.

Dose is expressed in terms of elemental iron

Severe iron deficiency anemia:

Notes:

4 to 6 mg/kg/day PO in two to three divided

See Ferrous Gluconate.

doses

Mild to moderate iron deficiency anemia:

FERROUS FUMARATE

3 mg/kg/day PO in 1 to 2 divided doses

Iron salt (33% elemental Fe)

328

Formulary

Tablet OTC: 90 mg (29.5 mg Fe), 200 mg

(ANC) is greater than

10⁹/L

(66 mg Fe), 324 mg (106 mg Fe), 325 mg

(per protocol; given beyond nadir period

(106 mg Fe), 350 mg (115 mg Fe)

7 to 10 days after chemotherapy admini-

Chewable tablets: 100 mg (33 mg Fe)

stration).

Timed-release

tablet

OTC:

150 mg

Peripheral blood progenitor cell mobilization:

(50 mg Fe)

10 mcg/kg SC daily for 4 days before the first

Pregnancy category A

leukapheresis procedure and continued

until the last leukapheresis.

Indications:

Congenital neutropenia:

Prevention and treatment of iron deficiency

2.5

6 mcg/kg/day SC; titrate dose to

anemia.

desired ANC to prevent infection.

Dosage:

Idiopathic or cyclic neutropenia:

5 mcg/kg SC once daily; titrate dose to

See Ferrous Gluconate.

desired ANC to prevent infection.

Notes:

Elevation of ANC is usually within

See Ferrous Gluconate.

hours, though it may be delayed in severe

myelosuppression. Transient increase in

FILGRASTIM

ANC may occur when granulocyte col-

ony-stimulating factor (G-CSF) is begun

G-CSF

Neupogen

shortly after completion of chemotherapy;

avoid premature discontinuation.

Blood formation, colony-stimulating factor

Injection: 300 mcg/mL (1, 1.6 mL)

SC route of administration is preferred due

to prolonged serum levels over IV route.

Pregnancy category C

If used IV and the G-CSF concentration

>15 mcg/mL, add 2 mg albumin/1 mL of

Indications:

IV fluid to prevent drug absorption in the

Used to decrease the period of neutropenia

IV administration set.

and the associated risk of infection in

patients with malignancies receiving mye-

Notes:

losuppressive chemotherapy associated with

Avoid in patients with hypersensitivity to

a significant incidence (i.e., >20%) of severe

Escherichia coli derived proteins or G-CSF.

neutropenia. Has been used in zidovudine-

May cause bone pain and increases in uric

associated neutropenia in human immuno-

acid and lactate dehydrogenase. Do not

deficiency virus infected patients and in

administer 24 hours before or after admin-

patients with nonchemotherapy-induced neu-

istration of chemotherapy.

tropenia (acquired and congenital). Should

be considered in patients with complicated

infection with underlying neutropenia.

FLUCONAZOLE

Diflucan

Dosage:

Antifungal

Neonates: 5 to 10 mcg/kg IV/SC daily for

Tablet: 50, 100, 150, 200 mg

Injection: 2 mg/mL

3 to 5 days in neutropenia with sepsis

Suspension: 10, 40 mg/mL

Children and adults: 5 to 10 mcg/kg IV/SC

once daily until absolute neutrophil count

Pregnancy category C

Formulary

329

Indications:

fluconazole metabolism. Consult the

Prophylaxis and treatment of susceptible

Physicians’ Desk Reference or a pharmacist

when ordering fluconazole in a patient

fungal infections, including oropharyngeal,

esophageal, and vaginal candidiasis and sys-

receiving many medications.

temic fungal infections with Candida sp. as

well as treatment and suppression of cryp-

FOLIC ACID

tococcal meningitis. Species of Candida

Folate

with decreased in vitro susceptibility to flu-

Folvite

conazole are being isolated. Fluconazole is

Blood formation, water-soluble vitamin

more active against candidal species such as

Tablet OTC: 0.4, 0.8, 1 mg

C. albicans than species such as C. parapsi-

Solution: 50 mcg/mL

losis, C. glabrata, and C. tropicalis.

Injection: 5 mg/mL

Dosage:

Pregnancy category A/C

Oropharnygeal candidiasis:

Indications:

6 mg/kg loading dose PO/IV followed by

Treatment of megaloblastic anemia result-

3 mg/kg/day

(dependent on severity of

ing from folate deficiency; supplementa-

infection) for 2 to 4 weeks (dependent on

tion for patients with chronic hemolytic

clinical response and immune status of the

anemia (e.g., sickle cell disease, hereditary

patient). Neonates under 14 days of age are

spherocytosis).

dosed every 24 to 72 hours.

Esophageal candidiasis:

Dosage:

12 mg/kg loading dose PO/IV, followed by

Infants to children <12 months: 15 mcg/kg

6 mg/kg/day for 2 to 4 weeks; maximum

daily; maximum 50 mcg/day

dose 400 mg/day

Children 1 to 11 years: initial dose 1 mg/day;

Invasive systemic candidiasis and cryptococcal

maintenance dose 0.1 to 0.4 mg/day

meningitis:

Children >11 years and adults: initial dose

12 mg/kg loading dose PO/IV, followed by 6

1 mg/day; maintenance dose 0.5 mg/day

to 12 mg/kg/day for 2 to 4 weeks or longer

Prophylaxis in immunocompromised hosts:

Notes:

3 to 6 mg/kg/dose PO/IV; maximum dose

May mask hematologic effects of vitamin

400 mg/day

B₁₂ deficiency but will not prevent progres-

sion of neurologic abnormalities.

Notes:

Do not give to patients with known hyper-

FOSCARNET

sensitivity to fluconazole or other azoles.

Foscavir, generic

May cause nausea, headache, rash, vomit-

Antiviral

ing, abdominal pain, hepatitis, cholestasis,

Injection: 24 mg/mL

and diarrhea. Antagonism may occur if

Pregnancy category C

amphotericin B and fluconazole are used

concurrently. Many drug interactions exist.

Indications:

May increase effects, toxicity, and/or levels

of cyclosporine, midazolam, tacrolimus,

Alternative to ganciclovir for treatment of

and many other drugs. Rifampin increases

CMV infection; treatment of acyclovir-

330

Formulary

resistant HSV infections in immunocom-

CMV Retinitis, children >3 years and adults:

promised hosts.

10 mg/kg/day divided q12h as a

1-hour

infusion for

14 to

21 days followed by

Dosage:

maintenance 5 mg/kg/day as a single daily

Children and adults:

dose for 7 days/week or 6 mg/kg/day for 5

days/week

CMV retinitis:

180 mg/kg/day IV divided

q8-12h for 14 to 21 days followed by daily

Treatment of CMV reactivation in trans-

IV maintenance of 90 mg/kg/day

plant recipients, children and adults:

10 mg/kg/day divided q12h for 1 to 2 weeks

Acyclovir-resistant HSV infection: 40 mg/kg/

followed by maintenance

5 mg/kg/day

dose IV q8-12h up to 3 weeks or until lesions

once daily for 7 days/week or 6 mg/kg/day

heal; repeat treatment may lead to resistance.

for

days/week until

100

days post-

Notes:

transplant

May cause renal impairment, adjust dose for

Other CMV infections, children and adults:

renal dysfunction. Assure adequate hydra-

10 mg/kg/day divided q12h for 14 to 21 days

tion. May adversely affect tooth and bone

or 7.5 mg/kg/day divided q8h followed by

growth in children, safety and efficacy not

maintenance 5 mg/kg/day once daily for 7

fully evaluated. May cause electrolyte imbal-

days/week or 6 mg/kg/day once daily for 5

ances and symptoms of hypocalcemia. May

days/week

cause seizures; risk factors include renal

Notes:

impairment, low serum calcium, and

underlying central nervous system condi-

Do not give to patients with known hyper-

tion. Foscarnet is a vesicant; only infuse into

sensitivity to ganciclovir, acyclovir, or

veins with adequate blood flow.

any component. Patients must use appro-

priate contraception due to teratogenic

GANCICLOVIR

effects for at least

90 days after therapy

Cytovene-IV

completion. Cytopenias may occur; do not

Antiviral

administer if ANC < 0.5

10⁹/L or plate-

Injection: 500 mg (can be prepared into oral

lets

<25

10⁹/L. Use with caution in

suspension)

patients with renal impairment.

Pregnancy category C

GEMTUZUMAB OZOGAMICIN

Indications:

Mylotarg

Treatment of CMV retinitis, pneumonitis,

Antineoplastic, monoclonal antibody

Injection: 5 mg

encephalitis, and gastrointestinal infection

in immunocompromised patients. Preven-

Pregnancy category D

tion of symptomatic CMV disease in trans-

plant patients with reactivation of latent

Indications:

disease. Has antiviral activity against

Treatment of acute myelogenous leukemia.

HSV-1 and HSV-2.

Dosage:

Children with body surface area (BSA) <0.6

Congenital CMV infections, neonates and

m²: 0.1 mg/kg/dose

infants:

12 mg/kg/day slow IV infusion

q12h for 6 weeks

Children with BSA

0.6 m²: 3 mg/m²/dose

Formulary

331

Notes:

Adults: 2 mg/24 hours PO divided q6-12h;

Do not give to patients with known hyper-

initiate first dose before chemotherapy.

sensitivity to gemtuzumab. Severe hyper-

Postoperative

nausea and vomiting

sensitivity reactions and infusion-related

prevention:

reactions may occur including pulmonary

Children

4 years to adults: 20 to 40 mcg/kg

edema, acute respiratory distress syndrome,

IV dosed prior to anesthesia or immediately

and anaphylaxis. Patients should be preme-

before anesthesia reversal; maximum dose

dicated with acetaminophen and diphenhy-

1 mg once

dramine. Administer by slow infusion over

Radiation-induced nausea and vomiting

2 hours. Severe hepatic toxicity including

prevention:

veno-occlusive disease (sinusoidal obstruc-

tive syndrome) has been reported. Use with

Adults: 2 mg PO daily administered 1 hour

caution in patients with renal or hepatic

prior to radiation

impairment or pulmonary disease. May

cause fetal harm; appropriate contraception

Notes:

is advised.

Inducers or inhibitors of the cytochrome

P450

drug-metabolizing enzymes may

GRANISETRON

increase or decrease, respectively, the drug’s

Kytril

clearance. Use with caution in liver disease.

Antiemetic agent, serotonin (5-HT₃)

May cause hypertension, hypotension,

antagonist

arrhythmias, agitation, and insomnia.

Tablet: 1 mg

Solution: 0.2 mg/mL

HEPARIN SODIUM

Injection: 1 mg/mL

Lipo-Hepin, Hep-Lock

Anticoagulant

Pregnancy category B

Injection: many vial sizes, porcine based

origin; preservative free

Indications:

Lock flush solution: 1, 10, 100 U/mL (porcine

Prevention and treatment of nausea and

based, some products may be preservative

vomiting associated with chemotherapy.

free or contain benzyl alcohol)

Has also been utilized in prevention of

Injection for IV infusion:

(porcine based,

postoperative and radiation-induced nausea

D₅W: 40 U/mL, 50 U/mL, 100 U/mL; 0.9%

and vomiting.

NaCl:

2 U/mL;

0.45% NaCl:

50 U/mL,

100 U/mL, contains EDTA)

Dosage:

120 U ¼ approximately 1 mg

Chemotherapy-induced

nausea

and

Pregnancy category C

vomiting:

Children

2 years to adults: 10 to 20 mcg/kg/

Indications:

dose IV 15 to 60 minutes before chemo-

Prophylaxis and treatment of thromboem-

therapy; may be repeated two to thee times

bolic disorders; thrombus prophylaxis for

following chemotherapy over

hours;

central venous access devices.

maximum dose 3 mg/dose or 9 mg/24 hour.

Alternatively, a single dose of 40 mcg/kg 15

Dosage:

60 minutes before chemotherapy has

been used.

Anticoagulation in infants and children:

332

Formulary

Initial: 75 U/kg IV bolus over 10 minutes

Pregnancy category C

Maintenance IV continuous infusion:

Indications:

<1 year: 28 U/kg/hour

Used to influence the dispersion and

1 year: 18 to 20 U/kg/hour

absorption of other drugs and increase rate

of absorption of parenteral fluids given by

hypodermoclysis

(subcutaneously); treat-

Maintenance intermittent dosing:

ment of IV extravasations.

100 U/kg/dose IV q4h

Adjust dose to keep APTT 1.5 to 2.5 times

Dosage:

upper limit of control reference range (best

Infants and children:

measure 6 to 8 hour after initiation or after

Dilute 150 unit vial in 10 mL normal saline

change in dosing).

(15 U/mL). Give 1 mL (15 U) by adminis-

Heparin flush:

tering five separate injections of

0.2 mL

Peripheral IV: 1 to 2 mL of 10 U/mL solution

(3 U) at borders of extravasation site SC

q4h

or intradermal using a

25- or

26-gauge

Central lines: 2 to 3 mL of 10 U/mL solution

needle. Administer as early as possible after

extravasation (minutes to 1 hour).

q24h and after access. Dosing often estab-

lished by institutional policy.

Notes:

Arterial lines and TPN lines (central lines):

Do not give to patients with known hypersen-

add heparin to make a final concentration of

sitivity to hyaluronidase or respective sources

0.5 to 1 U/mL.

(bovine, ovine). Do not inject in or around

Notes:

infected, inflamed, or cancerous lesions; do not

use with dopamine or alpha-agonist extrava-

Do not give to patients with known hyper-

sation. May cause urticaria.

sensitivity to heparin or pork products, severe

thrombocytopenia, suspected intracranial

HYDROCORTISONE

hemorrhage, shock, severe hypotension, and

Solu-Cortef, Cortef, and others

uncontrolled bleeding (unless secondary to

Corticosteroid

disseminated intravascular coagulation).

Tablet (Cortef): 5, 10, and 20 mg

Should discuss usage in patients with religious

Suspension: 2.5 mg/mL

beliefs which prohibit the consumption of

Injection, as sodium succinate (Solu-Cortef):

pork products. Use preservative free heparin

100, 250, 500, 1000 mg vial

in neonates and consider more dilute heparin.

Pregnancy category C

Antidote: protamine sulfate 1 mg per 100 U

heparin in previous 4 hour

Indications:

Treatment of inflammatory dermatoses and

HYALURONIDASE

adrenal insufficiency; also used as a chemother-

Amphdase, Hydase (bovine source, may

apeutic agent for intrathecal administration.

contain thimersol)

Hylenex (recombinant human source)

Dosage:

Vitrase (ovine source, preservative free)

Antidote (extravasation)

Physiologic replacement:

Injection: 150 U/mL (Vitrase 200 U/mL)

12 to 18 mg/m²/day PO divided q6-8h

Formulary

333

Stress dosing (consider for >2 weeks on glu-

pruritus than morphine. Approximate 6:1

cocorticoid therapy or patients in shock):

conversion from morphine (i.e., 6 mg mor-

phine is equivalent to 1 mg dilaudid).

Solu-Cortef, 25 to 100 mg/m²/day

Intrathecal chemotherapy with methotrexate

HYDROXYUREA

and/or cytarabine:

Hydrea, Droxia

Dose per protocol, range 15 to 30 mg

Antineoplastic

Notes:

Capsule: 500 mg (Hydrea); 200, 300, 400 mg

(Droxia)

Do not give to patients with known hyper-

sensitivity to hydrocortisone, polymyxin B

Pregnancy category D

sulfate, or neomycin sulfate. Avoid in

patients with infections from herpes sim-

Indications:

plex, vaccinia, and varicella.

Treatment of malignancies including

HYDROMORPHONE HYDROCHLORIDE

chronic myelogenous leukemia (CML), des-

moid tumors, and brain tumors; adjunct in

Dilaudid, Dilaudid-HP, generics

the management of sickle cell anemia to

Narcotic, analgesic

reduce pain events, acute chest syndrome,

Tablets: 2, 4, 8 mg

hospitalizations, transfusion needs, and

Solution: 1 mg/mL

mortality; utilized to treat hyperleukocyto-

Suppository: 3 mg

sis due to blast crisis in CML and in relapsed

Injection: 1, 2, 3, 4, 10 mg/mL

acute leukemias; treatment of hypereosino-

Pregnancy category C/D

philic syndrome.

Indications:

Dosage:

Management of moderate to severe pain.

Refer to individual protocol.

CML, hyperleukocytosis:

Dosage:

Initial dose 10 to 20 mg/kg PO once daily;

Children (not for use in neonates):

adjust dose according to hematologic

PO: 0.03

0.1 mg/kg/dose q4-6h PRN

response and symptoms.

(maximum 5 mg/dose)

Sickle cell anemia:

IV: 0.015 mg/kg/dose q4-6h PRN

Initial dose 15 mg/kg (range 10 to 20 mg/kg/

Adolescents to adults: 1 to 2 mg/dose IV,

day) once daily; increase dose in increments

IM, or SC q4-6h PRN; 1 to 4 mg PO

of 5 mg/kg/day every 12 weeks to a maxi-

q4-6h PRN

mum of 35 mg/kg/day. Discontinue for

bone marrow toxicity: ANC

<2 10⁹/L,

Notes:

platelets

<80

10⁹/L, reticulocyte count

<8 10⁹/L, or hemoglobin <9 g/dL. Restart

Do not give to patients with known hyper-

therapy after recovery at 2.5 mg/kg/day less

sensitivity to hydromorphone. Dose reduc-

than dose that produced toxicity.

tion recommended in renal insufficiency or

severe hepatic impairment. Avoid use in

Notes:

neonates because of potential central ner-

vous system effects. Use with caution in

Do not give to patients with known hyper-

infants and young children. Causes less

sensitivity to hydroxyurea or those with

334

Formulary

severe anemia or severe bone marrow sup-

Injection: 1 g vial

pression. Use with caution in renal

Pregnancy category D

impairment.

Indications:

IDARUBICIN

Used in combination with certain other

Idamycin, generic

antineoplastics in the treatment of Hodgkin

Antineoplastic antibiotic, anthracycline

and non-Hodgkin lymphoma, acute lym-

Injection: 5, 10 mg

phoblastic leukemia, osteosarcoma, rhab-

Pregnancy category D

domyosarcoma, Ewing sarcoma, and

advanced Wilms tumor.

Indications:

Dosage:

Treatment of acute promyelocytic leukemia

(APL), other types of acute myelogenous

Refer to individual protocol.

leukemia, and relapsed lymphoblastic

Usual dose is 700 to 1800 mg/m²/day for 5

leukemia.

days every 3 to 4 weeks

Dosage:

Notes:

Refer to individual protocol.

Do not give to patients with known hyper-

APL induction:

sensitivity to ifosfamide. Avoid in severe

bone marrow suppression. Use with cau-

12 mg/m²/day IV as 4 doses on alternating

tion in impaired renal function; hydrate the

days for 8 days

patient prior to administration and ensure

good urine flow (i.e., urine specific gravity

Notes:

1.010). Ifosfamide may lead to syndrome

Do not give to patients with known hyper-

of inappropriate antidiuretic hormone

sensitivity to idarubicin, severe congestive

(SIADH) secretion. Mesna is used for uro-

heart failure, or cardiomyopathy. Avoid in

protection with higher doses to decrease

preexisting bone marrow suppression

risk of hemorrhagic cystitis. Urinalysis

unless the potential benefit warrants the

should be monitored closely for specific

risk. May need to reduce dosage with

gravity and heme. May cause central ner-

impaired renal or hepatic function. Irrevers-

vous system toxicity including hallucina-

ible myocardial toxicity may occur as the

tion, somnolence, confusion, coma, or

cumulative dosage approaches 550 mg/m²

encephalopathy.

(or

400 mg/m² with chest irradiation or

concomitant cyclophosphamide adminis-

IMATINIB

tration; based on anthracycline dose equiva-

Gleevec

lents, see Chapter 30). This may be an acute

Antineoplastic, tyrosine kinase inhibitor

or late effect and monitoring with ECHO or

Tablet: 100, 400 mg

MUGA and ECG is required per protocol.

Secondary leukemia has been reported.

Pregnancy category D

IFOSFAMIDE

Indications:

Ifex

Treatment of newly diagnosed Philadelphia

Antineoplastic, alkylating agent

chromosome positive

(Ph^þ) chronic

Formulary

335

myelogenous leukemia (CML) in chronic

photosensitivity, puritus, rash, gastrointes-

phase ages

2 years to adult; recurrent Ph^þ

tinal disturbance, bone or joint pain, and

CML in chronic phase following stem cell

blurred vision.

transplantion; Ph^þ CML resistant to inter-

feron alpha therapy; Ph^þ acute lymphoblas-

IMMUNE GLOBULIN

tic leukemia (ALL) (relapsed or refractory);

Flebogamma 5% (50 mg/mL)

mastocytosis; desmoid tumor; gastrointesti-

Gamunex 10% (100 mg/mL)

nal stromal tumors (GIST); hypereosinophi-

Gammagard 10% (100 mg/mL)

lic syndrome or chronic eosinophilic leuke-

Octagam 5% (50 mg/mL)

mia; and myelodysplastic/myeloproliferative

Carimmune NF:

12 g for

disease associated with platelet-derived

reconstitution

growth factor receptor

(PDGFR) gene

Polygam S/D: 2.5, 5, 10 g for reconstitution

rearrangements.

Immunoglobulins

Dosage:

Pregnancy category C

Refer to individual protocol.

Indications:

Children

2 years: Ph^þ CML, chronic phase,

Treatment of immunodeficiency states (e.g.,

new diagnosis:

340 mg/m²/day divided

human immunodeficiency virus, agamma-

q12-24h; maximum dose 600 mg/day

globulinemia),

secondary immunode-

Ph^þ CML, chronic phase and recurrent after

ficiencies

(e.g., bone marrow transplant),

stem cell transplantion, resistant to interferon:

immune thrombocytopenic purpura (ITP),

260 mg/m²/day

Kawasaki disease, and lymphoproliferative

May need to adjust dose with hepatic or

disorders.

hematologic toxicity.

The optimal duration of therapy for CML or

Dosage:

ALL is not determined.

Immunodeficiency:

400 mg/kg/dose IV every 3 to 4 weeks.

Notes:

Chronic lymphocytic leukemia:

Do not give to patients with known hyper-

400 mg/kg/dose IV every 3 weeks.

sensitivity to imatinib. May cause fluid

ITP:

retention, weight gain, edema, pleural effu-

800 to 1000 mg/kg IV for 1 to 2 consecutive

sion, pericardial effusion, and pulmonary

days, then every

3 to 4 weeks based on

edema. Use with caution in patients where

clinical response and platelet count

fluid retention may be poorly tolerated such

HIV infection:

as congestive heart failure or left ventricular

400 mg/kg IV every 4 weeks

dysfunction. May cause Stevens-Johnson

HIV-associated thrombocytopenia:

syndrome, hepatotoxicity, hemorrhage, and

500 to 1000 mg/kg/day IV for 1 to 5 days

hematologic toxicity. Use with caution in

Kawasaki disease:

patients with preexisting hepatic or renal

2 g/kg IV as a single dose

impairment. Use with caution in patients

Post-bone marrow transplant:

receiving concurrent therapy that alters

400 to 500 mg/kg q4 weeks (refer to pro-

cytochrome P450 activity or requires meta-

tocol; based on desired IgG level, usually

bolism by these isoenzymes. May cause

>400 mg/dL)

336

Formulary

Notes:

discontinuing. May cause severe, dose-

Avoid in patients with hypersensitivity to

limiting, and potentially fatal diarrhea.

Early diarrhea (during or shortly after infu-

immune globulin or blood products and in

those with immunoglobulin A deficiency

sion) may be accompanied by symptoms of

rhinitis, increased salivation, flushing, mio-

(except with the use of IgA-depleted pro-

sis, lacrimation, diaphoresis, and abdomi-

ducts such as Gammagard or Polygam).

nal cramping. Atropine

0.01 mg/kg IV

May cause infusion-related toxicity requir-

(maximum dose 0.4 mg) may be used to

ing slower IV rate and premedication with

prevent or treat symptoms.

acetaminophen and diphenhydramine. May

Late diarrhea occurs >24 hours after

lead to aseptic meningitis.

therapy and can be prolonged leading to

life-threatening dehydration and electro-

IRINOTECAN

lyte imbalance. Treat promptly with loper-

Camptostar, generic

amide until a normal pattern of bowel

Antineoplastic, topoisomerase inhibitor

movements returns. Antibiotic support

Injection: 20 mg/mL

(cefixime or cefpodoxime has been used

Pregnancy category D

in children) as a prophylactic and treatment

measure.

Indications:

If the patient develops persistent diar-

rhea, ileus, fever, or severe neutropenia,

Treatment of neuroblastoma, hepatoblas-

interrupt or reduce subsequent doses. If

toma, brain tumors, Ewing sarcoma, and

grade 3 (7 to 9 stools/day, incontinence,

rhabdomyosarcoma.

and/or severe cramping) or grade 4 (

stools/day, grossly bloody stool, and/or

Dosage:

need for parenteral support) diarrhea

Referral to individual protocol

occurs, interrupt treatment and reduce sub-

Children: refractory solid tumor, low dose,

sequent dosing.

protracted: 20 mg/m²/day for 2 consecutive

May cause severe myelosuppression; halt

weeks, followed by a week of rest; repeat

for neutropenic fever. Use with caution in

q3 weeks.

patients with renal or hepatic impairment.

Children: refractory solid tumor or brain

tumor: 50 mg/m²/day for 5 days, repeat cycle

IRON COMPLEX, POLYSACCHARIDE

q3 weeks.

Niferex-150, Fe-Tinic 150, Ferrex 150

Iron polysaccharide and ascorbic acid

Notes:

Tablet: 50 mg

Capsule: 150 mg

Do not give to patients with known hyper-

Elixir: 100 mg/5 mL

sensitivity to irinotecan. Avoid concomi-

tant administration with St. John’s wort or

Pregnancy category C

ketoconazole and in patients with severe

bone marrow failure. A new cycle of irino-

Indications:

tecan should not begin until serious treat-

Treatment of iron deficiency anemia.

ment-induced toxicity has recovered:

ANC

1.5

10⁹/L and platelet count

Dosage:

>100

10⁹/L. If the patient has not recov-

ered following a

week rest, consider

See Ferrous Gluconate.

Formulary

337

Notes:

Maximum daily dose, IM/IV (United States):

See Ferrous Gluconate.

Infants <5 kg: 25 mg (0.5 mL)

Children 5 to 10 kg: 50 mg (1 mL)

IRON DEXTRAN COMPLEX

Children >10 kg to adults: 100 mg (2 mL)

Dexferrum, INFeD

Anemia of prematurity:

Iron salt

Injection: 50 mg elemental iron/mL (2 mL)

Neonates: 0.2 to 1 mg/kg/day or 20 mg/kg/

week with epoietin alfa therapy

Pregnancy category C

Anemia of chronic renal failure:

Indications:

There is insufficient data to support IV iron

if the ferritin level is >500 ng/mL.

Treatment of microcytic hypochromic

anemia resulting from iron deficiency in

Children: predialysis or peritoneal dialysis, as

patients in whom oral administration is not

a single dose repeated as necessary (outside the

feasible or is ineffective. Approved in chil-

United States):

dren

4 months.

<10 kg: 125 mg

Dosage:

10 to 20 kg: 250 mg

>20 kg: 500 mg

Begin with a test dose

1 hour prior to

starting iron dextran therapy:

Children: hemodialysis, given during each

dialysis for 10 doses:

Infants <10 kg: 10 mg (0.2 mL)

<10 kg: 25 mg

Children 10 to 20 kg: 15 mg (0.3 mL)

10 to 20 kg: 50 mg

Children >20 kg to adult: 25 mg (0.5 mL)

>20 kg: 100 mg

Total replacement dose of iron dextran for

iron deficiency anemia:

Parenteral administration:

(mL) ¼ 0.0442

LBW (kg)

(Hgb_n Hgb_o)

IM: use Z-track technique (deep into upper

þ [0.26

LBW (kg)],

outer quadrant of buttock); test dose at

same site using the same method.

where

IV: infuse test dose over at least 5 minutes

LBW ¼ lean body weight

(Dexferrum) or

seconds

(INFeD);

Males: 50 kg þ 2.3 kg for every inch over 5 ft

dilute replacement dose in normal saline

in height

(50 to 100 mL) to maximum concentra-

Females: 45.5 kg þ 2.3 kg for every inch over

tion of 50 mg/mL and infuse over 1 to 6

5 ft in height

hours at a maximum rate of 50 mg/min-

Hgb_n ¼ desired hemoglobin (g/dL) ¼ 12 if

ute. Avoid dilution in dextrose due to an

<15 kg or 14.8 if >15 kg

increased incidence of local pain and

phlebitis.

Hgb_o ¼ measured hemoglobin (g/dL)

Monitor vital signs and for symptoms of

Total replacement dose of iron dextran for

anaphylaxis during the IV infusion.

acute blood loss:

(Assumes 1 mL of normocytic, normochro-

Notes:

mic red cells ¼ 1 mg elemental iron)

Do not give to patients with known hyper-

Replacement iron (mg) ¼ blood loss (mL)

sensitivity to iron dextran (anaphylaxis may

hematocrit

occur), in anemia not associated with iron

338

Formulary

deficiency, with hemochromatosis, or with

1 mg (elemental iron)/kg/dialysis treatment

hemolytic anemia. Use with caution in

(repletion)

patients with histories of significant allergies,

0.3 mg

(elemental iron)/kg/dialysis treat-

asthma, serious hepatic impairment, preex-

ment (maintenance)

isting cardiac diseases, and rheumatoid arthri-

Children: iron deficiency anemia

(off-label

tis (may cause an exacerbation of arthritis).

use):

Discontinue oral iron prior to initiating par-

enteral iron. Sweating, urticaria, arthralgia,

Calculation of iron deficit: body weight [kg]

(target Hgb-actual Hgb) [g/dL]

2.4

fever, chills, dizziness, headache, and nausea

may be delayed 24 to 48 hours after large doses

Dose: 5 mg/kg/day IV until iron deficit is

of IV administered drug or 3 to 4 days fol-

corrected

lowing IM administration. The IV route is

Adults: Hemodialysis dependent:

preferred for patients with chronic renal dis-

100 mg IV 1 to 3 times/week during dialysis,

ease and cancer related anemia (adults).

total of 10 doses (1000 mg); may continue to

Agents for treatment of acute anaphylaxis

administer at lowest dose possible to main-

should be readily available. Adverse events

tain target hemoglobin and iron storage

are much more associated with the high

parameters

molecular weight formulation (Dexferrum)

than with the low molecular weight formu-

Adults: nondialysis-dependent chronic renal

lation (INFeD). We recommend usage of only

failure: 200 mg on 5 different days over a 2-

the low molecular weight formulation.

week period (total dose 1000 mg)

Total-dose infusions have been used

safely and are the preferred method of

Notes:

administration, though not currently

Do not give to patients with known hyper-

approved in the United States. Must wait

sensitivity to iron formulations, anemia not

14 days after a dose for reequilibration if

associated with iron deficiency, hemochro-

retesting iron stores.

matosis, hemolytic anemia, or iron overload.

Use with caution in patients with history

IRON SUCROSE

of significant allergies, asthma, hepatic

Venofer

impairment, or rheumatoid arthritis.

Iron salt

Injection: 20 mg elemental iron/mL (5, 10 mL)

ITRACONAZOLE

Pregnancy category B

Sporanox, generic

Antifungal

Indications:

Capsule: 100 mg

Solution: 100 mg/10 mL

Treatment of microcytic, hypochromic ane-

mia resulting from iron deficiency in

Pregnancy category C

chronic kidney disease patients, either dial-

ysis-dependent or nondialysis-dependent,

Indications:

who may or may not be receiving

Treatment of susceptible systemic fungal

erythropoietin

infections including blastomycosis, coccidio-

mycosis,histoplasmosis,paracocciodiomyco-

Dosage:

sis, and aspergillosis in patients who do not

Children: end stage renal disease:

respond to or cannot tolerate amphotericin B;

Formulary

339

treatment of oropharyngeal or esophageal

Maintenance dose:

0.5 mg/kg/dose IM/IV

candidiasis (oral solution only).

q6h; maximum dose 30 mg q6h or 120 mg

q24h

Dosage:

Children >50 kg and adults: 10 mg PO q6h

Children: limited data: 3 to 5 mg/kg/day PO

PRN; maximum dose 40 mg/24 h

once daily

Doses as high as 5 to 10 mg/kg/day divided

Notes:

q12-24h have been used in children with

Do not give to patients with known hyper-

chronic granulomatous disease and for pro-

sensitivity to ketorolac or other NSAIDs,

phylaxis against Aspergillus infection; 6 to

patients with active peptic ulcer disease, gas-

8 mg/kg/day has been utilized in the treat-

trointestinal bleeding or perforation, renal

ment of disseminated histoplasmosis.

dysfunction, bleeding diathesis, thrombocy-

topenia, or cerebrovascular bleeding. Use

Notes:

with caution in patients with congestive heart

Do not give to patients with known hyper-

failure, hypertension, or decreased renal or

sensitivity to itraconzaole or other azole

hepatic function. May cause impaired plate-

drugs. Do not use to treat onychomycosis

let function, nausea, dyspepsia, drowsiness,

in patients with evidence of left ventricular

and interstitial nephritis.

dysfunction, congestive heart failure (CHF)

or a history of CHF, or women who are

LEUCOVORIN CALCIUM

pregnant or intending to become pregnant.

Generic

Use with caution in patients with renal or

Antidote, methotrexate; folic acid derivative

hepatic impairment. Many drug interac-

Tablets: 5, 10, 15, 25 mg

tions exist; consult the Physician’s Desk

Injection: 50, 100, 200, 350 mg vials

Reference. Avoid drinking grapefruit juice

or soda while taking oral itraconazole due to

Pregnancy category C

altered absorption.

Indications:

KETOROLAC TROMETHAMINE

Reduction of toxic effects (leucovorin res-

Generic, previously available as Toradol

cue) of high-dose methotrexate, to coun-

NSAID

teract effects of impaired methotrexate

Tablet: 10 mg

elimination, or as an antidote for

Injection: 15, 30 mg/mL

folic acid antagonist overdose. Indicated for

the treatment of folate-deficient megalo-

Pregnancy category C/D

blastic anemia of infancy, sprue, or preg-

nancy; treatment of nutritional deficiencies

Indications:

when oral folate therapy is not possible.

Short-term management of pain (up to 5

days for parenteral therapy, 5 to 14 days for

Dosage:

oral therapy).

Rescue dose

(following administration of

high-dose methotrexate), see protocols:

Dosage:

15 mg/m² IV to start, then 15 mg/m² q6h; if

Loading dose: 1 mg/kg IM; maximum dose

serum creatinine 48 hours after the start of

60 mg (loading dose not necessary in IV

the methotrexate is elevated more than 50%

administration)

or the serum methotrexate concentration is

340

Formulary

10⁶ M, increase dose to 150 mg/m²

Usual dose is 75 to 130 mg/m² as a single

dose q3h until serum methotrexate level is

dose every

weeks; subsequent doses

10⁷ M or per protocol (refer to pub-

adjusted per platelet and leukocyte counts.

lished graphs for methotrexate clearance per

protocol). If methotrexate clearance is

Notes:

delayed, continue leucovorin until level

Do not give to patients with known hyper-

10⁷ M.

sensitivity to lomustine. May need to

Folate-deficient megaloblastic anemia:

adjust dose due to prolonged myelosup-

pression. Delayed pulmonary fibrosis may

1 mg/day IM/IV

occur with high cumulative doses (e.g.,

Megaloblastic anemia secondary to congenital

1g/m²).

deficiency of dihydrofolate reductase:

3 to 6 mg/day IM

MECLORETHAMINE

Folic acid antagonist (e.g., pyrimethamine,

Mustargen

trimethoprim) overdose:

Antineoplastic, alkylating agent

5 to 15 mg/day PO for 3 days or until the

Injection: 10 mg

blood counts are normal or

5 mg every

Pregnancy category D

3 days; doses of 6 mg/day are needed for

patients with platelet counts <100

10⁹/L.

Indications:

Following intrathecal methotrexate (investi-

Treatment of Hodgkin and non-Hodgkin

gational):

lymphoma and brain tumors; sclerosing

12 mg/m² PO/IV as a single dose

agent in intracavitary therapy of pleural,

pericardial, and other malignant effusions.

Notes:

Do not give to patients with known hyper-

Dosage:

sensitivity to leucovorin, pernicious anemia,

Refer to individual protocol.

or other megaloblastic anemia, such as sec-

ondary to vitamin B₁₂ deficiency. Do not

Children: MOPP regimen

(Mustargen

administer intrathecal or intraventricular

[mechlorethamine], Oncovin

[vincristine],

(may be harmful or fatal).

procarbazine, prednisone):

6 mg/m² IV on

days 1 and 6 of a 28 day cycle

LOMUSTINE

Brain tumors: MOPP regimen: 3 mg/m² IV

CCNU

on days 1 and 8 of a 28 day cycle

CeeNU

Intracavitary (adults): 10 to 30 mg or 0.2 to

Antineoplastic, alkylating agent

0.4 mg/kg

Capsules: 10, 40, 100 mg

Pregnancy category D

Notes:

Do not give to patients with known hyper-

Indications:

sensitivity to mechlorethamine, preexisting

Treatment of primary or metastatic brain

profound myelosuppression, or pregnancy.

tumors and Hodgkin lymphoma.

Extravasation may result in severe tissue

damage; treat promptly with cold com-

Dosage:

presses

hours) and sodium

Refer to individual protocol.

thiosulfate.

Formulary

341

MELPHALAN

MEPERIDINE HYDROCHLORIDE

Alkeran

Demerol, generic

Antineoplastic, alkylating agent

Narcotic, analgesic

Tablet: 2 mg

Tablets: 50, 100 mg

Injection: 50 mg

Elixir: 50 mg/5 mL

Injection: 10, 25, 50, 75, 100 mg/mL

Pregnancy category D

Pregnancy category C/D

Indications:

Treatment of neuroblastoma, rhabdomyo-

Management of moderate to severe pain;

sarcoma, brain tumors, acute myelogenous

used as an adjunct to anesthesia and pre-

leukemia, Ewing sarcoma, medulloblas-

operative sedation; treatment of rigors fol-

toma, Hodgkin lymphoma, and for condi-

lowing administration of amphotericin B.

tioning prior to hematopoietic stem cell

transplantation (HSCT).

Dosage:

Children: 1 to 1.5 mg/kg/dose PO, IM, IV, or

SC q3-4h PRN; maximum dose 100 mg

Refer to individual protocol.

Adults: 50 to 150 mg/dose q3-4h PRN

Children: rhabdomyosarcoma: 10 to 35 mg/

m²/dose IV every 21 to 28 days

Notes:

High-dose therapy with HSCT conditioning:

70 to 100 mg/m² IV on days -7 and -6 prior

Do not give to patients with known

to HSCT; or 140 to 220 mg/m² IV single

hypersensitivity to meperidine. Avoid in

dose prior to HSCT; or 50 mg/m²/day

patients receiving acyclovir, cimetidine, tri-

days; or 70 mg/m²/day

3 days

cyclic antidepressants, and monoamine

oxidase inhibitors within the past 14 days.

Children: oral dosing:

4 to 20 mg/m²/day

Use with caution in renal or hepatic dys-

days 1 to 21

function, sickle cell disease, and seizure

disorders. Accumulation of normeperidine

Notes:

metabolites may precipitate seizures. May

Do not give to patients with known hyper-

cause central nervous system and respira-

sensitivity or to those whose disease was

tory depression, nausea, vomiting, consti-

resistant to prior therapy. Long-term oral

pation, bradycardia, hypotension, periph-

therapy and high cumulative doses (i.e.,

eral vasodilation, miosis, sedation, drows-

>600 mg) can increase the incidence of

iness, biliary or urinary tract spasm,

secondary leukemia. May lead to amenor-

increased intracranial pressure, and physi-

rhea. Causes bone marrow suppression; use

cal and psychological dependence. Other

with caution in those with prior myelosup-

narcotics are generally preferred for pain

pressive chemotherapy or radiation therapy.

management.

Use with caution and consider dose reduc-

tion in patients with renal impairment. May

MERCAPTOPURINE

increase the effects/levels of cyclosporine

6-MP, 6-mercaptopurine

and carmustine.

Purinethol

342

Formulary

Antineoplastic, antimetabolite

With ifosfamide and cyclophosphamide:

Tablet: 50 mg

Mesna dose is 20% of alkylator dose IV

15 minutes before or combined with alky-

Pregnancy category D

lator, followed by repeat doses 4

and 8

hours later; for high-dose alkylator therapy,

Indications:

give dose 15 minutes before alkylator then

Used in conjunction with methotrexate for

q3h for 3 to 6 doses. Total daily Mesna dose

maintenance therapy in acute lymphoblastic

ranges from 60% to 160% of the daily

leukemia; combination regimen in acute

alkylator dose.

myelogenous and chronic myelogenous leu-

IV continuous infusion of Mesna is given at

kemias; non-Hodgkin lymphoma.

doses equivalent to 60% to 100% of the

ifosfamide or cyclophosphamide dose.

Dosage:

Refer to individual protocol.

Mesna is given by IV infusion over 15 to 30

minutes or by continuous IV infusion, or

50 to 100 mg/m² once daily

per protocol.

Notes:

Do not give to patients with known hyper-

sensitivity to mercaptopurine, severe liver

Do not give to patients with known hyper-

disease, or severe bone marrow suppression.

sensitivity to Mesna or thiol compounds.

Use with caution and adjust dose in patients

May cause false positive urinary ketone

with renal or hepatic dysfunction. Patients

measurements.

who receive allopurinol concurrently

should have their mercaptopurine dose

METHADONE HYDROCHLORIDE

reduced by 33%.

Dolophine

Antidote, analgesic

MESNA

Tablet: 5, 10 mg

Mesnex

Solution: 5 mg/5 mL, 10 mg/5 mL

Prophylaxis, cyclophosphamide or ifosfa-

Injection: 10 mg/mL (20 mL)

mide-induced hemorrhagic cystitis.

Pregnancy category B/D

Tablet: 400 mg

Injection: 100 mg/mL

Indications:

Pregnancy category B

Management of severe pain; used in nar-

cotic detoxification maintenance programs

Indications:

and for the treatment of iatrogenic narcotic

Detoxifying agent used to inhibit hemor-

dependency.

rhagic cystitis induced by ifosfamide and

cyclophosphamide.

Dosage:

Children: analgesia:

Refer to individual protocol.

0.7 mg/kg/24 hour divided q4-6h PRN PO,

SC, IM, or IV

Dose is dependent on which antineoplastic

agent it is used with.

Adults: analgesia:

Formulary

343

2.5 to 10 mg PO, IM, IV, or SC q3-4h PRN,

dosing or by continuous infusion IV over 6

up to 5 to 20 mg q6-8h

to 42 hours (dependent on phase of therapy);

50 to 400 mg/m² IV bolus every 10 days

Detoxification: see Physician’s Desk Reference:

Doses 100 to 500 mg/m² may require leu-

15 to 40 mg/day PO

covorin and doses >500 mg/m² require leu-

covorin rescue.

Notes:

Osteosarcoma/solid tumors:

Do not give to patients with known hyper-

sensitivity to methadone. Use with caution

Children <12 years: 12 g/m² IV over 4 hours

in patients with respiratory disease as respi-

(dose range 12 to 18 g) þ leucovorin rescue

ratory depression lasts longer than analgesic

Children

12 years: 8 g/m² IV over 4 hours

effects. May cause cardiac arrhythmias,

(maximum dose 18 g) þ leucovorin rescue

sedation, increased intracranial pressure,

Non-Hodgkin lymphoma:

hypotension, and bradycardia, in addition

to respiratory depression. Prolonged half-

200 to 500 mg/m² IV; repeat every 4 weeks,

life; average

19 hours in children and 35

as per protocol.

hours in adults. Repeated use can result in

Meningeal leukemia (and prophylaxis):

cumulative effects necessitating adjustment

10 to 15 mg/m² intrathecal (IT) (maximum

to the dose and frequency of administration.

15 mg) per protocol; dosed by age:

Conversion from other narcotics to meth-

Children <1 year: 6 mg

adone can be quite challenging; discussion

with a provider with experience in this area

Children 1 to <2 years: 8 mg

is warranted (see Chapter 28).

Children 2 to <3 years: 10 mg

Children

3 years: 12 to 15 mg

METHOTREXATE

Dilute in 4 to 6 mL 0.9% NaCl or Elliotts B

Rheumatrex, Trexall, generic

solution.

Antineoplastic, antimetabolite, antirheumatic

Intrathecal methotrexate may be combined

Tablet (Trexall): 2.5, 5, 7.5, 10, 15 mg

with other agents for IT administration (i.e.,

Injection: 1 g vial

cytarabine, hydrocortisone).

Pregnancy category X

Trophoblastic neoplasms (adults):

15 to 30 mg/day PO/IM for 5 days; repeat

Indications:

weekly for three to five courses.

Treatment of acute lymphoblastic leukemia

(ALL; including meningeal leukemia), tro-

Notes:

phoblastic neoplasms, osteosarcoma, non-

Do not give to patients with known hyper-

Hodgkin lymphoma, rheumatoid arthritis,

sensitivity to methotrexate, severe renal or

dermatomyositis, and psoriasis.

hepatic impairment, or preexisting profound

bone marrow suppression. High-dose meth-

Dosage:

otrexate (>1 g/m²) should not be adminis-

Refer to individual protocol.

tered to patients with a creatinine clearance of

Acute lymphoblastic leukemia (refer to pro-

less than 50% to 75% of normal. Patients

tocol, phase):

should receive alkaline fluids to maintain

7.5 to 30 mg/m² once per week or every 2

urine pH of 7 or higher while receiving

weeks PO/IM; 10 to 18,000 mg/m² bolus

high-dose methotrexate. Follow serum levels

344

Formulary

per protocol and administer leucovorin res-

Methemoglobinemia: 1 to 2 mg/kg (25 to

cue per protocol; follow methotrexate degra-

50 mg/m²) IV as a single dose; may be

dation curve per protocol. Methotrexate has

repeated after 1 hour as necessary

been associated with acute and severe chronic

NADPH-methemoglobin reductase defi-

hepatotoxicity, severe bone marrow suppres-

ciency: 1 to 1.5 mg/kg/day PO (maximum

sion, and renal failure with delayed clearance,

dose 300 mg/day) given with ascorbic acid 5

high-dose administration, concurrent neph-

to 8 mg/kg/day

rotoxic drugs, or inadequate hydration. Intra-

thecal and parenteral administration of meth-

Notes:

otrexate have been associated with acute neu-

Use with caution in patients with G6PD

rotoxicity. Severe dermatologic reactions and

deficiency or renal insufficiency. May cause

radiation dermatitis have been reported. May

nausea, vomiting, dizziness, headache,

accumulate in fluid collections (pleural effu-

abdominal pain, diaphoresis, phototoxicity,

sions, ascites) increasing local toxicity.

and skin staining. May cause transient blue-

Ensure no TMP-SMX, penicillin, NSAIDs,

green coloration of urine and stool. At high

or PPIs are given until the methotrexate level

doses, may cause methemoglobinemia.

is <1

10⁷ M due to competitive excretion

and risk of toxicity secondary to delayed

methotrexate clearance.

METHYLPREDNISOLONE

Intrathecal drugs should be prepared

Medrol, Medrol dose pack, Depo-Medrol,

and administered separately from other che-

Solu-Medrol

motherapeutic drugs to avoid inappropriate

Corticosteroid

administration.

Tablets: 2, 4, 8, 16, 24, 32 mg

Recommend giving patients one pill size

Tablets (dose pack): 4 mg

only to avoid accidental overdose with dose

Injection, sodium succinate

(Solu-Medrol):

modifications during maintenance therapy

40, 125, 500, 1000, 2000 mg (IV/IM)

for ALL.

Injection

(acetate)

(Depo-Medrol): 20, 40,

80 mg/mL (IM)

METHYLENE BLUE

Pregnancy category C

Urolene blue, generic

Antidote, drug-induced methemoglobinemia

Indications:

Tablet (Urolene Blue): 65 mg

Anti-inflammatory or immunosuppressive

Injection: 10 mg/mL

agent used to treat a variety of diseases of

Pregnancy category C/D

hematologic, allergic, inflammatory, neo-

plastic, and autoimmune origin.

Indications:

Dosage:

Antidote for cyanide poisoning and drug-

induced methemoglobinemia; treatment of

Anti-inflammatory/immunosuppressive:

NADPH-methemoglobin reductase defi-

0.5 to 1.7 mg/kg/24 hours PO, IM, or IV

ciency; treatment and prevention of ifosfa-

divided q6-12h

mide-induced encephalopathy (adults).

Chemotherapy:

Refer to individual protocols for dosing (in

Dosage:

lieu of prednisone; convert dose for steroid

Children:

potency, 80% of prednisone dose).

Formulary

345

Notes:

seizure disorder. Sedation, headache, anxi-

Do not give to patients with hypersensitivity

ety, depression, leukopenia, and diarrhea

may occur.

to methylprednisolone. Do not administer

with live-virus vaccines or during active infec-

tion with varicella or herpes zoster. Avoid use

MICAFUNGIN

in patients with systemic fungal infections.

Mycamine

May cause hypertension, glucose intolerance,

Antifungal, echinocandin

gastrointestinal bleeding, osteoporosis, pseu-

Injection: 50, 100 mg

dotumor cerebri, Cushing’s syndrome, adre-

nal axis suppression, and acne. May increase

Pregnancy category C

levels of cyclosporine and tacrolimus.

Indications:

METOCLOPRAMIDE

Treatment of patients with candidemia,

esophageal candidiasis,

disseminated

Reglan, Maxolon, generic

candidiasis; prophylaxis of Candida infec-

Antiemetic

tions in patients undergoing hematopoie-

Tablets: 5, 10 mg

tic stem cell transplantation; treatment

Syrup: 5 mg/5 mL

of invasive Aspergillosis. Not effective

Injection: 5 mg/mL

against cryptococcus, fusariosis, and

Pregnancy category B

zygomycosis.

Indications:

Dosage:

Treatment of gastroesophageal reflux (GER)

Not FDA approved for use in children.

and prevention of nausea and vomiting

Guidelines are per pharmacokinetic

associated with chemotherapy.

studies, short duration trials, and case

reports.

Dosage:

Prophylaxis of Candida infections in HSCT

GER or gastrointestinal (GI) dysmotility:

recipients:

Infants and children: 0.1 to 0.2 mg/kg/dose

Infants, children, and adolescents:

1.5

up to QID, PO, IV, or IM; maximum dose

2 mg/kg/day IV daily

0.8 mg/kg/24 hours

Adults: 50 mg IV daily

Adults: 10 to 15 mg/dose on awakening and

Disseminated candidiasis:

at night, IM, PO, or IV

Neonates <1000 g: 10 mg/kg/day IV daily

Antiemetic:

Neonates

1000 g: 7 mg/kg/day IV daily

1 to 2 mg/kg/dose q2-6h PO, IV, or IM.

Give first dose 30 minutes prior to emeto-

Infants, children, and adolescents: 2 to 4 mg/

genic drug. Premedicate with diphenhydra-

kg/day IV daily (maximum dose 200 mg)

mine to reduce incidence of extrapyramidal

Adults: 100 mg IV daily

symptoms.

Aspergillosis, esophageal candidiasis:

Neonates: 8 to 12 mg/kg/IV daily

Notes:

Infants, children, and adolescents:

Do not give to patients with known hyper-

8.6 mg/kg IV daily (maximum dose 325 mg)

sensitivity to metoclopramide, GI obstruc-

tion, pheochromocytoma, or history of

Adults: 150 mg IV once daily

346

Formulary

Notes:

occur as the cumulative dosage approaches

Do not give to patients with known hyper-

550 mg/m² (or 400 mg/m² with chest irra-

diation or concomitant cyclophosphamide

sensitivity to micafungin or other echino-

candins. Use with caution in patients with

administration; based on anthracycline dose

equivalents, see Chapter 30). This may be an

renal or hepatic impairment and in patients

acute or late effect and monitoring with

receiving concomitant hepatotoxic drugs;

ECHO or MUGA and ECG is required per

monitor for evidence of worsening. May

protocol. Extravasation may lead to severe

cause electrolyte disturbances, cytopenias,

tissue damage. Dosage may need to be

skin rash, central nervous system, and car-

reduced in patients with impaired hepato-

diovascular effects.

biliary function, preexisting bone marrow

suppression, or previous treatment with

MITOXANTRONE

cardiotoxic drugs or chest radiation.

Novantrone, generic

Antineoplastic, anthracenedione

MORPHINE SULFATE

Injection, solution: 2 g/mL

Roxanol, Oramorph SR, MS Contin

Pregnancy category D

Narcotic, analgesic

Tablets: 15, 30 mg

Indications:

Controlled-release tablets: 15, 30, 60 mg (100

Treatment of acute myelogenous leukemia;

and 200 mg for opioid tolerant patients)

active in pediatric sarcoma, Hodgkin and

Extended-release capsules:

30 mg (60,

90,

non-Hodgkin lymphoma, acute lympho-

120 mg for opioid tolerant patients)

blastic leukemia, and myelodysplastic

Sustained-release pellets in capsules: 10, 20,

syndrome.

30, 50, 60 mg (100, 200 mg for opioid tol-

erant patients)

Dosage:

Solution: 10, 20, 100 mg/5 mL

Suppository: 5, 10, 20, 30 mg

Leukemia: children

2 years: 0.4 mg/kg IV

Injection:

0.5,

10, 15, 25,

daily for 3 to 5 days

50 mg/mL

Children >2 years and adults: 12 mg/m²

IV daily for 2 to 3 days; acute leukemia

Pregnancy category C/D

in relapse:

8 to

12 mg/m² IV daily for

5 days; AML: 10 mg/m² IV daily for 3 to

Indications:

5 days

Relief of moderate to severe pain, acute and

Solid tumors: children: 18 to 20 mg/m² IV

chronic, after nonnarcotic analgesics have

q3-4 weeks or 5 to 8 mg/m² IV weekly

failed; preanesthetic medication; relief of

dyspnea from acute left ventricular failure

Adults:

14 mg/m² IV q3-4 weeks

and pulmonary edema.

(maximum total 80 to 120 mg/m²)

Dosage:

Notes:

Dose should be titrated to effect.

Do not give to patients with known hyper-

sensitivity to mitoxantrone. May cause

Neonates:

severe myelosuppression; use with caution

0.1 to 0.2 mg/kg IV q3-4h; q6h dosing may

in patients with preexisting myelosuppres-

be appropriate for extremely premature

sion. Irreversible myocardial toxicity may

infants or infants with hepatic dysfunction

Formulary

347

Infants and children:

MYCOPHENOLATE MOFETIL (MMF)

Tablet and solution (immediate release): 0.2

CellCept, Myfortic, generic (capsule, tablet)

to 0.5 mg/kg/dose PO q4-6h PRN

Immunosuppressive agent

Capsule, as mofetil or CellCept: 250 mg

Tablet (controlled release): 0.3 to 0.6 mg/kg/

Tablet, as mofetil or CellCept: 500 mg

dose PO q12h

Tablet, delayed release, as mycophenolic acid,

Injection: 0.05 to 0.2 mg/kg/dose IM, IV, or

Myfortic: 180, 360 mg (not recommended

SC q2-4h PRN; maximum 15 mg/dose

for children whose total body surface area

Adults:

[TBSA] is <1.19 m²)

Tablets and solution

(immediate release):

Injection, as mofetil or CellCept: 500 mg

10 to 30 mg PO q4h PRN

Powder for oral suspension, CellCept:

200 mg/mL

Tablet (controlled release): 15 to 30 mg PO

q8-12h PRN

Pregnancy category D

Injection: 2 to 15 mg/dose IV, IM, or SC

Indications:

Patient-controlled analgesia

(PCA) dosing

guidelines:

Used as an immunosuppressant drug fre-

quently in combination with other immuno-

PCA (on demand) dose: 0.01 to 0.04 mg/kg

suppressants (e.g., cyclosporine, corticoster-

Suggested lock out (between PCA doses): 10

oids) for the prophylaxis of organ rejection

to 20 minutes

(renal, hepatic, cardiac, and bone marrow

Continuous dose:

transplants), chronic graft-versus-host dis-

Neonate 0.01 to 0.02 mg/kg/h

ease, myasthenia gravis, proliferative lupus

Infant/child: 0.01 to 0.07 mg/kg/h

nephritis, and relapsing nephrotic syndrome.

Adult: 0.8 to 10 mg/h (higher doses with

tolerance)

Dosage:

Bolus (loading): 0.03 to 0.1 mg/kg

Limited data are available for pediatric

The one hour maximum is 0.1 to 0.15 mg/kg

dosing. Pharmacokinetic studies have indi-

(6 to 8 mg/h in tolerant adults), and typi-

cated that doses based on body surface area

cally equals the continuous dose plus 2 to 3

result in a more appropriate area under the

PCA bolus doses.

curve than doses based on body weight.

Notes:

Children: 600 mg/m²/dose BID or

Do not give to patients with severe renal or

by TBSA:

liver insufficiency. May cause severe pruritus,

1.25 to 1.5 mg/m²: 750 mg BID

urinary retention, respiratory depression,

>1.5 m²: 1 g BID

central nervous system depression, constipa-

tion, and ileus. Prolonged use can result in

physical and psychological dependence.

Notes:

Consider nighttime low continuous dose

Do not give to patients with known hyper-

infusion of 0.01 to 0.02 mg/kg/h without a

sensitivity to mycophenolate mofetil.

change in lock out so as to allow sleep. Avoid

Risk appears to be associated with the

narcotization with sedation and respiratory

intensity and duration of immunosup-

depression. Monitor vitals and encourage use

pression; may result in an increased inci-

of incentive spirometry and ambulation with

dence of lymphoma or other malignancies

repetitive dosing or PCA use.

especially in combination with other

348

Formulary

immunosuppressants. Patients should

Notes:

avoid excessive exposure to sunlight and

Do not give to patients with known hyper-

should use sun protection factor. Use with

sensitivity to naloxone. The dose for pediatric

caution and adjust dose in patients with

postoperative narcotic reversal is one-tenth

renal impairment.

of the dose for opiate intoxication. Endotra-

cheal administration can be done safely by

NALOXONE

diluting in 1 to 2 mL of normal saline. Will

Narcan, generic

produce narcotic withdrawal in patients with

Narcotic antagonist

dependence. Use with caution in patients

Injection: 0.4 mg/mL

with chronic heart disease. Abrupt reversal

of narcotic dependency may result in nausea,

Pregnancy category C

vomiting, diaphoresis, tachycardia, hyper-

tension, and tremulousness.

Indications:

Used to reverse central nervous system and

NELARABINE

respiratory depression in suspected narcotic

Arranon, ara-G

overdose; treatment of coma of unknown

Antineoplastic, antimetabolite

etiology.

Injection: 5 mg/mL

Pregnancy category D

Dosage:

Treatment of opiate intoxication:

Indications:

Neonates, children

<5 years or

<20 kg:

Treatment of T-cell acute lymphoblastic

0.1 mg/kg/dose; repeat q2-3 minutes PRN

leukemia and T-cell lymphoblastic

IM, IV, SC, or via ETT

lymphoma.

Children

>5 years or

20 kg:

2 mg/dose;

if no response, repeat q2-3 minutes PRN

Dosage:

IM, IV, SC, or via ETT

Refer to individual protocol.

Adults:

0.4

2.0 mg/dose q2-3 minutes

Children:

650 mg/m² daily, days

1 to

PRN IM, IV, SC, or via ETT. Use in 0.1

repeat cycle q21 days

to 0.2 mg increments in opioid-dependent

Adults: 1500 mg/m²/dose on days 1, 3, and

patients. If no response and cumulative dose

5; repeat cycle q21 days

>10 mg, reevaluate diagnosis.

IV continuous infusion: 0.005 mg/kg loading

Notes:

dose, then 0.0025 to 0.16 mg/kg/h. Taper

Do not give to patients with known hyper-

gradually to avoid relapse.

sensitivity to nelarabine. May cause severe

Patient-controlled analgesia side effect rever-

neurotoxicity, including severe somnolence,

sal

(pruritus and/or urinary retention with

seizure, and peripheral neuropathy. Observe

morphine):

closely for neurotoxicity. Adverse effects

IV continuous infusion: begin with 1 mcg/kg/

associated with demyelination or similar to

h, then titrate up or down to 0.25 to 2 mcg/

Guillain-Barre syndrome (ascending periph-

kg/h to abate opioid-related side effects;

eral neuropathies) have been reported.

taper infusion gradually over 2 to 4 hours

Neurotoxicity is dose limited and may not

when discontinuing.

reverse completely. Risk of neurotoxicity

Formulary

349

may increase in patients with concurrent

a history of cardiac arrhythmias. Long term

intrathecal chemotherapy or history of cra-

use may increase the incidence of gallstones

nial irradiation. May cause bone marrow

or sludge formation. May cause neuromus-

suppression. Use with caution in patients

cular, central nervous system, or cardiovas-

with renal or hepatic impairment. Monitor

cular toxicities. May decrease level/effects

blood counts, electrolytes, renal function,

of cyclosporine. Do not give with meals;

and transaminases frequently.

may decrease absorption of vitamin B₁₂

and dietary fats.

OCTREOTIDE ACETATE

Sandostatin, generic

ONDANSETRON

Antidiarrheal, antidote, antihemorrhagic,

Zofran

antisecretory, somatostain analog

Antiemetic, serotonin 5-HT₃ antagonist

Injection: 0.2, 1 mg/mL

Tablets: 4, 8, 16, 24 mg

Injection, preservative free:

0.05,

0.1,

Tablets (ODT, orally disintegrating): 4, 8 mg

0.5 mg/mL

Solution: 4 mg/5 mL

Pregnancy category B

Injection: 2 mg/mL

Injection, premixed in D5W: 32 mg/50 mL

Indications:

Pregnancy category B

Treatment of secretory diarrhea in patients

with metastatic carcinoid or vasoactive

Indications:

intestinal peptide-secreting tumors, chemo-

Prevention of nausea and vomiting associ-

therapy-induced diarrhea, graft-versus-host

ated with initial and repeat courses of eme-

disease associated diarrhea, and esophageal

togenic cancer chemotherapy or radiation,

varices/gastrointestinal (GI) bleeding.

prevention of postoperative nausea and

vomiting, treatment of emesis induced by

Dosage:

acute gastroenteritis.

Infants and children: (data limited to small

studies): diarrhea:

10 mcg/kg IV/SC

Dosage:

q12h; begin at low dose and titrate to effect

Prevention of chemotherapy-induced nausea

or IV continuous infusion 1 mcg/kg bolus

and vomiting:

followed by continuous infusion 1 mcg/kg/h.

IV: 0.15 mg/kg/dose 30 minutes prior to the

Esophageal varices/GI bleeding: 1 to 2 mcg/kg

start of emetogenic chemotherapy, with sub-

initial IV bolus followed by 1 to 2 mcg/kg/h

sequent doses administered 4 and 8 hours

continuous infusion; titrate to response,

after the first dose or every 8 hours until the

taper doses by 50% q12h when no active

chemotherapy is complete. For highly eme-

bleeding occurs for 24 hours, may discon-

togenic drugs, give 0.45 mg/kg as a single

tinue dose when at 25% of initial dose.

dose 30 minutes prior to the start of chemo-

therapy, followed by 0.15 mg/kg/dose q4h

Notes:

PRN. Maximum single dose 32 mg.

Do not give to patients with known hyper-

Oral: Dose based on total body surface area

sensitivity to octreotide. May need to adjust

(TBSA), weight, or age:

dose for patients with diabetes; may alter

TBSA:

insulin requirements. Use with caution in

patients with renal or hepatic impairment or

<0.3 m²: 1 mg TID PRN

350

Formulary

0.3 to 0.6 m²: 2 mg TID PRN

Indications:

0.6 to 1 m²: 3 mg TID PRN

Treatment of relapsed or refractory solid

tumors, brain tumors, and non-Hodgkin

>1 m²: 4 to 8 mg TID PRN

lymphoma.

Weight:

Same as IV dosing; round to closest conve-

Dosage:

nient dose

Refer to individual protocol.

Age:

Children:

1 year: 4.3 mg/kg IV over 2 hours

<11 years: dose based on TBSA

q3 weeks

Children

11 years and adults: 8 mg TID

Children:

>1 year: 130 mg/m² IV over 2

PRN; first dose 30 minutes prior to start of

hours q3 weeks

chemotherapy

Notes:

Do not give to patients with known hypersen-

Do not give to patients with known hyper-

sitivity to oxaliplatin, in pregnancy, or in those

sensitivity to ondansetron. Ondansetron is a

with grade 3 or 4 neuropathy (usually due to

substrate for the cytochrome P450 enzyme

prior exposure). Anaphylaxis may occur

system, so inducers or inhibitors of this

within minutes of administration; appropri-

system may affect the elimination of ondan-

ate supportive and resuscitative medications

setron. Data are limited for use in children

and equipment should be available. Two dif-

under 3 years of age. May need to adjust

ferent types of neuropathy may occur: (1) an

dose and interval for severe hepatic

acute

(within

2 days) reversible

(resolves

impairment. Side effects are usually mild,

within 14 days) sensory neuropathy with

with headache, sedation, constipation, and

peripheral symptoms that are often exacer-

dry mouth being the most common. May

bated by cold (may include pharyngolaryngeal

also cause bronchospasm, tachycardia,

dysesthesia), and (2) persistent (over 14 days)

hypokalemia, seizures, lightheadedness,

sensory neuropathy that presents with par-

diarrhea, transient increases in bilirubin

esthesias, dysesthesias, hypoesthesias, and

or transaminases, and transient blindness

impaired proprioception that interferes with

(minutes to 48 hours). ECG changes (QT

activities of daily living. Symptoms may

prolongation) have been reported. Data are

improve with discontinuing treatment. May

not available for use in children with radi-

cause pulmonary fibrosis or hepatotoxicity.

ation-induced nausea and vomiting. How-

When administered as sequential infusions,

ever, based on efficacy in adults and safety in

taxane derivatives should be administered

children, it is commonly used. Give 1 to 2

before platinum derivatives to limit myelo-

hours prior to radiation; may need round

suppression and enhance efficacy.

the clock dosing for abdominal radiation.

PENTAMIDINE ISETHIONATE

OXALIPLATIN

Pentam 300, NebuPent

Antibiotic, antiprotozoal

Eloxatin, generic

Antineoplastic, alkylating agent

Injection: 300 mg vial (Pentam 300)

Injection: 5 mg/mL

Inhalation: 300 mg vial (NebuPent)

Pregnancy category D

Pregnancy category C

Formulary

351

Indications:

Suspension: 40 mg/mL

Treatment of Pneumocystis jiroveci pneumo-

Pregnancy category C

nia (PCP) in patients who cannot tolerate or

who fail to respond to trimethoprim-sulfa-

Indications:

methoxazole, prevention of PCP infection in

Prophylaxis of invasive Aspergillus and

immunocompromised hosts, treatment of

Candida infections in high risk, severely

African trypanosomiasis, and treatment of

immunocompromised patients (e.g., he-

visceral and cutaneous leishmaniasis caused

matopoietic stem cell transplant recipient,

by Leishmania donovani.

graft-versus-host disease, hematologic

Dosage:

malignancy with prolonged chemother-

Prophylaxis for PCP:

apy-induced neutropenia); treatment of

oropharyngeal candidiasis

(including

4 mg/kg/24 hours IM/IV (over 1 to 2 hours)

those refractory to itraconzaole and/or

every 2 to 4 weeks

fluconazole); treatment of serious invasive

Inhalation (

5 years): 300 mg in 6 mL water

fungal infections including zygomycosis

via inhalation qmonth (use with Respirgard

and coccidioidomycosis in patients intol-

II nebulizer)

erant or refractory to other antifungal

Maximum single dose 300 mg

therapy.

Treatment of PCP:

4 mg/kg/dose IM/IV daily for 14 to 21 days

Dosage:

(preferably IV)

Children

13 years and adults:

Prophylaxis of invasive Aspergillus and Can-

Notes:

dida infections: 200 mg TID

Do not give to patients with known hypersen-

Treatment of refractory, invasive fungal infec-

sitivity to pentamidine isethionate. Adjust

tions:

800 mg/day in divided doses (given

dose in renal impairment. Use with caution

BID to QID)

in patients with diabetes mellitus, renal or

Treatment of orophargyngeal candidiasis:

hepatic dysfunction, hypertension, or hypo-

tension. Additive toxicity may occur with

Initial: 100 mg BID on day 1, then 100 mg

aminoglycosides, amphotericin B, cisplatin,

daily for 13 days

and vancomycin. Can see Jarisch-Herxhei-

Refractory: 400 mg BID

mer-like reaction

(fever, chills, headache,

myalgia). Inhalation therapy may cause irrita-

Notes:

tion of the airway, bronchospasm, cough,

Do not give to patients with known hyper-

oxygen desaturation, dyspnea, and loss of

sensitivity to posaconazole and avoid con-

appetite. May cause hypoglycemia, hypergly-

current administration with ergot alka-

cemia, hypotension (with infusion <2 hours),

loids. Cross sensitivity reactions with other

nausea, vomiting, fever, mild hepatotoxicity,

azoles have not yet been studied but may

pancreatitis, hypocalcemia, megaloblastic ane-

exist. May cause hepatotoxicity, and fre-

mia, granulocytopenia, and nephrotoxicity.

quent monitoring is recommended. May

alter drug levels of cyclosporine

(also

POSACONAZOLE

tacrolimus and sirolimus) resulting in

Noxafil

nephrotoxicity, leukoencephalopathy, and

Antifungal

death. Use with caution in neonates (oral

352

Formulary

solution contains sodium benzoate, a

thromboembolic disorders. May cause adre-

metabolite of benzyl alcohol, which has

nal axis suppression, hypertension, hyper-

been associated with a potentially fatal

glycemia, irritability, gastritis, skin atrophy,

toxicity).

osteoporosis, cataracts, fluid retention,

mood lability, nausea, diarrhea, bone pain,

PREDNISONE

acne, and weight gain. Consider use of

antacid in long-term therapy. Avascular

Deltasone, Liquid Pred, Orasone, generic

necrosis and growth retardation are seen

Corticosteroid

in patients with long-term or repeated

Tablets: 1, 2.5, 5, 10, 20, 50 mg

high-dose therapy. Ensure patients are

Solution: 1, 5 mg/mL

aware of risk of varicella infection in non-

Pregnancy category C/D

immune states.

Indications:

PROCARBAZINE HYDROCHLORIDE

Management of adrenocortical insuffi-

Matulane

ciency; used for anti-inflammatory or

Antineoplastic, alkylating agent

immunosuppressant effects in autoimmune

Capsule: 50 mg

diseases such as immune thrombocytopenia

Pregnancy category D

purpura; chemotherapy for acute lympho-

blastic leukemia and Hodgkin and non-

Indications:

Hodgkin lymphoma.

Treatment of Hodgkin lymphoma and

brain tumors.

Dosage:

Dose is dependent on condition being trea-

Dosage:

ted and response of patient. Consider alter-

Refer to individual protocol.

nate day dosing for long-term therapy. Dis-

continuation of long-term therapy requires

50 to 100 mg/m² daily for 10 to 14 days

gradual tapering.

Notes:

Anti-inflammatory or immunosuppressant

(includes immune thrombocytopenic pur-

Avoid in patients with known hypersensi-

pura, aplastic anemia):

tivity to procarbazine or with preexisting

bone marrow aplasia. May cause nausea,

0.5 to 2 mg/kg/day PO divided 1-3 times daily

vomiting, dry mouth, constipation, head-

Chemotherapy:

ache, dizziness, and hair loss. Use with

40 to 180 mg/m²/day, as per protocol

caution and reduce dose in patients with

renal or hepatic impairment or marrow

Notes:

suppression. May potentiate central ner-

Avoid use in patients with life-threatening

vous system depression when used with

infections (except septic shock or tubercu-

phenothiazine derivatives, barbiturates,

lous meningitis), systemic fungal infections,

narcotics, alcohol, tricyclic antidepres-

varicella, and in those with hypersensitivity

sants, and methyldopa. Drug (e.g., mono-

to prednisone. Use with caution in patients

amine oxidase inhibitors) and food inter-

with hypothyroidism, cirrhosis, hyperten-

actions are common. Avoid food with high

sion, congestive heart failure, ulcerative

tyramine content

(i.e., aged cheese or

colitis,

gastrointestinal bleeding, and

meats, tea, dark beer, coffee, cola drinks,

Formulary

353

wine, soybean products, peanuts, avoca-

bath and analyzed within 4 hours. Collec-

does, bananas) because hypertensive crisis,

tion at room temperature may lead to

tremor, excitation, cardiac palpitations,

spuriously low uric acid levels due to con-

and angina may occur.

tinued degradation by rasburicase in the

sample.

RASBURICASE

RHD IMMUNE GLOBULIN

Elitek

Recombinant urate oxidase, uric acid low-

WinRho SDF, Rhophylac

ering agent, antigout agent

Immune globulin

Injection: 1.5, 7.5 mg vials

Injection: 600, 1500, 2500, 5000, 15,000 IU

(1 mcg ¼ 5 IU)

Pregnancy category C

Indications:

Initial management or prevention of hyper-

Indications:

uricemia in high risk patients with leuke-

Treatment of immune thrombocytopenic

mia, lymphoma, or a select group of patients

purpura (ITP) in nonsplenectomized RhD-

with solid tumors at risk for tumor lysis

positive patients; suppression of RhD isoim-

syndrome with initiation of chemotherapy.

munization in an RhD-negative individual

Indicated only for short-term use; maxi-

exposed to RhD-positive blood or during

mum of 5 days.

delivery (or pregnancy) of an RhD-positive

infant (if father known to be RhD-positive

Dosage:

or status unknown).

0.15 to 0.2 mg/kg/dose IV over 30 minutes

(round down to nearest 1.5 mg). May repeat

Dosage:

q24h PRN up to 4 additional doses. Admin-

ITP:

ister until the uric acid is normal and the

Hemoglobin

10 g/dL: 50 mcg/kg IV (250 IU/

patient is stable. Most patients respond to

kg), administer dose over 3 to 5 minutes

1 dose.

Hemoglobin <10 g/dL: 25 to 40 mcg/kg IV

Give prior to chemotherapy if expected

(125 to 200 IU/kg)

massive tumor lysis and/or renal involve-

New onset ITP: 75 mcg/kg (375 IU/kg) as a

ment/dysfunction (e.g., Burkitt lymphoma

single dose has been used safely and effica-

with bulky disease).

ciously in pediatric patients with platelets

10⁹/L

Notes:

Dose frequency is dependent on duration of

Do not give to patients with known hyper-

response, clinical symptoms, and adverse

sensitivity to rasburicase. Contraindicated

effects; may be given q2-4 weeks.

in patients with G6PD deficiency

(may

cause hemolysis) or severe asthma. Methe-

Notes:

moglobinemia has been reported with

use. May cause vomiting, nausea, fever,

Avoid in patients with known hypersensi-

headache, abdominal pain, constipation,

tivity to immunoglobulins or thimerosal

diarrhea, and rash. When measuring serum

and in patients with IgA deficiency. Use

uric acid levels, ensure tubes are prechilled

with extreme caution in patients with a

and samples are placed in an ice water

hemoglobin less than 8 g/dL. Adverse events

354

Formulary

associated with administration in ITP in-

Notes:

clude headache, chills, fever, and reduction

Rare cases of progressive multifocal leu-

in hemoglobin (resulting from the destruc-

koencephalopathy due to Creutzfeldt-Ja-

tion of RhD-positive red cells). May inter-

kob virus have been reported. Infusional

fere with immune response to live-virus

toxicity is common and primarily avoided

vaccines. Causes acute hemolysis with

with a slow infusion and premedication.

an average hemoglobin decrease of 1.5 to

Most common, infusional toxicity is seen

2 g/dL at 1 week. Do not use in patients with

with the first infusion and reactions may

active bleeding. Current FDA guidelines

include development of hives, broncho-

strongly recommend that patients be mon-

spasm, hypoxia, hypotension, pulmonary

itored in a health care center for 8 hours

infiltrates, and respiratory distress syn-

after a dose of RhD immune globulin, with

drome. Some reactions have been fatal.

urinalyses at baseline and 2, 4, and 8 hours

Close monitoring is required for all infu-

after administration due to risk of severe

sions and appropriate resuscitative medi-

hemolysis.

cations and equipment must be close by. In

the case of mild reactions, temporary ces-

sation of the infusion is indicated with

RITUXIMAB

acetaminophen, diphenhydramine, and

Rituxan

fluids as indicated. Hydrocortisone may

Antineoplastic, monoclonal antibody

also be indicated. If symptoms resolve,

Injection: 10 mg/mL

reinitiate the infusion at a 50% reduced

Pregnancy category C

rate and monitor closely. Subsequent infu-

sions should run slowly and the patient

Indications:

should be premedicated. Rituximab should

be discontinued altogether following a life-

Treatment of relapsed or refractory low

threatening reaction. Use with caution in

grade or follicular CD20

positive, B-cell

patients with preexisting pulmonary or

non-Hodgkin lymphoma; first-line therapy

cardiac conditions and in those at risk for

for diffuse large B-cell non-Hodgkin lym-

development of tumor lysis syndrome.

phoma in combination with other che-

Causes immunosuppression. Quantitative

motherapeutics; systemic autoimmune dis-

immunoglobulins and specific antibody

orders including autoimmune hemolytic

response should be checked prior to and

anemia and immune thrombocytopenia

following treatment with rituximab to

purpura; posttransplant lymphoprolifera-

determine if immunoglobulin infusions

tive disorder; rheumatoid arthritis; refrac-

might be needed post treatment until

tory graft-versus-host disease; refractory

recovery of immune function. Reactivation

systemic lupus erythematosis.

of hepatitis B has been noted (mainly in

adult patients); thus, immune status to

Dosage:

hepatitis B virus should be documented.

Refer to individual protocol.

Although specific to B-cells, Pneumocystis

Children and adults: 375 mg/m² IV qweek

jiroveci pneumonia (PCP) infection after

for 4 weeks (range 3 to 6 weeks)

rituximab has been reported; therefore,

Courses may be repeated for treatment of

patients should receive PCP prophylaxis

malignancies or recurrent symptoms with

for 6 months or until recovery of immune

autoimmune disorders.

function is documented.

Formulary

355

SARGRAMOSTIM

purpura, known hypersensitivity to gran-

GM-CSF

ulocyte-macrophage colony-stimulating

factors, or yeast-derived products. Use

Leukine

Colony-stimulating factor

with caution in patients with autoimmune

or chronic inflammatory conditions,

Injection: 250, 500 mcg

hypertension, cardiovascular disease, pul-

Pregnancy category C

monary disease, or renal or hepatic

impairment.

Indications:

Accelerates myeloid recovery and engraft-

SIROLIMUS

ment after autologous or allogeneic

Rapamune

hematopoietic stem cell transplantation

Immunosuppressant agent

(HSCT); mobilizes hematopoietic progen-

Solution: 1 mg/mL

itor cells into peripheral blood for collec-

Tablet: 1, 2 mg

tion by leukapheresis; increases neutrophil

counts in patients receiving myelosup-

Pregnancy category C

pressive chemotherapy; used in neonatal

neutropenia.

Indications:

Graft-versus-host disease prophylaxis in

Dosage:

hematopoietic stem cell transplant recipi-

Neonates with neutropenia and sepsis:

ents; prophylaxis and treatment of rejection

in renal transplant patients; primary immu-

10 mcg/kg/day IV/SC for 5 days

nosuppression in other organ transplant.

Children and adults (no FDA approved dos-

ing in children) after HSCT:

Dosage:

250 mcg/kg/day IV/SC for 21 days, begin-

Refer to individual protocol.

ning 2 to 4 hours after marrow infusion on

Children

13 years of age and <40 kg: Load-

day 0 of HSCT or not sooner than 24 hours

ing dose 3 mg/m² on day 1 followed by

after chemotherapy. Administer as a 30-

maintenance

1 mg/m²/day divided q12h

minute, 2-hour, or 6-hour infusion. Reduce

or once daily; adjust dose to achieve target

dose to 125 mcg/kg if adverse effect (after

sirolimus trough blood concentration.

resolution).

Administer daily until the absolute neutro-

Notes:

phil count is

5.0

10⁹/L for 1 day or until

Do not give to patients with known hyper-

day þ21 post-HSCT, whichever comes first

sensitivity to sirolimus. Immunosuppres-

(or per protocol).

sion may result in increased susceptibility

Do not administer within 24 hours prior to

to infection. May increase risk for develop-

or after chemotherapy or 12 hours prior to

ment of lymphoma or other malignancy.

radiation therapy.

Avoid excessive sun exposure and use sun

protection factor. Severe hypersensitivity

Notes:

and skin reactions have been reported.

May lead to excessive immature myeloid

Monitor renal and hepatic function; dose

cells in the peripheral blood or bone mar-

reduction may be necessary. Use with cau-

row (>10%). Avoid in patients with a

tion in the perioperative period due to an

history of immune thrombocytopenic

increased risk of surgical complications

356

Formulary

from wound dehiscence and impaired

Dosage:

wound and tissue healing. Prophylaxis

Lead chelation, children:

against Pneumocystis jiroveci and cytomeg-

10 mg/kg/dose (350 mg/m²/dose) PO q8h

alovirus is recommended.

for 5 days, followed by 10 mg/kg/dose PO

q12h for 14 days. Repeat courses separated

SODIUM THIOSULFATE

by a minimum of 2 weeks may be necessary

Versiclear

to treat rebound lead concentrations

Antidote, extravasation of mechloretha-

(resulting from mobilization of lead from

mine, cisplatin, or cyanide; antifungal agent

bone stores).

(topical)

Injection: 100, 250 mg/mL

Notes:

Do not give to patients with known hyper-

Indications:

sensitivity to succimer. Use with caution

Treatment of extravasations of selected che-

in impaired hepatic or renal function. May

motherapeutic agents.

see gastrointestinal symptoms, increased

transaminases, rash, headache, and dizzi-

Dosage:

ness. Do not administer with other chela-

Chemotherapy infiltration: children and

tors. Treat iron deficiency and eliminate

environmental exposure to lead. Monitor

adults:

lead levels. May sprinkle contents of the

Mechlorethamine: use

2 mL for each mg

capsules on food if unable to swallow.

infiltrated

TACROLIMUS

Notes:

Prograf, generic

Do not give to patients with known hyper-

Immunosuppressant agent

sensitivity to sodium thiosulfate. Inject

Capsule: 0.5, 1, 5 mg

slowly, over at least

minutes; rapid

Injection: 5 mg/mL

administration may cause hypotension.

SUCCIMER

Indications:

Chemet

(2,3-dimercaptosuccinic acid;

Prevention of organ rejection in solid organ

DMSA)

transplant patients; prevention or treat-

Antidote (lead toxicity), chelating agent

ment of graft-versus-host disease (GVHD)

Capsule: 100 mg

in allogeneic hematopoietic stem cell trans-

plantation.

Pregnancy category C

Dosage:

Indications:

Children: younger children usually require

Treatment of lead poisoning in asymptom-

higher dosing on a mg/kg basis than older

atic children with blood levels between 45

and

69.9 mcg/dL. Can be considered at

children.

lower lead levels

(20

44.9 mcg/dL) if

Solid organ transplant: initial dose 0.15 to

aggressive environmental interventions

0.3 mg/kg/day PO divided q12h; may give

have not impacted level although not noted

IV continuous infusion 0.01 to 0.06 mg/kg/

to improve neurocognitive outcome.

day (refer to specific organ protocol)

Formulary

357

Prevention of GVHD: initial 0.03 mg/kg/day

Metronomic dosing: 75 mg/m²/day 5 days/

(based on lean body weight) as IV contin-

week, 21 to 42 day cycles

uous infusion. Begin 24 hours prior to stem

May also be administered concurrently with

cell infusion and continue until oral med-

radiation therapy.

ication can be tolerated. May occasionally

be given as a q12h IV infusion.

Notes:

Conversion from IV to PO dose (1:4 ratio):

Do not give to patients with known

Multiply total daily IV dose by 4 and admin-

hypersensitivity to temozolomide, dacar-

ister in two divided oral doses per day.

bazine, or any component. Thrombocyto-

penia and neutropenia are dose-limiting

Notes:

toxicities and may occur late in the treat-

Do not give to patients with known hypersen-

ment cycle and take 14 days to resolve.

sitivity to tacrolimus, castor oil, or any com-

Monitor blood counts and ensure platelet

ponent. Immunosuppression may increase

count

100

10⁹/L and ANC

1.5

10⁹/L

risk of infection or development of lymphoma

prior to initiation of each cycle of therapy.

or other malignancies. Risk is related to inten-

Rare cases of aplastic anemia, myelodys-

sity and duration of use. May cause nephro-

plasia, and secondary malignancies have

toxicity and neurotoxicity. Do not administer

been reported. Prophylaxis against Pneu-

concurrently with cyclosporine. Monitor elec-

mocystis jiroveci is required, especially

trolytes. Monitor tacrolimus drug levels and

with concurrent administration of irradia-

adjust dosages per protocol.

tion. Avoid in pregnancy; may cause fetal

harm.

TEMOZOLOMIDE

Temodar

THIOGUANINE

Antineoplastic, alkylating agent

6-TG, 6-Thioguanine

Capsule: 5, 20, 100, 140, 180, 250 mg

Antineoplastic, antimetabolite

Injection: 100 mg

Tablet (scored): 40 mg

Pregnancy category D

Indications:

Treatment of refractory anaplastic astrocy-

Remission induction and consolidation

toma; treatment of newly diagnosed glio-

phases in acute myelogenous leukemia;

blastoma multiforme; active against recur-

delayed intensification phase in acute lym-

rent glioblastoma multiforme, metastatic

phoblastic leukemia.

melanoma, brain stem glioma, ependy-

moma, medulloblastoma, primitive neu-

roectodermal tumor

(PNET), neuroblas-

Dosage:

toma, and anaplastic oligodendroglioma.

Refer to individual protocol.

Infants and children <3 years: 3.3 mg/kg/day

Dosage:

PO divided q12h for 4 days

Refer to individual protocol.

Children

3 years and adults: 50 to 200 mg/

Children:

100 to 200 mg/m² IV/PO once

m²/day PO divided q12-24h for 4 to 14 days

daily for 5 days every 28 days

or per protocol

358

Formulary

Notes:

THROMBIN, TOPICAL

Do not give to patients with known hyper-

Evithrom, Recothrom, Thrombi-Gel,

sensitivity to thioguanine. Use with caution

Thrombi-Pad, Thrombin-JMI (epistaxis kit,

and reduce dosage in patients with renal or

spray kit)

hepatic impairment. May cause nausea,

Hemostatic agent

vomiting, anorexia, stomatitis, diarrhea,

Powder (Recothrom): 5000, 20,000 unit vials

myelosuppression, and veno-occlusive dis-

Powder, topical

(bovine, Thrombin-JMI):

ease

(sinusoidal obstructive syndrome).

available in epistaxis kit

5000 IU, spray

Increases busulfan toxicity.

20,000 IU

Solution, topical (Evithrom): 800 to 1200 IU/

THIOTEPA

Sponge, topical

(Thrombi-Gel):

1000,

Thioplex, generic

2000 IU

Antineoplastic, alkylating agent

Pad, topical (bovine, Thrombi-Pad):

200 IU

Powder for injection: 15, 30 mg

Pregnancy category C

Pregnancy category D

Indications:

Hemostasis for minor bleeding from acces-

Treatment of superficial tumors of the blad-

sible capillaries and small venules.

der, brain tumors, and other meningeal

neoplasms (including intrathecal adminis-

Dosage:

tration); control of pleural, pericardial, or

Apply powder directly to the site of bleeding

peritoneal effusions caused by metastatic

or on oozing surface, or use

1000

tumors; also used in high-dose regimens

2000 IU/mL of solution where bleeding is

with autologous hematopoietic stem cell

profuse. May be diluted with NS to other

transplantation (HSCT).

concentrations as needed. Use 100 IU/mL

for bleeding from skin or mucosal surfaces.

Dosage:

May utilize epistaxis/spray kit for mucosal/

Refer to individual protocol.

nose bleeds.

Children, HSCT:

300 mg/m²/dose over

hours IV; repeat q24h for 3 doses. Maximum

Notes:

tolerated dose over

days is

900

Avoid in patients with known hypersensitiv-

1125 mg/m².

ity to thrombin. Some forms are of human or

Intrathecal: 5 to 11.5 mg/m² per dose weekly

bovine origin. May cause fever or allergic

for 2 to 7 doses

reactions. Topical use only. Not for admin-

istration systemically or directly into sites of

Notes:

brisk arterial bleeding. Avoid in patients with

factor V deficiency due to cross-reactivity.

Do not give to patients with known hypersen-

sitivity to thiotepa or severe myelosuppression.

TOPOTECAN

Reduce dose in patients with renal, hepatic, or

bone marrow dysfunction. May cause central

Hycamtin

nervous system changes, skin hyperpigmenta-

Antineoplastic, camptothecin, topoisomer-

tion, nausea, vomiting, hematuria, and eleva-

ase inhibitor

tion of liver transaminases and bilirubin.

Capsule: 0.25, 1 mg

Formulary

359

Injection: 4 mg

Indications:

Short-term use (2 to 8 days) in hemophilia

Pregnancy category D

or von Willebrand disease patients for

mucosal bleeding (including tooth extrac-

Indications:

tion) to reduce or prevent hemorrhage and

Treatment of pediatric solid tumors, includ-

reduce need for factor replacement. May

ing sarcoma and neuroblastoma.

be used to treat primary menorrhagia or

recurrent epistaxis, to prevent gastrointes-

Dosage:

tinal or ocular hemorrhage following

Refer to individual protocol.

trauma, and to decrease perioperative

Children:

blood loss and need for transfusion in

patients undergoing congenital heart dis-

Pediatric solid tumors: 1 mg/m²/day (range

ease or scoliosis surgery.

0.75

1.9 mg/m²/day) for

3 days as a

continuous IV infusion; repeat q3 weeks

Dosage:

Single agent therapy for refractory solid tumors

Children and adults:

or hematologic malignancy:

2.4 mg/m²/day

once daily for 5 days of a 21 day course

Tooth extraction in patients with hemophilia:

Combination therapy for solid tumors:

10 mg/kg immediately before oral surgery

0.75 mg/m²/dose once daily for

days

IV, then 10 mg/kg/dose IV/PO q6-8h; may

every

days in combination with

be used for 2 to 8 days

cyclophosphamide

Menorrhagia:

1300 mg PO TID for up to 5 days during

Notes:

monthly menstruation

Do not give to patients with known hyper-

sensitivity to topotecan. Bone marrow tox-

Notes:

icity is dose limiting, primarily neutropenia.

Do not use in patients with known sub-

Has been associated with neutropenic coli-

arachnoid hemorrhage, active intravascu-

tis; should be a strong consideration in

lar clotting process, or acquired defective

patients with neutropenia, fever, and

color vision. Use with caution in patients

abdominal pain. Severe diarrhea has been

with cardiovascular or cerebrovascular dis-

reported, may require dose adjustment.

ease. Dose modification is required in

May cause fetal harm; must ensure contra-

patients with renal impairment. May cause

ception to avoid pregnancy. Use with cau-

hypotension, thromboembolic complica-

tion in patients with renal or hepatic

tions, headache, and visual abnormalities

impairment.

(seen in animals). Do not administer con-

comitantly with factor IX and prothrom-

bin complex concentrates or hormonal

TRANEXAMIC ACID

contraception due to increased risk of

Cyklokapron, Lysteda

thrombosis. Use with caution in patients

Antifibrinolytic, antihemophilic, hemo-

with upper urinary tract bleeding due to

static agent

potential for clot formation and ureteral

Tablet (Lysteda): 650 mg

obstruction. Use with extreme caution in

Injection (Cyklokapron): 100 mg/mL

patients with disseminated intravascular

Pregnancy category B

coagulation.

360

Formulary

TRIMETHOPRIM/

with G6PD deficiency and impaired renal or

SULFAMETHOXAZOLE

hepatic impairment. Serious adverse reac-

tions include Stevens-Johnson syndrome,

Bactrim, Septra, Co-trimoxazole, Sulfatrim,

TMP-SMX, generic

toxic epidermal necrolysis, hepatic necrosis,

agranulocytosis, aplastic anemia, and other

Antibiotic, sulfonamide derivative

blood dyscrasias. Discontinue with rash.

Tablet, single strength: 80 mg trimethoprim

May need to be held temporarily in oncology

(TMP) and 400 mg sulfamethoxazole (SMX)

patients who are on TMP-SMX for PCP

Tablet, double strength:

160 mg TMP and

prophylaxis and subsequently develop neu-

800 mg SMX

tropenia. Numerous drug interactions are

Suspension: 40 mg TMP/200 mg SMX per

reported. TMP-SMX decreases the clearance

5 mL

of warfarin and methotrexate, decreases

Injection: 16 mg TMP/80 mg SMX per mL

serum cyclosporine concentrations, and

Pregnancy category C/D

increases the effect of sulfonylureas, pheny-

toin, and thiopental. Do not give to patients

Indications:

within 24 hours of receiving high-dose meth-

Oral treatment of urinary tract infection

otrexate and until level is <1

10⁷ M due

(UTI) and otitis media; prophylaxis for

to competitive excretion and increased risk of

Pneumocystis jiroveci pneumonia (PCP); IV

methotrexate toxicity due to delayed clearance.

treatment of documented or suspected PCP

infection in immunocompromised patients.

VALACYCLOVIR

Valtrex, generic

Dosage:

Antiviral

Dosage recommendations are based on the

Caplet: 500 mg, 1 g

TMP component. May be given PO or IV.

Pregnancy category B

Children >2 months of age:

Minor/moderate infection:

Indications:

8 to 12 mg TMP/kg/day PO divided q12h

Treatment of herpes zoster and herpes sim-

plex virus (HSV) in immunocompromised

Serious infection/PCP:

patients; treatment of varicella zoster virus

20 mg TMP/kg/day divided q6-8h PO/IV

(VZV) in immunocompetent children (ages

UTI or otitis media prophylaxis:

2 to 18 years); treatment of HSV labialis in

2 to 4 mg TMP/kg once daily

adolescents and adults.

Prophylaxis for PCP:

Dosage:

5 mg TMP/kg/day divided q12h 2 to 3 con-

Children:

secutive days a week

(maximum dose

Varicella, immunocompetent: 2 years to <18

320 mg TMP/day)

years:

20 mg/kg/dose PO TID for 5 days

(maximum 1 g TID); initiate within 24

Notes:

hours of onset of rash

Do not give to patients with known hyper-

Herpes labialis (cold sores): >12 years: 2 g

sensitivity to sulfa drugs or any component,

q12h for 1 day; initiated at earliest symptoms

porphyria, or megaloblastic anemia due to

folate deficiency. Do not use in infants under

Immunocompromised children at risk for

2 months of age. Use with caution in patients

HSV or VZV infection with normal renal

Formulary

361

function: (limited data) 15 to 30 mg/kg/dose

myalgia, paresthesia, constipation, abdom-

PO TID (maximum 2 g/dose)

inal pain, ileus, and mild alopecia.

Intrathecal administration is fatal.

Notes:

Do not give to patients with known hypersen-

VINCRISTINE SULFATE

sitivity to valacyclovir or acyclovir. Use with

Vincasar, generic

caution in patients with renal impairment or

Antineoplastic, mitotic inhibitor

those receiving concomitant nephrotoxic

Injection: 1, 2 mg vials (1 mg/mL)

drugs. Adjust dose in patients with renal

Pregnancy category D

impairment. Monitor renal function.

VINBLASTINE SULFATE

Indications:

Velban, generic

Treatment of acute lymphoblastic leukemia

Antineoplastic, mitotic inhibitor

(ALL), Hodgkin and non-Hodgkin lym-

Injection: 10 mg vial

phoma, neuroblastoma, Wilms tumor, and

rhabdomyosarcoma.

Pregnancy category D

Indications:

Dosage:

Treatment of Hodgkin and non-Hodgkin

Refer to individual protocol.

lymphoma, pediatric brain tumors (glio-

Children

10 kg or total body surface area

mas), Langerhans cell histiocytosis, chorio-

(TBSA) <1 m²:

carcinoma, and advanced testicular germ cell

0.05 mg/kg/dose IV once weekly; maximum

tumors.

single dose 2 mg

Children >10 kg or TBSA

1m²:

Dosage:

1 to 2 mg/m² IV; may repeat weekly for 3 to

Refer to individual protocol.

weeks. Maximum single dose is

2 mg

Hodgkin lymphoma:

(some protocols allow for higher dosing in

2.5 to 6 mg/m²/dose IV once every 1 to 2

Hodgkin lymphoma and high risk ALL).

weeks for 3 to 6 cycles; maximum weekly

Neuroblastoma:

dose 12.5 mg/m²

IV continuous infusion with doxorubicin:

Langerhans cell histiocytosis:

1 mg/m²/day for 72 hours

6 mg/m²/dose IV once every 1 to 3 weeks

Brain tumors:

Notes:

6 mg/m²/dose IV weekly

Do not give to patients with known hyper-

sensitivity to vincristine. Avoid in patients

Notes:

with the demyelinating form of Charcot-

Do not give to patients with known hyper-

Marie-Tooth disease. Asparaginase may

sensitivity to vinblastine or with severe leu-

decrease clearance of vincristine. Dose mod-

kopenia. Dose modification may be needed

ification may be required in patients with

in patients with hepatic impairment or neu-

impaired hepatic function, preexisting neu-

rotoxicity. Extravasation may cause local

romuscular disease, or severe side effects of

severe tissue damage. May cause peripheral

treatment with vincristine. Extravasation

neuropathy, myelosuppression, jaw pain,

may cause local severe tissue damage.

362

Formulary

May cause peripheral neuropathy, paresthe-

Adults: 2.5 to 5 mg/24 hours PO or 10 mg/

sias, ileus, jaw pain, cranial nerve paralysis

dose IM/SC/IV

(ptosis), vocal cord paralysis, hyponatremia,

syndrome of inappropriate antidiuretic hor-

Notes:

mone (SIADH) secretion, alopecia, and

Do not give to patients with known hyper-

constipation.

sensitivity to phytonadione. Antagonizes

Intrathecal administration is fatal. Vin-

action of warfarin. Protect product from

cristine should never be taken into the proce-

light. Parenteral dosing may cause flushing,

dure room for a patient undergoing a lumbar

dizziness, cardiac or respiratory arrest,

puncture for instillation of intrathecal

hypotension, or anaphylaxis. High doses

chemotherapy.

(10 to 20 mg) in neonates may cause hyper-

bilirubinemia and severe hemolytic anemia.

VITAMIN K₁/PHYTONADIONE

Monitor prothrombin time (PT), activated

AquaMEPHYTON, Mephyton

partial thromboplastin time (APTT); blood

Vitamin, water soluble

coagulation factors may increase within 6 to

Tablet: 5 mg

12 hours after oral dosing and within 1 to 2

Suspension: 1 mg/mL

hours after parenteral dosing.

Injection: 2, 10 mg/mL

VORICONAZOLE

Pregnancy category C

VFEND

Indications:

Antifungal agent

Prevention and treatment of hypopro-

Injection: 200 mg

thrombinemia caused by anticoagulants or

Powder for suspension: 200 mg/5 mL

drug-induced vitamin K deficiency; hemor-

Tablet: 50, 200 mg

rhagic disease of the newborn.

Pregnancy category D

Dosage:

Indications:

Hemorrhagic disease of the newborn:

Treatment of invasive aspergillosis, espe-

Prophylaxis: 0.5 to 1 mg IM within 1 hour of

cially in immunocompromised patients;

birth

treatment of candidemia in nonneutropenic

Treatment: 1 to 2 mg/24 hours IM, SC, or IV

patients; deep tissue Candida infections

Oral anticoagulant overdose:

including esophageal; treatment of serious

fungal infections caused by Scedosporium

Infants and children: 0.5 to 5 mg/dose PO,

apiospermum or Fusarium species in

IM, IV, or SC (give 5 mg for major bleeding,

patients intolerant or refractory to conven-

0.5 to 2.5 mg for minor bleeding)

tional antifungal therapy.

Adults: 2.5 to 10 mg/dose PO, IM, IV, or SC

Dose may be repeated 12 to 48 hours after

Dosage:

PO dose or 6 to 8 hours after parenteral dose

Limited information on pediatric dosing;

Vitamin K deficiency (due to drugs, malab-

children

12 years of age appear to require

sorption, or decreased synthesis of vitamin K

higher dosing than adults.

by the liver):

Children 2 to 11 years: loading dose 6 mg/kg/

Infants and children: 2.5 to 5 mg/24 hours PO

dose IV q12h for 2 doses on day 1 followed

or 1 to 2 mg/dose IM/IV/SC as a single dose

by maintenance dose 4 mg/kg/dose IV q12h

Formulary

363

(approximates exposure of adult dose of

Indications:

3 mg/kg/dose)

Prophylaxis and treatment of venous

Infectious Diseases Society of America (IDSA)

thromboembolic disorders; prevention of

guidelines: invasive aspergillosis: mainte-

arterial thromboembolism in patients with

nance dose 5 to 7 mg/kg/dose IV q12h

prosthetic heart valves or atrial fibrillation;

prevention of death, venous thromboembo-

Children

12 years and adults: loading dose

lism, and recurrent myocardial infarction

6 mg/kg/dose IV q12h for 2 doses on day 1;

(MI) after acute MI.

followed by maintenance dose:

Invasive aspergillosis and other deep tissue

fungal infections: 4 mg/kg/dose IV q12h

Dosage:

Candidemia: 3 to 4 mg/kg/dose IV q12h

Infants and children (to maintain an inter-

national normalized ratio

[INR] between

2 and 3):

Notes:

Initial dose: 0.2 mg/kg PO for 1 to 2 days;

Do not give to patients with known hyper-

maximum dose 10 mg

sensitivity to voriconazole. Use with cau-

Maintenance dose: 0.1 mg/kg/24 hours PO

tion in patients with known hypersensi-

daily; range

0.05

0.34 mg/kg/24 hours

tivity to azoles; cross-reactivity studies

(consult published charts based on INR)

have not been done. Tablets may contain

lactose and should be used with caution

Adults: 5 to 10 mg PO daily

2 to 5 days,

in patients with lactose intolerance. Avoid

adjust for desired INR; maintenance dose

concurrent administration with rifampin,

range 2 to 10 mg/day PO

CYP3A4 substrates, and ergot alkaloids.

Onset of action is within 36 to 72 hours and

Voriconazole is metabolized by cyto-

peak effects occur within 5 to 7 days. Mon-

chrome P450

enzymes and many drug

itor INR after 5 to 7 days of new dosage;

interactions exist. May cause severe

high risk patients may require more fre-

hepatic toxicity, visual changes, cardiac

quent monitoring.

arrhythmias, auditory hallucinations, and

Usual duration of therapy for first venous

photosensitivity. May cause fetal harm;

thrombotic event is 3 months (depending

must ensure contraception to avoid preg-

on elimination of procoagulant factor and

nancy. Use with caution in neonates; oral

based on resolution of clot).

suspension contains sodium benzoate, a

metabolite of benzyl alcohol, which may

cause a potentially fatal toxicity. Use with

Notes:

caution in patients with renal or hepatic

Do not give to patients with known hyper-

toxicity;

dose adjustment may be

sensitivity to warfarin, severe liver or kidney

necessary.

disease, uncontrolled bleeding, gastrointes-

tinal (GI) ulcers, status-post neurosurgical

procedures, and malignant hypertension.

WARFARIN SODIUM

Concomitant use with vitamin K may

Coumadin, Jantoven, generic

decrease anticoagulant effect. Concomitant

Anticoagulant

use with aspirin, nonsteroidal anti-inflam-

Tablets: 1, 2, 2.5, 3, 4, 5, 6, 7.5, 10 mg

matory drugs, or indomethacin may

Injection: 5 mg

increase warfarin’s anticoagulant effect and

Pregnancy category X

cause severe GI irritation. May cause fever,

364

Formulary

skin lesions, necrosis (especially in protein C

is vitamin K and prothrombin complex con-

deficiency),

hemorrhage, hemoptysis,

centrates (PCC; fresh frozen plasma if PCC

anorexia, nausea, vomiting, and diarrhea.

unavailable).

Many drug interactions exist; review all

medications prior to initiation of therapy.

The INR is the recommended test to mon-

References

itor anticoagulant effect. The absolute INR

desired is dependent on the indication and

Taketomo CK, Hodding JH, Kraus DM. Pediatric

has been extrapolated from adults. An INR

Dosage Handbook. 17th ed. Hudson, OH:

of 2 to 3 has been recommended for pro-

Lexi-Comp, 2010.

phylaxis and treatment of deep vein throm-

Physicians’ Desk Reference, 65th ed. Montvale,

bosis, pulmonary emboli, and bioprosthetic

NJ: Medical Economics Company, Inc., 2011.

heart valves. Younger children may require

Custer JW, Rau RE. The Johns Hopkins Hospital:

higher dosing. Certain foods and medica-

The Harriet Lane Handbook, A Manual for

tions may alter levels and should be

Pediatric House Officers, 18th ed. Philadel-

reviewed in detail with the patient. Antidote

phia, PA: Elsevier-Mosby, 2009.

Index

abdominal mass, 130, 178

clinical manifestations of, 152

evaluation of child with, 131

morphologic classification for, 153

ABO-incompatible transplantation

relapse, 155-6

transfusion in, 223

risk group classification, 153-6

absolute neutrophil count (ANC), 92-3, 215,

treatment, 154-5

226, 244

adenopathy

acquired von Willebrand syndrome (AVWS), 77

evaluation of child with, 126

acute chest syndrome (ACS), 19, 24-6

adrenocortical carcinoma (ACC), 204-5

etiology of, 26

afibrinogenemia, 79

laboratory evaluation of, 26

allergic transfusion reactions, 54

acute hemolytic transfusion reactions

allogeneic transplant

(ATHRs), 52-3

malignant conditions, 213

acute lymphoblastic leukemia (ALL), 144-51, 238

nonmalignant conditions, 214

clinical and laboratory features, 145

all-trans retinoic acid (ATRA), 154-5

clinical presentation, 145-6

alpha 2-antiplasmin deficiency, 80

diagnostic evaluation, 146-7

alpha-fetoprotein (AFP), 194, 203

differential diagnosis of, 147

alpha-thalassemia, 18, 36-8

initiation of therapy,

147-8

classification of, 41

risk group classification, 148-50

alveolar rhabdomyosarcoma (ARMS), 183, 185

new agents, 150

aminocaproic acid, 110

relapse, 150

amphotericin-B, 253

treatment, 148-50

analgesics

CNS directed therapy, 149

morphine, 23

complications of therapy, 150

patient-controlled analgesia, 23-4

consolidation, 149

anaplastic large cell lymphoma (ALCL), 170

delayed intensification, 149

anaplastic lymphoma kinase (ALK), 172

induction, 149

anemia, 1-17, 29-30, 47-8, 139

maintenance, 149

acute, 29-30

acute myelogenous leukemia (AML),

128,

anemic child

151-6, 244

approach to, 1-9

clinical presentation, 151-2

medical history of, 4

complications of therapy, 155

physical examination of, 5

diagnostic evaluation, 152-3

case study for, 8-9

etiology of, 151

child with, diagnostic approach to, 2

hyperleukocytosis

definition of, 1

Handbook of Pediatric Hematology and Oncology: Children’s Hospital & Research Center Oakland,

Second Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.

2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

366

Index

anemia (Continued )

evaluation of, 62-3

erythropoietin, 6-8

history, 63

evaluation of, 1-2

initial laboratory evaluation, 63-5

full-term newborn, approach to,

management, 64-70

interventions, 2-8

physical examination, 63

investigation steps, 1-2

bleeding disorder, 62, 129

oral iron challenge, 2-3

menorrhagia in young women with, 67

parenteral iron therapy, 3-6

bleomycin

treatment, 139

mechanism of action, 282

Ann Arbor staging system, 168

side effects, monitoring, and treatment, 282

anorexia/weight loss, 269

utilized in, 282

anthracyclines, 285

blood

induced cardiac toxicity, 169

loss, acute, 47

antibiotics

products, irradiation of, 46

as anaerobic drugs, 248

blood transfusion

dual therapy, 248

approach to fever, 53

monotherapy, 248

chronic transfusion therapy, 27, 33-4, 57

treatment modification, 249-51

guidelines, 45

vancomycin, 248

Bloom syndrome, 144

anticoagulants, 90

body surface area (BSA), 108, 281

anticoagulation, 88-9

bone marrow aspiration, 108, 160, 296-8

antithrombin III (ATIII), 53, 282

indications, 296

arsenic trioxide (ATO), 155

materials, 296

ascorbic acid (vitamin C) , 58

post-procedure monitoring and

asparaginase, 281-2

complications, 298

mechanism of action, 281

pretreatment evaluation, 296

side effects, monitoring, and treatment,

282

procedure, 297-8

utilized in, 282

bone marrow biopsy, 296-8

ataxia telangiectasia, 144

indications, 296

autoimmune hemolytic anemia

materials, 296

(AIHA), 13, 47

post-procedure monitoring and

autoimmune neutropenia, 94

complications, 298

autologous transplant

pretreatment evaluation to, 296

malignant conditions, 213

procedure, 297-8

avascular necrosis, 30-1

bone marrow transplantation, 40, 98, 101,

214,

223, 265

bacterial infections, 55, 93

bone pain,

127

Bart’s hemoglobin, 41

bone sarcomas, 183, 187-92

Beckwith-Wiedemann syndrome, 122, 202

case for review, 191-2

benign familial neutropenia, 98

clinical presentation, 187

beta subunit of human chorionic gonadotropin

diagnostic evaluation, 188

(b-HCG), 194, 195, 203

genetics, 183-4

beta-thalassemia, 38-40

late effects, 191

intermedia, 39

pathologic diagnosis, 188-9

clinical management, 40

prognosis, 190-1

major, 40

treatment, 189-90

Bethesda titers, 84

brain tumors, 123, 136, 142, 157-65, 197-8, 213,

Bethesda unit (BU), 84

221, 270. See also central nervous system

bleeding child, approach, 62-70

tumours

case study for, 70

Burkitt lymphoma (BL), 141, 170

Index

367

cancer

gliomas, 163-5

bleeding, 129

imaging studies, 159

fever management in child with, 244-55

lumbar puncture, 160

duration of therapy, 251-2

magnetic resonance imaging, 159

febrile neutropenia, initial evaluation of,

neurosurgery, 160-1

245-7

positron emission tomography, 159

fever in nonneutropenic oncology patient,

primitive neuroectodermal tumor

255

(PNETs), 162-3

initial antibiotic treatment modification,

radiation therapy, 161

249-51

single-photon emission CT, 160

initial management, 247-9

specific tumor types, 162-5

new site infections, 254-5

treatment, 160-2

persistent fever and neutropenia (FN),

central venous catheters (CVCs), 235-43,

empiric antifungal therapy for, 252-3

247, 298

Pneumocystis jiroveci (P. carinii)

catheter-related thrombosis

pneumonia, 254

assessment and management of, 240-2

viral infection, 253-4

complications

initial symptoms of, 122

infectious, 238-40

supportive care of child with, 226-34

mechanical, 238

adverse effects, 233

types of, 237

chemotherapy induced nausea and

maintenance, 237-8

vomiting, prevention of, 229-30

types of, 235

febrile neutropenia, treatment of, 233

use of, 238

granulocyte colony-stimulating factor

chelation therapy, 57-61

(filgrastim), 230-3

institution of, 57

hematopoietic growth factors

lead toxicity, 59-61

in children, 230-3

transfusional iron overload, 57-8

immunization during chemotherapy, 228-9

chemotherapy, 136, 162, 281-90

infection prophylaxis, 226-7

asparaginase, 281-2

monitoring, 233

mechanism of action, 281

primary prophylaxis, 233

side effects, monitoring, and treatment, 282

recombinant human erythropoietin, 233-4

utilized in, 282

viral prophylaxis and treatment, 227-8

bleomycin

carboplatin, 282-3

mechanism of action, 282

side effects, monitoring, and treatment, 282

utilized in, 282

cisplatin, 282-3

catheter-related infections, 238

mechanism of action, 282

catheter-related thrombosis

side effects, monitoring, and treatment, 283

assessment and management of, 240-2

utilized in, 282

central nervous system (CNS) tumors, 157-65

cyclophosphamide, 283-4

bone marrow aspiration, 160

mechanism of action, 283

bone scan, 160

side effects, monitoring, and treatment,

cause of, 157

283-4

chemotherapy, 162

utilized in, 283

clinical presentation, 157-9

cytarabine (Ara-C)

computerized tomography (CT), 159

mechanism of action, 284

diagnosis of, 157

side effects, monitoring, and treatment, 284

diagnostic evaluation, 159-60

utilized in, 284

germ cell tumors, 165

dactinomycin (actinomycin-D), 284-5

368

Index

chemotherapy (Continued )

vincristine, 289-90

mechanism of action, 285

mechanism of action, 290

side effects, monitoring, and treatment, 285

side effects, monitoring, and treatment, 290

utilized in, 285

utilized in, 290

daunorubicin, 285-6

chemotherapy induced nausea and

mechanism of action, 285

vomiting (CINV), 229

side effects, monitoring, and treatment,

treatment of, 230

285-6

chemotherapy injection, 295-6

utilized in, 285

indications, 295

etoposide

materials, 295

mechanism of action, 286

post-procedure monitoring and

side effects, monitoring, and treatment, 286

complications, 296

utilized in, 286

pretreatment evaluation, 295

extravasations treatment, 300-3

procedure, 295-6

imatinib (Gleevec

)

cisplatin, 282-3

mechanism of action, 286

side effects, monitoring, and treatment, 283

side effects, monitoring, and treatment, 286

utilized in, 282

utilized in, 286

coagulopathy, 139-40

induced nausea and vomiting, prevention of,

evaluation, 140

229-30

management, 140

intrathecal administration, 294

Cockcroft-Gault equation, 283

irinotecan, 286-7

cognitive-behavioral therapies (CBT), 263

mechanism of action, 286

combination estrogen-progestin oral

side effects, monitoring, and treatment,

contraceptive pills (COCP), 68

286-7

preparations of, 69

utilized in, 286

congenital amegakaryocytic thrombocytopenia

mercaptopurine (6-MP)

(CAMT), 118

mechanism of action, 287

constipation, 268-69

side effects, monitoring, and treatment, 287

causes of, 268

utilized in, 287

history, 268

methotrexate, 287-8

medications, 269

mechanism of action, 287

physical examination, 268-69

side effects, monitoring, and treatment,

consumptive thrombocytopenia

287-8

immune thrombocytopenic purpura (ITP), 1,

utilized in, 287

48-9, 64, 103, 111, 128

steroids

Coombs test. See direct antiglobulin test

mechanism of action, 288

craniospinal irradiation (CSI), 162

side effects, monitoring, and treatment, 288

cryoprecipitate, 50

utilized in, 288

dosing of, 51

temozolomide, 289

indications for, 50

mechanism of action, 289

Cushing’s syndrome, 204

side effects, monitoring, and treatment, 289

cyclic neutropenia, 95

utilized in, 289

cyclophosphamide, 168, 283-4

thioguanine (6-TG)

mechanism of action, 283

mechanism of action, 289

side effects, monitoring, and treatment,

side effects, monitoring, and treatment, 289

283-4

utilized in, 289

utilized in, 283

topotecan

cytarabine (Ara-C)

mechanism of action, 289

mechanism of action, 284

side effects, monitoring, and treatment, 289

side effects, monitoring, and treatment, 284

utilized in, 289

utilized in, 284

Index

369

cytomegalovirus (CMV), 228

epoetin alfa. See erythropoietin (EPO)

negative blood, 46

Erdheim-Chester disease, 207

cytosine arabinoside. See cytarabine (Ara-C)

erythropoietin (EPO), 8, 230

indications for, 8

dactinomycin (actinomycin-D), 284-5

side effects, 8

mechanism of action, 285

etoposide

side effects, monitoring, and treatment, 285

mechanism of action, 286

utilized in, 285

side effects, monitoring, and treatment, 286

dactylitis, 21

utilized in, 286

daunorubicin, 285-6

Evans syndrome, 13

mechanism of action, 285

Ewing sarcoma, 128, 183

side effects, monitoring, and treatment, 285-6

Ewing sarcoma family of tumors

utilized in, 285

(ESFTs), 184

decompression surgery, 31

active chemotherapy agents in, 190

delayed hemolytic transfusion reactions

immunophenotypic features, 189

(DHTRs), 52

excessive bruising, 63

delayed intensification (DI), 149

extravasation

Denys-Drash syndrome, 174

causes of, 300-1

desferoxamine (Desferal), 58

definition of, 300

desmopressin (DDAVP), 75, 77

of irritant drug, 300

intranasal form of, 75

recommendations to prevent, 301

diabetes insipidus (DI), 198

signs and symptoms, 303

Diamond-Blackfan anemia, 98

treatment, 302-3

diencephalic syndrome, 158

of vesicant drug, 300

diffuse large B-cell lymphoma (DLBCL), 170

direct antiglobulin testing (DAT), 13-14, 50,

faces, legs, activity, cry, consolability (FLACC)

55, 108

scale, 258

disseminated intravascular coagulation (DIC),

factor IX deficiency, 79

48, 116, 129

factor replacement therapy, 76

DNA index, 178

factor V deficiency, 79

donor selection criteria, 44

factor VII deficiency, 80

Down syndrome (DS), 122, 144, 194

factor VIII coagulant, 73

doxorubicin, 285-6

factor V Leiden mutation, 90

mechanism of action, 285

factor X deficiency, 80

side effects, monitoring, and treatment, 285-6

factor XI deficiency, 80

utilized in, 285

factor XIII deficiency, 80

dyskeratosis congenita (DKC), 98

familial adenomatous polyposis, 202

dyspnea, 271-2

Fanconi anemia, 98, 144

distress associated with, 275

fatigue, 269-71

treatment of, 271-2

model in life-threatening illness, 270

treatments for, 271

echocardiogram, 85

FDG-PET imaging. See fluorine-18-fluorodeoxy-

ektacytometry, 15

glucose positron emission tomography

electrophoresis, 41

febrile neutropenia

Embden-Meyerhof pathway (EMP), 11

initial evaluation of, 246-7

embryonal rhabdomyosarcoma (ERMS),

treatment of, 233

184-5

febrile nonhemolytic transfusion reactions

engraftment syndrome, 216, 224

(FNHTRs), 46, 52-4

epistaxis, 81

fetal alcohol syndrome, 202

management of, 65

fetal hemoglobin, 34

370

Index

fever

acute and chronic, signs and symptoms of, 219

definiton of, 245

grading of, 220

in nonneutropenic oncology patient, 255

prophylaxis and treatment, agents used for,

fever and neutropenia (FN), 245-6

220

empiric antifungal therapy for, 252-3

graft-versus-leukemia effect, 212

empiric therapy in, 252

granulocyte colony-stimulating factor (G-CSF),

evaluation and initial management of, 246

98, 212, 230-3, 255

laboratory evaluation, 247

granulocyte-macrophage colony-stimulating

on-going management of, 250

factor (GM-CSF), 230

pediatric oncology patients, risk stratification

granulocyte transfusions, 51-2

models for, 247

filgrastim. See granulocyte colony-stimulating

headaches, 28, 123, 293

factor (G-CSF)

Heinz bodies, 12

fingerstick hemoglobin, 8

hemarthroses, 81

Fitzgerald’s factor, 80

hematopoietic growth factors in children, 230-3

Fletcher’s factor, 80

hematopoietic stem cell transplantation

fluorescent in situ hybridization (FISH), 145

(HSCT), 34, 150, 212-25

fluorine-18-fluorodeoxyglucose positron

benefits of, 212

emission tomography (FDG-PET) imag-

case study for, 221-4

ing, 185, 188, 205

complications of, 216

folate

diet, 217-18

deficiencies of, 95

differential diagnosis, 224

free erythrocyte protoporphyrin (FEP), 61

graft-versus-host disease, 217

French-American-British (FAB) classification,

immune reconstitution, 221

153

infections, 216-17

fresh frozen plasma (FFP), 50, 140

late effects, 221

dosing of, 50

late sequelae, 217

indications for, 50

risks, 212

routine infection prophylaxis, 222

Gann Act, 44

sinusoidal obstructive syndrome (SOS),

Gardener syndrome, 202

216-18

germ cell tumors (GCTs), 160, 165, 193-9

surveillance in, 222

of central nervous system, 197-9

transfusion guidelines, 218-21

clinical presentation, 195-6

transplantable conditions, 212

diagnostic evaluation and risk stratification,

transplant patients, supportive care in, 217

196

types of transplantation, 212-13

epidemiology, 193-4

veno-occlusive disease (VOD), 216-17

histologic variants, 194

hematuria, 81

pathology and serum tumor markers, 194-5

hemoglobin E, 38

treatment and prognosis, 196-7

hemoglobin H, 37

gliomas, 163-5

hemoglobin H-constant spring, 37

glucose-6-phosphate dehydrogenase (G6PD)

hemoglobinopathies

deficiency, 12, 142

neonatal screening for, 40-3

diagnosis of, 13

hemoglobin S (Hgb S), 18

Mediterranean/Asian forms of, 12

hemolytic anemia, 10-17

variants of, 12

autoimmune hemolytic anemia, 13

glycogen storage disease 1b, 98

case study for, 16-17

glycoprotein Ib (GPIb), 71

child with, diagnostic approach to, 15

graft-versus-host disease (GVHD), 44, 139,

evaluation of, 14-15

213, 217

hemolytic disease of newborn, 14

Index

371

intrinsic causes, 13-14

hydroxyurea (HU)

microangiopathic hemolytic anemia, 14

therapy, 34

red cell enzyme defects, 11-13

hyperbilirubinemia, 31-2

red cell membrane disorders, 10-11

hypercalcemia, 142-3

treatment, 16

evaluation, 142-3

hemolytic transfusion reactions, 52-4

treatment, 143

hemolytic uremic syndrome (HUS), 116

hyperleukocytosis, 137-8

hemophagocytic lymphohistiocytosis (HLH),

definition of, 137

209-10

hypersplenism, 29, 117

diagnostic criteria for, 210

hyphema, 31

genetic mutations associated with, 209

hypoprothrombinemia, 79

hemophilia, 79-84

clinical presentation, 80-2

idarubicin, 285-6

definition of, 79

mechanism of action, 285

diagnosis, 82

side effects, monitoring, and treatment, 285-6

hemophilia A and B

utilized in, 285

guidelines for factor replacement in,

immune thrombocytopenic purpura (ITP), 103

inhibitors, 84

acute, 103-13

treatment, 82-3

natural history of, 109

hemostasis, 62

chronic, 111-13

heparin-induced thrombocytopenia

emergency therapy, 111-12

(HIT), 88, 115

evaluation, 105-9

hepatocellular carcinoma (HCC), 202-3

bone marrow examination, 129

hereditary spherocytosis (HS), 10

prognosis of, 120

family history of, 11

treatment for, 109-11

herpes simplex (HSV) infections, 228

ifosfamide, 283-4

high grade gliomas (HGG)

mechanism of action, 283

definition of, 163

side effects, monitoring, and treatment, 283-4

histiocytic disorders, 207-11

utilized in, 283

case study for, 210-11

iliopsoas hemorrhage, 81

classification of, 208

imatinib (Gleevec

)

hemophagocytic lymphohistiocytosis

mechanism of action, 286

(HLH), 209-10

side effects, monitoring, and treatment, 286

Langerhans cell histiocytosis (LCH),

utilized in, 286

207-9

immunization during chemotherapy, 228-9

Hodgkin and Reed-Sternberg (HRS) cells, 166

increased intracranial pressure

Hodgkin lymphoma (HL), 133, 166-70

(ICP), 136-7, 157

clinical presentation, 167

evaluation, 136

complications of treatment, 169-70

management, 136-7

evaluation, 167-8

indirect antiglobulin test (IAT), 13

intermediate and high-risk disease, 169

individualized care planning and coordination

low-risk disease,

169

model, 265

nodular lymphocyte predominant HL, 169

induced nausea and vomiting, prevention of,

staging, 168

229-30

treatment, 168

International Neuroblastoma Staging System,

homovanillic acid (HVA), 180

180-81

hook effect, 203

international normalized ratio (INR), 64, 89

Horner’s syndrome, 179

intracranial hemorrhage (ICH), 80-81, 105

human leukocyte antigen (HLA) system, 213

intracranial mass, 123

human platelet antigen 1a (HPA-1a), 113

intracranial pressure (ICP), 136

372

Index

intra-Ommaya reservoir tap, 295-6

low-molecular-weight heparin (LMWH), 88, 242

indications, 295

lumbar puncture (LP), 160, 185, 247, 291, 292-5

materials, 295

indications, 292

post-procedure monitoring and

materials, 293

complications, 296

post-procedure monitoring and

pretreatment evaluation, 295

complications, 294-5

procedure, 295-6

pretreatment evaluation, 292-3

intrathecal chemotherapy, 292-5

procedure, 293-4

indications, 292

lupus anticoagulant, 64

materials, 293

lymphadenopathy, 124

post-procedure monitoring and

differential diagnosis of, 124

complications, 294-5

physical examination, 125

pretreatment evaluation, 292-4

procedure, 293-4

macrophage activation syndrome (MAS), 210

intravenous immunoglobulin (IVIG), 110,

114

major histocompatibility complex (MHC), 213

involved field radiation therapy (IFRT),

malignancy

role of, 169

evaluation of child with, 122-32

irinotecan, 286-7

malignancy-associated hypercalcemia

mechanism of action, 286

(MAH), 142

side effects, monitoring, and

malignant tumors, 133

treatment, 286-7

massive hepatomegaly

utilized in, 286

evaluation, 137

iron chelators, 58

treatment, 137

iron deficiency

mean corpuscular volume (MCV), 1, 10

prevalence of, 9

mediastinal masses, 130

iron dextran, 3

membrane protein defects, 10

allergic reactions, 6

menorrhagia

management of, 68-70

Kasabach-Merritt syndrome, 117

mercaptopurine (6-MP)

ketorolac, 23

mechanism of action, 287

Knudson’s two-hit hypothesis, 200

side effects, monitoring, and treatment, 287

Kostmann syndrome, 95, 99-100

utilized in, 287

mesna, 284

lactate dehydrogenase (LDH), 16, 125

metaiodobenzylguanidine (MIBG)

Langerhans cell histiocytosis (LCH), 207-9

scan, 180

pathogenesis of, 207

methotrexate, 287-8

lead toxicity, 59-61

mechanism of action, 287

management of, 61

side effects, monitoring, and treatment, 287-8

screening for, 59-61

utilized in, 287

treatment, recommendations for, 60

microangiopathic hemolytic anemia

leukemias, acute, 144-56

(MAHA), 14, 115

evaluation of child with, 129

microcytic anemia

acute lymphoblastic leukemia (ALL), 144-8

child with, evaluation of, 6

acute myelogenous leukemia (AML), 151-6

minimal residual disease detection (MRD), 148

radiographic changes of bones, 146

mitosis-karyorrexis index, 178

leukopenia, 139

mixed lineage leukemia (MLL), 145

leukoreduction, 46

monoclonal antibodies

loss of heterozygosity (LOH), 175

epratuzumab, 150

low-estrogen oral contraceptives, 76

inotuzumab, 150

low grade gliomas (LGGs), 163

rituximab, 112

Index

373

Mosteller formula, 281

newborn

99m-technetium bone scan, 188

hemolytic disease of, 14

multimeric analysis, 73

screening, interpretation of, 41

myeloid cell surface markers, 147

nodular lymphocyte predominant Hodgkin

lymphoma (NLPHL), 166

narcotics

nongerminomatous germ cell tumors

side effects of, 24

(NGGCT), 197-9

National Marrow Donor Program, 214

diagnosis of, 161

nausea and vomiting, 267-8

non-Hodgkin lymphoma (NHL), 128, 133, 170-3

management of, 267

clinical presentation, 170-1

medications for treatment, 268

diagnostic evaluation, 171

neonatal alloimmune neutropenia, 95

histologic classification of, 170

neonatal alloimmune thrombocytopenia

staging, 171

(NAIT), 113-14

St. Jude staging system, 172

neonatal autoimmune thrombocytopenia, 114

subtypes of, 170

Neonatal Infant Pain Scale (NIPS), 257-8

treatment, 172-3

neuroblastoma, 178-82

nonimmune hemolytic anemia, 47

chemotherapy, 181

nonimmune thrombocytopenia, 115-17

clinical presentation, 178-9

noninvasive positive pressure ventilation

diagnostic evaluation, 179-80

(NIPPV), 272, 275

diagnostic studies, 180-1

decision making approach, 273-4

high-dose chemotherapy with autologous

nonrhabodomyomatous soft tissue sarcomas

transplant, 181-2

(NRSTS), 183, 187

history, 179

Nplate

113

laboratory studies, 179-80

nuclear medicine thyroid scintigraphy, 206

observation, 181

nutritional supplementation, 269

physical examination, 179

signs and symptoms, 179

oncologic emergencies, 133-43

staging, 180-2

anemia, 139

treatment, 181

brain herniation, 136-7

neurofibromatosis, 122

caused by abnormalities of blood and blood

neurokinin-1, 230

vessels, 137-9

neuron-specific enolase (NSE), 180

caused by space-occupying lesions, 133-4

neutropenia, 92, 102

coagulopathy, 139-40

autoimmune (See autoimmune neutropenia)

evaluation, 134

case study for, 101-2

hypercalcemia, 142-3

causes of, 94, 96-7

increased intracranial pressure, 136-7

chronic idiopathic (See chronic idiopathic

leukopenia, 139

neutropenia)

management, 134-5

cyclic (See cyclic neutropenia)

massive hepatomegaly, 137

etiology of, 93-9

metabolic emergencies, 140-2

fever management, 99-101

evaluation, 141

inherited conditions, 95

therapy, 141-2

initial evaluation, 99

tumor lysis syndrome, 140-1

management of, 99

spinal cord compression, 135-6

medications, 93

superior mediastinal syndrome, 133-4

neonatal alloimmune (See neonatal

superior vena cava syndrome, 133-4

alloimmune neutropenia)

opioids, 267

risk assessment, 92-3

opsoclonus-myoclonus-ataxia syndrome

neutrophils, 92

(OMAS), 179

374

Index

oral contraceptive pills (OCPs), 90

constipation, 268-9

oral pain therapy

dyspnea, 271-2

medications, 263

fatigue, 269-71

osmotic fragility test, 11, 15

nausea and vomiting, 267-8

osteonecrosis, 19

nutritional supplementation, 269

osteosarcomas, 184, 188

pain, 266

end of life care, 266

packed red blood cells (PRBCs), 46

individualized care planning and

transfusion, 44-6, 218

coordination, 264-6

acute blood loss, 47

questions, 276-8

autoimmune hemolytic anemia, 47

role for, 264

chronically transfused patients, 47-8

treatment, 272-5

dosing of, 48

sensation of dyspnea, 275

exchange transfusion, 48

support of gas exchange, 275

indications for, 46-8

support of respiration, 272-5

neonates, 46-7

World Health Organization definition of, 264

nonimmune hemolytic anemia, 47

parenteral iron therapy, 3-8

oncology patients, 47

Parinaud’s syndrome, 158

severe chronic anemia, 47

partial thromboplastin time (PTT), 63, 88

washing of, 46

validity of, 65

pain, 266

patient-controlled analgesia (PCA) pumps, 261

abdominal, 22

pediatric antiemetic agents, 232

assessment, 257-9

pediatric cancers

neonates and infants, 257

differential diagnosis, 123

preverbal/nonverbal children, 257-8

signs and symptoms of, 123

school aged and older children, 258-9

pediatric chemotherapeutic agents

nociceptive/neuropathic, 259

emetogenic potential, 231

nonpharmacological approaches, 261-4

penicillin

pediatric pain management

prophylaxis, 30

principles of, 266

perioperative transfusion, 33

pharmacology, 259-61

peripheral blood stem cell transplant

nonopioid analgesics, 259

(PBSCT), 213

strong opioids, 260-1

peripheral chemotherapy administration, 298-9

weak opioids, 259-60

indications, 298

therapy

materials, 299

medications, 260-61

post-procedure monitoring and

pain management, 22-4, 27, 32, 266

complications, 299

acute, 256-63

pretreatment evaluation, 298-9

in inpatient setting, 256-64

procedure, 299

pain assessment, 257-9

PET-CT, 167, 171

pain nonpharmacological approaches,

PFA-100 platelet function analyzer, 72

261-4

pit count, 29

pain pharmacology, 259-61

platelet alloantigen

world health organization analgesic

evaluation, 114

ladder, 256-7

platelet surface glycoprotein (Gp), 62

chronic, 256

platelet transfusions, 48-50

palliative care, 264-79

dosing of, 49-50

case study for, 276

indications for, 48-9

common symptoms at end of life, 266-75

Pneumocystis jiroveci (P. carinii) pneumonia, 100,

anorexia/weight loss, 269

112, 227, 246, 254

Index

375

pneumonia, 24-6

prothrombin time (PT), 63

positron emission tomography, 159

proton magnetic resonance imaging, 57

postthrombotic syndrome (PTS), 88

pulmonary sickling, 19

pretransplant preparative regimens

pyruvate kinase (PK) deficiency, 12

common agents in, 215

priapism, 27

radiation therapy (RT), 161, 189

definition of, 27

use of, 168

primary thrombophilia traits, 87

radical retroperitoneal lymph node

primitive neuroectodermal tumor (PNETs), 160,

dissection (RPLND), 205

162-3. See also Ewing sarcoma family of

radioiodine ablation, 206

tumors (ESFTs)

radioisotope bone scan, 185

primordial germ cells (PGCs), 193

rare coagulation factor deficiencies, 80

procedures

rare tumors of childhood, 200-206

bone marrow aspiration and biopsy,

296-8

adrenocortical carcinoma (ACC), 204-5

indications, 296

clinical presentation, 203

materials, 296

diagnosis and staging, 203-4

post-procedure monitoring and

liver tumors, 202-3

complications, 298

retinoblastoma, 200-202

pretreatment evaluation, 296

thyroid tumors, 205-6

procedure, 297-8

Raynaud’s phenomenon, 282

guide to, 291-9

rearranged during transfection (RET)

initiation of, 292

proto-oncogene, 206

intra-Ommaya reservoir tap and

recombinant human erythropoietin, 233-4

chemotherapy injection, 295-6

pediatric guidelines for, 233

indications, 295

red blood cells (RBCs), 1, 10

materials, 295

destruction of, 10

post-procedure monitoring and

enzyme defects, 11-13

complications, 296

membrane disorders, 10-11

pretreatment evaluation, 295

osmotic fragility of, 12

procedure, 295-6

values, 3

lumbar puncture, 292-5

respiratory failure

indications, 292

classification and features, 272

materials, 293

reticulocyte index (RI), 16

post-procedure monitoring and

reticulocytopenia, 30

complications, 294-5

retinal vascular occlusion, 31

pretreatment evaluation, 292-3

retinoblastoma, 200-202

procedure, 293-4

treatment for, 201

peripheral chemotherapy administration,

retinopathy, 19, 31

298-9

rhabdomyosarcoma (RMS), 118, 127-8, 130, 133,

indications, 298

142, 147, 180, 183, 186, 189, 202

materials, 299

Rho[D] Immune Globulin (RhoGAM ), 14

post-procedure monitoring and

ristocetin cofactor, 71

complications, 299

rituximab, 112

pretreatment evaluation, 298-9

Rosai-Dorfman disease, 207

procedure, 299

principles for, 291

sacrococcygeal tumors, 197

prolonged gingival oozing, 81

sargramostim. See granulocyte-macrophage

Promacta

113

colony-stimulating factor (GM-CSF)

prophylactic antibiotics, 100

screening coagulation tests

prothrombin complex concentrates (PCCs),

interpretation of, 66

376

Index

seizures, 158

clinical presentation, 184

selective IgA deficiency, 98

diagnostic evaluation, 184-5

septic shock, symptoms of, 245

genetics, 183-4

serotonin receptor antagonist antiemetics,

pathologic diagnosis and treatment, 185-6

ondansetron, 169

prognosis, 186-7

severe chronic anemia, 47

staging and classification, 185

severe congenital neutropenia (SCN), 95. See also

spinal cord compression, 135-6, 158

Kostmann syndrome

evaluation, 135

Shwachman-Diamond syndrome, 98

management, 135-6

sickle cell disease, 18-35

splenectomy, 11-12, 16, 29, 112

acute anemia, 29-30

splenomegaly, 95, 125

acute chest syndrome (ACS), 24-6

hemolytic anemia, 125

with acute pulmonary infiltrate, 25

immunological disease, 125

aplastic crisis, 30

infection, 125

avascular necrosis, 30-1

laboratory and imaging, 127

benign cholestasis, 32

malignancy, 126

case study for, 34-5

physical examination, 126

chronic transfusion therapy, 33-4

storage disease, 125

definition of, 18

steroids

fever and infection in, 19-20

mechanism of action, 288

fever in child, 20

side effects, monitoring, and treatment, 288

gallstones, 31-2

utilized in, 288

hematopoietic stem cell transplant in, 34

stroke (cerebrovascular accident), 28-9

hydroxyurea (HU) therapy, 34

Stroke Prevention Trial in Sickle Cell Anemia

hyperbilirubinemia, 31-2

(STOP) trial, 28

hyphema, 31

strong opioid

management, 26-7

characteristics, 262-3

pain management, 22-4

subacute bacterial endocarditis

analgesics, 23-4

prophylaxis for, 227

inpatient, 23

subarachnoid hemorrhage, 29

mild pain, 22

substance P receptors, 230

outpatient, 22

superior mediastinal syndrome, 133-4

severe pain, 22-3

superior vena cava syndrome (SVCS), 133-4

perioperative management of patients, 32-3

syndrome of inappropriate diuretic hormone

perioperative transfusion, 33

(SIADH), 284

pneumonia, 24-6

systemic lupus erythematosis (SLE), 112

priapism, 27

systemic multiagent chemotherapy, 189

retinopathy, 31

treatment of, 31

T-cell acute lymphoblastic leukemia (T-ALL), 133

splenic sequestration, 29-30

temozolomide, 289

stroke (cerebrovascular accident), 28-9

mechanism of action, 289

transfusion therapy, 33

side effects, monitoring, and treatment, 289

vaso-occlusive episodes, 21-2

utilized in, 289

single-photon emission CT, 160

thalassemia, 36-43

single-trait thrombophilia, 86

alpha-thalassemia, 36-8

sinusoidal obstructive syndrome

beta-thalassemia, 38-40

(SOS), 216-18

case study for, 42-3

treatments for, 219

hemoglobinopathies, neonatal screening

soft tissue hemorrhages, 81

for, 40-3

soft tissue sarcoma (STS), 184-7

phenotypic characteristics, 36

Index

377

thioguanine (6-TG)

bacterial infections, 55

mechanism of action, 289

case study for, 55-6

side effects, monitoring, and treatment, 289

granulocyte transfusion, 51-2

utilized in, 289

packed red blood cell transfusion,

thrombin time (TT), 63, 79

44-6

thrombocytopenia, 103-20

platelet transfusions, 48-50

acute immune thrombocytopenic

PRBC transfusion, 46-8

purpura, 103-13

hemolytic transfusion reactions, 52-4

approach to child with, 106-8

reactions, 52

case study for, 119-21

transfusion-associated acute lung injury

decreased platelet production, 117-19

(TRALI), 54

degree of, 115

transfusion-associated circulatory overload

differential diagnosis of, 104-5

(TACO), 54

drug-induced thrombocytopenia, 115

transfusion-associated graft-versus-host

neonatal alloimmune thrombocytopenia

disease (TA-GVHD), 54

(NAIT), 113-14

transfusion-associated acute lung injury

neonatal autoimmune thrombocytopenia,

(TRALI), 50, 54

114-15

transfusion-associated circulatory overload

nonimmune thrombocytopenia, 115-17

(TACO), 54

thrombocytopenia with absent radii (TAR), 118

transfusion-associated graft-versus-host disease

thromboembolism (TE)

(TA-GVHD), 54

evaluation, 241

transfusion factor, 55

thrombolysis, 88-9

transient ischemic attacks, 29

anticoagulation, 88-9

transplantation

duration of therapy, 89

conditions, 212

new agents, 89

types of, 212-13

thrombopoietin (TPO) mimetics, 112

traumatic lumbar punctures

thrombosis

definition of, 147

case study for, 89-91

trimethoprim/sulfamethoxazole

child with, 85-91

(TMP/SMX), 227, 254

evaluation of, 85-8

tumor lysis syndrome (TLS), 135, 140-1

management of, 88

tunneled central venous catheters

thrombolysis, 88-9

and related care, 236

thrombophilia, testing for, 86-7

thrombotic thrombocytopenic purpura

umbilical cord blood (UCB)

(TTP), 116

transplantation, 212

thyroid tumors, 205-6

unfractionated heparin (UH), 88-9

tissue plasminogen activator (TPA), 88

concomitant use, 89

vancomycin, 250

topotecan

indications for, 248

mechanism of action, 289

vanillylmandelic acid (VMA), 180

side effects, monitoring, and treatment, 289

Varicella Zoster Immune Globulin

utilized in, 289

(VariZIG), 228

total iron-binding capacity (TIBC), 3

vasoactive intestinal peptide (VIP), 179

total parenteral nutrition (TPN), 218

vaso-occlusive episodes (VOEs), 18, 21-2

transcranial Doppler (TCD), 28

veno-occlusive disease (VOD), 216-18

transfusion

treatments for, 219

allergic transfusion reactions, 54

venous thromboembolism (VTE), 85-6, 88,

guidelines,

44-56, 218-21

233, 240

antithrombin III (ATIII) concentrate, 51

evaluation of child with, 86

378

Index

vinblastine, 289-90

WAS protein (WASp), 99

mechanism of action, 290

white blood cells (WBCs), 1

side effects, monitoring, and treatment, 290

Wilms tumor, 174-7

utilized in, 290

clinical presentation, 174-5

vinca alkaloids, 113

evaluation, 175

vincristine, 289-90

genetics, 174-5

mechanism of action, 289-90

pathologic diagnosis, 175

side effects, monitoring, and treatment, 290

staging, 176

utilized in, 290

treatment, 176-7

vitamin B₁₂

Wilms tumor 1 (WT1) gene, 174

deficiencies of, 95

Wiskott-Aldrich syndrome (WAS), 64, 98

von Willebrand disease (VWD), 71-8

Wong-Baker FACES Pain Rating Scale,

acquired von Willebrand syndrome

258-9

(AVWS), 77

World Health Organization (WHO), 153, 170,

classification of, 71, 73

256, 264

clinical features of, 72

analgesic ladder, 256-7

diagnosis, 72-3

adaptation of, 257

algorithm for, 74

recommendations, 256

tests, 72-3

classification system for brain

treatment, 73-7

tumors, 157

von Willebrand factor (VWF), 62, 71, 175

von Willebrand factor activity (VWF:RCo), 73

X-linked neutropenia, 98

von Willebrand factor antigen (VWF:Ag), 73

X-linked red cell enzyme deficiency, 12

~StormRG~