Handbook of Pediatric Hematology

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

Dr. Caroline A. Hastings

Division of Hematology, Oncology and BMT, Children’s Hospital &
Research Center Oakland, Oakland, CA, USA

Dr. Joseph C. Torkildson

Division of Hematology, Oncology and BMT, Children’s Hospital &
Research Center Oakland, Oakland, CA, USA

Dr. Anurag K. Agrawal

Division of Hematology, Oncology and BMT, Children’s Hospital &
Research Center Oakland, Oakland, CA, USA

Third Edition
This edition first published 2021
© 2021 John Wiley & Sons Ltd
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Library of Congress Cataloging‐in‐Publication Data
Names: Hastings, Caroline, 1960– author. | Torkildson, Joseph C., author. |
Agrawal, Anurag K. (Anurag Kishor), author. | Children’s Hospital &
Research Center Oakland (Oakland, Calif.)
Title: Handbook of pediatric hematology and oncology : Children’s Hospital
& Research Center Oakland / Dr Caroline A. Hastings, Dr Joseph C.
Torkildson, Anurag K. Agrawal.
Description: Third edition. | Hoboken, NJ : Wiley-Blackwell, 2020. |
Includes bibliographical references and index.
Identifiers: LCCN 2020023659 (print) | LCCN 2020023660 (ebook) | ISBN
9781119210740 (paperback) | ISBN 9781119210764 (adobe pdf) | ISBN
9781119210757 (epub)
Subjects: MESH: Hematologic Diseases | Child | Neoplasms | Handbook
Classification: LCC RJ411 (print) | LCC RJ411 (ebook) | NLM WS 39 | DDC
618.92/994–dc23
LC record available at https://lccn.loc.gov/2020023659
LC ebook record available at https://lccn.loc.gov/2020023660
Cover Design: Wiley
Cover Images: © Billion Photos/Shutterstock
Set in 9.25/11.5pt Minion Pro by SPi Global, Pondicherry, India

10 9 8 7 6 5 4 3 2 1
On a day‐to‐day basis, the patients and their families continue to show us how to live gracefully
in even the most unbearable of times and inspire us to endeavor for improved outcomes. Our
experiences have taught us the magnitude of remembering our roles: “to cure sometimes, to
relieve often, to comfort always.” (anonymous, fifteenth century)
Contents

Preface, ix
Acknowledgments, xi

1 Approach to the Anemic Child, 1

2 Hemolytic Anemia, 15

3 Sickle Cell Disease, 27

4 Thalassemia, 51

5 Transfusion Medicine, 63

6 Chelation Therapy, 79

7 Approach to the Bleeding Child, 85

8 Von Willebrand Disease, 95

9 Hemophilia, 103

10 Thrombophilia, 111

11 The Neutropenic Child, 119

12 Thrombocytopenia, 133

13 Evaluation of the Child with a Suspected Malignancy, 157

14 Oncologic Emergencies, 173

15 Acute Leukemias, 191

16 Central Nervous System Tumors, 211

17 Hodgkin and Non‐Hodgkin Lymphoma, 227

18 Wilms Tumor, 239

19 Neuroblastoma, 245
viii Contents

20 Sarcomas of the Soft Tissues and Bone, 253

21 Germ Cell Tumors, 265

22 Rare Tumors of Childhood, 275

23 Histiocytic Disorders, 287

24 Hematopoietic Stem Cell Transplantation, 295

25 Supportive Care of the Child with Cancer, 313

26 Central Venous Catheters, 323

27 Management of Fever in the Child with Cancer, 333

28 Acute Pain Management in the Inpatient Setting, 347

29 Palliative Care, 361

30 Chemotherapy Basics, 377

31 Guide to Procedures, 393

32 Treatment of Chemotherapy Extravasations, 403

Formulary, 409
Index, 489
 Preface
The pace of change in the field of pediatric
hematology, oncology, and hematopoietic
cell therapies is staggering. Molecular biol-
ogy, genomics, and biochemistry have accel-
erated the knowledge and understanding of
disease states and further highlight the com-
plex interplay of clinical, genetic, and social
factors that constantly challenge us in the
rapid application of novel findings to treat
patients with the goal of improved outcomes.
This translation of knowledge to the unique
patient before us, the true art of the physi-
cian, encompassing experience, knowledge,
intuition, and understanding of the individ-
ual needs and goals of patients and families,
can be overwhelming. What is needed is a
practical, tested approach to analyze and
address these problems to ensure timely
evaluation, competent clinical care, and
avoidance of pitfalls that might negatively
impact the patient or future treatment
options. This practical approach is achieved
by spending time with patients and families
and observing the myriad variations in dis-
ease and individual nuances that are not
addressed in large studies or case reports,
all the while expanding foundational
knowledge.
This handbook represents the work of
our colleagues at Children’s Hospital &
Research Center Oakland toward this
endeavor. The guidelines offered here have
been used to instruct medical students,
pediatric residents, nurses, pediatricians,
and hematology/oncology fellows for over
25 years. This handbook provides clinical
approaches for common problems in pedi-
atric hematology, oncology, hematopoietic
stem cell transplant, and newer cellular ther-
apies; knowledge to organize and evaluate
the care of your patients; and a framework
to incorporate ever‐expanding psychosocial
needs, clinical studies, medical treatments,
and science. All of these are essential com-
ponents that encompass the care of the child
with blood disorders and cancer.
 Acknowledgments
We are grateful to Yoram Unguru, MD, MS,
MA, for submission of the expert case and
teaching guide in Chapter 29. Dr. Unguru is an
attending physician in the Division of Pediatric
Hematology/Oncology at the Herman &
Walter Samuelson Children’s Hospital at Sinai
and Chairman of the Sinai Hospital Ethics
Committee, as well as attending at the Johns
Hopkins Berman Institute of Bioethics.
We are also extremely appreciative of
patient cases submitted by Dr. Christina
Coleman Abadi, Assistant Professor of pedi-
atrics at UCSF Benioff Children’s Hospital
Oakland; Dr. Cheryl Peretz, senior research
fellow and clinical instructor at UCSF
Benioff Children’s Hospital Oakland; and
Dr. Monica Davini, attending physician in
the Division of Pediatric Hematology/
Oncology at Banner—University Medical
Center, Tucson Campus in Tucson, Arizona.
These cases appear in Chapters 18, 15,
and 11, respectively.
1 Approach to the
Anemic Child
Anemia is the condition in which the
concentration of hemoglobin or the red
­ and classification of anemia. They allow for
cell mass is reduced below normal. Anemia
results in a physiological decrease in the
oxygen‐carrying capacity of the blood and
reduced oxygen supply to the tissues. Causes
of anemia are increased loss or destruction
of red blood cells (RBCs) or a significant
decreased rate of production. When evalu­
ating a child with anemia, it is important
to determine if the problem is isolated to
one cell line (e.g., RBCs) or multiple cell
lines (i.e., RBCs, white blood cells [WBCs],
or platelets). When two or three cell lines
are affected, it may indicate bone marrow
involvement (e.g., leukemia, metastatic dis­
ease, and aplastic anemia), sequestration
(i.e., hypersplenism), immune deficiency,
or an immune‐mediated process (e.g.,
hemolytic anemia and immune thrombocy­
topenic purpura).
Evaluation of anemia
The evaluation of anemia includes a com­
plete medical history, family history, physi­
cal examination, and laboratory assessment
(see Figure 1.1).
The diagnosis of anemia is made after
reference to established normal controls for
age (Table 1.1). The blood smear and red
cell indices are very helpful in the diagnosis
­classification by the cell size (mean corpus­
cular volume [MCV]), give the distribution
of cell size (red cell distribution width
[RDW]), and may give important diagnos­
tic clues if specific morphological abnor­
malities are present (e.g., sickle cells, target
cells, and spherocytes). The MCV, RDW,
and reticulocyte count are helpful in the
differential diagnosis of anemia. A high
RDW, or anisocytosis, is seen in stress
erythropoiesis and is often suggestive of
iron deficiency or hemolysis. A normal or
low reticulocyte count is an inappropriate
response to anemia and suggests impaired
red cell production. An elevated reticulo­
cyte count suggests blood loss, hemolysis,
or sequestration.
The investigation of anemia requires
the following steps:
1. The medical history of the anemic child
(Table 1.2), as certain historical points
may provide clues as to the etiology of the
anemia.
2. Detailed physical examination (Table 1.3),
with particular attention to acute and
chronic effects of anemia.
3. Evaluation of the complete blood count
(CBC), RBC indices, and peripheral blood
smear, with classification by MCV, reticu­
locyte count, and RBC morphology.

Handbook of Pediatric Hematology and Oncology – Children’s Hospital & Research Center Oakland,
Third Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
2 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 Red cell aplasia Reticulocytosis
Chronic blood loss Malignancy Post splenectomy
Thalassemia, α or β Infection Liver disease
Hemoglobin E Renal failure Aplastic anemia
Lead toxicity^ Hypersplenism Bone marrow failure
Chronic disease/Infection Drugs syndromes
Severe malnutrition Acute blood loss Hypothyroidism
Sideroblastic anemia Hemolysis Down syndrome
Red cell enzyme deficiency Preleukemia
Red cell membrane defects Syndromes with elevated Hgb F
Megaloblastic anemia
Aplastic anemia
Folic acid deficiency
DBA, TEC
Malabsorption, drugs
Vitamin B12 deficiency
Evaluations Dietary
To Consider Pernicious anemia

Iron Studies Reticulocyte count Liver function tests

RDW, FEP, ferritin,
transferrin saturation, TIBC
Hemoglobin electrophoresis
Lead level
Family studies
Check newborn screen
Oral iron challenge
Complete metabolic panel Thyroid function tests
Red cell enzyme panel Hemoglobin electrophoresis
G6PD, Pyruvate kinase Folic acid level
Osmotic fragility/Ektacytometry Red cell
Coombs test (DAT) Serum
Hemoglobin electrophoresis Vitamin B12 level
Bone marrow aspirate 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 dehydro­
genase deficiency; DAT, direct antiglobulin test).
*Refer to Table 1.1 for age‐based normal values.
^Microcytosis with lead toxicity has been noted secondary to concomitant iron deficiency; see text.

Consideration should also be given to the

Interventions
WBC and platelet counts as well as their
respective morphologies.
Oral iron challenge
4. Determination of an etiology of the ane­
An oral iron challenge may be indicated in
mia by additional studies as needed (see
the patient with significant iron depletion,
Figures 1.1–1.3).
as documented by moderate‐to‐severe
 Approach to the Anemic Child 3

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 98
1–3 d (capillary) 18.5 14.5 108 95
1 wk 17.5 13.5 107 88
2 wk 16.5 12.5 105 86
1 mo 14.0 10.0 104 85
2 mo 11.5 9.0 96 77
3–6 mo 11.5 9.5 91 74
0.5–2 y 12.0 11.0 78 70
2–6 y 12.5 11.5 81 75
6–12 y 13.5 11.5 86 77
12–18 y female 14.0 12.0 90 78
12–18 y male 14.5 13.0 88 78
18–49 y female 14.0 12.0 90 80
18–49 y male 15.5 13.5 90 80

*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; Penttilä I, et al. Suomen Lääkärilehti 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.

a­ nemia and deficiencies in circulating and Administration of an oral iron challenge

storage iron forms (such as an elevated
total iron‐binding capacity [TIBC], low
serum iron, low transferrin saturation, and
low ­ferritin). Iron absorption is impaired in
­certain chronic disorders (autoimmune dis­
eases such as systemic lupus erythematosus,
peptic ulcer disease, ulcerative colitis, and
Crohn’s disease), by certain medications
(antacids and histamine‐2 blockers), and
by environmental factors such as lead
toxicity.
Indications for an oral iron challenge
include any condition in which a poor
response to oral iron is being questioned, such
as in: noncompliance, severe anemia sec­
ondary to dietary insufficiency (excessive
milk intake), and ongoing blood loss.
is quite simple: first, draw a serum iron level;
second, administer a dose of iron (3 mg/kg
elemental iron) orally; third, draw another
serum iron level 30–60 minutes later. The
serum level is expected to increase by at
least 100 mcg/dL if absorption is adequate.
The oral iron challenge is a quick and easy
method to assess appropriateness of oral
iron to treat iron deficiency—a safer,
cheaper, yet equally efficacious method of
treatment as parenteral iron.
Parenteral iron therapy
Due to the potential risks of older par­
enteral iron preparations (specifically
high‐molecular‐weight iron dextran),
practitioners have moved to newer (and
­
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 the abovementioned
factors or maternal iron deficiency
Ethnicity
African‐American Hgb S, C; α‐ and β‐thalassemia; G6PD deficiency
Mediterranean α‐ and β‐thalassemia; G6PD deficiency
Southeast Asian α‐ and β‐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 (also predisposed
to iron deficiency)
Sex
Male X‐linked enzymopathies (i.e., G6PD deficiency)
Early jaundice (<24 h of age) Isoimmune, infectious
Persistent jaundice Suggests hemolytic anemia
Diet (Usually >6 mo unless history of
prematurity)
Pica behavior Lead toxicity, iron deficiency
Excessive milk intake Iron deficiency
Macrobiotic/vegan diets Vitamin B12 deficiency
Goat 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

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, decreased red cell production
Parvovirus Anemia with reticulocytopenia

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

(CMV), herpes simplex virus; G6PD, glucose‐6‐phosphate dehydrogenase deficiency.
 Approach to the Anemic Child 5

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 (i.e.,
malar and maxillary bones thalassemia major, congenital hemolytic
anemia)
Icteric sclerae Congenital hemolytic anemia, hyperhemolytic
crisis associated with infection (i.e., red cell
enzyme deficiencies, red cell membrane
defects, thalassemias, hemoglobinopathies),
autoimmune hemolytic anemia
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,
hematologic malignancies, portal
hypertension
Extremities Radial limb dysplasia Fanconi anemia
Spoon nails Iron deficiency
Triphalangeal thumbs Red cell aplasia

perceived safer) f­ ormulations including fer­
ric gluconate and iron sucrose. Three addi­
tional compounds have been approved, one
only in Europe (iron isomaltoside) and two
in the United States (ferumoxytol and fer­
ric carboxymaltose). These newer agents
have the potential benefit of total dose
replacement in a very short and single infu­
sion as compared to ferric gluconate and
iron sucrose which require multiple doses.
Low‐molecular‐weight (LMW) iron dextran
is approved as a total dose infusion for
adults in Europe but not the United States.
Due to the smaller dose generally required
in pediatric patients, total iron replacement
is feasible in 1–2 doses of LMW iron
­dextran and has been shown safe. Refer to
the Formulary for calculation of LMW iron
dextran dosing.
Severe allergic reactions can occur with
iron dextran and therefore a LMW product
should be preferentially utilized. A test dose
(10–25 mg) should be given prior to the
first dose with observation of the patient
for 30–60 minutes prior to administering
the remainder of the dose. A common side
effect is mild to moderate arthralgias the
day after drug administration, especially
6 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
or
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
at 1 week Review smear Hospitalization
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 β-thalassemia major
Iron malabsorption Hemoglobinopathy
Iron studies Sickle cell disease
Oral iron challenge TEC
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 proto­
porphyrin; TIBC, total iron‐binding capacity; DAT, direct antiglobulin test; IBD, inflammatory bowel
disease).

in patients with autoimmune disease. by a maximum dose beyond which there

Acetaminophen frequently alleviates the
arthralgias. Iron dextran is contraindicated
in patients with rheumatoid arthritis.
Iron sucrose or ferric gluconate should
be considered in patients for whom multiple
doses are more feasible. Both are limited
is increased risk of adverse events.
Ferumoxytol and ferric carboxymaltose
have both received approval by the United
States Food and Drug Administration for the
treatment of iron deficiency anemia as well
as renal insufficiency in adults. Both have
 Approach to the Anemic Child 7

Low hemoglobin concentration

Low
Elevated or normal
reticulocyte
reticulocyte count Infection
count
TORCH
Coombs test (DAT) Congenital hypoplastic anemia
Transcobalamin II deficiency

Positive Immune hemolytic anemia

ABO incompatibility
Rh incompatibility
Minor blood group incompatibility
Negative

Microcytic

α-thalassemia syndrome
Normocytic
Macrocytic Chronic intrauterine blood loss
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‐phosphate dehydrogenase deficiency; TORCH, toxoplasmosis, other, rubella,
cytomegalovirus, herpes simplex virus).

the benefit of total dose replacement given regarding utilization in pediatric patients
as a rapid infusion due to slow release of are limited regarding appropriate per kg
elemental iron. Neither is immunogenic and dosage, although the infusions appear safe and
therefore no test dose is required. Studies therefore will likely replace use of iron
8 Chapter 1
sucrose and ferric gluconate in the future
due to the convenience of single dose
replacement. Refer to the Formulary for
dosing parameters for these products.
Erythropoietin
Recombinant human erythropoietin (EPO)
stimulates proliferation and differentiation
of erythroid precursors, with an increase in
heme synthesis. This increased prolifera­
tion creates an increased demand in iron
availability and can result in a functional
iron deficiency if not given with iron
therapy.
Indications for EPO include end‐stage
renal disease, anemia of prematurity, ane­
mia of chronic disease, anemia associated
with treatment for AIDS, and autologous
blood donation. EPO use for the treatment
of chemotherapy‐induced anemia remains
controversial and is not routinely recom­
mended in pediatric patients (see
Chapter 25). EPO has also been used in
autoimmune hemolytic anemia with low
production as well as in chemotherapy‐
induced anemia when the family has reli­
gious beliefs that preclude transfusion.
The use of EPO in this latter setting may
reduce transfusion exposures but has not
been validated.
The most common side effect of EPO
administration is hypertension, which may
be somewhat alleviated with changes in the
dose and duration of administration.
Typical starting dose of EPO is 150 U/kg
three times a week (IV) or subcutaneous
(SC). CBCs and reticulocyte counts are
checked weekly. Higher doses, and more
frequent dosing, may be necessary. Response
is usually seen within 1–2 weeks. Adequate
iron intake (3 mg/kg/day orally or inter­
mittent parenteral therapy) should be pro­
vided to optimize efficacy and prevent iron
deficiency.
Transfusion therapy
Children with very severe anemia (i.e.,
hgb < 5 g/dL) may require treatment with
red cell transfusion, depending on the
underlying disease and baseline hemo­
globin status, duration of anemia, rapidity
of onset, and hemodynamic stability. The
pediatric literature is scarce as to the best
method of transfusing such patients.
However, it appears to be common prac­
tice to give slow transfusions to children
with cardiovascular compromise (i.e., gal­
lop rhythm, pulmonary edema, excessive
tachycardia, and poor perfusion) while
being monitored in an ICU setting.
Transfusions are given in multiple small
volumes, sometimes separated by several
hours, with careful monitoring of the vitals
and fluid balance. For those children who
have gradual onset of severe anemia, with­
out cardiovascular compromise, continu­
ous transfusion of 2 mL/kg/h has been
shown to be safe and result in an increase
in the hematocrit of 1% for each 1 mL/kg
of transfused packed RBCs (based on RBC
storage method). The hemoglobin should
be increased to a normal value to avoid
further cardiac compromise (i.e., hgb
­
8–12 g/dL). Again, the final endpoint may
be dependent on several factors including
nature of anemia, ongoing blood loss or lack
of production, baseline hemoglobin, and
volume to be transfused. Care should be
taken to avoid unnecessary exposure to mul­
tiple blood donors by maximal use of the
unit of blood, proper division of units in the
blood bank, and avoidance of opening extra
units for small quantities to meet a total vol­
ume. See Chapter 5 for product preparation,
ordering, and premedication. A posttransfu­
sion hemoglobin can be checked if necessary
at any point after the transfusion has been
completed. Waiting for “reequilibration” is
anecdotal and unnecessary.

Case studies for review
1. You are seeing a 1‐year‐old for their well‐
child check in clinic. As part of routine
screening, a fingerstick hemoglobin is
recommended.
a. What questions in the history might
help screen for anemia?
b. What about the physical examination?
Multiple questions in the history can be
helpful. Dietary screening for excessive milk
intake is important in addition to asking
about intake of iron‐rich foods such as green
leafy vegetables and red meat. One should
also ask about pica behavior such as eating
dirt or ice and include questions regarding
the age of the house to help screen for lead
paint exposure and ingestion. Any sources
of blood loss should also be explored includ­
ing blood in the urine or stool as well as
­frequent gum or nose bleeding (more likely
in an older child). Finally, family history
should be explored regarding anemia dur­
ing pregnancy, previous history of iron
deficiency in siblings, and history of
­
hemoglobinopathies.
Physical examination to search for ane­
mia should be focused. Pallor, especially
subconjunctival, perioral, and periungual,
should be checked. Tachycardia, if present,
would be more consistent with acute anemia
rather than well‐compensated chronic ane­
mia. Splenomegaly, scleral icterus, and jaun­
dice may point to an acute or chronic
hemolytic picture.
You do the fingerstick hemoglobin in
clinic and it is 10.2 g/dL. The history is not
suggestive of iron deficiency and the exam is
unremarkable.
c. What are the reasonable next steps?
Depending on the prevalence of iron defi­
ciency in your population, it would be rea­
sonable at this point to give a 1‐month trial
of oral iron therapy. The family should be
counseled that oral iron tastes bad and
Approach to the Anemic Child 9
should be given with vitamin C (i.e., orange
juice) and not milk to improve absorption. If
there is a low likelihood of iron deficiency, a
family history of thalassemia or sickle cell
disease, or a suggestive newborn screen, an
empiric trial of oral iron supplementation
should not be performed. Similarly, if there
are signs that are consistent with a hemolytic
process or a significant underlying disorder,
further workup should be done. In these
cases, it would be correct to next perform a
CBC. If there are concerns for sickle cell dis­
ease or thalassemia, it would be reasonable
to also perform hemoglobin electrophoresis.
If there are concerns for hemolysis, labs
including reticulocyte count, total bilirubin,
lactate dehydrogenase, and a direct Coombs
should be performed. Finally, if there is con­
cern for a systemic illness such as leukemia,
a manual differential should be requested.
Further workup for iron deficiency (ferritin,
TIBC) as well as lead toxicity (lead level)
could be included or deferred until the ane­
mia is better characterized utilizing the
MCV and RDW on the CBC.
2. You are seeing a 15‐month‐old for a
routine well‐child check visit. The family
notes that the child has been well but
appears pale to them. You ask the same
questions as reviewed in case one, and the
family notes a recent viral illness with no
evidence of hemolysis, as there has been no
history of dark‐colored urine or jaundice.
The dietary history is unremarkable and on
review, the 1‐year fingerstick hemoglobin
was normal at 11.4 g/dL with a normal lead
level at that time. There has been no noted
diarrhea or blood loss, and the child is not
on any medications. On exam, the child is
pale but well appearing with a normal heart
rate, respiratory rate, and blood pressure
without scleral icterus or other signs of
jaundice. There is no lymphadenopathy or
hepatosplenomegaly. There are no pete­
chiae or bruising.
10 Chapter 1
a. What are some common diagnostic
considerations?
b. What are the next laboratory steps?
Microcytic causes of anemia, notably iron
deficiency anemia and secondary lead toxic­
ity as well as thalassemia syndromes, have
generally been ruled out with a history of a
normal recent hemoglobin as well as a reas­
suring dietary history. Congenital causes of
anemia, especially Diamond–Blackfan ane­
mia, a pure red cell aplasia, have also been
ruled out with a previous normal hgb.
Megaloblastic anemias are also less likely to
develop in the preceding 3 months after a
normal hemoglobin. Hemolytic anemia,
especially warm autoimmune hemolytic
anemia (AIHA), remains a possibility even
without a clinical history of jaundice in
patients with slow hemolytic rates. Many
other diagnostic possibilities remain at this
point including viral suppression secondary
to infections such as parvovirus, syndromes
that may have bicytopenia or pancytopenia
in addition to the clinical presentation of
anemia including severe aplastic anemia
and acute leukemias, as well as transient
erythroblastopenia of childhood (TEC).
Atypical hemolytic uremic syndrome
(aHUS) is an unlikely possibility, but should
be in the differential diagnosis in addition to
occult blood loss.
The initial laboratory workup should
include labs which will help make the diag­
nosis and potentially treat the patient:
CBC/diff, reticulocyte count, Coombs test,
complete metabolic panel (CMP), LDH,
type and screen, fecal occult blood, parvo­
virus PCR, and urinalysis (UA). CBC will
help evaluate the level of anemia noted
clinically as well as determine if there are
more cytopenias which will help direct the
differential diagnosis. The reticulocyte
count will be helpful in determining if the
bone marrow is responding correctly to the
anemia, as it should be high with a hemo­
lytic process and suppressed if this is post­
viral or secondary to TEC. Coombs is vital
to help determine if this is an underlying
warm autoimmune hemolytic anemia, not­
ing that the Coombs will not be positive in
all cases. Complete metabolic panel will
look at many important aspects including
renal function (to rule out aHUS), as well
as bilirubin and AST which may be ele­
vated along with the LDH if there is ongo­
ing hemolysis. Similarly, the urinalysis will
help rule out blood loss as well as hemoly­
sis. Parvovirus PCR is not vital given the
lack of clinical history, but this infection
should remain in the differential diagnosis.
Type and screen is important as the child
may require blood transfusion depending
on the level of anemia and the potential
presence of hemolysis.
Lab results include the following:
4.7 retic 11.9%
10.4 279
14.2
Normal LDH, total, and indirect bilirubin
Normal UA
Negative direct Coombs
Normal CMP
c. What is the likely diagnosis?
The elevated reticulocyte count in the set­
ting of a low hemoglobin should always
make the practitioner first think of a hemo­
lytic anemia, either a warm antibody or cold
agglutinin. Yet, in this case, there are no
other supporting laboratories for a hemo­
lytic process. With a slow hemolytic process,
it is possible that the UA, LDH, and indirect
bilirubin could be normal but the direct
Coombs should be helpful in the majority of
warm antibody‐mediated cases. In the case
of a cold agglutinin (usually associated with
Mycoplasma infection), it is possible there
would be no other positive lab findings.
The most likely diagnosis here is TEC in
recovery phase. TEC occurs due to unclear
reasons and may present with concomitant
neutropenia leading to workup for acute

lymphoblastic leukemia and aplastic anemia.
Patients will have a decrease in erythroid
precursors in the bone marrow and therefore
a decrease in peripheral reticulocytes. TEC
is an indolent process and thus patients will
generally present with a well‐compensated
but often severe normocytic anemia. Spon­
taneous recovery occurs with reticulocyto­
sis, and thus TEC in the recovery phase can
be mistaken for a hemolytic anemia.
Multiple choice questions
1. You are seeing a patient at their one year
clinic visit and perform a finger stick hemo­
globin. The hgb is 9.2 g/dl. The child has
been well without any recent illnesses or
significant findings on exam. What is the
next best step?
a. Empirically start iron therapy
b. Obtain further history
c. Check a full CBC/diff
d. Plan to repeat in one month
e. Perform a lead level
Explanation: It is first important to under­
stand underlying risk factors for anemia.
These could include a dietary intake of sig­
nificant milk consumption which would
lead to iron deficiency or a family history of
thalassemia. Also it is important to ask
about a bleeding history to determine if
there are ongoing losses. It important to ask
about any history of jaundice or scleral
icterus which would point to a hemolytic
anemia as well as other inflammatory condi­
tions which could lead to anemia of chronic
disease. Choice a. would likely be correct
after obtaining more history; choice c. is
reasonable in cases where the history is not
suggestive or the hgb does not increase with
empiric iron therapy; choice d. would not be
correct without other interventions; choice e.
is important to do but lead toxicity itself
does not lead to anemia, rather it is concom­
itant iron deficiency. The answer is b.
Approach to the Anemic Child 11
2. You are seeing a patient in the hospital
admitted at two months of age for sepsis
rule out secondary to high fever with asso­
ciated decreased feeds and decreased urine
output. The child has a urinary tract infec­
tion. A CBC is checked the hgb is 9.0 g/dl.
There is no relevant family history, the
mother received good prenatal care and
was not anemic during pregnancy and the
baby was born full term. What is the next
best step?
a. Empirically start iron therapy
b. Plan to repeat the CBC prior to
discharge
c. Plan to repeat the CBC in 1‐2 months
as an outpatient
d. Provide reassurance to the family
Explanation: Although anemia in a young
infant with an underlying infection can be
due to bone marrow suppression, this level
of hemoglobin is normal for age. The physi­
ologic nadir of infancy occurs around 2‐3
months of age as fetal hemoglobin goes
away (fetal hemoglobin lives 60‐90 days as
compared to hemoglobin A which lives
90‐120 days). A certain level of anemia
occurs prior to the bone marrow ramping
up production of hemoglobin A red blood
cells. Choice a. is incorrect as iron deficiency
would be unlikely in this age although can
occur in a very preterm infant or if the
mother had severe anemia during preg­
nancy. Choice b. and c. are not necessary
since the hb is normal for age. The answer is d.
3. You are seeing a patient in follow up. At
the one year visit the finger stick hemoglobin
was 9.4 g/dl. Given a nutritional history
of significant milk intake you previously
decided to empirically start iron therapy at a
dose of 3 mg elemental iron daily and see the
child today, one month later for a repeat finger
stick hemoglobin. The repeat hemoglobin is
now 10.2 g/dl. What is the next best step?
a. Stop iron therapy
b. Send a full CBC/diff
12 Chapter 1
c. Continue iron therapy and see the
patient back in one month
d. Continue iron therapy and see the
patient back in 2‐3 months
Explanation: Given the level of hemoglobin
and nutritional history, iron deficiency is
the most likely diagnosis. Reticulocyte counts
should increase in 1‐2 days after commence­
ment of iron therapy and hemoglobin
should rise within one week. A rise in hb in
one month is reassuring that the diagnosis
and treatment plan are correct. Choice a. is
incorrect because it is important to continue
iron therapy for 2‐3 months after resolution
of anemia to replete liver iron stores; as this
child is still anemic it is too early to stop iron
therapy. Choice b. is unnecessary at this
point since the hgb is appropriately increas­
ing with therapy but may be necessary at a
later point if the anemia persists on iron
therapy. Choice c. is reasonable although
given the amount of time of iron therapy
required to replete stores and the improve­
ment seen to date, it is not necessary to see
the patient so frequently. The answer is d.
4. You are seeing a patient in follow up. At
the one year visit the finger stick hemo­
globin was 9.4 g/dl. Given a nutritional his­
tory of significant milk intake you previously
decided to empirically start iron therapy at a
dose of 3 mg elemental iron daily and see the
child today, one month later for a repeat fin­
ger stick hemoglobin. The repeat hemo­
globin is now 9.2 g/dl. The mother states
that the child is taking the iron well, with
vitamin C, and she has decreased milk
intake to 16 oz (480 ml) on average in a
24 hour period. What is the next best step?
a. Continue iron therapy for another
month and recheck hb at that time
b. Check a CBC/diff
c. Stop iron therapy and check a CBC/
diff
d. Stop iron therapy and check iron
studies in addition to a CBC/diff
Explanation: As iron deficiency is the most
likely cause of anemia, an empiric trial of
iron is the correct first step. Assessing com­
pliance with iron therapy and nutritional
recommendations is very important in fol­
low up especially if the hgb is not improved.
In many cases the family is unable to give
the iron well and the excessive milk intake
continues. Assuming a reliable family as in
the case above, it is important to now check
a CBC/diff to further characterize the ane­
mia. It would also be important to test for
ongoing losses at this point with a urinalysis
and fecal occult blood test. Choice a. is
incorrect since iron therapy should show
improvement in the hgb in 1 week and if
that is not the case it is best to avoid iron
overload by unnecessarily continuing iron.
Choice b. though correct is not as good a
choice as choice c. Choice d. is reasonable
although it would be first important to
check for microcytosis on the full CBC—if
microcytic then it would be reasonable to
test iron studies (ferritin, TIBC) in addition
to checking hemoglobin electrophoresis for
β‐thalassemia trait given the non‐respon­
siveness to iron therapy. The answer is c.
5. You are seeing a 15-month-old for a rou­
tine clinic visit. The family notes the child
has been more tired and pale recently. There
was an antecedent viral illness about one
month prior but the child is now otherwise
well. The child had a normal finger stick hb
at one year of age, eats a varied diet, has had
no noted blood loss and had no signs of
jaundice. The child is pale and tachycardic
but otherwise well appearing without LAD
or HSM. A finger stick hemoglobin is 5.4 g/
dl. Follow up CBC shows a normocytic ane­
mia with normal WBC/diff and platelet
count. The retic count is very low. What is
the most likely diagnosis?
a. Transient erythroblastopenia of
childhood
b. Iron deficiency anemia

c. Hemolytic anemia
d. Anemia of chronic disease
e. Aplastic anemia
Explanation: Transient erythroblastopenia
of childhood (TEC) is a common etiology of
normocytic anemia in infants and is due to
unclear causes, possibly infection triggered
bone marrow suppression. The normal
MCV in addition to the low reticulocyte
count in a well appearing child is suggestive
of this diagnosis. TEC in recovery phase
presents with a high reticulocyte and can be
confused with hemolytic anemia. Choice b.
is less likely since the anemia is normocytic
and not microcytic. Choice c. is unlikely
without a history of jaundice, scleral icterus
or dark urine and with a low reticulocyte
count. Choice d., although possible, is not
suggested by a normal history without other
medical diagnoses. Choice e. is also possible
Approach to the Anemic Child 13
with a normocytic anemia but typically
­presents with additional cytopenias. Often
these patients have macrocytosis. The
answer is a.
Suggested reading
Camaschella, C. (2015). Iron deficiency: new
insights into diagnosis and treatment.
Hematology Am. Soc. Hematol. Educ. Program
1: 8–13.
DeLoughery, T.G. (2014). Microcytic anemia.
N Engl. J. Med. 371: 1324–1331.
Kaneva, K., Chow, E., Rosenfeld, C.G., and Kelly,
M.J. (2017). Intravenous iron sucrose for chil­
dren with iron deficiency anemia. J. Pediatr.
Hematol. Oncol. 39: e259–e262.
Wang, M. (2016). Iron deficiency and other types
of anemia in infants and children. Am. Fam.
Physician 93: 270–278.
2 Hemolytic Anemia
Red blood cells (RBCs) normally live for
about 100–120 days in the circulation.
Hemolytic anemia results from a reduced
red cell survival due to increased destruc-
tion. To compensate for a reduced RBC life
span, the bone marrow increases its output
of red cells, a response mediated by erythro-
poietin. Destruction of red cells can be
intravascular (within the circulation) or
extravascular (by phagocytic cells of the
bone marrow, liver, or spleen). Hemolytic
anemia may be inherited (i.e., thalassemias,
hemoglobinopathies, red cell enzyme defi-
ciencies, or membrane defects) or acquired
(immune‐mediated, associated with infec-
tion, or medication‐related). It can be
chronic or acute. Some types of low‐grade
chronic hemolytic anemias can have acute
exacerbations, such as a child with glu-
cose‐6‐phosphate dehydrogenase (G6PD)
deficiency with an exposure to fava beans or
other oxidative stress.
Red cell membrane disorders
Hereditary spherocytosis (HS) is the most
common congenital red blood cell mem-
brane disorder. The typical patient with HS
has intermittent jaundice, and hemolytic or
red cell aplastic episodes associated with
viral infections, splenomegaly, and chole-
lithiasis. However, the clinical presentation
Handbook of Pediatric Hematology and Oncology – Children’s Hospital & Research Center Oakland,
Third Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
is quite variable, with most severe cases pre-
senting in the newborn period or early
childhood and milder cases presenting in
adulthood.
Several membrane protein defects are
responsible for HS, and most result in the
instability of spectrin, one of the major red
cell skeletal membrane proteins. Structural
changes that result as a consequence of pro-
tein deficiency lead to membrane instability,
loss of surface area, abnormal membrane
permeability, and decreased red cell deform-
ability. Metabolic depletion accentuates the
defect in HS cells, which accounts for an
increase in osmotic fragility after a 24‐hour
incubation of whole blood at 37°C. The
splenic sinusoids prevent passage of nonde-
formable spherocytic red cells. This explains
the occurrence of splenomegaly in HS and
the therapeutic effect of splenectomy.
Patients with HS have a mild‐to‐mod-
erate chronic hemolytic anemia. Red cell
indices reveal a normal to low mean cor-
puscular volume (MCV) depending on the
number of microspherocytes. Cellular
dehydration increases the mean corpuscu-
lar hemoglobin concentration (MCHC)
characteristically >36%, which can be a
helpful diagnostic clue. The red cell distri-
bution width (RDW) is elevated because of
the variable presence of microspherocytes
and reticulocytes in proportion to the
degree of hemolysis. The peripheral blood
16 Chapter 2
smear can be highly suggestive with the
presence of spherocytes, although this can
be a normal finding in the patient with
severe anemia and a resultant reticulocy-
tosis. Osmotic fragility tests and ektacy-
tometry studies show characteristic
findings for HS, with increased red cell
f ragility in hypotonic environments.
­ ues after splenectomy unless an accessory
Confirmatory testing is done with RBC
band 3 protein reduction. Band 3 is the
most abundant transmembrane protein
found in the erythrocyte. This study is
done by flow cytometry utilizing a fluores-
cent dye to bind the band 3 protein. It is
93% specific for the diagnosis of HS,
though other diseases can test positive
(i.e., congenital dyserythropoietic anemia
type II, Southeast Asian ovalocytosis,
hereditary pyropoikilocytosis).
As with other hemolytic anemias,
affected individuals are susceptible to hypo-
plastic crises during viral infections. Human
parvovirus B19, a frequent pathogen and the
organism responsible for erythema infectio-
sum (fifth disease), selectively invades
erythroid progenitor cells and may result in
a transient arrest in red cell proliferation
(see Chapter 1). Recovery begins within
7–10 days after infection and is usually com-
pleted by 4–6 weeks. If the initial presenta-
tion of a patient with HS is during an aplastic
crisis, a diagnosis of HS might not be con-
sidered because the reticulocyte count will
be low and the peripheral blood smear may
be nondiagnostic. Anemia may also be more
marked in patients with any underlying
hemolytic disorder. A family history of HS
should be explored; if it is positive, the
patient should be evaluated for HS after
recovery from the aplastic episode.
Splenectomy is often considered for
patients who have severe hemolysis requir-
ing transfusions or repeated hospitalization.
In patients with mild hemolysis, the deci-
sion to perform splenectomy should be
delayed; in many cases, it is not required.
For pediatric patients who have excessive
splenic size, an additional consideration for
splenectomy is to diminish the risk of trau-
matic splenic rupture. The risks of splenec-
tomy must be considered before any clinical
decision is made regarding the procedure.
Red cell survival returns to normal val-
spleen develops. Although an increased
number of spherocytes can be seen in the
peripheral blood after splenectomy and the
osmotic fragility is more abnormal, the
hemoglobin value is normal. Platelet counts
frequently increase to more than 1000 × 109/l
immediately after splenectomy, but return
to normal levels over several weeks. No
therapeutic interventions are required for
postsplenectomy thrombocytosis in patients
with HS.
To minimize the risk of sepsis due to
Haemophilus influenza and Streptococcus
pneumoniae, the splenectomy procedure
(when necessary) is often postponed until
after the child’s fifth or sixth birthday and
when fully immunized. Patients should be
immunized against these organisms in addi-
tion to Neisseria meningitidis prior to sple-
nectomy and receive penicillin prophylaxis
following the procedure. The increase in
penicillin‐resistant strains of S. pneumoniae
has raised questions regarding the use of
prophylactic penicillin. No studies have
determined the frequency of this problem in
children receiving prophylactic penicillin
after splenectomy. Dietary supplementation
with folic acid (1 mg/day) is recommended
due to high cellular turnover.
Paroxysmal nocturnal hemoglobinuria
(PNH) is an acquired hemolytic anemia
with periods of increased hemolysis in addi-
tion to risk of venous thrombosis and is
associated with aplastic anemia. The red
blood cell backbone has a deficiency in gly-
cosylphosphatidylinositol (GPI) antigen
structure leading to complement activation
secondary to deficiency of CD55 or CD59.
 Hemolytic Anemia 17

patient’s clinical course. Unlike HS patients,

Red cell enzyme deficiencies
PK‐deficient patients, although they
improve after splenectomy, do not have
Glucose is the primary metabolic substrate
complete correction of their hemolytic ane-
for the red cell. Because the mature red cell
mia. As with all hemolytic anemias, these
does not contain mitochondria, it can
patients should have dietary supplementa-
metabolize glucose only by anaerobic mech-
tion with folic acid (1 mg/day) to prevent
anisms. The two major metabolic pathways
megaloblastic complications associated with
within the red cell are the Embden–
relative folate deficiency. Immunization
Meyerhof pathway (EMP) and the hexose
against H. influenza, S. pneumonia, and N.
monophosphate shunt.
meningitidis should be given, as well as life-
Red cell morphological changes are min-
long penicillin prophylaxis in the splenecto-
imal in patients with red cell enzyme defi-
mized patient.
ciency involving the EMP. Red cell indices
G6PD deficiency is the most common
are usually normocytic and normochromic.
X‐linked red cell enzyme deficiency, with par-
The reticulocyte count is elevated in propor-
tial expression in the female population and
tion to the extent of hemolysis. Because
full expression in the affected male popula-
many enzyme activities are normally
tion. The distribution of G6PD deficiency
increased in young red cells, a mild defi-
is worldwide, with the highest incidence
ciency in one of the enzymes may be
in Africans and African‐Americans.
obscured by the reticulocytosis.
Mediterraneans, American Indians, Southeast
Pyruvate kinase (PK) deficiency is the
Asians, and Sephardic Jews are also affected.
most common enzyme deficiency in the
In African‐Americans, 12% of the male popu-
EMP. The inheritance pattern of this disor-
lation has the deficiency, 18% of the female
der is autosomal recessive. Homozygotes
population is heterozygous, and 2% of the
usually have hemolytic anemia with spleno-
female population is homozygous. In
megaly, whereas heterozygotes are usually
Southeast Asians, G6PD deficiency is found
asymptomatic. The disorder is found world-
in approximately 6% of the male population.
wide, although it is most common in
Most likely, the prevalence of this enzyme
Caucasians of Northern European descent.
abnormality confers resistance to malaria,
The range of clinical expression is variable,
thus its geographic distribution.
from severe neonatal jaundice to a fully
Many variants of G6PD deficiency are
compensated hemolytic anemia. Anemia is
known and have been characterized at the
usually normochromic and normocytic, but
biochemical and molecular levels. A variant
macrocytes may be present shortly after a
found in Mediterraneans is associated with
hemolytic crisis, reflecting erythroid hyper-
chronic hemolytic anemia. Other variants
plasia and early release of immature red
are associated with an unstable enzyme that
cells. The osmotic fragility of red cells is
has normal levels in young red cells. These
normal to slightly reduced. Diagnosis is
variants result in hemolysis only in associa-
confirmed by a quantitative assay for PK, by
tion with an oxidant challenge (as found in
the measurement of enzyme kinetics and
African‐Americans). In some cases of G6PD
glycolytic intermediates, and by family
deficiency, hemolysis may be triggered by
studies.
the oxidant intermediates generated during
Splenectomy is a therapeutic option for
viral or bacterial infections or after inges-
PK‐deficient patients. As with HS, the deci-
tion of oxidant compounds. Shortly after
sion should be made on the basis of the
exposure to the oxidant, hemoglobin is
18 Chapter 2
oxidized to methemoglobin and eventually
denatured, forming intracellular inclusions
called Heinz bodies that attach to the red
cell membrane. This portion of the mem-
brane may be removed by reticuloendothe-
lial cells resulting in a “bite” cell that has a
shortened survival owing to its loss of mem-
brane components. To compensate for
hemolysis, red cell production is increased
and thus the reticulocyte count is increased.
Individuals with the Mediterranean or
Asian forms of G6PD deficiency, in addition
to being sensitive to infections and certain
drugs, often have a chronic, moderately
severe anemia, with non‐spherocytic red
cells and jaundice. Hemolysis usually starts
in early childhood. Reticulocytosis is pre-
sent and can increase the MCV.
When a hemolytic crisis occurs in G6PD
deficiency (or favism), pallor, scleral icterus,
hemoglobinemia, hemoglobinuria, and
splenomegaly may be noted. Plasma hapto-
globin and hemopexin concentrations are
low with a concomitant rise in plasma‐free
hemoglobin. The peripheral smear shows
the fragmented bite cells and polychromat-
ophilic cells. Red cell indices may be nor-
mal. Special stains can detect Heinz bodies
in the cells during the first few days of
hemolysis.
A diagnosis of G6PD deficiency should
be suspected based on family history, eth-
nicity, laboratory features, physical findings,
and recent exposure to oxidants with result-
ant acute hemolysis. The diagnosis is con-
firmed by a quantitative enzyme assay or by
molecular analysis of the gene. Since reticu-
locytes may have a normal level of G6PD
enzyme activity, screening tests during acute
hemolysis may be falsely elevated; therefore,
it is important to test once the hemolytic cri-
sis has ended and the patient again has
mature red blood cells. Treatment is directed
toward supportive care during the acute
event and counseling regarding prevention
of future hemolytic crises. In patients with
chronic hemolysis, dietary supplementation
with folic acid (1 mg/day) is recommended.
Use of vitamin E, 500 mg/day, may improve
red cell survival in patients with chronic
hemolysis.
Autoimmune hemolytic anemia
In addition to intrinsic causes of hemolytic
anemia, patients may develop an autoanti-
body or alloantibody toward their red blood
cells. The underlying cause for this antibody
formation is often idiopathic or precipitated
by a secondary condition including drugs,
infection, autoimmune diseases, or an onco-
logic process. A positive direct antiglobulin
test (DAT, direct Coombs) is pathogno-
monic for immune‐mediated hemolysis
with the appropriate clinical and laboratory
findings (i.e., jaundice, scleral icterus, ele-
vated bilirubin, and anemia with reticulocy-
tosis). Fortunately, many pediatric cases of
autoimmune hemolytic anemia (AIHA) are
acute and self‐limited. However, AIHA may
be a presenting feature in chronic immuno-
logic or hematologic conditions including
autoimmune lymphoproliferative disease,
common variable immune deficiency, and
systemic lupus erythematosus.
In the DAT, the patient’s erythrocytes are
washed and then incubated with specific
antiglobulin antisera (usually anti‐IgG and
anti‐C3d). Agglutination indicates a posi-
tive test confirming the presence of antibod-
ies or complement attached to the surface of
the patient’s red blood cells. In patients with
severe immune‐mediated hemolytic ane-
mia, the DAT is often strongly positive,
although the strength of the reaction does
not always correlate to the severity of the
disease. Similarly, up to 80% of patients will
have antibodies in the serum as well, meas-
ured by the indirect Coombs (indirect anti-
globulin test, IAT). In the IAT, test
erythrocytes are incubated with donor

serum, washed, and then incubated with
specific antiglobulin antisera. Agglutination
again indicates a positive test indicating
antibody in the patient’s sera against a for-
eign red cell antigen. Of note, patients with-
out symptoms of hemolysis may have a
positive DAT or IAT; therefore, screening is
only recommended in the setting of clinical
and laboratory signs of hemolysis. In
approximately 5–10% of cases, patients may
have an AIHA with a negative DAT.
The initiation of autoimmunity is poorly
understood. Viral syndromes are often pro-
posed as a culprit, although causation has
been hard to prove. A majority of cases of
AIHA in pediatrics are due to “warm” anti-
bodies, so named because they react at
37 °C. These are often secondary to a viral
syndrome, although patients with an under-
lying autoimmune disease or oncologic pro-
cess can also present with a warm AIHA.
Immune hemolytic anemia may also be seen
after allogeneic transplant, generally sec-
ondary to autoantibodies formed by donor
cells against donor RBCs. The formation of
IgG antibodies leads to extravascular hemol-
ysis in which pieces of the red cell mem-
brane are sequentially removed during
passages through the spleen. Patients may
also develop DAT positive hemolytic ane-
mia and immune‐mediated thrombocyto-
penia (Evans syndrome).
Patients may also develop AIHA second-
ary to cold agglutinins, often secondary to
infection with Mycoplasma, and occurs sec-
ondary to IgM and complement (C3d) rather
than IgG. IgM autoantibodies react with poly-
saccharide antigens on the RBC surface, spe-
cifically I/i heavy chains. IgM binding occurs
at lower temperatures in the periphery lead-
ing to acrocyanosis. Intravascular hemolysis is
rare with complement fixation leading to
removal of RBCs in the liver. Corticosteroids
are generally ineffective in cold agglutinin
syndrome; intravenous immune globulin
(IVIG) and avoidance of the cold are first‐line
Hemolytic Anemia 19
therapies. Cold agglutinins are more likely in
older patients though tend to be acute in chil-
dren and chronic in adults.
Finally, also secondary to infection, chil-
dren may develop paroxysmal cold hemo-
globinuria, a transient condition which is
often unrecognized with complement acti-
vation rather than IgG or IgM. This is spe-
cific to the P antigen on the RBC membrane.
Diagnosis is made in the DAT negative
patient with serum antibody demonstrated
by the Donath–Landsteiner test. The major-
ity of patients have self‐resolution though
corticosteroids may be required.
Hemolytic disease of the
newborn
Intrinsic causes of hemolytic anemia can
present as jaundice in the newborn period.
These syndromes must be differentiated
from hemolytic disease of the newborn
(HDN), in which alloimmunization in the
mother occurs due to foreign RBC antigens
from the fetus. RBC antigens can either be
major (ABO) or minor (Rh, Kell, Duffy,
etc.). For ABO hemolytic disease, typically
the mother is type O and the fetus is type A;
anti‐A antibodies subsequently produced by
the mother then traverse the placenta lead-
ing to hemolytic anemia in the fetus.
RhoGAM® (Rho[D] immune globulin) has
virtually eliminated hemolytic disease in the
Rh‐negative (D‐negative) mother with a
Rh‐positive (D‐positive) fetus, although is
still possible in the mother not receiving
prenatal care. Many cases of HDN are now
due to other minor RBC antigens with vary-
ing levels of clinical severity. AIHA in the
mother can also lead to HDN. In this case,
maternal IgG antibodies traverse the pla-
centa and are transferred to the fetus. If the
mother is DAT positive but does not have
clinical signs of hemolytic anemia, there is
usually no risk to the fetus.
20 Chapter 2

●● Anemia unresponsive to iron

Microangiopathic hemolytic
supplementation
anemia
●● Medications

●● Environmental exposures
Microangiopathic hemolytic anemias are
●● Ethnicity
due to extracorpuscular abnormalities and
●● Dietary history
are not associated with antibody formation.
The physical exam should be complete,
Causes include disseminated intravascular
but focused on:
coagulation (DIC), thrombotic thrombocy-
●● Skin color (pallor, jaundice, and icteric
topenic purpura/hemolytic uremic syn-
sclerae)
drome (TTP/HUS), transplant‐associated
●● Facial bone changes (extramedullary
microangiopathy, preeclampsia, malignant
hematopoiesis)
hypertension, valvular abnormalities, and
●● Abdominal fullness and splenomegaly
march hemoglobinuria. In these cases, red
The laboratory evaluation includes:
blood cells travel through damaged blood
●● Complete blood count, RBC indices, and
vessels or heart valves or are damaged by the
reticulocyte count
formation of an intravascular fibrin mesh
●● Peripheral blood smear (assess for frag-
due to hypercoagulability, leading to frag-
mented forms or evidence of inherited anemia
mentation (e.g., schistocytes) and intravas-
with specific morphological abnormalities)
cular hemolysis. In the case of TTP,
●● Bilirubin, AST, lactate dehydrogenase
ADAMTS13 is a useful evaluation as defi-
(LDH)
ciency can occur in hereditary TTP second-
●● Coombs test, direct and indirect (to exclude
ary to mutation and in acquired TTP
antibody‐mediated red cell destruction)
secondary to autoantibodies.
●● Urinalysis (for heme, bilirubin)
Transplant‐associated microangiopathy
●● Free plasma hemoglobin, haptoglobin
is increasingly being recognized, often sec-
●● Parvovirus PCR (if history is suspicious)
ondary to calcineurin inhibitors in alloge-
Specific tests for diagnosis may include:
neic transplant, though it has also been
●● Osmotic fragility
noted in patients after autologous transplan-
●● Ektacytometry
tation, likely secondary to irradiation,
●● RBC band 3
multiagent chemotherapy, or viral reactiva-
●● Red cell enzyme defects (G6PD and PK)
tion leading to endothelial injury.
●● Red cell membrane defects (HS)

●● CD 55/59

Evaluation ●● ADAMTS13

The osmotic fragility test is used to meas-

The evaluation of hemolytic anemia includes
a thorough history assessing for evidence of
chronic hemolytic anemia and possible pre-
cipitants of an acute event (see Figure 2.1).
The family history is equally important
and questions to ask include:
●● History of newborn jaundice
●● Gallstones
●● Splenomegaly or splenectomy
●● Episodes of dark urine and/or yellow
skin/sclerae
ure the osmotic resistance of red cells. Red
cells are incubated under hypotonic condi-
tions, and their ability to swell before lysis is
determined. The osmotic fragility of red cells
is increased when the surface area to volume
ratio of the red cells is decreased, as in hered-
itary spherocytosis, in which membrane
instability results in membrane loss and
decreased surface area. Conversely, osmotic
fragility is decreased in liver disease, as the
ratio of the red cell surface area to volume is
 Hemolytic Anemia 21

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

RBC enzyme studies

Consider
Ceruloplasmin
CD 55/59
DIC
Coagulation Family studies
Hemoglobin Enzyme deficiency
screen Osmotic fragility or
(fibrinogen, electrophoresis PK deficiency
ektacytometry
PT, PTT, FDP) G6PD deficiency
Platelet count Wilson disease
Blood cultures PNH
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 anti-
globulin test; ANA, anti‐nuclear antibody; DIC, disseminated intravascular coagulation; PT, prothrom-
bin 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; PNH, paroxysmal nocturnal hemoglobinuria).

increased. Ektacytometry measures the In chronic hemolysis, such as that associated

deformability of red cells subjected simulta-
neously to shear stress and osmotic stress.
Treatment
Determination of a treatment plan relies on
identification of the underlying cause of the
anemia and the degree of acute hemolysis.
with hereditary spherocytosis, splenectomy
is often recommended to decrease the
degree of splenic destruction and level of
anemia and to decrease the incidence of bili-
rubin gallstones. This therapy must be now
weighed against the potential long‐term
complications of splenectomy including risk
for infection, thrombosis, and pulmonary
hypertension. In other forms of inherited
22 Chapter 2
anemias in which the hemolysis is more sig-
nificant and even life‐threatening, such as
thalassemia or some forms of enzymopa-
thies, chronic transfusion therapy is recom-
mended. Other general measures include
folic acid replacement due to high cell turn-
over, avoidance of oxidant chemicals and
drugs, and iron chelation therapy as indi-
cated for transfusion‐related iron overload.
Immune hemolytic anemias resulting in
acute, symptomatic anemia require more
immediate and aggressive therapy. The
underlying disease, if present and identifiable,
warrants treatment. Additionally, the use of
corticosteroids in high doses is frequently
necessary (starting with prednisone at
2–4 mg/kg/day). Very high doses for 2–4 days
(up to 10 mg/kg/day [max 1 g]) may be neces-
sary prior to decreasing back to 2 mg/kg/day.
Splenectomy and immunosuppressive drugs
(such as rituximab) have also been successful
in steroid‐resistant disease. Immune globulin
infusions do not contribute to resolution of
the disease, but should be considered in
patients with severe hemolysis who are
requiring transfusion or are having a poor
response to transfusion. Plasmapheresis can
be considered in patients with severe IgG‐
induced AIHA and should always be com-
bined with an immune suppressive drug
to ensure both antibody production and
­antibody titer reduction. Microangiopathic
hemolytic anemias can also be severe and
life‐threatening. Treatment should again first
be directed toward the primary disorder to
remove the cause of trauma, if possible.
Transfusions are frequently necessary and
splenectomy may be needed in some patients
with severe hypersplenism.
Case studies for review
1. You are seeing a 6-year-old child in the
emergency department. The family notes
that the child has been jaundiced and
fatigued over the last few days with a red
color to the urine. Fingerstick hemoglobin
at the pediatrician’s office reveals a hemo-
globin of 5 g/dl prior to transfer to the ED.
On the basis of this history and hemoglobin,
it appears that the child is suffering from a
hemolytic anemia.
a. What initial lab studies will help con-
firm the diagnosis and also help with the
initial treatment plan?
Initial lab studies should include a complete
blood count with reticulocyte count. The
reticulocyte count is an important first step
to confirm that the patient is undergoing
hemolysis, which should present with a low
hemoglobin and a resultant increase in the
reticulocyte count. A low reticulocyte count
in this setting should lead to consideration
of alternative diagnoses of decreased red
cell production, such as viral suppression
(although one would not expect hemolysis).
A complete metabolic panel as well as lac-
tate dehydrogenase (LDH) should be done
to ensure that the patient is actually suffer-
ing from jaundice (elevated total bilirubin)
and hemolysis (elevated LDH and AST). A
DAT/IAT is an important first step to deter-
mine if the patient has an immune or non-
immune hemolytic anemia. If the DAT is
positive, the blood bank should be asked to
elute the antibody to determine if this is
IgM, IgG, or possibly complement-medi-
ated hemolysis.
The patient is noted to have a hemo-
globin of 4.6 g/dl with 12.6% reticulocytes.
One should first determine if the patient
is having an appropriate bone marrow
response to anemia by calculating the retic-
ulocyte index (RI):
RI Reticulocyte count %
current hemoglobin
expected hemoglobin
In this case, the RI is 12.6% × (4.6/13) = 4.5.

An RI ≥ 3.0 is consistent with an appro-
priate bone marrow response to anemia,
and therefore helps to rule out bone marrow
dysfunction in this case. Modern blood cell
analyzers have the ability to calculate the
absolute reticulocyte count and the fraction
of “immature” reticulocytes directly.
Patients who are demonstrating an appro-
priate response to hemolysis will have an
elevated absolute reticulocyte count and
immature reticulocyte fraction; these will be
low or normal in patients with an inade-
quate response.
Other labs include a total bilirubin of
6.7 mg/dl, LDH of 936 U/l (reference range
313–618 U/l), and AST of 161 U/l (reference
range 8–43 U/l). DAT is noted to be positive
for IgG and C3d.
b. What is the likely diagnosis?
With the positive DAT to IgG and comple-
ment and clinical and laboratory signs of
hemolysis, warm antibody-mediated AIHA
is the likely diagnosis. It should be noted
that a positive DAT without clinical and
laboratory signs of hemolysis is not suffi-
cient for the diagnosis of AIHA.
c. What should be the initial treatment
plan?
The patient is started on steroid therapy,
intravenous (IV) methylprednisolone 1 mg/
kg twice a day (BID). After a couple of days,
the hemoglobin has continued to decrease
to 3 g/dl even though the methylpredniso-
lone has been increased to 4 mg/kg BID and
the patient is showing signs of symptomatic
anemia and congestive heart failure.
d. How should your treatment change at
this point?
Since the patient has a falling hemoglobin
with clinical signs of cardiac instability and
volume overload, the patient should be trans-
fused. The term “least incompatible unit” has
been used in the past but is a misnomer if
phenotypically matched blood is given. The
patient may not have a normal increase in
hemoglobin with transfusion due to contin-
Hemolytic Anemia 23
ued hemolysis and the potential for
increased, bystander hemolysis with trans-
fusion. Because of the cardiac instability, it is
advisable to give the transfusion slowly and
monitor for worsening cardiac function.
Consideration can be given to IVIG infu-
sion concurrently with the packed red blood
cell (PRBC) transfusion. Finally, a change in
therapy would be advisable at this point
with an immunosuppressant drug such as
rituximab (monoclonal antibody to CD20),
cyclosporine, or cyclophosphamide.
2. You have been consulted on a now 4-day-
old full-term neonate with profound jaun-
dice (unconjugated hyperbilirubinemia)
that has risen from 11 mg/dl at 72 hours to
20 mg/dl. The neonatology team has initi-
ated phototherapy, but is asking for hema-
tology recommendations.
a. What are some background questions
that may be clarifying?
It is important to consider questions which
can help determine if the jaundice is physi-
ologic or non-physiologic. A conjugated
hyperbilirubinemia is never physiologic and
should prompt early referral. An unconju-
gated hyperbilirubinemia in the first 14 days
of life in the neonate can be physiologic sec-
ondary to liver immaturity and may be pre-
cipitated by prematurity, poor feeding,
Asian ethnicity, infection, breastmilk jaun-
dice, and drugs which impact liver metabo-
lism. A family history of extended
phototherapy may be indicative of physio-
logic or non-physiologic conditions. Family
history of enlarged spleen, splenectomy,
gallstones and/or cholecystectomy, or jaun-
dice at an older age could by indicative of a
membranopathy (i.e., hereditary spherocy-
tosis or elliptocytosis), while jaundice at an
older age could be indicative of an enzymo-
pathy (i.e., G6PD, PK deficiency, or Gilbert
syndrome). It is important to ensure that the
mother received prenatal care and was tested
for Rh incompatibility. ABO incompatibility
24 Chapter 2
as well as minor red cell antigen incompati-
bility (i.e., Kell) may also lead to jaundice,
though not as severe as Rh incompatibility
(with minor antigen incompatibility not
being as severe as ABO incompatibility).
Gilbert syndrome is due to a mild deficiency
of uridine diphosphate glucuronosyltrans-
ferase (UGT1A1), which conjugates biliru-
bin in the liver. UGT1A1 is lacking in
Crigler–Najjar syndrome type I leading to
severe hyperbilirubinemia after birth, while
Crigler–Najjar type II maintains approxi-
mately 10% activity and milder symptoms.
b. Given the high bilirubin level, what
are some follow up studies that should be
considered?
Hemoglobin levels, reticulocyte count, and
a DAT (direct Coombs) can be helpful.
Mothers who are type O blood type with a
type A infant are most likely (type B less
likely) to have a newborn with HDN. A nor-
mal hemoglobin level makes hemolysis less
likely, while a low hemoglobin with an ele-
vated reticulocyte makes hemolysis likely.
A positive DAT would be consistent with
HDN though may not always be present.
Low haptoglobin levels can also be a helpful
diagnostic clue. Nonimmune mediated
causes should be considered if there is not
blood group incompatibility or a positive
DAT. G6PD deficiency is the most likely
cause in the male infant of African-
American or Mediterranean descent and
may also be present in a lyonized or homozy-
gous female and can be diagnosed based on
red blood enzyme levels. Hereditary sphero-
cytosis can be diagnosed based on an ele-
vated MCHC (>36 g/dl) with follow-up
confirmatory genetic testing (RBC band 3).
Multiple choice questions
1. You are seeing a 1-day-old, 3.2 kg male
infant in the newborn nursery, born at
38 weeks gestational age to a G2P2 healthy
28 year old mother. The baby appears jaun-
diced but otherwise well so a CBC and bili-
rubin are checked. The CBC shows an anemia
to 9.4 g/dl (MCV 110) with normal WBC/
diff and platelets. Total bilirubin is 10.2 mg/dl
(all indirect). Mother’s blood type is O, the
baby is A. What is the next best test to order?
a. Blood culture
b. Reticulocyte count
c. Direct antiglobin test
d. G6PD screening
Explanation: The most likely diagnosis in
this scenario is hemolytic disease of the
newborn (HDN) which is typically due to
ABO incompatibility. Generally the mother
is O blood type and the baby is either A or B
blood type. Although reticulocytosis is
present, a positive direct Coombs (direct
antiglobin test; DAT) is diagnostic. HDN
typically presents in the first 24 hours with
minimal anemia and jaundice. With good
prenatal care, Rh incompatibility is quite
rare though if present would lead to a more
severe presentation. Choice a. is incorrect as
the baby is otherwise well appearing without
fevers. Choice b. is reasonable to include
with the DAT. Choice d. is more likely in the
male newborn of Mediterranean or Asian
descent with prolonged jaundice (the
African G6PD type does not lead to neona-
tal jaundice). The answer is c.
2. You are seeing a patient in the emergency
department who was noted to have scleral
icterus, jaundice and pallor. A CBC is done
with a hemoglobin of 5.8 g/dl and a reticulo-
cyte percent of 14.8%. WBC/diff and platelets
are within normal range. Direct antiglobin
test (DAT, direct Coombs) is positive for IgG
and C3d. What is the best next step?
a. Admit for observation
b. Give a PRBC transfusion secondary
to the anemia
c. Start steroids, 2 mg/kg/day methyl-
­prednisolone
d. Give PRBCs and start steroids

Explanation: This is a classic presentation
for warm antibody autoimmune hemolytic
anemia (AIHA). A positive DAT with retic-
ulocytosis is pathognomic for this diagnosis,
especially when positive to IgG and comple-
ment. The underlying etiology is often not
found but can but acutely related to a previ-
ous infection or may be due to an underly-
ing autoimmune condition such as SLE. As
there is an autoimmune etiology, steroids
are the appropriate treatment with transfu-
sion reserved to patients with severe anemia
not responsive to steroid therapy or with
cardiorespiratory compromise. PRBC trans-
fusion can increase hemolysis and also lead
to bystander hemolysis, worsening the
underlying condition. If blood is required
the blood bank should use the PRBC unit
that has the least cross‐reactivity. The ster-
oid dose should be increased as needed if
there is no response to the initial dose. The
answer is c.
3. You are seeing a 5-year-old African‐
American male in clinic who presents with
pallor after a viral illness. He has now
recovered from this illness. Mom notes that
his eyes appeared a bit yellow prior but have
normalized now. She notes that he has had
yellowing of his eyes a few times prior and
she remembers a maternal uncle with simi-
lar complaint. On exam the child is pale and
tachycardic with splenomegaly but otherwise
has a reassuring exam. Blood counts reveal
a hgb of 7.2 g/dl, retic of 11.1%, normal
WBC/diff, normal platelets. Chemistries
show an elevated LDH, indirect bilirubin
and AST. DAT is negative. What is the most
likely diagnosis?
a. G6PD deficiency
b. Hereditary spherocytosis
c. PK deficiency
d. Hemolytic uremic syndrome
e. Disseminated intravascular coagulation
Explanation: Although all of the above con-
ditions can cause a non‐immune hemolytic
Hemolytic Anemia 25
anemia, the history is most suggestive of
G6PD deficiency in an African‐American
male patient with a recent oxidative stress.
G6PD is the most common X‐linked red cell
enzyme deficiency. A hemolytic crisis can
occur with oxidative stress, secondary to
illness or oxidant foods or medications.
Hemoglobin is oxidized to methemoglobin
and then denatured, forming intracellular
inclusions called Heinz bodies. This portion
of the RBC may be removed by the reticu-
loendothelial system leading to “bite cells.”
The answer is a.
4. What would be the most appropriate
next step in the above case?
a. Start IV steroids
b. Admit for observation
c. Give a PRBC transfusion
d. Reassure the family and provide close
follow up
Explanation: The patient is actively
hemolyzing but is recovering from his ill-
ness and has a reassuring exam with resolu-
tion of his scleral icterus. Although he is
anemic he is well compensated and having
an appropriate reticulocyte response. If
there are concerns from the family’s or
clinician’s standpoint it would be reasonable
to admit for observation but this is not
necessary if close follow up can be ensured.
Choice a. is incorrect as this is a non‐
immune hemolytic anemia and there would
be no benefit to steroid administration.
Choice c. would be reasonable if the patient
were more symptomatic or if the family pre-
ferred transfusion but is not necessary at
this point in an otherwise stable‐appearing
patient. The answer is d.
5. You are following a 14-year-old female
who was admitted for further work up of
worsening ability to concentrate at school.
She has otherwise felt okay although her
school performance has dropped in the
last six months. There are no underlying
26 Chapter 2
psychosocial triggers and her exam is normal.
On routine labs her hemoglobin is 10.4 g/dl,
bilirubin is 2.4 mg/dl (all indirect), AST
and ALT are mildly elevated, BUN/Cr are
normal. You add on a retic and it is 2.4%.
Thyroid function studies are normal.
Coagulation studies are normal. What is the
next best step?
a. Provide reassurance
b. Send osmotic fragility studies
c. Check ceruloplasmin
d. Send RBC enzyme panel
e. Check ESR and ANA
Explanation: Wilson’s disease can often pre-
sent with subtle findings that remain undiag-
nosed for many years. Patients will Wilson’s
may present with a mild, nonimmune hemo-
lytic anemia which can be a clue to the diag-
nosis. Bronzing of the skin, liver failure and
Kayser‐Fleischer rings due to copper deposi-
tion are more often see at a later stage of dis-
ease presentation. Thyroid problems can
also lead to subtle neuropsychiatric symp-
toms as well as anemia so it is important to
rule that out at presentation. Choice a. is
incorrect as the patient has a mild anemia
with signs of hemolysis. Choice b. and d.
are reasonable when trying to rule out a
membranopathy and enzyme deficiency,
respectively, and would be reasonable to do
if the ceruloplasmin is not diagnostic. For
choice e., an underlying autoimmune condi-
tion such as SLE generally leads to an anemia
of chronic disease rather than a hemolytic
process. The answer is c.
Suggested reading
Cappellini, M.D. and Fiorelli, G. (2008).
Glucose‐6‐phosphate dehydrogenase defi-
ciency. Lancet 371: 64–74.
Ciepiela, O. (2018). Old and new insights into the
diagnosis of hereditary spherocytosis. Ann.
Transl. Med. 6: 339.
Grace, R.F. and Glader, B. (2018). Red cell mem-
brane disorders. Pediatr. Clin. North Am. 65:
579–595.
Haley, K. (2017). Congenital hemolytic anemia.
Med. Clin. North Am. 101: 361–374.
Lauer, B.J. and Spector, N.D. (2011).
Hyperbilirubinemia in the newborn. Pediatr.
Rev. 32: 341–349.
Liebman, H.A. and Weitz, I.C. (2017).
Autoimmune hemolytic anemia. Med. Clin.
North Am. 101: 351–359.
Noronha, S.A. (2016). Acquired and congenital
hemolytic anemia. Pediatr. Rev. 37: 235–246.
3 Sickle Cell Disease
Sickle cell disease (SCD) refers to a group of
genetic disorders that share a common
feature: hemoglobin S (hgb S) alone or in
combination with another abnormal
hemoglobin. The sickle cell diseases are
inherited in an autosomal codominant
manner. The molecular defect in hgb S is
due to the substitution of valine for glutamic
acid at the sixth position of the β‐globin
chain on chromosome 11. This substitution
results in polymerization of hemoglobin
causing the red cells to transform from
deformable biconcave discs into rigid,
sickle‐shaped cells. Hypoxia, acidosis, and
hypertonicity facilitate polymer formation.
The most common combinations of
abnormal hemoglobins are (i) hgb SS, (ii)
hgb SC, and (iii) hgb S with a β‐thalassemia,
either Sβ+ or Sβ0. The most severely affected
individuals have either hgb SS or Sβ0 (no
normal β‐globin production). Individuals
with hgb Sβ+ have decreased β‐globin
production and less severe disease, whereas
children who have hgb SC have intermediate
severity of disease. There is phenotypic
overlap between hgb SS and hgb SC; some
children with hgb SC are more symptomatic
than children with hgb SS. There are
many variables to expression of this hemo­
globinopathy including haplotype, hgb F
concentration, and other as yet to be deline­
ated factors. Currently it is not possible to
predict the severity of disease in advance of
Handbook of Pediatric Hematology and Oncology – Children’s Hospital & Research Center Oakland,
Third Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
severe complications, although children
who have vaso‐occlusion and other compli­
cations generally have a more severe course.
Increased leukocyte count, decreased hemo­
globin with concomitant increased reticu­
locytosis, as well as frequency and severity
of vaso‐occlusive episodes (VOEs) are
associated with increased morbidity and
­
mortality.
Alpha‐thalassemia (α‐thalassemia; fre­
quency 1–3% in African‐Americans) may
be coinherited with sickle cell trait or dis­
ease. Individuals who have both α‐thalas­
semia and sickle cell anemia are less anemic
than those who have sickle cell anemia alone
due to a more similar concentration of
α‐ and β‐globulins. However, α‐thalassemia
trait does not appear to prevent frequency or
severity of vaso‐occlusive complications,
resulting in eventual end‐organ damage.
Sickle cell disease is not uncommon, as
the genetic mutation occurred as a protective
mechanism from malaria in those with sickle
cell trait. In African‐Americans, the fre­
quency of genetic alteration is quite high: 8%
have the hgb S gene, 4% the hgb C gene, and
1% the β‐thalassemia gene. Approximately 1
in 600 African‐American infants has sickle
cell anemia. Sickle cell disease also occurs in
children from the Middle East, India, Central
and South America, and the Caribbean.
All children who have sickle cell hemo­
globinopathies have a variable degree of
28 Chapter 3
hemolytic anemia and vaso‐occlusive tissue
ischemia resulting in numerous clinical
complications. When subjected to a low‐
oxygen state, hgb S polymerizes and the red
cells become altered into a rigid sickled
form. The pathophysiology of vaso‐
occlusion is complex and involves many
factors and pathways including chronic
inflammation, oxidative stress, altered
hemostasis of the coagulation system,
hemolysis‐associated reduction in nitric
oxide availability, and increased viscosity.
Organs most sensitive to the ischemia and
reperfusion injury are the lungs, spleen,
kidneys, bone marrow, eyes, brain, and the
heads of the humeri and femurs. Sickling
has both acute and long‐term implications
for organ function. Cerebral vascular disease
can be subtle, causing only abnormal
neuropsychological testing or it can be
catastrophic, resulting in hemiparesis, coma,
or death; acute pulmonary sickling causes
lung injury leading to restrictive lung
disease and eventually pulmonary
hypertension; osteonecrosis of the femoral
head can be debilitating, resulting in the
need for hip replacement; untreated
retinopathy can lead to blindness; and,
sickle cell nephropathy can cause asymp­
tomatic proteinuria, an early sign of the risk
of eventual renal failure.
Now that newborn hemoglobinopathy
testing is mandatory in all states, children
are diagnosed early and receive appropriate
care before they are at risk for complications.
All infants who have an electrophoretic
pattern of hgb FS at birth will have some
form of sickle cell disease.
Preventive care
Preventive care is a critical aspect of ensur­
ing optimal health for children, teens, and
adults with sickle cell disease. Optimally,
patients should be cared for in specialized
sickle cell centers with access to multidisci­
plinary providers, with provision of age‐
based assessments. Patients should be
referred following positive newborn
screening for a definitive diagnosis with
hemoglobin electrophoresis and possibly
thalassemia genotyping. Frequent visits are
encouraged to provide education to pri­
mary caregivers on the disease process,
subtle signs and symptoms of infection,
pain, and complications at various points
of growth and development, as well as pro­
vide intervention as needed. A multidisci­
plinary team approach to care including
intervention and support by nurses, social
workers, genetic counselors, and therapists
is critical to comprehensive care. Important
elements of care are detailed in this chapter
and include:
●● Ensuring immunizations are up to
date, anticipating development of splenic
dysfunction.
●● Early initiation of penicillin and educa­
tion regarding recognition of infection.
●● Frequent nutritional and developmental
assessments; children may have delayed
growth and development including sexual
development.
●● Assessments of school or work perfor­
mance, neuropsychiatric assessments as
indicated.
●● Monitoring of CBCs and degree of
hemolysis as well as liver/kidney function.
●● Pulmonary monitoring (pulmonary func­
tion tests, oxygen saturation is tested but
may not correlate with PaO2 in steady state);
asthma is associated with an increased rate of
complications including pain, acute chest
syndrome (ACS), stroke, and pulmonary
hypertension.
●● Transcranial Doppler (TCD) ultrasonog­
raphy as primary stroke prevention.
●● Cardiac function assessments, echocardi­
ogram (ECG).
●● Monitoring for sickle retinopathy and
associated complications.

●● Bone health monitoring.
●● Red cell phenotype, anticipating red cell
transfusion at some point.
●● Early intervention and education regard­
ing newer preventive/curative therapies
including initiation of hydroxyurea (HU)
and potential clinical trials, as well as gene
therapy and stem cell transplant.
●● Management of pain in the outpatient
setting.
Fever and infection in sickle
cell disease
Susceptibility to infection is increased not
only because of loss of splenic function due
to infarction but also because of other
acquired immunologic abnormalities. This
can result in life‐threatening episodes of
sepsis. Recognition of this susceptibility and
aggressive medical management have
resulted in an increased life span for most
patients.
Most children with sickle cell disease are
identified at birth, started on prophylactic
penicillin by age 2 months, and aggressively
monitored and treated for signs of infection.
However, with the increasing concern for
bacterial antibiotic resistance, health care
providers need to be vigilant when con­
fronted with an infant or a child who has
fever (≥38.3°C) and/or appears ill. Overall,
Streptococcus pneumoniae is responsible for
>80% of the morbidity of infection. In some
areas of the United States, up to 50% of pneu­
mococcal isolates are penicillin‐resistant.
Infections can precipitate VOEs and other
complications of sickle cell anemia and, in
this population, can quickly become fulmi­
nant. Although the American Academy of
Pediatrics guidelines recommend the discon­
tinuation of penicillin prophylaxis after 6
years of age, our institutional practice is to
continue it as long as possible (until compli­
ance becomes an issue) due to the high risk of
Sickle Cell Disease 29
S. pneumoniae infection that does not change
with age.
Additional bacteria that cause morbidity
and mortality include Haemophilus influen-
zae, Neisseria meningitidis, Mycoplasma
pneumoniae, Staphylococcus aureus,
Salmonella species, Escherichia coli, and
Streptococcus pyogenes. The S. pneumoniae
and H. influenzae vaccines have importantly
resulted in a lowered case rate of sepsis from
these organisms. Meningococcal vaccination
should also be given during the adolescent
period. Viral infections, particularly parvo­
virus B19, can cause severe aplastic crises
as well as ACS in patients with sickle cell
disease.
All patients with a fever (≥38.3°C) should
have a complete evaluation and laboratories
including CBC with differential, reticulocyte
count, blood culture, urinalysis, and urine
culture (see Figure 3.1). A chest radiograph
should also be obtained. Meningitis can
occur in children with sickle cell disease, but
routine lumbar puncture without physical
signs of meningitis is not warranted.
Urosepsis is common in sickle cell patients
of all ages. Our practice remains that all
infants (up to 2–3 years of age) should be
admitted and cultures followed for 48 hours.
These patients should not be discharged
during this time even if they appear well and
are afebrile. Some practitioners would
recommend admission in all patients with a
fever. More recent data show the benefit of
vaccination against encapsulated organisms,
with very low rates of sepsis in young
patients with sickle cell disease. Therefore, a
more liberal policy in regard to admission
can be considered in the fully vaccinated
infant if appropriate follow‐up can be
ensured.
ACS should be high on the differential in
all children with sickle cell disease with
fever. While physical examination is
essential, 60% of pulmonary infiltrates in
children with sickle cell disease and fever
30 Chapter 3

Rapid assessment
history & physical

Septic appearing child Infant, child less than

2–3 years of age:
Non-toxic appearing child

Rapid assessment
for degree of respiratory and History (last dose of penicillin):
cardiovascular compromise; Cardiovascular and respiratory status,
meningismus; splenomegaly, jaundice, pain;
cardiovascular monitoring and neurologic screen for weakness and
pulse oximetry altered mental status

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
Catheterized urine culture Oxygen Catheterized urine culture
Consider LP Chest X-ray Consider LP
Type and cross match ABG Chest X-ray
Chest X-ray

Fluid bolus to
maintain blood pressure
Note: fluid overload can lead
to ACS
Antibiotics Antibiotics
Ceftriaxone 50 mg/kg IV push
Ceftriaxone 50 mg/kg
or rapid infusion (plus azithromycin if CXR findings
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).

will be missed on exam alone; therefore,
chest radiography is essential. If there is
another possible source of infection, appro­
priate cultures should be obtained. Rapid
antibiotic treatment with parenteral ceftriax­
one should occur in the emergency depart­
ment after obtaining labs and blood cultures.
If there is difficulty with intravenous (IV)
access, ceftriaxone can be given intramuscu­
lar (IM) while access is being obtained. Of
note, studies have shown that the higher the
temperature, the more likely the risk for
bacterial sepsis.
Children who do not appear septic, in
whom there is a low index of suspicion, vac­
cinated, and who are older than 2–3 years of

age (per institutional preference) can be
treated as outpatients with IV/IM ceftriax­
one while awaiting culture results, only if
close monitoring can be assured (parents
can be contacted by telephone and daily
evaluation is easily done while still febrile).
If all cultures are negative after 2–3 days and
the child is afebrile without clinical symp­
toms, the antibiotics and follow‐up can be
discontinued.
All patients who appear ill should be
hospitalized and treated for presumed infec­
tion. Children may develop increasing
symptoms after being evaluated and hospi­
talized, and should be monitored closely.
ACS commonly occurs after hydration and
is frequently precipitated by a vaso‐occlu­
sive pain episode.
Vaso‐occlusive episodes
The bones and joints are the major sites of
pain in sickle cell disease. In trabecular
bones, such as the vertebrae, infarction can
occur and eventually lead to collapse of the
vertebral plates and compression. The classic
radiographic appearance is of “fish mouth”
disc spaces and the “step” sign (a depression
in the central part of the vertebral body).
Back pain is a common symptom in sickle
cell disease, likely as a result of recurrent
infarction and vertebral compression.
Infarction in the long bones can cause swell­
ing and edema in the overlying soft tissues. It
may be difficult to differentiate a VOE from
acute osteomyelitis. Although uncommon,
infection should be considered. Osteomyelitis
may be ruled out by close clinical observa­
tion, blood cultures, and, occasionally, aspi­
ration of the affected area. Plain radiographs
are not helpful in the early stages of infection
and bone scans may not differentiate a sim­
ple infarct from osteomyelitis.
Dactylitis, or hand–foot syndrome,
refers to painful swelling of the hands and
Sickle Cell Disease 31
feet. This is seen exclusively in infants and
children (<5 years of age). It presents with
pain, low‐grade fever, and diffuse nonpit­
ting edema of the dorsum of the hands and
feet, which extends to the fingers. One or
more extremities may be affected at one
time. Radiographic changes (periostitis and
subperiosteal new bone formation with per­
iosteal elevation) may appear 1 week or
more after clinical presentation. Therapy is
supportive, with analgesics, hydration, and
parental reassurance. Although the swelling
or radiographic changes may persist for
weeks, the syndrome is almost always self‐
limited. Transfusions and antibiotics are not
necessary unless there is concern for infec­
tion or the medical condition worsens.
Occasionally, there is a precipitating
event such as hypoxia (e.g., obstructive sleep
apnea), fever, viral illness, or dehydration
that leads to the VOE. Few children have
frequent pain episodes; it should not be
taken for granted that each of these episodes is
similar, and a source for each painful event
should be sought. If the pain changes or is
very persistent, the child should be
reevaluated. If a young child has a symptom
that is interpreted as pain, such as refusal to
walk or a limp, also consider that the cause
may be due to an acute central nervous
system (CNS) event.
The most common type of pain is
musculoskeletal pain. The pain may be of
any configuration: isolated, multifocal,
symmetric, migratory, or associated with
erythema or swelling. There can be low‐
grade fevers, possibly associated with other
clinical symptoms. It can sometimes be
difficult to distinguish pain from infection,
synovitis, or another pathologic process.
Children are frequently seen with abdo­
minal pain. A surgical abdomen needs to
be considered. Children who have sickle
cell anemia have a high incidence of chole­
cystitis. Also consider pancreatitis, u ­ rinary
tract infection, pelvic inflammatory disease,
32 Chapter 3
and pneumonia presenting as abdominal
pain. Ileus and ACS are frequent complica­
tions of abdominal VOEs.
VOEs can last for many days. Do not
assume that the episode is controlled when
the acute administration of analgesia is effec-
tive. Children with these symptoms may
have a medical problem that needs aggres­
sive treatment beyond therapy for their
pain. A VOE is a diagnosis of exclusion. The
pain needs to be treated while there is a
workup for potential other causes of pain
beyond the VOE itself.
A reliable tool should be used to assess a
child’s level of pain. The assessment should
be modified depending on the age and
developmental level of the child, and the
pain tool should be able to rate both
subjective and objective aspects of the child’s
pain. Physicians should be familiar with
their use and refer to them when assessing
children and adolescents with pain. At our
institution, we use the validated adolescent
pediatric pain tool (APPT).
High‐risk factors for complications other
than VOE in children with pain:
●● Fever ≥101°F (38.3°C) and signs of
infection.
●● Acute pulmonary symptoms (chest pain,
hypoxia, abnormal auscultatory exam).
●● Persistent vomiting.
●● Pain that is unusual for the patient.
●● Severe abdominal pain.
●● Extremity weakness or loss of function.
●● Any neurological symptoms.
●● Severe headache.
●● Acute joint swelling.
Pain management
Following are the recommendations for
the management of vaso‐occlusive events.
However, many children and adolescents
need individualized care plans for their
routine treatment, especially those with
the development of chronic pain syn­
dromes. In addition to specific treatment
for the acute pain event, treatment with
hydroxyurea as a preventive intervention
should be considered in all patients with
sickle cell disease (see section on
hydroxyurea).
Outpatient
Mild pain
●● Increase fluids to 1–1.25× maintenance.
Water, fruit juice, and fruit drinks as well as
decaffeinated soda are recommended.
●● Acetaminophen without codeine (15 mg/kg
q4–6 hours) orally can be tried prior to
using acetaminophen with codeine (1 mg
codeine/kg q4–6 hours) depending on what
medications are currently being used by the
patient for pain. For many children,
acetaminophen alone is not sufficient for
vaso‐occlusive pain. Patients who utilize
hydrocodone or oxycodone with or without
acetaminophen should continue with this
regimen even if the pain is not severe.
Codeine is generally not recommended
though may be the only choice when the
patient cannot present for a prescription of a
controlled substance.
●● Ibuprofen (10 mg/kg q6–8 hours) orally
should be used routinely, every 8 hours,
even if pain is temporarily controlled.
Ketorolac IV (or IM) can be given if the
patient is seen as an outpatient.
●● Rest and heat to the area of pain.
●● Relaxation and biofeedback exercises, such
as positive visualization and meditation.
Severe pain
●● IV hydration: bolus to correct fluid losses,
then IV with D5W 1/2 NS (dextrose 5%
water, 0.45% normal saline) at 1 to 1.25×
maintenance (IV + PO). Use caution not to
overhydrate, especially if there are any
pulmonary symptoms (overhydration can

lead to pulmonary edema and precipitate
ACS). Note that if the patient does not
appear volume‐depleted, an IV fluid bolus is
not routinely required.
●● Analgesics (IN, intranasal): Due to the
rapid onset of action, a single dose of IN
fentanyl, 1–2 μg/kg, has been shown
beneficial while IV access is being obtained.
Given the very short duration of effect, IV
therapy should be utilized as soon as IV
access is available.
●● Analgesics (IV): Morphine: 0.1–0.15
mg/kg/dose q3–4 hours. In children <2
years who have not been exposed to narcotic
analgesics, 0.05–0.1 mg/kg should be used.
The pharmacokinetics of morphine differs
between individual children and doses must
be titrated for individual patients. Both
underdosing and overdosing need to be
avoided. Careful management is required!
Previous medication history is often a good
starting place. For patients with a previous
intolerance to morphine secondary to
nausea or pruritus, IV dilaudid
(hydromorphone) should be utilized while
calculating the dose based on morphine
equivalents. Dilaudid is approximately
8× stronger than morphine, so a dose of
0.01–0.02 mg/kg should be utilized.
●● Ketorolac: (child) IV: 1 mg/kg/load, then
0.5 mg/kg q6 hours (max 30 mg); (adult) IV:
30–60 mg/load, then 15–30 mg/kg q6 hours.
Gastrointestinal (GI) bleeding has been
reported, and an H2 blocker such as famo­
tidine is required if ketorolac is given IV.
Morphine and ketorolac can be given simul­
taneously or in succession for the initial treat­
ment of pain in children. Added to narcotic
therapy, ketorolac increases analgesia and has
a narcotic sparing effect. Ketorolac is very
useful in pain control, but should not be used
for more than 5 days.
●● Adjuvant medications (IV): We and other
centers have begun utilizing ketamine, an
N‐methyl‐d‐aspartic acid (NMDA) receptor
antagonist, as an adjuvant medication for
Sickle Cell Disease 33
the management of acute on chronic pain at
a dose of 0.2 mg/kg. For patients with
frequent utilization of opioids (i.e., oral
hydrocodone or oxycodone), upregulation
of the NMDA receptor decreases opioid
efficacy. Utilization of ketamine as a NMDA
receptor antagonist allows greater opioid
efficacy in addition to being synergistic due
to benefits in pain, anxiety, and depression.
Side effects of single low‐dose ketamine
include dysphoria and disassociation which
generally are mild and can be managed by
benzodiazepines, if necessary.
Upon presentation to the clinic or
emergency room, the child or adolescent
should be rapidly assessed and treated for
pain. Initially, both morphine and ketorolac
should be given at the maximum
recommended doses. If the pain worsens
again, repeat the parenteral narcotic dose; it
is unlikely that oral analgesics will be
successful if this regimen is not effective. If
pain relief can be achieved and maintained
for 3 hours, administer an oral narcotic and
observe for 1 hour. If this regimen is
successful, give a prescription of narcotic
and nonsteroidal anti‐inflammatory medi­
cations for several days (10–15 doses). There
should be follow‐up within 72 hours. If this
regimen is not successful, if other symptoms
develop with hydration, or a fever develops,
the patient should be admitted, treated, and
observed for possible evolution to ACS or
other life‐threatening infection.
Inpatient
As noted in the preceding text, the administra­
tion of narcotics to acutely ill patients requires
careful monitoring. A plan for pain manage­
ment should be defined on admission and
followed for the duration of hospitalization.
A recent statement by the Joint Commission
regarding pain management notes the
importance of both pharmacologic as well
34 Chapter 3
as non‐pharmacologic strategies. Routine
inpatient care is outlined in the following text.
General management
●● Correct acute losses due to dehydration.
Do not overhydrate children who have
pulmonary symptoms.
●● Total fluid intake (IV + PO) should be
1–1.25× daily maintenance fluids; do not
overhydrate.
●● Monitor daily weight, record strict intake
and output (I&O), and observe for signs of
fluid overload.
●● Encourage ambulation, sitting up in bed,
and taking deep breaths.
●● Incentive spirometry (IS), 10 times an
hour, every hour while awake.
Analgesics
●● Pain medication should be administered
on a fixed‐time schedule, with an interval
that does not extend beyond the duration of
the analgesic effect. Do not give narcotics on
a PRN (as needed) basis except for when the
patient is ready for discharge.
●● Titration schedules require a written
plan, close observation, and a flow sheet
to monitor effectiveness; sedation and
hypoventilation can lead to hypoxia and
increased sickling and pain in those
receiving excess narcotics, while patients
being underdosed will have continued pain
as well as potential splinting increasing the
risk of atelectasis which can lead to ACS.
●● Patient‐controlled analgesia (PCA): This
is the method of choice for controlling pain
in children who are ≥7 years of age or older.
PCA protocols may be hospital‐specific.
Generally, there is an initial bolus (0.1 mg/kg
morphine), and an on‐demand dose (0.01–
0.05 mg/kg morphine) with a 10–20‐minute
lock out, and a 1 hour maximum of 0.1–
0.15 mg/kg of morphine. At night, there
may be a need for a continuous low‐dose
infusion (0.01–0.02 mg/kg/h morphine) in
addition to the bolus dosing. Dilaudid is an
alternative to morphine and preferred by
some patients.
●● Low‐dose continuous ketamine drips
are being used with success to manage acute
severe pain requiring hospitalization. Recom­
mended dose is 1–5 mcg/kg/min. These doses
are typically well‐tolerated, though some
patients may experience disassociation at
higher doses which can be mitigated with
benzodiazepines. Ketamine may be initiated
at the outset to potentiate opioid efficacy
and can be continued safely for 7–10 days
of hospitalization and discontinued without
a taper.
●● Objective measurement of response to
analgesic therapy through utilization of
tools such as the APPT is vital to ensure that
the patient is having the appropriate
response to the therapy prescribed.
Side effects of narcotics include respira­
tory depression, nausea, vomiting, pruritus,
hypotension, constipation, inappropriate
secretion of anti‐diuretic hormone, and
change in seizure threshold. Low‐dose
naloxone drip (i.e., 1 μg/kg/h) has been used
for severe pruritus and urinary retention due
to morphine. The most common side effects
of nausea, vomiting, and pruritus resolve
over time. Diphenhydramine may be used
safely in this setting and can have a synergis­
tic positive effect with morphine. We suggest
oral administration, though it can be given
IV. Meperidine should not be substituted for
morphine. Metabolites of meperidine can
accumulate and cause seizures, especially
if used over a longer period at high doses.
A plan for withdrawal should be a part of
discharge planning; ­clonidine hydrochloride
has been used s­ uccessfully in this setting, but
should be carefully monitored.
All patients who are hospitalized for pain
should have an incentive spirometer at the
bedside. Ensure that the patient has been
instructed on its usage and can demonstrate
it appropriately. IS is effective in reducing
the incidence of ACS in the setting of VOE.

Alternative methods of pain control
(behavior modification, relaxation, visuali­
zation, self‐hypnosis, local heat, and trans­
cutaneous electrical nerve stimulation) are
helpful adjuvants in the outpatient and
inpatient setting, but should not replace
standard therapy. Children should have
access to a psychologist who is experienced
in the management of sickle cell pain.
Drug addiction is extremely rare and
should not be a primary concern. The goal
should be to provide patients with adequate
relief by understanding the pharmacology
of the medications, drug tolerance, and
physical dependence. Drug tolerance is
common, and withdrawal symptoms after
hospitalization are probably underreported
by patients. All patients should start a narcotic
taper while in the hospital and complete
this as an outpatient. On average, patients
admitted for the management of VOE
require 3–7 days of inpatient care.
Complementary therapies
●● Patient with acute pain and rare hospitali­
zation may be successfully managed with
analgesics alone.
●● More complicated patients with longer
or more frequent admission would bene­
fit from the addition of complementary
therapies to help manage pain with the
recognition that opioid therapy alone is
not sufficient to manage chronic pain syn­
dromes which can lead to hyperalgesia
and allodynia and have strong psychosocial
elements. Recognition that a multimodal,
interdisciplinary team approach is required
is vital.
●● Potential avenues for complementary
therapy for patients with vaso‐occlusive
pain include acupuncture, massage therapy,
cognitive behavioral therapy, biofeedback/
relaxation therapy, warm packs or whirlpool
therapy, and distraction therapies
Sickle Cell Disease 35
Acute chest syndrome/
pneumonia
ACS is defined as the development of a new
pulmonary infiltrate in the presence of fever
or respiratory symptoms. As chest radio­
graph changes may be delayed, the diagnosis
may not be apparent at presentation.
Approximately 50% of children with sickle
cell disease will experience ACS. ACS is
frequently caused by community‐acquired
pathogens such as chlamydia, mycoplasma,
and other bacterial or viral organisms. In
older children, adolescents, and young
adults, ACS may be more commonly associ­
ated with vaso‐occlusion, infarction, fat
embolism, or in situ sickling. These episodes
are characterized by chest pain, fever,
hypoxia, and pulmonary infiltrates.
Although ACS usually improves with medi­
cal management, it can present with or pro­
gress rapidly to respiratory failure (acute
respiratory distress syndrome), requiring
mechanical ventilation and emergent
exchange transfusion. Preventative therapy
with hydroxyurea has been shown to
decrease the incidence of ACS and should be
initiated in all patients with sickle cell ane­
mia (see section on hydroxyurea).
Sixty percent of children who have pneu­
monia on X‐ray will be missed by physical
exam alone. In addition, many children
with a negative chest film on admission
will develop findings after hydration. All
children who have symptoms of pulmonary
disease, such as fever, shortness of breath,
tachypnea, chest pain, cough, wheezing,
rales, or dullness to percussion, should have
an assessment of oxygen saturation, a chest
radiograph, receive parenteral antibiotics,
and be admitted to the hospital (see
Figure 3.2). Bronchodilators and IS are
helpful adjuncts in treatment and preven­
tion of worsening ACS. If there is an infil­
trate, the patient should be closely observed
36 Chapter 3

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 echocardiography

Figure 3.2 Sickle cell disease with acute pulmonary infiltrate (abbreviations: CBC, complete blood
count; ABG, arterial blood gas; ACS, acute chest syndrome).

for hypoxia and progression of pulmonary
infiltrates, with repeat chest radiographs.
Overhydration can lead to pulmonary edema
and exacerbate ACS. Oversedation with
narcotics can also lead to hypoventilation,
increasing the risk for ACS. Narcotics should
be used with caution in this setting.
ACS can develop in a matter of hours and
is associated with a high rate of morbidity
and mortality. Children should have oxygen
saturation monitored and, if indicated, arte­
rial blood gases. Oxygen therapy should be
used only for significant hypoxia (i.e., O2
saturation ≤ 92%). Supplemental oxygen can
decrease erythropoietin production and lead
to more severe anemia. Pulmonary infec­
tions should be treated aggressively, and
these children watched closely. If there is no

improvement, or worsening anemia, a red
blood cell transfusion (straight or exchange,
dependent upon the severity of the hypoxia,
anemia, and clinical status of the patient) may
help to correct the anemia, decrease the
percent hgb S, and improve oxygen‐carrying
capacity to aid in reversing the pulmonary
sickling and improve the clinical course.
Transfusions are more effective when admin­
istered early in the course of ACS, rather than
as a life‐saving measure in a critically ill child.
There is a distinct difference between the
etiology of ACS in children and that of adoles­
cents and adults. In children, the incidence of
ACS is seasonal, lower in the summer months
with increasing rates in the winter when viral
infections are prevalent. In adults and adoles­
cents, ACS is frequently a complication of an
episode of vaso‐occlusion (without fever) due
to pulmonary fat embolism. This event will
progress to include chest pain, fever, and a
pulmonary infiltrate (usually basilar with
pleural effusion). Adults and adolescents
more frequently need transfusions and less
frequently have a viral or bacterial infection
associated with their episode of ACS.
Individuals with hgb SC disease have rela­
tively more fat in their marrow and resultantly
can have more severe pulmonary fat emboli
when their course is complicated by ACS.
Stroke and other central nervous system
events are more common in children with
ACS in the 2‐week period after the event.
Laboratory evaluation of acute
chest syndrome
●● CBC with differential and reticulocyte
count.
●● Type and hold for possible blood trans­
fusion (phenotypically matched, sickledex
negative).
●● Chest radiograph, as often as clinically
indicated to monitor progression of disease.
●● Continuous pulse oximetry and baseline
arterial blood gas (on room air if possible).
●● Blood culture for fever.
Sickle Cell Disease 37
Management
All patients with evidence of acute pulmo­
nary pathology should be admitted to the
hospital. If fever is present or if an infectious
process is suspected, antibiotic therapy
should be started immediately. See
Section 3.2 and Figures 3.1 and 3.2.
●● Oxygen
Hypoxemic patients (PaO2 70–80 mmHg,
O2 saturation ≤ 92%): 2 l/min per nasal can­
nula. Goal should be 96% O2 saturation (not
100%).
Reevaluate arterial blood gas on oxygen.
●● Antibiotics
Initiate broad spectrum antibiotic: ceftri­
axone 50 mg/kg/d IV every 24 hours after
blood cultures obtained (maximum 2 g/dose).
Due to the frequency of atypical organ­
isms (e.g., chlamydia and mycoplasma), a
macrolide or quinolone antibiotic should be
included: azithromycin 10 mg/kg on day 1,
followed by 5 mg/kg on days 2–5 (maximum
500 mg on day 1, 250 mg on days 2–5).
●● Analgesics
As indicated for vaso‐occlusive pain
management, administration must be
monitored to provide the maximum pain
control and prevent hypoventilation or
atelectasis from splinting or narcotization.
●● Hydration
PO and IV hydration (D5W 1/2 NS) at a
maximum of 1.25× maintenance. Caution
should be used in patients with potential
ACS to avoid fluid overload. Monitor Is and
Os, daily weight.
●● Respiratory supportive measures
Continuous pulse oximetry.
IS, 10 times an hour, every hour while
awake (prevention of hypoventilation and
atelectasis).
Albuterol aerosols q4 hours (airway
hyperreactivity common in ACS).
●● Physical therapy
Warm packs.
Ambulation as tolerated, sitting up in
bed.
38 Chapter 3
●●Transfusion
Straight transfusion.
Exchange transfusion (for patients with
hematocrit > 30% or moderate‐to‐severe ACS
to more efficiently reduce hgb S%).
Transfusion decreases the proportion of
sickling red cells and increases blood oxygen
affinity. The main indication is worsening
respiratory function, as documented by
hypoxemia (PaO2 < 70 mmHg on room air),
worsening chest pain, evolving clinical
examination, or worsening infiltrates on
chest radiography. For patients with chronic
hypoxemia, a drop of >10% from baseline is
a reasonable level at which to transfuse.
Delays in instituting transfusion therapy,
particularly in rapidly deteriorating patients,
should be avoided.
Priapism
Forty percent of men who are homozygous
for hgb S report having priapism in their
adolescence and early adulthood. Priapism
has a second peak at 21–29 years. Priapism
is defined as a painful erection that lasts for
more than 30 minutes. It frequently results
in interference with the urinary stream.
Priapism can be precipitated by prolonged
intercourse or masturbation, frequently
occurs at night, and can be differentiated
from a nocturnal erection by its duration
and pain. Children will occasionally
complain of dysuria as the first complaint of
priapism. Prognosis is poorer in adolescents
and adults who have recurrent prolonged
priapism, and if aggressive treatment has
not been successful, impotence may result.
Children who have priapism generally have
a better prognosis than adolescents and
adults and usually do not have prolonged
episodes requiring aggressive therapy.
Priapism can occur with VOEs as well as
with fever and sepsis.
Priapism can last for hours, days, or
weeks with moderate‐to‐severe pain, or it
can occur as a pattern of painful erections
that recur over a period of days to several
weeks (stuttering priapism). Chronic
nonpainful priapism can also occur.
Since priapism can lead to impotence,
early medical management is indicated. A
urologist familiar with priapism in sickle cell
disease should be consulted. Treatment
includes hydration, pain management, intra­
cavernous injection of alpha‐adrenergic
agents, exchange transfusion, and shunting
surgery. Oral alpha‐adrenergics (e.g., pseu­
doephedrine hydrochloride 30 mg BID, twice
daily) have been used successfully to treat
stuttering priapism. Chronic transfusion
therapy has been used in patients with recur­
rent priapism (maintenance of hgb S below
30–40%), although no controlled trials have
been performed proving the efficacy of this
therapy.
Stroke (cerebrovascular
accident)
Stroke is a common event in children
homozygous for hgb S. Between 10 and 15%
of children with sickle cell disease suffer
from overt strokes. In children, strokes are
more frequently the result of cerebral
vascular stenosis and infarction. The mean
age of occurrence of clinically evident stroke
is 7–8 years with the highest risk occurring
between 2 and 9 years. Hemorrhage and
infarct may occur together.
Strokes in children who have sickle cell
disease involve stenosis and occlusion of
the major anterior arteries of the brain,
including the carotids. The presenting
symptoms of stroke can be dramatic and
acute, such as coma, seizure, hemiparesis,
hemianesthesia, visual field deficits, aphasia,
or cranial nerve palsies. Subtle limb weak­
ness (without pain) is often mistaken for an

acute VOE, but can be due to stroke. By defi­
nition, the symptoms must persist for at
least 24 hours to be classified as a stroke.
The presentation of severe headache and
vomiting with no other neurological find­
ings can be symptoms of an intracranial
hemorrhage.
Initially, a computed tomography (CT)
scan without contrast will be normal for up
to 6 hours after a stroke, but will rule out
intracerebral hemorrhage, abscess, tumor,
or other pathology that would explain the
neurological symptoms. Magnetic resonance
imaging (MRI) and magnetic resonance
angiography (MRA) are much more
sensitive methods to determine intracranial
infarct but can remain normal for 2–4 hours
after an event. All catastrophic neurological
events should first be evaluated with CT,
since it is generally more available and will
rule out acute pathology.
With clinical concern prior to definitive
diagnosis by MRI/MRA imaging, children
are exchange transfused to achieve a
concentration of hgb S of less than 30%.
Blood pressure should be continually
monitored during an exchange transfusion
realizing that, relative to the normal
population, children with sickle cell disease
are hypotensive. The diagnosis of stroke in
children should initially be made based on
clinical findings and treated emergently.
Children should be monitored until they are
stable and the hemoglobin electrophoresis is
documented. Those who have had a stroke
require chronic transfusion therapy for an
undetermined length of time.
Children with sickle cell disease have
more frequent and more severe headaches
than other children; these may be mani­
festations of cerebral hypoxia and vaso­
dilation. Children who have severe
headaches accompanied by vomiting need
extensive evaluation with imaging as well
as neurologic and neuropsychological
testing.
Sickle Cell Disease 39
TCD has been shown to predict increased
risk of stroke in children who have increased
flow velocity in major cerebral arteries.
Unsuspected cerebral vascular damage was
detected by CT and MRI in 25–30% of chil­
dren in the Cooperative Study of Sickle Cell
Disease. No clinical factors, with the excep­
tion of TCD, predicted the occurrence of
stroke. In this study, there was a correlation
between first stroke and transient ischemic
attack, ACS, elevated systolic blood pressure,
and severe anemia. All children who can
cooperate with TCD (usually by 2 years of
age) should have an annual evaluation if the
study is available locally. Normal middle cer­
ebral artery velocity in children with sickle
cell disease is approximately 120 cm/s.
Children who have velocities of 170–
199 cm/s are considered at high risk and
those with velocities ≥200 cm/s are at highest
risk. The Stroke Prevention Trial in Sickle
Cell Anemia (STOP) showed that transfu­
sion greatly reduces the risk of first stroke in
children who have abnormally high TCD
velocity (≥200 cm/s). Prophylactic chronic
transfusion should be strongly considered if
there are two studies at least 2 weeks apart
with velocities ≥200 cm/s. Compliance issues
and risks of chronic transfusions must also
be considered when deciding on this ther­
apy. The TCD With Transfusions Changing
to Hydroxyurea (TWiTCH) trial in high‐risk
children with sickle cell anemia and abnor­
mal TCD velocities (who have received at
least 1 year of chronic transfusion therapy
and have not MRA‐defined vasculopathy)
demonstrated that treatment with hydroxyu­
rea can be substituted for chronic transfu­
sions to maintain normal TCD velocities and
prevent primary stroke.
Transient ischemic attacks are defined as
focal neurological deficits with a vascular
distribution persisting for less than 24 hours,
although they typically last less than an
hour. Patients with transient ischemic
attacks are treated in a similar manner to
40 Chapter 3
those who have an infarct. The diagnosis is
made in retrospect when the follow‐up MRI
is negative for a persistent lesion that would
explain the neurological symptoms.
Silent cerebral infarcts are the most
common neurologic injury in children with
sickle cell anemia. In contrast to overt
strokes, children with silent infarcts do not
have apparent neurologic impairment on
examination. However, children with silent
infarcts are at increased risk from stroke,
new and enlarged silent infarcts, poor
academic achievement and lower IQ scores
compared to children with sickle cell anemia
and no evidence of silent stroke on MRI of
the brain or in siblings unaffected by sickle
cell anemia. Regular blood transfusion in
this population has significantly reduced the
incidence of recurrent cerebral infarcts.
Intracerebral hemorrhage or subarach­
noid hemorrhage may present without focal
neurologic symptoms. Exchange transfusion
should be carried out immediately.
Arteriography is used to identify the arterial
bleed and the patient may need emergent
surgical intervention. Mortality is very high
during the acute event (~50%).
Acute anemia
There are two common causes of acute life‐
threatening anemia in sickle cell disease:
splenic sequestration and aplastic crisis.
Splenic sequestration
Infants and young children who have hgb
SS and Sβ0 thalassemia and older children
(over 10 years) who have hgb SC or Sβ+
thalassemia syndromes can have intras­
plenic pooling of large amounts of blood
and platelets. This can lead to anemia,
thrombocytopenia, hypovolemia, cardio­
vascular collapse, and sudden death within
hours of the onset of sequestration. The
syndrome has been reported in infants as
young as 2 months of age. Classically, how­
ever, it occurs in children with hgb SS after
the disappearance of hgb F from approxi­
mately 6 months to 3 years of age when the
spleen becomes fibrotic due to multiple
infarctions. These crises can occur in older
children who have hgb SC or Sβ+ thalassemia
but are usually not as severe; still, fatal events
have been reported for these children. The
incidence is between 10 and 30% and the
recurrence rate is 50%. Mild events can
indicate the possibility of subsequent life‐
threatening sequestration events. Chronic
sequestration can be a sequela with chronic
anemia and thrombocytopenia.
The clinical presentation is usually rapid
in onset; the child will typically have sudden
weakness, pallor of the lips and mucous mem­
branes, breathlessness, rapid pulse, faintness,
and abdominal fullness. Evaluation of the
CBC will frequently show a precipitous drop
from the baseline hemoglobin.
The treatment for splenic sequestration is
transfusion to restore circulating blood vol­
ume, usually with phenotypically matched
blood (unless there is a life‐threatening situa­
tion). As the shock is reversed and the trans­
fused blood decreases the percentage of hgb
S, the splenomegaly regresses and much of
the blood is remobilized with a rapid rise in
the child’s hemoglobin.
Splenectomy should be strongly consid­
ered in all children who have a splenic
sequestration crisis. Transfusions can pre­
vent recurrence until surgery can be
arranged. Some children who have hgb SS
and older children who have other S hemo­
globinopathies can have massive spleno­
megaly with hypersplenism after an episode
of splenic sequestration. If hypersplenism
(with resultant anemia, neutropenia, or
thrombocytopenia) is persistent and severe,
splenectomy is indicated.
Prior to splenectomy, younger children
should have an evaluation of splenic func­
tion with a pit count and a spleen scan. In

normally eusplenic persons, fewer than 1%
of the circulating red cells are pitted; values
of 2–12% may represent decreased splenic
function. If they still have a functional
spleen, usually under 2 years of age, a partial
splenectomy can be performed. Children
should have appropriate immunizations,
including pneumococcal, haemophilus, and
meningococcal vaccinations, prior to sple­
nectomy. Penicillin prophylaxis is continued
indefinitely in all children who have been
splenectomized.
Aplastic crisis
Severe anemia can develop over several
days due to shortened red cell survival
without compensatory reticulocytosis.
­ have hgb Sβ+ thalassemia. Individuals who
Reticulocytopenia can last 7–10 days. The
primary cause of transient red cell aplasia is
parvovirus B19, though it can follow other
viral infections as well. Parvovirus B19, the
most common cause of aplasia in children
with hemoglobinopathies, can also cause
neutropenia. While many patients recover
spontaneously, the anemia can be profound.
Red cell transfusion is indicated for those
who become symptomatic from anemia or if
the hemoglobin falls 2 g/dl or more from
baseline. If the ability to follow‐up is of
concern, the child should be hospitalized for
observation. The patient should be isolated
from other patients with chronic hemolytic
anemias (sickle cell disease or thalassemia)
or red cell aplasia and should not have
pregnant caregivers (due to risk of parvo­
virus infecting the fetus and resulting in a
spontaneous abortion). If the child is mildly
anemic and asymptomatic, outpatient moni­
toring is reasonable.
Avascular necrosis
Bone pain is common in sickle cell disease.
Marrow infarcts can cause pain that can last
for weeks. Avascular necrosis (osteonecrosis)
Sickle Cell Disease 41
causes pain that can sometimes be confused
with a bone infarct. Symptoms of avascular
necrosis, such as limping, can sometimes
be confused with stroke. Limping with
weakness but without pain is stroke not
avascular necrosis.
Avascular necrosis is common in all age
groups, but is more frequently diagnosed in
the adolescent and usually involves the
humeral and femoral heads. Thorough
musculoskeletal examinations with a focus
on the hips should be performed on an
annual basis for all children with SCD. It is
more common in individuals who have hgb
Sβ0 thalassemia and hgb SS. It is also seen,
though with a lower frequency, in those who
have hgb SS are more frequently affected
than those with hgb SC.
Avascular necrosis is a result of an infarct
in the cancellous trabeculae in the head of
either the femur or the humerus. The
process of necrosis and repair can be
progressive, leading to collapse of the head
or arrest with varying degrees of disability
and sclerosis. A method of describing the
progression of avascular necrosis is provided
here:
Stage 0: no evidence of disease.
Stage 1: X‐ray normal, bone scan abnormal,
MRI abnormal.
Stage 2: X‐ray: sclerosis and cystic changes
without collapse.
Stage 3: Subchondral collapse (crescent
sign) without collapse.
Stage 4: Collapse and flattening of the femo­
ral head without acetabular involvement,
normal joint space.
Stage 5: Joint narrowing or acetabular
involvement.
Stage 6: Increased joint narrowing or acetab­
ular involvement.
Treatment for avascular necrosis of the
femur includes bed rest with crutch walking
42 Chapter 3
for 6 weeks, nonsteroidal anti‐inflammatory
drugs (NSAIDs), and core decompression
surgery for stages 1 or 2. Extensive physical
therapy has been found to be beneficial but
is often difficult to perform. Decompression
surgery is relatively simple; a core is removed
from the head of the femur. The coring
begins approximately 2 cm below the
trochanteric ridge extending through the
neck and into the head of the femur. Acutely,
this procedure provides relief of pain and is
thought to arrest the progression of
avascular necrosis if done in the early stages;
however, this has not been confirmed in a
prospective trial. Higher‐stage avascular
necrosis requires joint replacement.
Retinopathy/hyphema
The eye is particularly sensitive to hypoxia.
Vaso‐occlusion of retinal vessels and hypoxia
of the retina cause permanent retinal dam­
age. Blood in the anterior chamber of the
eye (hyphema) becomes rapidly deoxygen­
ated and permanently sickled, obstructing
the outflow from the aqueous humor. The
accumulation of aqueous humor in the ante­
rior chamber increases intraocular pressure
leading to decreased blood flow to the retina
until the perfusion pressure of the globe is
reached. This leads to sudden vascular stasis
and blindness. The events occurring in
hyphema can also occur in children who
have sickle cell trait.
Retinal vascular occlusion initially occurs
in peripheral retinal vessels without signifi­
cant sequelae. It eventually leads to neovas­
cularization from the retina into the vitreous
(sea fans). These abnormal vessels are fragile
and can bleed into the vitreous causing
“floaters” or blindness if the hemorrhage is
sufficient. If bleeds do not obscure vision
and are unnoticed, they can cause collapse
of the vitreous, traction on the retina, and
eventually cause retinal detachment. Retinal
disease of the eye is common in sickle cell
disease. It occurs most commonly in indi­
viduals who have hgb SC.
Treatment of sickle cell retinopathy
requires recognition. The damaged peripheral
vessels are not generally appreciated by direct
ophthalmic examination and require the use
of indirect binocular stereoscopic ophthal­
moscopy. Sea fanning, vitreous hemorrhage,
and retinal detachment can be observed by
direct ophthalmoscopy. Annual ophthalmic
evaluations should begin at age 10 for all chil­
dren with sickle cell disease. Treatment of
early neovascularization requires laser photo­
coagulation. Surgical approaches are required
for advanced lesions. Central retinal artery
occlusion can occur rarely in patients with
sickle cell disease.
Hyphema is a medical emergency in
sickle cell disease. It requires immediate oph­
thalmic evaluation and transfusion (exchange
or straight) to reduce sickling and improve
oxygenation. If a conservative approach is not
successful, anterior chamber paracentesis is
performed to relieve intraocular pressure and
remove the hyphema.
Hyperbilirubinemia/gallstones
Bilirubin gallstones can eventually be
detected in most patients with chronic
hemolytic anemia. In sickle cell disease,
gallstones occur in children as young as
3–4 years of age and are eventually found
in approximately 70% of patients. It may
be difficult to differentiate between gall­
bladder disease and abdominal vaso‐
occlusive crisis in patients with recurrent
abdominal pain. Cholecystectomy may be
necessary for patients with fat intolerance,
presence of gallstones, and recurrent
abdominal pain.
Hepatomegaly and liver dysfunction may
be caused by a combination of intrahepatic
trapping of sickled cells, transfusion‐acquired

infection, or transfusional hemosiderosis.
The combination of hemolysis, liver dysfunc­
tion, and renal tubular defects can result in
very high bilirubin levels. Benign cholestasis
of sickle cell disease may result in severe
asymptomatic hyperbilirubinemia without
fever, pain, leukocytosis, or hepatic failure.
Perioperative management
of sickle cell patients
Following are the guidelines for the man­
agement of sickle cell patients who have
surgical procedures or require anesthesia
for other purposes. General anesthesia
results in atelectasis and hypoxia, which is
poorly tolerated by the patient with sickle
cell disease; therefore, special precautions
must be taken perioperatively to decrease
morbidity and mortality associated with
even minor surgical procedures. Other risk
factors include the presence of chronic
organ damage in some patients, the effects
of asplenia, and the propensity for sickling
and obstruction of microvasculature with
even mild hypoxia. The guidelines suggested
in the following text are extrapolated from a
multicenter randomized trial of transfusion
(exchange vs. straight) in the perioperative
period.
Preoperative care
1. Admission to the hospital the afternoon
prior to scheduled surgery.
2. Hydration at 1.25× maintenance (IV + PO)
the evening and night prior to surgery.
3. Pulse oximetry on room air (spot checks).
4. IS at least 10 times per hour while awake.
5. Lab work: CBC with differential and
reticulocyte count, urinalysis, type and
cross, chemistry panel.
6. Transfusion: All sickle cell patients
should have a red cell phenotype study
Sickle Cell Disease 43
obtained prior to any transfusion (this
should be part of routine supportive care
and done in advance, anticipating an emer­
gent need for transfusion at some point).
Sickle cell patients should receive pheno­
typically matched blood to decrease the risk
of alloimmunization. In addition, all blood
should be sickledex negative and leukode­
pleted. The following transfusion guidelines
are recommended. See also Chapter 5.
a. Patients with hgb SS or Sβ0 disease
who are undergoing any procedure other
than myringotomy tube placement
should have a simple transfusion to
achieve a hemoglobin of 10–12 g/dl. Do
not exceed 12 g/dl due to the risk of
stasis/sludging.
b. Patients with hgb SC disease or Sβ+
who have baseline hemoglobin below
10 g/dl may need transfusions to achieve
a hemoglobin of 10–12 g/dl. However,
do not transfuse these patients prior to
consulting the hematologist. Many fac­
tors may affect this decision including a
history of significant complications of
their sickle cell disease (i.e., pneumonia,
VOEs, priapism, and aseptic necrosis).
c. Consult the hematologist if there is
confusion regarding individual patients.
7. Patients with central venous catheters or
those undergoing dental procedures should
receive antibiotic prophylaxis prior to
surgery.
Postoperative care
1. Adequate pain management to prevent
splinting and atelectasis, with care to prevent
narcosis.
2. Pulse oximetry for at least the first
12–24 hours postoperatively.
3. IS at least 10 times per hour while awake.
Be aggressive!
4. Ambulation as early as possible, taking
into account the specific surgical procedure.
44 Chapter 3
5. Lab work: CBC with reticulocyte count
daily.
6. Follow‐up in clinic approximately
1‐week post‐hospital discharge, or sooner if
there are ongoing problems.
Transfusion therapy
Red blood cell transfusion increases oxy­
gen‐carrying capacity and improves micro­
vascular perfusion by decreasing the
proportion of sickle red cells (hgb S%).
Transfusions are given to patients with
sickle cell disease to stabilize or reverse an
acute medical complication, or as part of
chronic therapy in certain situations to
prevent future complications.
Indications
Acute illnesses
Splenic sequestration
Transient red cell aplasia with severe
anemia
Hyperhemolysis (infection, ACS)
Patients should be transfused if there is
evidence of cardiovascular compromise
(heart failure, dyspnea, hypertension, or
marked fatigue). Generally, transfusion is
indicated if the hemoglobin falls below
5 g/dl or drops greater than 2 g/dl from the
steady state, or with any cardiovascular
instability related to anemia.
Sudden severe illness
ACS, hypoxia
Stroke
Sepsis
Acute multiorgan failure
These life‐threatening illnesses are often
accompanied by a falling hemoglobin.
Transfusion therapy has become standard
medical practice in the management of
these illnesses. When ACS is associated
with hypoxia and a falling hemoglobin,
transfusion is indicated. Many patients can
be treated with straight transfusion, though
in severe cases, exchange transfusion or red
cell pheresis is recommended. Studies sug­
gest early transfusion may prevent progres­
sion of acute pulmonary disease.
The efficacy of transfusion in the man­
agement of acute stroke has not been well
studied, though anecdotal reports indicate
that early exchange transfusion may limit
neuronal damage by improving local oxy­
genation and perfusion. Chronic transfusion
therapy reduces the rate of recurrence and is
indicated in all patients after a first stroke.
Perioperative transfusion
Patients with sickle cell anemia undergoing
major surgery should be prepared in
advance by transfusion to a hemoglobin of
approximately 10 g/dl and a decrease in hgb
S% to approximately 60%. While standard
practice guidelines have not been developed
for hgb SS patients undergoing minor pro­
cedures or those with hgb SC, it is generally
acceptable to not transfuse these patients,
assuming they are medically stable.
Chronic transfusion therapy
Chronic transfusions are indicated in several
conditions in which the potential medical
complications warrant the risks of alloim­
munization, infection, and transfusional
iron overload. Transfusions are given every
3–4 weeks, with a goal to maintain the hgb
S% at 30–50%. While straight transfusions
are acceptable, red cell pheresis or exchange
transfusions may be preferred to decrease the
rate of iron overload.
Indications
1. Primary stroke prevention
2. Pulmonary hypertension/chronic lung
disease
3. Frequent ACS
4. Chronic debilitating pain

Other indications for transfusions:
Transfusions are sometimes suggested
for a number of conditions in which efficacy
is unproven, but may be considered under
severe circumstances. Such circumstances
include:
Acute priapism
Pregnancy (frequent complications)
“Silent” cerebral infarcts
Leg ulcers
Hydroxyurea therapy
HU was originally utilized as an antineo­
plastic agent, but due to its effects on
increasing fetal hemoglobin (hgb F), it has
gained favor in the treatment of patients
with sickle cell disease. HU is a myelosup­
pressive agent that inhibits ribonucleotide
reductase leading to downstream cytotoxic­
ity of erythroid progenitors leading to
upregulation of fetal hemoglobin produc­
tion by an unclear mechanism. In addition,
hydroxyurea’s cytotoxic effects lead to leu­
kopenia and neutropenia, beneficial in
sickle cell disease secondary to the viscous
properties of these cells during vaso‐occlu­
sion. The Multicenter Study of Hydroxyurea
in Sickle Cell Anemia (MSH) demonstrated
HU’s effectiveness in decreasing VOEs and
ACS in addition to increasing levels of hgb F.
A meta‐analysis demonstrated reduction in
hospital days and further studies confirmed
decreased costs of care. In an extension of
the MSH trial, patients who had a cumula­
tive HU exposure of 15 years had reduced
mortality compared with patients who did
not receive HU.
Long‐term adult studies have shown no
significant complications of HU usage and,
given the impact on quality of life, addi­
tional data have continued to support its use
in pediatric patients as young as 9 months
of age. It is currently approved for use in
Sickle Cell Disease 45
patients 2 years of age and older. Current
recommendations for HU usage include the
following:
●● Frequent episodes of VOE including
dactylitis.
●● ACS.
●● Patients with abnormal TCD or history
of stroke who have received at least 1 year
of chronic transfusion and have no MRA‐
defined vasculopathies; HU can substi­
tute for chronic transfusion to maintain
TCD velocities and help prevent primary
stroke.
As experience grows with HU therapy,
practitioners are recommending HU as
prophylaxis in more patients. Some would
argue that all patients with hgb SS and Sβ0
thalassemia should be on HU therapy; this
may become the standard of care in the
future.
HU therapy dosing begins at 20 mg/
kg/d and should be titrated based on ben­
eficial increment in hgb F% and resultant
increase in hemoglobin and mean cor­
puscular volume (MCV). Potential toxici­
ties with HU therapy that should be
monitored closely include neutropenia,
leukopenia, and anemia. Elevation in ala­
nine aminotransferase (ALT) and throm­
bocytopenia can also occur, though less
commonly.
Novel agents
Glutamine
l‐glutamine is an essential amino acid
involved in many pathways throughout the
body including nitrogen transport, catabolic
signaling, and acid–base homeostasis. It is a
required element for the synthesis of other
amino acids, proteins, nucleic acids, nucleo­
tides, and hexosamines. It is a precursor for
the synthesis of glutathione (GSH), nicoti­
namide adenine dinucleotide (NAD), and
46 Chapter 3
arginine, all of which have a role in prevent­
ing erythrocyte oxidative stress and con­
tributing to maintaining vascular tone. It
was approved in 2017 by the United States
Federal Drug Administration as an oral
agent for patients with sickle cell disease
5 years and older to reduce the frequency of
vaso‐occlusive events and hospitalizations.
Work to date shows only a modest decre­
ment in VOEs in pediatric patients as com­
pared with adults. Combination therapy
with HU can be considered after optimizing
the dose of HU, and it may be of benefit to
the few individuals unable to tolerate HU.
Crizanlizumab is a monoclonal antibody
binding P‐selectin which impacts vascular
adhesion. Upregulation of P‐selectin in
endothelial cells and platelets contributes to
the cell–cell interactions involved in the
pathogenesis of vaso‐occlusion and sickle‐
cell‐related complications including pain.
Crizanlizumab has shown benefit in adult
patients in a phase II study with a low inci­
dence of adverse events. The median num­
ber of uncomplicated crises was decreased
with the addition of crizanlizumab, though
there was no impact on hospitalization days.
Voxelotor is an agent that increases
hemoglobin’s affinity for oxygen, theoreti­
cally decreasing sickle hemoglobin polym­
erization and subsequent sickling. Studies
are continuing on the potential benefit of
this intervention.
Hematopoietic stem cell
transplantation in sickle cell
disease
Hematopoietic stem cell transplantation is
curative for patients with sickle cell disease
and should be considered in young patients
with hemoglobin SS and Sβ0 thalassemia
who have a matched sibling donor.
Patients with severe manifestations of
sickle cell disease including multiple pain
episodes, recurrent ACS, stroke, and end‐
organ damage should be considered for
unrelated bone marrow or umbilical cord
blood transplantation when a matched
sibling donor is not available, ideally in the
setting of a clinical trial at a center with
expertise in the management of patients
with SCD in the peri‐transplant period.
Given the paucity of donors for the non‐
Caucasian population, studies regarding
haploidentical transplant in patients with
severe disease manifestations and without a
more suitable donor are also underway.
Due to underlying vasculopathy,
patients with SCD are at particular risk of
neurovascular events during the transplant
period which may occur secondary to the
preparative chemotherapy (i.e., busulfan)
or secondary to medications used as part
of the post‐transplant immunosuppressive
regimen (i.e., cyclosporine, tacrolimus,
sirolimus). Strict management of blood
pressure parameters must be utilized with
appropriate use of antihypertensives as
needed.
Gene therapy
Early phase trials have commenced on the
utilization of gene therapy to improve nor­
mal hemoglobin A production in order to
decrease the proportion of sickle cells, ide­
ally resulting in a relatively asymptomatic
sickle cell trait phenotype. Patients undergo
mobilization of their mononuclear cells
which are subsequently removed through a
peripheral blood apheresis or bone marrow
harvest procedure prior to processing to
alter the β‐globin. The processed cells are
subsequently reinfused in the patient after a
myeloablative preparative regimen. Gene
therapy offers the benefit of a non‐allogeneic
transplant with an improved safety profile
and mitigates the need to find a suitable
donor. Further study is required to deter­

mine the safety, viability, and longevity of
these genetically altered cells.
Case studies for review
1. You are a primary care physician taking
care of a 2-year-old with known sickle cell
disease (hgb SS). You are counseling the
family on particular risks for the patient at
this age.
a. What are some of the main areas of
discussion?
In evaluating the patient as a whole, one must
first discuss growth and development and the
risks of low hemoglobin on brain develop­
ment. Assuming the patient has had previous
laboratory studies, past hemoglobin values
can help objectively guide this discussion, as
phenotypic disease is related to level of ane­
mia and concomitant reticulocytosis, amount
of leukocytosis, as well as evidence of
hemolysis (total bilirubin and LDH levels).
In this discussion, newer treatment modali­
ties including hydroxyurea therapy and the
potential for hematopoietic stem cell trans­
plantation should be discussed.
Fortunately, this child has had a relatively
benign course to date.
b. What are some of the potential acute
risks that should again be discussed with
the family?
The major risks to the child include severe
infection, pain including dactylitis, and
splenic sequestration. These risks should all
be discussed in detail with the family.
In terms of severe infection, the family
should be aware that they should monitor
the child closely if the child appears ill and
check the temperature before administering
antipyretics, even if given for pain alone. In
addition, they should be aware that if the
child appears ill, they should immediately
call the on-call physician and will likely
require immediate evaluation including
blood work, chest radiography, parenteral
Sickle Cell Disease 47
antibiotics, and hospital admission and
observation. You should again reinforce
the need for the child to be on penicillin
prophylaxis. Finally, one should review the
child’s vaccinations to ensure they are up to
date, especially for encapsulated bacteria
including S. pneumoniae, H. influenzae, and
N. meningitidis.
Regarding episodes of pain, although it is
reassuring the child has had a relatively
unremarkable course to date, VOE can start
at any age. At 2 years of age, the child is still
at risk for developing episodes of dactylitis.
The family should be advised on the signs
and symptoms to monitor for pain in a
young child which may present as irritability,
refusal to walk, decreased appetite, as well as
localized swelling and/or tenderness. A pain
plan should be established with the family
which should include the availability of oral
medications at home (e.g., acetaminophen,
ibuprofen, Tylenol with codeine, and/or
Lortab elixir), as well as adjuvant strategies
such as warm bath and heating pads.
Finally, the practitioner should discuss
other potential acute complications such as
splenic sequestration. If the child has a palpa­
ble spleen, the family should be advised on
the current size and to monitor for changes in
size if the patient appears to be pale or weak
as a sign of splenic sequestration. In addition,
if the child does appear to have these symp­
toms without a change in the size of the
spleen or does not have a palpable spleen, the
family should be advised that these symptoms
should still lead to prompt evaluation, as they
could be signs of an aplastic crisis.
2. You are seeing parents for a prenatal
evaluation prior to the birth of their first
child. The mother of the child has sickle cell
disease with β0 thalassemia (hgb Sβ0) and
the father has sickle cell trait (hgb AS). The
mother has been receiving blood transfu­
sion during the pregnancy and it has other­
wise gone asymptomatically.
48 Chapter 3
a. What are the important genetic
implications in this case?
Given the known genotypes of the parents,
you should advise that they have a 25%
chance of having a child with hgb SS, a 25%
chance of hgb Sβ0, a 25% chance of sickle
cell trait, and a 25% chance of β-thalassemia
trait, dependent on which combination of
β-globins is passed on to the child in a
Mendelian pattern. You can advise them the
hgb SS and hgb Sβ0 phenotypes should likely
be similar to the mother’s level of disease
due to lack of hgb A production in both cases,
knowing there is some level of individual
phenotypic variability. You can advise that
the child with sickle cell trait should be gen­
erally asymptomatic, though it is still advisa­
ble to monitor fluid intake with high levels of
strenuous activity and at altitude; in the rare
patient, these scenarios may precipitate
symptoms of vaso-occlusion. The child with
β-thalassemia trait will also be asymptomatic
with a mild microcytic anemia that should
not be mistaken for iron deficiency anemia
given the low MCV in both conditions.
b. How will newborn screening be
useful?
Screening for hemoglobinopathies in the
United States is now standard of care with
hemoglobin electrophoresis, especially due
to the utility of diagnosing SCD and
β-thalassemia major at birth. In the normal
newborn, fetal hemoglobin (hgb F) will pre­
dominate with less hgb A production (i.e.,
normal newborn screen FA; written with
highest percentage hgb first). For the patient
with sickle cell trait, the normal β-globin
will produce more hgb A than the β-globin
with the mutation leading to the production
of hgb S (i.e., newborn screen FAS). For the
patient with hgb SS or Sβ0, neither β-globin
will produce hgb A (i.e., newborn screen
FS). And, for the patient with β-thalassemia
trait, due to the hgb F production at birth,
the newborn screen will be normal, as
the one normal β-globin will produce hgb
A (i.e., FA). Note that in conditions car­
rying a β-thalassemia mutation beyond
β-thalassemia major (which will present
with newborn screen of F only), hgb electro­
phoresis done after 6 months of age when
fetal hgb production has abated is necessary
for diagnosis, showing increased production
of hgb F and hgb A2 (see Chapter 4 for more
information).
Multiple choice questions
1. You are seeing a 2-year-old female in the
ED with Hgb SS disease. She has been gener­
ally well up to this point with only one pre­
vious admission for dactylitis at 9 months of
age. The parents note that she has been pale
appearing over the last 24 hours with
increased fatigue and decreased appetite.
She has been afebrile with no URI symp­
toms or rash. The most important consid­
eration to first rule out is:
a. Vaso‐occlusive episode
b. Acute chest syndrome
c. Splenic sequestration
d. Encapsulated bacteremia
e. Aplastic crisis from parvo virus
Explanation: Although all of the above condi­
tions are possible diagnoses, the most imme­
diate life‐threatening complication in a young
child is splenic sequestration which can lead
to rapid, uncompensated severe anemia.
Exam should reveal a spleen that is much
larger than the baseline examination. Type &
screen and rapid administration of PRBC
transfusion should occur to improve anemia
and ease the splenic sequestration. As the
child is without fever or pain and has no ante­
cedent history of viral symptoms, choice a.,
b., d. and e. are all less likely. The answer is c.
2. A 12-year-old female with Hgb SS is admit­
ted to the hospital for a vaso‐occlusive crisis.
She was admitted with the complaint of ster­
nal, back and leg pain which is the usual loca­

tion for her vaso‐occlusive events. She was
initially afebrile without respiratory symptoms
but overnight while inpatient she has devel­
oped fever with tachypnea, tachycardia and
hypoxia. Chest X‐ray reveals a white out of her
R lung. The most important next step is:
a. Straight transfusion of PRBCs
b. Exchange transfusion of PRBCs
c. Initiation of antibiotics
d. Initiation of oxygen therapy
e. Incentive spirometry
Explanation: Although all of the above are
important management steps, a reduction in
the hemoglobin S% is the most important step
to prevent significant morbidity and mortal­
ity. Although exchange transfusion is ideal to
reduce the hb S%, as it is overnight, it will take
time to arrange this procedure and in the
interim it is best to begin straight transfusion.
Initiation of antibiotics and symptomatic
oxygen therapy are also important supportive
care measures that should occur in conjunc­
tion with transfusion. The answer is a.
Sickle Cell Disease 49
Suggested reading
Chou, S.T. (2013). Transfusion therapy for sickle
cell disease; a balancing act. Hematology Am.
Soc. Hematol. Educ. Program 1: 439–446.
Kassim, A.A., Galdanci, N.A., Pruthi, S., and
DeBaun, M.R. (2015). How I treat and man­
age strokes in sickle cell disease. Blood 125:
3401–3410.
Piel, R.B., Steinberg, M.H., and Rees, D.C. (2017).
Sickle cell disease. N. Engl. J. Med. 376:
1561–1573.
Rees, D.C., Olujohungbe, A.D., Parker, N.E. et al.
(2003). Guidelines for the management of the
acute painful crisis in sickle cell disease. Br. J.
Haematol. 120: 744–752.
Vichinsky, E.P., Neumayr, L.D., Earles, A.N. et al.
(2000). Causes and outcomes of the acute
chest syndrome in sickle cell disease. National
Acute Chest Syndrome Group. N. Engl. J. Med.
342: 1855–1865.
Ware, R.E. (2015). Optimizing hydroxyurea ther­
apy for sickle cell anemia. Hematology Am.
Soc. Hematol. Educ. Program 1: 436–443.
4 Thalassemia

The thalassemias are a diverse group of An excess of alpha‐globin chains (beta‐

genetic diseases characterized by absent or
decreased production of normal hemo­
globin, resulting in a microcytic anemia.
The alpha‐thalassemias are concentrated in
Southeast Asia, Malaysia, and southern
China. The beta‐thalassemias are seen pri­
marily in the Mediterranean, Africa, and in
Southeast Asia. Due to global migration pat­
terns, there is an increase in the incidence of
thalassemia in North America, primarily
because of immigration from Southeast
Asia. Like with sickle cell anemia, develop­
ment of thalassemia is directly related to
evolutionary pressure secondary to malaria.
Normally, ≥95% of adult hemoglobin
found on electrophoresis is hgb A (α2β2).
Two minor hemoglobins occur: 2–3.5% is
hgb A2 (α2δ2) and ≤2% is hgb F (α2γ2). A
mutation affecting globin chain production
or deletion of one of the globin chains leads
to a decreased production of that chain and
an abnormal globin ratio. The globin that is
produced in normal amounts is in excess
and forms aggregates or inclusions within
the red cells. These aggregates become
oxidized and damage the cell membrane
­ obtained to determine the specific mutation.
leading to ineffective erythropoiesis, hemol­
ysis, or both. The quantity and properties
of these globin chain aggregates determine
the phenotypic characteristics of the
thalassemia.
thalassemia) leads to the formation of
alpha‐globin tetramers that accumulate in
the erythroblast. These aggregates are very
insoluble, and precipitation of these aggre­
gates interferes with erythropoiesis, cell
maturation, and cell membrane function
leading to ineffective erythropoiesis and
anemia.
An excess of beta‐globin chains (alpha‐
thalassemia) leads to tetramers of beta‐glo­
bin, hgb H. These tetramers are more stable
and soluble, but as the red cell ages in the
circulation and, under conditions of oxidant
stress, hgb H precipitates and interferes with
cell membrane function leading to an
increase in hemolysis.
Alpha‐thalassemia
The alpha‐thalassemias are caused by a
decrease in the production of alpha‐globin
due to a deletion or mutation of one or more
of the four alpha‐globin genes located on
chromosome 16. Alpha‐gene mapping can be
The alpha‐thalassemias are categorized as:
silent carrier, alpha‐thalassemia trait, hemo­
globin H disease, hemoglobin H‐constant
spring, and alpha‐thalassemia major. Fre­
quently, the diagnosis of alpha‐thalassemia

Handbook of Pediatric Hematology and Oncology – Children’s Hospital & Research Center Oakland,
Third Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
52 Chapter 4
trait in a parent is discovered after the birth
of an affected child.
Silent carrier status is characterized by
three functional genes for α‐globin: (−α/αα).
There is overlap between the red blood cell
indices of these individuals and normals,
although the mean corpuscular volume
(MCV) may be slightly lower. This state is
deduced when a “normal” individual has a
child with hgb H disease or with microcytic
anemia consistent with alpha‐thalassemia
trait. An unusual case of the silent carrier
state is the individual who carries the hemo­
globin constant spring mutation (αcsα/αα).
This is an elongated α‐globin due to a termi­
nation codon mutation. Individuals who
have this mutation have normal red blood
cell indices but can have children who have
hgb H‐constant spring if the other parent has
alpha‐thalassemia trait (αα/−). Generally,
these children are more affected clinically
than children who have hgb H.
Individuals who have alpha‐thalassemia
trait (−α/−α) or (αα/−) are identified by
microcytosis, erythrocytosis, hypochromia,
and mild anemia. The diagnosis is made by
genetic studies, ruling out both iron‐defi­
ciency anemia and beta‐thalassemia trait. In
the neonatal period, when hemoglobin
Bart’s (γ4) is present (~5% on newborn
screen), the diagnosis can be suspected
(though Bart’s at this quantity is not notated
on most newborn screens). In children,
there are no markers such as elevated hgb
A2 and hgb F (as seen in beta‐thalassemia
trait) to make the diagnosis. The diagnosis is
one of exclusion and is often mistaken for
iron‐deficiency anemia secondary to the
microcytosis. Clues for the diagnosis include
a normal red cell distribution width (RDW)
and an increase in red blood cells for the
level of hemoglobin. During pregnancy,
microcytic anemia due to thalassemia can be
mistaken for ­anemia of pregnancy (physi­
ologic or iron ­deficiency), and may be a
clue to a family history of alpha‐thalassemia
trait. Mutations in trans (αα/−) are most
likely in Southeast Asians, therefore these
populations have an increased chance of
having progeny with hemoglobin H or
alpha‐thalassemia major.
Hemoglobin H (−/−α) should be consid­
ered in the case of a neonate in whom all of
the red blood cells are very hypochromic.
Neonates who have hgb H will also have a
high percentage of hgb Bart’s on their new­
born screen (~20%). In children, this hemo­
globinopathy is characterized by moderate
anemia with a hemoglobin in the 8–10 g/dl
range, hypochromia, microcytosis, red cell
fragmentation, and a fast migrating hemo­
globin (hgb H) on electrophoresis.
Hemoglobin H does not function as a
normal hemoglobin, and has a high oxygen
affinity, so the measured hemoglobin in
these children is misleading. Individuals
who have hgb H generally have a persistent
stable state of anemia that may be accentu­
ated by increased hemolysis during viral
infections and by exposure to oxidant medi­
cations such as sulfa drugs, chemicals such
as benzene, and foods such as fava beans,
similar to individuals who have G6PD defi­
ciency. As the red cells mature, they lose
their ability to withstand oxidant stress and
hgb H precipitates, leading to hemolysis.
These precipitates in the RBC can be seen
by using a brilliant Cresyl blue (BCB) stain.
Therapy for individuals who have hgb H
disease includes folate, avoidance of oxi­
dant drugs and foods, genetic counseling,
education, and frequent medical care.
Uncommon occurrences in a child with
hgb H would be severe anemia, cholelith­
iasis, skin ulceration, and splenomegaly
requiring splenectomy. Unlike i­ndividuals
who have beta‐thalassemia, hemosiderosis
is rare in hgb H disease.
Children with hemoglobin H‐constant
spring (−/αcsα or αcs−/α–) have a more
severe course than children who have hgb
H. They have a more severe anemia, with a

steady‐state hemoglobin ranging between 7
and 8 g/dl. They more frequently have sple­
nomegaly and severe anemia with febrile ill­
nesses and viral infections, often requiring
transfusion. If anemia is chronically severe
and the child has splenomegaly, a splenec­
tomy may be performed. However, a known
complication of splenectomy in this popula­
tion is severe post‐splenectomy thrombocy­
tosis with hypercoagulability leading to
thrombosis of the splenic vein or hepatic
veins. This complication has also been
reported as recurrent pulmonary emboli
and clotting diathesis. Children who are
scheduled to have a splenectomy are treated
with low‐molecular‐weight heparin, fol­
lowed by low‐dose aspirin, continued
indefinitely.
The most severe form of alpha‐thalas­
semia is alpha‐thalassemia major (−/−).
This diagnosis is frequently made in the last
months of pregnancy when fetal ultrasound
indicates a hydropic fetus. Families who
have genetic counseling and appropriate
testing may have much earlier diagnosis in
the first trimester. The mother frequently
exhibits toxemia and can develop severe
postpartum hemorrhage. These infants are
usually stillborn. There can be other con­
genital anomalies, though none are pathog­
nomonic for alpha‐thalassemia major.
Because of in utero hypoxia, the hemoglob­
ins found in these infants are hgb Portland
(ζ2γ2), hgb H (β4), and hgb Bart’s (γ4), and no
hgb A, A2, or F. These babies often have
other complications associated with hydrops
such as heart failure, anasarca, and pulmo­
nary edema.
If the diagnosis is made early, intrauter­
ine transfusions can be performed. There
are reports of survival with chronic transfu­
sion in these infants, now more recently
replaced by curative hematopoietic stem cell
transplantation. Undoubtedly, more of these
infants could be saved if the diagnosis was
anticipated by prenatal diagnosis and treat­
Thalassemia 53
ment provided. Studies are underway
regarding early diagnosis and utilization of
in utero transplantation.
Beta‐thalassemia
Beta‐thalassemia is caused by mutations in
the beta‐globin gene. Although there have
been hundreds of mutations identified
within the beta‐globin gene locus, about 20
different alleles make up about 80% of the
mutations found worldwide. Within each
geographic population, there are unique
mutations. Individuals with beta‐thalas­
semia major are usually homozygous for
one of the common mutations (as well as
having one of the geographically unique
mutations) that lead to the absence or decre­
ment of beta‐chain production.
The beta‐thalassemia syndromes are
much more diverse than the alpha‐thalas­
semia syndromes due to the diversity of the
mutations that produce the defects in the
beta‐globin gene. Unlike the deletions that
constitute most of the alpha‐thalassemia
syndromes, beta‐thalassemias are caused by
mutations on chromosome 11 that affect all
aspects of beta‐globin production: tran­
scription, translation, and the stability of the
beta‐globin product. Most hematologists
feel there are three general categories of
beta‐thalassemia: beta‐thalassemia trait,
beta‐thalassemia intermedia, and beta‐
thalassemia major. However, with the lack of
genotypic differentiation, there remains
phenotypic overlap between these three
general categories.
Splice site mutations also occur and are
of clinical consequence when combined
with a thalassemia mutation. Three splice
site mutations occur in exon 1 of the beta‐
globin gene. These mutations result in three
different abnormal hemoglobins: Malay, E,
and Knossos. Hemoglobin E is a very
common abnormal hemoglobin in the
­
54 Chapter 4
Southeast Asian population, and when
paired with a β0‐thalassemia mutation
can produce severe transfusion‐dependent
thalassemia. Hemoglobin E is described in
the section on newborn screening.
Individuals who have beta‐thalassemia
trait have microcytosis and hypochromia;
there may be target cells and elliptocytes
seen on a peripheral blood smear, though
some individuals have normal morphology.
These hematologic features can be accentu­
ated in women with trait who are pregnant
and individuals who are folate or iron defi­
cient. If iron deficiency is concurrent with
beta‐thalassemia trait, there may be a rela­
tively normal hgb A2, potentially con­
founding the diagnosis. Free erythrocyte
protoporphyrin (FEP) is elevated in iron
deficiency and lead poisoning, while normal
in α‐ and β‐thalassemia, making it a poten­
tially helpful test in this situation. Iron
deficiency causes decreased hemoglobin
­ toxicity.
production, and folate or vitamin B12 defi­
ciency can lead to megaloblastic anemia
with increased hgb A2. Both of these defi­
ciencies need to be treated prior to evalua­
tion for thalassemia trait. In iron‐, B12‐, and
folate‐replete individuals, the hgb A2 can
be as high as 3.5–8% and the hgb F as high
as 2–5%. Generally, beta‐thalassemia trait is
milder in African‐Americans (who fre­
quently have a promoter gene mutation),
but has a similar presentation in individuals
of Chinese, Southeast Asian, Greek, Italian,
and Middle Eastern heritage.
Infants born in most states in the United
States are screened for hemoglobinopathies
(all states are required to perform screening
for sickle cell disease). In states without
newborn screening for hemoglobinopathies
and in recent immigrants to this country,
affected children are frequently found later
than the newborn period, and the evalua­
tion of their microcytic anemia includes
­differentiation between iron deficiency and
beta‐thalassemia trait. The red blood cell
indices can be helpful in this differentiation,
as the hemoglobin concentration and the
red cell count will generally be lower in iron
deficiency. The distinguishing finding in
beta‐thalassemia is a hemoglobin electro­
phoresis with an elevated hgb A2 and F. Both
will be increased in beta‐thalassemia trait
without iron deficiency, and will be normal
or decreased in alpha‐thalassemia and iso­
lated iron‐deficiency anemia. There are sev­
eral formulas to help in office screening, but
they are based on the assumption that the
child is not iron deficient. Usually, iron defi­
ciency can be ruled out using FEP, transfer­
rin saturation, or ferritin as a screening test
in children who have a hypochromic micro­
cytic anemia. The least expensive test is a
trial of iron and a repeat hemogram after a
month. A lead level should be obtained if
there is an index of suspicion for lead
Diagnostic problems may still arise if
both alpha‐thalassemia and beta‐thalas­
semia coexist, since the changes in hgb A2
and F will not be apparent as noted in the
preceding text. Family studies and DNA
analysis can be used to make a definitive
diagnosis.
Children who are diagnosed with thalas­
semia intermedia have a homozygous or
heterozygous beta‐globin mutation that
causes a greater decrease in beta‐chain pro­
duction than seen in thalassemia minor, but
not to the degree for which chronic transfu­
sion therapy is required. The phenotype can
also occur in children who have a mutation
that increases production of α‐globin
(alpha‐triplication) leading to increased dis­
symmetry between alpha‐ and beta‐globin
chains. Children who have thalassemia
intermedia are able to maintain a hemo­
globin of 7 g/dl or slightly higher with a
greatly expanded erythron and may mani­
fest bony deformities, pathological fractures,

and growth retardation. Children who
have thalassemia intermedia can also have
delayed pubescence, exercise intolerance,
leg ulcers, inflammatory arthritis, and
extramedullary hematopoiesis causing spi­
nal cord compression—a medical emer­
gency requiring radiation therapy and
transfusion. They can also have iron over­
load due to increased absorption of iron
from the gastrointestinal tract and intermit­
tent transfusion. They are at risk for the
cardiac and endocrine complications of
­ prevalent today in countries without the
hemosiderosis, but usually at an older age
than chronically transfused children.
Chelation therapy is indicated for increasing
ferritin and elevated liver iron.
Children who cannot maintain a hemo­
globin between 6 and 7 g/dl should have an
alternative diagnosis considered. If thalas­
semia is the cause of the anemia, transfusion
and/or splenectomy should be considered.
Frequently, adolescents and adults are una­
ble to tolerate the degree of anemia that
is seen in thalassemia intermedia. Poor
growth, hypersplenism, splenic pain, con­
gestive heart failure, severe exercise intoler­
ance, thrombocytopenia, and leukopenia
should be considered indications for trans­
fusion and/or splenectomy.
Appropriate clinical management of
thalassemia intermedia patients may be
more difficult than patients with thalas­
semia major requiring chronic transfusion
due to phenotypic heterogeneity. Patients
with clinically mild disease still may have
serious long‐term complications as
described in the earlier text due to ineffec­
tive erythropoiesis as well as chronic hemol­
ysis, leading to pulmonary hypertension
with resultant congestive heart failure and
thrombosis in addition to cholelithiasis.
Currently, transfusion therapy is limited to
patients with symptomatic anemia or in
children with delayed growth and deve­
lopment, and is generally tailored to the
Thalassemia 55
individual patient. Splenectomy has been
utilized but now is thought to be at least
partly responsible for the development of
pulmonary hypertension and thrombosis
secondary to chronic hemolysis. Some argue
that transfusion therapy is underutilized in
thalassemia intermedia and improved risk
stratification is needed.
Thalassemia major was first described by
a Detroit pediatrician, Thomas Cooley, in
1925. The clinical picture he described is
necessary resources to provide patients
with chronic transfusions and iron chelation
therapy. Children who have untreated
thalassemia major have ineffective erythro­
poiesis, decreased red cell deformability,
and enhanced clearance of defective red
cells by macrophages. The result is a very
hypermetabolic bone marrow with throm­
bocytosis, leukocytosis, and microcytic ane­
mia in young children prior to enlargement
of the spleen. At presentation, they have
almost 100% hgb F (these cells have a longer
life span due to a balanced globin ratio as γ,
rather than β, globin is present in hgb F).
These children have little or no hgb A2 and
a low reticulocyte count. The diagnosis can
be made with certainty by demonstrating
thalassemia trait in both parents, by globin
biosynthetic ratios, or by beta‐gene screen­
ing. Beta‐gene screening identifies the most
common and some uncommon mutations,
but not all mutations. An electrophoresis
showing only hgb F, a complete blood count,
and a peripheral blood smear will generally
be diagnostic. In most states, these children
will be discovered by newborn screening or
occasionally by the obstetrician who makes
a diagnosis of thalassemia trait in the mother
and obtains a family history of thalassemia
or anemia in both parents prior to the birth
of the baby.
Children who have untreated thalas­
semia die in the first decade of life from
56 Chapter 4
a­nemia, septicemia, and pathologic frac­
tures. When palliative transfusions are
introduced, children live into their late teens
eventually succumbing to heart failure due
to iron overload.
With the introduction of frequent
chronic transfusion therapy with regular
iron chelation, children are now surviving
into adulthood, adding to the complexity of
the disease. Patients with a matched sibling
donor should be offered transplantation;
haploidentical transplant may be an option
within the bounds of a clinical trial. Studies
utilizing genetic engineering of mononu­
clear cells collected by apheresis to produce
hgb A or hgb F which are subsequently
reinfused to the patient after a myeloabla­
tive preparative regimen are underway with
promising results to date. The longevity of
patients who are compliant with their chela­
tion therapy, or in those who have received
bone marrow transplantation, is not yet
known.
Delta beta thalassemia
Mutations in both δ‐ and β‐globins leads
to a reduction in hemoglobin A and A2
but with an increase in hemoglobin
F. Delta beta thalassemia trait will lead to
microcytosis (due to beta‐thalassemia trait)
without anemia (due to the increase in
hemoglobin F). Due to the decrease in A2
production (similar to iron deficiency),
beta‐thalassemia trait may not be consid­
ered, and therefore there must be a high
suspicion for delta beta thalassemia (and in
lieu of hereditary persistence of fetal hemo­
globin (HPFH) due to the elevated hgb F).
Homozygous mutations will lead to a
thalassemia intermedia phenotype, while
combination with a second β mutation can
lead to thalassemia intermedia or thalas­
semia major phenotype.
Hereditary persistence of fetal
hemoglobin
HPFH is also due to deletions in the δ‐ and
β‐globins, which leads to an increase in hgb
F (usually 15–30%). Association of HPFH
with other β‐hemoglobinopathies can miti­
gate clinical manifestations. HPFH leads to
pancellular expression of hgb F, which can
distinguish it from delta beta thalassemia.
Neonatal screening
for hemoglobinopathies
Newborn screening identifies patients with
beta‐thalassemia major, hemoglobin H, and
sickle cell disease. Patients with beta‐thalas­
semia major and sickle cell disease will be
asymptomatic at birth due to high fetal
hemoglobin levels but will become sympto­
matic over the next 2–3 months as normal
production of hgb F wanes. Patients with
significant Bart’s hemoglobin (see Table 4.1)
should be considered to have hemoglobin H
and require alpha‐gene screening to detect
the possibility of hgb H‐constant spring.
The presence of only hgb F on newborn
screen will be interpreted as beta‐thalas­
semia major (see Table 4.2). This diagnosis
must be confirmed with parental electro­
phoresis and repeat testing of the infant at
2–3 months after fetal hemoglobin wanes
with concomitant increase in hemoglobin A
and A2 in the normal patient. The pattern
FA is normal and should not be interpreted
as beta‐thalassemia trait. This is a diagnosis
made by the practitioner when microcytic
anemia is seen during routine childhood
screening, and an investigation for thalas­
semia confirms the diagnosis. All infants
with a suspected hemoglobinopathy should
be referred to a pediatric hematologist.
Hgb FE will be presumed to be hgb
E‐beta‐thalassemia until that diagnosis is
 Thalassemia 57

Table 4.1 Classification of the alpha‐thalassemias.

Diagnosis Genetic finding Symptoms Bart’s (%)

Silent carrier α−/αα Hematologically normal 1–3

α‐thalassemia trait α−/α– or αα/− Mild anemia with microcytosis 3–6
and hypochromia
Hemoglobin H α−/− Moderately severe hemolytic 5–20
disease or anemia
Hemoglobin ααCS/− or α−/αCS− Icterus and splenomegaly 5–20
H‐constant spring
α‐thalassemia major −/− Severe anemia not compatible 100
with life; hydrops fetalis
without intrauterine
transfusion

investigated and confirmed or ruled out by
repeat electrophoresis and family studies.
Hemoglobin E is the most common abnor­
mal hemoglobin discovered in the state of
California on newborn screening. It is com­
mon in Laos, Cambodia, and Thailand.
Hemoglobin E results from a mutation in an
exon (exon 1, codon 26: GAG to AAG) that
creates an alternate splice site competing
with the normal splice site. This results in
abnormal hemoglobin production and mild
microcytic anemia (hgb ≥ 10 g/dl) in the
homozygous state. Electrophoresis reveals
about 90% hgb E with varying amounts of

Table 4.2 Interpretation of common newborn screening results.*

Result Diagnostic possibilities Action required

FA Normal None
β‐thalassemia trait Genetic counseling
F β‐thalassemia major Referral to hematologist
FAS Sickle cell trait Genetic counseling
FS Sickle cell disease (Hgb SS) Repeat testing at 2–3 months
Hgb S/β0‐thalassemia Family studies
Referral to hematologist
FSA Hgb S/β+‐thalassemia Referral to hematologist
FSC Sickle cell disease (Hgb SC) Referral to hematologist
FAC Hemoglobin C trait Genetic counseling
FE Hgb E/β‐thalassemia Repeat testing at 2–3 months
Referral to hematologist
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).
58 Chapter 4
hgb F. The heterozygote has a hemoglobin of
about 12 g/dl with microcytosis and an elec­
trophoretic pattern consistent with hgb E
plus hgb A. When combined with other
more severe beta‐thalassemias, hgb E‐beta‐
thalassemia can produce an anemia that is
profound, requiring chronic transfusion
therapy. All children who have hgb E and
hgb F on their state screen require scrutiny
for the emergence of a severe thalassemia
syndrome. Individuals who are homozygous
for hgb E should not have a significant ane­
mia and do not require special care. Like
patients with alpha‐thalassemia, they should
not be treated with iron for their microcytic
anemia unless they are proven to have con­
comitant iron deficiency.
Case studies for review
1. You are seeing an infant that has been
following in your clinic since the newborn
period. The baby was born full-term with­
out any significant issues. You are now see­
ing the baby back at 4 months for the
well-child check and secondary vaccina­
tions. The parents note that the baby has
been more listless, not eating as well, and
looking paler. There are no recent infections
or fevers.
a. Assuming this baby is anemic, what
would your differential diagnosis be at
this point?
Causes of anemia are quite broad at this
point. Complete blood count with differen­
tial, MCV, and reticulocyte count would be
helpful to narrow the differential. Iron defi­
ciency is unlikely before 6 months of age
due to maternal iron stores unless the baby
was born prematurely (and would have been
routinely put on iron therapy), if the mother
had severe anemia during pregnancy, or if
there was acute or occult blood loss. Viral
suppression or aplasia from infections such
as parvovirus is possible, but less likely
without any history of recent infection or
fever. Beta-thalassemia as well as sickle cell
anemia should be high in the differential, as
fetal hemoglobin lives 60–90 days and
therefore by 4 months of age the infant will
be producing little fetal hemoglobin (α2γ2)
and should have moved to almost solely
hemoglobin A (α2β2) unless there is a prob­
lem with the β-globin chain. Additional
possibilities include a hemolytic anemia,
transient erythroblastopenia of childhood
(though rarely seen at this young of an age),
infant leukemia, and folate and vitamin B12
deficiency if the baby is being fed goat’s
milk or the mother is vegan, respectively.
b. What additional piece of information
may be helpful in this young child?
In addition to asking about a family history
of sickle cell anemia and thalassemias, the
provider should look for the results of new­
born screen which could be very helpful in
this case. If the patient has a newborn
screen that is FA, sickle cell anemia and
β-thalassemia major can be ruled out. More
concerning newborn screening results
would include F (β-thalassemia major), FS
(hgb SS disease or hgb S/β0-thalassemia),
and FSA (hgb S/β+-thalassemia).
β0-thalassemia and β+-thalassemia are dif­
ferentiated based on the presence (β+) or
absence (β0) of hemoglobin A, although
phenotypically the patient can have an
extremely variable clinical presentation, in
part due to the persistence of fetal hemo­
globin. If the patient had sickle cell trait,
their newborn screen result would be FAS,
as the percentage of hemoglobin A should
be greater than the percentage of hemo­
globin S. If necessary, results can be con­
firmed at 4 to 6 months of age after fetal
hemoglobin levels should be significantly
decreased or, if possible, the parents can be
tested. In this case, the newborn screen
results are F only.
c. How might repeat hemoglobin elec­
trophoresis be different at this age?

The patient that has no hemoglobin A will
be on the extreme end of the clinical spec­
trum with definitive β-thalassemia major.
For those patients with some β-globin pro­
duction, the clinical severity of disease at
this point cannot be determined on a molec­
ular level. Patients who are solely fetal
hemoglobin (α2γ2) on newborn screen will
likely continue to make some amount of
fetal hemoglobin in addition to hemoglobin
A2 (α2δ2). Their repeat hemoglobin electro­
phoresis will represent this with variable
amounts of hemoglobin A2 and F and no
hemoglobin A.
d. What would you expect the parents’
hemoglobin electrophoresis to show?
The parents likely both have β-thalassemia
trait. If they were tested as newborns, they
would be FA. As adults, after fetal hemo­
globin production has decreased, they
would have increased amounts of both A2
(>3.5%) and F (>2%) in addition to hemo­
globin A.
e. What other clinical signs might be
apparent in the infant?
One would expect to see increasing signs of
extramedullary hematopoiesis with increas­
ing age and decreasing fetal hemoglobin
production. Some of the early signs could be
frontal bossing as well as maxillary and
mandibular prominence. The infant may
have failure to thrive as well as the develop­
ment of hepatosplenomegaly.
2. You are seeing a 7-year-old male in your
primary care clinic who recently emigrated
from Southeast Asia. The family notes that
he has generally been well, though has peri­
ods of jaundice from which he has recovered
without significant issues. He has not
received frequent medical care in the past,
though the family does note that he had one
period of jaundice which required a blood
transfusion. He has no siblings. The parents
also have not received frequent medical
care, though do not note any significant
Thalassemia 59
medical issues. The mother did not note any
significant issues during the pregnancy.
a. Assuming this may be a thalassemia-
related condition, what are the most
likely diagnoses?
Given the lack of frequent transfusion,
β-thalassemia major is highly unlikely in a
generally well 7-year-old. Also given the
intermittent periods of symptomatic hemol­
ysis, β-thalassemia and α-thalassemia trait
are not possible diagnoses. The most likely
diagnosis would be hemoglobin H or
H-constant spring given the intermittent
periods of jaundice and minimal transfu­
sion needs. β-thalassemia intermedia is also
possible, though less likely. Splenomegaly
on exam could be diagnostic of both condi­
tions, though a more prominent spleen
would be most consistent with hemoglobin
H or H-constant spring.
b. What would be the best next testing?
Basic labs including a CBC and complete
metabolic panel should always be under­
taken. With the assumption of an underly­
ing thalassemia condition, hemoglobin
electrophoresis should be done in addition
to genetic testing for α-thalassemia muta­
tional deletions. BCB prep will be useful for
inclusion bodies (Heinz bodies) that would
be present with hemoglobin H or H-constant
spring. In both β-thalassemia intermedia as
well as hemoglobin H there will be a micro­
cytic anemia with potential elevation in the
indirect bilirubin secondary to chronic
hemolysis. Hemoglobin electrophoresis will
show a decrement in hemoglobin A and
increase in A2 and F with β-thalassemia
intermedia while should show elevated
hemoglobin Bart’s (β4 tetramers) with
hemoglobin H or H-constant spring. The
confirmatory diagnosis for hemoglobin H
or H-constant spring will be genetic testing
which would report three deletional or non-
functional (constant spring) mutations.
c. What counseling would you give the
family based on the underlying diagnosis?
60 Chapter 4
Although the hemoglobin level can reveal
moderate anemia with hemoglobin H or
H-constant spring, the general picture is
similar to the patient’s history, with infre­
quent transfusion requirements and periods
of jaundice and splenomegaly. The spleen
may need to be removed in the future,
depending on the symptoms and the size of
the spleen. In the case of β-thalassemia
intermedia, the clinical course is quite vari­
able, with some patients benefiting from
chronic transfusions, especially if there is
growth delay in the younger patient. On the
other hand, some patients with β-thalassemia
intermedia may not require or benefit from
chronic transfusion due to the lack of sig­
nificant symptomatology and therefore
have an unjustifiable risk of iron overload
from chronic transfusion.
Multiple choice questions
1. You are following up on newborn screen
results on a healthy 2-week-old male infant
of Southeast Asian descent with a strong
family history of microcytic anemia. You
note that the infant has an FA pattern on
newborn screening. All of the following are
potential diagnoses, EXCEPT:
a. Normal newborn
b. β‐thalassemia trait
c. β‐thalassemia major
d. α‐thalassemia trait
e. β+‐thalassemia
Explanation: Although not all hemoglo­
binopathies can be diagnosed at birth,
β‐thalassemia major will present on new­
born screen with F hemoglobin only. An FA
pattern is usually normal, as the normal
newborn will produce more fetal hemo­
globin and less adult hemoglobin A. The FA
pattern does not characterize how much
hemoglobin A is being produced except
being less than hemoglobin F. If there is an
abnormality in the β‐globin locus such that
the amount of hemoglobin A is decreased
but not absent, this will also present with a
normal newborn screen of FA as would be
seen in β‐thalassemia trait and β+‐thalas­
semia. α‐thalassemias including hemo­
globin H and α‐thalassemia major will
present with Bart’s hemoglobin (γ4 tetram­
ers) on newborn screen whereas α‐thalas­
semia trait will have a normal newborn
screen. The answer is c.
2. You are seeing an 8-month-old male infant
who recently immigrated from Southeast
Asia with no previous medical care. He had
a sibling that died at a young age of unknown
causes. His parents are unaware of any
known medical history. On exam he appears
pale with frontal bossing and a large spleen.
Hemoglobin electrophoresis is most likely
to show which of the following patterns:
a. 98% Hgb A, 1% A2, 1% F
b. 93% Hgb A, 4% A2, 3% F
c. 60% Hgb A, 40% Hgb S
d. 98% Hgb F, 2% Hgb A2
e. 100% Hgb S
3. Match the below with the correct
condition:
a. 9 8% Hgb A, Sickle cell trait
1% A2, 1% F
b. 93% Hgb A, Hgb SS
4% A2, 3% F
c. 6 0% Hgb A, β‐thal trait
40% Hgb S
d. 98% Hgb F, β‐thal major
2% Hgb A2
e. 100% Hgb S Normal
Explanation: The percentage of F, A2 and S
distinguishes between trait conditions and
disease. Patients with β‐thalassemia major
will not be able to produce any hemoglobin
A so in the newborn period they will have
Hgb F alone (answer d). After birth they may
produce a small amount of Hgb A2. Patients
with β‐thalassemia trait will have increased
production of Hgb F (normally <2%) and Hgb

A2 (normally 2%‐3.5%) after birth (answer
b). Patients with sickle cell trait will have an
S% of 40% or less, which can also be seen in
the frequently transfused patient with sickle
cell anemia (answer c). The patient with Hgb
SS will produce only Hgb S after the newborn
period (answer e). A normal hemoglobin
electrophoresis is represented by answer a.
Suggested reading
Hoppe, C.C. (2009). Newborn screening for non‐
sickling hemoglobinopathies. Hematology
Am. Soc. Hematol. Educ. Program 1: 19–25.
Thalassemia 61
Lal, A., Goldrich, M.L., Haines, D.A. et al. (2011).
Heterogeneity of hemoglobin H disease in
childhood. N. Engl. J. Med. 364: 710–718.
Richardson, M. (2007). Microcytic anemia.
Pediatr. Rev. 28: 5–14.
Taher, A.T., Musallam, K.M., Karimi, M. et al.
(2010). Overview on practices in thalassemia
intermedia management aiming for lowering
complication rates across a region of ende­
micity: the OPTIMAL CARE study. Blood
115: 1886–1892.
Vichinsky, E., Cohen, A., Thompson, A.A. et al.
(2018). Epidemiology and clinical characteris­
tics of nontransfusion‐dependent thalassemia
in the United States. Pediatr. Blood Cancer 65:
e27067.
5 Transfusion Medicine
Transfusion of blood products continues to
be an important and necessary part of
­therapy in children with hematologic and
oncologic diagnoses. Many complications
can result from transfusion, both infectious
and noninfectious. With continued improve­
ments in donor screening, and better testing
techniques, infections from known entities
have become a rarity. However, as long as
blood component therapy is derived from
human blood donation, the risk will persist.
Donor selection criteria are designed to
screen out potential donors with increased
risk of infection with HIV‐1/2 (human inm­
munodeficiency virus types 1 and 2),
HTLV‐I/II (human T‐cell leukemia virus
types I and II), and hepatitis B and C, as well
as other infectious pathogens. Despite rigor­
ous screening and testing for these infec­
tions, the risk of transmitting these viruses is
not totally eliminated.
Clerical errors and misidentification are
major risks for transfusion and can result in
serious consequences, including death. It is
essential that all blood samples drawn for a
type and crossmatch be clearly labeled with
the patient’s identification. Before adminis­
tration of the blood product, the order
should be checked, patient identification
reviewed (patient’s identification band), and
blood type verified. Many institutions have
moved toward testing two separate blood
type specimens for nonemergent ­transfusion
Handbook of Pediatric Hematology and Oncology – Children’s Hospital & Research Center Oakland,
Third Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
in previously untransfused patients to elimi­
nate the risk of clerical error.
Directed donation from first‐degree rela­
tives (especially maternal) should be dis­
couraged for patients who may be candidates
for an allogeneic bone marrow transplant
due to the possibility of antigen sensitiza­
tion. If it cannot be avoided, the blood
should be irradiated to prevent graft‐versus‐
host disease (GVHD). Studies have shown
that blood from directed donation is not
safer than the general donation pool due to
current sophisticated screening and testing
methods.
These risks must be carefully considered
and weighed against expected benefit
each time a transfusion is contemplated.
Informed consent should be obtained prior
to every nonemergent transfusion. In
California, the Gann Act must be renewed
on a yearly basis for those patients undergo­
ing frequent transfusion due to an underly­
ing hematologic or oncologic condition.
Packed red blood cell
transfusion
Transfusion decisions are made on the basis
of clinical context, rather than the level of
hemoglobin alone (see Figure 5.1). Prior
to transfusion, it is necessary to assess the
mechanism responsible for anemia (i.e., bone
64 Chapter 5

Symptomatic anemic patient

Chronically transfused patient?

Yes No

Give leukopoor, phenotypically Acute blood loss?

matched blood unless emergent Yes
condition does not allow time No

Patient with concern for Oncology patient or neonate?

autoimmune hemolytic anemia?

Review transfusion history Yes No

Yes No
Give 10–15 mL/kg over 4 hours
in majority of cases
Ensure leukopoor, Ensure leukopoor
Start Transfuse to irradiated blood blood
immunosuppressive normal
therapy hemoglobin level
For sickle cell patients:
Give sickledex negative blood Give CMV negative
Avoid Hgb > 12 g/dL blood if CMV
Consider exchange transfusion seronegative in the
(see Chapter 3 for details) If patient Transfuse for peri-transplant
symptomatic give continued blood period*
phenotypically losses
matched blood

Review transfusion history

Give 10 –15 mL/kg over 4 hours
in majority of cases

Figure 5.1 Blood transfusion guidelines (*refer to institutional guidelines, as transfusion of CMV‐seronegative PRBCs is controversial).

marrow infiltration, ineffective erythro­
poiesis of chronic disease, occult or obvious
blood loss, transfusion or drug‐related
­suppression of normal hematopoiesis, and
nutritional deficiency), the severity of the
signs and symptoms, and the likelihood of
resumption of normal hematopoiesis.
Whole blood is rarely, if ever, utilized in
standard practice, though may occasion­
ally be utilized for massive transfusion
after ­military trauma. Packed red blood
cells (PRBCs) are depleted of the majority
of platelets and white blood cells and need
to be ABO and RhD compatible, at the
­minimum. Phenotypically, and now more
recently genotypically, matched blood for
minor antigens should be utilized for
patients undergoing chronic transfusion
(e.g., sickle cell disease). One unit of
PRBCs is approximately 250–350 ml with a
hematocrit of 55–60% when prepared with
adsol. Based on the hematocrit of the
stored PRBCs, one can calculate the pre­
sumed rate of rise from blood transfusion.
For adsol‐preserved units, the transfusion
factor is approximately 5 (assuming no
hemolysis of transfused blood or blood
loss). The estimated hemoglobin (hgb)
increase can be derived utilizing this trans­
fusion formula:
Estimated hemoglobin rise g/dl
Volume of PRBC transfusion
n ml/kg
Transfusion factor
For example, for a transfusion of 15 ml/kg,
the estimated hemoglobin increase should
be 3 g/dl. Of note, waiting a certain period of
time for a posttransfusion “reequilibration”
prior to rechecking the hemoglobin is not
necessary.
Removal of the vast majority of remaining
white blood cells, or leukoreduction, is an
important step in reducing transfusion‐related
risks including risk of infection, febrile non­
hemolytic transfusion reactions (FNHTRs),
Transfusion Medicine 65
and alloimmunization from PRBC transfu­
sion. Although not universal as yet in the
United States (it is estimated that approxi­
mately 85% of RBCs distributed to United
States hospitals by their blood providers are
prestorage leukoreduced), l­eukoreduction is
becoming standard of care and is universal in
Canada and much of Europe.
Irradiation of blood products should
be utilized for all patients who are immu­
nocompromised in order to prevent
­transfusion‐associated graft‐versus‐host
disease (TA‐GVHD). This should include
all oncology patients as well as neonates.
Cytomegalovirus (CMV)‐negative blood
should be considered in patients in the
peri‐transplant period who are noted to be
CMV‐seronegative in addition to neonates
born to CMV‐negative mothers and patients
with immunodeficiencies. Institutional
guidelines vary and should be consulted in
determining the need for CMV‐negative
blood secondary to the limited supply of
this product.
Finally, washing of PRBCs is rarely indi­
cated and decreases the red cell mass by
approximately 20%. Washing is indicated
for severe allergic transfusion reactions,
hyperkalemia, large‐volume transfusions
(due to risk of hyperkalemia), and selective
IgA deficiency.
Indications for PRBC
transfusion
Neonates
Guidelines for transfusion in neonates and
infants vary widely in the literature. Clinical
correlation is required in addition to the
­following basic guidelines:
●● Transfusion of leukopoor, irradiated
blood in premature infants and low‐birth‐
weight neonates (CMV‐negative if CMV
status of mother is negative or unknown).
66 Chapter 5
●● High oxygen requirement or severe car­
diac disease, keep hgb ≥ 11–15 g/dl.
●● Mild‐to‐moderate respiratory distress or
perioperative care, keep hgb ≥ 10 g/dl.
●● Stable infants who become symptomatic
from anemia, keep hgb > 7–8 g/dl (based on
degree of symptoms and growth).
Acute blood loss
and nonimmune hemolytic
anemia
Unlike chronic conditions that result in a
slow drop in hemoglobin and time for com­
pensation, patients with acute blood loss or
nonimmune hemolytic anemia may be
symptomatic at much higher hemoglobin
levels and should be transfused accordingly.
In situations of continuing blood loss,
patients should be transfused to achieve an
expected hemoglobin level in addition to
receiving blood to compensate for ongoing
losses. In an emergent situation, transfusion
consent is not required, and if there is no
time for a crossmatch, O‐negative blood
should be given.
Severe chronic anemia
In pediatric patients, iron‐deficiency ane­
mia is the most likely cause of severe chronic
anemia (i.e., hgb < 5 g/dl), followed by viral
suppression, transient erythroblastopenia
of childhood, aplastic anemia, and newly
diagnosed leukemia. Pediatric patients can
present with an extremely low hemoglobin
(i.e., 2–3 g/dl) and yet appear to be relatively
well‐compensated. Patients should be assessed
closely for subtle signs of congestive heart
failure (cardiomegaly on chest radiograph,
increased diastolic blood pressures, hepato­
megaly, oliguria, and periorbital edema)
prior to transfusion. Slow transfusion (i.e.,
1 ml/kg/h) has been recommended in the
past, although studies have shown that
2–3 ml/kg/h is safe in patients with normal
underlying cardiopulmonary function. Those
with signs of cardiopulmonary dysfunction
should be transfused slowly with judicious
usage of diuretics, and exchange transfusion
should be considered in those with heart
failure.
Oncology patients
In general, a hemoglobin of 7 g/dl is used as
the threshold for transfusion in pediatric
oncology patients. This may be altered in
cases where the patient is asymptomatic
with imminent recovery of red blood cells
(often heralded by increase in platelet
count). Infants with effects on growth and
development due to anemia should be main­
tained at a higher hemoglobin; similarly,
adolescents may complain of headache and
fatigue and be less symptomatic with hemo­
globin in the 8–10 g/dl range. Those with
cardiopulmonary dysfunction and those
requiring procedural sedation with antici­
pated blood loss should be kept in the
8–10 g/dl range as well.
Autoimmune hemolytic anemia
In patients with an autoimmune hemolytic
anemia, immunosuppressive therapy is usu­
ally sufficient to abate the underlying pro­
cess. In those patients who are symptomatic
with a continuing drop in hemoglobin or
resultant significant cardiopulmonary dys­
function, phenotypically matched blood
may be given with close observation know­
ing that hemolysis is likely to continue and
may even be augmented.
Chronically transfused patients
Patients with β‐thalassemia major as well as
some with β‐thalassemia intermedia, hgb
SS, and hgb S/β0‐thalassemia require chronic
transfusion therapy, as outlined in previous
chapters. These patients should have a red
cell phenotype prior to initiating transfu­
sions and, based on institutional practice,
will usually receive blood phenotypically
matched to a small panel of antigens (at our
institution, other Rh antigens including C/c

and E/e as well as Kell). If the patient devel­
ops antibodies to other minor red cell anti­
gens (e.g., MNS, Duffy [Fya/Fyb], Kidd [Jka/
Jkb], and Lewis [Lea/Leb]), more extensive
phenotype matching is performed in order
to decrease the continued risk for alloim­
munization. Genotyping for a wider range
of antigens is becoming more universally
available and will likely become the future
standard of care. Sickle cell patients in
addition should receive sickledex‐negative
blood, as blood donors are not screened for
sickle cell trait. Transfusion is given on a
regular basis (i.e., every 3–4 weeks) in order
to suppress ineffective erythropoiesis.
Dosing of PRBC transfusion
The desired incremental increase in hemo­
globin should be considered when deter­
mining the amount of blood to be transfused.
In general, 10–20 ml/kg over 4 hours is given
in order to increase the hemoglobin by
2–4 g/dl, typically using a maximum of 3
units in consideration of ideal body weight
and total blood volume. Care should be
taken to not waste blood; therefore, orders
should be rounded to the nearest unit or half
unit, as feasible. Remaining blood may be
sterilely aliquoted and used later in the same
patient in order to decrease exposure to
multiple donors. Slow transfusion should
be given in patients with signs of volume
overload or cardiopulmonary dysfunction.
Patients with heart failure should be
exchange transfused. Care should be taken
to not increase the hemoglobin above 12 g/dl
in patients with sickle cell d
­ isease second­
ary to hyperviscosity and increased risk
of central nervous system (CNS) events.
Similarly, in patients with leukemia and
hyperleukocytosis at diagnosis (i.e., white
blood cell count >100 × 109/l), the hemo­
globin should preferably be kept below
10 g/dl and transfusion avoided if possible
due to the same risks of increasing viscosity
and the propensity for leukostasis.
Transfusion Medicine 67
Exchange transfusion/
erythrocytapheresis
Exchange transfusion or erythrocytaphere­
sis may be indicated in the severely anemic
patient with congestive heart failure, acute
sickle cell events, hyperbilirubinemia, or in
an anemic patient treated with severe fluid
restriction (e.g., increased intracranial pres­
sure, ICP). In sickle cell disease, exchange
transfusion quickly reduces the concentra­
tion of sickle cells without increasing the
hematocrit or whole blood viscosity. In
addition, red cell exchange transfusion
reduces iron accumulation, since an equal
volume of red cells and iron are removed
as infused. Therefore, for sickle cell dis­
ease, erythrocytapheresis is preferred over
straight transfusion in patients requiring
chronic transfusion in addition to those
patients with acute events. Automated
erythrocytapheresis can be done rapidly and
safely in most situations. Limitations of this
technique include increased red cell utili­
zation, venous access, local availability, and
increased cost.
Platelets
Platelet transfusions are indicated for
thrombocytopenic patients with bleeding
due to severely decreased platelet produc­
tion or for patients with bleeding secondary
to functionally abnormal platelets.
Transfusion is not indicated for those with
rapid destruction (e.g., immune thrombo­
cytopenic purpura and neonatal alloim­
mune thrombocytopenia) unless there is
life‐threatening hemorrhage; however,
transfusion may be useful in the bleeding
patient with rapid consumption (e.g., dis­
seminated intravascular coagulation [DIC])
or dilutional thrombocytopenia (massive
transfusion or exchange). Platelets are fre­
quently needed in the patient receiving
68 Chapter 5
chemotherapy or are thrombocytopenic
secondary to a marrow infiltrative process.
Indications for platelet
transfusion
1. Premature or sick infants
a. Stable infant with platelet count
<50 × 109/l.
b. Distressed infant (or requiring surgical
procedure) with platelet count <100 × 109/l.
2. Children
a. Platelet count <10 × 109/l; higher if
febrile, septic, or with active bleeding.
b. Platelet count <20–50 × 109/l with a
minor invasive procedure such as:
i. Lumbar puncture.
ii. Extracorporeal membrane oxy­
genation (ECMO) or cardiovascular
(CV) bypass.
iii. Other minor procedures such as
central line placement.
c. Invasive procedure in a patient with a
qualitative platelet defect.
d. More invasive procedures will require
discussion with the surgical team
regarding platelet transfusion threshold,
although recommendations are generally
not evidence‐based.
3. Patients undergoing therapy for
malignancy
a. Platelet count <10 × 109/l; higher if
febrile, septic, or with active bleeding.
b. Induction chemotherapy:
i. Acute lymphoblastic leukemia
(ALL) <10 × 109/l.
ii. Acute myeloid leukemia (AML)
<10–20 × 109/l.
c. Children undergoing intensive ther­
apy with active mucositis should have
their platelet count maintained at
20–50 × 109/l (i.e., Head Start protocol
for brain tumors, postallogeneic myeloa­
blative transplantation).
d. Lumbar puncture with platelet count
<20–50 × 109/l; potentially <50–100 × 109/l
with diagnostic lumbar puncture.
e. Bleeding patient with normal coagu­
lation studies, platelets <50 × 109/l; with
abnormal coagulation studies, platelet
count <100 × 109/l.
f. Patient requiring a moderately inva­
sive surgical procedure, with a platelet
count <50–100 × 109/l (requiring discus­
sion with surgical team secondary to lack
of evidence‐based guidelines). Most sur­
geons would like platelet count to remain
>50–75 × 109/l for 48–72 hours after the
surgical procedure (this is extended to
during chemotherapy after incomplete
resection of brain tumors due to contin­
ued risk of bleeding).
g. Intramuscular injection (i.e., Erwinia
asparaginase) with platelet count
<20 × 109/l.
h. Rapid consumption associated with
sepsis, DIC.
Dosing of platelet transfusion
One unit of random platelets (~40 ml)
per 10 kg will increase the platelet count
by 40–50 × 109/l if there is no active con­
sumptive process (e.g., fever, immune
thrombocytopenic purpura, sepsis, alloim­
munization, or DIC) or sequestration. This
is equivalent to an increment in platelet
count of 10 × 109/l/ml/kg of transfused
platelets (i.e., in a 10‐kg child, 10 ml/kg or
100 ml of transfused plates should raise the
platelet count by 100 × 109/l). The platelet
count should be checked 1–2 hours after
infusion to identify refractory patients.
A patient is refractory if 1 hour after trans­
fusion the platelet increment is less than
5–10 × 109/l per unit transfused for two sep­
arate transfusions.
A patient may have platelet refractori­
ness secondary to alloantibodies (immune‐
mediated). Nonimmune causes of platelet
refractoriness are common and include
splenomegaly, fever, infection, DIC, veno‐
occlusive disease posttransplant, and use of
amphotericin B.

For refractory patients, a trial of cross­
matched platelets should be given. Other pos­
sibilities for treatment should this fail include
leukocyte‐depleted, human leukocyte antigen
(HLA)‐matched platelets, intravenous immu­
noglobulin (IVIG) with HLA‐matched plate­
lets, or massive transfusion with random
donor platelets (to overwhelm the antibody).
Most institutions now utilize pheresed
platelets that are harvested from a single
donor and generally contain greater than
30 × 109/l of platelets, equivalent to approxi­
mately six to eight units of random platelets.
The volume is usually 250–350 ml. Secondary
to the apheresis, these platelet products are
considered to be leukoreduced. In addition,
although controversial, most believe that
apheresis is sufficient to reduce the risk of
CMV transmission. Plasma ABO compati­
bility should generally be utilized, especially
with increasing volume of transfusion. Type‐
specific platelets can be given in cases of
refractoriness and should be given to patients
in the peri‐transplant period to eliminate the
production of any potential platelet antibod­
ies. As with PRBC transfusion, platelet irra­
diation is required in oncology patients,
premature or low‐birth‐weight newborns,
and patients with immunodeficiencies.
Dosage of platelet transfusion is gener­
ally 10–15 ml/kg and can be given over
30 minutes to 1 hour. Due to the expected
increase in platelet count and short life span
of platelets, one unit of pheresed platelets is
usually sufficient for transfusion in patients
over 30 kg. As with PRBCs, pheresed platelet
units should be rounded to the nearest half
and full unit as feasible to decrease waste
and sterilely aliquot as needed.
Fresh frozen plasma
Fresh frozen plasma (FFP) is a source of
plasma proteins, including nonlabile clotting
factors, such as fibrinogen. It is used for the
Transfusion Medicine 69
treatment of stable clotting factor deficiencies
in which no concentrate is available (i.e., not
for factor VIII or IX). By definition, each mil­
liliter of undiluted plasma contains 1 interna­
tional unit (IU) of each coagulation factor.
Plasma consists of the anticoagulated
clear portion of blood separated by centrifu­
gation. FFP is collected from single donors,
with each unit being removed from a unit of
whole blood and frozen within 6 to 8 hours of
collection. FFP should not be used when the
coagulopathy can be corrected more effec­
tively with specific treatment such as vitamin
K, cryoprecipitate, or factor concentrate.
Due to the high concentration of plasma
antibodies, FFP is often the cause in cases of
transfusion‐related acute lung injury (TRALI)
and therefore should be used judiciously. The
direct antiglobulin test (DAT; Coombs test)
may also be positive for this reason.
Indications for FFP
●● Bleeding or invasive procedure with docu­
mented clotting factor deficiency and
appropriate factor not available.
●● Treatment of protein C or S deficiency,
factor XI deficiency (hemophilia C).
●● Bleeding during massive transfusion, not
from thrombocytopenia.
Dosing of FFP
The usual dosage of FFP is 10–15 ml/kg over
1 hour, which is expected to increase the con­
centration of coagulation factors by 25–50%.
Due to the presence of isohemagglutinins,
FFP should be ABO‐matched. White blood
cells are killed or made nonfunctional during
the freezing process; therefore, leukoreduc­
tion and irradiation are unnecessary.
Cryoprecipitate
Cryoprecipitate is prepared by thawing FFP
and recovering the cold precipitate. Each
bag contains >80 U factor VIII coagulant
70 Chapter 5

activity and >150 mg fibrinogen in approxi­

mately 15 ml of plasma. In addition, cryo­
precipitate contains factor XIII and von
Willebrand factor. Bags must usually be
pooled to achieve an adequate dose.
Indications for cryoprecipitate
●● Bleeding or invasive procedure with factor
VIII deficiency or von Willebrand disease
where specific factor concentrate is not
available.
●● Bleeding or invasive procedure with hypofi­
brinogenemia or factor XIII deficiency.
Dosing of cryoprecipitate
The usual dosage for cryoprecipitate is
1 unit/5 kg. For hypofibrinogenemia with
coagulopathy, the goal is to maintain fibrin­
ogen >100 mg/dl. Specific factor or coagula­
tion protein levels need to be determined in
addition to assessing clinical status to
decide on frequency of transfusion. As with
FFP, cryoprecipitate is preferably ABO com­
patible and leukoreduction and irradiation
are not required.
Antithrombin III
Antithrombin III (ATIII) concentrate is
available for use in patients with inherited
or acquired ATIII deficiency (i.e., sepsis,
throm­bosis, and medication‐induced). It
may also be needed in patients receiving
heparin therapy who have a low ATIII
level. Patients with thrombosis after aspar­
aginase therapy should have an ATIII level
checked and repleted as necessary. Dosing
of ATIII is based on the baseline and
desired level using the following calcula­
tion: units desired (IU) = (desired ATIII%
level − baseline ATIII%) × body weight
(kg). The target level is 80–120%. Vials are
typically 500 IU and the dose can be
adjusted ±10% (i.e., rounded to a full vial
to avoid wastage).
Granulocyte transfusion
Patients with profound and prolonged neu­
tropenia are at increased risk for serious life‐
threatening fungal and bacterial infections.
The beneficial effect of granulocyte transfu­
sion in this population with known persis­
tent infection, especially with Gram‐negative
organisms and fungus, is yet to be proven
by randomized controlled trials although
observational studies are available. Donor
mobilization with granulocyte colony‐stim­
ulating factor (G‐CSF) has increased granu­
locyte yields and therefore the therapeutic
benefit of transfusion, as the dose of granu­
locytes is the most important factor in suc­
cess of this treatment modality.
Granulocytes migrate toward, phagocyt­
ize, and kill bacteria. When given a granulo­
cyte transfusion, the cells migrate to the foci
of infection, though there is rarely a measur­
able increase in the peripheral granulocyte
count. This is likely from sequestration at
the site of infection, prior immunization to
leukocyte antigens, or a consumptive pro­
cess secondary to the infection. Side effects
of granulocyte transfusion include the risk
of CMV infection, TA‐GVHD, respiratory
distress with pulmonary infiltrates (due to
TRALI, concurrent administration of
amphotericin B, or secondary to granulo­
cyte sequestration), and alloimmunization.
Preparation of granulocyte
concentrates
Donor mobilization is recommended with
G‐CSF at 5 mcg/kg (maximum 300 mcg
IV/SC) and dexamethasone 8 mg orally,
12–24 hours prior to collection. Granulocytes
are then collected by apheresis and ideally
should be transfused within 8–12 hours of
collection. RBC contamination requires
ABO compatibility. Due to risks of TA‐
GVHD and CMV infection, irradiation
and CMV seronegativity are required (in

those that are CMV‐negative), respectively.
Amphotericin B and concomitant granulo­
cyte transfusion is potentially associated with
severe pulmonary reactions, although the
evidence is controversial; however, it is rea­
sonable to space these therapies apart by at
least 4 hours. HLA‐matched granulocytes
should be given in patients with known allo­
immunization. Since granulocyte half‐life is
only 7 hours, daily collection and transfusion
for several days are likely required for benefit.
Indications for granulocyte
transfusion
With a lack of randomized controlled trials,
there are no evidence‐based guidelines for
granulocyte transfusion. Limited data in
neonates with sepsis have failed to show a
significant benefit. After weighing the
potential risks and benefits, as well as deter­
mining the daily availability of an eligible
donor and collection site, granulocyte trans­
fusion can be considered in severely neu­
tropenic patients with a refractory or
progressive bacterial or fungal infection on
appropriate, aggressive therapy with neutro­
penia that is expected to continue for, at the
least, several days.
Transfusion reactions
Approximately 4% of transfusions are asso­
ciated with some form of adverse reaction,
ranging from brief episodes of fever to life‐
threatening episodes of hemolysis and
shock. Fortunately, the majority of reactions
are short‐term, specifically FNHTRs and
allergic reactions, and easily managed. Life‐
threatening reactions are nearly always due
to clerical error resulting in transfusion of
an ABO incompatible unit. The challenge
for the clinician is to promptly recognize
potential serious complications that may
present with common symptoms such as
fever. For any transfusion reaction, a ­bedside
Transfusion Medicine 71
check of all labels, forms, and patient identifi­
cation should be done, in addition to notify­
ing the blood bank. Transfusion reactions are
summarized in the following text and include
FNHTRs, allergic reactions, immune‐medi­
ated hemolysis, TRALI, transfusion‐associated
circulatory overload (TACO), TA‐GVHD,
and acute infection.
Hemolytic transfusion reactions
Hemolytic transfusion reactions can either
be acute or delayed. Acute hemolytic trans­
fusion reactions (AHTRs) are usually due to
clerical error resulting in the transfusion of
an ABO incompatible unit. AHTRs classi­
cally present with fever, chills, nausea, and
vomiting in addition to dyspnea, hypoten­
sion, shock, hemoglobinuria, and DIC.
Bacterial contamination must be considered
in the differential for an AHTR. Delayed
hemolytic transfusion reactions (DHTRs)
present 2–14 days after transfusion with
milder symptoms including low‐grade fever,
jaundice, and a posttransfusion hemoglobin
increment less than expected due to minor
antigen incompatibility (alloimmunization)
from prior transfusion.
Evaluation of a potential AHTR should
include workup of all recently transfused
blood products (see Figure 5.2). A bedside
check of labeling should occur followed by
laboratory evaluation including repeat cross­
matching and a DAT. The DAT may not
always be positive if all the antibodies have
been destroyed during the hemolytic crisis.
Other labs that should be sent to rule out
intravascular hemolysis include indirect bili­
rubin, lactate dehydrogenase (LDH), plasma
free hemoglobin (and/or haptoglobin), and
urinalysis to check for hemoglobinuria.
DHTRs lead to extravascular hemolysis
and should be evaluated in a patient with
clinical or laboratory symptoms after the first
24 hours. Labs to follow include a posttrans­
fusion hemoglobin level and reticulocyte
count, indirect bilirubin, LDH, and DAT.
72 Chapter 5

Fever (≥38.0°C or 100.4°F)

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 No

Stop transfusion ≥1–2°C ↑ in temperature

Initiate supportive care (IVF, compared to past 24 hours?*
antibiotics)
Contact Intensive Care
Yes No

Stop transfusion Continue 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 bilirubin, LDH, UA, DAT, plasma free hgb
Consider CXR if respiratory symptoms or new hypoxia

Positive workup?

Yes No

Provide appropriate care based on Restart transfusion

likely diagnosis and clinical symptoms Monitor clinical exam closely
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).
*see text for more detail

If an AHTR is suspected, emergent man­ FNHTRs were significantly more com­

agement is vital. The transfusion should be
immediately stopped, and IV fluid resuscita­
tion commenced. Inotropic support may be
required for hypotension and shock. Renal
perfusion and urine output should be fol­
lowed closely, and additional blood product
support may be required. DHTRs usually
do not require intervention, although may
rarely cause profound anemia.
mon prior to near universal leukoreduction
and occur due to pyrogenic cytokines
released by leukocytes during blood compo­
nent storage. FNHTR is defined as a tem­
perature increase of 1 °C (1.8 °F) without any
other attributable cause during or within
4 hours of transfusion. More serious causes
of fever including AHTR and bacterial con­
tamination must be ruled out prior to the

diagnosis of FNHTR being made. Trans­
fusion must therefore be discontinued until
an AHTR can be ruled out (see Figure 5.2).
Fever due to FNHTR is usually self‐limited
and resolves with antipyretic usage and
stopping the transfusion. Chills, rigors, and
discomfort can occur, mimicking an AHTR.
Transfusion can potentially be restarted
after AHTR has been ruled out based on the
clinical status of the patient and urgency of
the transfusion. Although patients with a
history of FNHTR often receive premedica­
tion with acetaminophen with future trans­
fusions, this practice is not evidence‐based.
Antipyretics should be c­onsidered for the
patient with multiple FNHTRs; if acetami­
nophen is not effective, a trial of washed
blood components can be considered. Of
note, transfusion can be given to the febrile
patient if urgently necessary, as the criteria
for workup (beyond a close and continued
clinical assessment) is an increase of 1–2 °C
in fever (dependent on institutional stand­
ard) compared to the fever curve from the
previous 24 hours.
Allergic transfusion reactions
Allergic reactions are typically type I hyper­
sensitivity reactions to plasma in blood
components. Allergic reactions are common,
occurring in 1–5% of transfusions, and
usually with mild symptoms such as urti­
caria, although anaphylaxis can occur. For
the majority of allergic reactions, an antihis­
tamine such as diphenhydramine is sufficient
to alleviate symptoms and the transfusion
can likely be completed in the allotted time.
For more severe symptoms, the transfusion
should be stopped. Steroids, an H2 blocker
(e.g., famotidine), epinephrine, volume
expansion, β2 agonists (e.g., albuterol), and
oxygen may be required. Patients with a
severe allergic reaction should be tested for
IgA deficiency. As with FNHTRs, premedica­
tion (with an antihistamine) remains contro­
versial in patients with a history of a reaction.
Transfusion Medicine 73
Patients with multiple episodes may benefit
from premedication with an antihistamine
and, if not effective, potentially corticoster­
oids. If ­allergic reactions continue, washed
blood products should be utilized.
Transfusion‐related acute lung
injury
TRALI is becoming increasingly recognized
as an important cause of morbidity after
transfusion with plasma‐containing blood
components. Signs and symptoms include
hypoxia, chest infiltrates (without volume
overload), dyspnea/tachypnea, fever, and
hypotension. TRALI generally occurs within
6 hours of transfusion completion. A major­
ity of patients with TRALI will recover in a
2‐ to 4‐day period although respiratory
support, and in some cases mechanical ven­
tilation, is often required. Pressor support
may be necessary, and treatment with cor­
ticosteroids may be helpful.
Transfusion‐associated
circulatory overload
TACO also is becoming more widely recog­
nized, but is likely rare in the pediatric popu­
lation. TACO occurs due to cardiogenic
edema from too rapid or too large a volume
of transfusion. Clinical signs such as dysp­
nea/tachypnea and hypoxia may be confused
with TRALI. Differentiating features include
hypertension rather than hypotension due to
pulmonary over‐circulation with a positive
fluid balance. Chest radiograph should be
more consistent with pulmonary edema/
effusion rather than infiltrates. Aggressive
diuresis should be utilized.
Transfusion‐associated graft‐
versus‐host disease
TA‐GVHD can occur in immunocompro­
mised patients who receive nonirradiated
blood or platelet transfusion due to donor
T‐lymphocytes that cannot be rejected by
the host. TA‐GVHD has also been reported
74 Chapter 5
in immunologically normal patients with an
HLA‐compatible donor such as in homoge­
neous populations or in cases where the
donor is a close relative (directed donation).
Clinical symptoms are equivalent to those
with transplant GVHD including fever, ano­
rexia, vomiting/diarrhea, and skin rash.
Hepatic dysfunction and pancytopenia can
similarly manifest.
Bacterial infections
Blood components may be contaminated
with bacteria at the time of collection or
during processing. Infection rates are higher
after platelet transfusion, since platelets are
stored at room temperature, although clini­
cal signs and symptoms are often more
severe after transfusion of contaminated
PRBCs. Due to the increased risk of infec­
tion with platelets, we utilize a temperature
increase of 1 °C (39 °C in the previously afe­
brile patient) over the past 24 hours versus
increase of 2 °C (40 °C in the previously afe­
brile patient) for PRBCs in the stable‐
appearing patient prior to commencing an
infection workup (i.e., blood culture of the
patient and bag, ceftriaxone, AHTR workup
for PRBCs). Infection is associated with a
rapid onset of symptoms and a high rate of
morbidity and mortality, especially from
Gram‐negative organisms. The patient may
present acutely septic with fever/chills,
hypotension, tachycardia, and shock. If bac­
terial contamination is suspected, the trans­
fusion should be stopped immediately.
Aggressive supportive treatment including
IV fluid resuscitation, initiation of broad‐
spectrum antibiotics, and potential therapy
for renal failure, shock, and/or DIC should
be started emergently.
Case studies for review
1. You are following a 12-year-old, 60-kg
boy admitted to the pediatric intensive
care unit (PICU) with septic shock. He is
secondarily found to be anemic and throm­
bocytopenic with coagulopathy and hypofi­
brinogenemia in DIC.
After initial stabilization of the patient
with intravenous fluids, antibiotics, mech­
anical ventilation, and vaso pressors, the
PICU team is determining their transfu­
sion plan. Current hemoglobin is 7.0 g/dl,
platelets are 34 × 109/l, PT (prothrombin
time) is 27.2 seconds, PTT (partial throm­
boplastin time) is 74.6 seconds, and
fibrinogen is 76 mg/dl. There is no noted
active bleeding. 1:1 mixing studies correct
both the PT and PTT, implying a factor
deficiency rather than an antibody. The
patient does appear to have some amount of
hemolysis with an elevated indirect biliru­
bin and LDH, but has a negative direct
Coombs test.
a. What blood products should be
transfused?
b. What amount of PRBCs should be
given?
c. Are there any special considerations
for the type of blood product required?
d. What are some specific risks with this
patient presentation?
First, the patient should be given PRBCs,
pheresed platelets (if possible), and FFP.
Cryoprecipitate may or may not be required
dependent on the increase in fibrinogen
with FFP. If the patient is clinically worsen­
ing (e.g., problems oxygenating, dropping
blood pressures), consideration should be
given to transfusing O-negative PRBCs
while awaiting crossmatching.
Second, one can utilize the transfusion
factor to estimate the increment in hemo­
globin with transfusion. In this case, the
transfusion factor will likely overestimate
the bump as the patient is actively septic and
therefore hemolyzing PRBCs and consum­
ing platelets. Still, estimating will help deter­
mine a reasonable plan. Assuming the
decision is made to give 15 ml/kg (3 units),

one would expect at most an increase in
hemoglobin of 3 g/dl:
Transfusion amount (ml/kg)/transfusion
factor = hgb increase (g/dl)
Therefore, in this case (15 ml/kg)/5 = 3 g/dl.
In general, platelet and FFP transfusion will
also be 10–15 ml/kg. Platelet transfusion
should initially be a maximum of one
­pheresed unit (approximately 250–350 ml).
Posttransfusion hemoglobin, platelets, and
coagulation studies can help determine the
need for additional transfusion as well as the
likely frequency of necessary transfusion
(directly dependent on the clinical status of
the patient). Time for “equilibration” after the
completion of transfusion is unnecessary.
Third, in this case, no significant special
arrangements need to initially be made in
regard to the transfusions. The patient does
not need sickledex-negative blood unless
they have concomitant sickle cell disease.
Also, phenotypically matched blood is
unnecessary. As the patient does not have a
known underlying reason to be immuno­
compromised, irradiated blood and platelets
are not required. Similarly, CMV-negative
blood is unnecessary.
Finally, specific risks exist for this patient
and must be considered during transfusion.
Due to the likelihood of continued transfu­
sions as well as the presence of sepsis, the
patient may develop volume overload and
potentially TACO; therefore, the judicious
use of diuretics with transfusion should
be considered. In addition, a significant
volume of PRBC transfusion can have a
­ receive 10–15 ml/kg while minimizing allo­
dilutional effect on platelets and coagulation
factors, thus increasing transfusion require­
ments for these blood products. The patient
is also at risk for hyperkalemia with
increasing PRBC transfusion. If hyper­
kalemia begins to occur, washed PRBCs
should be given. Massive PRBC or whole
blood transfusion has been shown to induce
Transfusion Medicine 75
­transfusion-associated microchimerism.
Microchimerism is the presence of donor
lymphocytes in the recipient’s circulation.
The significance of transfusion-associated
microchimerism is unknown. Patients
receiving large amounts of plasma are at risk
for developing TRALI that must be consid­
ered with worsening respiratory symptoms.
2. You are following a 10-year-old, 40-kg
female on the oncology ward that was
recently diagnosed with leukemia. She is
due for a lumbar puncture with chemother­
apy under anesthesia. She has had persistent
fevers to 39°C, has a central line, but has had
negative blood cultures to date. The assump­
tion is that her fevers are secondary to her
underlying leukemia. Her hemoglobin is
6.2 g/dl and her platelets are 8 × 109/l. She
has not had any active bleeding and she is
not symptomatic secondary to her anemia.
Her CMV status is pending.
a. What would you recommend in
regard to transfusion?
Although she is asymptomatic, strict trans­
fusion thresholds should be followed for
oncology patients to minimize symptoms,
specifically maintenance of the hemoglobin
≥7 g/dl and platelets ≥10 × 109/l. Additionally,
most anesthetic procedures require hemo­
globin around 7 g/dl. Thresholds for lumbar
punctures vary, though a minimum of
20–30 × 109/l should be utilized for all but
the first therapeutic lumbar puncture where
guidelines generally agree upon maintaining
a higher threshold (i.e., ≥75–100 × 109/l).
In regard to PRBC transfusion, she should
immunization risk by transfusing multiple
units from one donor. In this situation,
15 ml/kg is approximately 2 units of PRBCs
and therefore would be the ideal choice. The
PRBCs should be irradiated, since she has
started chemotherapy and is immunosup­
pressed to eliminate donor T-cells and risk
of transfusion-associated graft-versus-host
76 Chapter 5
disease. Since her CMV status is pending,
consideration can be given for CMV-
seronegative PRBCs, based on institutional
standards. Platelets should also be irradiated,
though generally do not need to be CMV-
seronegative (again based on institutional
standard) due to minimization of WBCs
through the platelet pheresis collection pro­
cedure. Platelets are also given at 10–15 ml/
kg, though are generally maximized to 1 unit
due to their short life (i.e., 3–4 days for trans­
fused platelets), unless the clinical scenario
dictates the need for additional platelets (i.e.,
ongoing bleeding, significant platelet
consumption).
b. Can the patient be transfused even
though she is febrile?
This is a common question that occurs on
the oncology unit. Although in the ideal sce­
nario the patient would be afebrile prior to
transfusion, this is often not the case.
Acetaminophen can be trialed prior to
transfusion if there is time to see if this
allows the patient to defervesce. The febrile
patient should be evaluated prior to transfu­
sion, and if stable should be okayed for
transfusion.
c. The nurse calls that the patient is
spiking a fever to 40.1°C during the
PRBC transfusion. What are the next
steps? What if the patient spiked a
40.1°C fever during the platelet
transfusion?
The patient should first be clinically evalu­
ated to ensure she is stable. Although an
acute hemolytic reaction due to ABO mis­
match is highly improbable, it must be first
ruled out in any PRBC transfusion. The
most likely diagnosis is a febrile nonhemo­
lytic transfusion reaction, though an allergic
reaction and sepsis from a tainted unit
should also be considered and may initially
present with fever. In the stable patient
­without signs of allergy or sepsis, the PRBC
transfusion can be continued, since the tem­
perature is less than 2°C greater than the
highest temperature in the last 24 hours. In
the case of platelet transfusion, a more strin­
gent threshold is utilized to rule out a septic
unit secondary to platelets being kept agi­
tated at room temperature. Our institutional
standard is to work up a platelet unit with
any temperature that is 1 °C greater than the
highest temperature in the last 24 hours or
with a new fever in the afebrile patient.
Patients again are most likely to be having a
febrile nonhemolytic reaction or allergic
reaction rather than sepsis, but the worst-
case scenario must be considered and ruled
out. In the case of a platelet transfusion, the
patient must first be evaluated and stabilized
as needed. The platelet transfusion should
be stopped and the patient cultured and
started on antibiotics (if not already on anti­
biotics). The platelet bag should be returned
to the blood bank where it should be worked
up for a transfusion reaction, which in this
situation would include a culture of the
platelet bag. An acute hemolytic reaction
with pheresed platelets is highly unlikely
given the small amount of RBC contamina­
tion, though workup for hemolysis is gener­
ally part of the transfusion-reaction workup,
including a DAT (Coombs), retyping of the
bag and patient, CBC/retic, LDH, and
urinalysis.
Multiple choice questions
1. You are on the oncology service following
a patient with acute myelogenous leukemia.
The patient is CMV seropositive. The patient
received myelosuppresive chemotherapy
10 days prior and now has a hgb of 6.1 g/dl.
Why should the patient receive irradiated
PRBCs?
a. Prevention of acute hemolytic trans­
fusion reaction
b. Prevention of allergic reaction
c. Prevention of febrile non‐hemolytic
transfusion reaction

d. Prevention of transfusion‐associated
graft‐versus‐host disease
e. Prevention of transfusion‐associated
acute lung injury (TRALI)
Explanation: Passive transfusion of donor
T‐cells in PRBCs can lead to a T‐cell donor
vs. recipient response in the severely immu­
nocompromised host leading to aplasia.
Irradiation kills these donor T‐cells and thus
prevents TA‐GVHD. Acute hemolytic trans­
fusion reactions occur due to clerical error
and ABO mismatch between donor and
recipient. Prevention of allergic reaction can
occur through the use of washed products.
Prevention of febrile non‐hemolytic trans­
fusion reactions occurs through the use of
leukofiltration which eliminates the major­
ity of WBCs and is standard of practice at
most blood banks in the United States.
TRALI can occur due to plasma compo­
nents, especially from fresh frozen plasma
(FFP) but also possibly platelets and PRBCs
and can be prevented through judicious use
of blood products. The answer is d.
2. You are on the oncology service follow­
ing a patient with acute myelogenous leuke­
mia. The patient is CMV seropositive. The
patient received myelosuppresive chemo­
therapy 10 days prior and now has a hgb of
6.1 g/dl. The patient weighs 45 kg and you
give 2 units of irradiated PRBCs. The total
volume of the 2 units is 650 ml. Assuming
no ongoing blood loss or hemolytic reaction
due to transfusion, what is the presumed
post‐transfusion hemoglobin?
a. 6.8 g/dl
b. 7.5 g/dl
c. 8.1 g/dl
d. 9.0 g/dl
e. 9.8 g/dl
Explanation: For PRBCs preserved in Adsol,
the transfusion factor is estimated to be 5
and can be used to calculate the estimated
rise in hemoglobin assuming no ongoing
losses from blood loss or loss due to red cell
Transfusion Medicine 77
breakdown due to antibody formation to
minor antigens in the chronically transfused
patient. The estimated rise in hgb can be cal­
culated by determining the amount of blood
transfused per kg (in this case 650 ml
divided by 45 kg or 14.4 ml/kg) and then
dividing that amount by 5. Therefore the
expected rise in hgb in this case is 14.4
divided by 5 or 2.9. The answer is d.
3. You are following a 12-year-old male
inpatient with sickle cell anemia with a hgb of
5.3 g/dl (baseline hgb 7‐8 g/dl) and reticulo­
cytopenia due to presumed viral suppression.
Studies for parvoviral infection are pending.
Based on the hgb and reticulocytopenia
you decide correctly to transfuse the patient.
Which of the below are the correct parame­
ters for PRBC transfusion in this patient?
a. Phenotypically matched
b. Phenotypically matched, sickledex
negative
c. Phenotypically matched, sickledex
negative, irradiated
d. Phenotypically matched, sickledex
negative, CMV negative
e. There are no requirements for this
urgently required PRBC unit
Explanation: Patients that are chronically
transfused (i.e., sickle cell anemia, thalas­
semia) should receive phenotypically
matched PRBCs to prevent alloimmuniza­
tion and refractoriness over time. As people
with sickle cell trait are not precluded from
donating blood, it is important to ensure
that any PRBC transfusion does not contain
sickle cells (i.e., sickledex negative).
Irradiated blood is limited to immunocom­
promised patients, as is CMV seronegative
blood for patients that may require hemat­
opoietic stem cell transplant and are immu­
nocompromised and CMV seronegative. In
an emergent situation if no phenotypically
matched blood is available, e. could be con­
sidered but this patient is relatively stable.
The answer is b.
78 Chapter 5
4. You are following a 10-year-old female
patient with aplastic anemia admitted to the
hospital for routine transfusions for anemia
and thrombocytopenia. She has a history of
febrile non‐hemolytic and allergic reactions
to both blood products so she receives pre‐
medications for both PRBCs and platelets.
About one hour into the PRBC transfusion
she spikes a fever to 102°F. You are called to
assess the patient and note that she is newly
hypotensive. All of the following are appro­
priate steps EXCEPT:
a. Order a transfusion reaction work up
including blood culture, urine, Coombs,
bilirubin
b. Start empiric ceftriaxone
c. Give an IVF bolus
d. Ask for a culture of the PRBC bag and
clerical check
e. Continue with the PRBC transfusion
Explanation: Acute transfusion reactions
can include febrile non‐hemolytic transfu­
sion reactions (FNHTR), acute hemolytic
reaction, allergic reaction and acute infec­
tion. A new fever or a fever 1‐2°C higher
than the previous highest temperature in the
last 24 hours should prompt a transfusion
reaction work up. ABO incompatibility is
highly unlikely and would present within
the first few minutes of transfusion with
hemolysis but should be considered even
beyond this point if with typical symptoms.
Fever is most likely secondary to a FNHTR
but allergic reaction and infection should be
ruled out especially with a high fever.
Although PRBC transfusion may be able to
be resumed, this should not occur until the
patient improves and the immediate work‐
up is negative. For the hypotensive patient,
given the potential concern for bacterial
contamination, the transfusion should not
be resumed. The answer is e.
5. You are following a new diagnosis patient
with ALL who is due for diagnostic bone
marrow aspiration and lumbar puncture in the
morning. You have been instructed to trans­
fuse platelets to reach a goal platelet count of
30 × 109/l and to maintain a hgb ≥7.0 g/dl for
anesthesia. The patient is 24 kg. Evening labs
result with a hgb of 6.0 and platelets of 14 ×
109/l. The patient is CMV seropositive. Which
is of the below is the best answer:
a. Give 1/2 unit platelets and PRBCs
b. Give 1/2 unit irradiated platelets and
1/2 unit irradiated PRBCs
c. Give 1 unit platelets and PRBCs
d. Give 1 unit irradiated platelets and
1 unit PRBCs
e. Give 1 unit irradiated platelets, 1 unit
irradiated PRBCs
Explanation: One unit of pheresed platelets
and one unit of PRBCs is generally 250–350
ml and the practitioner should aim to
transfuse in the range of half‐units so that
the blood bank can sterilely aliquot the
remainder. Transfusion should be given
with the goal of approximately 10‐15 ml/kg,
with a maximum transfusion of 1 unit plate­
lets and generally 2 units PRBCs. Although
the patient has not yet received chemother­
apy, they are likely still immunosuppressed
secondary to their underlying disease so it is
safest to irradiate the blood products to pre­
vent any potential risk of TA‐GVHD. The
answer is e.
Suggested reading
Delaney, M., Wendel, S., Bercovitz, R.S. et al.
(2016). Transfusion reactions: prevention,
diagnosis, and treatment. Lancet 388:
2825–2836.
Doctor, A., Cholette, J.M., Remy, K.E. et al. (2018).
Recommendations on Red Blood Cell
Transfusion in General Critically Ill Children
Based on Hemoglobin and/or Physiologic
Thresholds from the Pediatric Critical Care
Transfusion and Anemia Expertise Initiative.
Pediatr. Crit. Care Med. 19: S98–S113.
6 Chelation Therapy

proton magnetic resonance imaging (R2

Transfusional iron overload
MRI) is becoming widely utilized as an
accurate and noninvasive measure of organ
Iron overload may occur in any patient
iron content, and T2* MRI is becoming the
receiving intermittent transfusions for acute
standard for measuring cardiac iron stores.
illness (e.g., sickle cell disease), chronic
Institution of chelation therapy relative
transfusion therapy (e.g., thalassemia, sickle
to transfusion frequency is based on institu-
cell disease, red cell aplasia, bone marrow
tional practice. Patients that will require
failure syndromes), or in those having
chronic transfusion therapy should be che-
received an intensive period of frequent
lated before their liver iron reaches a high
transfusion (e.g., myelosuppressive chemo-
level, measured by liver biopsy, MRI quanti-
therapy/radiation for treatment of malig-
fication, or based on the number of transfu-
nancy and after hematopoietic stem cell
sions received (i.e., chelation initiated after
transplantation). Each milliliter of blood
receiving 10–20 transfusions, or approxi-
contains 1 mg of iron and normal iron stores
mately 3–6 g of transfusional iron in a 30‐kg
are approximately 3 g, with 2 g in the blood
patient). Thalassemia patients tend to have a
and 1 g in the liver. Therefore, patients
higher iron burden than sickle cell patients,
receiving frequent transfusion likely will
as the chronic inflammatory state in sickle
have received a large amount of transfused
cell disease limits gastrointestinal iron
iron and should be monitored for evidence
absorption due to upregulation of hepcidin.
of iron accumulation.
Thalassemia patients should be counseled to
There is no simple test for quantifying
be on a low‐iron diet.
total iron burden. Serial serum ferritin levels
Patients receiving intermittent transfu-
are helpful in determining hepatic iron
sion or those receiving frequent transfusion
stores, but values are altered in states of
therapy in a short period of time (e.g., with
inflammation. Liver biopsy remains the gold
intensive leukemia therapies) may have a
standard for quantification of total body
more insidious development of iron over-
iron, but is an invasive procedure. Liver iron
load. Patients with leukemia should have
levels ≥7 mg/g dry weight liver are indicative
serum ferritin levels checked at the end of
of iron overload. The superconducting
therapy. Those with ferritin levels >1000 ng/
quantum interference device (SQUID) is
ml should have serial checks every 3 months;
accepted as a noninvasive method to quanti-
if ferritin remains above this threshold after
tate total body iron, but its limited availabil-
6–12 months, the patient should undergo
ity does not allow for routine use. Currently,

Handbook of Pediatric Hematology and Oncology – Children’s Hospital & Research Center Oakland,
Third Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
80 Chapter 6

liver biopsy or R2 MRI for more accurate
iron quantification. These patients, espe-
cially male adolescents, may benefit from
monthly phlebotomy which can be discon-
tinued when the ferritin and liver iron
concentration reach normal levels (i.e.,
­ of two agents concomitantly is currently
<3 mg/g dry liver weight). Younger children
and menstruating females have been shown
to have reversible iron overload in most
such cases.
Current treatment strategies for iron
overload and potential side effects of iron
chelators are summarized in Table 6.1.
Desferoxamine (Desferal) has the longest
treatment record but requires parenteral
administration and has been widely replaced
by deferasirox (Exjade/Jadenu) due to the
convenience of oral intake and therefore
presumed increased compliance. Exjade and
Jadenu may not be effective in all patients,
which must be weighed against the risks of
noncompliance with Desferal. Deferiprone
(Ferriprox or Kelfer) is also available. Usage
undergoing clinical trials and may have par-
ticular benefit in chelation of cardiac iron.
Concomitant administration of ascorbic
acid (vitamin C) increases the excretion of
iron when given with chelation. Iron chela-
tors should not be administered when there is
concern for a bacterial infection. By mobiliz-
ing free iron, chelators promote bacterial
growth, in particular Yersinia enterocolitica.
For febrile patients on chelator therapy, chela-
tion should be stopped until blood c­ ultures
are definitively negative. Broad‐spectrum

Table 6.1 Iron chelators.

Name Desferoxamine (Desferal) Deferasirox (Exjade/ Deferiprone

Jadenu) (Ferriprox/Kelfer/L1)

Dose (mg/kg/d) 25–50 20–40 Exjade 75–100

14–28 Jadenu
Administration SC/IV, given as continuous PO (oral), daily PO, TID
infusion over 8–24 h,
5–7 d/wk
Side effects Irritation at infusion site, GI disturbance, rash, Agranulocytosis,
ototoxicity (tinnitus, renal and hepatic neutropenia, GI
transient hearing loss), impairment, GI disturbance,
ocular disturbance hemorrhage transaminitis,
(decreased night vision), arthropathy,
allergic reactions, progression of
growth failure, skeletal hepatic fibrosis
disturbance, pulmonary
hypersensitivity
Potential Highly effective but Long‐term data Long‐term data
therapeutic compliance may be an lacking; may not be lacking
issues issue due to route of effective in all
administration patients; has not
been studied in
combination with
other agents

Abbreviations: SC, subcutaneous; IV, intravenous; TID, three times a day; GI, gastrointestinal;
FDA, Food and Drug Administration.

antibiotic prophylaxis should be initiated in
the ill‐appearing or splenectomized patient
and include coverage for this unusual
organism.
Lead toxicity
Lead poisoning is an environmental disease
that has undergone a major evolution in the
past few decades. Recognition of the devas-
tating neurologic effects of high lead levels
and knowledge of the causes have led to
­universal efforts to decrease environmental
lead contamination, with a resultant decrease
in measured blood lead levels in children
over the past two to three decades. Sources of
lead have included gasoline additives, food‐
can soldering, lead‐based paints, ceramic
glazes, certain toys, drinking water systems
(lead pipes), and folk remedies. The use of
these products has been markedly reduced
as the result of federal guidelines and the
development of cost‐effective alternatives.
Lead in gasoline and paint is at extremely
low levels and has been eliminated altogether
from food‐can soldering. Housing built
prior to 1960 is likely to have been painted
with high‐content lead‐based paint, and
since lead isotopes are very stable, environ-
mental exposure presents an ongoing risk.
High‐risk populations have a greater likeli-
hood of living in older housing, which has
not had lead abatement. Risk factors for
excessive lead exposure include poverty, age
younger than 6 years, African‐American
ethnicity, and urban housing.
Lead may enter the body through direct
ingestion, inhalation, or via skin absorption.
The most common pathway among young
children is through the mouth. Lead absorp-
tion is enhanced in the presence of other
dietary mineral deficiencies, such as cal-
cium and iron, due to competitive biochem-
ical pathways. Pica behavior enhances the
likelihood of direct ingestion. Toddlers in
Chelation Therapy 81
particular are at risk due to normal develop-
mental behaviors such as putting objects
and toys in the mouth and chewing on unu-
sual surfaces (e.g., windowsills).
Lead entering the intravascular space
rapidly attaches to the red blood cell, with
minimal amounts (3%) detected in the
plasma. The half‐life in the blood is approxi-
mately 21–30 days. Excretion is primarily
through the kidneys, with small amounts
deposited in the hair, nails, and bile. The
lead that remains in the body accumulates
mostly in the bone (65–90%). Lead can
enter any cell and toxicity may occur in any
tissue or organ. Classically, in severe lead
intoxication, gastrointestinal and central
nervous system toxicities are the most clini-
cally apparent. Gastrointestinal symptoms
include anorexia, nausea, vomiting, abdom-
inal pain, and constipation. The blood lead
level is typically ≥50 mcg/dl when these
symptoms are present. Lead poisoning was a
lethal disease in the United States decades
ago, primarily related to neurotoxic effects.
At levels ≥100 mcg/dl, children may show
evidence of encephalopathy, including a
marked change in mentation or activity,
ataxia, seizures, and coma. Increased intrac-
ranial pressure may be present on examina-
tion. These effects are usually permanent
with long‐term sequelae of retardation, pal-
sies, and growth failure.
Most children who have elevated blood
lead levels have subclinical disease. Fewer
than 5% of children present with overt
symptoms of lead toxicity. An elevated
blood lead level, suggesting excessive envi-
ronmental exposure, is defined as 10 mcg/
dl. Many studies have shown associations
between blood lead levels and impaired
neurocognitive function. These results have
provided the primary impetus for current
public health efforts. Of note, no lead level is
normal and even lead levels below 10 mcg/dl
are thought to lead to subtle neurocognitive
dysfunction.
82 Chapter 6

Screening for lead toxicity Pediatrics (AAP) recommend venous blood

Prevention and treatment of lead toxicity
remains a major public health concern, and
efforts for screening have primarily focused
on high‐risk populations. All children
should have a screen of potential environ-
mental exposures by their primary health
care provider starting at 1 year of age and
repeated when the child is mobile and
attains hand‐to‐mouth behavior. The
Centers for Disease Control and Prevention
(CDC) and the American Academy of
lead sampling for children identified to be at
high risk (living in housing built prior to
1960, indigent, urban, and minority chil-
dren) at 1 and 2 years of age. Venous blood
samples should be used to assess blood lead
levels, as capillary samples may give falsely
low results. If the screening test confirms an
elevated blood lead level, specific manage-
ment guidelines have been developed by the
CDC and AAP and are summarized in
Table 6.2. The vast majority of children with

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 mentioned 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, dimercaptosuccinic acid) 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 (also called British anti‐Lewisite, BAL) 25 mg/kg/d IM, divided q4
h 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: TID, three times a day; BID, twice a day; CNS, central nervous system; EDTA,
ethylenediaminetetraacetic acid; IV, intravenous; IM, intramuscular.

elevated lead levels are not candidates for
chelation therapy with currently available
drugs. Children with low levels (<20 mcg/
dl) are asymptomatic and unlikely to have
significant increase in lead excretion with
chelation. These children benefit primarily
from decreased exposure.
Blood lead levels measure the blood con-
centration at a point in time and may not be
able to accurately predict bone stores. Bone
lead content may be assessed noninvasively
using a radiographic technique called X‐ray
fluorescence. Measurement of the heme
precursor, free erythrocyte protoporphyrin
­ routine lead screening at 1 year of age.
(FEP), may also provide a useful clue about
the duration of exposure and the degree of
lead accumulation. Excessively high FEP lev-
els classically are seen with severe lead toxic-
ity. Other causes of elevated FEP levels include
iron deficiency, inflammatory disorders (due
to decreased iron absorption), increased fetal
hemoglobin, and rarely, porphyria.
Management of lead toxicity
The primary aims of management are pre-
vention of future lead exposure and result-
ant absorption, as well as enhancement of
excretion. The steps to accomplish these
goals include:
1. Assessment of the environment to elimi-
nate the sources of exposure or removal of the
child from the contaminated environment.
2. Modifying the child’s behavior to
decrease hand‐to‐mouth activity.
3. Ensuring adequate nutrition, especially
minerals, to limit lead absorption, including
evaluation for concomitant iron deficiency.
4. Administering medications (chelators)
in children with very high lead levels to
increase lead excretion.
After chelation therapy, a period of re‐
equilibration for 10–14 days should be
allowed, prior to repeat assessment of the
blood lead concentration. Subsequent
treatments should be based on these levels,
Chelation Therapy 83
using the same criteria specified in
Table 6.2. Ongoing efforts should be made
to provide the family with education in
order to prevent exposure in the child’s
environment in addition to assuring ade-
quate nutrition. Family members and
­siblings should be screened as well.
Case study for review
1. You are working at a primary pediatric
clinic in an urban setting and have instituted
A routine screening result returns at
17 mcg/dl for a 14-month-old male whom
you screened at his first visit with you.
a. What are the initial steps?
The family should be contacted to return to
see you. We generally recommend repeating
a venous sample to ensure an accurate result
prior to contacting the public health depart-
ment and instituting any treatment (if
required). An environmental screen should
be conducted and the patient ruled out for
any pica behavior. Concomitant iron defi-
ciency should be ruled out as pica behavior
leading to ingestion of lead may be due to
underlying iron deficiency.
b. A repeat venous lead level comes
back at 24 mcg/dl. The patient is also
noted to have a microcytic anemia with
hemoglobin of 9.4 g/dl and mean cor-
puscular volume (MCV) of 69 fl. What
are the next steps?
The confirmatory testing shows that the
patient has lead toxicity. The public health
department must be contacted to do an
environmental assessment. Since the child
has concomitant iron deficiency, there is a
chance that he ingested lead and therefore
an abdominal radiograph should be under-
taken. Any siblings of the patient should
also be screened for lead toxicity with venous
samples and treated as appropriate based on
their levels. The mild iron deficiency anemia
84 Chapter 6
should be concomitantly treated with iron at
a dose of 3–4 mg/kg elemental iron daily to
prevent pica behavior. The family should be
counseled on appropriate nutrition as well
as methods to avoid lead. Potential unusual
sources of lead such as toys or candies from
international countries should be consid-
ered and ruled out. After these interven-
tions, the patient should be retested in 2
weeks to ensure improvement in lead level,
and treatment as appropriate based on the
subsequent level.
Suggested reading
Bellinger, D.C. (2008). Very low lead exposures
and children’s neurodevelopment. Curr. Opin.
Pediatr. 20: 172–177.
Brittenham, G.M. (2011). Iron‐chelating therapy
for transfusional iron overload. N. Engl. J.
Med. 364: 146–156.
Chandra, L. and Cataldo, R. (2010). Lead poison-
ing: basics and new developments. Pediatr.
Rev. 31: 399–406.
Gracia, R.C. and Snodgrass, W.R. (2007). Lead
toxicity and chelation therapy. Am. J. Health
Syst. Pharm. 64: 45–53.
Kwiatkowski, J.L. (2011). Real‐world use of iron
chelators. Hematology Am. Soc. Hematol.
Educ. Program 1: 451–458.
Marsella, M. and Borgna‐Pignatti, C. (2014).
Transfusional iron overload and iron chela-
tion therapy in thalassemia major and sickle
cell disease. Hematol. Oncol. Clin. North Am.
28: 703–727.
7 Approach to the
Bleeding Child
Hemostasis is a critical protective response
of the body to reverse a loss of vascular
integrity and prevent excessive blood loss. It
requires a coordinated interaction between
platelets, vascular endothelial cells, and
plasma clotting factors. The first and pri-
mary stage of hemostasis is the formation of
a platelet plug, which involves a complex
interaction between circulating platelets and
the exposed vascular subendothelial layer.
The steps in the process include platelet
adhesion, mediated by an interaction
between von Willebrand factor (VWF) and
platelet surface glycoprotein (Gp) Ib; and
platelet activation, mediated by platelet sur-
face glycoprotein IIb/IIIa and leading to
release of platelet contents. Gp IIb/IIIa inter-
acts with VWF and fibrinogen, leading to
platelet aggregation and enlargement of the
platelet plug. This lays the foundation for
the formation of a fibrin clot, the secondary
stage of hemostasis caused by the activation
of the coagulation cascade.
Clinical disorders associated with abnor-
malities of primary hemostasis include
­vascular abnormalities, qualitative abnormal-
ities of the platelets, quantitative abnormal-
ities of the platelets, and von Willebrand
disease (VWD). These aberrations in primary
hemostasis are characterized by ­bleeding of
the mucous membranes, epistaxis, and super-
ficial ecchymoses. Typical manifestations are
prolonged oozing from minor wounds or
Handbook of Pediatric Hematology and Oncology – Children’s Hospital & Research Center Oakland,
Third Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
abrasions, or abnormal intraoperative bleed-
ing. Aberrations in secondary hemostasis are
characterized by bleeding from large vessels
with subcutaneous, palpable hematomas,
hemarthroses, or intramuscular hematomas.
The hemophilias are examples of disorders in
this category and are reviewed in Chapter 9.
Evaluation of the bleeding
child
There are three critical questions that must
be addressed when faced with a child who is
actively bleeding or by history has experi-
enced a major hemorrhage. The first two
questions are, “is the patient continuing to
bleed?” and “is the patient hemodynami-
cally stable?” These questions should be
answered quickly and simultaneously.
Patients who are actively bleeding but are
hemodynamically stable should have efforts
directed at controlling the bleeding. While
therapies that are specific for a particular
bleeding disorder should not be provided
before a diagnosis is made, more general
strategies such as ice, pressure, and elevation
can be used. Recombinant factor VIIa is
being increasingly used to control severe or
life‐threatening bleeding caused by a variety
of mechanisms. Patients who do not appear
to be actively bleeding but are hemodynami-
cally unstable require rapid initiation of
86 Chapter 7
v­ascular re‐expansion and a search for
occult bleeding.
Once the patient is stabilized and bleed-
ing is controlled, the third critical question is
whether the child presenting with bleeding
warrants an evaluation for a bleeding disor-
der. Examples of excessive bleeding include
epistaxis lasting more than 15 minutes
despite the appropriate application of pres-
sure to the side of the nose, significant blood
loss following a dental procedure lasting
more than 24 hours or requiring blood
transfusion, bruising that seems excessive
following trauma, or menorrhagia (heavy
menstrual bleeding lasting for 7 days or loss
of more than 80 ml of blood per cycle). When
evaluating a child for “excessive bruising,” it
is essential to determine whether the bruis-
ing could be the result of nonaccidental
trauma. Bruising involving the scalp, back,
or chest or having a pattern suggestive of
common instruments of abuse such as belts,
cords, or wire should be reported. Excessive
bruising caused by underlying bleeding dis-
orders occurs on areas more commonly
involved in falls or trauma such as shins and
bony prominences.
History
Assessment of the child with a suspected or
known bleeding diathesis begins with a
complete history. The nature of the bleeding
should be explored with particular attention
to location, duration, frequency, and the
measures necessary to stop it. The time of
the patient’s first episode of bleeding should
be documented and a careful history of
bruising during the toddler age is impor-
tant. A previous history of bleeding asso-
ciated with trauma or surgery, dental
extraction, circumcision, or tonsillectomy is
also important, as is a history of petechial
rash, arthritis with hemarthroses, or blood
transfusion. In females, the duration and
severity of menstrual bleeding should be
documented.
A family history and pedigree are cru-
cial, as many bleeding disorders are heredi-
tary. The history should also address the use
of over‐the‐counter and prescription drugs
that can induce bleeding. Common offend-
ers include aspirin, ibuprofen, naproxen,
and other nonsteroidal anti‐inflammatory
drugs (NSAIDs). It is important to ask the
patient specifically about the use of medica-
tions for colds, sinus trouble, muscle aches,
or headaches, which may contain these
medications. It is also important to ask
whether the patient has access to oral anti-
coagulant medications prescribed to other
family members, such as warfarin, clopi-
dogrel, prasugrel, or ticagrelor. Some anti-
biotics, penicillins in particular, can affect
platelet function or be associated with
­specific inhibitors of clotting, while others
such as vancomycin can be associated with
thrombocytopenia through an immune‐
mediated process. Anticonvulsants can
cause thrombocytopenia, and procainamide
has been associated with an acquired lupus
anticoagulant.
Physical examination
In addition to the routine examination, the
skin should be scrutinized carefully for
petechiae, purpura, and venous telangiecta-
sias. The joints should be examined for
swelling or chronic changes such as contrac-
tures or distorted appearance with asymme-
try related to repeated bleeding episodes.
Mucosal surfaces, such as the gingiva and
nares, should be examined for bleeding.
Initial laboratory evaluation
The purpose of the initial laboratory
­evaluation is to screen for the presence of a
bleeding disorder, hopefully categorize the
disorder as primary or secondary, and direct
further evaluation. Appropriate screening
tests include a CBC, peripheral blood smear
(PBS), prothrombin time (PT), and acti-
vated partial thromboplastin time (APTT,

hereafter PTT). The international normal-
ized ratio (INR) corrects differences in PT
due to variable thromboplastin potency
across laboratories. In certain circum-
stances, this list will also include a fibrino-
gen and a thrombin time (TT).
A CBC provides several pieces of useful
information. It provides the platelet count,
identifying in most cases the presence or
absence of thrombocytopenia. However, it is
important to review an actual blood smear,
as a small number of patients with a low
measured platelet count will have pseudo-
thrombocytopenia, a condition caused by
platelet clumping in the presence of the anti-
coagulant EDTA. The CBC also provides
the hemoglobin and mean corpuscular vol-
ume (MCV), which can provide clues
regarding the duration and severity of the
patient’s bleeding. The presence of anemia
indicates a clinically significant bleeding
disorder; the concomitant presence of
microcytosis suggests the bleeding has been
prolonged and has led to iron deficiency. A
normocytic anemia suggests the bleeding
has been more recent and likely more severe,
as the blood loss has likely been more sig-
nificant. Abnormalities in more than one
cell line (anemia, thrombocytopenia, or
neutropenia) suggest the presence of a bone
marrow failure state such as aplastic anemia
or marrow infiltration as is seen in leuke-
mia. Most analyzers provide a measure of
the mean platelet volume (MPV) that can be
useful in evaluating the thrombocytopenic
patient, however visualization of the plate-
lets on the smear is often more accurate, as
automated MPV may be challenging with
severe thrombocytopenia or clumping.
Large platelets are often seen in consump-
tive thrombocytopenia such as active
bleeding or immune thrombocytopenia
­ plasma (with additional phospholipid) as is
purpura (ITP); normal‐sized platelets in
hypoproliferative thrombocytopenia; and
small platelets in inherited conditions such
as Wiskott–Aldrich syndrome.
Approach to the Bleeding Child 87
The PT measures the integrity of the
extrinsic system of coagulation (extrinsic
secondary to the necessity of activation by
tissue factor). Factor VII is the only coagula-
tion factor measured by the PT that is not
measured by the PTT. Thus, in isolated fac-
tor VII deficiency, the PT is prolonged with
a normal PTT. Factor VII is vitamin–K‐
dependent and has a very short half‐life, so
the PT is one of the most sensitive measures
of oral anticoagulant therapy with vitamin K
antagonists such as warfarin. The INR is
used primarily to evaluate the adequacy of
warfarin therapy; the PT should be used to
look for the presence of a clotting factor
deficiency.
The PTT assesses the integrity of the
intrinsic system of coagulation (intrinsic
secondary to direct endothelial activation).
Depending on the laboratory methods, the
PTT will be normal when the activity of all
measured coagulation factors is at least 30%
of normal. It is prolonged in patients with
hemophilia, and in some patients with
VWD due to decreased concentration of
factor VIII in the plasma. However, the PTT
is much more susceptible than the PT to
spurious abnormalities caused by errors in
collection or processing of the specimen.
These are outlined in Table 7.1.
The most commonly encountered inhib-
itors detected in children are so called lupus
anticoagulants. These are IgG antibodies
directed against phospholipids, and while
they are commonly identified in adults with
autoimmune disease, they occur frequently
in children as a postinfectious phenomenon
that is short‐lived. As phospholipid is an
essential cofactor in the PTT assay, antiphos-
pholipid antibodies will commonly cause
prolongation of the test. Addition of normal
done in mixing studies will often at least
partially normalize the test, but it will most
often remain abnormal. These antibodies
have no effect on clotting in vivo, and
88 Chapter 7
Table 7.1 Factors affecting the validity of the PTT test.
Aspect Problem
Sample Clots
collection
Plasma volume
Heparin contamination
Interpretation Age‐dependent normal
values
Inhibitor vs. factor
deficiency
Abbreviations: PTT, partial thromboplastin time; PT, prothrombin time.
patients with lupus anticoagulants do not
have clinical bleeding; in fact, their most
common coagulation problem is thrombo-
philia rather than bleeding.
The TT is useful in evaluating the ter-
minal steps of coagulation and identifying
anticoagulants present in plasma. The TT
is abnormal when the plasma concentra-
tion of fibrinogen is decreased (hypofibrin-
ogenemia or afibrinogenemia), when the
fibrinogen present is dysfunctional (dysfi-
brinogenemia), or when there are circulating
anticoagulants (heparin) or fibrin degrada-
tion products. As dysfibrinogenemia is
most often asymptomatic, a prolonged TT
in the face of a normal fibrinogen level is
Remarks
Clots caused by slow blood flow or delay in
transferring sample will cause abnormal results.
Volume of anticoagulant must be corrected for
plasma volume. If tube not completely filled, or
patient extremely anemic or polycythemic,
sample will not be appropriately anticoagulated.
Very small amounts of heparin will cause the PTT
to be abnormal.
Mild prolongation is normal in the newborn
period (immaturity of the coagulation system).
A number of agents can interfere with the PTT
assay and cause a factitious prolongation of
the test. If the concentration is high, they can
lead to a mild prolongation 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 in the text).
almost always associated with heparin or
an inhibitor.
Abnormalities in one or more of the
abovementioned screening tests will be
noted with most bleeding disorders. An
approach to identifying the most likely
coagulation disorders given the results of
these tests is presented in Table 7.2.
Once the diagnosis is made, specific
treatment can be provided based on the rec-
ommendations provided in the following
chapters. One exception is the management
of epistaxis. Though epistaxis is caused by a
variety of conditions, in most situations an
initial uniform management plan is appro-
priate and therefore presented here.
 Approach to the Bleeding Child 89

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 (FXIII screening;
do FXIII assay if abnormal)
Euglobulin clot lysis (replaced by
TEG in most places); can also
measure specific functional assays
Alpha‐2‐antiplasmin, PAI‐1, TPA
PT normal PTT inhibitor PTT mixing study
PTT prolonged von Willebrand disease Factor assays (i.e., VIII, IX, XI)
Platelet count Hemophilia A (FVIII deficiency) von Willebrand studies
normal or B (FIX deficiency) Thrombin time/reptilase time
Heparin contamination
PT prolonged PT inhibitor PT mixing study
PTT normal Vitamin K deficiency Factor assays (i.e., II, VII, IX, X)
Platelet count Warfarin
normal Factor VII deficiency
Liver dysfunction
PT prolonged Circulating inhibitor PT/PTT mixing studies
PTT prolonged Liver dysfunction TT
Platelet count Vitamin K deficiency Reptilase time (unaffected by
normal Factor deficiency (II, V, X, or heparin)
fibrinogen) Fibrinogen
Dysfibrinogenemia Factor assays
PT prolonged DIC TT
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 or Tests for Helicobacter pylori
immune deficiency (i.e., HIV, hepatitis panel
common variable Anticardiolipin antibodies
immunodeficiency) Direct antiglobulin test
Von Willebrand disease Serum immunoglobulin levels
Early stage of bone marrow failure Serum complement levels
syndrome von Willebrand factor multimer
analysis (type IIB)
Bone marrow aspirate
Marrow chromosomal analysis

Abbreviations: PT, prothrombin time; PTT, partial thromboplastin time; PFA‐100, platelet
function analyzer‐100; TEG, thromboelastography; PAI‐1, plasminogen activator inhibitor‐1;
TPA, tissue plasminogen activator; TT, thrombin time; DIC, disseminated intravascular
coagulation; ITP, immune thrombocytopenic purpura; HIV, human immunodeficiency virus.
90 Chapter 7
Management of epistaxis
1. Place patient in a sitting position to
decrease venous pressure or, if the patient is
recumbent in bed, turn head to the side.
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-
ing the chest.
3. With the thumb and index finger, pinch
the soft parts of the nose. Hold pressure
firmly over the lower half of the nose. Avoid
compressing the upper half of the nose.
4. Hold pressure for 20 minutes with the
head in a flexed position. If manual pres-
sure is stopped momentarily to examine or
change dressings, the 20‐minute digital
pressure will likely need to start again.
Pressure and time allow for clot formation
to occur. If bleeding continues, reassess
location of digital pressure and reapply. If
bleeding stops and recurs, repeat manual
pressure for 20 minutes. If bleeding contin-
ues and clot(s) can be visualized, remove
clot(s) and reapply digital pressure for
20 minutes.
5. Advise patient not to blow nose for at
least 12 hours to avoid dislodging the clot.
6. Nasal packing may be indicated if the
source of bleeding is not well‐visualized or
bleeding is profuse. Types of packing include
compressed sponge, Vaseline gauze packing,
Gelfoam, or topical thrombin packing.
Compressed sponges are compressed when
dry and expand when wet. The expansion
produces active and passive absorption and
places gentle pressure on the mucosa. The
nasal sponge should fit snugly through the
naris and be placed along the floor of the
nasal cavity. Sponges are easy to insert and
can be removed with little discomfort.
Neosporin can be applied to the sponge for
ease of insertion and act as an antimicrobial
agent. Topical thrombin powder (a vasocon-
strictor) applied to the inserted end of the
sponge can provide additional hemostasis.
Anterior packs may be left in place for
1‐5 days, though should be removed
within 24 hours in an immune‐compro-
mised patient due to the risk of infection.
Humidification and nasal saline spray can
help prevent drying and crusting of the oral
mucous membranes as a result of mouth
bleeding. Broad‐spectrum antibiotics, to
cover skin flora as well, should be consid-
ered in patients who are immunosuppressed
with a nasal pack in place. Vaseline gauze
packing, when placed correctly and snugly,
is a reliable means of packing. Packing may
be soaked in a solution of 4% lidocaine and
topical epinephrine (1:1000) to provide
local anesthesia and vasoconstriction.
Case study for review
A 3‐year‐old female presents to the emer-
gency department (ED) with petechiae and
repeated epistaxis. Two weeks earlier she
had been admitted to an outside hospital
with epistaxis accompanied by two episodes
of vomiting dark red blood. Results of the
laboratory evaluation included: WBC count
8.2 × 109/l; hemoglobin 10.7 g/dl; platelet
count 142 × 109/l, PT, 11.5 seconds (normal);
APTT 31.2 seconds (normal); and fibrino-
gen, 2.5 g/l (RI, 2.0–4.0 g/l). The patient was
discharged in good condition after inser-
tion of nasal packs. One day prior to the
current presentation, the patient again had
prolonged epistaxis, this time accompanied
by four episodes of hematemesis and a mel-
anotic stool. Her parents denied fever or
diarrhea. She is not currently receiving any
medications. The patient had a history of
easy bruising and recurrent gingival bleed-
ing, but no history of hemarthrosis. There
was no family history of abnormal
bleeding.

On examination, she appeared pale.
Her vital signs were normal. Her skin had
scattered petechiae. Crusted blood was
­present in both nares. The physical exami-
nation was otherwise unremarkable.
a. What would you do next?
It appears that at present the patient is not
actively bleeding and is hemodynamically
stable, so efforts can be directed to deter-
mining if a bleeding disorder is present.
The patient’s PT and PTT were normal
initially, making a coagulopathy less
likely. Also, epistaxis is more commonly
associated with VWD, thrombocytope-
nia, or platelet function abnormalities.
The platelet count was normal, ruling out
thrombocytopenia.
b. In order to identify a possible bleed-
ing disorder, what other laboratory stud-
ies might be helpful?
A repeat CBC would be indicated given the
additional bleeding that has occurred. The
WBC count was 21 × 109/l, hemoglobin 6.1
g/dl, MCV 84.7, platelet count 384 ×
109/l,and reticulocyte count 6.8%. These
results indicate that despite a healthy bone
marrow response the anemia is worsening,
consistent with significant blood loss. The
platelet count is normal, again ruling out
thrombocytopenia as a cause of the bleed-
ing. The MCV is normal, suggesting that the
anemia is due to acute blood loss rather than
to iron deficiency from chronic, ongoing
blood loss.
Repeat PT is 10.3 seconds, PTT is 25.5
seconds; both are normal. VWF antigen is
212%, factor VIII is 182%, ristocetin cofac-
tor activity is 160%. These results rule out
VWD.
Platelet aggregation studies reveal an
absent response to ADP, epinephrine, ara-
chidonic acid, and collagen, but a normal
response to ristocetin. This pattern of
response is diagnostic of Glanzmann
Approach to the Bleeding Child 91
t­hrombasthenia, an inherited platelet func-
tion abnormality discussed more fully in a
subsequent chapter.
Multiple choice questions
1. You are seeing a 12-year-old male patient
in the emergency department with recurrent
epistaxis. All of the following are reassuring
that there is no underlying bleeding diathesis
EXCEPT:
a. Normal coagulation studies
b. No family history of bleeding
problems
c. Patient has a mild microcytic anemia
d. No personal history of easy bleeding
or bruising beyond the epistaxis
e. No noted blood in the urine or stool
Explanation: Risk of bleeding can often be
determined by obtaining a thorough per-
sonal and family history. Important ques-
tions to ask include a family history of
bleeding which required blood transfu-
sions, which lead to difficulty with surger-
ies, and with special consideration to male
members of the maternal side when
­considering hemophilia A or B in a male
patient. History of menorrhagia and
­problems of bleeding during delivery are
also important questions to ask. Personal
history should concentrate on the type of
bleeding, frequency of symptoms, duration
of symptoms and previous need for inter-
ventions. Utilization of medications
including aspirin and NSAIDs should be
obtained. Finally, baseline screening evalu-
ation to look for anemia, thrombocytope-
nia and coagulopathy should be ascertained
through a CBC and coagulation panel.
Microcytic anemia may be due to chronic
occult blood loss and may point to an
underlying bleeding diathesis in this case.
The answer is c.
92 Chapter 7
2. You are seeing a 14-year-old female patient
who notes heavy periods as compared to her
older sister requiring >6 heavy pads per day.
She notes that her mother has a similar com-
plaint and suffers from anemia but has had
no further work up or diagnosis. She eats a
varied diet and has no other medical com-
plaints. She does not take any other medica-
tions. On screening labs you note she has a
microcytic anemia with normal coagulation
studies. Of the following the most likely
diagnosis is:
a. Vitamin K deficiency
b. Hemophilia A
c. Immune thrombocytopenic purpura
d. Von Willebrand disease
e. Dysfibrinogenemia
Explanation: The most likely diagnosis in
this case is dysfunctional uterine bleeding
which is common but given the above
choices, von Willebrand disease (VWD) is
most likely and affects as much as 1% of the
population. Symptoms can be non‐specific
and there may or may not be a family his-
tory. PTT may be prolonged in certain
cases due to concomitant deficiency of
FVIIIc. Similarly iron deficiency anemia
and/or thrombocytopenia may be present.
Screening for VWD should include meas-
urement of von Willebrand factor antigen,
ristocetin cofactor (von Willebrand factor
activity) and activated FVIII. The answer
is d.
3. You are seeing a 4-year-old male patient
in the hospital admitted with vomiting and
altered mental status eventually found to have
bilateral subdural hematomas on CT head
imaging. Non‐accidental trauma is possible
and a hematology work up is commenced.
The PT is normal while the PTT is prolonged.
The PTT corrects on 1:1 mix. Of the follow-
ing, all are possible diagnoses EXCEPT:
a. Vitamin K deficiency
b. Heparin contamination
c. Hemophilia A
d. Hemophilia B
e. Hemophilia C
Explanation: Disorders in the intrinsic path-
way include factor XI (hemophilia C), factor
IX (hemophilia B) and factor VIII (hemo-
philia A), especially in the male patient. For
prolonged PTT, heparin contamination can
be ruled out by repeating the test or check-
ing a thrombin time which is very sensitive
to heparin (i.e., normal thrombin time rules
out heparin contamination). A 1:1 mix will
help differentiate between a factor defi-
ciency in which addition of normal plasma
will correct the PT or PTT prolongation or
an antibody, in which case the 1:1 mix will
not correct. The answer is a.
4. You are following a patient who has been
in the PICU for quite some time recovering
from sepsis. There is concern for underlying
organ dysfunction and the patient has been
on total parenteral nutrition (TPN) for quite
some time. A coagulation panel is checked
and is notable for a prolonged PT with a
normal PTT. Of the following, all are possi-
ble diagnoses EXCEPT:
a. Vitamin K deficiency
b. Liver disease
c. FVII deficiency
d. Presence of an inhibitor
e. Heparin contamination
Explanation: Isolated prolongation of the
PT, or the extrinsic pathway can occur for
multiple reasons. Vitamin K deficiency
affects multiple coagulation factors includ-
ing FII, FVII, FIX and FX in addition to pro-
tein C and protein S. As FVII has the shortest
half‐life, mild vitamin K deficiency may
affect the extrinsic pathway prior to the
intrinsic pathway. This is similarly the case
in liver disease as the majority of coagula-
tion factors are produced in the liver. FVII
deficiency is extremely rare but would also
lead to isolated prolongation of the PT. As
no 1:1 mix was noted, the PT prolongation
could also be due to an antibody which

would lead to the PT remaining prolonged
on 1:1 mix. Heparin specifically affects the
intrinsic pathway and would only affect the
PT if there was significant heparinization,
but this would occur in conjunction with a
very high PTT. The answer is e.
5. You are seeing a 12-year-old male with
severe hemophilia A. He has been poorly
compliant with his prophylactic factor infu-
sions and presents to the ED complaining of
severe hip pain and inability to fully rotate
the hip. Of the following the most important
initial consideration is:
a. Checking factor levels
b. Administering recombinant FVIII
c. Performing a CT to rule out an occult
head bleed
d. Performing a CT to rule out an iliop-
soas bleed
e. Determining his full medical history
Explanation: Severe hemophilia implies a
factor level of <1%, with moderate hemo-
philia has a factor level of 1%‐5% and mild
hemophilia a factor level of 5%‐50%.
Patients with severe hemophilia are main-
tained on prophylactic factor to prevent
spontaneous bleeding episodes, one of the
most severe being an iliopsoas bleed.
Although it is important to rule out an
Approach to the Bleeding Child 93
i­ liopsoas bleed, the first step is to give factor
replacement, ideally with the patient’s home
medication supply. CT head is not indicated
in this case unless the exam or history are
concerning. The other steps are all impor-
tant but can be done after factor is given.
Factor levels will be important to follow to
ensure the patient is receiving therapeutic
dosing, with the goal of achieving 100%
­factor levels. In the case of hemophilia A,
the patient should receive a dose of 50 units
x weight (kg) to achieve 100% factor levels,
assuming there is no concomitant inhibitor
(and rounded up to the nearest vial size).
The answer is b.
Suggesting reading
Allen, G.A. and Glader, B. (2002). Approach to
the bleeding child. Pediatr. Clin. N. Am. 49:
1239–1256.
Bansal, D., Oberoi, S., Marwaha, R.K., and Singhi,
S.C. (2013). Approach to a child with bleeding
in the emergency room. Indian J. Pediatr. 80:
411–420.
Khair, K. and Liesner, R. (2006). Bruising and
bleeding in infants and children – a practical
approach. Br. J. Haematol. 133: 221–223.
Monagle, P., Ignjatovic, V., and Savoia, H. (2010).
Hemostasis in neonates and children: pitfalls
and dilemmas. Blood Rev. 24: 63–68.
8 Von Willebrand
Disease
Von Willebrand disease (VWD) is the most
common inherited bleeding disorder, affect-
ing as much as 1% of the general population,
and equally affects both sexes as well as all
races and ethnicities. The actual prevalence
is difficult to determine, as many affected
individuals are either asymptomatic or have
such mild symptoms that they do not seek
medical attention. While most patients with
VWD have the inherited form, an acquired
form also occurs. The three characteristic
clinical features of the inherited form are
excessive mucocutaneous bleeding, abnormal
von Willebrand factor (VWF) laboratory
studies, and a family ­history of abnormal
bleeding.
VWF is a large multimeric glycoprotein
that is synthesized and stored in megakary-
ocytes and endothelial cells. VWD is usually
inherited in an autosomal dominant man-
ner, but a rare autosomal recessive form and
an X‐linked recessive form have also been
described. VWD results from either a
­deficiency or a defect in the VWF protein.
This protein plays two critical roles in hemo-
stasis: the large multimers bind to platelet
­glycoprotein Ib (GPIb) causing platelet acti-
vation and adherence to damaged endothe-
lium, and it is the carrier protein for factor
VIII (FVIII), stabilizing it and protecting
it from degradation and clearance from
plasma. This accounts for the prolonged
APTT seen in some patients.
Handbook of Pediatric Hematology and Oncology – Children’s Hospital & Research Center Oakland,
Third Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
VWD is classified into three types: Type
1, found in up to 85% of cases, is charac-
terized by partial deficiency of normally
functioning VWF. Type 2 is characterized
by functional defects in VWF. It is broken
down into four subtypes. Type 2A is marked
by defects in multimerization and a con-
comitant decrease in platelet adhesion. The
measured amount of VWF:Ag (antigen) is
normal or only slightly decreased, but the
VWF:RCo (ristocetin cofactor) is much
lower. Type 2B is caused by mutations that
pathologically increase platelet–VWF bind-
ing, which leads to the proteolytic degrada-
tion and depletion of large, functional VWF
multimers. Circulating platelets are also
coated with abnormal VWF, which may
prevent the platelets from adhering at sites
of injury. The VWF‐coated platelets often
become sequestered in the microcircula-
tion, leading to thrombocytopenia. Type
2M is characterized by defects in ligand
binding between VWF and platelet GPIb or
connective tissue. The ratio of VWF:RCo
to VWF:Ag is low as in Type 2A, but the
multimer panel appears normal. Type 2N
is marked by decreased binding between
VWF and FVIII, resulting in a phenotype
of autosomal recessive hemophilia. Type 3
VWD is a rare condition affecting about
1 per one million individuals, and is charac-
terized by the almost complete absence
of VWF.
96 Chapter 8
The majority of affected patients experi-
ence mucocutaneous bleeding such as
epistaxis, easy bruising, and menorrhagia
in women. Gastrointestinal bleeding is a
particular problem for patients with Type
2A VWD. All VWD patients may also
experience post‐traumatic or postsurgical
­ ing symptoms seen in normal individuals.
bleeding. Patients with severe VWD may
experience bleeding into muscles and joints
as well. VWD should be suspected in the
patient with platelet‐type bleeding and a
family history of a bleeding diathesis.
Clinical presentation
The clinical features of VWD can be quite
variable. In most cases of VWD, the bleed-
ing is mild. Mucosal bleeding such as
epistaxis, gingival bleeding with tooth
brushing, ecchymoses, or menorrhagia are
classic. The initial presentation, however,
may be postoperative bleeding, such as fol-
lowing a tonsillectomy and adenoidectomy
or dental extraction. In retrospect, the child
who was thought to have normal childhood
complaints (bruising and epistaxis) is real-
ized to actually have a bleeding disorder.
Recurrent or severe epistaxis, particularly
in the older child or adult, is unusual and
warrants investigation. Since other affected
family members are often unaware they
have the condition, simply inquiring about a
history of bleeding problems often yields
negative results. Because the bleeding his-
tory is so important for the diagnosis of
VWD, many attempts have been made to
objectively quantify reported bleeding
symptoms by developing bleeding assess-
ment tools. The International Society on
Thrombosis and Haemostasis (ISTH) has
developed and performed initial validation
of a bleeding assessment tool for use in
screening patients for VWD. Normal ranges
have been established for children, adult
males, and adult females. A pediatric
­ leeding questionnaire (PBQ) has also been
b
shown to be useful as a screening tool
for VWD in the pediatric population.
Unfortunately, while its negative predictive
value is high, its positive predictive value is
low due to the wide range of normal bleed-
Often, once the child is diagnosed with
VWD, a parent or siblings are found to have
the disorder after screening.
In patients with mild VWD, the stress
associated with serious operations or child-
birth may prevent symptoms. VWF is an
acute phase reactant and the level will fre-
quently increase into the normal range fol-
lowing surgery, in pregnancy, or in patients
with active liver disease or collagen vascular
disease. It can be reduced in hypothyroid-
ism. Even the stress of phlebotomy can
increase the level of VWF, which can make it
difficult to confirm the diagnosis even with
repeat testing. Neonates have elevated VWF
levels following vaginal delivery, making it
difficult to diagnose in the neonatal period.
VWF levels can be up to 25% lower in indi-
viduals who are blood type O, increasing the
difficulty in distinguishing between VWD
and normal individuals with a low VWF
level. VWF levels also increase physiologi-
cally throughout life; patients diagnosed
with VWD in childhood may no longer
meet the VWF level criterion when they get
older. However, many of them do still appear
to be at risk for bleeding.
Diagnosis
Screening tests are of little value in making
the diagnosis of VWD. The CBC may dem-
onstrate iron‐deficiency anemia if the
patient’s blood loss has been significant, but
this is nonspecific. The rare patient with
Type 2B VWD may have mild thrombocy-
topenia. If the level of VWF is sufficiently
low, the APTT may be prolonged due to

decreased concentration of factor VIII, but
this is neither sensitive nor specific. The
platelet function analyzer (PFA‐100) is a
more useful screening test for VWD. It
measures the time required for blood, drawn
through a fine capillary, to block a mem-
brane coated with collagen and epinephrine
(CEPI) or collagen and adenosine diphos-
phate (CADP). Its sensitivity in identifying
patients with VWD is fairly high, but its
specificity is low. Four specific tests have
traditionally been used to diagnose VWD:
1. Factor VIII coagulant (FVIIIc): functional
measurement of FVIII coagulant activity,
which is carried in the circulation by VWF.
2. Von Willebrand factor antigen (VWF:
Ag): VWF protein as measured by protein
assays; does not imply functional ability.
Immunologic quantitation of VWF by
either the quantitative immunoelectropho-
retic assay (Laurell assay) or the enzyme‐
linked immunosorbent assay (ELISA).
3. Von Willebrand factor activity (VWF:
RCo): ristocetin induces the binding of
VWF to the GPIbα receptor on formalin‐
fixed platelets. The slope of the platelet
agglutination curve correlates with the level
of plasma VWF.
4. Multimeric analysis: an agarose gel
­electrophoretic study used to identify quanti-
tative or qualitative multimer abnormalities.
Table 8.1 Classification of VWD.
VWD VWF:Ag VWF:RCo FVIII:C
subtype
1 ↓ ↓ ↓ or N
2A ↓ ↓↓ ↓ or N
2B ↓ ↓↓ ↓ or N
2M ↓ ↓↓ ↓ or N
2N ↓or N ↓ or N 10%–40%
3 ↓↓↓ ↓↓↓ <10%
Abbreviations: VWD, von Willebrand disease; VWF:Ag, von Willebrand factor antigen;
VWF:RCo, von Willebrand ristocetin cofactor activity; FVIII:C, Factor VIII coagulant; N, normal.
Von Willebrand Disease 97
The most common type of VWD (Type 1)
has a normal multimeric analysis.
The classification of patients with VWD
based on the results of these tests is pre-
sented in Table 8.1.
Recent advances in diagnostic testing
include the use of the VWF:GPIbM assay in
place of measuring VWF:RCo due to several
issues with the latter that limit its usefulness.
The assay introduces gain‐of‐function
mutations into GPIbα, allowing it to bind
spontaneously to VWF without ristocetin.
At the present time access to this test is lim-
ited in the United States, but it is widely
available in Europe and Canada. VWF also
functions to bind collagen exposed follow-
ing tissue injury. The nature of this interac-
tion is complex, but is very dependent on
the presence of high‐molecular‐weight mul-
timers. Patients with increased bleeding
scores and unexplained bleeding symptoms
may benefit from collagen‐binding testing
to explore the possibility of an undiagnosed
collagen‐binding defect in VWF. The avail-
ability of this testing is unfortunately also
limited at the present time.
Leebeek and Eikenboom (see Suggested
readings) outline a system for diagnosing
VWD and identifying the subtype based
on available laboratory testing. Patients with
RCo:Ag ratio Multimer pattern
>60% Normal
<60% Abnormal
<60% Abnormal
<60% Normal
>60% Normal
— —
98 Chapter 8

undetectable (or <5 IU/dl) levels of VWF:Ag

Treatment
have Type 3 VWD. However, some patients
with severe Type 1 VWD also have antigen
The goal of treatment in VWD is to control
levels <5 IU/dl. Measurement of VWF pro-
or prevent serious or life‐threatening bleed-
peptide, produced during synthesis of VWF,
ing. There are no effective therapies to limit
allows distinction between these two enti-
the chronic bruising that many active chil-
ties. Patients with Type 3 disease have absent
dren experience, and parents need to be
or very low levels of VWF propeptide, while
given assistance to accept that reality. Many
patients with severe Type 1 have minimally
children and adults with Type 1 VWD,
reduced or normal levels.
especially males, never require therapy.
­
If patients have measurable levels of
Individuals with Type 2 or Type 3 VWD are
VWF:Ag, the next step is to compare the
much more likely to need treatment at
Ag level with the measured level of activity.
­various times throughout life.
Currently this is most commonly measured
There are three strategies used to treat
as VWF:RCo activity. Patients with a pro-
patients with VWD: (i) increase the plasma
portional decrease in activity (VWF:RCo/
concentration of VWF by releasing endoge-
VWF:Ag >0.6) have Type 1 VWD, while
nous VWF stores through stimulation of
patients with a disproportionate decrease
endothelial cells with desmopressin; (ii)
in activity have Type 2 disease. Further
replace VWF by infusing exogenous coagu-
subtyping testing such as VWF multimers
lation factors (high‐purity VWF concen-
and ristocetin‐induced platelet aggregation
trate or low‐purity factor VIII‐VWF
(RIPA) are then used to distinguish
concentrate); and (iii) use agents that pro-
between Types 2A, 2B, and 2M disease.
mote hemostasis and wound healing, but do
RIPA is normal in Type 2N and can be
not substantially alter the plasma concentra-
decreased in Types 2A and 2M. A ratio of
tion of VWF. These strategies are not mutu-
FVIIIc to VWF:Ag of ≤0.6 may indicate
ally exclusive; different bleeding episodes
Type 2N VWD; this can be confirmed by
may require a combination of two or even all
measuring the binding of factor VIII to
three of these strategies to be effective.
VWF. Normal binding confirms the diag-
Desmopressin (DDAVP) is the treatment
nosis of mild hemophilia A.
of choice in mild Type 1 disease (up to 85%
Using this algorithm, the diagnosis of
of all cases) and may be of benefit with some
Type 2 or Type 3 VWD is very straightfor-
of the other variants. It stimulates endoge-
ward. However, it remains difficult to deter-
nous release of VWF from endothelial cells.
mine an unambiguous level of VWF:Ag to
A good response is defined as an increase in
use to define Type 1 disease. There is a linear
VWF level of at least threefold, and to a
relationship between VWF:Ag level and
hemostatic level. The approximate half‐life
bleeding phenotype, inheritance pattern,
of these released factors is 8–10 hours, but
and identification of VWF mutations.
patients with VWF clearance defects will
Several current guidelines recommend that
have an accelerated decline in VWF level
patients with bleeding tendency and a
after treatment, limiting the utility of
VWF:Ag level between 30 and 50 IU/dl be
DDAVP in treating severe bleeds. An intra-
classified as having “low von Willebrand
nasal form of DDAVP (Stimate® 1500 mcg/
factor” or “possible Type 1 disease,” but they
ml) is available to treat bleeding in VWD.
are not classified as having VWD.
Typical dosing is one spray for patients
Nonetheless, they may require treatment
<50 kg and two sprays for patients ≥50 kg.
before surgery or with bleeding.

The peak effect is observed in 30–60 minutes.
A therapeutic trial of DDAVP should be
given to determine individual responsive-
ness to this therapy with measurement of
factor VIII and VWF levels before and after
administration. After baseline levels are
obtained, a standard dose of Stimate is
administered, and levels are measured again
60 minutes after administration. The peak
effect is typically seen 60–90 minutes after
infusion. A positive trial is defined as at
least a threefold increase in the VWF:Ag
and VWF:RCo activities. Ninety percent
of patients with Type 1 VWD demonstrate a
positive response to IV DDAVP. Levels can
be checked at later time points to confirm
a normal half‐life of the released VWF. If
the patient fails a Stimate challenge, an IV
DDAVP challenge can be performed by
administering 0.3 mcg/kg of DDAVP intra-
venously in 30–50 ml of normal saline over
15–30 minutes, and measuring levels
60 minutes after infusion.
Stimate is most useful for individuals
with more frequent episodes of bleeding
requiring therapy, such as women with
menorrhagia not controlled using other
measures. Given its high cost and relatively
short shelf life (6 months after the bottle is
opened), it is less suitable for individuals
with very infrequent bleeding episodes.
Though effective, there is some variability in
response due to inconsistent absorption.
Therefore, patients should be tested for
responsiveness prior to prescribing.
Patients undergoing surgical procedures
such as tonsillectomy or dental extractions
may need extended therapy to maintain
increased levels of VWF and factor VIII
until healing has occurred. Studies have
demonstrated that DDAVP can be repeated
daily for up to 4 days with little loss of effi-
cacy as measured by VWF levels or PFA‐100.
Tachyphylaxis with repeated dosing should
be considered following a major surgery or
when prolonged elevated levels of VWF are
Von Willebrand Disease 99
needed to promote healing and achieve
hemostasis. Preinfusion and postinfusion
measurements of VWF:Ag or VWF:RCo
can be done to establish continued clinical
responsiveness. However, it may be difficult
to obtain the results of these tests quickly.
Patients with Type 1 VWD who have
severe bleeding manifestations unrespon-
sive to DDAVP, or those patients with desm-
opressin‐unresponsive Type 2 or 3 disease,
require treatment with exogenous VWF.
The Food and Drug Administration (FDA)
has approved three plasma‐derived factor
VIII/VWF products for the treatment of
VWD, Humate‐P®, Wilate®, and Alphanate®.
Koate‐DVI is another combination product,
but it has not been studied extensively in
VWD and its use is not FDA approved. In
addition, in 2015, the FDA approved the
first recombinant VWF product, Vonvendi®,
for treatment of severe VWD in patients
18 years of age and older. It is important to
remember that patients with severe VWD
have decreased levels of both VWF and
FVIII, and both factors typically require
replacement. The available agents have dif-
fering ratios of FVIII to VWF, so should not
be considered interchangeable. Humate‐P
contains 50–100 IU/ml VWF:RCo activity
and 20–40 IU/ml FVIII activity. It has the
highest ratio of VWF:RCo to FVIII activity
and the highest concentration of high‐
molecular‐weight multimers. Alphanate
contains 40–180 IU/ml FVIII activity and at
least 16 IU/ml VWF:RCo activity. Wilate
has essentially equal amounts of VWF:RCo
and FVIII activity. It has demonstrated both
safety and efficacy in patients with VWD.
There are no head‐to‐head studies compar-
ing the efficacy of any of these products.
Wilate’s packaging promotes more frequent
dosing with lower doses of product, which
the company states is more physiologic and
more cost‐effective. Vonvendi contains no
FVIII activity. After administration, FVIII
levels increase due to Vonvendi’s binding of
100 Chapter 8
FVIII as it is released, but it takes 6–8 hours
to achieve hemostatic levels in severely
affected patients. If used for severe bleeding
or prior to urgent surgery, factor VIII
replacement is required as well.
The goal of VWF replacement therapy is
to reach a VWF:RCo level of 100 IU/ml and
nadir of >50 IU/ml. Recommended starting
doses are 40–60 IU/kg of VWF:RCo activity,
followed by 20–40 IU/kg every 8–24 hours
as needed to maintain desired levels. Major
surgical procedures should only be per-
formed at centers that have the capability of
measuring VWF activity levels in‐house on
a daily basis. To decrease the risk of throm-
botic events, VWF:RCo levels should be
kept <200 IU/ml, and FVIII levels should be
<250–300 IU/ml.
Other adjuvant therapies are available that
are often helpful in managing bleeding in
patients with VWD. Direct pressure is very
effective in managing epistaxis and bleeding
from tooth sockets or lacerations. Family
members must be taught to maintain continu-
ous pressure “without peeking” for at least
20 minutes for best results. If the bleeding
remains uncontrolled, a single dose of desmo-
pressin is usually effective to stop bleeding in
patients who have shown responsiveness. Low
estrogen oral contraceptives have been very
helpful in controlling menorrhagia, as they
minimize the amount of endometrial develop-
ment that takes place. Minor surgical proce-
dures, such as laceration repairs or dental
extractions, can frequently be managed with a
single treatment of desmopressin or factor
concentrate followed by antifibrinolytic ther-
apy for 7–10 days. Two antifibrinolytic agents
are available, epsilon aminocaproic acid
(Amicar®) and tranexamic acid (Lysteda®);
Amicar is the more widely used agent. The
oral dose of aminocaproic acid is 100–200
mg/kg (maximum dose, 10 g) as the initial
dose, followed by 100 mg/kg (maximum dose,
5 g) every 6 hours. To maintain e­ ffectiveness,
f­amilies must be instructed to adhere to the
every 6 hour schedule. The dose of tranexamic
acid is 10 mg/kg/dose IV prior to a procedure
and then every 6–12 hours for patients with
hemophilia. In VWD‐associated menorrha-
gia, it is recommended in an oral form
­(available in 650 mg tablets to be dosed twice a
day) to be taken at the initiation of menses for
up to 5 days per month. Both drugs are avail-
able in oral and intravenous forms. These
drugs are particularly effective in minimizing
bleeding from mucosal surfaces due to the
increased level of fibrinolytic activity present
in these areas.
Patients with Type 3 VWD have plasma
VWF and FVIII levels that are extremely low
(typically less than 5 IU/dl). Desmopressin is
usually ineffective in these cases, but a thera-
peutic trial of desmopressin may be given, as
occasionally patients will respond appropri-
ately. These patients often have significant
bleeding including profound epistaxis or
hemarthroses similar to that seen in patients
with hemophilia due to their low levels of
both FVIII and VWF. With bleeding, such
patients should be managed similarly to
patients with hemophilia, using the previ-
ously mentioned FVIII concentrates that con-
tain adequate levels of VWF and FVIII. Six to
ten percent of Type 3 patients will develop
alloantibodies to VWF replacement products.
As with hemophilia patients who develop
inhibitors, the most common manifestation is
an impaired response to infused concentrates.
However, some patients will develop anaphy-
lactic reactions as well. Management of bleed-
ing in these patients is complicated and may
involve use of recombinant FVIII product,
recombinant FVIIa, and/or activated pro-
thrombin complex. Although the use of these
products seems reasonable, experience is
quite limited, and caution is warranted.
Patients with Type 2A VWD have abnor-
mally small VWF multimers and desmo-
pressin, though frequently effective, often

has only a transient effect. Serious bleeding
should be treated with plasma‐derived
FVIII/VWF concentrates. These patients
may do well with desmopressin for the treat-
ment of minor bleeds or dental extractions.
Type 2B VWD is often associated with
mild thrombocytopenia due to excessive
platelet‐binding to an abnormal VWF mole-
cule and rapid clearance. Stress can exacer-
bate the thrombocytopenia. Desmopressin is
usually contraindicated due to the potential
for worsening thrombocytopenia and failure
to demonstrate a therapeutic response.
However, in mild bleeding, desmopressin
may be effective. For internal bleeding or sur-
gery, patients should receive FVIII/VWF
concentrate. If profound thrombocytopenia
exists, concomitant administration of plate-
lets may be necessary.
Patients with 2M VWD will demonstrate
an increase in VWF:Ag but not in VWF:RCo
in response to DDAVP, due to the defective
binding of their VWF to GPIb. These
patients routinely require replacement with
FVIII/VWF concentrates for bleeding epi-
sodes or for surgery. Patients with Type 2N
VWD similarly require factor replacement;
although they produce normal amounts of
FVIII, it is destroyed prematurely due to the
inability of their VWF to bind to the FVIII
molecule and protect it. Replacement with
functional VWF will typically normalize
their FVIII levels even if the relative concen-
tration of FVIII in the product is low, since
they are able to produce normal amounts.
Acquired von Willebrand
syndrome
Acquired von Willebrand syndrome
(AVWS) refers to defects in VWF concen-
tration, structure, or function that are not
inherited directly but are consequences of
other medical disorders. It is usually caused
Von Willebrand Disease 101
by one of three mechanisms: autoimmune
clearance or inhibition of VWF, increased
shear‐induced proteolysis of VWF, or
increased binding of VWF to platelets
or other cell surfaces. Autoimmune causes
of AVWS in children include postviral anti-
body production similar to immune throm-
bocytopenia purpura, lymphoproliferative
diseases, systemic lupus erythematosus, and
other autoimmune disorders, and some can-
cers, most commonly Wilms tumor. It can
also be seen related to certain drugs or
hypothyroidism. Pathological increases in
fluid shear stress can occur with cardiovas-
cular lesions such as ventricular septal
defect and aortic stenosis, or with primary
pulmonary hypertension. This leads to
increased destruction of VWF, particularly
the larger multimers; the multimer panel
often resembles that seen in Type 2A VWD.
Its occurrence in Wilms tumor and other
malignancies is believed to be due to expres-
sion of platelet GPIb on the tumor cell
­surface, leading to binding of VWF to the
tumor with subsequent degradation.
Hyaluronic acid secretion by nephroblas-
toma cells is another potential mechanism
in Wilms tumor patients leading to
decreased efficacy of VWF. Patients may
present with classic signs and symptoms of
VWD and their levels of VWF, VWF:Ag,
and FVIII are typically quite low.
Desmopressin may induce a transient rise
in VWF in AVWS. One small study demon-
strated that IVIG at a dose of 1 g/kg/day for
2 days was beneficial in improving VWF
­levels and decreasing clinical bleeding, but
this is only beneficial in immune‐mediated
AVWS. Plasmapheresis, corticosteroids, and
immunosuppressive agents have also been
successful in these patients. For serious
bleeding, treatment with factor concentrate
(high VWF content) should be given. The
antibodies typically disappear with control
or resolution of the underlying disease.
102 Chapter 8
Other considerations
As a general precaution, all children with
bleeding disorders should be immunized
with the hepatitis B vaccine, with boosters
given at appropriate time intervals, since
these children have a lifelong potential for
receiving blood products. Patients and fami-
lies should be counseled to avoid aspirin,
nonsteroidal anti‐inflammatory drugs
(NSAIDs), and other platelet‐inhibiting
drugs. Also, it is generally recommended
that children wear medical bracelets and
have information readily available (at
school, home, doctor’s office) specifying the
diagnosis and treatment for bleeding.
Suggested reading
Castaman, G. and Linari, S. (2016). Human von
Willebrand factor/factor VIII concentrates in
the management of pediatric patients with
von Willebrand disease/hemophilia A. Ther.
Clin. Risk Manag. 12: 1029–1037.
Leebeek, F.W. and Eikenboom, J.C. (2016). Von
Willebrand’s disease. N. Eng. J. Med. 375:
2067–2080.
Sharma, R. and Flood, V.H. (2017). Advances in
the diagnosis and treatment of Von Willebrand
disease. Blood 130: 2386–2391.
9 Hemophilia
Hemophilia is defined as an inherited
­bleeding disorder caused by low levels, or
absence, of a blood protein that is essential
for clotting. The congenital hemophilias are
uncommon disorders, with a total incidence
of 10–20 per 100 000 births. The most com-
mon form is factor VIII (FVIII) deficiency
(hemophilia A or classic hemophilia), with
an estimated incidence of 1 in 5000 males.
The second most common form is factor IX
(FIX) deficiency (hemophilia B), with an
incidence of approximately 1 in 25 000 males.
Both the FVIII and FIX genes are carried on
the X chromosome, thus both hemophilia
A and B are X‐linked recessive disorders.
Approximately 80% of hemophilia patients
have hemophilia A and 20% have hemo-
philia B. Both disorders are found through-
out the world and do not appear to have any
ethnic or racial predisposition.
Hemophilia A and hemophilia B are
clinically indistinguishable, since both FVIII
and FIX are essential factors in the intrinsic
clotting pathway for activating factor X
(FX). Factor levels are measured in compar-
ison to a reference standard that is assumed
to have a factor level of 100% (1.0 IU/ml). In
the normal individual, FVIII and FIX levels
range from 50–200% (0.50–2.0 IU/ml).
Disease severity is defined as severe (<1%),
moderate (1–5%), and mild (6–50%). The
frequency of bleeding symptoms generally
correlates well with the measured residual
Handbook of Pediatric Hematology and Oncology – Children’s Hospital & Research Center Oakland,
Third Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
factor activity. Boys with severe hemophilia
bleed with minimal trauma and bleeding
symptoms are usually apparent by the time
the infant begins to crawl or walk, whereas
those with mild hemophilia usually bleed
only with significant trauma or surgery and
may have a delayed diagnosis.
Several other congenital factor deficien-
cies have been described as well, but are all
very uncommon. They are described in
Table 9.1.
Afibrinogenemia is associated with fre-
quent and serious bleeding. Spontaneous
bleeding is rare if the fibrinogen level is
>50 mg/dl. The thrombin time (TT) is the
most sensitive test to diagnose this disorder.
Hypoprothrombinemia is an autosomal
recessive disorder associated with mild
bleeding. All patients have some prothrom-
bin activity. Prothrombin deficiency also
occurs in patients with vitamin K deficiency,
liver disease, and warfarin use. Factor V
(FV) deficiency is often characterized by
bleeding from mucous membranes includ-
ing epistaxis, menorrhagia, and bleeding
after dental procedures. Congenital defi-
ciency of both FV and FVIII can occur as a
result of a mutation in the ERGIC‐53 gene,
which acts as a chaperone for intracellular
transport of these factors through the endo-
plasmic reticulum. Patients with factor VII
deficiency who have levels less than 1% have
bleeding symptoms similar to that of classic
104 Chapter 9

Table 9.1 Rare coagulation factor deficiencies.

Deficiency Estimated Source of replacement Biological Gene on

prevalence half‐life chromosome

Fibrinogen 1/1 000 000 Cryoprecipitate 90 h 4

Prothrombin 1/2 000 000 Activated PCCs 60 h 11
Factor V 1/1 000 000 FFP 12 h 1
Factor VII 1/500 000 rFVIIa 2–6 h 13
Factor X 1/1 000 000 Activated PCCs or 24 h 13
plasma‐derived
concentrate
Factor XI 1/1 000 000 FFP 40 h 4
Factor XIII 1/2 000 000 Recombinant or 3–5 d 1 and 6
plasma‐derived
concentrate

Abbreviations: PCC, prothrombin complex concentrate; FFP, fresh frozen plasma; rFVIIa,
recombinant factor VII.

hemophilia with hemarthrosis, intramus- with α2‐antiplasmin deficiency are unable

cular hemorrhage, and intracranial hemor-
rhage (ICH). Heterozygotes are typically
asymptomatic. Two‐thirds of patients with
factor X (FX) deficiency have hemarthroses
and hematomas. The proportion of patients
with FX deficiency who require treatment is
higher than that of the other rare coagula-
tion deficiencies. Factor XI (FXI) deficiency
is characterized by mucocutaneous and
­genitourinary tract bleeding; the likelihood
of bleeding does not correlate well with
measured FXI levels. Only individuals with
factor XIII (FXIII) deficiency whose levels
are <1% are symptomatic. Bleeding mani-
festations include soft‐tissue hemorrhages,
hemarthroses, and hematomas, and patients
undergoing surgery or trauma may experi-
ence poor wound healing.
Alpha2‐antiplasmin deficiency, factor XII
deficiency, prekallikrein (Fletcher’s factor)
deficiency, and high‐molecular‐weight kini-
nogen (Fitzgerald’s factor) deficiency have
also been identified using appropriate clot-
ting measurements. Alpha2‐antiplasmin is
the primary inhibitor of plasmin, a key com-
ponent of the fibrinolytic pathway. Patients
to effectively inhibit plasmin, and therefore
lyse clots abnormally quickly leading to
abnormal bleeding. As clots are formed nor-
mally, all the usual screening coagulation
tests are normal except for the euglobulin
and urea clot lysis tests. Factor XII (FXII)
deficiency, prekallikrein deficiency, and
high‐molecular‐weight kininogen deficiency
all cause prolongation of the PTT but are
not associated with clinical hemorrhage.
Clinical presentation
Boys with hemophilia may develop symp-
toms very early in life, experiencing a
­hemorrhage after circumcision or with sep-
aration of the umbilical cord. However, up
to 50% of affected male infants have no dif-
ficulty during the neonatal period, and a
negative history of bleeding after circum-
cision does not rule out the diagnosis of
hemophilia. Mild hemophilia may go unsus-
pected for years until the patient experi-
ences trauma or has a surgical procedure.
Conversely, patients with severe hemophilia

often experience spontaneous hemorrhages,
both externally and internally, into the
head, joints, muscles, and retroperitoneum.
Bleeding from the mouth or frenulum often
occurs during infancy, and minimal lacera-
tions may cause very prolonged bleeding.
Intramuscular injections (as with immuni-
zations) often result in large hematomas.
Joint hematomas (hemarthroses) can result
in secondary joint degeneration. Life‐
threatening blood loss can occur with intra-
muscular bleeds. ICH occurs in 2–14% of
hemophilia patients and is associated with a
4–34% mortality. Although ICH is much
more common in severe hemophilia, it has
been reported in patients with mild hemo-
philia as well.
ICH is the most serious complication in
hemophilia. A history of trauma is elicited
in only 20–25% of patients with central
nervous system (CNS) hemorrhages, and
there may be a delay of days or weeks before
symptoms develop. Bleeding can be intrac-
erebral, subdural, subarachnoid, or epidural.
Patients who survive these episodes fre-
quently experience complications such as
mental retardation, seizure disorders, or
motor impairment. Any history of head
trauma should be considered emergent. A
nonfocal neurologic examination does not
exclude a diagnosis of an intracranial bleed.
Any suspicion of a significant intracranial
injury should prompt a computerized
tomography (CT) study of the head and
close neurological observation. Immediate
treatment to achieve a factor level of
80–100% should be provided and main-
tained until an intracranial bleed can be
fully excluded. An intraspinal hemorrhage
should be excluded with any back trauma or
symptoms of a peripheral neuropathy. A
lumbar puncture should never be performed
in a hemophilia patient without factor ther-
apy to avoid this complication.
Hemarthroses appear in young children as
they become mobile. The elbows are often first
Hemophilia 105
affected as the infant begins crawling, followed
by shoulders, wrists, hips, knees, and ankles.
The hands and spine are rarely involved. The
initial signs of a hemarthrosis are vague and
difficult to detect, especially in the nonverbal
infant. Early, aggressive treatment of an acute
hemarthrosis is recommended to relieve
symptoms and hopefully prevent recurrent
bleeding into the same joint, setting up the
situation of a ­“target” joint.
Bleeding into muscle is characterized by
pain and limitation of mobility. They can be
difficult to evaluate, particularly if they
occur in deep muscles such as the iliopsoas
muscle (see the following text). They can
result in long‐term complications such as
permanent muscle contractures. It is impor-
tant to exclude any potential neurovascular
compromise that can result from compres-
sion of adjacent nerves.
An iliopsoas hemorrhage can be quite
devastating due both to the long‐term con-
sequences and to the large volume of blood
loss that can occur acutely into this large
muscle bed and into the retroperitoneal
space. The presenting signs of groin or lower
abdominal/upper thigh pain can be difficult
to differentiate from a hip bleed. With an ili-
opsoas bleed, examination reveals inability
to extend the hip, with normal internal and
external hip rotation. Radiologic confirma-
tion by CT scan is recommended.
Soft tissue hemorrhages occur very com-
monly and do not require therapy unless
their location is near vital structures. For
instance, a retropharyngeal bleed with
potential airway compromise should be
aggressively treated. Vigorous examination
of the oropharynx with a tongue blade or
other manipulations should be avoided to
prevent injury with subsequent hemor-
rhage. A “straddle” injury resulting in a
hematoma of the perineal/perirectal area
should be closely evaluated for neurologic
compromise as evidenced by either bladder
or bowel dysfunction.
106 Chapter 9
About 70% of hemophilia patients will
have at least one episode of hematuria.
Usually, these episodes are painless, thus if
there is severe pain associated with hematu-
ria, a thrombus in the renal pelvis should
be excluded. Increased fluid intake and bed
rest is recommended. Factor replacement
may be warranted with persistent symp-
toms. Treatment with antifibrinolytic drugs
is contraindicated given the risk of upper
urinary tract obstruction caused by clot.
Epistaxis occurs in hemophilia patients,
most commonly in those with severe dis-
ease. Gastrointestinal bleeding can also
occur but is atypical; an underlying gastro-
intestinal lesion should be excluded.
Intramural bleeding into the bowel wall can
occur, with signs of severe pain and possible
intestinal obstruction. Appropriate therapy
may avoid an unnecessary laparotomy.
Prolonged gingival oozing is common
after shedding of deciduous teeth, eruption
of new teeth, or instrumentation. Treatment
with an antifibrinolytic medication (i.e.,
tranexamic or aminocaproic acid) is recom-
mended for prolonged symptoms. Routine
dental care is particularly important in the
patient with a bleeding disorder to prevent
the need for restorative care in the future
where extensive factor replacement therapy
is often indicated. Regional block anesthesia
is discouraged, even with factor coverage,
given the risk of hemorrhage that can lead to
nerve damage and extension into the neck
causing airway compromise.
Diagnosis
The diagnosis of FVIII deficiency should be
suspected in males presenting with a charac-
teristic bleeding history, especially if there is
a family history of males with abnormal
bleeding. However, 30% of patients with
hemophilia A and B have sporadic muta-
tions and no family history of ­ abnormal
bleeding. A prolonged PTT in conjunction
with a normal PT and platelet count is
­suggestive of the diagnosis; this can be con-
firmed by specifically measuring levels of
FVIII and FIX.
Newborn males with a possible or con-
firmed diagnosis of hemophilia should be
carefully evaluated for an intracranial hem-
orrhage, especially if delivered via assisted
vaginal delivery (vacuum extraction or
forceps). However, infants delivered via
­
cesarean section are also at risk for severe
bleeding. The initial PTT can be performed
on cord blood, but it must be remembered
that the upper limit of normal for newborns
is longer than for adults. The normal range
for FVIII levels in the newborn is the same
as for adults, but FIX levels are lower until
the concentrations of factors produced by
the liver mature to adult levels (approxi-
mately 6 months of age). Therefore, the
diagnosis of hemophilia B may be more dif-
ficult initially. Confirmatory studies should
be performed on a sample obtained by veni-
puncture if a cord blood sample was ini-
tially obtained. Arterial as well as femoral
or jugular venous sites to obtain plasma
samples should be avoided if possible.
Prenatal testing for both conditions is avail-
able to pregnant women who are known
carriers.
Treatment
After the newborn period, affected infants
rarely require treatment until they become
more mobile with increasing age. Treatment
recommendations for the hemophilia
patient depend on several factors: the type
and severity of disease (mild, moderate, or
severe; FVIII or FIX deficiency); the site of
the bleed (proximity to vital structures) with
consideration of long‐term debilitating con-
sequences; and therapy response (factor
recovery/survival and inhibitor status).
 Hemophilia 107

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

Site of hemorrhage Optimal factor Dose (units/kg body Minimum

level (%) weight) duration of
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 50 100 7–10
Central nervous system 80–100 50 100 14
Trauma or surgery 80–100 50 100 14

*Recombinant FIX should be dosed 1.2 times higher.

Treatment of patients with hemophilia and the challenge of adequate vascular

and bleeding is by replacement of factor in
a concentrated form. Many high‐purity
plasma‐derived preparations are currently
available, as are recombinant FVIII and FIX
products. World Federation of Hemophilia
guidelines do not recommend one type of
product versus another and each has their
pros and cons. Plasma‐derived factor
appears to have less development of inhibi-
tor than recombinant products, but requires
a larger volume than recombinant products
and has a theoretical risk of acquiring new
infections not currently screened.
There are two treatment strategies cur-
rently used for patients with hemophilia: (i)
episodic or on‐demand treatment, provid-
ing treatment at the time a bleeding episode
occurs; and (ii) prophylactic therapy, pro-
viding periodic infusion of factor replace-
ment to prevent such bleeding episodes. A
number of single institutional case series
have demonstrated the superiority of proph-
ylaxis regimens in the prevention of joint
disease, but widespread adoption of this
strategy for all patients has been limited by
the high cost of factor replacement therapy
access, particularly in young patients.
When providing on‐demand therapy, the
duration, frequency, and doses of factor pro-
vided depend on the severity of the hemo-
philia and bleeding episode. Factor vials
vary in the number of units of factor activity
they contain. The required factor dose
should be calculated, and vials should then
be selected that come closest to the calcu-
lated target dose. Doses are calculated using
the following formula:
Dose units of FVIII = Weight kg
desired % rise of FVIIII level 0.5
For FIX, multiply result by 2, for recom-
binant FIX, multiply by 2.4 (due to lower
recovery rate of unclear etiology).
Round up to the whole vial, since factor
is expensive and not uniformly dispersed in
suspension. Table 9.2 outlines the dose and
duration of therapy for commonly encoun-
tered bleeding episodes in hemophilia
patients. More serious bleeding episodes
should be treated using doses at the higher
end of the range.
108 Chapter 9

Other important interventions for a

Other considerations
hemarthrosis include initial immobilization
and application of ice to the area or use of a
In addition to aggressive factor replacement
Cryo/Cuff. For particularly critical joints
when bleeding has occurred and the use of
such as the shoulder or hip, where long‐
physical therapy programs to prevent or
term consequences of pressure‐induced
minimize chronic joint disease, comprehen-
avascular necrosis can be debilitating, a
sive medical care must be provided to all
longer treatment course is recommended.
patients with hemophilia. All immunizations
Iliopsoas bleeds should be treated as retrop-
including hepatitis B vaccine should be
eritoneal rather than as muscle bleeds.
given on schedule (subcutaneous rather than
intramuscular). Regular dental care is essen-
tial to prevent excessive decay and gingival
Inhibitors
disease that may predispose to complications
and need for more aggressive surgical man-
The development of an inhibitor, an antibody
agement. Psychological support is essential
that inactivates the coagulant function of
to assist patients and families cope with the
replacement factor, is one of the most serious
emotional and social burden imposed by the
complications of hemophilia treatment. FVIII
disease. A comprehensive program of patient
inhibitors develop in 20–30% of boys with
and family education will prevent complica-
severe hemophilia A, whereas FIX inhibitors
tions caused by failure to recognize or under-
develop in 3–5% with severe hemophilia B.
stand warning signs of hemorrhage as well as
These usually develop within the first 50
empower family members and eventually
exposures to factor replacement. Risk factors
the patient to take an active role in the man-
for inhibitor development include the nature
agement of the disease. Education regarding
of the underlying mutation, with those lead-
in‐home treatment is vital and should be
ing to substantial loss of coding information
used whenever possible given the benefit
representing greater risk, high‐intensity prod-
of prophylactic factor administration for
uct exposure, CNS bleeding, and African‐
patients with severe disease as well as in the
American race. Inhibitors are quantitated by
rapid recognition and treatment of bleeding,
Bethesda titers: one Bethesda unit (BU) is the
especially hemarthroses, which directly
amount of inhibitor that inactivates 50% of
relates to ­minimizing long‐term complica-
FVIII function in a one‐stage clotting assay.
tions of the disease.
Low‐titer inhibitors (<5 BU) can be managed
by using larger doses of factor replacement;
higher‐titer inhibitors require the use of alter-
native hemostatic agents. Alternative agents Novel agents
include prothrombin complex concentrates
(PCCs), activated PCCs (aPCCs), recombi- Over the last several years, multiple
nant factor VIIa (rFVIIa), and a newer extended half‐life agents for both factor VIII
bypassing agent emicizumab (see in the fol- and factor IX deficiencies have been studied
lowing text). Immune tolerance induction and approved. These products have been
with high, frequent doses of FVIII or FIX has most successful for factor IX deficiency,
also been successful. Management of patients increasing the half‐life threefold to sixfold
with inhibitors is difficult and complex and and thus decreasing prophylactic replace-
should be performed only by experienced ment therapy to once weekly (from twice
hematologists. weekly) in young patients and potentially

once every other week in the well‐controlled
older patient. Due to the interaction with
von Willebrand factor, the half‐life exten-
sion of factor VIII products is significantly
less, only 1.5‐fold to twofold, thus decreas-
ing the need for prophylactic dosing from
thrice weekly to twice weekly. Though a
smaller effect, for a young patient this can
still have a significant benefit for both
patient and family.
Emicizumab, a bispecific monoclonal
antibody, which bypasses factor VIII and
instead engages factor IX and factor X, has
shown benefit in studies for patients with
factor VIII inhibitors. More recent studies
have shown the benefit in pediatric and
adult patients with factor VIII deficiency
without inhibitors. As a bypassing agent,
emicizumab does not lead to inhibitor
development. Additionally, it has the benefit
of being given subcutaneously and with a
long half‐life allowing for dosing once every
4 weeks (after initial 4 weekly loading
doses). Emicizumab was FDA approved for
all patients with hemophilia A, with or with-
out inhibitors, in 2018.
Gene therapy
Gene therapy has been studied for decades in
hemophilia and remains a long‐term cura-
tive opportunity that is continuing to be
refined. Most recently, adeno‐associated
viral vectors (AAVs) have been utilized,
though there remains potential to utilize
gene editing in future through zinc‐finger
nucleases (ZFN) or clustered regularly inter-
spaced short palindromic repeat (CRISPR).
Current challenges with gene therapy include
differing manufacturing processes and a
wide range of AAV doses leading to variable
target clotting factory activity. Additionally,
there have been many patient groups
excluded to date including pediatric patients,
those with underlying hepatitis secondary to
Hemophilia 109
an AAV‐induced liver‐induced immune
response of unclear etiology, those with anti-
bodies to AAV above the cutoff, and patients
with factor VIII or IX inhibitors.
Case study for review
You have been following a patient with
severe hemophilia A since soon after birth
and his mother has questions about plans
for an upcoming second pregnancy. She is
worried about the chance of having another
child with hemophilia.
a. What are some initial important
points that you should discuss?
It is first important to ascertain if there is a
family history (i.e., maternal uncles, other
males on the maternal side) making this an
inherited trait rather than a sporadic muta-
tion which can occur in up to 30% of
patients. Even without a relevant (or known)
family history, this is more likely to be
inherited, and therefore genetic testing can
be performed to determine if the mother is
an obligate carrier especially if there is no
known family history.
b. Assuming the mother is a carrier,
what are the next important discussion
points?
Given the mother is a carrier, she will
have a 50% chance of passing this on to
either a symptomatic male or carrier female
(unless symptomatic due to lyonization
which is rare). It should be discussed that
prenatal diagnosis can be made through
chorionic villus sampling (CVS) or amnio-
centesis, if desired (the risks of which
should also be discussed). If the family is
utilizing in vitro fertilization, prenatal
genetic diagnosis (PGD) can also be
­utilized to ensure a an unaffected male or a
non‐carrier female.
c. Based on this information, the
mother decides to move forward with a
second pregnancy without any further
110 Chapter 9
testing. What information is it important
to pass on to her and her OB/Gyn?
Given the potential for a (male) child with
hemophilia, it is vital that the treating
team know of this risk and utilize the least
invasive methods during the delivery.
­ Suggested reading
Spontaneous vaginal delivery is not con-
traindicated but vacuum suction and for-
ceps should be avoided. After birth, the
umbilical cord blood can be tested to see if
there is prolongation of the PTT, knowing
the normal range for a newborn is different
(i.e., more prolonged) than for an adult.
Arterial, femoral, and jugular punctures
should be avoided in the new baby, and
intramuscular injection should be avoided
until a diagnosis is made. Head ultrasound
should be done immediately after birth
unless hemophilia is definitively ruled out.
Similarly, circumcision should be delayed
if the diagnosis is unclear of if the child has
hemophilia. The child with hemophilia
should be referred to hematology, although
routine factor prophylaxis is not typically
required at this age.
Doshi, B.S. and Arruda, V.R. (2018). Gene ther-
apy for hemophilia: what does the future
hold? Ther. Adv. Hematol. 9: 273–293.
Graf, L. (2018). Extended half‐life factor VIII
and factor IX preparations. Transfus. Med.
Hemother. 45: 86–91.
Pipe, S.W., Shima, M., Lehle, M. et al. (2019).
Efficacy, safety, and pharmacokinetics of emici-
zumab prophylaxis given every 4 weeks in
people with haemophilia A (HAVEN 4): a mul-
ticenter, open‐label, non‐randomised phase 3
study. Lancet Hematol. 6: PE295–PE305.
Srivastava, A., Brewer, A.K., Mauser‐Bunschoten,
E.P. et al. (2013). Guidelines for the management
of hemophilia. World Federation of Hemophilia
Guidelines. Haemophilia 19: e1–e47.
10 Thrombophilia

Virchow’s triad describes risk factors for

Evaluation of thrombosis
thrombus (blood clot) formation: (i) venous
stasis; (ii) endothelial injury; and (iii) 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 thrombo-
acquired risk factor for VTE is the presence
sis secondary to aberrations in the coagula-
of a central venous catheter (i.e., endothelial
tion system. Thrombophilia is becoming
injury). Other acquired risk factors include
increasingly recognized in pediatric patients
trauma, surgery, infection, nephrotic syn-
and can refer to multiple potential condi-
drome, inflammatory syndromes, diabetes,
tions: (i) spontaneous thrombus formation;
complex congenital heart disease, liver dis-
(ii) recurrent thrombosis; (iii) thrombosis
ease, and malignancy (e.g., acute lympho-
out of proportion to the underlying risk fac-
blastic leukemia in association with the use
tor; and (iv) thrombosis at a young age.
of asparaginase or solid tumors with tumor
Optimal prevention and treatment in
thrombus). Asymptomatic patients may be
pediatric patients with thrombosis differs
found to have an incidental clot on imaging,
from adult patients for several reasons.
or the patient may be symptomatic, most
These include physiologic age‐dependent
often with swelling, pain, or erythema in an
differences in the hemostatic system that
extremity. Venous ultrasonography with
influence the risk for venous thromboem-
Doppler flow remains the cornerstone of
bolism (VTE), differing underlying etiolo-
evaluation for thrombosis, as in adults. Lack
gies and location of clots, and differing
of venous compression or Doppler flow is
responses to antithrombotic agents. Little
diagnostic for thrombus. This imaging
evidence exists as how best to manage pedi-
modality is limited to the extremities, neck,
atric patients with thrombosis, both from a
distal subclavian veins, and, potentially, dis-
diagnostic and from a treatment standpoint.
tal iliac veins. Echocardiography can be uti-
Much of the currently utilized data are based
lized to evaluate for atrial clots and the
on adult studies, and here we summarize the
proximal superior and inferior vena cava.
generally accepted recommendations in lieu
Imaging of the abdomen and pelvis as well
of evidence‐based pediatric guidelines (see
as the upper venous system requires CT or
Figure 10.1).

Handbook of Pediatric Hematology and Oncology – Children’s Hospital & Research Center Oakland,
Third Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
112 Chapter 10

Initial evaluation
Physical examination
History (medications, family history)
Laboratory (PT, PTT, fibrinogen, CBC)

Diagnostic imaging confirming VTE

Laboratory assessment of primary
thrombophilia traits
Factor V Leiden mutation
Prothrombin gene mutation
ATIII deficiency
Protein C deficiency
Protein S deficiency
Hyperhomocysteinuria
Elevated lipoprotein (a)
Antiphospholipid antibodies
Elevated factor VIII
Multitrait (≥ 3)
thrombophilia
Assessment of risk
Unusual site without underlying risk factor (e.g., portal vein, renal vein)
Life-threatening without underlying risk factor (pulmonary embolism,
CNS event)
Recurrent
Family history of VTE
Yes Adolescent on OCPs
Neonatal stroke
No
Further assessment of risk factors:
Venous catheter
Trauma, surgery, immobilization
Prematurity
Congenital heart disease
Nephrotic syndrome
Inflammatory bowel disease
No multitrait Malignancy (ALL)
thrombophilia Collagen vascular disease
Yes

No

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, pro-
thrombin time; PTT, partial thromboplastin time; CBC, complete blood count; CNS, central nervous
system; OCP, oral contraceptive pill; ATIII, antithrombin III; ALL, acute lymphoblastic leukemia).

magnetic resonance venography (MRV).
Similarly, sinus venous thrombosis must be
evaluated by magnetic resonance imaging/
arteriography (MRI/MRA). Pulmonary
emboli or thrombosis can be identified with
a helical CT scan.
Testing for thrombophilia
Although often undertaken, clear guidelines
are lacking as to the utility of testing for an
underlying hypercoagulable state. In the
patient with a known acquired risk factor
and secondary thrombosis, it is unclear that
testing for thrombophilia will aid in the
management of the patient (e.g., asympto-
matic catheter‐related thrombosis). Patients
might have a single‐trait thrombophilia on
testing, but this alone may not contribute
significantly to thrombus development.
Patients with a consumptive process (e.g.,
disseminated intravascular coagulation and
sepsis) and secondary thrombosis such as
with deficiencies in protein C and S and
antithrombin III (ATIII) could benefit from
 Thrombophilia 113

Table 10.1 Primary thrombophilia traits.

Thrombophilia trait Description

Factor V Leiden G1691A polymorphism, present in ~5% of Caucasian population,

leads to inherited activated protein C resistance
Prothrombin gene PT G20210A polymorphism, present in ~2% of Caucasian population,
mutation leads to elevated prothrombin levels
Antithrombin III Can be seen in consumptive process (sepsis, DIC, active clot), liver
deficiency disease, heparin therapy, complex congenital heart disease,
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 against cell membrane phospholipid, called lupus
antibodies anticoagulant, paradoxically leads to elevated PTT without correction
on 1:1 mix. Secondary confirmatory testing includes anticardiolipin
antibodies and β2 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.

testing and factor replacement if found to be
deficient in the acute illness. Patients with
deficiencies should be re‐tested in the steady
state to determine if the patient is indeed
baseline deficient (heterozygous state) or
was low due to consumption. For patients
with spontaneous thrombosis, often found
in adolescents (e.g., adolescent female start-
ing oral contraceptives) and in neonates
(secondary to stroke or sinus venous throm-
bosis), testing should be considered. For
patients with a symptomatic catheter‐related
thrombosis or for an asymptomatic patient
with a positive family history, the decision to
test for thrombophilia must be made on an
individual basis after appropriate family
counseling. The family must be advised that
a positive screen for a single thrombophilia
trait will not result in a change in manage-
ment and may lead to unnecessary anxiety.
Similarly, negative testing may give false
reassurance and does not completely abro-
gate the potential for thrombosis. The pri-
mary thrombophilia traits are listed in
Table 10.1.
Management of thrombosis
Management of pediatric thrombosis is
again based on adult studies and expert
guidelines. Removal of the precipitating
114 Chapter 10
agent should be done as possible in cases
with an acquired risk factor. Treatment of
thrombosis is undertaken to prevent clot
propagation, pulmonary embolus, and post-
thrombotic syndrome (PTS). Although
reported frequently in adults, PTS is poorly
understood in children but can potentially
lead to chronic pain, swelling, skin changes,
and collateral venous formation. Neonatal
thromboembolism guidelines are generally
similar to pediatric guidelines, though a
more conservative approach may be consid-
ered given the potential increased risk of
hemorrhage in this population. The deci-
sion to initially utilize a thrombolytic (tissue
plasminogen activator, TPA) versus an anti-
coagulant (unfractionated heparin, UH,
low‐molecular‐weight heparin, LMWH, or
a direct oral anticoagulant, DOAC) must
be made in consultation with a pediatric
hematologist. In rare cases, thrombectomy
or thrombolysis by intervention radiology
should be considered.
Thrombolysis
In general, thrombolysis is not routinely
recommended except in situations with
­ if the patient has a nonocclusive thrombus
hemodynamic compromise or which are
life‐threatening. Data are lacking in pediat-
ric patients and expert consensus guidelines
have very low certainty based on the existing
evidence (see suggested further reading). In
consultation with hematology, a thrombo-
lytic can be considered in patients with an
occlusive thrombus without significant risk
factors for bleeding (recent surgery, central
nervous system hemorrhage). Patients with
a long‐standing occlusive thrombus (i.e.,
>14 days) or without evidence of improve-
ment on imaging studies after 24–48 hours
of TPA therapy may benefit from thrombec-
tomy or thrombolysis by interventional
radiology, though this is no longer routinely
recommended. Although not evidence‐based,
we typically treat with low‐dose systemic
TPA as suggested by Manco‐Johnson (see
suggested further reading) at a dose of 0.03–
0.06 mg/kg/h with a maximum of 2 mg/h for
24–48 hours to decrease the risk of signifi-
cant hemorrhage that is seen with bolus
TPA, unless there is a life‐threatening clot
(e.g., massive pulmonary embolism).
Arterial clots may benefit from a higher sys-
temic dose for a shorter time period. Also, if
possible, TPA should be instilled distal to
the clot in order to decrease first‐pass liver
metabolism, although this is mitigated with
the use of systemic TPA, as it is expected
that much of the TPA will bypass the
obstruction through collateral circulation.
Patients receiving systemic low‐dose TPA
therapy should have close monitoring of
coagulation studies (prothrombin time
[PT], partial thromboplastin time [PTT],
and fibrinogen), platelets, and plasminogen
to ensure hemostatic and fibrinolytic poten-
tial and the need for potential repletion with
fresh frozen plasma (FFP).
Anticoagulation
If TPA is thought to pose significant risk, or
or transient risk factors, UH or LMWH (or,
potentially, a DOAC) may be started. UH is
a natural anticoagulant and works by com-
plexing to the physiologic inhibitor ATIII,
accelerating the inhibition of thrombin and
other coagulant proteins. It is therefore
important to ensure adequate levels of ATIII
when administering heparin. Many poten-
tial issues are present with UH usage in chil-
dren: (i) rapid clearance; (ii) low ATIII levels
in the first few months of life; (iii) greater
variability in dosing compared to adults;
and (iv) lack of evidence assessing the opti-
mal target PTT range for the prevention and
treatment of VTE. The patient must also be
monitored for the development of heparin
antibodies that can most notably lead to
heparin‐induced thrombocytopenia (HIT).

Long‐term usage can also lead to osteoporo-
sis. LMWH is more widely utilized now due
to a narrower dosing range and wide thera-
peutic window secondary to direct targeting
of factor Xa as well as reduced incidence of
HIT and osteoporosis.
In general, we utilize LMWH unless
there is potential need for immediate rever-
sal of anticoagulation. Although protamine
can be utilized with LMWH, the reversal
effect is not complete (thought to be about
two‐thirds effective), and therefore a risk
of bleeding can still be present if, for
instance, surgical intervention is required
emergently. In these cases, UH should be
utilized due to its short half‐life and ability
to be fully reversed. UH is generally given
at a loading dose of 75 U/kg followed by a
maintenance dose of 20 U/kg/h with a goal
PTT of two to three times the upper limit
of the reference range or, preferably, unfrac-
tionated anti‐Xa levels of 0.3–0.7 U/ml, if
available in a timely manner. Currently, the
only LMWH approved by the FDA for
pediatric patients is enoxaparin, with a
half‐life of 4 hours and subcutaneous (SC)
dosing (though extended half‐life daily SC
fondaparinux is being increasingly uti-
lized). For treatment of thrombosis, enoxa-
parin must be given every 12 hours, usually
starting at 1.0–1.25 mg/kg (see Formulary
and Manco‐Johnson for more specific
dosing guidelines). Treatment effective-
ness is followed by fractionated anti‐Xa
levels, with goal levels of 0.5–1.0 U/ml
(checked 4 hours after the second or subse-
quent dose). For prophylaxis, 0.5 mg/kg is
typically given twice daily. Anti‐Xa levels
do not need to be checked with prophylac-
tic dosing. In practice, some hematologists
utilize 1 mg/kg once daily for prophylaxis,
although available data suggest this may
undertreat a group of patients, especially
those <5 years of age. Fondaparinux obvi-
ates the need for more than daily dosing
Thrombophilia 115
and is recommended at a dose of 0.1 mg/kg
SC once daily. Specific fondaparinux levels
should be obtained different from fraction-
ated anti‐Xa levels and dosing adjusted
accordingly.
Concomitant use of TPA and UH or
LMWH may also be beneficial in clot lysis
without significantly increasing hemor-
rhagic risk, although again this recommen-
dation is not evidence‐based in pediatric
patients and must be determined on a per
patient basis in consultation with a pediat-
ric hematologist, weighing the potential
risks of hemorrhage and potential benefits
of clot lysis (and is not recommended in
combination in the most recent consensus
guidelines). Therapeutic efficacy can sim-
ply be followed with repeat imaging,
although this can be difficult with central
venous clots that may require multiple CT
or MRI with resultant increased radiation
exposure and cost, respectively. Other
potential markers to follow for clot lysis
include d‐dimers or fibrin‐split products
which should increase with lysis, although
marker elevation may be confounded by
continuing inflammation.
Duration of therapy
Duration of therapy depends on multiple
factors including the time to removal of
inciting agents such as central venous cath-
eters, presence of thrombophilia traits, and
time to clot resolution. Patients initially
treated with TPA or UH therapy should be
transitioned to LMWH or warfarin therapy
for long‐term maintenance. Due to lack of
pediatric data, DOACs are not currently
recommended in consensus guidelines but
are being increasingly utilized. Because of
the time required to reach an appropriate
therapeutic level, warfarin therapy (if uti-
lized) should begin at least 48 hours prior
to discontinuation of heparin therapy.
Maintenance with LMWH is frequently
116 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 analog 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
Apixaban Like rivaroxaban except twice daily dosing
Endoxaban Can be used in adults at a reduced dose with CrCl 15–50 ml/
min, though has unclear safety in CrCl >95 ml/min due to
increased stroke compared with 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
fibrillation, in the United Kingdom as an alternative to
warfarin for thromboprophylaxis

Abbreviations: ATIII, antithrombin III; CrCl, creatinine clearance; HIT, heparin‐induced

thrombocytopenia; SC, subcutaneous; IV, intravenous.

used due to the difficulty in maintaining a

therapeutic international normalized ratio
(INR) with warfarin therapy.
For patients with clot resolution, antico-
agulation should be continued at prophylac-
tic dosing for 6 weeks to 3 months after
removal of the inciting agent (e.g., central
venous catheter) due to the likelihood of
continued endothelial injury. For patients
without clot resolution (potentially after
ineffective interventional thrombectomy
and/or thrombolysis), anticoagulation
should be continued for 6–12 months to
potentially decrease or resolve the clot and
prevent the development of PTS. Patients
that have a spontaneous or recurrent
thrombus and are found to have multitrait
thrombophilia (≥3 traits) or antiphospho-
lipid syndrome should continue lifelong
anticoagulation.
New agents
As described, multiple new agents will very
likely be FDA approved in the near future
for pediatric patients and are summarized in
Table 10.2 (many of which are increasingly
being used off‐label).
Case study for review
You are seeing a 17-year-old female in clinic
who is deciding on whether to start oral
contraceptive pills (OCPs). She has an aunt
that had a “blood clot” when she was in her
fifties. Your patient does not know any fur-
ther details about the incident but does
know about the potential increased risk of
blood clots with OCPs.

a. What advice would you give the patient?
All patients who are starting OCPs should
be made aware of the increased risk of blood
clots with estrogen-containing contracep-
tives (about a three-times increased risk).
This risk is thought to be about 2–3 per 10
000 per year on OCPs, or about 0.02–0.03%
incidences per year (baseline risk being
approximately 0.008% per year). Single-trait
thrombophilias, most commonly factor V
Leiden mutation, increase this risk signifi-
cantly. Specifically, for factor V Leiden, the
risk for a heterozygous carrier increases the
risk approximately 30 times to a yearly inci-
dence of 0.6–0.9%. This incidence is also
highest in the first year of OCP usage.
b. She asks about testing for clotting risk
factors, what do you advise her?
Thrombophilia testing can be considered on
an individual basis for the patient wishing to
start OCPs who has a family member with a
known thrombophilia. Additionally, the
patient should be offered alternative lower
risk forms of contraception. In this case, the
practitioner should try to get more informa-
tion regarding the episode of thromboembo-
lism in the aunt. Were there acquired risk
factors such as trauma, surgery, or immobil-
ity? Was the clot thought to be spontaneous?
If so, was the aunt tested for thrombophilia?
Current recommendations would not
advise testing your patient without further
information. If the aunt had a spontaneous
thrombus, one could advise that she should
be tested for thrombophilia, and if found
to be positive your patient could be tested
as well. If it was determined that there was
Thrombophilia 117
an underlying risk factor in the aunt’s
thromboembolism, testing her and/or your
patient would not be advised. In the situa-
tion where thrombophilia testing of your
patient is not advisable (the most likely
scenario in general), you should counsel
your patient closely on the risks and benefits
of OCPs and the potential lower-risk alter-
native therapies such as progesterone-only
preparations (e.g., Depo-Provera).
Suggested reading
Manco‐Johnson, M.J. (2006). How I treat venous
thromboembolism in children. Blood 107:
21–29.
Monagle, P., AKC, C., Goldenberg, N.A. et al.
(2012). Antithrombotic therapy in neonates
and children. Antithrombotic Therapy and
Prevention of Thrombosis, 9th ed.: American
College of Chest Physicians Evidence‐Based
Clinical Practice Guidelines. Chest 141:
e737s–e801s.
Monagle, P., Cuello, C.A., Augustine, C. et al.
(2018). American Society of Hematology
2018 Guidelines for management of venous
thromboembolism: treatment of pediatric
venous thromboembolism. Blood Adv. 2:
3292–3316.
Monagle, P., AWA, L., Thelen, K. et al. (2019;
https: //doi. org/1 0 . 1 0 1 6 /S2 3 5 2 ‐3 0 2 6 ) .
Bodyweight‐adjusted rivaroxaban for chil-
dren with venous thromboembolism
(EINSTEIN‐Jr): results from three multi-
center, single‐arm, phase 2 studies. Lancet
Hematol. 10: 30161–30169.
Raffini, L. (2008). Thrombophilia in children:
who to test, how, when, and why? Hematology
Am. Soc. Hematol. Educ. Program: 1: 228–235.
11 The Neutropenic Child
Neutrophils are a key component in the
defense against infection. They contain
toxic cytoplasmic granules that, following
ingestion of infecting bacteria and fungi, are
released into the phagocytic vacuole,
destroying them. Once released from the
bone marrow, they circulate in the blood for
a brief time (4–6 hours) before leaving the
circulation and entering the tissue where, in
response to the presence of infection, they
act to control the infection while sending
chemotactic signals to recruit additional
neutrophils to the area and stimulate the
accelerated production of neutrophils in
the bone marrow. While the presence of
adequate neutrophil numbers in the tissue is
the best predictor of the patient’s ability to
fight infection, there is no easy clinical
method to determine the number of tissue
neutrophils, so the number present in the
blood is used as a surrogate marker.
Neutropenia has traditionally been
defined as a decrease in the absolute neutro­
phil count (ANC) to <1.5 × 109/l. The ANC is
calculated by multiplying the white blood
cell (WBC) count by the total percentage of
segmented (mature) neutrophils plus bands.
Mild neutropenia is defined as an ANC of
1–1.5 × 109/l, moderate neutropenia is an
ANC of 0.5–1 × 109/l, and severe neutropenia
is an ANC below 0.5 × 109/l. This division is
useful for determining the individual’s risk
for infection and the urgency of medical
Handbook of Pediatric Hematology and Oncology – Children’s Hospital & Research Center Oakland,
Third Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
intervention. However, this definition fails to
take into account important variations in
normal neutrophil number related to age
and ethnicity. Greater than 10% of young
Arabic and African‐American children will
have an ANC between 1 and 1.5 × 109/l, and
this level should be considered normal for
these groups. This “mild neutropenia” also
extends into adulthood. Neutropenia is com­
mon in premature or small for gestational
age (SGA) newborns; 5–10% of these infants
will have an ANC < 1 × 109/l. Also, the nor­
mal range for ANC extends down to 1 × 109/l
in infants between 2 weeks and 6 months of
age and should not be considered abnormal.
Risk assessment
The first question when evaluating a child
with neutropenia is: “What is the risk that
this patient has or will develop a life‐threat­
ening infection?” This is particularly perti­
nent if the patient presents with fever. The
susceptibility to bacterial infection in neu­
tropenic patients is quite variable and
depends on a number of factors. The first is
the severity of neutropenia, as described in
the preceding text. Patients with mild neu­
tropenia have minimal to no increased risk
of infection, those with moderate neutrope­
nia have a mildly increased risk of frequent
or severe infections, and those with severe
120 Chapter 11

neutropenia are highly susceptible to bacte­

Etiology of neutropenia
rial infection. However, patients who are
neutropenic as a result of cytotoxic therapy
A large variety of conditions can lead to
(e.g., chemotherapy, radiation) may be at an
neutropenia in childhood. They can be
increased risk of infection because of the rate
classified as being either acquired causes or
of decline of the neutrophil count or other
inherited causes. Of these, acquired causes
immunosuppressive effects of chemother­
are much more frequent. These are
apy, even before the ANC falls below
presented in Table 11.1.
0.5 × 109/l. Another factor is the cause of the
Viral infection is the most common cause
neutropenia, if known. Patients with neutro­
of mild–moderate neutropenia. Transient
penia caused by intrinsic bone marrow fail­
marrow suppression is seen in children with
ure or hypoplasia have a greater risk of
EBV, respiratory syncytial virus (RSV), influ­
infection than those whose neutropenia is
enza A and B, hepatitis, HHV6, varicella,
due to factors extrinsic to the marrow such
rubella, and rubeola. This typically lasts for
as excessive neutrophil destruction or
3–8 days. Neutropenia can also be seen in
sequestration (e.g., immune neutropenia,
the setting of overwhelming bacterial infec­
splenomegaly). While patients with extrinsic
tion as well as with typhoid fever, Rocky
neutropenia may have a low circulating neu­
Mountain spotted fever, and tuberculosis.
trophil count, their tissue counts are near
Phagocytosis of microbes leads to release of
normal and they are more protected from
toxic metabolites, which then activate the
infection. A third factor is the presence or
complement system, inducing neutrophil
absence of other phagocytic cells. Many
aggregation and adherence of leukocytes to
patients with chronic neutropenia have an
the pulmonary capillary bed. Tumor necro­
elevated circulating monocyte count, which
sis factor and interleukin‐1 (IL‐1), released
provides some additional protection against
by macrophages, likely accelerate this pro­
pyogenic organisms. Conversely, patients
cess. Activated granulocytes sequestered in
being treated with steroids or other immuno­
the lungs may cause acute cardiopulmonary
suppressive therapy will have treatment‐
complications. Neonates have a limited gran­
related abnormalities in cell‐mediated,
ulocyte pool in their bone marrow, which
humoral, and macrophage–monocyte immu­
can be exhausted rapidly during overwhelm­
nity, and may be at increased risk of invasive
ing bacterial sepsis.
infection even with a normal neutrophil
Replacement of the bone marrow (as
count. Patients with a history of splenectomy
occurs with hematologic malignancies, gly­
have an increased risk of overwhelming
cogen storage diseases, granulomas associ­
infection caused by encapsulated bacteria
ated with infection, and fibrosis related to
regardless of their neutrophil count.
chemical or radiation injury or osteoporosis)
The age at presentation with neutropenia
results in neutropenia. Frequently, the eryth­
is an important factor in risk assessment.
roid and megakaryocytic lines are also
The younger the child is at the time of
affected.
diagnosis, the greater the concern that the
Medications are a common cause of neu­
patient could have a severe form of chronic
tropenia. Neutropenia is a common and
neutropenia, while children who are found
expected side effect of anticancer therapy.
to be neutropenic later in life, and who do
Many chemotherapeutic agents have a direct
not have a history of frequent bacterial
toxic effect on the early marrow stem cells.
infections or chronic illness, are more likely
The severity and duration of the neutropenia
to have a more benign form of neutropenia.
 The Neutropenic Child 121

Table 11.1 Acquired causes of neutropenia.

Condition Pathogenesis Occurrence Associated findings

Infection Viral marrow suppression, Common EBV, parvovirus,

viral‐induced immune HHV6, other
neutropenia viruses
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
Immune destruction Less common condition
Autoimmune Primary (molecular mimicry) Common Monocytosis
Secondary (SLE, Evans common
syndrome, common variable
immune deficiency)
Newborn Alloimmune: Maternal Rare Antigen difference in
immune sensitization newborn and
mother
Isoimmune: Due to maternal Maternal
autoimmune neutropenia neutropenia
Idiopathic Likely most common cause is Common Consider also
autoimmune with negative familial benign
antibody testing neutropenia
Often asymptomatic
Sequestration Hypersplenism Common if Mild neutropenia
spleen is Enlarged spleen—
enlarged many causes
Nutritional Vitamin B12 or Rare in children Hypersegmented
folate deficiency neutrophils
Copper deficiency Zinc excess

Abbreviations: EBV, Epstein–Barr virus; HHV6, Human herpesvirus‐6; SLE, Systemic lupus
erythematosus.

depend on the particular medication and
dosage as well as the patient’s underlying
disease, state of nutrition, and general
health. Many other medications can induce
neutropenia, including antibiotics (chlo­
ramphenicol, cephalosporins, penicillins,
sulfonamides), anticonvulsants (phenytoin,
valproic acid), anti‐inflammatory agents,
cardiovascular agents, tranquilizers, and
hypoglycemic agents. The severity and
duration of drug‐induced neutropenia are
variable. The underlying mechanism is not
known, although studies with certain drugs
have led to various hypotheses including
immune‐mediated destruction, toxic effect
of the drug or metabolites on the marrow
stem cells, and toxic effects on the marrow
microenvironment. After withdrawal of the
drug, the marrow can repopulate with early
myeloid forms within 3–4 days and appear
morphologically normal by 1–2 weeks. The
duration of neutropenia is likely related to
122 Chapter 11
the underlying mechanism; some chronic
idiosyncratic drug reactions can last from
months to years.
Autoimmune neutropenia (AIN) is
another common cause of neutropenia.
Primary AIN is a disorder of unknown
cause and may be associated with develop­
ment of neutrophil‐specific autoantibodies.
It has long been thought that AIN is trig­
gered by environmental antigens or viral
infections, but this has been difficult to
prove. Primary AIN most commonly occurs
in the first two years of life (occasionally in
the newborn period), and has a high sponta­
neous remission rate, perhaps as high as
90%. Cases in which no specific neutrophil
autoantibodies are identified are generally
given the diagnosis of idiopathic neutrope­
nia. Collectively these two conditions com­
prise the majority of chronic neutropenia
cases in young children. Until recently,
detection of antineutrophil antibodies was
challenging. Development of the granulo­
cyte immunofluorescence test (GIFT) and
the granulocyte agglutination test has made
detection of these antibodies more sensitive,
and current practice recommends using
both tests for diagnosis. GIFT demonstrated
a sensitivity of 60% with a single assay, and
82% with repeated testing. Management of
both AIN and idiopathic neutropenia is the
same and relies on the history of fever and
infections to guide treatment. Granulocyte
colony stimulating factor (G‐CSF) is recom­
mended only for patients with an
ANC < 0.5 × 109/l and recurrent fever/infec­
tions, using the minimal effective dose
(0.5–3 mcg/kg/day on a daily or every other
day basis). Prophylactic antibiotics, steroids,
or intravenous immunoglobulin (IVIG) are
not recommended for treatment.
Neonatal alloimmune neutropenia is
analogous to Rh‐related hemolytic disease
of the newborn; mothers generate IgG anti­
bodies against paternal neutrophil antigens
expressed on fetal neutrophils. These anti­
bodies, most commonly directed against
antigens in the human neutrophil antigen
(HNA) family, cross the placenta and cause
neutropenia in the fetus and newborn. The
consequences of this may be quite severe,
including omphalitis, cellulitis, bacteremia,
and meningitis. Although usually resolving
within 6 weeks, the neutropenia can persist
for as long as 6 months. Management is gen­
erally supportive given the brief duration of
neutropenia. Neonates with severe neutro­
penia and serious infection can be treated
with G‐CSF in hopes of accelerating neutro­
phil recovery.
Neonatal isoimmune neutropenia is
analogous to congenital thrombocytopenia
in infants of mothers with a history of
immune thrombocytopenia (ITP). The key
to diagnosis is to consider it; the newborn’s
ANC should be measured whenever a
mother is noted to be neutropenic. The risk
of severe infection is similar to infants with
alloimmune neutropenia, and the manage­
ment is the same.
Splenomegaly from any cause, including
chronic hemolytic anemia, portal hyperten­
sion, liver disease, hemoglobinopathies, and
storage disorders can cause mild neutrope­
nia, as well as anemia and thrombocytope­
nia. Rarely, splenectomy may be necessary
due to the consequences of hypersplenism.
Deficiencies of folate and B12 are rare in
children; the presence of hypersegmented
neutrophils caused by impaired neutrophil
nuclear maturation is a clue to this condition.
Similarly, copper deficiency is a rare cause of
neutropenia often secondary to an underly­
ing malabsorptive process or due to zinc
excess. These patients usually present with
concomitant anemia and thrombocytopenia.
Inherited causes of
neutropenia
A number of inherited conditions have neu­
tropenia as one of their characteristic features.
Hereditary neutropenias can present similarly

to acquired forms, but almost always present
in the first year of life with recurrent fever and
frequent episodes of fever, mouth ulcers, gin­
givitis, sinusitis, pharyngitis, cellulitis, and
respiratory and perianal infections. The more
common of these conditions are presented in
Table 11.2. Traditionally these have been
named descriptively or using eponyms, but
the current convention is to identify them by
the specific gene mutation leading to the neu­
tropenia, if known.
Children with severe congenital neutro­
penia (SCN) often present in early infancy
with umbilical infection, skin infections,
oral ulcers, pneumonia, or perineal infec­
tions. The most common forms are an
autosomal recessive (AR) form (Kostmann
syndrome) involving mutations in the
HAX1 gene that is involved in signal trans­
duction, and an autosomal dominant (AD)
form involving mutations in the neutrophil
elastase gene (ELANE) or, more rarely, in
the GFI1 gene that targets ELANE. Bone
marrow aspiration reveals a maturational
arrest at the promyelocyte stage. In addition
to the risk of death due to overwhelming
infection, patients with either of these con­
ditions have an increased risk of developing
myelodysplastic syndrome (MDS) or acute
myelogenous leukemia (AML). Multiple
additional SCN mutations have been
recently discovered.
Cyclic neutropenia is characterized by
approximately 21‐day cycles of changing
neutrophil counts, with frank neutropenia
developing at regular intervals and lasting
3–6 days. Fever and oral ulcerations usually
are seen during the nadir, as well as gingivi­
tis, pharyngitis, and skin infections.
Diagnosis is often delayed because the neu­
trophil count has often improved by the
time the patient seeks medical attention.
These patients also demonstrate mutations
in the ELANE gene, but at different loca­
tions than in those with SCN. They do not
have the same risk of developing MDS or
AML. Diagnosis is made by obtaining serial
The Neutropenic Child 123
complete blood counts (CBCs) 2–3 times
per week over 4–6 weeks to demonstrate the
periodicity of the cycle. G‐CSF has been
used in patients who develop recurrent
infections during their nadir.
Shwachman–Diamond Syndrome is an
autosomal recessive disorder attributable to
mutations in the SBDS gene. The protein
product of this gene is a critical component
of ribosomes, and the associated defect
in ribosomal functions affects multiple
organ systems. Defects include exocrine
pancreatic insufficiency, short stature, and
metaphyseal dysplasia. Mild to moderate
neutropenia is usually the first hematologic
manifestation, but bilineage and trilineage
hematological abnormalities are frequent.
Affected patients also have an increased risk
of MDS and AML. Intestinal malabsorption
with failure to thrive commonly occurs,
especially in infancy and early childhood.
Benign familial neutropenia is character­
ized by moderate neutropenia with minimal
risk of invasive bacterial infections. It has
been postulated that the underlying cause is
a defect in neutrophil mobilization from the
bone marrow, but the etiology is as yet
unknown. It occurs more commonly in
individuals of African, Arabic, and Yemenite
Jewish descent. Periodontal disease is the
most frequent complication.
Fanconi anemia is characterized by a
defect in DNA repair leading to extensive
chromosomal breakage. Affected patients
have mutations within the FANC family of
genes, including FANC A, C, and G. It pre­
sents most commonly during the early
school‐age years; patients with the charac­
teristic physical findings may be diagnosed
sooner. Thrombocytopenia is often the pre­
senting hematologic abnormality, with ane­
mia and neutropenia developing later. Up to
10% of patients ultimately develop MDS or
AML. Bone marrow transplantation is cura­
tive, but challenging to complete success­
fully given the underlying chromosomal
fragility.
 124 Chapter 11

Table 11.2 Inherited causes of neutropenia.

Condition Inheritance Pathogenesis Frequency Associated findings

Neutropenia
syndromes
Severe congenital AD ELANE mutations in neutrophil Rare (2‐3/106) Severe bacterial infections; overall risk of MDS/AML is
neutropenia elastase cause disturbed regulation of 20‐30% in patients treated with G‐CSF for >15 years
myeloid homeostasis with marrow
arrest at the promyelocyte state
Cyclic neutropenia AD Unclear mechanism due to separate Rare (1/106) 21‐day cycle with mouth ulcers, respiratory symptoms,
ELANE mutation leading to risk of cellulitis, abscesses, and severe infections
neutrophil apoptosis
Kostmann syndrome AR Mutation in HAX1 leads to impaired Quite rare, exact Severe bacterial infections; leukemia risk 15‐20%; patients
survival of myeloid precursors through frequency may have developmental delay, cognitive impairment
initiation of programmed cell death unknown and epilepsy
Familial benign AD Decreased marrow release Common Periodontal disease, otherwise not associated with an
increased infection risk; more common in Africans and
Yemenite Jews
 The Neutropenic Child 125

Condition Inheritance Pathogenesis Frequency Associated findings

Bone marrow failure

syndromes
Fanconi anemia AR Impaired response to DNA damage Rare (1/106) Dysplastic thumbs, short stature, café au lait spots, 10%
(DNA repair defect) due to risk of AML/MDS
mutations in FANC genes
Dyskeratosis Usually XR Telomerase defect and ribosomal Rare (1/106) Abnormal skin pigmentation, leukoplakia, dystrophic nails
congenita (also AR dysfunction; mutation in DKC1
and AD) (TERC or TERT in AD)
Schwachman‐ AR Defective ribosomal function due to Unknown; several Pancreatic exocrine insufficiency, short stature, metaphyseal
Diamond syndrome SBDS mutation affecting multiple hundred cases dysplasia, marrow failure and leukemia risk (15%)
organs described
Diamond‐Blackfan Sporadic RPS19 mutations that affect a ribosomal Rare (1/10 )
6
Erythroid failure syndrome, rarely with neutropenia; thumb
anemia (75%); AR protein in 25% of families and craniofacial anomalies, increased RBC adenosine
and AD deaminase, many patients respond to corticosteroids;
leukemia risk 2‐3%
Chédiak Higashi AR Nonsense or null mutations in CHS1 Very rare, 200 Oculocutaneous albinism, neurologic features, recurrent
syndrome gene resulting in absence of CHS1/ cases infections, abscesses, mastoiditis, severe immunologic
LYST protein worldwide deficiency with abnormal chemotaxis and NK function
leads to HLH
Glycogen storage AR Impaired glucose homeostasis due to Rare (2/106) Hypoglycemia, hepatosplenomegaly, dyslipidemia,
disease 1b SLC37A4 mutations hyperuricemia, lactic acidemia, seizures and failure to thrive
Selective IgA Unknown May be autoimmune Common (1/600) Infections of the upper and lower respiratory tracts in
deficiency or multi‐ one‐third of patients
factorial
X‐linked neutropenia XR Unique “gain of function” missense 1‐10/106 Associated with eczema, thrombocytopenia and immune
(Wiskott‐Aldrich mutation in the GTPase binding deficiency
syndrome related domain of WASp
disorder)

Abbreviations: AD, autosomal dominant; MDS, myelodysplastic syndrome; AML, acute myelogenous leukemia; G‐CSF, granulocyte colony stimulating factor; XR, X‐linked
recessive; AR, autosomal recessive, RBC, red blood cell; NK, natural killer; HLH, hemophagocytic lymphohistiocytosis; SLC37A4, solute carrier family 37 member 4
126 Chapter 11
Chédiak Higashi syndrome (CHS) is an
autosomal recessive disease that presents in
early childhood with moderate cytopenias
(neutrophil count often 0.2–2.0 × 109/l) and
recurrent pyogenic infections. Most patients
also have oculocutaneous albinism and neu­
rologic abnormalities. The genetic defects
occur within the CHS1 gene often resulting
in absent CHS1/LYST protein (a lysosomal
trafficking protein) leading to abnormal
granule formation. The granules are unable
to release lysosomal enzymes necessary for
phagocytic activity. Additionally, there is a
chemotaxis defect as well as the moderate
neutropenia, all contributing to an extreme
sensitivity to bacterial infection and sepsis,
particularly with Staphylococcus aureus,
Streptococcus pyogenes, Pseudomonas aerug-
inosa, Pneumococcus, and Candida albicans.
Most patients succumb to infection in early
childhood. Many patients develop lym­
phoproliferative infiltration of the bone
marrow and reticuloendothelium.
Dyskeratosis congenita (DKC) is charac­
terized clinically by the triad of abnormal
nails, reticular skin pigmentation, and oral
leukoplakia. Bone marrow failure occurs
during early adulthood and is associated
with a high risk of developing aplastic ane­
mia, MDS, leukemia, and solid tumors.
Patients have very short germline telomeres,
and approximately half have mutations in
one of six genes encoding proteins that
maintain telomere function. Affected
patients rarely present with hematologic
abnormalities during childhood.
Diamond–Blackfan anemia (DBA) is a
congenital anemia that presents in infancy.
There is typically a failure of erythropoie­
sis with preservation of myeloid and plate­
let production. Only 20–25% of cases
are inherited; the rest are sporadic.
Approximately 50% of affected persons
have developmental abnormalities, includ­
ing growth retardation and craniofacial,
upper limb/hand, cardiac, and genitouri­
nary malformations. Neutropenia is rarely
seen in affected children. Patients also
have an increased risk of MDS, AML, and
osteogenic sarcoma. Genetic studies have
identified heterozygous mutations in at
least one of eight ribosomal protein genes
in up to 50% of cases. Mutations in riboso­
mal protein L5 (RPL5) are associated with
multiple physical abnormalities, including
cleft lip/palate, thumb, and heart anoma­
lies. The diagnosis is often difficult due to
incomplete phenotypes and a wide varia­
bility of clinical expression. Up to 80% of
patients respond to steroids with improve­
ment in their anemia.
The etiology of neutropenia in glycogen
storage disease 1b is not definitively known,
but appears to be related to increased neu­
trophil apoptosis caused by an excess of
reactive oxygen species due to a defect in
neutrophil energy metabolism. Patients may
benefit from treatment with G‐CSF to pre­
vent infections.
Almost one‐third of patients with selec­
tive IgA deficiency have evidence of autoim­
mune disease; neutropenia in this condition
is felt most likely related to the presence of
antineutrophil antibodies.
Patients with a mild form of Wiskott–
Aldrich syndrome (WAS) known as X‐
linked neutropenia have a unique “gain of
function” mutation in the GTPase‐binding
domain of the WAS protein (WASp) that
leads to increased actin polymerization in
neutrophils, causing defective mitosis and
cell movement and ultimately severe
neutropenia.
Initial evaluation of the child
with neutropenia
Evaluation of the child with neutropenia
begins with a thorough history and physical
examination. It is critical to know whether
the child has had recent or recurrent bacterial

infections, and whether there is a family
history of neutropenia or recurrent bacterial
infections. On examination, attention
should be paid to any phenotypic abnormal­
ities, adenopathy, splenomegaly, evidence of
a chronic or underlying disease, and metic­
ulous evaluation of the skin and mucous
membranes (particularly in the oral and
perirectal areas). A CBC must be done to
determine if the patient has isolated neutro­
penia or neutropenia associated with ane­
mia and/or thrombocytopenia. The
approach to a child with bilineage or
trilineage abnormalities is different than
that in a child with isolated neutropenia;
multiple abnormal lineages increase the
likelihood of a more generalized marrow
failure state such as aplastic anemia or a
marrow infiltrative process such as
leukemia. It is valuable to repeat the CBC at
least once, especially if the child appears
well, to avoid proceeding with a major
evaluation due to a laboratory error or a
transient process.
Well‐appearing children with mild to
moderate neutropenia can typically be
observed over the next 2–3 weeks with serial
CBCs. Children with persistent or worsen­
ing neutropenia require further evaluation.
Patients with recurrent neutropenia should
have blood counts checked two to three
times per week for 6 weeks to evaluate for
cyclic neutropenia. Additional studies include
antineutrophil antibodies, assessment of cel­
lular and serum immune status, and careful
review of the peripheral smear for morpho­
logic abnormalities of the white cells. If SCN
or Kostmann syndrome is suspected, assess­
ment for ELANE, HAX1 and additional SCN
mutations should be made. A bone marrow
aspirate and biopsy may be necessary to iden­
tify granulocyte precursors and to search for
defects in myeloid maturation. In addition,
bone marrow aspirate and biopsy can be
used to exclude hematologic malignancies,
marrow infiltration, or fibrosis.
The Neutropenic Child 127
Management of the child
with neutropenia
Children identified with neutropenia but
who are free of fever or other signs of infec­
tion should be evaluated as outlined in the
earlier text, but require no other therapy at
that time. Managing the child with neutro­
penia and fever is more complex and
depends on many factors, including the
nature of the neutropenia (acute or chronic),
its severity, and the association with immune
defects, underlying illnesses, or malignan­
cies. Patients with acquired neutropenia aris­
ing from malignancy or chemotherapeutic
drugs have a diminished inflammatory capa­
bility and are unusually susceptible to sepsis.
Fever is not impacted by neutropenia and
may be the earliest and only warning sign.
Sepsis related to chemotherapy‐induced
neutropenia remains a leading cause of mor­
tality in these patients. Aggressive manage­
ment of the febrile, neutropenic cancer
patient in the hospital has markedly reduced
morbidity and mortality due to infection.
For management of oncology patients with
fever and neutropenia, see Chapter 27.
The management of the febrile child who
is discovered to be neutropenic depends on
several factors. Patients with fever and mild
or moderate neutropenia and symptoms
and signs suggestive of a viral illness that
otherwise look well may be managed sup­
portively without antibiotics, although in
most cases they will receive a long‐acting
cephalosporin such as ceftriaxone prior to
discharge from the clinic or emergency
department. Their parents should be
instructed to bring them back in 24 hours
for further evaluation, or sooner if they
develop additional symptoms or begin to
appear unwell. If they become afebrile, their
neutropenia should be evaluated as outlined
earlier. Patients with fever and mild or mod­
erate neutropenia who have evidence of
localized bacterial disease (otitis media,
128 Chapter 11
sinusitis, or local skin infections) may be
treated with appropriate oral antibiotics in
the outpatient setting. Patients with mild
neutropenia and evidence of bacterial pneu­
monia, GU tract infections, lymphadenitis,
or systemic symptoms should have cultures
of the infection site and of the blood. They
may be treated with appropriate oral antibi­
otics if their appearance is not concerning,
but should be seen back for re‐evaluation
within 24 hours. Similar patients with mod­
erate neutropenia can also be treated in the
outpatient setting if they appear totally well.
Febrile patients with moderate or severe
neutropenia who appear in any way unwell
require emergent medical assessment and
initiation of therapy, as do children who are
known to have severe forms of neutropenia
such as SCN or Kostmann syndrome. These
children require:
●● Hospital admission.
●● Coverage with broad‐spectrum antibiot­
ics due to their increased risk of mortality
due to sepsis, especially Gram‐negative
organisms. A fourth‐generation β‐lactam
cephalosporin antibiotic (i.e., cefepime)
provides initial broad coverage and covers
Pseudomonas species, but several different
antibiotic choices are appropriate and
depend on local practice; patients with skin
infection should be covered for Gram‐posi­
tive organisms with vancomycin.
●● Careful physical evaluation, paying
meticulous attention to potential sites of
occult infection (i.e., the oral cavity and
perineum).
●● Laboratory studies: CBC with differential,
blood cultures, urinalysis (UA) and urine
culture, and cultures from sites of suspected
infection, such as the skin, throat, and stool.
●● Chest radiograph if any pulmonary signs
or symptoms are present.
●● Daily blood cultures and a CBC with dif­
ferential every 24 hours in the persistently
febrile patient to help determine further
management.
●● CT scan of the chest (± sinuses and/or
abdomen/pelvis dependent on symptoms
and individual patient factors) looking for
evidence of occult infection in any patient
persistently febrile for >96 hours without a
specific cause being identified with initia­
tion of empiric antifungal coverage due to
the increased risk of invasive fungal infec­
tion in this patient population.
Prophylactic antibiotics have been used
in the past in an attempt to decrease the fre­
quency of serious infections in patients with
severe neutropenia; however, this has gener­
ally fallen out of favor. Exceptions include
the use of prophylactic penicillin or amoxi­
cillin in patients following splenectomy, and
the use of trimethoprim–sulfamethoxazole
prophylaxis to prevent Pneumocystis jiroveci
(previously known as Pneumocystis carinii)
pneumonia in patients with T‐cell dysfunc­
tion in addition to neutropenia.
Empiric antifungal coverage should be
considered dependent on the severity and
length of neutropenia; those with prolonged,
profound neutropenia should receive
antifungal prophylaxis with fluconazole at a
minimum due to the increased risk of
invasive fungal infection in this patient
population. Evidence for broader agents
such as extended‐spectrum azoles (i.e.,
voriconazole, posaconazole) is lacking.
The use of cytokines, particularly G‐CSF
has become increasingly popular in the
management of symptomatic neutropenia.
It is particularly useful in patients with
symptomatic cyclic neutropenia or in the
neutropenia‐accompanying disorders such
as glycogen storage disease 1b, as these
patients typically respond well to low dose
therapy (1–2 mcg/kg/dose) on a daily or
alternate day schedule with a goal of
maintaining an ANC between 1 and
1.5 × 109/l. It is also used frequently in
patients with severe chronic neutropenia.
However, the doses required to raise the
ANC into the desired range vary significantly

between patients. A typical starting dose is
3–5 mcg/kg/day, and the dose is increased
slowly until the desired ANC is achieved.
Patients with severe neutropenia who fail to
respond to doses as high as 50–100 mcg/kg/
day are considered poor responders. These
patients are candidates for bone marrow
transplantation given their high likelihood
of mortality due to infection as well as an up
to 30% chance of developing myeloid
malignancy.
Case study for review
A 2‐year‐old African‐American female
presents to your office for evaluation of a
fever to 38.7 °C. Her parents state that she
has had fever on and off for about a week
with a similar fever occurring about once a
month for the past few months, each time
associated with viral upper respiratory
infection (URI) symptoms. Otherwise, she
has been healthy, and her parents are with­
out major concerns, as the fevers resolve on
their own. Her vital signs are currently
within normal limits. Her physical exam
reveals a well female, nontoxic‐appearing.
There is no obvious source of infection
noted on exam.
a. What additional information would
you like?
Additional history including birth history,
recurrent hospitalizations/prolonged antibi­
otic courses, or recurrent or unusual infec­
tions will help to guide differential diagnosis.
Additional important information to obtain
should include travel/exposure history,
medication usage, family history, presence
of any dysmorphic features on physical
exam, and availability of any prior compara­
tor labs.
She was born full‐term, via normal sponta­
neous vaginal delivery (NSVD) after an
uncomplicated pregnancy and delivery, dis­
The Neutropenic Child 129
charged to home on day 2 of life. Her umbilical
cord fell off by 2 weeks of life. She has had no
emergency department (ED) visits, hospi­
talizations, recurrent infections, or pro­
longed antibiotic courses. Her growth
parameters are normal, she has normal
urine and stool output. She is non‐dysmor­
phic, and her skin exam is normal. Her
fevers never correlate with oral ulcers. She
has no recent travel or medication history.
Mom has been told before that “low white
blood cells” run in her family, but no other
family history of recurrent infections is elu­
cidated. Your patient has never had a CBC.
b. What initial studies would you like to
obtain?
A CBC is vital to assess her current white
blood cell count and differential, and to
determine if additional cell lines are affected.
Given the number of days of fever, it would
be worth obtaining a chest X‐ray (CXR) to
rule out a viral or bacterial pneumonia, as
well as urine studies (ideally catheterized
urinalysis with micro and urine culture) to
assess for occult infection. Viral studies
including RSV and influenza can be consid­
ered based on the time of year and clinical
picture.
CBC shows a WBC of 8 × 109/l, hemo­
globin of 11 g/dl, and a platelet count of
200 × 109/l. Differential reveals 8% neutro­
phils, 78% lymphocytes, and 12% mono­
cytes, with an ANC of 640. CXR is normal,
UA with micro is normal and urine culture
is subsequently normal, RSV and flu studies
are negative. Given the fever and moderate
neutropenia, a blood culture is drawn which
is later negative.
c. What are your considerations now?
This degree of marrow suppression may be
viral, the most common cause of mild to
moderate neutropenia. Clinical symptoms
usually last for 7–8 days and neutropenia
should resolve within weeks. The patient’s
increased monocyte count may be a harbin­
ger of impending neutrophil recovery.
130 Chapter 11
Autoimmune neutropenia is an additional
common cause, and difficult to distinguish
from viral suppression though is more pro­
longed in duration (i.e., several months to 2
years), with infection risk proportionate to
the level of neutropenia.
Familial benign neutropenia should be a
consideration given her family history of
“low white blood cells in the family,” which is
more common in the African‐American
population and can be seen in 25–40% of
those of African descent. African‐Americans
and Middle Easterners in general have a
lower WBC count, with WBC > 4.0 × 109/l
and ANC > 1000 considered normal.
Given the moderate degree of neutrope­
nia, congenital neutropenia syndromes (i.e.,
SCN and Kostmann syndrome) are highly
unlikely, as they require ANC < 500 for
potential diagnosis. Cyclic neutropenia is a
possible diagnosis, though is seen more
often in 19–21‐day cycles and associated
with fevers, oral lesions, pharyngitis, or skin
infections. The lack of dysmorphic or other
characteristic abnormal physical exam fea­
tures makes Fanconi anemia and dyskerato­
sis congenita unlikely, though physical exam
features may be quite subtle. Diamond–
Blackfan anemia is typically a pure red cell
aplasia, though may have associated neutro­
penia. DBA is also more often diagnosed in
the first year of life. Shwachman–Diamond
syndrome should be considered, though
usually presents with exocrine pancreatic
dysfunction.
d. What would be your next step?
Initially, given a fever in the setting of mod­
erate neutropenia (ANC 500–1000), in a
well‐appearing child, coverage could begin
with a broad‐spectrum antibiotic such as a
third‐generation cephalosporin, such as cef­
triaxone with activity against Gram‐positive
and Gram‐negative aerobic organisms.
Length of treatment is determined through
pending blood culture results and usually
can be in the outpatient setting if a family is
in close proximity and able to return in
24 hours or with any signs of clinical wors­
ening. Any patient with a specific focus on
infection (i.e., otitis media, UTI, etc.) noted
on exam should be treated with appropriate
antibiotic coverage as needed, though broad
coverage should still be ensured.
In general, given a well‐appearing child,
close outpatient clinical monitoring and fol­
low‐up with serial CBCs over the subsequent
2–4 weeks until normalization are sufficient
assuming continued well‐appearance. It is at
the discretion of the provider to determine if
antibiotic coverage is necessary.
In the setting of persistent neutropenia,
further workup may be required such as
evaluation for cyclic neutropenia, antineu­
trophil or additional infectious antibody
testing, genetic testing for inherited neutro­
penic syndromes, and possibly bone mar­
row studies. Chronic benign neutropenia or
autoimmune neutropenia are the most likely
diagnoses with persistent neutropenia in the
well‐appearing child with eventual self‐res­
olution, though this may take many months.
Families must be advised to monitor their
child closely for fever and should be evalu­
ated urgently if febrile or ill‐appearing given
the potential risk of bacterial infection with
underlying severe neutropenia.
Multiple choice questions
1. You are seeing a 2-year-old patient in
your clinic who is asymptomatic but ends up
getting a CBC due to a low finger stick
hemoglobin. The CBC incidentally shows
neutropenia with an absolute neutrophil
count (ANC) of 300 x 106/l. There is mild
microcytic anemia most likely secondary to
iron deficiency anemia. The child is well
appearing with no significant infections.
There were baseline counts done at birth

due to rule out sepsis and at that time the
ANC was 4200 x 106/l. All of the following
are potential diagnoses except:
a. Chronic benign neutropenia
b. Viral suppression
c. Kostmann syndrome
d. Cyclic neutropenia
e. Autoimmune neutropenia
Explanation: At this age, given the normal
exam and no history of infections, the most
likely diagnoses are viral suppression and
chronic benign neutropenia. Kostmann
syndrome is the autosomal recessive variant
of severe congenital neutropenia and given
the normal ANC at birth is ruled out as the
neutrophil count should never be normal in
these conditions. Cyclic neutropenia is pos­
sible in this case as for many patients there
are no significant infections. Autoimmune
neutropenia occurs in a similar fashion as
ITP or autoimmune hemolytic anemia and
is usually a transient antibody process at this
age. The answer is c.
2. You are seeing a 1-week-old neonate who
presents with severe omphalitis. A CBC is
checked which shows a WBC of 12 × 109/l
with 67% lymphs, 32% monos and 1%
neutrophils (ANC 120 × 106/l). You suspect
a congenital neutropenia. The mutated gene
would be:
a. ELANE
b. HAX1
c. PHOX2b
d. N‐Myc
e. Either a. or b.
Explanation: Congenital neutropenia can
have an autosomal dominant form, severe
congenital neutropenia, which is due to a
defect in the ELANE gene, or an autosomal
recessive form, Kostmann syndrome, which
is due to a defect in the HAX1 gene. A differ­
ent mutation in the ELANE gene leads to
cyclic neutropenia. PHOX2b is a gene seen
in familial neuroblastoma as well as central
The Neutropenic Child 131
hypoventilation syndrome. N‐Myc is a
prognostic genetic marker in neuroblas­
toma. The answer is e.
3. You are seeing a well appearing newborn
who has a CBC done as part of a rule out sepsis
work up due to prolonged rupture of mem­
branes with a maternal fever in a GBS+ mother.
Maternal history is otherwise unremarkable.
The CBC shows a WBC of 5.8 × 109/l but an
ANC of only 440 × 106/l. Assuming underly­
ing infection is not the cause, of the following,
the most likely diagnosis is:
a. Autoimmune neutropenia
b. Alloimmune neutropenia
c. Severe congenital neutropenia
d. Fanconi anemia
e. Chronic benign neutropenia
Explanation: A normal ANC is >1000‐1500
x 106/l. Neonates <32 weeks of age have
only 20% of adult neutrophil mass so neutro­
penia is common secondary to age but
should normalize by 4 weeks post‐birth.
Certain populations, namely Africans,
African‐Americans and Yemenite Jews, will
have a normal, lower ANC though this still
tends to run >1000 × 106/l. Although it may
be difficult to differentiate allo/autoimmune
neutropenia from severe congenital neutro­
penia at birth, alloimmune neutropenia is
more common. And given the ANC number
and lack of infection, alloimmune neutro­
penia is also more likely. Similar to auto­
immune thrombocytopenia, the lack of
maternal history makes auto­ immune
neutro­penia less likely. Alloimmune neutro­
penia is due to maternal alloimmunization
of human neutrophil antigen in the father
(HNA‐1A, ‐1B, ‐1C). This transient anti­
body usually clears by 2 months of age. Most
infants are asymptomatic though may pre­
sent with infection including cellulitis,
omphalitis, pneumonia or sepsis. If with
infection these infants should receive IVIG
and GCSF. The answer is b.
132 Chapter 11
4. You are seeing a 4 year old male that has
failure to thrive. He has had a work up for
cystic fibrosis which was negative after stool
studies revealed increased fecal fat. Baseline
CBC shows neutropenia. He has short stat­
ure. The likely diagnosis is:
a. Fanconi anemia
b. Dyskeratosis congenita
c. Diamond‐Blackfan
d. Shwachman‐Diamond Syndrome
e. Cartilage‐hair hypoplasia
Explanation: The constellation of findings,
exocrine pancreatic insufficiency, neutro­
penia and short stature are consistent with
Shwachman‐Diamond syndrome, the
­second most common cause of exocrine
pancreatic insufficiency after cystic fibro­
sis. Neutropenia is common though may
intermittent, with or without concomitant
anemia and/or thrombocytopenia. Exocrine
pancreatic function may improve with age.
Skeletal abnormalities are common. The
SBDS gene on chromosome 7 is mutated in
this condition. Fanconi anemia is a bone
marrow failure syndrome that typically
presents with short stature, skeletal abnor­
malities, skin abnormalities (often café au
lait spots) due to a defect in DNA repair.
Dyskeratosis congenita is also a bone
marrow failure syndrome characterized by
shortened telomeres and presents with
nail dystrophy, abnormal skin pigmen­
tation and oral leukoplakia. Finally,
Diamond‐Blackfan anemia is a pure red
cell aplasia and may also be characterized
by short stature, skeletal anomalies and car­
diac anomalies. Cartilage‐hair hypoplasia is
a rare condition with skeletal dysplasia,
dwarfism and immunodeficiency. The
answer is d.
5. All of the following are criteria for severe
aplastic anemia EXCEPT:
a. ANC < 500 x 106/l
b. Platelets <50 x 109/l
c. Bone marrow cellularity < 25%
d. Absolute reticulocyte count <20 x 109/l
Explanation: Severe aplastic anemia can be
due to multiple causes including bone mar­
row failure syndromes and acquired causes
such as viral hepatitis and drugs. The majority
of cases are idiopathic. In addition to sugges­
tive peripheral blood counts, bone marrow
biopsy is required to determine bone marrow
cellularity. Studies to rule out paroxysmal
nocturnal hemoglobinuria, congenital bone
marrow failure syndromes and viral hepatitis
should be conducted. The answer is b.
6. You are seeing a 7-year-old with multiple
medical problems on a host of medications
including valproic acid for seizures, famoti­
dine for gastroesophageal reflux, and INH
for latent TB infection. He also takes ibupro­
fen and acetaminophen for fever and pain
control. You note that his ANC tends to run
low, between 600‐800 x 106/l with a low total
WBC count and you suspect drug effect. He
has not had any notable infections on this
cocktail of medications. Which of the below
should not affect his neutrophil count?
a. Acetaminophen
b. Ibuprofen
c. Isoniazid
d. Ranitidine
e. Valproic acid
Explanation: The practitioner should be
aware of a host of medication classes which
can lead to neutropenia including anti‐
inflammatories, antipsychotics and antide­
pressants, anticonvulsants, antithyroid
medications, antihistamines, antimicrobials
and cardiovascular drugs (in addition to
chemotherapeutic agents). The answer is a.
Suggested reading
Dale, D.C. (2017). How I manage children with
neutropenia. Br. J. Haematol. 178: 351–363.
Al Ghaithi, I., Wright, N.A., Breakey, V.R. et al.
(2016). Combined autoimmune cytopenias
presenting in childhood. Pediatr. Blood Cancer
63: 292–298.
12 Thrombocytopenia
Thrombocytopenia, or low platelets, can
occur as an isolated finding or in conjunc­
tion with a multitude of underlying clinical
conditions. Normal platelet counts range
from 150 to 400 × 109/l and thrombocytope­
nia is generally defined as a platelet count
of less than 100 × 109/l. Thrombocytopenia
may further be defined as mild (50–
100 × 109/l), moderate (20–50 × 109/l), and
severe (<20 × 109/l). Thrombocytopenia is
typically subdivided into immune and non­
immune causes. Immune causes generally
cause increased platelet destruction.
Nonimmune causes may lead to increased
destruction or decreased bone marrow pro­
duction. In patients with splenomegaly,
platelet sequestration may also lead to
thrombocytopenia.
Acute immune
thrombocytopenic purpura
Immune thrombocytopenic purpura (ITP;
also referred to as idiopathic thrombocyto­
penic purpura) is an acquired, isolated disor­
der in which the patient typically presents
with a low platelet count and symptoms of
mucocutaneous bleeding. The diagnosis of
ITP is often one of exclusion (see Table 12.1
and Figures 12.1–12.3).
Handbook of Pediatric Hematology and Oncology – Children’s Hospital & Research Center Oakland,
Third Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
The most common cause of destructive
thrombocytopenia is autoimmunity. The
markedly shortened platelet survival seen in
this condition is a result of platelet auto‐anti­
body production (usually IgG), often stimu­
lated by infection or drug exposure.
Suppression of platelet production may also
be present, and therefore ITP may actually
be a disorder in which decreased platelet
production and destruction occur simulta­
neously. IgM antibodies and complement
activation are less frequently found but can
also be seen in childhood ITP.
ITP is an acute, self‐limited disease of iso­
lated thrombocytopenia that typically occurs
in children aged 2–5 years (though may
occur at any age from infancy to adoles­
cence), resolving in more than 80% of chil­
dren within 6 weeks to 6 months. The
incidence in boys and girls is approximately
equivalent. When ITP occurs in the child
over 10 years of age, the course may more
likely become chronic or be associated with
an underlying autoimmune disorder. The
otherwise healthy child presents with sud­
den onset of severe thrombocytopenia (usu­
ally <20 × 109/l), manifested by petechiae and
purpura and less frequently mucosal bleeding
such as severe epistaxis, hemoptysis, menor­
rhagia, hematuria, and hematochezia. There
is a seasonal fluctuation in ITP (highest in
134 Chapter 12

Table 12.1 Differential diagnosis of thrombocytopenia.

Destructive thrombocytopenias
Immunologic ITP
Drug‐induced (valproic acid, amphotericin B,
digoxin)
Infection‐induced (HIV, VZV, CMV, EBV,
parvovirus B19, TB, hepatitis, pertussis)
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 hereditary TAR syndrome
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
 Thrombocytopenia 135

Table 12.1 (Continued)

Associated with chromosomal defect Trisomy 13 or 18
Metabolic disorders Marrow infiltration
Malignancies (leukemia, neuroblastoma, metastatic
solid tumors)
Storage disease
Myelofibrosis
Acquired processes Aplastic anemia, paroxysmal nocturnal
hemoglobinuria
Liver disease/failure
Drug‐induced
Radiation‐induced
Anemia: severe iron deficiency, megaloblastic
(folate or vitamin B12 deficiency)
Sequestration Hypersplenism (portal hypertension, neoplastic,
infectious, metabolic storage disease, cyanotic
heart disease)
Hypothermia

Abbreviations: ITP, immune thrombocytopenic purpura; CMV, cytomegalovirus; SLE, systemic

lupus erythematosus; 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; TB, tuberculosis; ATRUS, amegakaryocytic thrombocytopenia
radio‐ulnar synostosis; RDS, respiratory distress syndrome; VZV, varicella zoster virus.

spring and lowest in fall) and the patient

Evaluation
often gives a history of an antecedent viral
illness within the past 1–3 weeks in up to
The initial evaluation of the child with sus­
60–70% of children or following vaccination
pected ITP begins with a complete history
with Measles‐Mumps‐Rubella (MMR) or
and physical examination. Other than a pos­
Varivax (live virus vaccines). This supports
sible antecedent illness (1–3 weeks prior)
the hypothesis that an aberrant immune
and the acute onset of minor bleeding and
response may be triggered by infection.
bruising, the child should be otherwise clin­
Severe bleeding such as protracted epistaxis,
ically well‐appearing. More significant
hemoptysis, or gastrointestinal bleeding
bleeding may be associated with trauma.
leading to severe anemia and need for trans­
Bleeding into joints (hemarthroses) should
fusion is rare. Intracranial hemorrhage
lead one to consider an alternative bleeding
(ICH) is the most feared complication, with
disorder (e.g., congenital or acquired factor
an estimated incidence of 0.1–0.5%; more
deficiency such as hemophilia). There
than 50% of patients with ICH present with
should be no history of unexplained fevers,
this finding at diagnosis or within 1 week of
bone pain, or weight loss which would be
diagnosis. More than 75% of patients with
concerning for an underlying malignancy or
ITP and ICH survive. It has yet to be defined
chronic infection. A medication history is
what risk factors predispose children with
critical as many drugs have been impli­
ITP to sustain this rare but extremely serious
cated in inducing drug‐mediated immune
complication.
136 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.

thrombocytopenia. Implicated drugs history should include an assessment for

include heparin, aspirin, aspirin‐containing
cold medications, nonsteroidal anti‐inflam­
matory drugs (NSAIDs), and seizure medi­
cations such as valproic acid. Chronic
infections with HIV, cytomegalovirus
(CMV), and hepatitis C may cause a low
platelet count and appropriate screening
should be done to determine risk.
Helicobacter pylori has been implicated in
adults with ITP and there are some reports
of this association in children as well. Family
autoimmune diseases, immune deficiency,
or congenital syndromes associated with
thrombocytopenia (see Table 12.1). The
physical exam should assess for lymphade­
nopathy, hepatosplenomegaly, short stature,
dysmorphic features, or the presence of con­
genital anomalies (e.g., radius, thumb, and
fingers) that may be associated with other
diagnoses.
The laboratory features of ITP include a
low platelet count in the face of an otherwise
 Thrombocytopenia 137

History, physical examination,

CBC, differential, platelet count,
peripheral smear evaluation

Isolated thrombocytopenia

Assess platelet morphology

Normal Abnormal

Assess for splenomegaly Negative Congenital Large platelets

and/or lymphadenopathy
Positive
Bone marrow aspirate
anomalies Bernard–Soulier syndrome
or MYH9 disorders (May–Hegglin)
Jacobsen syndrome
Platelet-type von Willebrand
disease
Benign Mediterranean
macrothrombocytopenia
Normal exam Gray platelet syndrome
Small platelets
Wiskott–Aldrich syndrome

DDx:
ITP (see Table 12.1)
Viral-induced
DDx:
Malignancy Drug-induced
HIV Skeletal
Infection Fanconi anemia
Autoimmune disease
HIV, EBV, CMV TAR, ATRUS
Infant
Storage disease Cyanotic heart disease
Alloimmune (NAIT)
Gaucher disease Eczema
Autoimmune (maternal Ab transfer)
Hypersplenism Wiskott-Aldrich syndrome
Hemangioma (may be visceral)
Aplastic anemia Hemangiomas
Fanconi anemia Kasabach–Merritt syndrome
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 alloimmune
thrombocytopenia; Ab, antibody; TAR, thrombocytopenia absent radius; ATRUS, amegakaryocytic
thrombocytopenia radio‐ulnar synostosis.

normal complete blood count (CBC).
However, the hemoglobin, white blood cell
count, and/or absolute neutrophil count
may be altered due to a recent infection, and
the hemoglobin may be low if there has
been significant or prolonged bleeding.
Coagulation screening tests including PT,
PTT, and fibrinogen and the complete meta­
bolic panel should be normal. Therefore, no
studies other than a CBC truly need to be
done if the diagnosis of ITP is strongly sus­
pected. The platelet count should be con­
firmed to be low on a second evaluation if
the physical findings do not correlate with
the laboratory value to rule out a falsely low
platelet count (i.e., platelet clumping or anti­
body to ethylenediaminetetraacetic acid
[EDTA]).
138 Chapter 12

History, physical examination,

CBC, differential, platelet count,
peripheral smear evaluation

Thrombocytopenia with anemia

DAT test no Assess for intravascular yes

Microangiopathic
(Coombs) hemolysis, red cell process
fragments Consumption
negative positive

Reticulocyte DDx:
count Evans syndrome
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 antiglobulin test (Coombs); DDx, differential diagnosis; DIC, disseminated
intravascular coagulation; HUS, hemolytic uremic syndrome; TTP, thrombotic thrombocytopenic
purpura; CHD, congenital heart disease.

If two cytopenias are present with any
findings on the history or physical sugges­
tive of another diagnosis such as malignancy
or marrow failure, consideration should be
given to performing a bone marrow aspira­
tion (BMA). However, a bone marrow eval­
uation is rarely necessary to confirm the
diagnosis of ITP. Marrow morphology in
ITP typically shows immature megakaryo­
cytes in normal or increased numbers (often
with maturation arrest) and normal eryth­
roid and myeloid lineages. Megakaryocytes
can be decreased in a subset of patients in
which immune destruction may affect early
platelet precursors. By convention, a BMA is
done on individuals with suspected ITP
only if steroids are to be part of the treat­
ment plan due to the small chance the
thrombocytopenia may be an early manifes­
tation of leukemia. However, even this prac­
tice is controversial and the recent American
Society of Hematology guidelines state this
is not routinely necessary for most children
who present with classic features of ITP.
Additional laboratory evaluations may be
required for specific clinical indications (e.g.,
screening for autoimmune or thyroid dis­
ease; viral testing for HIV, hepatitis C, CMV,

or parvovirus B19; direct antiglobulin testing
[DAT; Coombs] and reticulocyte count if
concern for autoimmune hemolytic anemia
(AIHA); and immunoglobulin levels and
T/B cell numbers if concern for underlying
immunodeficiency syndrome). Antiplatelet
antibody tests are not sensitive or specific
and not routinely helpful in diagnosing ITP.
Review of the peripheral blood smear con­
firms a low platelet count, and the few remain­
ing platelets typically are large. If platelet size
(mean platelet volume; MPV) is determined
by an automated cell counter (Coulter), it may
be elevated, consistent with young platelet age
(due to early marrow release associated with
rapid peripheral platelet destruction). More
often the platelet count is underestimated, as
very large immature platelets (megakaryocytic
fragments) are not counted by the Coulter.
The presence of these premature granular
platelets may in part explain the relative lack of
bleeding symptoms in children with very low
platelet counts in ITP as compared with
decreased production in association with mar­
row failure or following chemotherapy. The
erythrocyte and leukocyte counts and mor­
phology are typically normal and there should
be no evidence of hemolysis or microangio­
pathic disease (e.g., schistocytes or burr cells).
False values for platelet counts can result
from aggregation of platelets in the syringe
or collection tube, counting of small non‐
platelet particles (fragmented red or white
cells) by automated cell counters, and pseu­
dothrombocytopenia due to in vitro platelet
agglutination by anticoagulant‐dependent
EDTA antibodies. Review of the blood film
should assess for clumps of agglutinated
platelets at the periphery of the slide.
Treatment
The natural history of acute ITP is complete
resolution in the majority of children. ITP is
classified according to length of symptoms
Thrombocytopenia 139
and is referred to as acute within 3 months
of diagnosis, persistent from 3 to 12 months,
and chronic if the symptoms have persisted
beyond 12 months. Despite the relatively
benign course experienced by most children
with ITP, the sudden onset, concern for a
possible serious condition such as leukemia
or aplastic anemia, and concern for life‐
threatening bleeding often guide the initial
treatment decision‐making. Parents often
bring their child to see the primary care or
emergency physician, many of whom are
not accustomed to encountering such severe
thrombocytopenia. Risk factors for the rare
life‐threatening hemorrhage have yet to be
elucidated and dogma has been to treat the
patient according to platelet count rather
than being guided by the degree of clinical
symptoms. It is also not possible to predict
which patients will have a short or a
prolonged course, though in general
younger children tend to have shorter
courses and adolescents may be more at risk
for a chronic course. The concern for the
possibility of life‐threatening hemorrhage
and lack of predictability has led to
significant controversy as to whether
intervention is warranted, when it is
warranted, and with what treatment.
Contemporary therapies have not been
shown to alter the course or outcome of
children with acute ITP. As such, the concept
of nontreatment in ITP is increasingly
becoming the standard of care in most
pediatric hematology oncology centers.
Preventative care is an important element
in the management of patients with ITP. All
patients and families should be counseled
regarding rough play, contact sports, and
general anticipatory guidance such as the
use of protective gear (helmets) and seat
belts. Intramuscular injections should be
withheld until platelet counts increase.
Depo‐Provera or other progesterone
intervention can be helpful in decreasing or
stopping menstruation. Specific medications
140 Chapter 12
that interfere with platelet function (such as
fish oil, NSAIDs, selective serotonin
reuptake inhibitors [SSRI], anticonvulsants,
and aspirin) should be avoided.
The use of a bleeding score as the
framework for a consistent treatment
strategy is gaining in popularity and several
scoring systems have been published to date.
Patients are categorized by the presence of
clinical signs and symptoms of bleeding;
more than 80% present with mild clinical
bleeding (manifested by bruising, petechiae,
mild epistaxis, and no anemia). Moderate
clinical bleeding is characterized by more
significant mucosal bleeding such as more
severe epistaxis or menorrhagia, and severe
bleeding (usually <5% of patients) is marked
by unusual or severe bleeding requiring
hospitalization for control or blood
transfusion support, with symptoms
seriously interfering with quality of life. All
patients may present with very low platelet
counts (i.e., 1–20 × 109/l) though those with
severe symptoms tend to have initial platelet
counts <10 × 109/l.
Utilizing the bleeding score, many
patients with clinically mild or moderate
bleeding can be effectively managed with
observation. The anxiety of patients, fami­
lies, and other caregivers can often be
alleviated with education on the patho­
physiology and natural history of ITP in
addition to general preventive measures
and periodic clinical and laboratory assess­
ments. Platelet counts do not need to be
checked more often than every 1–2 weeks
(or even less often in the clinically stable
child). Disruption of school or work is not
necessary, though participation in competi­
tive contact sports or other situations that
could lead to head or abdominal injury
should be avoided until the platelet count
has returned to a safe level (typically
>50 × 109/l). Children should not sleep in
the top bunk bed and activities such as
climbing play structures should be avoided.
With observation, the majority of patients
with ITP will have resolution of symptoms
and the underlying thrombocytopenia
while avoiding unnecessary costs and side
effects of medications and hospitalization.
Pharmacological treatments to raise the
platelet count in children with moderate‐to‐
severe bleeding include two first‐line
therapies: intravenous immune globulin
(IVIG) and RhoGAM (anti‐Rh [anti‐D]
immune globulin, also Rhophylac).
Although these infusion therapies may be
more expensive than corticosteroids, they
are generally the preferred initial approach
in children due to less toxicity and
theoretical concerns over partially treating
unrecognized acute lymphoblastic leukemia.
Response to either of these infusion
therapies also may help confirm the diagno­
sis of ITP.
The mechanism of IVIG is thought to be
saturation of Fc receptors on the reticuloen­
dothelial cells in the spleen and liver, thereby
decreasing the clearance of opsonized plate­
lets. Recent studies suggest that inhibition of
Fc receptors may be upregulated. IVIG
treatment typically results in a quick yet
transient increase in the platelet count, often
sustained 2–4 weeks. More than 80% of
patients respond with an increase in the
platelet count which is sufficient to decrease
or eliminate bleeding symptoms. A recent
review suggests that responsive first‐line
treatment with IVIG may be predictive of a
lower rate of chronic disease. Families
should be counseled as to the transitory
effect of IVIG treatment due to the miscon­
ception that a subsequent decrease in plate­
let count is indicative of increased disease
severity or recurrence. The dose of IVIG is
0.8–1 g/kg over 4–6 hours. If necessary,
IVIG may be repeated two to three times for
a total dose of 2.4–3 g/kg; doses should be
given at least 24 hours apart to allow suffi­
cient time to determine response. A rise in
the platelet count is usually seen within

24–72 hours and peaks at approximately
9 days. A good initial response is an increase
in platelet count by 20–50 × 109/l. Side
effects of IVIG are usually immediate,
related to the rate of infusion, and include
nausea, lightheadedness, and headache. At
times, onset of a severe headache can
prompt an emergent head CT to assess for
potential ICH. These symptoms can be alle­
viated by slowing the rate of infusion and
premedicating with diphenhydramine if
further doses are needed. Fever may also
occur, and premedication with acetami­
nophen is advisable. Rare side effects include
anaphylaxis in an IgA‐deficient patient,
aseptic meningitis, acute renal failure, pul­
monary insufficiency, and thrombosis.
Although IVIG is a pooled blood product, it
is thought to be safe with regard to viral
transmission and does not require consent
as with blood product administration.
Subsequent dosing with IVIG may be indi­
cated depending on clinical symptomatol­
ogy and continued thrombocytopenia.
RhoGAM is an alternative therapy to
IVIG. The dose is 75 mg/kg IV over
20–30 minutes. Response rate and time to
onset are similar to IVIG. Anti‐D works by
binding the RhD antigen expressed on the
surface of red blood cells, leading to their
recognition by Fc receptors on cells of the
reticuloendothelial system. The coated red
cells are thought to compete with the anti­
platelet–antibody‐coated platelets for the
activated Fc receptor sites, thereby slowing
platelet clearance. Side effects include fever
and chills, intravascular hemolysis, head­
ache, emesis, and rarely anaphylaxis.
Premedication with acetaminophen and
diphenhydramine may prevent these
adverse effects with subsequent infusions.
A response is typically seen within
24–48 hours. Patients must be Rh‐positive,
have a functional spleen (at least not known
to be splenectomized or asplenic), and not
be anemic (i.e., >2–4 g/dl below expected
Thrombocytopenia 141
hemoglobin for age). RhoGAM does cause
transient hemolysis and a decrease in hemo­
globin of 1–2 g/dl over the ensuing 3–4 days
should be expected. The hemoglobin should
subsequently recover within 10 days.
Though a rare complication, the U.S. Food
and Drug Administration (FDA) currently
mandates that patients be monitored for 8
hours with serial dipstick urinalysis checks
for hematuria and hemoglobinuria after
administration of anti‐D due to reported
cases of severe, life‐threatening hemolysis.
Despite anti‐D therapy being considered a
first‐line intervention for ITP, its use as such
has diminished significantly.
Corticosteroids may be used in the initial
medical management of ITP, though typi­
cally are considered a second‐line therapy in
pediatrics. There are several mechanisms by
which steroids affect the platelet count: inhi­
bition of phagocytosis of the antibody‐
coated platelets leading to prolonged platelet
survival; inhibition of antibody production
by B‐lymphocytes; improvement of capil­
lary integrity reducing clinical bleeding; and
an increase in platelet production. Response
is good to oral or intravenous steroids but is
slower than with IVIG or RhoGAM and is
usually within 3–4 days. Typically, steroids
are prescribed at higher doses initially and
then tapered as tolerated to maintain effect
and limit adverse reactions. The most com­
monly prescribed steroid is prednisone at
1–2 mg/kg/day for 2–4 weeks, tapering the
dose post‐platelet response (i.e., >100 × 109/l)
over several weeks. The initial response rate
is 70–90%. An immune rebound may occur
with a taper that is too rapid and patients
will often require prolonged steroid therapy
to maintain the desired platelet count. Side
effects may occur with repeated treatment
or chronic use including gastritis, fluid
retention, weight gain, mood lability, acne,
striae, high blood pressure, osteopenia,
cataracts, increased infection risk, and
elevated serum glucose. An alternative to
142 Chapter 12
oral prednisone is high‐dose pulse infusion
of intravenous methylprednisolone. Some
patients become thrombocytopenic again
after therapy and require retreatment. A
relapse may be managed safely by
observation and restriction of activity and
medications, or with intermittent IVIG or
pulse steroids. High‐dose dexamethasone
has also been used with efficacy in refractory
patients (see in the following text), but
durable responses in children have not been
as likely as in adults.
Amicar (ε‐aminocaproic acid) or
tranexamic acid are antifibrinolytics which
may be utilized in patients with prolonged
thrombocytopenia and persistent mucosal
bleeding without anemia (mild bleeding).
Reports of efficacy with minimal side effects
make low‐dose therapy a good option (i.e.,
Amicar 10 mg/kg/dose every 6–8 hours).
Another option is low‐dose prednisone
which may benefit the patient with a long
course of ITP who secondarily develops
alteration in vascular integrity. Low‐dose
steroids would not be expected to raise the
platelet count, however, they would have
minimal side effects.
Emergency therapy
Patients with known or suspected life‐
threatening hemorrhage such as central
nervous system hemorrhage from ITP
(usually with concomitant platelet count
<10 × 109/l) should be treated emergently
with combination therapy including IVIG
1 g/kg daily for 2–3 days and intravenous
high‐dose methylprednisolone 30 mg/kg/
day (up to 1 g/day) for 1–3 days. Active life‐
threatening hemorrhage with refractory
thrombocytopenia is one of the only current
indications for emergency splenectomy.
Continuous infusion of platelets should be
considered in an emergent situation and
during surgery or childbirth in a severely
thrombocytopenic patient, in conjunction
with other therapies. Off‐label recombinant
factor VIIa (rFVIIa) may also be considered.
Chronic immune
thrombocytopenic purpura
Approximately 10–20% of children with
acute ITP that persists will have chronic ITP.
The child with chronic ITP is still likely to
have complete resolution within 2 years or
may have (or develop) an associated
autoimmune disease or underlying
immunodeficiency state. Most patients with
chronic ITP do not need treatment, as the
platelet count is often above 20 × 109/l and
bleeding is minimal. Platelet count alone
does not correlate with the risk of
hemorrhage, as platelets are large due to a
healthy marrow response to peripheral
thrombocytopenia and, as a consequence,
have greater than normal procoagulant
activity. In the rare patient with chronic,
refractory ITP who has clinical hemorrhage
or cannot tolerate the living restrictions
imposed by the thrombocytopenia,
intervention with medical therapies or
splenectomy should be considered.
ITP may be the initial manifestation of
aplastic anemia including Fanconi anemia
(before progression to pancytopenia), Evans
syndrome (association of ITP with AIHA),
systemic lupus erythematosus (SLE), or
autoimmune lymphoproliferative syndrome
(ALPS). HIV infection should be considered
in all patients with isolated thrombocytope­
nia, as this is frequently the first manifesta­
tion of disease in children. ITP may also be
present in children years before the diagno­
sis of immunodeficiency (e.g., common vari­
able immunodeficiency) is evident.
Therapies utilized in the treatment of
acute ITP may be utilized for chronic ITP,
though continued administration, cost,
and side effects frequently limit their use.

Other considerations include additional
medical approaches as discussed in the fol­
lowing text.
Rituximab is a chimeric human–mouse
monoclonal antibody directed against the
transmembrane CD20 antigen present on B
cells, leading to apoptosis and antibody‐
dependent cellular cytotoxicity. Children
with chronic ITP may have a 30–50%
response rate with rituximab. The standard
dosage is 375 mg/m2 IV weekly infusion
(over 4–6 hours) for 4 weeks. Most patients
start to show a response by the second week,
though delayed responses several weeks later
may occur. Responses may be short‐lived or
last for years. Acute toxicity is minimal,
though patients may experience fever and
chills (often abates with subsequent infu­
sions), serum sickness, headache, nausea,
emesis, and mucocutaneous reactions (con­
tinuum from hives and dermatitis to rarely
reported Stevens–Johnson syndrome and
toxic epidermal necrolysis). B‐cell depletion
lasts for approximately 6 months with a sig­
nificant decrement in humoral response,
although decreased total IgG immunoglobu­
lin levels and increased infections have not
been frequently reported. For the treatment
of ITP without an underlying immunodefi­
ciency, it remains unclear if there exists an
increased infection risk in pediatric patients
after receiving rituximab. Although consid­
ered a T‐cell‐dependent infection, B‐cell
depletion may lead to an increased risk of
PCP (Pneumocystis jiroveci pneumonia) and
cotrimoxazole prophylaxis should be consid­
ered. Hepatitis B reactivation and progres­
sive multifocal leukoencephalopathy
secondary to JC virus are rare considerations
in this population.
The thrombopoietin (TPO) receptor
agonists (RAs) are a novel class of drugs and
may diminish or eliminate the need for
immunosuppressive therapy in ITP. As ITP
is likely the result of impaired production in
addition to peripheral immune‐mediated
Thrombocytopenia 143
destruction, these drugs may have some
role in treatment to stimulate increased
production, even in patients with normal
thrombopoietin levels. The FDA recently
approved eltrombopag (Promacta®) for
pediatric patients with chronic ITP. The ini­
tial dosing is 50 mg orally once daily for
adult and pediatric patients aged 6 years
and above, with dose reduction to 25 mg
once daily for patients of East Asian ethnic­
ity or those with a history of mild to moder­
ate hepatic impairment. The maximum
daily dose is 75 mg and is available as a tab­
let and an oral suspension. Children ages
1–5 years, regardless of ethnicity, start at a
dose of 25 mg once daily. The dose is then
adjusted at 2‐week intervals by 12.5 or
25 mg to maintain a platelet count of ≥50
and <200 × 109/l. There are certain dietary
considerations with respect to timing of
drug administration due to interference of
absorption. The medication needs to be
taken on an empty stomach (1 hour before
or 2 hours after a meal) and 2 hours before
or 4 hours after consumption of polyvalent
cations (i.e., iron, calcium, aluminum, mag­
nesium, selenium, zinc) which are primar­
ily found in dairy products, supplements,
and antacids. The two studies leading to
FDA approval demonstrated that in chil­
dren with ITP, eltrombopag improved
platelet counts, allowed for reduction or
discontinuation of concomitant ITP medi­
cations and decreased the need for rescue
therapy. Concerning toxicities include mar­
row reticulin fibrosis, cataracts, liver
enzyme abnormalities, and thromboembo­
lism, as well as rebound thrombocytopenia
with abrupt discontinuation. It is likely that
these drugs or subsequent generations will
provide potential new therapeutic options
in the future.
Another TPO RA under investigation is
romiplostim (Nplate®). This drug is also
likely soon to receive a pediatric indication
for chronic ITP. It is administered as a weekly
144 Chapter 12
intramuscular injection and does not impose
the dietary timing issues of eltrombopag.
Clinical evidence demonstrates that eltrom­
bopag and romiplostim do not have cross‐
resistance, likely due in part to different
binding sites on the TPO receptor. Therefore,
patients not responsive or unable to tolerate
one TPO RA may still benefit from treat­
ment with the other. Early data suggest that
treatment with TPO RAs may help increase
the number of ITP patients who achieve a
remission before becoming chronic, and
therefore there may be a role for these medi­
cations in patients with acute or persistent
ITP. Early treatment with this class of drugs
may become a preferred intervention to
avoid exposure to conventional therapies
and the associated risks and may alter the
disease course. More studies need to be con­
ducted to elucidate these potential benefits.
Splenectomy may be considered for
patients with chronic ITP with bleeding or
limitation in activities negatively impacting
quality of life. Current guidelines agree that
it should only be considered in patients with
chronic ITP or the rare refractory patient
with life‐threatening bleeding. Splenectomy
is successful in 60–85% of patients; however,
relapse of ITP may occur due to immune‐
mediated platelet destruction in other
organs, especially the liver. Patients should
ideally receive appropriate immunization
several weeks prior to surgery due to the risk
of infection with encapsulated organisms
(i.e., pneumococcus, Haemophilus influenza,
or meningococcus). Lifelong penicillin
prophylaxis is recommended postsplenec­
tomy. Given the lifelong risk of overwhelm­
ing sepsis, and the recommended prophylaxis
and preemptive therapy for presumed bacte­
rial infection, the benefit of this approach
must be considered individually. In the field
of emerging innovative therapies, including
the recently introduced TPO RAs, the ques­
tion of who needs splenectomy is becoming
a more challenging question to answer.
Vinca alkaloids (vincristine and vinblas­
tine), danazol (a virilizing androgen), and
immunosuppressive agents such as azathio­
prine and cyclophosphamide have also been
used with some success. Ascorbic acid,
cyclosporine, and interferon α‐2b are other
agents that have also been investigated for
use in chronic ITP. Long‐term management
of chronic ITP includes periodic assess­
ments for development of other manifesta­
tions of immunodeficiency or autoimmune
disease, counseling regarding activities and
medications, and periodic assessments of
the platelet count to assess for continuation
or resolution of the underlying process.
Neonatal alloimmune
thrombocytopenia
Neonatal alloimmune thrombocytopenia
(NAIT) is the result of early transplacental
passage of maternal alloantibodies directed
against fetal platelets, similar in pathophysi­
ology to hemolytic disease of the newborn.
Unlike hemolytic disease of the newborn,
NAIT often affects the first‐born offspring.
Although rare, NAIT is the most common
cause of severe thrombocytopenia in the first
few days of life. Alloantibodies are present
due to human platelet antigen incompatibil­
ity, as fetal platelet antigens are inherited
from the father. Immunization in the mother
against fetal platelet antigens can occur dur­
ing the current or a previous pregnancy or
secondary to a previous platelet transfusion.
NAIT may lead to severe thrombocytopenia
in the fetal‐newborn period, with a high risk
of fatal hemorrhage. Thrombocytopenia
leading to fetal loss and hemorrhage has
been reported as early as 16–24 weeks of ges­
tation. Although several platelet antigens
have been implicated, 75% of cases are
related to human platelet antigen 1a (HPA‐1a)
incompatibility (i.e., HPA‐1a‐negative
mother with a HPA‐1a‐positive fetus).

HPA‐1a resides on the GP IIb/IIIa complex
that is responsible for fibrinogen receptor
activity and thus important in aggregation
and platelet‐plug formation. Therefore,
development of anti‐HPA‐1a antibodies may
interfere with normal platelet aggregation in
addition to decreasing platelet number,
resulting in both a qualitative and quantita­
tive platelet defect. This may in part explain
the high incidence of serious bleeding in
these infants as compared with those born to
mothers with ITP with alloantibodies
directed against alternate antigens. More
than 20 antigens are involved in NAIT with
HPA‐1a being most common in the
Caucasian population, in addition to
HPA‐5b. HPA‐4 incompatibility is more
common in Asian populations.
The infant with NAIT typically presents
with moderate‐to‐severe thrombocytope­
nia (i.e., <20–50 × 109/l) and may rapidly
develop petechiae, purpura, hematuria, and
bleeding from the umbilical cord, veni­
puncture sites, or gastrointestinal tract.
ICH is common, occurring in 10–20% of
neonates and may occur prenatally or ante­
natally. Therefore, head ultrasound should
always be part of the initial diagnostic
workup. ICH may be detected on ultra­
sonography during an apparently uncom­
plicated pregnancy and complications of
early central nervous system hemorrhage
include hydrocephalus, porencephaly, sei­
zures, and fetal loss. Early jaundice occurs
in 20% of cases owing to resolution of
intracranial or intraorgan hemorrhage. The
infant is otherwise generally healthy with­
out other perinatal complications and the
mother typically has an unremarkable
hematologic history (other than possibly a
previously affected fetus or newborn). For a
mother with a previous low platelet count,
the differential diagnosis should include
maternal idiopathic, autoimmune, or drug‐
dependent thrombocytopenia, infection,
and preeclampsia. Infants may also be
Thrombocytopenia 145
thrombocytopenic secondary to birth
asphyxia, infection, congenital bone mar­
row hypoplasia, or prematurity. The pres­
ence of hepatosplenomegaly, intrauterine
growth retardation, or intracranial calci­
fications with thrombocytopenia should
suggest a congenital viral infection.
However, if a secondary diagnosis is not
clearly delineated, it is important to exclude
alloimmune thrombocytopenia by appro­
priate immunologic testing as future‐
affected pregnancies tend to be more severe
and require close antenatal monitoring.
NAIT should be considered in all newborns
with thrombocytopenia.
Early platelet alloantigen evaluation of
the newborn and parents is important, both
in offering the affected infant appropriate
treatment and in order to minimize the risk
of devastating complications with future
pregnancies. Evaluation includes platelet
typing on the mother and father, specifically
assessing for known antigens responsible for
alloimmunization such as HPA‐1, ‐3, and ‐5
antibodies as well as HPA‐4 antibodies in
those of Asian descent. HPA‐9 and ‐15 are
the next most common antigen
incompatibilities. Serum from the mother
and infant is screened for antiplatelet
antibodies against either the infant’s or the
father’s platelets. We send blood for the
NAIT workup to the Blood Center of
Wisconsin™.
Several treatment options are available
for the infant with neonatal alloimmuni­
zation. Transfusion with antigen‐negative
platelets has been the mainstay of treat­
ment, when available. Since HPA‐1a‐neg­
ative platelets are present in only 2% of the
Caucasian population, the most available
source of platelets is from the mother
(though this is not always technically
feasible). Random platelet transfusions
(10–20 ml/kg) may provide a transient
increase, lasting 1–2 days, and should be
used in cases of serious hemorrhage, while
146 Chapter 12
antigen‐negative platelets are being
obtained and prepared. If random donor
platelets are ineffective, then cross‐
matched donor platelets or washed mater­
nal platelets may be used if available. An
excellent alternative treatment is IVIG.
The recommended dose is 1 g/kg/24 hours
for 1–2 doses (until the platelet count is
≥50 × 109/l). Platelet transfusion may still
be necessary with IVIG if immediate cor­
rection of the thrombocytopenia is needed.
Corticosteroids can be effective in reduc­
ing platelet destruction and increasing
vascular integrity. Methylprednisolone,
1 mg/kg IV every 6–8 hours (with IVIG), is
frequently effective. Regular head ultra­
sounds should be done while the infant
remains severely thrombocytopenic
(<50 × 109/l). If intracranial bleeding is
present, platelets should be kept
≥100 × 109/l. Head MRI is necessary to fur­
ther define the hemorrhage. Ultrasound
should be repeated at 1 month in children
with ICH to identify early hydrocephalus.
Resolution of thrombocytopenia typically
occurs within 2–4 weeks.
Mothers with an affected infant should
be counseled on the necessity for careful
monitoring with future pregnancies due to
the risk of increasingly severe NAIT. Fetal
platelet counts should be obtained starting
at 20 weeks of gestation (12 weeks if prior
history of ICH), with ultrasound monitoring
for hemorrhage. Maternal antiplatelet titers
cannot be used to accurately predict affected
fetuses. IVIG 1 g/kg/week given to the
mother from mid‐gestation until near term
has been shown to effectively increase fetal
platelet counts in the majority of cases.
Delivery should be planned near term with
an elective cesarean section or planned
induced vaginal delivery after documented
increase in fetal platelet count following
administration of maternal IVIG. Antigen‐
negative platelets, which can be obtained
from the mother by apheresis or from an
appropriately selected donor should be
obtained and prepared prior to delivery in
the event of extreme thrombocytopenia or
hemorrhage. The infant’s platelet count
should be checked at birth and every
6–12 hours for 1–2 days and be kept
>50 × 109/l. Frequency of monitoring can be
decreased depending on the stability of the
platelet count and the clinical status of the
infant.
Neonatal autoimmune
thrombocytopenia
Neonatal autoimmune thrombocytopenia
occurs due to the passive transfer of auto‐
antibodies from mothers with ITP or may
be caused by other maternal disorders
including autoimmune diseases such as
systemic lupus erythematosus, hypothy­
roidism, and lymphoproliferative states, or
secondary to m ­ edications. Unlike NAIT,
these antibodies recognize both maternal
and fetal platelet antigens. Maternal ITP
should be distinguished from gestational
thrombocytopenia that tends to occur late
in pregnancy and leads to mild thrombocy­
topenia in the mother (i.e., 70–100 × 109/l)
without the development of antibodies, in
which case the infant is not at risk for
thrombocytopenia. In gestational throm­
bocytopenia, maternal platelet counts
return to normal shortly after birth. The
degree of thrombocytopenia seen in neo­
nates born to mothers with ITP is less
severe than with NAIT, with only 10–15%
having platelet counts <50 × 109/l. Bleeding
is minimal and ICH is rare (i.e., 0–3%). The
platelet count may be normal at birth but
falls within 1–3 days after delivery. Platelet
counts should be monitored closely and a
head ultrasound obtained to exclude ICH.
Treatment should be initiated if the platelet
count falls below 30–50 × 109/l with the
same treatment regimen as for NAIT:

IVIG, IV methylprednisolone, and random
donor platelet transfusion for treatment of
hemorrhage. The duration of thrombocy­
topenia is usually 3–6 weeks but may last as
long as 12 weeks.
Drug‐induced
thrombocytopenia
In addition to immune‐mediated mecha­
nisms induced by drugs, many bone marrow
suppressive agents such as chemotherapy
cause thrombocytopenia, though typically in
the face of pancytopenia. Management is
usually with platelet transfusion, to prevent
or treat bleeding. The bone marrow effects of
these agents often define their dose‐limiting
toxicity, and thrombocytopenia is a common
effect. Patients respond well to platelet trans­
fusion but can become refractory because of
the underlying illness, organomegaly and
sequestration, development of alloimmun­
ization, sepsis, and other medications.
Other potential offending drugs include
anticonvulsants such as valproic acid, chlo­
rothiazides, estrogenic hormones, ethanol,
ristocetin, and protamine sulfate.
Heparin‐induced thrombocytopenia
(HIT) is caused by antibody formation to
complexes of heparin and platelet factor 4
leading to platelet activation, often resulting
in severely low counts as well as risk for
thrombosis. It is much less common in chil­
dren than adults. HIT should be suspected in
the child receiving heparin (usually second­
ary to unfractionated but can also occur with
low molecular weight) who develops unex­
plained thrombocytopenia of any degree
within 5–10 days of exposure, often defined
as a decrease of ≥50% from baseline (even if
still in the normal range). Testing for hepa­
rin‐induced antibodies is not very specific,
as many patients without HIT will have
­circulating antibody. Patients may develop
thrombosis (venous or arterial) and are at
Thrombocytopenia 147
risk for skin necrosis at subcutaneous hepa­
rin injection sites. If suspected, based on
clinical scoring that defines likelihood, func­
tional studies of platelet activation under the
presence of heparin can be done by special­
ized laboratories. This testing includes the
serotonin release assay and heparin‐induced
platelet aggregation assay. Heparin should be
discontinued and replaced by an anticoagu­
lant that does not lead to antibody formation
such as argatroban. Warfarin should not be
utilized immediately due to associated pro­
tein C deficiency with risk of microthrombo­
sis leading to skin necrosis and gangrene.
Nonimmune thrombocytopenia
Many nonimmune‐mediated processes
lead to increased platelet consumption.
Generalized platelet activation with trap­
ping of microaggregates in the small vascu­
lature contributes to microangiopathic
hemolytic anemia (MAHA) occurring in
congenital heart disease, hemolytic uremic
syndrome (HUS), and thrombotic throm­
bocytopenic purpura (TTP). HUS is pri­
marily associated with a prothrombotic state
induced by exposure to shiga‐toxin‐produc­
ing Escherichia coli (O157:H7) or Shigella
dysenteriae 1, particularly affecting the renal
vasculature and leading to the triad of
MAHA, platelet consumption, and renal
failure. HUS is the most common cause of
acute renal failure in children. Patients may
present with abdominal pain and bloody
diarrhea and are treated with supportive
care (i.e., red cell transfusions, dialysis as
necessary). Platelet transfusion may worsen
the clinical status and should be used with
caution.
Idiopathic TTP is a rare disease in chil­
dren, characterized by the pentad of throm­
bocytopenia, hemolytic anemia, renal
impairment, neurologic symptoms, and
fever, although few patients present with
148 Chapter 12
the full gamut of symptoms. Idiopathic TTP
is often clinically indistinguishable from
diarrhea‐negative HUS. There is also a rare
congenital form in which affected neonates
present with jaundice and thrombocytope­
nia, although patients may not have an epi­
sode of overt TTP for years until triggered
by infection, pregnancy, or stress. Patients
with congenital TTP have extremely low
levels of ADAMTS13, a protein that cleaves
unusually large multimers of von
Willebrand factor into biologically less‐
active forms. Absence of ADAMTS13
inhibits cleavage of these large multimers
allowing spontaneous platelet adhesion and
aggregation.
Patients with acquired TTP, which is
often idiopathic, commonly demonstrate
antibodies to the protein, unlike the con­
genital form in which there is a constitutive
deficiency. Affected individuals are more
commonly female, of African descent, and
diagnosis can be associated with pregnancy,
autoimmune disease, infection, or trans­
plantation. The hallmark of disease is the
presence of segmental hyaline micro­
thrombi in the microvasculature that can
also be seen in the lymph nodes and spleen.
Classic signs and symptoms include fever,
malaise, nausea and vomiting, abdominal
and chest pain, arthralgia and myalgia, pal­
lor, jaundice, purpura, progressive renal
failure, and fluctuating neurologic signs
and symptoms. Laboratory features include
thrombocytopenia and MAHA. The
peripheral blood smear will show polychro­
masia, basophilic stippling, schistocytes,
microspherocytes, and nucleated red cells.
The direct antiglobulin test (DAT; Coombs)
should be negative, as TTP is not an AIHA.
The LDH and unconjugated bilirubin will
be elevated and haptoglobin reduced due to
the MAHA, with associated hemoglobinu­
ria. Thrombocytopenia is often more severe
than the degree of hemorrhage would pre­
dict. Evidence of DIC may be present with
prolonged PT/PTT, elevated D‐dimer and
hypofibrinogenemia, as well as elevated
blood urea nitrogen (BUN) and creatinine.
Without treatment, mortality is >90%.
Plasmapheresis is the mainstay of therapy in
the acquired form. Fresh frozen plasma is
usually sufficient to treat the congenital
form. Patients may also benefit from rituxi­
mab and other immunosuppressive drugs
including steroids, cyclosporine, cyclophos­
phamide, vincristine, and azathioprine.
Increased utilization of platelets may
occur in active bleeding, infection, or sepsis.
In disseminated intravascular coagulation
(DIC), there is an imbalance between intra­
vascular thrombosis and fibrinolysis, with
increased platelet consumption, depletion of
plasma clotting factors, and formation of
fibrin. DIC can be initiated by many events,
including sepsis due to bacteria, viruses, or
fungi; malignancy, particularly acute pro­
myelocytic leukemia and neuroblastoma;
hemolytic transfusion reactions; and
trauma. Therapy is aimed at treating the
underlying etiologic process. Supportive
care consists of platelet transfusion to main­
tain platelet counts >50 × 109/l and plasma
protein replenishment to correct coagulopa­
thies and maintain fibrinogen >100 mg/dl.
Thrombocytopenia can occur in the sick
newborn for many reasons, most commonly
in association with infection, prematurity,
asphyxia, respiratory distress syndrome,
pulmonary hypertension, or meconium
aspiration. These infants appear to have
normal to increased platelet production, but
a decreased platelet life span for reasons that
are unclear. Thrombocytopenia is a frequent
occurrence in congenital cyanotic heart
disease associated with compensatory
polycythemia.
The association of thrombocytopenia
and giant hemangiomas occurs in the
infant with Kasabach–Merritt syndrome
and represents a form of localized intravas­
cular coagulation. The hemangiomas may

be multiple and may involve only viscera.
Therefore, in an infant with unexplained
thrombocytopenia, imaging studies should
be done to look for a vascular anomaly.
Hemangiomas are proliferative lesions that
grow rapidly for several months and then
regress spontaneously. Platelet thrombi
may develop in these lesions and platelet
life span may be decreased. These infants
may also have a consumptive coagulopathy
with low fibrinogen levels and elevated
concentrations of fibrin degradation prod­
ucts. The lesions are also prone to necrosis
and infection. A particular hemangioma’s
size or location cannot predict whether it
will lead to platelet trapping and thrombo­
cytopenia. These infants should be man­
aged by close observation and hematologic
monitoring while waiting for regression to
occur. However, the lesions may become
large enough to compromise the infant by
impinging on the airway or vital organs,
leading to compartment syndrome, and
resulting in serious illness or death.
External compression of hemangiomas by
firm bandaging, when possible due to loca­
tion, may reduce blood flow and platelet
trapping. Propranolol has become first‐line
therapy for regression of hemangiomas,
likely secondary to inhibition of angiogen­
esis. Corticosteroid treatment at a dose of
1–2 mg/kg/day may also bring about
regression of the lesion and normalization
of the platelet count. Interferon α‐2a has
been shown to be beneficial in correcting
the platelet count and shrinking the lesion.
Supportive transfusion therapy is indicated
with active bleeding due to thrombocyto­
penia. Platelet transfusion as well as infu­
sion of coagulation factors (fresh frozen
plasma, cryoprecipitate, and antifibrino­
lytic drugs) may be helpful but usually are
of only transient benefit. Antiplatelet med­
ications (aspirin and dipyridamole) have
been used in the past to interfere with
platelet trapping within the hemangioma,
Thrombocytopenia 149
but carry the risk of causing platelet
dysfunction in addition to the existing
­
thrombocytopenia.
A variety of conditions that result in sple­
nomegaly are associated with thrombocyto­
penia. The large spleen sequesters and
destroys circulating platelets. Anemia, leu­
kopenia, and neutropenia may also be pre­
sent. Megakaryocytic production in the
marrow is normal and may be accelerated in
response to a decrease in the circulation.
Storage diseases, early portal hypertension,
hemolytic conditions (red cell membrane
defects), infections such as with HIV,
Epstein–Barr virus (EBV), and CMV, and
malignancies are frequently associated with
splenomegaly and may result in hypersplen­
ism (increased splenic activity and resultant
red cell destruction).
Decreased platelet production
Thrombocytopenia due to decreased produc­
tion of platelets may be a result of an acquired
or inherited disease process. Decreased plate­
let production may be a direct effect of mar­
row crowding due to malignancy (leukemia
or metastatic solid tumors such as lymphoma,
neuroblastoma, medulloblastoma, and rhab­
domyosarcoma) or storage disease (Gaucher,
Neimann–Pick, etc.). Drugs may also be
implicated in decreased platelet production.
The liver is the site of TPO production and
liver disease is associated with chronic severe
thrombocytopenia. Severe iron deficiency can
result in decreased production of platelets,
though early iron deficiency states are associ­
ated with an elevated platelet count likely due
to marrow stress. Diseases affecting the mar­
row matrix (aplastic anemia and myelofibro­
sis) cannot support stem cell growth and
maturation with resultant development of
thrombocytopenia.
Thrombocytopenia related to an inher­
ited condition is frequently distinguished by
150 Chapter 12
characteristic clinical features, early presen­
tation and chronic course, family history,
platelet morphology, and lack of response to
classic treatments for ITP. A number of
these conditions are associated with
­macrothrombocytes and mild‐to‐moderate
thrombocytopenia including Bernard–
Soulier syndrome, MYH9‐related disorders
(May–Hegglin anomaly with bluish cyto­
plasmic inclusions including Sebastian‐,
Fechtner‐, Epstein‐, and Alport‐like syn­
dromes), platelet‐type von Willebrand dis­
ease, gray platelet syndrome (storage pool
disease), benign Mediterranean macro­
thrombocytopenia, Paris‐Trousseau‐type
thrombocytopenia, and more poorly
defined syndromes such as Montreal plate­
let syndrome. Microthrombocytes are seen
in Wiskott–Aldrich syndrome, an X‐linked
disorder resulting from a mutation on the
WAS gene. Wiskott–Aldrich syndrome is
characterized by thrombocytopenia, recur­
rent bacterial and viral infections secondary
to T‐cell dysfunction, chronic eczema, and
an association with autoimmune disorders.
Patients with defects in the WAS gene may
also have a milder syndrome called X‐linked
thrombocytopenia with small platelets and
immune dysregulation which may develop
over time. Of note, it is difficult to appreciate
small platelets in the newborn and the mean
platelet volume reported on the CBC is
unreliable in the face of thrombocytopenia.
Patients with inherited thrombocytopenia
may have normally sized platelets in certain
conditions including congenital amegakaryo­
cytic thrombocytopenia (CAMT), thrombocy­
topenia with absent radii (TAR), familial
platelet disorder and predisposition to acute
myelogenous leukemia (AML), amegakaryo­
cytic thrombocytopenia with radio‐ulnar syn­
ostosis (ATRUS), and autosomal dominant
thrombocytopenia. CAMT, a rare cause of
neonatal thrombocytopenia, is a bone marrow
failure syndrome inherited in an autosomal
recessive manner due to deficiency in the TPO
receptor c‐mpl. Bleeding symptoms lead to
diagnosis in infancy, although CAMT is often
initially confused with other more common
neonatal causes of thrombocytopenia such as
alloimmune‐ and autoimmune‐mediated pro­
cesses. However, unlike these other conditions,
the thrombocytopenia does not resolve with
time. There are no classic physical features.
Diagnosis is based on markedly reduced mega­
karyocytic precursors in the bone marrow with
normal erythroid and myeloid lineages with
elevated TPO levels. Current treatment is sup­
portive care, platelet transfusion as needed, and
consideration for curative hematopoietic stem
cell transplantation.
Children with ATRUS present similarly
to CAMT with severe thrombocytopenia at
birth, but in association with skeletal anom­
alies and sensorineural hearing loss.
Patients may have fusion of the radius and
ulna at the elbow, often with minor clinod­
actyly or anomalies involving the humeri or
lower limbs. The disease may progress to
aplastic anemia or leukemia. A HOXA11
mutation has been identified in two kin­
dreds and this mutation inhibits megakar­
yocyte differentiation. Most cases of TAR
are diagnosed at birth or in utero due to
bilateral absence of the radii manifested
as a shortening of the forearms and flexion
at the elbows, with preservation of the
thumbs. Patients may have platelet dys­
function and are at risk for significant
bleeding episodes. Typically, the thrombo­
cytopenia improves through childhood.
Associated clinical features include addi­
tional skeletal limb defects, renal and
­cardiac anomalies, facial capillary heman­
giomas, and cow’s milk intolerance. Fanconi
anemia is an inherited autosomal recessive
(>99%) and rarely X‐linked recessive
(FANCB, <1%) disorder characterized by
chromosomal instability with skeletal
anomalies and hypoproductive thrombocy­
topenia, although other cell lines are even­
tually affected. These patients have an

increased susceptibility to develop leuke­
mia and may benefit from early hematopoi­
etic stem cell transplantation if a suitable
donor is available.
Case study for review
A 9‐year‐old previously well Hispanic boy
presents to the emergency department with
a 2‐hour history of profuse epistaxis. On
presentation he is noted to be well‐developed
and well‐nourished, frightened, fatigued,
and pale, with numerous ecchymoses and
blood pouring from both nares. He is
emergently triaged and has bilateral nasal
packing placed. He continues to have
massive bleeding and has repeated emesis of
digested and bright red blood. His vitals are
T 37.2° C, HR 156, RR 30, and BP 62/38.
a. What are your immediate thoughts
regarding possible diagnosis? How do
you confirm this and what steps do you
take in treatment and stabilization of
your patient?
b. What pertinent history should you
obtain?
The first concern is to stop the bleeding and
treat the patient for acute, symptomatic
hemorrhage. You suspect a bleeding disor­
der and see that the patient is an otherwise
healthy child with no known inherited
bleeding diathesis. Although ITP presents
with acute massive bleeding in fewer than
5% of cases, you are appropriately concerned
that he has mucosal‐type bleeding associ­
ated with either an acquired or inherited
platelet problem, which may be qualitative
or quantitative. You order a emergent CBC
to determine both platelet and hemoglobin
levels and initiate fluid resuscitation await­
ing the results.
Additional historical points to elicit
include recent illness, medication expo­
sure, underlying disease, and prior symp­
toms. You are contemplating other
Thrombocytopenia 151
diagnoses such as von Willebrand disease
and acute leukemia and ask questions
related to these possibilities. In this case,
the mother states that he has been healthy,
with no prior medications, illnesses, hospi­
talizations, or other comorbidities. There is
no family history of a diagnosed bleeding
disorder (though you make a mental note
to pursue these questions later, as family
members may not have been evaluated for
symptoms suggestive of von Willebrand
disease). The mother states that he on
awakening this morning had unexplained
bruises over his torso and extremities and
blood blisters in his mouth. He complained
of feeling sick to his stomach and began to
have simultaneous emesis and nose bleed­
ing, which led to her calling an ambulance
as she could not stop it.
c. What findings do you look for on
examination to either confirm or dispute
your suspected diagnosis?
On examination, you note he is alert and
oriented, though frightened to see so much
blood and expresses to you he thinks he is
going to die. You provide reassurance and
quickly note his oral and skin findings of
diffuse petechiae and purpura. Purpuric
lesions on the torso are very unusual and
frequently not associated with trauma,
reflecting more spontaneous bleeding. He
has no adenopathy, organomegaly, other
skin rashes, and no pain on palpation of the
extremities and abdomen with full range of
motion of all joints, and in general appears
well‐developed and appropriate for age. All
these findings are supportive of a diagnosis
of ITP.
Your patient’s CBC comes back with a
platelet count of 2 × 109/l, hemoglobin
6.2 g/dl, and white blood cell count of
7.4 × 109/l with a normal differential. You
explain the anemia as secondary to massive
epistaxis.
Your patient now has evidence of gross
hematuria and melena, with a further drop
152 Chapter 12
in blood pressure despite having received a
unit of packed red blood cells and volume
support. The complete metabolic panel and
coagulation studies are normal.
d. What is your next thought for
treatment?
As you are now certain that this is acute
ITP and your patient is experiencing life‐
threatening hemorrhage, you initiate therapy
with IVIG 1 g/kg IV over 4 hours, methyl­
prednisolone 1 mg/kg IV every 8 hours,
continuous infusion of packed red blood
cells, and fluid support with lactated Ringer’s
or normal saline. Consideration should also
be given to continuous infusion of platelets.
Consultation with an otolaryngologist
should be obtained for nasal packing and
control of the bleeding in the posterior
pharynx.
e. How do you counsel the family?
The prognosis of ITP, even in the face of
such a dramatic presentation, is excellent.
However, this situation is tenuous due to
lack of therapies that could cause an imme­
diate rise in the platelet count. At this time,
his prognosis is guarded.
Your patient is hospitalized in the
Pediatric Intensive Care Unit (PICU) and
continues to receive red cell transfusions,
continuous platelet transfusion (1 pheresed
unit every 2–3 hours), fresh frozen plasma
(FFP) infusion, further doses of methyl­
prednisolone, and a second dose of IVIG.
On day 3, the hemoglobin drops to 4.6 g/dl
and the decision is made to perform an
emergent splenectomy. The family is coun­
seled that he may not survive this procedure.
Fortunately, however, he does very well
and is supported with transfusions without
a worsened clinical course. Unfortunately,
there is no immediate response to splenec­
tomy. Typically, in patients that do respond,
there is an immediate increase in postoper­
ative platelet count, often to above normal
levels due to an exaggerated marrow
response that persists after the source of
peripheral destruction or sequestration
has been removed. Splenectomy is not suc­
cessful in ≥30% of cases and it cannot be
predicted who will respond. Our patient
continues to receive massive blood product
support for 1 week, then starts to stabilize
with an increase in hemoglobin to 8 g/dl and
platelet count of 54 × 109/l. He continues on
a course of steroids, eventually transitioning
to oral prednisone, and tapering off by 6
weeks. By this time his platelet count nor­
malizes, and several years later he continues
to have a normal platelet count.
Of interest, the patient represents with
moderate epistaxis, no anemia, and a nor­
mal platelet count 1 year later. Further diag­
nostic workup reveals a diagnosis of type 1
von Willebrand disease.
f. How would the knowledge of this
comorbidity have influenced your man­
agement of the patient with the initial
presentation of ITP and massive
epistaxis?
Knowledge of this disease may have
led to the use of additional therapies
such as DDAVP to stimulate release of
von Willebrand factor, and Humate‐P, a
factor VIII concentrate that also con­
tains von Willebrand factor and is used
for von Willebrand factor replacement.
It is unknown whether such additional
therapies may have impacted the clinical
course.
Multiple choice questions
1. You are in the newborn nursery and have
a 1-day-old male infant, 2.6 kg, born at 37
weeks GA to a G1P1 healthy 34-year-old
mother with PROM and GBS+ leading to a
sepsis rule out. The baby is well appearing
with a small cephalohematoma but other­
wise normal exam. The baby’s CBC checked
at birth is normal except for a platelet count
of 27 × 109/l. Bcx is pending on antibiotics.

Assuming the sepsis work up is unremarkable,
the most likely diagnosis is
a. Autoimmune thrombocytopenic
purpura
b. Alloimmune thrombocytopenia
c. Bernard‐Soulier
d. Wiskott‐Aldrich
e. CMV infection
Explanation: Neonatal thrombocytopenia
is common, affecting 1%‐3% of newborns
and 20%‐30% of premature neonates. Neo­
natal alloimmune thrombocytopenia (NAIT)
occurs in about 1 in 1000 births and can
occur in the firstborn unlike Rh‐incom­
patibility. Patients typically present at birth
with a platelet count <50 × 109/l as com­
pared to autoimmune thrombocytopenia
which presents after 1‐3 days and usually
with a higher platelet count. The answer is b.
2. Given the above case and the presumed
diagnosis of NAIT, all of the following are
appropriate next management steps EXCEPT:
a. Check a head ultrasound for intracra­
nial hemorrhage
b. Give random donor platelets
c. Give maternal platelets if available
d. Give paternal platelets if available
e. Give IVIG
Explanation: Platelet count should be kept
>50 × 109/l at birth to prevent intracranial
hemorrhage (ICH). Additionally, all neo­
nates below this level should have a head
ultrasound to rule out intracranial hemor­
rhage which can be a presenting finding
with NAIT. Early exposure to paternal
human platelet antigen (HPA) leads to
maternal alloimmunization, usually due to
HPA1a in the father. The second most com­
mon difference is HPA5b and HPA4 should
be tested in the Asian father. There is a
10%‐20% risk of ICH and presentation can
be worse with subsequent pregnancies.
The patient should receive random donor
platelets and can receive maternal platelets,
if available. Blood from the neonate, mother
Thrombocytopenia 153
and father should be sent to the Blood
Center of Wisconsin™ for work up as it is
important, if positive, for future pregnan­
cies. IVIG can also be given to help dilute
the antibody response as well as compete
for Fc receptors in the spleen and liver to
decrease platelet clearance. Resolution of
thrombocytopenia occurs in 2‐3 weeks and
rules out other congenital causes which
should not have normalization of the plate­
let count. The answer is d.
3. You are following a 4-year old male
patient who is admitted for autoimmune
hemolytic anemia (AIHA) with a hgb of
4.5 g/dl with elevated reticulocyte count,
indirect bilirubin, LDH, AST and a positive
DAT (direct Coombs). He is on steroids for
the AIHA. You note that the platelet count
is 34 × 109/l. The most likely diagnosis is
a. Splenic sequestration
b. Decreased production due to bone
marrow suppression
c. Concurrent immune thrombocytopenic
purpura (ITP) (i.e, Evans syndrome)
d. Suppression from steroids
e. Increased destruction due to bystander
hemolysis
Explanation: Evans syndrome is the combi­
nation of AIHA and ITP. Evans syndrome
can occur due to transient antibodies which
occur concurrently after infection in a
young child although often signify, espe­
cially in the older child, the presence of an
underlying autoimmune condition. If there
is resolution without recrudescence of cyto­
penias after being weaned off steroids, the
patient can be monitored. If there is recur­
rent AIHA and/or ITP, this should prompt a
more thorough work up searching for an
underlying autoimmune process. The
answer is c.
4. You are seeing a 3-year-old in the emer­
gency department who presents with “red
dots” on the extremities and easy bruising.
154 Chapter 12
You note that the red dots are non‐blanch­
ing and diagnose these as petechiae. The
child is otherwise well with no other phys­
ical findings and without wet bleeding
(i.e., mucosal bleeding) although did have a
viral illness a few days prior. The presumed
diagnosis is immune thrombocytopenic
purpura (ITP). Follow up CBC confirms
this with normal WBC/diff and hgb with a
platelet count of 9 ×109/l. The most appro­
priate management is:
a. Administer IVIG
b. Administer platelets
c. Administer steroids
d. Administer RhoGAM
e. Provide reassurance
Explanation: Acute ITP is a common pres­
entation in young children often secondary
to a transient antibody which can occur due
to a viral illness. The majority of these
patients will clearance of the antibody and
resolution of the thrombocytopenia over
weeks. In rare cases and in the case of
older children/adolescents, ITP may become
a chronic condition and may be due to an
underlying autoimmune condition. Sponta­
neous bleeding can occur when the platelet
count is <50 x 109/l and especially when the
platelet count is <20 x 109/l. Spontaneous
bleeding may be the presenting sign of
ITP but in large multicenter analysis, treat­
ment for asymptomatic thrombocytopenia
has not been shown to mitigate this risk.
Therefore, the current recommendation is
to observe patients without active bleeding
rather than treating a number. Shared deci­
sion‐making should occur and parental
anxiety be considered when making this
decision. The answer is e.
5. How would your decision in the above
case be altered if the child had mucosal
bleeding (i.e., from the mouth, nose, or if
with hematuria)? Which of the following
would be the most appropriate treatment:
a. Administer IVIG
b. Administer platelets
c. Administer steroids
d. Administer RhoGAM
e. Provide reassurance
Explanation: In the case of the patient with
wet bleeding, observation alone is not suffi­
cient and the patient should be treated to
increase the platelet count. IVIG is the pre­
ferred primary treatment. IVIG dilutes the
antibody response as well as competes for
the Fc receptors in the spleen and liver. IVIG
is generally well tolerated although may lead
to headache secondary to aseptic meningi­
tis. Families should be advised of this risk as
the patient with thrombocytopenia and
severe headache would subsequently require
a head CT to rule out ICH. Platelets should
not be administered unless with a life‐
threatening bleed as these will be rapidly
consumed. Steroids can be administered by
do not have an immediate onset of action.
RhoGAM is a potential choice in the Rh+
patient and anti‐D coats the red blood cells
and thus competes with antibody‐coated
platelets at the Fc receptors in the spleen and
liver. Thus the major side effect of RhoGAM
is hemolysis and a drop in the hgb as much
as 2 g/dl or more which makes it a second­
ary choice to IVIG. The answer is a.
Suggested reading
Bennett, C.M., Neunert, C., Grace, R.F. et al. (2018).
Predictors of remission in children with newly
diagnosed immune thrombocytopenia: data
from the intercontinental cooperative ITP study
group registry II participants. Pediatr. Blood
Cancer 65: e26736.
D’Orazio, J.A., Neely, J., and Farhoudi, N. (2013).
ITP in children: pathophysiology and current
treatment approaches. J. Pediatr. Hematol.
Oncol. 35: 1–13.
Fernández, K.S. and de Alarcón, P. (2013).
Neonatal thrombocytopenia. NeoRev 14: e74.

Grainger, J.D. and Thind, S. (2017). A practical
guide to the use of eltrombopag in children
with chronic immune thrombocytopenia.
Pediatr. Hematol. Oncol. 34: 73–89.
Neunert, C., Lim, W., Crowther, M. et al. (2011).
The American Society of Hematology 2011
evidence‐based practice guidelines for immune
thrombocytopenia. Blood 117: 4190–4207.
Thrombocytopenia 155
Schultz, C.L., Mitra, N., Schapira, M.M., and
Lambert, M.P. (2014). Influence of the American
Society of Hematology guidelines on the man­
agement of newly diagnosed childhood immune
thrombocytopenia. JAMA Pediatr. 168: e142214.
Zdravic, D., Yougbare, I., Vadasz, B. et al. (2016).
Fetal and neonatal alloimmune thrombocyto­
penia. Semin. Fetal Neonatal Med. 21: 19–27.
13 Evaluation of the Child
with a Suspected
Malignancy
Each year, approximately 15,000 children
and adolescents under 20 years of age are
diagnosed with cancer in the United States.
The likelihood of a young adult having a his­
tory of childhood cancer is approximately 1
in 300. Although cancer remains the leading
cause of death in children except for acci­
dents, survival continues to steadily increase.
In adolescents, cancer deaths are less com­
mon than those caused by accidents, homi­
cide, and suicide. More than 80% of children
diagnosed with cancer are now expected to
be cured of their disease. That being said,
cancer remains a devastating diagnosis. The
initial approach to the child and family must
be with a heightened sensitivity to the emo­
tional impact. Once a diagnosis of cancer is
suspected, an immediate and thorough eval­
uation should proceed.
Initial symptoms of cancer may be some­
what elusive, given the subtle and overlap­
ping symptoms and signs that may be
present in both malignant and nonmalig­
nant diseases. Many pediatricians and clini­
cians may only see a new case of childhood
cancer every 5–7 years, and each case may
be so unique as to not allow for the increased
awareness of this possibility. Early detection
and treatment may reduce disease‐related
morbidity and complications.
The history is the first step in the diag­
nostic process, often providing important
clues. Most of the symptoms of childhood
cancer are either due to a mass and its effect
on the surrounding tissues, invasion of the
marrow, or secretion of a substance by the
tumor that disturbs normal function. The
most common presenting symptoms can be
insidious in onset and include fatigue, fevers,
weight loss, swelling, or a mass. Some of
these may be easily ascribed to more com­
mon childhood ailments. A careful family
history should be elicited and include famil­
ial cancers (though rare in childhood cancer)
and immune deficiency syndromes. Certain
conditions can predispose to malignancy
such as genetic diseases (e.g., Down syn­
drome, Beckwith–Wiedemann syndrome,
neurofibromatosis), prior history of a malig­
nancy (survivor of childhood cancer), or
radiation therapy.
Timely diagnosis is critical, though can
be difficult due to the nonspecific symptoms
and rarity of the diseases. Consideration
should be given to the nature of the
complaint by the child and family, potential
explanations for the complaint (or lack
thereof), persistence of symptoms, and lack
of response to common interventions (see
Table 13.1). Delays in diagnosis may be

Handbook of Pediatric Hematology and Oncology – Children’s Hospital & Research Center Oakland,
Third Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
158 Chapter 13

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 vomiting Migraine, sinusitis Brain tumor
Lymphadenopathy Infection Lymphoma, leukemia
Bone pain/limping Infection, trauma, Bone tumor, leukemia,
growing pains neuroblastoma
Abdominal mass Constipation, kidney Wilms tumor,
cyst, full bladder neuroblastoma
Extremity mass Cyst, infection, trauma Bone tumor, soft tissue
sarcoma
Mediastinal mass Infection, cyst Lymphoma, leukemia
Pancytopenia Infection Leukemia
Bleeding Coagulation disorders, Leukemia (APL),
platelet disorders, ITP neuroblastoma
Back pain Trauma Leukemia, lymphoma, CNS
tumor, extension of
abdominal tumor
compressing spinal cord
Chronic ear drainage Otitis media/externa Langerhans cell histiocytosis
Feminizing/masculinizing Precocious puberty Adrenocortical carcinoma,
symptoms brain tumor, germ cell
tumor

Abbreviations: APL, acute promyelocytic leukemia (AML M3); ITP, immune thrombocytopenic
purpura; CNS, central nervous system.

related to age of the child (with older chil­
dren having an increased risk of delay), type
of cancer, location of tumor, stage, clinical
presentation, and experience of the first
medical consultant. Referral should be made
to a pediatric oncologist early if there is a
suspicion of a cancer diagnosis.
Many types of cancer can develop in
children, though certain types are more
common in certain age groups.
Neuroblastoma and Wilms tumor are more
often seen in infancy to age 4 years, acute
lymphoblastic leukemia (ALL) in the 1‐ to
4‐year age group, and lymphoma and sar­
coma in children aged 10 years and older.
As common signs and symptoms may be
associated with common childhood illness,
it is the association of other factors, and
length and severity of these symptoms, that
will often provide the most significant
clues. For example, children that experience
weight loss due to an underlying malig­
nancy may likely have associated findings
including night sweats, pallor, bruising,
fevers, or findings on exam such as adenop­
athy, hepatosplenomegaly, or a mass/swell­
ing. Consideration of the history, physical,
and possible laboratory and imaging find­
ings are all critical in the initial diagnostic
evaluation and should be performed in a
timely manner.
Fever is common in childhood, most
commonly in association with an infec­
tious etiology and associated signs and
 Evaluation of the Child with a Suspected Malignancy 159
symptoms. Fever is also a common present­
ing symptom in acute leukemia, lymphoma,
as well as certain solid tumors (possibly due
to tumor necrosis) such as neuroblastoma
and Wilms tumor. Malignancy should be
considered if fever is persistent despite
appropriate intervention or seen in asso­
ciation with abnormal findings on the
complete blood count (CBC) (i.e., cytope­
nias, elevated white count, or circulating
blasts), chemistry panel (i.e., elevated lactate
dehydrogenase [LDH], liver transaminases,
uric acid), negative blood cultures, or in
association with clinical findings on exam
of organomegaly or adenopathy.
Headache is one of the most common
complaints in the pediatric population, the
majority of which are attributable to nonma­
lignant conditions. Although few headaches
are caused by intracranial masses, primary
brain tumors or metastases must be ruled
out when dealing with a patient with
repeated or persistent headaches. Headaches
are often the first symptom of a brain tumor
and, dependent on location, are frequently
accompanied by subtle findings on neuro­
logic examination. History should include
questions to characterize the headache
including worrisome signs such as recurrent
morning headache, headache that awakens
the child, intense incapacitating headache,
associated vomiting, or changes in the qual­
ity, frequency, and pattern of the headaches.
Associated neurologic symptoms or signs
should warrant an emergent evaluation for a
tumor in the central nervous system. These
include, but are not limited to, localizing
symptoms such as focal weakness, cranial
nerve palsies, ataxia, failure to thrive, and
developmental delays or regression. A thor­
ough neurologic examination, including
evaluation for papilledema, should precede
radiographic imaging. Other important his­
torical points include an assessment of
changes in visual acuity, behavior, and aca­
demic performance. MRI is recommended
to evaluate for the presence of an intracranial
mass in children with symptoms suggestive
of a brain tumor. CT may be appropriate as
an initial test in certain settings depending
on the availability of MRI. CT is a good,
rapid tool for the assessment of acute hemor­
rhage or increased intracranial pressure (see
Table 13.2).
Lymphadenopathy is a common finding
on examination in children. Enlarged lymph
nodes are a frequent presenting sign in
association with malignancies or infection,
and differentiation requires a meticulous
and systematic approach. Lymph nodes
become large in response to infection or
infiltration. Generally, a lymph node is con­
sidered enlarged if it measures greater than
10 mm, although inguinal nodes may be
15 mm or greater before being considered
worrisome and epitrochlear nodes are con­
cerning once greater than 5 mm. In addition
to size, other factors to consider in establish­
ing a differential between infection and
malignancy include persistence or rate of
Table 13.2 Conditions suggesting need
for brain imaging in children with headache.
Presence or onset of neurologic abnormality
Ocular findings such as papilledema,
decreased visual acuity, or loss of vision
Vomiting that is persistent, increasing in
frequency, or preceded by recurrent
headaches
Change in character of headache such as
increased severity and frequency
Recurrent morning headaches or headaches
that repeatedly awaken child from sleep
Short stature or deceleration of linear growth
Precocious puberty
Diabetes insipidus
Age 3 years or less
Neurofibromatosis
History of acute lymphoblastic leukemia with
irradiation of central nervous system
Loss of milestones or an abnormal increase in
head circumference in an infant or toddler
160 Chapter 13
growth, quality of the node, location and
distribution (i.e., adenopathy that is sym­
metric, localized, regional, or disseminated),
and presence of other signs or symptoms of
infection. Adenopathy in the supraclavicu­
lar, axillary, or epitrochlear areas is consid­
ered an abnormal finding. Adenopathy that
persists longer than 6 weeks is concerning
for malignancy as is a unilateral location.
Nodes that are hard, nonmobile, and non­
tender are worrisome for malignancy. In
certain malignancies, nodes may become
“matted” due to fixation with adjacent tissue
and each other and are palpated as an
enlarged group of nodes in one mass. Nodes
associated with fluctuance, tenderness,
warmth, or overlying erythema are more
consistent with infection. However, these
are only generalizations, as rapidly growing
malignant nodes may be tender and infec­
tious nodes may be quite firm and
nonmobile.
Important historical points to elicit
include:
●● Duration of lymphadenopathy or local­
ized mass
●● Presence of a recent infectious illness
●● Skin lesions, cuts, or abrasions (and rela­
tionship to nodal drainage patterns)
●● Recent immunizations
●● Medications
●● Animal contact (e.g., cat scratch, rodent
bite, tick bite)
●● Recent transfusion
●● Travel
●● Possible sexually transmitted infection
●● Presence of symptoms such as fever,
arthralgias, weight loss, or night sweats
The differential diagnosis of lymphadenop­
athy includes infectious etiologies (viral,
bacterial, spirochetal, and protozoan),
­connective tissue disease, hypersensitivity
states, lymphoproliferative disorders,
immunodeficiency states, storage diseases,
and malignancy. In infants, the differential
diagnosis of head and neck lumps includes
lymphadenopathy and congenital malfor­
mations, such as cystic hygroma, thyroglos­
sal duct cyst, branchial cleft cyst,
epidermoid cyst, and neonatal torticollis.
Localized adenopathy may be infectious in
origin including bacterial causes such as
Staphylococcus aureus, beta‐hemolytic strep,
cat‐scratch disease (Bartonella henselae),
and tuberculous and nontuberculous myco­
bacteria, in addition to nonbacterial causes,
such as HIV, Epstein–Barr virus (EBV),
cytomegalovirus (CMV), and toxoplasmo­
sis. The site of lymphadenopathy and age of
the child may also provide clues as to con­
cern for underlying malignancy. Young chil­
dren with head and neck adenopathy may
have neuroblastoma, rhabdomyosarcoma
(RMS), non‐Hodgkin lymphoma, or ALL.
Older children with Hodgkin and non‐
Hodgkin lymphoma may present with iso­
lated adenopathy in this area.
The physical examination of the child
with lymphadenopathy includes an
assessment of the size, location, and quality
of the node(s). A full examination should
include assessment of the skin and
mucocutaneous tissues draining to the
particular node in question, and evidence of
other signs related to an underlying disease
process such as hepatomegaly and
splenomegaly. Nodes should be measured in
largest diameter, the quality should be
assessed as to mobility, firmness, tenderness,
and overlying skin changes, and these
findings should be documented. Children
with mildly enlarged nodes should be
monitored with frequent examinations, and
when not associated with malignancy, most
of these nodes will revert to normal size.
If infection is considered the cause of the
adenopathy, as in localized cervical adenitis,
it is reasonable to treat the patient with a
2‐week course of antibiotics. Dependent on
the history, physical, and clinical suspicion, a
particular antibiotic regimen can be chosen
 Evaluation of the Child with a Suspected Malignancy 161

in addition to sending serology or further or as a result of antibiotic treatment (see

testing for likely organisms. A baseline CBC
with differential and peripheral blood smear
should be done if there is any concern for a
diagnosis other than infection. The patient
should be seen again following completion
of the antibiotics and if the node has not
changed or has increased in size, considera­
tion should then be given to excisional
biopsy. Many cases of infection‐related ade­
nopathy resolve spontaneously in 2–6 weeks
Figure 13.1).
For the large node (i.e., ≥2.5 cm in size) or
in the patient without response to antibiot­
ics, further evaluation is required. Patients
with adenopathy in the posterior neck or
supraclavicular areas, especially if there is no
history of recent infection, also warrant a
more immediate evaluation. Additional
studies should include a purified protein
derivative (PPD) skin test (or QuantiFERON

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
Growing in size or Infection confirmed or likely
Node ≥ 2.5 cm or Node < 2.5 cm
Hard, nonmobile or Empiric antibiotic therapy
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).
162 Chapter 13
gold), chest radiograph, CBC with differen­
tial (if not already done), chemistries includ­
ing LDH and uric acid, and serologies as
indicated by history and examination. An
excisional biopsy should be done on enlarg­
ing, matted, or persistently large nodes or if
adenopathy is also seen on chest radiogra­
phy. It is recommended that excisional
biopsies (i.e., removal of intact node) be per­
formed when malignancy is suspected to
evaluate the architecture of the node in addi­
tion to the cellular infiltrate. The largest
node should be biopsied when possible, with
avoidance of the upper cervical and inguinal
areas. Studies to be performed on the tissue
include Gram stain and culture (bacterial,
mycobacterial, viral, and fungal); histology
and immunohistochemistry for suspected
malignancy; and if malignancy is confirmed,
flow cytometry and specific cytogenetic test­
ing for further classification.
Splenomegaly is the finding of a palpable
spleen edge on examination. A 1–2‐cm
splenic tip is found in 30% of full‐term neo­
nates and in as many as 10% of healthy chil­
dren. Approximately 3% of healthy college
students have palpable spleens. Therefore,
this finding on a routine physical examina­
tion of an otherwise healthy child should
not create great concern. Children with
other signs of systemic disease, however,
should have their splenomegaly evaluated.
Splenomegaly is associated with many
disease states, both congenital and acquired:
Hemolytic anemia: hereditary spherocytosis,
thalassemia, splenic sequestration in
sickle cell disease, and autoimmunity.
Immunological disease: common variable
immune deficiency, connective tissue dis­
orders, and autoimmune lymphoprolif­
erative disease.
Infection: viral (EBV, CMV, HIV, hepatitis),
bacterial (tularemia, abscesses, tubercu­
losis, infective endocarditis), spirochetal,
protozoan, and fungal.
Storage disease: Gaucher, Neimann–Pick,
acid sphingomyelinase deficiency, and
mucopolysaccharidoses.
Malignancy: leukemias as well as Hodgkin
and non‐Hodgkin lymphoma.
A detailed history should be obtained to
gain clues as to the etiology of the enlarged
spleen. The patient should be questioned
regarding current or recent infectious symp­
toms, fevers or rigors (e.g., in subacute bacte­
rial endocarditis, infectious mononucleosis,
and malaria), jaundice (with hemolytic
anemia or liver disease), abnormal bleeding
or bruising (malignancy), travel to endemic
areas (malaria), trauma (splenic hematoma),
and family history (hemoglobinopathies,
thalassemia, and hereditary spherocytosis
with prior splenectomy or cholecystectomy).
The physical examination should include a
measurement of the spleen size (centimeters
below the mid‐costal margin), consistency,
and presence of tenderness (which suggests
rapid increase in size) in addition to the
presence of adenopathy or hepatomegaly.
The vitals should be reviewed for evidence of
fever or hypotension and the skin assessed
for cutaneous bleeding. Other considera­
tions include evaluation for stigmata of
specific disease states including jaundice,
cardiac murmurs, arthritis, as well as spe­
cific findings of endocarditis including Roth
spots (retinal hemorrhages), Janeway lesions
(nontender hemorrhagic lesions on the
palms/soles), Osler nodes (tender microem­
boli on the fingers and toes), and presence of
neurologic or cognitive concerns (metabolic
storage diease).
The laboratory and imaging assessment
is determined based on suspicion of the
underlying etiology of splenomegaly.
Consideration should also be given to a
secondary effect of hypersplenism in which
the child may have cytopenias due to a large
spleen. Persistent splenomegaly should be
fully investigated as follows:
 Evaluation of the Child with a Suspected Malignancy 163
CBC: evaluate red cell indices, reticulocyte
count, platelet count, white blood cell
count, and review peripheral blood
smear (all to help rule out hematologic
disorders such as hemolytic anemia;
membrane disorders with spherocytes or
elliptocytes; increased red cell indices
and anemia in thalassemia; atypical lym­
phocytes as in EBV; leukemic blasts; and
cytopenias secondary to leukemia or
hypersplenism).
Infection: blood culture, viral studies, PPD
(or QuantiFERON gold), thick and thin
smear, and serologies to rule out EBV,
CMV, HIV, histoplasmosis, tuberculosis,
and malaria.
Hemolytic evaluation: CBC, reticulocyte
count, direct antiglobulin test (Coombs),
haptoglobin, serum bilirubin, LDH, red
cell enzyme assays (G6PD, pyruvate
kinase deficiency), osmotic fragility
testing or ektacytometry, and urinalysis.
Liver disease: complete metabolic panel,
coagulation studies, hepatitis panel, α‐1
antitrypsin, ceruloplasmin (Wilson dis­
ease), and 24‐hour urine copper.
Connective tissue disease: erythrocyte
sedimentation rate (ESR), complement
(C3, C4, CH50), antinuclear antibody,
and rheumatoid factor.
Infiltrative diseases: bone marrow aspirate
and biopsy (looking for blasts, storage
cells) and enzyme study for Gaucher
(glucocerebrosidase).
Lymph node biopsy: can be done if performed
with coexistent lymphadenopathy.
Imaging: volumetric and heterogeneity
assessment with ultrasound, CT, or MRI;
liver–spleen scan with 99mTc‐sulfur col­
loid for functional analysis; can also send
pit count for pitted red blood cells.
Bone or joint pain is unusual in children
and adolescents except when associated with
trauma. Growing pains are a common com­
plaint and consist of bilateral (80% of cases)
lower extremity pain occurring in the after­
noon, evening, or night, and affect children
between 3 and 14 years of age. These can
occur most commonly on a weekly or
monthly basis (and, much less frequently
daily), and are relieved with massage in the
majority of cases. Pain is otherwise usually
due to bone, bone marrow, or nerve infiltra­
tion. Back pain in young people is pathologic
and may be due to a tumor in the spinal cord
or one causing external compression such as
neuroblastoma, lymphoma, Ewing sarcoma,
RMS, or a leukemic chloroma. This finding
should prompt an MRI of the spine, as these
conditions typically result in no abnormali­
ties on plain film.
Patients with primary bone tumors often
present with localized pain, frequently in
association with a growing mass. Pain may
be attributed to recent mild trauma or
growing pains. In approximately 5–10% of
cases, patients sustain a pathological fracture
after seemingly mild trauma due to
infiltration of the periosteum and weakening
of the bone. Bone pain is typically a
presenting symptom in patients with
osteogenic sarcoma and Ewing sarcoma.
Langerhans cell histiocytosis very often
involves bone and may present with
localized bone pain anywhere in the body,
often with overlying soft tissue swelling.
Diffuse or multifocal bone pain is a
common presenting symptom in acute leu­
kemia. It is reported in more than 25% of
patients diagnosed with ALL due to mar­
row crowding by leukemic cells and is seen
less commonly in acute myelogenous leuke­
mia (AML). Patients will often complain of
back or leg pain that is persistent and
increasing in intensity and very young chil­
dren may become irritable with refusal to
walk or to participate in normal activities.
Musculoskeletal pain in children is often
diagnosed as arthritis or bone or joint
infection. Pain may be asymmetric and
often children present with a limp with pain
164 Chapter 13
seemingly disproportionate to the findings
on examination. In contrast to children with
arthritis, children with leukemia will have
worsened pain at night, severe pain that may
shift to other locations, no morning stiffness
or swelling, and may have associated consti­
tutional symptoms such as weight loss and
night sweats. Associated laboratory findings
that may suggest malignancy include an ele­
vated ESR, elevated serum LDH or uric acid
anemia, thrombocytopenia, neutropenia,
leukopenia, or leukocytosis. Any of these
findings should prompt an examination of
the bone marrow.
Bone pain may also be a direct result of
bony metastatic disease or marrow infiltra­
tion secondary to other tumors including
neuroblastoma, RMS, Ewing sarcoma, and
non‐Hodgkin lymphoma. Localized bone
pain warrants radiographic evaluation (two‐
view plain radiographs) for the assessment of
a lesion or leukemic changes. Patients with
leukemia and bone pain may show evidence
of osteopenia, lytic lesions, metaphyseal
bands, periosteal new bone or sclerotic
lesions. Malignant bone tumors can show
characteristic onion skinning or a sunburst
phenomenon. The onion skin appearance is
a result of repetitive periosteal reactions,
with layers of calcium accumulating with
growth beyond the periosteum and is classi­
cally seen in Ewing sarcoma. The sunburst
phenomenon is common in osteosarcoma
and occurs as a result of deposition of cal­
cium in blood vessels by malignant osteo­
blasts that radiate perpendicular from the
tumor. MRI is the imaging of choice for eval­
uation of a suspected bone tumor and can
show the extent of medullary and extramed­
ullary soft tissue involvement, as well as skip
lesions (disease in the same bone not con­
tiguous with the primary lesion). Children
with bone tumors also need whole body
technetium bone scanning to screen for dis­
tant lesions as well as CT imaging of the
chest to evaluate for metastatic involvement.
Cytopenias or abnormalities on the
peripheral blood smear are suspicious for
a marrow infiltrative process, primarily
­leukemia. Isolated anemia, leukopenia, or
thrombocytopenia can occur in leukemia
but much more commonly the patient will
present with bicytopenia or pancytopenia.
Pancytopenia may also indicate the lack of
hematopoietic cell production as in aplastic
anemia or as caused by the proliferation of
malignant cells in the marrow with result­
ant crowding. The anemia is frequently
characterized as one of chronic disease (i.e.,
normochromic with low reticulocyte count).
Leukocyte counts are variable at presentation
in acute leukemia and may be normal,
decreased, or elevated. The cell differential,
however, is likely to show neutropenia and
the peripheral blood smear will likely,
though not always, demonstrate blasts or
immature cells (see Table 13.3). Unless
metastasis to the marrow has occurred,
leukopenia and thrombocytopenia are
rarely associated with extramedullary
malignancies such as neuroblastoma, Ewing
sarcoma, or RMS.
Patients with bicytopenia and pancytope­
nia require bone marrow aspiration, and
possibly bone marrow biopsy, for a suspected
diagnosis of a marrow infiltrative process
such as acute leukemia or aplastic anemia.
The situation can be more complex in the
case of a single depressed lineage. Children
with persistent or worsening normocytic,
normochromic anemia without manifesta­
tions of hemolysis, clinical suspicion of tran­
sient erythroblastopenia of childhood, or
renal disease with low erythropoietin pro­
duction should have diagnostic bone mar­
row studies performed.
Children with leukemia may also present
with an elevated white blood cell count, some­
times with marked elevation over 100 × 109/l
(i.e., hyperleukocytosis). Leukemoid reac­
tions (a white blood cell count >50 × 109/l
often associated with immature forms [i.e.,
 Evaluation of the Child with a Suspected Malignancy 165

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, aspartate aminotransferase,
alanine aminotransferase (AST, ALT), alkaline phosphatase, 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 and possibly bone marrow biopsy
Specimens for morphology, immunophenotyping, and cytogenetics
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 or per institutional protocol for initial study)
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 thrombo­
plastin 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 simplex virus.

bands] or lymphocytosis) can be seen in Any cytopenia associated with unexplained

infants with Down syndrome (i.e., transient
myeloproliferative disorder) or in cases of
severe bacterial infection such as pertussis in
the young child.
Bone marrow examination with aspirate
and/or biopsy is indicated in the following
situations:
Significant depression of one or more
peripheral blood lineages (white cells, red
cells, platelets) without an obvious infec­
tious cause.
Presence of circulating blasts on the
peripheral blood smear.
lymphadenopathy, splenomegaly, hepatomeg­
aly, anterior mediastinal mass, or bone pain.
Bleeding as a presenting sign in cancer is
usually related to severe thrombocytopenia
and occurs commonly in children with
acute leukemia. Manifestations typically
involve mucocutaneous tissues with clinical
signs including petechiae, purpura, epistaxis,
and menorrhagia. Patients with APL (AML
M3) are at risk for severe bleeding at pres­
entation due to underlying coagulation
abnormalities and DIC, whereas Wilms
166 Chapter 13
tumor patients may have acquired von
Willebrand disease (aVWD) at presentation
increasing bleeding risk. Coagulopathy has
also been seen at presentation in T‐cell acute
lymphoblastic leukemia, lymphoma, and
neuroblastoma. Bleeding may also be due to
defective platelet function and a medical
cause of impairment (such as use of ibu­
profen or other NSAIDs) should be consid­
ered. Evaluation should consist of a CBC,
reticulocyte count, review of the peripheral
blood smear, coagulation studies with PT,
international normalized ratio (INR), PTT,
and fibrinogen, as well as a bone marrow
evaluation.
Mediastinal masses may lead to com­
pression of respiratory, vascular, or other
structures and can range from an asympto­
matic incidental finding to significant com­
promise and an emergent situation.
Common symptoms include orthopnea (i.e.,
inability to lie flat), cough, shortness of
breath, fatigue, hoarseness, and wheezing.
Most mediastinal masses in children are
malignant and often are associated with
adenopathy, abnormal cell counts, and pos­
sibly neck swelling. Imaging with chest radi­
ography and chest CT yields information
with respect to location in the mediastinum
and potential for cardiac compromise. There
are three anatomic compartments of the
mediastinum, and location may provide
clues to etiology. Evaluation of the child
should include laboratory studies (i.e., CBC,
complete metabolic panel, coagulation
panel), and the physical status and stability
of the patient will help determine next steps
such as feasibility of safely performing a
bone marrow aspirate and lymph node
biopsy.
Anterior mediastinal masses are more
typically seen in older children and adoles­
cents and frequently are associated with lym­
phoma, T‐cell leukemia, thymic tumors,
thyroid tumors, and some benign tumors
(teratomas, lipomas, and angiomas) or
hernia. Malignant tumors, especially lym­
phoma and leukemia, may have rapid growth
rates and quickly lead to compromise with
presentation of orthopnea, superior vena
cava/superior mediastinal syndrome, airway
obstruction, dysphagia, and symptoms of
increased intracranial pressure due to
decreased cerebral venous return. The mass
may cause a pericardial effusion or directly
obstruct cardiac outflow leading to cardiac
compromise. See Chapter 14 for assessment
and management.
Middle mediastinal masses are likely
malignant. Infections should be in the dif­
ferential diagnosis with consideration for
tuberculosis or histoplasmosis in addition to
structural anomalies such as pericardial
cysts, bronchogenic cysts, or esophageal
lesions. Malignant tumors common in this
location include Hodgkin lymphoma and
nodal masses of neuroblastoma, RMS, and
germ cell tumors. Direct extension of an
abdominal mass may also present in the
middle mediastinum.
Posterior mediastinal masses are
generally neurogenic in origin and include
benign and malignant tumors. These
include ganglioneuroma, neurofibroma,
lymphoma, Ewing sarcoma, and
neuroblastoma. Most of these lesions are
asymptomatic but may present with
symptoms of spinal cord compression such
as pain or focal neurological signs.
A palpable abdominal mass is one of the
most common presenting findings of a
malignant solid tumor in children.
Nonmalignant etiologies include impacted
stool, intussusception, abdominal aorta, a
distended bladder, hydronephrotic kidneys,
and pregnancy.
The age of the child can provide a clue
to diagnosis. In the newborn, an abdomi­
nal mass is most likely to be a congenital
abnormality of renal origin. The most
common malignant tumors in young chil­
dren are neuroblastoma and Wilms tumor.
 Evaluation of the Child with a Suspected Malignancy 167
Children with Wilms tumor most often
are well‐appearing and the mass is an inci­
dental finding noted by a family member
or during a well‐child check. Unlike
Wilms tumor, neuroblastoma will often
present with evidence of spread and sys­
temic symptoms including weight loss,
fever, and bone pain. In older patients, the
mass may be related to leukemia or lym­
phoma with enlargement of the spleen
and liver. The most common lymphoma
in children is Burkitt lymphoma which
may present as a rapidly enlarging abdom­
inal mass leading to pain and obstructive
symptoms (gastrointestinal and urinary
tracts) in association with metabolic
derangements from tumor lysis. Burkitt
and other lymphoma, as well as primary
gastrointestinal tumors, may also occur in
the ileocecal area and serve as a lead point
for intussusception.
The history is important to determine if
the symptoms are related to the mass. A
careful genitourinary history should be
obtained to determine if the mass may be of
renal origin. Historical points may provide
suspicion of catecholamine production such
as flushing, palpitations, diarrhea, and
sweating (very rare). Constitutional
symptoms such as failure to thrive, fever,
night sweats, and sudden weight loss should
lead one to suspect a disseminated process
such as neuroblastoma in young children or
lymphoma in older children and adolescents.
A meticulous and careful physical exam­
ination of the child should be done by first
attempting to have the child relax. When
examining the abdomen, keep in mind the
normal structures that may be present such
as the liver or spleen edges, kidneys, aorta,
sigmoid colon, stool, or spine. A rectal
examination and pelvic/vaginal examina­
tion may be indicated but should be per­
formed only by an experienced practitioner
and after obtaining laboratory studies
(should not be neutropenic for a rectal
examination). Care should be taken to pal­
pate the mass gently and limit the number of
examiners. Imaging will also help determine
size and location. A careful general physical
examination is vital, as many tumors may
have associated signs and symptoms or
underlying syndromes. Aniridia, hemihy­
pertrophy, and genitourinary abnormalities
have been reported in association with
Wilms tumor. Subcutaneous nodules (typi­
cally bluish), periorbital ecchymoses, opso­
clonus–myoclonus, and presence of
organomegaly are seen with neuroblastoma.
Signs of precocious puberty may be seen
with tumors involving the liver, adrenal
glands, or gonads (i.e., germ cell tumors).
The neurological examination may show
evidence of a Horner’s syndrome with apical
tumors (often neuroblastoma) or spine
compression with large abdominal masses.
See Table 13.4 for the workup of a child with
an abdominal mass. A surgical consultation
should be obtained and the decision made
whether to obtain a biopsy or perform a
resection of the mass. Surgical staging is
done by assessing tumor margins, nodal
involvement, presence of locally invasive or
distant disease, and for possible tumor spill­
age (see Chapters 18 and 19).
Case study for review
A 14‐year‐old female presents with progres­
sive bilateral neck swelling in the setting of
anemia and fatigue.
Six months prior to presentation, her
physician sent labs for a complaint of fatigue
and noted the following: hgb 8.3 g/dl, WBC
7.8 × 109/l, platelets 517 × 109/l, mean cor­
puscular volume (MCV) 81, neutrophils
74%, lymph 10%, serum iron 14, transferrin
saturation 7%, ferritin 441, fibrinogen 788,
INR 1.3, PTT 42. Due to suspected iron
deficiency anemia, she was placed on an oral
iron supplement.
168 Chapter 13

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/pelvic 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, α‐fetoprotein, β‐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, metaiodo­
benzylguanidine; CBC, complete blood count; LDH, lactate dehydrogenase; BUN, blood urea
nitrogen; VMA, vanillylmandelic acid; HVA, homovanillic acid; HCG, human chorionic
gonadotropin; ESR, erythrocyte sedimentation rate.

Six weeks prior to presentation, she
noted increasing bilateral neck swelling,
without tenderness or overlying erythema.
Two weeks prior to presentation, she
traveled with her family to Mexico and after
several days felt dizzy and more fatigued.
She was seen in a local hospital and a CBC
was essentially unchanged. CT imaging
showed hepatosplenomegaly and diffuse
adenopathy involving anterior cervical,
mediastinal, and retroperitoneal nodes. She
was given a blood transfusion and her symp­
toms improved. She also underwent a fine
needle aspiration of an enlarged right ante­
rior cervical node, and the pathology
showed follicular hyperplasia.
Past history included travel to Mexico
4 years previously. Her brother is in the
army and recently returned home after
3 years in Germany.
a. What elements of the history and
evaluation to date are concerning and
what additional information should you
seek?
The patient has a normocytic anemia, mild
elevation of the platelet count, a predomi­
nance of neutrophils on the differential, and
elevated ferritin and fibrinogen. These are
suggestive of a chronic inflammatory state.
There is evidence of iron deficiency based
on the low transferrin saturation, but this
is more likely secondary to macrophage
 Evaluation of the Child with a Suspected Malignancy 169
trapping secondary to inflammation as in
chronic disease states. The diffuse adenopa­
thy and hepatosplenomegaly suggest this is a
systemic illness and could possibly represent
infection, malignancy, immune deficiency,
or autoimmune disease. Of note, a fine nee­
dle aspirate is not an ideal method to obtain
tissue for diagnostic purposes, as nodal
architecture often provides important clues
and diagnostic information (also in more
sufficient quantity).
The history should seek information on
travel, ill contacts (including TB exposure),
the presence of fever or infectious symp­
toms, respiratory symptoms, weight loss,
night sweats, and familial diseases.
Given the diffuse nature of her adenopa­
thy, imaging with a CXR should be obtained
to determine if mediastinal adenopathy (or a
mass) may be present with imminent danger
(i.e., compromise to heart, trachea, or great
vessels).
Upon questioning, she has an intermit­
tent nonproductive cough several times a
day. She has not had fever or infectious
symptoms and she has not noted a change in
breathing pattern or endurance. She gets
sweaty at night but not drenching or need­
ing to change her linens. No known sick
contacts, GI symptoms, pain, or arthralgia.
Over the past 5–6 months she has lost 20 lbs
unintentionally. Her appetite and food
intake have not changed. Her menses are
regular. No unusual bleeding or easy bruis­
ing. She has been attending school, missing
only the days her family traveled to Mexico.
Several days prior to presentation, she also
noted a small tender bump on the inner
aspect of her right thigh and noted it bled
the day before.
Immunizations are up to date; four sib­
lings and parents are healthy without
known autoimmune disease. Recent PPD is
negative.
On exam she is well‐appearing and
comfortable. She is obese. Neck swelling is
not obvious but adenopathy is noted on
palpation with many small (<1 cm), non­
tender, mobile, rubbery nodes detected in
the anterior and posterior cervical chains
extending to the supraclavicular regions, left
side > right. The largest palpable node meas­
ures 1.5 cm in the left supraclavicular fossa
(which the patient notes to be the first lump
she felt). Axillary and inguinal adenopathy
are also noted. There is mild diffuse tender­
ness of the abdomen in the bilateral upper
quadrants. You are unable to appreciate
organomegaly due to the obese abdomen,
even with percussion. She has a tender drain­
ing lesion (serosanguinous) on the upper
inner right thigh.
Labs: UA neg, complete metabolic panel
(CMP) wnl, uric acid nl, LDH 708, INR 1.2,
APTT 38.2, hgb 9.5 g/dl, WBC 6.8 × 109/l,
platelets 368 × 109/l, MCV 81, polymorpho­
nuclear neutrophils (PMNs) 62%, bands 6%,
lymphs 14%, retic 0.6%; DAT neg, beta‐
human chorionic gonadotropin (βHCG)
neg.
CXR: prominent anterior mediastinal
and right paratracheal lymphadenopathy,
no mediastinal mass.
b. What considerations are in the differ­
ential diagnosis and what studies should
you seek?
Consideration should be given to an infec­
tious etiology that could explain the chro­
nicity and progressive nature of the illness
and include (with appropriate testing
modality): HIV (ab), CMV by polymerase
chain reaction (PCR), EBV (serology and
PCR), coccidioides (IgM, IgG), and TB
(PCR, acid fast bacillus‐AFB). The prior
negative PPD and no history of ill contacts
(i.e., coughing contacts) suggest TB is less
likely but should give consideration to
obtaining a QuantiFERON gold test.
Malignancy is a major consideration
given the degree of enlarged nodes, organo­
megaly, as well as weight loss. The elevations
of ferritin and fibrinogen, both acute phase
reactants, can be elevated with malignancy.
An elevated LDH can support this diagnosis
170 Chapter 13
as well. A diagnosis of lymphoma especially
Hodgkin disease should be ruled out (given
the chronicity). An excisional lymph node
biopsy should be performed. The left supra­
clavicular node appears to be the ideal lesion
to remove (in its entirety) given the patho­
logic site, and that it was the first lump felt
and is the largest. This is a surgically acces­
sible site with an expected short healing
process. Night sweats, fevers, and/or unin­
tentional weight loss are all considered “B”
symptoms of lymphoma, and therefore her
unintentional weight loss is suggestive.
The physical exam is less suggestive of an
autoimmune process and this evaluation
can be deferred until after the biopsy.
The patient had an infectious evaluation
with negative studies for HIV, CMV, EBV, TB,
and cocci. Additionally, the draining lesion
on the left thigh was incised and drained
and grew mixed anaerobic bacteria. It was
packed and the patient received a 7‐day
course of cephalexin with full resolution.
The pathology on the excised lymph
node reveals nodular sclerosing classical
Hodgkin disease, with effaced nodal archi­
tecture, replaced by histiocytic cells sepa­
rated by thick fibrous bands. This type of
pathology is best appreciated in a fully
excised node as opposed to a fine needle
core specimen. Occasional Reed–Sternberg
cells are noted as well.
c. What are the next steps for the patient
at this time?
Given the diffuse adenopathy, organomeg­
aly and pathology findings, as well as weight
loss, she is at a minimum stage IIIB.
Complete staging will include further imag­
ing with positron emission tomography‐
computer tomography (PET‐CT) (full
body) and bilateral bone marrow aspirate
and biopsy. A number of chemotherapeutic
regimens offer excellent outcomes and
potential radiation sparing, which must be a
significant consideration especially in a
female patient given the high risk of breast
cancer in those receiving radiation to the
mediastinum.
Multiple choice questions
1. You are seeing a 6-month-old male
patient in your clinic and you palpate an
enlarged liver/mass. There is no hyperten­
sion or hematuria. Follow up CBC reveals a
microcytic anemia with thrombocytosis.
The most likely diagnosis is:
a. Neuroblastoma
b. Hepatoblastoma
c. Wilms tumor
d. Embryonal sarcoma of the liver
e. Abdominal lymphoma
Explanation: Hepatoblastoma, although rare,
is the most common liver tumor of infancy
and early childhood. Hepatoblastoma has an
increased risk in premature, very low birth
weight infants. Hemihypertrophy and
overgrowth syndromes are a risk factor for
hepatoblastoma as well as Wilms tumor
(less likely neuroblastoma and sarcoma and
rarely adrenocortical carcinoma). Elevation
of alpha‐fetoprotein is diagnostic for hepa­
toblastoma. Thrombocytosis is commonly
seen due to thrombopoietin (TPO) produc­
tion by the hepatoblastoma tumor cells and
can be a clue to diagnosis. The answer is b.
2. You are seeing a 4-year-old female admit­
ted for work up of an abdominal mass. She
had a CT of the chest, abdomen and pelvis
which showed her disease was limited to
the abdomen/pelvis. She underwent open
biopsy and has been having some oozing at
the biopsy site. You are concerned about
acquired von Willebrand disease. Her most
likely underlying tumor is:
a. Neuroblastoma
b. Hepatoblastoma
c. Wilms tumor
d. Rhabdomyosarcoma
e. Osteosarcoma
 Evaluation of the Child with a Suspected Malignancy 171
Explanation: Although acquired von
Willebrand disease (AVWD) has been
reported in other tumor types, it has been
most commonly reported in Wilms tumor.
AVWD has also been reported in other
miscellaneous conditions including car­
diovascular disorders, autoimmunity and
hypothyroidisim. AVWD can be similar to
type I or type IIA VWD and therefore the
suspected patient should have testing to
include von Willebrand factor (VWF)
antigen, ristocetin cofactor assay and high
molecular weight multimers. Initiation of
therapy usually rapidly resolves the AVWD,
thought to be due to absorption of VWF
antigen by tumor cells or, specifically in the
case of Wilms tumor, due to secretion of
hyaluronic acid. The answer is c.
3. Neuroblastoma can present with many
different clinical findings as well as paraneo­
plastic syndromes. All of the following are
potentially consistent with neuroblastoma
EXCEPT:
a. Seizure disorder
b. Opsoclonus myoclonus ataxia
syndrome
c. Secretory diarrhea secondary to VIP
hypersecretion
d. Horner’s syndrome
e. Raccoon eyes
Explanation: Neuroblastoma occurs due to
lack of maturation of neural crest cells and
can therefore occur anywhere along the
sympathetic chain. Infants may present with
an incidental finding of neuroblastoma
which often regresses spontaneously and
does not require any therapy. Older infants
and children require therapy dependent on
the extent of disease (i.e., stage) as well as
presence of N‐Myc which is a poor prognos­
tic genetic marker. Low stage neuroblastoma
may present along the cervical chain leading
to Horner’s syndrome or heterochromia.
Retrobulbar involvement can lead to prop­
tosis or raccoon eyes, similar to what is seen
in a basilar skull fracture. Opsoclonus myo­
clonus ataxia syndrome (OMAS) and VIP
hypersecretion are both paraneoplastic syn­
dromes seen with neuroblastoma. In OMAS,
it is thought that antibodies to the tumor
cells attack the cerebellum. Brain and CSF
involvement generally do not occur in
neuroblastoma although the tumor may
wrap around or even impinge upon the
spinal column. The answer is a.
4. Prognosis of neuroblastoma is based
on multiple factors. All of the following
are important baseline prognostic factors
EXCEPT:
a. Age
b. Stage of disease
c. N‐Myc status
d. Urine HVA and VMA
e. Histology
Explanation: Although urine HVA and
VMA are important diagnostic modalities,
they are not baseline prognostic factors.
They are important as markers of response
in addition to imaging response. Patient age
is a very important prognostic marker as
younger children do better and those <1
year of age may be diagnosed with stage IVS
neuroblastoma which can often resolve
without treatment. Stage of disease is also an
important prognostic marker as stage III
and IV patients (based on the older INSS
staging system) are harder to treat and
require more intensive therapy. Generally
these patients also harbor the N‐Myc genetic
mutation which is also correlated with poor
prognosis. Finally, histology as well as DNA
index are utilized as prognostic markers.
The answer is d.
5. You are seeing a patient with rhabdomyo­
sarcoma. All of the following are important
baseline prognostic factors EXCEPT:
a. Extent of disease (i.e. disease stage)
b. Loss of heterozygosity (LOH) at 1p
and 16q
172 Chapter 13
c. Alveolar vs. embryonal histology
d. Presence of the fusion protein PAX3
and FOXO1
e. Site and resectability of primary
tumor
Explanation: Younger patients with rhab­
domyosarcoma (RMS) tend to have the
embryonal histologic subtype which has
a better prognosis than the alveolar sub­
type. Alveolar RMS is more likely in older
patients and is more likely to present with
metastatic disease. Alveolar histology is
confirmed with fusion of PAX3 (or rarely
PAX7) with FOXO1. Patients with alveolar
histology but without the PAX3/FOXO1
fusion protein do better due to some overlap
in histology with the embryonal subtype.
Patients with smaller, more easily resectable
tumors do better as do patients with localized
disease. Certain sites of disease including
the head and neck as well as the genito­
urinary (GU) (non‐bladder, non‐prostate)
regions do better. LOH of 1p and 16q is a
prognostic marker in Wilms tumor. The
answer is b.
Suggested reading
Allen‐Rhoades, W. and Steuber, C.P. (2015).
Clinical assessment and differential diagnosis
of the child with suspected cancer. In:
Principles and Practice of Pediatric Oncology,
7e (eds. P.A. Pizzo and D.G. Poplack), 101–
112. Wolters Kluwer.
Siegel, D.A., King, J., Tai, E. et al. (2014). Cancer
incidence rates and trends among children
and adolescents in the United States, 2001‐9.
Pediatrics 134: e945–e955.
14 Oncologic
Emergencies
The prognosis for children diagnosed with
cancer has steadily improved over the past
50 years, and it is now estimated that more
than 80% of children newly diagnosed with
cancer will ultimately be cured of their
disease. Given this positive outlook, it
becomes even more important that life‐
threatening complications arising either as a
result of the patient’s cancer diagnosis or the
treatment being provided be promptly
recognized and appropriately treated.
Oncologic emergencies can be
categorized based on their pathogenesis,
including emergencies caused by space‐
occupying lesions, those caused by
abnormalities of blood and blood vessels,
and metabolic emergencies.
Emergencies caused by space‐
occupying lesions
Superior vena cava syndrome
and superior mediastinal
syndrome
The superior vena cava (SVC) is a thin‐
walled vessel with low intraluminal pressure,
prone to thrombosis, and surrounded by
thymus and nodes that drain the right side
and lower left side of the chest. Part of the
SVC is also in the pericardial reflection.
Lymph nodes, thymus, and the pericardium
may become enlarged from infection or
Handbook of Pediatric Hematology and Oncology – Children’s Hospital & Research Center Oakland,
Third Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
tumor involvement and compress the SVC.
Adjacent coronary and collateral vessels can
become clotted. Compression, clotting, and
edema lead to diminished blood flow and
compromised cardiac return. Additionally,
the trachea and right mainstem bronchus
are less rigid in children as compared to
adults potentially impacting air flow as well.
Superior vena cava syndrome (SVCS)
refers to the signs and symptoms resulting
from the compression or obstruction of the
SVC caused by an anterior mediastinal
mass. These include orthopnea, headache,
facial swelling, dizziness or fainting, sudden
pallor, and exacerbation of symptoms with
the Valsalva maneuver. The physical
examination often reveals a plethoric,
edematous face and neck, jugular venous
distension, papilledema, and pulsus
paradoxus. Blood pressure changes, pallor,
and even cardiac arrest can result from
postural changes. Superior mediastinal
syndrome (SMS) is the combination of
SVCS and tracheal compression that leads to
symptoms of cough, dyspnea, air hunger,
and wheezing. These names are often used
interchangeably. Examination often reveals
decreased breath sounds, wheezing, stridor,
or cyanosis. Affected children are often
incredibly anxious as well.
Malignant tumors are the most common
primary cause of SVCS. The most common
cause is non‐Hodgkin lymphoma (NHL;
174 Chapter 14
usually lymphoblastic lymphoma or diffuse
large B‐cell lymphoma). Other malignant
causes include Hodgkin lymphoma, T‐cell
acute lymphoblastic leukemia (T‐cell ALL),
malignant teratoma or germ cell tumor, thy­
moma, neuroblastoma, rhabdomyosarcoma,
or Ewing sarcoma. A secondary cause can be
thrombosis of the major vessels caused by
the presence of a central venous catheter.
Nonmalignant causes include mediastinal
granulomas (histoplasmosis), aortic aneu­
rysms, vascular thrombosis complicating
cardiovascular surgery for congenital heart
disease, shunting for hydrocephalus, cathe­
terizations, and infections (e.g., tuberculosis
and syphilis).
Clinical findings and evaluation
1. History and physical examination: The
history is nonspecific, with a typically short
period of progressively worsening
symptoms. Patients with ALL may have a
short history of fever, bone pain, bruising,
petechiae, or other signs of marrow
dysfunction. Presenting symptoms and
signs include cough and dyspnea
(commonest), closely followed by dysphagia,
orthopnea, hoarseness, chest pain, facial
edema, wheezing, pleural effusion,
pericardial effusion, features of carbon
dioxide retention like anxiety, confusion,
lethargy, headache, distorted vision, altered
mental status, and syncope, and occasionally
other symptoms like conjunctival suffusion
and cyanosis. The respiratory symptoms are
often much worse in a lying position and the
patient will often assume a position of being
upright for comfort. Engorgement of
collateral veins may be apparent.
2. Laboratory assessment: Screening labs
including a CBC, chemistries, LDH, and
uric acid should be done for diagnostic clues
as well as determination of general well‐
being of the patient.
3. Chest radiography including a lateral
view: This usually shows mediastinal
widening, tracheal deviation or compression,
and possibly pleural effusions.
4. CT scan of the chest: This helps delineate
distortion of normal anatomy, identify
tracheal compression, and allow assessment
of mediastinal mass width. This may be
done in the prone or somewhat sitting
position if the patient is unable to lie supine.
5. Tissue diagnosis with least invasive
procedures, with no sedation, and local
anesthesia only: A biopsy is often essential
for diagnosis, but must only be performed if
safe to do so. General anesthesia may
cause cardiovascular and/or respiratory
compromise by increasing abdominal tone
and decreasing respiratory muscle tone and
lung volume. Sedatives can also decrease
venous return and should be used cautiously.
6. Bone marrow aspiration under local
anesthesia: If the bone marrow is involved,
this test will allow the diagnosis to be made
without a biopsy of the mass itself.
7. Examination of pleural fluid/pericardial
fluid/ascitic fluid: In addition to relieving
distress, removal of fluid and subsequent
cytological examination may allow a
definitive diagnosis to be made, especially in
the case of NHL.
8. Echocardiography: This is necessary to
look for pericardial effusion and cardiac
tamponade and to evaluate myocardial
function.
9. Pulmonary function tests: The patient’s
peak expiratory flow rate and the shape of
the flow volume loop can reliably predict the
patient’s ability to tolerate various diagnostic
and therapeutic procedures.
10. Measurement of β‐HCG (β‐subunit of
human chorionic gonadotropin) and AFP (α‐
fetoprotein). Elevations in these markers are
diagnostic of a malignant germ cell tumor.
Management
1. Children should be under close observa­
tion in the intensive care unit with comfort­
able positioning with elevation of the head,

continuous cardiovascular and respiratory
monitoring, and pulse oximetry.
2. Extreme care to ensure oxygenation, air­
way patency with emergency staff readily
available is critical. Management of pain,
anxiety, and stress with procedures should
consider the possibility of an emergent
decline in status. Anesthesiology and criti­
cal care staff should monitor the child.
Avoid the use of medications that may
cause relaxation of the intercostal muscles
and decrease intravascular resistance.
Diagnostic procedures that cause pain or
require special positioning or sedation may
not be possible.
3. Empiric therapy for suspected malig­
nancy may need to be initiated due to the
life‐threatening situation. Steroids, cyclo­
phosphamide, vincristine, or anthracyclines
have been given in this situation to children
with suspected leukemia or lymphoma.
Prednisone is commonly used, as most of
these children are ultimately diagnosed
with lymphoma or leukemia, especially in
those with typical laboratory abnormalities
or clinical findings (i.e., organomegaly, gen­
eralized adenopathy, evidence of tumor
lysis syndrome [TLS], elevated WBC [white
blood cell] counts). Intravenous methyl­
prednisolone is started at a dose of 50 mg/
m2/day divided twice daily (BID). Hydration
should be given and the child monitored for
TLS, which may be exacerbated by the ini­
tiation of therapy (discussed later). If the
patient does not respond to steroids within
24–48 hours and the patient is less stable,
then additional chemotherapeutic agents
should be started, although other diagnos­
tic conditions must be considered.
4. Children with impending or actual air­
way obstruction may be candidates for
emergent radiation therapy, given in 1–2 Gy
fractions for 1–4 days. A small area of the
tumor should be shielded to prevent
radiation‐induced changes if a biopsy still
needs to be performed to establish the
Oncologic Emergencies 175
diagnosis. Radiation may not provide any
quicker response than steroids or other
chemotherapy and may require moving the
patient outside the critical care setting and
possibly positioning or sedating the patient.
All risks and benefits need to be carefully
considered before entertaining this
intervention. Tracheal swelling and further
airway compromise can occur as a result of
radiation.
5. Patients that have symptomatic venous
thrombosis as the etiology for SVCS should
be treated with unfractionated heparin,
75 U/kg as a loading dose followed by 18 U/
kg/h in children or 28 U/kg/h in infants to a
goal unfractionated anti‐Xa level of 0.3–
0.7 U/ml. Low‐molecular‐weight heparin is
a suitable therapeutic alternative at a dose of
1 mg/kg every 12 hours with a goal
fractionated anti‐Xa level of 0.5–1.0 U/ml.
Spinal cord compression
Acute spinal cord (or cauda equina)
compression occurs in <5% of children with
cancer. Prolonged cord compression leads
to irreversible neurological injury with
paralysis, sensory loss, and loss of bowel and
bladder control. Once a neurological deficit
occurs, it often progresses to paraplegia
within days or even hours. The most
frequent cause of cord compression is
external compression caused by extension
of a paravertebral tumor through an
intervertebral foramen into the epidural
space, most typically a sarcoma. The tumor
compresses the vertebral venous plexus
leading to cord edema, venous hemorrhage,
myelopathy, and ischemia. The most
common tumors leading to spinal cord
compression include neuroblastoma, Ewing
sarcoma, germ cell tumors, NHL, Hodgkin
lymphoma, as well as drop metastases from
central nervous system tumors. Tumor
masses cause compression of the epidural or
subarachnoid space, and metastases cause
compression typically within the cord
176 Chapter 14
parenchyma. Intraspinous chloromas in
patients with acute myelogenous leukemia
(AML) are a less common cause. Spinal cord
astrocytomas and ependymomas can also
cause cord compression, more commonly
from an intramedullary location.
Clinical findings and evaluation
1. Localized back pain or radicular pain
extending down the leg occurs in up to 80%
of children with cord compression. Any
child with known cancer and back pain
should be presumed to have spinal cord
compression and an evaluation is warranted
emergently. The duration of symptoms is
variable but generally short; one series
reported a range of 5 days to 4 weeks.
Characteristically, straight leg raising, neck
flexion, or the Valsalva maneuver aggravates
the pain. Pain is almost always the first
presenting symptom, with weakness and
bowel or bladder dysfunction occurring
later. Sensory loss may occur but is often
difficult to identify, especially in young
children. Any objective neurological deficit
requires further immediate evaluation.
2. Plain radiographs are generally not
helpful in identifying abnormalities in
children, as cord compression typically
occurs via extension of tumor through the
intervertebral foramina without bony
erosion or injury. MRI is the best study for
demonstrating intraspinous extension. While
CT is less sensitive in identifying extension
of disease into the spinal canal, it will
effectively identify paraspinous disease.
3. Examination of the cerebrospinal fluid
(CSF) is rarely helpful, and patients may expe­
rience rapid neurological deterioration fol­
lowing a lumbar puncture (spinal coning).
Management
1. Patients with rapidly progressing spinal
cord dysfunction require immediate inter­
vention following a thorough history and
meticulous neurologic examination.
Dexamethasone 0.1–0.2 mg/kg (loading
dose) should be given IV even before imag­
ing is performed, and an MRI should be
obtained immediately. Dosing should con­
tinue at 0.1 mg/kg every 6–8 hours. Patients
with suspicious findings but without spe­
cific neurologic deficits can be started on a
lower dose of oral dexamethasone (0.025–
0.05 mg/kg every 6 hours) with MRI per­
formed within 24 hours.
2. If imaging reveals a tumor with spinal
cord compression, this must be promptly
relieved. Surgical decompression with a
laminectomy quickly relieves pressure and
allows tumor to be removed for diagnosis. It
should be performed if the diagnosis is
unknown. If the diagnosis is known and the
tumor is radiosensitive, emergent radiation
therapy should be promptly initiated.
Chemotherapy is an alternative for
chemotherapy‐responsive tumors such as
neuroblastoma, Ewing sarcoma, Hodgkin
lymphoma, and NHL; the onset of action in
these tumors is similar to radiation therapy.
The prognosis for recovery of function is
directly related to the degree of disability at
diagnosis. This is associated with the
duration of symptoms and the length of
time required to make the diagnosis.
Patients who are ambulatory at diagnosis
typically remain ambulatory; approximately
50% of children who are nonambulatory at
diagnosis regain the ability to ambulate.
Increased intracranial pressure
and brain herniation
Brain tumors are the most common solid
tumor in childhood, and the majority of
patients present with signs and symptoms of
increased intracranial pressure (ICP).
Fortunately, few of these patients progress to
actual brain herniation. Most pediatric
brain tumors are infratentorial and cause
increased ICP by obstructing the third or
fourth ventricle with resultant obstructive
hydrocephalus. They can also cause

increased ICP simply by mass effect. This
most commonly occurs with astrocytomas,
as well as with primitive neuroectodermal
tumors including medulloblastoma.
The presentation can vary significantly
depending on patient age. Common
symptoms in infants include vomiting,
lethargy, personality changes, loss of
developmental milestones, and increased
head circumference. Older children
commonly complain of headache. This is
frequently intermittent at first, and then
becomes more frequent and severe. It
characteristically occurs in the morning,
and is often but not always accompanied by
vomiting without diarrhea. Other signs and
symptoms include diplopia, ataxia,
hemiparesis, speech disturbance, neck
stiffness, dizziness, lethargy, and coma.
Some tumors may also cause focal neuro­
logical changes. Cerebellar astrocytomas
may lead to ipsilateral weakness, hypotonia,
and ataxia. Herniation of a cerebellar tonsil
often causes head tilt and neck stiffness.
Tumors near the third ventricle (craniophar­
yngiomas, germ cell tumors, optic gliomas,
and hypothalamic and pituitary tumors)
may cause visual loss, increased ICP, and
hydrocephalus. A pineal tumor may lead to
Parinaud’s syndrome (impairment of upward
gaze, convergence nystagmus, and altera­
tions in pupillary response).
Clinical findings and evaluation
1. Assessment of vital signs is critical.
Increased ICP can result in Cushing’s triad:
bradycardia, hypertension, and apnea.
2. A careful physical examination looking
for signs of increased ICP or impending her­
niation must be done quickly. In addition to
the findings mentioned in the preceding text,
impending brain herniation may cause
changes in respiratory pattern, pupil size and
reactivity, extraocular movements, spontane­
ous motor function, and responsiveness to
verbal and physical stimuli.
Oncologic Emergencies 177
Management
If increased ICP or impending brain hernia­
tion is suspected, appropriate management
must be initiated prior to more definitive
testing to hopefully avoid death or perma­
nent neurological injury. The following
steps should be initiated:
1. Fluid intake should be limited to no
more than 75% maintenance. Hypertonic
saline and mannitol are often utilized.
2. A loading dose of dexamethasone
0.1 mg/kg should be given IV followed by
0.05 mg/kg every 6 hours.
3. An emergent CT scan of the head should
be performed. A noncontrast scan will
effectively identify bleeding, most tumors,
cerebral edema, and hydrocephalus.
4. If the diagnosis of increased ICP is
confirmed, the patient should be admitted
to the ICU. Neurosurgical consultation
should be immediately obtained if a tumor
is identified or the patient has hydrocephalus.
5. Acetazolamide 5 mg/kg/dose every 6
hours can be given to decrease CSF
production.
6. Intubation and hyperventilation to
decrease the pCO2 to 20–25 mmHg will
decrease cerebral perfusion. Care must be
taken not to cause cerebral ischemia.
7. Surgical options (external ventricular
drainage, third ventriculostomy) should be
considered.
8. Prophylaxis with antiseizure medication
should also be considered.
9. Intracranial pressure monitoring may be
beneficial.
10. An MRI should be obtained as soon as
possible to look for or confirm the presence
of a tumor.
Massive hepatomegaly
Massive hepatomegaly is the most emergent
complication of stage 4S neuroblastoma in
infants, especially those under 4 weeks of
age. While 4S neuroblastoma often regresses
spontaneously, when it occurs during early
178 Chapter 14
infancy the resulting hepatomegaly can
cause death due to respiratory insufficiency
or hepatic failure. Patients with hepato­
blastoma and transient myeloproliferative
disorder may also present with massive
hepatomegaly, while those with Wilms
tumor may present with a massive abdomi­
nal tumor with similar clinical presentation.
Clinical findings and evaluation
1. The patient should be examined for evi­
dence of gastrointestinal dysfunction, res­
piratory compromise (respiratory rate >60/
min or oxygen requirement), poor venous
return (leg edema), renal dysfunction (poor
urine output and azotemia), hypertensive
urgency or emergency, or disseminated
intravascular coagulation (DIC).
2. Baseline laboratory and imaging studies
should be performed urgently to help
determine underlying etiology to allow for
prompt initiation of appropriate therapy.
Treatment
1. If the patient is stable and does not
exhibit any of the findings mentioned in the
earlier text, careful observation and sup­
portive care should be provided. Positive
pressure can be helpful given the low lung
volumes secondary to the large abdominal
tumor. Coagulation studies may be altered if
there is significant liver involvement.
2. If the patient is unstable, treatment
with chemotherapy or radiation therapy
should be considered dependent on the
underlying diagnosis. Definitive surgical
resection for massive Wilms tumor may
also be required.
Emergencies caused by
inflammation/infection
Fever and neutropenia
Neutropenia is commonly seen in the newly
diagnosed cancer patient (primarily acute
leukemia), as well as during therapy with
chemotherapy and/or radiation. Patients are
immune suppressed and at risk for infection
with bacteria, viruses, fungi, and protozoa.
Fever in a patient with neutropenia is a
medical emergency and standards of
practice should be in place at institutions
caring for these patients to immediately
assess and provide treatment for these
patients. Details of this management are
provided in Chapter 27.
Neutropenic colitis
Patients experiencing severe neutropenia,
particularly those in treatment for leukemia
or stem cell transplant, are at particular risk
to develop colitis. Acute inflammation of the
cecum in particular is termed typhlitis,
though neutropenic colitis is generally the
more accepted term, since colitis can occur
beyond the cecum. Chemotherapy is usually
the initial inciter of mucosal injury,
predisposing the patient to inflammation
and infection. Patients presenting with signs
and symptoms of an acute abdomen with
sudden onset of severe pain (often localized
to the right lower quadrant) suggestive of an
obstruction (functional or physical) should
be assumed to have neutropenic colitis until
proven otherwise. This condition is the
result of mucosal invasion by bacteria or
fungi and can quickly progress to full
thickness mucosal involvement, perforation,
peritonitis, and septic shock. Pathogens
most commonly implicated are Pseudomonas
spp., Escherichia coli, nonspecific Gram‐
negative bacteria, Staphylococcus aureus, α‐
hemolytic streptococcus, Clostridium spp.,
Aspergillus spp., and Candida spp. Acute
appendicitis must also be a consideration.
Clinical Findings and Evaluation
1. Careful history of recent chemotherapy
(or stem cell transplant) and presentation
with right lower quadrant pain, with
physical exam findings revealing absent

bowel sounds, bowel distention (may lead to
abdominal distention), tenderness of
palpation, or a palpable mass, are highly
suspicious of an acute functional bowel
obstruction and neutropenic colitis. Serial
examinations are warranted.
2. Imaging studies may prove diagnostic
and include: plain radiograph of the
abdomen which may reveal pneumatosis
intestinalis, free air in the peritoneum or
bowel wall thickening; abdominal
ultrasound may show thickening of the
cecum or affected large bowel (most
common initial imaging assessment); CT
scan is the definitive imaging technique and
should be done in all patients with the
suspected diagnosis. It may demonstrate
diffuse thickening of the colonic wall and
suspicion of necrotic bowel. Mortality has
decreased significantly in the past decade
due to early recognition and intervention
with bowel rest and antimicrobials.
However, patients may progress to bowel
necrosis, perforation, and sepsis in a short
period of time and require close monitoring
and quick intervention.
3. Laboratory assessment should include
blood cultures (from all central catheter
lumens), CBC, and complete metabolic
panel. Patients should be tested for
Clostridium difficile toxin.
Treatment
1. Supportive medical management is the
mainstay of treatment and includes: nothing
by mouth (NPO) status, a nasogastric tube
(NG) in place to suction (if tolerated);
initiation of broad‐spectrum antibiotics to
ensure coverage for anaerobic and Gram‐
negative organisms; intravenous fluids
(IVF) and electrolyte replacement.
Transfusion support may be indicated as
often patients present with severe
pancytopenia.
2. The patient should be placed on
cardiovascular monitoring with meticulous
Oncologic Emergencies 179
assessment of urine output to guide
hydration. Bolus hydration is often
necessary on admission with continuation
of one to two times maintenance intravenous
hydration. Vasopressors may be needed if
hypotension is present. Sepsis protocols
should be followed for any patient presenting
with clinical evidence of sepsis.
3. Surgical consultation is considered
standard of care upon admission, though
surgical intervention is rarely required with
current supportive care measures. The
patient should be monitored for a clinical
change (i.e., drop in blood pressure,
worsening pain, evidence on imaging of free
air in the peritoneum) suggesting rupture of
the mucosa or suspicion for necrotic bowel,
both indications for acute surgical
intervention. Surgery consists of resection
of infarcted bowel and diversion via
colostomy.
Emergencies caused by
abnormalities of blood
and blood vessels
Hyperleukocytosis
Hyperleukocytosis is defined as a peripheral
WBC count >100 × 109/l. It is most
commonly seen at presentation or relapse of
AML, ALL, or chronic myelogenous
leukemia (CML). Using this definition, the
incidence of hyperleukocytosis at
presentation is 9–13% of children with ALL,
5–22% with AML, and almost all children in
chronic phase of CML. However, clinically
significant hyperleukocytosis occurs when
the WBC counts are >200 × 109/l in patients
with AML or >300 × 109/l in patients with
ALL or CML. The most common
complication of hyperleukocytosis in AML
and CML is stroke, whereas in ALL it is TLS.
Hyperleukocytosis is more common in
infantile ALL and AML, T‐cell ALL, and in
any phase of CML.
180 Chapter 14
Hyperleukocytosis leads to occlusion of
small veins in the brain, lung, and other
organs through the formation of WBC
aggregates (white thrombi). The rheology of
blasts (large, non‐deformable cells,
adherence to each other and the vascular
endothelium, elevated leukocrit) leads to
sludging and resultant tissue ischemia. A
vicious cycle of worsening leukostasis,
thrombosis, and secondary hemorrhage
may ensue. As myeloblasts and monoblasts
are less deformable than lymphoblasts or
granulocytes, leukostasis is far more likely to
occur in AML than in ALL or CML, whereas
patients with ALL are more likely to develop
metabolic derangements from TLS. Other
factors that can increase the risk of
leukostasis include dehydration and an
elevated hemoglobin level.
Poor perfusion and anaerobic
metabolism in the microcirculation lead to
lactic acidosis. Thrombi develop in the
circulation leading to vascular damage and
parenchymal ischemia, and resultant edema
and hemorrhage in the small vessels of the
lungs and central nervous system initially
(and then widespread in larger vasculature).
Clinical evidence of small vessel occlusion is
associated with early morbidity and
mortality.
Clinical findings and evaluation
1. Signs and symptoms of leukemia are
usually present (pallor, fatigue, fever,
bleeding, bone pain, adenopathy,
organomegaly, anemia, thrombocytopenia).
2. Signs and symptoms of leukostasis in the
lungs or brain include tachypnea, hypoxia,
acidosis, dyspnea, cyanosis, blurred vision,
papilledema, stupor/confusion, coma, or
ataxia. Oliguria, anuria, and priapism may
also occur in this setting. Intracranial
hemorrhage may also occur.
3. The laboratory assessment should
include frequent monitoring (i.e., every
4–12 hours) of CBC, renal function panel
(inclusive of phosphorus), and uric acid, to
follow the rate of rise of the WBC or
response to therapy, as well as monitor for
evidence of TLS and renal dysfunction (see
the section “Tumor Lysis Syndrome”).
4. Assess risk for hemorrhage and DIC.
Patients with AML (especially acute
promyelocytic leukemia, APL) and those
with ALL and WBC >400 × 109/l are at
particular risk for coagulopathy and
intracranial hemorrhage and therefore
coagulation studies, platelets and fibrinogen
should be monitored closely and replenished
as necessary.
Treatment
1. Therapeutic intervention should be
immediate.
2. If the child is being transported, the fol­
lowing simple measures are to be initiated
prior to transport. The mainstay of therapy is
aggressive hydration, typically two to three
times maintenance IVF. Alkalinization of
IVF promotes excretion of uric acid by con­
verting it to a more soluble urate salt. A fluid
such as D5W 1/4NS with 40 mEq/l NaHCO3
is quite suitable. Allopurinol or urate oxidase
(rasburicase) should also be started to pre­
vent or decrease the severity of hyperurice­
mia. If urate oxidase is given, alkalinization
is not required (or recommended), as the
uric acid level falls precipitously and uric
acid solubility is no longer an issue.
Alkalinization should also not be given with
underlying hyperphosphatemia due to
increased propensity for calcium phosphate
precipitation. This topic is discussed more
fully in the section on TLS.
3. Therapy for the underlying malignancy
should begin as soon as possible and is the
most important intervention for
hyperleukocytosis. Prompt initiation of
therapy can mitigate the potential risks of
hyperleukocytosis. Diagnosis can be made
using peripheral blood flow cytometry given
the high peripheral WBC count.

4. In situations where prompt initiation of
chemotherapy cannot be initiated or in the
patient with rapidly rising WBC count or
clinical deterioration (pulmonary or CNS
leukostasis), leukapheresis can be
considered, though impact on mortality is
controversial. Leukapheresis should not be
initiated if it will delay start of chemotherapy.
5. Emergency cranial radiation therapy has
not been demonstrated to improve outcome
and is not recommended.
6. Platelet transfusions can be given safely,
as platelets have not been shown to increase
viscosity or worsen leukostasis and may
decrease risk of hemorrhage. Platelets
should be given if the child is bleeding or the
platelet count is <50 × 109/l. Red cell
transfusions should be given with extreme
caution due to the potential to increase total
blood viscosity and worsen leukostasis. The
main indications are cardiovascular
compromise caused by anemia as well as
threshold requirements for anesthesia. The
hemoglobin level should be kept <10 g/dl.
Anemia
Anemia is a common finding in children
presenting with malignancy. Up to 80% of
children presenting with ALL will be anemic
at diagnosis. This can result from bleeding,
inflammation, or marrow infiltration by
tumor. It is rarely an emergency; children
can tolerate a hemoglobin level as low as
2–3 g/dl if it develops slowly from decreased
production. Conversely, levels as low as 5 g/
dl can be life‐threatening if they occur as a
result of sudden hemorrhage.
Treatment
1. Anemia in this situation is treated with
packed red blood cell (PRBC) transfusions.
As a general rule, 10 ml/kg of PRBCs will
increase the hemoglobin level by 2–3 g/dl. In
practice, children with acute anemia due to
blood loss may need 15–20 ml/kg to reach
this level.
Oncologic Emergencies 181
2. Several authors of textbooks on pediatric
oncology recommend that children with
profound anemia (hemoglobin <5 g/dl) that
has developed over an extended period of
time be transfused more slowly (1 vs. 3 ml/
kg over 4 hours) to avoid causing congestive
heart failure. This concern is based on an
extrapolation of the Starling law of cardiac
physiology, but there are few data supporting
this concern. Two published studies as well
as experience in our own institution suggest
that this practice is unnecessary, especially if
these children are being cared for in the ICU
where more careful monitoring is being
performed. If there are signs or symptoms of
congestive heart failure or cardiomegaly on
chest X‐ray, furosemide can mitigate
circulatory overload. More aggressive
transfusion can avoid potentially exposing
patients to additional donor units and
prevent delay in diagnostic procedures.
3. All blood products given to known or
potential oncology patients should be
leukoreduced to decrease the risk of CMV
transmission and irradiated to prevent
transfusion‐associated graft‐versus‐host
disease (TA‐GVHD).
4. Erythropoietin is not used in children at
this time to increase the hemoglobin and
decrease the need for transfusion due to
data from adult studies that suggest adult
patients receiving erythropoietin have
increased risk of thrombosis and subsequent
mortality.
Metabolic emergencies
Tumor lysis syndrome
TLS is a pattern of specific metabolic
abnormalities that occurs as a result of
extremely rapid cellular turnover. It is
almost always encountered in the context of
malignant tumors that either have a rapid
rate of apoptosis or after initiation of therapy
in bulky tumors that are exquisitely sensitive
182 Chapter 14
to the therapy being provided. The rapid
lysis of tumor cells in either situation causes
large amounts of potassium, phosphate, and
nucleic acids to be released into the
circulation, resulting in hyperuricemia,
hyperphosphatemia (often associated with
hypocalcemia), and hyperkalemia. Cell lysis
and release of intracellular contents often
exceed the excretory capacity of the kidneys
further compromising renal function.
Tumor infiltration of the kidney and
decreased intravascular volume can further
impair renal function and accelerate the
development of TLS. When uric acid
concentration in the renal tubule exceeds its
solubility coefficient, urate crystals form in
the tubule causing obstruction. Lactic
acidosis, secondary to poor tissue
oxygenation in patients with high WBC
counts, may contribute to uric acid
deposition. In addition, phosphates are
released when tumor cells lyse. When the
calcium–phosphorus product exceeds 60,
precipitation occurs in the microvasculature,
particularly in an alkaline environment,
further obstructing the renal tubules and
resulting in hypocalcemia. Lymphoblasts
are particularly rich in phosphate,
containing up to four times the amount
found in normal lymphocytes. Potassium is
also released from tumor cells, is secondarily
elevated with poor renal function, and can
lead to fatal arrhythmia. The complete
syndrome includes all these components,
with progressively worsening renal failure.
Insufficiently treated TLS can lead to cardiac
arrhythmia, renal failure, seizure, coma,
DIC, or death.
In children, TLS develops most
frequently in association with malignancies
presenting with a high tumor burden or
rapid rate of malignant cell proliferation
such as Burkitt lymphoma and other NHL
as well as pre‐B‐cell and T‐cell ALL. These
malignancies typically present with a large
tumor burden (i.e., elevated LDH), short
doubling time (38–116 hours in Burkitt
lymphoma), poor urine output (often
secondary to tumor infiltration in the
kidneys), and elevated uric acid. TLS has
also been rarely reported in children with
hepatoblastoma and advanced stage
neuroblastoma.
Clinical findings and evaluation
1. Evaluate for signs and symptoms of met­
abolic abnormalities, specifically hyper­
kalemia and hyperphosphatemia. These
include lethargy, nausea, vomiting, hypo­
tension, muscle spasm, and cardiac
dysrhythmia.
2. Perform a metabolic panel in all children
with suspected malignancy to assess for
TLS. Frequent reassessments should be
performed early in therapy as well,
particularly in patients with high tumor
burdens and those expected to respond
rapidly to treatment. The timing of serial
assessments will depend on the underlying
disease, evidence of preexisting renal
dysfunction, timing of initiation of therapy,
and the risk of TLS. A uric acid level of
≥8 mg/dl, potassium of ≥6 mEq/dl, or
phosphate of ≥2.1 mmol/l is of concern, as
well as a creatinine that is above the normal
range for age (or known for the patient).
3. Carefully monitor vital signs, intake and
output for evidence of renal insufficiency,
and possible symptoms of hypocalcemia
(anorexia, vomiting, cramps, spasms, tetany,
and seizures). A renal ultrasound may be
indicated in suspected renal dysfunction.
Prevention and intervention
1. Aggressive hydration should be provided
at a rate of two to three times (up to four
times) maintenance to promote excretion of
uric acid and phosphorus. Diuretics
(furosemide, mannitol) may also be needed
to promote good urine output (>3 ml/kg/h).
Alkalinization with D5W 1/4NS + 40 mEq/l
NaHCO3 can be utilized to aid with uric acid

excretion, but will worsen calcium
phosphate precipitation so should be not
ordered in the patient with
hyperphosphatemia. The bicarbonate
should be titrated to keep the urine pH
between 7 and 7.5, which will optimize the
excretion of uric acid without leading to
clinically significant metabolic alkalosis.
2. An agent to prevent or reverse
hyperuricemia should also be initiated
immediately. Allopurinol (xanthine analog
that blocks the conversion of xanthine and
hypoxanthine to uric acid by competitively
inhibiting xanthine oxidase) is the most
commonly used agent for this purpose, and
it can be given at presentation and as needed
during the early phase of therapy for the
prevention or treatment of TLS. Allopurinol
does not eliminate existing uric acid and
therefore may not be the optimal choice in
the patient presenting with a markedly
elevated uric acid and high tumor burden.
The urine is typically alkalinized when
allopurinol is used, as it often does not cause
a significant decrease in the uric acid level
until the rate of tumor lysis slows. It is given
at a dose of 300 mg/m2/day divided every 8
hours (800 mg/day maximum). Another
agent, rasburicase (urate oxidase), is a
recombinant enzyme that acts as a catalyst
in the degradation of uric acid into allantoin,
a highly soluble product compared with uric
acid. It works quickly (within 30 minutes of
IV infusion) and keeps the uric acid level
low for 12–24 hours or longer, depending on
the underlying rate of cell turnover.
Rasburicase has been studied in children
with cancer who have hyperuricemia as a
result of tumor lysis and has been found to
be safe and effective. Rasburicase is the
preferred agent in the setting of
hyperuricemia and any degree of renal
insufficiency, concern for rapidly increasing
tumor burden, or massive lysis. Rasburicase
is given at a dose of 0.15–0.2 mg/kg/day in
50 ml preservative‐free normal saline IV
Oncologic Emergencies 183
over 30 minutes (though even lower doses of
0.03–0.05 mg/kg may be sufficient in
consideration for vial size/usage). This dose
can be repeated daily for up to 5 days;
however, a single dose will often keep the
uric acid level low for 48 hours or more, and
may be sufficient to prevent clinical TLS for
the entire course. Patients treated with
rasburicase do not require alkalinization,
which is an advantage when managing other
electrolyte abnormalities. It can potentiate
hemolysis in patients with G6PD deficiency
and has caused methemoglobinemia in
susceptible individuals. Routine screening
for G6PD deficiency is not recommended
before use, but families should be asked
about this possibility. It also has rarely
caused anaphylaxis.
3. Potassium should not be added to IV
fluids until it is clear that the potassium is
stable and not increasing due to TLS or renal
insufficiency.
4. The patient’s intake and output must be
closely monitored to ensure it remains
balanced, taking into account insensible
losses.
5. Careful metabolic monitoring should be
performed with assessment of renal function
(blood urea nitrogen (BUN), creatinine),
electrolytes, calcium, phosphorus, and uric
acid every 4–12 hours depending on rapidity
of change, degree of TLS or renal
dysfunction, and timing of chemotherapy.
6. Hyperkalemia (<6 mEq/l and asympto­
matic) can typically be treated with hydration
and diuretics as described in the earlier text.
Sodium polystyrene sulfonate (kayexalate) at
a dose of 1 g/kg every 6 hours with sorbitol
50–150 ml will remove 1 mEq of potassium
per liter per gram of resin over 24 hours.
Patients with potassium ≥6 mEq/l ± symp­
toms should have cardiac monitoring and
receive directed therapy with rapid infusions
of insulin (0.1 U/kg/h) and glucose (dextrose
0.5 g/kg/h) with close glucose monitoring.
The electrocardiogram (ECG) may show
184 Chapter 14
widened QRS complexes and peaked T waves
in hyperkalemia. Symptomatic hyperkalemia
requires immediate therapy with calcium
gluconate, albuterol, and glucose and insulin,
along with kayexalate to remove excess potas­
sium from the body. In emergent situations,
50% dextrose can be given at a dose of 1 ml/
kg through a central line. Patients who
develop life‐threatening arrhythmias should
receive calcium gluconate (100–200 mg/kg)
or calcium chloride (10 mg/kg) slow IV infu­
sion. Calcium infusions cannot be given in
the same line as NaHCO3. NaHCO3 stabilizes
cardiac cell membranes and is used to reverse
acidosis (1–2 mEq/kg IV). These interven­
tions should be done in the critical care set­
ting. Dialysis should be considered in patients
in which these emergent interventions are
necessary, especially in those patients at high
risk for continuation or worsening of TLS.
7. If hyperphosphatemia is present, treat­
ment is forced saline diuresis with furosem­
ide and dietary phosphate restriction. Oral
phosphate binders are typically not effective,
as they do nothing to remove phosphate from
the circulation. Persistent hyperphos­
phatemia may require dialysis.
8. Hypocalcemia may develop in the face of
hyperphosphatemia. As the calcium‐
phosphate product increases, compensatory
hypocalcemia may develop with resultant
clinical symptoms (e.g., tetany). Treatment
of symptomatic hypocalcemia is with
administration of elemental calcium, such
as 10% calcium gluconate 0.5–1.0 ml/kg (10
mg/kg) until symptoms abate. Dosing
should be judicious to treat symptoms but
not exacerbate calcium phosphate
precipitation. Calcium should not be given
in the same line as NaHCO3.
Hypercalcemia
Malignancy‐associated hypercalcemia (MAH)
is a rare complication of childhood cancer,
occurring in 0.4–1.3% of newly diagnosed
cases. It is seen most frequently in ALL
and alveolar rhabdomyosarcoma, but has
also been reported in children diagnosed
with rhabdoid tumor, hepatoblastoma,
Hodgkin lymphoma, NHL, AML, brain
tumors, and neuroblastoma. The cause of
MAH can be increased bone resorption
from skeletal metastases or production of
calcium‐mobilizing substances such as
parathyroid hormone (PTH)‐related pep­
tide or osteoclast‐activating factor by the
tumor. MAH in turn adversely affects the
ability of the kidney to concentrate the
urine, leading to dehydration, decreased
glomerular filtration rate (GFR), a further
reduction in calcium excretion, and wors­
ening hypercalcemia.
Evaluation
1. Symptoms of mild hypercalcemia (12–
15 mg/dl) include generalized weakness,
poor appetite, nausea, vomiting,
constipation, abdominal or back pain,
polyuria, and drowsiness. More severe
hypercalcemia (>15 mg/dl) results in
profound muscle weakness, severe nausea
and vomiting, coma, and bradydysrhythmias
with broad T waves and prolonged PR
interval on the ECG.
2. Patients exhibiting any of these
symptoms should have a serum Ca2+ level
measured immediately. Measurement of an
ionized Ca2+ should be done if there is any
question about the validity of the total
­calcium measurement or to rule out primary
hyperparathyroidism or pseudohyper­
calcemia due to increased plasma protein
binding capacity.
3. Measurement of the intact PTH level
should be performed to exclude concomitant
hyperparathyroidism. PTH levels are usually
low, normal, or suppressed in MAH. The
serum concentration of calcitriol should be
measured when the hypercalcemia is
suspected to be due to Hodgkin lymphoma
or NHL, as it has been implicated as a key
mediator of hypercalcemia in almost all

cases of Hodgkin lymphoma and 30–40% of
cases of NHL.
Treatment
1. The goals of treatment are to increase
renal clearance of calcium and decrease
bone resorption.
2. Aggressive hydration will help increase
renal excretion of calcium. Forced diuresis
with normal saline at two to three times
maintenance and furosemide 2–3 mg/kg
every 2 hours was previously recommended.
Furosemide blocks calcium reabsorption by
the kidney, and can decrease the calcium
level in 24–48 hours. However, a recent
meta‐analysis suggests the data to support
this approach are limited, and it can also
cause severe loss of sodium, potassium,
and magnesium. At present, the use of furo­
semide is recommended only for patients
experiencing fluid overload following
aggressive saline diuresis.
3. If the patient is hypophosphatemic,
phosphate replacement at a dose of 10 mg/
kg/dose 2–3 times per day may inhibit
osteoclastic activity and promote calcium
deposition into bone.
4. Bisphosphonates have become the
treatment of choice for adults with MAH,
but these have not been widely studied in
children. The most published experience is
with pamidronate at a dose of 0.5–2 mg/kg
given IV over 2–24 hours. This has been
highly successful in correcting MAH within
1–4 days of treatment. When MAH is
associated with ALL, rapid initiation of
induction therapy has been shown to be
very important in reversing the
hypercalcemia.
Case study for review
You are called by the radiologist to review a
chest X‐ray obtained on a 4‐year‐old boy
referred for evaluation of an unusual
Oncologic Emergencies 185
breathing pattern. The X‐ray shows a large
anterior mediastinal mass occupying over
two‐thirds of the chest volume and severely
compressing the trachea, which appears
flattened on the lateral view. The heart size
appears large as well. After reviewing this
film and recognizing the threat for
immediate airway compromise, you locate
the patient in the waiting area with his
mother. He is quiet and appears to be
making significant efforts to breath and is
cautious in his movements. He is
immediately taken into the CT scanner
(performed with the patient in a semi‐
upright position due to discomfort and
desaturations with lying down). The CT
confirms pressure on the entire trachea by
the mass, as well as the lower airways,
confirming the suspicion that an
endotracheal (ET) tube would not secure
the airway. Additionally, a large pleural
effusion is present.
a. What are the immediate next steps?
The patient is in imminent danger of los­
ing his airway due to compression along
the entire airway including below the
bifurcation. Potential emergencies the
patient is at risk for include: airway com­
pression/obstruction, cardiac compro­
mise, TLS, and SVC syndrome. The patient
should be positioned in a comfortable
position, likely upright and often bending
forward. Additional immediate steps
should include: initiation of oxygen by
nasal cannula, cardiovascular and pulse
oximetry moni­toring, IV access, alerting
anesthesia of the patient’s critical airway,
and moving the patient to the critical care
unit. It is important to keep the patient
calm and comfortable and avoid sedation,
which would lead to decreased vascular
tone, decreased cardiac return, and poten­
tial cardiovascular decompensation. Pain
medications should be given with caution
given the potential for smooth muscle
relaxation.
186 Chapter 14
Upon further questioning, the patient has
a history of 1 month of intermittent fevers of
unknown etiology, increasing fatigue, and a
1‐lb weight loss. Over the past 1–2 weeks, he
has complained of headaches and has an odd
cough or grunting sound. He was thought to
have croup or a viral upper respiratory infec­
tion (URI) and received oral antibiotics and
a single dose of prednisone with an albuterol
aerosol treatment, without improvement.
The parent denies bone pain, night sweats,
bruising, or overt bleeding. He has not been
eating much, but is drinking well and urinat­
ing normally.
On exam, his temp is 37.4 °C, HR 142,
RR 30, BP 123/30, SaO2 97% on 10 l/min
non‐rebreather (NRB) facemask. Prior to
the oxygen and pulse oximetry, he was noted
to have perioral cyanosis with movement as
well as with placement of the peripheral
intravenous catheter (PIV). His skin is clear,
with mild pallor and no petechiae or ecchy­
moses. He has no adenopathy, lungs are
clear with diminished breath sounds bilater­
ally, noted systolic murmur, and no gallop or
friction rub. The patient has no hepatosple­
nomegaly or testicular abnormality.
b. What is the most likely diagnosis and
what studies would you obtain?
Most likely the patient has acute lympho­
blastic leukemia or lymphoma. T‐cell dis­
ease is more likely to present in this manner.
Another consideration for a large mediasti­
nal mass is a germ cell tumor. The patient
should have a CBC, comprehensive meta­
bolic panel (CMP), and labs to evaluate for
TLS. Large mediastinal masses may be asso­
ciated with rapid cell turnover and the
patient may have hyperleukocytosis and
metabolic derangements associated with
TLS including hyperkalemia, hyperphos­
phatemia, and hyper­ uricemia. Ideally, a
bone marrow aspirate (as well as lumbar
puncture to evaluate CSF) would be done to
confirm or rule out the diagnosis of ALL
or lymphoma. However, the patient’s airway
is too tenuous to risk anesthesia. Diagnosis
by flow cytometry from peripheral blood
can be done if sufficient blasts are present.
Depending on the lab findings, other
interventions may include transfusion sup­
port and correction of metabolic
derangements.
The patient’s lab findings are as follows:
WBC 25.1 × 109/l, hgb 14.0 g/dl, platelets
480 × 109/l
Na+ 149, K+ 5.2, Cl− 108, CO2 22, Ca++
11.2, Phos 5.6, Cr 0.4, LDH 4998 (nl 425–
975), uric acid 8.7 (nl 2.3–6.1)
Review of the peripheral blood smear shows
a large population of abnormal WBCs with
clumped chromatin, high nuclear:cytoplasmic
ratio, and an increased number of eosinophils
and basophils.
Germ cell tumor markers: βHCG <2
mIU/ml (nl); AFP 1.0 ng/ml (nl).
c. What intervention(s) would you
start? What are the potential
consequences?
IV hydration should be initiated, as the
patient has evidence of rapid cell turnover
with an elevated uric acid and LDH as
well as elevated Na+ and K+. Ideally start at
2× maintenance IVF, though patients may
require bolus fluids if dehydrated or renal
function is compromised. Avoid K+ or phos
in the IVF. This patient must be monitored
for signs of fluid overload given the pleural
effusions and potential vascular congestion
from tumor compression.
Rasburicase is indicated given the bulky
disease, elevated uric acid, and likely contin­
ued rise when therapy is initiated (assuming
this is a lymphoblastic leukemia/lymphoma
that would be highly sensitive to chemother­
apy). This patient’s calcium‐phosphorus
product exceeds 60 (11.2 × 5.6 = 62.72),
putting the patient at risk for renal compro­
mise. This may improve initially with IVF
but it is important to anticipate worsening
TLS and potential interventions to avoid
renal­­compromise. The patient should not

be alkalinized given the use of rasburicase
as well as elevated ­ calcium‐phosphorus
product.
d. The patient is worsening after
24 hours of steroid treatment and maxi­
mal supportive care. What are the next
steps to be considered?
Given the patient is likely immune sup­
pressed and has a history of fever, blood cul­
tures should be drawn and broad‐spectrum
antibiotics initiated. Continuous assess­
ment of cardiac and respiratory status is
vital with an echocardiogram to evaluate
cardiac function. Oxygen delivered in a
comfortable manner via NRB mask or with
positive pressure (given severe airway com­
pression) should be given. He was placed on
BiPAP and did not fight this, suggesting he
was more comfortable with the mask and
pressure.
The electrolytes normalized with IV
hydration and the uric acid dropped to
<0.5 ng/dl with rasburicase. The WBC also
dropped to 10.5 × 109/l with stable hgb and
platelets.
Steroids (methylprednisolone) 1 mg/kg
IV q12 hours is the treatment of choice for
life‐threatening presumed leukemia (given
the chest mass, circulating abnormal cells,
and evidence of TLS) prior to definitive
diagnostic studies. The benefits of shrinking
the mass and relieving airway pressure out­
weigh the need for obtaining a bone marrow
aspirate. Emergent radiation is also a con­
sideration to shrink the mass, though does
not confer an added benefit over steroids.
The patient therefore received steroids
for 24 hours, but unfortunately with worsen­
ing clinical status and no improvement on
CXR. Response to treatment in this short
period of time is not predictable and may
not be a clue to diagnosis. T‐cell leukemia/
lymphoma may not respond this rapidly to
steroids.
Consideration should be given to adding
another chemotherapeutic agent including
Oncologic Emergencies 187
cyclophosphamide, vincristine, and dauno­
mycin. If the diagnosis is uncertain, other
diagnostic considerations must be enter­
tained including germ cell tumor, Ewing
sarcoma, undifferentiated sarcoma, thy­
moma, and thyroid cancer.
The patient continued on steroids and
cyclophosphamide 1000 mg/m2 was initiated.
The patient continued to worsen. Repeat
echocardiogram showed an increasing peri­
cardial effusion and evidence of pulsus para­
doxus due to right outflow obstruction by the
mass. With the continued deterioration, the
patient was put on extra‐corporeal mem­
brane oxygenation (ECMO) for heart–lung
bypass, so that diagnostic procedures could
be performed, and for more time for treat­
ment to work and shrink the mass. The
patient was carefully transitioned to the oper­
ating room (OR) and while in the upright
position and with mild sedation and meticu­
lous care, cannulation of the vessels was per­
formed. The patient then had the pericardial
effusion drained which immediately dropped
his BP (due to the weight of the mass now
fully compressing the heart, which had been
protected by the effusion) and the patient was
immediately placed on ECMO. In quick suc­
cession, flow cytometry of the peripheral
blood resulted with confirmation of T‐cell
ALL and the pericardial fluid also showed
malignant cells of T‐cell origin. Four‐drug
induction with prednisone, daunomycin,
vincristine, and PEG‐asparaginase was
immediately initiated. The patient showed
significant response to treatment by hour 96
and was able to come off ECMO after
48 hours and was completely neurocogni­
tively intact. The diagnostic lumbar puncture
was delayed several weeks, and the patient
was treated for presumed CNS involvement
given the lack of diagnostic studies in lieu of
the patient’s precarious status. IVF hydration
and management/prevention of TLS contin­
ued for 4 more days without significant fur­
ther abnormality.
188 Chapter 14

a. Placing the patient on a CR monitor

Multiple choice questions
and giving calcium gluconate
b. Giving albuterol
1. You are seeing a 12-year-old male patient
c. Giving insulin/glucose
in the emergency department with the
d. Consulting the oncology fellow and
complaint of trouble breathing while lying
the PICU
flat (orthopnea). All of the following are
e. All of the above
appropriate next steps EXCEPT:
Explanation: Tumor lysis syndrome occurs
a. Imaging to include CXR and CT scan
most commonly in non‐Hodgkin lymphoma
of chest, abdomen, pelvis
and ALL, especially in patients with bulky dis­
b. General anesthesia for bone marrow
ease and after the commencement of chemo­
aspirate and lumbar puncture in the am
therapy. Hyperuricemia, hyperphosphatemia
c. Checking baseline labs to include
and hyperkalemia can all occur. Hydration is
CBC/diff, CMP, phos, LDH, uric acid
key to preventing tumor lysis and for the
d. Starting IVF, D5 1/2NS without KCl
patient with hyperkalemia sudden cardiac
at 2x maintenance
arrest can occur, especially as the potassium
e. Starting allopurinol
increases above 6.5–7.0 mEq/l. Therefore the
Explanation: Given the symptomatology
patient should be placed on a CR monitor to
this patient likely has an anterior mediastinal
check for peaked T waves as well as giving
mass, most likely T‐cell lymphoblastic lym­
medications to shift potassium intracellular,
phoma (the other terrible Ts include thymoma,
namely with insulin and albuterol. These are
thyroid, teratoma are much rarer). Cardiac
temporizing mechanisms and such patients
return is compromised with an anterior medi­
may require dialysis so the PICU should be
astinal mass which is best determined by
contacted and the patient transferred.
orthopnea and CT of the chest. General
Kayexalate should also be started although
anesthesia can decrease cardiac return and
does take some time to work. The answer is e.
lead to cardiac arrest in these patients and is
contraindicated. Diagnostic procedures are
3. For the above patient you recheck the
still vital and are done with mild conscious
potassium and it is again now 4.0 mEq as it
sedation. In the emergent situation patients
turns out that the previous sample was
can receive steroids or radiation to treat the
hemolyzed. You do note that the uric acid
likely anterior mediastinal lymphoma. Tumor
has risen from 6 mg/dl to 7.5 mg/dl and the
lysis can occur so it is important to hydrate the
phosphorus has increased from 5 mg/dl
patient without potassium and start allopu­
to 7 mg/dl. The calcium has concomitantly
rinol to prevent formation of additional uric
dropped to 5.7 mg/dl. The patient is com­
acid. The answer is b.
plaining of mild paresthesias in the fingers
but otherwise is stable. Which of the follow­
2. You are following the above patient after ing is the best treatment at this point?
they have been diagnosed with T‐lympho­ a. Start alkalinizing fluids, D5 1/4NS
blastic lymphoma and chemotherapy has with 40 mEq/l NaHCO3
commenced. You are checking tumor lysis b. Increase fluids from 2x maintenance
labs every 6 hours and note that the potas­ to 3x maintenance
sium has increased from 4 mEq/l to now 6.7 c. Give a calcium bolus for the paresthesias
mEq/l. The patient is on 2x maintenance d. Give rasburicase (urate oxidase)
IVF without KCl. Which of the following e. No changes required, continue to moni­
interventions should be considered? tor labs q6 hourly

Explanation: Similar to hyperkalemia, there
are no significant beneficial treatments for
hyperphosphatemia beyond renagel, a phos­
phate binder which decreases GI absorption
of phosphate, increased IVF and dialysis.
Alkalinization increases renal excretion of
uric acid but also leads to increased calcium
phosphate precipitation so should not be
used with hyperphosphatemia. Giving
calcium increases the calcium phosphate
product and also leads to increased calcium
phosphate precipitation in the kidneys.
Urate oxidase is an effective treatment for
hyperuricemia but is generally reserved for
uric acid continuing to rise over 10 mg/dl
and should be given as a dose of 0.05 mg/kg
to a max of 3 mg. Similar to question 2.,
the oncology fellow and PICU should be
consulted as this patient may require dialy­
sis if the phosphorus continues to rise. The
answer is b.
4. You are seeing an expected arrival to the
ED, a 4-year-old female with rhabdomyo­
sarcoma who had a fever at home. She is tri­
aged immediately to a room where she is
noted to be tachycardic and hypotensive.
There is no history of chills with line flush­
ing. All of the following next considerations
are correct EXCEPT:
a. First assure that her airway and
breathing are reassuring
b. Give a 20 ml/kg IV bolus with a
peripheral IV
c. Give a 20 ml/kg bolus through her
central line
d. Start meropenem
e. Start vancomycin
Explanation: This patient is having distribu­
tive shock, most likely from sepsis. First
always ensure that you check the A and B of
ABCs prior to treating the circulatory issues.
Given the hypotension, a fluid bolus should
be given and can be given through the cen­
tral line. If there are problems accessing the
central line, if the hypotension worsens
Oncologic Emergencies 189
upon using the central line, or if there is a
history of chills with flushing the line, a
larger gauge peripheral IV should be placed
for IVF and antibiotics rather than using the
central line. For septic appearing patients,
administer meropenem and vancomycin for
broad coverage for potential GNR and GPC
bacteremia/sepsis, respectively. For the
non‐septic appearing patient, monotherapy
with cefepime is generally sufficient. The
answer is b.
5. You are seeing a 13-year-old male patient
who developed altered mental status and a
seizure at home and is rushed to the ED. In
the ED his mentation is slowed and he has
right sided weakness. A STAT head CT shows
a left sided intracranial hemorrhage. Of note,
his CBC shows a hemoglobin of 8, platelets of
24, fibrinogen of 75 mg/dl with a prolonged
PT and PTT. The WBC count is 2.4 × 109/l
and the lab reports out blasts. Of the follow­
ing, the most likely diagnosis is:
a. Acute lymphoblastic leukemia
b. Immune thrombocytopenic purpura
c. DIC due to sepsis
d. Acute promyelocytic leukemia
e. Chronic myelogenous leukemia
Explanation: Patients with acute leukemia
can have a bleeding diathesis, especially
with thrombocytopenia. Patients with ALL
and severe hyperleukocytosis (generally
WBC >200‐400 × 109/l) may present with
the acute onset of intracranial bleeding.
Patients with acute promyelocytic leukemia
(APL; M3 on the FAB classification for
AML) are at particular risk of coagulopathy.
Although all patients with AML may have
bleeding and coagulopathy, the promyelo­
cytes in APL characteristically have intra­
cellular granules which when release due
to cell lysis lead to coagulopathy. These
patients may often present with severe
bleeding in addition to labs consistent with
DIC. Choice a. is incorrect as patients with
ALL will generally not have significant
190 Chapter 14
bleeding with a low WBC count. Choice b.
is not supported by the total lab findings.
Choice c. could be correct although there is
nothing in the history that supports sepsis
as a cause for DIC. Choice e. will often lead
to hyperleukocytosis but generally the
platelet count will be normal and there will
not be an increased risk of hemorrhage. The
answer is d.
Suggested reading
Henry, M. and Sung, L. (2015). Supportive care in
pediatric oncology: oncologic emergencies
and management of fever and neutropenia.
Pediatr. Clin. North Am. 62: 27–46.
Prusakowski, M.K. and Cannone, D. (2017).
Pediatric oncologic emergencies. Hematol.
Oncol. Clin. North Am. 31: 959–980.
15 Acute Leukemias
Acute leukemia (AL) is the most common
type of malignancy in children, accounting
for approximately 25% of newly diagnosed
cancers in patients less than 15 years of age.
Approximately 2500–3000 new cases are
diagnosed each year in the United States
with a peak incidence between 2 and 5 years
of age. Acute lymphoblastic leukemia (ALL)
accounts for 75% of cases of AL, followed by
acute myelogenous leukemia (AML) in 20%,
and the remainder being undifferentiated or
mixed phenotypic ALs (MPALs). The ALs
are biologically classified by blast morphol­
ogy, surface proteins, cytogenetic abnor­
malities, and cytochemical staining. This
information, in addition to clinical features,
is utilized for risk stratification into treat­
ment groups. Risk‐based therapy optimizes
curative potential while minimizing risks
and side effects.
The etiology of AL is not known, though
most cases are likely associated with somatic
genetic alterations. Ionizing radiation and
exposure to benzene have been associated
with an increased risk of developing leuke­
mia. Exposure to alkylating agents, with or
without radiation, has also been associated
with an increased risk of developing AML.
Certain syndromes with unique chromo­
somal abnormalities are associated with a
high incidence of developing leukemia such
as Down syndrome (DS), Fanconi anemia,
and Bloom syndrome. There is also an
Handbook of Pediatric Hematology and Oncology – Children’s Hospital & Research Center Oakland,
Third Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
increased incidence of developing AL with
certain genetic conditions including: agam­
maglobulinemia, ataxia telangiectasia,
Shwachman–Diamond, Li–Fraumeni, neu­
rofibromatosis, Diamond–Blackfan anemia,
and Kostmann disease/severe congenital
neutropenia. When a child is affected, the
siblings have a risk up to four times the gen­
eral population of developing AL, with this
risk markedly increased in identical twins
(noting though that the baseline risk is
extremely low and therefore the risk in sib­
lings remains extremely low). Though
unclear at this time, inciting events in the
development of leukemia in children and
adolescents involves complex relationships
between host genetic polymorphisms, envi­
ronmental exposures, and infections.
Acute lymphoblastic leukemia
The majority of cases of ALL arise from B‐cell
committed progenitors (pre‐B‐ALL). T‐cell
acute lymphoblastic leukemia (T‐ALL) repre­
sents approximately 15% of ALL cases. T‐ALL
is associated with certain features at diagnosis
including older age, higher white blood cell
(WBC) count, and presence of extramedul­
lary (i.e., outside the bone marrow) disease.
Until recently, outcomes for T‐ALL were sub­
optimal, but with tailored high‐risk therapies,
outcomes between pre‐B‐ALL and T‐ALL are
192 Chapter 15
similar. Most patients (75%) have evidence of
chromosomal changes in the malignant cell
population. The molecular characteristics
have important biologic and prognostic sig­
nificance and have contributed to a sophisti­
cated understanding of the interplay between
these features and treatment stratification.
Hyperdiploidy (an excess of chromosomes;
e.g., >50) is present in approximately one‐
third of children with pre‐B‐ALL.
Hyperdiploidy and specific trisomies (chro­
mosomes 4 and 10) are associated with good
outcomes. The ETV6–RUNX1 fusion gene
(formerly TEL–AML1) translocation t(12;21)
(p13;q22) detected by fluorescent in situ
hybridization (FISH) is present in 25% of
cases and also associated with an excellent
prognosis. Hypodiploidy (i.e., ≤44 chromo­
somes) is present in about 6% of cases with
extremely poor prognosis, especially if with
<40 chromosomes in the malignant clone.
The MLL rearrangement (now KMT2A gene
mutations) at chromosome band 11q23
affects 80% of infants, 3% of ALL cases, and
85% of secondary AML cases, and is associ­
ated with a very poor prognosis despite inten­
sive therapy. The BCR–ABL fusion gene
t(9;22)(q34;q11) (Philadelphia chromosome)
occurs in 3% of childhood ALL in contrast to
adult ALL (25%) and chronic myelogenous
leukemia (CML) (95%). The breakpoint in
pediatric ALL produces a 190‐kDa fusion
protein in contrast to the classic 210‐kDa
fusion protein in CML. This fusion gene has
previously been associated with exceptionally
poor outcomes, but now with the addition of
tyrosine kinase inhibitors (i.e., imatinib), out­
comes are approaching other high‐risk (HR)
ALL patients. The intrachromosomal amplifi­
cation of chromosome 21 (iAMP21) present
in 2% of ALL cases has been associated with
inferior outcomes, but patients treated on
more intensive regimens are seeing improved
outcomes.
Gene expression profiling and next‐
generation sequencing technology have
helped to identify and refine biologically
distinct ALL subsets. This technology helps
determine targeted therapy by identifying
unique genes and pathways. Patients with
“Ph‐like” (Philadelphia‐like) ALL comprise
up to 15% of patients and have a uniquely
devastating prognosis. Recent discoveries
have categorized this group into JAK path­
way and CRLF mutations, with now an
opportunity to study directed therapy with
JAK1/2 inhibitor ruxolitinib. Identification
of other high‐risk genes such as IKZF1 is
further refining risk stratification and
treatment algorithms.
Another area of active discovery is related
to host pharmacogenomics and identifying
gene polymorphisms that encode for drug‐
metabolizing enzymes which influence the
efficacy and toxicity of certain chemothera­
peutic agents. For example, patients that
carry the polymorphism for thiopurine
methyltransferase catalyze the inactivation of
mercaptopurine. Up to 10% of the population
carry these genes, resulting in high levels of
active metabolites with increased side effects
and the need for marked reduction in dosing
of 6‐mercaptopurine (6MP) during treat­
ment. NUDT15 is a recently discovered
genetic polymorphism which also impacts
6MP metabolism.
Clinical presentation
The clinical manifestations of leukemia are a
direct result of marrow invasion with result­
ant cytopenias (i.e., anemia, thrombocytope­
nia, leukopenia, neutropenia) and, rarely,
extramedullary (outside the marrow)
involvement (see Table 15.1). Children typi­
cally present with nonspecific symptoms
related to these cytopenias. Symptoms of
fatigue, irritability, and anorexia as well as
clinical signs of pallor, tachycardia, and more
rarely evidence of congestive heart failure
are a result of the anemia. Low‐grade fever
may be present due to leukemia‐related cyto­
kine release or secondary to infection with

Table 15.1 Common clinical and laboratory features of acute
lymphoblastic leukemia (ALL) at presentation.
Finding
Fever
Pallor
Bleeding
Bone pain
Lymphadenopathy
Splenomegaly
Hepatosplenomegaly
White blood cell count (× 109/l)
<10
10–49
≥50
Hemoglobin (g/dl)
<7.0
7.0–11.0
>11.0
Platelet count (× 109/l)
<20
20–99
≥100
underlying neutropenia and immunosup­
pression. Bleeding secondary to thrombocy­
topenia is usually mild with petechiae,
bruising, gingival oozing, or epistaxis. Life‐
threatening hemorrhage is very rare. Bone
pain (typically long bones) is common and
may result in refusal to walk or irritability in
young children. The pain is usually due to
leukemic infiltration of the periosteum or
expansion of the marrow cavity by leukemic
cells. Pathologic fractures may also be pre­
sent at diagnosis and cause acute severe
pain (see Table 15.2). Patients with T‐ALL
may present with some distinctive clinical
features. T‐ALL is more frequent in males
and associated with a higher incidence of
central nervous system (CNS) leukemia at
diagnosis compared to pre‐B‐ALL (10–15%
vs. 2–5%). T‐ALL patients are more likely to
present with a mediastinal mass (nearly
50%), bulky lymphadenopathy, or a WBC
Acute Leukemias 193
Percentage of patients (%)
60
40
50
25
50
60
70
50
30
20
40
45
15
30
45
25
count >100 × 109/l (30–50%). The presence
of an anterior mediastinal mass may cause
airway or cardiovascular compromise (see
Chapter 14).
Laboratory abnormalities frequently pre­
sent at diagnosis include elevated liver
enzymes, uric acid (UA), and lactate dehydro­
genase (LDH). Evidence of tumor lysis related
to a large tumor burden and rapid cell turno­
ver may result in hyperuricemia, hyper­
kalemia, and hyperphosphatemia (with
resultant hypocalcemia due to maintenance of
the calcium phosphate product). Tumor lysis
syndrome (TLS) may also occur with the ini­
tiation of treatment and should be anticipated
to become clinically significant in those with
elevated WBC (i.e., >100 × 109/l) or bulky dis­
ease (organomegaly, adenopathy, mediastinal
mass) (see Chapter 14).
CNS involvement is usually detected in
an asymptomatic child with analysis of the
194 Chapter 15
Table 15.2 Radiographic changes
of the bones in leukemia.
Osteolytic lesions involving the medullary
cavity or cortex
Subperiosteal new bone formation;
pathologic fracture
Transverse metaphyseal radiolucent bands
Transverse metaphyseal lines of increased
density (growth arrest lines)
cerebrospinal fluid (CSF). Rarely, a patient
may present with signs or symptoms of
increased intracranial pressure (e.g., cranial
nerve VI palsy with resultant esotropia and
diplopia, papilledema, visual changes,
morning headache, vomiting, lethargy, irri­
tability, possible seizures) or evidence of
parenchymal involvement, hypothalamic
syndrome, or diabetes insipidus. Other rare
complications such as chloromas (mass of
malignant cells) causing compression of the
spinal cord or CNS hemorrhage (related to
leukostasis and coagulopathy) are more
likely to be associated with AML.
Leukemic involvement of the testes
occurs in 2–5% of boys at diagnosis and pre­
sents as painless enlargement, either unilat­
erally or bilaterally. Early testicular
involvement is also associated with T‐cell
disease, elevated WBC count, and lympho­
matous features.
Infants with ALL may present with skin
infiltration known as leukemia cutis. Skin
lesions are a result of dermal infiltration by
malignant cells and may appear skin‐colored
or violaceous. They may also be seen in chil­
dren with AML.
Diagnostic evaluation
Children presenting with more than one
cytopenia and clinical symptomatology sug­
gestive of bone marrow infiltration should
undergo a diagnostic evaluation to investi­
gate for the possibility of AL. Other diagno­
ses to be considered are in Table 15.3.
Table 15.3 Differential diagnosis of acute
lymphoblastic leukemia (ALL).
Nonmalignant disorders
Aplastic anemia
Immune thrombocytopenia
Infections: EBV, CMV, pertussis,
parapertussis
Malignant disorders (round blue cell
tumors with marrow involvement)
Lymphoma
Neuroblastoma
Retinoblastoma
Medulloblastoma
Rhabdomyosarcoma
Abbreviations: EBV, Epstein–Barr virus;
CMV, cytomegalovirus.
Laboratory and imaging studies indi­
cated are:
●● Complete blood count (CBC), differen­
tial, review of peripheral blood smear by an
experienced individual.
●● Bone marrow aspirate (consider biopsy
for dry tap or inadequate specimen) for
morphology, blast count, immunopheno­
typing by flow cytometry, karyotype, and
molecular studies.
●● Metabolic panel, to include liver function
studies, electrolytes, LDH, UA, phosphorus,
calcium, blood urea nitrogen, and
creatinine.
●● Blood culture if febrile; cultures of any
suspected sites of infection.
●● Chest radiography to evaluate for the
presence of a mediastinal mass.
●● Plain films of the long bones for patients
presenting with pain to evaluate for patho­
logic fracture or evidence of leukemic
changes.
Typically, the bone marrow is 80–100%
replaced with lymphoblasts at diagnosis, and
there is a paucity of normal cellular differen­
tiation. Megakaryocytes tend to be absent. At
times, due to the packed condition of the mar­
row, it may be difficult to aspirate a sample

(dry tap) and a bone marrow biopsy can pro­
vide diagnostic samples. The diagnosis of AL
requires the presence of 25% or more blasts
(M3 bone marrow); however, the diagnosis is
suspected when the marrow contains 5% or
more blasts (M2 bone marrow, with M1 being
a normal bone marrow with <5% blasts)
(Table 15.3). Lymphoblasts have a typical
morphology with a high nuclear to cytoplas­
mic ratio, fine nuclear chromatin, and the
presence of nucleoli. In addition, the cells
tend to have a uniform size and appearance.
Immunophenotyping and immunohisto­
chemistry are used to differentiate ALL and
AML and identify T‐ALL and pre‐B‐cell
ALL. Lymphoid malignancies should lack
myeloid cell surface markers (i.e., myeloper­
oxidase [MPO], CD13 and CD33; CD [clus­
ter of differentiation]). Pre‐B‐ALL should
have B‐cell surface markers such as CD10,
CD19, kappa, and lambda, whereas T‐cell
ALL should have T‐cell surface markers
including CD2, CD5, and CD7. ALL cells
should also stain for ­terminal deoxynucle­
otidyl transferase (TdT), an immature lym­
phoid marker.
After the diagnosis is confirmed, evalua­
tion of the CSF by lumbar puncture (LP)
should be done to determine CNS involve­
ment. CNS status is defined based on the
WBC chamber count and the presence of
leukemic blasts on a centrifuged specimen.
Many patients require a platelet transfusion
prior to the initial LP, which should be per­
formed by an experienced clinician to
decrease the chance of a traumatic tap, which
may theoretically predispose the patient to
CSF seeding with leukemic blasts. There is
evidence that a platelet count ≥100 × 109/l
for the diagnostic LP may decrease this risk.
Subsequent LPs should be done with platelet
counts of ≥20–50 × 109/l, per institutional
guidelines. A cell count and cytocentrifuge
examination for cell morphology is done
on the fresh CSF (i.e., within 1 hour). The
diagnosis of overt CNS leukemia (CNS3
Acute Leukemias 195
status) requires the presence of five or more
WBCs/μl and identification of blasts on the
CSF cytocentrifuge examination. CNS leu­
kemia is classified as follows:
●● CNS1: no detectable blasts.
●● CNS2a,b,c: <5 WBCs/μL, blasts present
(a: <10 RBC; b: ≥10 RBC; c: ≥ 10 RBC, ≥5
WBC, but negative by Steinherz/Bleyer
algorithm, see below).
●● CNS3a,b,c: ≥5 WBCs/μL and blasts pre­
sent (a: <10 RBC; b: ≥10 RBC, positive by
Steinherz/Bleyer algorithm, see below; c:
signs of CNS leukemia [i.e., facial nerve
palsy, hypothalamic syndrome, brain/eye
involvement].
A traumatic LP is defined as the presence of
≥10 red blood cells/μl. Formulas are avail­
able to assist with interpretation of CNS
status in the event of a traumatic initial tap
with blasts on cytospin (Steinherz/Bleyer
algorithm in which CNS disease is present
[positive] if CSF WBC/CSF RBC >2× blood
WBC/blood RBC).
Other assessments prior
to initiation of therapy
Echocardiogram and electrocardiogram are
done as baseline studies in all patients who
will receive anthracyclines. These drugs are
frequently given in induction for high‐risk
patients and in the delayed intensification
(DI) phase for all patients. Acute and delayed
cardiotoxicity may occur, though late com­
plications are more often related to high
cumulative doses (i.e., >300 mg/m2) given at
a young age (<4 years) and asso­ciated with
other risk factors for cardiac disease such as
mediastinal radiation, obesity, family history
of early cardiovascular disease, and abnormal
lipid profiles.
Viral serologies for hepatitis B and C,
cytomegalovirus (CMV), herpes simplex
virus (HSV), and varicella zoster virus
(VZV) are obtained as baseline information
(see Chapter 25). This aids in determining if
196 Chapter 15
later infection with one of these viral agents
could be related to transfusion (potentially
in the case of hepatitis B and C), and whether
the infection is primary or reactivation (in
the case of CMV, HSV, and VZV). Baseline
knowledge of previous exposure may impact
later treatment choices. Other screening
includes immunoglobulin G in patients with
increased risk of infection such as infants
and those with DS.
Risk group classification
The concept of risk stratification allows
patients at comparatively higher risk of
relapse to be treated with more intensive,
molecularly guided, and potentially more
toxic therapies, whereas patients at lower risk
of relapse are treated with lower intensity
regimens that maintain the same low risk of
recurrence while minimizing exposure to
unnecessary agents, decreasing toxicity.
Classification into risk groups previously
was based on clinically apparent prognostic
factors identified by retrospective analysis
and then verified by prospective studies.
Age, WBC, and immunophenotype (i.e.,
AML vs. ALL, T‐ALL vs. B‐cell ALL) are uti­
lized for initial classification while awaiting
cytogenetic results from the leukemia clone
to determine high‐ and low‐risk features and
subsequently treatment response.
The National Cancer Institute (NCI) crite­
ria classify standard risk (SR) ALL as children
1 to <10 years of age with a WBC <50 × 109/l
and HR ALL as children with age ≥10 years
and/or WBC ≥50 × 109/l. Utilizing these crite­
ria, approximately two‐thirds of B‐ALL and
one‐third of T‐ALL patients are classified as
SR. Children under 1 year of age are catego­
rized as infant ALL, with a worse prognosis.
Overall, better outcomes are observed in
younger children (over the age of 1), females,
pre‐B‐ALL, and those with more favorable
cytogenetic features.
Further stratification into treatment
groups is done within the first few weeks of
therapy based on flow cytometric response
to therapy (as measured by day 8 periph­
eral blood and day 29 [end of induction]
bone marrow aspirate) and cytogenetic/
molecular features identified from the diag­
nostic marrow. Patients with negative bone
marrow minimal residual disease (MRD)
measured by multiparameter flow cytometry
at end of induction have an excellent prog­
nosis. Other considerations include presence
of extramedullary disease such as testicular
or CNS disease.
Treatment
Treatment of childhood leukemia is one of
the success stories in pediatric oncology,
though much remains to be accomplished.
Patients with SR ALL have a 4‐year event‐
free survival (EFS) of over 90%. High‐risk
patients have an EFS of 75%, though certain
subgroups including infants and those with
very‐high‐risk molecular features may be
at 50% or less. Remarkable advances have
occurred by the identification of more effec­
tive drug combinations, recognition of drug
sanctuary sites with routine presympto­
matic CNS‐directed therapy, response‐based
intensification of therapy in early phases,
and identification of clinical and biological
variables predictive of outcome. Certain fea­
tures, such as CNS2 involvement, continue
to be analyzed and treatment refined to
ensure the best possible outcomes. Most
children with cancer in the United States are
treated at specialized pediatric oncology
centers and have access to participation in
clinical trials. These studies have accelerated
the advances made in the diagnosis and
treatment of pediatric cancers and clearly are
a major reason for many of the successes.
Pediatric oncology centers provide expertise
in the management of pediatric oncology
patients with consi­deration of the unique
aspects of protocol management and sup­
portive care that are critical to optimizing
survival and quality of life. The Children’s

Oncology Group (COG) is a national col­
laborative group of multidisciplinary profes­
sionals involved in the treatment of children
with cancer. Most pediatric cancer centers
(over 200 nationally) register patients on
COG trials. Families are asked to give
informed consent to participate in these
trials, which may include epidemiological,
clinical, and biological questions. For fami­
lies not wishing to participate, the standard
of care is offered (best published clinical
regimen). Many centers also participate in
other smaller multicenter collaborative
studies or have sufficient numbers of patients
to support their own clinical protocols.
The purpose of therapy in ALL is to induce
a permanent biologic and clinical remission
(no evidence of disease on laboratory and
physical assessment). Overall, approx­imately
85% of children with ALL will be cured of
their disease. Treatment regimens are classi­
cally divided into phases of therapy:
●● Induction: refers to the first 28–35 days of
therapy, after which the child should be in a
morphologic remission. Remission induc­
tion rate in SR ALL is 98%.
●● Consolidation: further systemic chemo­
therapy is given, in addition to a focus on
CNS prophylaxis.
●● Interim Maintenance (IM): similar drugs
as maintenance, but in a more intensified
manner.
●● Delayed Intensification (DI): refers to
re‐induction and reconsolidation with many
of the same medications as these phases.
●● Maintenance: continuation of therapy; this
phase lasts 2-3 years, timed from start of IM
(possibly longer in males due to increased
risk for relapse, per institutional guidelines).
●● CNS‐directed therapy: intrathecal cytara­
bine (Ara-C), methotrexate; cranial radiation
(treatment or prophylaxis) in select groups
(i.e., CNS3, certain T‐ALL subgroups).
Open clinical trials will likely alter some
aspect of therapy for certain risk groups in
Acute Leukemias 197
an attempt to improve outcomes and dimin­
ish acute and late toxicity. Some examples
may include adding a new agent in certain
phases, altering chemotherapy dosing or
timing in specific phases, or possibly asking
a radiation‐related question. The addition of
new agents such as molecularly targeted and
immunotherapeutics is becoming more fre­
quent and can be expected to continue to be
integrated into phase 3 trials.
Conventional induction therapy includes
prednisone or dexamethasone, PEG‐aspara­
ginase, and vincristine in addition to intrath­
ecal cytarabine and methotrexate. Patients
with HR ALL also receive daunorubicin for a
four‐drug systemic induction. Consolidation
for HR patients incorporates cyclophospha­
mide, cytarabine, PEG‐asparaginase, 6‐mer­
captopurine (6‐MP), and intensified therapy
directed toward the CNS (either intrathecal
methotrexate alone or with radiation for
patients with CNS3 disease and certain
T‐ALL subgroups). SR patients receive
intensified CNS therapy with intrathecal
chemotherapy. The DI phase has led to sig­
nificantly improved outcomes as has further
intensification of the IM phase. DI is a re‐
intensification of therapy following attain­
ment of remission with some alteration in
drugs utilized previously in the induction
and consolidation phases. Maintenance
classically consists of pulses of steroid (pred­
nisone or dexamethasone) and vincristine in
addition to oral methotrexate and 6‐MP.
Individualized drug dosing is required to
maintain certain hematologic levels with
differences in metabolism and tolerability
related to individual polymorphisms (e.g.,
thiopurine methyltransferase (TMPT) with
6‐MP metabolism).
CNS prophylaxis continues with intra­
thecal methotrexate throughout therapy.
Children with CNS3 disease receive augmented
therapy with 1800 cGy cranial radiation, in
addition to intrathecal methotrexate. Sub­
groups of patients with T‐ALL may require
198 Chapter 15
cranial radiation prophylaxis to 1200 cGy,
though this continues to be studied within
newer protocols. Treatment of children with
CNS2 disease has been a focus of recent
review and these patients now receive addi­
tional intrathecal therapy. CNS‐directed
therapy includes intrathecal drug delivery as
well as systemic medications that penetrate
the blood–brain barrier in cytotoxic concen­
trations. Substituting dexamethasone for
prednisone in some phases of treatment as
well as using high‐dose methotrexate in lieu
of lower doses has led to decreased CNS
relapses. Patients that are CNS1 (no overt
CNS disease) also benefit from CNS‐directed
treatment. Without CNS prophylaxis, it is
estimated that 60–70% of children would
relapse in the CNS (based on historical data).
Complications of therapy
Due to the myelosuppressive nature of
therapy, and the underlying disease state,
children undergoing chemotherapy or
radiation should expect to experience com­
plications during the course of their treat­
ment. Many of these complications can be
anticipated and prevented or ameliorated
(see Chapter 25). Most patients will require
transfusion support with packed red blood
cells and/or platelets (see Chapter 5).
Children with neutropenia are instructed to
take special precautions to decrease the risk
of infection exposure. Any child receiving
chemotherapy who develops a fever should
have emergent medical attention, especially
during phases of anticipated neutropenia
(i.e., induction, consolidation, DI; see
Chapter 27). Certain therapies are associated
with specific toxicities: anthracyclines with
cardiotoxicity, vincristine with peripheral
neurotoxicity, intrathecal methotrexate with
neurotoxicity, steroids (especially dexameth­
asone) with avascular necrosis of bone, and
radiation with acute and late effects depend­
ing on site and dosage (see Chapter 30).
These anticipated side effects should also be
discussed in detail with the patient and fam­
ily in the consent process and as part of
ongoing care, to help with earlier recognition
and supportive care initiation as needed.
Potential late toxicities are monitored
throughout the course of treatment and in
off‐therapy follow‐up.
Relapse
Despite the dramatic improvements in our
knowledge of the biology of ALL, prognostic
factors, and more targeted therapy, up to 20%
of children with ALL will relapse, with only
about one‐third of those patients going on to
have a long‐term remission with intensified
therapy. Due to the frequency of ALL as com­
pared to other pediatric malignancies,
relapsed ALL is the fourth most common
oncologic diagnosis in children. Timing and
site of relapse are prognostic and important
determinants for future therapy. Sites of
relapse include the bone marrow or an
extramedullary site, such as the CNS or testes,
or some combination of sites. Early relapse
(<18 months since therapy initiation) is asso­
ciated with a particularly grim prognosis.
MRD status at the end of the first block of re‐
induction therapy also strongly correlates
with outcome, with improved survival in
those who are negative. Novel agents such as
blinatumomab (anti‐CD19 antibody conju­
gated to CD3) and inotuzumab (anti‐CD22
monoclonal antibody) are examples of tar­
geted therapies being studied in this setting.
Concepts of therapy include systemic retreat­
ment and radiation therapy to sites of
extramedullary relapse, though emerging tar­
geted therapies and immunotherapies may
become more important in this group of
patients. Hematopoietic stem cell transplant
(HSCT) may improve the outcome of patients
with bone marrow or combined relapse.
Overall survival after relapse is also impacted
by cumulative toxicity from prior therapy and

high infection rates due to the increased
intensity of therapy. In general, children with
late bone marrow (i.e., >36 months from ther­
apy initiation) or isolated relapse (>18 months
from therapy initiation) fare better.
Novel agents
Various novel agents are under investigation
to improve outcomes for high‐risk and
relapsed patients. Previous such targeted
agents included the tyrosine kinase inhi­
bitors (imatinib, dasatinib and others) for
Philadelphia‐chromosome‐positive ALL
and now JAK1/2 inhibition in “Ph‐like” ALL
(i.e., CRLF2‐rearranged and JAK pathway‐
mutant). Finding agents with favorable tox­
icity profiles for use in highly treated relapse
patients is a challenge. Targeted antibodies
such as blinatumomab and inotuzumab are
attractive due to their efficacy and decreased
off‐target effects. Immunologic therapies
are of great interest at this time and offer tre­
mendous hope. Rituximab, an anti‐CD20
monoclonal antibody utilized in many con­
ditions such as non‐Hodgkin lymphoma,
is being investigated in mature B‐cell ALL
(a notoriously poor prognostic group).
Blinatumomab, a bispecific T‐cell engager
anti‐CD19 antibody, which acts by directing
the patient’s cytotoxic CD3‐postive T‐cells
to CD19‐positive leukemic cells and thereby
activating T‐cells to destroy the malignant
cells, has shown benefit for relapsed and
refractory pre‐B‐ALL. Engineering autolo­
gous T‐cells to express chimeric antigen
receptors targeting leukemia cells (CAR‐T
cells) has been an extremely exciting, poten­
tially curative therapy in refractory or multi­
ply relapsed CD19‐positive pre‐B‐ALL with
recent FDA approval of a Novartis product
called tisagenlecleucel. Harnessing other
cell populations which are important for
tumor cell surveillance and destruction
such as natural killer cells, macrophages,
and dendritic cells are likely to become
Acute Leukemias 199
increasingly important and effective therapies
in the treatment of conditions such as ALL.
Acute myelogenous leukemia
Approximately 20% of acute childhood
leukemia is myelogenous, equating to about
500 new cases per year in the United States.
Unlike ALL, AML does not have a peak age
incidence in children, as there are only subtle
increases in incidence from infancy to ado­
lescence. AML is associated with a poorer
prognosis than ALL, with long‐term survival
expected to be 50–60%. Additionally, therapy
for AML, which includes multiagent chemo­
therapy and HSCT, is one of the most toxic
therapies in childhood cancer. Hispanic
children are noted to have a higher incidence
of AML, mostly accounted for by the acute
promyelocytic leukemia (APL) subtype.
The etiology of AML is mostly sporadic,
although several inherited and acquired risk
factors may significantly predispose to this
disease. Children with DS have a 10–20‐fold
increased risk of developing AL compared
to other children. In early life, children
with DS have a particularly high risk of the
megakaryoblastic subtype of AML (AMKL).
Overall, children with DS constitute approx­
imately 10% of children with AML. In addi­
tion, approximately 10% of neonates with
DS may develop a transient myeloprolifera­
tive disorder (TMD) that mimics congenital
AML but typically improves spontaneously
by 4–6 weeks of age. However, these chil­
dren have a 20–30% risk of developing AML
before 4 years of age. Children with TMD or
presumed congenital AML who do not
display phenotypic features of DS should
have a karyotype performed to look for
possible trisomy 21 mosaicism.
Patients with inherited bone marrow
failure syndromes such as Fanconi anemia,
severe congenital neutropenia or Kostmann
200 Chapter 15

syndrome, and Shwachman–Diamond marrow and other body organs. Depending on

syndrome have very high rates of deve­
­ the total WBC and percentage of circulating
loping AML (30–50% risk). Other genetic
­conditions that predispose to development of
AML (and some other malignancies) include:
Bloom syndrome, dyskeratosis congenita,
congenital amegakaryocytic thrombocyto­
penia, Li–Fraumeni syndrome, neurofibro­
matosis‐1, and Diamond–Blackfan anemia.
Acquired conditions with an increased risk
of AML include aplastic anemia, acquired
paroxysmal nocturnal hemoglobinuria,
myeloproliferative syndrome, and myelod­
ysplastic syndrome. Twins and siblings of
AML patients have an increased risk of
AML, though this is much more significant
in monozygotic twins within 6 years of initial
diagnosis. The incidence of secondary AML
following treatment of childhood cancer is
rising, due in part to increased survival after
primary malignancy as well as increased
use of agents that cause direct DNA damage
(e.g., alkalytors [cyclophosphamide, ifosfa­
mide], anthracyclines [doxorubicin, dauno­
rubicin], radiation therapy), and those that
inhibit topoisomerase II (e.g., epidophyllo­
toxins [etoposide] and anthracyclines).
Exposure to ionizing radiation has also been
convincingly implicated, especially following
the atomic bombs in World War II.
Clinical presentation
AML and ALL are indistinguishable at pres­
entation, with the majority of signs and
symptoms being related to infiltration of the
myeloblasts, some of the presenting mani­
festations may be life‐threatening. Chil­dren
with extreme leukocytosis (i.e., WBC >200
× 109/l) may present with metabolic abnor­
malities and leukostasis (see Chapter 14) and
be at risk for sudden events. Clinically, they
are at risk for hypoxia in the small vessels of
the brain and lungs as a result of increased
blood viscosity related to the rheology of the
myeloblasts (large, adherent, and nondeform­
able cells) and decreased flow through small
vessels. This may translate to sludging in the
small vasculature of the retinal, pulmonary,
and CNSs with resultant decreased oxygen
delivery, hypoxia, and stroke (Table 15.4).
Patients typically present with signs and
symptoms related to pancytopenia with pal­
lor, fatigue, anorexia, and bleeding. Fever is
very common at presentation, often with no
apparent infectious etiology. Bone pain is
also common, though not typically associ­
ated with fractures. Some unique and sug­
gestive features of AML at presentation
include leukemia cutis in infants (blueberry
muffin rash thought secondary to extramed­
ullary hematopoiesis) and myeloid sarcomas
(also known as chloromas) which are
extramedullary collections of myeloblasts.
Extramedullary disease occurs in 10–20% of
patients with AML, much higher than seen
in ALL. Myeloid sarcomas may occur in up
to 10% of children with AML and present
most commonly in the orbit, periorbital

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 (increasing risk for tumor lysis syndrome)

Abbreviation: CNS, central nervous system.


areas, bones, skin, soft tissues, and lymph
nodes, but may occur anywhere in the body.
Gingival hypertrophy is a unique finding in
AML secondary to gum infiltration by
malignant cells. A particularly rare yet
important presentation is spinal cord com­
pression due to myeloid sarcoma in the par­
aspinal/epidural region. AML may present
with only evidence of extramedullary dis­
ease, but is treated in the same manner as
with marrow involvement.
Life‐threatening bleeding is another
complication somewhat unique to AML.
Although the majority of patients will be
thrombocytopenic secondary to marrow
infiltration with myeloblasts, patients with
concomitant coagulopathy due to dissemi­
nated intravascular coagulation are at par­
ticularly high risk of bleeding, a finding seen
most commonly in APL. This association is
thought to be secondary to the release of
thromboplastin from cytoplasmic granules
in the promyelocytic blasts.
TLS is unlikely in AML. See Chapter 14 for
management of hyperleukocytosis and TLS.
Diagnostic evaluation
The same studies suggested for the evalua­
tion of ALL should be obtained in the evalu­
ation of the child with suspected AML. It is
common to see severe anemia and thrombo­
cytopenia in association with an elevated
total WBC count. The definitive diagnosis is
made with the evaluation of the bone mar­
row, with at least 20% of the cellular elements
identified as myeloblasts based on immu­
nophenotyping and cytochemistry and con­
firmed by flow cytometric assessment.
Morphologic review may also reveal Auer
rods (clumps of azurophilic granules shaped
into elongated needles and located in the
cytoplasm), classically only seen in some
subtypes of AML (i.e., M2 and M3). A LP
should be done to evaluate for CNS involve­
ment. A coagulation evaluation should be
performed consisting of PT, INR, PTT,
Acute Leukemias 201
fibrinogen, and D‐dimers to evaluate for the
possibility of disseminated intravascular
coagulation (most typically seen in M3).
Decreased factors VII, IX, and X may be seen
related to consumption. Other necessary
assessments are similar to ALL, as previously
outlined.
Risk group classification
As with ALL, classification of AML is based on
morphologic features, as well as immunohis­
tochemical, biologic, and molecular character­
istics. Several morphologic classification
systems are available for AML, including the
classic French–American–British (FAB) clas­
sification of M0 to M7 (Table 15.5) and the
World Health Organization (WHO) catego­
rization (now the preferred classification
method). The WHO classification system was
developed to include cytogenetic, disease biol­
ogy, and clinical history. Categories include: (i)
AML with recurrent genetic abnormalities; (ii)
AML with myelodysplasia‐related changes;
(iii) therapy‐related myeloid neoplasms; (iv)
AML not otherwise specified; (v) myeloid sar­
coma; (vi) myeloid proliferations related to DS
(transient abnormal myelopoiesis and myeloid
leukemia associated with DS); and (vii) blastic
plasmacytoid dendritic cell neoplasm.
Chromosome analysis is performed to
obtain important diagnostic and prognostic
information. Approximately 60% of children
with primary AML demonstrate clonal abnor­
malities in the blast lineage prior to therapy
initiation. The t(8;21)(q22;q22) RUNX1–
RUNX1T1 translocation is the most common
chromosomal translocation and is associated
with the FAB M2 subgroup and a more favora­
ble prognosis. The t(15;17)(q22;q12) produces
a balanced translocation of the retinoic acid
receptor‐alpha (RARα gene at 17q12) and the
PML gene at 15q22 leading to APL (FAB M3).
Defect in RARα induces an arrest in myeloid
differentiation at the promyelocytic (PML)
stage. All‐trans retinoic acid (ATRA) over­
comes this blockage at the RAR site, allowing it
202 Chapter 15

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

AML Subtype Clinical/biologic features

M0 Acute undifferentiated Similar to ALL, requires CD13, CD33, CD117, and

leukemia absence of lymphoid markers
M1 Acute myeloblastic MPO+ by special stains/flow cytometry
leukemia without
differentiation
M2 Acute myeloblastic Auer rods, t(8;21)(q22;q22), AML1–ETO fusion gene
leukemia with common, chloromas, good prognosis
differentiation
M3 Acute promyelocytic Auer rods, DIC/bleeding, t(15;17), good prognosis
leukemia with ATRA/arsenic therapy
M4 Acute myelomonoblastic Mixed myeloblasts (20%) and monoblasts, peripheral
leukemia monocytosis, inv(16), t(16;16) producing chimeric
protein CBFB–MYH11, favorable prognosis
M5 Acute monocytic ≥80% marrow nonerythroid cells are monocytic, KMT2A
leukemia (11q23) rearrangements in infants, CNS disease more
common, chloromas (e.g., gingival hyperplasia)
M6 Erythroleukemia (Di Rare in children
Guglielmo disease)
M7 Acute megakaryoblastic Classically seen in Down syndrome with GATA1
leukemia mutation, good prognosis; rare in non‐DS with
t(1;22), poor prognosis; associated with myelofibrosis

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

intravascular coagulation; ATRA, all‐trans retinoic acid; CNS, central nervous system; DS, Down
syndrome.

to function normally while arsenic clears the
PML molecule. Inversion of chromosome 16,
inv(16)(p13.1;q22) or t(16;16)(p13.1;q22),
CBFB–MYH11, is associated with acute
myelomonoblastic leukemia (FAB M4) and
also portends a favorable prognosis.
Megakaryoblastic AML (FAB M7) is associ­
ated with t(1;22)(p13;q13), RBM15–MKL1.
FMS‐like tyrosine kinase mutations internal
tandem duplications (FLT3‐ITD) or point
mutations are identified in up to 30% of chil­
dren with AML. ITDs result in constitutive
activation of the kinase and uncontrolled
proliferation of malignant blasts. FLT3‐ITD is
associated with a high WBC at diagnosis
and poorer prognosis. Chromosomal aber­
rations including monosomy 7 or 7q deletion,
monosomy 5 or 5q deletion, and complex
abnormalities (≥3 or more unrelated
changes) all impart a worse prognosis.
Monosomy 5 and 7 are also highly associated
with cases of secondary myeloproliferative
disorders and AML that develop following
treatment with chemotherapy for a primary
malignancy. Gene expression profiling by
microarray technology has identified distinct
expression profiles of AML based on many
genetic mutations, and will likely become
more important in the future to connect
molecular signatures with targeted therapies
and clinical outcomes.
Host factors such as age, sex, race, and
constitutional abnormalities all have prog­
nostic influence. Females do slightly better

than males, older children do better than
infants (though outcomes in infants are
improving with current therapies), and
Caucasians fare better than non‐white
patients. Children with DS, particularly those
under the age of 4 years at diagnosis (driven
primarily by GATA1 mutation), have an
improved outcome with less intensive ther­
apy (overall survival 80%) but also show
increased toxicity with therapy. Children
with an initial WBC <20 × 109/l have an
improved outcome and those with hyperleu­
kocytosis (i.e., WBC >100 × 109/l) have a
worse outcome. Risk features have been sim­
plified to include cytogenetics and MRD
response at the end of induction.
Treatment
As with ALL, the goal of induction therapy in
AML is to induce a clinical and biological
remission by rapidly reducing the number of
malignant cells. Approximately 80% of chil­
dren achieve remission with induction ther­
apy, and approximately 60–70% achieve a
long‐term remission. Two distinct subsets of
AML do particularly well: APL (survival
>95%) and children with DS (survival >80%).
Treatment failure is due to relapse or treat­
ment‐related mortality. Improvements in
survival rates are due to more intensified
treatment regimens based on risk stratifica­
tion, early identification of complications and
aggressive supportive care, and better treat­
ment options for relapsed/refractory disease.
The most effective induction regimens
use a combination of cytarabine and an
anthracycline, typically daunorubicin.
Individual trials have built upon this back­
bone with changes in dosing and timing,
alternative anthracyclines, and inclusion
of aggressive supportive care strategies to
better manage potential adverse effects at
presentation or with therapy including
coagulopathy, side effects of hyperleukocy­
tosis and infection. Other important agents
utilized in continuation therapy include
Acute Leukemias 203
etoposide, 6‐thioguanine, and L‐asparagi­
nase. Gemtuzumab, a monoclonal antibody
to CD33, continues to be studied but appears
beneficial in inducing remission, especially
in those patients with increased CD33
expression. Patients with FLT3‐ITD should
be treated with a tyrosine kinase inhibitor
such as sorafenib, with more specific agents
such as quazartinib and gilteritinib being
studied for improved efficacy. Prior studies
have shown no added benefit for a main­
tenance phase following intensification.
Allogeneic HSCT is recommended for
high‐risk groups and those without induc­
tion remission. Patients with favorable risk
cytogenetics and good early responses to
induction therapy receive allogeneic HSCT
only in the case of relapse and if a second
remission has been achieved.
The morphologic subtypes of AML with
highest involvement of the CNS are FAB M4
and M5. Overall, the frequency of CNS
involvement is between 15 and 20% at diag­
nosis. Unlike ALL, CNS disease in AML
does not affect survival, so is not included in
risk stratification. Intrathecal chemotherapy
is given to all patients, regardless of detection
of blasts in the CSF. All patients receive CNS
consolidative therapy with intrathecal cyta­
rabine in addition to systemically adminis­
tered high‐dose cytarabine, which has good
blood–brain barrier penetration. AML
patients with myeloblasts in the CNS receive
intrathecal cytarabine on a biweekly basis in
induction until the CSF is clear. Cranial irra­
diation is reserved for those children with
refractory CNS involvement. Children with
DS rarely have CNS involvement, and due to
their increased risk of toxicity, CNS prophy­
laxis has been greatly reduced without nega­
tive consequence in these patients.
APL is distinctly unique from the other
AML subtypes, comprises approximately
5–10% of pediatric AML cases, and has a
particularly good prognosis due to the devel­
opment of targeted therapies. Approximately
204 Chapter 15
3% of patients with APL die in the early
phases of therapy as a result of the unique
hemorrhagic complications of this disease.
Patients receive treatment with a combina­
tion of ATRA and arsenic trioxide (ATO).
ATRA induces the differentiation of imma­
ture promyelocytes into mature granulocytes,
followed by restoration of normal hemat­
opoiesis. ATRA does not cross the blood–
brain barrier and is therefore ineffective in
treating CNS involvement with APL. A WBC
≥10 × 109/l is associated with a higher risk of
relapse, and those with a WBC <10 × 109/l are
considered SR. Higher WBC count is also
associated with the microgranular variant
(M3v), presence of the FLT3‐ITD muta­
tion, and the bcr3 isoform. Treatment with
ATRA should be started immediately when
APL is suspected to quickly drive the malig­
nant blasts into terminal differentiation and
prevent further proliferation. Treatment with
ATRA and anthracyclines has now led to
clinical remission rates of over 90% and EFS
of 70–80%. ATO works synergistically with
ATRA and binds the PML moiety of the
oncoprotein PML–RARα resulting in partial
differentiation and apoptosis in promyelo­
cytic blasts. Recent studies suggest this com­
bination will likely lead to improved long‐term
outcomes. HR patients receive idarubicin in
addition to ATRA and ATO.
Complications of therapy
Given the intensity of therapy for AML,
children can expect to experience a number
of complications that include cytopenias
requiring frequent blood product support,
mucositis, liver toxicity, need for parenteral
hyperalimentation, and severe, prolonged
marrow suppression. Infection is common
and should be anticipated. Once neutropenic,
these children are at particularly high risk for
the development of sepsis with Gram‐nega­
tive organisms in addition to invasive fungal
disease. Routine antifungal prophylaxis with
fluconazole or an extended‐spectrum azole
(i.e., voriconazole or posaconazole) is rec­
ommended in addition to antibacterial
(i.e., fluoroquinolone) and PCP prophylaxis.
Streptococcus viridans sepsis is associated with
the use of high‐dose cytarabine and resultant
altered integrity of the gastrointestinal
mucosa. Sepsis with this organism can be rap­
idly fatal. Empiric therapy for fever and neu­
tropenia should include coverage for S.
viridans (i.e., vancomycin) and be started
immediately with the first fever. Prolonged
hospitalization is expected during the course
of treatment for AML and these patients
should be in protective environments.
Utilization of protocols to minimize central‐
line‐associated bloodstream infections is vital.
Toxicities with ATRA may be significant,
specifically ATRA induced differentiation
syndrome in 2–6% of patients. This syn­
drome should be suspected in the patient
with fever, respiratory distress, weight gain,
edema, and importantly, hyperleukocytosis.
The incidence of ATRA syndrome has
decreased due to the addition of anthracy­
cline therapy in induction and can be treated
by temporary discontinuation of ATRA and
ATO with administration of dexamethasone
q12 hours until the symptoms have resolved
for a minimum of 3 days. Additional support­
ive care measures may be needed including
diuretics, blood products, mechanical venti­
lation, or dialysis. ATRA may cause other
side effects including dryness of the lips and
mucosa, fever, transaminitis, and headache
associated with pseudotumor cerebri. ATO
can lead to prolongation of the QTc interval
and therefore electrocardiograms (EKGs)
must be regularly followed while on therapy.
Coagulopathy at diagnosis is not uncom­
mon, especially in the child with APL.
Coagulation studies should be done rou­
tinely. In general, platelet counts should be
maintained above 10 × 109/l (>50 × 109/l for
the APL patient at diagnosis). The use of
fresh frozen plasma, cryoprecipitate, and
platelets are important supportive care meas­
ures due to the frequently observed coagu­
lopathy, hypofibrinogenemia (fibrinogen

<100 mg/dl), and thrombocytopenia, respec­
tively. The total anthracycline dose used in
AML protocols is quite high (i.e., approxi­
mately 450 mg/m2 of doxorubicin equiva­
lents), therefore left ventricular ejection
fraction must be followed closely during and
after therapy. Utilization of a cardioprotect­
ant (i.e., dexrazoxane) should also be consid­
ered routinely.
Relapse
Prognosis for AML patients in relapse remains
poor. Chemotherapy alone results in <10%
1‐year disease‐free survival (DFS). For those
patients that can again obtain MRD remission
after re‐induction chemotherapy, HSCT
improves survival. Re‐induction regimens
include FLAG therapy (G‐CSF, fludarabine,
cytarabine, with or without daunorubicin),
CPX‐351 (liposomal daunorubicin and cyta­
rabine), and TVTC (thiotepa, vinorelbine,
topotecan, and clofarabine). Additional agents
that may have benefit alone or in combination
include demethylating agents (azacitidine and
decitabine), histone deacetylase inhibitors
(vorinostat), and bcl2 inhibitors (venetoclax).
Chimeric antigen receptor T‐cell immuno­
therapy to target CD33 or CD123 is currently
being investigated, but has not shown simi­
lar benefit of CAR‐T cell therapy as in ALL,
to date.
Case study for review
You are seeing a 12‐year‐old girl who pre­
sents to the emergency department for eval­
uation of “hard bumps” in her neck. She had
initially thought they were related to her
“cold,” since she has cough, tactile fever, and
looked pale and tired to her parents. On exam,
vital signs are notable for a temperature of
39 °C and respiratory rate of 24 breaths
per minute. She has pale conjunctiva, dry
cracked lips with mild bleeding, multiple
firm cervical lymph nodes bilaterally 1–3 cm
in diameter, and a 0.5‐cm left epitrochlear
Acute Leukemias 205
lymph node. You get a CBC with differen­
tial, which shows a normal white blood cell
count, absolute neutrophil count (ANC) of
750 × 106/L, hgb 5.9 g/dl, and platelet count
of 23 × 109/l.
a. What is the differential diagnosis and
how will definitive diagnosis be made?
Lymph nodes that are very firm, matted, or
larger than 1.5–2 cm in diameter are con­
cerning for neoplasm. Lymph nodes may
be tender with infection or rapid growth.
Additionally, certain locations such as
epitrochlear or supraclavicular, as well as
lack of association with mild or transient
infectious illness, may indicate a more
severe illness such as chronic infection,
rheumatologic disease, or malignancy.
Cytopenias affecting two or more cell lines
(in this case all three, as the ANC is low)
suggest a bone marrow infiltrative process
(such as AL) or decreased production
(such as aplastic anemia). Definitive diag­
nosis is made via bone marrow aspiration
(BMA; bone marrow biopsy should be
done as well if aplastic anemia is a consid­
eration) unless there are adequate abnor­
mal circulating cells to assess by flow
cytometry (typically requires an elevated
white cell count with a large percentage of
abnormal peripheral blasts).
Traditionally, the diagnosis of ALL is
defined as a blast (malignant cell line) popu­
lation represented by at least 25% of the
bone marrow cells (AML is defined by the
presence of ≥20% myeloblasts by BMA),
often seen in association with a markedly
hypercellular marrow (monotonous cell
population) and crowding with little evi­
dence of normal cell production of red cells,
white cells, or platelets. In addition to this
morphologic assessment of the bone marrow
in patients with evidence of leukemia, a
sample is sent to assess for specific known
cytogenetic anomalies (which may be
confirmative of a malignant process if the
marrow has fewer than 20–25% blasts).
Immunophenotyping is done to differentiate
206 Chapter 15
AML and ALL, and subsequently a B‐ or T‐
cell lineage in ALL. This information in
combination with the cytogenetic results
yields important diagnostic and prognostic
information, and is the basis of the initial
treatment plan.
b. What additional workup should be
done from the emergency department?
Additional laboratory evaluations are helpful
to determine if an oncologic emergency may
be eminent, such as TLS or a mediastinal
mass compromising heart function. A com­
plete metabolic panel with electrolytes and
renal and hepatic function assessments are
important to assess the degree of cellular
turnover and impact on end‐organ function.
Particularly important to assess are evi­
dence of hyperkalemia, hyperphosphatemia,
hypocalcemia, and hyperuricemia in addi­
tion to creatinine. LDH is a marker of cell
turnover and is often markedly elevated in
the presence of ALL. Transaminases, blood
urea nitrogen (BUN), and creatinine are
helpful in supporting the diagnosis and are
often elevated at diagnosis. Coagulation stud­
ies should be sent to determine appropriate
intervention if AML is suspected (especially
APL), or if with clinically significant bleeding
with a possible underlying coagulopathy.
However, in general the PT/INR, PTT and
fibrinogen are likely to be normal.
Any patient with suspected leukemia
should have a CXR to evaluate for the
presence of a mediastinal mass. The patient
with a mediastinal mass may be asympto­
matic or present with mild symptoms like
cough, or have evidence of airway com­
promise (hypoxia, positional discomfort
[orthopnea]) or cardiovascular compromise
(poor pulses, hypotension, or superior vena
cava/mediastinal syndrome). This informa­
tion is vital prior to any anesthesia due to
risk of sedation‐associated decompensation
(i.e., decreased cardiac return).
Fever is common at presentation of leu­
kemia and may be caused by inflammation
related to cytokine release. However, risk of
infection is also increased in the setting of a
low white blood cell count or neutropenia.
Patients should always be considered to
have infection and have blood cultures
drawn and started on empiric broad‐spec­
trum antibiotics.
c. What additional studies should be
done to confirm the diagnosis of AL once
the patient is admitted to the hospital?
As mentioned in the preceding text, the
definitive diagnostic study is BMA which
includes a morphologic interpretation, as well
as immunophenotyping and cytogenetic
studies. FISH for known mutations with prog­
nostic and therapeutic significance should be
sent in conjunction with chromosomal analy­
sis. About 2-5% of patients with AL will have
overt evidence of CNS involvement at diagno­
sis. In ALL, this is defined as an elevated white
blood cell count (chamber count of five or
more cells) and presence of blasts on the cyto­
centrifuge slide. Additionally, ALL patients
may have presence of rare blasts in the face of
normal chamber count and be classified as
CNS2. No overt evidence of CNS involvement
is referred to as CNS1. Patients may also rarely
manifest neurological signs of CNS involve­
ment. Additional interpretation of CNS
involvement of a traumatic (bloody) tap (CSF
contaminated by many red blood cells sugges­
tive of peripheral blood contamination) is
required. Classification of the leukemia with
all these components is critical for precise
diagnosis and determining a therapeutic plan,
with possible eligibility to participate in a clin­
ical trial.
BMA reveals 84% lymphoblasts which is
confirmed on flow cytometry by presence of
TdT. Additionally, flow is positive for CD2,
CD3, CD4, CD5 and CD7, and negative for
CD10, CD19 and CD33. CNS studies are
negative.
d. Does this confirm your suspected
diagnosis? What can you tell the family
generally about treatment options?

These bone marrow and immunohisto­
chemistry results are consistent with T‐ALL
without evidence of CNS disease. Given her
age above 10 years, she is considered to be
“high risk” and therefore would be treated
on a protocol for HR T‐ALL. She will receive
systemic chemotherapy in addition to CNS
prophylaxis with intrathecal chemotherapy.
Without CNS-directed therapy, the majority
of patients would have a CNS relapse as the
CNS (in addition to the testes in males) is a
sanctuary site for leukemia given limited
chemotherapy penetration due to the blood-
brain barrier. T‐ALL patients have a higher
CNS relapse rate compared to B‐ALL and
many will receive prophylactic cranial radia­
tion as well. Generally, treatment for lymph­
oblastic leukemia is about two and a half
years in length, the majority of which is
delivered in an outpatient setting. The initial
8–10 months however are more rigorous,
require frequent clinic visits and periodic
hospitalization for treatment or complica­
tions of treatment. Additionally, many sup­
portive care measures will be in place to
anticipate and treat adverse effects of treat­
ment and include transfusion therapy, pain
management, infection prophylaxis and
treatment, as well as monitoring for specific
adverse effects of the chemotherapeutic
agents (such as cardiac dysfunction from
anthracyclines). Current EFS (event free
relapse) is approximately 80–85%. Early
response to treatment (as measured by end
of induction bone marrow MRD detection)
is of prognostic significance. Identification
of cytogenetic risk factors more precisely
categorize the pre-B-ALL and AML patient
but are not as useful in the T-ALL patient.
Multiple choice questions
1. You are seeing a 4‐year‐old female in
clinic. She had been well appearing until
2 weeks ago when the family noted that she
Acute Leukemias 207
developed off and on low grade fever with­
out URI symptoms. She also appears more
pale and tired to them. All of the following
should prompt a follow up CBC to rule out
acute leukemia EXCEPT:
a. Presence of bruising or petechiae
b. Notable diffuse cervical lymphade­
nopathy on exam
c. Fever to 101°C with pharyngeal
exudates
d. Refusal to walk
e. Pallor
Explanation: For the general pediatrician,
acute leukemia will be a rare diagnosis and
many symptoms will overlap with viral
illnesses, even without URI symptoms.
Non‐specific symptoms including fever and
fatigue will not help rule in or out leukemia.
Specific questions that are helpful include a
description of bone pain or refusal to walk
in a young child due to the bone marrow
being packed with lymphoblasts. Similarly,
signs or symptoms of anemia, thrombocyto­
penia or neutropenia can be helpful such as
with pallor, petechiae or bruising. Focal
symptoms related to a viral or bacterial pro­
cess may be reassuring as long as symptoms
resolve—close follow up is warranted and
there should be a low threshold to check a
CBC/diff. The answer is c.
2. You end up performing a CBC on the
above child with findings concerning for
acute lymphoblastic leukemia. All of the
following are high‐risk features EXCEPT:
a. Age between 1 and 10 years
b. WBC >50 × 109/l
c. Disease in the cerebrospinal fluid
(CNS3)
d. KMT2A rearrangement (11q23)
e. Positive minimal residual disease
(MRD) at the end of induction therapy
Explanation: Early clinical findings showed
that infants and those 10 years of age of greater
did more poorly than younger children.
Additionally, patients presenting with a high
208 Chapter 15
WBC count also did more poorly in earlier
studies. With more sophistication of testing, it
has been found that older children and those
with a high WBC count are more likely to
harbor a genetic mutation which makes their
leukemia more difficult to treat, such as
KMT2A rearrangement or Philadelphia chro­
mosome t(9;22). Similarly, these patients are
more likely to have residual leukemia at the
end of induction, the most prognostic high‐
risk features. CNS disease is another inde­
pendent high‐risk feature. The answer is a.
3. You are seeing the above patient in the ED
after the primary physician sends the patient
in for admission. The CBC is notable for a
WBC of 22 × 10 9/l, hemoglobin is 5.5 g/dl
and platelets are 15 × 109/l. Manual differen­
tial reports 58% blasts. All of the following
are initial considerations EXCEPT:
a. Initiation of fluids at 2x maintenance,
D5 1/2NS with 10 mEq of KCl/l
b. Checking a CXR to rule out a medias­
tinal mass
c. Checking tumor lysis labs to include
potassium, phosphorus, uric acid
d. Planning for platelets prior to diag­
nostic lumbar puncture
e. Planning for PRBCs prior to anesthesia
and to keep hgb >7 g/dl
Explanation: Multiple supportive care
measures are vital to stabilize a new diagno­
sis with leukemia. Fever due to leukemia is
often present and these patients should be
started on cefepime for functional neutro­
penia. Anemia and thrombocytopenia are
common and transfusion is often indicated,
often emergently depending on the level as
well as underlying signs and symptoms.
Elevation in potassium, phosphorus, and/or
uric acid can be seen, especially with higher
WBC counts and should be followed closely,
especially after the initiation of therapy.
Twice maintenance fluids are vital to start
immediately to help prevent symptoms of
tumor lysis syndrome (TLS); these fluids
should always be without any potassium
though. It is important to check a CXR to
rule out an associated mediastinal mass
especially prior to anesthesia for diagnostic
bone marrow aspirate and lumbar puncture.
The answer is a.
4. In the above scenario, this 4‐year‐old
female would be standard risk at the outset
given her age and presenting WBC count.
Per the hematology fellow the blasts look
consistent with acute lymphoblastic leuke­
mia (ALL). The family has many questions
for you about the diagnosis and plan of care.
All of the following are reasonable state­
ments EXCEPT:
a. Definitive diagnosis will require bone
marrow aspiration
b. Based on what we know now she
would be standard‐risk ALL but this
depends on the findings on bone mar­
row aspirate and lumbar puncture
c. If this is standard risk ALL, she will
definitely be cured
d. If this is standard risk ALL, the total
treatment time is about 2 and a half years
e. If this is standard risk ALL, the major­
ity of treatment will be in the clinic rather
than in the hospital
Explanation: When delivering bad news it
is important to be concise, avoid medical
jargon, provide accurate information, be
reassuring and hopeful but without misrep­
resenting the truth, and to spend time
concentrating on the next steps. In this case
it is okay to be hopeful as the majority of
children with standard risk ALL will be
cured. In general practice it is best to avoid
giving percentages unless specifically asked.
Definitive diagnosis requires a bone marrow
aspirate with immunophenotyping to deter­
mine if this is ALL or AML. Also a lumbar
puncture is necessary to rule out CNS
disease. Cytogenetics will help determine
underlying genetic risk. For standard risk
leukemia the treatment is about 2 and a half

years for girls. Due to worse outcomes, boys
may be treated with a longer maintenance
though this is decreasingly a standard prac­
tice. For standard risk leukemia the large
majority of treatment is outside the hospital
setting. The answer is c.
5. You are seeing a 3‐year‐old male with
Down syndrome in the ED due to easy bruis­
ing and some pallor. His CBC is concerning
for a WBC of 1.8 × 109/l, hemoglobin 6.2 g/dl
and platelets of 17 × 109/l. Of note, he had
transient myeloproliferative disorder when
born with a high WBC count that self‐
resolved over several days after birth. The
most likely underlying diagnosis is:
a. ALL
b. Aplastic anemia
c. Acute myelomonoblastic leukemia
(AML, M4 based on the FAB classification)
d. Acute megakaryoblastic leukemia
(AML, M7 based on the FAB classification)
e. Juvenile myelomonocytic leukemia
(JMML)
Explanation: Children with Down syndrome
(DS) are at increased risk of leukemia, both
myelogenous and lymphoblastic. Infants
that had transient myeloproliferative disor­
der (TMD) have about a 25% risk of devel­
oping acute megakaryoblastic leukemia
(AMKL, AML M7) and should be followed
closely with serial CBCs. This risk is due to a
mutation in GATA1 which is unique to chil­
dren with DS. Fortunately, those children
with DS who present with AMKL prior to
4 years of age have a very high rate of cure.
Although ALL is possible in this child, the
history of TMD makes AML much more
likely. Similarly, M4 AML is possible but
much less likely in DS with the history of
TMD. Aplastic anemia can present with
Acute Leukemias 209
similar findings and has been rarely reported
in DS. Finally, JMML is a rare condition
found in young children with increased
monocytes and a small percentage of
peripheral blasts and elevation in hemo­
globin F usually due to an underlying
mutation in the RAS pathway or with NF1.
The answer is d.
Suggested reading
Bhojwani, D., Yang, J.J., and Pui, C.H. (2015).
Biology of childhood acute lymphoblastic leu­
kemia. Pediatr. Clin. North Am. 62: 47–60.
Hunger, S.P. and Mullighan, C.G. (2015). Acute
lymphoblastic leukemia in children. N. Engl. J.
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Karol, S.E., Coustan‐Smith, E., Cao, X. et al. (2015).
Prognostic factors in children with acute mye­
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loid leukemia in children and adolescents:
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385–394.
16 Central Nervous
System Tumors
Central nervous system (CNS) tumors are
the most common cancer diagnosis in chil-
dren after leukemia, accounting for 20% of all
pediatric malignancies. The most common
location is infratentorial in children up to
14 years of age, while supratentorial tumors
are more common in adolescents. Spinal cord
tumors are also more common in adolescents
than in younger children (9 vs. 3%).
The cause of most pediatric CNS tumors
is unknown. The majority of them are spo-
radic, although a small percentage is associ-
ated with genetic disorders such as
neurofibromatosis, tuberous sclerosis, von
Hippel–Lindau syndrome, and Li–Fraumeni
syndrome (germline mutation of p53, a sup-
pressor oncogene). Radiation therapy is the
most frequently identified cause of pediatric
CNS tumors; these occur as second malig-
nancies in children who have previously
received radiation therapy for treatment of
leukemia or primary CNS tumors. A variety
of epidemiologic studies have looked for an
association between cellular telephone use
and an increased risk of brain tumors, pri-
marily gliomas. The results remain unclear;
if a risk exists, it appears not to emerge until
greater than 10 years (or >1640 hours) of
exposure, making this an unlikely cause of
pediatric gliomas, even if the risk is real.
The World Health Organization (WHO)
Classification System for brain tumors is the
internationally accepted standard for brain
Handbook of Pediatric Hematology and Oncology – Children’s Hospital & Research Center Oakland,
Third Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
tumor classification. The version released in
2016 was the first to incorporate a tumor’s
genomic profile into the diagnostic scheme.
This version contains 59 primary diagnoses
with several sub‐diagnoses. The current
structure makes it easier for a pathologist to
make a diagnosis in many cases, but can lead
to a delay in diagnosis while waiting for the
results of the genomic profiling. Historically,
microscopic criteria used in grading the
aggressiveness of CNS tumors have included
cellular pleomorphism, mitotic rate, degree
of anaplasia, and presence or absence of
necrosis. While these remain relevant, the
current classification also identifies certain
mutations such as H3.3K27M in glial
tumors as being sufficient to identify a
tumor as Grade 4 regardless of its histologic
appearance. A growing number of chromo-
somal abnormalities and copy number vari-
ations have also been included in the
classification system.
Clinical presentation
It is often difficult to make the diagnosis of a
CNS tumor in a child. The presenting symp-
toms of CNS tumors can be quite variable,
depending on the location of the tumor, its
rate of growth, and the age of the child.
Additionally, most of the symptoms are
nonspecific, and occur more commonly in
212 Chapter 16
children with a variety of benign conditions.
Prompt diagnosis of a CNS tumor requires
an appropriate index of suspicion and a good
understanding of the duration of symptoms
that is expected with other disorders.
Due to the frequent association of hydro-
cephalus with infratentorial tumors, 50% of
children with brain tumors will present with
signs of increased intracranial pressure (ICP),
including lethargy, vomiting, and irritability.
These symptoms may be less prominent in
infants because the cranial sutures remain
open and the skull can accommodate the
increase in ventricular size. For this reason,
accurate measurement of the head size
should be part of every well‐baby examina-
tion. Headache is a presenting symptom in
70% of children with posterior fossa tumors
and 50% of central tumors. Features that are
helpful in distinguishing tumor‐related head-
ache from a primary headache syndrome
include nausea and vomiting (particularly in
the morning), increasing frequency and/or
severity over a few weeks, and abnormalities
on neurologic examination. Neurologic defi-
cits such as ataxia, visual changes, and hemi-
paresis occur in about 25% of cases. Weakness
is sometimes subtle, but parents often relate a
loss of physical function or developmental
milestones. Visual changes include diplopia
caused by cranial nerve dysfunction and loss
of visual acuity caused by optic nerve involve-
ment or papilledema.
Two specific clinical syndromes are fre-
quently associated with childhood brain
tumors. Parinaud’s syndrome consists of
paralysis of upward gaze, accommodative
paresis, nystagmus during attempts at
upward gaze, eyelid retraction (Collier’s
sign), and “setting‐sun sign” or conjugate
downward gaze. It is most commonly associ-
ated with pineal region tumors, but it can
also be caused by obstructive hydrocephalus
from any cause, posterior fossa tumors, or a
number of infectious or vascular abnormali-
ties leading to ischemia or damage to the
dorsal midbrain. Diencephalic syndrome is a
rare cause of failure to thrive (FTT) in infants
and young children. Characteristic features
include profound emaciation with normal
caloric intake, absence of subcutaneous fat,
locomotor hyperactivity, euphoria, and
alertness. It is almost always associated with
hypothalamic/suprasellar tumors, most
commonly optic pathway gliomas.
Seizures are relatively uncommon in
younger children and occur twice as often in
adolescents (13 vs. 25%). They can be focal or
generalized. When focal, they may provide a
clue as to the location of the tumor. An often
overlooked symptom in school‐age children
is deterioration in school performance and
behavioral changes. It is not uncommon for
these children to be referred by a psychologist
or psychiatrist after many months of unsuc-
cessful therapy for these symptoms.
Symptoms of spinal cord tumors are
caused by compression of the spinal cord or
nerve roots by the mass. The most common
symptom in children with spinal cord
tumors is back pain. Unlike adults, the com-
plaint of back pain is very rare in childhood.
“Benign” causes of back pain include trauma,
medical conditions such as sickle cell dis-
ease, or involvement in aggressive sports
such as football, gymnastics, skateboarding,
or motocross bicycling. In the absence of
such a history, there should be concern that a
tumor might be the cause. Tumor‐related
pain is often described as being worse in the
supine position or with Valsalva’s maneuver.
Other symptoms associated with spinal cord
tumors include sciatica, weakness, numb-
ness, problems with or loss of bowel and/or
bladder control, and spinal deformity.
Tumors within the spinal canal are either
intramedullary (within the spinal cord or
nerve roots) or extramedullary. Intramedullary
spinal cord tumors are almost always glial in
origin, the most common histologies being
astrocytoma, myxopapillary ependymoma,
and oligodendroglioma. Extramedullary

tumors are either intradural or extradural.
Extramedullary intradural tumors are most
commonly neurofibromas, schwannomas, or
more rarely meningiomas. Extradural tumors
are usually not CNS tumors at all, but meta-
static tumors from other locations such as
neuroblastoma, lymphoma, or Ewing sar-
coma. Tumors within the vertebral bodies
such as primary bone tumors, tumors meta-
static to bone, and histiocytosis can also extend
into the spinal canal and cause the abovemen-
tioned symptoms.
Diagnostic evaluation
Imaging studies
The first step in evaluating a child with a
suspected CNS tumor is neuroimaging. A
variety of imaging techniques can be useful
in this assessment.
Computerized tomography (CT)
CT was the first imaging modality to revolu-
tionize the diagnosis of CNS tumors both in
children and adults. It is often still the first
imaging study obtained when evaluating
patients suspected of having a tumor.
However, magnetic resonance imaging (MRI)
has largely replaced it as the definitive neuro-
imaging study. Advantages of CT include
widespread availability, rapid acquisition
time, superior resolution of bone and vascular
structures including lesions of the skull base,
and utility in patients with contraindications
to MRI (i.e., ferrous metal implants). It also
more clearly identifies intratumoral calcifica-
tion. Its limitations include inferior resolution
of the brain itself, particularly within the pos-
terior fossa, and significant radiation expo-
sure, especially with regular monitoring.
MRI
An MRI, with and without gadolinium
enhancement, is the single best study for
evaluating the majority of tumors within the
Central Nervous System Tumors 213
brain and spine. It provides greater sensitivity
in areas that may be obscured by proximity
to bone, such as the temporal lobe and
posterior fossa. It also provides multiplanar
images. Contrast MRI allows for identifica-
tion of tumor within areas of surrounding
edema or hemorrhage, detects focal areas of
blood–brain barrier (BBB) breakdown, and
improves delineation of cysts from solid
tumor.
Extensions of MRI technology include
MR spectroscopy, tractography, and func-
tional MRI scanning. MR spectroscopy
allows the determination of the chemical
makeup of tissue within a predefined region
of interest. Different types of tumors have
characteristic spectroscopic signatures,
allowing the identification of the most likely
tumor type before surgery takes place.
Tractography is a software technique that
allows identification of the location of white
matter tracts and their associated nuclei.
This has become very useful as a preopera-
tive planning tool that allows the neurosur-
geon to avoid disruption of eloquent nuclei
and fiber tracts during surgery. Functional
MRI is another technique that precisely
identifies specific motor regions, speech and
language centers, and other eloquent areas
for preoperative planning purposes.
Positron emission tomography
(PET)
PET imaging is a useful modality for evalu-
ating a variety of tumors. It detects the rela-
tively higher rate of metabolism present in
many neoplasms by measuring the rate of
metabolism of one of a growing number of
radioactively labeled compounds, most
commonly 2‐deoxy‐2[18F]fluoro‐d‐glucose
(FDG). Similar to many high‐grade tumors
elsewhere in the body, malignant brain
tumors also show high FDG uptake because
of increased glucose transport and glycoly-
sis. However, images are more difficult to
interpret because of the high and regionally
214 Chapter 16
variable glucose metabolism in normal
brain gray matter. Its utility in young chil-
dren is limited due to the need for a 30–60
minute period of limited mental activity
between injection and scanning to optimize
the distinction between normal and abnor-
mal structures. Other compounds have been
developed in order to overcome some of
these limitations, particularly the large neu-
tral amino acid (LNAA) tracers 11C‐methio-
nine (MET), 18F‐fluoroethyltyrosine (FET),
and 18F‐fluorodopa (FDOPA). MET‐PET
has been found to demonstrate presence of
tumor in non‐contrast enhancing regions of
pediatric high‐grade gliomas, and to predict
areas of relapse.
Traditionally, PET images have been co‐
registered with CT images to provide ana-
tomic detail. More recently, technology has
been developed to allow co‐registration of
PET images with MRI scan images. This
provides better definition and decreases the
amount of radiation exposure associated
with the scan. Use of these compounds in
the diagnosis of adult brain tumors has
become well‐established, but experience in
children is still largely lacking.
Single‐photon emission
computed tomography (SPECT)
SPECT is a three‐dimensional imaging tech-
nique introduced in the early 1980s for the
investigation of regional cerebral blood flow
that often correlates with tumor metabolic
activity. In this technique, radioactive thal-
lium and radiolabeled tyrosine have been
used to localize brain tumors as well as dis-
tinguish viable tumor from radiation necro-
sis. It is less expensive than PET scanning,
but the resolution is less and the 20–30 minute
acquisition times needed for high‐quality
pictures again limit utility in young children.
It has also typically been co‐registered with
CT images to provide anatomic detail. As of
2018, it was not yet possible to co‐register
SPECT images with MRI.
Other studies
Lumbar puncture (LP)
Certain primary CNS tumors, such as
medulloblastoma, primitive neuroectoder-
mal tumor (PNET) (now classified as CNS
embryonal tumor, not otherwise specified
(NOS) in the 2016 WHO CNS tumor clas-
sification), ependymoma, malignant germ
cell tumors (GCTs), and, to a lesser extent,
malignant gliomas, have a propensity to
metastasize throughout the subarachnoid
space. As with other malignant tumors,
the presence of metastatic disease alters
both treatment and prognosis. For this
reason, LP is a routine part of the diagnos-
tic workup of these patients. Spinal fluid is
collected and sent for cell count and differ-
ential, glucose, protein, and cytological
examination to look for malignant cells.
Children with malignant GCTs should also
have measurements of α‐fetoprotein (AFP)
and the beta subunit of human chorionic
gonadotropin (β‐HCG) performed. These
markers, while not diagnostic of metastatic
disease, can, if present, be used to measure
response to therapy. The diagnostic LP
should be delayed for at least 10‐14 days
following tumor resection to allow any non-
viable tumor cells present in the cerebrospinal
fluid (CSF) as a result of the surgery itself
to be cleared.
Bone marrow aspiration
In the past, it was recommended that
patients with medulloblastoma undergo a
bone marrow aspiration at the time of diag-
nosis to rule out metastatic disease prior to
starting therapy. However, more recent
studies have indicated that fewer than 3% of
patients diagnosed with medulloblastoma
have extraneural metastases at diagnosis,
with fewer than 25% of these having disease
in the marrow. Therefore, recent clinical tri-
als have no longer recommended routine
examination of the bone marrow, but have

instead recommended this only for patients
with unexplained cytopenias. Extraneural
metastases are almost unheard of with other
types of pediatric CNS tumors at diagnosis,
making bone marrow aspiration at diagno-
sis unnecessary.
Bone scan
While 90% of extraneural metastases in
patients with medulloblastoma are to bone,
this remains an unlikely presenting finding,
since, as mentioned in the earlier text, fewer
than 3% of patients have extraneural metas-
tases at diagnosis. Therefore, bone scan
should be reserved for patients who present
with the underlying diagnosis of medullo-
blastoma that is accompanied by bone pain.
Treatment
Children with CNS tumors are typically
treated with some combination of neurosur-
gery, radiation therapy, and chemotherapy.
The specific treatment chosen is dependent
on the histology, location, resectability, and
prognosis of the patient’s tumor.
Neurosurgery
Initial neurosurgical intervention is indi-
cated in the majority of patients. Exceptions
include: (i) diffuse intrinsic pontine glioma
(DIPG), due to the infiltrative nature of the
tumor throughout the pons (however, tumor
biopsy has become a more standard part of
treatment to obtain tissue for molecular
analysis and this innovation has led to more
specific tumor‐directed therapies that will
hopefully improve outcomes for these typi-
cally fatal tumors); (ii) tumors that are radio-
graphically consistent with GCTs and present
with elevation of both AFP and β‐HCG, con-
firming the diagnosis of nongerminomatous
germ cell tumor (NGGCT) without a biopsy
for which aggressive surgery at diagnosis has
not been shown to improve survival; and
Central Nervous System Tumors 215
(iii) functioning ­pituitary adenomas, as the
role of surgery in children is limited, except
when they are large and causing mass effect
or threatening vision through compression
of the optic chiasm.
The goals of neurosurgical intervention
are to achieve the maximum tumor removal
possible while minimizing morbidity and
mortality and to obtain tissue for a histologic
diagnosis. In the case of medulloblastoma
and other CNS embryonal tumors, epend-
ymoma, and high‐grade gliomas, extent of
surgical resection is one of the major predic-
tors of outcome. A number of surgical
advances have increased the likelihood of
safely achieving complete tumor resections,
including use of an operating microscope
with neuronavigation; intraoperative ultra-
sound, CT and MRI; intraoperative neuro-
physiological monitoring; and use of dyes
that selectively stain tumor tissue. The latter
is not yet approved for use in children, but
clinical trials are ongoing.
Children with increased ICP caused by
obstructive hydrocephalus will likely have a
CSF diversion procedure performed as well,
either before their definitive surgery if they
are unstable or at the time of resection. An
external ventricular drain (EVD) will often
be placed initially and will be clamped at
some point after surgery to determine if nor-
mal CSF flow has been restored. Children
who redevelop symptoms of increased ICP
will likely require placement of a permanent
shunt. Most often this is a ventriculoperito-
neal shunt (VPS), but shunts to other sites
may be done in specific circumstances.
Radiation therapy
Radiation therapy has played a pivotal role in
the management of children with malignant
brain tumors for decades. It has been used to
destroy remaining tumor in cases of incom-
plete surgical resection, and to treat micro-
scopic residual disease and metastatic disease
in children who have malignant tumors with
216 Chapter 16
a high likelihood of tumor regrowth. The
dose of radiation used is dependent on the
type of tumor and the location and volume
to be irradiated.
Unfortunately, the use of radiation ther-
apy is associated with significant adverse
late effects, particularly in young children.
Those children receiving higher doses of
radiation before 6 years of age, especially to
the entire craniospinal axis (craniospinal
irradiation, CSI), can be expected to suffer
significant impairment of intellectual and
physical development as a result of this ther-
apy. Another concern is the development of
secondary malignancies in the radiation
field. Children receiving prophylactic crani-
ospinal radiation for leukemia have been
shown to have a >20‐fold increase in the risk
of secondary CNS tumors; over 80% of these
tumors occurred in children who were radi-
ated before 5 years of age. Children with
standard risk medulloblastoma who survive
5 years following conventional treatment
that includes CSI are more likely to die from
a radiation‐induced cancer than from a
recurrence of their primary tumor.
A variety of innovations in radiation
therapy delivery have been developed to
minimize the side effects of radiation. These
include 3D conformal planning techniques
and intensity modulated radiation therapy
(IMRT), which minimize the dose of radia-
tion delivered to adjacent normal tissue.
Another innovation is proton beam therapy
(PBT), which takes advantage of the shorter
decay path of high‐energy protons com-
pared to gamma rays (photons). This mini-
mizes the exit dose delivered beyond the site
of the tumor. These innovations have proven
very valuable in decreasing the radiation
exposure to heart, lung, bowel, and repro-
ductive organs in children receiving total
spine radiation. PBT has had limited availa-
bility until recently due to the significant
cost of building PBT centers. As it has
become more available, a concern has arisen
regarding a possible association with PBT
and the development of intracranial vascu-
lopathy. Research to further evaluate this
potential risk is ongoing.
Despite these innovations, the use of
radiation therapy continues to carry the risk
of significant morbidity. Work continues to
develop novel strategies that will allow the
avoidance of radiation therapy completely
in children with CNS tumors, or at least to
delay it in very young children.
Chemotherapy
The utility of chemotherapy in the treatment
of CNS tumors was recognized more slowly
than in other tumors. It was initially felt that
the BBB would prevent the delivery of effec-
tive concentrations of chemotherapeutic
agents to the tumor. However, it became
apparent that many drugs do adequately
cross the BBB, or that this barrier is abnor-
mally permeable in many malignant brain
tumors. Other factors, such as tumor hetero-
geneity, cell kinetics, drug distribution, and
drug excretion may also have a significant
impact on effectiveness of chemotherapy.
Lower‐grade tumors are characterized by a
low mitotic index and relatively slow growth
rate; it was long felt that these tumors would
be less sensitive to chemotherapy, while
more malignant tumors would be more sen-
sitive. However, several studies over the last
three decades have demonstrated that many
low‐grade tumors are sensitive to chemo-
therapy. Commonly used drugs for the treat-
ment of brain tumors include vincristine,
methotrexate, temozolomide, procarbazine,
lomustine (CCNU), cisplatin, carboplatin,
cyclophosphamide, and etoposide.
The genomic alterations that have been
identified in a growing number of CNS
tumors have led not only to the modifica-
tion of tumor classification mentioned ear-
lier, but to a major evolution in the treatment
of these tumors in both children and adults.
There is a growing appreciation that tumors

of many different histologies can share iden-
tical genetic mutations (BRAF V660E in
melanoma and a variety of CNS tumors),
and that the same drugs can be equally
effective in treating any of these tumors. In
the case of CNS tumors, a major considera-
tion is whether the drug is able to cross the
BBB, especially in lower‐grade tumors
where the BBB is more often intact. A grow-
ing number of these agents have shown
promise and are discussed in more detail in
the following text.
Specific tumor types
Medulloblastoma
Medulloblastoma is the most common CNS
tumor in children, accounting for up to 20%
of all childhood brain tumors. It has a pro-
pensity to metastasize early; in up to 35% of
cases, seeding of the subarachnoid space is
present. Extraneural spread is unusual at
diagnosis but may develop later if tumor
recurrence occurs.
Until recently, medulloblastomas had
been considered as a single tumor entity.
However, years of highly sophisticated
genomic profiling of many of these tumors
led in 2010 to a consensus classification sys-
tem that divided medulloblastoma into four
main molecular subgroups (wingless [WNT],
sonic hedgehog [SHH], Group 3, and Group
4). Figure 16.1 compares the features of these
subgroups. WNT tumors have activated
WNT pathway signaling. They rarely metas-
tasize, have a longer prediagnostic interval,
occur in older patients, and have a balanced
sex ratio. SHH tumors are characterized by
activation of the SHH pathway. SHH tumors
are almost exclusively located within the cer-
ebellum rather than in the fourth ventricle,
consistent with their cells of origin (granule
cerebellar progenitors).
Infants with SHH tumors frequently har-
bor germline or somatic mutations in
Central Nervous System Tumors 217
PTCH1 or SUFU. Infants harboring ­germline
PTCH1 mutations present with Gorlin syn-
drome (nevoid basal‐cell carcinoma syn-
drome). Older children have mutually
exclusive somatic mutations in PTCH1 or
germline and/or‐somatic TP53 mutations,
the latter of which frequently co‐occur with
amplifications of GLI2 and MYCN. TP53
mutations are present in approximately 30%
of childhood SHH, are frequently germline,
and confer a poor prognosis. Outcomes of
SHH tumors are age‐specific. Infants have an
excellent outcome, even with chemotherapy‐
only regimens. Conversely, children with
TP53‐mutant SHH tumors have a dismal
prognosis compared with that of TP53‐
wildtype tumors. Group 3 tumors are char-
acterized transcriptionally by the activation
of the GABAergic and photoreceptor path-
ways. Group 3 tumors occur in younger chil-
dren, 40–50% are metastatic at diagnosis,
have short prediagnostic intervals, and a
male preponderance. The most common
cytogenetic aberration is amplification of
MYC (10–20% of tumors). Isochromosome
17q (i17q) is seen in 40% of Group 3 tumors.
Patients with Group 3 tumors have a poor
outcome overall, particularly nonirradiated
infants, but likely benefit from myeloablative
treatment regimens. Group 4 tumors are
characterized transcriptionally by overrepre-
sentation of neuronal and glutaminergic
pathways. Group 4 tumors are the predomi-
nant subgroup in children 3–16 years of age,
have long prediagnostic intervals, and 30
and 40% are metastatic at diagnosis. The
most common cytogenetic aberration is
i17q, seen in almost 80% of tumors, with less
frequent aberrations in 8p, 7q, 11p, and 18q.
Group 4 tumors have an intermediate prog-
nosis, although in some series, patients with
nonmetastatic Group 4 tumors can have an
excellent prognosis with >90% survival. The
molecular classification of medulloblastoma
continues to evolve. More recent publica-
tions have suggested increasing the number
218 Chapter 16

Feature WNT SHH Group 3 Group 4

Age group Children/adults Infants/adults Infants/children Children/adults

Metastases at < 5% 20% 40%–50% 35%–40%

diagnosis
Sex ratio 1:1 1:1 2:1 2:1

Somatic CTNNB1 (90%) PTCH1 (25%) SMARCA4 (10%) KDM6A (10%)

nucleotide SMARCA4 (25%) SUFU (10%, CTDNEP1 (5%) MLL3 (5%)
variants DDX3X (50%) infants) MLL2 (4%)
TP53 (12%) SMO (15%, adults)
TERT (20%, adults)
IDH1 (< 5%, adults)
TP53 (15%,
children)
MLL2 (12%)
Germline variants APC (< 5%) PTCH1 (25%
infants,
10% older)
SUFU (20% infants)
TP53 (8% older)
Focal copy MYCN (8%) MYC (15%) SNCAIP (10%)
number GLI2 (5%) OTX2 (7%), MYCN (6%)
aberrations GFI1/1b activation CDK6 (5%)
(25%) GFI1/1b activation
(5%)
Broad copy Monosomy 6 9q loss (35%) i17q loss (22%) i17q loss (70%)
number (85%) 10q loss (22%) 8 loss (29%) 8p loss (49%)
aberrations 17p loss (18%) 10q loss (45%) 11p loss (28%)
11 loss (30%) X loss (80% of
16q loss (48%) females)
1q gain (23%) 7q gain (40%)
7 gain (25%) 18q gain (20%)
18 gain (20%)
Pattern of relapse Local and Predominantly Metastatic Metastatic
metastatic local
High risk TP53 mutation Infants Metastases
MYCN amp Metastases
Low risk Age < 16 years Infants Whole chr 11 loss

Figure 16.1 Molecular subgroups of medulloblastoma. Amp, amplification; Chr, chromosome; i17q,
isochromosome17q; SHH, sonic hedgehog; WNT, wingless.

of medulloblastoma subclasses to as many as Patients with <1.5 cm3 of residual tumor

12. However, it remains unclear how this will
improve our understanding of the disease
and, more important, how it will lead to
more rational treatment strategies.
The initial mode of therapy for all sub-
types is surgery, and extent of surgical resec-
tion directly affects prognosis and treatment.
after surgery and no evidence of metastatic
disease are defined as standard risk. Patients
with metastatic disease or a larger postop-
erative residual tumor volume have been
considered high‐risk. Once the diagnosis is
confirmed, patients should be staged with a
MRI of the spine and LP. As mentioned,

additional studies looking for extraneural
metastases are no longer considered neces-
sary unless the patient is symptomatic.
Medulloblastomas are very sensitive to
radiation therapy, and radiation has tradi-
tionally been considered the mainstay of
postsurgical therapy. Due to the high likeli-
hood of metastases throughout the CNS, it
has been necessary to deliver radiation to the
entire brain and spine (i.e., CSI), with a
higher (boost) dose delivered to the region of
their tumor. As the long‐term consequences
of radiation have become more apparent,
especially for young children, strategies to
delay or avoid radiation in young children
have become more widely used, and attempts
have been made to decrease the doses of
radiation given to older children.
The value of chemotherapy both in
improving survival among patients with prim-
itive neuroectodermal tumors (PNETs) and in
allowing a reduction in the dose of radiation
therapy required for cure has become increas-
ingly evident over the past three decades. For
the past several years a combination of cispl-
atin, vincristine, CCNU, and cyclophospha-
mide has been used following completion of
radiation therapy with good effect. Vincristine
is also used during radiation therapy, and the
Children’s Oncology Group (COG) is evaluat-
ing whether the addition of carboplatin dur-
ing radiation therapy will improve outcomes
further in children with high‐risk disease.
Due to the devastating effects that CSI can
have in children less than 6 years of age at the
time of treatment, an alternative strategy was
developed in the early 1990s that substituted
very intensive chemotherapy followed by
consolidative myeloablative chemotherapy
and hematopoietic stem cell rescue without
radiation therapy for these young children.
Known as the Head Start regimen, this strat-
egy proved fairly effective for children with
standard risk, but results were suboptimal for
patients with high‐risk medulloblastoma or
supratentorial PNET, including pineoblas-
Central Nervous System Tumors 219
toma. In 1995, the second Head Start study
added high‐dose methotrexate to the existing
chemotherapy; results from this modification
were very encouraging. Patients with stand-
ard‐risk medulloblastoma had 5‐year event‐
free survival (EFS) rates of 50% and overall
survival rates of 75%. Children who relapsed
following chemotherapy alone were effec-
tively salvaged with reoperation and radia-
tion therapy in half of the cases. This strategy
led to over 70% of children with standard risk
disease treated on Head Start II being cured
without radiation therapy. COG has investi-
gated a similar strategy for children <3 years
of age with high‐risk medulloblastoma and
supratentorial embryonal tumors. The results
of this trial have not yet been published.
The outlook for children >3 years of age
with standard risk medulloblastoma is quite
good; 5‐year EFS with current multimodal-
ity therapy is >80%. Children with high‐risk
medulloblastoma and pineoblastoma do less
well; the most recently published 5‐year EFS
rates are 50–60%.
Gliomas
Gliomas account for just over 50% of all CNS
tumors in childhood. As the name implies,
they arise from glial cells, which surround
neurons and provide support for and insula-
tion between them. Types of glial cells
include oligodendrocytes, astrocytes, epend-
ymal cells, Schwann cells, microglia, and sat-
ellite cells. Gliomas can occur anywhere in
the CNS, although certain subtypes have a
propensity to occur in specific locations.
Gliomas are classified histologically into
Grades 1–4 based on cellular pleomor-
phism, cell density, mitotic index, and
necrosis. Grades 1 and 2 tumors are defined
as low‐grade (LGG), while Grades 3 and 4
gliomas are defined as high‐grade (HGG)
and are clearly malignant. The 2016 revision
of the WHO Classification of Tumors of the
CNS dramatically changed the classification
of glial tumors through the use of integrated
220 Chapter 16
phenotypic and genotypic parameters for
tumor classification. This has added a level
of objectivity that had been missing from
some aspects of the diagnostic process in the
past. This is particularly true for glial
tumors; in the event that there is discord-
ance between the histologic appearance and
the genomic profile, the diagnosis is based
on the genomic characteristics of the tumor.
A midline glioma may have the histologic
appearance of a juvenile pilocytic astrocy-
toma (JPA, a Grade 1 tumor), but if profiling
reveals an H3.3K27M mutation, the final
diagnosis is “diffuse midline glioma,
H3.3K27M‐mutated, WHO Grade 4.”
Surgical resection is a key component of
therapy for most gliomas that are amenable
to this approach. This includes cerebellar
gliomas and supratentorial gliomas that are
not centrally located or within the optic
pathway. Gliomas occurring in the tectal
region of the midbrain are an exception to
this rule; these are typically very indolent
tumors that often require no intervention.
LGG that are completely resected do not
require adjuvant therapy and are simply
observed. This is most frequently seen with
JPAs, even if low‐grade, diffuse gliomas are
infiltrative in nature and can rarely be com-
pletely resected. If JPAs recur, re‐resection is
generally curative. Surgery should be used
judiciously, however. Many LGG can be
controlled successfully with chemotherapy,
so surgery that leaves the patient with sig-
nificant postoperative morbidity should be
avoided. HGG always require adjuvant ther-
apy, although at this time the ability to cure
patients with these tumors remains poor.
Radiation therapy was a key part of the
treatment of all gliomas for many years, but
it is used very rarely now to treat children
with LGG due to the frequency of long‐term
consequences and the realization that these
tumors can be managed successfully with
chemotherapy. It remains a component of
therapy for HGG, however. Since these
tumors metastasize much less frequently
than PNETs, patients do not require CSI but
they do require focal radiation doses of
50–60 Gy to their tumors to achieve local
control.
The value of chemotherapy in the man-
agement of children with low‐grade gliomas
has become increasingly apparent over the
past 30 years. This is especially true for chil-
dren with neurofibromatosis‐associated
LGG, as the frequency of secondary malig-
nant tumors in these children after treat-
ment with radiation therapy is alarmingly
high. The goal of therapy in this situation is
different than with other tumors.
Chemotherapy rarely leads to total disap-
pearance of the tumor, but rather produces a
state of stable disease that is hopefully main-
tained after therapy discontinuation. In this
regard, management of incompletely
resected LGG is similar to managing a
chronic illness like asthma, with periods of
stability, occasional flares of disease, and a
hope that the child will eventually “grow
out” of their condition.
As more of these low‐grade tumors have
undergone molecular profiling, it has
become apparent that mutations within the
mitogen‐activated protein kinase (MAPK)
pathway are a hallmark of JPAs. The most
commonly mutated gene in low‐grade glio-
mas is the BRAF oncogene, one of three
RAF kinases which act as downstream effec-
tors of growth factor signaling leading to cell
cycle progression, proliferation, and sur-
vival. Over 70% of JPAs are characterized by
a fusion between BRAF and KIAA1549 that
leads to constitutive activation of BRAF.
Another common mutation of BRAF is the
point mutation BRAF V600E. This muta-
tion is observed in a variety of cancers
including melanoma, papillary thyroid can-
cer, and colorectal cancer. This mutation is
also seen in a variety of CNS tumors, includ-
ing two‐thirds of pleomorphic xanthoastro-
cytomas (PXAs), 20% of gangliogliomas,

and 10% of extracerebellar JPAs. Tumors
possessing the BRAF V600E mutation can
be successfully treated with BRAF inhibitors
including vemurafenib and dabrafenib.
Tumors with the KIAA1549:BRAF fusion
have been shown to actually grow more
quickly when treated with such agents, but
they do respond to MEK inhibitors such as
trametinib and selumetinib; the latter had
just received FDA approval as of the time of
publication.
Gliomas arising in the brain stem
deserve special mention. These comprise
about 15% of brain tumors in children.
About 70% of these arise in the pons, are
diffusely infiltrative, and are termed DIPG.
These are among the deadliest of all child-
hood brain tumors; median survival of chil-
dren with this diagnosis is 8–9 months, and
90% of affected children are dead within
2 years of diagnosis regardless of the treat-
ment provided. Radiation therapy has been
estimated to prolong survival for a median
of 3 months. Traditionally a course of radia-
tion has taken 6 weeks to deliver, which has
limited the benefit of this treatment on
improving quality of life, especially for
children requiring anesthesia for their radi-
ation. More recently, hypofractionated regi-
mens that take only 2–3 weeks to deliver
have made this a more attractive option.
Many trials have been conducted over the
past 25 years trying to improve the survival
of children with this tumor, all with disap-
pointing results.
Although ependymomas are tradition-
ally classified with other glial tumors, their
behavior and management are quite differ-
ent. They represent about 5–10% of child-
hood primary brain tumors. About 60% of
intracranial ependymomas occur in the
posterior fossa, and 40% are supratentorial.
Grade 1 ependymomas are rare and almost
never occur in the brain, although Grade 1
(myxopapillary) ependymomas of the
spine comprise about 10% of childhood
Central Nervous System Tumors 221
ependymomas. Grade 4 ependymoma does
not exist.
Molecular profiling of ependymomas
has revealed that these tumors also have
subgroups with unique molecular charac-
teristics and prognoses. These are outlined
in Figure 16.2. The initial separation is
based on anatomic location and is divided
into supratentorial, posterior fossa, and spi-
nal locations. Within each location there
have been three subgroups defined based on
molecular characteristics that align well
with outcome data. Each subgroup has a
specific age group or groups where they
occur commonly. Prognosis is also associ-
ated with the subgroup of the tumor. Grade
1 tumors tend to require surgery alone for
cure. This is even true in the spine due to the
well‐circumscribed, noninfiltrative nature
of these tumors that allows gross total resec-
tion to be accomplished in the majority of
cases. As with medulloblastoma, the identi-
fication of these subgroups has not yet
resulted in the development of molecularly
based therapies. In fact, the role of chemo-
therapy in the management of ependymoma
remains controversial. A recent COG trial
that prospectively randomized patients to
receive or not receive chemotherapy follow-
ing surgery and radiation has completed
patient accrual, but the results have not yet
been published.
The extent of surgical resection is the
most important prognostic factor in chil-
dren with ependymoma. The 5‐year EFS for
patients having a complete resection is 80%,
versus 40% for those patients having a near‐
total or subtotal resection. Unfortunately,
ependymomas are often difficult to com-
pletely resect, especially in the posterior
fossa due to their predilection to surround
cranial nerves and other vital structures. It
appears that while adjuvant chemotherapy
has not been demonstrated to improve sur-
vival in patients with ependymoma, it does
improve outcome when given to patients
222 Chapter 16

WHO Age
Region Subtype Prognosis
Grade Group
ST-SE I
Subependymoma
Supratentorial Excellent
Balanced
Genome
ST-EPN-YAP1 II / III
(Anaplastic)
Supratentorial Good
Ependymoma
YAP1-Fusion
ST-EPN-RELA II / III
(Anaplastic)
Ependymoma
Supratentorial Chromothripsis; Poor
RELA-fusion

PF-SE I
Posterior Subependymoma
Excellent
Fossa Balanced
Genome
PF-EPN-A II / III
(Anaplastic)
Posterior
Ependymoma Poor
Fossa
Balanced
Genome
PF-EPN-B II / III
(Anaplastic)
Ependymoma
Posterior
Chromosomal Fair
Fossa
Instability

SP-SE I
Spine Subependymoma Excellent
6q deletion

SP-MPE I
Myxopapillary
Spine Ependymoma Good
Chromosomal
Instability
SP-EPN II / III
(Anaplastic)
Spine Good
Ependymoma
NF2 mutation

Figure 16.2 Molecular subgroups of ependymoma.

before second look surgery to improve the
likelihood that a complete resection can be
achieved for patients unable to be com-
pletely resected at diagnosis. Radiation ther-
apy remains an important component of
therapy for this tumor; the doses required
are similar to those needed to achieve local
control of other glial tumors. Ependymomas
are more likely to metastasize within the
CNS than other gliomas, especially if they

originate in the posterior fossa or are Grade
3. Assessment of the spinal fluid postopera-
tively is important, although negative spinal
fluid cytology does not reliably identify
patients less likely to recur away from their
primary tumor site.
Atypical teratoid/rhabdoid
Tumor (ATRT)
ATRTs are the most common malignant
CNS tumors in children ≤1 year of age and
represent approximately 1–2% of all pediat-
ric brain tumors. In the past, they were fre-
quently confused with medulloblastoma
when they occurred in the posterior fossa.
Once it was appreciated that these tumors
were characterized by mutations in genes for
components of the chromatin remodeling
complex SWItch/sucrose nonfermentable
(SWI/SNF), most commonly in SMARCB1,
it became possible to identify them fairly
easily with immunohistochemistry through
the loss of the intracellular protein INI1.
Rhabdoid tumors can arise from many other
areas within the body, including peripheral
nerve roots, kidneys, head and neck, para-
vertebral muscles, liver, mediastinum, retro-
peritoneum, bladder, pelvis, heart, scrotum,
and subcutis. They may arise synchronously
in more than one area, especially in patients
harboring a germline SMARCB1 mutation.
However, in most of these instances, one
location is the CNS.
Recent work has demonstrated that
rather than being a single entity, ATRT in
fact is comprised of at least three distinct
genomic and epigenomic subtypes, identi-
fied as types 1, 2A, and 2B.
The survival rate for children with ATRT
has traditionally been poor, but is improving
due to the development of treatment proto-
cols specific to this tumor. However, a stand-
ard of care had yet to be defined. Previous
reports suggested that complete surgical
resection greatly increases the likelihood of
survival. However, more recent publications
Central Nervous System Tumors 223
have demonstrated that patients can be suc-
cessfully treated with aggressive multiagent
chemotherapy even without radical surgery.
The question of whether patients can be
cured without radiation therapy under any
circumstances remains unanswered.
Germ cell tumors
CNS GCTs are relatively uncommon. Their
management shares many similarities with
GCTs occurring outside the CNS. They are
discussed in Chapter 21.
In summary, although brain tumors occur
relatively commonly in children, the varia-
tions in histologic appearance, presentation,
treatment, and prognosis make their manage-
ment quite challenging. The best outcomes
for these children occur when they are treated
at a center with a multidisciplinary neuro‐
oncology program, and every effort should be
made to ensure that this happens.
Case studies for review
1. A 9‐year-old right‐handed male presents
to the ED with his parents, who report that
over the past 2 months the patient has been
experiencing worsening weakness on his
right side. Initially they noted that he
seemed to be dragging his right foot when
walking. However, he subsequently began
falling more frequently, and for the past day
has been unable to walk. His parents also
note that he has been having increasing dif-
ficulty with writing, and his teachers have
been complaining that they are having dif-
ficulty reading what he has written. His par-
ents have also noted that his right eye
appears “droopy.”
a. What elements of the history are con-
cerning, and what additional informa-
tion should you seek?
The patient has a right hemiparesis that has
been present for several weeks. The onset
224 Chapter 16
was insidious, and the deficit has been
becoming progressively worse. The weak-
ness involves both cranial and peripheral
nerves on the same side of the body, sug-
gesting a centrally located (brainstem)
lesion. These symptoms could be caused by
an infectious or inflammatory lesion, or by a
tumor.
Additional information to be elicited
includes presence of fever, chills, malaise, or
other signs of infection. Inquire about any
prior history of similar symptoms, as condi-
tions like multiple sclerosis are character-
ized by symptomatic episodes separated in
time and space. Be sure to inquire about
sensory loss, as this is often an early
complaint.
If the symptoms are caused by a midline
tumor, these can also lead to obstruction of
CSF pathways. Inquire about any recent
sleepiness, irritability, headache, nausea, or
vomiting. Headache due to increased ICP is
often worse at night or in the early morning,
and may be worsened by coughing, bending
over, or straining in the bathroom.
The parents report that the patient has
never had any other neurological symptoms.
They also deny any recent history of fever,
chills, or other signs of illness. They deny
any recent headaches, nausea, vomiting, or
abnormal sleep patterns or increased fatigue.
b. Given what you have learned thus far,
what items do you want to pay particular
attention to when doing your physical
examination?
c. Are there any diagnostic tests you
would like to obtain that could help you
narrow the differential diagnosis?
A careful assessment of the vital signs is
important. Although there are no clinical
symptoms suggestive of increased ICP, the
presence of hypertension and bradycardia
could suggest this. Careful cranial nerve
examination can be very useful in localizing
a brainstem tumor. Sixth nerve involvement
is very common in conditions affecting the
pons but is typically absent with lesions
higher in the brainstem. The third cranial
(oculomotor) nerve nucleus resides in the
midbrain. Injury to the oculomotor nerve
results in paralysis of the intraocular and
extraocular muscles, as well as the levator
palpebrae muscle, and leads to downward
and lateral deviation of the eye. Facial sen-
sory loss may be present as well. Midbrain
lesions lead to contralateral weakness, as the
decussation of long tract fibers occurs at the
level of the medulla. In addition to weak-
ness, these lesions cause spasticity, hyperre-
flexia, and typically ataxia as well.
Based on the available information, a
neoplastic process seems more likely than
an infectious or inflammatory one. However,
it is still useful to obtain a CBC with differ-
ential, an erythrocyte sedimentation rate
(ESR), and a C‐reactive protein (CRP) to
look for evidence of inflammation. Multiple
sclerosis is still on the differential diagnosis,
but the only laboratory test that is likely to
help in making that diagnosis is an analysis
of the CSF. Given the possibility of a tumor
causing these symptoms, a lumbar puncture
should be deferred until after imaging is
obtained.
The most useful test in this situation is
an MRI scan of the brain with and with-
out contrast. A properly done scan will
include T1, T2, and fluid‐attenuated
inversion recovery (FLAIR) sequences,
diffusion‐weighted images, and postcon-
trast T1‐weighted images in axial, sagittal,
and coronal planes.
A CBC, ESR, and CRP are done and are
normal. MRI is performed and reveals a
1.5 × 1 × 1.7 cm sharply defined mass in the L
cerebral peduncle that is isointense on T1,
hyperintense on T2 and FLAIR, has facilitated
diffusion on diffusion‐weighted imaging, and
has a nodular area of intense enhancement
within the mass.

d. What does the MRI tell you about the
patient’s diagnosis? and prognosis?
e. What would be the next steps in the
patient’s management?
Tumors within the cerebral peduncle are
almost always glial tumors. They are con-
sidered midline tumors and can be either
low‐grade or high‐grade. However, the MRI
characteristics favor a low‐grade neoplasm.
These include the sharp demarcation, the
hyperintensity on T2 and FLAIR, and the
facilitated diffusion. Both low‐grade and
high‐grade gliomas can enhance, but low‐
grade gliomas tend to have solid areas of
enhancement, while high‐grade gliomas
often have ring enhancement around
necrotic‐appearing regions.
Given the patient’s recent history of pro-
gressive symptoms, serious consideration
needs to be given to initiating treatment.
Given the location of the tumor and the
patient’s symptoms, surgical removal is not a
realistic option without leaving the patient
with permanent, significant neurological
dysfunction. In fact, even a biopsy could
represent significant risk of permanent
injury. However, depending on location, it
may be possible to obtain sufficient tissue
for diagnosis using a stereotactic approach.
With the recent advances in genomic analy-
sis and the possibility that molecular profil-
ing could identify mutations for which novel
treatment options exist, an attempt should
be made to obtain sufficient tissue to per-
form such testing. If this is deemed too risky,
initiation of therapy with conventional
chemotherapy should definitely be consid-
ered. While radiation therapy is effective
therapy for low‐grade gliomas, it should not
be considered without a biopsy‐proven
diagnosis. Given the patient’s age and the
tumor’s proximity to the brainstem, pitui-
tary gland, and primary cerebral vascula-
ture, radiation therapy should be considered
second‐line therapy.
Central Nervous System Tumors 225
The patient should also be carefully
examined for stigmata of neurofibromato-
sis type 1 (NF1). Patients with NF1 are at
increased risk of developing low‐grade glial
tumors. Many of these are in the optic path-
way, but they can occur in other locations
including the midbrain. Patients with NF1
tend to be short and have relative macro-
cephaly. Careful examination looking for
café‐au‐lait spots, axillary freckling, and
cutaneous neurofibromas should be done.
The presence of attention problems or
learning disabilities should be identified, as
these occur in ~50% of patients with NF1.
Slit lamp examination can reveal Lisch
nodules on the iris. If there is concern about
the possibility of NF1, it is important to
perform germline genomic analysis along
with tumor genomics. Mutations of the
NF1 gene are not uncommon in low‐grade
glial tumors, and without concomitant
germline testing it will not be possible to
know whether an intratumoral NF1 muta-
tion is somatic or germline. This could have
major implications for future therapy.
Treating patients with NF1 with radiation
therapy carries a risk of significant mor-
bidity, including secondary malignancy
and the development of potentially fatal
Moyamoya disease.
2. A 12‐month‐old girl is referred for imag-
ing by a neurologist, after presenting with
bilateral nystagmus for several weeks. Her
past history is significant for FTT, with min-
imal weight gain since 9 months of age. She
was admitted at 10 months of age due to
concern for malnutrition and not receiving
adequate oral intake. She is breastfeeding
and taking solid foods, often eating through
the night.
At the time of presentation to the neu-
rologist, she is noted to be alert and attentive
but cachectic. Her weight to length ratio is
<3rd percentile. Her body mass index (BMI)
226 Chapter 16
is 12.2 kg/m2. She is very thin and irritable,
but consolable by her mother. Her anterior
­fontanelle is flat. She has symmetric tone
and strength and no localizing neurologic
findings and normal cranial nerves. She
appears to have good vision, with extraocu-
lar movements intact, though has easily
elicited nystagmus bilaterally.
a. What is the most likely diagnosis and
how is her history relevant?
This patient most likely has a slow growing
low‐grade glioma or astrocytoma located in
the hypothalamic‐optic chiasmatic region.
The association of a tumor in this location
in an infant or young child with features of
FTT is referred to as “diencephalic syn-
drome.” This is a rare disorder and children
often present severely emaciated despite
a normal to slightly decreased caloric
intake. These children may also appear to be
in a hypermetabolic state with hyperactivity,
hyperalertness, tachycardia, fever, excessive
sweating, and skin flushing. They are often
thought to have been neglected, poorly fed,
or have an underlying malabsorption prob-
lem. It is not unusual that these children have
seen multiple specialists including gastroen-
terology and endocrinology to evaluate for
celiac disease, pancreatic insufficiency, or an
endocrine problem. These children are not
developmentally affected. Diencephalic syn-
drome should be included in the differential
diagnosis of FTT in an infant or very young
child without apparent cause.
b. Will treatment of her tumor result in
reversal of her FTT?
It is unclear how a tumor in the hypotha-
lamic region affects appetite and metabo-
lism. The therapy is focused on treating the
underlying lesion as well as optimizing
nutrition. Most children do recover and
begin to gain weight again normally, though
it may take many months to see improve-
ment. However, diencephalic syndrome
has been associated with a worse tumor
outcome.
c. How should diagnosis and treatment
be approached in this patient?
MRI of the brain shows a homogenously
enhancing suprasellar mass which is
5.1 × 2.4 × 2.7 cm. The patient subsequently
has a spine MRI which reveals metastatic
spinal lesions. The patient undergoes a
biopsy of the mass which reveals a juvenile
pilomyxoid astrocytoma (JPA). Given the
location and size of the tumor, concurrent
diencephalic syndrome, and spinal metas-
tases, treatment with chemotherapy is
warranted. The patient is referred for an
ophthalmology evaluation and ongoing
monitoring given the risk of visual deficits
due to optic chiasm involvement. Additio­
nally, given the risk for development of
endocrinopathies secondary to the supra-
sellar location, she has assessments of follicle
stimulating hormone (FSH), luteinizing
hormone (LH), thyroid stimulating hormone
(TSH), and growth hormone (GH).
Suggested reading
Millard, N.E. and De Branga, K.C. (2016).
Medulloblastoma. J. Child Neurol. 31:
1341–1353.
Neill, S.G., Saxe, D.F., Rossi, M.R. et al. (2017).
Genomic analysis in the practice of surgical
neuropathology: the Emory experience. Arch.
Pathol. Lab Med. 141: 355–365.
Pickles, J.C., Hawkins, C., Pietsch, T., and Jacques,
T.S. (2018). CNS embryonal tumors: WHO 2016
and beyond. Neuropathol. Appl. Neurobiol.
44: 151–162.
17 Hodgkin and Non‐
Hodgkin Lymphoma
Hodgkin and non‐Hodgkin lymphoma (HL
and NHL) together account for approxi-
mately 10–12% of malignancies in children;
they are third in relative frequency after
acute leukemia and brain tumors. NHL com-
prises approximately 60% of all lymphomas.
Utilization of a risk‐ and response‐based
treatment approach in lymphoma has
resulted in improved outcomes and decreased
long‐term adverse effects.
Hodgkin lymphoma
HL is rare among children <5 years of age
and relatively rare in the adult population,
but is the most commonly diagnosed cancer
among adolescents aged 15–19 years. HL is
classified into two general groups: classical
HL (95% of cases) and nodular lymphocyte‐
predominant HL (NLPHL, 5% of cases).
Classical HL is further subdivided into
nodular sclerosis, mixed cellularity,
lymphocyte‐depleted, and lymphocyte‐rich
forms. The tumor cells in classical HL are
designated Hodgkin and Reed–Sternberg
(HRS) cells, whereas in NLPHL they are
designated lymphocyte‐predominant (LP)
cells. HRS cells are thought to derive from
germinal center B‐cells that have acquired
unfavorable immunoglobulin V gene
mutations and normally would have
undergone apoptosis, whereas LP cells
Handbook of Pediatric Hematology and Oncology – Children’s Hospital & Research Center Oakland,
Third Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
derive from antigen‐selected germinal
center B‐cells. In both forms of the disease,
the tumor cells comprise only 0.1–10% of
the cells within the tumor.
Epidemiologic studies suggest that two
different forms of pediatric HL exist: child-
hood and adolescent/young adult (AYA). The
childhood form is defined as occurring in
those ≤14 years of age, and is characterized by
a male predominance and a histologic sub-
type that is more likely to be mixed cellularity
(30–35%) or nodular lymphocyte‐predomi-
nant (10–20%). AYA HL occurs in patients
between 15 and 35 years of age. There appears
to be a complex interaction between Epstein–
Barr virus (EBV) virus and HL development,
with EBV‐transformed lymphoid and Reed–
Sternberg cells effecting apoptotic and repair
mechanisms. Incorporation of EBV into the
tumor genome is more commonly seen in a
younger male population (i.e., below 10 years
of age), in underdeveloped countries and in
immune‐deficient patients. It is more com-
monly associated with the mixed cellularity
histologic subtype of HL. In the AYA popula-
tion, the incorporation of EBV into the tumor
genome is unusual, though these patients
often have a history of infectious mononu-
cleosis with high EBV titers. Other infectious
agents that have been associated with HL
include human herpesvirus 6 and cytomeg-
alovirus. There is clearly an association
between HL and alterations in immune
228 Chapter 17
f­unction, and HL is associated with congenital
and acquired forms of immune deficiency
including HIV disease, post‐hematopoietic
stem cell or solid organ transplant, and auto-
immune disease.
Clinical presentation
The most common presentation of HL is
painless, progressive enlargement of superfi-
cial lymph nodes, most commonly cervical,
followed by supraclavicular, axillary, or
inguinal adenopathy. The nodes are typically
described as feeling rubbery or firm and
non‐tender, although may be sensitive to
touch with rapid growth. As the disease pro-
gresses, the nodes enlarge and often aggre-
gate into larger masses that may become
fixed to the underlying tissue. Bulky disease
is defined as a node or nodal mass measur-
ing >6 cm in the largest diameter. Bulky dis-
ease is much more common in the AYA
population. As children often have reactive
or infectious adenopathy, it is common to
have received treatment with several courses
of antibiotics before ultimately coming to
biopsy. This is more common with cervical
than with supraclavicular adenopathy, as the
latter is less frequently associated with infec-
tion or inflammation and leads more quickly
to referral for possible malignancy. At least
two‐thirds of patients with cervical or supra-
clavicular adenopathy have mediastinal
involvement as well. This is frequently
asymptomatic but may be associated with
cough (usually nonproductive), dyspnea,
orthopnea, hoarseness, dysphagia, chest
pain, or evidence of superior vena cava syn-
drome (SVCS) (with distended neck veins
and worsening respiratory or cardiac dys-
function). HL limited to sub‐diaphragmatic
sites occurs in <5% of pediatric cases, occur-
ring most commonly in femoral, superficial
iliac, or inguinal nodes.
Constitutional symptoms occur in
approximately 25% of patients with HL.
They are caused by cytokines produced by
the HRS cells within the tumor. Certain
­specific symptoms known as “B symptoms”
have been demonstrated to have a negative
prognostic significance. These are unplanned
weight loss of >10% of body weight over the
6 months preceding diagnosis, drenching
night sweats, or unexplained, recurrent fever
>38 °C. Other common constitutional symp-
toms include generalized pruritus and alco-
hol‐induced pain. HL may present with
discrete lesions in the lungs, liver, spleen,
bone, bone marrow, or kidneys, and is often
asymptomatic. A diffusely enlarged liver or
spleen is not characteristic of HL.
Evaluation
1. A careful history and physical
examination are imperative, including
assessment for the presence of B symptoms.
All superficial nodal groups should be
carefully examined, and the size of any
enlarged nodes and their character should
be documented.
2. The laboratory evaluation includes a
complete blood count (CBC) with
differential, complete metabolic panel with
assessment of liver and kidney function,
lactate dehydrogenase (LDH), and alkaline
phosphatase. Acute phase reactants,
nonspecific markers of tumor activity, may
correlate with prognosis or response
measures and include erythrocyte
sedimentation rate (ESR), C‐reactive protein
(CRP), serum copper, and serum ferritin.
3. A posterior–anterior (PA) and lateral
chest radiograph is requisite to determine if a
mediastinal mass is present. Before initiating
a diagnostic surgical procedure under anes-
thesia, it is important to determine if the
patient may be at risk for complications due
to an obstructing mediastinal mass. Other
important imaging studies include a CT scan
of the neck (inclusive of Waldeyer’s ring),
chest, abdomen, and pelvis. Oral and intrave-
nous contrasts are required for accurate iden-
tification of intra‐abdominal adenopathy.
 Hodgkin and Non‐Hodgkin Lymphoma 229
Splenic involvement occurs in 30–40% of
children at diagnosis. Positron emission
tomography (PET) is now used at diagnosis
as a very sensitive tool for identifying sites of
involvement as well as to evaluate subsequent
treatment response.
4. Bone marrow involvement at initial pres-
entation of pediatric HL is uncommon and
rarely occurs as an isolated site of extranodal
disease. However, it is more commonly
associated with advanced stage (Stage III or
IV) disease or in patients with B symptoms
(though likely less in Stage I or II patients).
These patients should undergo bone mar-
row aspiration and biopsy from at least two
sites as part of their diagnostic evaluation.
All patients experiencing a recurrence of
their disease should have their bone marrow
examined.
5. Skeletal metastases are also rare at diag-
nosis. FDG‐PET is a sensitive test for identi-
fying bone metastases and has replaced
technetium bone scan. It is important to
include the entire distal extremities in the
imaging.
6. Surgical procedures are limited to a diag-
nostic biopsy, as resection of mass disease is
not indicated in the majority of cases. The
exception is the Stage IA patients with
NLPHL who may be observed without fur-
ther treatment after full resection. Excisional
biopsy should be performed (not fine‐needle
aspiration) to obtain sufficient tissue for diag-
nostic studies including tumor characteriza-
tion for potential targeted therapies.
Additionally, excisional biopsy allows for
preservation of the lymph node architecture
which aids in diagnosis. Subtypes of HL are
determined based on histology, gross appear-
ance, and presence of Reed–Sternberg cells.
Staging
The most widely used staging system for
pediatric HL is the Ann Arbor staging system
(Table 17.1). This system divides lymph node
regions into nodal sites (i.e., neck, axilla, and
mediastinum), and the number of involved
sites then determines the stage. Stage I dis-
ease involves only a single nodal site, whereas
Stage II involves two or more sites that lie
together on one side of the diaphragm. Stage
III disease spans the diaphragm and Stage IV
is disseminated systemic disease. Additional
modifiers include A or B, to describe the
absence or presence of specific systemic
symptoms, respectively, and E, involvement
of a single extranodal site that is contiguous
or proximal to a known nodal site. The pres-
ence of bulky mediastinal disease, defined as
greater than one‐third of the intrathoracic
diameter, is also considered. Staging is
divided into low‐, intermediate‐, and high‐
risk disease categories (early‐, intermediate‐,
and advanced‐stage diseases in Europe)
based on prognostic factors such as the extent
of disease (including extralymphatic and
splenic involvement) as well as absence or
presence of bulky disease as well as B
symptoms.
Disease categorization into these risk
groups is not uniform with some potential
overlap:
1. Low‐risk disease: Stage IA or IIA without
bulky disease, splenic, or extralymphatic
involvement (potentially IB).
2. Intermediate‐risk disease: IA/IIA with
bulky disease, IB, IIB without bulky disease,
IIIA (potentially also IIB with bulky disease
and IVA).
3. High‐risk disease: IIB with bulky disease,
IIIB, IV.
Initial clinical and laboratory risk assess-
ment, stage, and FDG‐PET response to ini-
tial treatment cycles form the basis of risk
stratification and the development of treat-
ment algorithms. Additional risk factors
include elevated acute phase reactants, age,
anemia, and male sex.
Treatment
The first successful treatment strategy for
HL was based solely on the use of radiation
230 Chapter 17

Table 17.1 Ann Arbor staging system for Hodgkin lymphoma.

Stage Description

I Single lymph node region (I) or extralymphatic organ or site (IE)

II Two of more lymph node regions on the same side of the diaphragm (II) or
single extralymphatic organ with regional or other lymph node involvement
on same side of diaphragm (IIE)
III Involved lymph node regions on both sides of diaphragm (III), potentially inclusive
of contiguous extralymphatic organ (IIIE) or spleen (IIIS) or both (IIIE+S)
IV Disseminated involvement of one or more extra‐lymphatic tissues or organs or
single extra‐lymphatic organ involvement with distant nodal involvement

B symptoms: (i) unexplained and documented weight loss >10%; (ii) unexplained recurrent
documented fever >38.0 °C; and/or (iii) drenching night sweats.
Bulk disease: (i) mediastinal mass ≥ 1/3 thoracic diameter measured on upright PA CXR; and/or
(ii) aggregate nodal tissue >6 cm in longest transverse diameter.

therapy (RT). While this approach was fairly
effective in curing the disease in low‐risk
patients, it resulted in unacceptable muscu-
loskeletal hypoplasia, cardiovascular and
pulmonary dysfunction, and the develop-
ment of subsequent secondary cancers. This
led to the development of combined modal-
ity therapy with the goal of improving event‐
free and overall survival, especially in
higher‐risk patients, and decreasing the
long‐term adverse effects of a radiation‐only
approach. Current research efforts in HL
treatment seek to maintain the excellent sur-
vival rates presently achieved while continu-
ing to decrease the frequency of later adverse
events by utilizing a risk‐based and early‐
response approach to decrease chemother-
apy and radiation exposure. Today, patients
with favorable disease presentations receive
fewer cycles of multi‐agent chemotherapy
than those with advanced and unfavorable
clinical presentations, either alone or com-
bined with low‐dose, involved‐field radia-
tion (intensity‐modulated radiation therapy,
IMRT). The current approach to therapy
relies on a response‐based assessment and
risk stratification utilizing FDG‐PET imag-
ing after two to four cycles of chemotherapy.
Patients with early response can typically be
treated without IMRT. A variety of chemo-
therapy agents have been shown to be effec-
tive in treating HL and many regimens have
proven successful. Current strategies include
minimizing radiation especially in females
to decrease risk of breast cancer secondary to
mediastinal radiation and minimizing
alkylator therapy especially in males to
decrease risk of infertility. With current ther-
apy, more than 90% of children diagnosed
with classical HL are expected to be long‐
term disease‐free survivors, regardless of
stage at diagnosis.
Classical HL—low‐risk disease
A number of studies have attempted to elim-
inate the use of RT completely in children
with low‐risk disease based on PET response
after two cycles of chemotherapy. Multiple
therapeutic options exist with similar excel-
lent outcomes utilizing a response‐based
approach to RT. Current commonly used
regimens that are radiation‐sparing include
the German OPPA/OEPA (vincristine
[Oncovorin], procarbazine or etoposide,
prednisone, Adriamycin [doxorubicin]) reg-
imen and VAMP (vinblastine, Adriamycin,
methotrexate, prednisone). Other regimens
may also be considered with evaluation of
 Hodgkin and Non‐Hodgkin Lymphoma 231
chemotherapeutic agents, their long‐term
side effects, and the potential of the regimen
to be radiation‐sparing. FDG‐PET response
after two cycles of therapy helps to define
which patients can avoid IMRT.
Classical HL—intermediate‐risk
disease
Similar to low‐risk disease, the goal for
patients with intermediate‐risk disease is to
utilize a response‐based approach to mini-
mize need for RT, as well as potentially mini-
mizing alkylator therapy in males. As
mentioned, there is overlap in staging in
regard to which groups are classified as inter-
mediate‐risk. Additionally, there are multiple
acceptable treatment regimens. Current ther-
apies include ABVE‐PC (Adriamycin, bleo-
mycin, vincristine, etoposide, prednisone,
and cyclophosphamide) as well as OEPA/
COPDAC for males (cyclophosphamide,
Oncovorin, prednisone, dacarbazine) and
OPPA/COPP for females (procarbazine
rather than dacarbazine). FDG‐PET response
after two cycles of therapy helps to define
which patients can avoid IMRT, depending
on the treatment regimen utilized.
Classical HL—high‐risk disease
Given the excellent prognosis and ability to sal-
vage even high‐risk patients with HL, reduction
in radiation remains a priority in this subgroup,
especially in females. There is no standardized
approach, and risk‐grouping may be overlap-
ping for some between intermediate‐ and
high‐risk. Early response may still allow for
elimination of IMRT in some groups, depend-
ent on the treatment protocol, such as in the
use of BEACOPP (bleomycin, etoposide,
Adriamycin, cyclophosphamide, Oncovorin,
procarbazine, prednisone) followed by COPP/
ABV in females. Additional treatment regimens
include BEACOPP + RT, BEACOPP/ABVD
(Adriamycin, bleomycin, vinblastine, dacar-
bazine) + RT in males, as well as OEPA/
COPDAC + RT in males and OPPA/COPP + RT
in females. Many reasonable regimens exist,
thus there is not a standardized approach. The
practitioner must weigh the particular side
effects of each regimen and the potential desire
to avoid RT.
Nodular lymphocyte‐
predominant HL
Several studies have demonstrated that
patients with NLPHL who present with Stage
I disease and a single involved lymph node
can be successfully treated with surgery
alone. Stage I patients with more than one
involved node and Stage II patients, which
represent more than 80% of patients with
NLPHL, are successfully treated with similar
protocols used in low‐risk classical HL
patients and can avoid RT if with a complete
response to this therapy. A recent analysis of
intermediate‐risk NLPHL patients treated
with ABVE‐PC showed excellent early
response and event‐free response, superior to
classical HL and with high rates of RT avoid-
ance. Salvage rates are excellent for those that
are observed after surgery and in those that
recur after chemotherapy.
Novel agents
Refractory or recurrent HL may require
alternative approaches including salvage
therapies with conventional chemotherapy,
IMRT, autologous hematopoietic stem cell
transplant, or targeted antibody therapy.
Brentuximab vedotin is a promising new
agent in HL, and is a targeted antibody–drug
conjugate that has shown an excellent
response and toxicity profile in CD30+ lym-
phomas, including HL. A highly toxic agent
monomethyl auristatin E is delivered to
CD30+ cells after internalization and proteo-
lytic cleavage. Brentuximab is generally well–
tolerated, though may cause fever, fatigue,
diarrhea, nausea, neutropenia, peripheral
neuropathy, and pneumonitis. Brentuximab
has been used successfully in the relapse set-
ting either as a single agent or in combination
232 Chapter 17
with bendamustine, a bifunctional alkylating
agent with only partial cross‐resistance to
other alkylators. Brentuximab has also
proved important in preventing relapse in
high‐risk patients when given as an every 3‐
week 1‐year maintenance therapy after autol-
ogous stem cell transplantation (ASCT).
Other new agents are also in develop-
ment and include targeted PD‐1 blockade
(PD: programmed cell death), which has
recently been shown effective given the PD‐1
pathway effect on limiting T‐cell‐mediated
tumor killing. Upregulation of PD‐L1 (ligand
of PD‐1) has been shown in certain tumor
types including HL as a method to evade
immunosurveillance. Blocking PD‐1
through antibodies such as nivolumab and
pembrolizumab has proven effective, espe-
cially in tumors with PD‐L1 expression.
Studies in heavily pretreated HL patients
have shown a response to nivolumab. Early
studies with nivolumab and brentuximab in
combination in heavily pretreated patients
have shown efficacy and are ongoing. PD‐1
antibodies have been shown tolerable with
rash, diarrhea, and pruritus being common
side effects in addition to less common
immune‐mediated effects including pneu-
monitis, colitis, thyroiditis, hepatitis, and
hypophysitis (pituitary inflammation).
Tumor pseudoprogression after initiation of
a PD‐1 antibody should be a consideration
due to the initial inflammatory response.
Non-Hodgkin lymphoma
NHL is about 1.5 times as common as HL in
the pediatric and AYA populations, with a
median age of 10 years. The incidence is
extremely low in children less than 5 years of
age, but from that point it increases steadily
with age throughout life. In all age groups,
there is a significant male predominance,
particularly among patients with Burkitt
lymphoma (BL). During childhood, the
disease is more common among non‐
­
Hispanic whites and Asians/Pacific Islanders;
after age 20 years, it occurs more commonly
in African–Americans. The incidence of dif-
ferent histologic subtypes is very different in
children and adults.
Children with congenital or acquired
immune system dysfunction have a high risk
of developing lymphoma. Congenital condi-
tions include ataxia‐telangiectasia, autoim-
mune lymphoproliferative syndrome, as well
as Bloom, Wiskott–Aldrich, and Chédiak–
Higashi syndromes; acquired conditions
include HIV and prolonged immunosup-
pressive therapy following bone marrow or
solid organ transplant or treatment for auto-
immune conditions. EBV is clearly associ-
ated with BL in low‐income countries, and
has been linked to several subtypes of NHL
in high‐income countries. Other identified
risk factors include Helicobacter pylori infec-
tion, tobacco exposure, and chemical or
other environmental exposures. It is likely
that there is not a single etiology responsible
for the development of all cases of NHL.
The histologic classification of NHL has
changed frequently over time and has become
more precise, as our understanding of the
development of lymphoma has improved and
better diagnostic tools (immunophenotyp-
ing, cytogenetics, molecular biology, and
gene profiling) have been developed. The
World Health Organization classification is
now widely used and was most recently
revised in 2016. There are four major histo-
logic subtypes of NHL that occur commonly
in children (in order of frequency): diffuse,
large B‐cell lymphoma (DLBCL), T‐ and
B‐lymphoblastic lymphoma (LL), BL, and
anaplastic large cell lymphoma (ALCL).
Other considerations in adolescents in par-
ticular with mediastinal disease are primary
mediastinal B‐cell lymphoma (PMBCL) as
well as marginal gray zone lymphoma.
 Hodgkin and Non‐Hodgkin Lymphoma 233
DLBCL and ALCL tend to be heterogene-
ous immunologically. Most are B‐cell‐derived,
although some are T‐cell‐derived or arise
from the macrophage‐histiocyte lineage.
Burkitt and Burkitt‐like subtypes are virtually
all B‐cell tumors, distinguished only by the
amount of cellular heterogeneity. The most
common site of occurrence of LL is the medi-
astinum, and these tumors are virtually all of
T‐cell origin. Less commonly LL occurs in
bone or subcutaneously; these tumors are
typically of B‐cell origin. All of these subtypes
can invade the bone marrow and undergo
leukemic transformation. Pediatric NHL is
mostly high‐grade, which is distinctly differ-
ent from the adult population in which many
cases are indolent.
Clinical presentation
The clinical presentation of NHL varies and
depends on the primary site of disease, histo-
logic subtype, and extent of disease. More than
70% of children present with advanced‐stage
disease and up to 25% of patients present with
a mediastinal mass (usually T‐LL or PMBCL).
NHL can arise anywhere in the body, but
occurs most frequently in the lymph nodes,
thymus, Waldeyer’s ring, Peyer’s patches, and
bone marrow. In the United States, BL typi-
cally presents in the intestine at the ileocecal
region, resulting in obstruction and may lead
to intussusception. These children usually pre-
sent with nausea, vomiting, and abdominal
distention. It is not unusual for NHL to be con-
fused with a surgical abdomen, such as appen-
dicitis. BL also presents in Waldeyer’s ring or
in the facial bones. T‐LL most commonly
arises from the thymus and these children
typically present with evidence of mediastinal
obstructive symptoms such as respiratory
symptoms (cough, dyspnea, orthopnea), cer-
vical or supraclavicular adenopathy, or SVCS.
Children may have very limited disease affect-
ing the tonsils, nasopharynx, or Waldeyer’s
ring, and the diagnosis often results from
pathologic examination following a “routine”
tonsillectomy and adenoidectomy.
Diagnostic evaluation
It is not unusual to begin with a surgical pro-
cedure for excision or biopsy of a node or
laparotomy in the case of an acute abdominal
presentation and incidentally diagnose the
patient with NHL. Many times, the diagnosis
is not suspected prior to these procedures.
Histologic confirmation is required for diag-
nosis. The diagnosis of NHL is usually made
using biopsy tissue, but can also be confirmed
by cytological examination of bone marrow,
cerebrospinal fluid, or pleural or paracentesis
fluids. In cases where the patient may be too
unstable for biopsy (i.e., mediastinal mass
with significant compression of the great ves-
sels or trachea), sampling from these sources
may be sufficient to make a diagnosis and
initiate treatment. If possible, sufficient mate-
rial should be obtained for immunologic and
cytogenetic or molecular biology studies.
Many therapeutic trials now have require-
ments for submission of material for central
pathology review or b ­iology studies; these
requirements should be taken into considera-
tion when planning a diagnostic procedure.
The laboratory studies that should be
obtained include:
●● A CBC with differential and review of the
peripheral smear to assess for possible bone
marrow involvement or leukemia.
●● Serum chemistries to include liver transam-
inases, blood urea nitrogen, creatinine, LDH,
uric acid, electrolytes, calcium, and phospho-
rus. Lymphomas, particularly LL and BL, can
present with overt tumor lysis syndrome
(TLS) and/or renal dysfunction. The LDH
can be useful prognostically, especially in
patients with advanced‐stage disease.
●● Bilateral bone marrow aspiration and
biopsy, as the child may have leukemia
(defined as a marrow with >25% lympho-
blasts) or lower‐level bone marrow disease.
234 Chapter 17

This assessment may be omitted in certain ❍ PET to include all identified sites of

subsets in which it is a rare site of disease
involvement (i.e., DLBCL, ALCL, PMBCL).
●● A lumbar puncture to assess the cerebro-
spinal fluid for involvement by NHL.
●● Consideration of testing for immune‐
deficiency‐specific infections (HIV), or
immune dysfunction if appropriate.
●● Radiologic procedures that should be per-
disease. Ideally, this should be performed
following the diagnostic procedure, as
these patients frequently have residual
abnormalities in their surgical bed on
plain CT that are discovered on FDG‐
PET to not represent active disease.

formed based on associated symptoms, but Staging

should include:
❍ A prompt PA and lateral chest radio-
graph to evaluate for mediastinal
involvement.
❍ CT scan of the neck, chest, abdomen,
and pelvis if the patient is sufficiently
stable.
❍ MRI of the brain for patients with
immunodeficiency‐related NHL, as these
patients more commonly present with
parenchymal brain disease.
❍ MRI of the brain and spine for patients
with focal neurologic symptoms.
NHL is staged using the St. Jude (Murphy)
staging system that is presented in Table 17.2.
Treatment
Therapy is based on clinical staging, localized
versus disseminated disease, and histologic
subtype. Those patients presenting with an
oncologic emergency (i.e., SVCS, respiratory
compromise, clinical TLS) must have emer-
gent therapy to ensure their safety, with
correction of metabolic derangements and/or
minimal diagnostic studies prior to therapy
initiation. Patients with LL are treated with

Table 17.2 St. Jude staging system for non‐Hodgkin lymphoma.

Stage Description

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

mediastinum or abdomen
II 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
IV Any of the above with central nervous system or bone marrow involvement
(<25%) at diagnosis
 Hodgkin and Non‐Hodgkin Lymphoma 235
acute lymphoblastic leukemia‐type therapy
with similar excellent outcomes. Patients with
B‐cell lymphoma (i.e., DLBCL/BL) or ALCL
(in addition to other lymphoma subtypes)
require a shorter, more intensive treatment
regimen with excellent outcomes. In gen-
eral, the chemotherapeutic regimens include
steroids, anthracyclines, vinca alkaloids,
topoisomerase inhibitors, and alkylating
agents in different combinations and sched-
ules. Patients with low‐stage DLBCL or LL
(i.e., Stage I resected and abdominal Stage II)
can be treated effectively with two cycles of
chemotherapy, consisting of cyclophospha-
mide, Oncovorin (vincristine), prednisone,
and Adriamycin (doxorubicin) (COPAD).
Patients with more advanced DLBCL, BL, and
ALCL require an initial therapy “prophase”
secondary to the very high risk of TLS due to
tumor bulk as well as the exquisite sensitivity
to chemotherapy. Patients should be moni-
tored closely for metabolic abnormalities
and may require rasburicase prophylaxis
especially in the setting of bulky disease or
evidence of renal involvement or impairment.
For B‐cell lymphoma and mature acute B‐cell
leukemia, rituximab is now recommended in
addition to combination chemotherapy for
high‐risk patients (i.e., Stage III with LDH > 2×
the upper limit of normal (ULN) and Stage
IV) with evidence of benefit.
Radiotherapy is generally reserved for
patients with CNS‐positive LL, relapsed
patients, or oncologic emergencies due to
tumor compression. CNS prophylaxis is
indicated in LL and advanced‐stage B‐cell
lymphoma, as well as in those patients with
parameningeal or overt CNS disease at
diagnosis.
Novel agents
Similar to HL, utilization of brentuximab
has shown benefit in CD30+ tumors such as
ALCL as well as PD‐1 blockade in tumors
which express PD‐L1 such as PMBCL. Gene
expression of anaplastic lymphoma kinase
(ALK) is common in ALCL and therefore
ALK inhibitors crizotinib and ceritinib are
attractive agents for treating ALCL in addi-
tion to brentuximab.
Additional immunotherapies being stud-
ied in NHL target CD19‐positivity which is
common in B‐cell lymphoma, similar to
pre‐B‐ALL and inclusive of bispecific T‐cell
engaging antibodies such as blinatumomab
as well as chimeric antigen receptor T‐cell
(CAR‐T) cell therapy (see Chapter 15).
Blinatumomab has shown benefit in adult
patients with DLBCL and has not been stud-
ied systematically in pediatric patients.
Similarly, the FDA recently approved axi-
cabtagene ciloleucel (Yescarta) CD19+
CAR‐T cell therapy for adult patients with
relapsed/refractory DLBCL. Response rates
have been less than CD19+ ALL secondary to
the solid tumor microenvironment and loss
of CAR‐T cell persistence. Pediatric studies
are ongoing and although have shown excel-
lent CAR‐T tolerability, responses have not
been durable. There is potential to combine
these agents with PD‐1 blockade to improve
CAR‐T cell persistence; further study is
required.
Case study for review
You are a pediatrician seeing a 17‐year‐old
female patient for a sick visit who notes
weight loss over the last several weeks as
well as generalized itching. She had
checked her weight a couple months ago at
school and then again yesterday which
showed a 5‐pound weight loss. Her mother
was concerned about this and asked her to
see you.
a. What are some important follow‐up
questions?
It is first important to ask questions regarding
the weight loss—Has the weight loss been
intentional? Has she been exercising intensely
or have concerns regarding body image? Are
236 Chapter 17
there any concerns regarding anorexia or
bulimia? Has she been ill? Are there are any
food resource issues? Is she skipping meals
especially at school? Any recent travel (to rule
out infectious diarrhea and tuberculosis) or
unprotected sexual encounters (consideration
for HIV)? Assuming her answer to all of these
questions are no, you should be concerned
about unintentional weight loss without evi-
dence of an infectious cause. It is important
then to ask about other B symptoms including
recurrent fever and drenching night sweats.
Itching could be due to an infestation such as
scabies, but may be a manifestation of under-
lying HL. It is important to inquire regarding
other systemic manifestations of disease such
as fatigue (anemia can also be seen in HL due
to chronic disease/inflammation), secondary
amenorrhea, as well as any noted shortness of
breath, orthopnea, or lumps/bumps.
She answers no to all of these follow‐up
questions.
b. What are some important considera-
tions for physical exam?
Physical exam should be complete but spe-
cifically focus on potential findings which
would support the diagnosis of lymphoma,
specifically the presence of lymphadenopa-
thy or hepatosplenomegaly, as well as
symptoms consistent with superior vena
­ next steps?
cava/superior mediastinal syndrome (see
Chapter 14; can see plethora, distended neck
veins, jugular venous distension, hepato-
megaly). It is important to review the vital
signs to confirm the weight loss as well as
document potential fever and tachypnea
(secondary to pleural effusion or very large
mediastinal mass) or tachycardia (second-
ary to anemia or very large mediastinal
mass). Cardiac tamponade would be highly
unlikely especially with a slow‐growing
mass as seen in HL, but must be a considera-
tion especially in a more rapidly growing
NHL; checking for pulsus paradoxus should
be done if other concerning findings for
SVCS are present. The patient should be
examined for respiratory distress as well as
auscultation to rule out a pericardial rub or
diminished breath sounds consistent with
pleural effusion.
The exam is concerning for bilateral
neck fullness with palpable bilateral cervical
nodes, some >1 cm but otherwise normal.
c. What are the next steps given the
concerns?
The clinical history and exam are concern-
ing for a HL. Given the paucity of physical
symptoms, it appears the patient has a slow
growing process rather than a rapidly
enlarging NHL, though this is still a possi-
bility. Baseline labs should be done to assess
for anemia, metabolic derangements, as well
as potential tumor markers. The practi-
tioner should order a CBC/diff, complete
metabolic panel, phosphorus, LDH, uric
acid, as well as an ESR and ferritin. Copper
can also be a potential tumor marker in HL,
though is no longer routinely sent. A screen-
ing chest X‐ray (CXR) is a simple way to rule
out a mediastinal mass.
The labs reveal a mild normocytic ane-
mia, no metabolic derangements, and ele-
vated LDH, ferritin, and ESR. CXR reveals
mediastinal widening.
d. What is your diagnosis? What are the
The patient has mediastinal adenopathy,
though will need histologic proof to confirm
lymphoma and specifically HL. The age of
the patient, presentation with B symptoms,
labs, and CXR are all consistent with HL,
though other etiologies including T‐cell acute
lymphoblastic leukemia and other NHL as
well as germ cell tumors and sarcomas are
still possible. You want to talk with the patient
and the family regarding your concerns.
Given the difficult nature of the conversa-
tion, you want to ensure that the patient has
some family support available. It should be
understood that limited information will be
processed at a time of family stress and it will
be important to repeat the information at a
 Hodgkin and Non‐Hodgkin Lymphoma 237
later time. It is okay to focus on next steps
which will include need for a biopsy, likely
from one of the cervical nodes to confirm
the diagnosis. If there are concerns about any
cardiorespiratory instability or metabolic
abnormalities, the patient should be admit-
ted and diagnostic steps undertaken more
urgently. Given the reassuring exam and labs
and small amount of mediastinal disease
without orthopnea, it is reasonable to refer
the patient for urgent evaluation (within
days) to a pediatric oncologist, as well as
pediatric surgeon for an excisional lymph
node biopsy. Following histologic confirma-
tion of disease, the patient will require a stag-
ing evaluation including a PET/CT prior to
determining the appropriate treatment plan.
Suggested reading
Cairo, M.S. and Beishuizen, A. (2019). Childhood,
adolescent and young adult non‐Hodgkin lym-
phoma: current perspectives. Brit. J. Haematol.
185: 1021–1042.
Metzger, M.L. and Mauz‐Körholz, C. (2019).
Epidemiology, outcome, targeted agents and
immunotherapy in adolescent and young adult
non‐Hodgkin and Hodgkin lymphoma. Br. J.
Haematol. 185: 1142–1157.
Shanbhag, S. and Ambinder, R.F. (2018). Hodgkin
lymphoma: a review and update on recent
progress. CA Cancer J. Clin. 68: 116–132.
Von Keudell, G. and Younes, A. (2019). Novel ther-
apeutic agents for relapsed classical Hodgkin
lymphoma. Br. J. Haematol. 184: 105–112.
18 Wilms Tumor
Wilms tumor, also known as nephroblastoma,
is the most common renal tumor in children,
accounting for approximately 6% of child­
hood malignancies and 10% of all cancers in
the 1–4‐year age group. It was named after Dr.
Max Wilms (1867–1918), a German surgeon
who first described the tumor. A tumor of the
developing kidney, it typically occurs in young
children between the ages of 1 and 5 years
with a peak incidence at 3–4 years of age and
approximate equal incidence among boys and
girls (though interestingly occurs at earlier
ages in boys). Bilateral Wilms tumor is more
common in girls (ratio of 0.6 boys to 1.0 girls)
and in younger children, with a median age of
diagnosis of 32 months versus 44 months in
unilateral cases. Most cases of Wilms tumor
are sporadic, with approximately 1% familial
and 2–4% associated with rare congenital syn­
dromes. Familial cases are more likely to pre­
sent with bilateral tumors and occur at a
younger age. Rarer renal tumors in young
children include clear cell sarcoma of the kid­
ney (CCSK) and rhabdoid tumor of the kid­
ney (RTK). The most common renal tumor in
adolescents is renal cell carcinoma.
Genetics
Congenital anomalies occur in 12–15% of
cases, the most common being hemihyper­
trophy, aniridia, and genitourinary tract
Handbook of Pediatric Hematology and Oncology – Children’s Hospital & Research Center Oakland,
Third Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
(GU) anomalies, such as cryptorchidism,
hypospadias, horseshoe kidney, ureteral
duplication, and polycystic kidney. Aniridia
is present in approximately 1.2% of children
with Wilms tumor. Most children with Wilms
tumor have a normal karyotype; however,
mutations of the Wilms tumor 1 (WT1) gene
on chromosome 11p13 and PAX6 gene are
observed in approximately 20% of patients
(PAX6 is highly implicated in children with
congenital aniridia). The WT1 gene encodes
a transcription factor important in normal
kidney development and deletion of this gene
imposes a 30–40% risk of developing Wilms
tumor. Mutations within the WT1 gene have
also been identified in several syndromes
associated with Wilms tumor: WAGR syn­
drome (Wilms tumor, Aniridia, GU anoma­
lies, and mental retardation), Denys–Drash
syndrome (Wilms tumor, nephropathy, and
GU anomalies including pseudohermaphro­
ditism), and Frasier syndrome (ambiguous
genitalia, streak gonads, and focal segmental
glomerulosclerosis). Beckwith–Wiedemann
syndrome (macroglossia, omphalocele, vis­
ceromegaly, with or without hemihypertro­
phy) is associated with imprinting defects at
several genes at chromosome 11p15.5, a
locus referred to as the WT2 gene. Patients
with this syndrome have a genetic predis­
position to develop Wilms tumor, with an
incidence as high as 5–10%. Other genetic
syndromes associated with Wilms tumor
240 Chapter 18
include: Perlman, mosaic ­variegated aneu­
ploidy, Fanconi anemia, and Simpson–
Golabi–Behmel syndrome.
Clinical presentation
Most children with Wilms tumor are gener­
ally in good health at presentation and come
to medical attention due to abdominal
enlargement or mass detected by a family
member or primary care physician on a rou­
tine check‐up. A palpable abdominal mass is
the presenting sign in 60% of children with
Wilms tumor. Associated signs and symp­
toms include abdominal pain (usually
related to obstipation or bleeding within the
tumor), malaise, fever, hypertension (25%,
more likely with bilateral disease or com­
pression of renal vessels by the mass), and
microscopic hematuria (15–20%). Bleeding
within the tumor may occur spontaneously
or as a result of trauma and result in anemia,
pallor, and fatigue. Tumor thrombus may
extend into the vena cava, causing partial
obstruction, hypertension, and distention of
abdominal veins. Polycythemia may be seen
in Wilms tumor and its association with
erythropoietin levels is not clear. Acquired
von Willebrand disease with reduced von
Willebrand factor (VWF), factor VIII coag­
ulant, and ristocetin cofactor levels is
reported in approximately 8% of patients
newly diagnosed with Wilms tumor and
typically resolves with therapy initiation. Its
occurrence in Wilms tumor is thought to be
secondary to binding of VWF to the tumor
with subsequent degradation as well as hya­
luronic acid secretion by nephroblastoma
cells leading to decreased efficacy of VWF.
All children with unexplained polycythemia,
the presence of a syndrome highly associ­
ated with Wilms tumor, or congenital
aniridia or GU anomalies, should be evalu­
ated for Wilms tumor during the period of
greatest risk.
Evaluation of suspected Wilms
tumor
●● History: include family history of malig­
nancies, congenital anomalies, or syndromes
known to be associated with Wilms tumor.
●● Physical examination: vitals including
temperature and blood pressure, gently
assess for abdominal/flank mass (usually
distinct and not crossing the midline), con­
genital anomalies (hemihypertrophy, GU
malformations, aniridia), abdominal venous
distention, and liver enlargement.
●● Laboratory studies: urinalysis with micro­
scopic evaluation, complete blood count
(polycythemia and anemia), serum chem­
istries (hypercalcemia in rhabdoid tumor
or congenital mesoblastic nephroma), and
coagulation studies including von
Willebrand panel.
●● Diagnostic imaging studies to assess uni­
lateral/bilateral involvement, metastatic
disease, or presence of tumor thrombus in
the renal inferior vena cava (IVC) or renal
vessels:
❍ Doppler abdominal ultrasound to evalu­
ate the size and extent of tumor, presence of
tumor thrombus, and contralateral kidney.
❍ Abdominal CT or MRI with special
attention to evidence of bilateral involve­
ment, renal vessel involvement or exten­
sion into the IVC, lymph node involvement,
and liver metastases.
❍ Chest radiography and chest CT to assess
for lung metastases (most common site).
❍ Bone scan to assess for metastases
(more common in CCSK) and for all
patients with Wilms tumor or renal cell
carcinoma with bony symptoms.
❍ MRI of the brain for metastases if the
tumor is a RTK or CCSK.
❍ Echocardiogram for detecting tumor
extension from the IVC to the right atrium
and also indicated in the child receiving
anthracycline chemotherapy.
 Wilms Tumor 241

association with congenital anomalies and

Pathologic diagnosis
familial cases. Loss of heterozygosity (LOH)
for polymorphic DNA markers at both chro­
Children with suspected Wilms tumor should
mosomes 1p and 16q occurs in about 5% of
have an immediate consultation with a pedi­
patients with FH Wilms and is associated with
atric surgeon. Surgical removal of the involved
poorer outcomes and increased risk of relapse.
kidney and intact tumor is indicated at diag­
Gain of chromosome 1q is frequently seen in
nosis if possible. Most tumors are encapsu­
association with LOH and appears to be an
lated and vascular, and due to the fragile
independent poor prognostic factor.
nature of these tumors, it is imperative that a
meticulous surgical approach be undertaken
by an experienced surgeon. Rupture may
Staging
occur and increase the risk of bleeding or
peritoneal dissemination and upstage the
Staging is based on anatomic findings, surgical
patient. Cases with tumor in the renal pelvis
outcome, histology, and presence or absence of
and IVC require a detailed imaging assess­
regional or distant disease. Patients unable to
ment to guide the surgeon. In some cases,
undergo a radical nephrectomy at diagnosis
complete removal of the primary tumor at
due to excessive risk receive preliminary staging
diagnosis may not be possible. In these cases,
and preoperative chemotherapy with delayed
open biopsy is indicated for pathologic con­
resection. A careful pathologic evaluation at the
firmation and determination of histology.
time of excision should be performed, as the
The classic pathologic features of Wilms
histology may be different than that seen on
tumor show a triphasic pattern of nephroblas­
initial biopsy. This evaluation includes looking
toma tissue elements: blastema, stroma (mes­
for extension of disease outside the kidney,
enchyme), and epithelium. Tumors are also
including penetrance of the tumor through the
classified as either favorable histology (FH)
renal capsule into the renal pelvis and vessels
(well‐differentiated components) or unfa­
and presence of nodal involvement.
vorable (presence of anaplasia with poor dif­
Clinicopathologic staging is as follows:
ferentiation). Anaplastic features include
●● Stage I: tumor limited to the kidney and
nuclear enlargement and atypia, as well as
completed excised with an intact capsule
irregular mitotic figures. Anaplasia is further
without tumor rupture or biopsy prior to
defined as focal or diffuse based on the distri­
resection; negative regional nodes.
bution of the anaplastic elements. Histology
●● Stage II: tumor penetrates the renal cap­
confers a significant prognostic element, with
sule either by biopsy or rupture prior to
the best outcome in cases of FH, followed by
excision, with spillage confined to the flank;
focal anaplasia and then diffuse anaplasia.
tumor may involve the perirenal soft tissue
Nephrogenic rests refer to areas of persistent
or infiltrate vessels outside the kidney but is
embryonal tissue within the kidney, and, if
completely excised; negative regional nodes.
identified, confer increased risk for develop­
●● Stage III: residual nonhematogenous dis­
ment of Wilms (or recurrent disease if present
semination of tumor confined to the abdo­
in residual kidney or contralateral kidney).
men; tumor may extend beyond surgical
Other malignant tumors of the kidney need to
margin at resection or be removed in more
be considered including RTK, CCSK, and
than one piece, may involve local lymph
renal cell carcinoma. Chromosome analysis
nodes, or have tumor spillage with perito­
on the tumor (and potentially germline from
neal implants; patients with initial biopsy in
the peripheral blood) may prove useful in
lieu of resection are considered Stage III.
242 Chapter 18
●● Stage IV: hematogenous dissemination of
tumor outside the abdomen to lungs, liver,
bone, brain, or distant lymph nodes.
●● Stage V: bilateral renal involvement.
Patients with bilateral involvement of
tumor (Stage V) should have each side inde­
pendently staged (abdominal stage) with
treatment based on the side with the highest
stage.
Treatment
Wilms tumor is highly responsive to treat­
ment with approximately 90% of children
being cured of their disease. Histology is
more prognostic for outcome than surgical
staging; for example, patients with Stage IV
disease but with FH still have a 4‐year sur­
vival of more than 85%, compared to chil­
dren with diffuse anaplasia and advanced
disease who have very poor outcomes.
Children with Stages I and II FH tumors have
a 5‐year event‐free survival exceeding 95%.
Many tumors are low stage at presenta­
tion (43% Stage I and 23% Stage II) and are
able to be fully resected. Radical resection
(nephrectomy) of the involved kidney is
typically the primary approach if the tumor
is confirmed on imaging to be unilateral and
there is marginal “normal” renal paren­
chyma at the periphery. High‐quality CT
imaging is critical in surgical planning.
Surgical sampling of lymph nodes should
include the perihilar, para‐aortic, and para­
caval regions in addition to any visibly
abnormal appearing nodes. In the case of
bilateral tumors (and those with increased
risk to develop bilateral tumors including
syndromes, familial cases, known nephro­
genic rests), a renal sparing approach may
be warranted. Should the tumor be deemed
inoperable (i.e., complete resection not
possible) due to tumor extension in the
renal vessels or IVC, or invasion into adjacent
organs, biopsy and nodal sampling should
be done by an experienced surgeon. Chemo­
therapy is then initiated and the tumor
reassessed by imaging at 6 weeks. If tumor
shrinkage has occurred but risk for spillage
or incomplete resection is still thought to
be high, another 6 weeks of chemotherapy
is indicated; however, definitive surgery
should be performed no later than 12 weeks
after therapy initiation.
Wilms tumors are very sensitive to chem­
otherapy and radiation. Based on the exceed­
ingly good outcomes, contemporary studies
have looked to decrease therapy in the lower
risk stratum. This includes the elimination
of chemotherapy in patients younger than
2 years with Stage I FH disease and tumor
mass of <550 g without LOH at 1p and 16q.
For patients receiving chemotherapy, the
backbone of therapy is based on previous
studies by the National Wilms Tumor Study
Group. Treatment consists of an 18‐week
course of vincristine and actinomycin‐D for
Stages I and II FH patients; 24 weeks of treat­
ment with vincristine, actinomycin‐D, and
doxorubicin for those with Stages III and IV
FH as well as Stages I–IV with focal anaplasia
or Stage I with diffuse anaplasia. Patients
with Stages II, III, or IV with diffuse anapla­
sia receive a 24‐week course of chemother­
apy with vincristine, cyclophosphamide, and
etoposide. Patients who are determined to
have LOH at 1p and 16q are upstaged after 6
weeks of therapy with the addition of
­cyclophosphamide and etoposide. Gain of
chromosome 1q, a common cytogenetic
finding in Wilms tumor, is also indepen­
dently associated with poorer survival and is
being incorporated into future risk stratifica­
tion models of treatment.
High‐risk patients (Stages III and IV FH
and abdominal stages I–III anaplastic) gen­
erally receive radiation therapy in addition
to a chemotherapeutic backbone. Radiation
is usually begun within 10–14 days of tumor
resection and the size of the radiation field
is dependent on tumor extension or spill

during surgery. The dose to the tumor bed is
1080 cGy. Whole abdominal radiation is
given in the situation of peritoneal seeding
or gross tumor spillage as a result of capsular
rupture prior to or during surgery. Radiation
at higher doses (1980 cGy) may be given in
unresectable tumor or metastatic nodal
involvement. In general, patients with pul­
monary metastasis will require lung irradia­
tion (1200 cGy), although newer trial results
suggest this can be eliminated in patients
with a rapid response to chemotherapy and
no additional risk factors.
Relapse is uncommon in Wilms tumor;
patients may be salvaged with aggressive
multiagent chemotherapy that may include
agents not given initially such as cyclophos­
phamide, ifosfamide, carboplatin, etopo­
side, topotecan, and irinotecan. Radiation
may be utilized depending on the site and
extent of recurrence and if previously not
given. High‐dose chemotherapy with autol­
ogous stem cell rescue has been shown to
improve outcomes after relapse in those that
have a complete response to chemotherapy
and radiation therapy.
As survival is excellent for most children
with Wilms tumor, much attention has
focused on late effects related to therapy and
limiting potential toxicities. Patients are at
risk for hypertension and renal insufficiency,
as most children will have a solitary remain­
ing kidney. Patients with bilateral disease,
partial resection, and radiation exposure are
particularly at risk for developing proteinu­
ria and renal compromise in addition to
hypertension. Cardiac complications may be
seen in those patients who receive anthracy­
clines and lung irradiation. Additionally,
patients with right‐sided tumors who receive
flank irradiation or those who received
whole abdomen irradiation have an
increased risk of developing a secondary
liver cancer. Treatment interventions should
be considered when generating a long‐term
follow‐up care plan for the patient. These
Wilms Tumor 243
adverse effects have influenced modern
treatment protocols with the aim of decreas­
ing therapy as possible in future to mitigate
side effects without decrement in outcomes.
Screening of children at risk for Wilms
tumor is recommended for those with known
congenital anomalies (hemihypertrophy,
aniridia) or presence of one of the associated
syndromes discussed in the earlier text.
Screening consists of a careful physical exam­
ination and an abdominal ultrasound.
Children with Beckwith–Wiedemann syn­
drome should be screened every 3 months
until 8 years of age in addition to screening
for hepatoblastoma with a serum alpha‐feto­
protein (AFP) through 5 years of age. Testing
for the 11p15 mutation and methylation
analysis (to identify epigenetic changes asso­
ciated with increased risk) should be consid­
ered. Children with Denys–Drash or WAGR
syndromes should be screened to age 5 years
and 7 years, respectively. Children with con­
genital aniridia should be screened for the
presence of the WT1 gene mutation and, if
present, be screened until age 6 years; if not
present, the risk of developing Wilms is simi­
lar to the general population. Children with
Wilms tumor who have had nephrogenic
rests identified in the tumor are at risk for late
recurrence or development of tumor in the
contralateral kidney (or both if renal sparing
surgery is done in the face of potential bilat­
eral involvement) and should be screened for
10 years post treatment.
Case study for review
You are seeing an 8‐year‐old girl in the
emergency department for a history of 2
weeks of early satiety and abdominal pain.
Her exam is significant for a left‐sided
abdominal mass as well as hepatomegaly.
Her initial CBC is significant for microcytic
anemia, hgb 7.4 g/dl, elevated LDH, hyper­
uricemia, and a prolonged APTT.
244 Chapter 18
a. What would your differential diagnosis
be, given this information?
Initially, this case should be concerning for a
rapidly dividing hematologic malignancy
with organ infiltration such as Burkitt’s
lymphoma, given the high uric acid and LDH,
as well as anemia. However, the left‐sided
mass also raises concern for a renal mass. The
most common primary renal malignancy in
­children is Wilms tumor. In this case, the
hepatomegaly is concerning for hepatic
metastases. Other renal tumors should also
be considered including CCSK (which can
also present with hepatic involvement), renal
cell carcinoma (though this is more common
in adolescents and adults), and RTK (more
common in infants and young children). It is
also important to look closely at the vital
signs, as the patient may have hypertension
secondary to involvement or compromise of
the renal vasculature.
b. What are the next steps in the diag­
nostic evaluation?
Imaging with an abdominal ultrasound is
the next logical step in the assessment, pro­
viding relatively quick information on the
location and potential etiology of the mass.
In this case, the abdominal ultrasound
revealed a mass arising from the left kidney
as well as multiple hepatic nodules. A subse­
quent MRI of the abdomen and pelvis con­
firmed these findings as well as multiple
peritoneal lesions. The finding of a mass
arising from the kidney is suggestive of a pri­
mary renal tumor. Chest CT imaging with­
out contrast is recommended to determine
if lung metastases are present. Laboratory
assessment should include a ­ urinalysis
(assessing for bleeding), CBC (can see ane­
mia, thrombocytosis), and a von Willebrand
panel, as 8% of children with Wilms tumor
have acquired von Willebrand disease. In the
setting of a prolonged APTT, this should be
suspected. After careful review by experi­
enced pediatric surgeons and radiology, a
determination is made whether the renal
tumor can be safely removed intact, and, if
not, then a biopsy alone will be performed.
Histology is critical to staging and determi­
nation of a treatment plan. Further imaging
with a bone scan (to determine if bone
metastases are present) as well as positron
emission tomography‐computer tomogra­
phy (PET‐CT) can be considered if the
patient is symptomatic or has RTK or CCSK,
but is generally not required for Wilms
tumor. In this case, the renal tumor was fully
resected and pathology revealed FH Wilms
tumor.
c. How does this case differ from a typi­
cal presentation of Wilms tumor?
There are several factors which are atypical
in this patient’s presentation. This patient is
significantly older than the average child
with Wilms tumor, with a mean age of pres­
entation of 44 months. Older age at diagnosis
is associated with an adverse prognosis.
While lung metastases are common in
Wilms tumor (15%), liver involvement and
peritoneal nodules are far less common.
Given the hematogenous metastases in this
case, the patient is classified as a Stage IV
Wilms tumor which represents 11% of all
patients. Of note, hepatic involvement at
diagnosis is not an independent adverse
prognostic factor. Even for higher‐stage
disease, the 4‐year overall survival for FH
Stage IV disease with the current standard of
care chemotherapeutic regimens is 86%.
Suggested reading
Dome, J.S., Fernandez, C.V., Mullen, E.A. et al.
(2013). Children’s Oncology Group 2013
blueprint for research: renal tumors. Pediatr.
Blood Cancer 60: 994–1000.
Irtan, S., Ehrlich, P.F., and Pritchard‐Jones, K.
(2016). Wilms tumor: “State of the art” update,
2016. Semin. Pediatr. Surg. 25: 250–256.
Nakamura, L. and Ritchey, M. (2010). Current
management of Wilms tumor. Curr. Urol. Rep.
11: 58–65.
19 Neuroblastoma
Neuroblastoma is a neoplasm of the
­sympathetic nervous system and the most
common solid tumor of early childhood,
with a peak incidence around 2 years of age.
Neuroblastoma is a disease of developing
neural crest tissue and has an extremely
­heterogeneous prognosis based on multiple
factors such as the age of the patient, differ-
entiation and biology of the tumor, and
extent of disease spread. Screening in the
Japanese infant population found a high
incidence of neuroblastoma, although the
majority of these cases matured or involuted
spontaneously, again implying the heteroge-
neous prognosis based on patient age.
Survival rates for neuroblastoma have
improved over the last 30 years, initially lim-
ited to patients with lower‐risk disease.
Recent breakthroughs utilizing immuno-
therapy have increased survival in those
with high‐risk disease as well.
Familial cases of neuroblastoma are quite
rare. However, genetic risk factors for neuro-
blastoma have been identified including the
anaplastic lymphoma kinase 1 and PHOX2B
homeobox genes. Patients with Hirschsprung’s
disease, neurofibromatosis type I, and con-
genital hypoventilation syndrome may have
genetic alterations in PHOX2B and an
increased risk of developing neuroblastoma,
although clear genetic links have not as yet
been identified. More commonly, amplifica-
tion of the oncogene N‐myc in tumor tissue
has been found to have a profound negative
Handbook of Pediatric Hematology and Oncology – Children’s Hospital & Research Center Oakland,
Third Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
impact on prognosis. Similarly, a near diploid
(low DNA index, DNA index = 1) chromo-
some number in the tumor has also been
found to be a negative prognostic indicator as
compared to patients with a DNA index >1.
Based on these factors, in addition to age,
stage, and histology (favorable or unfavorable
based on mitosis‐karyorrhexis index [MKI]
and maturity of the tumor), a complicated
risk‐stratified treatment regimen has been
created and was recently modified.
Clinical presentation
As neuroblastoma originates from primor-
dial neural crest cells that normally give rise
to the adrenal medulla and the sympathetic
ganglia, tumors present in the abdomen and
along the sympathetic neural pathway. The
most common presentation is an abdominal
mass with primary tumor in the adrenal
gland, often with metastatic disease via lym-
phatic and hematogenous spread. Tumors
are often seen along the paraspinal ganglion
and may be found in the neck, thorax, and
pelvis. Infants are more likely to have tho-
racic and cervical tumors. Common sites of
metastasis are the lymph nodes, bone mar-
row, bone, liver, and skin.
The signs and symptoms at presentation
depend on the site of the tumor, size, and the
degree of spread. Patients with locoregional
disease may be relatively asymptomatic,
246 Chapter 19
whereas patients with widely metastatic dis-
ease are often ill‐appearing with fever, pain,
weight loss, and irritability. Abdominal
tumors are usually palpable, hard, fixed
masses. Compression of the renal vascula-
ture may lead to hypertension in addition to
potential catecholamine secretion from
tumor cells. The liver may be enlarged, lead-
ing to respiratory compromise due to com-
pression of the diaphragm, especially in the
infant. There may be evidence of anemia
(pallor, weakness, and fatigue), coagulopa-
thy (bruising and bleeding), and bone pain
or limping with bone or bone marrow
involvement. Thoracic masses are usually
picked up in the posterior mediastinum
incidentally by imaging studies done for
other reasons. Cervical masses may initially
be treated as cervical adenopathy related to
infection. The presence of Horner’s syn-
drome (miosis [contracted pupil], ptosis,
enophthalmos [posterior eye displacement],
and anhidrosis), or heterochromia iridis
should prompt an evaluation for cervicotho-
racic neuroblastoma. Pelvic masses may
cause bowel or bladder symptoms and
tumors along the sympathetic ganglia may
cause spinal cord compression. Skin lesions
tend to be limited to infants and appear as
bluish, nontender subcutaneous nodules.
Sphenoid or retro‐orbital bone involvement
may occur and appear clinically as “raccoon
eyes” secondary to periorbital hemorrhage.
In addition to Horner’s syndrome, the
­clinician should be aware of potential para-
neoplastic syndromes with neuroblastoma.
One unusual presentation is opsoclonus‐
myoclonus‐ataxia syndrome (OMAS), also
referred to as “dancing eyes/dancing feet.”
These children have cerebellar and truncal
ataxia as well as myoclonus (muscle jerks)
and opsoclonus (rapid, involuntary, uncoor-
dinated eye movements). Developmental
delay, language deficits, and behavioral
abnormalities (e.g., irritability) may also be
present. Children with OMAS should be
carefully evaluated for the presence of an
occult neuroblastoma. Children with OMAS
tend to have a low‐stage, highly curable
neuroblastoma. Unfortunately, cure often
­
has little impact on the OMAS, and these
children are frequently left with severe,
chronic neurologic deficits. The pathophysi-
ology of this syndrome is not well‐defined,
but is likely due to formation of an antibody
directed against the neuroblastoma cells also
targeting cerebellar neurons. In addition to
treatment of the neuroblastoma, these chil-
dren may benefit from immunosuppressive
therapy with agents such as dexamethasone,
cyclophosphamide, intravenous immune
globulin (IVIG), and rituximab; adrenocor-
ticotropic hormone (ACTH) may also be
potentially beneficial. Neuroblastoma
patients may also present with hypersecre-
tory diarrhea secondary to hypersecretion of
vasoactive intestinal peptide (VIP) from the
neuroblastoma cells. In most cases, treat-
ment of the underlying disease will eliminate
the VIP hypersecretion.
Diagnostic evaluation
History
Assess for constitutional symptoms, abdom-
inal pain, bowel or bladder control prob-
lems, bleeding, bone pain, and limping.
Physical examination
Assess vital signs (fever and hypertension)
and evaluate for abdominal mass, spinal
cord compression, unusual signs/symptoms
associated with neuroblastoma (heterochro-
mia, raccoon eyes, Horner’s syndrome),
subcutaneous nodules in infants, enlarged
liver or lymph nodes, and evidence of ane-
mia or coagulopathy.
Laboratory studies
Obtain complete blood count with differen-
tial, serum chemistries (liver function
­studies and lactate dehydrogenase), ferritin
(may be a tumor marker and elevated in

neuroblastoma, though also an acute‐phase
reactant), and urine for catecholamines
­ should have baseline thyroid function (FT4
including homovanillic acid (HVA) and
vanillylmandelic acid (VMA). These urine
metabolites are elevated in more than 90%
of children with neuroblastoma, especially
in the higher stages of disease. In patients
with clinical suspicion for neuroblastoma
and negative urine markers, urine dopamine
can be measured in addition to 24‐hour
urine collections for HVA and VMA.
Neuron‐specific enolase (NSE), a serum
marker specific to the sympathetic nervous
system, is relatively specific to neuroblas-
toma, although it can be elevated after brain
injury and seizures.
Diagnostic studies
Patients with confirmed neuroblastoma
should have bilateral bone marrow aspira-
tion and biopsy performed to assess for
bone marrow involvement. Special stains
(S100, synaptophysin, and NSE) are used to
differentiate this tumor from other small,
round blue cell tumors of childhood such as
rhabdomyosarcoma, Ewing sarcoma, lym-
phoma, and primitive neuroectodermal
tumor.
Imaging studies should include:
CT or MRI of the primary site (MRI is
preferred due to the radiation exposure
associated with repeated CT imaging).
Calcifications and hemorrhage are com-
monly seen, especially in large abdominal
masses. The tumors tend to be large and dis-
place adjacent organs; however, the tumor
can wrap around major structures, causing
obstruction and dysfunction. If there is
suspicion of paraspinal or intraspinal
­ International Neuroblastoma Risk Group
involvement, MRI and plain films of the
spine should be done.
Bone scan (technetium‐99 m) or prefer-
rably, MIBG (metaiodobenzylguanidine)
scan (123I‐MIBG scan preferred over 131I‐
MIBG due to decreased risk to thyroid
function). Prior to MIBG scanning, the
­ tiple potential treatment categories that
patient must receive thyroid protection
Neuroblastoma 247
with ­ potassium iodide (SSKI) drops and
[free thyroxine] and TSH [thyroid stimulat-
ing hormone]) checked. MIBG, a functional
analog of norepinephrine, is taken up by
sympathetic neurons and is a sensitive test
for neuroblastoma cells. It is also positive in
pheochromocytoma. Due to the high radia-
tion doses with both bone scan and MIBG
scanning, patients can be followed solely
with MIBG, if available and lesions are
MIBG-avid. In the case of non-MIBG-avid
tumors, PET scanning may be required.
Localized tumors should be surgically
removed if deemed safe and feasible. Many
tumors are initially unresectable. These
tumors should be surgically biopsied at the
most easily accessible site (often a metastatic
lymph node). Diagnosis is generally estab-
lished by pathologic assessment of the resec-
tion or biopsy and can be confirmed by
diagnostic features such as bone marrow
involvement with appropriate immunohis-
tochemical markers, MIBG avidity, and
positive urine catecholamines and serum
NSE. Genetic studies should be conducted
to determine N-myc and loss of heterozygo-
sity (LOH) as well as ALK (as a potential
therapeutic target) and segmental chromo-
somal aberration testing (in potential lower
risk patients).
Staging
The International Neuroblastoma Staging
System was replaced by a new risk‐stratified
pretreatment classification system by the
(INRG) in 2015 and is outlined in Table 19.1.
Treatment
Risk stratification divides patients into mul-
are continually evaluated through clinical
Table 19.1 International Neuroblastoma Risk Group pretreatment staging system.

INRG stage Age (Mos) Histologic category Grade of tumor N-MYC 11q aberration Ploidy Pretreatment risk
differentiation group

L1/L2 GN maturing, GNB A (very low)

intermixed
L1 Any, except GN maturing NA B (very low)
or GNB intermixed Amplified K (high)
L2 <18 Any, except GN maturing NA No D (low)
or GNB intermixed Yes G (intermediate)
L2 ≥18 GNB nodular, Differentiating NA No E (low)
neuroblastoma Yes H (intermediate)
Poorly differentiated or NA H (intermediate)
undifferentiated Amplified N (high)
M <18 NA Hyperdiploid F (low)
<12 NA Diploid I (intermediate)
12 to <18 NA Diploid J (intermediate)
<18 Amplified O (high)
≥18 P (high)
MS <18 NA No C (very low)
Yes Q (high)
Amplified R (high)

GN, ganglioneuroma, GNB, ganglioneuroblastoma; NA, not amplified.


s­ tudies. For simplicity, we divide treatment
strategies into three main groups: (i) obser-
vation, (ii) chemotherapy, and (iii) high‐
dose chemotherapy with autologous stem
cell rescue and adjuvant therapy with immu-
nomodulators. Generally, patients which are
in the very‐low‐risk and low‐risk pretreat-
ment groups (INRG A–F) can be observed
(potentially after surgical resection), while
those in the high‐risk groups (INRG K–R)
require multimodal therapy.
As mentioned, clinical studies are ongo-
ing to refine treatment groups. Specifically,
attempts are being made to reduce treat-
ment in some of the lower‐risk subgroups
that still require therapy but have an excel-
lent overall prognosis (>90% survival).
Survival in patients with high‐risk disease
has improved significantly with a combina-
tion of chemotherapy, surgical resection,
autologous transplant (i.e., high‐dose
chemotherapy with stem cell rescue), radia-
tion, and immunotherapy. The chemother-
apy backbone includes drugs such as
carboplatin, cyclophosphamide, doxoru-
bicin, and etoposide. A recent Children’s
Oncology Group study showed that tandem
transplantation with cyclophosphamide/
thiotepa and carboplatin/etoposide/mel-
phalan (CEM) was superior to single trans-
plant with CEM alone. It is unclear if this
tandem regimen is superior to busulfan/
melphalan, which is the preparative regimen
utilized in Europe as a single transplant. The
single greatest advance in the treatment of
high‐risk neuroblastoma has been the
advent of a monoclonal antibody directed
against ganglioside (GD2), an antigen on
neuroblastoma cells. Combination therapy
with anti‐GD2 antibodies and cytokine
therapy (GM‐CSF, granulocyte‐macrophage
colony‐stimulating factor), in addition to
therapy with isotretinoin (cis‐retinoic acid;
cis‐RA), a neuroblastoma cell maturing
agent, together has augmented survival
Neuroblastoma 249
s­ignificantly. Novel therapeutics modalities
including difluoromethylornithine (DFMO),
131
I‐MIBG therapy, and targeted molecular
therapies are being studied to determine
if treatment outcomes can be further
improved.
Case studies for review
1. You are seeing a 2-month-old female
infant for routine well-child check and first set
of vaccinations. Birth history is unremarka-
ble. The parents overall feel that the child is
doing well, though note that she appears to
tire a little bit with feeding over the past few
weeks and that her abdomen seems more dis-
tended. There has been no fever or intercur-
rent illness. She has been stooling and
urinating normally. On exam, the infant is
well-appearing with normal vital signs except
for mild tachypnea. There is no pallor or lym-
phadenopathy. The skin and eye exams are
normal. There is no cyanosis. You note mild
increased work of breathing with clear lung
sounds. The abdomen though is distended
with a large, nontender palpable liver. There
are no other concerning clinical findings.
a. What is your initial differential
diagnosis?
Several entities can cause hepatomegaly
in a young infant including infections,
oncologic processes, storage diseases, and
intrinsic liver pathology. Infection seems
unlikely, as the infant is well-appearing
without any concerning history in the peri-
natal period. Common neonatal oncologic
processes include hepatoblastoma and
neuroblastoma, with more rare entities
including embryonal sarcoma of the liver.
Focal nodular hyperplasia, hamartoma,
hepatic adenoma, hemangioendothelioma
(with associated Kasabach–Merritt), and
Kaposiform hemangioendothelioma are
processes intrinsic to the liver.
250 Chapter 19
b. What are the next best steps?
Baseline laboratory workup should be done
to ensure no significant issues with hemo-
globin and platelets. Kasabach–Merritt may
cause significant thrombocytopenia second-
ary to platelet trapping (see Chapter 12).
Abdominal ultrasound would be most
helpful in this case. Alpha-fetoprotein
(AFP) can be done if there is concern for
hepatoblastoma.
Abdominal ultrasound shows a small
right adrenal mass with heterogeneous
liver involvement most consistent with
neuroblastoma.
c. What should be done next?
Diagnosis of neuroblastoma should be
confirmed with a combination of imaging,
laboratories, and ultimately, surgical biopsy.
Laboratories should include urine HVA and
VMA in addition to serum NSE. Urine
catecholamines (dopamine, epinephrine,
­ been no intercurrent illness, no past medical
norepinephrine) can be ordered if the diag-
nosis is equivocal. Imaging should include
MRI of the primary site and metastatic sites
to further characterize the tumor in addi-
tion to 123I-MIBG scan. Although a positive
123
I-MIBG scan is pathognomonic for
­neuroblastoma, surgical biopsy is necessary
to confirm the diagnosis. Additionally,
­bilateral bone marrow aspirate and biopsy
should be done concomitant with surgical
biopsy to determine potential bone marrow
metastatic disease.
Laboratory studies show a positive urine
HVA and NSE. Follow-up imaging studies
show disease limited to the right adrenal
with heterogeneous uptake in the liver. Bone
marrow studies are negative. Tumor pathol-
ogy is consistent with neuroblastoma with
a high DNA index and low MKI. The tumor
is not N-myc amplified and otherwise has a
favorable genetic profile.
d. What is the patient’s stage? What are
the next steps?
Fortunately, for young children with lim-
ited extent of disease, the large majority of
neuroblastoma will mature spontaneously
over time. In the case of the relatively
asymptomatic patient without concerning
findings on tumor pathology, the patient
can be monitored with serial laboratories to
follow tumor markers (NSE, urine HVA in
this case) in addition to imaging. Any dis-
ease progression or symptomatic involve-
ment would prompt chemotherapy to
mitigate continued tumor growth or absolve
symptoms, especially respiratory distress
with massive hepatomegaly.
2. You are working in the emergency
department and are seeing a 3-year-old male
who presents with irritability. The parents
also note that his eyes look “funny” at times.
These symptoms have been worsening over
the last few days. It also seems that he has
been having trouble walking. There has
history, he is on no medications, and there is
no concern for any toxic ingestion. Vital
signs are normal. Exam shows eyes with
random movements rather than particularly
horizontal or vertical nystagmus. The child
is irritable and is difficult to console by the
parents. He refuses to walk. The neurologi-
cal exam is otherwise unremarkable, with
no noted loss of tone or hyporeflexia/­
hyperreflexia. The cranial nerves appear
normal and there are no signs of Horner’s
syndrome. There is no palpable abdominal
mass.
a. What is the likely diagnosis? What are
the next steps?
The child’s presentation seems most con-
sistent with OMAS. As mentioned, timely
diagnosis and treatment of the underlying
neuroblastoma can minimize long-term
sequelae in regard to cerebellar damage. As
with Case 1, the patient should undergo rou-
tine laboratory workup in addition to urine
HVA, VMA, and serum NSE. Considering
that many of the patients with OMAS may
have early stage disease, these laboratory

markers may be normal (often NSE is ele-
vated with normal HVA and VMA). Since
there are no focal findings on clinical exam,
screening abdominal ultrasound would be a
reasonable next step, though likely the
patient will need 123I-MIBG scan for defini-
tive diagnosis.
Workup shows localized uptake along
the cervical spine on 123I-MIBG scan with an
elevated NSE and otherwise unremarkable
workup.
b. What are the next steps?
In the case of localized disease, surgical
resection should be undertaken if safe and
feasible. Local lymph node resection should
be done to assess appropriate disease stage.
The patient undergoes surgical resection
which achieves a gross total resection. Local
lymph nodes are negative for disease involve-
ment. Concomitant bone marrow studies
are negative. Tumor pathology shows a low-
stage neuroblastoma without N-myc ampli-
fication. The patient continues to have
concerning symptoms postsurgical includ-
ing the aforementioned irritability, motor
and speech dysfunction, and opsoclonus.
c. Is this expected? What should be
done?
OMAS occurs likely secondary to antibody
production directed towards neuroblas-
toma cells which cross-react with cerebellar
tissue. This autoantibody therefore contin-
ues to cause cerebellar destruction even
after tumor resection. The goal of therapy
for OMAS is immunosuppression to hope-
fully suppress and ultimately e­ liminate this
Neuroblastoma 251
autoantibody. There is no standardized
treatment for OMAS, though many centers
use dexamethasone (due to its enhanced
ability to cross the blood–brain barrier com-
pared with prednisone) in combination
with IVIG and cyclophosphamide. Steroids
lead to nonspecific immunosuppression
while cyclophosphamide inhibits T-cell
replication. IVIG helps to overwhelm the
antibody response (similar to immune
thrombocytopenic purpura, ITP), though
this action is transient. Patients who fail to
improve or relapse after this initial therapy
may benefit from treatment with rituxi-
mab (CD20 monoclonal antibody). Most
patients will need monitoring and therapy
to ensure the best possible speech and
motor development.
Suggested reading
Davidoff, A.M. (2012). Neuroblastoma. Semin.
Pediatr. Surg. 21: 2–14.
Maris, J.M. (2010). Recent advances in neuroblas-
toma. N. Engl. J. Med. 362: 2202–2211.
Park, J.R., Eggert, A., and Caron, H. (2010).
Neuroblastoma: biology, prognosis, and treat-
ment. Hematol. Oncol. Clin. N. Am. 24:
65–86.
Pinto, N.R., Applebaum, M.A., Volchenbourn,
S.L. et al. (2015). Advances in risk classifica-
tion and treatment strategies for neuroblas-
toma. J. Clin. Oncol. 33: 3008–3017.
Yu, A.L., Gilman, A.L., Ozkaynak, M.F. et al.
(2010). Anti‐GD2 antibody with GM‐CSF,
interleukin‐2, and isotretinoin for neuroblas-
toma. N. Engl. J. Med. 363: 1324–1334.
20 Sarcomas of the Soft
Tissues and Bone
mutations and may benefit from targeted
Soft tissue sarcomas
therapy with tyrosine kinase inhibitors.
●● Fibrosarcoma: infantile and adult types.
Sarcomas comprise a heterogeneous group of
●● Fibromyxoid sarcoma: slow‐growing,
malignant tumors that arise in the soft tissues
affects primarily young adults.
or bone. Soft tissue sarcomas (STS) are
●● Leiomyosarcoma: smooth muscle tumor
derived from primitive mesenchymal cells
often linked to Epstein–Barr virus or HIV;
such as muscle, connective tissue (tendons
also seen as a second cancer in retinoblas­
and synovial tissue), supportive tissue (fat and
toma survivors.
nerves), and vascular tissue (lymph and blood
●● Malignant peripheral nerve sheath tumors:
vessels). Rhabdomyosarcoma (RMS) is the
often linked with neurofibromatosis type 1
most common STS in younger children, com­
(NF‐1), may be low‐grade or high‐grade.
prising more than half of these tumors in chil­
●● Synovial sarcoma: aggressive tumor,
dren up to 9 years of age. RMS is the third
which often forms in tissues around joints.
most common solid tumor in children with
●● Angiosarcoma: aggressive tumor that
approximately 250–400 new cases diagnosed
forms in blood vessels or lymph vessels.
per year in the United States. Other nonrhab­
●● Alveolar soft part sarcoma: more commonly
domyosarcoma soft tissue sarcomas (NRSTS)
seen in teens and young adults and most often
that occur in children and teenagers are:
affects orbit, head, neck, and extremities.
●● Liposarcoma: a rare cancer of the fat cells,
●● Undifferentiated sarcoma: sarcoma that
often low‐grade (i.e., locally grow and
does not fit into the abovementioned cate­
spread slowly) and amenable to surgical
gories (among others) due to lack of clarity
resection.
in malignant cell of origin.
●● Desmoid tumors: also known as aggressive
STS account for approximately 6–7% of
fibromatosis, can be seen in association with
cancer cases in children and adolescents less
adenomatous polyposis coli (APC) gene
than 19 years of age (annual incidence 11 cases
mutations in familial adenomatous polyposis
per million in the United States). The relative
(FAP), low‐grade, but often recurs locally
incidence of various STS varies by age, sex, and
(requires large resection margins). May
race. For instance, NRSTS such as fibrosar­
respond to hormone therapy, nonsteroidal
coma and malignant hemangiopericytoma are
anti‐inflammatory drugs or targeted therapy
more common in infants (less than 1 year of
(i.e., tyrosine kinase inhibitors).
age). NRSTS also account for the majority of
●● Dermatofibrosarcoma protuberans: rare
STS in patients over 10 years of age.
tumor in deep tissues, often have ALK

Handbook of Pediatric Hematology and Oncology – Children’s Hospital & Research Center Oakland,
Third Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
254 Chapter 20
Genetics
The majority of soft tissue and bone sarco­
mas develop without a predisposing genetic
risk factor, although certain diseases and
inherited disorders can increase the risk of
developing childhood STS. These include
NF‐1 (primarily peripheral nerve sheath
tumors), Beckwith‐Wiedemann syndrome,
Costello syndrome, Li–Fraumeni familial
cancer syndrome, FAP, Werner syndrome,
SMARCB1 (IN11) gene changes, retinoblas­
toma 1 (RB1) gene changes, and cardio‐
facial‐cutaneous syndrome. Germline
mutations in the p53 suppressor gene, as in
Li–Fraumeni syndrome, are associated with
early onset breast cancer, sarcomas, brain
tumors, and adrenocortical tumors in fam­
ily members. There may be an association
with parental use of marijuana and cocaine,
as well as maternal first‐trimester exposure
to radiation, including diagnostic radio­
graphs. Environmental triggers such as ion­
izing radiation may lead to STS in genetically
susceptible individuals.
Genetic information may contribute to
the diagnostic and treatment decision‐mak­
ing process, especially in some cases in
which cytochemical subtyping may be
equivocal. Approximately 90% of alveolar
RMS (ARMS) harbor the characteristic
translocation of the FOXO1 gene (previously
FKHR gene) at 13q14 with PAX3 at 2q35
(t(2;13)(q35;q14)) or less commonly (25% of
cases with the fusion gene) PAX7 at 1p36
(t(1;13)(p36;q15)), leading to a fusion tran­
scription factor that inappropriately activates
gene transcription and resultant tumorigenic
behavior. This FOXO1–PAX3 fusion prod­
uct leading to classic ARMS may be a poten­
tial target in development of future therapies.
Approximately 25% of patients with ARMS
lack a FOXO1–PAX translocation and tend
to behave clinically more like embryonal
RMS (ERMS). ERMS display a loss of hete­
rozygosity in the short arm of chromosome
11, most commonly at 11p15.5. This allelic
loss of 11p15.5 is associated with multiple
oncogenes and potential loss of function
mutations (including p53). In general,
patients with ERMS have a better prognosis
than patients with ARMS, in large part due
to the increased risk of metastatic disease at
presentation with ARMS. DNA content or
ploidy has also been implicated in prognosis
with hyperdiploid tumors (≤51 chromo­
somes) having a better outcome. NRSTS can
occur in sites of prior radiation, and children
with human immunodeficiency virus may
develop leiomyosarcoma (often in associa­
tion with Epstein–Barr virus).
Clinical presentation
STS may occur anywhere in the body and
are not limited to muscle or connective
tissues. The most common sites for RMS are
head and neck (35%), genitourinary system
(26%), and extremities (20%). Younger
children less than 10 years of age tend to
develop ERMS in head and neck or
genitourinary locations, whereas adolescents
tend to develop extremity, truncal, or
paratesticular ARMS. A majority of RMS are
localized, and, of the 15–20% of cases with
metastatic disease at presentation, most
involve the lungs, bone marrow, lymph
nodes, or bone.
As RMS can arise anywhere in the body,
the presenting symptoms are highly variable.
Typically, RMS presents as a painless growing
mass. Depending on location, adjacent struc­
tures may be compressed and lead to symp­
toms such as airway obstruction or cranial
nerve findings with nasopharyngeal tumors,
orbital swelling and proptosis with orbital
tumors, cranial nerve dysfunction, sinusitis,
headaches, ear or facial pain with paramenin­
geal tumors, and urinary obstruction with
bladder or prostate tumors. Prevalence of
head and neck tumors in younger children
often leads to earlier diagnosis given their
more apparent signs and symptoms.
 Sarcomas of the Soft Tissues and Bone 255
Approximately 15–20% of patients with
RMS present with metastatic disease at
diagnosis, most commonly in the bone
marrow or lung. Other potential sites
include the lymph nodes and bone. NRSTS
rarely present with metastases at diagnosis
with the most common site being the lungs.
Diagnostic evaluation
Patients presenting with an enlarging mass
suspected to be malignancy should have an
open surgical biopsy for confirmation of
diagnosis. Sufficient tissue should be
obtained for pathologic evaluation and stain­
ing in addition to cytogenetic and molecular
biologic studies. Patients may be eligible to
participate in a clinical therapeutic or bio­
logic trial that also mandates submission of
tissue. A complete assessment of extent of
disease with meticulous attention to sites of
metastatic disease is mandated prior to initi­
ating definitive therapy. Some protocols also
mandate biopsy of regional nodes or a senti­
nel node in patients with primary extremity
tumors. These evaluations include:
●● Complete history and physical examina­
tion with careful assessment of the mass,
adjacent structures, and regional lymph
nodes.
●● Laboratory studies including complete
blood count, complete metabolic panel with
renal and liver function studies, coagulation
testing, and urinalysis.
●● Radiographic studies including magnetic
resonance imaging (MRI) or computed
tomography (CT) scan of the primary lesion,
depending on the location and regions of
draining lymph nodes. Chest CT and radio­
isotope bone scan should also be conducted
to evaluate for potential lung metastases and
bone metastases, respectively. Further site‐
specific studies may include: brain MRI for
parameningeal head and neck tumors, ultra­
sound and cystourethroscopy in bladder or
prostate tumors, abdominal MRI or CT to
evaluate lymph node involvement in parates­
ticular disease, and spine MRI in patients
with evidence of medullary compression.
Fluorine‐18‐fluorodeoxyglucose positron
emission tomography (FDG‐PET) imaging
may be helpful to determine initial extent of
disease and to monitor response to therapy.
Patients with lesions in the maxilla or man­
dible should have a Panorex radiograph to
evaluate extent of local infiltration. Patient
outcomes are strongly tied to the extent of
disease, so all attempts should be made to
identify completely the sites and extent of
disease extension.
●● Bilateral bone marrow aspirate and biopsy
should be performed, especially in patients
with metastatic disease or alveolar histologic
subtype of RMS.
●● Lumbar puncture in patients with para­
meningeal head and neck primary lesions to
evaluate for metastatic disease.
Pathologic diagnosis
RMS is classified pathologically as embryonal
(ERMS) with botryoid and spindle cell
variants, alveolar (ARMS) or anaplastic.
­
Inves­tigation for particular translocations (see
Genetics section above) should be done to
assist with definitive tissue diagnosis in com­
bination with histochemical studies. STS are
one of the small round blue cell tumors of
childhood, based on the H&E stain appear­
ance. Tissue diagnosis is important and ample
material needs to be provided (typically by
open biopsy or tumor resection). RMS may
appear similar to striated muscle, and immu­
nohistochemical staining for muscle‐specific
proteins is done with myosin, muscle‐specific
actin, desmin, D‐myosin, and myoD1. ERMS
accounts for approximately 60–70% of cases
of RMS and typically evolves from mucosal
lined organs, primarily in very young children
<1 year of age. The appearance of early primi­
tive cells is classic for the botryoid variant.
The spindle variant is rare and resembles
smooth muscle tissues, and is most com­
monly seen in paratesticular tumors (and is
256 Chapter 20
associated with an excellent prognosis with
>95% overall survival at 5 years). The alveolar
variant (ARMS) is seen in approximately
20–25% of RMS and is more commonly seen
in teens and young adults. Histologically, the
cells appear as densely arranged round cells in
alveolar patterns, resembling lung alveoli.
They tend to be in extremity locations and act
very aggressively. Anaplastic, or pleomorphic,
variants have highly anaplastic large cells with
lobate hyperchromatic nuclei and numerous
multipolar mitotic figures, extremely poor
differentiation, and increased heterogeneity.
Areas of anaplasia can be seen diffusely or
localized in tissue samples and confer a worse
prognosis.
Staging and classification
RMS are stratified into clinical groups based
on extent of surgical resection. Staging is also
done and takes into account the size and
location of the tumor, spread to local or
regional lymph nodes, and distant (meta­
static) disease. The principal determinants of
prognosis are primary site, tumor size, histo­
logic subtype, degree of regional spread and
nodal involvement, distant metastatic dis­
ease, and extent of prechemotherapy tumor
resection. Risk stratification is essential to
tailoring therapy to maximize outcome. A
unique aspect of the RMS staging is the post­
operative clinical grouping system that is
based on extent of surgical resection and
results of lymph node evaluation. Risk group
classification is then based on pretreatment
stage, postoperative clinical group, and his­
tology. Favorable sites include the orbit, gen­
itourinary (nonbladder nonprostate), and
nonparameningeal head and neck locations.
Unfavorable sites are bladder/prostate,
extremity, cranial parameningeal, trunk, and
retroperitoneum. Risk grouping is as men­
tioned in the following text:
Low‐risk group: patients with nonmeta­
static favorable site ERMS (Stage I, regard­
less of degree of initial resection) and
completely resected (groups I and II)
nonmetastatic unfavorable site ERMS.
Intermediate‐risk group: patients with
any nonmetastatic ARMS and all ERMS
with unfavorable sites (Stage 2 or 3) that
have been incompletely resected (group III).
High‐risk group: patients with metastatic
tumors, both ARMS and ERMS (a subset of
patients age 10 years and older with ARMS
and regional node involvement may do bet­
ter with treatment per the high‐risk group).
NRSTS are generally staged using the
same criteria mentioned in the preceding
text. The major determinants of outcome
include tumor grade, size, extent of initial
resection, and presence of metastatic
disease. Tumor size and extent of resection
are strongly correlated with treatment
stratification and prognosis.
Treatment
A multidisciplinary approach to the
treatment of STS is crucial. Basic principles
of therapy include systemic treatment of
micrometastatic disease with adjuvant
chemotherapy and aggressive local control
with definitive surgery and addition of
radiation as necessary. Some of the less
common forms of STS may be treated with
surgery alone.
RMS is often in sites not amenable to
gross total resection with negative margins
without morbidity or loss of function (e.g.,
orbit, genitourinary, and parameningeal
sites). Survival is <20% for patients who do
not have resection with negative margins.
Fortunately, RMS is a highly chemosensitive
cancer and about 80% are expected to
respond favorably. Local control is achieved
with either complete surgical resection
(with negative margins) or surgery and
radiation (if microscopic or gross residual
disease remains after surgical intervention).
Primary re‐excision may be indicated prior
to initiation of chemotherapy in certain
situations such as: if the diagnosis was not
 Sarcomas of the Soft Tissues and Bone 257
suspected and only a biopsy was performed;
gross or microscopic residual disease is
amenable to wide excision without undue
morbidity; or if there is uncertainty about
residual disease or margins which would
negatively impact survival. Sentinel lymph
node biopsy should be attempted in all
cases.
STS are moderately sensitive to radiation
therapy (RMS more sensitive than NRSTS),
and this treatment modality is critical for
tumors that cannot be fully excised
surgically with negative margins. Treatment
volume is determined by the extent of the
tumor prior to surgical resection, and the
margin is influenced by the surrounding
normal tissue and vital structures. Intensity‐
modulated radiation therapy (IMRT) or
proton beam radiation may offer advantages
to sparing surrounding critical tissues.
Optimal timing of radiation therapy remains
unclear, and local control may be given after
4–20 weeks of systemic chemotherapy.
Earlier definitive therapy may be indicated
in patients with intracranial primary tumors
or in those with compromise of function
that may be debilitating or life‐threatening.
Chemotherapy provides the backbone of
treatment for patients with RMS and is initi­
ated following the initial surgical procedure.
After definitive local control, chemotherapy
continues due to the risk of microscopic
residual or metastatic disease. The most
active drugs in the treatment of RMS remain
vincristine, dactinomycin, and cyclophos­
phamide (VAC). Although multiple addi­
tional treatment regimens have been
attempted to decrease alkylator exposure,
VAC remains the standard of therapy, often
with the addition or substitution of doxoru­
bicin, ifosfamide, etoposide, and irinotecan
depending on the underlying risk group.
Recent European trials have shown benefit
with a maintenance phase after intensive
chemotherapy for patients with intermedi­
ate‐risk RMS (high‐risk patients nonran­
domly received this maintenance with
pending results). Recent trials have not been
able to show improvement in survival in
patients with metastatic rhabdomyosar­
coma. High‐dose chemotherapy with hemat­
opoietic stem cell rescue has not shown
benefit in patients with high‐risk and meta­
static disease.
Prognosis
Overall, survival without relapse is >70% in
children and adolescents 5 years from
diagnosis. Low‐risk groups, representing
approximately 30% of RMS, can be expected
to have an excellent outcome with long‐term
survival >90%. Of the 55% of patients with
intermediate‐risk disease, 5‐year overall
survival is approximately 55–65%. In
patients with metastatic alveolar disease
(15–20% of the population), survival is
poor, at less than 20%. Several caveats are
present that help determine prognosis:
●● Site of the primary tumor has a major
impact on survival and is associated with
pathologic subtypes, ease of surgical resect­
ability, timing to presentation, and involve­
ment of regional nodes. Favorable sites
include nonparameningeal head and neck
tumors, nonbladder, nonprostate genitouri­
nary tumors or those affecting the biliary
tract.
●● Extent of disease is the most significant
predictive factor for survival. Children with
localized, completely resected disease do
better than those with widespread or dis­
seminated disease.
●● Patients with smaller tumors (<5 cm) have
improved survival compared to children
with tumors >5 cm.
●● The alveolar subtype of RMS has an
adverse prognosis and is often associated
with an aggressive clinical course and meta­
static disease at diagnosis and relapse.
●● Patients between 1 and 9 years of age have
a better prognosis compared to infants and
older children.
258 Chapter 20
Children with recurrent RMS have a dis­
mal prognosis with long‐term survival of
<15%, particularly if the disease recurs in a
metastatic site or area of prior irradiation.
The majority of relapses occur within 3 years
of therapy completion. Metastatic recur­
rence is essentially incurable, though treat­
ment may offer palliation. Treatment with
surgical resection and adjuvant multiagent
chemotherapy can be considered with drug
combinations such as ifosfamide/carbopl­
atin/etoposide, docetaxel/gemcitabine, and
irinotecan in combination with temozolo­
mide or vinorelbine. Durable remissions for
several years may be obtained with aggres­
sive local retreatment and systemic therapy.
High‐dose chemotherapy followed by
hematopoietic stem cell rescue has not been
shown to be advantageous in this group.
Nonrhabdomyomatous soft
tissue sarcomas
Few clinical trials and prospective studies
have been conducted in this population of
children. Surgery is the mainstay of effective
therapy and every effort should be made to
completely excise the tumor with clear tumor
margins. Patients with completely excised
low‐grade tumors, or high‐grade tumors
<5 cm, have a favorable outcome with sur­
vival exceeding 85%. Patients with high‐
grade NRSTS larger than 5 cm and those
with unresectable, localized disease have an
intermediate prognosis with approximately
50% survival. Patients with high‐grade
tumors and positive tumor resection mar­
gins typically receive adjuvant radiation
therapy. It is not clear if adjuvant chemother­
apy confers a survival advantage in this
group of patients. Radiation is considered in
unresectable tumors or if tumor shrinkage
may lead to complete resection. Patients with
metastatic NRSTS have a dismal long‐term
prognosis and fewer than 20% survive 5
years from diagnosis. Neoadjuvant chemo‐
radiotherapy is being explored in this group,
but there continues to be a paucity of new
potential therapeutic agents.
Bone sarcomas
Primary malignant bone tumors in children
constitute approximately 6% of all childhood
malignancies. The two most common bone
tumors are osteosarcoma (OS) and Ewing
sarcoma family of tumors (ESFT), which
include Ewing sarcoma, extraosseous Ewing
sarcoma, primitive neuroectodermal tumor
(PNET), and Askin tumors (i.e., chest wall
and pulmonary area). Other rare malignant
bone tumors include chondrosarcoma and
non‐Hodgkin lymphoma of bone. Bone
lesions may also represent Langerhans cell
histiocytosis, benign tumors, or metastatic
disease. Osteosarcoma arises from primitive
cells of mesenchymal origin (thus a sarcoma)
and exhibits osteoblastic differentiation
producing malignant osteoid. OS is an
aggressive cancerous tumor of bone with a
bimodal age distribution peaking in early
adolescence and in adults >60 years of age.
ESFT are malignant tumors of bone and soft
tissue thought to derive from neural crest
cells and harboring the Ewing sarcoma
translocation. Eighty percent of ESFT arise
in children <20 years of age and have a racial
predilection with rare presentation in
African‐American and Asian ethnicities.
Genetics
Osteosarcoma is characterized by complex
unbalanced karyotypes with alterations in
the Rb and p53 tumor suppressor pathways,
linking this tumor to retinoblastoma and Li–
Fraumeni syndrome, respectively. Other
genetic associations include fibrous dyspla­
sia, enchondromatosis, hereditary multiple
exostosis, and Rothmund–Thomson syn­
drome (AR‐associated congenital bone
defects; teeth, hair, and skin dysplasia; hypo­
gonadism and cataracts). Osteosarcoma has
 Sarcomas of the Soft Tissues and Bone 259
long been thought to be associated with ado­
lescent growth spurts and the higher inci­
dence in large dog breeds and taller people
supports this correlation. Girls have a peak
incidence younger than boys (12 vs. 16 years)
correlating with the different average age for
pubertal onset. Well‐documented risk fac­
tors include radiation exposure, Paget’s dis­
ease, and other disorders associated with
increased bone turnover. Soft tissue and
bone sarcomas also occur as secondary
malignancies.
Unlike OS, ESFT are not associated with
familial cancer syndromes and do not appear
to increase in risk following radiation expo­
sure. The translocation t(11;22)(q24;q12) is
present in >95% of ESFT and some consider
this finding to be pathognomonic and suffi­
cient to confirm the diagnosis. This translo­
cation results in the EWS–FLI1 fusion
transcript that acts as an aberrant transcrip­
tion factor altering tumor suppressor gene
pathways.
Clinical presentation
Patients typically present with a growing
mass or swelling in the involved area and
pain, with symptoms preceding diagnosis
often by several months. Patients frequently
attribute the pain to a minor trauma and
indeed may present with a pathologic frac­
ture in the affected weakened bone. A palpa­
ble mass or swelling of the involved site
typically arises after the onset of pain.
Systemic symptoms such as weight loss or
shortness of breath may be late sequelae and
secondary to metastatic disease. Fever is a
common symptom of ESFT (20%) and may
lead to confusion with osteomyelitis result­
ing in delayed diagnosis.
Osteosarcoma may occur in any bone
but primarily occurs in the metaphyses of
the most rapidly growing bones. The most
common primary sites of origin are the
distal femur, proximal tibia, and proximal
humerus with approximately 50% of tumors
originating around the knee. Approximately
10% of patients have primary tumors in the
axial skeleton including the pelvis, and
15–20% present with metastatic disease
(lung, bone, lymph nodes, and rarely brain).
Most ESFT occur in bones and their loca­
tions tend to differ from that of OS. Flat
bones of the axial skeleton are more com­
monly affected; in long bones, the diaphyseal
portion is usually involved. The most com­
mon primary locations include the pelvic
bones, the long bones of the lower extremi­
ties, and the bones of the chest wall. Metastatic
disease is present in 25% of patients at diag­
nosis and is primarily located in the lungs,
bones, or bone marrow. Site of primary dis­
ease influences the relative incidence of
metastases at diagnosis; central primaries are
associated more frequently with distant dis­
ease (40%), whereas distal primary lesions
have the lowest incidence (15%).
Diagnostic evaluation
The diagnostic evaluation should determine
site and extent of disease, including presence
and location of metastatic disease. The
requisite elements of evaluation include:
●● A complete history and physical
examination.
●● Routine laboratory studies include a com­
plete blood count, complete metabolic panel
with renal and liver function tests, serum
creatinine, creatinine clearance, and urinal­
ysis. A measured or calculated glomerular
filtration rate should be obtained prior to
initiation of nephrotoxic chemotherapy. The
alkaline phosphatase may be elevated and
has been associated with an inferior out­
come in OS. The serum lactate dehydroge­
nase may also be elevated and may correlate
with tumor burden.
●● Imaging studies should begin with plain
radiographs to visualize osseous changes and
confirm suspicion of a malignant tumor.
Osteosarcoma usually produces dense scle­
rosis in the metaphyses of long bones with
260 Chapter 20
soft tissue extension seen in 75% of tumors,
radiating calcifications (sunburst pattern) in
60% of tumors, osteosclerotic lesions in 45%
of cases, lytic lesions in 30% of cases, and
mixed lesions in 25% of cases. A triangular
area of periosteal calcification in the border
region of the tumor and healthy tissue is
known as a Codman triangle. ESFT are
described as lytic with an “onion peel” peri­
osteal reaction and typically occur in the dia­
physis or flat bones. Patients with soft tissue
ESFT only may have normal radiographs.
Additional assessment of the primary tumor
site with MRI should be undertaken to view
the soft tissue component, surrounding
structures, vessels and nerves, and the
intramedullary extension to assist with sur­
gical planning. MRI should include the
entire involved bone and neighboring joints
to evaluate for skip lesions. Metastatic dis­
ease is typically in the lungs or bone and
therefore imaging with chest CT and techne­
tium‐99m bone scan is essential in the initial
workup for staging. FDG‐PET imaging is a
sensitive screening tool for the detection of
bone metastases in ESFT, but its role in eval­
uation of OS has yet to be determined.
●● Bilateral bone marrow aspirate and biopsy
should be performed in patients with ESFT.
●● Baseline audiogram and echocardiogram
should be obtained prior to initiation of oto­
toxic and cardiotoxic chemotherapies,
respectively.
●● Fertility preservation should be discussed
with patients prior to chemotherapy. Sperm
banking should be offered as well as oocyte
cryopreservation. Age, pubertal status, and
time may determine feasibility.
Pathologic diagnosis
Patients presenting with a bone mass
suspicious for malignancy should undergo a
diagnostic incisional or core biopsy. It is
imperative that an experienced oncologic
orthopedic surgeon who will also be
performing the definitive procedure
perform the biopsy, so that the biopsy tract
can be excised en bloc with the planned
surgical resection. Sufficient tissue should
be obtained for diagnostic histopathology as
well as for any submissions required for
participation in a clinical trial. Biopsy may
be taken from an extraosseous component,
if present, to prevent pathologic fracture.
A characteristic feature of OS is
malignant osteoid (bone formation) in the
tumor. This may appear pleomorphic
(anaplastic), and giant atypical mitotic
features are often present. Tumors are sub‐
classified by resemblance to bone, cartilage,
or fibroblast cells. The three major subtypes
are: osteoblastic, chondroblastic, and
fibroblastic, reflecting the predominant type
of matrix in the tumor. Histologic variants
include telangiectatic, small cell, periosteal,
and parosteal.
To differentiate ESFT from other small
round blue cell tumors of childhood, an
expanded immunohistochemical panel is
done to include detection of CD99 (a cell sur­
face glycoprotein with strong expression in
ESFT) with a characteristic honeycomb
staining pattern. Though CD99 may be pre­
sent in other tumors (including Wilms tumor,
clear cell sarcoma of the kidney, T‐cell lym­
phoma and leukemia, and rhabdomyosar­
coma), the pattern of staining in ESFT is
membranous, distinct from the cytoplasmic
pattern present in these other tumors.
Molecular genetic studies using fluorescent
in situ hybridization or reverse transcriptase‐
polymerase chain reaction are valuable in
diagnosis, specifically for the detection of
characteristic translocations that allow for
definitive diagnosis of ESFT, RMS, and syno­
vial cell sarcoma.
Treatment
Osteosarcoma
Systemic multiagent chemotherapy prior to
and following definitive radical surgery is the
standard of care for treatment of OS. Complete
 Sarcomas of the Soft Tissues and Bone 261
en bloc resection of the primary site, as well as
all sites of metastatic disease, is critical to
long‐term survival. The ability to perform
such procedures is affected by tumor location,
neurovascular involvement, ability for wide
resection with a normal margin of muscle/tis­
sue, and the ability to perform functional
reconstruction. Preoperative (neoadjuvant)
chemotherapy following initial biopsy offers
several advantages which include a decrease
in tumor‐related edema, shrinkage of the pri­
mary tumor, treatment of presumed micro­
metastases, and assessment of sensitivity
(histologic response). The orthopedic onco­
logic surgeon determines the type of surgical
procedure performed, and factors used in this
determination include the location and size of
the tumor, patient age and skeletal maturity,
presence of metastatic disease, and patient
lifestyle choices. Limb‐sparing procedures are
feasible in the great majority of patients and
the development of expandable endoprosthe­
ses has allowed the use of these techniques in
younger children. Tumors of the pelvis or
axial skeleton present a difficult situation, as
resection with adequate margins may not be
possible.
Chemotherapy is the backbone of treat­
ment for OS, with the exception of the com­
pletely resected paraosteal subtype (often
cured with radical surgery alone). Without
adjuvant chemotherapy, more than 80% of
patients will recur, often with metastatic dis­
ease. Standard components of multiagent
chemotherapy include high‐dose metho­
trexate, doxorubicin (Adriamycin), and cis­
platin, referred to as MAP. The addition of
dexrazoxane, a cardioprotectant, is now
commonplace in patients with OS receiving
MAP therapy. Ifosfamide and etoposide are
additional agents shown to have activity but
not beneficial in the upfront management of
OS. Treatment cycles are given for approxi­
mately 30–40 weeks with a definitive surgical
procedure performed at approximately week
11–12, followed by continuation of multi­
agent chemotherapy. The degree of tumor
necrosis, as determined post definitive surgi­
cal resection, is a significant independent
predictor of survival, both event(relapse)‐
free and overall. Those good responders
whose tumors show ≥90% necrosis have
superior outcomes compared to those with
poor (<90% necrosis) response.
Radiation therapy has limited utility in
patients with OS, but may play a role in
those unable to undergo complete resection.
Patients presenting with metastatic dis­
ease undergo the same therapeutic approach
with systemic chemotherapy and definitive
surgery of the primary site in addition to
surgery of metastatic sites, as feasible.
Approximately one‐third of OS patients with
pulmonary metastases will have additional
microscopic pulmonary nodules not visible
on the current, highest resolution CT imag­
ing. It is recommended that pulmonary nod­
ules identified on CT imaging be surgically
resected.
Ewing sarcoma family of tumors
As with OS, cure in ESFT can be achieved
only with a multimodal approach, using sur­
gery and/or radiation therapy for local con­
trol of the primary lesion and chemotherapy
for eradication of subclinical micrometasta­
ses. Definitive surgery follows a period of
induction chemotherapy and many patients
are candidates for complete surgical resec­
tion with limb‐salvage procedures. Induction
chemotherapy may also render initially
unresectable tumors resectable. ESFT are
radiation‐responsive, although typically this
therapeutic modality is reserved for surgi­
cally unresectable tumors or in tumors with
positive margins after resection. Patients
who receive radiation therapy as the only
local control modality have an inferior out­
come. Frequently, these patients have other
adverse features including large tumor size,
unfavorable locations (e.g., vertebral
tumors), or both. Radiation is also utilized in
262 Chapter 20
the treatment of metastatic disease.
Debulking procedures have not been shown
to improve outcome and should not be part
of local control therapy.
Systemic chemotherapy has significantly
improved outcomes in ESFT with rapid
reduction in tumor volume facilitating suc­
cessful complete surgical resections or allow­
ing for limb‐sparing procedures. Active
chemotherapy agents include vincristine,
cyclophosphamide, and doxorubicin (VDC)
alternating with ifosfamide and etoposide
(IE). As with OS, definitive local control
occurs at week 12 followed by additional
chemotherapy. Compressed interval, every 2
weeks with the use of filgrastim, rather than
3‐week cycles, has led to superior outcomes
and is now standard of care in ESFT, though
this increased time–dose intensity schedule
has shown benefit in pediatric patients only.
Outcomes of patients with metastatic
ESFT are dismal, related to site of metastasis,
and with tumors that may have more chemo­
therapy resistance. High‐dose chemotherapy
with autologous stem cell rescue is being
investigated, though has not shown clear
benefit in those with metastatic disease.
Prognosis
Most patients with bone sarcomas have
micrometastatic disease at diagnosis as evi­
denced by a high percentage of patients who
develop lung metastases following local con­
trol therapy (i.e., surgery and/or radiation)
alone. Prior to the use of systemic chemo­
therapy, survival rates at 2 years were
15–20%. Currently, patients with localized
disease can expect a long‐term survival of
>70%. Survival in patients with metastatic
disease remains dismal, estimated at 2 years
to be 10–30%. The degree of tumor necrosis
following neoadjuvant (pre‐surgery) chemo­
therapy is an independent predictor of
event‐free and overall survival, presumably
reflecting superior tumor sensitivity to
chemotherapy. In addition to the presence of
metastasis at diagnosis and poor response to
neoadjuvant chemotherapy, other factors
associated with a poor prognosis include:
incomplete resection, axial skeletal prima­
ries, larger tumor size, and proximal location
on the limb. To date, intensified treatment
for those with less‐favorable tumor necrosis
has not improved outcome.
The 5‐year overall survival rate in
patients with ESFT treated upfront with
chemotherapy, surgery, and radiation is
approximately 60–70%. As with OS, those
presenting with evidence of metastatic
disease have a dismal expected survival of
10–30%, though patients with lung
metastasis alone may have a survival benefit.
The most significant adverse prognostic
factors are: older age, axial skeletal tumor
location, larger tumor size, and elevated
serum LDH at diagnosis.
The prognosis for patients with recur­
rence is quite poor. Most local recurrences
are associated with concomitant distant dis­
ease. Time to relapse and tumor burden cor­
relate with post‐relapse outcome. Late
recurrence (i.e., >5–10 years) has been
reported in bone sarcoma. Surgical resection
remains the mainstay of therapy for curative
second‐line therapy. Patients with OS who
develop pulmonary lesions after completion
of therapy can be cured with surgery alone.
The role of adjuvant chemotherapy in relapse
is controversial, though patients are often
offered such treatments including cyclo­
phosphamide/topotecan, irinotecan/temo­
zolomide, and gemcitabine/taxotere.
Radiation has a role in the treatment of
patients with ESFT who develop new meta­
static sites and for palliation and pain control
in either OS or ESFT.
Targeted and biologically based therapies
are being investigated in patients with poor
response to initial chemotherapy, those with
metastatic disease, and those with recurrent
disease. A range of mutations associated
with OS do not provide obvious therapeutic
 Sarcomas of the Soft Tissues and Bone 263
targets, as they primarily reflect loss of
tumor suppressor genes (i.e., p53, Rb1,
PTEN) rather than activation of targetable
oncogenes. Recent novel therapies for OS
including receptor activator of nuclear fac­
tor kappa beta ligand (RANKL), antibody
(denosumab), and anti‐GD2 antibody
(dinutuximab with sargramostim) have not
shown benefit. Transcription inhibition of
the EWSR1–FLI1 translocation is an area of
interest in ESFT in addition to utilization of
an antibody to insulin growth factor recep­
tor‐1 (IGFR‐1; ganitumab).
Late effects in soft tissue
and bone sarcomas
Site and extent of disease, as well as therapeu­
tic interventions with chemotherapy, radia­
tion, and surgery all contribute to late sequelae
in sarcoma patients. A majority of first‐line
protocols utilize high cumulative doses of
anthracyclines (i.e., doxorubicin), resulting in
a lifelong risk of developing cardiomyopathy.
Addition of a cardioprotectant, dexrazoxane,
is now commonly used to decrease the risk of
cardiac late effects. For all patients, lifelong
cardiac monitoring with serial echocardio­
grams and periodic functional assessments is
recommended. Alkylator therapy (ifosfamide
and cyclophosphamide) can lead to gonadal
toxicity (primarily in males) and increased
risk of secondary malignancy. Second malig­
nant neoplasms occur in approximately 3% of
patients within 10 years of therapy comple­
tion, likely related to both a genetic predispo­
sition and treatment with mutagenic
therapies. Platinum therapy (cisplatin) can
lead to long‐term ototoxicity and nephrotox­
icity. High‐frequency hearing loss is common
and some patients will require hearing aids.
Renal dysfunction is rare but could result in
chronic electrolyte wasting due to proximal
tubular damage (see Chapter 30 for more
details).
For OS patients, contemporary orthope­
dic surgery techniques are aimed at preser­
vation of function and improved limb
salvage without compromising survival.
Amputation may result in superior limb
function in some cases. In a skeletally imma­
ture child, expandable prostheses may
require subsequent revisions, though some
may benefit from newer self‐expanding
prostheses. Late prosthetic failures or infec­
tion can occur, requiring surgical revision or
delayed amputation. Radiation therapy can
lead to local effects including growth
impairment, muscle fibrosis, and increased
risk of secondary malignancy, in a dose‐
dependent manner.
Case study for review
A 9‐year‐old boy presents with a nontender
3 × 4 cm2 mass in the right inguinal region.
He denies fever, weight loss, or pain
elsewhere. The mass has been present and
growing for several weeks.
a. What key elements should you obtain
in the history?
Key elements in the history include length
of symptoms, possible relationship to infec­
tion (could this be a lymph node?), animal
exposures and bites, travel, cuts or injuries
to the affected leg, systemic symptoms such
as malaise, fevers, unexplained weight loss,
or discomfort that limits activities or neces­
sitates pain medication.
b. What are you looking for on the phys­
ical examination?
The physical examination should be
­complete, head to toe. The mass should be
measured and characterized for mobility,
­tenderness, warmth and erythema. The mass
may be hard and nontender if malignant
disease is present. If the mass is suspected to
be a node, it may be enlarged as a result of
disease spread and therefore the distal
extremity must be carefully examined. All
264 Chapter 20
other lymph node chains as well as the liver
and spleen should also be carefully assessed.
c. What is your differential diagnosis
for this boy?
The differential diagnosis of a mass in the
inguinal area consists of lymphadenopathy
secondary to an infectious or malignant eti­
ology. Infections may be bacterial, protozoal,
fungal, or viral, and may be the result of
introduction by a cut (which may have since
healed), animal bite, or scratch. A mass that
is hard, nontender, and nonmobile, without
signs and symptoms of infection, is con­
cerning for malignancy. Malignancies that
can lead to regional spread in an extremity
include sarcomas (bone and soft tissue).
d. How do you approach diagnostic
evaluation and staging?
Assuming you could find no lump or tender
area on the extremity exam, it is prudent to
begin a detailed investigation with imaging
and biopsy. Imaging should consist of MRI
of the inguinal area and leg (to the tips of
the toes). An excisional biopsy should be
performed as well given the concern for
malignancy (and to prevent potential tumor
tracking which can occur with an incisional
biopsy). Once the mass is a biopsy‐proven
malignancy, further staging should evaluate
for distant disease and include CT of the
chest in addition to bone scan for OS and
FDG‐PET scan for Ewing sarcoma.
e. What do you tell the child and his
family?
Prior to initiation of the biopsy and imag­
ing, it is best to be straightforward with the
family and let them know your concern that
this mass likely represents a malignancy. As
the mass is in the inguinal area, it could rep­
resent regional spread of a distant tumor.
f. Assuming you find out this is a local­
ized undifferentiated sarcoma, what is
the child’s prognosis and what is the gen­
eral treatment plan?
In this case, the child had a nonpalpable
mass in the fifth distal toe found on MRI.
The pathologic diagnosis of undifferenti­
ated sarcoma was made on excisional
biopsy of the inguinal mass. No other evi­
dence of distant tumor was found on fur­
ther imaging. Prognosis for undifferentiated
sarcoma is generally similar to ARMS, and
patients with localized disease who receive
systemic chemotherapy and local control
(complete surgical excision with negative
margins) can expect to have approximately
a 70% event‐free survival. This is in stark
contrast to patients with metastatic disease
in which case survival is less than 20%
despite aggressive therapy. Those patients
with regional spread, similar to this case,
have an intermediate prognosis. Such cases
should be treated with multiagent chemo­
therapy in addition to local control. In this
child, local control will involve treatment of
the toe and the inguinal mass in addition to
other potential draining nodes.
Suggested reading
Borenstein, S.C., Steppan, D., Hayasi, A. et al.
(2018). Consensus and controversies regard­
ing the treatment of rhabdomyosarcoma.
Pediatr. Blood Cancer 65: e26809.
Reed, D.R., Hayasi, M., Wagner, L. et al. (2017).
Treatment pathway of bone sarcoma in chil­
dren, adolescents, and young adults. Cancer
123: 2206–2218.
21 Germ Cell Tumors
Germ cell tumors (GCTs) arise from pri-
mordial cells involved in gametogenesis and
occur primarily in the testes and ovaries.
These tumors represent approximately 4%
of pediatric cancers. Primordial germ cells
(PGCs) are thought to originate in the yolk
sac endoderm and migrate along the genital
ridge and thus may also present in midline
extragonadal sites, such as the sacrococcy-
geal region, midline of the brain, mediasti-
num, and retroperitoneum. Due to the
pluripotentiality of PGCs, GCTs are an array
of different histologic subtypes, adding to
the complexity of the disease. In addition,
GCTs can occur due to tumorigenesis or as
part of normal embryonal development, in
part explaining the pediatric bimodal age of
distribution (2 and 20 years). In addition,
age of presentation and histologic subtype
varies significantly between males and
females. This is thought to be due in part to
the differential timing of male and female
development; female germ cells enter meio-
sis at 11–12 weeks of gestation, while male
germ cells begin meiosis with the onset of
puberty.
Epidemiology
Due to the differential timing of germ cell
maturation, GCTs are more common in
females until adolescence and then become
Handbook of Pediatric Hematology and Oncology – Children’s Hospital & Research Center Oakland,
Third Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
more frequent in males. Testicular GCTs
have several known risk factors including
infertility/testicular atrophy as well as cryp-
torchidism. Males with cryptorchidism have
a higher incidence of testicular cancer in
both the undescended testis and the nor-
mally descended contralateral testis despite
surgical correction, hormonal therapy, or
spontaneous descent. However, early cor-
rection may partially ameliorate this risk.
The incidence of testicular GCTs in the
Caucasian population is increasing at a rate
of 3–6% per year. Perinatal and environ-
mental risk factors are thought to play a role,
although these are yet to be clearly eluci-
dated. Young parental age at birth, low birth
order, low birth weight, and breech birth
have all been noted to be statistically signifi-
cant risk factors in multiple studies.
Maternal exposure to pesticides or hor-
mones, parental smoking, and alcohol con-
sumption may also be factors. Genetic risk
factors also play a role, specifically in tes-
ticular GCT, as a family history of cancer,
especially at a young age, has been associ-
ated with increased risk in pediatric patients.
Additionally, there is a higher incidence in
monozygotic twins and some familial
­clusters have been reported. A number of
congenital genitourinary anomalies such as
retrocaval ureter, bladder diverticulum,
and inguinal hernia have been associated
with increased risk, emphasizing that
266 Chapter 21
a­ bnormalities in development likely play a
role. Similarly, disorders of sexual develop-
ment, especially in cases with excess Y chro-
mosome material (e.g., gonadal dysgenesis),
pose an increased risk in both males and
females. Children with Down syndrome,
who generally have a decreased risk of solid
tumors, are at a predisposition to develop
testicular GCT, whereas patients with
Klinefelter syndrome have an increased risk
of mediastinal GCT. Gain of chromosome
12p is also seen in the majority of testicular
and malignant ovarian GCT. Approximately
half of all pediatric GCT are extragonadal in
origin, with about 15% of these being
malignant.
Pathology and serum tumor
markers
The main histologic variants of GCTs
include germinomas (dysgerminoma in the
ovary and seminoma in the testis), embryo-
nal carcinoma, yolk sac tumor (endodermal
sinus tumor), choriocarcinoma, and tera-
toma (mature and immature). Mixed GCTs
are composed of two or more histologies.
Teratomas contain tissues from all three
germ layers (ectoderm, endoderm, and
mesoderm). Mature teratomas contain no
malignant germ cell elements and are most
commonly located in the ovary or sacrococ-
cygeal region. The vast majority of female
GCTs are teratomas. Teratomas in the pre-
pubertal male are benign, whereas those
occurring during or after the onset of
puberty are always malignant, as they arise
from other forms of testicular GCT (specifi-
cally embryonal carcinoma). Therefore, ter-
atomatous elements in the testis largely
occur as a component of a mixed GCT. In
the female or prepubertal male, these
tumors are thought to derive from a benign
germ cell but may rarely develop malignant
components (i.e., squamous cell carcinoma)
and therefore are treated with complete sur-
gical resection. Immature teratomas are
tumors of intermediate malignant potential
with less differentiated tissues.
Germinomas may be of pure histology
or mixed. Syncytiotrophoblastic cells
occur in about 5% of germinomas and
secrete the beta subunit of human chori-
onic gonadotropin (β‐HCG). Embryonal
carcinoma is most often found as a compo-
nent of testicular mixed GCT and is
thought to be the driver for the develop-
ment of other histologic subtypes includ-
ing teratoma, yolk sac tumor, and
choriocarcinoma. Yolk sac tumor is gener-
ally found as a part of testicular mixed
GCT but can also be seen as a pure histo-
logic variant in young children. Yolk sac
tumor secretes α‐fetoprotein (AFP).
Choriocarcinoma contains syncytio-
trophoblastic cells and therefore also
secretes β‐HCG. Ovarian cases should be
distinguished from metastatic gestational
choriocarcinoma.
In the ovary and testis, GCT should be
distinguished from sex cord stromal tumors,
which arise from the nongerminative com-
ponents of gonadal tissue and include
tumors involving the Sertoli–Leydig cells of
the testis and granulosa cells of the ovary.
Sarcoma as well as gonadal infiltration by
leukemia and non‐Hodgkin lymphoma
should also be considered in the differential
diagnosis of gonadal tumors.
Due to the specific histologies that
secrete AFP and β‐HCG, these tumor mark-
ers can be quite helpful in distinguishing
tumor type as well as following disease.
Mature teratomas secrete neither marker;
therefore, if a serum marker is present in the
patient diagnosed with a mature teratoma,
one must consider that the tumor contains
one or more foci of yolk sac tumor if the
AFP is positive, choriocarcinoma or germi-
noma if the β‐HCG is positive, and that the
patient in fact has a mixed malignant GCT.

Due to physiologic changes in the secretion
of fetal AFP, this marker can be difficult to
utilize in young infants. AFP is made in the
fetal liver and does not decline to adult levels
until approximately 6–8 months of age. Age‐
appropriate levels can be obtained from
published tables. AFP can also be secreted
by regenerating liver postinjury or by cer-
tain liver tumors such as hepatoblastoma.
Degree of AFP elevation may be related to
tumor volume. β‐HCG is elevated in preg-
nancy and can also be seen in association
with childhood hepatic tumors and other
cancers involving the breast, stomach, and
pancreas in adults. Nonspecific markers of
GCT include lactate dehydrogenase (LDH)
isoenzyme 1, neuron‐specific enolase, and
placental alkaline phosphatase.
Clinical presentation
GCT should be considered in children who
present with a pelvic, ovarian, or testicular
mass, or a midline mass in the sacrococcy-
geal region, retroperitoneum, mediastinum,
or pineal or suprasellar regions of the brain.
GCTs present with signs and symptoms
related to the site and size of the primary
tumor. Compression of internal structures
can lead to pain, constipation, and urinary
obstruction. Large ovarian tumors can addi-
tionally lead to decreased lung volumes and
respiratory distress. GCTs can metastasize,
most commonly to the lungs, but patients
rarely present with clinical symptoms refer-
able to these metastases. Occasionally,
patients may present with hormonal mani-
festations secondary to secretion of β‐HCG.
Specifically, peripheral conversion of andro-
gen to estrogen can lead to gynecomastia or
uterine bleeding.
Boys with gonadal GCT typically pre-
sent with a slowly enlarging, painless tes-
ticular mass, occasionally complicated by
acute severe pain due to testicular torsion.
Germ Cell Tumors 267
The differential diagnosis of a testicular
mass includes hydrocele, hematocele, vari-
cocele, inguinal hernia, and torsion of a
normal testis. Girls most frequently present
with abdominal pain, distention, and
weight gain. Torsion of an involved ovary,
hemorrhage, or tumor rupture may occur
and present as an acute surgical abdomen.
Secretion of β‐HCG may lead to isosexual
precocity. Occasionally, the increasing
abdominal girth and elevated urine and
serum β‐HCG have been confused with
pregnancy.
The most common site of extragonadal
tumors is the sacrococcygeal region.
Although usually benign, patients can have
malignant tumors of higher stage. Older age
at diagnosis is associated with a greater risk
of malignancy. Sacrococcygeal tumors are
classified as four anatomic variants: type I
(predominantly outside the body), type II
(equally inside and outside the body), type
III (largely intra‐abdominal), and type IV
(completely within the body). More than
90% of tumors present with some compo-
nent of an externally visible mass. These
tumors are often detected in utero with pre-
natal ultrasonography. They may also pre-
sent later in children with constipation,
urinary obstruction, urgency or frequency,
lower back or pelvic pain, lower extremity
weakness, or sensory changes, all signs and
symptoms due to compression of normal
structures by tumor.
Approximately 20% of children with
GCTs will present with metastatic disease,
most commonly to the lung, liver, or
lymph nodes, and rarely to the central
nervous system, bone, or bone marrow.
Regional spread resulting in surgically
unresectable tumors occurs in approxi-
mately 25% of patients at presentation.
Tumor dissemination occurs by local
extension, intracavitary seeding, or hema-
togenous spread. Intracavitary seeding
may involve the omentum, bowel, spleen,
268 Chapter 21
diaphragm, or pelvic organs. Rarely, bone
involvement can occur by direct extension.
Diagnostic evaluation and risk
stratification
The following studies should be performed
in a child with a suspected or confirmed
GCT:
●● Physical examination.
●● Baseline laboratory studies consisting of a
complete blood count, transaminases, blood
urea nitrogen, creatinine, and electrolytes.
●● Baseline tumor markers including AFP,
β‐HCG, and LDH.
●● Imaging studies to evaluate the extent of
the mass and potential metastatic sites:
ultrasound, CT, or MRI of the primary mass
(testicular ultrasound in males, abdominal
and pelvic ultrasound, CT, or MRI in
females); abdominal and pelvic MRI or CT
as well as baseline chest radiography with or
without CT of the chest to evaluate for met-
astatic disease (all CTs should be done with
contrast).
Determination of the extent of disease at
diagnosis allows proper decision‐making
regarding the safest and most reasonable
place to biopsy. Localized tumors of the
ovary or testis should be completely
removed. Resection of ovarian tumors
should include abdominal exploration and
peritoneal washings for cytologic assess-
ment. Risks and benefits of lymph node
sampling and biopsy of the contralateral
testis or ovary should be discussed with
the surgeon, patient, and family.
GCTs are known to grow rapidly and
metastasize frequently. Diagnostic studies
should be done expeditiously to allow ini-
tiation of therapy. Due to the potential
underlying risk of contralateral testicular
atrophy, infertility, or carcinoma in situ,
sperm banking should be discussed with
the patient and family prior to radical
inguinal orchiectomy.
Treatment and prognosis
Staging is done postoperatively and is based
on pathologic degree of tumor invasion,
presence of lymph node involvement, con-
tinued positivity of tumor markers, positive
peritoneal washings (in ovarian tumors),
and presence of residual or metastatic dis-
ease. Factors known to affect prognosis
include extreme tumor marker elevation
and failure of these markers to appropriately
decline following tumor resection, based on
the appropriate half‐life for each marker.
Site of tumor is prognostic, with mediastinal
tumors fairing more poorly. Histology is
also important, as pure germinomas are
generally very chemotherapy‐sensitive and
have a high response rate. Patients with
higher‐stage, metastatic disease also fair
more poorly.
In the patient with suspected GCT, every
effort should be made to perform a com-
plete resection with negative margins. In
situations where the patient presents emer-
gently with torsion, there may not be time to
wait for a definitive diagnosis prior to sur-
gery; every effort should be made in these
cases to perform a gross total resection
(GTR), assuming there is low operative risk,
after sending the appropriate tumor mark-
ers. In the case of a large, invasive tumor,
biopsy should be done followed by adminis-
tration of chemotherapy and delayed surgi-
cal resection. Due to the location of some
extragonadal tumors, especially those in the
mediastinum and retroperitoneum, neoad-
juvant chemotherapy is often required prior
to surgery in order to help facilitate the
chance of a safe GTR.
Depending on tumor location and his-
tology, some GCTs can be observed after
GTR without additional therapy. Young

patients with extragonadal tumors and a
GTR can generally be observed after sur-
gery, as these tumors rarely have malignant
elements. Sacrococcygeal tumors must be
removed with the coccyx in order to
decrease the risk of local recurrence. Young
patients are more likely to present with pure
yolk sac tumors, and these patients can also
be observed after GTR. Gonadal tumors
that are histologically consistent with
mature teratoma similarly require only
observation after GTR. Localized testicular
seminoma can be observed, although
patients with continued elevation of tumor
markers should undergo adjuvant chemo-
therapy. Patients with this pure histology are
very chemotherapy‐sensitive and easily sal-
vaged in the event of relapse. In general,
patients with localized testicular‐mixed
GCT can also be observed assuming that
tumor markers normalize after surgery,
again due to the high rate of salvage with
potential relapse. Due to this risk of relapse,
which is directly related to the amount of
vascular tumor invasion, size of the primary
tumor, and percent embryonal carcinoma,
patients should be presented the options of
observation versus chemotherapy. Due to
the rarity of malignant ovarian GCT, recom-
mendations for chemotherapy versus obser-
vation generally follow those presented for
testicular tumors.
Higher‐stage, nonlocalized GCTs are
treated with chemotherapy and are gener-
ally very chemotherapy‐sensitive. Patients
are treated with bleomycin, etoposide, and
cisplatin (BEP) regimens for three to four
cycles. These tumors exhibit a steep dose–
response curve to platinum compounds,
though the risk of toxicity (ototoxicity and
nephrotoxicity) must be considered. Due to
the potential risk of long‐term pulmonary
fibrosis from bleomycin, etoposide/cisplatin
(EP) and etoposide (VP‐16), ifosfamide, and
cisplatin (VIP) regimens have been devel-
oped as alternative therapies to BEP. Bilateral
Germ Cell Tumors 269
retroperitoneal lymph node dissection may
also be recommended in patients with
extensive disease at presentation. Patients
with a poor response to therapy or recurrent
disease may benefit from second‐line thera-
pies such as paclitaxel (Taxol), ifosfamide,
cisplatin (TIP); vinblastine, ifosfamide, cis-
platin (VeIP); or gemcitabine/oxaliplatin.
GCTs are also quite radiosensitive, although
the high cure rates seen with chemotherapy
alone have obviated the need for radiation in
most cases. Radiation may be considered in
refractory or recurrent disease, or for pallia-
tion. Additionally, high‐dose chemotherapy
with autologous stem cell rescue may be
beneficial in a subset of refractory patients.
Patients treated with high‐dose platinum
agents may develop high‐frequency hearing
loss and require hearing assistive devices.
Additionally, these drugs may lead to tran-
sient proximal tubule renal dysfunction and
resultant electrolyte wasting. Patients who
receive alkylator therapy (e.g., ifosfamide) are
at risk for secondary malignancy and infertil-
ity (especially in males). Topoisomerase II
inhibitors (etoposide) also increase risk for
secondary neoplasms. Bleomycin may lead to
pulmonary fibrosis, although the risk is
poorly quantified.
Germ cell tumors of the central
nervous system
Intracranial GCTs comprise approximately
3% of primary childhood brain tumors with
a peak incidence between the second and
third decades of life. The majority of these
tumors are germinomas, which account for
50–70% of cases. Nongerminomatous germ
cell tumors (NGGCT) account for the
remaining third and consist of multiple his-
tologies including endodermal sinus (yolk
sac) tumors, choriocarcinoma, mature and
immature teratoma, and embryonal carci-
noma. Most NGGCT are of mixed histology
270 Chapter 21
and may contain germinomatous elements,
but will not have this as a pure histology.
Mature and immature teratomas predomi-
nate in the neonatal period. Patients typi-
cally present with symptoms depending on
the location and size of the tumor, further
influenced by the extent of pituitary dys-
function and the presence or absence of
hydrocephalus. Midline pineal tumors are
often associated with symptoms related to
increased intracranial pressure due to
obstruction of the cerebral aqueduct and
Parinaud’s syndrome (paralysis of upward
gaze) due to involvement of the tectal plate.
Tumors in the suprasellar area often lead to
endocrinopathies such as diabetes insipidus
(DI) and visual field defects. Occasionally,
DI is related to occult involvement of the
infundibulum. In children with clinical
symptoms of DI and consistent MRI find-
ings (i.e., absence of a posterior pituitary
bright spot, possibly in association with
thickening of the pituitary stalk), the differ-
ential diagnosis should include GCT and
Langerhans cell histiocytosis. The presence
or absence of CSF tumor markers may assist
with this diagnostic dilemma.
Children with midline brain tumors
should be assessed for a GCT. CSF should
be obtained for routine studies (glucose,
protein, chamber count, and cytology) in
addition to assessment of tumor markers
(AFP and β‐HCG). Patients with classic
findings on MRI and elevated AFP with or
without a significantly elevated β‐HCG do
not require a biopsy for diagnosis, as they
have chemical evidence of NGGCT. Patients
with negative markers or a modest elevation
in β‐HCG only should have a biopsy per-
formed. Central nervous system GCTs often
spread along the CSF pathways; thus, MRI
of the spine should be obtained in addition
to head imaging for diagnostic and staging
purposes.
Patients with benign tumors such as
mature teratoma should have a curative
surgical GTR, as safely feasible. In other
tumor types, the value of a surgical resec-
tion has not been clearly delineated and is
recommended only in specific situations
(i.e., persistence of tumor following induc-
tion chemotherapy). Pure germinomatous
tumors are highly sensitive to both radio-
therapy and chemotherapy. In the past,
radiotherapy was the modality of choice for
these tumors due to the high cure rate (5‐
year survival >80%). Due to the recognized
long‐term risks from this therapy (neu-
ropsychological and endocrine), adjuvant
chemotherapy is now being used to allow a
reduction in the dose and extent of radio-
therapy without increasing relapse rate.
Chemotherapeutic agents are similar to
those used for systemic GCTs and include
platinum agents (cisplatin and carbopl-
atin), alkylators (cyclophosphamide and
ifosfamide), and topoisomerase II inhibi-
tors (etoposide). Of note, patients with DI
should be carefully monitored in an ICU
setting while receiving alkylators or plati-
num therapy due to the increased risk of
nephrotoxicity. Management during this
therapy can be simplified by the use of IV
vasopressin administered as a continuous
infusion.
Patients with NGGCT have had a poorer
outcome in the past, as these tumors are
generally less radiosensitive than pure ger-
minoma. Outcome is related to tumor his-
tology, as those patients with pure embryonal
carcinoma, endodermal sinus tumor, and
choriocarcinoma fair much more poorly
than those with mixed histology, especially
those with a high proportion of teratoma or
germinoma. Neoadjuvant platinum‐based
chemotherapeutic regimens have shown
benefit in patients with NGGCT prior to
radiation therapy. Second‐look surgery is
beneficial in those patients with an incom-
plete radiologic response or persistently
elevated tumor markers following induction
chemotherapy, prior to radiation therapy.

High‐dose chemotherapy with autologous
stem cell rescue has been shown to be of
benefit in patients with residual malignant
disease after chemotherapy and surgery.
Patients with recurrent disease may be
successfully treated, depending on initial
therapy. Patients with pure germinoma
treated solely with chemotherapy may ben-
efit from additional chemotherapy fol-
lowed by radiation therapy. Those that have
previously received radiation may benefit
from high‐dose chemotherapy with autolo-
gous stem cell rescue. Patients with recur-
rent NGGCT have a much more dismal
outcome, though may benefit from addi-
tional chemotherapy, surgery, radiation,
and/or high‐dose chemotherapy with stem
cell rescue.
Paraneoplastic syndromes
Neurological manifestations can occur at
presentation as a clue to the underlying
diagnosis of a GCT. The most common
paraneoplastic syndrome is the develop-
ment of NMDA (anti‐N‐methyl‐d‐
a­spartate) receptor antibody encephalitis
seen most commonly in mature ovarian
­teratoma and less frequently in immature
ovarian teratoma. Patients present with
psychiatric symptoms and progressive neu-
rologic dysfunction including seizures,
dyskinesia, and autonomic dysfunction.
Diagnosis can be determined by the pres-
ence of autoantibodies against the gluta-
mate receptor. Female patients with these
findings must be screened for ovarian
pathology and, if found, proceed to emer-
gent tumor resection.
Concomitant malignancies
Patients with GCTs may in rare cases pre-
sent with concomitant or secondary
Germ Cell Tumors 271
acute myelogenous leukemia (AML) or
myelodysplasia (MDS). This often occurs
secondary to the presence of isochromo-
some 12p in both malignancies. Patients
may also present in rare cases with a
mixed tumor with both germ cell as well
as primitive neuroectodermal tumor
(PNET) elements. Finally, patients may
develop a growing mature teratoma or
other nongerm cell malignancy after
chemotherapy.
Case study for review
You are seeing a 17‐year‐old male who was
admitted from the emergency department
(ED) after presenting with acute onset of
shortness of breath and a near syncopal
episode. Follow‐up questioning in the ED
reveals no prior illness, no fever, no loss of
appetite or weight loss, no recent travel,
and no night sweats. The ED resident
astutely asks about orthopnea and the
patient does note that it has been more dif-
ficult to lie flat, and he has been using
about two to three pillows now to feel com-
fortable sleeping. He has been having
increasing coughing which he attributes to
a “stitch” on his right side. The patient’s
vitals are abnormal with an elevated heart
rate (120), elevated respiratory rate (16),
and decreased O2 sat (93%). Exam reveals
decreased breath sounds in the bilateral
bases with egophony. He is unable to take a
big breath without coughing. There is no
increased jugular venous pressure (JVP),
plethora, or hepatomegaly. There are no
palpable cervical, supraclavicular, axillary,
or inguinal nodes.
You are initially concerned about an
anterior mediastinal mass causing ortho-
pnea and order a chest X‐ray (CXR). CXR
reveals a large mediastinal mass with associ-
ated bilateral pleural effusions, R > L.
a. What is the differential diagnosis?
272 Chapter 21
b. What are the appropriate next steps?
The most common etiologies in pediatric
patients with an anterior mediastinal mass
are acute lymphoblastic leukemia (ALL) and
non‐Hodgkin lymphoma (NHL). These
typically will present with clinical findings
and laboratory abnormalities suggestive of
these underlying etiologies. ALL will likely
present with cytopenias, possibly peripheral
blasts, as well as potential elevation in mark-
ers of increased cellular turnover (i.e., LDH,
uric acid, most commonly). NHL often will
­present with increased LDH and uric acid as
well as markers of inflammation including
ESR and ferritin. Hodgkin lymphoma is also
­common in an adolescent patient and may
present with B symptoms (objective fever,
night sweats, objective weight loss), as well
as elevation in inflammatory markers.
Lymphoma and ALL may have clinical signs
of tumor bulk including lymphadenopathy
and hepatosplenomegaly. Other possible
causes of an anterior mediastinal mass
include GCTs, Ewing s­ arcoma, undifferenti-
ated sarcoma, and rarely thymoma or thy-
roid carcinoma.
Given the likely etiologies, you order the
following labs: CBC/diff, CMP, phosphorus,
uric acid, LDH, ESR, ferritin, AFP, and
β‐HCG. The initial labs are all normal with
β‐HCG and AFP pending. Given the lack of
any signs of tumor bulk you wonder if this will
be something other than ALL or NHL.
c. What are the next steps?
Given the orthopnea, there is risk for
cardiovascular decompensation. As there
­ infants will have a physiologic elevation in
are no markers that this is ALL or NHL, it is
unclear that steroids will be of benefit in an
emergent situation. Fortunately, the other
potential ­etiologies in the differential diag-
nosis have a slower doubling time meaning
that the risk of acute decompensation is less.
Either way, it is important to obtain a CT
chest with/without contrast to evaluate the
great vessels and determine the extent of
­vascular and airway compromise—this will
assist the anesthesiologist’s assessment of
the airway and risk of decompensation with
different levels of sedation. The patient will
need a mediastinal biopsy and thoracentesis
with cytology of the pleural effusion may
assist with diagnosis as well as alleviate
symptoms. Depending on the extent of
orthopnea as well as compromise noted on
the CT imaging, the patient may benefit
from observation in the critical care unit.
CT chest returns with the finding of a
large mediastinal tumor and a large right‐
sided pleural effusion compromising the
lower half of the right lung. There is minimal
compromise of the superior vena cava and
bilateral subclavian veins. In the interim,
the AFP returns elevated at 30 000 ng/ml
(normal <10 ng/ml), while the β‐HCG is
normal.
d. How does this aid in diagnosis?
e. What are the next steps?
Given the very elevated AFP, the patient has
a GCT, likely yolk sac histology with possi-
ble embryonal carcinoma pathology (i.e.,
non‐seminomatous). Male patients with
elevated β‐HCG can present with gyneco-
mastia secondary to β‐HCG stimulating
androgen production (secondary to com-
monality with luteinizing hormone [LH])
subsequently converted to estrogen). β‐
HCG is produced by syncytiotrophoblastic
elements within the tumor. Male patients
with underlying Klinefelter’s syndrome are
at increased risk of GCTs. Remember that
AFP with standard available normal refer-
ence ranges for age. Though laboratory
markers are important in assisting with
diagnosis as well as following for response
and tumor recurrence, it is still vital to prove
pathology based on a biopsy specimen. The
patient should still proceed with mediastinal
biopsy and thoracentesis of the pleural
effusion.

Biopsy shows a pure yolk sac tumor and
the patient is started on standard therapy with
BEP. You perform baseline pulmonary func-
tion testing and audiology screening given the
risk of pulmonary fibrosis from bleomycin
and ototoxicity from cisplatin. Additionally, a
PET/CT is performed as a staging workup and
does not show any sites of disease. Although
the overall prognosis for GCTs is quite good,
mediastinal GCTs have a poorer prognosis.
AFP response is important and the AFP
should be followed closely to review whether
it is decreasing as appropriate (based on a
half‐life of 5 days). In this case, with an initial
AFP of 30 000 ng/ml, the AFP should drop to
around 500 ng/ml after 1 month (i.e., six half‐
lives). Patients with mediastinal GCTs may
require definitive resection of the mass and
additional ­chemotherapy cycles as compared
to the standard three to four cycles of BEP for
most GCTs.
Germ Cell Tumors 273
Suggested reading
Fetcko, K. and Dey, M. (2018). Primary central
nervous system germ cell tumors: a review
and update. Med. Res. Arch. 6: 1719.
Frazier, A.L., Hale, J.P., Rodriguez‐Galindo, C.
et al. (2015). Revised risk classification for
pediatric extracranial germ cell tumors based
on 25 years of clinical trial data from the
United Kingdom and United States. J. Clin.
Oncol. 33: 195–201.
Olson, T.A., Murray, M.J., Rodriguez‐Galindo, C.
et al. (2015). Pediatric and adolescent extrac-
ranial germ cell tumors: the road to collabora-
tion. J. Clin. Oncol. 33 205: 3018–3028.
Plant, A.S., Chi, S.N., and Frazier, L. (2016).
Pediatric malignant germ cell tumors: a com-
parison of the neuro‐oncology and solid
tumor experience. Pediatr. Blood Cancer 63:
2086–2095.
22 Rare Tumors of
Childhood
The rarer tumors of childhood collectively
comprise fewer than 20% of all pediatric
cancers. The more frequently seen of these
include retinoblastoma (2–3%), liver tumors
(1%), and epithelial tumors of the adrenal or
thyroid gland (2–3%), which are discussed
herein. Many other rare pediatric malignan-
cies also exist that are beyond the scope of
this chapter.
Retinoblastoma
Retinoblastoma is the most common malig-
nant ocular tumor in childhood, affecting
200–300 children per year in the United
States. Retinoblastoma is rarely diagnosed
after 5 years of age, and the median age of
diagnosis is 2. This unique neoplasm has a
strong genetic component related to loss of
function mutations of the RB1 gene located
on chromosome 13q14. It was the model for
the development of Knudson’s two‐hit
hypothesis after observation that children
with bilateral retinoblastoma developed dis-
ease at a much earlier age compared to those
with unilateral disease, typically in the first
year of life. The genetic form of the disease is
inherited in an autosomal dominant man-
ner with high penetrance, yet only approxi-
mately 15% of children have a family history,
suggesting the acquisition of a new germline
or somatic mutation in the majority of
Handbook of Pediatric Hematology and Oncology – Children’s Hospital & Research Center Oakland,
Third Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
affected children. Genetic counseling is of
utmost importance in affected families due
to the risk of tumors in siblings as well as
offspring of survivors, especially in those
with bilateral retinoblastoma.
The RB1 gene is a tumor suppressor gene
and individuals with loss of function of both
allelic copies are predisposed to malignancy.
Multiple tumors developing within the eye
may be synchronous or metachronous.
Germline de novo mutations of the RB1
gene largely occur during spermatogenesis.
Secondary mutations may then be germline
or somatic depending on the timing of
events. Those mutations that are germline
are heritable for future generations. In spo-
radic cases, two somatic mutations occur
postconception in the RB1 gene, resulting in
a tumor that is typically unifocal or unilat-
eral. Prenatal diagnosis can identify ger-
mline mutations.
Retinoblastoma arises from the photo-
receptor cells of the innermost layer of the
retina. The tumor frequently extends into
the vitreous cavity, presenting with a
fleshy nodular mass visible on ophthal-
mologic examination. Large tumors may
occupy most of the posterior chamber.
Less frequently, tumors may extend exter-
nally resulting in retinal detachment. The
tumor tends to outgrow its blood supply
and may develop areas of necrosis and
calcification.
276 Chapter 22
Clinical presentation
Due to the large mass or retinal detachment,
the normal papillary red reflex is replaced by
leukocoria (white papillary discoloration)
and is often first noticed by the family (or in
a photo with a white reflex). Strabismus is
the second most common presenting sign
and is due to visual impairment from the
tumor. Other less common presenting signs
include heterochromia, inflammatory
changes, hyphema, and glaucoma. Familial
cases are often detected early when the fam-
ily is appropriately advised on the need for
frequent and careful screening with ophthal-
mologic examinations under anesthesia. The
differential diagnosis of leukocoria includes
a number of rare nonmalignant conditions
such as Coats disease, congenital cataracts,
toxocariasis, retinopathy of prematurity, and
persistent hyperplastic primary vitreous.
Careful retinal examination by an ocular
oncologist or retinal specialist can rule out
these other diseases. The ophthalmologic
exam is done typically under anesthesia with
careful assessment of the extent of intraocu-
lar tumor and evaluation of both eyes with
maximal dilation. Patients with advanced
disease may present with proptosis and
swelling depending on the degree of extraoc-
ular invasion. Metastatic spread can occur
through infiltration of the optic nerve, dis-
semination into the subarachnoid space,
invasion into the choroid plexus, and anteri-
orly into the conjunctiva. Invasion through
the optic nerve and subarachnoid can lead to
involvement of the brain and spinal cord,
invasion of the vascular choroid plexus can
lead to vascular spread, and anterior invasion
can lead to regional lymph node involve-
ment. Given the concern for rupture of the
tumor, surgical biopsy is not recommended
for tissue confirmation.
Patients with bilateral retinoblastoma may
present with a concurrent intracranial neuro-
blastic tumor (typically of the pineal gland)
referred to as trilateral retinoblastoma. These
patients tend to have a poor prognosis. The
intracranial tumor may present at the same
time as the retinoblastomas, or after the iden-
tification and treatment of the original
tumors, emphasizing the need for close
­follow‐up after initial treatment.
Diagnosis and staging
Retinal imaging, magnetic resonance imag-
ing (MRI), and computed tomography (CT)
are typically used in addition to ophthalmo-
logic examination to further characterize
the tumor. CT is the most useful test, as it
effectively demonstrates intraocular calcifi-
cations that confirm the diagnosis, but it
creates risk due to radiation that increases
the likelihood of secondary malignancy.
MRI of the orbits and brain is most useful
for identification of extraocular extension
and trilateral retinoblastoma. MRI of the
spine and lumbar puncture for cerebrospi-
nal fluid cytology should be done in patients
with intracranial spread, involvement of the
optic nerve, or evidence of tumor invasion
beyond the lamina cribrosa on pathology
after eye enucleation. In patients with delay
in diagnosis and concern for metastatic dis-
ease, bone marrow studies and bone scan
should be performed.
Treatment
Patients with known or suspected retino-
blastoma should be referred to a pediatric
oncologist in specialized centers with both
oncologists and ophthalmologists with
expertise in the management of these chil-
dren. Goals for treatment of children with
retinoblastoma include preservation of life,
as much vision as possible, and avoidance of
radiation in patients with RB gene muta-
tions given the high risk of second malig-
nancies. Treatment for retinoblastoma is
individualized and dependent on multiple
factors including unilaterality or bilaterality
of disease, potential for preserving vision,
and extent of intraocular and extraocular

disease. Enucleation performed by an expe-
rienced ophthalmologist is indicated for
large tumors filling the vitreous and in those
with little or no likelihood of vision preser-
vation. The eye must be removed intact to
avoid seeding and care must be taken to
resect enough optic nerve to ensure negative
margins. After enucleation, patients are fit-
ted with a prosthetic implant.
Treatments aimed at local tumor control
include cryotherapy, infrared laser (ther-
motherapy), laser photoablation, or a
­radioactive plaque (I‐125 brachytherapy).
Chemotherapy may be utilized for tumor
reduction to facilitate more effective focal
treatment and prevent the need for enuclea-
tion. Systemic chemotherapy may also
be given in combination with enucleation
in unilateral or bilateral disease (unifocal
enucleation) or following enucleation in
­ Follow‐up
patients with high‐risk pathologic features
predisposing to recurrence or metastatic
disease (i.e., massive choroidal involve-
ment, postlaminar optic nerve involvement
[ONI], or any uveal involvement in the
presence of ONI). A number of different
chemotherapeutic regimens have been
studied and most typically include carbopl-
atin, etoposide, and vincristine (CEV) for
six cycles. Intra‐arterial chemotherapeutic
(IAC) delivery under fluoroscopic guidance
into the ophthalmic artery is a more recent
intervention and may aid in preserving the
eye and preventing systemic effects of
chemotherapy in a young child.
External beam radiation therapy is gen-
erally reserved for patients with refractory
or recurrent disease after these other treat-
ment modalities have been exhausted due to
the high incidence of side effects including
increased risk of secondary malignancy
both in and out of the radiation field.
Current protocols with conformal, stereo-
tactic, and proton‐beam radiotherapy, as
well as intensity‐modulated radiotherapy,
have been developed to minimize exposure
Rare Tumors of Childhood 277
to non‐target tissues. Lower doses of radia-
tion are also being investigated.
Patients who have undergone enuclea-
tion and determined to have disease at the
cut edge of the optic nerve or extension into
the sclera or extrascleral tissues should con-
tinue with either adjuvant chemotherapy or
local radiation.
Patients with regional extraocular dis-
ease and metastatic disease have historically
faired very poorly. Newer studies have
shown the potential benefit of chemother-
apy (or high‐dose chemotherapy with autol-
ogous stem cell rescue in those with
metastatic disease) with external beam radi-
ation therapy. Impacts on outcomes utiliz-
ing this treatment plan are still to be
determined.
Children treated for retinoblastoma are at
high risk for cosmetic and functional
impairment related to either enucleation or
radiation. Patients with a heritable muta-
tion in the RB1 gene have an especially high
rate of secondary malignancy after radia-
tion therapy. Reported second malignancies
include head and neck cancers, osteosar-
coma, soft tissue sarcoma, and melanoma.
Adult tumors also have an increased inci-
dence in those with germline RB1 muta-
tions, especially epithelial tumors such as
lung cancer. Radiation therapy may also
lead to decreased visual acuity, eye irrita-
tion, and dry eye, as well as growth abnor-
malities in the orbital bones. After therapy,
patients should be followed closely due
to the risk of recurrent disease. Patients
with bilateral retinoblastoma and those
diagnosed with unilateral retinoblastoma at
a young age (i.e., <1 year of age) should
be observed for the development of an
intracranial mass and, in the case of
­
unilateral disease, a contralateral retinal
­
mass. Recurrence or new disease rarely
occurs after 5 years of age, although an
278 Chapter 22
­phthalmologist should examine these
o Patients
patients annually under anesthesia.
Liver tumors
Primary hepatic tumors in childhood
and adolescence account for just >1% of
malignancies in these age groups.
Hepatoblastoma (HBL) is the most com-
mon, representing more than 60% of
hepatic tumors, and occurs almost exclu-
sively during infancy and young child-
hood. The incidence of hepatoblastoma is
increasing, possibly due to increased sur-
vival in very low birth weight infants.
Hepatocellular carcinoma (HCC), approx-
imately 20–25% of childhood primary liver
tumors, is seen most often in children
above 10 years of age. Although chronic
hepatitis B infection is the leading cause of
HCC in Asia, few American children with
HCC have an apparent etiology. Benign
hepatic tumors, such as hemangioendothe-
lioma, hemangioma, hamartoma, mature
teratoma, angiolipoma, biliary cyst, and
adenoma, also occur in childhood and
account for up to 20% of liver tumors in
this age group. Other extremely rare malig-
nant hepatic tumors include cholangiocar-
cinoma, rhabdoid tumor, yolk sac tumor,
rhabdomyosarcoma, undifferentiated sar-
coma, angiosarcoma, leiomyosarcoma, and
lymphoma.
Malignant hepatic tumors of childhood
have been associated with a number of
genetic syndromes and environmental risk
factors. HBL has been reported in children
with Beckwith–Wiedemann syndrome,
familial adenomatous polyposis (which
includes Gardner syndrome), Li–Fraumeni
syndrome, trisomy 18, glycogen storage
disease type I, Prader–Willi syndrome,
­ emesis, and abdominal pain. Rarely, chil-
Meckel’s diverticulum, congenital absence
of an adrenal gland or kidney, umbili-
cal hernia, and isolated hemihypertrophy.
with Beckwith–Wiedemann
­syndrome or hemihypertrophy should be
screened every 3 months with serum α‐
fetoprotein (AFP) and abdominal ultra-
sound until 5 years of age given the
significant association with HBL (with
continued ultrasound screening until age 8
to rule out Wilms tumor). The strongest
association has been reported in infants
born at <1500 g. Additional associations
may include maternal smoking (independ-
ent of birth weight), fetal alcohol syn-
drome, use of oral contraceptives during
pregnancy, and occupational exposure to
metals, petroleum, paints, and pigments.
HCC is seen in association with hereditary
tyrosinemia, biliary cirrhosis, glycogen
storage diseases, hemochromatosis, ataxia
telangiectasia, Wilms tumor with liver
metastasis treated with hepatic radiation,
and α1‐antitrypsin deficiency. Infection
with hepatitis B or C has been identified as
a risk factor for HCC as have exposure to
alcohol, anabolic steroids, aflatoxin, and
certain carcinogens such as pesticides and
vinyl chloride.
Factors influencing survival include
staging, histology, resectability, and treat-
ment response. Overall survival for children
with HBL is 70% and only 25% for HCC.
Patients with stage I HCC have a good out-
come while those with stage IV disease have
a high mortality.
Clinical presentation
The most common presenting signs of a
malignant hepatic tumor in childhood are
generalized abdominal enlargement or an
asymptomatic abdominal mass palpated by
the family or physician. Patients with HBL
or HCC may present with constitutional
symptoms including weight loss, anorexia,
dren may present with jaundice including
cases with biliary tree involvement.
Occasionally, males with HBL present with

signs of isosexual precocious puberty due to
excessive production of the beta subunit of
human chorionic gonadotropin (β‐HCG)
that is converted to testosterone. Metastatic
disease (typically asymptomatic) may occur
at presentation in up to 20% of children with
HBL or HCC. Extrahepatic extension may
include peritoneal implants as well as spread
to regional and distant lymph nodes, bone,
bone marrow, and rarely the central nervous
system. Liver tumors may also invade into
adjacent intra‐abdominal structures.
Diagnosis and staging
Work‐up of a suspected hepatic mass
should include a complete history and
physical including assessment of co‐mor-
bid or predisposing genetic syndromes,
laboratory measurement of liver function
with coagulation studies, urinalysis, testing
for hepatitis B (surface antigen, core anti-
gen, core antibody) in addition to transam-
inases, total bilirubin, and alkaline
phosphatase. Patients should have a base-
line complete blood count (CBC) in addi-
tion to metabolic studies, as patients may
present with thrombocytosis (>500 × 109/l)
and/or moderate leukocytosis. Patients
with suspected HBL typically present with
an elevation of AFP and, less commonly, of
β‐HCG. In certain cases with an extremely
high AFP, the value reported may be falsely
low due to overwhelming of the assay
(hook effect). When the index of suspicion
is high, serial dilution of serum can allow
for more accurate reporting. Those with
HCC may also have elevation in AFP
but not to the same magnitude as hepato-
blastoma. β‐HCG may be elevated in
patients with carcinoma of the biliary tract.
Carcinoembryonic antigen (CEA) and vita-
min‐B12‐binding capacity may be elevated
in some cases of HCC (with elevated B12‐
binding capacity associated with the
fibrolamellar variant of HCC). Imaging
studies should begin with abdominal and
Rare Tumors of Childhood 279
specifically liver ultrasound with Doppler
flow to characterize the tumor as well as the
relationship between the tumor and hepatic
vessels. Abdominal CT or MRI should also
be obtained prior to surgical intervention.
MRI angiography and cholangiogram may
be useful to assess degree of intrahepatic
disease and aid in determining a surgical
plan, but is rarely needed now due to the
excellent resolution of current generation
CT and MRI. Evaluation for metastatic dis-
ease should include chest radiographs and
CT, as up to 10–20% of patients with liver
tumors will have pulmonary metastases.
Dependent on extent of disease and symp-
toms, consideration can be given to obtain-
ing a bone scan and bone marrow aspirate/
biopsy. The right lobe of the liver is most
commonly affected in both HBL and HCC,
but can involve both lobes in up to 30% of
cases of HBL.
Staging of liver tumors is complex and
both presurgical (PRETEXT, stages 1–4)
and postsurgical (stages I–IV) staging sys-
tems are utilized. The PRETEXT staging for
HBL is utilized internationally, though some
differences in treatment are employed in
Europe and the United States with similar
outcomes and current study of a more uni-
fied approach.
Treatment
In cases where clinical presentation, imag-
ing, and tumor markers are highly suggestive
of HBL, patients should undergo a primary
complete resection if it is deemed safe and
feasible. Only patients who achieve a com-
plete surgical resection have a reasonable
chance of cure. Decisions regarding an initial
surgical approach (as opposed to presurgery
chemotherapy) are dependent on expected
degree of resectability with suitable candi-
dates including those with tumor confined to
one lobe of the liver or originating in the right
lobe and not extending beyond the medial
segment of the left lobe. Patients should be
280 Chapter 22
referred to a pediatric liver transplant center
with an experienced liver transplant surgeon
for initial decisions regarding attempted
resection upfront or delayed resection post
chemotherapy. Orthotopic liver transplant
may also be warranted in patients. In cases
where a complete resection is not feasible or
the diagnosis is uncertain, the patient should
first undergo biopsy.
Patients with low‐stage (I and II) disease
and pure fetal histology can be safely
observed without adjuvant chemotherapy.
Patients who cannot obtain a complete
resection (stages III and IV; metastatic dis-
ease) or have a less‐favorable histology
should receive chemotherapy followed by
resection (including orthotopic liver trans-
plant if not resectable), with resection of
residual pulmonary metastasis in stage IV
patients if unresolved with chemotherapy
alone. Various combinations of chemother-
apy have been utilized and most commonly
employ cisplatin, 5‐FU (fluorouracil) vin-
cristine, and doxorubicin. Chemotherapy is
utilized preoperatively to shrink tumor and
facilitate complete surgical resection (or pro-
vide time for identification of an orthotopic
liver) in addition to after resection for treat-
ment of potential micrometastatic disease.
In general, HCC has a poor prognosis
and often presents with multifocal liver and
metastatic disease. Previous studies treated
pediatric patients with a similar chemother-
apeutic regimen as HBL with disappointing
results. Cisplatin and doxorubicin may be
given presurgically, but clinical trials have
not shown a survival benefit. Gross total
surgical resection remains the mainstay of
cure for HCC. In cases where resection is
not safe or feasible at presentation, neoadju-
vant chemotherapy may be of benefit and
allow for a later total resection or for ortho-
topic liver transplantation.
A distinct pathologic variant, fibrolamel-
lar HCC, has been associated with a higher
resection rate and improved survival com-
pared to other forms of HCC. Novel tar-
geted agents have shown a modest benefit at
best, but may have promise when used as
part of multimodal therapy.
Radiation therapy has not been proven
to be effective in the treatment of HCC, but
it may have a role in palliation of lung
metastases. Similarly, high‐dose chemother-
apy with autologous stem cell rescue has not
as yet been found beneficial. Local therapies
including hepatic artery chemoemboliza-
tion, percutaneous radiofrequency ablation,
and percutaneous ethanol injection may be
beneficial in patients with localized yet
unresectable HCC.
Follow‐up
AFP is the most sensitive marker for dis-
ease, especially in HBL. Approximately 90%
of children with HBL and 50% of those with
HCC present with an elevated AFP. Patients
with small‐cell undifferentiated histology
have a poorer prognosis and tend to have
low serum AFP, which is a poor prognostic
marker. Decline in AFP levels with courses
of treatment is prognostic and AFP should
be followed for normalization after surgical
resection and as a marker for residual dis-
ease or recurrence. Of note, serum AFP lev-
els vary with age in infancy and are normally
elevated in the newborn period, declining
to adult levels by around 6–8 months of age.
In addition, AFP has a long serum half‐life
(5–6 days) and therefore may take several
weeks to normalize in cases with an
extremely high level at presentation.
Adrenocortical carcinoma
Adrenocortical carcinoma (ACC) is a rare
malignancy in childhood and adolescence
(0.2% of childhood malignancies) with a
median presentation of 3–4 years of age and

female predominance (two to three times
the number of affected boys). ACC is also
seen in adults. The incidence varies world-
wide with a ten times higher incidence in
southern Brazil associated with a high pop-
ulation prevalence of the R337H germline
mutation in the TP53 tumor suppressor
gene. ACC has been reported in association
with specific genetic syndromes such as
Beckwith–Wiedemann syndrome, isolated
hemihypertrophy, Li–Fraumeni syndrome,
and in association with congenital adrenal
hyperplasia and multiple endocrine neo-
plasia type 1 (MEN‐1 syndrome). Germline
mutations in the TP53 tumor suppressor
gene have been implicated in the majority of
pediatric cases in the United States and
Brazil. In addition to the association with
constitutional genetic abnormalities, ACC
can also be seen with somatic genetic muta-
tions, including overexpression of IGF‐2
and constitutive activation of the Wnt/β‐
catenin pathway.
Clinical presentation
ACC may be functionally inactive or secrete
hormones such as glucocorticoids, sex ster-
oids and their precursors, and mineralocor-
ticoids. Benign adrenocortical tumors are
more common and must be carefully differ-
entiated from ACC. Patients frequently
present with clinical signs and symptoms of
excessive cortisol production (Cushing’s
syndrome) and/or excessive androgen pro-
duction (virilization). The diagnosis is often
delayed. Patients may present with an
abdominal mass, pain, weight loss, or hyper-
tensive urgency/emergency, but typically
come to medical attention due to the high
rate of endocrinopathy.
Diagnosis and staging
The diagnosis is made based on the pres-
ence of elevated concentrations of adreno-
cortical hormones and their intermediates
Rare Tumors of Childhood 281
in the serum or urine. Baseline studies
should include a 24‐hour free cortisol,
­dexamethasone suppression test, basal cor-
tisol, and adrenocorticotropic hormone
(ACTH) to measure glucocorticoid
­secretion; ­testosterone, estradiol, andros-
tenedione, dehydroepiandrosterone sulfate
(DHEA‐S) (most commonly elevated), and
17‐OH‐progesterone to measure sex ster-
oids and their precursors; and aldosterone
and renin in patients with hypertension or
hypokalemia to rule out mineralocorticoid
excess. Pheochromocytoma can be ruled
out by checking catecholamines and
metanephrines. Imaging with CT or MRI
of the abdomen confirms the presence of a
suprarenal mass. Radiologic features of a
malignant adrenal tumor include the pres-
ence of a large inhomogeneous enhancing
mass in the adrenal gland (or appearing to
replace it) with areas of hemorrhage, calci-
fication, and necrosis. FDG‐PET may be
utilized in equivocal cases or if CT and
MRI are negative with positive hormone
markers. FDG‐PET is negative in benign
adrenocortical tumors. The differential
diagnosis of an adrenal mass noted on
imaging includes other malignant tumors
such as neuroblastoma, ganglioneuroblas-
toma, and teratoma. Therefore, the compi-
lation of hormonal lab results and imaging
findings should be considered in a diag-
nostic approach. Many patients present
with large primary tumors and evidence of
metastatic disease involving the lungs,
liver, or bones. CT of the chest, abdomen,
and ­pelvis in addition to bone scan should
be done for staging purposes prior to surgi-
cal ­resection. Several staging systems are
utilized for ACC. Prognosis is linked to
stage, tumor size, invasion of major blood
vessels, degree of resection (i.e., complete
or not), tumor spillage during surgery, his-
tologic characteristics, and presence of
metastatic disease.
282 Chapter 22
Treatment
ACCs are locally aggressive tumors with thin
pseudocapsules; an open adrenalectomy
should be performed to prevent ­extensive
hemorrhage, tumor rupture, or seeding
along the needle tract. Surgical resection is
the only known curative therapy for ACC,
both for primary and metastatic sites.
Surgery is also indicated in recurrent disease
to prolong survival. Patients with evidence
of hypercortisolism should be assumed to be
adrenal‐insufficient and receive appropriate
stress dosing of steroids.
Due to the poor response to chemother-
apy, patients with advanced disease have a
very poor prognosis. A low tumor
weight <200 g (<5 cm in diameter in adults)
is a good prognostic factor. Patients with
small tumors and localized disease should
undergo aggressive gross total surgical
resection. Patients with advanced disease
(invasive or metastatic) should be treated
with aggressive en bloc surgical resection of
the primary tumor and metastatic lesions. If
resection of metastases is not feasible,
­resection of the primary tumor may not be
of benefit.
Systemic chemotherapy is recom-
mended for patients with unresectable or
metastatic disease. Mitotane, a synthetic
derivative of the insecticide dichlorodiphe-
nyltrichloroethane (DDT), has a specific
cytotoxic effect on adrenocortical cells. It
has shown benefit in a subset of patients
with invasive, metastatic, or recurrent dis-
ease. Mitotane may have benefit in patients
with localized, fully resected disease,
although this question has not been clearly
answered. Mitotane is used as monotherapy
or in combination with typical antineoplas-
tic drugs including doxorubicin, etoposide,
and cisplatin (EDP). Monthly monitoring
of mitotane levels is important to achieve a
therapeutic level of 14–20 mg/l. Toxicities
that may limit dosing or treatment with
mitotane include gastrointestinal and
­ eurologic side effects. As mitotane is an
n
adrenocorticolytic agent, replacement with
hydrocortisone and fludrocortisone is nec-
essary to prevent adrenal insufficiency and
supraphysiologic dosing is often necessary
due to mitotane’s effect on steroid metabo-
lism. Multiple chemotherapeutic regimens
and targeted therapies have been utilized
in the treatment of ACC, but treatment of
refractory or recurrent disease remains
challenging. The combination of mitotane,
gemcitabine, and capecitabine has been
used with some success as second‐line or
third‐line therapies. ACC is considered
radioresistant, but some studies indicate a
possible role of radiation therapy as an
adjuvant post resection. Radiation therapy
in children has not been established and
given the tumor’s association with TP53
mutations, it is not considered a therapeutic
option.
Follow‐up
The initial hormonal evaluation assists with
diagnosis, but also provides useful tumor
markers that may be utilized to detect persis-
tent or recurrent disease. Long‐term follow‐
up includes assessment of tumor marker(s)
and periodic imaging. Patients who have
received mitotane can take many months to
recover from the adrenal suppressive effects
and may require replacement or stress dos-
ing. Patients with identified genetic syn-
dromes or TP53 mutations need lifelong
surveillance for other malignancies.
Thyroid tumors
The incidence of malignant thyroid carci-
noma in children is very low, comprising
less than 2% of pediatric cancers. The peak
incidence is in the older adolescent age
group, 15–19 years of age, with a prepon-
derance in females (this gender difference is

not present in children <10 years of age).
Childhood ­thyroid carcinomas are clinically
and bio­logically distinct from those seen in
adults. The majority of malignant thyroid
cancers arise from the follicular epithelium
and include papillary and follicular carcino-
mas. Fewer than 10% of malignant child-
hood thyroid tumors are medullary
carcinomas, arising from neural crest cells.
Exposure to head and neck radiation is asso-
ciated with an increased risk of thyroid car-
cinoma (more commonly the papillary
variant), particularly in children <5 years of
age. An increased incidence has been seen
in children receiving therapeutic radiation
with a median latency of 13 years and has
also been observed in survivors following
the Chernobyl nuclear accident. Incidence
of medullary thyroid carcinoma is highest in
the 0–4‐year age group. Genetic predisposi-
tion plays a major role in the development of
these tumors which are thought to arise
from inherited or de novo activating muta-
tions of the RET proto‐oncogene. Hereditary
medullary carcinoma is highly associated
with MEN types 2A and 2B or as part of
familial medullary carcinoma. Patients with
MEN type 2A develop medullary thyroid
carcinoma, pheochromocytoma, and para-
thyroid tumors. Patients with MEN type 2B
may develop medullary carcinoma or pheo-
chromocytoma and are associated with a
marfanoid body habitus, mucosal neuro-
mas, and ganglioneuromatosis. A high inci-
dence of papillary carcinoma of the thyroid
is seen in familial adenomatous polyposis
coli and Cowden disease.
Clinical presentation
Patients typically present with a painless
solitary thyroid nodule (approximately
70–75%) and up to 35–40% present with
palpable cervical adenopathy. If the tumor
has invaded locally, patients may present
with dysphagia or dysphonia. Children are
Rare Tumors of Childhood 283
much more likely than adults to present with
advanced or metastatic disease (primarily
lungs) and metastatic disease is commonly
seen with the papillary variant.
Diagnosis and staging
The initial evaluation of the child with a
thyroid nodule should include thyroid
ultrasound as well as measurement of free
thyroxine (FT4) and thyroid‐stimulating
hormone (TSH) (though thyroid function
studies are typically normal). Up to 20% of
thyroid nodules in children will be malig-
nant, and younger age, past history of radia-
tion, genetic cancer syndromes, and family
history are all highly predictive of malig-
nant disease. Ultrasound characteristics may
guide the clinician in the diagnosis, as
malignant tumors are more likely to have
indistinct margins, enhanced vascularity, an
absence of an echogenic halo around the
nodule, and presence of calcifications.
Nuclear medicine thyroid scintigraphy (usu-
ally with 123I) can be utilized for surgical
planning, screening for postoperative persis-
tent or metastatic disease, and to determine
if a patient may benefit from treatment with
131
I. The majority of thyroid nodules are cold
on thyroid scan and most of these are benign
follicular adenomas. Image‐guided fine
needle aspiration is recommended to obtain
tissue diagnosis. Surgical removal may be
considered in higher‐risk patients with sus-
picious features on imaging, positive family
history, or past history of radiation. When
a thyroid carcinoma is diagnosed, staging is
completed with a neck ultrasound, CT, or
MRI to evaluate possible lymph node
involvement. Chest CT is done to evaluate
for metastasis (often not visualized on plain
radiographs), and neck MRI can assess for
degree of local invasion. Staging in children
is based on the presence or absence of metas-
tases. Children diagnosed before age 10 years
may have an increased risk of recurrence.
284 Chapter 22
Presence of metastatic disease, age, size of
tumor, and degree of extrathyroid invasion
are predictive of outcome.
Treatment
Surgical resection performed by an experi-
enced surgeon is key to curative therapy
in thyroid carcinoma. Patients should
undergo a total thyroidectomy, particularly
for tumors >1 cm in size. This approach has
been associated with lower rates of recur-
rence and better survival than with lobec-
tomy. Lymph node dissection should be
compartment‐focused and comprehensive.
When lymph node involvement is con-
firmed by imaging or biopsy, a modified
lateral neck dissection is recommended.
Following surgery, a diagnostic whole‐body
scan with 123I (preferred) or 131I is recom-
mended to define areas of residual disease.
Radioiodine ablation is then recommended
and has been shown to reduce the incidence
of locoregional recurrence. Recombinant
TSH can also be utilized in low‐risk patients
in lieu of 131I. Patients with progressive dis-
ease not amenable to surgery and no longer
responsive to 131I may benefit from treat-
ment with chemotherapy, typically doxoru-
bicin alone or in combination with cisplatin
or α‐interferon. Molecular therapies tar-
geted against tyrosine kinase inhibitors are
showing promise and sorafenib is currently
FDA approved in adults. External beam
radiation to treat microscopic residual dis-
ease in the neck is not recommended, but
may have a role in palliation of sympto-
matic distant metastases. Lifetime thyroid
replacement is required after surgery and/
or radioablation. Most children with follic-
ular or papillary carcinomas have an excel-
lent prognosis with 10‐year survival of
almost 100%, even in the presence of meta-
static disease. Lifelong surveillance is war-
ranted in these patients to monitor for
recurrence as well as late effects of treat-
ment including development of second
cancers.
Patients with medullary carcinomas are
treated with surgical excision, but should
undergo biochemical evaluation for pheo-
chromocytoma preoperatively. These
tumors may also express serum calcitonin
or CEA which can serve as useful tumor
markers. Genetic testing for RET should be
done and the patient and family referred
for genetic counseling. Medullary thyroid
carcinoma does not trap iodine and there-
fore is not treated with 131I. Molecular ther-
apies targeting tyrosine kinase inhibitors
that inhibit RET and other receptor tyros-
ine kinases known to inhibit angiogenesis
are currently under investigation. These
tumors are not sensitive to chemotherapy.
Post-operatively, patients are treated with
thyroid hormone to normalize and not sup-
press TSH levels.
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Aronson, D.C. and Meyers, R.L. (2016).
Malignant tumors of the liver in children.
Semin. Pediatr. Surg. 25: 265–275.
Chen, Q.L., Su, Z., Li, Y.H. et al. (2011). Clinical
characteristics of adrenocortical tumors in
children. J. Pediatr. Endocrinol. Metab. 24:
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Dermody, S., Walls, A., and Harley, E.H. Jr.
(2016). Pediatric thyroid cancer: an update
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Med. 9: 1–6.
Yikilmaz, A., George, M., and Lee, E.Y. (2017).
Pediatric hepatobiliary neoplasms: an over-
view and update. Radiol. Clin. North Am. 55:
741–766.
23 Histiocytic Disorders
Histiocytes (composed of dendritic cells and
monocytes/macrophages; also called tissue
macrophages) are cells of the mononuclear
phagocytic system that fight infection and
clear debris. Histiocytic disorders occur due
to abnormal proliferation or activity of
these cells and have a wide variety of clinical
presentations, from localized and mild to
generalized and severe.
The classification of these conditions
can be as confusing as the conditions them­
selves. The most recent World Health
Organization (WHO) classification was
revised in 2016 and is presented in
Table 23.1. While most of the histiocytic
disorders are considered nonmalignant
conditions, many are treated similarly to
malignant disease, and the mortality of sev­
eral conditions is quite high. The etiology of
most types is unknown but appears second­
ary to poorly understood pathophysiologi­
cal mechanisms. This chapter focuses on
the more common presentations of disease,
specifically Langerhans cell histiocytosis
(LCH) and hemophagocytic lymphohistio­
cytosis (HLH). Less common disorders
include juvenile xanthogranuloma (includ­
ing Erdheim–Chester disease) and sinus
histiocytosis with massive lymphadenopa­
thy (Rosai–Dorfman disease).
Handbook of Pediatric Hematology and Oncology – Children’s Hospital & Research Center Oakland,
Third Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
Langerhans cell histiocytosis
LCH is now the accepted umbrella term
for a wide variety of other conditions pre­
viously described, including histiocytosis
X, ­eosinophilic granuloma, Hand–Schüller–
Christian syndrome, Letterer–Siwe disease,
Hashimoto–Pritzker syndrome, self‐heal­
ing histiocytosis, pure cutaneous histiocy­
tosis, Langerhans cell granulomatosis,
Langerhans cell (eosinophilic) granuloma­
tosis, type II histiocytosis, and nonlipid
reticuloendotheliosis. The pathogenesis of
LCH is poorly understood. Immune dys­
regulation likely plays a role and may be
reactive, occurring secondary to trauma
and infection, e­ specially in those patients
with remitting disease. A neoplastic pro­
cess may also be possible in cases that are
systemic and widely disseminated. LCH is
a misnomer, as the Langerhans cell, an epi­
dermal dendritic cell, is not the sole cul­
prit; rather, like other histiocytic disorders,
LCH is due to abnormalities in the mono­
nuclear phagocytic system. Diagnosis is
based on histologic features of these
Langerhans cells (characterized by Birbeck
granules on electron microscopy) in addi­
tion to specific immunophenotypic mark­
ers (CD1a and CD207).
288 Chapter 23
Table 23.1 Classification of histiocytic disorders.
Group Disease
L Langerhans‐related
C Cutaneous and mucocutaneous
R Rosai–Dorfman disease
M Malignant histiocytosis
H Hemophagocytic lymphohistiocytosis
(HLH) and macrophage activation
syndrome
LCH most often presents in the bone as a
solitary or as multifocal lesions and may also
be localized to the skin or lymph nodes.
Bone lesions may be painful or painless.
On plain film, lesions appear lytic, often
with a “punched out,” beveled appearance
and may have an associated periosteal
reaction with soft tissue swelling. Skin
­ dation for observation excludes sites that put
lesions are scaly, erythematous papules
often involving the scalp. Localized disease
in these areas ­portends a good prognosis
with chance for spontaneous remission due
to “burning out” of the underlying immune
reaction. Observation is generally favored in
this situation, with certain caveats:
1. Vertebral lesions have an inherent risk of
causing vertebral compression (vertebra
plana) or spinal cord compression if
Condition
Langerhans cell histiocytosis (LCH)
Indeterminate cell histiocytosis
Erdheim–Chester disease (ECD)
• Juvenile xanthogranuloma
Mixed LCH/ECD
Cutaneous non‐LCH
• Xanthogranuloma family
• Non‐xanthogranuloma family
Cutaneous non‐LCH with a major
systemic component
Familial Rosai–Dorfman Disease (RDD)
Sporadic RDD
• Classical RDD
• Extra‐nodal RDD
• RDD with neoplasia or immune disease
• Unclassified
Primary malignant histiocytosis
Secondary malignant histiocytosis
• Histiocytic
• Interdigitating
• Langerhans
• Indeterminate cell
Primary HLH
Secondary HLH
HLH of unknown/uncertain origin
s­ignificant soft tissue swelling exists, there­
fore radiation therapy should be considered.
2. Large or symptomatic solitary bone
lesions may benefit from surgical curettage
or resection, intralesional steroid injection,
or radiation therapy.
3. For solitary bone lesions, the recommen­
the patient at increased risk for the develop­
ment of diabetes insipidus (DI) (facial bones
and anterior/middle cranial fossa). For these
“special sites,” and for multifocal bone, skin,
or lymph node involvement, chemotherapy
with 12 months of prednisone and vinblas­
tine is recommended.
Systemic disease, which involves multiple
organs including the bone marrow, liver,
 Histiocytic Disorders 289

spleen, or lungs, has a much worse prog­ Hemophagocytic

nosis, especially in those patients without
an early response to therapy. Poor respond­
ers likely will require more intensive ther­
apy including, potentially, hematopoietic
stem cell transplantation. Initial staging
should include a skeletal survey and poten­
tial PET/CT scan to rule out additional
sites of disease. Brain MRI imaging should
be done in patients with symptoms con­
cerning for DI and can be considered in all
patients at presentation. MRI may demon­
strate a thickened pituitary stalk or change
in the brightness of the posterior lobe
of the pituitary gland. Patients, especially
those with recurrent disease, should be
screened for the BRAF‐V600E mutation,
for which there is potentially ­beneficial tar­
geted therapy. A neurodegenerative central
nervous system disease has been rarely
reported as a late finding after LCH diag­
nosis and treatment.
lymphohistiocytosis
Like other histiocytic disorders, immune
dysregulation is the key feature in HLH.
This condition presents with prolonged and
excessive activation of macrophages, histio­
cytes, and cytotoxic T‐lymphocytes (CTL).
Natural killer (NK) cells, vital to antigen
­recognition and killing as well as contrac­
tion of the immune response from T‐cells
and histiocytes, often have decreased activ­
ity, in part allowing for this hyperprolifera­
tive immune response. Viral infection by
Epstein–Barr virus is the most common
known acquired cause, although multiple
other viruses have been implicated, and
often the pathogen is not identified. Familial
HLH can occur secondary to multiple
known genetic causes that lead to NK and
CTL dysfunction. The familial causes are
outlined in Table 23.2. An underlying

Table 23.2 Genetic mutations associated with hemophagocytic lymphohistiocytosis.

Gene Screening result Pathophysiology

Perforin 1 (PRF1) Perforin decreased Synthesized in natural killer and cytotoxic

T‐cells, permeabilizes target membrane
allowing granzyme B to initiate
apoptotic pathways
MUNC13–4 (UNC13D) CD107a decreased Important for cytolytic granule fusion to
target membrane
RAB27A (Griscelli syndrome) CD107a decreased Docking of secretory granules
Syntaxin (STX11/STXBP2) CD107a decreased Failure of degranulation when
encountering susceptible targets
LYST (Chédiak–Higashi Involved in maturation of cytolytic
syndrome) enzyme granules
AP3B1/BLOC1S6 (Heřmanský– Polarization/intracellular movement of
Pudlák syndrome type II) cytolytic granules
SH2D1A (X‐linked SAP decreased Abnormal signaling for T‐ and NK‐cell
lymphoproliferative activation, impaired cytokine
syndrome type I) production
BIRC4 (X‐linked XIAP decreased Immune dysregulation, increased
lymphoproliferative T‐cell apoptosis, impaired cytokine
syndrome type II) production

Additional mutations include: ITK deficiency, CD27 deficiency, lysinuric protein intolerance
(SLC7A7), GATA2 deficiency.
290 Chapter 23

Table 23.3 Diagnostic criteria for hemophagocytic lymphohistiocytosis.

Diagnosis by molecular criteria (summarized in Table 23.2)

OR
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)

genetic predisposition may still require a underlying pathogenesis is due to an auto­

“second hit,” such as a viral infection, to
develop HLH.
Clinical findings are secondary to the
chronic inflammatory state and most nota­
bly include fever, splenomegaly, cytopenias,
and hepatitis. Diagnostic criteria for HLH
are summarized in Table 23.3. For the
patient with high clinical suspicion for
HLH, treatment should be initiated
promptly even while pending pertinent
laboratory evaluation. Current therapy
includes dexamethasone and etoposide.
Cyclosporine was previously utilized but
has been eliminated from the treatment
regimen, as it has been shown to provide no
additional benefit in HLH. For patients that
have a complete response after 8 weeks,
treatment can be stopped, unless they are
shown to have an underlying familial muta­
tion which predisposes them to HLH. For
those that have not responded completely
or relapse after stopping therapy, as well as
patients with a genetic mutation, hemat­
opoietic stem cell transplantation is the
treatment of choice.
Excessive activation of macrophages and
T‐lymphocytes may also lead to a secondary
or reactive HLH known as macrophage
­activation syndrome (MAS). Clinical crite­
ria for MAS are similar to HLH, and the
immune condition, infection, or underlying
malignancy. Systemic onset juvenile
­idiopathic arthritis (adult Still’s disease) is
the most common autoimmune culprit.
Multiple other autoimmune diseases have
been reported to cause MAS. NK cells are
vital in the prevention of autoimmunity;
decreased NK activity could result in both
the development of an autoimmune disease
and secondary HLH. Often it is difficult to
separate the symptoms of MAS from the
underlying cause or primary HLH. Patients
may have leukocytosis, thrombocytosis, and
hyperfibrinogenemia secondary to the
underlying inflammatory state, but these
levels will trend down with the development
of MAS. Fevers may become non‐remitting,
and there may be a paradoxical improve­
ment in inflammatory markers such as the
erythrocyte sedimentation rate (ESR) and
fibrinogen which can help differentiate
MAS from HLH. Treatment for MAS
includes pulse steroids and cyclosporine. In
the very sick patient, a monoclonal antibody
again IL‐1 should be considered though has
not been studied systematically. Duration of
therapy is dependent on clinical response;
patients that do not respond or relapse
may benefit from primary HLH therapy,
although outcomes are poor.
 Histiocytic Disorders 291

HLH less likely. In addition, the high CRP

Case studies for review
makes HLH less likely.
You review the lab trends:
1. You are seeing a 6‐year‐old child that
presents to the emergency department with
3 weeks of an erythematous and painful dif­ Hemoglobin: 12.5 → 10.3 → 8.9
Platelets: 150 → 98 → 67
fuse and spreading rash. Fever began soon
White blood cell count: 18.4 → 28.7 → 39.7
after the rash with associated weakness,
(continued left shift)
malaise, and anorexia. Initial laboratory ESR: 50 → 47
tests include the following: CRP 6.3 → 12.9 → 18.1
Complete blood count: Fibrinogen: 441 → 387 mg/dl

12.5
19.8 150
A ferritin is sent and is very elevated at 68 300
mcg/l. Fasting triglycerides are 253 mg/dl.
 Differential: 35% segs, 44% bands, 6% lymphs, b. How do these lab values help with the
and 12% monos differential?
The patient continues to have signs of an
ESR: 47 mm/h CRP: 6.3 mg/dl underlying inflammatory picture and hyper­
Complete metabolic panel: cytokinemia. Sepsis should still be consid­
ered on the differential with the continued
131 103 12
3.7 28 0.7
222 elevated ESR, CRP, and fibrinogen. The
worsening bicytopenia though should make
Total protein 5.2 g/dl
Albumin 2.1 g/dl
HLH and MAS higher on the differential.
AST 146 U/l The extremely elevated ferritin is relatively
ALT 44 U/l specific for HLH and MAS, and a level this
Total bili 0.3 mg/dl high is concerning for MAS. The decreasing
ESR and fibrinogen also raise the concern
that the patient is moving from symptoms of
On examination, the patient is alert and an underlying autoimmune disorder to
interactive, but seems somewhat uncom­ frank MAS. Finally, the elevated white blood
fortable from the rash. There is mild spleno­ cell count with neutrophilia makes MAS
megaly and no hepatomegaly. The patient is much more likely than HLH.
started on antibiotics for presumed sepsis/
toxic shock with initial resolution of fever. 2. You are seeing a 3‐year‐old female in
Cultures are all normal. Due to worsening your clinic. Mom notes that she has devel­
labs and rash, as well as no source of infec­ oped a non‐tender scalp swelling over the
tion, the differential diagnosis is revisited. last couple of months. There was a previous
The patient again becomes febrile. fall that may have precipitated the swelling,
a. What findings in the initial labora­ but the mom is surprised the area is still
tory tests suggest sepsis as well as HLH swollen. The child has otherwise been well
and MAS? without complaint: no fever, no weight
The patient has elevated inflammatory loss, no skin rash, good appetite, no gastro­
markers (CRP and ESR). Hyponatremia intestinal symptoms. On examination, the
and hypoalbuminemia are often seen with child is well‐appearing with a 2 × 3 cm2 area
an underlying inflammatory condition. of swelling in the right parietal region of
There are no significant cytopenias, ­making the scalp. There are no skin findings and
292 Chapter 23

there is no hepatosplenomegaly. There are

Multiple choice questions
no other areas of swelling or tenderness
noted.
1. You are seeing a 5-year-old in the pedi­
a. What potential complication of LCH
atric intensive care unit who was admitted
is it important to inquire about?
for hypotension and thought to have
Diabetes insipidus due to pituitary involve­
hypovolemic shock secondary to sepsis.
ment may occur at presentation, so it is
The sepsis rule out has been unremarka­
important to ask questions to help deter­
ble although the patient continues with
mine if this may be a consideration. You ask
features worrisome for DIC. All of the
the mother if the child has been drinking
following support a diagnosis of HLH
­
more and urinating more and she has not
EXCEPT:
noted any change in this regard. She is
a. Splenomegaly
potty‐trained and does not use the bath­
b. Transaminitis
room at night while sleeping.
c. Cytopenias
b. What is the best first diagnostic step?
d. Fever
In a young child, LCH should always be a
e. Elevated fibrinogen
consideration with localized swelling, espe­
Explanation: HLH should be considered in
cially in the scalp which is a common loca­
an ill‐appearing child who does not have
tion and may occur after trauma. A plain
an underlying etiology. Generally these
film of the scalp is often sufficient to make
patients will continue to worsen, though in
the likely diagnosis of LCH. Plain film shows
certain cases may have an indolent course.
the classic “punched‐out” lytic lesion that is
Their picture will often mimic the patient
most common with LCH.
with sepsis but will not improve with nor­
c. What are the next best steps?
mal supportive care measures. The previ­
The patient will need to be staged to
ous HLH guidelines suggested a diagnosis
determine if this is truly LCH and also
­
based on 5 of 8 criteria including: 1) daily
whether this is a solitary lesion or is present
fevers; 2) splenomegaly; 3) bicytopenia;
with additional lesions. Baseline laboratory
4) hypertriglyceridemia or hypofibrino­
markers should include complete blood
genemia; 5) hemophagocytosis; 6) low or
count (to rule out associated systemic
absent NK function; 7) elevated ferritin; 8)
involvement), complete metabolic panel (to
elevated soluble CD25 (IL2). Newer guide­
rule out p ­otential pituitary involvement),
lines also suggest additional helpful criteria
ESR (as a potential tumor marker), and a uri­
including hepatitis and hyponatremia.
nalysis for specific gravity to rule out a dilute
The answer is e.
urine with DI. Additional imaging with a full
skeletal survey and bone scan can be done to
2. True or False; Hemophagocytosis is
determine if additional lesions are present
required for the diagnosis of HLH.
which may be more amenable to biopsy.
Explanation: Although hemophagocytosis is
More institutions are doing PET/CT rou­
suggestive of the diagnosis of HLH it is not
tinely to determine if additional lesions are
required for diagnosis. As above, 5 of 8 crite­
present which may not be seen on X‐rays.
ria are useful and may or may not include
Additionally, many are doing MRI brain on
hemophagocytosis. Additionally patients
all patients rather than only in patients with
may be considered to have HLH even if they
symptoms of DI or in those with “special
do not meet the 5 criteria but have sugges­
sites” (i.e., craniofacial bone, ear, eye, central
tive symptoms. The answer is false.
nervous system involvement).

3. All of the following lab values are con­
sistent with the diagnosis of HLH EXCEPT:
a. Elevated IL2
b. Elevated ferritin
c. Low fibrinogen
d. Low trigylcerides
e. Low NK activity
Explanation: As above, patients may have
high triglycerides as a marker of HLH. The
answer is d.
4. You are seeing a 14-year-old female who
presents with altered mental status after a
seizure like event. She has fever and a rash.
Her inflammatory markers are elevated and
her ferritin is significantly elevated. What is
the most likely underlying diagnosis?
a. Systemic onset JIA
b. Systemic lupus erythematosus
c. Sepsis
d. Macrophage activation syndrome
e. Hodgkin lymphoma
Explanation: The patient appears to have
enough symptoms consistent with second­
ary HLH or macrophage activation syn­
drome (MAS). MAS can be secondary to
many of the other listed conditions, espe­
cially autoimmune conditions. Sepsis or
viral infections may also trigger HLH or
­secondary HLH (i.e., MAS). Additionally,
neoplastic conditions may present with
HLH or lead to secondary development of
HLH (i.e., anaplastic large cell lymphoma,
other non‐Hodgkin lymphomas, Hodgkin
lymphoma). The answer is d.
5. All of the following potential presenta­
tions of Langerhans cell histiocytosis (LCH)
require chemotherapy or radiation therapy
EXCEPT:
a. Multifocal bone LCH
b. Systemic LCH
c. Spinal cord compression with verte­
bra plana
Histiocytic Disorders 293
d. Asymptomatic solitary bone lesion of
the femur
e. Asymptomatic solitary bone lesion
involving the mastoid
Explanation: Unifocal bone lesions can
often be monitored or could potentially
receive surgical curettage if symptomatic
unless there is involvement of “special sites,”
specifically bones in the face and anterior/
medial cranial fossa which may lead to pitu­
itary involvement and the development of
diabetes insipidus. Multifocal bone lesions
have an increased risk of recurrence or pro­
gression without chemotherapy. A solitary
bone lesion involving the spine can be
asymptomatic and be monitored but also
may lead to soft tissue swelling and spinal
compression necessitating therapy. Systemic
LCH has a much worse prognosis and
involves multiple organs including the skin,
liver, spleen or lungs. Young children may
manifest the rash of LCH as a severe
­sebhorrheic dermatitis (i.e. cradle cap) that
does not respond to normal therapy. The
answer is d.
Suggested reading
Emile, J.F., Abla, O., Fraitag, S. et al. (2016).
Revised classification of histiocytosis and
neoplasms of the macrophage‐dendritic cell
lineages. Blood 127: 2672–2681.
Filipovich, A., McClain, K., and Grom, A. (2010).
Histiocytic disorders: recent insights into
pathophysiology and practical guidelines.
Biol. Blood Marrow Transplant. 16: S82–S89.
Haupt, R., Minkov, M., Astigarraga, I. et al.
(2013). Langerhans cell histiocytosis (LCH):
guidelines for diagnosis, clinical work‐up, and
treatment for patients till the age of 18 years.
Pediatr. Blood Cancer 60: 175–184.
Jordan, M.B., Allen, C.E., Weitzman, S. et al.
(2011). How I treat hemophagocytic lympho­
histiocytosis. Blood 118: 4041–4052.
24 Hematopoietic Stem
Cell Transplantation
Hematopoietic stem cell transplantation
(HSCT) has become increasingly accepted as a
therapeutic modality for a variety of malignant
and nonmalignant conditions. HSCT involves
the full or partial ablation of the recipient’s bone
marrow with high doses of chemotherapy as
well as, in some cases, radiation ­therapy in
order to allow engraftment of the donor’s stem
cells. Collected stem cells can either be allo-
geneic (from a separate donor) or autologous
(from the patient). The rationale for HSCT is
based on the logarithmic dose–response curve
for many chemotherapeutic agents: a much
higher dose effectively increases tumor killing
at the cost of p ­ rofound myelosuppression.
Secondarily, multidrug therapy is required to
overcome resistance and heterogeneity within
the malignant cell population. And finally, for
those undergoing allogeneic transplantation,
the addition of a new immune system allows
for potential improved tumor surveillance
after donor cell engraftment.
Transplantable conditions
Diseases treated using HSCT can be divided
into malignant and nonmalignant conditions.
Recommendations for malignant conditions
are continually being updated due to changes
in the effectiveness of standard chemother-
apy and the risks and benefits of HSCT. In
pediatric patients, allogeneic transplantation
Handbook of Pediatric Hematology and Oncology – Children’s Hospital & Research Center Oakland,
Third Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
is generally recommended for hematologic
malignancies due to the underlying bone
marrow involvement (Table 24.1). In addi-
tion to the effectiveness of high‐dose chemo-
therapy in tumor killing, there is b ­ enefit of
a “graft‐versus‐leukemia” (or lymphoma)
effect in allogeneic transplant in which the
immunosensitized donor T‐cells can theoreti-
cally kill residual malignant cells. By contrast,
autologous transplant is generally reserved
for patients with solid tumors and no evi-
dence of bone marrow involvement as part of
a standard regimen or after failure of stand-
ard chemotherapeutic regimens (Table 24.2).
Chimeric antigen receptor T‐cell (CAR‐T)
therapy is a novel methodology to re-engineer
the patient’s T‐cells to recognize a particular
target, such as CD19+ acute lymphoblastic
leukemia (ALL) cells. CAR‐T cells can be
reinfused to the patient in an autologous
fashion after a lymphodepleting preparative
chemotherapeutic regimen.
Recommendations for allogeneic HSCT
in nonmalignant conditions are summarized
in Table 24.3. Genetic engineering (i.e., gene
therapy) is being used in an increasing
­number of nonmalignant conditions, whereby
altered nucleated cells are reintroduced to
the patient after a myeloablative preparative
regimen, often single agent busulfan. Studies
are ongoing in the utilization of this technology
in sickle cell disease, transfusion‐dependent
thalassemia as well as hemophilia.
296 Chapter 24
Table 24.1 Malignant conditions potentially
benefiting from allogeneic transplant.
Acute lymphoblastic leukemia (ALL) in first
remission and high risk for relapse
Relapsed ALL in second or subsequent
remission
Acute myelogenous leukemia (AML) with
high‐risk features in first remission
Acute myelogenous leukemia (AML) in
second or subsequent remission
Juvenile myelomonocytic leukemia (JMML)
Hodgkin or non‐Hodgkin lymphoma in
second or subsequent partial or complete
remission
Myelodysplastic syndromes (MDS)
Relapsed, refractory, or familial
hemophagocytic lymphohistiocytosis
Table 24.2 Malignant conditions potentially
benefiting from autologous transplant.
High‐risk neuroblastoma
High‐risk brain tumors (medulloblastoma/
PNET)
Metastatic retinoblastoma
Recurrent high‐risk germ cell tumors
Relapsed Hodgkin or non‐Hodgkin
lymphoma
Relapsed Wilms tumor
Abbreviation: PNET, primitive neuroecto­
dermal tumor.
Types of transplantation
Stem cells for allogeneic transplantation are
collected from bone marrow, peripheral
blood, or umbilical cord blood (UCB),
whereas stem cells for autologous trans-
plantation are collected most commonly
from peripheral blood. Collection of
stem cells from peripheral blood occurs
after mobilization with granulocyte col-
ony‐stimulating factor (G‐CSF). The usual
v­ olume of bone marrow required to ensure
successful engraftment of donor cells is
10–20 ml/kg of recipient body weight.
Younger donors have a higher proportion
of marrow repopulating cells. Peripheral
blood stem cells are ­collected via apheresis
and identified by the presence of a cell sur-
face marker, CD34 (CD, cluster of differen-
tiation). In general, 5 × 106 CD34+ cells/kg
are required to ensure engraftment. For
allogeneic transplant, the physician must
balance the risks, benefits, and availability
of cells derived from bone marrow, periph-
eral blood, and UCB. Peripheral blood has
the highest yield of CD34+ cells (with G‐CSF
mobilization), whereas UCB has the lowest
(due to the ­volume of UCB). The risk of
graft‐versus‐host disease (GVHD) is lowest
after UCB transplantation and highest
after peripheral blood stem cell transplant
(PBSCT). Engraftment of donor cells occurs
earliest after PBSCT. Availability of alloge-
neic stem cells is often limited by the lack of
an eligible donor.
Donor matching in allogeneic
transplantation
The major histocompatibility complex
(MHC) is a large genomic region on chro-
mosome 6 that encodes the human leukocyte
antigen (HLA) system. MHC is vital for the
immune system to recognize self versus non‐
self and varies greatly between individuals.
MHC is divided into two major classes, class
I and class II. MHC class I molecules are
found on nucleated cells and present the
MHC to cytotoxic T‐cells and natural killer
cells. MHC class I molecules include HLA‐A,
HLA‐B, and HLA‐C. MHC class II mole-
cules are located on antigen‐presenting cells
(B‐cells and macrophages) and present the
MHC to T helper cells. MHC class II includes
HLA‐DP, HLA‐DQ, and HLA‐DR. Many
other minor histocompatibility complexes
 Hematopoietic Stem Cell Transplantation 297

Table 24.3 Nonmalignant conditions benefiting from allogeneic transplant.

Congenital syndromes
Immunodeficiency syndromes
Hematologic disorders
Metabolic disorders
Acquired syndromes
Severe aplastic anemia
Paroxysmal nocturnal hemoglobinuria
SCID, congenital agammaglobulinemia (Bruton’s),
DiGeorge syndrome, Wiskott–Aldrich syndrome,
chronic mucocutaneous candidiasis,
lymphoproliferative syndromes, familial HLH
Sickle cell disease, β‐thalassemia major, Fanconi
anemia, Shwachman–Diamond syndrome,
Diamond–Blackfan anemia, dyskeratosis congenita,
chronic granulomatous disease, Chédiak–Higashi
syndrome, leukocyte adhesion deficiency
Storage diseases, lysosomal diseases, mucolipidosis,
mucopolysaccharidoses

Abbreviations: HLH, hemophagocytic lymphohistiocytosis; SCID, severe combined immunodefi-

ciency syndrome.

are important in the immune response; how-
ever, current donor matching for HSCT is
limited to class I and II molecules.
Identification of a suitable donor requires
matching the recipient’s MHC class I and II
antigens with those of the donor. Greater dis-
parity between donor and recipient leads to
increasing risk of rejection of the donor cells
and, if engraftment occurs, GVHD. Matched
family member donor grafts have been found
to be the least immunogenic. Unfortunately,
60–70% of patients will not have a matched
family donor. In these cases, unrelated volun-
teer donors can be found through bone mar-
row donor registries, such as the National
Marrow Donor Program in the United States
and Bone Marrow Donors Worldwide that
coordinates multiple worldwide registries.
Due to the unavailability of a matched donor
in many cases, haploidentical transplantation
is becoming a more widely studied and uti-
lized approach due to ready availability of a
parent or sibling with this level of matching.
In the past, ­ haploidentical transplantation
would have invariably led to severe GVHD,
but novel techniques such as the addition of
post‐transplant cyclophosphamide as well as
depletion of donor αβT‐cells have both been
successful modalities to mitigate GVHD
from cytotoxic T‐cells and T helper cells.
Currently, HLA matching is limited to
HLA‐A, HLA‐B, HLA‐C, HLA‐DR, and
HLA‐DQ. National Marrow Donor Program
retrospective reviews on HLA matching in
unrelated donor bone marrow transplanta-
tion have shown that mismatches at MHC
class I (HLA‐A, HLA ‐B, and HLA ‐C) and
MHC class II DR (specifically HLA‐DRB1)
each had a separate, significant effect on sur-
vival and risk of GVHD. Additionally, an
increasing number of mismatches led to
decreasing survival. HLA‐DQB1 was also
found to have an additive negative effect in
patients with other mismatches. UCB trans-
plantation has been shown to not require the
same level of HLA matching, and matching
is limited to HLA‐A, HLA‐B, and HLA‐DR.
UCB transplantation is thought to be less
immunogenic secondary to the decreased
alloreactivity of these immature cells.
298 Chapter 24
Ultimately, the physician must balance the
availability of a matched donor with other
factors such as the patient’s disease stage,
remission status, and general condition. In
most cases, disease stage has a greater impact
on survival than the level of HLA mismatch.
Pretransplant preparative
regimens
High‐dose chemotherapy, with or without
radiation, is administered in order to maxi-
mize tumor killing and, in patients undergo-
ing allogeneic transplant, to affect a
sufficient amount of immunosuppression to
overcome recipient rejection of the HSCT.
Commonly used conditioning agents, their
mode of action, and potential side effects are
summarized in Table 24.4.
Engraftment and graft failure
Evidence of donor replacement of the recipi-
ent’s bone marrow begins with increasing
white blood cell counts and decreasing trans-
fusion dependency. Engraftment is defined to
occur when the transplant recipient achieves
three consecutive days of an absolute neutro-
phil count (ANC) > 0.5 × 109/l. Due to the
­volume of CD34+ stem cells, engraftment of
donor cells occurs earliest after PBSCT and
latest after UCB transplantation.
Engraftment syndrome, characterized by
fever, rash, as well as pulmonary symptoms
and weight gain (secondary to capillary
leak), may take place during the initial rapid
rise in the white blood cell count. After
infection has been ruled out, a short course
of intravenous steroid therapy can alleviate
symptoms.
Primary graft failure is defined as a
lack of engraftment within 6 weeks after
­transplant. Chimerism studies, either of the
peripheral blood or bone marrow, measure
percentage of donor and recipient cells and
thus also help determine marrow engraft-
ment or primary graft failure. Factors in
graft failure include: a nonmyeloablative
preparative regimen, insufficient volume of
stem cells (i.e., UCB transplant), increased
immunogenicity due to mismatched HSCT,
and the use of myelosuppressive agents (i.e.,
medications for GVHD). Secondary graft
failure (graft rejection) occurs after the ini-
tial wave of engraftment secondary to the
continued presence of recipient cytotoxic
T‐cells. Chimerism studies must again be
utilized to show that the majority of cells are
of host origin. Other causes of graft failure
including infection and recurrence of an
underlying hematological malignancy
should be ruled out.
Complications of hematopoietic
stem cell transplantation
HSCT recipients have a unique set of poten-
tial complications that must be well under-
stood when caring for these patients. The
pretransplant preparative regimen can lead
to a number of post‐transplant complica-
tions as outlined in Table 24.4. A com-
mon complication is veno‐occlusive disease
(VOD) of the liver, now known as sinusoi-
dal obstructive syndrome (SOS). The pro-
found immunosuppression that occurs
both before and after engraftment puts
HSCT patients at high risk for infection
with a variety of organisms. Finally, immu-
nogenic donor T‐cells can lead to GVHD
due to the recognition of host alloantigens
as foreign. Multiple late sequelae of HSCT
must also be considered as summarized in
Table 24.11.
Infections
Practitioners must be cognizant of the
many potential infectious complications
in the HSCT patient. The duration of
 Hematopoietic Stem Cell Transplantation 299

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,

elimination of T‐cells
BCNU, Alkylation leading to DNA
bischloroethylnitrosurea damage
(Carmustine)
Busulfan Alkylating agent
Carboplatin Inhibits DNA synthesis by
forming
DNA cross‐links
Cyclophosphamide Alkylating agent, inhibition
of T‐cell replication
Etoposide Inhibits topoisomerase II
causing DNA strand
breakage
Fludarabine Purine analog inhibiting
DNA synthesis,
immunosuppressant
Melphalan Alkylating agent
Thiotepa Alkylating agent
Topotecan Inhibits topoisomerase I
causing DNA strand
breakage
Total body irradiation Antitumor activity,
immunosuppressant
anaphylaxis, serum sickness
Nausea and vomiting, pulmonary
infiltrates and fibrosis,
transaminitis, nephrotoxicity
Nausea and vomiting, electrolyte
abnormalities, seizures,
mucositis, alopecia,
hyperpigmentation, sterility
Nausea and vomiting, type I
hypersensitivity, renal
impairment and electrolyte
wasting, ototoxicity
Fluid retention (SIADH),
hemorrhagic cystitis, nausea,
vomiting, and anorexia,
cardiomyopathy, sterility
Hypotension, nausea, skin blisters
or erythema, nephropathy,
hemorrhagic cystitis, alopecia,
stomatitis, transaminitis
Nausea, vomiting, and anorexia,
mucositis, hemolytic anemia
Nausea and vomiting, mucositis
Nausea, vomiting, and anorexia,
sterility, excretion through the skin
Nausea, vomiting, and anorexia,
diarrhea, mucositis, peripheral
neuropathy
Fever, myelosuppression, mucositis,
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.

severe neutropenia (ANC < 0.5 × 109/l)
and time to engraftment are significant
risk factors, as the large majority of
patients will have a documented infection
after 4–5 weeks of neutropenia. Even
though the white blood cell count recovers
in weeks after transplant, functional
recovery of humoral and cellular immu-
nity takes months to years depending on
the type of transplant (autologous vs.
300 Chapter 24
Table 24.5 Common infections seen at different time points following hematopoietic stem cell
transplantation.
First 30 days Bacterial
Fungal
Viral
30–120 days Fungal
Viral
Protozoal
* Formerly Pneumocystis carinii, generally considered to be a fungal organism.
a­ llogeneic) as well as the continued use of
immunosuppressive agents to prevent or
treat GVHD. The presence of a central
venous catheter is a secondary risk factor.
Infections tend to occur at different times
after transplant as outlined in Table 24.5.
Workup of fever in the post‐transplant
period is outlined in Table 24.6.
Engraftment syndrome, GVHD, and med-
ications such as G‐CSF can all be causes of
fever in the post‐transplant period but are
diagnoses of exclusion. Clostridium diffi-
cile should be considered in the patient
with associated symptoms such as fever,
abdominal pain, and diarrhea. Infection
prophylaxis is an important aspect of sup-
portive care and is outlined in more detail
in the following text (and Table 24.12).
Veno‐occlusive disease/sinusoidal
obstructive syndrome
VOD, now referred to as SOS, results from
hepatic injury caused by high‐dose chemo-
therapy (especially alkylators) and total
body irradiation leading to fibrosis of small
Gram‐negative aerobes and anaerobes
Staphylococcus epidermidis
Aspergillus species
Candida
Herpes simplex type I reactivation
Candida albicans and Candida tropicalis
Aspergillus
Other Candida sp., Trichosporon sp., Fusarium sp.
Pneumocystis jiroveci*
Cytomegalovirus (CMV)
Adenovirus
Epstein–Barr virus (EBV)
Human herpesvirus 6 (HHV‐6)
Toxoplasma sp.
hepatic vessels. SOS typically occurs in the
first 21 days after allogeneic transplant and
presents with weight gain, jaundice, and
hepatomegaly. Reversal of portal flow on
Doppler ultrasound of the liver is pathogno-
monic for SOS, though not required for
diagnosis. In the past, the treatment of SOS
was supportive, although now early initia-
tion of defibrotide is considered standard of
care; general guidelines are outlined in
Table 24.7.
Graft‐versus‐host disease
GVHD occurs due to the proliferation of
donor T‐cells that recognize host antigen as
foreign. Direct effects of the T‐lymphocytes
and cytokine response lead to the signs and
symptoms of GVHD. Acute GVHD can
begin within weeks of transplantation;
chronic GVHD is defined as GVHD lasting
beyond 100 days after transplant. Signs and
symptoms of acute and chronic GVHD are
summarized in Table 24.8, grading of
GVHD is outlined in Table 24.9, and proph-
ylaxis and treatment are described in
 Hematopoietic Stem Cell Transplantation 301

Table 24.6 Evaluation and empiric treatment of fever in the post‐transplant period.

Rule out bacterial infection
Rule out pneumonia
Rule out fungal infection
Rule out occult infection
Rule out viral infection
Rule out pneumonia or
interstitial pneumonitis
Treatment
Daily blood cultures from central catheter (aerobic and
anaerobic) while febrile
Consider non‐catheterized urinalysis and culture
Chest radiography at first fever and then as clinically indicated
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
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
CMV serology; consider studies for adenovirus, HHV‐6, EBV,
BK virus (urine) if prolonged fever (i.e., ≥5–7 days) and
consistent clinical symptoms
CT of the chest if with consistent symptoms or CXR equivocal
If not on empiric antibiotic therapy (see Table 24.12), begin
antipseudomonal cephalosporin (i.e., cefepime)
If with prolonged fevers (i.e., ≥5–7 days), consider switching
empiric cephalosporin to carbapenem for broader coverage
Addition of an echinocandin (i.e., micafungin) or broad‐spectrum
azole (i.e., voriconazole) for broader fungal coverage with
prolonged fevers (i.e., ≥3–7 days)
Consider vancomycin for staphylococcal and streptococcal
coverage if patient worsening clinically
Directed antimicrobial coverage or further studies based on
positive workup

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

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

Table 24.7 Treatments for sinusoidal obstructive syndrome (SOS).

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 [twice daily] PO
[orally])
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 Defibrotide has fibrinolytic and antithrombotic properties, and has
shown therapeutic benefit in SOS. Patients must not receive other
thrombolytic therapies. Defibrotide is given at 25 mg/kg/day div Q6 h
IV for at least 21 days
302 Chapter 24

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
GI 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
GI 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 or
corneal inflammation caused by dryness)
Pulmonary Interstitial pneumonitis, bronchiolitis obliterans
Other Arthritis, immunologic abnormalities

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

Table 24.9 Grading of graft‐versus‐host disease.

Clinical Skin Liver (TB, Diarrhea (children; Diarrhea (adults; ≥70 kg)
grade mg/dl) <70 kg) (ml/kg/day) (ml/day)

I <25% involvement, 1.5–3.0 10–15 500–1000, nausea/vomiting

maculopapular
II 25–50% involvement, 3.0–6.0 16–20 1000–1500, nausea/vomiting
maculopapular
III >50% involvement, 6.0–15.0 21–25 >1500, nausea/vomiting
maculopapular or
generalized
erythroderma
IV Desquamation/bullae >15 >25, pain/ileus >2500, pain/ileus

Abbreviation: TB, total bilirubin; adapted from Lanzkowsky (2011).

Source: Based on Lanzkowsky P. Hematopoietic stem cell transplantation. In: Manual of Pediatric
Hematology and Oncology, 5th ed. New York: Elsevier, 2011.

Table 24.10. Patients should be checked
daily for signs and symptoms of acute
GVHD while hospitalized following HSCT.
Medications including cyclophosphamide,
methotrexate, cyclosporine, tacrolimus, and
sirolimus are used for prevention of GVHD
through inhibition of T‐cell replication.
Steroids remain the mainstay of treatment of
acute and chronic GVHD through nonspe-
cific T‐cell suppression. Multiple newer
agents have been trialed recently for patients
with GVHD refractory to steroids or to
spare steroids given the multitude of side
effects. Ibrutinib and ruxolitinib were both
recently approved for steroid‐refractory
GVHD and both lead to profound T‐cell
Table 24.10 Agents used for prophylaxis and treatment of graft‐versus‐host disease.
Agent Mode of action
Cyclosporine Inhibits T‐cell activation
Cyclophosphamide Selective depletion of
alloreactive donor and host
T‐cells
Methotrexate Cell cycle specific; inhibits
T‐cells division
Tacrolimus Inhibits T‐cell activation
Methylprednisolone Immunosuppressant;
mechanism not well
understood
Mycophenolate mofetil Inhibits T‐cell proliferative
(MMF) response
Anti‐thymocyte Alteration of function and
globulin (ATG) elimination of T‐cells
Sirolimus Blockage of mTOR leading to
inhibition of T‐ and B‐cells
Etanercept/infliximab TNFα inhibitors; consideration
in refractory GVHD
Mesenchymal stem cells Immunomodulation with
suppression of T‐cell
proliferation
Subcutaneous IL2 Immunomodulation through
expansion of T‐regulatory cells
Extracorporeal Leukocyte apoptosis; cytokine
photopheresis modulation, tolerogenic
response
Ruxolitinib JAK1/2 inhibitor; T‐cell
suppression
Ibrutinib Bruton’s tyrosine kinase and
IL‐2 inducible T‐cell kinase
inhibitor; B‐cell and CD4
T‐cell suppression
Abbreviations: SIADH, syndrome of inappropriate antidiuretic hormone;TNF, tumor necrosis
factor; GVHD, graft‐versus‐host disease.
Common potential risks
Hypomagnesemia, bicarbonate
wasting, renal insufficiency,
nausea, vomiting, hyperglycemia,
gingival hypertrophy,
hirsutism, hypertension,
seizures, paresthesias, tremors
Fluid retention (SIADH),
hemorrhagic cystitis, nausea,
vomiting, and anorexia,
cardiomyopathy, sterility
Transaminitis, mucositis, renal
insufficiency, effusions, nausea,
vomiting, anorexia, bone
marrow suppression
Hypomagnesemia, hyperkalemia,
renal insufficiency,
hypertension, seizures,
paresthesias, nausea, vomiting,
hyperglycemia
Hypertension, increased blood
sugars, increased appetite,
insomnia, mood swings, acne,
truncal obesity
Nausea, vomiting, anorexia, bone
marrow suppression, multiple
others
Fever and chills, pruritus,
anaphylaxis, serum sickness
Peripheral edema,
hypertriglyceridemia,
hypertension,
hypercholesterolemia,
increased creatinine
Severe immunosuppression
Fever, infection, organ
dysfunction
Immune suppression, infection,
local reaction
Immune suppression, infection,
anemia
Immune suppression, infection,
neutropenia,
thrombocytopenia
Infection, bleeding, diarrhea,
cough
304 Chapter 24
suppression. Immunomodulation through
stimulation of the T‐regulatory cell popula-
tion has more recently been found to be an
important way to mitigate GVHD through
inhibition of the T‐effector cell populations.
Methods to do this include subcutaneous
IL2 and extracorporeal photopheresis.
The most common acute symptoms of
GVHD are related to the integument and
gastrointestinal systems. Skin findings are
often nonspecific with the development of
an erythematous, pruritic, maculopapular
rash. This finding in conjunction with white
blood cell count recovery can be a harbinger
of acute GVHD, though generally skin
biopsy should be performed for confirma-
tion. Additional diagnostic considerations
including viral infection and drug reaction
should be ruled out. Gastrointestinal symp-
toms are often lower‐tract‐related including
abdominal pain and diarrhea. Bloody stool
is possible, though C. difficile and other
stool pathogens should be sought. Upper
tract symptoms including nausea and ano-
rexia may also be present. Additionally, eti-
ologies including infection, mucositis, and
post‐transplant anorexia should be
considered.
Idiopathic pneumonia syndrome
(IPS)
IPS is severe, non‐infectious lung injury
that occurs post‐transplant. Immune acti-
vation leading to progressive inflammation
is the underlying driver for IPS and
explains the benefit of blockade of tumor
necrosis factor (TNFα) with etanercept.
Evidence of widespread alveolar injury
without an infectious etiology is the hall-
mark of IPS. A myeloablative preparative
regimen with total body irradiation (TBI)
and acute GVHD are risk factors for the
development of IPS. Rapid progression of
symptoms is common with IPS with a high
mortality rate.
Transplant‐associated
thrombotic microangiopathy
(TA‐TMA)
TA‐TMA occurs due to small vessel
endothelial injury and typically occurs sec-
ondary to calcineurin inhibitors (i.e., cyclo-
sporine, tacrolimus) for immunosuppression
after allogeneic transplantation, though may
also occur after autologous transplantation
for unclear reasons. Typical symptoms of
TA‐TMA include unremitting hyperten-
sion, kidney injury leading to proteinuria, as
well as signs and symptoms of microangio-
pathic hemolytic anemia with elevation in
LDH, presence of schistocytes on peripheral
blood smear, as well as activation of termi-
nal complement (sC5b‐C9). Early diagnosis
is vital for appropriate management of
TA‐TMA.
Late sequelae
Multiple late effects must be considered and
are summarized in Table 24.11.
Supportive care in transplant
patients
Routine care for the HSCT patient is a
unique and vital aspect of preventing infec-
tions and a multitude of other potential
complications including bleeding, transfu-
sion‐associated GVHD, and cytomegalovi-
rus (CMV) reactivation, as well as ABO
incompatibility between recipient and
donor.
Infection prophylaxis
Due to profound immunosuppression,
HSCT patients are at risk for reactivation of
latent viral infections in addition to fungal
and bacterial infection. Guidelines for infec-
tion prophylaxis and surveillance are out-
lined in Table 24.12.
 Hematopoietic Stem Cell Transplantation 305

Table 24.11 Late effects of hematopoietic stem cell transplantation.

Late effect Underlying cause

Endocrine disorders (gonadal failure, delayed TBI

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
Post‐transplant lymphoproliferative disorder Immunosuppressive therapy
Poor dentinogenesis (in young children) TBI
Decreased bone mineral density Multiple factors

Abbreviations: GVHD, graft‐versus‐host disease; TBI, total body irradiation; ATG, anti‐thymocyte
globulin; IT, intrathecal; adapted from Lanzkowsky (2011).
Source: Based on Lanzkowsky P. Hematopoietic stem cell transplantation. In: Manual of Pediatric
Hematology and Oncology, 5th ed. New York: Elsevier, 2011.

Diet post‐transplant anorexia, many centers have

Due to the pretransplant preparative regi-
men, patients will have an extended period
of anorexia requiring total parenteral nutri-
tion (TPN). Triglycerides should be fol-
lowed weekly while on TPN in addition to
routine monitoring of electrolytes. Trace
elements should be included in the TPN. If
possible, the patient should be transitioned
to enteral feeds through a nasogastric tube.
Once the patient is eating, it is vital that the
patient’s family be aware of the bone marrow
transplant low microbial diet of acceptable
foods and appropriate methods of handling,
preparation, and storage in order to prevent
infection from food‐borne pathogens. Due
to the lack of evidence on the need for a sig-
nificantly restricted diet in the setting of
liberalized this practice.
Transfusion guidelines
Due to immunosuppression, all HSCT
patients should receive irradiated blood
products in order to eliminate the risk of
transfusion‐associated GVHD. In addi-
tion, packed red blood cell (PRBC) trans-
fusions should be CMV‐negative for HSCT
recipients who are identified as CMV
seronegative during the pretransplant
period. CMV seronegative platelets are not
routinely required, as leukofiltered plate-
lets are considered sufficiently leukore-
duced to prevent transmission of CMV. In
order to diminish the risk of spontaneous
bleeding, the platelet count is kept above
306 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 6 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 immunosuppressive
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 Antipseudomonal cephalosporin (i.e., cefepime) or carbapenem (i.e.,
infection 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 Weekly to three times weekly blood culture if on steroids and afebrile
infection (controversial)
Pneumonia Weekly chest radiograph (controversial)
Deficient IgG Monthly quantitative IgG; replace with IVIG if IgG < 400 mg/dl

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

zole; 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.
* Based on institutional preference.

20 × 109/l following HSCT. This threshold
is increased to above 50 × 109/l in certain
cases, including patients with sickle cell
disease, brain tumor patients, and patients
with severe mucositis, SOS, or problems
with hemostasis (e.g., epistaxis and GI
bleeding). A lower threshold of 10 × 109/l
can be utilized in stable patients who are
out of the immediate post‐transplant
period. Hemoglobin levels are usually kept
above 8–9 mg/dl depending on institu-
tional practice. Platelet transfusions should
be limited to 1 pheresed unit (see
Chapter 5). ABO blood types of both the
donor and recipient must be considered
when transfusing platelets and PRBCs.
Appropriate transfusion in ABO‐incom-
patible donor and recipient is summarized
in Table 24.13. It is critical that the blood
bank maintain this information on file to
ensure proper ­transition of blood type pre-
transplant and post‐transplant.
Immune reconstitution
Even with the recovery of white blood
cell counts and specifically lymphocyte
counts, HSCT patients take months to
years to recover immune function. Loss of
memory B‐lymphocytes due to the pre-
transplant preparative regimen leads to
loss of antibody secondary to vaccination
and lifetime environmental exposures.
Immune recovery is variable but generally
occurs once the patient is off immunosup-
pressant therapy, and therefore is ­generally
earlier in patients undergoing autologous
 Hematopoietic Stem Cell Transplantation 307

Table 24.13 Transfusion in ABO‐incompatible transplantation.

Recipient Donor Transplant Choice for Choice for First‐choice Second‐

type type incompatibility PRBC plasma platelets choice
transfusion platelets

A O Minor O A, AB A AB, B, O
A B Major O AB AB A, B, O
A AB Major A, O A, AB AB A, B, O
B O Minor O B, AB B AB, A, O
B A Major O AB AB B, A, O
B AB Major B, O B, AB AB B, A, O
O A Major O A, AB A AB, B, O
O B Major O AB B AB, A, O
O AB Major O AB AB A, B, O
AB O Minor O AB AB A, B, O
AB A Minor A, O AB AB A, B, O
AB B Minor B, O AB AB 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)
Mitogens (Concanavalin A,
pokeweed,
phytohemagglutinin)
Antigens (tetanus toxoid,
Candida albicans)
PRP (If done by institution)
Measures response to CMV, HSV, and VZV,
and defines length of acyclovir prophylaxis
Concanavalin A measures T‐ and B‐cell
function
Pokeweed measures B‐cell function
Phytohemagglutinin measures T‐cell
function, must be reactive before PCP
prophylaxis is discontinued
Lack of response to tetanus toxoid indicates
need for revaccination
Response to Candida defines length of
fluconazole prophylaxis
Measurement of T‐ and B‐cell function;
indicates need for PCP prophylaxis as well
as ability to respond to conjugated vaccines

Abbreviations: CMV, cytomegalovirus; HSV, herpes simplex virus; VZV, varicella zoster virus;
PCP, Pneumocystis jiroveci pneumonia; PRP, polyribose phosphate.

transplantation. Once there is sufficient begin once the absolute lymphocyte count is
evidence of immune reconstitution, HSCT >1 × 109/l and generally when the patient
patients will proceed with revaccination. is off immunosuppressive therapy, are
Studies of immune reconstitution, which summarized in Table 24.14.
308 Chapter 24

cefepime (a fourth‐generation cephalo-

Case study for review
sporin). Fungal infection must be seriously
considered with testing for Aspergillus by
A 14‐year‐old boy is on the bone marrow
serum galactomannan at a minimum.
transplant unit after receiving a HSCT for
Fluconazole will cover Candida albicans but
acute myelogenous leukemia (AML) in
not other candidal species or Aspergillus.
remission. His peripheral blood stem cell
You should consider discontinuing flucona-
reinfusion took place 10 days ago. He has
zole and starting an antifungal agent with a
been having daily fevers up to 39.5 °C for
broader spectrum of activity such as an echi-
3 days with negative blood cultures to date.
nocandin (i.e., micafungin). Micafungin has
He is not in any respiratory distress and his
a broader spectrum of activity than flucona-
physical exam is unremarkable except for a
zole, but only has moderate coverage against
mild rash. His complete blood count is
Aspergillus and does not cover most mold
remarkable for a WBC count that has been
species. Therefore, antimold coverage with
increasing, most recently 0.2 × 10 /l. He has
9
voriconazole or posaconazole is the better
a double lumen central catheter and is on
choice for empiric coverage in lieu of an
total parenteral nutrition. He has moderate‐
echinocandin. Finally, the addition of ster-
to‐severe mucositis that is improving. His
oids for acute graft‐versus‐host disease with
weight has been stable, and his chemistries
fever and rash should be a consideration if
are otherwise unremarkable. His medica-
infection is relatively well ruled out after
tions include cefepime as well as prophylac-
negative blood cultures and chest
tic fluconazole and acyclovir.
radiography.
a. What is the differential for fever at
After a few days, the patient defervesces
this point after HSCT?
but has developed an increase in his bilirubin.
Differential diagnosis:
The infectious workup has been negative to
●● Bacterial infection (Gram‐negative rods,
date. On looking at his fluid status for the
S. epidermidis, Streptococcus viridans species).
last 48 hours, you note that he is 2 liters posi-
●● Viral infection (CMV, herpes simplex I).
tive and his weight has increased by 2 kg
●● Fungal infection (Candida, Aspergillus).
from the time of his transplant.
●● Graft‐versus‐host disease.
c. What is the differential diagnosis for
●● Mucositis.
hyperbilirubinemia and weight gain at
b. What medications would you con-
this point after transplant?
sider adding based on the above men-
Differential diagnosis:
tioned differential?
●● Sinusoidal obstructive syndrome.
The patient is well‐covered for Gram‐­
●● Viral infection.
negative infections with cefepime. Gram‐
●● Acute graft‐versus‐host disease.
positive infections usually lead to a positive
●● Heart failure (secondary to infection,
blood culture, although vancomycin
fluid overload, or previous anthracycline or
should be considered if the patient is clini-
mediastinal radiation therapy).
cally worsening in the face of a negative
At this time point after transplant, with a
blood culture (i.e., respiratory distress or
negative infectious workup, SOS is the most
hypotension). The patient is at risk for S. epi-
likely diagnosis. If the patient is having
dermidis secondary to the central catheter
increasing WBC counts with rash and diar-
and S. viridans secondary to mucositis, nei-
rhea, acute GVHD is possible but should
ther of which is adequately covered with
 Hematopoietic Stem Cell Transplantation 309
be a diagnosis of exclusion. Heart failure is a
possibility secondary to toxicity from ther-
apy or an underlying infection and should
be ruled out with echocardiogram.
d. What changes in therapy should you
institute?
Most patients with SOS ultimately recover
with supportive care alone. Fluid and
sodium restriction should be initiated. An
abdominal ultrasound with elastography
and Doppler flow should be undertaken to
look for hepatic fibrosis and changes in por-
tal venous flow. Antioxidants including
vitamin C, E, and selenium should be
added to the TPN for liver protection. If
the patient develops increasing weight
gain and liver dysfunction (evidence of
developing SOS), early intervention with
defibrotide should be instituted.
Multiple choice questions
1. All of the following are potential indica-
tions for allogeneic hematopoietic stem cell
transplantation EXCEPT:
a. Relapsed acute lymphoblastic leuke-
mia (ALL)
b. High risk acute myelogenous leuke-
mia (AML)
c. Severe aplastic anemia
d. High‐risk neuroblastoma
e. Sickle cell anemia
Explanation: Conditions with underlying
bone marrow disease or dysfunction should
routinely undergo allogeneic rather than
autologous transplantation in pediatric
patients. These conditions include leuke-
mias as well as myelodysplastic syndromes,
hemophagocytic lymphohistiocytosis (HLH),
and non‐malignant conditions including
aplastic anemia, sickle cell anemia, severe
congenital neutropenia, beta‐thalassemia
major, alpha‐thalassemia major, and
severe immunodeficiencies, amongst other
conditions. Although transplantation is
required as part of the multi‐modal treat-
ment for neuroblastoma, this can be done
with autologous transplant rather than allo-
geneic. The answer is d.
2. All of the following are potential condi-
tions requiring autologous transplantation
(i.e., high dose chemotherapy with stem cell
rescue) EXCEPT:
a. Relapsed Hodgkin lymphoma
b. High‐risk medulloblastoma
c. Metastatic osteosarcoma
d. High‐risk neuroblastoma
e. Relapsed Wilms tumor
Explanation: Many pediatric solid tumors in
relapse or with very high‐risk disease bene-
fit from high‐dose chemotherapy with
stem cell rescue (i.e., autologous transplan-
tation). Sarcomas on the other hand includ-
ing osteosarcoma and rhabdomyosarcoma
have not shown benefit from autologous
transplantation. Although still somewhat
controversial most centers also agree that
transplant is not beneficial for Ewing sar-
coma. The answer is c.
3. All of the following are potentially concern-
ing for the development of vaso‐occlusive
disease (VOD; sinusoidal obstructive syn-
drome, SOS) EXCEPT:
a. Refractory thrombocytopenia
b. White blood cell engraftment
c. Weight gain
d. Hyperbilirubinemia
e. Hepatomegaly with reversal of portal
flow
Explanation: VOD occurs due to the pre-
transplant chemotherapy which leads to
fibrosis at the sinusoidal level causing
obstruction to returning blood flow which
manifests as hepatomegaly, weight gain
due to decreased liver synthetic function
of oncotic proteins, hyperbilirubinemia
and transaminitis. Due to the reversal of
310 Chapter 24
portal flow there is resultant splenomegaly
with trapping of platelets leading to refrac-
tory thrombocytopenia. Patients with exist-
ing liver disease prior to transplant are at
higher risk of developing VOD.
Additionally, alky­lator therapy with medi-
cations including busulfan, cyclophospha-
mide and melphalan put the patient at
higher risk. Generally supportive care with
fluid restriction, gentle diuresis with aldac-
tone, platelet and red cell transfusion, urso-
diol and antioxidants is sufficient to allow
the liver to heal. In rare cases a more novel
medication defibrotide must be utilized.
The answer is b.
4. All of the following are potential post-
transplant complications after autologous
transplant EXCEPT:
a. Veno‐occlusive disease
b. Lack of engraftment
c. Infection—viral, bacterial, fungal
d. Mucositis
e. Infertility
Explanation: All of the above are potential
posttransplant complications, some though
are specific for allogeneic rather than
autologous transplantation. Veno‐occlusive
disease is a complication specific to the pre-
parative chemotherapy regimen, especially
those that include alkylator therapy and
can be seen with both autologous and allo-
genic transplant. Since the patient gets
their own stem cells back at a high cell dose,
lack of engraftment is generally not an issue
with autologous transplant. Infection is
more common with allogeneic transplant
but can be seen after autologous transplant.
Mucositis is common after both allogeneic
and autologous transplant depending on
the intensity of the pretransplant chemo-
therapy regimen. Similarly, infertility is
common for both autologous and allogeneic
transplant and dependent on the intensity
of the pretransplant chemotherapy regimen.
The answer is b.
5. Which of the following statements is
FALSE?
a. Time to engraftment is shortest with
umbilical cord blood transplantation
(versus peripheral blood and bone
marrow)
b. Risk of graft‐versus‐host disease
(GVHD) is highest after peripheral
blood stem cell transplant (versus bone
marrow and umbilical cord blood)
c. Risk of failure to engraft is highest
after umbilical cord blood transplant
(versus peripheral blood and bone
marrow)
d. Risk of GVHD is directly related to
the amount of HLA mismatch between
donor and recipient
e. Risk of veno‐occlusive disease is
highest after alkylator preparative
chemotherapy
Explanation: Stem cell source, stem cell size
and mismatch between donor and recipient
are important considerations when deter-
mining risk of posttransplant complica-
tions. Umbilical cord blood units have the
lowest total nucleated cell (TNC) count and
therefore time to engraftment is the longest
(peripheral blood is the fastest due to the
highest TNC count and highest CD34+
cells/kg). Goal stem cell dose for bone mar-
row and peripheral blood is 5 × 106 CD34+
cells/kg. Due to the maturity of the stem
cells, GVHD is highest after peripheral
blood stem cell transplant and lowest after
umbilical blood stem cells (while factoring
in the level of mismatch between donor and
recipient). Risk of GVHD is lowest with a
10/10 matched sibling (matching entails
looking at MHC‐I antigens HLA‐A, ‐B, and
–C as well as MHC‐II antigens HLA‐DR
and –DQ) and risk increases with mismatch
(in addition to peripheral blood stem cell
source). As explained previously, existing
liver disease and alkylator preparative
chemotherapy are risk factors for VOD. The
answer is a.
 Hematopoietic Stem Cell Transplantation 311
Suggested reading
Lanzkowsky, P. (2011). Hematopoietic stem cell
transplantation. In: Manual of Pediatric
Hematology and Oncology, 5e. New York:
Elsevier.
Ricahrdson, P.G., Grupp, S.A., Pagliuca, A. et al.
(2017). Defibrotide for the treatment of hepatic
veno‐occlusive disease/sinusoidal obstruc-
tion syndrome with multiorgan failure. Int. J.
Hematol. Oncol. 6: 75–93.
Sahdev, I. and Abdel‐Azim, H. (2016).
Hematopoietic stem cell transplantation. In:
Lanzkowsky’s Manual of Pediatric Hematology
and Oncology, 6e (eds. P. Lanzkowsky, J. Lipton
and J.D. Fish). New York: Elsevier. 577–604.
25 Supportive Care of the
Child with Cancer
Much of the dramatic improvement in
­outcomes in pediatric oncology over the last
50 years can be attributed to the develop­
ment of novel chemotherapeutic agents and
an increase in therapeutic intensity. Under­
standing, anticipating, and managing the
adverse effects and complications of therapy
lead to optimal supportive care measures, a
practice now recognized to save lives and
improve quality of life during and after
­therapy. The practitioner should be familiar
with the potential risks of chemotherapy
(Chapter 30), guidelines for transfusional
supportive care (Chapter 5), and treatment for
febrile neutropenia (Chapter 27). Additionally,
practitioners should become familiar with the
burgeoning novel therapies such as immuno­
therapeutics and their unique side effects such
as cytokine release syndrome, neurotoxicity,
and pneumonitis. Here we discuss infection
prophylaxis, antiemetic therapy, and the use
of hematopoietic growth factors. Supportive
care for patients receiving hematopoietic stem
cell transplantation (HSCT) is discussed in
Chapter 24.
Infection prophylaxis
Children receiving chemotherapy for treat­
ment of their malignancies are susceptible to
acquiring infection from bacterial, viral,
­fungal, and protozoal organisms. They are
Handbook of Pediatric Hematology and Oncology – Children’s Hospital & Research Center Oakland,
Third Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
chronically immunosuppressed as a direct
result of chemotherapy and immune‐modify­
ing therapies, and are at times severely myelo­
suppressed. While on the inpatient unit,
patients are exposed to nosocomial organ­
isms as well. Many of these children have cen­
tral venous catheters and may intermittently
have mucosal breakdown secondary to chem­
otherapy, both factors disrupting the integrity
of the body’s physical defense barriers. Poor
nutrition also plays a significant role in host
susceptibility. Certain standards of care are
indicated to minimize the risk of acquiring
infection in these children. Infection prophy­
laxis remains the cornerstone of supportive
care in children with malignancies, decreas­
ing morbidity and mortality.
General measures for the prevention of
infection include avoidance of crowded envi­
ronments, construction areas and soil (in the
garden, playground), wearing a mask in pub­
lic when severely neutropenic (i.e., absolute
neutrophil count [ANC] <0.5 × 109/l), and,
most importantly, careful hand washing (by
the patient and all those who have direct con­
tact). Good nutrition and proper dental
hygiene cannot be overemphasized. Oral
hygiene should include daily brushing (with a
soft brush) and oral rinsing with tap water or
saline solution. Cleanliness of the perianal
area is important, especially in the neutro­
penic state. Constipation should be avoided
with an age‐appropriate diet, and, if necessary,
314 Chapter 25
a stool softener (e.g., docusate sodium) or
laxative (e.g., MiraLAX). Rectal suppositories
and rectal temperatures should be avoided to
decrease the possibility of a mucosal tear and
infection with enteric organisms.
Trimethoprim/sulfamethoxazole (TMP/
SMX) prophylaxis is indicated in immuno­
suppressed children to reduce the risk of
acquiring Pneumocystis jiroveci pneumonia
(PCP) due to T‐lymphocyte dysfunction
secondary to chemotherapy. Current pro­
phylactic dosing is 5 mg/kg/day of the TMP
component in two divided doses on two to
three successive days per week. Evidence
indicates that this regimen also provides
good general antibacterial prophylaxis,
although probably more effectively in
patients given daily prophylaxis, which must
be balanced with potential allergy or intol­
erance to TMP/SMX and especially second­
ary to myelosuppression from the therapy.
For patients unable to take TMP/SMX,
inhaled pentamidine or oral dapsone may
be given. Pentamidine is preferred, however,
due to the need for a cooperative patient
who can appropriately inhale the medica­
tion, is usually limited to children above the
age of 7 years. The dose is 300 mg inhaled on
a monthly basis. Dapsone is given orally
once weekly at 4 mg/kg, with a maximum
dose of 200 mg. Patients should commence
prophylaxis at the initiation of immune sup­
pressive therapy and continue until 3
months after completion of therapy to
ensure T‐lymphocyte immune reconstitu­
tion. Prophylaxis with TMP/SMX should be
discontinued one day prior to the adminis­
tration of high‐dose IV methotrexate (doses
>1 g/m2) and restarted after the serum
methotrexate level has fallen to below
1 × 10−7 m due to competitive excretion
between TMP/SMX and methotrexate and
the risk for delayed methotrexate clearance.
Temporary interruption of TMP/SMX, or a
change to an alternative therapy, may be
necessary in the setting of prolonged marrow
suppression or transaminitis, rather than
decreasing the dose of maintenance chemo­
therapy for children with acute lymphoblas­
tic leukemia (ALL).
Bacterial prophylaxis can be considered
in patients receiving high‐intensity chemo­
therapy when the ANC is <0.5 × 109/l, though
further data are required to prove benefit
without significant risk of development of
resistance. We utilize levofloxacin for
­children ≥6 months of age at a dose of 10 mg/
kg/dose to a maximum of 250 mg for c­ hildren
under 5 years and 750 mg for older children.
High‐intensity regimens that may benefit
from bacterial prophylaxis include relapsed
leukemias, acute myelogenous leukemia
(AML), high‐risk leukemia during induction
therapy, infant ALL, ALL in Down syndrome,
and intensive Head Start chemotherapy for
brain tumors.
Fungal prophylaxis is indicated in
severely myelosuppressed patients. Mouth
care with brushing and oral rinsing is rou­
tinely recommended for the prevention or
treatment of mouth sores and yeast prolif­
eration. Voriconazole (see Formulary for
age‐based dosing) or posaconazole (200 mg
suspension PO TID, three times daily, or
300 mg BID, two times daily, tablets in
patients ≥40 kg) is indicated in patients that
are at very high risk of developing infection
due to periods of prolonged, severe neutro­
penia (e.g., AML, relapsed ALL patients).
The most common fungal infections in
patients receiving intensive chemotherapy
include candidiasis and aspergillosis. Efforts
to prevent invasive fungal disease (especially
Aspergillus sp., an airborne organism)
include respiratory isolation, laminar air
flow rooms, and high‐efficiency particulate
air (HEPA) filters. Patients should not have
live plants in the room, play in dirt or gar­
dens, or be in proximity to construction
work. Some patients may receive an echino­
candin (e.g., micafungin 1.5–2 mg/kg IV
daily, 50 mg maximum prophylaxis dose) for
 Supportive Care of the Child with Cancer 315
prophylactic fungal coverage while inpatient
with prolonged fevers and severe neutrope­
nia due to multiple potential drug interac­
tions with voriconazole or posaconazole,
most notably vincristine for ALL patients
(see Chapter 27). Micafungin may also be
given at a treatment dose (i.e., 3–4 mg/kg IV
daily, max 150 mg) with prolonged fevers.
Prophylaxis for subacute bacterial endo­
carditis is recommended for patients with
central venous catheters or surgical hardware
undergoing invasive procedures that could
cause transient bacteremia and seeding of the
catheter or heart valves. Such interventions
include dental cleaning or procedures and
potentially surgery involving the gastrointes­
tinal or genitourinary tract (controversial).
The standard regimen is that recommended
by the American Heart Association for children
with congenital heart disease: amoxicillin
50 mg/kg (maximum 2 g) orally 1 hour prior
to the procedure. Azithromycin may be given
to penicillin‐allergic patients (15 mg/kg, max
500 mg, 1 hour prior to the procedure).
Viral prophylaxis and treatment
Common viral infections may be particu­
larly virulent in immunocompromised
children. These viruses include varicella
­ The decision to hold chemotherapy during
zoster (VZV), herpes simplex (HSV), cyto­
megalovirus (CMV), Epstein–Barr virus,
hepatitis types A and B, respiratory syncytial
virus, and rubeola (measles). Infection with
these viruses may result in prolonged viral
excretion, increased morbidity, or death. At
the time of diagnosis, an immunization and
infection history should be determined. In
addition, serologies for VZV, HSV, and
CMV should be obtained, as potential future
exposure to and infection with these agents
will result in different treatment recommen­
dations depending on the potential for
primary infection versus reactivation. CMV
serology should also be known in determining
whether a potential HSCT patient needs
CMV‐negative blood (see Chapter 5).
The child exposed to varicella or zoster
with known negative varicella immune sta­
tus (negative titers [IgG] and no history of
varicella infection) should receive varicella
zoster immune globulin (VariZIG) within
96 hours of exposure (of note, VariZIG
remains an investigational agent in the
United States and requires institutional
review board approval and completion of an
investigational new drug form). Parents
should be counseled on the risk of exposure
for the child with negative immune status
and the need for immediate evaluation and
treatment if exposed. The dosage is one vial
(125 units) per 10 kg, with a minimum dose
of 125 units and a maximum of 625 units (5
vials), intramuscularly. Administration of
VariZIG extends the incubation period from
14 to 28 days and decreases, but does not
eliminate, the possibility of clinical infection
with VZV (the incubation period generally
is shortened in the immunocompromised
patient who does not receive VariZIG). If
VariZIG is not available, then intravenous
immune globulin can be given at 400 mg/kg.
Myelosuppressive chemotherapy may need
to be stopped 7 days after the exposure and
held until the end of the incubation period.
the incubation period should be based on
the intensity of exposure, condition of the
patient, and intensity of the chemotherapy.
If >96 hours have passed since exposure, the
patient should be given acyclovir at 80 mg/
kg/day (max dose 800 mg/dose) divided
QID (four times daily) PO (orally) for 7
days. In the event of varicella or zoster
­infection, chemotherapy should be stopped
and IV acyclovir should be given, 30 mg/kg/
day divided TID for 7–10 days, until all
lesions are crusted and no new lesions have
appeared for 24–48 hours. Monitor renal
function and fluid status daily due to poten­
tial nephrotoxicity from acyclovir. Of note,
it is safe for household contacts to receive
varicella vaccination, as transmission from
316 Chapter 25
healthy recipients rarely occurs. If skin
lesions occur after vaccination, exposure
should be avoided until all lesions have
crusted over.
Children with a history of recurrent her­
pes simplex infections are at an increased
risk of reactivation with subsequent courses
of chemotherapy or during and after HSCT.
Acyclovir administered prophylactically can
prevent or decrease the severity of recurrent
herpes infection; the recommended oral
dose is 200 mg TID or QID for children
above 2 years of age. Immunocompromised
patients with active HSV infection should
receive IV acyclovir (30 mg/kg/day or
1500 mg/m2/day divided q8h). HSCT guide­
lines for HSV and VZV prophylaxis are
summarized in Chapter 24.
Immunization during
chemotherapy
Patients receiving chemotherapy, or who are
otherwise immunocompromised, should
not receive live virus vaccines (Measles‐
Mumps‐Rubella, MMR), live attenuated
influenza vaccine [LAIV; FluMist®], vari­
cella, rotavirus, and oral polio). Siblings or
household contacts should not receive oral
polio, although MMR, varicella, and rotavi­
rus are safe, as transmission is rare. Limited
information is available regarding risk of
transmission with LAIV; since an ­inactivated
form of influenza vaccination is available,
this should be the preferred immunization
in family members as well as health care
providers. Although varicella vaccination
has been shown to be safe in patients with
ALL in maintenance, the benefits and risks
of this immunization should be weighed
carefully. Consideration should be given to
the likelihood of developing a protective
response while still on chemotherapy and
the potential to develop active infection
with administration of a live attenuated vac­
cine. This must be weighed with the signifi­
cant risks from natural varicella infection in
the immunocompromised, although the
chance of infection has decreased signifi­
cantly with herd immunity.
Inactivated vaccines (e.g., DTaP, Tdap
(both diphtheria‐tetanus‐pertussis vaccines),
Hepatitis A, Hepatitis B, pneumococcal, Hib,
IPV (inactivated polio vaccine), meningo­
coccal, and influenza) can be safely given
during therapy, although response will be sig­
nificantly attenuated based on the level of
immunosuppression. Yearly influenza vacci­
nation is reasonable during therapy, as the
potential benefit of immunization outweighs
the risks, especially for children with ALL in
maintenance. In order to increase the chance
of an appropriate antibody response, vaccina­
tion should be spaced out from chemo­
therapy as much as feasible. Due to potential
risks of pneumococcal and Hib infection in
patients with Hodgkin lymphoma (HL),
some experts recommend vaccination
against these pathogens prior to starting
therapy. Although not immunocompro­
mised, untreated patients with HL have an
underlying B‐lymphocyte dysfunction and
the benefits of immunization prior to therapy
are often significantly diminished. Evidence
is lacking to make firm recommendations.
Catch‐up immunizations should occur
after the completion of therapy. Most sources
feel that waiting 3–6 months after therapy
completion will produce sufficient immune
reconstitution to allow an appropriate
response to inactivated vaccines. Patients who
had not previously completed their ­primary
vaccination series should restart from the
beginning. Patients who previously com­
pleted the primary series can have antibody
titers drawn to determine what protection
they may have lost, if any, or receive booster
vaccinations. Children above 5 years of age
(not including patients with HL) have a small
risk of developing significant disease from
pneumococcus or Hemophilus influenza, but
revaccination against these pathogens should
be considered in all patients after therapy.
Postvaccination titers can be considered,
although the likelihood of an insufficient
 Supportive Care of the Child with Cancer 317

response is minimal in patients who are
vaccinated more than 6 months after
­ has been completed. Poor control of nausea
chemotherapy has been completed. Little
evidence exists as to the appropriate and safe
timeframe to receive live vaccinations after
chemotherapy. In general, we recommend
waiting 6–12 months after therapy comple­
tion before reimmunizing with MMR and
varicella, depending on intensity of the
chemotherapy received. HSCT immunization
guidelines are briefly discussed in Chapter 24.
Prevention of chemotherapy‐
induced nausea and vomiting
Antiemetics are a vital component of the
supportive care regimen for patients receiv­
ing chemotherapy or radiation. There are
three types of chemotherapy‐induced nau­
sea and vomiting (CINV): (i) anticipatory,
(ii) acute, and (iii) delayed. Anticipatory
emesis occurs before chemotherapy is
administered and may be a result of nausea
and vomiting experienced during previous
cycles of therapy. Acute emesis occurs
within the first 24 hours of therapy; delayed
emesis occurs at least 24 hours after therapy
and vomiting may prolong, or result in, hos­
pitalization and lead to dehydration and
electrolyte abnormalities. The single most
important factor in CINV is the emetogenic
potential of a particular chemotherapeutic
agent, which, in pediatric patients, is also
dose dependent for some drugs (Table 25.1).
Multiple agents are useful for the preven­
tion and treatment of CINV. Recognition of
the chemoreceptor trigger zone and the
importance of the 5‐HT3 receptor have been
instrumental in better controlling CINV.
Cytotoxic chemotherapy appears to be
­associated with release of local mediators
such as 5‐HT and substance P from the
enterochromaffin cells of the small intestine.
The release of these local mediators subse­
quently stimulates vagal afferents that initi­
ate vomiting. 5‐HT3 receptors and substance
P receptors (called neurokinin‐1) are located
both peripherally (vagal nerve terminals)
and centrally in the chemoreceptor trigger
zone; thus, 5‐HT3 and substance P antago­
nists may have both peripheral and central
effects in inhibiting vomiting.

Table 25.1 Emetogenic potential of common pediatric chemotherapeutic agents.

High (>90%) Moderate–high Moderate (30–60%) Moderate–low Minimal

(60–90%) (10–30%) (<10%)

Cytarabine Cytarabine Carboplatin Cytarabine Bleomycin

(>1000 mg/m2) (250–1000 mg/m2) (<250 mg/m2)
Cisplatin Cisplatin Cyclophosphamide Etoposide Decadron
(>50 mg/m2) (<50 mg/m2) (<750 mg/m2)
Cyclophosphamide Cyclophosphamide Daunomycin Mercaptopurine Prednisone
(>1500 mg/m2) 750–1500 mg/m2)
Dactinomycin Doxorubicin Methotrexate Fludarabine
(<60 mg/m2) (50–250
mg/m2)
Doxorubicin Idarubicin Topotecan Methotrexate
(>60 mg/m2) (<50 mg/m2)
Methotrexate Ifosfamide Vinblastine Thioguanine
(>250 mg/m2)
Irinotecan Radiation therapy Vincristine
318 Chapter 25
The major pediatric antiemetics, and
their specific mechanisms of action and
dose, are summarized in Table 25.2.
Generally, based on the antiemetic potential
of the chemotherapeutic regimen, a combi­
nation of antiemetics is utilized to prevent
and treat CINV. At a minimum, patients
receiving low emetogenic chemotherapy
should receive ondansetron. The addition of
a NK1 receptor antagonist, such as aprepi­
tant, is an excellent second‐line agent but
should be used with caution with concomi­
tant vincristine or ifosfamide due to syner­
gistic risk of neurotoxicity. Dexamethasone
is an effective antiemetic if started prior to
chemotherapy onset, although should be
avoided in patients with brain tumors due to
theoretical risk of causing decreased influx
of systemic chemotherapy beyond the
blood–brain barrier. Dexamethasone should
also be avoided in patients receiving steroids
as part of their chemotherapeutic regimen
(i.e., acute lymphoblastic leukemia and lym­
phoma). The dose must also be halved if
used concomitantly with a NK1 receptor
antagonist.
Hematopoietic growth factors
in children with cancer
Several hematopoietic growth factors have
been approved for clinical use in children
including granulocyte colony‐stimulating
factor (G‐CSF, filgrastim or pegylated G‐CSF,
pegfilgrastim) granulocyte–macrophage col­
ony‐stimulating factor (GM‐CSF, sargra­
mostim), and erythropoietin (EPO, epoetin
alfa). Thrombopoietin (TPO) receptor ago­
nists (i.e., rivaroxaban) are discussed in
Chapter 12 and have not shown benefit to
date in chemotherapy‐induced thrombocyto­
penia. The indications for each of these
growth factors are based on limited evidence
in pediatric patients and are generally derived
from adult data. Here we summarize general
recommendations for the use of these agents
in pediatric oncology.
Granulocyte colony‐stimulating
factor
G‐CSF is a lineage‐specific cytokine that
stimulates the proliferation of neutrophils
(granulocytes). As patients may have pro­
longed periods of myelosuppression after
chemotherapy, G‐CSF is recommended for
adult patients with: (i) the expectation for
prolonged myelosuppression to prevent epi­
sodes of febrile neutropenia and infection,
(ii) a history of febrile neutropenia, (iii) the
history of a delay between chemotherapy
cycles, and (iv) a diagnosis of febrile neutro­
penia. Pediatric evidence is minimal com­
pared to adult studies but supports the use
of G‐CSF for patients with two of these four
scenarios: (i) prevention of febrile neutrope­
nia and infection (primary prophylaxis),
and (ii) treatment of febrile neutropenia.
Although infection‐related morbidity has
not been shown to decrease with G‐CSF
usage in these scenarios, risk of infection
and length of hospitalization have been
shown to be significantly reduced in meta‐
analyses, with potential benefits for quality
of life and decreased cost from shorter hos­
pitalization. GM‐CSF has shown similar
results to G‐CSF but has not been shown
to be superior in clinical studies. In general,
G‐CSF is the colony‐stimulating factor of
choice in pediatric patients. Clinical studies
have also established that the appropriate
doses of G‐CSF and GM‐CSF are 5 mcg/kg/
day and 250 mcg/m2/day, respectively, given
SC or IV. It should be noted that the IV dose
may be less effective than the SC dose. A
longer lasting pegylated form of G‐CSF
(pegfilgrastim) has been shown to be equally
efficacious in adult studies with less fre­
quent dosing; pediatric randomized con­
trolled studies are lacking but pegfilgrastim
can be prescribed in children at a dose of
0.1 mg/kg.
Primary prophylaxis
G‐CSF should be given to patients receiving
multiagent chemotherapy who are expected
to experience a high incidence of febrile
Table 25.2 Common pediatric antiemetic agents.

Agent Mechanism of action Dose Comments

Ondansetron 5‐HT3 receptor 0.15 mg/kg Well‐tolerated; common side

(also granisetron, antagonist q8h IV/PO effects include headache,
palonosetron) (max 32 mg/day) fatigue, constipation,
diarrhea. Can cause QTc
prolongation. Also available
as orally disintegrating tablet
Lorazepam Interaction with 0.25–0.5 mg Used as adjunctive; can be
GABA (gamma q4–6 h IV/ PO, utilized for anticipatory
aminobutyric acid) max dose 2 mg nausea. At higher doses has
receptor; poorly more sedation/anxiolytic
understood effect than antiemetic effect
antiemetic effects
Diphenhydramine H1 histamine 0.5–1 mg/kg Used as adjunctive; can be
receptor q6 h IV/PO, utilized for anticipatory
antagonist max dose 50 mg nausea. Higher dose used
for prevention of dystonic
reaction with
metoclopramide
Metoclopramide Dopamine 1 mg/kg q4–6 h IV/ Used as adjunctive; higher dose
antagonist PO, max dose required for antiemetic effect
50 mg; may also as compared to prokinetic.
use 0.075 mg/kg Must be given with
PO q6h after 1 mg/ diphenhydramine at higher
kg loading dose dose
Dexamethasone 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 Must be changed q72 h; patient
for adolescents/ must be advised to not touch
adults patch and then rub eyes, as
this will lead to mydriasis
Dronabinol Cannabinoid; 5 mg/m2 q2–4 h, No established pediatric
agonist max dose dosing. Teens and young
antiemetic effect 15 mg/m2 in adults should be advised to
adults not smoke cannabinoids
that can contain impurities
or increase the risk of fungal
infection
Aprepitant Neurokinin‐1 80–125 mg daily PO Must halve decadron dose if
receptor in adults; 3 mg/kg used concomitantly; use
antagonist on day 1, 2 mg/kg with caution with ifosfamide
on days 2 and 3 in
pediatric patients
Olanzapine Antipsychotic; 0.1 mg/kg PO Used as adjunctive for
5HT3‐receptor nightly, max dose anticipatory, delayed, or
antagonist 10 mg refractory nausea; can cause
sedation, weight gain, QTc
prolongation
320 Chapter 25
neutropenia or severe, prolonged neutrope­
nia (i.e., ANC <0.5 × 109/l for 7 or more
days). G‐CSF should not be given on the
same days patients are given myelosuppres­
sive chemotherapy or radiation therapy. G‐
CSF is generally not administered to patients
with myeloid leukemia due to the theoreti­
cal risk of stimulating proliferation of the
leukemic clone.
Treatment of Febrile Neutropenia
Pediatric guidelines are not clear but treat­
ment should be considered in patients with
profound neutropenia (ANC <0.1 × 109/l),
uncontrolled primary disease, pneumonia,
hypotension, multiorgan failure, and inva­
sive fungal infection.
Duration
G‐CSF should be started between 1 and 5
days after the last dose of myelosuppressive
chemotherapy or radiation. G‐CSF should
be continued until the ANC is greater than
1.5 × 109/l for 1–2 days following the
expected neutrophil nadir from chemother­
apy. Specific protocols may call for different
ANC thresholds.
Monitoring
Once G‐CSF is initiated, a complete blood
count (CBC) and differential should be
monitored at least weekly.
Adverse Effects
The most common side effects of G‐CSF are
bone pain and elevation of uric acid, LDH,
or alkaline phosphatase. Occasionally G‐
CSF has been reported to cause fever, nausea
and vomiting, diarrhea, splenomegaly, and
erythema at the injection site.
Recombinant human
erythropoietin (rHuEPO)
Erythropoietin induces proliferation and
differentiation of red blood cell progeni­
tors. The recombinant product erythropoi­
etin alfa (rHuEPO) has been approved in
pediatric patients, although administration
of rHuEPO to oncology patients with
chemotherapy‐induced anemia remains
controversial. A second recombinant, dar­
bepoetin alfa, which has a twofold to three­
fold longer half‐life, has been approved in
adult patients only.
Meta‐analysis of adult data has shown
that although rHuEPO decreases transfu­
sion requirements in cancer patients, there
is a significant increase in venous thrombo­
embolism and, potentially, mortality.
Pediatric data are limited but have not to
date shown a significant difference in sur­
vival with the use of rHuEPO, although
quality of life may be improved. In addition,
venous thromboembolism has not been
seen in pediatric patients. Concern remains
that the decrease in adult survival rates with
rHuEPO may be secondary to the ubiqui­
tous expression of the EPO‐receptor on
tumor cells and therefore tumor upregula­
tion with rHuEPO usage. Conclusive in vivo
data are lacking.
Pediatric guidelines for rHuEPO there­
fore include the following: (i) use of
rHuEPO is not recommended in pediatric
oncology patients, and (ii) rHuEPO should
be considered on a case‐by‐case basis
in special populations where blood
pr­oduct usage is relatively contraindicated.
Specifically, Jehovah’s Witnesses forbid
blood product transfusion and therefore
the potential risks and benefits of rHuEPO
should be discussed with the practicing
patient and their family. A candid discus­
sion should occur between the provider,
patient, family, and potentially patient
advocate, to discuss this complex situation.
Although rHuEPO may ameliorate some
transfusion need, it may not be able to
eliminate this need completely. Many hos­
pitals have minimal blood use policies to
assist in this situation. Additionally, the
patient and family should be made aware of
 Supportive Care of the Child with Cancer 321
the theoretical risks regarding survival with
rHuEPO usage.
Case studies for review
1. You are following a patient with a new
diagnosis of AML. The patient started stand­
ard therapy with cytarabine, daunorubicin,
and etoposide. The patient has been overall
well appearing to date without fever.
a. What are some initial considerations
to prevent infection?
Given the high risk of infection with treat­
ment of AML, patients should remain hos­
pitalized until count recovery in a HEPA
filtered immunocompromised unit. Patients
(and caregivers) should be instructed on
appro­priate oral care as well as appropriate
sterile technique regarding central venous
catheter care to prevent introduction of
infection. Patients should be started on
TMP/SMX on the weekends (i.e., 2–3 days a
week) to prevent PCP. For patients with
severe risk of infection such as the patient
receiving treatment for AML, antifungal
and antibacterial prophylaxis should be
instituted once the ANC <0.5 × 109/l. Either
an echinocandin or an extended spectrum
azole (i.e., posaconazole in the older patient)
can be utilized for fungal prophylaxis.
Levofloxacin is generally utilized for anti­
bacterial prophylaxis until the patient has a
fever requiring initiation of parenteral anti­
biotics (i.e., cefepime and vancomycin in
this case due to risk of Streptococci viridans
with cytarabine therapy).
b. What are some initial considerations
to prevent CINV?
Reviewing the emetogenic potential of the
chemotherapeutic agents, there is a moder­
ate risk of CINV. Patients should be on
scheduled ondansetron at the minimum for
prevention of CINV. Given the interpatient
variability, it is difficult to fully determine
risk of CINV prior to the initiation of the
first cycle of chemotherapy. We utilize loraz­
epam, diphenhydramine, and scopolamine
as initial additional as needed medications.
The practitioner can also consider the use
of metoclopramide and dronabinol. For
patients with more refractory nausea,
aprepitant and olanzapine can be of bene­
fit. Generally, we utilize dexamethasone in
non-central nervous system solid tumors.
Dexamethasone should not be given with
brain tumors given the theoretical decre­
ment in influx of chemotherapy due to seal­
ing of the blood-brain barrier and should be
avoided in AML secondary to the increased
risk of infection.
c. What are the considerations for utili­
zation of GCSF?
Although some AML regimens utilize GCSF,
it is generally avoided in leukemia treatment
given the theoretical (though generally dis­
proven) belief that GCSF can stimulate the
leukemic clone. GCSF is utilized regularly in
solid tumors with high rates of neutropenia.
Patients with solid tumors and a previous
history of febrile neutropenia or delayed
count recovery may also be prescribed GCSF
following chemotherapy. For the patient
with AML and serious infection or symp­
toms of sepsis, GCSF should be utilized.
2. You are now seeing the above mentioned
patient with AML who has completed ther­
apy successfully. Treatment went relatively
smoothly beyond need for transfusion (a
total of 14 packed red blood cell [PRBC]
transfusions) as well as two episodes of bac­
teremia. Total anthracycline (doxorubicin
equivalents) was 492 mg/m2.
a. What are your recommendations
regarding infection prophylaxis?
With removal of the central venous catheter,
risk of infection decreases dramatically. With
ANC recovery after the last cycle of therapy,
the patient can slowly resume normal activ­
ity, though should be advised that normal
immune function will take months to
322 Chapter 25
recover. TMP/SMX should be continued for
3 months after the completion of therapy.
b. What are your recommendations
regarding immunization?
Patients after AML therapy will be immune
suppressed for some period of time and also
are highly likely to have lost immunity to
some prior vaccines. Patients can receive
booster vaccines (or restart the primary series
if not previously completed) or can have vac­
cine titers checked to determine which anti­
bodies are lacking prior to immunization. For
the patient with AML, we recommend wait­
ing 6 months after completion for therapy
for inactivated or dead immunizations and
12 months for live viral vaccinations.
c. What are your recommendations
regarding cardiac screening?
Patients that have received this total
anthracycline dose should have biannual
echocardiogram per the current Children's
Oncology Group guidelines for monitoring
of late effects. Risk of long-term left ventric­
ular dysfunction is more likely with time,
with increasing risk over 10–20 years and in
situations such as pregnancy. Age at time of
treatment also affects development of late
cardiotoxicity. Dexrazoxane prophylaxis can
be considered in young children at the ini­
tiation of anthracyclines if the total planned
anthracycline dose equivalent is 300mg/m2,
and for older patients once the total dose
equivalent has reached 300mg/m2.
d. Is there a risk of iron overload sec­
ondary to PRBC transfusion? What are
the next steps?
Patients that have received 4 or more PRBC
transfusions are at risk for iron overload.
Once the peripheral blood counts have recov­
ered, patients should have a screening ferritin
level. Patients with a ferritin >1000ng/ml are
at risk for iron overload and should have
additional screening with a hepatic R2 MRI
or superconducting quantum interference
device (SQUID). Patients with confirmation
of iron overload with increased liver stores
should receive regular phlebotomy until
normalization of the ferritin. Young children
and menstruating females often can normal­
ize their ferritin and iron overload with time,
especially if the ferritin level and imaging
studies are borderline.
Suggested reading
Feusner, J. (2009). Guidelines for Epo use in children
with cancer. Pediatr. Blood Cancer 53: 7–12.
Feusner, J.H., Hastings, C.A., and Agrawal, A.K.
(eds.) (2015). Supportive Care of the Child with
Cancer: A Practical Evidence‐Based Approach.
Springer. New York.
Freifeld, A.G., Bow, E.J., Sepkowitz, K.A. et al.
(2011). Clinical practice guideline for the use
of antimicrobial agents in neutropenic patients
with cancer: 2010 update by the Infectious
Diseases Society of America. Clin. Infect. Dis.
32: e56–e93.
Hesketh, P.J., Bohlke, K., Lyman, G.H. et al.
(2016). Antiemetics: American Society of
Clinical Oncology focused guideline update.
J. Clin. Oncol. 34: 381–386.
Seelisch, J., Sung, L., Kelly, M.J. et al. (2018).
Identifying clinical practice guidelines for the
supportive care of children with cancer: a
report from the Children’s oncology group.
Pediatr. Blood Cancer 66: e27471.
Sung, L. (2015). Priorities for quality care in pedi­
atric oncology supportive care. J. Oncol. Pract.
11: 187–189.
Sung, L., Aplenc, R., Alonzo, T.A. et al. (2013).
Effectiveness of supportive care measures to
reduce infections in pediatric AML: a report
from the Children’s Oncology Group. Blood
121: 3573–3577.
Sung, L., Zaoutis, T., Ullrich, N.J. et al. (2013).
Children’s oncology group cancer control
and supportive care committee. Children’s
Oncology Group’s 2013 blueprint for research:
cancer control and supportive care. Pediatr.
Blood Cancer 60: 1027–1030.
26 Central Venous
Catheters
Indwelling central venous catheters (CVCs)
have revolutionized the care of children
with cancer by simplifying the administra-
tion of therapy, increasing safety, decreasing
pain, and improving quality of life by
­reducing physical and psychological stress.
Peripheral venous access can become
increasingly difficult in young children.
Additionally, peripheral administration of
certain antineoplastic drugs may cause
injury due to extravasation. CVCs provide a
safe, accessible route for infusion of chemo-
therapy, total parenteral nutrition, blood
products, antibiotics, pain medications,
hematopoietic stem cells, and other medica-
tions and infusions. External devices also
allow for frequent and convenient blood
sampling, which can be taught to home care
providers. CVCs are now an integral aspect
of management of cancer or chronic illness
in children. The optimal type and timing of
placement of a CVC are not standardized.
Many types of CVCs are available and are
divided between temporary (peripherally
inserted central catheters) and more perma-
nent, tunneled catheters. This chapter
focuses on the permanent catheters, placed
to provide access for months to years.
Tunneled catheters can either be entirely
under the skin (i.e., Mediport or Portacath)
or have an external portion that allows
access (i.e., Hickman, Broviac, Powerline).
The decision about the type of CVC to be
Handbook of Pediatric Hematology and Oncology – Children’s Hospital & Research Center Oakland,
Third Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
placed is based on multiple factors including
length and intensity of therapy; frequency of
lab draws; the need for multiple lumens to
support simultaneous administration of
chemotherapy, hydration, pain medication,
parenteral nutrition, antibiotics, and other
agents; age; and lifestyle. In general, external
and multilumen devices are associated with
greater risk, primarily due to an increased
incidence of infection and thrombosis. Ports
are generally utilized with lower‐intensity
therapies and in older children and adoles-
cents. Ports are cosmetically more satisfac-
tory, do not require routine care, cannot be
accidentally self‐removed, have less impact
on body image, and allow for easy bathing
and swimming. However, ports may be dif-
ficult to place and access in obese or very
thin or small patients. Ports require special
needle (i.e., Huber) access through the skin,
and topical anesthetics are used routinely to
decrease or eliminate pain with access.
When left accessed for prolonged periods,
the Huber needle needs to be replaced every
seven days. Subcutaneous ports also require
monthly access with heparinization. The use
of ports for routine blood draws is limited
due to their need to be accessed prior to use,
therefore an external CVC should be used in
patients requiring frequent laboratory mon-
itoring. External CVCs and ports may be
used immediately after placement. In the
case of a port, the surgeon should be asked
324 Chapter 26
Table 26.1 Type of central venous catheter to be placed by diagnosis.
CVC type Number of lumens
External Double
Internal Single
Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myelogenous leukemia;
CVC, central venous catheter; HSCT, hematopoietic stem cell transplantation.
to access the device when it is placed, prior
to development of postoperative edema.
This allows immediate use, decreasing
patient discomfort and reducing the poten-
tial for introduction of infection. Ultimately,
in cases where an external catheter is not
essential, the decision on the type of cathe-
ter to utilize must include a discussion with
the patient and family reviewing the pros
and cons of each type of device. Table 26.1
summarizes the type of CVC to consider
based on diagnosis and subsequent therapy
intensity.
Insertion of catheters
Central venous catheters are typically made
of plastics with flexible silicone rubber
tubing. They are surgically placed (and
­ nally as well that may be removed after
removed) by experienced practitioners via
a percutaneous or cutdown technique. The
patient should be assessed for bleeding
risk by having a platelet count and coagula-
tion studies checked preoperatively. CVCs
are typically inserted into the subclavian,
­internal jugular, or external jugular vein
and tunneled to an exit site on the anterior
Diagnosis
AML
Neuroblastoma, advanced‐stage
Brain tumors on Head Start therapy
Solid tumors, advanced‐stage (potentially)
Patients requiring HSCT
ALL, standard and high‐risk
Hodgkin and non‐Hodgkin lymphoma
Solid tumors except as mentioned above
or lateral chest. Placement in other loca-
tions may be necessary for patients with a
history of thrombosis, multiple previous
CVCs, or in the patient with compression
of the upper venous system due to tumor.
The location of the catheter tip should be
confirmed by fluoroscopy or chest radiog-
raphy to be at the junction of the superior
or inferior vena cava and the right atrium
prior to the catheter being used.
Ultrasonography or angiography may assist
the surgeon in determining the most acces-
sible vein for CVC placement. External
CVCs have a Dacron cuff attached to the
catheter wall that is positioned 1–2 cm
from the skin exit site. This allows for the
growth of fibrous tissue (scar) into the cuff,
preventing migration and loss of the line.
Surgeons will typically place sutures exter-
healing. Ports are secured to the deep fascia
on the anterior chest wall with sutures.
Ports are made of nonimmunogenic mate-
rials and some now allow for high‐pressure
infusion of contrast for radiographic imag-
ing (i.e., PowerPort). The silicone membrane
of the reservoir is accessed by a special
non‐coring needle (Huber) and is self‐sealing
 Central Venous Catheters 325

Table 26.2 Common tunneled central venous catheters and related care.

Catheter type Saline flush Heparin Site care

Hickman/Broviac ≤10 kg: 5 ml/lumen; 10 units/ml Dressing change weekly

>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 catheter 10 ml each lumen 100 units/ml Dressing change weekly
q24 hours >30 kg: 2 ml/lumen or per institution policy
15–30 kg: 1.5 ml/ (or when wet, dirty)
lumen Do not use iodine or
<15 kg: 1 ml/lumen iodine‐based disinfectants
q24 hours and after
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; PRN, pro re nata, as necessary.

with needle removal. Topical anesthesia is
typically applied over the reservoir prior to
access. Risks of CVC insertion include
pneumothorax, hemothorax, chylothorax,
malpositioning, and arterial puncture. As
with all surgical procedures, risk and ben-
efits need to be assessed, discussed, and
consent obtained.
Single lumen ports and double lumen
external catheters are used most commonly
in children. Patients that require pheresis for
stem cell collection early in their course of
therapy benefit from placement of a pheresi-
ble catheter, such as a Medcomp. These lines
require meticulous maintenance and are not
repairable, unlike the standard external tun-
neled catheters. The Bard PowerLine is a
popular double lumen pheresible catheter
due to the higher flow rates that are possible
through it, and it can frequently be placed in
children who are too small to safely receive a
conventional double lumen catheter (see
Table 26.2).
Maintenance
External catheters require daily heparin
flushes and periodic dressing changes (see
Table 26.2). Families require detailed educa-
tion on the care and potential complications
of CVCs. They should be taught sterile
technique to access the CVC for blood
draws or flushes and to provide external
care. Frequency of dressing changes may be
dependent on institution policy, type of
CVC, and local factors such as a wet, dirty,
or loose dressing. At all times, the CVC exit
site should be kept dry and clean. Patients
are instructed to protect it during bathing
and not immerse the dressing or exit site in
a bath, hot tub, or pool. Should this occur,
326 Chapter 26
the dressing should be changed immediately
with careful cleansing of the exit site. Ports
require less care, and heparin flushes, which
are required only monthly, are typically per-
formed by the health care team. No dressing
is needed for implantable devices when
they are not accessed. Each institution has a
standardized approach to the care and
maintenance of CVCs that is followed by
staff, family members, and home health care
agencies (CVC bundle) to help minimize
the risk of central line‐associated blood
stream infection (CLABSI).
Complications: mechanical
The use of CVCs can result in a number
of short‐ and long‐term complications.
Immediate complications related to CVC
placement include malposition, hemor-
rhage, pneumothorax, chylothorax, arterial
cannulation, cardiac dysrhythmia, and fail-
ure to place the line. Rarely, complications
may occur due to the anesthetic required for
surgical placement. Long‐term complica-
tions include mechanical failure, catheter
breakage, leakage, and port extrusion.
Mechanical failures have been reported in
up to 10% of patients and may result in
removal of the CVC. Some types of external
CVCs may be repaired if the break is distal
to the catheter exit site. Children with
implanted ports are at risk for the Huber
needle becoming dislodged during infusion,
leading to extravasation with resultant skin
irritation or breakdown. These require care-
ful periodic assessment.
Complications: infectious
Infection is the most common complica-
tion of CVCs. Most catheter‐related infec-
tions arise by one of two mechanisms: (i)
infection at the exit site with migration of
the pathogen along the external catheter
surface, and (ii) contamination of the hub,
leading to intraluminal colonization and
consequent seeding of the pathogen into
the circulation (see Chapter 27 for com-
mon pathogens and management of fever
in patients with CVCs). Patients with CVCs
require constant attention for prevention
and early recognition of infection. Despite
the meticulous techniques used by health
care providers and caregivers to maintain
sterility, many children with CVCs will
develop a line infection or bacteremia.
Infection is often related to organisms that
are ubiquitous but can lead to true infec-
tion in the immunosuppressed patient
(such as gut and skin flora), or be due to
organisms introduced with venous access
or with blood product or medication/fluid
administration. Coagulase‐negative staph-
ylococci, Staphylococcus aureus, aerobic
Gram‐negative bacilli, and Candida albi-
cans most commonly cause catheter‐related
bloodstream infection. Additionally, devel-
opment of a thrombus in the catheter may
serve as a nidus for infection. Occasionally,
despite best efforts and appropriate antibi-
otic therapy, the line may be colonized and
need to be removed. Recent techniques for
catheter sterilization include antibiotic and
ethanol locks. Additionally, many manu-
facturers have created antibacterial sub-
stances bonded to the catheters.
Risk factors for CVC infection include
the placement of an external catheter, young
patient age, multilumen catheter, early
placement (i.e., within 2 weeks of diagnosis
of acute lymphoblastic leukemia [ALL]),
stem cell transplant, solid tumor, lack
of perioperative prophylactic antibiotics,
high‐intensity protocol, and placement dur-
ing periods of neutropenia. These factors
must be weighed against the benefits of
early line placement, type of line placed, and
number of catheter lumens. The ­relatively
higher infection rate seen with external

catheters favors the use of implanted cathe-
ters when possible.
Approximately 50% of catheter‐related
infections occur locally at the exit site, along
the tunneled catheter or as a “pocket” infec-
tion around the implanted reservoir. Skin
irritation may occur with external CVCs
and requires alteration of the prescribed exit
site care and dressing to avoid repeated irri-
tation, skin breakdown, infection, and pain.
Patients with local catheter infections typi-
cally have local signs and symptoms with
tenderness on palpation, erythema, puru-
lent drainage, lack of healing, swelling, and
pain. Severely neutropenic patients may
only have pain and tenderness as these
symptoms do not require the presence of
neutrophils. If drainage is present, the site
should be cultured. Tunnel infections are
characterized by a spreading cellulitis along
the subcutaneous tract of long‐term cathe-
ters. The catheter should be removed if the
administration of appropriate parenteral
antibiotics does not result in resolution of
the signs and symptoms within 24–48 hours.
When evaluating a child with fever and a
CVC, palpate along the tunnel to assess for
tenderness or to express drainage. Pocket
abscesses may need to be surgically drained
and packed and almost always will require
removal of the reservoir and catheter. Site
infections with minor exit site erythema and
tenderness are treated with topical antibiot-
ics and monitored with careful, daily assess-
ment; systemic antibiotics should be added
for clinical worsening, lack of improvement,
or a positive blood culture from the line.
Tunnel and pocket infections should be
treated with both topical and systemic anti-
biotics, as well as a daily sterile dressing
change. The patient should be treated sys-
temically with broad‐spectrum antibiotics
providing good Gram‐positive coverage and
be monitored for the development of an
abscess requiring surgical drainage. The
antibiotic regimen may be altered with
Central Venous Catheters 327
­culture results, but if the patient is neutro-
penic it should include both broad‐spec-
trum and directed antibiotic therapy. Site
infections provide an opportunity to review
meticulous local CVC management with the
caregivers.
In addition to site infections, coloniza-
tion of the catheter may occur. In this case,
the patient will have repeatedly positive cul-
tures with the same organism, often without
systemic symptoms of infection. In cases of
colonization, cultures may become quickly
positive and may persist through appropri-
ate antibiotic therapy. At times, catheters
may be reseeded from distant sites of occult
infection (e.g., cardiac vegetations, osteo-
myelitis, deep abscesses). Colonized cathe-
ters must be removed.
The CVC should always be considered
the source of infection in a patient who pre-
sents with fever until proven otherwise.
Fever, chills, or hypotension temporally
related to line flushing increase the likeli-
hood of a line infection. Broad‐spectrum
empiric antibiotics should be administered
after drawing cultures from each lumen of
the CVC. Persistent bacteremia despite
appropriate antibiotic coverage (>72 hours),
signs of sepsis (hypotension, chills, persis-
tent fever, cool extremities, delayed capillary
refill), or infection with fungus, mycobacte-
rium, S. aureus, or water‐borne bacteria
(e.g., Pseudomonas aeruginosa) warrant
CVC removal. If placement of a new CVC is
deemed necessary, the patient should first
complete an appropriate course of antibiotic
therapy allowing for sufficient healing time
and decreasing the risk of subsequent rein-
fection of the new CVC. Patients who expe-
rience bacterial sepsis with hemodynamic
instability, septic thrombosis, or endocardi-
tis should have their CVCs removed.
CVC infection may be over‐diagnosed,
resulting in either prolonged antibiotic
administration or unnecessary removal of
the catheter. Differential time to positivity
328 Chapter 26
can be a reliable diagnostic technique to
differentiate a true line infection from bac-
teremia. Paired blood samples (aerobic and
anaerobic) from a peripheral vein and the
central catheter are obtained and com-
pared with respect to time to positivity. If
the culture from the catheter turns positive 2
or more hours before the peripheral cul-
ture, this is diagnostic of a catheter‐related
infection. A positive differential time to
positivity may not change management,
although consideration should be given to
the type and duration of systemic antibi-
otic therapy, utility of an antimicrobial or
ethanol lock, and the need for catheter
removal. Addi­ tional factors include the
type of catheter, prior history of infection,
current neutrophil count, likelihood of
short‐term recovery, and current chemo-
therapeutic regimen. When a specific
pathogen has been identified, antibiotic
therapy should be targeted, with additional
broad empiric coverage in the neutropenic
patient (see Chapter 27). The possibility of
an infected catheter‐related thrombus
should be considered, and treatment may
also involve thrombolytic agents or
anticoagulation.
Assessment and management
of catheter‐related thrombosis
Venous thromboembolism is another com-
mon complication of long‐term CVCs. The
extent of thrombosis may include the cath-
eter tip (ball‐valve clot), the length of the
catheter (fibrin sheath), or the catheterized
vessel (e.g., the upper limb with or without
the central vasculature of the neck or medi-
astinum). Catheter‐related venous throm-
boembolism can result in significant
morbidity, and subclinical thrombosis may
occur in up to 50% of patients with CVCs.
The risk of thrombosis is influenced by
catheter location, insertion technique, cath-
eter kinking or compression by a mass or
other structure, ratio of the catheter size to
the intraluminal vessel diameter, blood
flow rheology, genetic predisposition, and
administration of prothrombotic medica-
tions or infusions (e.g., asparaginase, ster-
oids, total parenteral nutrition). Primary
thromboprophylaxis is not currently recom-
mended as standard practice; however, it
may be warranted in certain situations with
documented increased risk.
Thrombosis should be suspected in
patients whose catheter does not flush or
draw easily or in the event of suggestive
clinical findings (pain or swelling in
extremity, prominent vasculature or swell-
ing on side of neck/chest with CVC, inabil-
ity to successfully access an implanted
port). It should be noted that a line that
does not draw or flush might be occluded
by the vessel wall or a valve. Patients sus-
pected of having a thrombosis should
undergo imaging to confirm this and deter-
mine the extent (see Figure 26.1). Based on
the timing of line dysfunction or symptom
development, the age of the clot can be
approximated. Additionally, pertinent fam-
ily history of thrombosis should be sought
to help guide the necessity of genetic evalu-
ation for thrombophilia (see Chapter 10).
Finally, environmental and medication pro-
thrombotic factors should be considered
(e.g., immobilization, steroids, and other
medications).
Treatment of thrombosis may require
thrombolytic therapy, anticoagulation, or
catheter removal. Guidelines are provided
here for the assessment and treatment of a
suspected CVC‐associated thrombus:
●● Examine the catheter for any kinks in the
tubing.
●● Reposition the patient; flush the CVC
with normal saline (if possible) and again
attempt to withdraw blood. Have the patient
hold their hands above their head, turn,
cough, or hold their breath.
 Central Venous Catheters 329

Initial evaluation
Physical examination, including assessment of malfunctioning CVC
History (prothrombotic medications, family history)
Laboratory assessment (fibrinogen, PT, PTT, CBC)

Diagnostic imaging for confirmation of TE:

Ultrasound with Doppler and/or
CT with venography and/or
Catheter dye study

Is CVC essential for care?

no
yes

Thrombophilia risk assessment Occlusive: initiate thrombolysis,

(see Chapter 10) then anticoagulation
Nonocclusive: anticoagulation

Occlusive: initiate thrombolysis up to 48–72 hours;

anticoagulation
Nonocclusive: consider thrombolysis up to 48–72 hours;
anticoagulation

Functional CVC?

no
yes

Successful lysis Residual thrombus

of TE Continue therapeutic
Remove CVC
anticoagulation
Continue therapeutic anticoagulation
Consider CVC removal
if still with residual clot until clot
dissolution
Continue prophylactic anticoagulation
Therapeutic anticoagulation for 3 months for 6 weeks to 3 months after clot
followed by prophylaxis until CVC resolution
removed

Figure 26.1 Evaluation of suspected thromboembolism in patients with tunneled central venous cath-
eters. Abbreviations: CVC, central venous catheter; PT, prothrombin time; PTT, partial thromboplastin
time; CBC, complete blood count; TE, thromboembolism; CT, computed tomography.

●● Attempt a tissue plasminogen activator ⚪⚪ After the first dwell, attach an empty 3 ml

(TPA) dwell if the catheter can be flushed:
⚪⚪ Infants <3 months receive 0.25 mg
(0.5 ml) per lumen; other children <10 kg
receive 0.5 mg (1 ml) per lumen, while
those 10–30 kg receive 1 mg and >30 kg
syringe and attempt to withdraw blood. If
successful, obtain blood work and flush line
per protocol. If unsuccessful, instill a second
TPA dwell for an additional 30 minutes.
●● If the TPA dwell is unsuccessful, further

receive 2 mg. Dwell should be adminis- workup is required to determine the extent
tered for 30 minutes. of thrombus.
330 Chapter 26
⚪⚪ Obtain a chest radiograph to confirm
appropriate line position.
⚪⚪ Obtain further imaging studies such as
a dye study of the line, ultrasound with
Doppler flow, or CT with venography to
evaluate for thrombosis location and
extent. Assess for sleeve thrombus,
mechanical failure of the CVC, or migra-
tion of the catheter outside the vessel.
⚪⚪ If a thrombus is identified and the time
from symptom onset is <14 days, throm-
bolytic therapy with low‐dose systemic
TPA should be attempted if the catheter
can be flushed.
⚪⚪ Infants <3 months receive 0.06 mg/kg/h
for 6–24 hours; older children receive
0.03 mg/kg/h. If no clinical improvement in
24 hours, double the dose to 0.06–0.12 mg/
kg/h (max dose 2 mg/h).
⚪⚪ Systemic TPA can be given for up to
96 hours.
⚪⚪ Monitor the fibrinogen level and main-
tain above 100 mg/dl with cryoprecipitate.
●● Monitor the patient for signs of sepsis, as
bacteria can be released into the blood-
stream with dissolution of the thrombus.
●● If the catheter becomes functional after
administration of systemic TPA, obtain a
follow‐up radiographic study to assess for
clot resolution.
●● Remove the catheter if the thrombus
­cannot be cleared after 24–48 hours.
If the thrombus dissolves, or is stabilized
with normal CVC function, determination
should be made as to the current necessity of
the line and risk for recurrent thrombosis. If
the CVC can be safely removed, some practi-
tioners recommend short‐term prophylactic
anticoagulation to mitigate the risk for
rethrombosis (usually 6 weeks to 3 months
of low‐molecular‐weight heparin [LMWH]).
If the line needs to be maintained and the
clot has resolved, the patient should continue
on therapeutic LMWH for 3 months and
then switch to prophylactic LMWH until the
line is removed. For the patient with a stable
clot and a functional CVC, therapeutic anti-
coagulation with LMWH should be contin-
ued until approximately 3 months after clot
dissolution and then switched to prophylac-
tic anticoagulation until line removal (see
Chapter 10 and Formulary for dosing guide-
lines). Additionally, if the patient is deter-
mined to have a genetic predisposition to
thrombosis based on family history or a per-
sonal history of previous thromboembolism,
a thrombophilia trait workup should be sent
(see Chapter 10 for details). If the patient has
multitrait thrombophilia and therefore a
higher risk of rethrombosis, every effort
should be made to remove the CVC once the
risk of having an indwelling line outweighs
the benefit (i.e., maintenance therapy in the
ALL patient).
If the patient on prophylactic anticoagu-
lation develops rethrombosis, management
should be the same as with the initial clot
with systemic low‐dose TPA followed by
therapeutic anticoagulation with LMWH
until clot dissolution. If the patient is on
therapeutic anticoagulation with clot exten-
sion, the CVC will need to be removed. In
cases where the clot cannot be dissolved or
stabilized and the line needs to be removed,
3–5 days of anticoagulation is recommended
for clot stabilization prior to catheter
removal. Special circumstances will warrant
disruption in anticoagulation, such as lum-
bar punctures to administer intrathecal
chemotherapy or other surgical procedures.
In general, LMWH should be held for
24 hours in advance of these procedures and
resumed 12–24 hours after procedure com-
pletion, depending on the nature of the pro-
cedure and risk of postoperative bleeding.
Additionally, LMWH should be held during
periods of moderate thrombocytopenia (i.e.,
<50 × 109/l) to minimize additional risk of
bleeding. Longer‐acting medications such as
fondaparinux should be held for a ­minimum
of 48–72 hours prior to lumbar puncture. If

the CVC is removed and it is necessary to
place a new catheter, consideration should
be given to anticoagulation prophylaxis to
prevent recurrence of thrombosis.
Suggested reading
Bundy, D.G., Gaur, A.H., Billet, A.L. et al. (2014).
Preventing CLABSIs among pediatric hema-
tology/oncology inpatients: national collabo-
rative results. Pediatrics 134: e1678–e1685.
Chen, K., Agarwal, A., Tassone, M.C. et al.
(2016). Risk factors for central venous
Central Venous Catheters 331
catheter‐related thrombosis in children:
­
a retrospective analysis. Blood Coagul.
Fibrinolysis 27: 384–388.
Hord, J.D., Lawlor, J., Werner, E. et al. (2016).
Central line associated blood stream ­infections
in pediatric hematology/oncology patients
with different types of central lines. Pediatr.
Blood Cancer 63: 1603–1607.
Mermel, L.A., Allon, M., Bouza, E. et al. (2009).
Clinical practice guidelines for the diagnosis
and management of catheter‐related infec-
tion: 2009 update by the Infectious Diseases
Society of America. Clin. Infect. Dis. 49:
1–45.
27 Management of Fever
in the Child
with Cancer
Children with cancer are at an increased risk
for serious bacterial, viral, and fungal infec-
tions. Many factors contribute to this suscep-
tibility in immunocompromised children.
The two most important determinants of
susceptibility to bacterial and fungal infec-
tion are the number of circulating neutro-
phils (absolute neutrophil count; ANC) and
the duration of severe neutropenia. One of
the most significant advances in decreasing
mortality and improving survival for chil-
dren and adolescents undergoing cancer
therapy is the recognition of fever as a medi-
cal emergency and the prompt administra-
tion of broad‐spectrum antibiotics.
Risk factors for febrile neutropenia (FN)
include:
●● Underlying disease: leukemia, especially
acute myelogenous leukemia (AML) and
relapsed acute lymphoblastic leukemia
(ALL), advanced stage lymphoma, and
hematopoietic stem cell transplant (HSCT)
are at higher risk due to increased therapy
intensity.
●● Remission status: patients not in remis-
sion are at higher risk.
●● Recent administration of chemotherapy
anticipated to cause prolonged myelo-
suppression.
Handbook of Pediatric Hematology and Oncology – Children’s Hospital & Research Center Oakland,
Third Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
●● Type of therapy with dose‐ or time‐inten-
sive therapies: administration of high‐dose
cytarabine, AML and ALL induction, and
HSCT conditioning regimens confer the
highest risk.
●● Nutritional status: malnutrition adversely
affects immune function.
●● Disruption of protective barriers such as
skin, mucocutaneous tissues, gastrointesti-
nal tract, and exit sites of catheters.
●● Defects in humoral immunity related to
therapy, impaired splenic function, or B‐cell
malignancies.
●● Defects in cellular immunity such as seen
in patients with T‐cell malignancies or those
receiving steroids or radiation; persistence
of lymphopenia due to chemotherapy.
●● Colonization from endogenous microflora.
●● Presence of indwelling catheters or shunts
(e.g., ventriculoperitoneal).
The ANC is calculated by multiplying the
percentage of neutrophils (segmented neu-
trophils + bands) by the total white blood
cell (WBC) count.
Example: WBC = 1.0 × 109/l, segmented
neutrophils = 10%, bands = 10%.
ANC = 20% × 1.0 × 109/l = 0.2 × 109/l (often
referred to as an ANC of 200).
334 Chapter 27
Neutropenia: ANC < 1.5 × 109/l.
Moderate neutropenia: ANC < 1.0 × 109/l.
Severe neutropenia: ANC < 0.5 × 109/l.
Profound neutropenia: ANC < 0.1–0.2 × 109/l.
In general, patients with an ANC of
<0.5 × 109/l or those with dropping counts
after chemotherapy expected to be
<0.5 × 109/l within 48 hours are considered
severely neutropenic. The ANC at time of
presentation with respect to the most recent
chemotherapy gives important information.
For instance, if a child is neutropenic with-
out recent myelosuppressive therapy, infec-
tion (and less likely relapse of a hematologic
malignancy) should be considered as the
most likely etiology due to marrow suppres-
sion. In general, the expected nadir in ANC
occurs 7–14 days from the start of myelo-
suppressive chemotherapy. This timing
should be considered when assessing the
patient and determining the management
plan. Practitioners may also utilize the abso-
lute phagocyte count (APC), which is the
summation of the ANC and absolute mono-
cyte count, in determining the risk of bacte-
rial infection, as monocytes also possess
bacteria‐fighting ability. An increasing
monocyte count is often seen prior to and
often heralds neutrophil recovery.
Fever is defined as a single temperature
from any source of 38.3 °C (101.0 °F) or
greater, two temperatures of 38.0–38.2 °C
(100.4–100.9 °F) within a 24‐hour period,
or a temperature of 38.0–38.2 °C (100.4–
100.9 °F) persistently for 1 hour. Once a
fever is documented, it should be consid-
ered as real no matter what the underlying
circumstances are, even if the patient
defervesces without any intervention.
Patients who develop a low‐grade fever
(38.0–38.2 °C) should be monitored with-
out antipyretics to determine if a fever
spike will occur. Rectal temperatures
should never be taken in potentially neu-
tropenic children.
Fever and neutropenia
FN is an emergent situation and the
patient should be considered septic until
proven otherwise. These children may
have fever as the first or only symptom of
infection. It should be noted that neutro-
penia will not prevent the patient from
having a temperature spike with infection;
one exception is the patient on steroids
(such as in ALL induction and delayed
intensification) who may not mount a
fever with an underlying infection. A
careful clinical examination is critical, as
the patient’s status may change quickly
and dramatically. As neutropenic hosts
may have blunted inflammatory responses,
even subtle signs and symptoms of infec-
tion should be considered significant.
Neutropenic patients who develop clinical
signs or symptoms suggestive of infection
without fever should be managed in the
same emergent manner as the neutropenic
patient presenting with fever.
Septic shock results from overwhelming
infection with microorganisms in the
blood leading to central vascular dilation
with resultant circulatory failure and inad-
equate tissue perfusion. Symptoms of sep-
tic shock include hypotension, tachycardia,
tachypnea, clammy extremities (although
can be warm with initial sepsis), decreased
urine output, and deterioration of mental
status. Although septic shock can be seen
with any organism, the usual culprits with
acute and overwhelming sepsis are Gram‐
negative rods.
The most common organisms causing
bacteremia and sepsis are:
●● Gram‐positive: Staphylococci (coagu-
lase‐negative, Staphylococcus epidermidis,
Staphylococcus aureus including methicil-
lin‐resistant [MRSA]); Streptococci (α‐
hemolytic) including Streptococcus viridans
and Streptococcus mitis.
 Management of Fever in the Child with Cancer 335
●● Gram‐negative: Enterobacteriaceae (Esche­
richia coli, Enterobacter, Klebsiella, Serratia),
Pseudomonas aeruginosa, Stenotrophomonas
maltophilia, Acinetobacter sp.
●● Anaerobic: Clostridium difficile, Bacteroides
sp., Propionibacterium acnes.
Other pathogens infecting cancer
patients include:
●● Fungi: Pneumocystis jiroveci, Candida sp.,
Aspergillus sp., zygomycetes, cryptococci.
●● Viruses: Herpes simplex virus (HSV),
varicella zoster virus (VZV), cytomegalovi-
rus (CMV), Epstein–Barr virus, respiratory
syncytial virus, adenovirus, influenza, para‐
influenza, human herpesvirus 6.
●● Other: Toxoplasma gondii, Strongyloides
stercoralis, cryptosporidium, Bacillus sp.,
atypical mycobacterium.
Initial evaluation of febrile
neutropenia
See Figure 27.1.
1. History and physical examination (PE)
●● Determination of vitals (temperature,
blood pressure, heart rate, respiratory
rate, oxygen saturation) and rapid assess-
ment for shock.
●● The history should include a determi-
nation of the presence of chills or rigor
following flushing of the central line,
concerns for the site of the central venous
catheter (CVC), recent chemotherapy or
radiation therapy including dosage,
medications (antibiotics, prophylaxis),
recent infectious exposures or travel, and
prior history of infections including
infected CVCs.
●● Meticulous physical examination with
particular attention to sites of occult
infection such as the skin, exit sites of
catheters (and the tunnel path of the
catheter), sites of any invasive procedure
including bone marrow aspiration, oral
cavity, and perianal areas. Even subtle
evidence of inflammation (faint ery-
thema, tenderness, or minimal discharge)
may represent a source of infection, as
neutropenia diminishes classic inflam-
matory changes. Pain, however, is always
a concerning finding and should be con-
sidered a potential clue to site and source
of infection.
2. Laboratory evaluation
●● Complete blood count (CBC) with
manual differential to determine ANC.
●● Blood cultures from each lumen of the
CVC; peripheral culture is necessary if the
child does not have a central line or it is
unobtainable from the central line.
Simultaneous peripheral blood culture
and CVC blood culture can be considered
based on differential time to positivity
and may be helpful in differentiating
central line‐associated bloodstream
infections (CLABSI) from the non‐
CLABSI infection. It remains unclear of
the utility of this assessment in treat-
ment‐related decision‐making in febrile
neutropenic patients (see Chapter 26).
Some practitioners do not routinely
collect peripheral blood cultures due to
patient discomfort and possibility of
contamination. Do not flush the cathe-
ter after labs are obtained in the patient
with a recent history of high fever, hypo-
tension, chills, or rigors within 1 hour of
flushing the catheter, suggestive of a line
infection.
●● Serum chemistries to include electro-
lytes, liver, and renal function studies.
●● Clean catch urinalysis and urine cul-
ture (no catheter sample for neutropenic
patients) should be obtained, ideally
prior to the start of antibiotics, but
should not delay initiation of treatment.
●● Chest radiograph only if the patient
has auscultatory signs or symptoms of
infection or respiratory compromise.
The finding of a pulmonary infiltrate
should then prompt the practitioner to
336 Chapter 27

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

Initial Evaluation
History: Chills, rigors, fever within 1 hour of CVC flush
Recent immunosuppressive therapy
Symptoms of AGE, URI, pain
Physical examination: Vitals, CVC exit site(s), skin/mucosa, perineum
Laboratory assessment: CBC with differential
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, creatinine, liver transaminases
Imaging: CXR if signs/symptoms of pulmonary process
CT as necessary per physical findings (sinuses, chest, abdomen, pelvis)

Risk group assessment

Low risk
Diagnosis: ALL, NHL, solid tumors in
remission
Neutropenia: Duration <7 days
Nontoxic appearance
No focal infection, mucositis, diarrhea
Empiric antibiotic therapy; monotherapy
Consider outpatient management
High risk
Any malignancy not controlled (i.e., relapse, refractory, induction)
AML, high risk ALL in consolidation or delayed intensification
High dose cytarabine
Prolonged neutropenia anticipated ≥7 days
Profound neutropenia <0.1 x 10 9/L
Toxic appearance: Hypotensive, rigors, shock, tachypnea, hypoxia
Evidence of infection: Pneumonia, cellulitis, abdominal pain and
diarrhea, neurologic (mental status) changes
Known colonization with MRSA
Prior history of bacteremia/sepsis
Mucositis following chemotherapy

Empiric therapy, broad spectrum, initiated promptly

Hospitalization
Treatment of co-morbidities as appropriate
Pain management as appropriate
Directed therapy as appropriate:
Vancomycin for recent high dose cytarabine, new fever in AML patient
Metronidazole 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.

consider further evaluation with chest causes with serologies and culture, if
computed tomography (CT) and possi- possible.
bly bronchoscopy to identify an organ- ●● Cultures and bacterial Gram stain or

ism (and sensitivity pattern). fungal stains from suspicious sites such
●● Patients with tenderness over the as the oropharynx, skin breakdown sites,
sinuses, perform diagnostic imaging to and catheter sites.
evaluate for sinusitis (sinus CT). ●● If diarrhea is present, send a stool sam-

●● Patients with symptoms of esophagitis ple for stool culture, rotavirus, and C. dif­
should be evaluated for viral or fungal ficile antigen.
 Management of Fever in the Child with Cancer 337
●● In contrast to non‐oncology patients,
lumbar puncture (LP) is not routinely
done as part of a serious bacterial infec-
tion evaluation in oncology patients with
FN. If LP appears clinically indicated,
evaluation for increased intracranial pres-
sure with appropriate imaging (i.e., head
CT) should be considered and the pediat-
ric oncology attending notified prior to
the procedure. An adequate platelet count
and coagulation studies should be con-
firmed in advance of the LP.
●● If another implanted device is pre-
sent (e.g., ventriculoperitoneal shunt
or Ommaya reservoir), do not attempt
to obtain a culture without speaking to
the appropriate attending physicians.
Intervention by a neurosurgeon may be
required. It is uncommon for these
devices to be the source of infection if
it has been more than 2–4 weeks since
they were inserted.
Initial management
Risk stratification models for pediatric
oncology patients with FN have yet to be
validated and widely accepted. Despite
­publication of numerous risk stratification
studies in FN, no single validated risk strati-
fication strategy has been adopted as stand-
ard of care. It is generally accepted that
patients with high‐risk features (as deline-
ated in the earlier text) should be hospital-
ized until count recovery, while certain
low‐risk groups may be able to be treated in
an outpatient setting after defervescence
(especially in the setting of a study). FN is an
oncologic emergency and all measures
should be taken to ensure prompt evaluation
and treatment. Antibiotics should be chosen
based on microbial prevalence and antibiotic
sensitivity patterns at each institution. In
general, due to the more acute risk from
Gram‐negative organisms, broad coverage
for these organisms (including Pseudomonas)
should be initiated. Many antibiotic combi-
nations are effective, and the decision about
the use of a specific agent or combination
approach should take into consideration the
institution’s bacterial susceptibility patterns,
cost, toxicity, and local standards of care.
Most institutions have adopted monother-
apy, as published meta‐analyses have not
proven monotherapy to be noninferior to
dual therapy. Common regimens include:
1. Fourth generation cephalosporin (anti‐
pseudomonal β‐lactam):
Cefepime 100 mg/kg/day intravenous
(IV) divided Q 8 hours:
2. Carbapenems:
Imipenem/Cilastatin 50 mg/kg/day (dosed
on Imipenem component) IV divided Q
6 hours.

Meropenem 60–120 mg/kg/day IV
divided Q 8 hours.
3. Piperacillin/Tazobactam

(Zosyn) 300 mg/kg/day (dosed on
Piperacillin component) IV divided Q 4
hours.
Additional antibiotics used in specific cir-
cumstances (see in the following text) are:
1. Gram‐positive coverage:
Vancomycin 40–60 mg/kg/day IV
divided Q 6 hours.
2. Anaerobic coverage:
 Metronidazole 30 mg/kg/day (loading
dose 15 mg/kg) IV divided Q 6 hours.
Clindamycin 40 mg/kg/day IV divided Q
6–8 hours.
Gram‐positive organisms are frequent
offenders in certain populations and
empiric coverage is recommended in select
situations. Patients with AML receiving
high‐dose cytarabine (Ara‐C) should have
vancomycin as part of their empiric regimen
in combination with broad‐spectrum cover-
age due to the high risk of S. viridans
­infection (associated with septic shock and
338 Chapter 27
acute respiratory distress syndrome).
Cytarabine is known to alter mucosal integ-
rity and allow entry of this organism. Other
indications for vancomycin in the empiric
regimen include:
●● Presentation with hypotension or other
evidence of shock.
●● Mucositis.
●● Patients with prior history of α‐hemolytic
Streptococcus bacteremia.
●● Catheter site infection or other skin
breakdown.
●● Patients colonized with resistant organ-
isms treatable only with vancomycin.
●● Vegetations on echocardiogram.
●● Severe pneumonia.
Anaerobic therapy should be considered
empirically in patients who have significant
mucosal breakdown, perineal skin break-
down, peritoneal signs, or in cases of neu-
tropenic colitis, or with presumed or proven
C. difficile infection.
Patients receiving vancomycin should
have trough levels monitored weekly (once
therapeutic) due to the risks of nephrotox-
icity and ototoxicity, especially in those
receiving other concurrent nephrotoxic or
ototoxic drugs (e.g., furosemide). The goal
for a vancomycin trough level is 10–15 mcg/
ml when treating a proven infection. Dose
increases are often required in pediatric
patients to reach these levels (thus, gener-
ally recommend starting at 60 mg/kg/day in
the young patient). Monitor daily electro-
lytes, fluid balance, renal function studies,
and ensure adequate hydration. Patients
with renal dysfunction should receive renal
dosing with more frequent trough levels to
prevent toxicity.
Any patient presenting with hypoten-
sion, chills, rigors, or fever immediately fol-
lowing, or within 1 hour, of CVC flushing
should be evaluated emergently due to the
risk of bacteremia and septic shock. We elect
not to use the central venous line for IV
f­ luids or medication administration initially
in this situation due to the risk of infusing a
large amount of bacteria into the blood-
stream and worsening the signs of clinical
sepsis. Patients should have central catheter
cultures, placement of a peripheral IV,
peripheral blood cultures obtained, and
receive broad‐spectrum antibiotics immedi-
ately in addition to fluid boluses (e.g., NS/
LR 20 ml/kg). The central catheter should
not be flushed or utilized until the patient
improves clinically with defervescence, res-
olution of hypotension, and negative follow‐
up blood cultures. If the line cannot be
flushed, a tissue plasminogen activator
(TPA) dwell can be attempted; if unsuccess-
ful, the line will need to be removed (see
Chapter 26). It is advisable to give an IV
fluid bolus prior to reusing the catheter in
the event the patient again develops symp-
toms of bacteremia with hypotension fol-
lowing the flush. In the event the initial
blood culture from the catheter is positive,
the clinician will need to decide whether to
remove the catheter or attempt to reuse it
depending on the patient’s clinical condi-
tion, ongoing need for central access, and
the organism’s identification and sensitivity
pattern. Patients that have persistent fever
and Gram‐negative organisms may do best
with removal of the line; patients that have
defervesced and are looking clinically well
can generally have their line reused and ulti-
mately salvaged.
Modification of initial
antibiotic treatment
Subsequent modifications to the treatment
plan are made on the basis of the clinical
course, emergence of positive cultures, and
estimated length and severity of neutrope-
nia. A careful daily clinical assessment
includes a review of the vital signs, height
and persistence of fever or change in the
 Management of Fever in the Child with Cancer 339

fever curve, alterations in blood pressure,
and presence of any new symptoms or signs
of infection on a meticulous physical exami-
nation. The laboratory evaluation includes
daily CBCs/ANC until count recovery,
review of prior cultures, and possible diag-
nostic imaging (see Figure 27.2).
Modifications should be made to the ini-
tial broad‐spectrum antibiotic regimen if a
source of infection is found that explains the
initial fever, or the fever persists for more
than 3–7 days. If the source of the infection
is a catheter site with accompanying signs or
symptoms of inflammation (discharge, pal-
pable tenderness, local abscess), vancomy-
cin should be added for Gram‐positive
coverage. If the source is perineal, gingival,
or intra‐abdominal, anaerobic coverage
should be added to the regimen (metronida-
zole, clindamycin or meropenem).
Vancomycin is the most effective antibi-
otic to treat skin flora such as coagulase‐
negative staphylococci (i.e., S. epidermidis) as
well as mouth flora, most commonly

Empiric therapy

Negative cultures 48–72 hours, unknown

site of infection

Blood or site
cultures positive or site
organism suspected Persistent Afebrile ≥24 hours
fever/neutropenia

Evidence of neutrophil
Broaden coverage: Continue 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 consecutive days)
Mucositis/perineal breakdown: add metronidazole or 24 hours with PE Discontinue antibiotics
meropenem and cultures
Esophagitis: add acyclovir, consider antifungal
Pulmonary infiltrates: add triazole and/or
echinocandin after BAL/bronchoscopy
Catheter associated bacteremia >72 hours or Persistent neutropenia:
fungemia: remove CVC Continue antibiotics, until neutrophil
recovery*
If fever recurs, reassess with PE and
cultures, broaden antibiotics, and
consider antifungal therapy
*see text; consider outpatient management
for “low-risk” patients per institutional
guidelines
Persistent fever 3–5 days with neutropenia:
Imaging for infection if with expected
continuation of neutropenia: CT chest, other
areas based on symptoms
Urine cytospin for hyphae, fungal culture
Continue broad spectrum antibiotics,
broaden as indicated clinically
Initiate empiric antifungal 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.
340 Chapter 27
Streptococcal species (S. viridans, Pepto­
streptococcus). Vancomycin is also effective
against bacillus non‐anthracis species that
can be true pathogens in the immunocom-
promised patient. Finally, though rarely
seen, MRSA should be a consideration in
the very sick patient. Vancomycin should be
used judiciously due to emerging resistance
patterns such as vancomycin‐resistant ente-
rococcus (VRE). Vancomycin should not be
part of the empiric antibiotic regimen unless
the institutional experience and susceptibil-
ity patterns require it or there are special cir-
cumstances warranting its use (as mentioned
in the preceding text).
Protracted fever may signify the presence
of an additional or previously untreated
infection. Patients should be reassessed daily
for new signs or symptoms of infection and
appropriate interventions and studies per-
formed. Antibiotic‐induced colitis may
occur after any antibiotic. C. difficile over-
growth may be asymptomatic, lead to mild
diarrhea, or may have moderate‐to‐severe
diarrhea and abdominal pain. The patient
may also develop pseudomembranous colitis
with peritoneal signs, mucosal erosions, and
bloody diarrhea. Since C. difficile is a normal
bowel inhabitant, the toxin must be docu-
mented to diagnose this condition. If oral
therapy is possible, vancomycin (40 mg/kg
divided q8h) or metronidazole (30 mg/kg
divided q6h) may be given; in the patient
unable to tolerate oral medications, IV met-
ronidazole (same as PO dose) should be
given. Abdominal pain may also be due to
infection with aerobic Gram‐negative bacte-
ria, enterococcus (which no cephalosporin
covers in vivo), or anaerobes.
If the patient is determined to have a
catheter‐associated bacteremia with a spe-
cific organism, broad‐spectrum antibiotics
should be continued (as long as the patient
remains neutropenic) with the addition of
antibiotics as needed to ensure adequate
coverage of the identified organism until
sensitivity patterns are reported. Once
microbial sensitivities are determined, fur-
ther narrowing of the antibiotic coverage
may be done. If daily cultures are persis-
tently positive with the same organism for
72 hours after initiation of appropriate anti-
biotics, it will be necessary to remove the
catheter. In addition, several organisms
including S. aureus, Pseudomonas, Bacillus
cereus, Corynebacterium, Mycobacterium
sp., Stenotrophomonas, and fungi usually
require line removal. General care measures
to assess and manage a CVC with possible
infection are as follows:
●● Hand washing with clean or sterile gloves
prior to manipulation of CVC.
●● Monitor CVC site on a daily basis; change
CVC dressing weekly.
●● Assess site for skin infection (including
tunnel infection) with any fever, and daily.
●● For multilumen devices, the antibiotic
infusion should be rotated among the
lumens, as infection may not be limited to
one lumen. If one particular lumen has the
positive blood culture, it is reasonable to run
the majority of the antibiotic(s) through this
lumen. If more than one antibiotic is being
given, they should each be rotated to opti-
mize exposure of the lumens.
●● Daily blood cultures should be obtained
(from each lumen of CVC) for the continu-
ally febrile patient or if growth is present,
until afebrile and negative cultures for 3 days.
●● Assess cardiac valves for vegetations with
an echocardiogram for repeatedly positive
cultures with Gram‐positive organisms.
●● If bacteremia persists for more than 3 days
with appropriate therapy, the catheter
should be removed.
For patients with a history of multiple posi-
tive cultures or a difficult‐to‐eradicate
organism, consideration should be made for
the use of ethanol or vancomycin lock ther-
apy to possibly prevent the need for line
removal. Ethanol locks should not be used
 Management of Fever in the Child with Cancer 341
with polyurethane catheters (PowerLine,
MedComp), as ethanol can damage the
catheter material.
Duration of therapy
Daily determination of the ANC is impor-
tant for patients who have defervesced, and
have negative cultures, to determine the
appropriate length of therapy. When the
neutropenic patient becomes afebrile (no
fever for 24 hours) and cultures are negative
(obtained daily while febrile), broad‐spec-
trum coverage should be continued until
there is evidence of adequate marrow recov-
ery and an appropriate period of therapy for
any initially positive cultures has been pro-
vided (typically 48–72 hours). Resolution of
neutropenia is defined as an ANC of
>0.5 × 109/l and evidence of bone marrow
recovery is an ANC of >0.2 × 109/l and rising
on two consecutive days. Some practitioners
also use an APC of >0.5 × 109/l as sufficient
evidence of recovery from neutropenia, dis-
continue antibiotics, and monitor in the hos-
pital or outpatient setting. Should the patient
have a localized infection, such as diarrhea
or skin breakdown, tailored therapy should
continue, but may be able to be done in the
outpatient setting. The decision to discharge
a patient from the hospital without resolu-
tion of neutropenia must include considera-
tion of risk factors as well as logistics of
outpatient management such as reliable
transportation and compliance with care.
When a pathogen has been identified, its
antibiotic susceptibility pattern must be
determined and appropriate antibiotic cov-
erage provided along with broad‐spectrum
coverage until the patient is afebrile and has
evidence of bone marrow recovery. Once the
child is afebrile and the ANC recovers, anti-
biotics can be tailored to the specific organ-
ism for a 10–14‐day course, with day 1 being
the day of the first negative culture.
Patients that defervesce but do not have
recovery of the ANC should continue on
broad‐spectrum antibiotics to prevent
secondary infection. Some practitioners
may discontinue antibiotics after a period
of time if the patient continues to be neutro-
penic but afebrile, although our general
practice is to continue until there is some
evidence of count recovery.
Empiric antifungal therapy
When FN persists for 4–7 days, empiric
treatment should be broadened to include
fungal prophylaxis. The risk of fungal infec-
tion is directly related to the duration and
severity of neutropenia, which is secondary
to the intensity of chemotherapy or radia-
tion cytotoxicity. Patients with fever for 7 or
more days and associated profound neutro-
penia (ANC <0.1 × 109/l) are at the highest
risk for developing invasive fungal infec-
tion. Thus, patients undergoing more inten-
sive therapy, such as for AML, relapsed
ALL, and hematopoietic stem cell trans-
plantation, are particularly susceptible. The
major causative fungi are Aspergillus and
Candida, with mortality as high as 30–60%
with documented invasive disease. Fungal
infections can be difficult to detect due to
the frequent absence of localizing signs or
symptoms and lack of means of detection
by culture. Prompt diagnostic assessment
and initiation of antifungal empiric therapy
are paramount for improving outcomes in
these patients.
Invasive fungal disease is not uncommon
in the patient undergoing highly immuno-
suppressive therapy. Invasive aspergillosis
(especially Aspergillus fumigatus) may be
associated with isolated pulmonary disease,
with characteristic findings on chest CT
imaging of cavitating lesion or nodules.
Invasive candidiasis is often suspected fol-
lowing positive blood or urine cultures or
342 Chapter 27
suspicious skin lesions, and pan-CT imaging
as well as ophthalmic evaluation should be
done to assess for possible disseminated dis-
ease. Patients with sinus signs and symptoms
may have infection with Zygomycetes sp. (i.e.,
Mucor, Rhizomucor, Rhizopus).
Empiric antifungal therapy prevents
fungal overgrowth in patients with pro-
longed neutropenia. It also provides early
treatment of clinically occult infection.
Clinical trials have found that antifungal
treatment of children with persistent or
recurring fever reduced morbidity and
mortality from invasive fungal disease.
This is especially true in patients with pro-
found neutropenia not receiving antifungal
prophylaxis. The current recommendation
is that high‐risk groups (i.e., those expected
to have neutropenia >7 days) should receive
antifungal prophylaxis during episodes of
prolonged FN.
A meticulous physical examination,
laboratory assessments, and radiographic
studies in search of deep‐seated infections
are also warranted in FN patients with
prolonged unexplained fever (i.e., 4–7
days). Particular attention should be paid
to the skin examination, as it can reveal
fungal nodules. Fungal cultures should be
sent from the blood and urine, as well as
from any suspicious skin site. A serum
galactomannan is done to screen for
Aspergillus infection (also can be done on
urine of fluid from a bronchoalveolar lav-
age, BAL). Serial repetition of this bio-
marker in conjunction with corroborative
clinical and radiographic findings
increases its sensitivity as a useful diagnos-
tic tool. CT imaging of the sinuses, chest,
as well as imaging of other symptomatic
areas (abdomen or pelvis) should be per-
formed. It should be noted that in the
severely neutropenic patient, areas of
infection may not be appreciated on imag-
ing until neutrophil recovery has occurred.
In these cases, the patient will generally
have continued or new fevers with count
recovery that should alert the clinician to
the need for repeat CT imaging.
Risk factors and signs of development of
invasive fungal disease include:
●● Prolonged use of corticosteroids.
●● Persistence of fevers.
●● Prolonged fevers, over 4–7 days, in the
face of severe or profound neutropenia.
●● Recrudescence of fever after neutrophil
recovery.
●● Active graft‐versus‐host disease (GVHD).
●● Development of a new, focal nodular skin
rash or eschar.
●● Development of new respiratory findings
or periorbital swelling.
●● Tenderness over the sinuses and concom-
itant CT findings such as bony erosion.
●● New findings on chest CT (nodules, infil-
trates, cavitation, halo or crescent sign).
●● Shoulder pain.
●● Positive galactomannan (serum, BAL),
especially serial.
●● Positive fungal culture(s) (blood, urine).
Treatment of invasive fungal disease includes
the following antifungal medications:
●● Invasive aspergillosis
○○ Voriconazole IV
■■ 2 to <12 years: 7 mg/kg loading dose
Q 12 hours × two doses followed by
7 mg/kg Q 12 hours.
■■ ≥12 years: 6 mg/kg loading dose Q 12
hours × two doses followed by 4 mg/kg
Q 12 hours.
○○ Voriconazole PO
■■ 2 to <12 years: 8 mg/kg loading
dose × two doses followed by 7 mg/kg BID.
■■ ≥12 years:
●● <40kg: 100mg BID (max. dose 150mg).
●● ≥40kg: 200mg BID (max. dose 300mg).
○○ Posaconazole
■■ >13 years: 400 mg PO BID with meals.
○○ Micafungin 3–4 mg/kg IV Q 24 hours.
○○ Caspofungin 70 mg/m IV loading dose
2
followed by 50 mg/m IV Q 24 hours.
2
 Management of Fever in the Child with Cancer 343
●● Mucormycosis
○○ Liposomal amphotericin B (Ambisome)
3 mg/kg IV Q 24 hours for empirical cov-
erage and 5 mg/kg IV Q 24 hours for
­documented infection.
●● Invasive candidiasis
○○ Fluconazole 12 mg/kg IV loading dose
followed by 6–12 mg/kg IV Q 24 hours.
The echinocandins (micafungin, caspo-
fungin, anidulafungin) have largely replaced
amphotericin B as the empiric antifungal
agent of choice due to their once daily dos-
ing, significantly decreased side effect pro-
file, and broad coverage. Echinocandins are
fungicidal to most Candida species and at
least fungistatic against Aspergillus species.
They also have limited activity against
Fusarium species and Zygomycetes. The tria-
zoles are derivatives of fluconazole with
broad‐spectrum antifungal activity and lim-
ited side effects. Of note, the triazoles are
fungicidal against Aspergillus species. In gen-
eral, we utilize the echinocandins as first‐line
empiric therapy and consider adjustment in
patients that are worsening clinically or have
signs consistent with Aspergillus infection.
Possible drug interactions with extended‐
spectrum azole agents should be considered.
Patients on either an echinocandin or tria-
zole should be monitored closely for hepato-
toxicity; voriconazole may also cause visual
disturbance that is more common in adult
patients. Posaconazole may provide better
coverage against Aspergillus species but is
only available as an oral medication and clin-
ical trial data are limited in younger pediatric
patients.
Viral infection
Immunosuppressed children are able to tol-
erate many viral infections without difficulty.
However, defects in cellular immunity pre-
dispose them to unusually severe infections
with certain viruses, particularly the herpes
family of viruses. Primary varicella infection
is associated with high morbidity and
mortality. In transplant patients, primary
­
infection or reactivation with CMV is an
important cause of interstitial pneumoni-
tis, marrow aplasia, and other infections.
Antiviral drugs are available for a limited
number of infections including HSV, VZV,
CMV, and influenza and should be utilized
in the treatment of immunocompromised
patients. Other patients may also be candi-
dates for prophylaxis (i.e., solid organ trans-
plant patients and patients with a prior
history of infection on therapy).
Patients with documented HSV infec-
tion should be treated with IV or oral
­acyclovir (or valacyclovir) (30 mg/kg/day
if <12 years; 15 mg/kg/day for ≥12 years
divided Q 8 hours for 7–14 days). Dosing for
valacyclovir is 500 mg per os (PO) twice
daily (BID) for patients under 35 kg and
500 mg three times daily (TID) for patients
weighing over 35 kg. Infection with VZV is
potentially life‐threatening and therefore
chemotherapy should be stopped while
treating with IV acyclovir (30 mg/kg/day
divided Q 8 hours for 7–10 days or until all
lesions are crusted and no new lesions have
appeared for 24–48 hours). It is important to
monitor renal function and ensure adequate
fluid intake due to potential nephrotoxicity
from acyclovir.
Patients with symptomatic primary CMV
infection or reactivation can be treated with
ganciclovir (10 mg/kg/day IV divided Q
12 hours for 14 days, then 5 mg/kg/day for
maintenance [beginning after clearance of
CMV PCR], until resolution of viremia by
polymerase chain reaction). Patients with
persistent infection may require longer ther-
apy or may have resistant disease and require
alternate therapy with foscarnet or cidofovir.
Of note, ganciclovir can be myelosuppres-
sive, whereas foscarnet and cidofovir are
quite nephrotoxic. Concomitant therapy
344 Chapter 27
with intravenous immune globulin (IVIG)
may be beneficial especially in the setting of
CMV pneumonitis. Data regarding prophy-
lactic therapy in this setting is lacking,
although once daily dosing (or with oral
valganciclovir) can be considered in
patients that complete a course of antiviral
therapy and remain neutropenic or severely
immunocompromised.
Patients who develop influenza while on
therapy should be treated with neuramini-
dase inhibitors (i.e., oral oseltamivir or
inhaled zanamivir, dosed as below):
●● Oseltamivir
○○ 3–11 months of age: 3 mg/kg once daily.
○○ 1–12 years:
■■ <15 kg: 30 mg once daily.
■■ >15 kg to <23 kg: 45 mg once daily.
■■ >23 kg to <40 kg: 60 mg once daily.
■■ >40 kg: 75 mg daily.
○○ >12 years: 75 mg once daily.
●● Zanamivir
○○ ≥5 years: two inhalations (10 mg) once
daily.
Patients are treated within 48 hours of
exposure for 10 days to reduce symptom
duration and severity of disease. Oseltamivir
may also be given as daily prophylaxis for
5 days to patients that have been exposed to
the virus.
P. jiroveci pneumonia
P. jiroveci (formerly Pneumocystis carinii) is
an atypical fungus and is a ubiquitous organ-
ism that may cause severe or fatal pneumo-
nitis in immunocompromised patients
(most notably patients with HIV and those
being treated for cancer). Patients typically
develop a rapid onset of fever in association
with tachypnea and other symptoms of res-
piratory compromise such as nasal flaring
and intercostal retractions. Lung sounds
may be clear and typically patients do not
have rales. Hypoxemia is evident by pulse
oximetry and arterial blood gas. Chest radi-
ography or CT shows an interstitial pattern.
Without appropriate therapy, patients rap-
idly progress to respiratory failure.
Diagnosis is made by demonstrating the
organism by Gomori methenamine silver
stain on a sample obtained by induced
sputum, BAL, percutaneous needle biopsy,
or open lung biopsy. Patients who are at risk
and present with the classic signs and
symptoms should be treated while awaiting
definitive diagnosis, given the rapidity of
clinical deterioration.
For documented or highly suspected
infection with P. jiroveci, trimethoprim/sul
famethoxazole (TMP/SMX) is the treat-
ment of choice, at a dose based on the
TMP component of 20 mg/kg/day IV
divided Q 12 hours for 14–21 days. If the
patient fails to respond to TMP/SMX
within 72 hours, or develops this infection
while on prior TMP/SMX prophylaxis
with good compliance, initiate therapy
with pentamidine, 4 mg/kg IV daily. In
patients with moderate or severe proven
infection, concomitant administration of
corticosteroids may be beneficial with IV
methylprednisolone or prednisone given
two to four times per day for 5–7 days, fol-
lowed by a taper over 1–2 weeks.
New sites of infection
New or persistent fever and neutropenia
may be associated with the development of
new sites of infection due to continued
severe immunosuppression. Particular
symptoms may provide clues to site and
potential pathogen.
●● Burning retrosternal pain may be esophagi-
tis from Candida sp. or HSV. Cytotoxic treat-
ment may also cause severe pain due to
mucosal erosions. Empiric micafungin or
acyclovir, or both, may be needed. Esophagitis
 Management of Fever in the Child with Cancer 345
may also be bacterial, especially as a result of
Gram‐positive aerobes.
●● Pulmonary infiltrates may be due to
resistant bacteria, Pneumocystis, fungi, or
viruses. Neutropenic patients may not
show evidence of pulmonary infiltrates
due to lack of an appropriate local inflam-
matory response. However, with the recov-
ery of the ANC, these sites of infection
may become evident. If FN has been less
than 7 days, pulmonary infiltrates are very
likely to be of bacterial origin. If the neu-
tropenia persists for greater than 7 days,
the patient is at particularly high risk for
fungal infection. BAL or induced sputum
may identify Pneumocystis, viruses, or
fungi. The risks and benefits of open lung
biopsy and pursuing an aggressive diag-
nostic evaluation must be considered. It is
important to remember that the child may
rapidly become very ill and this decision
must be made expeditiously after discus-
sion among the oncologist, surgeon, radi-
ologist, pulmonologist, as well as the
patient and family.
Other supportive measures
Granulocyte colony‐stimulating factor (G‐
CSF) may be indicated in the setting of FN;
however, there are no specific standards for
its use. A standard dose of 5 mcg/kg/day sub-
cutaneously (or IV) is recommended under
certain conditions in which the clinical
course is likely to worsen before the antici-
pated marrow recovery (see Chapter 25).
Patients who remain severely neutropenic
with life‐threatening infections should
receive G‐CSF. Granulocyte transfusions
may be considered in the setting of profound
neutropenia and sepsis, especially in the face
of an invasive bacterial or fungal infection
that is not improving on appropriate therapy
with expected continuation of profound
neutropenia (see Chapter 5).
Fever in the non‐neutropenic
oncology patient
The febrile, non‐neutropenic patient remains
susceptible to infection secondary to
immune dysfunction related to underlying
malignancy and its treatment, as well as the
presence of an indwelling CVC. As with the
neutropenic patient, these patients should
have a careful assessment with history, phys-
ical examination, and pertinent laboratory
studies including blood cultures from any
in‐dwelling catheters. Patients with localiz-
ing findings should have appropriate diag-
nostic procedures (stool cultures in patients
with diarrhea, brain imaging, and possible
LP for patients with mental status changes,
etc.). Clinical judgment must be utilized to
determine the risk for the patient without an
obvious source of infection. Issues in the
social history such as family reliability, com-
pliance, and ability to travel to the outpa-
tient center should be factored into a
decision plan. If the patient has recently
received chemotherapy and is expected to
reach a nadir in the next few days, consid-
eration should be given to more frequent
assessment or hospital admission given
impending neutropenia and a blunted
response to infection.
As with the neutropenic patient, blood
cultures should be drawn and empiric anti-
biotics initiated. The risk for Pseudomonas
is significantly decreased in the patient
without severe neutropenia and therefore
ceftriaxone IV/IM at 50 mg/kg (maximum
2 g) can be given daily while febrile in the
outpatient setting in the otherwise well‐
appearing child for at least the first 48 hours,
while awaiting results of the blood
culture(s). Hospitalization may be required
in patients who are persistently febrile with
a dropping ANC and in those with a posi-
tive blood culture or the development of
localizing signs.
346 Chapter 27

improving care and focusing research. J. Clin.

Suggested reading Oncol. 30: 4292–4293.
Freifeld, A.G., Bow, E.J., Sepkowitz, K.A. et al.
Lehrnbecher, T., Robinson, P., Fisher, B. et al. (2011). Clinical practice guideline for the use
(2017). Guideline for the management of fever of antimicrobial agents in neutropenic patients
and neutropenia in children with cancer and with cancer: 2010 update by the infectious dis-
hematopoietic stem cell transplant recipients: ease Society of America. Clin. Infect. Dis. 52:
2017 update. J. Clin. Oncol. 35: 2082–2094. e56–e93.
Pulsipher, M.A. (2012). Pediatric specific guide-
lines for fever and neutropenia: a ­catalyst for
28 Acute Pain
Management in the
Inpatient Setting
Pain is a common problem for children with
hematologic or oncologic conditions, as it
can result both from the condition itself and
from its management. A number of studies
have demonstrated that effective pain man­
agement not only increases a patient’s com­
fort level but can also effect long‐term
changes in a patient’s pain threshold, and, in
critically ill patients, it has been demon­
strated to improve morbidity and mortality.
Despite this, other studies have demon­
strated that pediatric pain management is
often suboptimal. This results from percep­
tions on the parts of both parents and care
providers that pain is less frequent or less
severe than is the case, or from concerns of
causing dependence or addiction.
The management of chronic pain is a fre­
quent challenge for pediatric hematologists
and oncologists, but is outside the scope of
this chapter. For pain management at the
end of life, see Chapter 29. For pain manage­
ment in patients with sickle cell disease, see
Chapter 3.
The World Health Organization
analgesic ladder
In 1986, the World Health Organization pre­
sented the analgesic ladder as a framework
Handbook of Pediatric Hematology and Oncology – Children’s Hospital & Research Center Oakland,
Third Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
that physicians could use when developing
treatment plans for cancer pain, paving the
way for significant improvements in its man­
agement. Over the subsequent 30 years, it
has undergone much scrutiny and several
modifications have been proposed. A recent
adaptation is presented in Figure 28.1.
The cornerstone of the ladder rests on
five simple recommendations that remain
valid today:
1. The oral form of medication should be
chosen whenever possible.
2. Analgesics should be given at regular
intervals. It is necessary to respect the
­duration of the medication’s efficacy and to
prescribe doses at specific intervals in
accordance with the patient’s level of pain.
The dose should be adjusted until the
patient is comfortable.
3. Analgesics should be prescribed accord­
ing to pain intensity as evaluated by a scale
of intensity of pain. The prescription must
be given according to the level of the patient’s
pain and not according to the medical staff ’s
perception of the pain.
4. Dosing of pain medication should be
adapted to the individual. The correct
dosage is one that will allow adequate relief
of pain. The dosing should be adapted to
achieve the best balance between the analge­
sic effect and the side effects.
348 Chapter 28
Neurosurgical
procedures
Acute pain
Chronic pain without control
Acute crises of chronic pain
STEP 2
Weak opioids
STEP 1
Nonopioid
analgesics
NSAIDs
Figure 28.1 Adaptation of the World Health Organization analgesic ladder. Abbreviations: NSAID,
nonsteroidal anti‐inflammatory drug; PCA, patient‐controlled analgesia.
5. Analgesics should be prescribed with a
constant concern for detail. The regularity
of analgesic administration is crucial for the
adequate treatment of pain.
It is important to remember that these are
guidelines and that there are situations
where a stepwise approach to pain is not
the best choice for management. For exam­
ple, management of sickle cell vaso‐occlu­
sive crises typically involves early
introduction of step 3 medications without
waiting for the patient to fail steps 1 and 2
therapies.
Assessment of pain
The accurate and reproducible assessment
of pain is essential to effective management,
allowing the provider to determine when
intervention is necessary and to more
objectively measure the response to inter­
vention. However, the subjective nature of
pain and the impact of developmental stage
on the best method of assessment have
STEP 4
Nerve block
Epidurals
STEP 3 PCA pump
Neurolytic block therapy
Spinal stimulators
Strong opioids
Methadone
Oral administration
Transdermal patch
Chronic pain
Non-malignant pain
Cancer pain
NSAIDs
(with or without adjuvants
at each step)
made its measurement a challenge. As a
result, a variety of pediatric pain assessment
scales have been developed to assist in
this process.
Neonates and infants
The Neonatal Infant Pain Scale (NIPS),
developed at the Children’s Hospital of
Eastern Ontario, is a widely used method of
assessing pain in this patient population. It
evaluates a series of six parameters, with a
range of scores between 0 and 7. Scores
above 3 are considered indicative of a pain
level sufficient to require intervention. The
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
respond appropriately or are receiving a
paralyzing agent.
Preverbal/Nonverbal children
Pain assessment for children who are una­
ble to describe their pain or use an interac­
tive pain assessment scale due to young age,
cognitive dysfunction, injury, or medical
­
interventions such as intubation requires an
 Acute Pain Management in the Inpatient Setting 349

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 —

alternative similar to the NIPS that allows
the subjective evaluation of pain‐related
behaviors by another individual. One of the
more commonly used assessment tools is
the Face, Legs, Activity, Cry, Consolability
(FLACC) Behavior Scale. Developed at the
University of Michigan as a tool to assess
postoperative pain, it has been shown to
reliably measure pain in a variety of clinical
situations. It is presented in Table 28.2. The
range of possible scores is from 0 to 10, con­
sistent with other commonly used numeri­
cal rating scales used for older children.
School‐aged and older children
Children 5 years of age and older have been
shown to have the ability to accurately rate
their level of pain using a numerical rating
scale. A commonly used tool is the Wong–
Baker FACES Scale, presented in
Figure 28.2. Developed in the early 1980s,
it remains one of the most widely used
tools for assessing pain in both children
and adults.
When pain assessment scales are used
appropriately, they can be very valuable in
helping the care team know whether their

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
350 Chapter 28
0 2 4 6
No pain Little pain Mild pain
Figure 28.2 The Wong–Baker FACES Pain Rating Scale.
pain management interventions are appro­
priate or need to be adjusted. However, there
is no “magic number” that indicates when
interventions need to be initiated. Studies
consistently show that there is little correla­
tion between a child’s pain score and their
perception as to whether or not they need
pain medication. Therefore, in situations
where patients are likely to have pain, it is
essential to question them regularly regard­
ing their need for medication.
Pain pharmacology
Pain can be subdivided into two categories,
nociceptive and neuropathic. Acute pain in
children is most often nociceptive, and a vari­
ety of drugs can be used to treat this pain.
Much of the information regarding this ther­
apy is empiric, as there are few formal drug
studies for many of these agents, especially in
children less than 12. Nonsteroidal anti‐
inflammatory drugs (NSAIDs), opioids,
muscle relaxants, local anesthetics, and tram­
adol can be used. Some other adjuvant thera­
pies can also be utilized, such as psychological
intervention, distraction, and biofeedback.
When treating pain in neonates, it is
important to remember that several factors
can modify their response and clearance of
drugs. They have increased body water con­
tent and decreased fat, which can alter drug
distribution. A relative increase in blood
flow to the brain and a somewhat “leaky”
blood–brain barrier can cause a prolonga­
tion of drug effect. Renal clearance of drugs
8 10
Moderate pain Severe pain Worst pain
can be relatively decreased up to 1 year of
age. Hepatic enzymes are initially immature,
but these mature quickly. Children 2–6 years
of age develop a larger relative hepatic size
for weight and often metabolize drugs more
quickly than younger or older children; this
can translate to a need for larger doses of
drug given more frequently to achieve ade­
quate analgesia. Variations in age, weight,
blood flow, and organ function can all affect
effective drug dosing.
Step 1 therapy: nonopioid
analgesics
Drugs that are commonly used for step 1
therapy of pain in children are presented in
Table 28.3. These should be first‐line ther­
apy for pain unless the clinical situation
dictates that therapy should begin at a
higher step.
The use of NSAIDs in children with
cancer is generally discouraged due to the
common occurrence of thrombocytopenia
in this population and concern for an
increased risk of bleeding due to an inhibi­
tion of platelet function. However, there
have been no large, controlled trials dem­
onstrating the validity of this concern.
Several clinical trials have demonstrated
that ibuprofen can safely be used following
dental surgery, tonsillectomy, and neuro­
surgery in healthy children and in vitro
data suggest that ibuprofen causes no sig­
nificant prolongation of the platelet func­
tion assay, PFA‐100.
 Acute Pain Management in the Inpatient Setting 351

Table 28.3 Step 1 pain therapy medications.

Drug Dose Comments

NSAIDs • Block conversion of

Ibuprofen 1–3 months: 5 mg/kg 3–4 times daily
3 months–1 year: 50 mg 3 times daily
1–4 years: 100 mg 3 times daily
4–7 years: 150 mg 3 times daily
7–10 years: 200 mg 3 times daily
10–12 years: 300 mg 3 times daily
12–18 years 300–400 mg 3 times daily
Maximum dose 30 mg/kg/day; 2.4 g/day
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
Maximum 5 doses/day; maximum
4 grams/day
arachidonic acid into
prostaglandins and
thromboxanes
• Nonselective; variably impair
platelet function
• Ketorolac can affect renal
function or bone growth with
prolonged use
• Has no antiplatelet effect
• Can be hepatotoxic
• Avoid rectal dosing in
neutropenic patients
• Parenteral form recently
licensed in United States

Abbreviations: NSAIDs, non‐steroidal anti‐inflammatory drugs; IV, intravenous;

IM, intramuscular.

pruritus, constipation, physical tolerance,

Step 2 therapy: weak opioids
Patients whose pain is inadequately con­
trolled with step 1 therapy or who are being
weaned from step 3 therapy require treat­
ment with step 2 agents. In the United States,
the most common agents used are those that
combine acetaminophen with a weak opi­
oid. These include codeine or hydrocodone,
although there is some disagreement about
the inclusion of hydrocodone in the weak
opioid category. Commonly used agents in
this category are presented in Table 28.4.
It is important to remember that the des­
ignation “weak opioid” does not translate to
“without side effects.” The use of codeine
and hydrocodone can cause the same side
effects seen with stronger opioids: respira­
tory depression, hypoxia, nausea, vomiting,
and dependence. Although the Food and
Drug Administration (FDA) classifies them
as Schedule III medications, the risks of
abuse and diversion still exist. In addition,
in 2013, the FDA added a black box warning
contraindicating the use of codeine after
tonsillectomy.
Step 3 therapy: strong opioids
Patients not responding to step 2 therapy or
whose condition indicates the need for
stronger pain therapy at the outset are can­
didates for step 3 therapy. All of the medica­
tions in this category are strong opioids.
They act by binding to μ‐receptors in the
spinal cord and central nervous system
352 Chapter 28

Table 28.4 Step 2 pain therapy medications.

Drug Dose Comments

Codeine 0.5–1 mg/kg q4–6 hours • Comes as 30 and 60 mg tablets

Max: 60 mg/dose
Acetaminophen with 0.5–1.0 mg/kg/dose of codeine
codeine q4–6 hours
Max: 2 tablets/dose; 15 ml/dose
Acetaminophen with >2 years: 0.135 mg/kg/dose
hydrocodone hydrocodone
<40 kg: do not exceed 5 mg
hydrocodone per dose
>40 kg: do not exceed 7.5 mg
hydrocodone per dose
• Up to 35% of children are
inefficient metabolizers of
codeine to morphine; they
will achieve minimal benefit
from this product
• Tablet: 300 mg/15 mg, 300 mg/
30 mg
• 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
• Tablet: 5 mg/500 mg
• Liquid: 7.5 mg/500 mg per
15 ml
• Elixir contains 7% alcohol

(CNS). These receptors are also found
throughout the body, and binding to periph­
eral sites accounts for many of the side
effects seen with opioid therapy. Opioids
vary both by their duration of action and by
the emotional effect they produce.
Meperidine and oxycodone typically cause
euphoria; conversely, morphine more com­
monly causes dysphoria. Equivalent doses of
the strong opioids and the pharmacokinet­
ics of their oral formulations are presented
in Table 28.5.
Oral starting doses of step 3 medications
are presented in Table 28.6. It is important to
remember that patients with severe chronic
pain will often be on doses much larger than
this due to tolerance. Tactics such as opioid
rotation can be used to deal with tolerance
or with side effects resulting from large
doses. N‐methyl‐D‐aspartate (NMDA)‐
receptor upregulation leading to tolerance
with chronic opioid utilization can be miti­
gated through utilization of methadone or,
potentially, ketamine. However, these steps
should be performed under the guidance of
individuals who are well‐versed in such
measures. Transdermal fentanyl has not
been included; practitioners familiar with its
usage should transition patients to this agent
when deemed necessary.
Step 4 therapy
As can be seen in Figure 28.1, step 4 therapy
does not introduce new medications.
Patient‐controlled analgesia (PCA) pumps
are listed; this does not refer to short‐term
PCA pump use such as following surgery or
to deal with postchemotherapy mucositis or
sickle cell vaso‐occlusive crisis. Rather, it
refers to long‐term, ambulatory PCA pump
 Acute Pain Management in the Inpatient Setting 353

Table 28.5 Strong opioid characteristics.

Equianalgesic doses (mg) Pharmacokinetic profile (oral

formulations unless specified)
Medication IV PO Onset Duration
Morphine sulfate 10 30 IV: 2–4 minutes IV: 2–4 hours
IR 20–30 minutes 3–6 hours
CR (MS Contin) 2–4 hours 8–12 hours
ER (Kadian) 1–2 hours 12–24 hours
Hydromorphone 1.5 4.5 20–30 minutes 2–4 hours
Oxycodone 20 20–30 minutes 4–6 hours
IR 2–4 hours 8–12 hours
CR (for regular, not as 2–4 hours 8–12 hours
needed (PRN) use)
Fentanyl 180 mg oral morphine/24 hours = 100 mcg transdermal fentanyl/hour TD: 12–16 hours TD: 48–72 hours
1 mg IV morphine = 10 mcg IV fentanyl IV: 1–5 minutes IV: 0.5–2 hours
Methadone Conversion ratios: • Interindividual variability exists;
• Oral:IV = 2:1 methadone should be used by
• Oral morphine: methadone based on 24‐hour morphine total experienced clinicians only
24‐hour oral morphine Oral morphine: methadone ratio • Doses may need to be decreased after
total (mg) several days of administration; monitor
vital signs daily and consult a specialist
<30 2:1
• May cause QT interval prolongation at
31–99 4:1 higher doses
100–299 8:1
300–499 12:1
500–999 15:1
>1000 20:1

Abbreviations: IV, intravenous; IR, immediate release; CR, controlled release; ER, extended release; TD, transdermal.
354 Chapter 28

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 hours
• Sustained release: for patient
taking >20 mg/day of oxycodone
can administer 10 mg q12 hours
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 hours (mg/ml): 1, 5
PRN for immediate release tablets • Oral solution (mg/ml): 2, 4, 20
or 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 hours; max: 5 mg/dose
Methadone 0.03–0.08 mg/kg/dose PO
q4–6 hours; max: 5 mg/dose

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

use for severe chronic pain. With the
increased availability of highly concentrated
oral narcotics and novel delivery systems,
the use of home PCA therapy has declined
significantly. Additional step 4 therapies
include nerve blocks, epidural injections,
and other alternative interventions routinely
provided by a specialized pain service.
developmentally appropriate terms, mini­
mizing wait times once the patient arrives in
the operating room, child‐friendly waiting
spaces, and cognitive behavioral therapies
(CBT) such as directed imagery, deep
breathing, and role playing. These interven­
tions are typically provided and coordinated
by the child life program.
●● The use of CBT, relaxation therapy, and

biofeedback to decrease the perception of

Nonpharmacologic approaches pain among children suffering from chronic
to pain pain caused by cancer, headache, and
abdominal pain.
The effectiveness of psychological inter­ ●● The use of CBT, relaxation, self‐hypnosis,

ventions to decrease the perception of pain
and the anxiety associated with it, and to
improve the quality of life in patients with
chronic pain, has been clearly demon­
strated in a number of clinical settings.
These include:
●● Minimizing postoperative pain and anxi­
ety through the use of preoperative inter­
ventions before painful procedures. These
include the explanation of the event in
biofeedback, and social support groups to
decrease painful episodes and improve qual­
ity of life in patients with sickle cell disease.
It is vital that child‐life specialists become
involved with children admitted with a pos­
sible diagnosis of cancer very shortly after
admission. Data indicate that psychological
interventions are most effective in decreas­
ing anxiety related to painful procedures
when initiated before the first painful
 Acute Pain Management in the Inpatient Setting 355
experience. It is also important to obtain
input from a psychologist early on for
children with conditions causing chronic
pain so that appropriate interventions can
be started.
Case study for review
You have been following a now 13‐year‐old,
40‐kg male with sickle cell disease (hgb SS)
since he was a newborn. In the first year of
life, he had a few episodes of dactylitis which
required pain medicine and hospital admis­
sion. He then had a relatively asymptomatic
period of time until the last 24 months. Over
the last two years, he has had multiple
admissions for pain control secondary to
chest and back pain. His admissions for pain
have become more complex and of longer
duration during this time. He is now again
admitted for chest pain.
a. What are some initial considerations?
It is not uncommon for patients with
sickle cell disease to have increasing pain
during the adolescent years after a period
of relatively less symptoms. This can be
exacerbated by multiple different factors.
It would be first important to assess that
there are no other concerning findings for
his symptoms other than pain, therefore it
is important to check a chest X‐ray to rule
out acute chest syndrome as well as check­
ing a baseline CBC with reticulocyte
count and complete metabolic panel
(CMP) to ensure he is not having a hyper­
hemolytic episode which would be repre­
sented by a drop in his hemoglobin from
baseline with compensatory elevation in
his reticulocyte count as well as increase
in indirect bilirubin from baseline. WBC
count and platelets are often elevated with
acute vaso‐occlusive pain crisis. If these
studies are reassuring and point to an
acute vaso‐occlusive crisis rather than
additional pathology, the next step is to
better understand his pain and what inter­
ventions have been effective in the past.
For the patient with frequent pain, there
ideally would be a pain contract or pain
plan agreed upon as an outpatient when
well that would be available for the inpa­
tient practitioner as a guide for pain
management.
b. What pain medications would it be
important to begin?
Opioids remain the mainstay of pain man­
agement for vaso‐occlusive events (VOE). It
is important to determine which opioid has
been effective in the past with the least side
effects. Many patients will be treated effec­
tively with morphine, while ­others will pre­
fer hydromorphone due to improved pain
control with decreased nausea. It is impor­
tant to be aggressive at the outset to get on
top of the pain and help to break the pain
cycle. This will allow for more rapid decrease
in pain medication dosing and overall less
pain medication requirement. In the non‐
opioid naïve patient, there is minimal to no
risk of respi­ratory depression with giving
0.1 mg/kg morphine equivalents as the ini­
tial IV bolus doses in the emergency depart­
ment (ED). In this particular case, the
patient should receive 4 mg doses of IV
morphine (or approximately 0.4 mg IV
hydromorphone) based on his weight of
40 kg. Ketorolac should also be initiated as
an adjuvant in the ED. For patients with fre­
quent admissions for pain as well as chronic
opioid ­utilization, we also utilize bolus dos­
ing of ketamine in the ED as well as low‐
dose ketamine infusion on the floor to assist
with pain control and decrease need for opi­
oids. Patients chronically using opioids have
upregulation of the NMDA receptor making
opioids less effective. Ketamine works syn­
ergistically with opioids by antagonizing the
NMDA receptor in addition to anti‐anxiety
and antidepressant properties.
356 Chapter 28
c. What medications should be contin­
ued when the patient is admitted to the
inpatient floor?
If the patient is not able to achieve pain
control after two to three doses of IV opi­
oids in the ED, admission is likely required.
This should be a discussion between the
practitioner and the patient to help deter­
mine what is the best course. If the patient
is being admitted, he should be transi­
tioned to patient‐controlled analgesia. We
typically give 0.05 mg/kg of morphine
equivalents as the push dose without a
basal infusion. We give a 10‐minute lock­
out based on the onset of action (i.e.,
5–10 minutes for IV morphine) and two
push doses per hour. This would be
reported out as 2/0/10/4 (i.e., push dose/
basal dose/lockout time/hourly maxi­
mum). Note these are guidelines and there
must be individual adjustment as needed
based on the patient’s prior history of
response as well as pain plan (if avai­
lable). Adjuvant medications including
acetaminophen and ketorolac should be
continued. We utilize oral diphenhy­
dramine which can treat pruritus with IV
opioids in addition to being synergistic for
pain control.
d. What additional medications and
therapies should be initiated?
Consideration for side effects of pain med­
ications must be considered and therapy
initiated. This includes a bowel regimen
for prevention of opioid‐induced constipa­
tion as well as a H2 blocker for gastric pro­
tection with toradol. The patient should be
started on incentive spirometry to pre­
vent atelectasis and the development of
acute chest syndrome (ACS). The patient
should be encouraged to get out of bed as
much as possible. Warm packs may be of
benefit. Complementary therapies should
also be initiated, as available. We typically
utilize transcutaneous electrical nerve
stimulation (TENS), massage therapy,
immersive virtual reality therapy, and acu­
puncture (as available).
e. What other considerations are impor­
tant in the patient with frequent pain
admissions?
This patient has developed chronic pain,
which requires complex management by a
multidisciplinary team. Psychology should be
involved to help explore stressors and other
pain exacerbators and how to mitigate these
symptoms. Psychology may be able to provide
biofeedback and cognitive behavioral therapy
to help patients better understand their pain
as well as methods to decrease their pain.
Regular follow‐up is required. There may be
benefit to being on chronic pain medications
(i.e., methadone, Neurontin, amitriptyline,
and others) or antidepressants. Involvement
of a pain specialist is also vital. Utilizing thera­
pies which minimize opioid utilization as
much as possible are important. In the patient
with sickle cell disease, it is also important to
initiate medical therapies to aid in decreasing
pain such as chronic transfusion or hydroxyu­
rea therapy. Practitioners should be familiar
with the concepts of allodynia and hyperalge­
sia and recognize that chronic pain presents
very differently than acute pain. There
remains significant implicit and explicit bias
in the treatment of patients with chronic pain,
and the practitioner must be cognizant of
these issues which may impact the patient
from receiving ideal medical management.
Multiple choice questions
1. You are taking care of a 5‐year‐old boy
with metastatic neuroblastoma. He has
diffuse bony metastases and is complaining
of pain in his extremities which he describes
as “throbbing and sharp.” Based on this
presentation and description, his pain is
most likely to be:
a. Somatic
b. Visceral
 Acute Pain Management in the Inpatient Setting 357
c. Neuropathic
d. None of the above
Explanation: While there are several catego­
ries of pain, visceral and somatic pain are
two of the main subtypes. Pain from bony
metastases is typically somatic pain, often
described as “sharp, squeezing, throbbing.”
On the contrary, visceral pain is not well
defined and the patient often uses the terms
“dull, aching” to describe it. Visceral pain is
caused due to stretching, blockage or irrita­
tion of visceral organs in the chest, abdomen
and pelvis. The answer is a.
2. You are taking care of a 7‐year‐old girl
with rhabdomyosarcoma who is receiving
chemotherapy with a regimen that includes
vincristine. She has been increasingly com­
plaining of “burning” pain in her hands and
legs. Which of the following are appropriate
treatment options for her?
a. Venlafaxine
b. Amitriptyline
c. Gabapentin
d. Tramadol
e. Low dose ketamine
f. All of the above
Explanation: This patient is describing
neuropathic pain most likely caused due to
chemotherapy induced peripheral neuropa­
thy. The most likely chemotherapeutic agent
involved in her case would be vincristine.
Neuropathic pain in children with cancer
can be treatment‐related (such as due to
Vinca alkaloids) or due to the disease pro­
cess itself. Neuropathic pain can be difficult
to describe, especially for younger children.
Typical descriptions can include “burning,
numbing, stabbing.” Physical exam may
reveal signs of peripheral neuropathy. Treat­
ment options for neuropathic pain include
anti‐epileptics (such as gabapentin), TCAs
(amitriptyline) and certain opioids such as
tramadol. Serotonin‐norepinephrine recep­
tor uptake inhibitors such as venlafaxine
(Effexor) have been shown to be beneficial
in adult studies for diabetic neuropathy.
Ketamine is a NMDA receptor antagonist
and low dose ketamine can be beneficial in
neuropathic pain. Strong pain stimuli acti­
vate NMDA receptors causing hyperexcita­
bility of dorsal root neurons. This induces
central sensitization, wind‐up phenomenon
and pain memory. NMDA‐receptor antago­
nism may prevent the induction of central
sensitization caused by stimulation of
peripheral nociception, as well as block the
wind‐up phenomenon. The answer is f.
3. You are seeing a 15‐year‐old boy with
diffusely metastatic multiply relapsed rhab­
domyosarcoma. The family has agreed to
allow natural death and is he is now receiving
home hospice care. His pain is increasingly
difficult to control. He has had chronic
diffuse body pain and is on > 60mg of oral
morphine a day. He is also having trouble
swallowing pills and liquids. A good analge­
sic option for him would be:
a. Subcutaneous morphine
b. Oral methadone
c. Transdermal fentanyl
d. Intranasal fentanyl
Explanation: Fentanyl is the only opioid
available in the transdermal formulation in
the United States. It is highly potent (about
80‐100 times more than morphine).
Transdermal fentanyl is not used as the ini­
tial opioid for pain management in the opi­
oid naïve patient. It is a good option for
patients with chronic pain who are tolerant
to high doses of morphine. A child must be
tolerant to 30–60 mg per 24‐ hours oral
morphine equivalent before being able to be
rotated to the smallest fentanyl patch, 12.5
mcg/hr. Due to pre‐set patch doses, it can be
difficult to titrate the dose of a fentanyl
patch. Because of a long onset time, inability
to rapidly titrate drug delivery and long
elimination half‐life, transdermal fentanyl is
contraindicated for acute pain management.
The patient in the vignette clearly has
358 Chapter 28
chronic pain, high opioid tolerance and dif­
ficulty taking oral medications. Transdermal
fentanyl patch will be a good analgesic option
in this situation. Oral methadone is the ideal
choice in the patient still able to take oral
medications. Intranasal fentanyl is very
short acting and is only beneficial in acute
pain scenarios. The answer is c.
4. You are taking care of a 4‐year‐old boy
with newly diagnosed medulloblastoma. He
underwent a gross total resection with a VP
shunt placement and is due to begin chemo­
therapy in a few weeks. His family requests a
palliative care consult and has several
questions for you. All the following are true
regarding pediatric palliative care EXCEPT:
a. Palliative care is not an option when
a child is receiving disease directed
treatment
b. Palliative care teams can provide
comprehensive physical, mental and
spiritual support to the child as well as
his family
c. Palliative care can be initiated at the
time of diagnosis of a chronic illness,
clinical worsening of an illness or at the
end of life
d. Palliative care can be provided in an
inpatient, outpatient or home setting
Explanation: WHO has laid down guiding
principles and definitions for pediatric pal­
liative care. Pediatric palliative care be initi­
ated at the time of diagnosis of a chronic or
life threatening health condition. Receiving
disease directed treatment is NOT a con­
traindication to simultaneously receive pedi­
atric palliative care. While it can be easy to
confuse pediatric palliative care with “end of
life” or “hospice care,” these are in fact sub‐
categories of pediatric palliative care. For the
patient in our clinical vignette, a pediatric
palliative care consult can be initiated now if
the family so wishes. The palliative care team
is usually multi‐disciplinary and can include
combinations of medical providers, nurses,
social workers, psychologists and spiritual
personnel. They are equipped to provide
comprehensive care for the child’s body,
mind and spirit. Providing support to the
family is also a major function of a pediatric
palliative care team. This support can also
extend after the death of a patient with
bereavement care. The answer is a.
5. You are following an inpatient with
chronic, worsening pain from bony metas­
tases. The patient is currently on high dose
dilaudid PCA with a basal rate of 2 mg and
pushes of 1 mg. The patient is pushing the
PCA about 15 times per day with tolerable
pain. The patient is starting to have worsen­
ing opioid side effects including myoclonus
from the high dose PCA. You are planning
on switching to PO methadone so that the
patient can be discharged for home hospice.
What is the most appropriate BID oral dos­
ing of methadone given the patient’s daily
dilaudid requirement?
a. 10 mg
b. 30 mg
c. 50 mg
d. 100 mg
e. 200 mg
Explanation: When calculating opioid con­
version it is best to first consider the mor­
phine equivalence and then re‐convert to
the new opioid. In this case, the patient is
taking 63 mg of dilaudid per day (24 hours ×
2 mg + 1 mg x 15 pushes). The morphine to
dilaudid conversion is 6.67 (see Table 28.5).
Therefore, the daily IV morphine equivalent
is 420 mg of morphine, which is 1260 mg of
oral morphine (IV to oral morphine conver­
sion of 1:3). Therefore, based on Table 28.5,
oral morphine of >1000 mg converts at a
ratio of 20:1 with methadone, which in this
case is 1260 divided by 20 or 63 mg of oral
methadone per day (note this is only coinci­
dentally the same dose of IV dilaudid). Also
 Acute Pain Management in the Inpatient Setting 359
note the 2:1 oral to IV conversion ratio for
methadone. Methadone will concentrate in
fat over time allowing for steady state and
effective daily dosing (somewhat less likely
in the cachectic cancer patient). Patients
should generally be started on twice or
thrice daily methadone and then weaned to
daily or twice daily methadone at the same
total daily dose. The answer is b.
Suggested reading
Friedrichsdorf, S.J. and Kang, T.I. (2017). The
management of pain in children with life‐
limited illnesses. Pediatr. Clin. North Am. 54:
645–672.
Verghese, S.T. and Hannallah, R.S. (2010). Acute
pain management in children. J. Pain Res. 3:
105–123.
29 Palliative Care
The World Health Organization defines
pediatric palliative care as care that “aims to
improve the quality of life of patients facing
life‐threatening illnesses, and their families,
through the prevention and relief of
suffering by early identification and
treatment of pain and other problems,
whether physical, psychosocial, or spiritual.”
It is the active total care of the child’s body,
mind, and spirit, and also involves giving
support to the family. It begins when illness
is diagnosed, and continues irrespective of
whether or not a child receives disease‐
directed treatment. It requires that health
providers evaluate and alleviate a child’s
physical, psychological, and social distress at
all times during their treatment. To be
effective, it requires a broad multidisciplinary
approach that includes the family and makes
use of available community resources.
However, it can be successfully implemented
even if community resources are limited.
Palliative care can and should be provided in
tertiary‐care facilities, community health
centers, and at home.
This definition contains several concepts
that deserve consideration. It contains the
broadly defined term “life‐threatening” that
includes situations in which a cure is
possible, instead of the more limited “life‐
limiting” that includes only those conditions
for which there is no realistic hope of cure.
There is a role for palliative care for all
children diagnosed with cancer, even those
Handbook of Pediatric Hematology and Oncology – Children’s Hospital & Research Center Oakland,
Third Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
whose cancers have an excellent prognosis
with appropriate therapy. It also applies to
the large number of children with life‐
threatening non‐oncologic conditions. The
definition stresses the importance of “early
identification and treatment of pain and
other problems.” Palliative care is not
synonymous with “end‐of‐life” care;
palliative care must begin at the time of
diagnosis and continue on throughout the
period of disease‐directed therapy. It also
must include many resources from
throughout the patient’s and family’s range
of experience: physicians, nurses, social
workers, psychologists, spiritual counselors,
and a variety of other support personnel
chosen because of each child’s unique
situation. During any hospitalization, an
important responsibility of the medical
team is to ensure that each child has access
to all needed services and is being supported
to the greatest extent possible.
Individualized care planning
and coordination
At the time of diagnosis, parents and car-
egivers of children with life‐threatening ill-
ness have two goals: a care‐directed goal of
cure and a comfort‐directed goal of decreas-
ing suffering. Introducing palliative care
principles early on in the care process is
respectful and supportive of these goals. A
362 Chapter 29

model developed by the Palliative and End‐
of‐Life Care Task Force at St. Jude Children’s
Research Hospital, the Individualized Care
Planning and Coordination Model is
designed to facilitate this introduction
(Figure 29.1). Although developed to assist
in making care decisions for children under-
going bone marrow transplantation, the
model is useful in helping to define what care
options are acceptable to the patient and
family given the prognosis and goals of treat-
ment. Key concepts in this model include the
establishment of a close and caring relation-
ship with the patient and family, clarifying
patient and family values and priorities,
determining the goals of care based on the
patient’s and family’s understanding of prog-
nosis, and allowing them to choose from

Eligibility

Step 1 : Relationship

Understanding Sharing
illness Relevant
Experience Information

Needs assessment

Step 2 : Negotiation

Prognosis Goals

Treatment
options

Step 3 : Plan

Medical plan Life plan

Comperhensive
Care Plan

Action
(Care Coordination)
Figure 29.1 The Individualized Care Planning and Coordination Model. Source: From Justin N. Baker,
Pamela S., Integration of Palliative Care Practices into the Ongoing Care of Children with Cancer:
Individualized Care-Planning and Coordination, Pediatric Clinics of North America Pediatric
Clinic, 2008. Reproduced with permission from Elsevier.

available goal‐directed treatment options.
From this foundation, the members of the
care team can coordinate the provision of
care to ensure the social, psychological, and
emotional needs of the patient and family are
addressed at the same time that appropriate
medical care is provided.
End‐of‐life care
Despite the tremendous advances made in
the care of children with cancer over the
past 50 years, at the present time one in five
children diagnosed with cancer will ulti-
mately die of their disease. The death of a
child affects the physical and psychological
well‐being of family members for the rest of
their lives. Events occurring around the
time of death, both positive and negative,
play a critical role in defining how family
members grieve and ultimately come to
terms with the event. Families who have lost
a child have identified several needs regard-
ing end‐of‐life care. These include the need
to have complete information honestly com-
municated, to have easy access to essential
staff members who will be supportive, to
have assistance in coordinating necessary
services, to have their relationship with their
child maintained as much as possible, and to
be allowed to feel that their child’s life and
death have meaning.
Research studies involving pediatric
palliative care are limited, but they have
identified several important shortcomings
in the level of palliative care provided to
children. Several studies have demon-
strated a lack of successful management of
pain and other distressing symptoms.
Other studies have demonstrated that the
majority of children dying of life‐threaten-
ing diseases die in the hospital, often in the
intensive care unit (ICU). The impact of
this outcome on the appropriateness of care
provided and its effect on the family’s
Palliative Care 363
bereavement process are not totally clear.
Studies have also demonstrated that
­significant levels of parental dissatisfaction
with hospital staff can arise from confus-
ing, inadequate, or uncaring communica-
tion regarding treatment and prognosis as
well as discrepancies between parents and
care providers in understanding the termi-
nal condition. When a language barrier
exists between family and staff, these prob-
lems are often exacerbated.
Common symptoms at the end
of life
Pain
Parents and caregivers report that their
child’s pain is the symptom they fear most. A
large survey of parents whose children died
of cancer revealed that 75% of them felt their
child suffered pain at the end of life, but only
37% felt the pain was successfully managed.
The principles of pediatric pain man-
agement are presented in Chapter 28 and
pain management at the end of life follows
these same principles. However, it becomes
particularly important to clarify and
understand the goals of treatment as eluci-
dated by the patient and parents. The desire
to maintain alertness and interaction early
in treatment may give way to a desire to
keep the patient comfortable, even if it
means the patient will be more sedated and
less aware. Acceding to the family’s wishes
that the patient not be hooked up to moni-
tors might outweigh concern that the doses
of pain medications being used could result
in respiratory depression. These decisions
often run counter to what physicians see as
their primary goal of care, to prolong life as
long as possible. Working through some of
these difficult philosophical issues with the
help of a mentor can be essential to work-
ing comfortably and effectively in this type
of setting.
364 Chapter 29
Nausea and vomiting
Nausea and vomiting at the end of life can
be triggered by many different stimuli. A
variety of toxins such as medications and
their metabolites, urea resulting from renal
failure, or metabolic byproducts of hepatic
failure can all stimulate the chemoreceptor
trigger zone and cause nausea. Increased
intracranial pressure (ICP) and a variety of
emotional and sensory stimuli can mediate
nausea and vomiting through cortical path-
ways. The gastrointestinal (GI) tract can
stimulate the vomiting center in response to
local receptor stimulation caused by
obstruction, stasis, toxins, or drugs. In addi-
tion, pharyngeal stimulation by mucus or
mucosal breakdown can also trigger the
vomiting center.
Table 29.1 Management of nausea and vomiting.
Step Objective
1 Attempt to identify causes
2 Initiate environmental changes
3 Clarify scope of interventions
that will be acceptable to
patient and family
4 Choose treatment based on
etiology and goals of care
Abbreviations: NSAIDs, nonsteroidal anti‐inflammatory drugs; ICP, intracranial pressure.
A stepwise approach to the manage-
ment of nausea and vomiting in the palli-
ative care setting is outlined in Table 29.1.
A key feature of this approach is to ensure
that the interventions selected are in
keeping with the patient’s and family’s
goals of care.
A number of medications can be tried to
control nausea and vomiting. The ideal
agent is one that targets the specific cause of
the patient’s distress if such an agent can be
identified. A list of useful medications is
outlined in Table 29.2.
Opioids frequently cause nausea and
vomiting due to a direct effect on the chem-
otherapy trigger zone or secondarily to their
effect on GI motility leading to gastroparesis
and constipation.
Intervention
History (timing, quality, severity of nausea;
description of vomiting)
Physical exam focused on neurological, abdominal
symptoms
Medication history (opioids, chemotherapy,
antibiotics, NSAIDs, other drugs)
Small meals
Minimize strong smells
Create a comfortable environment
Provide support for emotional distress
Discuss goals of care with patient and family
Chemically induced: stop medications if possible,
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
consistent with goals of care; medical
management (steroids, octreotide, opioids with
scopolamine, haloperidol)
Other/unknown cause: trial of antiemetics
 Palliative Care 365

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

dopamine antagonist)
Ondansetron (serotonin receptor
antagonist)
Scopolamine (anticholinergic)
Meclizine (antivertigo agent)
Dexamethasone (anti‐inflammatory)
Dronabinol (cannabinoid)
Lorazepam (benzodiazepine)
6 hours
Dopamine antagonist (antiemetic) dose: 0.5–1
mg/kg/dose
IV or orally every 6 hours; use with diphenhydramine
to prevent extrapyramidal symptoms
0.45 mg/kg/day IV or orally; may be dosed once daily
or divided every 8 hours
For children >40 kg: 1.5 mg patch behind ear every
72 hours
For children >12 years of age: 25–75 mg/day orally in
up to three divided doses
Antiemetic: 10 mg/m2 IV or orally daily; maximum
dose 20 mg daily
Increased ICP: increase dosing frequency to two–four
times daily, with a maximum dose of 40 mg/day
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
0.025 mg/kg/dose IV or orally every 6 hours

Abbreviations: IV, intravenous; ICP, intracranial pressure.

Constipation activity, neurological dysfunction, and intes-

Constipation often causes pain and distress
for children at the end of life, both physically
and psychologically. Prevention of constipa-
tion should therefore be a primary goal of
end‐of‐life care.
tinal obstruction due to presence of tumor.
Assessment
History
●● Stool frequency, consistency, and associ-

One of the most common causes of con- ated discomfort.

stipation are opioids, which decrease GI ●● Abdominal pain, nausea, vomiting, and

motility and fluid secretion, leading to hard, anorexia.

dry stools. Unlike other narcotic side effects, ●● Neurological symptoms: urinary prob-

constipation does not seem to decrease with lems, lower extremity numbness, weakness,
ongoing use. Patients and families should be and paresthesias.
informed ahead of time about this side ●● Diarrhea (signs of encopresis or
effect, as children in severe pain may not obstipation?).
consider regular bowel movements a prior- ●● Prior episodes, previously effective therapies.

ity. Once well established, constipation may

require quite aggressive and unpleasant Physical Examination
therapies to correct it. ●● Abdominal palpation.
Other factors that contribute to constipa- ●● External rectal exam (digital exam rarely
tion in terminal patients include poor oral needed and may be dangerous).
intake of fluids and food, decreased physical ●● Neurologic exam.
366 Chapter 29

Medications Table 29.3 Appetite stimulants for cancer‐

●● Stool softeners (docusate): rarely effective associated anorexia.
alone.
●● Osmotic agents (MiraLAX, magnesium Drug Dose
sulfate, and lactulose): effective for long‐
Cyproheptadine 2–6 years: 2 mg BID
term use; MiraLAX requires 4–8 oz. of fluid
(Periactin) >6 years: 4 mg BID
which can be a limitation. Megestrol acetate 7.5–10 mg/kg/day in 1–4
●● Stimulants (senna, bisacodyl): often use-
(Megace) divided doses
ful and necessary in the end‐of‐life setting Maximum 800 mg/day
when less concern exists regarding develop- or 15 mg/kg/day
ment of dependence. Dronabinol 2.5 mg/m2/dose every
(Marinol) 4–6 hours
Use with caution in
Anorexia and weight loss children with
depression; avoid in
children with
Anorexia or loss of appetite is a familiar
sensitivity to sesame oil
symptom in children with cancer. It can
occur at any point in treatment; institu-
tional studies indicate that it affects as many
as 40% of children with cancer at diagnosis Support for emotional distress.
and the prevalence increases to as high as Discontinue medications that might be
70% in children with advanced‐stage dis- causing anorexia.
ease. Early in treatment it is most often a
side effect of chemotherapy or radiation, or Step 3: more aggressive
a result of stomatitis, dysphagia, constipa- therapies (if consistent with
tion, pain, or depression. As the child’s can- plan of care)
cer becomes progressive, it is often a Medications (see Table 29.3).
component of the anorexia/cachexia syn-
drome, a complex set of central nervous Nutritional supplementation
system (CNS) and metabolic abnormalities If acceptable to patient and family, enteral
caused by a combination of tumor byprod- feeding with a nasogastrostomy (NG) or
ucts and host cytokine release. gastrostomy tube is often reasonably well
tolerated unless the patient has a GI obstruc-
Step 1: assessment tion or is chronically nauseated.
State of primary disease. Total parenteral nutrition (TPN) is
Diet and fluid history. rarely useful in the end‐of‐life setting
Nausea/vomiting/constipation. except for short‐term use in the patient
Oral lesions (including candidiasis). with GI obstruction.
Medication history.
History of prior eating disorder.
Sense of smell. Fatigue

Step 2: environmental changes The National Comprehensive Cancer

Small meals. Network defines cancer‐related fatigue as
Regular mouth care. “a distressing persistent, subjective sense
Comfortable environment. of physical, emotional, and/or cognitive

tiredness or exhaustion related to cancer
or cancer treatment that is not propor-
tional to recent activity and interferes
with usual functioning.” It is pervasive,
multidimensional, and incapacitating; as
such it significantly decreases health‐
related quality of life in children. While it
can exist throughout the entire period of
cancer treatment, fatigue is most often
seen as significant as the child’s disease
progresses. In several studies, parents
have identified fatigue as the most signifi-
cant symptom that moderately or severely
impacted their child’s well‐being toward
the end of life. These same studies have
also demonstrated that it is the symptom
most likely to be missed by care providers;
fewer than 50% of children whose parents
described them as suffering highly from
fatigue had this documented in their med-
ical record.
Cancer‐related fatigue is more common
and more severe in children with brain tumors
than in those with other cancers. Pediatric
patients tend more often to associate their feel-
ings of fatigue to sleep disturbance or side
effects of therapy, whereas parents are more
likely to include emotions and nutritional sta-
tus as potential causes. A recent study sug-
gested that pain and dyspnea were frequently
associated with fatigue; the authors postulated
that opioids and benzodiazepines, common
therapies for pain and dyspnea, might have sig-
nificantly contributed to their patients’ fatigue.
In a review on the assessment and man-
agement of fatigue and dyspnea in pediatric
palliative care, Dr. Christina Ullrich defined
a conceptual model for understanding
fatigue in this population. This framework
is outlined in Figure 29.2.
Data are very limited regarding effective
treatments for cancer‐related fatigue in
children, although a number of interventions
have been shown to be effective in adults.
These are outlined in Table 29.4.
Palliative Care 367
Psychosocial and activity‐based inter-
ventions have been shown to be quite effec-
tive in adults with cancer‐related fatigue;
data in children are lacking. Exercise has
the strongest data regarding its value, but
this is largely in adult cancer survivors suf-
fering from fatigue after the completion of
curative therapy. Its utility in ameliorating
fatigue in patients near the end of life is less
well‐established.
Dyspnea
Dyspnea is the term used to describe the
feeling of breathlessness that occurs when
the respiratory system fails to meet the
body’s need for oxygen uptake or carbon
dioxide removal. It occurs under normal
circumstances such as after brisk exercise,
but in pathological conditions it can cause
severe distress. It occurs very frequently at
the end of life, as respiratory failure occurs
very commonly as a terminal event.
Therefore, recognition of dyspnea and its
effective treatment are key components of
end‐of‐life care.
Dyspnea can result from either an
increased metabolic demand or an inability
to maintain a normal minute ventilation.
The former can be caused by complications
of the disease or its treatment, such as infec-
tion, metabolic acidosis, or increased meta-
bolic demands caused by extensive tumor
burden. The latter can result from conditions
such as decreased lung compliance due to
tumor, infection, or fluid, or by other condi-
tions such as interstitial lung disease, ane-
mia, or fatigue.
It follows that treatment of dyspnea
would involve steps to decrease metabolic
demand or improve the efficiency of respira-
tion. However, this can prove to be quite
challenging in practice. It is often difficult to
determine whether the cause of dyspnea is in
368 Chapter 29

Psychosocial factors
• Depression • Familial stressors
• Anxiety • Spiritual concerns
• Fear • Caregiver status
• Boredom • Practical concerns

Sleep disturbance
• Unrelieved symptoms
• Change in environment Fatigue experience
• Circadian rhythm alteration
• Medication effect

Physical factors
• Underlying illness • Metabolic abnormalities
Type, site, stage • Nutritional impairment
Disease-directed treatment Cachexia
• Unrelieved symptoms Dehydration
• Side effects of symptom treatment • Comorbidities
• Changes in muscle Anemia
Deconditioning Infection
Abnormal muscle structure, function Hormone imbalance
Organ dysfunction

Figure 29.2 A model of fatigue in life‐threatening illness. Source: Modified from Fatigue in Children
with Cancer at the End of Life, Journal of Pain and Symptom Management.

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.


fact respiratory or metabolic, and once dis-
covered, the unwillingness of the patient or
family to accept certain interventions can
create additional challenges for the treat-
ment team.
Appropriate therapies to decrease meta-
bolic demand depend on the cause of the
increased demand. For the patient who
becomes dyspneic with activity, it may be as
simple as recommending that the patient use
a wheelchair instead of walking or decrease
physical activity in other ways. Increased
metabolic demand caused by infection or
inflammation can be treated with aggressive
use of antibiotics or anti‐inflammatory
agents, as long as such therapies are in keep-
ing with the patient’s and family’s wishes.
Respiratory failure can result from two
general causes: lung parenchymal dysfunc-
tion and respiratory muscle fatigue or fail-
ure. It is important to distinguish between
these, as the treatments are different. An
algorithm for distinguishing between these
causes is presented in Table 29.5. It is impor-
tant to note that hypercarbia can be a late
finding in parenchymal dysfunction as well.
Treatment
Treatment for dyspnea can be divided into
three general categories: mechanical sup-
port of respiration, support of gas exchange,
and therapies to decrease the sensation of
dyspnea.
Table 29.5 Classification and features of respiratory failure.
Parenchymal dysfunction
Causes Airway obstruction
• Interstitial, bronchial inflammation
• Excessive secretions
External compression
• Pleural fluid
• Pleural‐based nodules
• Infiltration of interstitium by metastases
Blood gas Hypoxemia
findings
Palliative Care 369
Support of respiration
When intubation and mechanical ventila-
tion are not appropriate or acceptable to the
patient and family, noninvasive positive
pressure ventilation (NIPPV) can be useful
in supporting respiration. However, the use
of NIPPV in adult patients who have elected
to forgo intubation or other aggressive
respiratory support is controversial. Its use
in children with cancer is unstudied; there
have been a handful of papers published
regarding its use in children with neuro-
muscular disorders.
From the adult literature, it appears clear
that the most important issue when deciding
on the use of NIPPV to support respiration
is a clear understanding of the goals of
therapy among all involved. In 2007, the
Society of Critical Care Medicine Palliative
Noninvasive Positive Pressure Ventilation
Task Force published its recommendations
on the use of NIPPV in the palliative care
setting. While intended for adults, the con-
cepts can be applied to the pediatric care set-
ting as well. The task force proposed a
three‐category approach to assist in
decision‐making regarding this technology.
An overview of this approach is presented in
Table 29.6.
The key areas of distinction in this model
are goals of care, determination of success,
appropriate endpoints, and response to
­failure. It is imperative that each member of
Muscle failure/fatigue
Neuromuscular disease
• Weak musculature
• Lowered fatigue threshold
• Prolonged recovery time
Abnormal load on
respiratory system; weakness
caused by systemic disease
Hypoxemia, hypercarbia
 370 Chapter 29

Table 29.6 Approach to decision‐making regarding noninvasive positive pressure ventilation.

Approach Category 1 Category 2 Category 3

Definition Life support; no preset limits Life support; do not intubate Comfort measures only
Primary goals of care Assist ventilation and/or oxygenation Includes same as category 1 except Palliation of symptoms (relief
Alleviate dyspnea intubation declined of dyspnea)
Achieve comfort Also could include briefly prolonging
Reduce risk of intubation life for a specific purpose (e.g.,
Reduce risk of mortality arrival of family member)
Avoidance of intubation
Main goals to Goal is to restore health and use Goal is to restore health without using Goal is to maximize comfort
communicate with intubation if necessary and indicated endotracheal intubation and without while minimizing adverse
patient and family causing unacceptable discomfort effects of opiates
Determination of Improved oxygenation and/or Improved oxygenation and/or Improved symptoms
success ventilation ventilation Tolerance of NIPPV
Tolerance of NIPPV or minor Tolerance of NIPPV or minor
discomfort that is outweighed by discomfort that is outweighed by
potential benefit potential benefit
Endpoint for NIPPV Unassisted ventilation adequately Unassisted ventilation adequately Patient is not more comfortable
supporting life supporting life having NIPPV on or wants
Intolerance of NIPPV Intolerance of NIPPV NIPPV stopped
Patient becomes unable to
communicate
Response to failure Intubation and mechanical ventilation Change to comfort measures only and Palliate symptoms without
(if indicated) palliate symptoms without NIPPV NIPPV
Likely location of ICU but may include step down unit or Variable but may include ICU, step Acute care bed but could be
NIPPV acute care bed in some hospitals down unit, or acute care bed applied in hospice by
with appropriately monitored setting appropriately trained
and trained personnel personnel

Abbreviations: NIPPV, noninvasive positive pressure ventilation; ICU, intensive care unit.

the care team agrees on each of these com-
ponents to avoid confusion and conflict
later in the course.
Support of gas exchange
NIPPV can also be used to augment gas
exchange in patients with low lung volumes
in whom the surface area for gas exchange is
reduced and the caliber of the airways is
decreased, increasing the likelihood of
obstruction. Continuous positive airway
pressure and bilevel positive airway pressure
are useful in situations in which the pressure
necessary to maintain airway patency is too
high to allow for efficient exhalation.
In the setting of respiratory failure with-
out hypercapnia, supplemental oxygen is the
most appropriate intervention to facilitate
gas exchange. It is often better tolerated than
NIPPV devices, especially by young chil-
dren, facilitating pulmonary vasculature
dilatation and inhibiting cerebral artery dil-
atation, a frequent cause of headaches. It is
important to remember, however, that
patients with hypercapnic respiratory failure
frequently rely on a “hypoxic drive” to main-
tain respiration. Provision of supplemental
oxygen to these patients can lead to hypo-
pnea or apnea.
Therapies to decrease
the sensation of dyspnea
In end‐of‐life settings, respiratory failure is
often the ultimate cause of death and the
main goal of therapy is minimizing the dis-
tress resulting from the sensation of dyspnea
as this occurs. This goal can be achieved with
a combination of pharmacologic and non-
pharmacologic therapies.
The two most effective classes of drugs
for minimizing the perception of dyspnea
are opioids and benzodiazepines. Morphine
is the opioid used most often for this pur-
pose, but fentanyl and hydromorphone
(Dilaudid) have been shown to be effective
as well. The dose that is required is lower
Palliative Care 371
than what is commonly used for pain; a
morphine dose of 0.025 mg/kg, or an equiv-
alent dose of fentanyl or Dilaudid, is often
effective in the narcotic‐naїve child, and an
increase in the dose by 25% will often be
effective in the child already receiving mor-
phine. The dose should then be titrated to
achieve symptom relief, with no set upper
limit. Benzodiazepines can help with the
anxiety associated with dyspnea; lorazepam
0.05 mg/kg (maximum 2 mg) can be given
every 4–8 hours for this purpose.
A variety of nonpharmacologic inter-
ventions have been shown to decrease the
distress associated with dyspnea. These
include:
1. Cool air blown on the face.
2. Chest wall percussion.
3. Relaxation therapy and counseling.
4. Proper positioning.
5. Limitation of activities.
6. Cooler room temperature.
7. Avoidance of respiratory irritants
(tobacco smoke and cleaning fluids).
Most experts agree that these interventions
work best as an adjunct to pharmacologic
therapy; they are rarely effective alone.
Conclusion
Unfortunately, many questions remain
about how to best care for children who are
destined to die before they reach adulthood.
These include practical issues such as how
to best manage distressing symptoms such
as those listed in the preceding text, how to
best communicate with children about the
dying process and involve them in decisions
regarding their care, and how to avoid
aggressive end‐of‐life therapies that only
delay death and prolong suffering instead of
extending life. After the child’s death,
families must continue to move forward,
raising questions about how best to help
372 Chapter 29
them deal with the bereavement that
inevitably accompanies such an event. It is
fortunate that research into these questions
has expanded greatly over the past few years,
and it is likely that answers to these questions
will soon be available in the medical
literature. The children we care for, but can-
not save, deserve no less.
Case study for review
Julie, a 13‐year‐old girl with widely meta-
static alveolar rhabdomyosarcoma diag-
nosed 6 months earlier, continues to have
extensive bony disease, including possible
new metastatic lung lesions. Julie’s treat-
ment has been complicated by chronic
pain and a challenging family situation.
Although Julie lives with her mother, her
father oversees her care. Her parents do
not get along with one another. They fre-
quently argue and scream in her presence,
which clearly upsets her.
Since diagnosis, her father has adamantly
refused to let caregivers have one‐on‐one
conversations with Julie. He insists on
remaining the only one to relate to Julie any
disease‐related information, as he knows
her best and can gauge how she will react.
He has stated that Julie need not know that
she will likely die of her disease and he has
forbidden the medical team from discussing
issues related to prognosis.
Julie is to undergo a CT‐guided lung biopsy
to determine the nature of the lung lesions.
Her parents state that she is already anxious
enough and do not want the medical team to
tell her about the biopsy or the possibility that
her disease has progressed. Instead, they ask
that Julie be told that she is to be sedated only
for a “scan.” Moreover, should she prove to
have new disease, they do not want Julie to be
informed and ask that her caregivers not dis-
cuss end‐of‐life matters with her.
Questions
●● As Julie’s physician, are you comfortable
with her parents’ approach?
●● Should Julie’s parents prevent her from
knowing information relevant to her disease?
●● How do you reconcile your responsibility
to be forthright with Julie while simultane-
ously being respectful of her parents’ request?
●● If you believe that her parents’ approach is
not in Julie’s best interest, how might you
proceed?
●● Should children with life‐limiting ill-
nesses be involved in end‐of‐life decisions?
Understanding familial adaptation toward
the dying process is imperative. As health
care providers, our goal is to anticipate and
identify problems and to assist dying chil-
dren and their families as they adjust to and
cope with the emotional responses, which
are part of the dying process.
Many children, parents, and physicians
are hesitant to discuss death and dying so
that opportunities for planning how to cope
are often missed. Failure to prepare ade-
quately for death can deprive families of the
chance to enjoy what time they have left
with one another.
Each child and family grieve in their own
unique way, determined by personal experi-
ences with death, religious and cultural
backgrounds, and individual makeup.
Dying is a process and all parties need to
learn to live with dying or, as stated by the
American Academy of Pediatrics, “the goal
[of palliative care] is to add life to the child’s
years, not simply years to the child’s life” [1].
Parents’ natural tendency to protect their
children influences the amount of informa-
tion children receive and the degree to
which they are involved in decision‐making
about their care [2]. Some parents feel that
by giving their child a choice their responsi-
bilities are being usurped, while others per-
ceive including their sick child in decisions

as overly burdensome. For many parents,
the sicker their child, the more they assume
decisional priority and attempt to minimize,
veto, or even preclude their child from hav-
ing a role in decisions at all. Seemingly, such
an approach is understandable; however,
parents need to be aware of the conse-
quences of not preparing their children for
medical outcomes that are inevitable, such
as anxiety, stress, and confusion.
Children frequently know more about
their disease than for which they are cred-
ited. Even when kept in the dark by parents
and providers, children often know that the
endpoint of a life‐threatening illness is
death [3–5]. As children appreciate certain
facts about their diseases and know that they
are dying, it stands to reason that they
should be involved in decisions about their
care so that they can voice their prefer-
ences [6, 7]. Therefore, the question we ask
ourselves should not be “should I tell?”
rather it should be “how do I tell?”
Increasingly, research supports the need for
direct communication between parents,
physicians, and children with life‐limiting
illnesses. This includes discussions relating
to prognosis and even death [1, 2, 8, 9].
Hinds et al. [10] found that children with
life‐limiting cancer between ages 10 and
20 years were capable of participating in
end‐of‐life decision‐making.
Physicians must be aware of the unique
barriers to a child’s ability to participate in
decision‐making as it relates to the dying
process. The first question we must ask is,
“does this child have the ability to understand
that he/she is dying and what dying entails?”
As children mature, their intellectual and
emotional understanding of serious illness
and the prospect of death matures too.
Discussions about death should be honest
and take into consideration the child’s emo-
tional and developmental level. It is impor-
tant to follow the child’s lead [11]. In other
words, answer what children ask and on
Palliative Care 373
their terms. Often, rather than being direct,
a child’s question or statement may be sug-
gestive of something they are uncomfortable
asking and therefore it is vital to determine
what their underlying intention is and not to
give too much or too little information or
answer the wrong question. Finally, failure
to inform and involve children can lead to
feelings of isolation and distress [12].
Ideally, discussions should occur early
and routinely and physicians should reassess
how the child and parents understand the
plan and goals of care. This helps the dying
child and parents make appropriate deci-
sions. Discussions should be in language
that parents and children can understand
and be presented gently, accurately, and
repeatedly. Doing so will help minimize
misunderstandings and defuse conflicts.
The challenge is to do so in a way that is
both sensitive and respectful of the child’s,
parents’, and providers’ needs, needs that are
often in conflict with one another.
According to the Institute of Medicine
(IOM), “conflicts may . . . be productive or
beneficial” [11]. Confronted with a disa-
greement, parties tend to engage in a more
in‐depth discussion allowing for a greater
appreciation of each other’s position, and, in
the process, each side may become more
sensitive to the other’s values and concerns.
Mack et al. [13] surveyed parents of chil-
dren with cancer and found that parents
rated the quality of care provided by physi-
cians more favorably when physicians com-
municated directly with children (when
appropriate). Similarly, in a survey of more
than 400 Swedish parents of children who
died of cancer, Kreicbergs et al. [14] found
that none of the parents who spoke with
their child about death regretted doing so,
whereas more than one‐quarter of parents
who did not speak with their child regretted
not doing so. The latter parent group had
higher levels of anxiety and depression than
parents who did speak to their children.
374 Chapter 29
Parents are not alone in valuing the
importance of direct communication
between children and physicians. Recent
research has shown that children with cancer
consider direct communication between
doctors and children more important than
any other aspect [15]. Nearly 40 years ago,
following parental approval, Nitschke
et al. [4] began including children aged
5 years and older who were near death from
cancer in end‐of‐life discussions. They found
that the majority of children and parents
found the child’s inclusion a positive experi-
ence. They also reported that some children
from whom information was withheld expe-
rienced fear and isolation prior to dying.
Conclusions and practical
suggestions
Situations like Julie’s do not lend themselves
to easy solutions. Dishonesty, evading the
question at hand, inconsistencies, and white
lies are to be avoided at all costs. Deception
is difficult to maintain. When the truth is
ultimately discovered, the patient–parent–
physician relationship is often irrevocably
damaged, an unfortunate circumstance in
any situation, but particularly for a child
such as Julie who is nearing the end of life.
Such action may lead Julie to withdraw and
even to experience feelings of isolation and
fear, let alone profoundly disrespect her
developing autonomy.
By helping to facilitate, clarify, and
resolve areas of contention, pediatricians
can be extremely helpful. As appreciated by
the IOM, the following steps may be useful:
(i) postpone decisions to allow for time to
think about concerns and to discuss goals;
(ii) rather than making definitive decisions
that offer no room for compromise, con-
sider temporary steps that accommodate
each party’s goals; and (iii) periodically
reevaluate each party’s views concerning the
goals of care and the options to achieve
those goals [11].
Case resolution
Since Julie’s diagnosis, her father has peri-
odically sought the guidance of the unit’s
social worker. Prior to the lung biopsy, Julie’s
father agreed to meet with her oncologist
and the social worker in the latter’s office, a
place where he is comfortable speaking.
Following a brief update by the oncologist of
Julie’s current medical status, the social
worker asked her father to share his con-
cerns about Julie not being included in dis-
ease‐related discussions. Her father stated
that Julie is “just a kid,” and that it was “his
job to protect, and to decide what is best for
her.” He recounted his limited parental role
in Julie’s life prior to her cancer diagnosis
and blamed himself for not being more pre-
sent in her life, admitting that Julie’s illness
and likely death “terrify” him and that he is
resolute not to abandon her again.
The social worker asked Julie’s father
what he believes she knows of her disease
and its prognosis. He replied that Julie
knows she has cancer and that it is “treata-
ble,” and nothing more. She then asked if he
would allow Julie to join them, which would
permit the oncologist (in his presence) to
answer any questions she may have about
the “scan” and to clarify what she indeed
knows. Hesitant at first, he ultimately
agreed. After greeting and thanking her for
joining them, the oncologist asked Julie if
she has any questions about the upcoming
CT scan. Julie asked why she has to have
another CT when re-evaluation scans,
including a chest CT, were just completed
one week ago. Directing her words to the
oncologist, Julie asked, “is something
wrong?” Before the oncologist or her father
could reply, Julie stated, “I’ve been online
talking to other kids with cancer. A few of
them said that the only reason to repeat a
scan so soon is to see if the disease is back.”
Without hesitation and still speaking to her
oncologist, Julie said, “I know that most kids
with my kind of cancer die.”

The social worker encouraged Julie and
her father to speak openly and freely.
Tentatively, and with the support of the
oncologist and social worker, they began to
speak to one another and share their respec-
tive concerns and goals. Following their
conversation, Julie’s father cautiously agreed
to include Julie in future discussions. The
oncologist assured both Julie and her father
that although he remains hopeful, her dis-
ease is difficult to cure and that she might
indeed die of her cancer. However, the med-
ical team would continue to treat both her
cancer and her pain, all along adhering to
her and her parents’ wishes.
Successful care of the dying child requires
that health care providers acknowledge fam-
ilies’ emotions, assure families that their
responses are normal, provide a balanced
and honest perspective, and communicate
frequently and consistently.
We would like to acknowledge and thank
Yoram Unguru, MD, MS, MA, for writing
this case and instructor guide. Dr. Unguru is
an attending physician in the Division of
Pediatric Hematology/Oncology, The
Herman & Walter Samuelson Children’s
Hospital at Sinai, and Berman Institute of
Bioethics, Johns Hopkins University.
Suggested reading
Feudtner, C. (2007). Collaborative communica-
tion in pediatric palliative care: a foundation
for problem‐solving and decision‐making.
Pediatr. Clin. North Am. 207 54: 583–607.
Freyer, D.R. (2004). Care of the dying adolescent:
special considerations. Pediatrics 113: 381–388.
Himelstein, B.P., Hilden, J.M., Boldt, A.M., and
Weissman, D. (2004). Pediatric palliative care.
N. Engl. J. Med. 350: 1752–1762.
Kazak, A.E., Rourke, M.T., Alderfer, M.A. et al.
(2007). Evidence‐based assessment, inter-
vention and psychosocial care in pediatric
oncology: a blueprint for comprehensive ser-
vices across treatment. J. Pediatr. Psychol. 32:
1099–1110.
Palliative Care 375
Liben, S., Papadatou, D., and Wolfe, J. (2008).
Paediatric palliative care: challenges and
emerging ideas. Lancet 371: 852–864.
Wolfe, J., Grier, H.E., Klar, N. et al. (2000). Symptoms
and suffering at the end of life in children with
cancer. N. Engl. J. Med. 342: 326–333.
References
1. American Academy of Pediatrics (2000).
Committee on bioethics and committee on
hospital care. Palliative care for children.
Pediatrics 106: 351–357.
2. Bluebond‐Langer, M. (1978). The Private
Worlds of Dying Children. Princeton, NJ:
Princeton University Press.
3. Hilden, J.M., Watterson, J., and Chrastek, J.
(2000). Tell the children. J. Clin. Oncol. 18:
3193–3195.
4. Nitschke, R., Meyer, W.H., Sexauer, C.L. et al.
(2000). Care of terminally ill children with
cancer. Med. Pediatr. Oncol. 34: 268–270.
5. McConnell, Y., Frager, G., and Levetown, M.
(2004). Decision making in pediatric pallia-
tive care. In: Palliative Care for Infants,
Children, and Adolescents: A Practical
Handbook (eds. B. Carter and M. Levetown),
69–111. Baltimore: JHU Press.
6. Informed consent, parental permission, and
assent in pediatric practice (1995).
Committee on bioethics, American Academy
of Pediatrics. Pediatrics 95: 314–317.
7. Spinetta, J.J., Masera, G., Jankovic, M. et al.
(2003). Valid informed consent and partici-
pative decision‐making in children with can-
cer and their parents: a report of the SIOP
working committee on psychosocial issues in
pediatric oncology. Med. Pediatr. Oncol. 40:
244–246.
8. Wolfe, J., Hinds, P., and Sourkes, B. (eds.)
(2011). Textbook of Interdisciplinary Pediatric
Palliative Care. Philadelphia: Elsevier.
9. Himelstein, B.P., Hilden, J.M., Morstad Boldt,
A., and Weissman, D. (2004). Pediatric pallia-
tive care. N. Engl. J. Med. 350: 1752–1762.
10. Hinds, P.S., Drew, D., Oakes, L.L. et al.
(2005). End‐of‐life care preferences of pedi-
atric patients with cancer. J. Clin. Oncol. 23:
9146–9154.
376 Chapter 29
11. Field, M.J. and Behrman, R.E. (eds.)
(2003). When Children Die: Improving
Palliative and End‐of‐Life Care for Children
and Their Families. Committee on Palliative
and End‐of‐Life Care for Children and
Their Families. Board on Health Sciences
Policy, Institute of Medicine. Washington,
DC: National Academies Press.
12. Sourkes, B. (1995). Armfuls of Time: The
Psychological Experience of the Child with a
Life‐Threatening Illness. Pittsburgh:
University of Pittsburgh Press.
13. Mack, J.W., Hilden, J.M., Watterson, J. et al.
(2005). Parent and physician perspectives on
quality of care at the end of life in children
with cancer. J. Clin. Oncol. 23: 9155–9161.
14. Kreicbergs, U., Valdimarsdottir, U., Onelov,
E. et al. (2004). Talking about death with
children who have severe malignant disease.
N. Engl. J. Med. 351: 1175–1186.
15. Unguru, Y., Sill, A., and Kamani, N. (2010).
The experiences of children enrolled in pedi-
atric oncology research: implications for
assent. Pediatrics 125: e876–e883.
30 Chemotherapy Basics

Chemotherapeutic agents have multiple

Arsenic trioxide (ATO)
mechanisms of action and many potential
side effects. In order to be prepared for the
ATO is a naturally occurring substance in
potential complications, we discuss the
the Earth’s crust as well as soil, rock, water,
most common pediatric agents, their
and air, and is also found in shellfish.
mechanisms of action, the types of malig-
nancies for which they are utilized, and
Mechanism of action
finally, the most likely side effects. We dis-
ATO impacts multiple signal induction
cuss how best to monitor for these adverse
pathways and specifically leads to degrada-
events, and how to manage them should
tion of the PML–RARα fusion protein in
they occur. Note that side effects from
acute promyelocytic leukemia (APL), lead-
chemotherapy are numerous and we detail
ing to differentiation of promyelocytes.
some of the more common ones rather
than provide a comprehensive list; further
Utilization
reading may be required in appropriately
APL
diagnosing and managing a patient. We
also include common immunobiological
Side effects, monitoring,
agents which are more targeted and there-
and treatment
fore may have less off‐target effects.
Patients with APL utilizing ATO may
Emetogenic potential of common pediatric
undergo differentiation syndrome in induc-
agents is included in Chapter 25. The
tion as well as elevated white count (i.e.,
majority of agents are dosed depending on
WBC count >10 × 109/l), which should be
the patient’s body surface area (BSA) rather
treated with early initiation of steroids.
than weight, especially for patients older
Differentiation syndrome leads to cardio-
than 1 year of age. Multiple formulas exist
pulmonary distress and may also include
for the calculation of BSA; we prefer the
hypoxemia, fever, rash, pulmonary infil-
Mosteller formula:
trates and effusion, pericardial effusion,
weight gain, peripheral edema, renal failure,
Height cm Weight kg heart failure, and hypotension. Patients
BSA
3600 should be monitored for prolongation of the

Handbook of Pediatric Hematology and Oncology – Children’s Hospital & Research Center Oakland,
Third Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
378 Chapter 30
QTc interval. Allergic reaction to ATO may
occur as well as fatigue, pain, peripheral
neuropathy, fever, chills, nausea, vomiting,
constipation, and diarrhea.
Asparaginase
Asparaginase comes in three forms in the
United States: L‐asparaginase (Elspar®),
polyethylene glycol (PEG)‐asparaginase
­ for at least 1 hour after injection or infusion.
(Oncaspar®), and Erwinia (Erwinase®).
Asparaginase is a naturally occurring
enzyme produced by many microorganisms.
In the L‐asparaginase and PEG‐asparaginase
forms, the enzyme is produced by Escherichia
coli, whereas the Erwinia form is produced
by Erwinia chrysanthemi. PEG‐asparaginase
is a modified form of L‐asparaginase with a
much longer half‐life resulting from its cova-
lent binding to PEG, allowing the same ther-
apeutic effect from fewer doses.
Intramuscular (IM) PEG‐asparaginase has
been replaced with intravenous (IV) as the
standard of care, as there has not been clear
increased risk of antibody formation or ana-
phylaxis. Since Erwinia is produced by a dif-
ferent microorganism, it is immunologically
distinct and can be utilized in patients that
have had a hypersensitivity reaction to the E.
coli forms. Erwinia is only available in an IM
formulation and has not yet been pegylated.
Mechanism of action
L‐asparagine is a nonessential amino acid
that cannot be synthesized by malignant cells
of lymphoid and myeloid origin. Asparaginase
depletes L‐asparagine from leukemic cells by
catalyzing the conversion of L‐asparagine to
aspartic acid and ammonia.
Utilization
Acute lymphoblastic leukemia (ALL)
Acute myelogenous leukemia (as rescue
post‐cytarabine)
Non‐Hodgkin lymphoma
Side effects, monitoring,
and treatment
The most immediate side effect from asparagi-
nase compounds is an allergic reaction that
can range from local irritation to anaphylaxis.
Premedication with diphenhydramine and
famotidine is becoming more routine as aspar-
aginase levels can be monitored to ensure a
therapeutic level and no silent antibody devel-
opment. Patients should be monitored closely
Based on the level of allergic symptoms, treat-
ment can range from an antihistamine such as
diphenhydramine to treatment of anaphylaxis
with steroids, an antihistamine, an H2 blocker
(i.e., famotidine), and epinephrine. A com-
mon later side effect is coagulopathy second-
ary to decreased synthesis of antithrombin III
(ATIII), fibrinogen, and other clotting factors.
Currently, routine monitoring of ATIII and
fibrinogen and repletion of low levels are not
recommended without clinical symptoms.
Rare side effects that should be considered
include pancreatitis, thrombosis, and seizures.
Azacitidine/decitabine
Azacitidine and decitabine are pyrimidine
analogs.
Mechanism of action
Azacitidine and decitabine block or decrease
the methylation of cytosine leading to DNA
hypomethylation.
Utilization
Acute myelogenous leukemia
Mixed lineage acute leukemias (MLL;
KMT2A), such as infant acute lymphoblas-
tic leukemia
Side effects, monitoring,
and treatment
Azacitidine and decitabine are generally
well‐tolerated, though may lead to a decrease
 Chemotherapy Basics 379

in blood counts as well as fatigue, nausea,

Bendamustine
vomiting, constipation, diarrhea, and injec-
tion site reactions with both intramuscular
Bendamustine is a unique alkylator that was
and IV routes of administration.
originally formulated in the former East
German Democratic Republic in the 1960s.

Bleomycin Mechanism of action

Bendamustine is an alkylator with similar
Bleomycin is obtained as a mixture of antibi- properties as cyclophosphamide and other
otics isolated from Streptomyces verticillus. alkylators, though also has a benzimidazole
ring similar to cladribine. This leads to dif-
Mechanism of action ferential mechanism of action compared to
Bleomycin leads to the formation of oxygen‐ other alkylators in terms of its effects on
free radicals that cause single‐strand and DNA repair, as well as activity on both apop-
double‐strand DNA breaks. In addition, totic and nonapoptotic pathways. This also
bleomycin leads to cellular degradation leads to potential benefit in patients that have
­
of cellular RNA. Bleomycin is cell‐cycle‐­ previously received other alkylator therapy.
specific, targeting the G2 and M phases, thus
inhibiting cell growth and division, especially Utilization
in rapidly dividing cells. Hodgkin lymphoma

Side effects, monitoring,

Utilization
Germ cell tumors
Hodgkin lymphoma
Side effects, monitoring,
and treatment
Bleomycin can cause infusional fever and
chills followed later by mucositis, as well as
pruritus and excoriation leading to hyper-
pigmentation. Raynaud’s phenomenon can
also commonly occur later, especially with
combination chemotherapy. Patients may
occasionally complain of rash, dysgeusia,
and anorexia. Due to the formation of oxy-
gen‐free radicals, patients are at risk for
dose‐dependent pneumonitis and rarely
pulmonary fibrosis, and therefore should
be monitored with pulmonary function
testing (PFTs), especially diffusing capacity
of lung for carbon monoxide (DLCO). An
anaphylactoid‐type reaction may also
rarely occur.
and treatment
Bendamustine has a significantly better side
effect profile compared with other alkylators.
Bendamustine can cause an infusional reac-
tion, and is better tolerated with premedica-
tions and when given over 60 minutes.
Bendamustine requires less prehydration,
though some amount of prehydration and
posthydration is reasonable. Common side
effects include decrease in blood counts,
fatigue, anorexia, headache, cough, as well as
constipation, diarrhea, nausea, and vomiting.
Blinatumomab
Blinatumomab is a bispecific T‐cell engager
which binds CD3 and CD19.
Mechanism of action
Blinatumomab combines a CD3 binding site
with a CD19 binding site and thus induces
380 Chapter 30
direct cytotoxicity of CD19+ cells by engag-
ing cytotoxic CD3+ T‐cells. CD3 is part of
the T‐cell receptor, thus leading to potentia-
tion of otherwise unstimulated T‐cells to
direct cytotoxicity against all CD19+ cells.
Utilization
Acute lymphoblastic leukemia
Side effects, monitoring,
and treatment
Due to an extremely short half‐life, blinatu-
momab is given as a 28‐day continuous infu-
sion. Due to activation of CD3+ T‐cells,
patients may have cytokine release syndrome
(CRS), especially if with a higher tumor bur-
den. CRS manifests as fever, hypotension,
capillary leak, hypoxemia, and pulmonary/
pericardial effusion. Patients may also pre-
sent with neurotoxicity, likely due to T‐cell
stimulation within the central nervous sys-
tem (CNS). Neurotoxicity should be moni-
tored closely with a daily writing sample and
measuring dysmetria and dysdiadochokine-
sia. Patients may develop altered mental sta-
tus, seizure, and encephalopathy; early
initiation of dexamethasone with recogni-
tion of subtle neurological changes is vital.
Other common side effects of blinatumomab
include anemia, nausea, fatigue, diarrhea,
and headache. Due to CD19 cytotoxicity,
hypogammaglobulinemia can occur.
Brentuximab vedotin
Brentuximab is a monoclonal antibody to
CD30.
Mechanism of action
Brentuximab consists of a chimeric anti-
body specific to human CD30, the microtu-
bule disrupting agent MMAE (monomethyl
auristatin E [vedotin]), and a protease‐
cleavable linker that attaches MMAE to the
antibody. Brentuximab binds the CD30
receptor and is internalized via endocytosis
with subsequent cleavage of the linker
attaching MMAE to the antibody. MMAE is
released into the tumor microenvironment
leading to direct effects on the targeted
tumor cells.
Utilization
Hodgkin lymphoma
Side effects, monitoring,
and treatment
As a targeted monoclonal antibody, brentuxi-
mab is generally well‐tolerated. Brentuximab
is utilized pretransplant and posttransplant in
upfront and relapsed Hodgkin lymphoma.
Potential side effects include lymphopenia,
peripheral neuropathy, fatigue, nausea, diar-
rhea, fever, and rash.
Cisplatin/carboplatin
Cisplatin was the first of the platinum‐based
chemotherapeutic agents. Carboplatin has
less severe side effects, in particular
decreased nephrotoxicity and ototoxicity. It
is more myelosuppressive, however.
Mechanism of action
The platinum agents, like the alkylators,
cause interstrand DNA cross‐linking. In
addition, they bind to replicating DNA
causing single‐strand breaks.
Utilization
Brain tumors
Germ cell tumors
Hepatoblastoma
Hodgkin lymphoma
Neuroblastoma
Osteogenic sarcoma
Soft tissue sarcomas
Wilms tumor
 Chemotherapy Basics 381

Side effects, monitoring, urements of the glomerular filtration rate

and treatment and likely platinum dose reduction.
Infusional nausea and vomiting are common,
as platinum agents have an extremely high
emetogenic potential. This is followed later by
cis‐retinoic acid/all‐trans
myelosuppression. Electrolyte abnormalities
retinoic acid
including hypokalemia, hypomagnesemia,
hypocalcemia, and hyponatremia are com-
cis‐Retinoic acid (isotretinoin) and all‐trans
mon and the patient may develop Fanconi
retinoic acid (ATRA) are naturally occur-
syndrome (diminished reabsorption of solutes
ring analogs of vitamin A.
by the proximal tubule resulting in hypophos-
phatemia, metabolic acidosis, and secondary
Mechanism of action
hypokalemia). Nephrotoxicity and ototoxicity
Retinoid mechanism of action is not known,
(high‐frequency sensorineural hearing loss)
though is thought to contribute to matura-
occur occasionally with carboplatin, but are
tion/differentiation of tumor cells.
more common and severe with cisplatin.
Ototoxicity must be monitored with
Utilization
serial audiograms during therapy. Due to
APL
the risk of electrolyte abnormalities, chem-
High‐risk neuroblastoma
istry panels including magnesium should
be followed daily while receiving platinum‐
Side effects, monitoring,
based therapy. In addition, due to the risk of
and treatment
nephrotoxicity, the patient’s intake and out-
Retinoids commonly lead to dry skin/mucosa
put should be followed closely and be well‐
and may also lead to headache and the devel-
matched. If it appears the patient is
opment of pseudotumor cerebri. Consideration
developing a negative fluid balance, addi-
should be made for formal ophthalmologic
tional fluids should be provided. If the
exam in patients with moderate to severe head-
patient develops a positive fluid balance,
ache to rule out papilledema. Patients with
mannitol should be used to increase urine
APL utilizing ATRA may undergo differentia-
output. Renal function should be moni-
tion syndrome in induction as well as elevated
tored closely, as a reduction in the glomeru-
white count (i.e., WBC count >10 × 109/l),
lar filtration rate will necessitate a dose
which should be treated with early initiation of
reduction. In general, for pediatric patients
steroids. Differentiation syndrome leads to car-
with no previous history of nephrotoxicity,
diopulmonary distress and may also include
serum creatinine can serve as a measure of
hypoxemia, fever, rash, pulmonary infiltrates
renal function utilizing the Cockcroft–
and effusion, pericardial effusion, weight gain,
Gault equation:
peripheral edema, renal failure, heart failure,
and hypotension. Photosensitivity, arthralgias,
Estimated creatinine clearance elevated liver enzymes, triglycerides, and cho-
140 Age years Mass kg 0.85 if female lesterol, as well as hypercalcemia are additional
72 serum creatinine mg / dl potential side effects with retinoids. Retinoids
are thought to be teratogenic and cannot be uti-
lized in women of child‐bearing potential
Decrease in the estimated creatinine unwilling or unable to utilize standard contra-
clearance should lead to more formal meas- ceptive methods.
382 Chapter 30
Cladribine/clofarabine
Cladribine and clofarabine are purine nucle-
oside antimetabolites/analogs.
Mechanism of action
As purine analogs, cladribine and next‐gen-
eration clofarabine are resistant to deamina-
tion by adenosine deaminase, leading to
direct inhibition of DNA synthesis.
Utilization
Relapsed/refractory acute lymphoblastic
leukemia
Relapsed/refractory acute myelogenous
leukemia
Recurrent/refractory histiocytosis (Langer­hans
cell histiocytosis, Rosai–Dorfman dis-
ease, juvenile xanthogranuloma)
Side effects, monitoring,
and treatment
Cladribine and clofarabine are likely to cause
cytopenias and therefore potential resultant
infection. Though otherwise generally well‐
tolerated, these agents can lead to diarrhea,
nausea, vomiting, anorexia, fatigue, fever,
hypotension or hypertension, arrhythmias,
liver damage, as well as headache.
Cyclophosphamide/ifosfamide
Cyclophosphamide (Cytoxan) and ifosfamide
are alkylating agents and structural analogs.
They are related to nitrogen mustard.
Mechanism of action
Cyclophosphamide and ifosfamide require
conversion by the hepatic P450 system to
their active form that ultimately leads to the
intracellular release of two compounds,
acrolein and phosphoramide mustard.
­ toxic metabolites in the urine to detoxify
Phosphoramide mustard causes interstrand
DNA cross‐linking.
Utilization
Acute lymphoblastic leukemia
Acute myelogenous leukemia
Brain tumors
Ewing sarcoma
Germ cell tumors
Hodgkin and non‐Hodgkin lymphoma
Neuroblastoma
Osteogenic sarcoma
Soft tissue sarcomas
Wilms tumor
Side effects, monitoring,
and treatment
Cyclophosphamide and ifosfamide com-
monly cause nausea, vomiting, and anorexia
with drug infusion. Myelosuppression,
immunosuppression, and alopecia are com-
mon later adverse effects. Sterility is dose‐
dependent (greatest with cumulative doses
of cyclophosphamide >7.5 g/m2) and occurs
more commonly in pubertal males (though
prepubertal males and females are also at
risk). Due to the risk of nephrotoxicity, par-
ticularly with ifosfamide, patients should be
well‐hydrated prior to and after infusion.
Though the syndrome of inappropriate anti-
diuretic hormone (SIADH) is rare, patients
should be monitored for appropriate urine
output by following their intake and output.
Electrolytes are also routinely followed for
hyponatremia. If there are signs of fluid
retention, the patient should initially be
given increased hydration followed by diu-
resis with furosemide or mannitol if hydra-
tion is ineffective.
Excretion of acrolein into the urine can
cause hemorrhagic cystitis. The addition of
MESNA for bladder protection when the
cyclophosphamide dose exceeds 1.0 g/m2/
day has significantly decreased the fre-
quency of this adverse event. MESNA
specifically binds to acrolein and other
­
them and protect the bladder wall. The
urine should be monitored for the presence

of occult blood during and after infusion
and, if positive, should be examined micro-
scopically. If red blood cells are noted on
microscopy, hydration should be increased.
Of note, MESNA can cause a false positive
test for ketones on urine dipstick. Finally,
metabolism of ifosfamide leads to forma-
tion of chloroacetaldehyde, a byproduct
thought responsible for nephrotoxicity
as well as the neurotoxicity seen occasion-
ally with ifosfamide (somnolence, depres-
sive psychosis, and confusion). Thiamine
prophylaxis may have benefit in a patient
with prior neurotoxicity.
Cytarabine (Ara‐C)
Cytarabine, also known as cytosine arabino-
side or Ara‐C (arabinofuranosyl cytidine), is
utilized in the treatment of hematologic
malignancies.
Mechanism of action
Cytarabine is an antimetabolite and pyrimi-
dine analog that inhibits DNA polymerase.
In addition, it is cell‐cycle‐specific, killing
cells during synthesis (S phase); it therefore
specifically targets rapidly dividing cells.
Utilization
Acute lymphoblastic leukemia
Acute myelogenous leukemia
Hodgkin and non‐Hodgkin lymphoma
Side effects, monitoring,
and treatment
Cytarabine commonly causes nausea, vom-
iting, and anorexia immediately after infu-
sion. Later, myelosuppression, stomatitis,
and alopecia are common. Although not
common, the patient should be monitored
for Ara‐C syndrome that includes fever,
myalgias, bone pain, malaise, conjunctivitis,
maculopapular rash, and occasionally chest
Chemotherapy Basics 383
pain. High‐dose IV cytarabine requires
prophylaxis with dexamethasone eye drops
to prevent conjunctivitis. A flu‐like syn-
drome with fever, chills, and rash occurs
occasionally with cytarabine; infection must
still be ruled out with bacterial cultures.
Streptococcus viridans sepsis and acute res-
piratory distress syndrome are possible after
high‐dose cytarabine, therefore the addition
of vancomycin with fever or clinical deterio-
ration should be strongly considered.
Intrathecal (IT) cytarabine similarly can
cause fever, nausea, and vomiting in addi-
tion to headache. More serious and immedi-
ate side effects including arachnoiditis,
somnolence, meningismus, convulsions,
and paresis are rare but should be consid-
ered as clinically indicated.
Dactinomycin (Actinomycin‐D)
Dactinomycin is an antibiotic compound
isolated from Streptomyces parvulus, similar
to the anthracycline class.
Mechanism of action
Dactinomycin intercalates with DNA, inhib-
iting RNA and DNA synthesis. In addition,
dactinomycin interacts with topoisomerase,
which is required for DNA replication, and
leads to single‐strand DNA breaks.
Utilization
Soft tissue sarcomas
Wilms tumor
Side effects, monitoring,
and treatment
Infusional nausea and vomiting are com-
mon, followed later by alopecia and myelo-
suppression. Anorexia, fatigue, diarrhea,
and mucositis also occur occasionally.
Radiation recall can occur in patients who
previously received radiation therapy.
384 Chapter 30
Daunorubicin/doxorubicin/
idarubicin/mitoxantrone
Daunorubicin and doxorubicin are both
anthracycline antibiotics isolated from
Streptomyces species (Streptomyces coerule-
orubidus and Streptomyces peucetius,
respectively). Idarubicin is an analog of
daunorubicin used less commonly in pedi-
atric oncology. Mitoxantrone belongs to a
separate structural class of antineoplastic
agents called anthracenediones and was
produced synthetically.
Mechanism of action
Anthracyclines as a group are cytotoxic to
malignant cells due to nucleotide base inter-
calation and cell membrane lipid‐binding
activity. Nucleotide intercalation inhibits
replication as well as DNA and RNA poly-
merases. The anthracyclines also interact
with topoisomerase II, which is vital for
DNA replication. Cell membrane binding
affects a variety of cellular functions. In addi-
tion, electron reduction of the anthracyclines
produces free radicals leading to DNA dam-
age and lipid peroxidation. Daunorubicin
differs from doxorubicin structurally, as the
side chain terminates in a methyl group
rather than an alcohol. Idarubicin lacks a
methoxy group which increases its lipophi-
licity as compared with other anthracyclines.
Mitoxantrone specifically has been shown to
have cytotoxic effects on both proliferating
and nonproliferating cells.
Utilization
Acute lymphoblastic leukemia
Acute myelogenous leukemia
Hepatoblastoma
Hodgkin and non‐Hodgkin lymphoma
Neuroblastoma
Osteogenic sarcoma
Soft tissue sarcomas
Wilms tumor
Side effects, monitoring,
and treatment
Anthracyclines commonly cause nausea and
vomiting with treatment. Due to the color of
the infusion, the patient should be warned
that urine, saliva, tears, and sweat may all have
a pink or red coloring (blue with mitox-
antrone). After treatment, myelosuppression,
alopecia, and mucositis commonly occur.
Due to the production of free radicals during
electron reduction of anthracyclines, patients
are at risk for dose‐dependent cardiotoxicity
occurring as a late finding. Echocardiographic
monitoring is required during and after treat-
ment at regular intervals based on the total
anthracycline dose received as well as con-
comitant radiation therapy to the chest.
Cardioprotection with continuous versus
rapid infusion remains controversial and is
not yet routinely recommended in pediatric
patients. Dexrazoxane, an iron chelator and
free radical scavenger, has shown benefit as a
cardioprotectant when patients receive high
cumulative doses of anthracyclines (i.e.,
≥300 mg/m2 doxorubicin equivalents [see in
the following text]) and is recommended to
commence in adults when they have received
a cumulative dose of 300 mg/m2. Young chil-
dren (i.e., <4 years of age) anticipated to
receive a cumulative dose >300 mg/m2 may
benefit with earlier addition of dexrazoxane.
Anthracyclines provide different cumulative
toxicity, and dose conversion based on doxo-
rubicin isotoxic dose equivalents must be per-
formed as provided in the following text:
Doxorubicin: multiply total dose × 1
Daunorubicin: multiply total dose × 0.5
Epirubicin: multiply total dose × 0.67
Idarubicin: multiply total dose × 5
Mitoxantrone: multiply total dose × 4
(though data are increasing that the con-
version factor may be 10)
Radiation recall is also a potential rare com-
plication of anthracyclines when given after
radiation therapy.

Dinutuximab
Dinutuximab is a monoclonal chimeric
14.18 antibody to the glycolipid disialogan-
glioside (GD2).
Mechanism of action
Dinutuximab binds to cell surface GD2 on
neuroblastoma cells leading to cell lysis
through antibody‐dependent cell‐mediated
cytotoxicity and complement‐dependent cyto-
toxicity. Dinutuximab has been found to be
effective with immune stimulation with either
IL‐2 or GM‐CSF (granulocyte‐macrophage
colony‐stimulating factor), and is also given
with the cell differentiator cis‐retinoic acid.
Utilization
High‐risk neuroblastoma
Side effects, monitoring,
and treatment
Dinutuximab is given over 10–20 hours daily
for 4 days in combination with GM‐CSF.
Dinutuximab can lead to life‐threatening
infusion reactions and severe neurotoxicity
and pain. Dinutuximab can lead to CRS with
fever, hypotension, capillary leak, edema/
ascites, hypoxemia, and pulmonary/pericar-
dial effusion. Patients should have weight
monitoring twice daily in addition to contin-
uous low‐dose opioid support. Urinary
retention, hypertension, bleeding/clotting,
­ Gemtuzumab
anorexia, diarrhea, nausea/vomiting, periph-
eral neuropathy, and anemia are additional
potential side effects. Institutions utilizing
dinutuximab generally will have a standard
monitoring and treatment protocol that
should be reviewed when using dinutuximab.
Etoposide
Etoposide is derived from podophyllotoxin,
a toxin found in the American mayapple.
Chemotherapy Basics 385
Mechanism of action
Etoposide binds to topoisomerase II, which
is vital for DNA replication, leading to DNA
strand breakage. Etoposide is cell‐cycle‐spe-
cific and appears to act mainly on the G2
and S (synthesis) phases, thus targeting
rapidly dividing cells.
Utilization
Acute myelogenous leukemia
Brain tumors
Ewing sarcoma
Germ cell tumors
Hodgkin and non‐Hodgkin lymphoma
Hemophagocytic lymphohistiocytosis
Neuroblastoma
Osteogenic sarcoma
Soft tissue sarcomas
Wilms tumor
Side effects, monitoring,
and treatment
Infusional nausea and vomiting are com-
mon followed by myelosuppression and
alopecia. Although rare, the patient should
be monitored closely for hypotension and
anaphylaxis during the infusion. In addi-
tion to fluid support, the infusional rate
can be slowed if the patient develops
hypotension.
Gemtuzumab ozogamicin is a monoclonal
antibody to CD33.
Mechanism of action
Gemtuzumab is a monoclonal antibody
which binds to the CD33 antigen on hemat-
opoietic cells which leads to internalization.
Gemtuzumab is linked to a calicheamicin
cytotoxic agent, which exerts cell cytotoxic
effects through DNA double‐strand breaks
once internalized.
386 Chapter 30
Utilization
Acute myelogenous leukemia
Side effects, monitoring,
and treatment
Gemtuzumab can lead to cytopenias in
addition to nausea and vomiting, headache,
fever and chills, shortness of breath, ano-
rexia, fatigue, and hypokalemia. Infusion
reactions can occur and premedications
should be given. Sinusoidal obstructive syn-
drome (veno‐occlusive disease) risk can be
increased posttransplant due to prior utili-
zation of gemtuzumab.
Imatinib (gleevec®)/dasatinib/
ponatinib
Imatinib was the first successful targeted
drug therapy for oncology patients.
Mechanism of action
Imatinib is a selective inhibitor of the tyros-
ine kinase activity of the BCR–ABL fusion
protein, a product of the Philadelphia chro-
mosome (reciprocal translocation of chro-
mosomes 9 and 22) seen mainly in chronic
myeloid leukemia and rarely with acute
lymphoblastic leukemia. Dasatinib is a sec-
ond‐generation inhibitor of the BCR–ABL
fusion protein, being more specific to the
protein binding site. Ponatinib is a third‐
generation inhibitor which is effective in
patients with the T315I mutation.
Utilization
Acute lymphoblastic leukemia (Philadelphia
chromosome‐positive)
Chronic myelogenous leukemia
Side effects, monitoring,
and treatment
Imatinib and other tyrosine kinase inhibitors
(TKIs) have multiple potential side effects.
Common immediate effects include fluid
retention, nausea, and diarrhea. Later com-
mon effects include fatigue, muscle cramps,
rash, arthralgias, and myelosuppression.
TKIs may impact growth. Dasatinib can
cause heart dysfunction and echocardio-
gram should be followed on a routine basis.
Inotuzumab ozogamicin
Inotuzumab ozogamicin is a monoclonal
antibody to CD22.
Mechanism of action
Inotuzumab is a monoclonal antibody which
binds to the CD22 receptor on B‐cells, which
leads to internalization. Inotuzumab is linked
to a calicheamicin cytotoxic agent, which
exerts cell cytotoxic effects through DNA
double‐strand breaks once internalized.
Utilization
Relapsed/refractory acute lymphoblastic
leukemia
Side effects, monitoring,
and treatment
Inotuzumab can lead to cytopenias in addi-
tion to nausea and vomiting, headache,
fever and chills, fatigue, transaminitis,
mucositis, diarrhea/constipation, and
hyperbilirubinemia. Infusion reactions can
occur and premedications should be given.
Sinusoidal obstructive syndrome (veno‐
occlusive disease) risk can be increased
posttransplant due to prior utilization of
inotuzumab.
Irinotecan
Irinotecan is a semisynthetic analog isolated
from the plant alkaloid Camptotheca
acuminata.

Mechanism of action
Irinotecan in its active form is a potent
inhibitor of topoisomerase I which is vital
for DNA replication. Inhibition of topoi-
somerase inhibits replication and also leads
to DNA damage.
Utilization
Brain tumors
Ewing sarcoma
Hepatoblastoma
Neuroblastoma
Soft tissue sarcomas
Side effects, monitoring,
and treatment
Patients receiving irinotecan can suffer from
cholinergic symptoms including intestinal
hyperperistalsis that can lead to abdominal
cramping and early diarrhea. Patients should
be monitored closely for early diarrhea; if it
occurs, loperamide should be given prior to
an anticholinergic (e.g., atropine). Other cho-
linergic symptoms that may occur with drug
administration include rhinitis, increased
salivation, miosis, lacrimation, diaphoresis,
and flushing. Common later side effects
include diarrhea, alopecia, transaminitis,
neutropenia, mucositis, and hyperbilirubine-
mia. Diarrhea is due to the active metabolite
of irinotecan SN‐38 which can be mitigated
with the use of a prophylactic antibiotic such
as cefixime or cefpodoxime.
Mercaptopurine (6‐MP)
Mercaptopurine is a purine analog.
Mechanism of action
Mercaptopurine is converted into several
active metabolites that inhibit RNA and DNA
synthesis. As a purine analog it can also inter-
fere with purine biosynthesis. Mercaptopurine
is converted to nucleotide metabolites, some
of which can lead to DNA toxicity.
Chemotherapy Basics 387
Utilization
Acute lymphoblastic leukemia
Non‐Hodgkin lymphoma
Side effects, monitoring,
and treatment
Mercaptopurine is generally well‐tolerated,
although myelosuppression occurs com-
monly. Mercaptopurine is usually adminis-
tered at night as patients may occasionally
complain of anorexia, nausea, and vomiting.
Morning hypoglycemia may also rarely
occur. Separation from food or milk is no
longer required; giving the medicine at the
same time daily is highly recommended for
efficacy. Diarrhea and an erythematous rash
(often perioral) may also occasionally occur.
Monitoring of mercaptopurine metabolites
(thioguanine nucleotides) can be utilized to
objectively measure questionable compli-
ance and ensure appropriate dosing for
patients on either subtherapeutic or supra-
therapeutic dosing.
Methotrexate
Methotrexate was the first successful chem-
otherapeutic agent utilized in children after
the observation that folic acid worsened leu-
kemia and dietary deficiency of folic acid
could improve leukemia symptoms.
Mechanism of action
Methotrexate inhibits folic acid by prevent-
ing the reduction of folic acid by the enzyme
dihydrofolate reductase. This inhibition
subsequently limits the synthesis of purines
and DNA. Some of the methotrexate metab-
olites also lead to DNA damage.
Utilization
Acute lymphoblastic leukemia
Acute myelogenous leukemia
Brain tumors
Non‐Hodgkin lymphoma
388 Chapter 30
Osteogenic sarcoma
Side effects, monitoring,
and treatment
Because of significant enterohepatic circula-
tion of methotrexate, transaminitis is com-
mon. Nausea, vomiting, and anorexia may
also occur; therefore, oral doses are generally
given at bedtime. Many side effects of metho-
trexate are due to delayed clearance after
high‐dose IV treatment. Aggressive hydration
and alkalinization of fluids can improve renal
clearance. Drugs including trimethoprim/sul-
famethoxazole, penicillin, nonsteroidal anti‐
inflammatories (NSAIDs), and proton pump
inhibitors (PPIs) can competitively inhibit
renal clearance and must be held during high‐
dose therapy. Leucovorin (folinic acid) is used
to decrease many of the toxic effects of folic
acid antagonists such as methotrexate.
Leucovorin can participate in metabolic reac-
tions requiring folic acid without the necessity
of reduction by dihydrofolate reductase which
is inhibited by methotrexate. This mechanism
of action can also counteract the therapeutic
effect of methotrexate; therefore, leucovorin
should not be started until 18–24 hours after
the methotrexate infusion has been com-
pleted. For this reason, patients should be
advised to not take folic acid supplements
during methotrexate therapy, as this may sim-
ilarly reduce efficacy.
Urine pH should be monitored closely
and kept above 7.5 during high‐dose therapy
to facilitate renal excretion of methotrexate.
The patient’s intake and output should also
be followed. Methotrexate levels are usually
drawn starting 24 hours after the infusion is
started. Leukemia protocols provide a meth-
otrexate nomogram that allows the practi-
tioner to determine if methotrexate levels are
declining appropriately or are in a toxic
range requiring an increase in hydration and
leucovorin frequency or dose. Rarely, renal
failure occurs and can be managed with car-
boxypeptidase G2. Toxicity is typically worse
after delayed clearance and includes severe
mucositis and myelosuppression. Patients
may benefit from glutamine prophylaxis for
the prevention of mucositis with subsequent
methotrexate doses. IT methotrexate often
causes nausea and headache. Arachnoiditis
occasionally occurs and the patient should
be monitored for symptoms including fever,
vomiting, and meningismus. Long‐term
cognitive dysfunction and learning disabili-
ties occasionally occur. Leukoencephalopathy
and progressive cognitive deterioration
rarely occur, especially in adolescents and
adults, with high‐dose IV methotrexate and
accentuated by cranial radiation therapy.
­
Management of patients with neurotoxicity
including ­seizures, confusion, ataxia, cranial
nerve palsies, speech disorders, and parapa-
resis is controversial. Practitioners may rec-
ommend leucovorin rescue after future IT
doses or replacement with IT cytarabine,
with or without hydrocortisone. Conclusive
evidence is lacking on the use of dex-
tromethorphan as a neuroprotectant but
may also be trialed. The majority of patients
will tolerate rechallenge of IT methotrexate
without issue.
Nelarabine
Nelarabine is a prodrug of Ara‐G.
Mechanism of action
Nelarabine is a substrate for adenosine
deaminase which converts the prodrug to
Ara‐G. Ara‐G is internalized into T‐lymph-
oblasts and subsequently phosphorylated
into the active nucleotide Ara‐GTP which
competes in leukemic blasts cells for incor-
poration into cellular DNA, inhibiting fur-
ther DNA synthesis.
Utilization
T‐cell acute lymphoblastic leukemia/
lymphoma

Side effects, monitoring,
and treatment
Neurotoxicity is the most identifiable
unique toxicity of nelarabine and can be
either central or peripheral. Nelarabine is
otherwise generally well‐tolerated, though
can lead to cytopenias, nausea, and fatigue.
Nivolumab/pembrolizumab
Nivolumab and pembrolizumab are mono-
clonal antibodies to the receptor of pro-
grammed cell death‐1 (PD‐1) and therefore
called immune checkpoint inhibitors.
Mechanism of action
Nivolumab and pembrolizumab bind to
the PD‐1 receptor which blocks interac-
tion with its ligands PD‐L1 and PD‐L2.
This binding limits T‐cell exhaustion on
activated T‐cells and leads to T‐cell persis-
tence of these cells, increasing tumor cell
killing.
Utilization
Hodgkin lymphoma
Renal cell carcinoma
Side effects, monitoring,
and treatment
Immune checkpoint inhibitors are gener-
ally well‐tolerated. The most common
adverse events include fatigue, anorexia,
diarrhea, nausea, cough, dyspnea, consti-
pation, vomiting, rash, fever, and headache.
Immune‐related c­ omplications with these
medications can occur, most notably pseu-
doprogression after initiation of the medi-
cation due to local inflammatory reaction
as well as pneumonitis due to this response
in the lungs. Pneumonitis may require ster-
oids. Other potential immune complica-
tions include vitiligo, colitis, hepatitis,
hypophysitis (pituitary inflammation), and
thyroiditis.
Chemotherapy Basics 389
Rituximab
Rituximab is a monoclonal antibody to
CD20.
Mechanism of action
Rituximab has multiple proposed mecha-
nisms of action including direct signaling of
apoptosis, complement‐dependent cellular
toxicity, and antibody‐dependent cell‐medi-
ated toxicity.
Utilization
Non‐Hodgkin lymphoma
Side effects, monitoring,
and treatment
Rituximab can cause an infusion reaction
and should be given with premedications
per a standard protocol. Other common
side effects include nausea, fever, chills, and
fatigue. Due to inhibition of CD20, infection
and hypogammaglobulinemia are possible.
Progressive multifocal leukoencephalopathy
(PML) has been reported in adult patients
but is unlikely in younger patients.
Steroids
Dexamethasone and prednisone are the
steroids used most commonly as chemo-
therapeutic agents.
Mechanism of action
Steroids have a variety of actions on the
body. Although not completely under-
stood, steroids are thought to destroy
lymphoblasts by binding to the cortisol
receptor found on lymphoid cells and spe-
cifically in large number on lymphoblasts.
Steroids are immunosuppressive and target
T‐lymphocytes, monocytes, and eosino-
phils. Steroids may also function by halting
DNA synthesis. Dexamethasone has better
390 Chapter 30
CNS penetration than prednisone and has
benefit in preventing CNS relapse in ALL.
Utilization
Acute lymphoblastic leukemia
Hemophagocytic lymphohistiocytosis
Hodgkin and non‐Hodgkin lymphoma
Langerhans cell histiocytosis
Side effects, monitoring,
and treatment
Steroid treatment results in a multitude of
side effects. Common ones include hyper-
phagia, insomnia, personality changes, adre-
nal suppression, acne, immunosuppression,
and Cushing’s syndrome. Occasional side
effects include gastritis, hyperglycemia, poor
wound healing, facial erythema, striae, thin-
ning of the skin, proximal muscle weakness,
osteopenia, and cataracts. Avascular necrosis
of various joints, most commonly hips, knees,
and ankles, occurs rarely. It is more common
in adolescents, and females are at higher risk.
It appears to occur more commonly with
dexamethasone than with prednisone.
Hypertension occurs rarely; blood pressure
should be monitored closely in addition to
blood glucose. Patients should be on an H2
blocker (i.e., famotidine) while receiving
daily steroids to prevent gastritis and peptic
ulcer disease. Potassium chloride may be tri-
aled to decrease mood effects from steroids.
Temozolomide
Temozolomide (Temodar®) is an oral alkylat-
ing agent.
Mechanism of action
As with other alkylators, temozolomide
leads to DNA interstrand cross‐linking.
Utilization
Brain tumors
Ewing sarcoma
Side effects, monitoring,
and treatment
Temozolomide commonly causes anorexia,
nausea, vomiting, and constipation followed
by myelosuppression. Occasionally, temozo-
lomide may cause abdominal pain, diarrhea,
headache, and mucositis. Continuous low‐
dose (metronomic) therapy may be effective
in some patients with a decreased side‐effect
profile.
Thioguanine (6‐TG)
Like mercaptopurine, thioguanine is an oral
antimetabolite and purine analog.
Mechanism of action
Metabolites of thioguanine interfere with
purine synthesis and DNA replication. The
intercalation of nucleotide metabolites into
DNA also leads to DNA strand breaks.
Utilization
Acute lymphoblastic leukemia
Acute myelogenous leukemia
Non‐Hodgkin lymphoma
Side effects, monitoring,
and treatment
Thioguanine commonly leads to myelo-
suppression and occasionally causes
fatigue, nausea, vomiting, diarrhea, and
anorexia. Although rare, the patient should
be monitored for transaminitis as well as
signs of veno‐occlusive disease (sinusoidal
obstructive syndrome) and hepatic
fibrosis.
Tisagenlecleucel (Kymriah)
Tisagenlecleucel is a chimeric antigen recep-
tor re‐engineered T‐cell (CAR‐T) targeting
CD19+ cells.

Mechanism of action
Patients with multiply relapsed or refrac-
tory CD19+ acute lymphoblastic leukemia
may be eligible for tisagenlecleucel. Patients
have apheresis of their mononuclear cells
which are sorted such that cytotoxic and
helper T‐cells can be re‐engineered to spe-
cifically target CD19+ cells. These re‐engi-
neered CAR‐T cells are subsequently
reinfused to the patient after lymphodeple-
tion. Generally, there is rapid elimination
of the CD19+ cells by the CAR‐T cells.
There can be loss of the CAR‐T cells due to
an immune response or secondary to anti-
gen escape, which is usually due to a CD19–
CD22+ clone. A surrogate marker of the
loss of persistence of CAR‐T cells is the loss
of B‐cell aplasia.
Utilization
Relapsed acute lymphoblastic leukemia
Side effects, monitoring,
and treatment
CRS is common after CAR‐T cell infusion
and presents as unremitting fever with
associated symptoms including hypoten-
sion, capillary leak, ascites, respiratory dis-
tress, hypoxemia, and pleural/pericardial
effusions. Patients with CRS are at increased
risk of neurotoxicity (ICANS; immune
effector cell associated neurotoxicity syn-
drome) which can manifest as severe
headache, altered mental status, seizure,
encephalopathy, and coma/death.
Treatment of CRS includes early diagnosis
based on clinical and laboratory criteria
and rapid initiation of tocilizumab (anti‐
IL6) and potentially dexamethasone.
Neurotoxicity is managed with the use of an
anti‐epileptic and supportive care.
Institutions utilizing tisagenlecleucel will
have detailed protocols to monitor and
manage potential side effects of CAR‐T
therapy.
Chemotherapy Basics 391
Topotecan
Like irinotecan, topotecan is a semisynthetic
analog isolated from the plant alkaloid C.
acuminata.
Mechanism of action
Topotecan is a potent inhibitor of topoi-
somerase I that is vital for DNA replication.
Inhibition of topoisomerase inhibits replica-
tion and also leads to DNA damage.
Utilization
Brain tumors
Neuroblastoma
Side effects, monitoring,
and treatment
Topotecan can commonly cause nausea,
vomiting, diarrhea or constipation, fever,
pain and later myelosuppression, fatigue,
and alopecia. The patient should also be
monitored for the occasional findings of
headache, rash, hypotension, transaminitis,
and mucositis.
Vincristine/vinblastine/
vinorelbine
Vincristine and vinblastine are alkaloids iso-
lated from the Madagascar periwinkle plant
(Vinca rosea, now Catharanthus roseus) and
therefore often referred to as vinca alkaloids.
Vincristine and vinblastine are structurally
identical except for a single substitution (a
formyl group in vincristine is replaced by a
methyl group in vinblastine), which leads
to significant differences in their cytotoxic
effects. Vinorelbine was subsequently pro-
duced semi‐synthetically, though can be
produced from byproducts of C. roseus and
is therefore considered to be in the family of
vinca alkaloids.
392 Chapter 30
Mechanism of action
The vinca alkaloids bind to microtubules
especially in the mitotic spindle leading to
metaphase arrest, thus targeting rapidly
dividing cells. They have other disruptive cel-
lular functions that may or may not be related
to their effects on tubulin and microtubules.
Utilization
Acute lymphoblastic leukemia
Brain tumors
Ewing sarcoma
Hepatoblastoma
Hodgkin and non‐Hodgkin lymphoma
Langerhans cell histiocytosis
Neuroblastoma
Soft tissue sarcomas
Wilms tumor
Side effects, monitoring,
and treatment
Vinblastine and vinorelbine more com-
monly cause myelosuppression, whereas
vincristine more commonly causes neuro-
toxicity including constipation and loss of
deep tendon reflexes. All can lead to alope-
cia. Jaw pain, peripheral paresthesias, wrist
and foot drop, and abnormal gait occa-
sionally occur, especially with vincristine.
Ptosis, vocal cord dysfunction, and dam-
age to the eighth cranial nerve (clinically
with dizziness, nystagmus, vertigo, and
hearing loss) are rare findings. Vinca alka-
loids are vesicants; therefore, extravasa-
tion, if it occurs, can lead to local ulceration
(see Chapter 32 for management of
extravasation).
Suggested reading
Adamson, P.C., Blaney, S.M., Bagatell, R. et al.
(2016). General Principles of Chemotherapy, 7e
(eds. Pizzo and Poplack), 239–315. Wolters
Kluwer/Lippincott.
31 Guide to Procedures
Procedures yield critical diagnostic and
treatment information for patients with
suspected or known oncologic or hemato-
logic diseases. Traditionally, tumor biopsies
(depending on tumor site) are performed
on patients while under general anesthesia
by pediatric surgeons, pediatric orthopedic
oncologists, and pediatric interventional
radiologists. Common procedures per-
formed by the pediatric hematologist/
oncologist include bone marrow aspiration
(BMA) and biopsy, lumbar puncture (LP)
to obtain cerebral spinal fluid (CSF) and
administer intrathecal (IT) chemotherapy,
as well as the administration of chemother-
apy via a peripheral vein or Ommaya reser-
voir (another form of directed central
nervous system [CNS] therapy).
Basic principles for performing proce-
dures include: (i) ensuring the procedure
is indicated for diagnosis, assessment of
response to therapy, or to determine pos-
sible relapse; (ii) ensuring the proper
medication is being administered at the
proper time; (iii) providing a safe and
sterile environment; and (iv) obtaining
informed consent with proper documen-
tation. The patient’s medical record
should be carefully reviewed prior to the
procedure and the purpose and nature
of the procedure be reviewed with the
patient and family. This discussion should
include anticipated risks and benefits with
Handbook of Pediatric Hematology and Oncology – Children’s Hospital & Research Center Oakland,
Third Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
documentation in the medical record with
the signed informed consent.
All procedures should be performed or
supervised by practitioners with technical
expertise. For patients undergoing anesthe-
sia, a skilled caregiver (i.e., anesthesiologist,
nurse anesthetist, or critical care physician)
should administer the sedation and monitor
the patient. In addition to the practitioners
performing the procedure and sedation,
another skilled caregiver (i.e., nurse or physi-
cian) should be present to assist with posi-
tioning, sterile transfer of chemotherapy per
institutional policy, and general patient care
and monitoring. Many centers perform all
LPs and BMAs under deep sedation or anes-
thesia; however, some patients prefer to have
these procedures performed awake, or with
mild sedation.
Prior to initiation of the procedure, a
time‐out should be done to ensure proper
identification of the patient (hospital wrist
band, medical record, and labels on medi-
cations) and the planned procedure. All
chemotherapeutic medications should be
brought into the room and checked by at
least two skilled practitioners. If multiple
medications are to be administered, care
should be taken to avoid an error in
administration by bringing in one drug at
a time. An exemption to this is if the
patient is receiving multiple IT medica-
tions and the pharmacy dispenses these
394 Chapter 31
separately. Standardized procedures should
be followed to minimize error. Procedures
may be performed in an outpatient or inpa-
tient setting by individuals who have been
properly trained and supervised.
Lumbar puncture/intrathecal
chemotherapy
Pediatric hematology/oncology physicians
and their trained staff perform LPs to assess
for involvement of the CSF by malignancy
as well as to administer IT chemotherapy
(drug delivery directly into the subarach-
noid space of the spinal column). Drugs are
administered in this manner to bypass the
blood–brain barrier. The three agents typi-
cally given IT are: methotrexate, cytarabine
(Ara‐C), and hydrocortisone.
Indications
Patients with suspected leukemia or lym-
phoma (diagnosis, staging), history of leuke-
mia or CNS lymphoma (treatment or new
signs or symptoms suggestive of relapse),
CNS metastases, and therapy complications
related to the CNS, specifically infection
or neurotoxicity (suspected meningitis,
encephalitis, or change in mental status
without evidence of increased intracranial
pressure).
Pretreatment evaluation
1. Review patient history for use of antico-
agulants (should be discontinued with appro-
priate time interval prior to procedure),
seizures, or other CNS concerns including
prior complications with LPs or IT chemo-
therapy. The review of systems should include
history of headaches, altered mental status,
fevers, bleeding, back pain, or lower extremity
weakness. Consideration should be given to
imaging with assessment of possible increased
intracranial pressure or spinal compression
with any of these signs or symptoms.
2. Physical examination should be per-
formed prior to the procedure with atten-
tion on a focused neurologic evaluation
including assessment for papilledema or
other evidence of increased intracranial
pressure such as high blood pressure,
widened pulse pressure, or altered level of
consciousness. Evaluate vitals and assess for
any evidence of infection or metabolic
abnormalities to ensure safety for anesthesia.
Evaluate site of procedure to assure no
localized infection or skin breakdown.
3. Laboratory studies must be checked to
confirm that parameters are met for admin-
istration of chemotherapy per protocol
(e.g., platelet count, absolute neutrophil
count, and hemoglobin). Patients with
­moderate thrombocytopenia (platelet count
<50 × 109/l) may need a platelet transfusion,
although this varies with the skill of the
practitioner and institutional protocol. The
literature recommends a platelet count
≥100 × 109/l for a diagnostic LP in a patient
with suspected or newly diagnosed leuke-
mia to decrease the possibility of a traumatic
tap with potential increased risk of CNS
relapse. A highly skilled practitioner should
be performing all diagnostic LPs.
The chemotherapy to be administered
should be checked to ensure the correct
drug, dose, mode of infusion, and patient
identification.
Materials
1. Standard LP tray, 22‐gauge spinal needle
(1.5 in. for infants, 2.5 in. for older children,
longer needles available as needed for larger
patients), 25‐gauge needle for lidocaine
injection if needed, providone iodine and
alcohol, mask, and sterile gloves. A Quincke
needle is the standard needle used for LP;
however, the pencil point Whitacre needle
may be indicated in patients with prior
­history of severe spinal headache (see Post-
procedure monitoring and complications).

2. Chemotherapy agent (s) to be adminis-
tered. Errors have occurred in the past with
vincristine being inadvertently administered
intrathecally. This is almost uniformly fatal.
This drug should never be brought into the
room of a patient undergoing a LP with IT
chemotherapy. Many institutions now require
vincristine be made in small infusion bags to
prevent this complication. Patients receiving
double or triple IT therapy likely benefit from
these medications being mixed by the chem-
otherapy pharmacy prior to instillation to
prevent missed medication as well as transfer
in the operating room without a hood.
Procedure
1. Proper positioning is key to a successful
procedure. The lateral decubitus position
may be used for a sedated or small patient.
The patient should be placed on a firm bed,
head flexed with chin to chest, and legs
maximally flexed toward the head. Ensure
the hips and shoulders are aligned and the
back is straight. Alternatively, an awake
patient may prefer the sitting position,
flexed forward, and supported by the
assistant or using a Mayo stand.
2. Identify the landmark with palpation of
the interspaces. The L4–5 interspace is
located by a perpendicular line at the top of
the iliac crests; either this space or the one
above (L3–4) may be used.
3. The practitioner should wear a mask to
decrease infection risk. Put on sterile gloves
and set up the tray.
4. Perform a sterile prep by cleansing the
skin surface with providone iodine solution
beginning at the anticipated site of puncture,
working outward with friction. Repeat for a
total of three scrubs. The skin may then be
cleansed with alcohol. Some centers utilize a
chlorhexidine scrub in lieu of providone
iodine. Place a fenestrated drape over the
site and ensure an adequate sterile field with
additional drapes as needed.
5. Open all CSF collection tubes.
Guide to Procedures 395
6. Administer local anesthetic with
preservative‐free 1% lidocaine with a 25‐
gauge needle, if desired. Awake patients may
prefer application of a topical lidocaine
anesthetic (LMX or EMLA) applied
20–30 minutes in advance of the procedure
or ethyl chloride cold spray at the moment
of the puncture. Local anesthesia is not
necessary in the anesthetized patient.
7. Insert the spinal needle into the midline
of the interspace with the bevel parallel to the
spinal column, directed at a slight (10°–20°)
angle toward the umbilicus. Ensure the nee-
dle is perpendicular to the surface. Advance
the needle; if bony resistance is noted, draw
back and reposition. The less experienced
practitioner should check for CSF flow every
2–3 mm by withdrawing the stylet and look-
ing at the translucent window hub for visu-
alization of CSF. If blood is returned, the
needle should be removed and the procedure
re‐attempted one interspace higher. The
most experienced practitioner should
assume responsibility for subsequent LPs.
8. Once clear CSF return is established,
some practitioners rotate the needle 90°
counterclockwise (bevel in transverse plane)
for patients in the lateral decubitus position
to increase rapidity of CSF flow and allow
for easier administration of IT chemother-
apy. Patients in the sitting forward position
do not usually need repositioning of the
needle. Obtain the desired amount of CSF in
two or three collection tubes. Traditionally,
the volume of CSF withdrawn should
approximate the volume of medication
administered (minimum 50% of adminis-
tered volume). CSF should be collected in
one tube for a chamber count (red blood cell
and white blood cell counts) and a second
tube for cytology (assessment of morphol-
ogy). Additional tubes may be necessary for
culture, immunohistochemistry, or any spe-
cial studies such as myelin basic protein,
tumor markers, or research studies. Glucose
and protein are checked initially for all
396 Chapter 31

patients, though not routinely for leukemia anesthesia monitoring. Most centers direct
patients receiving IT chemotherapy. that patients remain in a supine position
9. For IT administration of chemotherapy, (without head pillow, mild Trendelenburg
attach the chemotherapy syringe to the spinalposition) for 1 hour postprocedure to mini-
needle, ensuring no advancement or with- mize the risk of spinal headache and assure
appropriate chemotherapy distribution within
drawal of the spinal needle and a tight fit to
avoid leakage. One can attempt to withdraw the CSF. More advanced Trendelenburg posi-
tioning is not routinely recommended.
CSF to assure proper placement (will see a mix
2. Patients should be monitored for signs of
in the syringe), but this may not be possible and
bleeding, pain at site, headache, nausea,
is not necessary. Slowly inject the chemother-
apy over 30–60 seconds. There should be no vomiting, or change in neurologic status. In
resistance. Most institutions do not perform addition to monitoring for postprocedure
complications, the patient’s cardiovascular
sterile transfer of chemotherapy (due to lack of
a hood), but rather break sterility with one and respiratory status should be monitored
hand which administers the chemotherapy along with frequent vital signs until
recovered from anesthesia.
while the second hand sterilely holds the hub of
the spinal needle. The system remains closed 3. Headache occurs following LP in a small
percentage of patients, primarily adoles-
so as to not put the patient at risk for infection.
10. Chemotherapy should not be adminis- cents and females. Typically, onset of head-
tered when any of the following situations ache is within 12 hours to 5 days of the
exist: the spinal fluid is bloody indicating procedure and is due to slow leakage of CSF
from the puncture site (though may not be
puncture of a vessel; the patient is moving pre-
visible externally). Other complications or
venting safe administration of the drug(s); the
chemotherapy does not advance easily and adverse effects include nausea, vomiting,
when the syringe is removed the flow of CSF dizziness, neck stiffness, light sensitivity,
has stopped or greatly diminished; the chemo-and diminished hearing or vision. These
symptoms may be worse when the patient
therapy drug or dose is incorrect; or the awake
patient experiences pain with injection. assumes a standing position.
11. Remove the needle. Apply gentle pres- a. Patients are instructed to take fluids
sure, cleanse as necessary with alcohol, and liberally in addition to caffeine (highly
place a spot bandage. caffeinated sodas or coffee), though this
12. Assess patient for any adverse effect of latter intervention is not evidence‐based.
the procedure. Have the patient in the supine b. Patients with severe headache or neu-
position. rologic symptoms should be evaluated
13. Label all CSF tubes and send to the lab. immediately. If a postdural puncture
14. Document the procedure in the medical headache is suspected, treatment is initi-
record. ated with caffeine, fluids, and analgesics.
15. Follow up with the patient and family as If these steps are ineffective, a dural blood
to the results of the procedure, including patch may be performed by an anesthesi-
interpretation of the CSF specimens. ologist to provide immediate relief.
c. Use of a pencil point spinal needle
Post-procedure monitoring (Whitacre) for subsequent LPs should be
and complications considered for these patients. These
1. Observe the patient for a minimum of needles are designed to spread the dural
1 hour (or longer if necessary) for recovery fibers and help reduce the frequency and
from anesthesia with appropriate post-­ severity of postdural headaches. They

can be more difficult to use and may
require an introducer to puncture the
skin and soft tissues.
4. Fever may occur following administration
of IT chemotherapy. Some drugs (e.g., cytara-
bine) have been more implicated in causing
fever; however, fever should never be assumed
to be due to drug and the patient should be
assessed for presumed infection. Frequently,
patients have indwelling central venous cathe-
ters (CVCs) and are receiving other immuno-
suppressive therapy. Evaluation should be
comprehensive with appropriate clinical, physi-
cal, and laboratory assessments and may include
hospitalization for observation with adminis-
tration of intravenous (IV) antibiotics.
5. Patients may experience pain or bleeding
at the LP site for several days. The patient
should be evaluated and, if experiencing
minor bleeding, be treated with local therapy
(dry sterile bandaging) and pain medication
as needed. Prolonged or heavy bleeding
requires immediate evaluation including
physical examination and imaging.
6. Neurotoxicity may occur related to the
IT medication or related to nerve damage
secondary to the procedure. Patients should
be evaluated immediately and intervention
be taken as appropriate with subsequent
neurologic assessments and possible
imaging. Decisions regarding further IT
therapy are made pending resolution of
symptoms and findings on imaging, as well
as clinical protocol.
Intra‐Ommaya reservoir tap
and injection of chemotherapy
Indications
The Ommaya reservoir is an intraventricular
catheter with a reservoir implanted under
the scalp that allows for administration of
chemotherapy or other medication directly
into the ventricular system, in addition to
facilitating sampling the CSF. Although they
Guide to Procedures 397
are placed infrequently, they are useful in the
management of patients for whom it is tech-
nically difficult to perform LPs for any rea-
son. Lumbar catheters have also been placed
in patients with unusual anatomy or in the
presence of obesity; however these catheter
reservoir systems are more prone to dysfunc-
tion than the intraventricular systems.
Ommaya reservoirs are also used in patients
who suffer a CNS relapse of their leukemia
and require frequent administration of IT
chemotherapy. Practitioners may opt to
administer chemotherapy in reduced dosing
compared to standard IT dosing (50–100%
of IT dosing) or give small daily dosing for
up to 4 days (based on the concept of con-
centration × time to optimize therapeutic
benefit).
Pretreatment evaluation
The same principles apply as in LP/IT
chemotherapy. Patients are not sedated for
this procedure.
Materials
1. Standard LP tray, two 5 ml sterile syringes
for CSF collection, 25‐gauge butterfly nee-
dle, mask, razor, antibacterial soap, 4 × 4
sterile gauze, providone iodine and alcohol,
and two sets of sterile gloves.
2. Chemotherapy agent(s) to be adminis-
tered. Do not bring vincristine into the room.
Procedure
1. The patient is placed in a supine or sitting
position. If needed, a small area over the
reservoir is shaved.
2. Topical anesthesia may be achieved with
lidocaine gels (EMLA or LMX) applied
20–30 minutes prior to the procedure.
3. While wearing a mask and sterile gloves,
the LP tray is set up.
4. A double sterile preparation is routinely
done when accessing intraventricular reser-
voirs due to concern for infection. Prepare
the skin surface overlying the reservoir site
398 Chapter 31
by cleansing with sterile gauze moistened
with an antibacterial soap (e.g., chlorhex-
idine) in a circular fashion, three times.
Change sterile gloves. Continue with a rou-
tine sterile prep with three providone iodine
scrubs and alcohol. Place a fenestrated drape
over the site and ensure an adequate sterile
field with additional drapes as desired.
5. Open all CSF collection tubes.
6. Holding the reservoir firmly with one
hand, puncture the reservoir site with a 25‐
gauge butterfly needle. The CSF is allowed to
drip (or is slowly withdrawn) from the but-
terfly into a sterile tube. The total volume
collected should approximate the total vol-
ume of chemotherapy and normal saline
flush to be delivered. CSF should be collected
in one tube for a chamber (cell) count and a
second tube for cytology. Additional tubes
may be necessary for culture, immunohisto-
chemistry, or any special studies such as
myelin basic protein, tumor markers, or
research studies. Glucose and protein are
checked initially for all patients, though not
routinely for leukemia patients receiving
intra‐Ommaya chemotherapy.
7. The chemotherapy is injected slowly
after nonsterile transfer of the chemotherapy
syringe similar to the LP procedure, keeping
one hand sterile at the hub of the butterfly
needle to ensure a closed system. Do not
give the chemotherapy if the CSF is blood‐
tinged. A small amount of sterile saline or
the patient’s CSF is then injected to ensure
the tubing is flushed and all the medication
is delivered (typically <0.5 ml, the volume of
tubing and reservoir).
8. The needle is removed, and firm pressure
is applied to the site. A spot bandage may be
applied.
9. Assess the patient for any adverse effects
from the procedure.
10. Label all CSF tubes and send to the lab.
11. Follow up with the patient and family as
to the results of the procedure, including
interpretation of the CSF specimens.
Postprocedure monitoring
and complications
1. Document in the patient’s chart details of
the procedure, chemotherapy administered,
specimens collected, and the patient’s status
after the procedure.
2. See Postprocedure monitoring for LP
regarding complications such as headache,
fever, bleeding, or neurologic changes.
Bone marrow aspiration
and biopsy
Indications
The purpose of a BMA or biopsy is to obtain
tissue for diagnostic and staging evaluation
of malignancies, marrow infiltrative dis-
eases, or marrow failure states. Bone marrow
examination is required for the diagnosis of
leukemia, lymphoma, bone marrow failure
states, evaluation of pancytopenia of
unknown etiology, suspected storage dis-
eases, and certain causes of anemia. Bone
marrow studies are also done as staging eval-
uations in certain solid tumors including
high‐risk neuroblastoma and Ewing sar-
coma. The bone marrow produces the cellu-
lar elements of the blood including platelets,
red blood cells, and white blood cells in addi-
tion to the supporting matrix to allow for cell
growth and maturation. Aspirates are rou-
tinely obtained for morphologic as well as
immunohistochemical and flow cytometric
evaluation in patients with suspected leuke-
mia. Those with suspected or known solid
tumors, storage diseases, aplastic anemia, or
other marrow failure states require evalua-
tion by bone marrow biopsy as well. A core
section of the marrow matrix is obtained in
order to assess the suitability of the marrow
environment for growth of normal cellular
elements, the cellularity of the marrow, and
the presence of abnormal cells that may be
adherent to the trabeculae. Samples are typi-
cally taken from more than one site when

looking for evidence of marrow involvement
by solid tumors in order to increase the sen-
sitivity of the test. The most common site for
sampling in the child or adolescent is the
posterior iliac crest. At times, other locations
for bone marrow specimen collection are
necessary (i.e., infants, children on ventila-
tors) and may include the anterior iliac spine,
tibia, sternum, or other sites.
Pretreatment evaluation
1. Review of systems including recent
illnesses or back pain.
2. Physical examination should be
performed prior to the procedure, with
vitals and assessment for any evidence of
infection or metabolic abnormalities to
assure safety for anesthesia. Evaluate site of
procedure to assure no localized infection or
skin breakdown.
3. Routine laboratory studies may include a
complete blood count, chemistries, and
coagulation studies. No specific platelet
threshold is necessary for the procedure and
it can be safely done at counts of 1 × 109/l
with pressure bandages applied. The
anesthesiologist will want to ensure an
adequate hemoglobin level for anesthesia
and be aware of any metabolic abnormalities.
4. The technician to assist with the marrow
slide preparation should be present at the
start of the procedure with appropriate
materials.
Materials
1. Biopsy tray with providone iodine, alco-
hol, 4 × 4 gauze, 20 ml syringes (two to four
depending on samples to be collected),
15‐gauge bone marrow aspirate needle,
11‐gauge Jamshidi biopsy needle (or simi-
lar), 22–25‐gauge needles, sterile gloves, and
Elas­toplast adhesive or other pressure
dressing.
2. Ethylendiaminetetraacetic acid (EDTA)
and heparin to anticoagulate samples (if
done), lidocaine 1% for local anesthesia.
Guide to Procedures 399
Procedure
1. Position patient in a prone or lateral
decubitus position with a small lift under the
hip to accentuate the posterior iliac crests.
Identify the posterior superior iliac spine.
Have assistant secure patient’s position. Put
on gloves and set up sterile tray.
2. Scrub the site with providone iodine,
applying some friction, beginning at the site
and moving outward, and repeating for a
total of three scrubs. Repeat procedure with
alcohol swabs. Allow to dry and apply sterile
drapes.
3. Administer local anesthetic with a 22–25‐
gauge needle. This is often done in the
sedated patient to minimize postprocedure
discomfort. Local anesthesia is achieved with
lidocaine 1% (2–3 ml depending on size of
the patient) injected down to and including
the periosteum.
4. Prepare marrow aspirate and/or biopsy
needles, ensuring the stylets are freely
removable. Prime syringes as per institu-
tional protocol with heparin, EDTA, etc.
Ensure inner side of syringe is coated with
anticoagulant, if being used.
5. Holding skin taught with outstretched
fingers, insert the BMA needle (with stylet
in place) initially at an angle to the skin and
then perpendicular to the iliac spine once
through the skin. With gradual, controlled
pressure and a gentle twisting motion,
insert the needle into the iliac spine. Once
through the cortex, the needle will “give” as
it enters the marrow space and a crunching
sound or feeling may be appreciated. The
stylet should then be removed, and the nee-
dle should remain firmly in place. A 20‐ml
syringe is then firmly attached to the hub of
the aspiration needle. Holding onto both the
needle and syringe, constant and strong
pressure should be applied to draw up mar-
row into the syringe. If awake, the patient
may experience a shooting sensation down
the legs at the time of aspiration. Aspirate
approximately 1–2 ml of marrow, detach the
400 Chapter 31
syringe carefully, and hand the specimen
immediately to the technician for quick vis-
ual inspection for marrow tissue (fat, spic-
ules). Once this has been confirmed, obtain
additional marrow as needed with the other
syringes, obtaining not more than 3–5 ml
per pull. In order to obtain optimal speci-
men, repositioning of the bone marrow
aspirate needle should also be considered
between pulls and should always be
attempted if the first specimen does not con-
tain spicules. Once complete, remove the
needle. If spicules are not present even with
repositioning, a biopsy should be consid-
ered for adequate sampling.
6. A bone marrow biopsy may be obtained
from the same side and skin puncture site as
the aspirate. The needle should be inserted
into a fresh spot on the iliac spine (although
should utilize the same skin puncture site).
Holding the skin tight, insert the bone mar-
row (trephine) biopsy needle (with cutting
trocar in place) holding at an angle until
through the skin, then placing perpendicular
to the spine and inserting with strong, con-
trolled pressure until the needle is firmly
anchored into the cortex. Remove the trocar
and holding the forefinger along the needle
at the desired depth of the core biopsy
(5–20 mm depending on size of the patient),
insert the needle with a firm twisting pres-
sure. The needle is then rocked in four angles
(i.e., sideways as well as up and down) to
break off the core marrow biopsy sample at
the base (unless a cutting needle is used) and
then the needle is removed. The provided
push rod (no sharp edge) is inserted into the
sharp end of the needle and the biopsy is
pushed out gently onto sterile gauze. It is
then examined to ensure that adequate mar-
row tissue is present and given to the
technician.
7. Apply pressure for several minutes,
cleanse the site with alcohol swabs, and
apply a bandage. If needed, a dry 4 × 4 gauze
folded into quarters may be applied over the
site and secured with an elastic pressure tape
such as Elastoplast.
8. Assess the patient for any adverse effect
of the procedure.
9. Document procedure(s) in the medical
record.
10. Follow up with the patient and family to
ensure completion of procedure, explanation
of any complications, review care of wound,
and follow up on results of studies done on
specimens obtained.
Post-procedure monitoring
and complications
1. Patients may be discharged from the
recovery area after appropriate monitoring
post-anesthesia.
2. The pressure dressing, if used, should be
removed after 6 hours and the bandage after
24 hours. The parents should inspect the site
for evidence of infection, bleeding, or other
drainage. Pain medications including aceta-
minophen, acetaminophen with codeine, or
occasionally an IV narcotic may be adminis-
tered for local pain (especially following
biopsy). Patients may feel achy or bruised
for several days following the procedure.
Discomfort can also be alleviated with a
warm pack.
3. Patients may resume normal activities as
desired.
Administration of peripheral
chemotherapy
Indications
IV chemotherapy may be given into a CVC
or by peripheral vein administration in
patients without a CVC. Many patients may
have had their catheters removed due to
infection, thrombosis, or electively in order
for the patient to resume more normal activ-
ities. In the hands of experienced practition-
ers, administration of push IV chemotherapy
is a safe alternative to the use of a CVC.

Vincristine is frequently administered via
peripheral vein in the outpatient setting dur-
ing maintenance phases of treatment for
acute lymphoblastic leukemia. Peripheral
access should not be used routinely for
longer infusional chemotherapy due to the
difficulty in monitoring and ensuring con-
tinued patency of the IV during infusion.
Many chemotherapeutic drugs are vesicants
and may cause significant injury with
extravasation (see Chapter 32).
Pretreatment evaluation
1. Review the patient’s chemotherapy regi-
men to determine what medications are to be
administered and at what dose. The patient’s
height, weight, and total body surface area are
verified with the dosage calculations.
2. Ensure that required laboratory criteria
have been met (e.g., absolute neutrophil
count, platelet count, transaminases) as
directed by the treatment protocol.
3. Complete a physical examination on the
patient and assess the adequacy of
venipuncture sites, avoiding joints.
4. Verify the labels on the syringe(s) of the
drug(s) against the patient’s chart and orders
to ensure accuracy.
5. Prepare the patient for the procedure.
Explain the procedure, taking into account
the patient’s age, developmental status, and
prior experience with the procedure. Elicit
the patient’s help by encouraging him/her
to hold as still as possible. Enlist the assis-
tance of the parent(s), staff (including child
life specialist if available), and other distrac-
tions (iPad, virtual reality) as available and
needed. Explain each step as you go; be
honest, thorough, and patient. Establish a
routine with each patient; many also like to
have the same practitioner if possible (con-
fidence boosting).
6. Patients desiring topical anesthesia
should have a topical lidocaine gel (EMLA
or LMX) applied 20–30 minutes in advance
of the procedure. This however may result
Guide to Procedures 401
in vasoconstriction and increase difficulty
of access in some patients.
Materials
1. Chemotherapy (premixed by pharmacy
in enclosed syringe).
2. 25‐gauge butterfly needle, stopcock,
alcohol wipes, gauze (2 × 2), tourniquet,
10 ml saline flush, bandage, and gloves.
Procedure
1. Assemble equipment; attach butterfly
tubing to stopcock, attach chemotherapy
syringe to right side of stopcock, attach
saline flush syringe to remaining junction of
stopcock, and flush stopcock and butterfly
with saline.
2. Select an appropriate vein, preferably on
the dorsum of the hand or foot. Ask the child
to assume a comfortable position that also
allows for easy access to the desired vein.
Avoid the antecubital fossae or joint spaces
due to the possibility of deep extravasation of
chemotherapy with resultant injury such as
contractures. These deeper spaces also pre-
vent immediate knowledge of extravasation.
3. Clean the venipuncture site with alcohol
and apply a tourniquet. Let air dry or wipe
dry with clean gauze. Insert butterfly needle
with bevel pointed up. Advance needle until
blood returns. When blood returns, remove
tourniquet, connect stopcock, and flush line
with 2–3 ml of saline.
4. If no sign of infiltration occurs (e.g., pain
or swelling) and blood return continues,
administer chemotherapy slowly via IV push,
checking intermittently every 5–10 seconds
for blood return or swelling. When chemo-
therapy administration is completed, flush
with remaining saline.
5. Remove butterfly and apply pressure
for 1 to 2 minutes with clean gauze. Apply
bandage.
6. Document in the patient’s chart the indi-
cation for and details of the procedure, med-
ication, dosage, site, and any complications.
402 Chapter 31

Postprocedure monitoring should not be used for future administration

and complications of chemotherapy. At times, subclinical burns
If infiltration has occurred, see Chapter 32. and scarring may occur and can appear as
Areas that may have sustained tissue damage hyperpigmented areas.
32 Treatment of
Chemotherapy
Extravasations
In addition to potential acute and late
adverse reactions to chemotherapy, acciden-
tal extravasation is a major safety concern.
Preventative strategies to minimize compli-
cations of administration, early recognition,
and an understanding of unique manage-
ment approaches and antidotes are critical
to lessening the acute injury as well as long‐
term consequences.
Extravasation is the leakage of an intra-
venous (IV) drug into the surrounding tis-
sues. Local reactions from extravasation of a
vesicant chemotherapy agent can range
from mild pain and erythema to tissue
necrosis, ulceration, and damage to tendons
and nerves. Cytotoxic drugs are classified as
irritants or vesicants (causing blisters),
based on their potential for local toxicity,
though this distinction is not absolute. The
tissue injury may also be related to the
amount of drug extravasated.
Although this complication is frequently
encountered with antineoplastic agents, a
number of other drugs can also act as vesi-
cants if extravasated into the surrounding
tissues. These noncytotoxic drugs include
alcohol, aminophylline, digoxin, nafcillin,
phenytoin, tetracycline, and total parenteral
nutrition. In terms of cytotoxic drugs that
cause extravasation injury, the anthracy-
Handbook of Pediatric Hematology and Oncology – Children’s Hospital & Research Center Oakland,
Third Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
clines are among the most important, both
because of their widespread use in various
chemotherapeutic protocols and because of
their ability to produce severe tissue damage
and necrosis. The extent of tissue damage
depends on the chemotherapeutic agent’s
binding capacity to DNA:
●● Extravasation of an irritant drug may
cause an inflammatory reaction, with pain,
burning, tightness, or phlebitis at the needle
insertion site or along the vein. Clinical
signs include warmth, erythema, and ten-
derness in the area of extravasation, but
there is no tissue sloughing or necrosis.
Symptoms are typically of short duration
(days) without long‐lasting sequelae.
●● Extravasation of a vesicant drug may
cause tissue necrosis with a more severe or
lasting injury. Clinical signs and symptoms
may be similar to extravasated irritants.
Vesicant extravasation may result in loss of
the full thickness of the skin and, if severe,
underlying structures.
The true incidence of vesicant extravasa-
tion injury is unclear, but it is estimated to
range from 0.5–6% with peripheral IV infu-
sions, and 0.3–4.7% with implanted venous
access port infusions. Realistically, the inci-
dence is likely higher, as there is no central
mechanism of reporting these events.
404 Chapter 32
Treatment of an extravasation is determined
by the particular chemotherapy agent
involved, although the efficacy of such ther-
apy may be modest.
Prevention of extravasation is key, and
every possible measure should be taken to
avoid such a complication. If it is anticipated
that a patient will need frequent or pro-
longed infusions of vesicants, it is advisable
to place a central venous catheter (CVC) for
safer drug administration by providing reli-
able venous access, high flow rates, and
rapid drug dilution. Rarely, extravasation
may occur even with such a device due to
injection technique or device failure, includ-
ing catheter migration. Providing education
to patients and families is important, and
they should be instructed to immediately
report any burning sensation related to the
drug infusion, swelling, redness, or pain.
The causes of extravasation are multiple
and largely preventable. Risk factors for
peripheral IV extravasation include: poor
vein selection, multiple venous punctures to
establish a patent IV, obesity, dehydration,
inability to report pain at the injection site, a
moving patient, and inexperience of the
individual administering the chemotherapy.
Risk factors for extravasation from CVCs
include needle displacement, catheter
migration, or fibrin sheath formation and
thrombosis. Mechanical occlusions may be
due to thrombus formation, drug precipita-
tion, and positional catheter occlusion or
kinking of the line. Avoidance of extravasa-
tion depends on proper placement and
maintenance of IV access and frequent
monitoring.
Recommendations to prevent extravasa-
tion are:
●● Venipuncture and placement of the can-
nula or other IV access should be performed
by experienced personnel.
●● Vesicants should be administered in
accordance with the manufacturers’
recommendations (i.e., proper dilution
and specified administration time) with
proper verification and identification
(patient and protocol specific).
●● Avoid multiple venipunctures in the same
area. Do not use a vein distal to a recent
venipuncture site, as the vesicant may leak
from one of these proximal sites.
●● Instruct the patient to avoid movement.
In young children, this may require addi-
tional physical assistance for holding or
coaxing with diversion techniques.
●● Never use a previously placed IV access
device; a new IV cannula should be placed
immediately prior to delivery of the
medication.
●● Choose a large, intact visible vein with
good blood flow.
●● Use the smallest needle or cannula possi-
ble for venipuncture. Check the patency of
the device by aspirating blood, as well as
patency of the vein by flushing with the car-
rier solution (normal saline), before admin-
istering the medication. Obtain a blood
return prior to, and during, vesicant
administration.
●● The IV infusion should flow freely with-
out pressure. The local area should not swell,
become erythematous, or cause pain. If this
occurs, immediately stop the infusion and
attempt to withdraw any medication in the
needle/cannula.
●● After infusing the medication, flush the
vein with 3–10 ml of the carrier solution. Do
not continue to flush if resistance is met or a
local reaction suggesting a blown vein
occurs.
●● For ports, it is vital to ensure appropriate
securement of the Huber needle with dress-
ings that enable the provider to visualize the
site of access.
Each extravasation incident should be
documented and reported, according to
local institutional guidelines. Standards of
practice as well as documentation should be
 Treatment of Chemotherapy Extravasations 405
in place and most centers utilize national
guidelines (including management) based
on the ASCO (American Society of Clinical
Oncology) or ONS (Oncology Nursing
Society) published safety standards for
chemotherapy administration.
DNA‐binding agents including anthracy-
clines, antitumor antibiotics, platinum ana-
logs, and some alkylating agents can cause
tissue damage by propagating lethal DNA
cross‐linking or strand breaks caused by free
radicals, which lead to cell apoptosis. As the
cells die, the drug is released and enters
undamaged cells. This further increases the
area of damage and slows healing.
Anthracyclines have the greatest vesicant
potential compared to other chemotherapeu-
tic agents and are characterized by immediate
burning or severe pain, and lesions may con-
tinue to evolve slowly over weeks due to tis-
sue retention of the extravasated vesicant.
Non‐DNA‐binding antineoplastics
(vinca alkaloids, taxanes, and topoisomer-
ase inhibitors) also function as vesicants by
interfering with mitosis. These agents clear
more easily from extravasation sites and
cause less damage than the DNA‐binding
agents. The tissue often resembles a chemi-
cal burn and blisters may develop.
The signs and symptoms of extravasa-
tion may be readily apparent with a burning
sensation, swelling, pain, or erythema,
although it may take days for the full extent
of the epithelial damage to be evident.
Caregivers should be careful to never under-
estimate the significance of any symptom
the patient may report related to the infu-
sion, and perform a careful assessment of
the infusion and site. Sometimes patients
are not symptomatic and the tissue damage
becomes evident days to weeks later.
Discoloration and skin induration may pro-
gress with the development of blisters or
necrosis and possibly ulceration or deep tis-
sue injury. Patients may develop scarring or
permanent hyperpigmentation at the site of
drug extravasation. Tissue damage can
injure tendons, nerves, and joints in the
affected area. For this reason, it is recom-
mended that peripheral access for IV chem-
otherapy administration never be in an area
near a joint or deep tissue site, as extravasa-
tion may lead to contractures or serious
injury before the leakage is recognized.
Extravasation sites should not be utilized for
subsequent administration of chemotherapy
or placement of an IV device.
Treatment should begin immediately
with discontinuation of the chemotherapy
and thermal application and possible dilu-
tion of the site. The line should not be
flushed and avoid applying pressure to the
site. The needle/catheter should not be
removed immediately, but should be left in
place to attempt to aspirate fluid from the
extravasated area with a 10‐ml syringe, as
well as administer an antidote if appropriate
(see Table 32.1). Clinicians should work
quickly to reduce morbidity and avoid fur-
ther patient harm. Management of non‐­
vesicant extravasation includes elevation
and cooling and does not usually include the
use of pharmacologic therapy. Cold com-
presses can reduce pain and local inflamma-
tion by causing vasoconstriction and
reducing the potential for continued spread
of the drug. Cold compresses are contrain-
dicated however in the case of extravasation
with vinca alkaloids, as it may cause further
tissue damage. In these situations, warm
compresses and heat can be applied to the
affected area leading to vasodilation and
absorption of extravasated drug from the
tissue site (see Table 32.1). Other interven-
tions under investigation include local
administration of granulocyte‐macrophage
colony‐stimulating factor or local injection
of normal saline. Removal of the CVC may
be indicated for extensive extravasations or
in the case of device malfunction.
406 Chapter 32

Table 32.1 Extravasation treatment.

Drug Local care Pharmacologic treatment

DNA‐binding vesicants
Anthracyclines Cold pack, 20 min Dexrazoxane 1000 mg/m2 IV over
Doxorubicin 4 times/d × 48–72 h 1–2 h (within 6 h) on days 1 and 2;
Daunomycin Elevate 500 mg/m2, day 3
If dexrazoxane unavailable or minor
extravasation: DMSO 99% topical
4 drops per 10 cm2 over twice the size
of the affected area within 10–25 min,
then q8 hour × 7–14 d; allow to dry,
then apply nonocclusive dressing*
Do not use Dexrazoxane and DMSO
concurrently
Alkylating agents Cold pack, 20 min None
Nitrogen mustard 4 times/d × 48–72 h Sodium thiosulfate
Elevate 10% 2 ml in 6 ml sterile water for
IV/SC injection*
Other Cold pack, 20 min None
Dactinomycin 4 times/d × 48–72 h DMSO as mentioned above*
Mitomycin C Elevate Hydrocortisone 1% cream topically
Dacarbazine
Non‐DNA‐binding vesicants
Vinca alkaloids Warm pack, 20 min None
Vinblastine 4 times/d × 48–72 h Hyaluronidase 150 units in 1 ml injected
Vincristine Elevate SC in multiple sites with small gauge
Vindesine needle*
Taxanes Cold pack, 20 min Hyaluronidase as mentioned above*
Docetaxel 4 times/d × 48–72 h
Paclitaxel Elevate
Irritants
Alkylating agents
Carboplatin Cold pack as Hydrocortisone 1% cream topically
Cisplatin mentioned above
Topotecan None None
Ifosfamide No local care
Cyclophosphamide
Melphalan
Antimetabolites
Cytarabine, fludarabine None None
Methotrexate Cold pack as Hydrocortisone 1% cream topically
5‐fluorouracil mentioned above
Gemcitabine None None
Other
Bleomycin None None
Etoposide, irinotecan Cold pack as Hydrocortisone 1% cream topically
mentioned above

* Suggested as possible antidote in the literature; lack of prospective studies to currently advocate
as treatment. Abbreviations: DMSO, Dimethyl Sulfoxide; IV, intravenous; SC, subcutaneous.
 Treatment of Chemotherapy Extravasations 407
The placement of extravasation kits con-
taining syringes and cannulas, cold and hot
packs, gauze pads, sterile and chemoprotec-
tive gloves, and medications to treat extrava-
sation in locations where chemotherapy is
administered facilitate early treatment (see
Table 32.1). In addition to local care and pos-
sible pharmacologic antidotes, topical hydro-
cortisone 1% and oral pain medications may
alleviate local discomfort. Patients should be
instructed to continue to elevate the affected
area as possible for 24–48 hours and apply the
appropriate thermal intervention four times a
day for 20 minutes for 2–3 days. Monitoring
the area with daily photos may be helpful.
Clinical follow‐up is recommended, as the
extent of damage may not become apparent
until days or weeks following the injury.
Rarely, referral for surgical intervention, such
as debridement of necrotic tissue or skin
grafting, may be necessary.
Suggested reading
Jacobson, J.O., Polovich, M., Gilmore, T.R. et al.
(2012). Revisions to the 2009 American Society
of Clinical Oncology/Oncology Nursing
Society chemotherapy administration safety
standards: expanding the scope to include
patient inpatient settings. J. Oncol. Pract. 8: 2.
Kreidieh, F.Y., Moukadem, H.A., and El Saghir,
N.S. (2016). Overview, prevention and man-
agement of chemotherapy administration.
World J. Oncol. 7: 87–97.
Neuss, M.N., Polovich, M., McNiff, K. et al.
(2013). 2013 updated American Society of
Clinical Oncology/Oncology Nursing Society
chemotherapy administration standards
including standards for the safe administra-
tion and management of oral chemotherapy.
Oncol. Nurs. Forum. 40: 225.
 Formulary
Sample entry:
Generic name
Trade and other names
Drug category
How supplied
Pregnancy category (see explanation in the
following text)
Indications
Dosage
Notes, including adverse events, monitor­
ing, and dose modification
Pregnancy categories:
A. Adequate studies in pregnant women
have not demonstrated a risk to the fetus in
the first trimester of pregnancy, and there is
no evidence of risk in later trimesters.
B. Animal studies have not demonstrated a
risk to the fetus, but there are no adequate
studies in pregnant women; or animal stud­
ies have shown an adverse effect, but ade­
quate studies in pregnant women have not
demonstrated a risk to the fetus during the
first trimester of pregnancy, and there is no
evidence of risk in later trimesters.
C. Animal studies have shown an adverse effect
on the fetus, but there are no adequate studies in
humans; or there are no animal reproduction
studies and no adequate studies in humans.
D. There is evidence of human fetal risk,
but the potential benefits from the use of the
Handbook of Pediatric Hematology and Oncology – Children’s Hospital & Research Center Oakland,
Third Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
drug in pregnant women may be acceptable
despite its potential risk.
E. Studies in animals or humans demon­
strate fetal abnormalities or adverse reaction;
reports indicate evidence of fetal risk. The
risk of use in a pregnant woman clearly out­
weighs any possible benefit.
ACTINOMYCIN D, see DACTINOMYCIN
ACYCLOVIR
Zovirax, generics
Antiviral
Capsules: 200 mg
Tablets: 400, 800 mg
Suspension: 200 mg/5 ml
Injection: 500 mg vial
Pregnancy category B
Indications:
Treatment of initial, and prophylaxis for
recurrent, mucosal, and cutaneous herpes
simplex virus (HSV‐1 and HSV‐2) infections,
herpes simplex encephalitis, herpes zoster
infections, and varicella zoster infections.
Dosage:
Children over age 12 years:
Mucocutaneous HSV
Initial infection: 750 mg/m2/day IV divided
q8h or 15 mg/kg/day IV divided q8h for
410 Formulary
5–7 days; 1000–1200 mg/day PO divided
into 3–5 doses for 7–10 days.
Recurrence: 1000 mg/day divided into 5
doses or 1600 mg/day divided q12h or
2400 mg/day divided q8h for 5–10 days
(maximum pediatric dose 1000 mg/day).
Immunocompromised host (all ages)
HSV: 750–1500 mg/m2/day IV divided q8h
for 7–14 days or (≥2 years) 100 mg/day PO
divided into 3–5 doses for 7–14 days (maxi­
mum child dose 80 mg/kg/day).
HSV prophylaxis: 750 mg/m2/day IV divided
q8h or 600–1000 mg/day divided q6–8h
during risk period (maximum child dose
80 mg/kg/day).
Varicella or zoster: 1500 mg/m2/day IV
divided q8h or 20 mg/kg/dose IV divided q8h
for 7–10 days (maximum PO dose 800 mg).
Notes:
Adjust dose in renal impairment. Adequate
hydration and slow IV (1 hour) administration
are essential to prevent crystallization in the
renal tubules. Oral absorption is unpredictable
(15–30%), consider use of valacyclovir for bet­
ter absorption. Use ideal body weight for obese
patients when calculating dosage.
ADRIAMYCIN, see DOXORUBICIN
ALLOPURINOL
Zyloprim, Alloprim, generics
Uric acid lowering agent, xanthine oxidase
inhibitor, antigout agent
Tablets: 100, 300 mg
Suspension: 20 mg/ml
Injection (Alloprim): 500 mg vial
Pregnancy category C
Indications:
Prevention of uric acid nephropathy in mye­
loproliferative neoplastic disorders that may
occur as a result of tumor lysis syndrome;
prevention of recurrent calcium oxalate cal­
culi; prevention of gouty arthritis and
nephropathy.
Dosage:
Children: 10 mg/kg/day PO divided q6–8h;
maximum dose 800 mg/day or 200–300 mg/
m2/day IV q8–24h; maximum 800 mg/day
or 200 mg/m2/day IV divided q6–12h (max­
imum dose 600 mg/day).
Adolescent to adult: 200–800 mg/day PO
divided q8–12h for the prevention of acute
uric acid nephropathy; or 200–400 mg/m2/
day IV divided q6–12h (maximum dose
600 mg/day).
Notes:
Reduce dosage in renal impairment; discon­
tinue with rash (may be exacerbated with
ampicillin or amoxicillin). Risk of hypersen­
sitivity may be increased in patients receiving
thiazides/angiotensin‐converting enzyme
inhibitors. It may cause fever, neuritis, gastro­
intestinal (GI) disturbance, hepatotoxicity,
bone marrow suppression, and drowsiness.
Avoid concomitant use of amoxicillin, ampi­
cillin, mercaptopurine, cyclophosphamide,
theophylline derivatives, and vitamin K
antagonists.
ALTEPLASE
Tissue plasminogen activator (TPA)
Activase, Cathflo Activase, TPA
Thrombolytic
Injection:
Cathflo Activase: 2 mg/2 ml vial
Activase: 50 mg (29 million units), 100 mg
(58 million units)
Pregnancy category C
Indications:
Treatment of recent severe or massive
deep vein thrombosis (DVT) or arterial
thrombosis, pulmonary embolus, or
occluded central venous catheter (CVC).

Dosage:
Pulmonary embolus, DVT, central venous
thrombosis, superior vena cava syndrome:
Systemic thrombolytic therapy should be
given in consultation with a hematologist.
Safety and efficacy have not been estab­
lished in pediatric patients.
<3 months of age: 0.06 mg/kg/hour for
6–24 hours.
≥3 months of age: 0.03 mg/kg/hour (maxi­
mum 2 mg/hour).
If no clinical improvement in 24 hours, dou­
ble the dose to 0.06–0.12 mg/kg/hour.
Systemic TPA can be given for up to 96 hours.
In the case of a pulmonary embolus, bolus
dosing of 1 mg/kg up to a maximum of
50 mg may be given.
Maximum duration of therapy is 96 hours or
based on the patient’s clinical course.
Preferable to infuse thrombolytic agent dis­
tal to (and as close to) the site of thrombus
as possible.
Occluded CVC (dosage per lumen, treating
one lumen at a time):
Weight < 30 kg: instill volume to equal 110%
of internal volume of the catheter, not to
exceed 2 mg.
Weight ≥ 30 kg: 2 mg per lumen.
Instill a dose in each lumen of the CVC;
allow to dwell for 30 minutes. If unsuccess­
ful, repeat the dose. If the catheter remains
obstructed, begin systemic thrombolytic
therapy as outlined in the preceding text.
Notes:
Avoid central venous puncture and noncom­
pressible arterial sticks during infusion.
Avoid use in excessive hypertension, within
10 days of a cerebral vascular accident, with
gastrointestinal bleeding or trauma, within
1 week of surgery, in patients with a bleeding
diathesis, or with suspicion of a subarach­
noid hemorrhage. Plasminogen levels should
Formulary 411
be followed daily and fresh frozen plasma be
given for replenishment if level <50%.
AMIFOSTINE
Ethyol
Antidote for cisplatin, cytoprotective agent
Injection: 500 mg vial
Pregnancy category C
Indications:
A cytoprotective drug that scavenges free
radicals and binds to reactive drug deriva­
tives reducing toxicity of radiation and
platinum‐containing and alkylating agents
such as cisplatin, carboplatin, ifosfamide,
carmustine, melphalan, mechlorethamine,
and cyclophosphamide. The safety and
effectiveness of amifostine have not yet
been established in pediatric patients and
its use has been primarily in the setting of
clinical trials.
Dosage:
Refer to individual protocol.
Usual dosage is 740–910 mg/m2 IV daily
over 15 minutes starting 30 minutes prior to
the dose of a platinum or alkylating agent.
Infusions over less than 15 minutes are asso­
ciated with a higher incidence of adverse
reactions.
Notes:
Avoid in hypotension or dehydration. Can
cause severe nausea and vomiting and usu­
ally requires antiemetic premedication.
Allergic reactions, severe cutaneous toxicity
(more commonly when used as a radiopro­
tectant), and hypocalcemia have been
reported. Ensure adequate hydration and
monitor calcium levels.
AMINOCAPROIC ACID
Amicar, generics
Hemostatic agent
412 Formulary
Tablet: 500, 1000 mg
Syrup: 250 mg/ml
Injection: 250 mg/ml (20 ml)
Pregnancy category C
Indications:
Enhances hemostasis when fibrinolysis con­
tributes to clinical bleeding. Excessive activ­
ity of the fibrinolytic system may be present
following cardiac surgery, portacaval shunt,
hepatic cirrhosis, aplastic anemia, and
abruptio placentae. Typically used to treat
mucosal‐type bleeding in patients with
bleeding diatheses (i.e., von Willebrand dis­
ease, mild hemophilia, immune thrombocy­
topenia purpura).
Dosage:
100–200 mg/kg IV/PO loading dose (maxi­
mum 10 g), followed by 50–100 mg/kg
q4–6h maintenance dose; maximum
30 g/24 hour. Treat until symptoms resolve
(1–14 days).
Low doses (10 mg/kg) have been reported to
control bleeding in patients with thrombo­
cytopenia for long periods of time (i.e.,
weeks to months).
Continuous IV infusion: Loading dose of
100 mg/kg, then 10–33 mg/kg/hour in 5%
dextrose in water (maximum 1.25 g/hour).
Notes:
May accumulate in patients with decreased
renal function and require decreased dos­
ing. Avoid in patients with disseminated
intravascular coagulation or upper uri­
nary tract bleeding (hematuria) due to
increased risk of forming clots in the col­
lecting system. Increased risk of thrombo­
sis with oral contraceptives, estrogens,
and factor IX or prothrombin complex
concentrates (PCC). May cause nausea,
diarrhea, malaise, headache, decreased
platelet function, and false increase in uri­
nary amino acids.
AMPHOTERICIN B (Conventional)
Generics (previously available as Fungizone)
Polyene antifungal
Injection: 50 mg vial
Pregnancy category B
Indications:
Treatment of severe systemic infections and
meningitis caused by susceptible fungi such
as Candida species, Histoplasma capsulatum,
Cryptococcus neoformans, Aspergillus spe­
cies, Blastomyces dermatitidis, Torulopsis
glabrata, Coccidioides immitis, Mucormycoses,
and Rhizopus. Also used empirically to treat
suspected invasive fungal disease in immu­
nocompromised hosts with prolonged fever
and neutropenia. May be given intrathecally
or via bladder irrigation for localized ther­
apy. Note, currently the lipid formulations of
amphotericin are used as first line.
Dosage:
Optional test dose: 0.1 mg/kg to a maximum
of 1 mg IV over 20–60 minutes.
Initial dose: 0.5–1.0 mg/kg/day IV.
The daily dose is increased by 0.25 mg/kg
until the desired daily dose is reached. In
critically ill patients, rapid escalation of dos­
ing may be needed.
Empiric dose is 0.6 mg/kg/day IV.
Therapeutic dose for confirmed invasive
fungal infection is 0.5–1 mg/kg/day IV.
Daily infusion is over 2–6 hours, depending
on the infusion tolerability. Every other day
dosing can be given at 1.5 mg/kg/dose. Salt
loading with 10–15 ml/kg of normal saline
prior to each infusion may prevent hypoka­
lemia and nephrotoxicity. Premedication is
frequently needed with acetaminophen and
diphenhydramine 30 minutes prior to dose
(with repeat 4 hours later, if necessary).
Hydrocortisone (1 mg/mg of amphotericin,
maximum 25 mg) may be added to the bot­
tle to possibly prevent immediate reactions.

If the patient experiences rigors, meperidine
hydrochloride may be given. Once therapy
has been established, alternate‐day dosing
may be administered at a dose of 1–1.5 mg/
kg/IV every other day. For obese patients,
use total body weight for dose calculation.
Notes:
Administration of other nephrotoxic drugs
may result in synergistic toxicity and should
be avoided if possible. Monitor daily electro­
lytes, renal and hepatic studies, and urine
output. Common metabolic abnormalities
include hypokalemia, hypomagnesemia,
and hypocalcemia. Other problems that
may occur are thrombocytopenia, hypergly­
cemia, diarrhea, dyspnea, back pain, and
increases in transaminases and bilirubin.
Common infusion‐related toxicities are fever,
chills, rigors, nausea, vomiting, hypoten­
sion, and headache.
AMPHOTERICIN B LIPID COMPLEX
(ABLC)
Abelcet, ABLC
Polyene antifungal
Injection: 5 mg/ml (10, 20 ml)
Pregnancy category B
Indications:
Treatment of aspergillosis or invasive fungal
infection. Higher concentrations are achieved
in the spleen, lung, and liver, and therefore
may be more beneficial in the treatment of
hepatosplenic candidiasis. Cerebrospinal
fluid (CSF) levels may be lower than with
amphotericin B or the liposomal compound.
Dosage:
Usual dose is 2.5–5 mg/kg IV once daily
over 2 hours. Rate should not exceed 2.5 mg/
kg/hour.
Notes:
See Amphotericin B.
Formulary 413
AMPHOTERICIN B, LIPOSOMAL
AmBisome
Polyene antifungal
Injection: 50 mg vial
Pregnancy category B
Indications:
Treatment of systemic or invasive fungal
infection. Cerebrospinal fluid concentrations
are higher than with other amphotericin
products as well as higher concentrations in
the liver and spleen than with conventional
amphotericin B.
Dosage:
Systemic fungal infections: 3–5 mg/kg/once
daily IV over 2 hours (may be reduced to a
1‐hour infusion if well‐tolerated). Doses as
high as 10 mg/kg/day have been used in
patients with Aspergillus sp.
Empiric therapy for fever and neutropenia:
3 mg/kg IV once daily.
Infusion may be shortened to 1 hour if
well‐tolerated.
Notes:
See Amphotericin B.
ANTI‐THYMOCYTE GLOBULIN (ATG)
Thymoglobulin (rabbit ATG, rATG,
Genzyme)
Atgam (equine ATG, eATG, Pfizer)
Injection: 50 mg/ml
Pregnancy category C
Indications:
Anti‐thymocyte globulin is an infusion of
rabbit‐ or horse‐derived antibodies against
human T‐cells, which is used in the preven­
tion and treatment of acute rejection in
organ or hematopoietic transplantation and
therapy of aplastic anemia and refractory
histiocytic disorders.
414 Formulary
Dosage:
Aplastic anemia: rATG 3.5 mg/kg/day IV on
days 1–5 or hATG 40 mg/kg/day IV on days
1–4. Cyclosporine is given following the last
day of hATG or rATG infusion and adjusted
to maintain a serum level of 200–400 ng/ml
or based on renal toxicity or tolerability.
Patients typically receive corticosteroids,
usually methylprednisolone, at a dose of
1 mg/kg per day, from day 1 until day 14; the
dose is thereafter tapered down to prevent
serum sickness.
Skin testing before the first infusion is rec­
ommended. Patients are tested with an
intradermal injection of 0.1 ml of a 1:1000
dilution of ATG in sodium chloride injec­
tion with a contralateral sodium chloride
injection control. The patient, and specifi­
cally the skin test site, should be observed
every 15–20 minutes over the first hour after
intradermal injection. A local reaction of
10 mm or greater with a wheal or erythema,
or both, with or without pseudopod forma­
tion, and itching or a marked local swelling
should be considered a positive test.
Notes:
Thymoglobulin and Atgam are currently
licensed for use in the treatment of renal
allograft rejection; Atgam is additionally
licensed for use in the treatment of aplastic
anemia. Both drugs are used in a number of
off‐label applications.
The predictive value of the skin test has not
been proved clinically. Allergic reactions
such as anaphylaxis have occurred in
patients whose skin test is negative. In the
presence of a locally positive skin test to
ATG, serious consideration to alternative
forms of therapy should be given. The risk
to benefit ratio must be carefully weighed. If
therapy with ATG is deemed appropriate
following a locally positive skin test, treat­
ment should be administered in a setting
where intensive life support facilities are
immediately available and with a physician
familiar with the treatment of potentially
life‐threatening allergic reactions in attend­
ance. A systemic reaction such as a general­
ized rash, tachycardia, dyspnea, hypotension,
or anaphylaxis precludes any additional
administration of ATG.
ATG administration very substantially
reduces immune competence in patients with
normal immune systems. rATG in particular
affects large reductions (through cell lysis) in
the number of circulating T‐lymphocytes,
hence preventing (or at least delaying) the cel­
lular rejection of transplanted organs or
hematopoietic cells. In the United States, it is
frequently given at the time of the transplant
to prevent graft‐versus‐host disease (GVHD).
ATG use can induce cytokine release syn­
drome (CRS), and has been thought to
increase the risk of posttransplant lymphopro­
liferative disorder (PTLD); however, this asso­
ciation may not apply when lower‐dosing
regimens are used. There is some evidence to
suggest that inducing immunosuppression
with rATG at organ transplantation may cre­
ate conditions in the patient’s immune system
favorable to the development of immunologi­
cal tolerance, but the exact basis for such a
development remains largely speculative.
Temporary depletion of the T‐cell population
at the time of the transplant also risks delayed
acute rejection, which may be missed and
cause severe damage to the graft.
APREPITANT
Emend
Substance P/neurokinin 1 (NK1) receptor
antagonist
Solution: 125 mg
Capsules: 40, 80, 125 mg
Injection (fosaprepitant): 150 mg
Pregnancy category B

Indications:
Aprepitant is indicated, in combination with
other antiemetic agents, in patients 6
months of age and older for prevention of
acute and delayed chemotherapy‐induced
nausea and vomiting (CINV) associated
with initial and repeat courses of highly
emetogenic drugs including high‐dose cis­
platin and CINV associated with initial and
repeat courses of moderately emetogenic
cancer chemotherapy.
Aprepitant is also indicated for prevention
of postoperative nausea and vomiting
(PONV) in adults. It has not been studied
for treatment of established nausea and
vomiting. Chronic continuous administra­
tion of aprepitant is not recommended.
Dosage:
Prevention of CINV in adults and pediatric
patients 12 years of age and older: 125 mg cap­
sule PO on day 1 and 80 mg capsule on days 2
and 3. Fosaprepitant (prodrug), 115 mg IV
infused over 15 minutes, can be substituted
for 125 mg oral aprepitant on day 1 only. The
oral suspension is available for pediatric
patients 6 months to less than 12 years of age
or pediatric and adult patients unable to
swallow capsules. Administer 1 hour prior to
chemotherapy on days 1, 2, and 3. If no
chemotherapy is given on days 2 and 3,
administer in the morning.
Patients aged 6 months to <12 years:
Day 1: 3 mg/kg or 72 mg/m2 PO, maximum
125 mg.
Days 2 and 3: 2 mg/kg or 46 mg/m2, maxi­
mum 80 mg.
Concomitant administration of dexametha­
sone and 5‐HT3 antagonist is recommended
as follows:
Highly emetogenic regimen: Adults:
Dexamethasone 12 mg on day 1; 8 mg on
days 2, 3, and 4 with 5‐HT3 antagonist per
Formulary 415
regular dosing recommendations. Pediatrics:
Administer 50% of the recommended dexa­
methasone dose and regular 5‐HT3 dosing.
Moderately emetogenic regimen: Adults:
Dexamethasone 12 mg on day 1. Pediatrics:
Administer 50% of the recommended dexa­
methasone dose and regular 5‐HT3 dosing.
Notes:
Oral capsules and suspension can be admin­
istered with or without food. Swallow cap­
sules whole. Known hypersensitivity is a
contraindication.
Aprepitant is a substrate, weak‐to‐moderate
(dose‐dependent) inhibitor, and an inducer
of CYP3A4. Concomitant administration of
the oral or IV form (fosaprepitant is rapidly
converted to aprepitant) may result in
increased plasma concentrations of the con­
comitant drug.
Warfarin is a CYP2C9 substrate and con­
comitant use may result in a decreased inter­
national normalized ratio (INR); monitor
INR over a 2‐week period, particularly at
7–10 days, following initiation of aprepitant.
There is concern for increased neurotoxicity
with aprepitant and certain chemotherapeu­
tics including vincristine and ifosfamide.
Use with caution, consider prophylaxis with
thiamine with ifosfamide.
Adverse reactions may include:
Adults (≥3%): fatigue, diarrhea, asthenia,
dyspepsia, abdominal pain, hiccups, white
blood cell count decreased, dehydration,
and alanine aminotransferase increased.
Pediatrics (≥3%): neutropenia, headache,
diarrhea, decreased appetite, cough, fatigue,
hemoglobin decreased, dizziness, and
hiccups.
Aprepitant does not affect the QTc interval.
Aprepitant does not affect the pharmacokinet­
ics of 5‐HT3 inhibitors such as ondansetron or
416 Formulary
granisetron. Corticosteroids: Dexamethasone
and methylprednisolone are CYP3A4
­substrates, and concomitant use with aprepi­
tant leads to an increased area under the curve
(AUC) for these drugs, therefore doses should
be reduced by approximately 50% when co‐
administered with a regimen of fosaprepitant
followed by aprepitant, to achieve exposures of
dexamethasone similar to those obtained
when dexamethasone is given without aprepi­
tant. The daily dose of dexamethasone admin­
istered in clinical CINV studies with oral
aprepitant reflects an approximate 50% reduc­
tion of the dose of dexamethasone.
The co‐administration of fosaprepitant or
aprepitant may reduce the efficacy of hor­
monal contraceptives during and for 28 days
after administration of the last dose of
either. Alternative or backup methods of
contraception should be used during treat­
ment with fosaprepitant or aprepitant and
for 1 month following the last dose.
Concomitant administration of fosaprepi­
tant or aprepitant with strong CYP3A4
inhibitors (e.g., ketoconazole, itraconazole,
nefazodone, troleandomycin, clarithromy­
cin, ritonavir, nelfinavir) should be
approached with caution. Co‐administra­
tion of fosaprepitant or aprepitant with
drugs that strongly induce CYP3A4 activity
(e.g., rifampin, carbamazepine, phenytoin)
may result in reduced plasma concentra­
tions and decreased efficacy.
ARSENIC TRIOXIDE (ATO)
Trisenox
Injection: 12 mg in 6 ml vials
Pregnancy category D
Indications:
Treatment of adults with newly diagnosed
low‐risk acute promyelocytic leukemia
(APL), as well as induction of remission and
consolidation in patients with APL who are
refractory to, or have relapsed from, retinoid
and anthracycline chemotherapy, and whose
APL is characterized by the presence of the
t(15; 17) translocation or PML/RAR‐alpha
gene expression.
Dosage:
Newly diagnosed low‐risk APL:
Induction: 0.15 mg/kg intravenously daily in
combination with tretinoin until bone mar­
row remission. Do not exceed 60 days of
induction.
Consolidation: 0.15 mg/kg intravenously
daily 5 days per week during weeks 1–4 of
an 8‐week cycle for a total of four cycles in
combination with tretinoin.
Relapsed or refractory APL:
Induction: 0.15 mg/kg intravenously daily
until bone marrow remission. Do not exceed
60 doses for total induction.
Consolidation: 0.15 mg/kg intravenously
daily for 25 doses over a period up to 5 weeks.
Notes:
Refer to specific protocol for dosing infor­
mation and modifications. Do not adminis­
ter to patients with known hypersensitivity
to ATO. The most common adverse reac­
tions (>30%) are leukocytosis, neutropenia,
thrombocytopenia, nausea, vomiting, diar­
rhea, abdominal pain, hepatic toxicity,
fever, rigors, fatigue, insomnia, tachycardia,
QTc prolongation, edema, hyperglycemia,
hypokalemia, hypomagnesemia, dyspnea,
cough, rash or itching, sore throat, arthral­
gia, headaches, paresthesia, and dizziness.
Patients treated with ATO have experienced
differentiation syndrome and cardiac con­
duction abnormalities. Symptoms of differ­
entiation syndrome, which can be fatal if not
treated, may include fever, dyspnea, acute
respiratory distress, pulmonary infiltrates,
pleural or pericardial effusions, weight gain
or peripheral edema, hypotension, and renal,

hepatic, or multi‐organ dysfunction, in the
presence or absence of leukocytosis. If differ­
entiation syndrome is suspected, immedi­
ately initiate high‐dose corticosteroid therapy
and hemodynamic monitoring until resolu­
tion of signs and symptoms. Temporary dis­
continuation of ATO may be required. ATO
can cause QTc interval prolongation, com­
plete atrioventricular block, and a torsade de
pointes‐type ventricular arrhythmia, which
can be fatal. Before initiating therapy, assess
the QTc interval, correct pre‐existing electro­
lyte abnormalities, and consider discontinu­
ing drugs known to prolong QTc interval. Do
not administer to patients with ventricular
arrhythmia or prolonged QTc interval.
ASPARAGINASE
PEG‐aspargase (Escherichia coli asparagi­
nase, Pegaspargase, Oncaspar), Asparaginase
Erwinia chrysanthemi (Erwinaze)
Antineoplastic, results in asparagine deple­
tion in malignant cells
Injection:
10,000 unit vial (Erwinaze)
3750 unit vial (Oncaspar)
Pregnancy category C
Indications:
Treatment of acute lymphoblastic leukemia
(ALL). Current Children’s Oncology Group
(COG) trials have adopted pegaspargase as the
preparation of choice secondary to a longer
half‐life compared to the prior native E. coli
asparaginase. Erwinia‐derived asparaginase is
FDA approved in the setting of hypersensitiv­
ity to E. coli‐derived asparaginase.
Dosage:
Refer to individual protocol.
Usual dose in ALL of pegaspargase is
2500 IU/m2 IV over 1–2 hours every 2–4
weeks (Induction, Delayed Intensification,
and Interim Maintenance phases). Other
Formulary 417
protocols may utilize different frequency or
patient‐specific dosing.
In the setting of hypersensitivity, the replace­
ment dose for Erwinia asparaginase is
25,000 IU/m2/dose IM or IV, given three times
per week (every 48–72 hours or Monday–
Wednesday–Friday) for six doses to replace
one dose of pegaspargase. IV administration
may result in shorter duration of serum aspar­
aginase activity levels compared to IM admin­
istration. When administered IM, maximum
volume is 2 ml per injection site. Many
patients require multiple injections.
Patients should be observed in a clinic or
hospital setting for at 1–2 hours after admin­
istration to monitor for a hypersensitivity
reaction. Appropriate agents for treatment
of hypersensitivity should be readily availa­
ble (oxygen, epinephrine, antihistamines,
intravenous steroids) in addition to resusci­
tative equipment.
Notes:
Do not give any form of asparaginase to
patients with prior life‐threatening throm­
bosis or hemorrhage or significant pan­
creatitis (grade 3 or 4) associated with
asparaginase.
Hypersensitivity to Oncaspar pegaspargase
necessitates a switch to Erwinaze. Some
centers may consider desensitization or re‐
challenge, though this should be done with
caution. Use with caution in patients with
hepatic impairment or in those receiving
other hepatotoxic drugs as well as in those
receiving anticoagulation or nonsteroidal
anti‐inflammatory agents (NSAIDs).
Asparaginase may cause hyperglycemia,
hyperuricemia, hyperammonemia, hypofi­
brinogenemia, thrombosis, hemorrhage,
anaphylaxis, and hemorrhagic cystitis.
Dose modifications related to hyperglyce­
mia or hyperlipidemia are not recom­
mended; treat underlying conditions as
418 Formulary
medically indicated. Dexamethasone may
alleviate allergic symptoms.
Premedication for hypersensitivity is not
recommended though is given at some insti­
tutions. In the event of hypersensitivity dur­
ing a pegaspargase infusion, substitution
with Erwinia asparaginase should begin
within 48 hours in patients who are clini­
cally stable. Up to six doses of Erwinia
asparginase may be given to replace the
incomplete administration of the IV pegas­
pargase dose. Erwinia doses are based on
nadir serum asparaginase activity detected
at 48 and 72 hours after dosing.
Asparaginase activity assays are commer­
cially available to determine activity, length
of asparagine depletion, and evaluate for the
presence of neutralizing antibodies. Some
clinicians/treatment centers may elect to dis­
continue pegaspargase and switch to Erwinia
asparaginase based on lab evidence of silent
antibodies or decreased asparaginase activity
suggesting silent inactivation in the absence
of overt hypersensitivity. Similarly, patients
with a clinical hypersensitivity reaction but
without evidence of antibody development
can be considered for re‐challenge.
AZACITIDINE
Vidaza
Nucleoside metabolic inhibitor; DNA hypo­
methylating agent
Injection: IV, SC; 100 mg single dose vials
Pregnancy category D
Indications:
Treatment of acute myelogenous leukemia
(AML) and myelodysplastic syndrome
(MDS). Being studied in infant ALL with
hypermethylating KMT2A mutation as well
as posttransplant in AML patients.
Dosage:
The recommended starting dose for the first
treatment cycle, for all patients regardless of
baseline hematology values, is 75 mg/m2
daily for 7 days by SC or IV infusion.
Premedicate for nausea and vomiting.
Repeat cycles every 4 weeks or per protocol.
After two cycles, may increase dose to
100 mg/m2 if no beneficial effect is seen and
no toxicity other than nausea and vomiting
has occurred.
Notes:
Azacitidine is contraindicated in patients
with prior hypersensitivity to this drug
or mannitol, or advanced liver tumors.
May cause cytopenias; monitor complete
blood count (CBC), liver, and kidney
function. Patients with severe preexisting
hepatic impairment are at higher risk for
toxicity. Azacitidine and its metabolites
are primarily excreted by the kidneys,
and patients with renal insufficiency
should be monitored for increased risk of
toxicity. The most common adverse reac­
tions by the SC route are: nausea, anemia,
thrombocytopenia, vomiting, pyrexia,
leukopenia, diarrhea, injection site ery­
thema, constipation, neutropenia, and
ecchymosis. The most common adverse
reactions by the IV route also include
petechiae, rigors, weakness, and
hypokalemia
BRENTUXIMAB VEDOTIN
Adcetris
Antibody–drug conjugate
Injection: 50 mg vials, 5 mg/ml solution
Pregnancy category D
Indications:
Treatment of relapsed or refractory Hodgkin
lymphoma (HL) and systemic anaplastic large
cell lymphoma (ALCL). It selectively targets
tumor cells expressing the CD30 antigen, a
defining marker of Hodgkin lymphoma
and ALCL (a type of T‐cell non‐Hodgkin
lymphoma)

Dosage:
1.2–1.8 mg/kg (maximum 120–180 mg) 30‐
minute IV infusion every 2–3 weeks.
Notes:
Brentuximab vedotin had been linked with
two cases of progressive multifocal leukoen­
cephalopathy, requiring the addition of
a black box warning to the drug label regard­
ing this potential risk. Pneumonitis has also
been reported. Common adverse events
include cytopenias, nausea and vomiting,
constipation, decreased appetite, weight loss,
abdominal pain, fever, as well as peripheral
sensory neuropathy. Pediatric trials down to
2 years of age are ongoing.
BEVACIZUMAB
Avastin
Angiogenesis inhibitor; monoclonal anti­
body to vascular endothelial growth factor
(VEGF)
Injection: 25 mg/ml
Pregnancy category C
Indications:
Treatment of metastatic colon cancer, non‐
small cell lung cancer, metastatic renal cell
carcinoma and recurrent glioblastoma mul­
tiforme. Currently being investigated in
pediatric protocols for the treatment of
brain tumors, refractory or recurrent solid
tumors, and neurofibromatosis.
Dosage:
Refer to individual protocol.
5–15 mg/kg q2–3 weeks as a single agent or
in combination regimens.
Notes:
Avoid use in patients with recent surgery,
hemoptysis, gastrointestinal or central nerv­
ous system bleeding, or any other serious
bleeding. The interval required between
surgery and drug administration to avoid
Formulary 419
impairment in wound healing has not been
determined. General recommendation is to
allow 28 days prior to and following major
surgery. Use with caution in patients with
thrombocytopenia. An increased risk of
thromboembolic events has been reported
in combination regimens. May impair fertil­
ity and have adverse effects on fetal develop­
ment; adequate contraception must be used
during therapy. May cause infusional toxic­
ity (discontinue infusion until symptoms
abate) or proteinuria. May potentiate car­
diac effects of anthracyclines. Discontinue
therapy in patients who develop fistulas,
hypertensive crises, encephalopathy, or
nephrotic syndrome. Common adverse
effects include epistaxis, rhinitis, dry eye,
altered taste, headache, hypertension, and
rectal bleeding.
BLEOMYCIN SULFATE
Blenoxane, generic
Antineoplastic antibiotic
Injection: 15 unit vial (1 unit = 1 mg)
Pregnancy category D
Indications:
Treatment of Hodgkin and non‐Hodgkin
lymphoma, squamous cell carcinoma, tes­
ticular carcinoma, and germ cell tumor. Used
as a sclerosing agent to control malignant
pleural effusions.
Dosage:
Refer to individual protocol.
10–20 IU/m2 IV infusion over 10 minutes
(may be given IM or SC) one to two times
per week per protocol.
Notes:
Do not give to patients with known
hypersensitivity to bleomycin.
Premedication with acetaminophen,
hydrocortisone, and antihistamine may
decrease infusional toxicity. Dose may
420 Formulary
need to be modified for renal or pulmo­
nary toxicity. Monitor renal function stud­
ies and pulmonary function, including
pulmonary diffusion capacity for carbon
monoxide (DLCO). If symptoms of pneu­
monitis appear (i.e., fine rales, decreased
DLCO), assess CXR and pulmonary func­
tion. Pulmonary fibrosis is a rare and
potentially fatal complication. Direct instil­
lation into the pleural space may be used to
control malignant effusion.
BLINATUMOMAB
BLINCYTO
Antineoplastic, monoclonal antibody,
bispecific T‐cell engager (BiTE)
Injection: 35 mcg/vial (includes IV solution
stabilizer)
Pregnancy category C
Indications: Treatment of Philadelphia chro­
mosome‐negative relapsed or refractory
CD19+ B‐cell precursor ALL.
Dosage:
Refer to individual protocol.
Given as a continuous infusion, generally for
28 days. Goal dosing is 15 mcg/m2/day, as tol­
erated. Often utilized as bridging therapy to
hematopoietic stem cell transplant (HSCT)
in patients with refractory disease or low
minimal residual disease (MRD) positivity.
Premedicate with dexamethasone (5 mg/m2;
per protocol) IV 30–60 minutes prior to
start of infusion, change in dosing or when
restarting an infusion after an interruption
of ≥4 hours.
The blinatumomab solution for infusion must
be administered using IV tubing that contains
a sterile, non‐pyrogenic, low protein‐binding,
0.2 μm in‐line filter. Blinatumomab must be
changed every 48 hours to 7 days but can be
done as an outpatient infusion if tolerated in
the initial week.
Notes:
Blinatumomab is contraindicated in patients
with known hypersensitivity. Common
adverse effects include pyrexia, headache,
peripheral edema, fever, nausea, hypoka­
lemia, and constipation. Severe effects
include fever with neutropenia, pneumonia,
sepsis, confusion, and encephalopathy.
Black box warnings exist for CRS and severe
neurologic toxicity. Symptoms of CRS include
pyrexia, hypotension, increased alanine ami­
notransferase and aspartate aminotransferase,
increased total bilirubin, headache, and nausea.
Evidence of capillary leak syndrome and dis­
seminated intravascular coagulation (DIC) may
be seen rarely. Symptoms of CRS warrant imme­
diate cessation of the infusion and ­supportive
care as medically indicated. Approximately 50%
of patients may experience neurologic toxicity
with a median time of onset of 7 days, with 15%
resulting in grade 3 or higher (encephalopathy,
convulsions, speech changes, altered conscious­
ness, confusion or disorientation, or coordina­
tion or balance disorders). The majority of
events resolve with interruption of blinatu­
momab, often require dose reduction and may
lead to treatment discontinuation.
BUSULFAN
Busulfex, generic
Antineoplastic
Tablet: 2 mg
Injection: 6 mg/ml
Pregnancy category D
Indications:
Treatment of chronic myelogenous leukemia
(CML) and for myeloablative conditioning
regimens prior to bone marrow or periph­
eral blood stem cell transplantation.
Dosage:
Refer to individual protocol.
HSCT regimen: dose based on actual body
weight (ABW); adjustments based on

therapeutic drug monitoring per protocol
and goal AUC).
>10 kg and ≤4 years: 4 mg/kg/dose IV daily
over 4 consecutive days
<10 kg or ≥4 years: 3.2 mg/kg/dose IV daily
over 4 consecutive days
Notes:
Do not give to patients with known hyper­
sensitivity to busulfan; should not be used
in pregnancy or while nursing. May cause
severe bone marrow suppression, sinusoi­
dal obstructive syndrome (SOS) (hepatic
veno‐occlusive disease [VOD]), or sei­
zures when given at high doses. Use with
caution with other myelosuppressive
drugs or radiation. May cause hemor­
rhagic cystitis. Use with thioguanine may
increase hepatic toxicity. Patients should
be placed on a prophylactic antiepileptic
drug (i.e., Keppra, lorazepam) while
receiving busulfan.
Therapeutic drug monitoring is done with
dose 1. To calculate the AUC, obtain levels
before and after infusion, per protocol.
Metabolism of busulfan may be inhibited
by antifungal agents (azoles), CYP3A4
inhibitors, dasatinib, and metronidazole
leading to increased levels and effect.
Busulfan metabolism may be potentiated
by CYP3A4 inducers, deferasirox, and
Echinacea, leading to decreased levels
and effect.
CARBOPLATIN
Paraplatin, generic
Antineoplastic, alkylating agent
Injection: 10 mg/ml; 50, 150, 450, 600 mg vials
Pregnancy category D
Indications:
Treatment of pediatric brain tumors, neuro­
blastoma, testicular tumors, relapsed leuke­
mia, and solid tumors.
Formulary 421
Dosage:
Refer to individual protocol. May require dose
calculation using the modified Calvert for­
mula (total dose in mg) to achieve the appro­
priate AUC for concentration over time rather
than dosing by body surface area (BSA).
Solid tumors: 400–560 mg/m2 every 3–4 weeks
or per protocol.
Brain tumor protocols:
175 mg/m2 weekly for 4 weeks, then 2‐week
recovery; alternatively 540 mg/m2 q month.
Dose is adjusted based on suppression of neu­
trophil and platelet counts or renal toxicity.
Bone marrow transplant preparative regi-
men: 500 mg/m2/day for 3 days.
Notes:
Do not give to patients with known hypersen­
sitivity to carboplatin, cisplatin, or other plati­
num‐containing compounds. Anaphylaxis
may occur within minutes of administration.
May cause hypotension, electrolyte abnor­
malities (hypomagnesemia in particular),
nausea, hearing loss, and peripheral neuropa­
thy. Highly emetogenic; increasing the length
of infusion or giving smaller doses on con­
secutive days may alleviate the severity. Severe
marrow suppression may occur, and the
postchemo nadir may be delayed. Anemia
occurs from cumulative effects and transfu­
sion is likely with high or repetitive dosing.
Reduce dose in impaired renal function (cre­
atinine clearance <60 ml/minute) utilizing the
modified Calvert formula. Aminoglycosides
may increase serum levels/effects of carbopl­
atin and augment ototoxicity and nephrotox­
icity; nephrotoxic drugs may increase renal
toxicity of carboplatin. Children are particu­
larly susceptible to ototoxicity and care should
be taken to avoid concomitant drugs with oto­
toxic potential. Recent study has shown oto­
protection with sodium thiosulfate; concern
still remains on worse outcomes in patients
with high‐risk diseases. Avoid concomitant
administration of topotecan and taxanes.
422 Formulary
All patients should receive hydration prior
to and following administration with
sodium‐chloride‐containing solution, with
or without mannitol or furosemide, to
ensure good urine output and decrease risk
of nephrotoxicity. Reduce dose for young
children (<6 months) and with renal impair­
ment. Electrolytes and magnesium should
be monitored. Acute leukemia has been
reported as a second malignant neoplasm.
CARMUSTINE
BCNU
BiCNU, Gliadel
Antineoplastic, alkylating agent
Injection: 100 mg vial
Implant: Gliadel wafer
Pregnancy category D
Indications:
Treatment of brain tumors and Hodgkin
and non‐Hodgkin lymphoma. Wafer
implant (Gliadel) may be an adjunct to sur­
gery and radiation for glioblastoma multi­
forme and high‐grade glioma.
Dosage:
Refer to individual protocol.
Typical dose may be 150–200 mg/m2/dose
IV every 6 weeks.
Bone marrow transplant: 300 mg/m2 gener­
ally given as one dose as part of BEAM
(BCNU, etoposide, cytarabine, melphalan)
conditioning regimen.
Notes:
Do not give to patients with known hyper­
sensitivity to carmustine. Severe, prolonged
(4–6 weeks) marrow suppression may
necessitate change in dosing for subsequent
cycles. Toxicity is cumulative and delayed
pulmonary fibrosis may occur in patients
receiving very high doses (7 701 800 mg/m2).
CASPOFUNGIN
Cancidas
Antifungal agent, echinocandin
Injection: 50, 70 mg
Pregnancy category C
Indications:
Treatment of candidemia, candidal intra‐
abdominal abscess, or esophageal candidia­
sis; empiric therapy of presumed fungal
infection in febrile neutropenic patients.
Dosage:
Preterm neonates to infants <3 months:
25 mg/m2/dose IV once daily.
Infants ≥3 months to adults: 70 mg/m2 loading
dose IV over 1 hour (maximum dose 70 mg),
followed by 50 mg/m2/dose IV once daily
over 1 hour (maximum dose 50–70 mg/day).
Patients may benefit from increased daily
dosing to 70 mg/m2 once daily dependent on
clinical status and response.
Empiric therapy should be given until neu­
tropenia resolves. In neutropenic patients,
continue treatment for at least 7 days after
signs and symptoms of infection and neu­
tropenia have resolved and at least 14 days
following a positive culture in patients with
documented fungal infection.
Notes:
Modify dose in patients with hepatic impair­
ment. Drug interactions exist with cyclo­
sporine, tacrolimus, and rifampin and may
require dose modification.
CISPLATIN
Platinol, generic
Antineoplastic, alkylating agent
Injection: 1 mg/ml; 50, 100, 150 mg vials
Pregnancy category D

Indications:
Treatment of soft tissue sarcoma, osteosar­
coma, Hodgkin and non‐Hodgkin lym­
phoma, brain tumors, metastatic ovarian
and testicular tumors, germ cell tumors, and
neuroblastoma.
Dosage:
Refer to individual protocol. Verify any dos­
ing schedule in which the cisplatin dose
exceeds 120 mg/m2 per course. Doses are
lower when used in combination protocols.
Daily dosing schedule: 15–20 mg/m2/day for
5 days every 3–4 weeks.
Osteosarcoma and neuroblastoma: 60–100
mg/m2 once every 3–4 weeks.
The rate of intravenous infusion is dose‐
dependent and ranges from a 15–20‐minute
infusion to a 6–8‐hour infusion; 24‐hour
continuous infusions are also used.
Notes:
Do not give to patients with known hyper­
sensitivity to cisplatin or platinum‐contain­
ing compounds, preexisting renal
impairment, hearing impairment, and mye­
losuppression. Increased risk of nephrotox­
icity when given with other nephrotoxic
drugs (aminoglycosides and amphotericin
B). Reduces renal elimination of methotrex­
ate. Cisplatin may increase the levels/effects
of aminoglycosides, taxane derivatives,
topotecan, and vinorelbine. Effects or levels
of cisplatin may be increased with concomi­
tant administration of loop diuretics.
Electrolyte abnormalities are common and
include hypomagnesemia, hypokalemia,
hyponatremia, and hypophosphatemia.
Cisplatin is highly emetogenic and com­
monly has delayed nausea and vomiting.
Potential toxicities include peripheral neu­
ropathy and hepatic and ocular toxicity.
Ototoxicity is common and risk factors for
Formulary 423
severe hearing loss include pediatric age
(especially <5 years), concurrent or prior
cranial radiation, renal impairment, and
concomitant use of other ototoxic drugs.
Ototoxicity in the pediatric population is
common, occurring in 40–60%, and war­
rants frequent and care audiologic evalua­
tions at baseline, prior to each dose, and for
several years after treatment. Sodium thio­
sulfate has been shown to be otoprotective,
though concerns remain regarding worse
outcomes in high‐risk patients.
All patients should receive hydration prior to
and for 24 hours after administration with a
sodium‐chloride‐containing solution (with
or without mannitol or furosemide), to
ensure good urine output and decrease risk
of nephrotoxicity. Reduce dose for young
children (<6 months) and with renal impair­
ment. Electrolytes and magnesium should be
monitored. Acute leukemia has been
reported as a second malignant neoplasm.
CLADRIBINE
2‐chlorodeoxyadenosine, 2‐CdA
LeustatinTM, generic
Anti‐neoplastic, anti‐metabolite; purine analog
Injection: single dose 10 mg vials (1 mg/ml)
Pregnancy category D
Indications:
Cladribine is highly effective in the treat­
ment of Langerhans cell histiocytosis and
rare histiocytic disorders of the juvenile
xanthogranuloma group.
2‐CdA is an active salvage monotherapy for
patients with risk‐organ involvement refrac­
tory to initial therapy or patients with recur­
rent, low‐risk Langerhans Cell Histiocytosis
(LCH) (i.e., patients with non‐risk‐organ
involvement, including multifocal bone dis­
ease). Cladribine appears to be more effective
424 Formulary
in low‐risk patients or patients with multifo­
cal bone disease. Patients older than 2 years
and those with a longer time between diag­
nosis and 2‐CdA therapy have better
responses, presumably because their disease
is less aggressive.
Combination therapy with 2‐chlorodeoxy­
adenosine and cytarabine (Ara‐C) has been
studied in patients with refractory, risk‐
organ–positive LCH and the combination
regimen appears to be an effective therapy
for refractory multisystem LCH.
2‐CdA may be effective in the treatment of
LCH with CNS involvement.
2‐CdA is also used in adults with hairy cell
leukemia or multiple sclerosis.
Dosage:
Safety and effectiveness in pediatric patients
have not been established. Patients 1–21 years
age have received doses ranging from 3 to
10.7 mg/m2/day for 5 consecutive days. See
protocols for specific dosing regimen.
Notes:
Adverse effects include severe bone marrow
suppression and resultant cytopenias, fever,
and neurotoxicity manifested as peripheral
neuropathy or pain. Fatal bacterial and fun­
gal infections have followed drug adminis­
tration. Limited pediatric data are available.
CLOFARABINE
Clolar
Antineoplastic, antimetabolite
Injection: 1 mg/ml
Pregnancy category D
Indications:
Treatment of relapsed or refractory ALL,
AML, MDS.
Dosage:
Children (≥1 year) to adults: 40 mg/m2/day
for 5 days every 28 days or per protocol.
Notes:
Cytokine release may develop into a sys­
temic inflammatory response with resultant
capillary leak syndrome and organ failure. If
this occurs, discontinue clofarabine and ini­
tiate therapy with diuretics, corticosteroids,
and albumin. If hypotension resolves with­
out pharmacologic intervention, clofarabine
may be resumed. The risk for hepatic toxic­
ity and veno‐occlusive disease is increased
in patients who have previously undergone
HSCT. Avoid concomitant use of nephro­
toxic and hepatotoxic drugs.
CYCLOPHOSPHAMIDE
Generic
Antineoplastic, alkylating agent
Tablets: 25, 50 mg
Injection: 500 mg, 1 g, 2 g vials
Pregnancy category D
Indications:
Treatment of Hodgkin and non‐Hodgkin lym­
phoma, acute and chronic leukemia, retinoblas­
toma, mycosis fungoides, and neuroblastoma.
Conditioning therapy for bone marrow trans­
plantation (BMT) and posttransplant after
haplo‐identical transplantation. Treatment of
nephrotic syndrome, systemic lupus erythema­
tosus, and other rheumatic diseases.
Dosage:
Refer to individual protocol.
Acute lymphoblastic leukemia: 1000–1200
mg/m2/dose IV, in Consolidation and
Delayed Intensification phases.
Bone marrow transplant conditioning: 50 mg/
kg/day IV for 3–4 days.
Nephrotic syndrome: 2 mg/kg/day PO for
8–12 weeks; maximum cumulative dose
168 mg/kg.
Systemic lupus erythematosus: 500–750 mg/
m2 IV monthly; maximum dose 1 g/m2.
Juvenile idiopathic arthritis/vasculitis: 10 mg/
kg IV every 2 weeks.

Notes:
Do not give to patients with known hyper­
sensitivity to cyclophosphamide. Dose may
need to be adjusted for myelosuppression or
impaired renal function. Mesna should be
given with high‐dose therapy (>1 g/m2/day)
to reduce potential of hemorrhagic cystitis.
Allopurinol may increase the myelotoxicity
of cyclophosphamide by inhibiting its
metabolism. Ensure aggressive hydration
with sodium‐chloride‐containing fluids and
frequent bladder emptying. High cumula­
tive doses may cause amenorrhea associated
with decreased estrogen and elevated gon­
adotropin levels in females and azoospermia/
infertility in males. Some reversibility of
infertility may occur after cessation of
therapy.
CYCLOSPORINE
Sandimmune, Neoral, Gengraf, generics
Immunosuppressant
Capsules: 25, 50, 100 mg
Solution: 100 mg/ml
Injection: 50 mg/ml
Pregnancy category C
Indications:
Used with corticosteroids to prolong organ
and patient survival in kidney, liver, heart,
and bone marrow transplants; treatment of
aplastic anemia and other bone marrow fail­
ure syndromes.
Dosage (Sandimmune):
Due to better absorption, lower doses of
Neoral and Gengraf may be required com­
pared to Sandimmune.
Oral:
Initial: 15 mg/kg single oral dose, beginning
4–12 hours pretransplant.
Maintenance: 15 mg/kg/day PO divided q12–
24h for 1–2 weeks posttransplant, decrease
by 5% per week to 3–10 mg/kg/day divided
q12–24h.
Formulary 425
Intravenous:
Initial: 5–6 mg/kg IV single dose, administered
over 2–6 hours, beginning 4–12 hours pre­
transplant. Continue same IV dose posttrans­
plant until patient able to tolerate oral form.
Conversion from IV to PO dose (1:3 ratio):
Multiply total daily IV dose by 3 and admin­
ister in two divided oral doses per day.
Notes:
Do not give to patients with known hyper­
sensitivity to cyclosporine (castor oil is an
ingredient in the preparation). May cause
nephrotoxicity, hepatotoxicity, hypomagne­
semia, hyperkalemia, hyperuricemia, hyper­
tension, hirsutism, acne, gastrointestinal
symptoms, tremor, leukopenia, headache,
and gingival hyperplasia. Use with caution
with concomitant administration of other
nephrotoxic drugs (e.g., amphotericin B, ami­
noglycosides, tacrolimus, acyclovir, NSAIDs).
Requires close monitoring of renal and hepatic
function and frequent determination of trough
levels (drawn just prior to dose at steady state).
Cyclosporine is a substrate for the cytochrome
P450 3A4 oxidase system. Drug interactions
include ketoconazole, itraconazole, flucona­
zole, erythromycin, and methylprednisolone,
which increase the cyclosporine concen­
tration by inhibiting hepatic metabolism.
Refer to the Physicians’ Desk Reference
(PDR) for more extensive drug interaction
information.
CYTARABINE HYDROCHLORIDE
Ara‐C
Cytosar‐U, generic
Antineoplastic, antimetabolite; pyrimidine
antagonist
Injection: 100 mg/ml; 100 and 500 mg, 1 and
2 g vials
Pregnancy category D
Indications:
Treatment of ALL and AML, refractory non‐
Hodgkin lymphoma, and may be used in
426 Formulary
conditioning regimens for BMT. Treatment
and prophylaxis of CNS leukemia.
Dosage:
Refer to individual protocol.
Infants <3 years: 3.3 mg/kg/day IV/SC for 4
days.
Children and adults:
AML Induction: 100 mg/m2/24 hours for 7
days. Give IV q12h or as continuous
infusion.
High‐dose cytarabine: (AML, relapsed or
refractory ALL, non‐Hodgkin lymphoma)
3 g/m2/dose q12h for up to 12 doses.
ALL (Delayed Intensification): 75 mg/m2/
dose IV/SC daily for 4 consecutive days,
repeat in 7 days for total of two courses.
Intrathecal (IT) dosing (CNS treatment and
prophylaxis): Dosing per age. May be com­
bined with other intrathecal agents such as
hydrocortisone and methotrexate per proto­
col (e.g., intrathecal double/triple).
Children <1 year: 20 mg.
Children 1 to <2 years: 30 mg.
Children 2 to <3 years: 50 mg.
Children ≥3 years and adults: 70 mg.
Notes:
Do not give to patients with known hyper­
sensitivity to cytarabine. May need to reduce
dose with myelosuppression or hepatic dys­
function. Causes significant bone marrow
suppression. Particular risk of Strep viridans
sepsis. High doses have been associated with
gastrointestinal, CNS, pulmonary, and ocular
toxicities, as well as cardiomyopathy. May
cause nausea, vomiting, mucositis, fever,
headache, somnolence, anorexia, alopecia,
conjunctivitis, ataxia, diarrhea, hepatic dys­
function, and peripheral neuropathy.
Prophylaxis with dexamethasone ophthalmic
drops may decrease conjunctivitis. Acute
neurotoxicity has been reported following
intrathecal administration. Concurrent
administration of IV and IT therapy increases
risk of spinal cord toxicity.
When prepared for intrathecal use, added
precautions should be taken when other
medications are also being delivered to
ensure appropriate labeling and handling
such that only medications intended for
administration in the CNS are with the
patient for the procedure.
DACARBAZINE
DTIC
Antineoplastic
Injection: 200 mg/20 ml
Pregnancy category C
Indications:
Treatment of Hodgkin lymphoma and met­
astatic malignant melanoma.
Dosage:
Refer to individual protocol.
Metastatic malignant melanoma: 2–4.5 mg/
kg/day IV for 10 days every 4 weeks or
250 mg/m2 IV for 5 days, every 3 weeks.
Hodgkin lymphoma: 375 mg/m2 IV on days 1
and 15 of each course, every 4 weeks or
150 mg/m2 IV for 5 days every 4 weeks.
Notes:
Do not give to patients with known hyper­
sensitivity to dacarbazine. Dosage reduction
may be necessary in patients with renal or
hepatic insufficiency. Drug extravasation
may result in tissue damage and severe pain.
Nausea and vomiting are common; if severe
and protracted, treatment with phenobarbi­
tal or prochlorperazine may be beneficial.
Hematopoietic toxicity primarily results in
leukopenia and thrombocytopenia.
DACTINOMYCIN
Actinomycin D
Cosmegen

Antineoplastic antibiotic
Injection: 0.5 mg (500 mcg) vial
Pregnancy category D
Indications:
Treatment of Wilms tumor, rhabdomyosar­
coma, Ewing sarcoma, ovarian germ cell tumor,
and gestational trophoblastic neoplasm.
Dosage:
Refer to individual protocol. Note that medi-
cation orders for dactinomycin may be written
in micrograms (mcg) or milligrams (mg).
Children ≥6 months to adult: 15 mcg/kg/
day IV or 400–600 mcg/m2/day IV once
daily for 5 days; cycles every 3–6 weeks.
Higher doses are given in some protocols.
Notes:
Do not give to patients with known hyper­
sensitivity to dactinomycin. Avoid in infants
<6 months of age due to increased adverse
events. Use with caution in patients with
hepatobiliary dysfunction or who have
received radiation (radiation recall effect).
Reduce dosage in patients receiving concur­
rent radiation. Gastrointestinal and marrow
suppressive effects are increased with con­
current radiation treatment. Avoid extravasa­
tion. May cause myelosuppression, anorexia,
vomiting, diarrhea, stomatitis, hepatic toxic­
ity including veno‐occlusive disease, elevated
transaminases, hepatomegaly, and hepatitis.
DAPSONE
Aczone, Diaminodiphenyl sulfone, DDS,
generics
Antibiotic
Tablet: 25, 100 mg
Oral suspension: 2 mg/ml
Pregnancy category C
Indications:
Prevention and treatment of Pneumocystis
jiroveci pneumonia (PCP) (formerly carinii)
Formulary 427
in immunocompromised hosts; treatment
of Toxoplasma gondii and Mycobacterium
leprae.
Dosage:
Children 1 month to <12 years: 2 mg/kg/day
PO or 4 mg/kg/dose PO once weekly (maxi­
mum 100 mg/dose daily or 200 mg/dose
weekly).
Children >12 years and adults: 100 mg/
day PO or 200 mg PO once weekly.
Notes:
Do not give to patients with known hyper­
sensitivity to dapsone. Dapsone is a strong
oxidizing agent and may cause hemolysis in
susceptible individuals. Screening for glu­
cose‐6‐phosphate dehydrogenase (G6PD)
deficiency is suggested in high‐risk popula­
tions (e.g., Mediterranean) and should not be
used if positive. May be safe to use in the
African‐American variant of G6PD defi­
ciency, though some degree of hemolysis may
occur. May also cause marrow suppression or
methemoglobinemia. Drug interactions
occur, primarily with rifampin. May be given
to immunosuppressed patients who cannot
tolerate or are allergic to cotrimoxazole.
DARBEPOETIN ALFA
Aranesp
Erythropoiesis stimulating protein
Injection: 25, 40, 60, 100, 200, 300 mcg/1 ml
(1 ml); 10 mcg/0.4 ml (0.4 ml)
Pregnancy category C
Indications:
Anemia in chronic renal disease, chemo­
therapy‐induced anemia.
Dosage:
Renal failure on dialysis: 0.45 mcg/kg/dose IV/
SC once weekly or 0.75 mcg/kg/dose IV/SC
every 2 weeks. IV dose is recommended while
on hemodialysis (infuse over 1–3 minutes).
428 Formulary
Renal failure not on dialysis: 0.45 mcg/kg/
dose IV/SC once every 4 weeks.
Adjust dosing after 4 weeks based on
response: increase by 25% for hgb rise
<1 g/dl (do not adjust more than monthly);
decrease dose 25% if hgb ≥ 11 g/dl or
increases by >1 g/dl over a 2‐week period.
Chemotherapy‐induced anemia: 2.25 mcg/kg/
dose SC once weekly.
Adjust dosing after 6 weeks: increase dose to
4.5 mcg/kg/dose weekly SC/IV for <1 g/dl
increase in hgb or if hgb <10 g/dl; decrease
dose 40% if hgb increases >1 g/dl in any 2‐
week period or if hgb >12 g/dl. Discontinue
therapy if lack of response at 8 weeks or
chemotherapy completed.
Notes:
Monitor hemoglobin (hgb), blood pressure,
serum chemistries, and reticulocyte count
on treatment. Dose increases should not be
made more frequently than once monthly.
Evaluate iron status (ferritin, serum iron,
and total iron‐binding capacity [TIBC]);
concurrent iron supplementation may be
necessary. Concern remains secondary to
meta‐analyses in adult oncology patients
which have shown increased morbidity with
erythropoietin utilization; should be used
with caution, and potentially limited to
patients aiming to minimize transfusion
(i.e., Jehovah’s Witness).
DASATINIB
Sprycel
Kinase inhibitor
Tablet: 20, 40, 50, 70, 80, 100, 140 mg
Pregnancy category D
Indications:
Treatment of adult and pediatric patients
with Philadelphia positive (Ph+) CML in
chronic phase; adults with CML in acceler­
ated or blast phase unresponsive or refractory
to prior therapy with imatinib; and adults
with Ph+ ALL (off label use in pediatrics).
Dosage:
Refer to individual protocol.
Children: 60 mg/m2, do not crush or cut tab­
lets. Take with or without food.
Adults:
CML, chronic phase: 100 mg PO QD.
CML, accelerated or blast phase: 140 mg PO
QD.
Notes:
Dasatinib is contraindicated in patients with
known hypersensitivity. It is metabolized via
the CYP450 enzyme. Common adverse
effects include myelosuppression, fluid
retention, cardiac dysfunction and/or QTc
prolongation, pulmonary arterial hyperten­
sion, and severe mucocutaneous reactions.
Avoid concomitant strong CYP3A4 induc­
ers including St. John’s Wort and grapefruit
juice. Due to drug interactions avoid simul­
taneous administration of antacids, H2
antagonists, and proton pump inhibitors.
Severe bleeding has occurred and patients
should have frequent monitoring of blood
counts with platelet and red cell trans­
fusions as clinically indicated. Avoid con­
comitant use of drugs affecting platelet
function.
DAUNORUBICIN HYDROCHLORIDE
Cerubidine
Antineoplastic antibiotic, anthracycline
Injection: 2 mg/ml; 5, 25, 100 ml vials
Pregnancy category D
Indications:
Treatment of ALL, AML, Wilms tumor,
Hodgkin lymphoma, soft tissue and bone
sarcomas, primary breast carcinoma, and
many other carcinomas and sarcomas.

Dosage:
Refer to individual protocol.
Infants <2 years or BSA <0.6 m2 should have
dosing based on body weight: 0.67–1.7 mg/
kg/day IV (dosing/frequency per protocol).
Children ≥2 years, BSA ≥0.6 m2: 25–60 mg/m2
IV with frequency dependent on protocol.
Infusion should ideally be via CVC given
significant risk of tissue necrosis with
extravasation. If administered via peripheral
vein, care should be taken to ensure good
venous flow through a new IV in a large vein,
avoiding joints, and monitoring carefully for
signs/symptoms of extravasation with
immediate cessation if suspected.
Notes:
Do not give to patients with known hyper­
sensitivity to daunorubicin, congestive heart
failure, arrhythmias, or preexisting bone
marrow suppression. Reduce dosage in
patients with hepatic, biliary, or renal impair­
ment. May cause myelosuppression, nausea,
vomiting, alopecia, stomatitis, and pigmenta­
tion of nail beds. Risk of developing irre­
versible myocardial toxicity increases rapidly
at doses over 400 mg/m2. Risk factors that
increase risk of cardiac toxicity include prior
treatment with anthracyclines, concomitant
cardiotoxic drugs, prior or concomitant
mediastinal/pericardial radiation, and pedi­
atric age group (increased in younger
patients and female sex). Concomitant usage
of dexrazoxane should be considered in
young patients with planned doxorubicin
equivalent >300 mg/m2 (see doxorubicin for
conversion) and in all patients for doses
>300 mg/m2. Evidence of cardiac impair­
ment of function (signs, symptoms,
decreased left ventricular ejection fraction
[LVEF]) may occur during treatment or
months to years after completion of therapy.
Long‐term cardiac monitoring is warranted
and dependent on cumulative dose and other
risk factors as mentioned in the preceding
Formulary 429
text (see doxorubicin). Secondary AML and
MDS have been reported, with risk increase
in association with use of radiation, alkyla­
tors, or topoisomerase II inhibitors. Keep
drug protected from light.
Extravasation may result in severe local tis­
sue necrosis and require intervention (see
dexrazoxane, dimethyl sulfoxide [DMSO]).
A transient red‐orange discoloration of the
urine, sweat, saliva, and tears may occur for
up to 48 hours after a dose.
DEFEROXAMINE MESYLATE
Desferal, generics
Chelating agent; antidote, iron toxicity
Injection: 500 mg
Pregnancy category C
Indications:
Treatment of acute iron intoxication and
chronic transfusional iron overload.
Dosage:
Acute iron toxicity (age 3 years to adult):
Used as an adjunct to intervention with
syrup of ipecac, gastric lavage, and support­
ive care measures.
1000 mg IM (preferred route if patient not in
shock) followed by 500 mg IM q4h for two
doses. Dependent on clinical response, sub­
sequent doses may be given q4–12 hours,
24‐hours dose not to exceed 6000 mg.
For patients with evidence of shock, may
give abovementioned doses IV, with IV
infusion rate not to exceed 15 mg/kg/hour.
Chronic iron overload: 25–50 mg/kg/day IV/
SC over 8–24 hours once daily for 5–7 days per
week; maximum 2 g/24 hours. Doses should
not exceed 1000 mg if the IM route is chosen.
Notes:
Avoid in patients with known hypersensitiv­
ity, severe renal disease, anuria, or primary
hemochromatosis. Prolonged use can lead
430 Formulary
to ocular or auditory disturbances including
cataracts, decreased visual acuity, impaired
peripheral, night, and color vision, and neu­
rotoxicity‐related auditory abnormalities
(i.e., high‐frequency hearing loss). Periodic
hearing and vision exams should be per­
formed. High doses (>60 mg/kg), especially
in children ≤3 years, have been associated
with growth retardation; reduction in dos­
age may increase growth velocity. Vitamin C
50 mg <10 years; 100 mg >10 years, 200 mg
adolescent/adult PO is often given to
increase bioavailability of iron to chelate.
Discontinue use in febrile patients because
of increased susceptibility to infection with
Yersinia enterocolitica. Avoid rapid IV
administration as flushing, urticaria, hypo­
tension, and shock have been reported.
DEFERASIROX
Exjade, Jadenu
Chelating agent, iron; antidote, iron toxicity
Tablet, for oral suspension: Exjade: 125, 250,
500 mg; Jadenu: 90, 180, 360 mg; Jadenu
sprinkles: 90, 180, 360 mg
Pregnancy category C
Indications:
Treatment of chronic iron overload due to
blood transfusions in patients ≥2 years and
for treatment of chronic non‐transfusion
iron overload in thalassemia syndromes in
patients ≥10 years.
Dosage:
Transfusion‐associated iron overload:
Exjade:
Children ≥2 years to adults: 20–40 mg/kg PO
daily (round to nearest whole tablet).
Initiate therapy at 20 mg/kg/day. Adjust
dose every 3–6 months based on serum fer­
ritin levels or other measurement of iron
overload; increase by 5–10 mg/kg/day
(round to nearest whole tablet). Consider
higher doses for ferritin >2500 ng/ml.
Consider holding dose or discontinuing for
ferritin <500 ng/ml. Maintenance range:
20–40 mg/kg/day.
Jadenu:
Children ≥2 years to adults: 14–28 mg/kg PO
daily (calculate dose to the nearest whole
tablet). Adjust dose in 3.5–7 mg/kg incre­
ments according to response and goals; if
not adequately controlled with doses of
21 mg/kg (i.e., serum ferritin levels persis­
tently >2500 ng/ml), doses of up to 28 mg/kg
may be considered; do not exceed 28 mg/kg.
Non‐transfusion‐associated iron overload
in thalassemia syndromes:
Exjade:
Children ≥10 years to adult: 10 mg/kg PO
daily starting dose, titrate by monitoring
LIC (liver iron concentration) and ferritin
levels up to 20 mg/kg/dose.
Jadenu:
Children ≥10 years to adult: 7 mg/kg PO daily
(calculate dose to nearest whole tablet); if
LIC >7 mg Fe/g liver dry weight after 6
months, increase dose by 3.5–7 mg/kg up to
14 mg/kg/day; do not exceed 14 mg/kg/day.
Notes:
Before initiating treatment, obtain serum
ferritin level, baseline serum creatinine, cre­
atinine clearance (calculated), serum
transaminases, bilirubin, and baseline audi­
tory and ophthalmic examinations. Measure
serum ferritin monthly.
Consider giving daily dose divided BID to
patients experiencing abdominal discom­
fort or nausea and vomiting.
Do not chew or swallow whole tablets.
Disperse tablets in water, apple juice, or
orange juice (use 3.5 oz for doses <1 g; 7 oz
for doses ≥1 g); stir to form suspension and

drink entire contents. Rinse remaining resi­
due in glass and drink. Administer at the
same time every day, at least 30 minutes
prior to food ingestion.
Do not give to patients with known hyper­
sensitivity to deferasirox, low platelet counts
(<50 × 109/l), creatinine clearance (eGFR)
<40 ml/minute/1.73 m2, or serum creatinine
>2× age‐appropriate upper limit of normal.
Dosing at 50% is suggested for eGFR >40 to
<60 ml/minute/1.73 m2. Assess patients for
renal impairment and concurrent nephro­
toxic drugs. May cause intermittent protein­
uria. Monitor serum electrolytes and
urinalysis. Use with caution in patients with
hepatic disease as well as in patients with
concomitant anticoagulant, NSAID, or cor­
ticosteroid usage. Monitor transaminases
and liver function. Monitor LIC by liver
biopsy, MRI, or superconducting quantum
interference device (SQUID). May cause
ocular or auditory disturbances, skin rash,
gastrointestinal pain, headache, diarrhea,
sore throat, nausea, and vomiting. Monitor
hearing and vision, especially in children.
Interruption or dose modification may be
necessary for evidence of renal, hepatic, or
gastrointestinal dysfunction.
Safety and efficacy data are not available
when used in combination with other iron
chelators. Safety and efficacy have not been
established in children under 2 years of age.
DEFIBROTIDE
Defitelio (defibrotide sodium)
Injection: 200 mg/2.5 ml vial, (80 mg/ml)
Pregnancy category not assigned (pregnancy
and breastfeeding not recommended)
Indications:
Defibrotide is approved for the treatment of
adult and pediatric patients with hepatic
VOD, also known as SOS, with renal or pul­
monary dysfunction following HSCT.
Formulary 431
Dosage:
Children and adults: 6.25 mg/kg IV every 6
hours given as a 2‐hour infusion for at least
21 days, and continued until VOD/SOS res­
olution or up to 60 days of treatment.
Notes:
In vitro defibrotide sodium has profibrino­
lytic activity and there is no known reversal
agent. The use of defibrotide sodium is con­
traindicated in patients being treated con­
currently with anticoagulants or fibrinolytic
therapies. For patients requiring an invasive
procedure, discontinue the infusion at least
2 hours prior and then resume after the pro­
cedure when it has been determined that the
risk of bleeding is no longer present.
Hemorrhage and hypersensitivity reactions
are the major potential adverse reactions.
The most common adverse reactions (inci­
dence greater than or equal to 10%) are
hypotension, diarrhea, vomiting, nausea,
and epistaxis.
DEFERIPRONE
Ferriprox/Kelfer/L1
Chelation agent, iron
Tablet: 500 mg
Pregnancy category D
Indications:
Treatment of transfusional iron overload
due to thalassemia syndromes when current
chelation therapy is inadequate.
Dosage:
Adults: Initial dose: 25 mg/kg, orally, three
times a day (total daily dose: 75 mg/kg).
Maximum dose: 33 mg/kg, orally, three
times a day (total daily dose: 99 mg/kg).
Round dose to the nearest 250 mg (half tablet).
Tailor dose to response and therapeutic goals
(maintenance or reduction of iron burden).
432 Formulary
Notes:
Approval based on reduction in serum fer­
ritin; there are no trials showing a direct
treatment benefit (i.e., improved symptoms,
functioning, or survival).
Safety and efficacy have not been estab­
lished for transfusional iron overload with
other chronic anemias. Safety and efficacy
have not been established in patients
younger than 18 years of age.
There is a FDA black box warning that
this drug may cause granulocytosis that
can lead to serious infections and death;
neutropenia may precede granulocytosis.
It is recommended to monitor the abso­
lute neutrophil count (ANC) prior to and
every week during therapy. Patients
should be advised to immediately report
any signs or symptoms suggesting infec­
tion such as fever, sore throat, or flu‐like
symptoms.
DESMOPRESSIN ACETATE
DDAVP, Stimate, generics
Antihemophilic, hemostatic agent
Injection: 4 mcg/ml (1, 10 ml)
Tablets: 0.1, 0.2 mg
Solution: 1500 mcg/ml, 150 mcg/spray (25
sprays, 2.5 ml) (Stimate)
100 mcg/ml, 10 mcg/spray (50 sprays, 5 ml,
with rhinal tube) (DDAVP)
Pregnancy category B
Indications:
Intranasal Stimate or IV DDAVP are indi­
cated for maintenance of hemostasis in
patients with mild or moderate hemophilia
A during surgery and postoperatively as well
as treatment of mucosal bleeds in patients
with von Willebrand disease and mild
hemophilia A. DDAVP is indicated for the
treatment of central diabetes insipidus and
primary nocturnal enuresis.
Dosage:
Von Willebrand disease, hemophilia A, bleed-
ing diathesis:
IV: 0.2–0.4 mcg/kg/dose, dilute in normal
saline (10 ml for patients <10 kg and 50 ml for
≥10 kg), infuse slowly over 15–30 minutes.
or
Intranasal spray (Stimate): One puff
(150 mcg) for children under 50 kg and two
puffs (300 mcg) for children over 50 kg.
Peak effect is 1–5 hours with intranasal route,
1–3 hours with IV route, and 2–7 hours with
PO route. Duration of effect is 5–24 hours.
Tachyphylaxis may occur with repeated dos­
ing within 72 hours.
Diabetes insipidus:
Children ≤12 years: Start with 0.05 mg/dose
BID and titrate to effect (i.e., control of
excessive thirst and urination); usual dose
range is 0.1–0.8 mg/24 hours.
Children >12 years and adults: Start with
0.05 mg/dose BID and titrate to effect; usual
dose range is 0.1–1.2 mg/24 hours divided
BID or TID.
Children 3 months to 12 years: 5–30 mcg/24 hours
intranasally divided BID.
Children >12 years and adults:
10–40 mcg/24 hours intranasally divided
daily to TID; titrate dose to effect.
Nocturnal enuresis (≥6 years):
0.2 mg PO at bedtime, titrate to effect (maxi­
mum dose 0.6 mg) or
20 mcg intranasal at bedtime; divide and
administer 10 mcg in each nostril.
Notes:
Do not give to patients with known hyper­
sensitivity to desmopressin. Avoid in patients
with severe type I, type IIB, or platelet‐type
von Willebrand disease, hemophilia B, and
severe hemophilia A (<1% factor VIII activ­
ity). Patients with moderate hemophilia

A may not demonstrate an adequate response.
Use cautiously in patients with a predisposition
to thrombophilia, electrolyte imbalance, and
hypertensive cardiovascular disease. May cause
headache, nausea, emesis, seizures, blood pres­
sure changes, hyponatremia, nasal congestion,
abdominal cramps, and hypertension. Avoid in
young children <2 years due to hyponatremia
and seizures. Not FDA approved in <6 years for
treatment of nocturnal enuresis.
A desmopressin challenge to document
responsiveness to these agents is typically
done in patients with bleeding disorders to
document benefit prior to emergent use.
Note: intranasal forms come in two concen-
trations, use as specifically indicated.
DEXAMETHASONE
DexPak, TaperPak, Maxidex, generics (pre­
viously available as Decadron and Hexadrol)
Corticosteroid, anti‐inflammatory,
immuno­suppressant
Tablets: 0.25, 0.5, 0.75, 1.5, 2, 4, 6 mg
Solution: 1 mg/ml
Ophthalmic solution: 0.1% (5 ml)
Injection: 4 mg/ml
Pregnancy category C
Indications:
Used systemically for chronic inflammation,
allergic, hematologic, neoplastic (i.e., leuke­
mia), autoimmune disease, cerebral edema
and increased intracranial pressure, and
septic shock. Utilized as an antiemetic for
chemotherapy‐induced nausea and vomit­
ing and as an ophthalmic solution for con­
trol of chemical conjunctivitis from
concomitant administrations of agents such
as high‐dose cytarabine.
Dosage:
Antiemetic: 0.2 mg/kg/dose (5 mg/m2/dose)
IV 30 minutes prior to and every 6 hours
after chemotherapy.
Formulary 433
Brain‐tumor‐associated cerebral edema:
Loading dose: 1–2 mg/kg IV as a single dose;
maintenance: 1–2 mg/kg/day IV in four to
six divided doses for 1–5 days, or longer;
maximum dose 16 mg/24 hours.
Spinal cord compression with neurologic
abnormalities: 2 mg/kg/24 hours IV divided
q6h.
Chemotherapy:
Refer to individual protocol.
Doses range from 6 to 20 mg/m2/day PO/IV
for 5–7 days (may be longer in induction
therapy for ALL.
Ophthalmic use: Instill one to two drops into
the conjunctival sac bilaterally. May use
q1–2h as needed to prevent and control
symptoms.
Notes:
Do not administer during active, untreated
infections with viral, fungal, or bacterial
organisms. Prolonged use may cause bone
pain, glucose intolerance, hypertension, fat
redistribution and striae, and avascular
necrosis of bone.
DEXRAZOXANE
Zinecard, Totec (extravasation kit)
Antidote, anthracycline; antidote (anthracy­
cline extravasation)
Injection: 250, 500 mg
Pregnancy category D
Indications:
Reduction of anthracycline‐induced cardio­
toxicity (approved in metastatic breast cancer
for patients who have received a cumulative
dose of 300 mg/m2 of doxorubicin equiva­
lents with plan for further dosing). Treatment
for local tissue extravasation of anthracy­
clines. Currently FDA approved in adults
only, off label use in pediatrics.
434 Formulary
Dosage:
Refer to individual protocol.
Children and adults: 10:1 dose ratio with
doxorubicin equivalents (i.e., 300 mg/m2
dexrazoxane for 30 mg/m2 doxorubicin).
Complete anthracycline administration
within 30 minutes of start of dexrazoxane.
Treatment for extravasation: Adolescents
≥18 years to adults: 1000 mg/m2/dose within
6 hours on days 1 and 2; maximum dose
2000 mg; followed by 500 mg/m2/dose on
days 3; maximum dose 1000 mg. If using ice
to affected area, remove 20 minutes prior to
infusion. Infuse in extremity/area other
than the affected area at room temperature
in a large vein IV over 1–2 hours. Administer
same time every day. Do not mix or admin­
ister with any other drug.
Infuse over 15 minutes, do not administer
IV push.
Do not use DMSO in patients receiving dexra-
zoxane for anthracycline‐induced extravasation.
Notes:
Suggested use in young children at anthracy­
cline outset when expected total dose to
exceed 300 mg/m2 doxorubicin equivalents.
Otherwise recommended in patients with a
cumulative doxorubicin equivalent dose of
300 mg/m2 who are continuing to receive
anthracyclines (or as directed by protocol).
Dose‐limiting toxicity is myelosuppression,
which may be additive to chemotherapy. May
chelate heavy metals, leading to increases in
calcium, iron, and triglycerides and decreases
in sodium and zinc. May have antitumor
effects. Dose reduction in renal or hepatic
impairment may be needed. Dexrazoxane
has topoisomerase II inhibition activity and
secondary AML and MDS have been
reported when used in combination with
other anti‐cancer drugs with known links to
second malignant neoplasms.
DIMERCAPROL
British anti‐Lewisite (BAL), generics
Chelating agent (antidote for gold, mercury,
lead, and arsenic toxicity)
Injection: 100 mg/ml
Pregnancy category C
Indications:
Antidote to gold, mercury, and arsenic poison­
ing; used in conjunction with edetate calciu12
m disodium to treat severe lead poisoning.
Dosage:
For severe lead poisoning (lead level >70 mcg/
dl) or encephalopathy: 25 mg/kg/day divided
q4h deep IM for a minimum of 72 hours, may
give up to 5 days in severely symptomatic
patients. Calcium sodium ethylenediamine­
tetraacetic acid (EDTA) should be started at a
separate site with the second dimercaprol
dose. If symptoms of encephalopathy persist,
a second course of treatment can begin after a
minimum of 2 days of rest following the initial
5‐day course. Therapy should continue until
the patient is clinically stable. Once stable, a
10–14‐day period of equilibration should be
instated before again measuring the lead level.
If the level remains ≥70 mcg/dl, another
course of double therapy should be initiated.
Less severe lead poisoning (45–70 mcg/dl):
Treatment with dimercaprol is not recom­
mended in this situation due to toxicity;
patients should be treated with succimer or
calcium disodium EDTA instead.
Notes:
Do not give to patients with hepatic or renal
insufficiency. Do not use in iron, selenium,
or cadmium poisoning. Use with caution in
patients with G6PD deficiency (may cause
hemolysis) and peanut sensitivity. Hydrate
and alkalinize urine to protect the kidneys.

May cause hypertension, tachycardia, gas­
trointestinal disturbance, headache, fever,
transient neutropenia, and nephrotoxicity.
Symptoms may be relieved by antihista­
mines. Do not use concomitantly with iron.
Ensure calcium salt is given if edetate calcium
disodium is used in conjunction with BAL.
DIMETHYL SULFOXIDE
RIMSO‐50, DMSO
Antidote (anthracycline extravasation)
Topical: 50% solution
Pregnancy category C
Indications:
FDA indication for treatment of interstitial
cystitis. Limited information for use after
cooling for local control of extravasation of
anthracyclines. May also be used for extrava­
sation of ifosfamide, cisplatin, fluorouracil,
and carboplatin.
Dosage:
Apply 1–2 ml topically within 10–25 minutes
to affected area, then every 4–8 hours for 7–14
days, until resolution. Allow to dry and apply
clean, dry non‐occlusive dressing. Vitamin E
or Aloe vera has been used topically following
the first application to alleviate local burning
or stinging (ensure DMSO has dried).
Notes:
The role of DMSO in the treatment of
anthracycline extravasation remains contro-
versial. Do not use concurrently with dexra-
zoxane. Use with local cooling of tissues.
DINUTUXIMAB
Unituxin
Chimeric monoclonal antibody, Ch14.18
Injection: 17.5 mg/5 ml
Pregnancy category
Formulary 435
Indication:
Part of standard treatment for children
with high‐risk neuroblastoma. Each anti­
body is made of both mouse and human
components and targets glycolipid GD2,
expressed on neuroblastoma cells and on
normal cells of neuroectodermal origin,
including the central nervous system and
peripheral nerves. Dinutuximab is indi­
cated in combination with granulocyte‐
macrophage colony‐stimulating factor
(GM‐CSF), interleukin‐2 (IL‐2), and 13‐
cis‐retinoic acid (RA) after completion of
chemotherapy, surgery, autologous trans­
plant, and radiation therapy.
Dosing:
17.5 mg/m2/day IV over 10–20 hours for 4
consecutive days for maximum of five
cycles:
Cycles 1, 3, and 5 (24 days duration): Administer
on days 4, 5, 6, and 7.
Cycles 2 and 4 (32 days duration): Administer
on days 8, 9, 10, and 11.
Initiate at infusion rate of 0.875 mg/m2/hour
for 30 minutes; may gradually increase infu­
sion rate, as tolerated, to maximum of
1.75 mg/m2/hour.
Prior to each course: Verify that patient has
adequate hematologic, respiratory, hepatic,
and renal function.
Pretreatment and guidelines for pain
management:
IV hydration:
administer 0.9% NaCl injection, USP 10 ml/
kg IV over 1 hour.
Analgesics:
Morphine sulfate (50 mcg/kg) IV immediately
prior to initiation of dinutuximab; continue as
drip at infusion rate of 20–50 mcg/kg/hour
436 Formulary
during and for 2 hours following completion
of dinutuximab.
Administer additional 25–50 mcg/kg IV
morphine sulfate doses pro re nata, as neces­
sary (PRN) for pain up to once q2h followed
by an increase in morphine sulfate infusion
rate in clinically stable patients (may also
initiate nurse‐controlled analgesia).
May use fentanyl or hydromorphone if mor­
phine sulfate not tolerated.
Antihistamines and antipyretics:
Administer antihistamine such as diphen­
hydramine (0.5–1 mg/kg; not to exceed
50 mg) IV over 10–15 minutes starting
20 minutes prior to initiation of dinutuxi­
mab and as tolerated q4–6h during dinu­
tuximab infusion.
Administer acetaminophen (10–15 mg/kg;
not to exceed 650 mg) 20 minutes prior to
each dinutuximab infusion and q4–6h PRN
for fever or pain; administer ibuprofen
(5–10 mg/kg) q6h PRN for control of persis­
tent fever or pain.
Notes:
Dinutuximab can cause severe side effects,
including severe pain that must be controlled
with morphine, and a high risk of infusion
reaction that must be controlled with antihista­
mines and anti‐inflammatory drugs. Morphine
is administered prior to, during, and for 2
hours after infusion of dinutuximab to manage
the severe pain that this drug causes. An anti­
histamine and an anti‐inflammatory are also
given before, during, and after to manage
the infusion reaction. Capillary leak is com­
mon and the patient should be weighed twice
daily in addition to daily measures of blood
counts and albumin. Ideally, low blood pres­
sure should be treated with an oncotic load;
vasopressor support may be required.
The United States’ label for dinutuximab car­
ries a black box warning for life‐­threatening
infusion reactions and neurotoxicity, as it
causes severe neuropathic pain, and can cause
severe sensory neuropathy and severe periph­
eral motor neuropathy.
More than 25% of children taking these
drugs experience pain, fever, hives, vomit­
ing, diarrhea, bone marrow suppres­
sion causing decrease of platelets, red blood
cells, white blood cells, and albumin, hypo­
tension, electrolyte imbalance including low
sodium, potassium, and calcium, elevated
transaminases, infusion reactions, and cap­
illary leak syndrome. Other common
adverse effects include retention or urine for
weeks to months after receiving the drugs,
protein in urine, blurred vision or dilated
pupils, infections, edema, high blood pres­
sure, intractable bleeding, tachycardia, and
weight gain.
DIPHENHYDRAMINE
Benadryl, generics
Antihistamine
Capsules/tablets over the counter (OTC): 25,
50 mg
Chewable tablets: 12.5 mg
Elixir: 12.5 mg/5 ml
Injection: 50 mg/ml
Pregnancy category B
Indications:
Treatment of allergic symptoms, anaphy­
laxis, medication and transfusion reac­
tions, chemotherapy and other induced
nausea and vomiting, and motion sickness;
used as an antitussive or for mild sedation.
Prevents or treats metocloperamide‐
induced and phenothiazine‐induced dys­
tonic reactions.
Dosage:
Antiemetic and antivertigo: 0.5–1 mg/kg/
dose q6h PO, IM, or IV (maximum dose
50 mg and 300 mg/24 hour).
Pruritus: 0.5–1 mg/kg/dose q6h PO, IM, or IV
(maximum dose 50 mg and 300 mg/24 hour).

Notes:
Do not give to patients with known hyper­
sensitivity to diphenhydramine. Do not use
with concurrent monoamine oxidase (MAO)
inhibitors, in acute attacks of asthma, or in
patients with gastrointestinal or urinary
obstruction. Use with caution in patients
with glaucoma, peptic ulcer disease, urinary
tract obstruction, and hyperthyroidism.
Avoid alcohol. Note: many preparations con­
tain alcohol. May cause sedation, nausea,
vomiting, xerostomia, blurred vision, and
central nervous system effects. May cause
paradoxical activation in children.
DOXORUBICIN HYDROCHLORIDE
Adriamycin, Doxil (liposomal formulation)
Antineoplastic antibiotic, anthracycline
Injection: 10, 50 mg vials (protect from light)
Pregnancy category D
Indications:
Treatment of ALL, AML, Hodgkin lym­
phoma, lymphoma, Wilms tumor, neuroblas­
toma, and soft tissue and bone sarcomas.
Dosage:
Refer to individual protocol.
20–90 mg/m2 IV in repeated doses (may be
weekly or monthly or per phase of therapy).
Infusions may be over 15 minutes, several
hours, or as a continuous infusion over
24–48 hours. Although controversial, longer
infusions may be more cardioprotective,
especially when high cumulative doses (i.e.,
>450 mg/m2) are anticipated (though cannot
be given with dexrazoxane in such cases).
Children <12 kg and infants are dosed based
on weight rather than BSA.
Notes:
Do not give to patients with known hyper­
sensitivity to doxorubicin, severe congestive
heart failure or cardiomyopathy, or preexist­
Formulary 437
ing myelosuppression. Use with caution in
patients who have received very high cumu­
lative doses of anthracyclines (i.e., ≥550 mg/
m2 or ≥400 mg/m2 with concomitant use of
cyclophosphamide or chest radiation; based
on anthracycline dose equivalents). Monitor
cardiac function with LVEF and electrocar­
diogram (ECG) after every 75–100 mg/m2 of
anthracycline given. Cardiac toxicity may be
early (acute) or late (delayed months to years)
and long‐term cardiac monitoring is essen­
tial. Evidence of early cardiac toxicity may
include sinus tachycardia and/or ECG
changes with non‐specific ST‐T wave
changes. Delayed cardiotoxicity may be man­
ifested by tachyarrhythmias and other abnor­
mal rhythms including premature ventricular
contractions as well as evidence of bundle
branch block, and/or signs/symptoms of con­
gestive heart failure. Monitor cardiac func­
tion during treatment in addition to blood
counts, creatinine, and total bilirubin.
Modify dosage in renal impairment. May
cause severe bone marrow suppression, alo­
pecia, mucositis, and transient (48 hour)
red‐orange discoloration of the urine, sweat,
saliva, and tears. Extravasation may result in
severe local tissue necrosis; ensure adminis­
tration in CVC or large vein and monitor
closely. May cause photosensitivity reactions
and patients should be instructed to avoid
excessive exposure to sunlight and utilize
sunblock sun protection factor (SPF) ≥ 15.
DRONABINOL
Marinol, tetrahydrocannabinol (THC),
generics
Cannabinoid
Capsules: 2.5, 5, and 10 mg
Pregnancy category C
Indications:
Treatment of nausea and vomiting associ­
ated with chemotherapy in patients who
have failed to respond to conventional
438 Formulary
antiemetic therapy; treatment of anorexia
associated with weight loss in patients with
human immunodeficiency virus (HIV).
Evidence of benefit in chemotherapy‐induced
anorexia is mixed; no well‐controlled studies
have been performed in children.
Dosage:
Antiemetic: 5 mg/m2/dose 1–3 hours PO
prior to chemotherapy, then q2–4h; maxi­
mum 6 doses/24 hour, 15 mg/m2/dose in
adults. Titrate dose to effect.
Appetite stimulant: Adult dosing: 2.5 mg PO
BID 1 hour prior to lunch/dinner; if not toler­
ated, reduce dose to 2.5 mg every night at bed­
time (QHS); maximum dose 20 mg/24 hour.
Notes:
Do not give to patients with known hyper­
sensitivity to any cannabinoid or sesame oil.
Do not use in patients with history of sub­
stance abuse or mental illness. Use with cau­
tion in heart disease, seizures, and hepatic
disease. A dose‐related “high” (easy laugh­
ing, elation, or heightened awareness) is
reported in one‐quarter of patients using
cannabinoids as antiemetics. Other side
effects include dizziness, anxiety, difficulty
concentrating, hypotension, and increased
appetite. Psychological and physiologic
dependence may occur, but addiction is
uncommon. It is a controlled (Schedule III)
substance.
EDETATE CALCIUM DISODIUM
Calcium EDTA, CaNa2EDTA, generics
Calcium disodium versenate
Heavy metal antagonist; antidote, lead
toxicity
Injection: 200 mg/l
Pregnancy category B
Indications:
Used as an adjunct in the treatment of acute
and chronic lead poisoning.
Dosage:
For severe lead poisoning (lead level >70 mcg/
dl) and/or encephalopathy: 1000–1500 mg/
m2/24 hours as an 8–24 hours infusion or
divided q12h, given in combination with
dimercaprol (BAL). Use the higher dose in
the presence of encephalopathy. Give at a
separate site starting with the second dimer-
caprol dose.
Less severe lead poisoning (20–70 mcg/dl):
1000 mg/m2/24 hours IV as an 8–24 hours
infusion or intermittent dosing q12h for 5
days. May repeat course as needed after 2–4
days of re‐equilibration without EDTA.
Maximum daily dose 75 mg/kg.
Notes:
Do not give to patients with severe renal dis­
ease or anuria. Requires inpatient admission
with aggressive intravenous hydration and
frequent monitoring of serum electrolytes
including calcium and phosphorus, renal
function, and urinalyses. Establish urine
flow prior to administration and maintain
hydration/urine output throughout course
of therapy. Dose reduction is recommended
for mild renal disease. Monitor with contin­
uous ECG due to risk for arrhythmias.
Rapid IV infusion can result in sudden
increase in intracranial pressure in patients
with cerebral edema. May cause zinc and
copper deficiency. May be administered IM;
give with 0.5% prilocaine. Ensure calcium
salt is given.
ELTROMBOPAG
Promacta
Thrombopoietin receptor agonist
Tablets: 12.5, 25, 50, 75, 100 mg
Oral suspension: 25 mg packet
Pregnancy category C
Indications:
In children (>1 year) and adults with severe
thrombocytopenia and chronic immune

thrombocytopenia purpura (cITP) who have
had a suboptimal response to corticosteroids,
immunoglobulins, or splenectomy; chronic
hepatitis–C‐associated thrombocytopenia to
allow initiation/maintenance of treatment with
interferon; aplastic anemia with insufficient
response to immunosuppressive therapy.
Dosage:
Chronic ITP:
Children ≥6 years and adult: 50 mg PO QD
(maximum 75 mg QD).
Children 1–5 years: 25 mg PO QD.
Aplastic anemia:
50 mg PO QD (maximum dose 150 mg QD);
based on adult data.
Notes:
Administer on an empty stomach (1 hour
before or 2 hours after a meal). Take at least 2
hours before or 4 hours after any medication
or products containing polyvalent cations
including antacids, calcium‐rich foods, and
mineral supplements. Do not crush tablets;
prepare oral suspension in water only and
administer within 30 minutes. Dose adjust­
ment for hepatic impairment and for some
patients of East‐Asian ancestry. Adjust dose to
maintain platelet count ≥50 × 109/l. Side effects
are uncommon and include nausea, vomiting,
diarrhea, respiratory tract infections, myalgia,
and increased alanine aminotransferase.
ENOXAPARIN
Lovenox, generics
Anticoagulant, low‐molecular‐weight hepa­
rin (LMWH)
Injection (prefilled syringe): 30 mg/0.3 ml,
40 mg/0.4 ml, 60 mg/0.6 ml, 80 mg/0.8 ml,
100 mg/ml
Approximate anti‐factor Xa activity:
100 IU/mg
Pregnancy category B
Formulary 439
Indications:
Prophylaxis and treatment of thromboem­
bolic disorders such as DVT following sur­
gery or trauma, due to central line infection
and pulmonary embolus.
Dosage:
Treatment of DVT or thromboembolus
(TE):
Infants <2 months: 1.5 mg/kg/dose q12h SC;
higher doses of 1.7–2 mg/kg/dose q12h SC
have been recommended for neonates.
>2 months through adult: 1 mg/kg/dose q12h
SC; 1.5 mg/kg/dose q24h can be used in
adults. Higher doses may be required in
children to reach therapeutic levels.
Titrate dose to achieve peak anti‐factor Xa
levels of 0.5–1.0 U/ml (based on fraction­
ated anti‐Xa level). Peak anti‐Xa levels
should be drawn 4 hours after administra­
tion of a steady state dose (minimum two to
three prior doses).
See Chapter 10 for further guidelines. Some
centers advocate that TPA be given concom­
itantly with enoxaparin in high‐risk situa­
tions (i.e., large central embolism).
Prophylaxis or treatment with enoxaparin
may continue for prolonged periods
dependent on the underlying risks for
thrombophilia and response to therapy. For
those patients that will be maintained with
oral anticoagulation (e.g., warfarin), 4–5
days of overlap with enoxaparin should be
given in order to achieve a therapeutic INR.
DVT/TE prophylaxis:
Infant <2 months: 0.75 mg/kg/dose q12h SC.
Infant ≥2 months–18 years: 0.5 mg/kg q12h
SC or 1 mg/kg/dose q24h, maximum dose
30 mg.
Anti‐factor Xa levels do not need to be fol­
lowed in patients on prophylactic dosing.
Data are limited but 1 mg/kg once daily dos­
ing can be considered in patients with compli­
ance issues and in those with difficulty giving
440 Formulary
twice daily SC injections. An insuflon catheter
should also be considered.Recommended
anti‐Xa fractionated levels (obtained 4 hours
after second or third SC dose):
DVT treatment: 0.5–1 units/ml.
DVT prophylaxis: 0.1–0.3 units/ml.
Note: LMWH may be given IV at the same
dose as SC.
Notes:
Do not give to patients with known hyper­
sensitivity to enoxaparin or pork products
(derived from porcine intestinal mucosa),
active major bleeding, prosthetic heart
valves, acute heparin‐induced (or LMWH‐
induced) thrombocytopenia, and recent
major surgery or cerebral hemorrhage. Use
of the medication should be discussed in
patients with religious beliefs which prohibit
the consumption of pork products. Do not
give to patients with drug‐induced throm­
bocytopenia. Use with caution in patients
with recurrent gastrointestinal ulcers, bleed­
ing diathesis, and severe renal dysfunction;
lower initial doses should be given to
patients with renal insufficiency and failure.
Do not use with concurrent spinal or epi­
dural anesthesia or lumbar puncture for
chemotherapy. May cause fever, confusion,
edema, nausea, hemorrhage, hypochromic
anemia, thrombocytopenia, and pain/ery­
thema at the injection site.
In case of overdose, protamine sulfate can be
given, although the reversal is not complete
as with unfractionated heparin (UFH). 1 mg
of protamine sulfate neutralizes approxi­
mately 0.6–0.7 mg of enoxaparin.
Note that unfractionated anti‐Xa level (used
for monitoring heparin infusions) is not the
same as fractionated anti‐Xa level (used for
monitoring enoxaparin dosing).
EPOETIN ALFA
Recombinant human erythropoietin
Epogen, Procrit, erythropoietin
Injection (preservative‐free single use vials):
2000, 3000, 4000, 10,000, 20,000, 40,000 U/
ml (1 ml)
Pregnancy category C
Indications:
Treatment of anemia associated with
chronic renal failure, anemia related to ther­
apy with zidovudine (AZT) in HIV‐infected
patients, and anemia of prematurity. Usage
in cancer patients remains controversial.
May be considered as an adjunct for anemia
treatment in patients with religious beliefs
against utilization of blood transfusion (see
Darbepoetin).
Dosage:
Anemia in chronic renal failure: Start at 50 U/
kg (dose range 50–250 U/kg) administered
SC/IV three times a week; higher doses may
be needed. Dose is individualized to achieve
and maintain the lowest hemoglobin suffi­
cient to avoid transfusion, not to exceed
11 g/dl.
Anemia in AZT‐treated HIV patients: 100 U/
kg SC three times a week; dose range
50–4000 U/kg two to three times per week;
hgb should not exceed 12 g/dl.
Anemia in cancer patients: 600 U/kg IV once
weekly; dose titrated to effect (maximum
40,000 U). Do not initiate therapy if
hgb ≥ 10 g/dl; adjust dose to maintain the
lowest hgb level needed to avoid transfu­
sions. Adult dose 150 U/kg. SC three times a
week or 40,000 U SC once weekly.
Discontinue use after 8 weeks of therapy if
transfusions are still required or chemother­
apy is completed.
Anemia of prematurity: 250 U/kg/dose SC
three times per week for ten doses; alterna­
tively, 200–400 U/kg/dose IV/SC three to
five times per week. Administer supplemen­
tal iron 3–6 mg elemental iron/kg/24 hours
(many other regimens exist).

Notes:
Do not give to patients with known hyper­
sensitivity to albumin, uncontrolled hyper­
tension, and in newborns with neutropenia.
Use with caution in patients with porphyria
or a history of seizures. May cause headache
and elevated blood pressure. Meta‐analyses
have shown that usage leads to a significant
increased risk of death, thrombosis, and
serious cardiovascular events in cancer
patients.
Evaluate iron stores (ferritin and TIBC)
before therapy initiation. Iron supplementa­
tion is recommended unless iron stores are
already in excess.
ETOPOSIDE
VP‐16
Toposar, Etopophos
Antineoplastic, mitotic inhibitor
Capsule, softgel: 50 mg
Injection: 20 mg/ml; 5, 25, 50 ml vials
Pregnancy category D
Indications:
Treatment of germ cell tumors, lymphoma,
brain tumors, acute leukemias, neuroblas­
toma, rhabdomyosarcoma, histiocytosis,
and conditioning for BMT.
Dosage:
Refer to individual protocol.
AML: 100–150 mg/m2/day IV for 2–5 days
in Induction and Intensification courses.
Dose per body weight in patients with
BSA < 0.6 m2 (3.3 mg/kg/dose).
Brain tumors: 100–150 mg/m2/day IV for
1–3 days; may also be given long‐term PO
(using injection solution for oral adminis­
tration); good central nervous system
penetration
Neuroblastoma: 100 mg/m2/day IV (dose
by weight for BSA < 0.6 m2, 3.3 mg/kg/
dose) over 1 hour for days 1–5 or alternate
Formulary 441
day for three doses q3–4 weeks for three to
four courses.
Notes:
Do not give to patients with known hyper­
sensitivity to etoposide. Use with caution
and consider dose reduction in patients with
renal or hepatic impairment. May cause
facial flushing, fever, fatigue, nausea, vomit­
ing, bone marrow suppression, alopecia,
and peripheral neuropathy. Associated with
second malignant neoplasms, primarily
acute leukemia, dose and frequency related.
Give IV infusions over at least 1 hour due
to associated hypotension with rapid infu­
sion. Infusion should be stopped or infu­
sion rate be decreased with hypotension.
After fluid resuscitation, the infusion may
be restarted at a slower rate if stopped and
the hypotension resolved. Patients with
hypersensitivity to etoposide can usually be
safely treated with etoposide phosphate
(Etopophos; secondary to vehicle used to
dissolve etoposide).
EUTECTIC MIXTURE OF LIDOCAINE
AND PRILOCAINE
EMLA
Local anesthetic, topical anesthetic
Cream: 5, 30 g tubes
Pregnancy category B
Indications:
Used as a topical anesthetic applied to nor­
mal intact skin to provide local anesthesia
for minor procedures such as venipuncture,
placement of peripheral venous access line,
lumbar puncture, circumcision, and minor
dermatologic procedures.
Dosage:
Apply 2.5 g per site to normal intact skin and
cover with occlusive dressing for 30–60 minutes
prior to procedure.
442 Formulary
Notes:
Do not give to patients with known hyper­
sensitivity to lidocaine, prilocaine, or other
local anesthetic. Commonly causes blanch­
ing of skin or erythema. May cause mild
burning or altered temperature sensation.
FERRIC CARBOXYMALTOSE
Injectafer
Iron
Injection: 50 mg elemental Fe/ml; 750 mg/15 ml
vial
Pregnancy category C
Indications:
Treatment of iron deficiency anemia in
adults who have intolerance or insufficient
response to oral iron; and in patients with
non‐dialysis‐dependent chronic renal
disease.
Dosage:
<50 kg: 15 mg/kg/dose IV for two doses sep­
arated by at least 7 days; maximum 740 mg/
dose and 1500 mg per course; may be
repeated if iron deficiency anemia recurs.
≥50 kg: 750 mg IV for two doses, separated
by at least 7 days; maximum dose 1500 mg
per course; may be repeated if iron defi­
ciency anemia recurs.
Notes:
Serious hypersensitivity reactions, including
anaphylactic‐type reactions, some of which
have been life‐threatening and fatal, have
been reported in patients receiving
Injectafer. Patients may present with shock,
clinically significant hypotension, loss of
consciousness, and/or collapse. Monitor
patients for signs and symptoms of hyper­
sensitivity during and after Injectafer
administration for at least 30 minutes and
until clinically stable following completion
of the infusion. Only administer Injectafer
when personnel and therapies are immedi­
ately available for the treatment of serious
hypersensitivity reactions.
Safety and efficacy have not been estab­
lished in pediatrics. Recent studies suggest
this is a safe alternative for treatment of
hypoferritinemia‐associated fatigue in
adolescent and adult women. Other
adverse effects may include hypertension,
flushing, injection site discoloration, and
transient decrease in phosphorus levels
(<2 mg/dl).
FERRIC GLUCONATE
Ferrlecit
Iron
Injection: 62.5 mg elemental iron in 5 ml
(12.5 mg/ml)
Pregnancy category B
Indication:
Ferrlecit is utilized for the repletion of iron
stores in adults and children ≥6 years of age
undergoing hemodialysis.
Dosage:
Adults: 10 ml (125 mg of elemental iron,
maximum dose). Ferrlecit may be diluted in
100 ml of 0.9% sodium chloride adminis­
tered by IV infusion over 1 hour per dialysis
session. Ferrlecit may also be administered
undiluted as a slow intravenous injection (at
a rate of up to 12.5 mg/minute) per dialysis
session. For repletion treatment most
patients may require a cumulative dose of
1000 mg of elemental iron administered
over eight dialysis sessions.
Children ≥6 years to adult: 0.12 ml/kg
Ferrlecit (1.5 mg/kg of elemental iron, maxi­
mum dose 125 mg) diluted in 25 ml 0.9%
sodium chloride and administered by IV
infusion over 1 hour per dialysis session.

Notes:
The most commonly reported adverse reac­
tions (≥10%) in adult patients are nausea,
vomiting and/or diarrhea, injection site
reaction, hypotension, cramps, hyperten­
sion, dizziness, abnormal erythrocytes (e.g.,
changes in morphology, color, or number
of red blood cells), dyspnea, chest pain, leg
cramps, and pain. In patients 6–15 years of
age, the most common adverse reactions
(≥10%) were hypotension, headache, hyper­
tension, tachycardia, and vomiting.
Ferrlecit may cause clinically significant hypo­
tension. Hypotension associated with light­
headedness, malaise, fatigue, weakness, or
severe pain in the chest, back, flanks,
or groin has been reported. These hypoten­
sive reactions may or may not be associated
with signs and symptoms of hypersensitivity
reactions and usually resolve within 1–2 hours.
FERROUS GLUCONATE
Ferate, generics
Iron (12% elemental Fe)
Tablets (OTC): 240 mg (27 mg Fe), 325 mg
(36 mg Fe)
Pregnancy category A
Indications:
Prevention and treatment of iron deficiency
anemia.
Dosage:
Dose is expressed in terms of elemental iron.
Iron deficiency anemia:
Premature infant: 2–4 mg/kg/day PO
divided QD BID; maximum dose
15 mg/24 hour.
Child: 3–6 mg/kg/day PO in 1–3 divided
doses.
Adult: 60–100 mg PO in 1–2 divided doses;
up to 240 mg/day.
Formulary 443
Prophylaxis:
Premature infant: 2 mg/kg/day, maximum
dose 15 mg/24 hour.
Term infant: 1–2 mg/kg/day, maximum dose
15 mg/24 hour.
Child 2–12 years: 2 mg/kg/day, maximum
dose 30 mg/24 hour.
Adolescent to adult: 60 mg PO QD.
Notes:
Do not give to patients with known hyper­
sensitivity to iron salts, hemochromatosis,
and transfusional iron overload. Absorption
of iron is decreased when given with tetra­
cycline, antacids, or milk. Less gastrointesti­
nal irritation when given with food.
Concurrent administration of 200 mg or
more of vitamin C per 30 mg elemental iron
increases absorption of oral iron; iron
replacement products should be given with
orange juice. May cause constipation, dark
stools, nausea, and epigastric pain. Recent
studies suggest once daily dosing (or even
alternate day dosing) may optimize iron
absorption in iron deficiency states.
FERROUS SULFATE
Fer‐In‐Sol, FeroSul, Slow FE, generics
Iron (20% elemental Fe)
Tablet OTC: 325 mg (65 mg Fe)
Drops (Fer‐In‐Sol) OTC: 75 mg (15 mg
Fe)/1 ml
Elixir (FeroSul and generics)
OTC: 220 mg (44 mg Fe)/5 ml
Extended release tabs (Slow FE, generics)
OTC: 140 mg (45 mg Fe), 160 mg (50 mg Fe),
324 mg (65 mg Fe), 325 mg (65 mg Fe)
Pregnancy category A
Indications:
Prevention and treatment of iron deficiency
anemia.
444 Formulary

Dosage: Dosage:
See Ferrous Gluconate. Neonatal sepsis with neutropenia: 5–10 mcg/
kg IV/SC daily for 3–5 days.
Notes: Chemotherapy‐induced neutropenia:
See Ferrous Gluconate. Children and adults: 5–10 mcg/kg IV/SC
once daily until ANC is greater than
FERROUS FUMARATE 2–10 × 109/l (per protocol; given beyond
Ferrets, generics nadir period 7–10 days after chemotherapy
Iron salt (33% elemental Fe) administration).
Tablet OTC: 90 mg (29.5 mg Fe), 324 mg Peripheral blood progenitor cell mobilization:
(106 mg Fe), 325 mg (106 mg Fe), 456 mg 10 mcg/kg SC daily for 4 days before the first
(150 mg Fe) leukapheresis procedure and continued
until the last leukapheresis.
Pregnancy category A
Congenital neutropenia: 2.5–6 mcg/kg/day
Indications: SC; titrate dose to desired ANC to prevent
infection.
Prevention and treatment of iron deficiency
anemia. Idiopathic or cyclic neutropenia: 5 mcg/kg SC
once daily; titrate dose to desired ANC to
prevent infection.
Dosage:
Elevation of ANC is usually within 24 hours,
See Ferrous Gluconate.
though it may be delayed in severe myelo­
suppression. Transient increase in ANC may
Notes:
occur when granulocyte colony‐stimulating
See Ferrous Gluconate. factor (G‐CSF) is begun shortly after com­
pletion of chemotherapy; avoid premature
FILGRASTIM discontinuation.
Neupogen, Granix, Zarxio, G‐CSF SC route of administration is preferred due
Blood formation, colony‐stimulating factor to prolonged serum levels over IV route. If
Injection: 300 mcg/ml (1, 1.6 ml) used IV and the G‐CSF concentration is
Pregnancy category C >15 mcg/ml, add 2 mg albumin/1 ml of IV
fluid to prevent drug absorption in the IV
Indications: administration set.

Used to decrease the period of neutropenia

and the associated risk of infection in
patients with malignancies receiving myelo­
suppressive chemotherapy associated with a
significant incidence (i.e., >20%) of severe
neutropenia. Has been used in zidovudine‐
associated neutropenia in HIV‐infected
patients and in patients with nonchemo­
therapy‐induced neutropenia (acquired and
congenital). Should be considered in
patients with complicated infection with
underlying neutropenia.
Notes:
Avoid in patients with hypersensitivity to E.
coli‐derived proteins or G‐CSF. May cause
bone pain and increases in uric acid and lac­
tate dehydrogenase. Do not administer
24 hours before or after administration of
chemotherapy due to potential for pro­
longed myelosuppression from increased
chemosensitivity of myeloid progenitors
stimulated by G‐CSF.

FLUCONAZOLE
Diflucan, generics
Antifungal
Tablet: 50, 100, 150, 200 mg
Injection: 2 mg/ml
Suspension: 10, 40 mg/ml
Pregnancy category C (vaginal candidiasis)/D
for all other indications
Indications:
Prophylaxis and treatment of susceptible
fungal infections, including oropharyngeal,
esophageal, and vaginal candidiasis, and
systemic fungal infections with Candida sp.
as well as treatment and suppression of
cryptococcal meningitis. Species of Candida
with decreased in vitro susceptibility to flu­
conazole are being isolated. Fluconazole is
more active against candidal species such as
Candida albicans than species such as
Candida parapsilosis, Candida glabrata, and
Candida tropicalis.
Dosage:
Oropharyngeal candidiasis: 6 mg/kg load­
ing dose PO/IV followed by 3 mg/kg/day
(dependent on severity of infection) for
2–4 weeks (dependent on clinical response
and immune status of the patient).
Neonates under 14 days of age are dosed
every 24–72 hours. Maximum dose 400 mg/
day.
Esophageal candidiasis: 12 mg/kg loading
dose PO/IV, followed by 6 mg/kg/day for
2–4 weeks; maximum dose 400 mg/day.
Invasive systemic candidiasis and cryptococ-
cal meningitis: 12 mg/kg loading dose PO/
IV, followed by 6–12 mg/kg/day for
2–4 weeks or longer. Maximum dose 12 mg/
kg/day or 800 mg/day in adults.
Prophylaxis in immunocompromised hosts/
bone marrow transplant prophylaxis:
3–6 mg/kg/dose PO/IV; maximum dose
400 mg/day.
Formulary 445
Notes:
Do not give to patients with known hyper­
sensitivity to fluconazole or other azoles.
May cause nausea, headache, rash, vomit­
ing, abdominal pain, hepatitis, cholestasis,
and diarrhea. Antagonism may occur if
amphotericin B and fluconazole are used
concurrently. Many drug interactions exist;
contraindicated concurrently with other
medications that prolong QT interval and
are metabolized via the CYP450 3A4
enzyme. May increase effects, toxicity, and/
or levels of cyclosporine, midazolam, tac­
rolimus, and many other drugs. Rifampin
increases fluconazole metabolism. Consult
the PDR or a pharmacist when ordering
fluconazole in a patient receiving many
medications.
FLUDARABINE
Fludara
Antineoplastic, antimetabolite; purine analog
Injection: 50 mg vial
Pregnancy category D
Indications:
Treatment of leukemias including ALL,
AML, CLL, and non‐Hodgkin lymphoma.
Conditioning regimen for HSCT.
Dosage:
25 mg/m2 IV over 30 minutes daily for 5
consecutive days. Dosage may be decreased
or delayed based on evidence of hemato­
logic or nonhematologic toxicity.
Conditioning regimen pretransplant: 40 mg/
m2 IV daily for 4 days. For patients <10 kg,
use weight‐based dosing: 1.33 mg/kg/dose.
Notes:
Common adverse effects include marked
myelosuppression and lymphopenia, increas­
ing the risk of opportunistic infections.
Edema, skin rash, and peripheral neuropathy
446 Formulary
are reported. Has been associated with
autoimmune hemolytic anemia and transfu­
sion‐associated graft‐versus‐host disease.
Pretreatment may result in difficulty collect­
ing peripheral blood stem cells for transplant.
FONDAPARINUX
Arixtra
Anticoagulants, hematologic; Factor Xa
inhibitors
Injection: (Single‐dose, prefilled syringes)
2.5, 5, 7.5, or 10 mg
Pregnancy category B
Indications:
Prophylaxis of DVT in patients undergoing
hip fracture surgery (including extended
prophylaxis), hip replacement surgery, knee
replacement surgery, or abdominal surgery.
Treatment of DVT or acute pulmonary
embolism (PE) when administered in con­
junction with warfarin.
Dosage:
Fondaparinux is given subcutaneously once
daily. The dose in individuals with normal
renal function is based on body weight and
the indication for anticoagulant use (e.g.,
prophylaxis for venous thromboembolism
[VTE] versus therapy). Fondaparinux is not
currently indicated in the pediatric popula­
tion and guidelines exist for treatment based
on a weight of 50 kg or greater.
VTE prophylaxis: 2.5 mg SC once daily in
patients weighing ≥50 kg. In the periopera­
tive setting, the first dose is given 6–8 hours
postoperatively (after skin closure), as done
in all of the major clinical trials.
Superficial vein thrombosis (treatment): 2.5 mg
SC once daily in patients weighing ≥50 kg.
VTE or pulmonary embolus (treatment):
Patients weighing <50 kg – 5 mg SC once
daily.
Patients weighing 50–100 kg – 7.5 mg SC
once daily.
Patients weighing >100 kg – 10 mg SC once
daily.
Notes:
Fondaparinux cannot be given intramuscu­
larly. Safety and efficacy in pediatric patients
have not been established. Because risk for
bleeding during treatment is increased in
adults who weigh <50 kg, bleeding may be an
important safety concern in pediatric
patients. Fondaparinux does not require rou­
tine monitoring with coagulation studies or
drug levels, though can be initially assessed
with a fondaparinux level 3 hours after the
second or subsequent dose. Renal function
should be evaluated as renal dosing may be
indicated. Pediatric trials are ongoing, and
weight‐based dosing (i.e., 0.1 mg/kg) in
patients 1–18 years of age has been reported.
A specific fondaparinux reversal agent is in
development, though protamine would par­
tially reverse the medication in an emergent
situation. Given the longer half‐life com­
pared with enoxaparin, fondaparinux must
be held a minimum of 48 hours prior to lum­
bar puncture and longer with more invasive
procedures.
FOLIC ACID
Folate
Folvite, generics
Blood formation, water‐soluble vitamin
Tablet OTC: 0.4, 0.8, 1 mg
Solution: 50 mcg/ml
Injection: 5 mg/ml
Pregnancy category A/C
Indications:
Treatment of megaloblastic anemia resulting
from folate deficiency; supplementation for
patients with chronic hemolytic anemia (e.g.,
sickle cell disease, hereditary spherocytosis).

Dosage:
Infants to children <12 months: 15 mcg/kg
daily PO; maximum 50 mcg/day.
Children ≥1–11 years: Initial dose 1 mg/day
PO; maintenance dose 0.1–0.4 mg/day PO.
Children >11 years and adults: Initial dose
1 mg/day PO; maintenance dose 0.4–0.8
mg/day PO.
Notes:
May mask hematologic effects of vitamin B12
deficiency but will not prevent progression
of neurologic abnormalities.
FOSCARNET
Foscavir, generics
Antiviral
Injection: 24 mg/ml
Pregnancy category C
Indications:
Alternative to ganciclovir for treatment of
cytomegalovirus (CMV) infection; treat­
ment of acyclovir‐resistant HSV infections
in immunocompromised hosts.
Dosage:
Children and adults:
CMV retinitis: 180 mg/kg/day IV divided
q8–12h for 14–21 days (with or without gan­
ciclovir) followed by daily IV maintenance
of 90–120 mg/kg/day.
Acyclovir‐resistant HSV infection: 40 mg/kg/
dose IV q8–12h up to 3 weeks or until
lesions heal; repeat treatment may lead to
resistance.
Varicella zoster unresponsive to acyclovir:
40 mg/kg/dose q8–12h for 7–10 days (ado­
lescent give 90 mg/kg/dose q12h).
Notes:
May cause renal impairment, adjust dose
for renal dysfunction. Assure adequate
Formulary 447
hydration. May adversely affect tooth and
bone growth in children, safety and effi­
cacy not fully evaluated. May cause elec­
trolyte imbalances and symptoms of
hypocalcemia. May cause seizures; risk
factors include renal impairment, low
serum calcium, and underlying central
nervous system condition. Foscarnet is a
vesicant; only infuse into veins with ade­
quate blood flow.
GANCICLOVIR
Cytovene, Zirgan, generics
Antiviral
Injection: 500 mg (can be prepared into oral
suspension)
Pregnancy category C
Indications:
Treatment of CMV retinitis, pneumonitis,
encephalitis, and gastrointestinal infection in
immunocompromised patients. Prevention of
symptomatic CMV disease in transplant
patients with reactivation of latent disease.
Has antiviral activity against HSV‐1 and
HSV‐2.
Dosage:
Congenital CMV infections, neonates and
infants: 12 mg/kg/day slow IV infusion
divided q12h for 6 weeks.
CMV retinitis, children >3 years to adults:
10 mg/kg/day IV divided q12h for
14–21 days followed by maintenance 5 mg/
kg/day IV as a single daily dose for 7 days/
week or 6 mg/kg/day IV for 5 days/week.
Prevention of CMV in transplant recipients,
children and adults: 10 mg/kg/day IV
divided q12h for 1–2 weeks followed by
maintenance 5 mg/kg/day IV once daily for
7 days/week or 6 mg/kg/day IV for 5 days/
week until 100–120 days posttransplant.
Minimum dilution is 10 mg/ml and should
be infused ≥1 hour.
448 Formulary
Notes:
Do not give to patients with known hyper­
sensitivity to ganciclovir, acyclovir, or any
component. Patients must use appropriate
contraception due to teratogenic effects for
at least 90 days after therapy completion.
Immunosuppressive drugs may increase
risk of cytopenias. Concurrent ampho­
tericin B, tacrolimus, or cyclosporine
increase risk of nephrotoxicity. Use with
caution in patients with renal impairment.
GEMCITABINE
Gemzar
Antineoplastic; pyrimidine antagonist
Injection: 200 mg, 1 g
Pregnancy category D
Indications:
Treatment of ovarian, breast, non‐small cell
lung, pancreatic cancer, and other solid
tumors. Recently evaluated in refractory/
relapsed pediatric ALL.
Dosage:
Refer to individual protocol.
Pediatric ALL: 10 mg/m2/minute IV over
360 minutes weekly for 3 weeks, followed by
1 week of rest.
Notes:
Contraindicated in patients with known
hypersensitivity to gemcitabine. Common
adverse effects include myelosuppression,
nausea and vomiting, hepatic transaminitis,
and peripheral edema. Toxicities requiring
cessation of treatment include: severe pul­
monary toxicity, capillary leak syndrome,
hemolytic uremic syndrome or severe renal
toxicity, and posterior reversible encepha­
lopathy syndrome (PRES). Can rarely cause
radiation recall.
GEMTUZUMAB OZOGAMICIN
Mylotarg
Antineoplastic, monoclonal antibody
Injection: 5 mg
Pregnancy category D
Indications:
Treatment of AML (newly diagnosed adults
and refractory/relapsed pediatric AML).
Dosage:
Refer to individual protocol; used as single
agent or in combination treatment.
Children with BSA <0.6 m2: 0.1 mg/kg/dose.
Children with BSA ≥0.6 m2: 3 mg/m2/dose,
as a single dose or multidosing.
Premedicate children with acetaminophen
15 mg/kg (maximum 650 mg) and diphen­
hydramine 1 mg/kg (maximum 50 mg).
Consider addition of methylprednisolone
1 mg/kg PO or IV; additional doses of aceta­
minophen and diphenhydramine may be
administered every 4 hours after the initial
pretreatment dose. Give methylpredniso­
lone or an equivalent corticosteroid for any
sign of an infusion reaction such as fever,
chills, hypotension, or dyspnea during the
infusion or within 4 hours afterward.
Notes:
Do not give to patients with known hyper­
sensitivity to gemtuzumab. Severe hyper­
sensitivity reactions and infusion‐related
reactions may occur including pulmonary
edema, acute respiratory distress syndrome,
and anaphylaxis. Administer by slow infu­
sion over 2 hours. Severe hepatic toxicity
including veno‐occlusive disease (SOS) has
been reported. Use with caution in patients
with renal or hepatic impairment or pulmo­
nary disease. May cause prolonged QTc.
GLUCARPIDASE
Voraxaze
Antidote, recombinant glutamate carboxy­
peptidase (carboxypeptidase G2)
Solution: 1000 unit vial, reconstitute with
1 ml NS
Pregnancy category C

Indications:
Adjunct to leucovorin rescue for the treat­
ment of toxic plasma methotrexate concen­
trations (>0.454 mcg/ml [1 μmol/l]) in
patients with delayed methotrexate clear­
ance due to renal impairment.
Dosage:
Children and adults: Single 50‐unit/kg dose
IV, administer over 5 minutes.
Notes:
Provides an alternative, nonrenal route for
methotrexate elimination (in patients with
delayed methotrexate clearance due to renal
impairment) by converting circulating
methotrexate to inactive metabolites that
are primarily eliminated hepatically.
Administration of glucarpidase 2 hours
before leucovorin reduces peak concentra­
tions and AUC of leucovorin and of its
active metabolite 5‐methyl‐tetrahydrofolate.
Do not administer leucovorin within 2
hours before or after glucarpidase
Plasma methotrexate concentrations meas­
ured by immunoassay within 48 hours follow­
ing glucarpidase administration are
unreliable. During first 48 hours after glucarp­
idase administration, use chromatographic
method to obtain reliable measurements of
plasma methotrexate concentrations.
Common adverse effects include paresthe­
sia, flushing, nausea and/or vomiting, hypo­
tension, and headache. The drug is
distributed primarily in the intravascular
compartment and does not cross the blood–
brain barrier.
GRANISETRON
Sancuso, Sustol, generics (previously availa­
ble as Kytril)
Antiemetic agent, serotonin (5‐HT3)
antagonist
Tablet: 1 mg
Formulary 449
Solution: 0.2 mg/ml, 50 mcg/ml
Injection: 0.1 mg/ml, 1 mg/ml (prefilled
syringe for SC extended release [Sustol]
10 mg/0.4 ml)
Pregnancy category B
Indications:
Prevention and treatment of nausea and
vomiting associated with moderately eme­
togenic chemotherapy. Has also been uti­
lized in prevention of postoperative and
radiation‐induced nausea and vomiting.
Dosage:
Chemotherapy‐induced nausea and
vomiting:
IV:
Children ≥2 years to adults: 10–20 mcg/kg/
dose IV 15–60 minutes before chemother­
apy; may be repeated two to three times fol­
lowing chemotherapy over 24 hours;
maximum dose 3 mg/dose or 9 mg/24 hours.
Alternatively, a single dose of 40 mcg/kg
15–60 minutes before chemotherapy has
been used.
PO:
Infant, child, adolescent: 40 mcg/kg/dose
PO/IV BID, initiate first dose 1 hour prior to
chemotherapy.
Adults: 2 mg/24 hours PO divided q12–24h;
initiate first dose 1 hour before
chemotherapy.
SC (Sustol): 10 mg SC at least 30 minutes
prior to first dose in combination with dexa­
methasone; do not administer more than
every 7 days.
Transdermal patch (Sancuso): Adult: Apply 1
patch 24–48 hours prior to chemotherapy,
may be worn for up to 7 days.
PONV prevention: Children ≥4 years to
adults: 20–40 mcg/kg IV dosed prior to
anesthesia or immediately before anesthesia
reversal; maximum dose 1 mg once.
450 Formulary
Radiation‐induced nausea and vomiting
prevention:
Adults: 2 mg PO daily administered 1 hour
prior to radiation.
Notes:
Inducers or inhibitors of the cytochrome
P450 drug‐metabolizing enzymes may
increase or decrease, respectively, the
drug’s clearance. Use with caution in liver
disease. May cause hypertension, hypoten­
sion, arrhythmias, agitation, and insom­
nia. Safety and efficacy in pediatric
patients for the prevention of PONV has
not been established.
HEPARIN SODIUM
Generics
Anticoagulant
Injection: many vial sizes, porcine‐based ori­
gin; preservative free
Lock flush solution: 1, 10, 100 U/ml (por­
cine‐based, some products may be preserva­
tive free or contain benzyl alcohol)
Injection for IV infusion: Porcine‐based,
D5W: 40 U/ml, 50 U/ml, 100 U/ml; 0.9%
NaCl: 2 U/ml; 0.45% NaCl: 50 U/ml, 100 U/
ml, contains EDTA
120 U = approximately 1 mg
Pregnancy category C
Indications:
Prophylaxis and treatment of thromboem­
bolic disorders; thrombus prophylaxis for
central venous access devices.
Dosage:
Anticoagulation in infants and children:
Initial: 75 U/kg IV bolus over 10 minutes in
infants to <16 years; 70 U/kg in >16 years
(maximum dose 7700 U).
Maintenance IV continuous infusion:
<1 year: 28 U/kg/hour.
≥1–16 years: 20 U/kg/hour (maximum rate
1650 U/hour).
>16 years: 15 U/kg/hour (maximum rate
1650 U/hour).
Adjust dose per one of the following labora­
tory goals:
UFH anti‐Xa level: 0.3–0.7 units/ml.
or
Activated partial thromboplastin time
(APTT) level (reagent specific to reflect anti‐
Xa level of 0.3–0.7 units/ml): 50–80 seconds.
or
If anti‐Xa levels not available, use APTT
1.5–2.5 times the control value.
Lab samples should be collected 4–6 hours
after initiation or dose/infusion rate change;
do not collect from a heparinized line or the
same extremity as the site of heparin infusion.
Note that measurement of unfractionated
anti‐Xa will provide the most accurate level.
Heparin flush:
Peripheral IV: 1–2 ml of 10 U/ml solution q4h.
Central lines: 2–3 ml of 100 U/ml solution
q24h and after access. Dosing often estab­
lished by institutional policy.
Arterial lines and TPN lines (central lines):
Add heparin to make a final concentration
of 0.5–1 U/ml.
Notes:
Do not give to patients with known hypersen­
sitivity to heparin or pork products, severe
thrombocytopenia, suspected intracranial
hemorrhage, shock, severe hypotension, and
uncontrolled bleeding (unless secondary to
disseminated intravascular coagulation).
Avoid IM injections and medications affecting
platelet function. Use actual body weight when
dosing. Should discuss usage in patients with
religious beliefs which prohibit the consump­
tion of pork products. Use preservative free
heparin in neonates and consider more dilute
heparin.
Unfractionated anti‐Xa level is not the same
as fractionated anti‐Xa level (used for moni­
toring enoxaparin dosing).

Reversal agent: Protamine sulfate 1 mg per
100 U heparin infused in previous 4 hours.
HYALURONIDASE
Amphadase, Hydase (bovine sources, may
contain edetate disodium and thimerosal)
Hylenex (recombinant human source)
Vitrase (ovine source, preservative free)
Antidote (extravasation)
Injection: 150 U/ml (Vitrase 200 U/ml)
Pregnancy category C
Indications:
Used to influence the dispersion and absorp­
tion of other drugs and increase rate of
absorption of parenteral fluids given by
hypodermoclysis (subcutaneously); treat­
ment of IV extravasations.
Dosage:
Infants and children: Dilute 150‐unit vial
(1 ml) in NS to volume of 10 ml (15 U/ml).
Give 1 ml (15 U) by administering five sepa­
rate injections of 0.2 ml (3 U) at borders of
extravasation site SC or intradermal using a
25‐ or 26‐gauge needle. Administer as early
as possible after extravasation (minutes to
1 hour).
Notes:
Do not give to patients with known hyper­
sensitivity to hyaluronidase or respective
sources (bovine, ovine). Do not inject in or
around infected, inflamed, or cancerous
lesions; do not use with dopamine or alpha‐
agonist extravasation. May cause urticaria.
HYDROCORTISONE
Solu‐Cortef, Cortef, generics
Corticosteroid
Tablet (Cortef, generics): 5, 10, and 20 mg
Suspension: 2.5 mg/ml
Injection, as sodium succinate (Solu‐Cortef):
100, 250, 500, 1000 mg vial
Pregnancy category C
Formulary 451
Indications:
Treatment of inflammatory dermatoses and
adrenal insufficiency; also used as a chemother­
apeutic agent for intrathecal administration.
Dosage:
Physiologic replacement: 12–18 mg/m2/day
PO divided q6–8h.
Stress dosing (consider for >2 weeks on gluco-
corticoid therapy or patients in shock): Solu‐
Cortef, 25–100 mg/m2/day PO/IV.
Intrathecal chemotherapy with methotrexate
and/or cytarabine: Dose per protocol, range
15–30 mg/dose.
Notes:
Do not give to patients with known hyper­
sensitivity to hydrocortisone, polymyxin B
sulfate, or neomycin sulfate. Avoid in
patients with infections from herpes sim­
plex, vaccinia, and varicella.
HYDROMORPHONE
HYDROCHLORIDE
Dilaudid, Dilaudid‐HP, Exalgo, generics
Narcotic, analgesic
Tablets: 2, 4, 8 mg
Tablets (extended release, Exalgo, generics):
8, 12, 16, 32 mg
Solution: 1 mg/ml
Suppository: 3 mg
Injection: 1, 2, 4, 10 mg/ml
Pregnancy category C/D (prolonged use,
high doses at term)
Indications:
Management of moderate to severe pain.
Dosage:
Children <50 kg (not for use in neonates):
PO: 0.03–0.1 mg/kg/dose q3–4h PRN (max­
imum 5 mg/dose).
IV: 0.015 mg/kg/dose q3–6h PRN.
Adolescents–adults ≥50 kg (doses not weight
based):
452 Formulary
PO: 1–2 mg (up to 4 mg/dose in adults)
q4–6h PRN.
IV: 0.2–0.6 mg/dose q2–4h PRN (up to
1 mg/dose in adults).
IM/SC: 0.8–1 mg/dose q4–6h PRN.
PR: 3 mg q4–8h PRN.
Notes:
Do not give to patients with known hyper­
sensitivity to hydromorphone. Dose reduc­
tion recommended in renal insufficiency or
severe hepatic impairment. Avoid use in
neonates because of potential central nerv­
ous system effects. Use with caution in
infants and young children. Causes less pru­
ritus than morphine. Approximate 6:1 con­
version from morphine (i.e., 6 mg morphine
is equivalent to 1 mg dilaudid).
HYDROXYUREA
Hydrea, Droxia
Antineoplastic
Capsule: 500 mg (Hydrea); 200, 300, 400 mg
(Droxia)
Pregnancy category D
Indications:
Treatment of malignancies including CML,
desmoid tumors; adjunct in the manage­
ment of sickle cell anemia to reduce pain
events, acute chest syndrome, hospitaliza­
tions, transfusion needs, and mortality;
hyperleukocytosis due to blast crisis in CML
and in relapsed acute leukemias; hypereo­
sinophilic syndrome.
Dosage:
Refer to individual protocol.
CML, hyperleukocytosis: Initial dose 10–20
mg/kg PO once daily; adjust dose according to
hematologic response and symptoms.
Sickle cell anemia: Initial dose 15 mg/kg
(range 10–20 mg/kg/day) once daily;
increase dose in increments of 5 mg/kg/day
every 12 weeks to a maximum of 35 mg/kg/
day. Discontinue for bone marrow toxicity:
ANC <2 × 109/l, platelets <80 × 109/l, reticu­
locyte count <8 × 109/l, or hemoglobin
<9 g/dl. Restart therapy after recovery at
2.5 mg/kg/day less than dose that produced
toxicity.
Notes:
Do not give to patients with known hyper­
sensitivity to hydroxyurea or those with
severe anemia or severe bone marrow sup­
pression. Use with caution in renal impair­
ment. Common adverse reactions are
hematologic and gastrointestinal.
IDARUBICIN
Idamycin, generic
Antineoplastic antibiotic, anthracycline
Injection: 1 mg/ml; 5, 10, 20 ml vials
Pregnancy category D
Indications:
Treatment of AML and relapsed ALL.
Dosage:
Refer to individual protocol.
APL induction: 12 mg/m2/day IV over
15–20 minutes for 3–4 consecutive days;
often given concurrently with cytarabine.
Notes:
Do not give to patients with known hypersen­
sitivity to idarubicin, severe congestive heart
failure, or cardiomyopathy. Avoid in preexist­
ing bone marrow suppression unless the
potential benefit warrants the risk. May need to
reduce dosage with impaired renal or hepatic
function. Irreversible myocardial toxicity may
occur as the cumulative dosage approaches
550 mg/m2 doxorubicin equivalents (or
400 mg/m2 with chest irradiation or concomi­
tant cyclophosphamide administration).

This may be an acute or late effect and cardiac
monitoring with echocardiogram, LVEF deter­
mination, and ECG is required during and
after completion of therapy. Secondary leuke­
mia has been reported.
IFOSFAMIDE
Ifex
Antineoplastic, alkylating agent
Injection: 1 g vial
Pregnancy category D
Indications:
Used in combination with other antineo­
plastics in the treatment of Hodgkin and
non‐Hodgkin lymphoma, ALL, osteosar­
coma, rhabdomyosarcoma, Ewing sarcoma,
and advanced Wilms tumor.
Dosage:
Refer to individual protocol.
Usual dose is 700–1800 mg/m2/day IV for 5
consecutive days every 3–4 weeks.
Notes:
Do not give to patients with known hyper­
sensitivity to ifosfamide. Avoid in severe
bone marrow suppression. Use with caution
in impaired renal function; hydrate the
patient prior to administration and ensure
good urine flow (i.e., urine specific gravity
≤1.010). Ifosfamide may lead to syndrome of
inappropriate antidiuretic hormone (SIADH)
secretion. Mesna is used for uroprotection
with higher doses to decrease risk of hemor­
rhagic cystitis. Urinalysis should be moni­
tored closely for specific gravity and heme.
May cause central nervous system toxicity
including hallucination, somnolence, confu­
sion, coma, or encephalopathy.
IMATINIB MESYLATE
Gleevec
Antineoplastic, tyrosine kinase inhibitor (TKI)
Formulary 453
Tablet: 100, 400 mg
Pregnancy category D
Indications:
Treatment of newly diagnosed adult and
pediatric Philadelphia chromosome positive
(Ph+) CML in chronic or accelerated phase;
Ph+ CML in blast phase adult Ph+ ALL
(relapsed or refractory); pediatric Ph+ ALL;
aggressive systemic mastocytosis without
KIT mutation; KIT positive (CD117) unre­
sectable gastrointestinal stromal tumors
(GIST); hypereosinophilic syndrome or
chronic eosinophilic leukemia with specific
mutations; and myelodysplastic/myelopro­
liferative disease associated with platelet‐
derived growth factor receptor (PDGFR)
gene rearrangements.
Dosage:
Refer to individual protocol.
Children ≥2 years:
Ph+ CML, chronic phase, new diagnosis:
340 mg/m2/day PO q24h.
Ph+ ALL: 340 mg/m2/day PO q24h postin­
duction and through maintenance.
If daily dose exceeds 400–600 mg, give doses
divided q12h. Do not crush tablets, but may
dissolve in water or apple juice if patient
cannot swallow tablets.
May need to adjust dose with hepatic or
hematologic toxicity.
The optimal duration of therapy for CML or
ALL is not determined.
Notes:
Do not give to patients with known hyper­
sensitivity to imatinib. May cause fluid
retention, weight gain, edema, pleural effu­
sion, pericardial effusion, and pulmonary
edema. Use with caution in patients where
fluid retention may be poorly tolerated such
454 Formulary
as congestive heart failure or left ventricular
dysfunction. May cause Stevens–Johnson
syndrome, hepatotoxicity, hemorrhage, and
hematologic toxicity. Use with caution in
patients with preexisting hepatic or renal
impairment. Imatinib is metabolized via the
CYP3A4 enzyme system, use with caution
in patients receiving concurrent therapy
that may be an inducer or inhibitor and
affect drug concentrations. Avoid warfarin.
May cause photosensitivity, pruritus, rash,
gastrointestinal disturbance, bone or joint
pain, and blurred vision.
IMMUNE GLOBULIN
Flebogamma 5% (50 mg/ml)
Gamunex‐C 10% (100 mg/ml)
Gammagard 10% (100 mg/ml)
Octagam 5% (50 mg/ml)
Carimmune NF: 1, 3, 6, 12 g for reconstitution
Hizentra (SC): 20% (200 mg/ml) (check
package insert for dose conversion)
Pregnancy category C
Indications:
Treatment of immunodeficiency states (e.g.,
HIV, agammaglobulinemia), secondary
immunodeficiencies (e.g., bone marrow
transplant), immune thrombocytopenic
purpura (ITP), Kawasaki disease, and lym­
phoproliferative disorders.
Dosage:
Immunodeficiency/HIV infection/post bone
marrow transplant (replacement dose): 400–
500 mg/kg/dose IV q3–4 weeks; maintain
trough IgG level ≥400–500 mg/dl
ITP: 800–1000 mg/kg IV for 1–2 consecu­
tive days pending response; may be given
repeatedly q3–6 weeks based on clinical
need.
Kawasaki disease: 2 g/kg IV as a single dose;
consider second dose for persistent
symptoms.
Notes:
Avoid in patients with hypersensitivity to
immune globulin or blood products and in
those with immunoglobulin A (IgA) defi­
ciency; consult pharmacist for IgA‐depleted
products. Give slow intravenous infusion,
over 4–8 hours, and consider premedication
with acetaminophen and diphenhydramine
to avoid infusional toxicity (nausea, vomit­
ing, flushing, fever, chills, severe headaches).
If toxicity develops, stop infusion and treat
symptomatically, then resume at slower rate
of infusion. Future doses should be given at
slower rate with premedications before and
every 4 hours during infusion. May cause
aseptic meningitis or acute renal failure.
INOTUZUMAB OZOGAMICIN
Besponsa
Antibody–drug conjugate
Injection: 0.9 mg in single dose vial
Pregnancy category not assigned, can cause
fetal harm
Indication:
Approved in adults for the treatment of
relapsed or refractory B‐cell precursor ALL.
Dosage:
Adults:
For the first cycle, the recommended dose of
inotuzumab ozogamicin for all patients is
1.8 mg/m2 per cycle, administered as three
divided doses on day 1 (0.8 mg/m2), day 8
(0.5 mg/m2), and day 15 (0.5 mg/m2). The
recommended dosing for subsequent cycles
depends on response to treatment.
Pediatric:
Refer to protocol.
Notes:
The medication consists of the humanized mon­
oclonal antibody against CD22 (inotuzumab),

linked to a cytotoxic agent from the class of cali­
cheamicins called ozogamicin.
The drug prolongs the QT interval in some
people, so it should be used with caution in
people with heart arrhythmias.
The United States’ label for the use of inotu­
zumab ozagamicin carries an FDA black box
warning concerning the risk of liver toxicity,
in particular hepatic VOD/SOS, which has
been fatal in some people. The risk of this is
higher in adults who take the drug before
having HSCT and more people die who have
HSCT following treatment with this drug
than people who have HSCT taking other
chemotherapies. The risk increases as more
rounds of treatment with inotuzumab ozo­
gamicin are administered. There is unclear
risk for VOD/SOS in pediatric patients.
The most common serious adverse reac­
tions are infection, neutropenia with fever,
hemorrhage, stomach pain, fever, VOD/
SOS, and fatigue.
Between 10 and 20% of people also report
loss of appetite, vomiting, diarrhea, mouth
sores, constipation, chills, and injection site
reactions.
IRINOTECAN
Camptosar, generic
Antineoplastic, topoisomerase inhibitor
Injection: 20 mg/ml; 2, 5 ml vial
Pregnancy category D
Indications:
Treatment of metastatic colon carcinoma, neu­
roblastoma, hepatoblastoma, brain tumors,
Ewing sarcoma, and rhabdomyosarcoma.
Dosage:
Referral to individual protocol.
Children: refractory solid tumor, low dose,
protracted: 20 mg/m2/day IV daily for 2 con­
secutive weeks, followed by a week of rest;
repeat q3 weeks.
Formulary 455
Children: refractory solid tumor or brain
tumor: 50 mg/m2/day IV for 5 days, repeat
cycle q3 weeks.
Notes:
Do not give to patients with known hyper­
sensitivity to irinotecan. Avoid concomitant
administration with St. John’s Wort or keto­
conazole and in patients with severe bone
marrow failure. A new cycle of irinotecan
should not begin until serious treatment‐
induced toxicity has recovered: ANC
≥1.0 × 109/l and platelet count >100 × 109/l. If
the patient has not recovered following a 2‐
week rest, consider discontinuing. May
cause severe, dose‐limiting, and potentially
fatal diarrhea. Early diarrhea (during or
shortly after infusion) may be accompanied
by symptoms of rhinitis, increased saliva­
tion, flushing, miosis, lacrimation, diapho­
resis, and abdominal cramping. Atropine
0.01 mg/kg IV (maximum dose 0.4 mg) may
be used to prevent or treat cholinergic
symptoms and early diarrhea.
Late diarrhea occurs >24 hours after therapy
and can be prolonged leading to life‐threat­
ening dehydration and electrolyte imbalance.
Treat promptly with loperamide until a nor­
mal pattern of bowel movements returns.
Antibiotic support (cefixime or cefpodoxime
starting several days prior to treatment) can
be utilized as a prophylactic and treatment
measure by preventing gastrointestinal bacte­
rial conversion of irinotecan to SN‐38, the
metabolite which causes diarrhea.
If the patient develops persistent diarrhea,
ileus, fever, or severe neutropenia, interrupt
or reduce subsequent doses. If grade 3 (seven
to nine stools/day, incontinence, and/or
severe cramping) or grade 4 (≥10 stools/day,
grossly bloody stool, and/or need for paren­
teral support) diarrhea occurs, interrupt
treatment and reduce subsequent dosing.
Moderately emetogenic, therefore premedication
with an anti‐emetic regimen is recommended.
456 Formulary
May cause severe myelosuppression; halt for neu­
tropenic fever. Use with caution in patients with
renal or hepatic impairment.
IRON COMPLEX, POLYSACCHARIDE
Myferon 150, PIC 200, Poly‐Iron 150,
NovaFerrum, NovaFerrum Pediatric drops,
many brands (previously available as Niferex)
Capsule (OTC): 50 mg (NovaFerrum 50),
150 mg (Myferon 150, Poly‐Iron 150, oth­
ers), 200 mg (PIC 200); 150 mg strength may
contain 50 mg vitamin C
Oral liquid: (NovaFerrum 125, OTC)
125 mg/5 ml
Oral drops: (NovaFerrum Pediatric drops
OTC) 15 mg/ml
Pregnancy category A
Indications:
Treatment of iron deficiency anemia.
Dosage:
See Ferrous Gluconate.
Notes:
See Ferrous Gluconate.
IRON DEXTRAN COMPLEX
Dexferrum, INFeD
Iron salt
Injection: 50 mg elemental iron/ml (2 ml)
Pregnancy category C
Indications:
Treatment of microcytic hypochromic ane­
mia resulting from iron deficiency in
patients in whom oral administration is not
feasible or is ineffective. Approved in chil­
dren ≥4 months.
Dosage (IV or IM):
Begin with a test dose 1 hour prior to start­
ing iron dextran therapy:
Infants <10 kg: 10 mg (0.2 ml).
Children 10–20 kg: 15 mg (0.3 ml).
Children >20 kg to adult: 25 mg (0.5 ml).
Total replacement dose of iron dextran for iron
deficiency anemia:
(ml) = 0.0442 × LBW (kg) ×
(Hgbn − Hgbo) + [0.26 × ABW up to
maximum 14 ml];
ABW = actual body weight; LBW = lean
body weight.
Males: 50 kg + 2.3 kg for every inch over 5 ft.
in height.
Females: 45.5 kg + 2.3 kg for every inch over
5 ft. in height.
Hgbn = desired hemoglobin (g/dl) = 12 if
<15 kg or 14.8 if >15 kg.
Hgbo = measured hemoglobin (g/dl).
Total replacement dose of iron dextran for
acute blood loss:
(Assumes 1 ml of normocytic, normochro­
mic red cells = 1 mg elemental iron).
Replacement iron (mg) = 0.02 × blood loss
(ml) × hematocrit expressed as a decimal
fraction.
Maximum daily dose, IM/IV:
Infants <5 kg: 25 mg (0.5 ml).
Children 5–10 kg: 50 mg (1 ml).
Children >10 kg to adults: 100 mg (2 ml).
Parenteral administration:
IM: use Z‐track technique (deep into upper
outer quadrant of buttock); test dose at same
site using the same method.
IV: infuse test dose over at least 5 minutes
(Dexferrum) or 30 seconds (INFeD). May ini­
tiate treatment 1 hour after test dose and com­
plete replacement doses in two to three daily
infusions if replacement exceeds daily maxi­
mum dose. Dilute replacement dose in normal
saline (50–100 ml) to maximum concentra­
tion of 50 mg/ml and infuse over 2–6 hours at
a maximum rate of 50 mg/minute. Avoid dilu­
tion in dextrose due to an increased incidence
of local pain and phlebitis.
Monitor vital signs and for symptoms of
anaphylaxis during the IV infusion.

Notes:
Do not give to patients with known hyper­
sensitivity to iron dextran (anaphylaxis may
occur), in anemia not associated with iron
deficiency, with hemochromatosis, or with
hemolytic anemia. Use with caution in
patients with histories of significant aller­
gies, asthma, serious hepatic impairment,
preexisting cardiac disease, and rheumatoid
arthritis (may cause an exacerbation of
arthritis). Discontinue oral iron prior to ini­
tiating parenteral iron. Sweating, urticaria,
arthralgia, fever, chills, dizziness, headache,
and nausea may be delayed 24–48 hours
after large doses of IV administered drug or
3–4 days following IM administration. The
IV route is preferred for patients with
chronic renal disease and cancer‐related
anemia (adults).
Agents for treatment of acute anaphylaxis should
be readily available. Adverse events are much
more associated with the high‐molecular‐
weight formulation (Dexferrum) than with
the low‐molecular‐weight formulation
(INFeD). The low‐molecular‐weight formu-
lation is recommended.
Total‐dose infusions have been used safely
and are the preferred method of administra­
tion, though not currently approved in the
United States. Must wait 14 days after a dose
for reequilibration if retesting iron stores.
IRON SUCROSE
Venofer
Iron salt
Injection: 20 mg elemental iron/ml (2.5, 5,
10 ml)
Pregnancy category B
Indications:
Treatment of microcytic, hypochromic
anemia resulting from iron deficiency in
chronic kidney disease patients, either dial­
ysis‐dependent or non‐dialysis‐dependent,
who may or may not be receiving
erythropoietin.
Formulary 457
Dosage:
Test dose (optional): Infuse 25% of the first
day’s dose up to a maximum of 25 mg undi­
luted over 30 minutes. A 10 mg test dose can
be given in dialysis patients.
IV administration is undiluted over
2–5 minutes. May infuse 100 mg with a
maximum of 100 ml NS over 15 minutes. IM
administration is not possible with this
product.
Children: end stage renal disease on
hemodialysis:
1 mg (elemental iron)/kg/dialysis treatment
(repletion).
0.3 mg (elemental iron)/kg/dialysis treat­
ment (maintenance), administer at last hour
of dialysis treatment at a frequency of three
times a week.
Children: iron deficiency anemia, refractory
to PO therapy:
Calculation of iron deficit: 0.6 × body weight
(kg) × [100 − (measured hgb divided by
desired hgb × 100]. Replacement dose is
administered by giving an initial dose of
5–7 mg/kg (maximum dose 300 mg/24 hour)
q3–7 days until total iron replacement is
achieved.
Adults: hemodialysis‐dependent: 100 mg one
to three times/week during dialysis, total of
10 doses (1000 mg); may continue to admin­
ister at lowest dose possible to maintain tar­
get hemoglobin and iron storage parameters.
Adults: non‐dialysis‐dependent chronic renal
failure: 200 mg on 5 different days over a 2‐
week period (total dose 1000 mg).
Notes:
Do not give to patients with known hyper­
sensitivity to iron formulations, anemia not
associated with iron deficiency, hemochro­
matosis, hemolytic anemia, or iron over­
load. Use with caution in patients with
history of significant allergies, asthma,
hepatic impairment, or rheumatoid
arthritis.
458 Formulary
ISOTRETINOIN
13‐cis‐retinoic acid; Accutane, Amnesteem,
Absorica, Claravis, Myorisan, Zenatane
Anti‐neoplastic, retinoid
Capsule: 10, 20, 30, and 40 mg soft gelatin
capsules
Pregnancy category X
Indications:
Isotretinoin is a form of concentrated vita­
min A that is a standard part of neuroblas­
toma treatment in combination with other
immunotherapy drugs after completion of
chemotherapy, surgery, autologous trans­
plant, and radiation therapy.
Dosage:
160 mg/m2/day, divided into two daily doses,
for 14 consecutive days within each of six
consecutive 28‐day cycles (see protocol).
Isotretinoin can be given by mouth whole,
buried in food whole, or dissolved and
mixed with food. Caregivers should wear
disposable gloves to avoid touching the liq­
uid inside the capsule.
If the medicine is removed from inside the
capsule and then mixed with food, it must
be given within 1 hour. Isotretinoin is
extremely sensitive to light and air.
Isotretinoin is better absorbed by the body
when taken with foods high in fat like whole
(4%) milk, ice cream, pudding, peanut but­
ter, or whipped cream. It does not mix well
with liquids made with water or juice.
Parents may try any favorite food to help the
child take the medicine.
Notes:
Because of the dangers of birth defects with
isotretinoin, the patient, physician, and
pharmacist must register with the iPLEDGE™
program (www.ipledgeprogram.com).
Adverse effects include severe dry peeling
skin, dry eyes, itching, red/chapped lips, dry
mouth, dry nares and bleeding, headaches
(including potential development of pseudo­
tumor cerebri), joint or muscle pain, hair
loss, sunburn, constipation, and mood shifts.
KETOROLAC
Generic (previously available as Toradol)
NSAID
Tablet: 10 mg
Injection: 15, 30 mg/ml
Pregnancy category C/D if used in third
trimester
Indications:
Short‐term management of pain; systemic
treatment not to exceed 5 days regardless of
route of administration.
Dosage:
Children ≥2 years: 0.5 mg/kg/dose IM/IV
q6–8h (maximum dose 30 mg q6h or 120 mg
q24h).
Adult: 30 mg IV/IM q6h (maximum dose
120 mg/24 hour).
Children >16 years (>50 kg) and adults:
10 mg PO q6h PRN (maximum dose
40 mg/24 hour).
Notes:
Do not give to patients with known hyper­
sensitivity to ketorolac or other NSAIDs,
patients with active peptic ulcer disease, gas­
trointestinal bleeding or perforation, renal
dysfunction, bleeding diathesis, thrombocy­
topenia, or cerebrovascular bleeding. Use
with caution in patients with congestive
heart failure, hypertension, or decreased
renal or hepatic function. May cause
impaired platelet function, nausea, dyspep­
sia, drowsiness, and interstitial nephritis.
LEUCOVORIN CALCIUM
Generic
Antidote, methotrexate; folic acid derivative

Tablets: 5, 10, 15, 25 mg
Injection: 50, 100, 200, 350 mg vials
Pregnancy category C
Indications:
Reduction of toxic effects (leucovorin res­
cue) of high‐dose methotrexate, to counter­
act effects of impaired methotrexate
elimination, or as an antidote for folic acid
antagonist overdose. Indicated for the treat­
ment of folate‐deficient megaloblastic ane­
mia of infancy, sprue, or pregnancy;
treatment of nutritional deficiencies when
oral folate therapy is not possible.
Dosage:
Refer to individual protocol.
Rescue dose (following administration of
high‐dose methotrexate: 15 mg/m2 IV to
start, then 15 mg/m2 q6h; dependent on
protocol, leucovorin may be increased to
100–1000 mg/m2 based on methotrexate
level/clearance.
Folate‐deficient megaloblastic anemia: 1 mg/day
IM/IV.
Megaloblastic anemia secondary to congeni-
tal deficiency of dihydrofolate reductase:
3–6 mg/day IM.
Folic acid antagonist (e.g., pyrimethamine,
trimethoprim [TMP]) overdose: 5–15 mg/
day PO for 3 days or until the blood counts
are normal or 5 mg every 3 days; doses of
6 mg/day are needed for patients with plate­
let counts <100 × 109/l.
Following intrathecal (IT) methotrexate
(Down syndrome): 5 mg/m2/dose PO/IV at
48 hours and 60 hours post IT dose.
Notes:
Do not give to patients with known hyper­
sensitivity to leucovorin, pernicious anemia,
or other megaloblastic anemia, such as sec­
ondary to vitamin B12 deficiency. Do not
Formulary 459
administer intrathecal or intraventricular
(may be harmful or fatal).
LOMUSTINE
CCNU
CeeNU, Gleostine, generic
Antineoplastic, alkylating agent
Capsules: 10, 40, 100 mg
Pregnancy category D
Indications:
Treatment of primary or metastatic brain
tumors and Hodgkin lymphoma.
Dosage:
Refer to individual protocol.
Usual dose is 75–130 mg/m2 PO as a single
dose every 6 weeks; subsequent doses
adjusted per platelet and leukocyte counts.
Notes:
Do not give to patients with known hyper­
sensitivity to lomustine. May need to adjust
dose due to prolonged myelosuppression.
Delayed pulmonary fibrosis may occur with
high cumulative doses (i.e., ≥1 g/m2).
MECHLORETHAMINE
Mustargen
Antineoplastic, alkylating agent
Injection: 10 mg
Pregnancy category D
Indications:
Treatment of Hodgkin and non‐Hodgkin
lymphoma and brain tumors; sclerosing
agent in intracavitary therapy of pleural,
pericardial, and other malignant effusions.
Dosage:
Refer to individual protocol.
Children: MOPP regimen (Mustargen
[mechlorethamine], Oncovin [vincristine],
460 Formulary
procarbazine, prednisone): 6 mg/m2 IV on
days 1 and 6 of a 28‐day cycle.
Brain tumors: MOPP regimen: 3 mg/m2 IV
on days 1 and 8 of a 28‐day cycle.
Intracavitary (adults): 10–30 mg or 0.2–
0.4 mg/kg.
Notes:
Do not give to patients with known hyper­
sensitivity to mechlorethamine, preexisting
profound myelosuppression, active infec­
tion, or pregnancy. Extravasation may result
in severe tissue damage; treat promptly with
cold compresses (6–12 hours) and sodium
thiosulfate. Mechlorethamine is highly
toxic, handle with care; consider benefits of
treatment carefully.
MELPHALAN
Alkeran
Antineoplastic, alkylating agent
Tablet: 2 mg
Injection: 50 mg
Pregnancy category D
Indications:
Treatment of multiple myeloma, epithelial
carcinoma of the ovary; palliation in refrac­
tory cancers; conditioning prior to HSCT.
Dosage:
Refer to individual protocol.
HSCT conditioning: 70–100 mg/m2 IV on
days 7 and 6 prior to HSCT; or 140–220 mg/
m2 IV single dose prior to HSCT; or 50 mg/
m2/day × 4 days; or 70 mg/m2/day × 3 days.
Children: 4–20 mg/m2/day PO days 1–21.
Notes:
Do not give to patients with known hyper­
sensitivity or to those whose disease was
resistant to prior therapy. Long‐term oral
therapy and high cumulative doses (i.e.,
>600 mg) can increase the incidence of
secondary leukemia. May lead to amenor­
rhea. Causes bone marrow suppression; use
with caution in those with prior myelosup­
pressive chemotherapy or radiation therapy.
Use with caution and consider dose reduc­
tion in patients with renal impairment. May
increase the effects/levels of cyclosporine
and carmustine.
MERCAPTOPURINE
6‐MP, 6‐mercaptopurine
Purinethol
Antineoplastic, antimetabolite; purine
antagonist
Tablet: 50 mg
Pregnancy category D
Indications:
Used in conjunction with methotrexate for
maintenance therapy in ALL; combination
regimen in acute myelogenous and CMLs;
non‐Hodgkin lymphoma.
Dosage:
Refer to individual protocol.
50–100 mg/m2 PO once daily. Many proto­
cols have dosing charts by BSA, including
recommended dose modifications for toxic­
ity or thiopurine methyltransferase
(TPMT)/NUDT15 metabolization status
(based on genotyping).
Notes:
Do not give to patients with known hyper­
sensitivity to mercaptopurine, severe liver
disease, or severe bone marrow suppression.
Use with caution and adjust dose in patients
with renal or hepatic dysfunction. Patients
who receive allopurinol concurrently should
have their mercaptopurine dose reduced by
33–50%.
6‐MP and 6‐thioguanine (6‐TG) are methyl­
ated by TPMT to an inactive metabolite.
TPMT activity varies significantly among

patients. Approximately 1 in 300 patients is
completely deficient in the TPMT enzyme
(homozygous) and 10% have intermediate
activity (heterozygous). Patients who have
low TPMT are most susceptible to toxicity
(primarily manifested as severe/prolonged
myelosuppression) due to higher concentra­
tions of thioguanine nucleotides (TGNs).
Homozygous patients may tolerate less than
10% of 6‐MP protocol dosing and approxi­
mately 35% of heterozygotes will require
lower doses of 6‐MP to avoid dose limiting
toxicity with resultant interruption in dosing.
Germline mutations resulting in the NUDT15
polymorphism may also lead to intolerance of
protocol dosing. Many protocols recommend
TPMT genotyping to predict potential intol­
erance. For patients with high transaminases,
concern regarding compliance or elevated
6MP dosing without resulting decrement in
ANC, thiopurine metabolites can provide
helpful information in regard to 6‐TGN and
6‐MMPN metabolization and assist in guid­
ing treatment decisions.
MESNA
Mesnex
Prophylaxis, cyclophosphamide, or ifosfa­
mide‐induced hemorrhagic cystitis.
Tablet: 400 mg
Injection: 100 mg/ml
Pregnancy category B
Indications:
Detoxifying agent used to inhibit hemor­
rhagic cystitis induced by ifosfamide and
cyclophosphamide.
Dosage:
Refer to individual protocol.
Mesna dose is 20% of alkylator dose IV
15 minutes before or combined with alkyla­
tor, followed by repeat doses 4 and 8h later;
for high‐dose alkylator therapy, give dose
Formulary 461
15 minutes before alkylator then q3h for three
to six doses. Total daily Mesna dose ranges
from 60 to 160% of the daily alkylator dose.
IV continuous infusion of Mesna is given at
doses equivalent to 60–100% of the ifosfa­
mide or cyclophosphamide dose.
Mesna is given by IV infusion over 15–30 min­
utes or by continuous IV infusion, or per
protocol.
Notes:
Do not give to patients with known hyper­
sensitivity to Mesna or thiol compounds.
May cause false positive urinary ketone
measurements.
METHADONE HYDROCHLORIDE
Dolophine, Methadose, generics
Antidote, analgesic
Tablet: 5, 10 mg
Solution: 5 mg/5 ml, 10 mg/5 ml
Concentrated solution: 10 mg/ml
Injection: 10 mg/ml (20 ml)
Pregnancy category C
Indications:
Management of severe pain; used in nar­
cotic detoxification maintenance programs
and for the treatment of iatrogenic narcotic
dependency.
Dosage: Analgesia
Children: 0.7 mg/kg/24 hours divided q4–6h
PO/SC/IM/IV PRN (maximum dose 10 mg/
dose).
Adults:
2.5–10 mg/dose q3–4 hours PO/IM/IV/SC
PRN.
Detoxification: see PDR: 15–40 mg/day PO.
Notes:
Do not give to patients with known hypersen­
sitivity to methadone. Use with caution in
462 Formulary
patients with respiratory disease as respiratory
depression lasts longer than analgesic effects.
May cause cardiac arrhythmias (must follow
for QTc prolongation), sedation, increased
intracranial pressure, hypotension, and brady­
cardia, in addition to respiratory depression.
Prolonged half‐life; average 19 hours in chil­
dren and 35 hours in adults. Peak effect is much
more rapid with IV dosing. Repeated use can
result in cumulative effects necessitating
adjustment to the dose and frequency of
administration. Duration of action PO is
6–8 hours initially and then 22–48 hours after
repeated dosing. Methadone is a substrate for
CYP450 3A4, 2D6, and 1A2, and inhibitor of
206. Conversion from other narcotics to meth­
adone can be quite challenging; discussion
with a provider with experience in this area is
warranted (see Chapter 28).
METHOTREXATE
Rheumatrex, Trexall, generic
Antineoplastic, antimetabolite, antirheu­
matic; folic acid antagonist
Tablet (Trexall): 2.5, 5, 7.5, 10, 15 mg
Injection: 1 g vial
Pregnancy category X
Indications:
Treatment of ALL (including CNS leuke­
mia), trophoblastic neoplasms, osteosar­
coma, non‐Hodgkin lymphoma, rheumatoid
arthritis, dermatomyositis, and psoriasis.
Dosage:
Refer to individual protocol.
Acute lymphoblastic leukemia (refer to proto-
col, phase for specific dosing, modifications,
and frequency):
Starting doses:
20 mg/m2 PO once per week, may be held in
weeks intrathecal methotrexate is given;
1000–5000 mg/m2 bolus dosing or by continu­
ous infusion IV over 6–42 hours (dependent
on phase of therapy);
100 mg/m2 IV bolus every 10 days (Interim
Maintenance), with dose escalation up to
450 mg/m2 per protocol.
Doses >500 mg/m2 require leucovorin
rescue.
Osteosarcoma/solid tumors:
Children <12 years: 12 g/m2 IV over 4 hours
(dose range 12–18 g) with leucovorin rescue.
Children ≥12 years: 8 g/m2 IV over 4 hours
(maximum dose 18 g) with leucovorin
rescue.
Non‐Hodgkin lymphoma: 200–500 mg/m2
IV; repeat every 4 weeks, as per protocol.
CNS leukemia (and prophylaxis):
Dosed by age:
Children <1 year: 6 mg.
Children 1 to <2 years: 8 mg.
Children 2 to <3 years: 10 mg.
Children 3 to <9 years: 12 mg.
≥9 years: 15 mg.
Use preservative‐free formulation for IT
administration. Dilute in 0.9% NaCl or
Elliotts B solution for a total volume of
5–10 ml.
Intrathecal methotrexate may be combined
with other agents for IT administration (i.e.,
cytarabine, hydrocortisone).
Notes:
Do not give to patients with known hyper­
sensitivity to methotrexate, severe renal or
hepatic impairment, or preexisting pro­
found bone marrow suppression. High‐dose
methotrexate (>1 g/m2) should not be
administered to patients with a creatinine
clearance of less than 50–75% of normal.
Patients should receive alkaline fluids to
maintain urine pH of 7 or higher while
receiving high‐dose methotrexate. Follow
serum levels per protocol and administer
leucovorin rescue per protocol. Methotrexate
has been associated with acute and severe
chronic hepatotoxicity, severe bone marrow

suppression, and renal failure with delayed
clearance, high‐dose administration, con­
current nephrotoxic drugs, or inadequate
hydration. See treatment with Glucarpidase
in the event of acute renal failure and
delayed clearance resulting in toxic levels.
Intrathecal and parenteral administration of
methotrexate have been associated with
acute neurotoxicity. Severe dermatologic
reactions and radiation dermatitis have
been reported. May accumulate in fluid col­
lections (pleural effusions, ascites) increas­
ing local toxicity.
Ensure no TMP–sulfamethoxazole (SMX),
penicillin, NSAIDs, or PPIs are given until the
methotrexate level is <0.1 μm. Urinary acidi-
fiers may cause precipitation of methotrexate
in the urinary tract.
When IT and parenteral dosing of metho­
trexate is scheduled for the same day, deliver
the IT therapy within 6 hours of the begin­
ning of the IV infusion.
Patients with Down syndrome may have
protocol‐specific adjustments or limitations
in dosing. Current ALL trials do not include
HD MTX infusions in interim maintenance
and leucovorin (5 mg/m2/dose at 48 and
60 hours post IT MTX) is recommended
during all phases except maintenance.
Intrathecal drugs should be prepared and
administered separately from other IV
chemotherapeutic drugs to avoid inappro­
priate administration.
METHYLENE BLUE
ProvayBlue, generics
Antidote, drug‐induced methemoglobinemia
Tablet (Urolene Blue): 65 mg
Injection: 10 mg/ml
Pregnancy category X
Indications:
Antidote for cyanide poisoning and
drug‐induced methemoglobinemia; treat­
ment of NADPH‐methemoglobin reductase
Formulary 463
deficiency; treatment and prevention of
ifosfamide‐induced encephalopathy.
Dosage:
Children and adults: Methemoglobinemia:
1–2 mg/kg (25–50 mg/m2) IV as a single
dose over 5 minutes; may be repeated after 1
hour if needed.
Notes:
Use with caution in patients with G6PD
deficiency or renal insufficiency. May cause
nausea, vomiting, dizziness, headache,
abdominal pain, diaphoresis, phototoxicity,
and skin staining. May cause transient blue‐
green coloration of urine and stool. At high
doses, may cause methemoglobinemia.
METHYLPREDNISOLONE
Medrol, Medrol Dosepak, Depo‐Medrol,
Solu‐Medrol, generics
Corticosteroid
Tablets: 2, 4, 8, 16, 32 mg
Tablets (dose pack, generics): 4 mg
Injection, sodium succinate (Solu‐Medrol,
generics): 40, 125, 500, 1000, 2000 mg (IV/
IM)
Injection (acetate) (Depo‐Medrol, generics):
20, 40, 80 mg/ml (IM; not for IV use)
Pregnancy category C
Indications:
Anti‐inflammatory or immunosuppressive
agent used to treat a variety of diseases of
hematologic, allergic, inflammatory, neo­
plastic, and autoimmune origin.
Dosage:
Anti‐inflammatory/immunosuppressive: 0.5–
1.7 mg/kg/24 hours PO/IM/IV divided
q6–12h.
Chemotherapy (IV Solu‐Medrol, generics):
Refer to individual protocols for dosing (in
lieu of prednisone; convert dose for steroid
464 Formulary
potency, 80% of prednisone dose; note some
protocols recommend 1:1 conversion).
Notes:
Do not give to patients with hypersensitivity
to methylprednisolone. Do not administer
with live‐virus vaccines or during active
infection with varicella or herpes zoster.
Avoid use in patients with systemic fungal
infections. May cause hypertension, glucose
intolerance, gastrointestinal bleeding, osteo­
porosis, pseudotumor cerebri, Cushing’s
syndrome, adrenal axis suppression, and
acne. May increase levels of cyclosporine
and tacrolimus.
METOCLOPRAMIDE
Reglan, Metozolv, generics
Antiemetic
Tablets: 5, 10 mg
Tablets (orally disintegrating [ODT],
Metozolv, and generics): 5, 10 mg
Syrup: 5 mg/5 ml
Injection: 5 mg/ml
Pregnancy category B
Indications:
Treatment of gastroesophageal reflux (GER)
and prevention of nausea and vomiting
associated with chemotherapy.
Dosage:
GER or gastrointestinal dysmotility: Give
30 minutes before meals and at bedtime.
Infants and children: 0.1–0.2 mg/kg/dose up
to QID PO/IV/IM (maximum dose 0.8 mg/
kg/24 hours or 10 mg/dose).
Adults: 10–15 mg/dose on awakening,
before each meal (QAC), and at bedtime
(QHS) PO/IV/IM
Antiemetic: All ages.
1‐mg/kg/dose q6h PO/IV/IM. Give first
dose 30 minutes prior to emetogenic drug.
Must be given with diphenhydramine to
reduce incidence of extrapyramidal symp­
toms. Consensus guidelines now advocate
for initial 1 mg/kg dose (with diphenhy­
dramine) followed by 0.0375 mg/kg dose
q6h subsequently (does not have to be given
with diphenhydramine).
Notes:
Do not give to patients with known hyper­
sensitivity to metoclopramide, gastrointesti­
nal obstruction, pheochromocytoma, or
history of seizure disorder. Sedation, head­
ache, anxiety, depression, leukopenia, and
diarrhea may occur. Reduce dose in renal
impairment.
MICAFUNGIN
Mycamine
Antifungal, echinocandin
Injection: 50, 100 mg
Pregnancy category C
Indications:
Treatment of patients with candidemia,
esophageal candidiasis, disseminated can­
didiasis; prophylaxis of Candida infections
in patients undergoing HSCT. Not effective
against cryptococcus, fusariosis, and zygo­
mycosis. Fungistatic again Aspergillus.
Dosage:
Limited data in neonates and infants.
Guidelines are per pharmacokinetic studies,
short duration trials, and case reports.
Prophylaxis of Candida infections in HSCT
recipients:
Children and adolescents (<50 kg): 1.5 mg/
kg/day IV once daily (maximum dose
50 mg/dose).
Adolescents/adults (≥50 kg): 50 mg IV once
daily.

Disseminated candidiasis:
Neonates <1 kg: 10–15 mg/kg IV once daily.
Neonates ≥1 kg: 7–10 mg/kg IV once daily;
10–12 mg/kg IV once daily for HIV infected/
exposed neonates.
Children and adolescents (<50 kg): 3–4
mg/kg IV once daily (maximum dose
200 mg/dose).
Adolescents/adults (>50 kg): 100–150 mg IV
once daily.
Aspergillosis, esophageal candidiasis:
Children and adolescents (<50 kg): 3–4 mg/
kg IV once daily (doses up to 7.5 mg/kg have
been tolerated in invasive aspergillosis).
Adolescents/adults (≥50 kg): 150 mg IV once
daily (mean duration of therapy in esopha­
geal candidiasis 15 days, range 10–30 days).
Notes:
Do not give to patients with known hyper­
sensitivity to micafungin or other echino­
candins. Use with caution in patients with
renal or hepatic impairment and in patients
receiving concomitant hepatotoxic drugs;
monitor for evidence of worsening. May
cause electrolyte disturbances, cytopenias,
skin rash, central nervous system, and car­
diovascular effects. Micafungin is a CYP450
3A isoenzyme substrate and weak inhibitor,
may increase effects/toxicity of nifedipine
and sirolimus.
MITOXANTRONE
Novantrone, generic
Antineoplastic, anthracenedione
Injection: 2 mg/ml
Pregnancy category D
Indications:
Treatment of AML and multiple sclerosis;
active in pediatric sarcoma, Hodgkin and
non‐Hodgkin lymphoma, ALL, and MDS.
Formulary 465
Dosage:
Refer to individual protocol.
Leukemia:
Children ≥2 years, BSA < 0.6 m2: 0.4 mg/kg
IV daily for 35 days.
Children >2 years and adults: 12 mg/m2 IV
over 10 minutes daily for 2–3 days.
Acute leukemia in relapse: 8–12 mg/m2 IV
daily for 5 days;
AML: 10 mg/m2 IV daily for 3–5 days.
Solid tumors:
Children: 18–20 mg/m2 IV q3–4 weeks or
5–8 mg/m2 IV weekly.
Adults: 12–14 mg/m2 IV q3–4 weeks (maxi­
mum total 80–120 mg/m2).
Notes:
Do not give to patients with known hyper­
sensitivity to mitoxantrone. May cause
severe myelosuppression; use with caution
in patients with preexisting myelosuppres­
sion. Irreversible myocardial toxicity may
occur as the cumulative dosage approaches
550 mg/m2 doxorubicin equivalents (or
400 mg/m2 with chest irradiation or con­
comitant cyclophosphamide administra­
tion). This may be an acute or late effect and
cardiac monitoring with ECHO, measure­
ment of LVEF, and ECG is highly recom­
mended during therapy as well as months to
years following cessation of therapy.
Extravasation may lead to severe tissue
damage. Dosage may need to be reduced in
patients with impaired hepatobiliary func­
tion, preexisting bone marrow suppression,
or previous treatment with cardiotoxic
drugs or chest radiation.
MORPHINE SULFATE
Roxanol, Oramorph SR, MS Contin, Avinza,
Kadian, generics
Narcotic, analgesic
466 Formulary
Tablets: 15, 30 mg
Controlled‐release tablets (MS Contin,
Oramorph SR): 15, 30, 60 mg (100 and
200 mg for opioid‐tolerant patients)
Extended‐release capsules (Avinza): 30 mg
(60, 90, 120 mg for opioid tolerant patients)
Sustained‐release pellets in capsules (Kadian,
generics): 10, 20, 30, 50, 60 mg (100, 200 mg
for opioid tolerant patients)
Solution: 10, 20, 100 mg/5 ml
Suppository: 5, 10, 20, 30 mg
Injection: 0.5, 1, 2, 3, 4, 5, 8, 10, 15, 25,
50 mg/ml
Pregnancy category C/D (prolonged use or
in higher doses at term)
Indications:
Relief of moderate to severe pain, acute and
chronic, after non‐narcotic analgesics have
failed; preanesthetic medication; relief of
dyspnea from acute left ventricular failure
and pulmonary edema.
Dosage:
Dose should be titrated to effect.
Neonates: Analgesia: 0.05–0.2 mg/kg/dose
IM/slow IV/SC q4h.
Opiate withdrawal: 0.08–0.2 mg/kg/dose PO
q3–4h PRN.
Infant 1–6 months:
PO: 0.08–0.1 mg/kg/dose q3–4h PRN.
IV: 0.025–0.03 mg/kg/dose q2–4h PRN.
Infant > 6 months and children:
PO: 0.2–0.5 mg/kg/dose (initial maximum
dose 15–20 mg/dose) q4–6h PRN (immediate
release) or 0.3–0.6 mg/kg/dose q12h PRN
(controlled release).
IM/IV/SC: 0.1–0.2 mg/kg/dose q2–4h PRN
(maximum initial dose infant 2 mg/dose;
1–6 years 4 mg/dose; 7–12 years 8 mg/dose;
>12 years 10 mg/dose)
Adults:
PO: 10–30 mg PO q4h PRN (immediate
release) or 15–30 mg q8–12h PRN (con­
trolled release).
IM/IV/SC: 2–15/dose q2–6h PRN.
Patient‐controlled analgesia (PCA) IV dosing
guidelines:
PCA (on demand) dose: 0.01–0.04 mg/kg.
Suggested lock out (between PCA doses):
10–20 minutes.
Continuous IV dose:
Neonate: 0.01–0.02 mg/kg/hour.
Infant/child: 0.01–0.07 mg/kg/hour.
Adult: 0.8–10 mg/hour (higher doses with
tolerance).
Bolus (loading): 0.03–0.1 mg/kg.
The 1 hour maximum is 0.1–0.15 mg/kg
(6–8 mg/hour in tolerant adults), and typi­
cally equals the continuous dose plus two to
three PCA bolus doses.
Notes:
Do not give to patients with severe renal or
liver insufficiency. May cause severe pruri­
tus, urinary retention, respiratory depres­
sion, central nervous system depression,
nausea, constipation, and ileus. Prolonged
use can result in physical and psychological
dependence. Consider nighttime low con­
tinuous dose infusion of 0.01–0.02 mg/kg/
hour without a change in lock out so as to
allow sleep. Avoid narcotization with seda­
tion and respiratory depression. Monitor
vitals and encourage use of incentive
spirometry and ambulation with repetitive
dosing or PCA use. Naloxone may be used
to reverse effects of respiratory depression.
Low‐dose naloxone has been used to coun­
ter effects of pruritus and urinary retention.
MYCOPHENOLATE MOFETIL (MMF)
CellCept, Myfortic, generic (capsule, tablet)
Immunosuppressive agent

Capsule, as mofetil or CellCept: 250 mg
Tablet, as mofetil or CellCept: 500 mg
Tablet, delayed release, as mycophenolic acid
Myfortic: 180, 360 mg (not recommended
for children whose total body surface area
[TBSA] is <1.19 m2)
Injection, as mofetil or CellCept: 500 mg
Powder for oral suspension, CellCept: 200 mg/ml
Pregnancy category D
Indications:
Used as an immunosuppressant drug fre­
quently in combination with other immuno­
suppressants (e.g., cyclosporine, corticosteroids)
for the prophylaxis of organ rejection (renal,
hepatic, cardiac, and BMT), chronic GVHD,
myasthenia gravis, proliferative lupus nephritis,
and relapsing nephrotic syndrome.
Dosage:
Limited data are available for pediatric dos­
ing. Pharmacokinetic studies have indicated
that doses based on BSA result in a more
appropriate AUC than doses based on body
weight.
Children and adolescents: 600 mg/m2/dose PO/
IV BID (maximum dose 2000 mg/24 hours) or
alternatively dose by BSA if ≥1.25 m2 as
follows:
1.25–1.5 m2: 750 mg PO BID.
>1.5 m2: 1 g PO BID.
Adult (in combination with corticosteroids
and cyclosporine per specific transplant pro-
tocol): 2000–3000 mg/24 hours PO/IV
divided BID or
Delayed release tabs (Myfortic): 720–
1080 mg PO BID.
Notes:
Check specific transplant protocol for dosing.
Due to differences in bioavailability, the
delayed release tablets are not interchangeable
Formulary 467
with the other oral dosage forms on a mg to
mg basis. Do not give to patients with known
hypersensitivity to MMF. Common side
effects include headache, hypertension, vom­
iting, diarrhea, abdominal pain, bone marrow
suppression, fever, and opportunistic infec­
tions. Risk appears to be associated with the
intensity and duration of immunosuppres­
sion; may result in an increased incidence of
lymphoma or other malignancies especially in
combination with other immunosuppres­
sants. Patients should avoid excessive expo­
sure to sunlight and should use sun protection
factor. Use with caution and adjust dose in
patients with renal impairment.
NALOXONE
Narcan, Evzio, generics
Narcotic antagonist
Injection: 0.4 mg/ml
Injection in syringe: 2 mg/2 ml
Autoinjector (Evzio): 0.4 mg/0.4 ml
Nasal liquid (Narcan): 4 mg/0.1 ml
Pregnancy category C
Indications:
Used to reverse central nervous system and
respiratory depression in suspected narcotic
overdose; treatment of coma of unknown
etiology.
Dosage:
Treatment of opiate intoxication: May be
given via endotracheal tube (ETT), use two
to ten times IV dose).
Neonates, children <5 years or <20 kg: 0.1 mg/
kg/dose; repeat q2–3 minutes PRN IV/IM/SC.
Children >5 years or ≥20 kg: 2 mg/dose; if no
response, repeat q2–3 minutes PRN IV/IM/SC.
Adults: 0.4–2.0 mg/dose q2–3 minutes PRN
IV/IM/SC. Use in 0.1–0.2 mg increments in
opioid‐dependent patients. If no response and
cumulative dose >10 mg, reevaluate diagnosis.
468 Formulary
IV continuous infusion (children and adults):
0.005 mg/kg loading dose, then 0.0025–
0.16 mg/kg/hour. Taper gradually to avoid
relapse.
PCA side effect reversal (pruritus and/or
urinary retention with morphine):
IV continuous infusion: Begin with 1 mcg/
kg/hour, titrate up or down to 0.25–2 mcg/
kg/hour to abate opioid‐related side effects;
taper infusion gradually over 2–4 hours
when discontinuing.
Notes:
Do not give to patients with known hyper­
sensitivity to naloxone. Short duration of
action may necessitate repeated doses. The
dose for pediatric postoperative narcotic
reversal is one‐tenth of the dose for opiate
intoxication. Endotracheal administration
can be done safely by diluting in 1–2 ml of
normal saline. Will produce narcotic with­
drawal in patients with dependence. Use
with caution in patients with chronic heart
disease. Abrupt reversal of narcotic depend­
ency may result in nausea, vomiting, dia­
phoresis, tachycardia, hypertension, and
tremulousness.
NELARABINE
Arranon
Antineoplastic, antimetabolite; purine
nucleoside analog
Injection: 5 mg/ml; 250 mg vial
Pregnancy category D
Indications:
Treatment of relapsed or refractory T‐cell
ALL and T‐cell lymphoblastic lymphoma.
Dosage:
Refer to individual protocol.
Children: 650 mg/m2 IV daily, for 5 consecu­
tive days; repeat per protocol.
Adults: 1500 mg/m2/dose IV on days 1, 3,
and 5; repeat per protocol.
Notes:
Do not give to patients with known hyper­
sensitivity to nelarabine. May cause severe
neurotoxicity, including severe somnolence,
seizures, confusion, ataxia, and peripheral
neuropathy. Observe closely for neurotoxic­
ity. Adverse effects associated with demyeli­
nation or similar to Guillain–Barré syndrome
(ascending peripheral neuropathies) have
been reported. Neurotoxicity is dose‐limited
and may not reverse completely. Risk of neu­
rotoxicity may increase in patients with con­
current intrathecal chemotherapy or history
of cranial irradiation. May cause bone mar­
row suppression. Use with caution in patients
with renal or hepatic impairment. Monitor
blood counts, electrolytes, renal function,
and transaminases frequently.
NILOTINIB
Tasigna
TKI of BCR–ABL
Capsules: 50, 150, 200 mg
Pregnancy category D
Indications:
Treatment of adult CML newly diagnosed
chronic phase, or chronic and accelerated
phases not responsive to imatinib; pediatric
CML in chronic phase, newly diagnosed or
resistant/intolerant of prior TKI therapy.
Dosage:
Pediatric dose: 230 mg/m2 PO twice daily,
rounded to the nearest 50 mg dose (to a
maximum single dose of 400 mg).
Adult dose: 400 mg PO twice daily.
Notes:
Patients must have typical BCR–ABL tran­
scripts. Contraindicated in patients with
hypokalemia, hypomagnesemia, or long
QTc syndrome. Most common adverse
events include nausea, vomiting, headache,
fatigue, pruritus, rash, arthralgia, pyrexia,

night sweats, and diarrhea. Serious adverse
effects include myelosuppression, electro­
lyte abnormalities (hypophosphatemia,
hypokalemia, hyponatremia, hypocalce­
mia), pancreatitis and elevated serum lipase,
hemorrhage, fluid retention, cardiovascular
and arterial occlusive events, and growth
and developmental retardation in children.
ONDANSETRON
Zofran, Zofran ODT, Zuplenz, generics
Antiemetic, serotonin 5‐HT3 receptor
antagonist
Tablets: 4, 8, 24 mg
Tablets (ODT): 4, 8 mg
Solution: 4 mg/5 ml
Injection: 2 mg/ml
Pregnancy category B
Indications:
Prevention of nausea and vomiting associ­
ated with initial and repeat courses of eme­
togenic cancer chemotherapy or radiation,
prevention of PONV, treatment of emesis
induced by acute gastroenteritis.
Dosage:
Prevention of chemotherapy or radiation‐
induced nausea and vomiting:
IV: 0.15 mg/kg/dose 30 minutes prior to the
start of emetogenic chemotherapy, with sub­
sequent doses administered q8h until chem­
otherapy is complete. Maximum single dose
is 16 mg, though is generally maxed at 8 mg
with q8h dosing.
PO/IV: Dose based on BSA or age:
<0.3 m2: 1 mg TID PRN.
0.3–0.6 m : 2 mg TID PRN.
2 >23–40 kg: 60 mg PO BID for 5 days.
0.6–1 m2: 3 mg TID PRN.
>1 m : 4–8 mg TID PRN.
2 Children >13 years to adult: 75 mg PO BID
Age:
<4 years: Dose based on BSA.
4–11 years: 4 mg TID PRN.
>11 years to adult: 8 mg TID.
Formulary 469
Notes:
Do not give to patients with known hyper­
sensitivity to ondansetron. Ondansetron is a
substrate for the cytochrome CYP450
enzyme, so inducers or inhibitors of this sys­
tem may affect the elimination of ondanse­
tron. May need to adjust dose and interval
for severe hepatic impairment. Side effects
are usually mild, with headache, sedation,
constipation, and dry mouth being the most
common. May also cause bronchospasm,
tachycardia, hypokalemia, seizures, light­
headedness, diarrhea, transient increases in
bilirubin or transaminases, and transient
blindness (minutes to 48 hours). ECG
changes (QTc prolongation) have been
reported. Give 1–2 hours prior to radiation;
may need around the clock dosing for
abdominal radiation.
OSELTAMIVIR
Tamiflu, generics
Antiviral
Capsules: 30, 45, 75 mg
Oral suspension: 6 mg/ml
Pregnancy category C
Indications:
Treatment of influenza A and B strains (ini­
tiate therapy within 2 days of onset of
symptoms).
Dosage:
Children ≥1–12 years:
<15 kg: 30 mg PO BID for 5 days.
>15–23 kg: 45 mg PO BID for 5 days.
>40 kg: 75 mg PO BID for 5 days.
for 5 days.
Notes:
The most common adverse symptoms are
nausea and vomiting. Reduce dosage in
470 Formulary
renal impairment. Not for use in children
<1 years due to animal studies suggesting
increased CNS penetrance and fatalities.
OXALIPLATIN
Eloxatin, generic
Antineoplastic, alkylating agent
Injection: 5 mg/ml
Pregnancy category D
Indications:
Treatment of colon carcinoma, relapsed or
refractory solid tumors, brain tumors, and
non‐Hodgkin lymphoma.
Dosage:
Refer to individual protocol.
Children: ≤1 year: 4.3 mg/kg IV over 2 hours
q3 weeks.
Children: >1 year: 130 mg/m2 IV over 2 hours
q3 weeks.
Notes:
Do not give to patients with known hyper­
sensitivity to oxaliplatin, in pregnancy, or in
those with grade 3 or 4 neuropathy (usually
due to prior exposure). Anaphylaxis may
occur within minutes of administration;
appropriate supportive and resuscitative
medications and equipment should be avail­
able. Two different types of neuropathy may
occur: (i) an acute (within 2 days) reversible
(resolves within 14 days) sensory neuropa­
thy with peripheral symptoms that are often
exacerbated by cold (may include pharyngo­
laryngeal dysesthesia), and (ii) persistent
(over 14 days) sensory neuropathy that pre­
sents with paresthesias, dysesthesias,
hypoesthesias, and impaired proprioception
that interferes with activities of daily living.
Symptoms may improve with discontinuing
treatment. May cause pulmonary fibrosis or
hepatotoxicity. When administered as
sequential infusions, taxane derivatives
should be administered before platinum
derivatives to limit myelosuppression and
enhance efficacy.
PALONOSETRON
Aloxi
Anti‐emetic, serotonin 5‐HT3 receptor
antagonist
Tablets: 0.5 mg capsule
Injection: 5 mL vial (0.25 mg)
Pregnancy category B
Indications:
Prevention of CINV in patients receiving ini­
tial and repeat courses of moderate to highly
emetogenic regimens, especially if previous
history or high risk of delayed nausea.
Dosage:
Ages 1 month to <17 years: 20 μg/kg IV 30 min­
utes prior to chemotherapy.
Adult dosing: 0.5 mg capsule PO 1 hour prior
to chemotherapy.
Notes:
Contraindicated in known hypersensitivity.
May cause headache or constipation. Use with
caution in combination with other serotonin
receptor antagonists due to risk for serotonin
syndrome. Given the extended half‐life, gen­
erally given as a single dose prior to chemo­
therapy initiation, though may be repeated
after 72 hours. Should be considered in
patients with significant, refractory delayed
nausea/vomiting (particularly from platinum
chemotherapy) in lieu of ondansetron or
granisetron and especially if unable to receive
decadron (i.e., brain tumors) or aprepitant
(i.e., potential drug interactions).
PAZOPANIB
Votrient
Antineoplastic, kinase inhibitor
Tablet: 200 mg
Pregnancy category D

Indications:
Treatment of advanced soft tissue sarcomas,
rhabdomyosarcoma, and renal cell carcinoma.
Dosage:
Refer to individual protocol. Safety and effi­
cacy in pediatrics have not been established.
Adult: 800 mg po QD
Notes:
Most common adverse reactions are nausea,
vomiting, diarrhea, hair color changes,
fatigue, decreased appetite, decreased
weight, hypertension, tumor pain, headache,
myalgia, dysgeusia, gastrointestinal pain,
and dyspnea. Use with caution with other
medications, CYP34A inducers and inhibi­
tors. Avoid proton pump inhibitors and H2
antagonists; separate antacids and pazopanib
dosing by several hours.
PENTAMIDINE ISETHIONATE
Pentam 300, NebuPent
Antibiotic, antiprotozoal
Injection: 300 mg vial (Pentam 300)
Inhalation: 300 mg vial (NebuPent)
Pregnancy category C
Indications:
Treatment of PCP in patients who cannot
tolerate or who fail to respond to TMP–
SMX, prevention of PCP infection in immu­
nocompromised hosts, treatment of African
trypanosomiasis, and treatment of visceral
and cutaneous leishmaniasis caused by
Leishmania donovani.
Dosage:
Prophylaxis: 4 mg/kg/24 hours IM/IV (IV
preferred route, over 1–2 hours) q2–4 weeks;
maximum single dose 300 mg.
Inhalation (≥5 years), use with Respigard II
nebulizer: 300 mg in 6 ml water via inhala­
tion qmonth.
Formulary 471
Treatment of PCP: 4 mg/kg/dose IM/IV
daily for 14–21 days (preferably IV).
Notes:
Do not give to patients with known hyper­
sensitivity to pentamidine isethionate.
Adjust dose in renal impairment. Use with
caution in patients with diabetes mellitus,
renal or hepatic dysfunction, hypertension,
or hypotension. Additive toxicity may occur
with aminoglycosides, amphotericin B, cis­
platin, and vancomycin. Can see Jarisch–
Herxheimer‐like reaction (fever, chills,
headache, myalgia). Inhalation therapy may
cause irritation of the airway, bronchos­
pasm, cough, oxygen desaturation, dyspnea,
and loss of appetite. May cause hypoglyce­
mia, hyperglycemia, hypotension (with
infusion <2 hours), nausea, vomiting, fever,
mild hepatotoxicity, pancreatitis, hypocalce­
mia, megaloblastic anemia, granulocytope­
nia, and nephrotoxicity. Unclear efficacy of
IV/IM route.
POSACONAZOLE
Noxafil
Antifungal, azole
Injection: 300 mg/16.7 ml
Tablet (delayed release): 100 mg
Suspension: 40 mg/ml
Pregnancy category C
Indications:
Prophylaxis of invasive Aspergillus and
Candida infections in high‐risk, severely
immunocompromised patients (e.g., HSCT
recipient, GVHD, hematologic malignancy
with prolonged chemotherapy‐induced
neutropenia); treatment of oropharyngeal
candidiasis (including those refractory to
echinocandins and/or fluconazole).
Dosage:
Injection form has not been approved for
<18 years of age. Oral solution and tablets
472 Formulary
are not interchangeable due to differences
in dosing.
Prophylaxis of invasive Aspergillus and
Candida infections:
Children ≥13 years and adults:
Oral solution: 200 mg PO TID.
DR tablet: 300 mg PO BID on day 1, fol­
lowed by 300 mg PO QD.
≥18 years: Option to use injection form:
300 mg IV BID on day 1, followed by 300 mg
IV QD.
Length of treatment is dependent on recov­
ery of immune suppression.
Treatment of oropharyngeal candidiasis:
Initial: 100 mg BID (oral solution) on day 1,
then 100 mg daily for 13 days.
Refractory: 400 mg BID (oral solution).
Notes:
Do not give to patients with known hyper­
sensitivity to posaconazole and avoid con­
current administration with ergot alkaloids.
Cross‐sensitivity reactions with other azoles
have not yet been studied but may exist. May
cause hepatotoxicity, and frequent monitor­
ing is recommended. May alter drug levels
of cyclosporine (also tacrolimus and siroli­
mus) resulting in nephrotoxicity, leukoen­
cephalopathy, and death. Concomitant
utilization with vincristine may lead to
increased neurotoxicity.
PREDNISONE
Deltasone, Rayos, generics
Corticosteroid
Tablets: 1, 2.5, 5, 10, 20, 50 mg
Solution: 1, 5 mg/ml
Pregnancy category C/D
Indications:
Management of adrenocortical insuffi­
ciency; used for anti‐inflammatory or
immunosuppressant effects in autoimmune
diseases such as immune thrombocytopenia
purpura; chemotherapy for ALL and
Hodgkin and non‐Hodgkin lymphoma.
Dosage:
Dose is dependent on condition being
treated and response of patient. Consider
alternate day dosing for long‐term therapy.
Discontinuation of long‐term therapy
requires gradual tapering.
Anti‐inflammatory or immunosuppressant
(includes ITP, aplastic anemia): 0.5–2 mg/
kg/24 hours PO divided one to three times
daily.
Chemotherapy: 40–180 mg/m2/24 hours, as
per protocol.
Notes:
Avoid use in patients with life‐threatening
infections (except septic shock or tubercu­
lous meningitis), systemic fungal infections,
varicella, and in those with hypersensitivity
to prednisone. Use with caution in patients
with hypothyroidism, cirrhosis, hyperten­
sion, congestive heart failure, ulcerative
­colitis, gastrointestinal bleeding, and throm­
boembolic disorders. May cause adrenal axis
suppression, hypertension, hyperglycemia,
irritability, gastritis, skin atrophy, osteoporo­
sis, cataracts, fluid retention, mood lability,
nausea, diarrhea, bone pain, acne, and weight
gain. Consider use of antacid in long‐term
therapy. Avascular necrosis and growth retar­
dation are seen in patients with long‐term or
repeated high‐dose therapy. Ensure patients
are aware of risk of varicella infection in non‐
immune states.
PROCARBAZINE HYDROCHLORIDE
Matulane
Antineoplastic, alkylating agent
Capsule: 50 mg
Pregnancy category D

Indications:
Treatment of advanced Hodgkin lymphoma
and brain tumors.
Dosage:
Refer to individual protocol.
50–100 mg/m2 PO daily for 10–14 days.
Notes:
Avoid in patients with known hypersensitiv­
ity to procarbazine or with preexisting bone
marrow aplasia. Delay treatment for 1 month
or longer following radiation due to potenti­
ating effect on marrow suppression. May
cause nausea, vomiting, dry mouth, consti­
pation, headache, dizziness, and hair loss.
Azoospermia and infertility have been
reported when procarbazine has been given
in combination with other antineoplastics.
Use with caution and reduce dose in patients
with renal or hepatic impairment or marrow
suppression. May potentiate central nervous
system depression when used with pheno­
thiazine derivatives, barbiturates, narcotics,
alcohol, tricyclic antidepressants, and
methyldopa. Drug (e.g., monoamine oxidase
inhibitors) and food interactions are com­
mon. Avoid food with high tyramine content
(i.e., aged cheese or meats, yogurt, tea, dark
beer, coffee, cola drinks, wine, soybean prod­
ucts, peanuts, avocadoes, bananas) because
hypertensive crisis, tremor, excitation, car­
diac palpitations, and angina may occur.
RASBURICASE
Elitek
Recombinant urate oxidase, uric acid lower­
ing agent, antigout agent
Injection: 1.5, 7.5 mg vials
Pregnancy category C
Indications:
Initial management or prevention of hyper­
uricemia in high‐risk patients with leukemia,
Formulary 473
lymphoma, or a select group of patients with
solid tumors at risk for tumor lysis syndrome
with initiation of chemotherapy. Indicated
only for short‐term use; maximum of 5 days.
Dosage:
0.05–0.2 mg/kg/dose IV over 30 minutes
(round down to nearest 1.5 mg vial). Patients
usually respond to one dose, but may repeat
q24h PRN up to four additional doses.
Give prior to chemotherapy if expected
massive tumor lysis and/or renal involve­
ment/dysfunction (e.g., Burkitt lymphoma
with bulky disease), especially if evidence of
tumor lysis or renal compromise.
Notes:
Do not give to patients with known hyper­
sensitivity to rasburicase. Contraindicated in
patients with G6PD deficiency (may cause
hemolysis) or severe asthma.
Methemoglobinemia has been reported with
use. May cause vomiting, nausea, fever,
headache, abdominal pain, constipation,
diarrhea, and rash. When measuring serum
uric acid levels, ensure tubes are prechilled,
contain heparin, are placed in an ice water
bath, and analyzed within 4 hours. Collection
at room temperature may lead to spuriously
low uric acid levels due to continued degra­
dation by rasburicase in the sample.
Rho(D) IMMUNE GLOBULIN
WinRho SDF, Rhophylac
Immune globulin
Injection: 1500, 2500, 5000, 15 000 IU
(1 mcg = 5 IU)
Prefilled injection (Rhophylac): 1500 IU (2 ml)
Pregnancy category C
Indications:
Treatment of ITP in non‐splenectomized
Rho(D)‐positive patients; suppression of Rho(D)
isoimmunization in an Rho(D)‐negative
474 Formulary
individual exposed to Rho(D)‐positive blood or
during delivery (or pregnancy) of an Rho(D)‐
positive infant (if father known to be Rho(D)‐
positive or status unknown).
Dosage:
ITP:
Hemoglobin ≥10 g/dl: 50 mcg/kg IV (250 IU/
kg), administer dose over 3–5 minutes.
Hemoglobin <10 g/dl: 25–40 mcg/kg IV
(125–200 IU/kg).
New onset ITP: 75 mcg/kg (375 IU/kg) as a
single dose has been used safely and effica­
ciously in pediatric patients with platelets
≤20 × 109/l. Subsequent dosing may be
adjusted (125–3000 IU/kg) dependent on
response.
Patients who do not respond to an initial
dose can be re‐dosed, and if hemoglobin
>10 g/dl can increase to 250–300 IU/kg).
Dose frequency is dependent on duration of
response, clinical symptoms, and adverse
effects; may be given q2–4 weeks.
Notes:
Avoid in patients with known hypersensitiv­
ity to immunoglobulins or thimerosal and
in patients with IgA deficiency. Not recom­
mended for use in patients with hemoglobin
<8 g/dl. Adverse events associated with
administration in ITP include headache,
chills, fever, and reduction in hemoglobin
(resulting from the destruction of Rho(D)‐
positive red cells). May interfere with
immune‐response to live‐virus vaccines.
Causes acute hemolysis with an average
hemoglobin decrease of 1.5–2 g/dl at 1 week.
Do not use in patients with active bleeding.
Current FDA guidelines strongly recom­
mend that patients be monitored in a health
care center for 8 hours after a dose of Rho(D)
immune globulin, with urinalyses at base­
line and 2, 4, and 8 hours after administra­
tion due to risk of severe hemolysis.
RITUXIMAB
Rituxan
Antineoplastic, monoclonal antibody
Injection: 10 mg/ml
Pregnancy category C
Indications:
Treatment of relapsed or refractory low‐
grade or follicular CD20 positive, B‐cell non‐
Hodgkin lymphoma; first‐line therapy for
diffuse large B‐cell non‐Hodgkin lymphoma
in combination with other chemotherapeu­
tics; systemic autoimmune disorders includ­
ing autoimmune hemolytic anemia and
immune thrombocytopenia purpura; post­
transplant lymphoproliferative disorder;
rheumatoid arthritis; refractory GVHD;
Epstein Barr Virus (EBV) reactivation;
refractory systemic lupus erythematosus.
Dosage:
Children and adults: 375 mg/m2 IV qweek
for 4 weeks (range 3–6 weeks).
Courses may be repeated for treatment of
malignancies or recurrent symptoms with
autoimmune disorders.
Notes:
Refer to individual protocol for treatment
doses and frequency. Rare cases of progres­
sive multifocal leukoencephalopathy due to
Creutzfeldt–Jakob virus have been reported.
Infusional toxicity is common and primarily
avoided with a slow infusion and premedi­
cation. Most commonly, infusional toxicity
is seen with the first infusion and reactions
may include development of hives, bron­
chospasm, hypoxia, hypotension, pulmo­
nary infiltrates, and respiratory distress
syndrome. Some reactions have been fatal.
Close monitoring is required for all infu­
sions and appropriate resuscitative medica­
tions and equipment must be close by. In the
case of mild reactions, temporary cessation

of the infusion is indicated with acetami­
nophen, diphenhydramine, and fluids as
indicated. Hydrocortisone may also be indi­
cated. If symptoms resolve, reinitiate the
infusion at a 50% reduced rate and monitor
closely. Subsequent infusions should run
slowly, and the patient should be premedi­
cated. Rituximab should be discontinued
altogether following a life‐threatening reac­
tion. Use with caution in patients with pre­
existing pulmonary or cardiac conditions
and in those at risk for development of
tumor lysis syndrome. Causes immunosup­
pression. Quantitative immunoglobulins
and specific antibody response should be
checked prior to and following treatment
with rituximab to determine if immunoglob­
ulin infusions might be needed posttreat­
ment until recovery of immune function.
Reactivation of hepatitis B has been noted
(mainly in adult patients); thus, immune sta­
tus to hepatitis B virus should be docu­
mented. Although specific to B‐cells, PCP
infection after rituximab has been reported;
therefore, patients should receive PCP
prophylaxis for 6 months or until recovery of
immune function is documented.
RIVAROXABAN
Xarelto
Anticoagulant
Tablet: 2.5, 10, 15, 20 mg
Pregnancy category C
Indications:
Indicated for treatment of DVT and PE;
reduction in risk of recurrence and/or PE in
patients at continued risk for recurrence
after completion of initial treatment lasting
≤6 months; reduction of stroke risk and sys­
temic embolism in patients with non‐valvu­
lar atrial fibrillation; prophylaxis of DVT
which may lead to PE in patients undergo­
ing knee or hip surgery.
Formulary 475
Dosage:
Safety and efficacy have not yet been estab­
lished in pediatrics, but clinical trials are
ongoing. In patients ≥18 years of age, the fol­
lowing doses are recommended:
DVT or PE treatment: 15 mg PO q12h for
21 days, then 20 mg PO daily.
Reduction of recurrence risk of DVT/PE in
at‐risk patients following ≥6 months initial
treatment with anticoagulation: 10 mg PO
daily.
Notes:
This is the first available direct oral antico­
agulant (DOAC) inhibiting factor Xa. The
maximum inhibition of factor Xa is 4 hours
following a dose, with effects lasting
8–24 hours and necessitating only once daily
administration. Inhibition of factor Xa
interrupts the intrinsic and extrinsic coagu­
lation cascades, inhibiting both thrombin
formation and development of thrombi.
Rivaroxaban does not inhibit thrombin
(activated factor II) and has no effect on
platelet function. Dose adjustments and
routine coagulation monitoring are not
needed, nor are dietary restrictions needed.
Adverse effects include bleeding, including
severe intestinal bleeding. A reversal agent is
available (Andexanet alfa/AndexXa), though
bleeding may still be difficult to control.
Contraindicated in patients with severe liver
or end‐stage renal disease.
ROMIPLOSTIM
Nplate
Thrombopoietin receptor agonist
Injection: 250, 500 mcg vial
Pregnancy category C
Indications:
Treatment of thrombocytopenia in patients
with chronic immune thrombocytopenia
476 Formulary

who have had an insufficient response to Colony‐stimulating factor

corticosteroids, immunoglobulins, or sple­ Injection: 250, 500 mcg
nectomy. It should be used only in patients
Pregnancy category C
with ITP whose degree of thrombocytope­
nia and clinical condition increase the risk
Indications:
for bleeding, and not to normalize a platelet
count. Used to stimulate Ch14.18 antibody in high‐
risk neuroblastoma patients.
Dosage:
Dosage:
Safety and efficacy have not been estab­
250 mcg/m2 daily SC/IV (SC preferred
lished in pediatrics. Dosing is for ≥18 years.
route) before, during, and after Ch14.18
Initial dose: 1 mcg/kg SC based on ABW.
antibody infusion (see protocol for details).
Obtain weekly CBCs during dose adjust­ May be given differently in relapse setting.
ment until stable platelet count ≥50 × 109/l is
achieved for ≥4 weeks without further Notes:
changes in dose.
May lead to excessive immature myeloid cells
If platelet count is <50 × 109/l, increase by
in the peripheral blood or bone marrow
1 mcg/kg.
(>10%) as well as fever and bone pain. Avoid
If platelet count is >200 × 109/l for 2 consec­
in patients with a history of ITP, known hyper­
utive weeks, reduce by 1 mcg/kg.
sensitivity to GM‐CSFs, or yeast‐derived
products. Use with caution in patients with
If platelet count is >400 × 109/l, DO NOT
autoimmune or chronic inflammatory condi­
DOSE. Assess platelet count weekly. After
tions, hypertension, cardiovascular disease,
platelet count is <200 × 109/l, resume at
pulmonary disease, or renal or hepatic impair­
dose decreased by 1 mcg/kg.
ment. May need to be held with excessively
If platelet count is 50–200 × 109/l, maintain high white blood cell count (i.e., 50 × 109/l).
dose and assess CBCs weekly until stable
platelet count ≥ 50 × 109/l is achieved for SIROLIMUS
≥4 weeks without further changes in dose.
Rapamune, generics
After achieving stable platelet count and sta­ Immunosuppressant agent
ble dose, obtain monthly CBCs. Solution: 1 mg/ml
Tablet: 0.5, 1, 2 mg
Notes:
Pregnancy category C
Most common adverse reactions are head­
ache, arthralgia, dizziness, insomnia, myal­
Indications:
gia, extremity pain, abdominal pain,
shoulder pain, dyspepsia, and paresthesia. GVHD prophylaxis in HSCT recipients;
Administration may increase the risk for prophylaxis and treatment of rejection in
development or progression of reticulin renal transplant patients; primary immuno­
fiber formation within the bone marrow, suppression in other organ transplant.
which may improve upon discontinuation.
Dosage:
SARGRAMOSTIM Refer to individual protocol.
GM‐CSF Children ≥13 years of age and <40 kg:
Leukine Loading dose 3 mg/m2/dose PO on day 1

immediately after transplant, followed by
maintenance 1 mg/m2/24 h divided q12–
24h; adjust dose to achieve target sirolimus
trough blood concentration.
Children >40 kg to adults: 6 mg PO once
immediately following transplant, followed
by 2 mg PO once daily.
Notes:
Do not give to patients with known hyper­
sensitivity to sirolimus. Refer to individual
protocol for optimal dosing and target
trough concentrations. Monitor whole
blood trough levels (just prior to dose at
steady state) especially with concurrent use
of CYP450 3A4 and/or P‐gp inducers and
inhibitors. Steady state is usually achieved
at 5–7 days. Immunosuppression may result
in increased susceptibility to infection. May
increase risk for development of lymphoma
or other malignancy. Avoid excessive sun
exposure and use sun protection factor.
Severe hypersensitivity and skin reactions
have been reported. Monitor renal and
hepatic function; dose reduction may be
necessary. Use with caution in the periop­
erative period due to an increased risk of
surgical complications from wound dehis­
cence and impaired wound and tissue heal­
ing. Prophylaxis against P. jiroveci (carinii)
and CMV is recommended. Can lead to
hypertension, electrolyte wasting, renal
insufficiency, and transplant‐associated
microangiopathy.
SODIUM THIOSULFATE
Versiclear
Antidote, extravasation of mechlore­
thamine, cisplatin, or cyanide; antifungal
agent (topical)
Injection: 100, 250 mg/ml
Indications:
Treatment of extravasations of selected
chemotherapeutic agents.
Formulary 477
Dosage:
Chemotherapy infiltration: Children and
Adults:
Mechlorethamine: Use 2 ml for each mg
infiltrated.
Notes:
Do not give to patients with known hyper­
sensitivity to sodium thiosulfate. Inject
slowly, over at least 10 minutes; rapid
administration may cause hypotension.
SUCCIMER
Chemet (2,3‐dimercaptosuccinic acid;
DMSA)
Antidote (lead toxicity), chelating agent
Capsule: 100 mg
Pregnancy category C
Indications:
Treatment of lead poisoning in asympto­
matic children with blood levels between 45
and 69.9 mcg/dl. Can be considered at lower
lead levels (20–44.9 mcg/dl) if aggressive
environmental interventions have not
impacted level, although not noted to
improve neurocognitive outcome.
Dosage:
Lead chelation, children: 10 mg/kg/dose
(350 mg/m2/dose) PO q8h for 5 days, fol­
lowed by 10 mg/kg/dose PO q12h for
14 days. Repeat courses separated by a mini-
mum of 2 weeks may be necessary to treat
rebound lead concentrations (resulting
from mobilization of lead from bone stores).
Notes:
Do not give to patients with known hyper­
sensitivity to succimer. Use with caution in
impaired hepatic or renal function. May see
gastrointestinal symptoms, increased
transaminases, rash, headache, and dizziness.
Do not administer with other chelators. Treat
iron deficiency and eliminate environmental
478 Formulary
exposure to lead. Monitor lead levels. May
sprinkle contents of the capsules on food if
unable to swallow.
TACROLIMUS
Prograf, Astagraf XL, Envarsus XR, FK506,
generics
Immunosuppressant agent
Capsule (Prograf, generics): 0.5, 1, 5 mg
Extended release capsule (Astagraf XL): 0.5,
1, 5 mg
Extended release tablet (Envarsus XR): 0.75,
1, 4 mg
Injection (Prograf): 5 mg/ml
Indications:
Prevention of organ rejection in solid organ
transplant patients; prevention or treatment
of GVHD in allogeneic HSCT.
Dosage:
Children: Younger children usually require
higher dosing on a mg/kg basis than older
children.
Solid organ transplant:
Children: Initial dose 0.15–0.2 mg/
kg/24 hours PO divided q12h or IV continu­
ous infusion 0.03–0.05 mg/kg/24 hours.
Titrate to therapeutic level.
Adult: Initial dose 0.075–0.2 mg/kg/24 hours
divided q12h or 0.01–0.05 mg/kg/24 hours
by IV continuous infusion. Titrate to thera­
peutic level.
Prevention of GVHD: Initial 0.03 mg/
kg/24 hours (based on LBW) IV continuous
infusion. Begin 24 hours prior to stem cell
infusion and continue until oral medication
can be tolerated. May occasionally be given
as a q12h IV infusion.
Conversion from IV to PO dose (1:4 ratio):
Multiply total daily IV dose by 4 and admin­
ister in two divided oral doses per day.
Notes:
Do not give to patients with known hypersen­
sitivity to tacrolimus, castor oil, or any compo­
nent. Refer to specific transplant protocol for
dosing guidelines and therapeutic monitoring.
Monitor trough levels just prior to steady state
(generally achieved after 2–5 days of dosing).
Oral dosing should be given 1 hour prior or 2
hours after a meal. Immunosuppression may
increase risk of infection or development of
lymphoma or other malignancies. Risk is
related to intensity and duration of use. May
cause nephrotoxicity and neurotoxicity. Do
not administer concurrently with cyclo­
sporine. Monitor electrolytes, magnesium
wasting is common. Monitor tacrolimus drug
levels and adjust dosages per protocol.
Hypertension may lead to PRES; therefore,
blood pressure must be followed closely and
treated promptly if high. Transplant‐associ­
ated microangiopathy is also possible.
TEMOZOLOMIDE
Temodar
Antineoplastic, alkylating agent
Capsule: 5, 20, 100, 140, 180, 250 mg
Injection: 100 mg
Pregnancy category D
Indications:
Treatment of refractory anaplastic astrocy­
toma; treatment of newly diagnosed glioblas­
toma multiforme; active against recurrent
glioblastoma multiforme, metastatic mela­
noma, brain stem glioma, ependymoma,
medulloblastoma, primitive neuroectoder­
mal tumor (PNET), neuroblastoma, Ewing
sarcoma, and anaplastic oligodendroglioma.
Dosage:
Refer to individual protocol.
Children: 100–200 mg/m2 IV/PO once daily
for 5 days every 28 days.

Metronomic dosing: 75 mg/m2/day 5 days/
week, 21–42 day cycles.
May also be administered concurrently with
radiation therapy.
Notes:
Do not give to patients with known hyper­
sensitivity to temozolomide, dacarbazine, or
any component. Thrombocytopenia and
neutropenia are dose‐limiting toxicities and
may occur late in the treatment cycle and take
14 days to resolve. Monitor blood counts and
ensure platelet count ≥100 × 109/l and ANC
≥1.5 × 109/l prior to initiation of each cycle of
therapy. Rare cases of aplastic anemia, myelo­
dysplasia, and secondary malignancies have
been reported. Prophylaxis against P. jiroveci
is required, especially with concurrent
administration of irradiation.
THIOGUANINE
6‐TG
Antineoplastic, antimetabolite; purine
antagonist
Tablet (scored): 40 mg
Pregnancy category D
Indications:
Induction and consolidation phases in
AML; delayed intensification phase in ALL.
Dosage:
Refer to individual protocol.
Infants and children <3 years: 3.3 mg/kg/day
PO divided q12h for 4 days.
Children ≥3 years and adults: 50–200 mg/m2/
day PO divided q12–24 hours for 4–14 days
or per protocol.
Notes:
Do not give to patients with known hyper­
sensitivity to thioguanine. Use with caution
and reduce dosage in patients with renal or
Formulary 479
hepatic impairment. May cause nausea, vom­
iting, anorexia, stomatitis, diarrhea, myelo­
suppression, and veno‐occlusive disease
(sinusoidal obstructive syndrome). Increases
busulfan toxicity.
THIOTEPA
Thioplex, generic
Antineoplastic, alkylating agent
Powder for injection: 15, mg
Pregnancy category D
Indications:
Treatment of superficial tumors of the blad­
der, brain tumors, and other CNS neoplasms
(including intrathecal administration); con­
trol of pleural, pericardial, or peritoneal
effusions caused by metastatic tumors; also
used in high‐dose regimens with autologous
HSCT.
Dosage:
Refer to individual protocol.
Children, HSCT: 300 mg/m2/dose over
3 hours IV; repeat q24h for three doses.
Maximum tolerated dose over 3 days is 900–
1125 mg/m2.
Intrathecal: 5–11.5 mg/m2 per dose weekly
for 2–7 doses.
Notes:
Do not give to patients with known hyper­
sensitivity to thiotepa or severe myelosup­
pression. Reduce dose in patients with renal,
hepatic, or bone marrow dysfunction. May
cause central nervous system changes, skin
hyperpigmentation, nausea, vomiting,
hematuria, and elevation of liver transami­
nases and bilirubin. Due to skin excretion
and risk for irritation, frequent bathing is
required until 48 hours after completion of
thiotepa when given as part of a transplant
preparative regimen.
480 Formulary
THROMBIN, TOPICAL
Evithrom, Recothrom, Thrombi‐Gel,
Thrombi‐Pad, Thrombin‐JMI (epistaxis kit,
spray kit)
Hemostatic agent
Powder (recombinant, Recothrom): 1000 IU
Powder, topical (bovine, Thrombin‐JMI):
Available in epistaxis kit 5000 IU, spray
20,000 IU
Solution, topical (human origin, Evithrom):
800–1200 IU/ml
Sponge, topical (bovine, Thrombi‐Gel):
1000 IU, 20,000 IU
Pad, topical (bovine, Thrombi‐Pad): 200 IU
Pregnancy category C
Indications:
Evithrom, Recothrom, Thrombin‐JMI: As an
aid to hemostasis whenever oozing blood,
and minor bleeding from capillaries and
small venules is accessible and control of
bleeding by standard surgical techniques is
ineffective or impractical.
Thrombi‐Gel, Thrombi‐Pad: As a trauma
dressing for temporary control of moder­
ately to severely bleeding wounds and for
the control of surface bleeding from vascu­
lar access sites and percutaneous catheters
and tubes.
Dosage:
Apply powder directly to the site of bleeding
or on oozing surface, or use 1000–2000 IU/
ml of solution where bleeding is profuse.
May be diluted with NS to other concentra­
tions as needed. Use 100 IU/ml for bleeding
from skin or mucosal surfaces. May utilize
epistaxis/spray kit for mucosal/nosebleeds.
Notes:
Avoid in patients with known hypersensitiv­
ity to thrombin. Some forms are of human or
bovine origin. May cause fever or allergic
reactions. Topical use only. Not for adminis­
tration systemically or directly into sites of
brisk arterial bleeding. Avoid in patients with
factor V deficiency due to cross‐reactivity.
TOPOTECAN
Hycamtin
Antineoplastic, camptothecin, topoisomer­
ase inhibitor
Capsule: 0.25, 1 mg
Injection: 4 mg
Pregnancy category D
Indications:
Treatment of pediatric solid tumors, includ­
ing sarcoma and neuroblastoma.
Dosage:
Refer to individual protocol.
Safety and efficacy have not been estab­
lished in pediatrics.
Children:
Pediatric solid tumors: 1 mg/m2/day (range
0.75–0.9 mg/m2/day) for 3 days as a continu­
ous IV infusion; repeat q3 weeks.
Single agent therapy for refractory solid
tumors or hematologic malignancy: 2.4 mg/
m2/day PO once daily for 5 days of a 21‐day
course.
Combination therapy for solid tumors:
0.75 mg/m2/dose PO once daily for 5 days
every 21 days in combination with
cyclophosphamide.
Notes:
Do not give to patients with known hyper­
sensitivity to topotecan. Bone marrow toxic­
ity is dose‐limiting, primarily neutropenia.
Has been associated with neutropenic coli­
tis; should be a strong consideration in
patients with neutropenia, fever, and
abdominal pain. Severe diarrhea has been

reported, may require dose adjustment. Use
with caution in patients with renal or hepatic
impairment. Extravasation can cause tissue
injury.
TRANEXAMIC ACID
Lysteda, generic
Antifibrinolytic, antihemophilic, hemo­
static agent
Tablet (Lysteda): 650 mg
Injection: 100 mg/ml
Pregnancy category B
Indications:
Short‐term use (up to 5 days) to treat men­
orrhagia primarily associated with von
Willebrand disease. Has been used to treat
or prevent mucosal bleeding (including
tooth extraction) in patients with mild
hemophilia or von Willebrand disease
(maximum 2–8 days). May be used to treat
recurrent epistaxis, to prevent hemorrhage
following trauma, delivery, and postpartum
blood loss, and to decrease perioperative
blood loss and need for transfusion in
patients undergoing repair of congenital
heart disease, craniosynostosis, or scoliosis
surgery.
Dosage:
Children and adults:
Tooth extraction in patients with hemophilia:
10 mg/kg immediately before oral surgery
IV, then 10 mg/kg/dose IV/PO q6–8h; may
be used for 2–8 days.
Menorrhagia: 1300 mg PO TID for up to 5
days during monthly menstruation.
Notes:
Do not use in patients with known sub‐
arachnoid hemorrhage, active intravascular
clotting process, history of seizures, or
acquired defective color vision. Use with
Formulary 481
caution in patients with cardiovascular or
cerebrovascular disease. Dose modification
is required in patients with renal impair­
ment. May cause hypotension, thromboem­
bolic complications, headache, and visual
abnormalities (seen in animals). Do not
administer concomitantly with factor IX
and PCC or hormonal contraception due to
increased risk of thrombosis. Use with cau­
tion in patients with upper urinary tract
bleeding due to potential for clot formation
and ureteral obstruction. Use with extreme
caution in patients with disseminated intra­
vascular coagulation.
TRETINOIN
Vesanoid, all trans‐retinoic acid (ATRA),
Retin‐A, generic
Antineoplastic, retinoid
Capsule: 10 mg
Pregnancy category D
Indications: Tretinoin is used to induce
remission in people with APL who have
the PML/RARα gene mutation. The topi-
cal form is used to treat acne.
Dosage:
See specific protocol for dosing, doses may
differ when combined with other medica­
tions including arsenic trioxide.
APL Induction/Consolidation:
Children ≥1 year and adolescents: 45 mg/
m2/24 hours PO in two divided doses after
meals until complete remission is docu­
mented. Therapy should be discontinued
30 days after remission or after 90 days of
treatment, whichever occurs first.
Adults: 45 mg/m2/24 hours PO in two
equally divided doses until complete remis­
sion is documented. Therapy should be dis­
continued 30 days after remission or after
90 days of treatment, whichever occurs first.
482 Formulary
APL Maintenance:
Children, adolescents, and adults: 45 mg/m / 2 Tablet, single strength: 80 mg TMP and
day PO daily or divided q12h alone or with
regimens containing 6‐MP and methotrex­
ate for 1–2 years following induction and
consolidation therapy has been studied in
randomized clinical trials.
Notes:
The oral form of the drug has boxed warn­
ings concerning the risks of retinoic acid syn­
drome (RA‐APL) and leukocytosis. Other
significant side effects include a risk of throm­
bosis, benign intracranial hypertension in
children, hypercholesterolemia and/or hyper­
triglyceridemia, and liver damage.
Side effects include malaise, shivering, hem­
orrhage, infections, peripheral edema, pain,
chest discomfort, edema, disseminated
intravascular coagulation, weight increase,
injection site reactions, anorexia, weight
decrease, and myalgia.
Respiratory side effects usually signify RA‐
APL, and include upper respiratory tract dis­
orders, dyspnea, respiratory insufficiency,
pleural effusion, pneumonia, rales, and expir­
atory wheezing. This is seen most commonly
when given in combination with arsenic tri­
oxide (see ATO, differentiation syndrome).
Immediate intervention is required with dex­
amethasone 10 mg q12h × 3 days or until
symptoms resolve.
Also reported are earache or a feeling of full­
ness in the ears, abdominal pain, diarrhea,
constipation, dyspepsia, and swollen belly.
Cardiovascular side effects include arrhyth­
mias, flushing, hypotension, hyperten­
sion, phlebitis, and rarely cardiac failure or
arrest. Nervous system side effects include
dizziness, paresthesias, anxiety, insomnia,
depression, and confusion.
TRIMETHOPRIM/
SULFAMETHOXAZOLE
Bactrim, Septra, Co‐trimoxazole, Sulfatrim,
TMP–SMX, generics
Antibiotic, sulfonamide derivative
400 mg SMX Tablet, double strength: 160 mg
TMP and 800 mg SMX
Suspension: 40 mg TMP/200 mg SMX per
5 ml
Injection: 16 mg TMP/80 mg SMX per ml
Pregnancy category D
Indications:
Oral treatment of urinary tract infection
(UTI) and otitis media; prophylaxis for
PCP; IV treatment of documented or sus­
pected PCP infection in immunocompro­
mised patients.
Dosage:
Dosage recommendations are based on the
TMP component. May be given PO or IV.
Minor/moderate infection:
Children >2 months: 8–12 mg TMP/
kg/24 hours PO divided BID (maximum
160 mg/dose).
Adults (>40 kg): 160 mg TMP/dose BID.
Severe infection/PCP:
Children and adults: 20 mg TMP/kg/24 hours
divided q6–8h PO/IV.
UTI or otitis media prophylaxis:
Children: 2–4 mg TMP/kg PO once daily.
Prophylaxis for PCP:
Children >1 month: 5 mg TMP/kg/24 hours
PO divided q12h 2–3 consecutive days a
week (maximum dose 320 mg
TMP/24 hours).
Adolescent and adults: 160 mg PO twice
daily for 2–3 consecutive days/week.
Notes:
Do not give to patients with known hyper­
sensitivity to sulfa drugs or any component,
porphyria, or megaloblastic anemia due to

folate deficiency. Do not use in infants
under 2 months of age. Use with caution in
patients with G6PD deficiency and renal or
hepatic impairment. Serious adverse reac­
tions include Stevens–Johnson syndrome,
toxic epidermal necrolysis, hepatic necrosis,
agranulocytosis, aplastic anemia, and other
blood dyscrasias. Discontinue with rash.
May need to be held temporarily in oncol­
ogy patients who are on TMP–SMX for PCP
prophylaxis and subsequently develop neu­
tropenia. Numerous drug interactions are
reported. TMP–SMX decreases the clear­
ance of warfarin and methotrexate,
decreases serum cyclosporine concentra­
tions, and increases the effect of sulfonylu­
reas, phenytoin, and thiopental. Do not give
to patients within 24 hours of receiving high‐
dose methotrexate and until level is <0.1 μm
due to competitive excretion and increased
risk of methotrexate toxicity due to delayed
clearance.
VALACYCLOVIR
Valtrex, generics
Antiviral
Tablets/caplet: 500 mg, 1 g
Oral suspension: 50 mg/ml
Pregnancy category B
Indications:
Treatment of herpes zoster and HSV in
immunocompromised patients; treatment of
varicella zoster virus (VZV) in immunocom­
petent children (ages 2–18 years); treatment
of HSV labialis in adolescents and adults.
Dosage:
Varicella, immunocompetent:
2 to <18 years: 20 mg/kg/dose PO TID for
5 days (maximum 1 g TID); initiate within
24 hours of onset of rash.
Adults: 1 g/dose PO TID for 7 days within
48–72 hours of onset of rash.
Formulary 483
Herpes labialis (cold sores): >12 years: 2 g q12h
for 1 day; initiated at earliest symptoms.
Immunocompromised children at risk for
HSV or VZV infection with normal renal
function: (limited data) 15–30 mg/kg/dose
PO TID (maximum 2 g/dose).
Notes:
Do not give to patients with known hyper­
sensitivity to valacyclovir or acyclovir. Use
with caution in patients with renal impair­
ment or those receiving concomitant nephro­
toxic drugs. Adjust dose in patients with
renal impairment. Monitor renal function.
VALGANCICLOVIR
Valcyte
Trade and other names
Antiviral
Tablets: 450 mg
Oral solution: 50 mg/ml
Pregnancy category D
Indications:
Valganciclovir is indicated for the preven­
tion of CMV disease in kidney transplant
patients (4 months to 16 years of age) and
heart transplant patients (1 month to
16 years of age) at high risk for infection.
Dosage:
For pediatric kidney transplant patients
4 months to 16 years of age, the recom­
mended once daily PO mg dose
(7 × BSA × CrCl) should start within 10 days
of posttransplantation until 200 days
posttransplantation.
For pediatric heart transplant patients
1 month to 16 years of age, the recommended
once daily PO mg dose (7 × BSA × CrCl)
should start within 10 days of transplanta­
tion until 100 days posttransplantation.
The recommended once daily dosage is
based on BSA and creatinine clearance
(CrCl) derived from a modified Schwartz
484 Formulary
formula, and is calculated using the equa­
tion provided in the following text:
Pediatric dose (mg) = 7 × BSA × CrCl. If the
calculated Schwartz creatinine clearance
exceeds 150 ml/minute/1.73 m2, then a max­
imum value of 150 ml/minute/1.73 m2
should be used in the equation.
Notes:
Take tablets or oral solution with food.
Valganciclovir is frequently used in the set­
ting of severe immune suppression associ­
ated with BMT for the prevention of CMV
infection. Use with caution in renal impair­
ment, and dosing should be adjusted for
changes in creatinine (see package insert for
dose calculation). Side effects may include:
diarrhea, pyrexia, fatigue, nausea, tremor,
neutropenia, anemia, leukopenia, thrombo­
cytopenia, headache, insomnia, UTI, and
vomiting.
Severe leukopenia, neutropenia, anemia,
thrombocytopenia, pancytopenia, and bone
marrow failure including aplastic anemia
have been reported in patients treated with
valganciclovir or ganciclovir. Valganciclovir
should be avoided if the ANC is <500/μl, the
platelet count is <25 × 109/l, or the hemo­
globin is <8 g/dl. Use with caution in patients
with pre‐existing cytopenias and in patients
receiving myelosuppressive drugs or irradi­
ation. Cytopenias may occur at any time
during treatment and may worsen with con­
tinued dosing. Cell counts usually begin to
recover 3–7 days after drug discontinuation.
In patients with severe leukopenia, neutro­
penia, anemia, and/or thrombocytopenia,
treatment with hematopoietic growth fac­
tors may be considered.
Frequent monitoring of CBC with differen­
tial as well as renal function should be per­
formed frequently, especially in infants,
patients with renal impairment, those in
whom ganciclovir or other nucleoside ana­
logs have previously resulted in leukopenia,
or if neutrophil counts are <1000/μl at the
beginning of treatment.
VINBLASTINE SULFATE
Velban, generic
Antineoplastic, mitotic inhibitor, vinca
alkaloid
Injection: 1 mg/ml; 10 mg vial
Pregnancy category D
Indications:
Treatment of Hodgkin and non‐Hodgkin
lymphoma, pediatric brain tumors (glio­
mas), Langerhans cell histiocytosis, chorio­
carcinoma, advanced testicular germ cell
tumors, maintenance therapy in intermedi­
ate risk rhabdomyosarcoma.
Dosage:
Refer to individual protocol.
Hodgkin lymphoma: 2.5–6 mg/m2/dose IV
once every 1–2 weeks for three to six cycles;
maximum weekly dose 12.5 mg/m2.
Langerhans cell histiocytosis: 6 mg/m2/dose
IV once every 1–3 weeks.
Brain tumors (low‐grade gliomas): 6 mg/m2/
dose IV weekly or biweekly.
Notes:
Do not give to patients with known hyper­
sensitivity to vinblastine or with severe leu­
kopenia. Dose modification may be needed
in patients with hepatic impairment or neu­
rotoxicity. Extravasation may cause local
severe tissue damage. May cause peripheral
neuropathy, myelosuppression, jaw pain,
myalgia, paresthesia, constipation, abdomi­
nal pain, ileus, and mild alopecia.
The metabolism of vinca alkaloids has been
shown to be mediated by hepatic CYP450
isoenzymes in the CYP3A subfamily. This
metabolic pathway may be impaired in

patients with hepatic dysfunction or who
are taking concomitant potent inhibitors of
these isoenzymes.
Intrathecal administration is fatal. Vinblastine
should never be taken into the procedure room
for a patient undergoing a lumbar puncture
for instillation of intrathecal chemotherapy.
VINCRISTINE SULFATE
Vincasar, Oncovin, generic
Antineoplastic, mitotic inhibitor, vinca
alkaloid
Injection: 1 mg/ml; 1, 2 mg vials
Pregnancy category D
Indications:
Treatment of ALL, Hodgkin and non‐Hodgkin
lymphoma, neuroblastoma, brain tumors,
Wilms tumor, and rhabdomyosarcoma.
Dosage:
Refer to individual protocol.
Children ≤10 kg or BSA <1 m2: 0.05 mg/kg/
dose IV once weekly; maximum single dose
2 mg.
Children >10 kg or BSA ≥1 m2: 1–2 mg/m2
IV; may repeat weekly for 310 weeks.
Maximum single dose is 2 mg (some proto­
cols allow for higher dosing [i.e., 2.8 mg] in
Hodgkin lymphoma).
Neuroblastoma: IV continuous infusion
with doxorubicin: 1 mg/m2/day for 72 hours.
Notes:
Do not give to patients with known hyper­
sensitivity to vincristine. Avoid in patients
with the demyelinating form of Charcot–
Marie–Tooth disease. Asparaginase may
decrease clearance of vincristine. Dose modi­
fication may be required in patients with
impaired hepatic function, preexisting neu­
romuscular disease, or severe side effects of
treatment with vincristine. Extravasation
Formulary 485
may cause local severe tissue damage. May
cause peripheral neuropathy, paresthesias,
ileus, jaw pain, cranial nerve paralysis (pto­
sis), vocal cord paralysis, hyponatremia,
SIADH secretion, alopecia, and constipation.
The metabolism of vinca alkaloids has been
shown to be mediated by hepatic CYP450
isoenzymes in the CYP3A subfamily. This
metabolic pathway may be impaired in
patients with hepatic dysfunction or in
those taking concomitant potent inhibitors
of these isoenzymes.
Intrathecal administration is fatal. Vincristine
should never be taken into the procedure room
for a patient undergoing a lumbar puncture
for instillation of intrathecal chemotherapy.
VINORELBINE
Navelbine, generic
Antineoplastic, mitotic inhibitor, vinca
alkaloid
Injection: 10 mg/ml; 50 mg/5 ml vials
Pregnancy category D
Indications:
Indicated for the treatment of non‐small cell
lung cancer and used off label for rhabdo­
myosarcoma and other cancers.
Dosage:
Refer to individual protocol.
30 mg/m2 IV over 6–10 minutes weekly, or
per protocol.
Notes:
Dose modifications may need to be made
for neutropenia and/or hyperbilirubinemia.
Side effects include peripheral neuropathy,
cytopenias, immune suppression, constipa­
tion, nausea, vomiting, and fatigue.
Extravasation can cause severe local tissue
damage. Less common adverse effects
include hair loss and allergic reaction.
486 Formulary
The metabolism of vinca alkaloids has been
shown to be mediated by hepatic CYP450 iso­
enzymes in the CYP3A subfamily. This meta­
bolic pathway may be impaired in patients with
hepatic dysfunction or in those taking concom­
itant potent inhibitors of these isoenzymes.
VITAMIN K1/PHYTONADIONE
Mephyton, generics
Vitamin, water soluble
Tablet: 5 mg
Suspension: 1 mg/ml
Injection: 2, 10 mg/ml
Pregnancy category C
Indications:
Prevention and treatment of hypoprothrom­
binemia caused by anticoagulants or drug‐
induced vitamin K deficiency; hemorrhagic
disease of the newborn.
Dosage:
Hemorrhagic disease of the newborn:
Prophylaxis: 0.5–1 mg IM within 1 hour of
birth (for preterm infants <1 kg 0.3–0.5 mg/kg).
Treatment: 1–2 mg/24 hours IV/IM/SC.
Oral anticoagulant (warfarin) overdose with-
out significant bleeding, INR >4 <10:
Infants and children (<40 kg): 0.03 mg/kg PO
once.
Adolescents and adults (≥40 kg): 1–2.5 mg
PO once.
Oral anticoagulant (warfarin) overdose with-
out significant bleeding, INR ≥10:
Infants and children (<40 kg): 0.06 mg/kg PO
once, may repeat q12–24h.
Adolescents and adults (>40 kg): 5–10 mg PO
once, may repeat q12–24h.
Vitamin K deficiency (due to drugs, malab-
sorption, or decreased synthesis of vitamin K
by the liver):
Infants and children: 2.5–5 mg/24 hours PO
or 1–2 mg/dose IV/IM/SC.
Adolescents and adults: 2.5–25 mg/24 hours
PO or 2.5–10 mg/dose IV/IM//SC once.
Minor bleeding (any elevated INR):
<40 kg: 0.03 mg/kg PO once or 0.5–2.5 mg
IV once.
≥40 kg: 1–2.5 mg PO once or 0.5–2.5 mg IV
once.
Repeat dosing q12–24h if bleeding persists
and INR not corrected.
Significant bleeding (any elevated INR):
5–10 mg IV.
Consider additional measures including
fresh frozen plasma (FFP) (10–15 ml/kg).
Monitor INR q4–6h, repeat dosing if full
correction not achieved at 12–24 hours and
bleeding continues.
Notes:
Monitor INR until <4. For INR >10 monitor
q12h and repeat dose q12–24h until INR <4.
Do not give to patients with known hypersen­
sitivity to phytonadione. Antagonizes action
of warfarin. Protect product from light.
Parenteral dosing may cause flushing, dizzi­
ness, cardiac or respiratory arrest, hypoten­
sion, or anaphylaxis. High doses (10–20 mg)
in neonates may cause hyperbilirubinemia
and severe hemolytic anemia. Monitor pro­
thrombin time (PT), APTT, INR; blood coag­
ulation factors may increase within 6–12 hours
after oral dosing and within 1–2 hours after
parenteral dosing. Parenteral IM or IV dosing
is indicated when the oral route is not feasible
in emergency situations.
VORICONAZOLE
Vfend, generics
Antifungal agent
Injection: 200 mg
Oral suspension: 200 mg/5 ml

Tablet: 50, 200 mg
Pregnancy category D
Indications:
Treatment of invasive aspergillosis, especially
in immunocompromised patients; treatment
of candidemia in nonneutropenic patients;
invasive Candida infections including esoph­
ageal; treatment of serious fungal infections
caused by molds including Scedosporium or
Fusarium species in patients intolerant or
refractory to conventional antifungal therapy.
Dosage:
Invasive aspergillosis or candidiasis or other
rare molds (Scedosporium or Fusarium):
Children 2–11 years: 7–9 mg/kg/dose PO/IV
q12h (maximum initial dose 350 mg).
Children ≥12 years and adolescents (≥50 kg):
6 mg/kg/dose IV q12h × two doses, followed
by 4 mg/kg/dose IV q12h.
Convert to oral therapy when significant
clinical improvement after 1 week of IV
therapy at 9 mg/kg/dose PO q12h (maxi­
mum dose 350 mg) or if ≥50 kg administer
200 mg PO q12h.
Esophageal candidiasis:
Children 2–11 years: 4 mg/kg/dose q12h IV
or 9 mg/kg/dose PO q12h (maximum dose
350 mg q12h).
Children >12 years and adolescents (≥50 kg):
3 mg/kg/dose IV q12h or 200 mg PO q12h.
Prophylaxis (pediatric acute leukemia):
6 mg/kg/dose PO q12h × two doses, fol­
lowed by 4 mg/kg/dose PO q12h.
Notes:
Do not give to patients with known hypersen­
sitivity to voriconazole. Use with caution in
patients with known hypersensitivity to
azoles; cross‐reactivity studies have not been
done. Tablets may contain lactose and should
be used with caution in patients with lactose
intolerance. Avoid concurrent administration
Formulary 487
with rifampin, CYP3A4 substrates, and ergot
alkaloids. Voriconazole is metabolized by
CYP450 enzymes and many drug interac­
tions exist. May cause severe hepatic toxicity,
visual changes, cardiac arrhythmias, audi­
tory hallucinations, and photosensitivity.
May cause fetal harm; must ensure contra­
ception to avoid pregnancy. Use with caution
in neonates; oral suspension contains
sodium benzoate, a metabolite of benzyl
alcohol, which may cause a potentially fatal
toxicity. Use with caution in patients with
renal or hepatic toxicity; dose adjustment
may be necessary. Considerable interpatient
variability; monitor trough levels and adjust
dosing as necessary. Limited data for use in
children <2 years. Due to risk of concomitant
neurotoxicity with vincristine, should be
held around vincristine doses (as feasible).
WARFARIN SODIUM
Coumadin, Jantoven, generics
Anticoagulant
Tablets: 1, 2, 2.5, 3, 4, 5, 6, 7.5, 10 mg
Pregnancy category D/X
Indications:
Prophylaxis and treatment of venous throm­
boembolic disorders; prevention of arterial
thromboembolism in patients with pros­
thetic heart valves or atrial fibrillation; pre­
vention of death, VTE, and recurrent
myocardial infarction (MI) after acute MI.
Dosage:
Infants and children (to achieve/maintain
INR between 2 and 3):
Initial dose: 0.2 mg/kg PO for 1–2 days; max­
imum dose 10 mg.
Maintenance dose: 0.1 mg/kg/24 hours PO
daily; range 0.05–0.34 mg/kg/24 hours (con­
sult published charts based on INR).
Adults: 5–10 mg PO daily × 2–5 days, adjust
for desired INR; maintenance dose range
2–10 mg/day PO.
488 Formulary
Onset of action is within 36–72 hours and
peak effects occur within 5–7 days. Monitor
INR after 5–7 days of new dosage; high‐risk
patients may require more frequent
monitoring.
Usual duration of therapy for first venous
thrombotic event is 3 months (depending
on elimination of procoagulant factor and
based on resolution of clot).
Notes:
Do not give to patients with known hyper­
sensitivity to warfarin, severe liver or kidney
disease, uncontrolled bleeding, gastrointes­
tinal ulcers, status–post neurosurgical pro­
cedures, and malignant hypertension.
Concomitant use with vitamin K may
decrease anticoagulant effect. Concomitant
use with aspirin, nonsteroidal anti‐inflam­
matory drugs, or indomethacin may
increase warfarin’s anticoagulant effect and
cause severe gastrointestinal irritation. May
cause fever, skin lesions, necrosis (especially
in protein C deficiency), hemorrhage, hem­
optysis, anorexia, nausea, vomiting, and
diarrhea. Many drug interactions exist;
review all medications prior to initiation of
therapy. The INR is the recommended test
to monitor anticoagulant effect. The abso­
lute INR desired is dependent on the indica­
tion and has been extrapolated from adults.
An INR of two to three has been recom­
mended for prophylaxis and treatment of
DVT, pulmonary emboli, and bioprosthetic
heart valves. Younger children may require
higher dosing. Certain foods and medica­
tions may alter levels and should be reviewed
in detail with the patient. Antidote is vitamin
K and PCC (fresh frozen plasma if PCC una-
vailable). Due to time to effect, must bridge
with anti‐Xa (i.e., enoxaparin) for 3 days.
References
Hughes, H.K. and Kahl, L.K. (2018). The Johns
Hopkins Hospital: The Harriet Lane Handbook,
A Manual for Pediatric House Officers, 21e.
Philadelphia, PA: Elsevier‐Mosby.
(2019). Physicians’ Desk Reference, 73e. PDR
Network.
Taketomo, C.K., Hodding, J.H., and Kraus, D.M.
(2016). Pediatric & Neonatal Dosage
Handbook, 23e. Lexi‐Comp.
 Index

abnormal hemoglobins, 27, 53 risk group classification, 201–203

absolute neutrophil count (ANC), 119, 333, 334, treatment, 203–204
394, 401, 432 twins and siblings, 200
absolute phagocyte count (APC), 334 acute promyelocytic leukemia (APL), 148, 180,
acetaminophen, 6, 32, 73, 76, 141, 448, 454, 475 199
acquired von Willebrand disease, 101, 166, 240 acyclovir, 315, 409–410
acute anemia adjuvant medications, 33, 356
PRBCs, 181 adrenocortical carcinoma (ACC)
splenic sequestration, 40–41 clinical presentation, 281
acute chest syndrome (ACS), 35–38, 355 diagnosis and staging, 281
acute leukemia (AL) incidence, 281
etiology of, 191 treatment, 282
molecular characteristics, 192 afibrinogenemia, 88, 103
prevalence, 191 allergic transfusion reactions, 65, 73
acute lymphoblastic leukemia (ALL), 158, allopurinol, 180, 183, 188, 410–411, 460
333 all‐trans retinoic acid (ATRA), 201, 481
clinical manifestations, 192–194 alpha2‐antiplasmin deficiency, 104
complications of therapy, 198 alpha‐thalassemias, 27
diagnostic evaluation, 194–195 alpha‐globin production, 51
echocardiogram and electrocardiogram, 195 diagnosis, 52
novel agents, 199 diagnosis of, 51–52
relapse, 198–199 genetic counseling and testing, 53
risk group classification, 196 Hemoglobin H, 52
T‐cell acute lymphoblastic leukemia (T‐ALL), mean corpuscular volume (MCV), 52
191 silent carrier state, 52
treatment, 196–198 alveolar soft part sarcoma, 253
acute myelogenous leukemia (AML), 308, 333 alveolar variant (ARMS), 256
acquired conditions, 200 Amicar, 100, 142
clinical presentation, 200–201 amifostine, 411
complications of therapy, 204–205 aminocaproic acid, 411–412
diagnostic evaluation, 201 amphotericin B, 412–413
etiology of, 199 anaerobic therapy, 338
post‐test, 207–209 analgesics, 33–35
relapse, 205 anaplastic lymphoma kinase (ALK), 235

Handbook of Pediatric Hematology and Oncology – Children’s Hospital & Research Center Oakland,
Third Edition. Caroline A. Hastings, Joseph C. Torkildson, and Anurag K. Agrawal.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
490 Index

anemia, 181 hemoglobin E, 54

Coombs, 10
definition, 1
diagnosis of, 1
Diamond–Blackfan anemia, 10
erythropoietin, 8
hemolytic anemia (see also hemolytic anemia)
investigation of, 1–2
medical history of, 4
microcytic anemia, 6
microcytic causes of, 10
oral iron challenge, 2–3
parenteral iron therapy, 3, 5–8
physical examination, 5, 9
TEC, 11
transfusion therapy, 8
angiosarcoma, 253, 278
Ann Arbor staging system, 229, 230
anterior mediastinal masses, 166
anti‐thymocyte globulin (ATG), 413–414
aplastic crisis, 41
aprepitant, 414–416
arsenic trioxide (ATO), 416–417
mechanism of action, 377
side effects, monitoring, and treatment,
377–378
asparaginase, 378, 417–418
atypical teratoid/rhabdoid Tumor (ATRT), 223
autoimmune hemolytic anemia, 18–19
autoimmune neutropenia (AIN), 122
autologous stem cell transplantation (ASCT),
232
avascular necrosis, 41–42, 198, 472
azacitidine/decitabine, 418
mechanism of action, 378
side effects, monitoring, and treatment, 378
utilization, 378
bacterial prophylaxis, 314
Bard PowerLine, 325
B‐cell depletion, 143
BEACOPP, 231
bendamustine, 232, 379
benzodiazepines, 34, 371
beta‐thalassemia
children, 54, 55
chronic transfusion therapy, 56
clinical management, 55
diagnostic problems, 54
genotypic differentiation, 53
infants, 54
splice site mutations, 53
bevacizumab, 419
biopsy, 273
bleeding child
evaluation of, 85–86
history, 86
initial laboratory evaluation, 86–89
management of epistaxis, 90
physical examination, 86
bleomycin, 379
bleomycin, etoposide, and cisplatin (BEP), 269
bleomycin sulfate, 419–420
blinatumomab, 420
mechanism of action, 379
side effects, monitoring, and treatment, 380
bone marrow aspiration, 214–215
indications, 398–399
pretreatment evaluation, 399
bone marrow transplantation, 123
bone scan, 247
brentuximab vedotin, 380, 418–419
busulfan, 46, 295, 420–421
carboplatin, 219, 249, 421–422
carmustine, 411, 422
caspofungin, 342, 422
catheters
CVCs (see central venous catheters (CVCs))
insertion of, 324–325
central line‐associated blood stream infection
(CLABSI), 326
central nervous system (CNS) tumors
atypical teratoid/rhabdoid Tumor (ATRT), 223
bone marrow aspiration, 214–215
bone scan, 215
cause of, 211
chemotherapy, 216–217
clinical presentation, 211–213
computerized tomography (CT), 213
germ cell tumors, 223, 269–271
gliomas, 219–223
imaging studies, 213
lumbar puncture (LP), 214
medulloblastoma, 217–219
microscopic criteria, 211
MRI, 213
neurosurgery, 215
PET imaging, 213–214

radiation therapy, 215–216
single‐photon emission computed
tomography (SPECT), 214
central venous catheters (CVCs)
assessment and management, 328–331
complications, 326–328
external and multilumen devices, 323
external CVCs, 323
insertion of catheters, 324–325
maintenance, 325–326
subcutaneous ports, 323
tunneled catheters, 323
type of, 324
cerebral vascular disease, 28
cervical masses, 246
Chédiak Higashi syndrome (CHS), 126
chelation therapy
lead toxicity, 81–83
transfusional iron overload, 79–81
chemotherapeutic agents, 270
chemotherapy, 250, 280
extravasation
causes of, 404
clinical follow‐up, 407
DNA‐binding agents, 405
incidence of, 403
non‐DNA‐binding antineoplastics, 405
prevention of, 404
signs and symptoms of, 405
treatment, 405–406
immunization, 316–317
intra‐ommaya reservoir tap
indications, 397
materials, 397
postprocedure monitoring and
complications, 398
pretreatment evaluation, 397
procedure, 397–398
LP/IT chemotherapy
indications, 393
materials, 393–394
patient’s medical record, 393
postprocedure monitoring and
complications, 396–397
pretreatment evaluation, 393
procedure, 395–396
prevention of, 317–318
chemotherapy‐induced nausea and vomiting
(CINV), 317–318
chest radiography, 240
Index 491
chimeric antigen receptor T‐cell (CAR‐T) cell
therapy, 235
choriocarcinoma, 266
chromosome analysis, 201
cisplatin, 280, 422–423
cisplatin/carboplatin, 380–381
cis‐retinoic acid/all‐trans retinoic acid, 381
cladribine, 423–424
cladribine/clofarabine, 382
clofarabine, 424
coagulopathy, 204
Codman triangle, 260
complementary therapies, 35
complete blood count (CBC), 137
concomitant malignancies, 271
congenital amegakaryocytic thrombocytopenia
(CAMT), 150
congenital deficiency, 103
cryoprecipitate, 69–70
cyclic neutropenia, 123
cyclophosphamide, 23, 144, 148, 175, 187, 197,
200, 219, 231, 235, 242, 243, 246, 251,
382–383, 424–425
cyclophosphamide/ifosfamide, 382–383
cyclosporine, 425
cytarabine, 383
cytarabine hydrochloride, 425–426
dacarbazine, 426
dactinomycin, 426–427
dactinomycin (Actinomycin‐D), 383
dapsone, 427
darbepoetin alfa, 427–428
dasatinib, 428
daunorubicin and doxorubicin, 383–384
daunorubicin hydrochloride, 428–429
deferasirox, 430–431
deferiprone, 431–432
deferoxamine mesylate, 429–430
defibrotide, 431
delta beta thalassemia, 56
dermatofibrosarcoma protuberans, 253
desmoid tumors, 253
desmopressin acetate, 432–433
dexamethasone, 318, 433
dexrazoxane, 433–434
diabetes insipidus (DI), 270
Diamond–Blackfan anemia (DBA), 10, 126, 130,
200
dimercaprol, 434–435
492 Index

dimethyl sulfoxide, 435 ferrous gluconate, 443

dinutuximab, 384–385, 435–436 ferrous sulfate, 443–444
diphenhydramine, 436–437 fever, 206
disseminated intravascular coagulation (DIC), antibiotic treatment, 338–341
20, 112, 138, 148 definition, 334
Doppler abdominal ultrasound, 240 duration of therapy, 341
doxorubicin, 280 empiric antifungal therapy, 341–343
doxorubicin hydrochloride, 437 initial management, 337–338
dronabinol, 437–438 and neutropenia, 334–337
dyskeratosis congenita (DKC), 126, 130, 200 new sites of infection, 344–345
dyspnea non‐neutropenic oncology patient, 345
cause of, 367 P. jiroveci pneumonia, 344
pathological conditions, 367 rectal temperatures, 334
respiratory failure, 369 supportive measures, 345
treatment for, 369 viral infection, 343–344
fibromyxoid sarcoma, 253
echocardiogram, 36, 174, 187, 240, 263, 322 fibrosarcoma, 253
edetate calcium disodium, 438 filgrastim, 444
ektacytometry, 20 fluconazole, 445
electrocardiograms (EKGs), 204 fludarabine, 445–446
eltrombopag, 438–439 Fluorine‐18‐fluorodeoxyglucose positron
Embden‐Meyerhof pathway (EMP), 17 emission tomography (FDG‐PET), 255
end‐of‐life care folic acid, 446–447
parental dissatisfaction, 363 fondaparinux, 446
symptoms foscarnet, 447
constipation, 365 Free erythrocyte protoporphyrin (FEP), 54
nausea and vomiting, 364–365 fresh frozen plasma, 69
pain, 363 fungal prophylaxis, 314–315
engraftment syndrome, 298
enoxaparin, 439–440 ganciclovir, 447–448
epistaxis, 106 gastrointestinal GI bleeding, 96
epoetin alfa, 440–441 gastrointestinal (GI) tract, 364
Epstein‐Barr virus (EBV) virus, 227 gemcitabine, 448
etoposide, 385, 441 gemtuzumab, 385–386
ETV6–RUNX1 fusion gene, 192 gemtuzumab ozogamicin, 448
Ewing sarcoma family of tumors (ESFT), gene expression profiling, 192, 202
261–262 gene therapy, 46–47, 109
germ cell tumors (GCTs), 223
Face, Legs, Activity, Cry, Consolability (FLACC) central nervous system, 269–271
Behavior Scale, 349 clinical presentation, 267–268
factor V (FV) deficiency, 103 concomitant malignancies, 271
factor VIII (FVIII) deficiency, 103 diagnostic evaluation and risk stratification,
factor XI (FXI) deficiency, 104 268
factor XIII (FXIII) deficiency, 104 epidemiology, 265–266
Fanconi anemia, 123 paraneoplastic syndromes, 271
fatigue, 366–367 pathology and serum tumor markers,
febrile neutropenia (FN), 333 266–267
ferric carboxymaltose, 442 treatment and prognosis, 268–269
ferric gluconate, 442–443 germinomas, 266
ferrous fumarate, 444 Gilbert syndrome, 24
 Index 493

gliomas, 219–223 hemophagocytic lymphohistiocytosis (HLH),

glucarpidase, 448–449 287
glucose‐6‐phosphate dehydrogenase (G6PD) clinical findings, 290
deficiency, 15, 17, 18 cyclosporine, 290
glutamine, 45–46 diagnostic criteria, 290
gonadal tumors, 269 feature in, 289
graft‐versus‐host disease, 296, 300, 302–304 macrophages and T‐lymphocytes, 290
granisetron, 449–450 NK cells, 290
granulocyte colony‐stimulating factor (G‐CSF), hemophilia
122, 318, 345 afibrinogenemia, 103
granulocyte immunofluorescence test (GIFT), alpha2‐antiplasmin deficiency, 104
122 clinical presentation, 104–106
granulocyte transfusion, 70–71 definition, 103
gross total resection (GTR), 268 dental care, 108
diagnosis, 106
hematopoietic growth factors, 318 factor VIII (FVIII) deficiency, 103
hematopoietic stem cell transplantation (HSCT), factor XI (FXI) deficiency, 104
46, 333 gene therapy, 109
complications of, 298 hemophilia A, 103
diet, 305 hemophilia B, 103
donor matching, 296–298 heterozygotes, 104
engraftment and graft failure, 298 hypoprothrombinemia, 103
graft‐versus‐host disease, 296, 300, 302–304 incidence, 103
idiopathic pneumonia syndrome (IPS), 304 inhibitors, 108
immune reconstitution, 306–307 novel agents, 108–109
infection prophylaxis, 304, 306 prothrombin deficiency, 103
infections, 298–300 psychological support, 108
late sequelae, 304, 305 rare coagulation factor deficiencies, 104
multidrug therapy, 295 treatment, 106–108
pretransplant preparative regimens, 298, 299 hemophilia A, 103
supportive care, 304 hemophilia B, 103
transfusion guidelines, 305–306 heparin‐induced thrombocytopenia (HIT), 147
transplantable conditions, 295–296 heparin sodium, 450–451
transplant‐associated thrombotic hepatoblastoma (HBL)
microangiopathy (TA‐TMA), 304 clinical presentation, 278–279
types of transplantation, 296 diagnosis and staging, 279
veno‐occlusive disease/sinusoidal obstructive factors, 278
syndrome, 300, 301 incidence of, 278
hemolytic anemia, 8, 162 malignant hepatic tumors, 278
autoimmune hemolytic anemia, 18–19 treatment, 279–280
evaluation, 20–21 hereditary neutropenias, 122
immature reticulocytes, 23 heterozygotes, 104
lab studies, 22 histiocytic disorders
microangiopathic hemolytic anemias, 20 classification, 287, 288
newborn period, 19 LCH (see langerhans cell histiocytosis (LCH))
red cell enzyme deficiencies, 17–18 hodgkin lymphoma
red cell membrane disorders, 15–16 childhood and adolescent/young adult (AYA),
reticulocyte index (RI), 22–23 227
treatment, 21–22 classical HL, 227, 230–231
hemolytic uremic syndrome (HUS), 147 clinical presentation, 228
494 Index

hodgkin lymphoma (cont’d ) inotuzumab ozogamicin, 386, 454–455

evaluation, 228–229 intensitymodulated radiation therapy (IMRT),
nodular lymphocytepredominant HL, 227, 231 257
non‐hodgkin lymphoma (see non‐hodgkin International Neuroblastoma Staging System,
lymphoma) 247, 248
novel agents, 231–232 intracranial hemorrhage (ICH), 106, 135
staging system, 229 invasive fungal disease, 341
treatment strategy, 229–230 irinotecan, 386–387, 455–456
tumor cells, 227 iron complex, polysaccharide, 456
host factors, 202 iron dextran complex, 456–457
human leukocyte antigen (HLA) system, 296 iron overload, 79–81
hyaluronidase, 451 iron sucrose, 457
hydrocortisone, 451 isotretinoin, 458
hydromorphone hydrochloride, 451–452 IV hydration, 32–33
hydroxyurea, 452
hydroxyurea therapy, 45 Kasabach–Merritt syndrome, 148, 249
hyperbilirubinemia/gallstones, 42–43 ketamine, 352
hypercalcemia ketorolac, 32, 458
evaluation, 184–185
treatment, 185 lactate dehydrogenase (LDH), 22
hyperleukocytosis langerhans cell histiocytosis (LCH)
clinical findings and evaluation, 180 brain MRI imaging, 289
complication, 179 diagnosis, 287
definition, 179 large/symptomatic solitary bone lesions, 288
treatment, 180–181 neoplastic process, 287
hypoprothrombinemia, 103 pathogenesis of, 287
skin lesions, 288
ibuprofen, 32 solitary bone lesions, 288
idarubicin, 452–453 systemic disease, 288–289
idiopathic pneumonia syndrome (IPS), 304 vertebral lesions, 288
ifosfamide, 453 lead toxicity, 81–83
imatinib, 386 leiomyosarcoma, 253
imatinib mesylate, 453–454 leucovorin calcium, 458–459
immune globulin, 454 lidocaine, 441–442
immune hemolytic anemias, 22 liposarcoma, 253
immune reconstitution, 306–307 lomustine, 459
immune thrombocytopenic purpura, 122 low‐molecular‐weight heparin (LMWH), 330
diagnosis of, 133 lumbar puncture (LP), 214
emergency therapy, 142 lymph nodes, 205
evaluation, 135–139 lymphocyte‐predominant (LP) cells, 227
mucosal bleeding, 133
treatment, 139–142 malignant peripheral nerve sheath tumors,
immunization, 28, 68, 71, 108, 144, 169 253
chemotherapy, 316–317 massive hepatomegaly, 177–178, 250
immunological disease, 162 mean platelet volume (MPV), 87
immunophenotyping, 205, 206 Measles‐Mumps‐Rubella (MMR), 135
increased intracranial pressure (ICP), 364 mechlorethamine, 459–460
Individualized Care Planning and Coordination medulloblastoma, 217–219
Model, 361–363 melphalan, 460
infection prophylaxis, 304, 306 meperidine, 352

mercaptopurine, 387, 460–461
6‐mercaptopurine (6MP), 192
mesna, 461
metabolic depletion, 15
methadone hydrochloride, 461–462
methotrexate, 387–388, 462–463
methylene blue, 463
methylprednisolone, 463–464
metoclopramide, 464
micafungin, 464–465
Microangiopathic hemolytic anemias, 20
microarray technology, 202
microcytic anemia, 6
middle mediastinal masses, 166
mitoxantrone, 465
morphine, 371
morphine sulfate, 465–466
mycophenolate mofetil (MMF), 466–467
naloxone, 467–468
nelarabine, 388–389, 468
neonatal alloimmune neutropenia, 122
Neonatal Infant Pain Scale (NIPS), 348
neonatal isoimmune neutropenia, 122
neuroblastoma
clinical presentation, 245–246
diagnostic studies, 247
genetic risk factors, 245
history, 246
laboratory studies, 246–247
physical examination, 246
staging, 247, 248
treatment, 247, 248
neuron‐specific enolase (NSE), 247
neutropenia
febrile neutropenia, 335–337
and fever
bacteremia and sepsis, 334–335
septic shock, 334
neutropenic colitis
clinical findings and evaluation, 178–179
treatment, 179
neutrophils
child management, 127–129
component, 119
etiology of, 120–122
inherited causes of, 122–126
initial evaluation, 126–127
post‐test, 130–132
risk assessment, 119–120
Index 495
nextgeneration sequencing technology, 192
nilotinib, 468–469
nivolumab and pembrolizumab, 389
N‐methyl‐d‐aspartic acid (NMDA) receptor
antagonist, 33
nongerminomatous germ cell tumors (NGGCT),
269
non‐Hodgkin lymphoma, 199
non‐Hodgkin lymphoma, 199
clinical presentation, 233
congenital conditions, 232
diagnostic evaluation, 233–234
DLBCL and ALCL, 232–233
histologic classification, 232
incidence of, 232
novel agent, 235
staging, 234
treatment, 234–235
noninvasive positive pressure ventilation
(NIPPV), 369
nonopioid analgesics, 350–351
nonrhabdomyomatous soft tissue sarcomas
bone sarcomas, 258
clinical presentation, 259
diagnostic evaluation, 259–260
genetics, 258–259
pathologic diagnosis, 260
prognosis for, 262–263
treatment, 260–262
nonrhabdomyosarcoma soft tissue sarcomas
(NRSTS), 253
oncologic emergencies
anemia, 181
hypercalcemia, 184–185
hyperleukocytosis, 179–181
intracranial pressure and brain herniation,
176–177
massive hepatomegaly, 177–178
neutropenic colitis, 178–179
post‐test, 188–190
spinal cord compression, 175–176
superior vena cava and superior mediastinal
syndrome, 172–175
tumor lysis syndrome, 181–184
ondansetron, 469
opioids, 364
opsoclonusmyoclonus‐ataxia syndrome
(OMAS), 246
oseltamivir, 469–470
496 Index

osteosarcoma, 260–261 palonosetron, 470

oxaliplatin, 470 paraneoplastic syndromes, 271
oxycodone, 352 parenteral iron therapy, 3, 5–8
paroxysmal nocturnal hemoglobinuria
packed red blood cell transfusion (PRBC), 23 (PNH), 16
acute blood loss and nonimmune hemolytic patient‐controlled analgesia (PCA), 352
anemia, 66 pazopanib, 470–471
autoimmune hemolytic anemia, 66 pediatric antiemetics, 318, 319
blood transfusion guidelines, 64 pediatric cancers
chronically transfused patients, 66–67 abdominal mass, 168
cytomegalovirus (CMV)‐negative blood, 65 adenopathy, 160, 161
dosing of, 67 back pain, 163
exchange transfusion/erythrocytapheresis, 67 bicytopenia and pancytopenia, 164
neonates, 65–66 bleeding, 165
oncology patients, 66 bone marrow examination, 165
platelets and white blood cells, 65 bone or joint pain, 163
severe chronic anemia, 66 bone pain, 164
pain management, 32 cytopenias/abnormalities, 164
analgesics, 347, 348 diagnosis of, 157
assessment of, 348 diffuse/multifocal bone pain, 163
dosing of pain medication, 347 excisional biopsy, 162
neonates and infants, 348 fever, 158, 159
nonpharmacologic approaches, 354 headache, 159
oral form of medication, 347 incidence, 157
pain pharmacology, 350 laboratory and imaging findings, 158, 162
post‐test, 356–357 lymphadenopathy, 159
preverbal/nonverbal children, 348–349 mediastinal masses, 166
school‐aged and older children, 349–350 musculoskeletal pain, 163
step 1 therapy, 350–351 neuroblastoma and Wilms tumor, 158, 166
step 2 therapy, 351, 352 palpable abdominal mass, 166
step 3 therapy, 351–353 post‐test, 170–172
step 4 therapy, 352, 354 splenomegaly, 162–163
palliative care surgical staging, 167
anorexia and weight loss, 366 suspected leukemia, 165
assessment symptoms and signs, 157, 158
history, 365 pelvic masses, 246
medications, 366 pentamidine isethionate, 471
physical examination, 365–366 perioperative management, 43
definition, 361 perioperative transfusion, 44–45
dyspnea (see dyspnea) peripheral blood stem cell transplant (PBSCT),
end‐of‐life care 296
parental dissatisfaction, 363 platelet surface glycoprotein, 85
symptoms, 363–365 platelet transfusions, 306
fatigue, 366–367 cryoprecipitate, 69–70
gas exchange, 371 dosing of, 68–69
individualized care planning and fresh frozen plasma, 69
coordination, 361–363 indications, 68
nonpharmacologic interventions, 371 posaconazole, 471–472
nutritional supplementation, 366 positron emission tomography (PET), 229
supporting respiration, 369–371 posterior mediastinal masses, 166
 Index 497

postoperative care, 43–44 sickle cell disease (SCD)

prednisone, 472 abnormal hemoglobins, 27
preoperative care, 43 acute anemia, 40–41
pretransplant preparative regimens, 298, 299 acute chest syndrome/pneumonia, 35–38
priapism, 38 alpha‐thalassemia, 27
prilocaine, 441–442 analgesics, 34–35
primary mediastinal B‐cell lymphoma (PMBCL), aplastic crisis, 41
232 avascular necrosis, 41–42
primordial germ cells (PGCs), 265 complementary therapies, 35
procarbazine hydrochloride, 472–473 fever and infection in, 29–31
prophylactic antibiotics, 128 general management, 34
prophylaxis hyperbilirubinemia/gallstones, 42–43
bacterial prophylaxis, 314 inpatient, 33–34
fungal prophylaxis, 314–315 mild pain, 32
invasive procedures, 315 novel agents, 45–46
nutrition and dental hygiene, 313 pain management, 32
prevention of, 313 perioperative management, 43
rectal suppositories and rectal temperatures, perioperative transfusion, 44–45
314 postoperative care, 43–44
trimethoprim/sulfamethoxazole (TMP/SMX) preoperative care, 43
prophylaxis, 314 preventive care, 28–29
prothrombin deficiency, 103 priapism, 38
protracted fever, 340 retinopathy/hyphema, 42
pyruvate kinase (PK) deficiency, 17 severe pain, 32–33
stroke, 38–40
radiation therapy, 215–216, 261, 280 transfusion therapy, 44
radiotherapy, 235 vaso‐occlusive episodes, 27, 31–32
rasburicase, 473 single‐photon emission computed tomography
recombinant factor VIIa, 85 (SPECT), 214
red blood cells (RBCs), 15 sirolimus, 476–477
red cell membrane disorders, 15–16 skeletal metastases, 229
retinoblastoma skin irritation, 327
clinical presentation, 276 skin lesions, 246
diagnosis and staging, 276 sodium thiosulfate, 477
follow‐up, 277–278 soft tissue hemorrhages, 105
secondary mutations, 275 soft tissue sarcomas
treatment, 276–277 clinical presentation, 254–255
retinopathy/hyphema, 42 diagnostic evaluation, 255
rhabdomyosarcoma, 253 genetics, 254
RhoGAM, 141 late effects in, 263
Rho(D) immune globulin, 473–474 pathologic diagnosis, 255–256
Rituximab, 199 prognosis, 257–258
rituximab, 143, 389, 474–475 rhabdomyosarcoma, 253
rivaroxaban, 475 staging and classification, 256
romiplostim, 475–476 treatment, 256–257
spinal cord compression
sacrococcygeal tumors, 267, 269 cause of, 175
sargramostim, 476 clinical findings and evaluation, 176
severe congenital neutropenia (SCN), 123 management, 176
severe pain, 32–33 splenectomy, 16, 17, 144
498 Index

splenomegaly, 122 novel anticoagulants, 116

staging, 241 prevention and treatment, 111
steroids, 389–390 testing for, 112–113
storage disease, 162 thrombolysis, 114
stroke, 38–40 thyroid tumors
Stroke Prevention Trial in Sickle Cell Anemia clinical presentation, 283
(STOP), 39 diagnosis and staging, 283–284
succimer, 477–478 genetic predisposition, 283
superior vena cava (SVC), 173 incidence of, 282
superior vena cava syndrome (SVCS), 173, 228 treatment, 284
surgical procedures, 229 tisagenlecleucel, 390–391
synovial sarcoma, 253 tissue plasminogen activator (TPA), 329, 338
systemic antibiotic therapy, 328 topical anesthesia, 323
topotecan, 391, 480–481
tacrolimus, 478 total parenteral nutrition (TPN), 305, 366
temozolomide, 390, 478–479 tranexamic acid, 481
teratomas, 266 transdermal fentanyl, 352
thalassemias transfusion‐associated circulatory overload, 73
alpha‐globin chains, 51 transfusion‐associated graft versus‐host disease,
alpha‐thalassemias, 51–53 73–74
beta‐globin chains, 51 transfusion medicine
beta‐thalassemia, 53–56 clerical errors and misidentification, 63
delta beta thalassemia, 56 complications, 63
globin chain production/deletion, 51 cryoprecipitate, 69–70
HPFH, 56 granulocyte transfusion, 70–71
newborn screening, 56–58 platelet transfusions, 67–69
thioguanine, 390, 479 PRBC (see packed red blood cell transfusion
thiotepa, 479 (PRBC))
thoracic masses, 246 transfusion reactions, 71–74
thrombin, 480 transfusion reactions
thrombin time (TT), 103 allergic transfusion reactions, 73
thrombocytopenia, 123 bacterial infections, 74
acute immune thrombocytopenic purpura, hemolytic transfusion reactions, 71–73
133–135 transfusion‐associated circulatory overload, 73
chronic immune thrombocytopenic purpura, transfusion‐associated graftversus‐host
142–144 disease, 73–74
decreased platelet production, 149–151 transfusion‐related acute lung injury, 73
differential diagnosis of, 134–135 transfusion‐related acute lung injury, 73
drug‐induced thrombocytopenia, 147 transfusion therapy, 44
neonatal alloimmune thrombocytopenia, transient myeloproliferative disorder (TMD), 199
144–146 transplant‐associated microangiopathy, 20
neonatal autoimmune thrombocytopenia, transplant‐associated thrombotic
146–147 microangiopathy (TA‐TMA), 304
nonimmune thrombocytopenia, 147–149 tretinoin, 481–482
post‐testt, 151–154 trimethoprim/sulfamethoxazole, 314, 482–483
thrombophilia tumor dissemination, 267
anticoagulation, 114–115 tumor lysis syndrome, 192
duration of therapy, 115–116 clinical findings and evaluation, 182
evaluation of, 111–112 definition, 181–182
management of, 113–114 prevention and intervention, 182–184

undifferentiated sarcoma, 253
uridine diphosphate glucuronosyltransferase
(UGT1A1), 24
urine catecholamines, 250
valacyclovir, 483
valganciclovir, 483–484
vancomycin, 339–340
vancomycin‐resistant enterococcus (VRE), 340
vaso‐occlusive episodes, 27, 31–32
vaso‐occlusive events (VOE), 355
venlafaxine, 357
veno‐occlusive disease (VOD), 298
venous thromboembolism, 328
vinblastine sulfate, 484–485
vinca alkaloids, 144
vincristine and vinblastine, 391–392
vincristine sulfate, 485
vinorelbine, 485–486
viral prophylaxis and treatment, 315–316
visceral pain, 357
vitamin K1/phytonadione, 486
Index 499
Von Willebrand disease (VWD)
acquired von willebrand syndrome, 101
autosomal dominant manner, 95
clinical presentation, 96
diagnosis, 96–98
treatment, 98–101
types, 95
von Willebrand factor (VWF), 85
voriconazole, 486–487
warfarin, 147
warfarin sodium, 487–488
white blood cell (WBC), 119
Wilms tumor
clinical presentation, 240
evaluation of, 240
incidence and prevalence, 239
pathologic diagnosis, 240–241
staging, 241
treatment, 241–242
Wiskott–Aldrich syndrome (WAS), 126, 150
Wong‐Baker FACES Pain Rating Scale, 350