Pediatric Leukemias

Cyrine-Eliana Haidar, Pharm.D., BCPS, BCOP; and Jennifer L. Pauley,

Pharm.D., BCPS
Reviewed by Betsy Bickert Poon, Pharm.D.; Todd P. Semla, Pharm.D., M.S., FCCP, BCPS, AGSF;
and Maya A. Thompson, Pharm.D., BCPS

Learning Objectives Acute Lymphoblastic

1. Analyze the prognostic factors for acute lymphoblastic Leukemia
leukemia and determine the outcome based on the
patients individual risk factors and pharmacogenetics. Epidemiology
2. Design a treatment plan based on the diagnosis and Acute lymphoblastic leukemia is the most common
individual risk factors for acute pediatric leukemias. childhood malignancy. It accounts for one-fourth of all
3. Construct individualized therapy for patients with acute pediatric malignancies and 75% to 80% of childhood
leukemias. leukemias. The annual incidence of ALL in the United
4. Demonstrate an understanding of some of the States is 29.2 per million, with a peak incidence occurring
between the ages of 2 years and 5 years. In the United States,
pharmacogenetic tests that can be performed in patients
ALL affects white children more often than African
with leukemia.
American children, and its incidence is higher in boys than
5. Demonstrate an understanding of the incidence,
girls.
pathophysiology, classification, and risk factors for
acute myeloid leukemia (AML).
Genetics
6. Develop an understanding of the therapeutic Acute leukemia is a clonal disorder of the hematopoietic
management of AML. system, arising from a single cell mutation that is then
7. Devise a plan for the use of antimicrobial drugs in passed on. In most cases, acquired genetic abnormalities
patients receiving AML therapy. are associated with leukemia. However, inherited genetic
8. Demonstrate an understanding of the incidence and abnormalities have been implicated in 5% of acute leukemias.
etiology of the late complications of chemotherapy in Down syndrome is the most common genetic syndrome
leukemia survivors. associated with acute leukemias, with studies suggesting
a 10- to 20-fold increased risk of leukemia. Other genetic
disorders associated with acute leukemias include Bloom
syndrome, neurofibromatosis type I, Shwachman syndrome,
Introduction and ataxia-telangiectasia.

Childhood acute leukemias represent a heterogeneous Pathophysiology

group of disorders. Although recent advancements have been Leukemia arises from a single mutant hematopoietic
made in improving the survival rate of children with acute progenitor cell that is capable of indefinite self-renewal and
lymphoblastic leukemia (ALL) and acute myeloid leukemia gives rise to malignant, poorly differentiated hematopoietic
(AML), the survival rates of AML remain substantially lower precursors. It is unknown where in normal differentiation
than ALL. Because more pediatric patients are surviving the leukemia arises, and it may be highly variable. This
their malignancies and living into adulthood, there is an event most likely occurs in committed lymphoid precursors
increased focus on managing late effects of survivors. many years before clinical presentation.

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 Diagnosis
Abbreviations in A bone marrow aspirate is generally necessary to confirm
the diagnosis of ALL. A biopsy may be performed in
This Chapter select instances. Examining the bone marrow is diagnostic
because it is usually replaced with leukemic lymphoblasts.
ALL Acute lymphoblastic leukemia Cerebrospinal fluid should also be obtained. Central nervous
AML Acute myeloid leukemia system leukemia is defined as the presence of at least five
CNS Central nervous system WBC per microliter of cerebrospinal fluid, with leukemic
CR Complete remission blast cells or cranial nerve palsies.
HSCT Hematopoietic stem cell
transplantation Classification
MRD Minimal residual disease Because ALL is a heterogeneous disease, its classification
MTX Methotrexate involves the use of morphology, immunophenotype, and
WBC White blood cell genetics. There have been many attempts to classify ALL
based on morphology. These systems have classified cells
based on criteria such as size, nuclear-to-cytoplasmic ratio,
Clinical Presentation nuclear shape, nucleoli, and other similar features. The
The presentation of pediatric ALL is quite variable French-American-British Cooperative Working Group
and depends on the extent of bone marrow involvement system is the only one that has been routinely accepted.
and extramedullary spread of the disease. The clinical This group defines three categories of lymphoblasts (L1,
findings and symptoms are a result of the neutropenia, L2, and L3); about 85% of children have L1 morphology,
thrombocytopenia, and anemia associated with ALL. The 14% have L2, and 1% have L3. Currently, the World Health
most common presenting features are fever, pallor, fatigue, Organization recognizes two immunophenotypic subtypes
bone pain, petechiae, and bleeding. Signs of extramedullary of ALL: precursor B-cell and precursor T-cell lymphoblastic
disease spread include lymphadenopathy, hepatomegaly, leukemia/lymphoma.
and splenomegaly. The duration of these symptoms may The cytogenetics of pediatric ALL can be analyzed
vary from days to months before diagnosis. by conventional or molecular cytogenetics. Conventional
T-cell ALL, which accounts for about 15% of ALL cases, cytogenetics uses standard chromosomal analysis and is
the initial screening method used to detect abnormalities
has distinct clinical features. This type of ALL usually
in leukemic cells. These conventional studies detect only
occurs in adolescent boys, presents with an elevated white
chromosomal abnormalities in mitotically active cells.
blood cell (WBC) count, and is commonly associated with Molecular cytogenetic studies are able to detect chromosomal
a mediastinal mass. About half of the children with T-cell abnormalities in nonmitotically active leukemic cells. These
ALL have mediastinal masses, and one-third to one-half types of screenings include DNA probes, fluorescence in
have initial WBC counts greater than 100 103 cells/mm3. situ hybridization, and reverse transcriptase polymerase
Patients with T-cell leukemia are also more likely to have chain reaction. Cytogenetic abnormalities associated with
central nervous system (CNS) disease at diagnosis. pediatric ALL include chromosomal number (ploidy)
Extramedullary disease spread is manifested by the and structural rearrangements (translocations). Ploidy is
site of organ involvement. Ocular leukemia may present determined by directly counting the number of chromosomes
as retinal hemorrhage; it may also be associated with in a metaphase or by an indirect method of measuring DNA
leukemic infiltration of the orbit, optic nerve, retina, iris, by flow cytometry. When measured by flow cytometry, the
cornea, or conjunctiva, which may produce blurred vision, DNA content is expressed as the DNA index. The DNA
photophobia, or pain. A painless, enlarged scrotum may be a index, or ploidy, is a ratio of the amount of fluorescence in a
sign of testicular involvement or hydrocele. Overt testicular normal diploid cell to the fluorescence in the bone marrow
leukemia is rare at diagnosis, occurring in about 2% of blast. Among the different ploidy groups, only hyperdiploidy
male patients. Typically, testicular leukemia is diagnosed in (more than 50 chromosomes per cell) and hypodiploidy
infants or adolescents with T-cell ALL who present with a (less than 44 chromosomes per cell) have clinical relevance.
mediastinal mass and elevated WBC count. Hyperdiploidy mostly occurs between the ages of 1 year and
Abnormal WBC counts are reflective of the degree of bone 10 years and is associated with a lower WBC count and a
marrow involvement and the extent that the bone marrow has favorable prognosis. Hypodiploidy is associated with a poor
prognosis.
been replaced by leukemic lymphoblasts. The median WBC
Structural rearrangements or translocations are common
count at diagnosis is 12 103 cells/mm3. Hyperleukocytosis
in ALL. These chromosomal translocations are found only
(WBC greater than 100 103 cells/mm3) occurs in 15% of in the leukemic cells. Only the most common translocations
patients. Thrombocytopenia (platelets less than 50 103 are discussed in this chapter. TEL-AML1 fusion, or t(12;21),
cells/mm3) is typically present at diagnosis. Even with a low is the most common translocation associated with pediatric
platelet count, severe hemorrhage is uncommon. More than ALL. This fusion occurs in up to 25% of pediatric patients
75% of the patients present with anemia that is typically and is associated with a good prognosis. Another common
normochromic, normocytic, and associated with normal to translocation associated with pediatric ALL is E2A-
low reticulocyte counts. Patients who present with increased PBX1 fusion or t(1;19). This rearrangement occurs in 3%
WBC count or heavy tumor burden are at a higher risk of of white patients and 11% of African American patients.
developing tumor lysis syndrome on initiation of therapy. This translocation is commonly seen with precursor B-cell

Pediatric Leukemias 108 Pharmacotherapy Self-Assessment Program, 6th Edition

phenotype, pseudodiploidy, increased WBC count, and Risk stratification varies among institutions. The
CNS disease, and it is associated with an improved outcome National Cancer Institute has developed a risk classification
if intensive therapy is administered. MLL rearrangements, system that is used by most institutions that treat pediatric
including t(4;11), are typically associated with a poor leukemias. According to the National Cancer Institute,
outcome. The t(4;11) is common in infant ALL and is patients with precursor B-cell ALL are initially assigned to
associated with an increased WBC count and CNS leukemia. a standard-risk or high-risk group based on age and initial
BCR-ABL fusion or t(9;22) occurs in less than 5% of ALL WBC count (age 19.99 years and WBC count less than 50
cases and has a dismal prognosis. It is positively associated 103 cells/mm3 are considered standard risk). All children with
with age and elevated WBC count. T-cell phenotype are considered high risk. Early treatment
response (assessed by day 7 or day 14 marrow morphology
Prognostic Factors and end induction MRD assessment) and cytogenetics are
Patients are assigned to various treatment groups based subsequently used to modify initial classification.
on prognostic factors that can be predicted at diagnosis. Patients with standard-risk ALL and rapid morphologic
Various clinical and laboratory features have prognostic response (day 14 marrow with less than 5% blasts, MRD
significance. less than 0.1%, and day 29 marrow with less than 5% blasts)
For patients with precursor B-cell ALL, initial WBC are assigned to one of two groups based on cytogenetics.
count is predictive of outcome. Patients who present with a Patients with t(12;21) or trisomies of chromosomes 4, 10,
higher WBC count have a worse outcome. Although there is and 17 are considered standard risk low; patients presenting
no definitive WBC count, a presenting WBC count greater without these cytogenetic abnormalities are considered
than 50 103 cells/mm3 correlates with a poorer outcome. standard risk average. Patients with standard-risk ALL
Infants and patients with T-cell leukemia often present with and either slow morphologic response (day 7 or day 14
increased WBC count. marrow with less than 5% blasts or MRD greater than 0.1%
Age, associated with precursor B-cell ALL, is predictive on day 29) are assigned to a standard-risk high group and
of outcome. Patients younger than 1 year or older than 10 receive more intensive consolidation treatment. Patients
years have a worse prognosis. Adolescents often present with high-risk precursor B-cell ALL are divided into rapid
with other high-risk features, including increased WBC responder and slow responder groups. Patients are classified
count, T-cell leukemia, and extramedullary disease. Infants as very high risk if they have any of the following features
also have a very poor prognosis. In addition to presenting (regardless of initial risk group): t(9;22); hypodiploidy; MLL
translocation with a slow early morphologic response; day
with an increased WBC count and extramedullary disease,
29 marrow with greater than 5% blasts or day 29 and day 43
including CNS leukemia, up to 60% of infants also have
MRD greater than 1%.
t(4;11) translocation. In most studies, girls typically have a
better prognosis than boys. This may be because boys can
Treatment
have a testicular relapse; however, it is most likely associated
Therapy has been influenced by the realization that ALL
with the frequency of diagnosis of T-cell leukemia in boys is a heterogeneous group of disorders and the identification
and a lower DNA index. Commonly, patients with T-cell that patients should be classified based on risk group.
leukemia have fared worse compared with those with Combination chemotherapy is the primary treatment
precursor B-cell leukemia. However, with the use of more modality used. The goal of therapy for pediatric ALL is
intensive treatment, long-term survival is now 70% or cure. Table 1-1 contains a list of chemotherapy agents used
better. in the treatment of ALL and AML.
The prognostic value of race is a controversial topic.
Older studies have shown poorer outcomes associated with Remission Induction
African American race, but studies from the 1980s and The goal of initial therapy is to induce remission
early 1990s showed equivalent outcomes when patients by the eradication of 99% of the initial leukemic cell
were stratified for risk group at diagnosis. Historically, the burden. This phase of treatment usually uses three or four
difference in outcomes based on race has been attributed agents: (1) vincristine, (2) glucocorticoid (prednisone or
to socioeconomic factors. In addition, differences in the dexamethasone), plus either (3) asparaginase or (4) an
pharmacogenetic profile of patients from various ethnic anthracycline, or both. Prednisone has typically been the
backgrounds may play a significant role in outcome. glucocorticoid of choice. However, studies have shown
Although the above factors are important in determining a that dexamethasone may be a more potent cytotoxic agent
patients risk group, the most important prognostic indicator and have better CNS penetration. For this reason, some
is initial response to therapy. Patients who do not achieve cooperative groups have switched to this glucocorticoid.
remission within 46 weeks of induction therapy have a Dexamethasone may be associated with more acute
higher rate of relapse and shortened survival. The response infections and long-term neurologic sequelae. Patients
to therapy is based on both leukemic cell genetics and treated with glucocorticoids are also at risk of osteonecrosis
host pharmacogenetics. Minimal residual disease (MRD) or avascular necrosis (10% to 20% incidence in children
measurement can assess a level of sensitivity and specificity with ALL older than 10 years). Several anthracyclines have
not obtained by morphologic examination. Patients who been used during remission induction treatment. No one
achieve a remission with less than 10 4 cells (0.01%) at the anthracycline has superior efficacy.
completion of 6 weeks remission induction therapy have There are various formulations of asparaginase:
a higher rate of survival than those who have measurable asparaginase (derived from Escherichia coli); pegaspargase
disease at this time. (E. coli asparaginase bound to polyethylene glycol, also

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Table 1-1. Antineoplastic Agents Used in Pediatric ALL and AML
Name Therapeutic Category Major Adverse Effects
Asparaginase Enzyme antineoplastic Pancreatitis, thrombosis, hyperglycemia, hypersensitivity
reactions
Cyclophosphamide Alkylating agent Hemorrhagic cystitis, SIADH, hepatotoxicity, sterility
Cytarabine Pyrimidine antimetabolite Chemical conjunctivitis, mucositis, neurotoxicity
Daunorubicin, doxorubicin Anthracycline Congestive heart failure; cardiotoxicity; mucositis; neutropenia;
radiation recall; discoloration of saliva, sweat, urine, and
tears; vesicant
Dexamethasone, prednisone Corticosteroid Hyperglycemia, avascular necrosis, osteopenia, osteoporosis
Etoposide Epipodophyllotoxin Hypotension, secondary leukemia
Gemtuzumab ozogamicin CD33 antimetabolite Sinusoidal obstructive syndrome, neutropenia, hepatotoxicity,
mucositis, thromboembolic events
Mercaptopurine Purine antimetabolite Neutropenia, hepatotoxicity
Methotrexate Antifolate antimetabolite Mucositis, encephalopathy, hepatotoxicity, nausea, vomiting
Mitoxantrone Anthracenedione Cardiotoxicity, discoloration of skin and urine, interstitial
pneumonitis, vesicant
Vincristine Vinca alkaloid Peripheral neuropathy, constipation, paralytic ileus, jaw pain,
SIADH, vesicant
ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; SIADH = syndrome of inappropriate antidiuretic hormone.

called PEG-L asparaginase); and crisantaspase (asparaginase Delayed intensification or reinduction involves a
derived from Erwinia chrysanthemi, available in the repetition of the chemotherapy used during remission
United States on a compassionate use basis only). All three induction at 3 months after remission. Investigators found
preparations differ pharmacokinetically, and dosages are that one course of delayed intensification was most beneficial
different. Studies that have shown differences in efficacy for standard-risk leukemias. It was then shown that two
and toxicity used nonequivalent doses. courses of delayed intensification improved outcomes in
Patients who have the BCR-ABL translocation should high-risk patients.
be treated with a tyrosine kinase inhibitor (e.g., imatinib,
dasatinib) throughout therapy. Reintensification Therapy
Patients with high-risk ALL may receive reintensification
Intensification (Consolidation) Therapy therapy to maximize killing of leukemic cells before
Although oncologists now agree that this phase of therapy hematopoietic stem cell transplantation (HSCT). At St.
is essential to the treatment of ALL, there is no consensus Jude Childrens Research Hospital, the chemotherapy
regarding the best treatment. For example, St. Jude Childrens agents used include dexamethasone, cytarabine, etoposide,
Research Hospital uses high-dose methotrexate (MTX) asparaginase, and triple intrathecal therapy with
given every 2 weeks with continuous mercaptopurine. The methotrexate, hydrocortisone, and cytarabine.
dose of MTX is 5 g/m 2 given intravenously over 24 hours
for standard-risk and high-risk patients and 2.5 g/m 2 given CNS Therapy
intravenously over 24 hours for low-risk patients. Patients The need for CNS prophylaxis is based on the idea that
with T-cell leukemia accumulate fewer MTX polyglutamates the CNS can act as a sanctuary site for leukemic cells.
(active metabolites) than patients with B-lineage leukemia; Prophylaxis of the CNS can be achieved by various modalities,
patients with T-cell leukemia therefore require higher including radiation, intrathecal therapy, high-dose systemic
serum concentrations. The Childrens Oncology Group chemotherapy, or a combination of these. Cranial radiation
uses different regimens based on the risk classification. is the most effective CNS-directed therapy; however,
The regimens include combinations of vincristine, toxicity (including neurotoxicity, endocrinopathy, and brain
mercaptopurine, pegaspargase or cyclophosphamide, and tumors) offsets its efficacy. A study performed on survivors
cytarabine. 10 years after ALL diagnosis demonstrated that patients
who received cranial radiation were at a 21% higher risk of
Continuation (Maintenance) and Reinduction Therapy developing a second neoplasm than the general population
Children with ALL require long-term treatment to and had an increased unemployment rate. An earlier study
maintain remission. In general, treatment should continue resulted in a similar outcome for children who received
for at least 2.5 years. Many oncologists prefer to treat triple intrathecal therapy with MTX, hydrocortisone, and
boys for 3 years based on their higher risk of relapse. The cytarabine together with systemic chemotherapy compared
backbone of maintenance therapy is weekly MTX and daily with cranial radiation. The St. Jude Childrens Research
mercaptopurine. In addition, pulses of a glucocorticoid Hospital reported two studies that suggested early intensive
and vincristine have improved survival. Dexamethasone is triple intrathecal therapy decreased CNS relapse and
typically the glucocorticoid of choice during maintenance. increased event-free survival.

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Pharmacogenetics of Therapy Compared with other agents in this class (cladribine or
Mercaptopurine is anabolized by hypoxanthine fludarabine), clofarabine has the theoretical advantage of
phosphoribosyl transferase to thioinosine monophosphate working through two antiproliferative mechanisms as well
and eventually to triphosphates of 6-thioguanosine, called as having proapoptotic effects. Clofarabine may be more
6-thioguanine nucleotides. These metabolites interfere resistant to bacterial purine nucleoside phosphorylase, which
with normal DNA and RNA synthesis. Mercaptopurine may reduce the toxicity of the drug, especially the neurotoxic
is catabolized by thiopurine S-methyltransferase to effects. Clofarabine achieved an overall response rate of 32%
methylmercaptopurine. The activity of this enzyme (five complete remissions [CRs], two partial remissions)
undergoes a common genetic polymorphism. About in a Phase I study of 25 pediatric patients (median age 12
1 in 300 individuals is homozygous deficient for the years) with relapsed or refractory ALL. In this study, six
enzyme, 10% are heterozygous, and the remaining are dosage levels were used (11.2570 mg/m 2/day); the maximal
homozygous wild type. Patients heterozygous for thiopurine tolerated dose was 52 mg/m 2/day given intravenously for 5
S-methyltransferase mutations require a dosage reduction days. In an open-label study of 49 pediatric patients with
to avoid myelosuppression compared with patients who relapsed or refractory ALL, clofarabine induced a CR in
are homozygous wild type. However, patients who are 12.2% of patients. All of the patients in the study group had
homozygous deficient may require a 10-fold dosage reduction received at least two previous treatment regimens.
of mercaptopurine. Nelarabine, a prodrug of the deoxyguanosine analog
9-beta-d-arabinofuranosyl guanine (ara-G), is demethylated
Hematopoietic Stem Cell Transplantation by adenosine deaminase to ara-G, monophosphorylated
Hematopoietic stem cell transplantation has been reserved by deoxyguanosine kinase and deoxycytidine kinase, and
for individuals with Philadelphia chromosomepositive then converted to active 5-triphosphate. Accumulation
ALL, patients whose disease fails to achieve a remission at of the triphosphate form in leukemic blast cells permits
the end of 46 weeks of induction therapy, and patients with its incorporation into DNA, leading to inhibition of DNA
early hematologic relapse. Other high-risk patients (e.g., synthesis and cell death. Nelarabine is indicated for the
infants who have ALL with MLL rearrangements) have not treatment of patients with T-cell ALL whose disease has not
shown an improvement in outcomes with HSCT. responded to or has relapsed after treatment with at least
two chemotherapeutic regimens. In a study conducted by the
Treatment of Specific Risk Groups Childrens Oncology Group (COG P9673), 84 patients age
Infant ALL 21 years or younger with relapsed or refractory T-cell ALL
Infant ALL accounts for 2.5% to 5% of children with or T-cell lymphoblastic lymphoma received nelarabine 650
leukemia. The most common genetic abnormality is the mg/m2 intravenously over 1 hour/day for 5 days. Complete
MLL gene rearrangement of 11q23 seen in up to 80% of remission was achieved in 13% of the patients. The number
the infants. Very young age (younger than 6 months), high of patients who achieved CR combined with the number of
initial WBC count, any 11q23/MLL rearrangement, and a patients with partial hematologic recovery was 23%. The
poor early response to therapy predict a poor outcome in median time to CR was 3.4 weeks, and the duration of
this population. It is known that infant blasts in vitro have response ranged from 3.3 weeks to 9.3 weeks. The median
an increased sensitivity to cytarabine. overall survival was 13.1 weeks.

Down Syndrome
Children with Down syndrome have a 10- to 20-fold Acute Myeloid Leukemia
increased risk of developing leukemia (either ALL or AML).
Until the age of 5 years, the risk of developing AML is 4 Epidemiology and Risk Factors
times higher than for ALL; after the age of 5 years, ALL Acute myeloid leukemia is the second most common
is more common. Patients with Down syndrome are more acute pediatric leukemia. The annual incidence of AML in
likely to have a precursor B-cell phenotype. These patients the United States is 1.6 per million. Its rate of occurrence
are less likely to be hyperdiploid, have a T-cell phenotype, differs by race: Hispanics are more likely to have AML than
or have CNS leukemia at diagnosis. Patients with Down African American children, followed by white children.
syndrome and AML and ALL have an outcome similar to This disease is more common in patients 2 years or younger.
other patients, excluding patients with non Down syndrome Although AML accounts for only 15% to 20% of all acute
AML M7; however, they are more likely to have mucositis, leukemia cases, it is responsible for more than 30% of
myelosuppression, and infection. Patients with Down pediatric leukemia deaths. Recent advances in both therapy
syndrome are more sensitive to MTX and require a dosage for AML and supportive care measures have increased the
reduction. These patients also have a delayed clearance overall survival from this disease to 60%.
of MTX; this is most likely caused by the reduced folate Genetic and nongenetic risk factors have been identified
carrier gene on chromosome 21, which may lead to increased in the development of AML. Patients with genetic disorders
accumulation of MTX polyglutamates and therefore to such as Fanconi anemia, Li-Fraumeni syndrome, Down
increased toxicity. syndrome, neurofibromatosis type I, and severe congenital
neutropenia have a greater risk of developing AML.
Relapsed ALL Nongenetic risk factors include exposure to ionizing
Clofarabine is a deoxyadenosine nucleoside analog radiation, organic solvents (e.g., benzene), herbicides, and
approved for the treatment of patients with relapsed ALL or pesticides. Although the number of de novo AML cases
ALL refractory to at least two previous treatment regimens. has reached a plateau, the incidence of secondary AML has

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Table 1-2. French-American-British Classification of Acute Myeloid Leukemia
Subtype Common Name (pediatric incidence %) Characteristic Associated Translocations Prognosis
Findings and Rearrangements
M0 Acute myeloblastic leukemia with no maturation (< 3%) CD13, CD33, inv(3q26) and t(3;3)
CD117
M1 Acute myeloblastic leukemia with minimal maturation (20%) CD13, CD15,
CD33, CD34
M2 Acute myeloblastic leukemia with maturation (30%) t(8;21) and t(6;9) Good
M3 Acute promyelocytic leukemia (5% to 10%) Auer rods t(15;17), t(11;17), t(5,17) Good
M4 Acute myelomonocytic leukemia (25% to 30%) CD13, CD15, 11q23, inv(3q26) and t(3;3),
CD33 t(6;9)
M4Eo Acute myelomonocytic leukemia with abnormal eosinophils inv(16), t(16;16) Good
M5 Acute monocytic leukemia (15%) CD14, CD33 11q23, t(8;16) Poor
M6 Acute erythroleukemia (5%) Poor
M7 Acute megakaryoblastic leukemia (5% to 10%) CD13, CD33, t(1;22) Poor
CD41, CD61

increased in the past three decades because of exposure to chemotherapy, followed by a consolidation (postremission)
alkylating agents or topoisomerase II inhibitors. phase. The goal of induction is to achieve a complete molecular
and morphologic remission, whereas consolidation therapy
Clinical Presentation aims at maintaining this remission and preventing relapse.
The clinical presentation of AML is identical to that The role of maintenance therapy remains controversial; it
of ALL with a couple of exceptions. Chloromas (solid is not discussed here because most cooperative groups no
collections of leukemic cells outside the bone marrow) longer incorporate it in AML trials.
and leukemic infiltration of the gum are more common in
AML, whereas mediastinal masses are less common. In Induction Therapy
addition, the median WBC count at diagnosis for patients This phase of treatment usually consists of administering
with AML is 2050 103 cells/mm3 (70% of the patients a backbone of cytarabine and an anthracycline agent.
present with a WBC in this range). Moreover, the incidence This backbone, usually called a 7+3 regimen, consists of
of hyperuricemia and the development of tumor lysis giving cytarabine for 7 days and daunorubicin for 3 days.
syndrome is lower compared with ALL. Certain groups have incorporated etoposide or thioguanine
into their induction therapy. However, it is unclear if the
Diagnosis, Classification, and Prognostic Factors addition of these agents contributes to increased remission
The diagnostic work-up of AML is similar to that of rates or if they are attributed to the better use and dosing
ALL. The bone marrow aspirate and biopsy should contain of the cytarabine and anthracycline. The optimal dosage of
at least 20% of myeloid blasts for a diagnosis of AML. The
cytarabine has yet to be determined and varies significantly
classification of AML involves the use of morphologic,
among study groups. Dosages from as low as 100 mg/m 2/
histochemical, immunophenotyping, and cytogenetic
day to as high as 6000 mg/m2/day given intravenously have
characteristics. Currently, there is no classification method
been used, and no one regimen has shown a significant
for AML that is specific to pediatric patients. The French-
American-British classification (Table 1-2) has been widely improvement in the remission rate. Because cytarabine is
used, but its application to pediatric AML has several secreted through the tear ducts, it can irritate the cornea
shortcomings, leading to an inability to classify some and cause chemical conjunctivitis. To decrease this adverse
children. Another classification now gaining acceptance effect, all patients who receive high dosages of cytarabine
and being incorporated in most pediatric AML trials is that should receive corticosteroid or lubricating eye drops from
of the World Health Organization. the beginning of cytarabine therapy until 24 hours after the
Patient age and cytogenetics are among the most last dose of this agent.
important prognostic factors of newly diagnosed AML. The Several anthracyclines are used during the induction
older the patient, the poorer the prognosis; this is because phase, including daunorubicin (most commonly used),
these patients tend to have more genetic mutations leading to idarubicin, and mitoxantrone. Idarubicin is thought to
multidrug resistance, which in itself carries a poor prognosis. be taken up by the leukemic blasts faster and retained
In general, inversion(16) AML carries a favorable prognosis, in the cells for a longer period; it is speculated to be
whereas monosomy 5 or 7 carries a poor prognosis. Finally, less cardiotoxic. The active metabolite of idarubicin is
the faster remission is achieved, the better the prognosis. also longer acting than all the other anthracyclines and
has been reported to have antileukemic activity in the
Treatment cerebrospinal fluid. Mitoxantrone, however, is thought to
The goal of therapy for pediatric AML is cure. Most be more myelosuppressive, leading to increased risk of
AML treatment regimens consist of intensive induction infection. Studies comparing daunorubicin with idarubicin

Pediatric Leukemias 112 Pharmacotherapy Self-Assessment Program, 6th Edition

or mitoxantrone have demonstrated that they are equally analogs such as fludarabine or cladribine and, more recently,
efficacious in the treatment of AML. clofarabine. This class of drugs inhibits the activity of
ribonucleotide reductase while increasing the activity of
Consolidation (Intensification) Therapy deoxycytidine kinase, leading to a higher intracellular
Consolidation therapy is important to maintain disease concentration of cytarabine triphosphate (the active form
remission; however, there is no consensus about the of cytarabine). Studies with gemcitabine (another purine
antineoplastic agents that should be combined. The number analog) are now under way to determine its effectiveness
of courses and the intensity at which chemotherapy is for relapsed pediatric AML.
administered vary by institution. This phase of treatment Most AML blast cells express the CD33 antigen, which
consists of giving patients cytarabine together with a variety
makes them a target for the anti-CD33 monoclonal antibody
of agents that include, but are not limited to, anthracycline,
gemtuzumab ozogamicin. This drug is approved for the
cladribine, asparaginase, etoposide, mitoxantrone, and
gemtuzumab ozogamicin. At St. Jude Childrens Research treatment of adult patients older than 60 years with AML
Hospital, the consolidation regimen differs based on the in their first relapse if they are not candidates for HSCT.
diseases response to induction therapy and the patients Gemtuzumab ozogamicin is now being used in pediatric
cytogenetics. In some institutions, standard-risk and high- patients with AML who have refractory or relapsed disease;
risk patients who have a matched related donor usually at a dosage of 6 mg/m 2 intravenously, this drug achieves
undergo HSCT if they achieve remission after the first remission in about 30% of the children, thus allowing them to
course of consolidation. undergo HSCT. Patients receiving gemtuzumab ozogamicin
should be premedicated with methylprednisolone to decrease
CNS Prophylaxis infusion-related adverse effects such as fever, chills,
Cranial radiation to prevent CNS relapses is no longer hypotension, and dyspnea. Sinusoidal obstruction syndrome
routinely used in the management of patients with AML, (previously known as hepatic venoocclusive disease) is a
mostly because of the devastating neurologic sequelae rare but potentially life-threatening adverse effect of this
associated with radiating the brains of children. Triple drug. It is manifested by right upper quadrant pain, rapid
intrathecal therapy is used to prevent leukemic spread to weight gain, increased abdominal girth, hepatomegaly, and
the CNS. To date, all but one of the major AML treatment elevation of bilirubin and transaminase concentrations.
groups have shown CNS relapse rates of less than 5% with Patients who receive an HSCT after having received therapy
the use of intrathecal chemotherapy. with gemtuzumab ozogamicin have a higher incidence of
developing sinusoidal obstruction syndrome (up to 40% in
Antimicrobial Prophylaxis
some reports). To avoid this complication, there should be
The morbidity and mortality of patients with AML
during therapy remains an issue. Chemotherapy for AML at least 48 weeks between the last dose of gemtuzumab
is very dose-intensive, and patients remain pancytopenic ozogamicin and the HSCT.
for most of their therapy. In addition, the administration of Tipifarnib, an oral farnesyltransferase inhibitor, has
high-dose cytarabine has increased the odds of developing demonstrated promising results in the treatment of relapsed
oral mucositis and typhlitis, both of which disrupt the AML. Phase II studies of tipifarnib in elderly patients with
integrity of the wall of the gastrointestinal tract, which relapsed or refractory AML have shown a 54% response rate.
allows translocation of organisms into the bloodstream. The Clinical trials are under way to determine its effectiveness
most common and life-threatening bacterial infection these in the pediatric population. Another class of drugs that has
patients develop is Viridans streptococcus sepsis. High rates shown promising results is tyrosine kinase inhibitors (e.g.,
of fungal infections (mostly aspergillosis and candidiasis) sorafenib, sunitinib). These agents have mostly been used in
have also been reported. Some institutions place patients on adult patients with relapsed or refractory AML who have an
a third- or fourth-generation cephalosporin or quinolones FLT3 mutation. An advantage of these agents is that they are
and an antifungal agent to minimize these events and orally bioavailable and can be given at home.
improve survival. The use of prophylactic antibiotics in this
fashion is controversial because of the risk of developing Treatment-Related AML
resistance. Although the cure rates of most pediatric cancers have
increased during the past decades, so has the occurrence of
Relapsed AML treatment-related AML (also called secondary AML). Most
Although 80% to 90% of patients with AML achieve a
treatment-related AML cases are caused by the patients
CR during induction therapy, about 30% to 50% of these
exposure to DNA topoisomerase II inhibitors (including
patients suffer a relapse of their disease. Overall survival
after a first relapse of AML is less than 25%, with the most epipodophyllotoxins and anthracyclines) or alkylating
common site of relapse being the bone marrow. Patients agents. The prognosis for these patients is usually dismal,
whose disease relapses early have a worse prognosis than with survival rates varying between 10% and 20%. Treatment
those who relapse later because the former group tends options include chemotherapy, HSCT, targeted therapies
to be resistant to chemotherapy. Central nervous system (e.g., imatinib), and palliative care. The best strategy is
relapse accounts for 10% to 20% of all cases and is often prevention. Avoiding excessive use of agents known to
seen in patients who had CNS involvement on presentation. cause secondary leukemias can decrease the incidence of
Cytarabine and anthracyclines remain the mainstay drugs secondary AML; however, there is no clear information yet
used in relapsed disease. Other drugs include the purine about what is a safe maximal lifetime exposure.

Pharmacotherapy Self-Assessment Program, 6th Edition 113 Pediatric Leukemias

Long-Term Complications Gonadal Dysfunction
Oncologists should present the option of sperm and
After Leukemia Therapy oocyte preservation to all eligible patients once malignancy
is diagnosed. Patients who undergo bone marrow
transplantation, as well as patients with solid tumors who
Almost 80% of children with a diagnosis of a malignancy receive high doses of alkylating agents, experience varying
become long-term survivors, but almost half of them have degrees of gonadal dysfunction. Fertility of patients who
a moderately to severely decreased health status. Studies undergo treatment for low-risk or standard-risk leukemia
comparing cancer survivors with their siblings have shown therapy is usually preserved.
that survivors suffer from long-term complications of their The ovaries of girls are relatively resistant to
therapy, most commonly chronic cardiovascular, skeletal, chemotherapy-induced damage but are much more sensitive
and endocrine conditions. Survivors are also more likely to radiation therapy. Almost all girls who receive total body
to develop secondary malignancies, whether caused by irradiation during adolescence develop acute ovarian failure,
their inherited genetic condition or the therapy they receive whereas only 50% of those younger than 10 years suffer this
for the treatment of their primary malignancy. For a more complication. For patients who survive through puberty
comprehensive overview, the reader is referred to the and achieve normal ovarian function, the risk of developing
Childrens Oncology Group long-term follow-up guidelines early menopause (before age 40) is elevated. Options for
for survivors of childhood, adolescent, and young adult oocyte preservation in girls are limited compared with
sperm preservation in boys. Cryopreservation of unfertilized
cancers at www.survivorshipguidelines.org.
oocytes is an option, but it must be performed before the
start of radiation and chemotherapy.
Cardiac Toxicity Spermatogenesis is also affected by radiation and exposure
By limiting anthracyclines to a total cumulative lifetime to alkylating agents. Testicular radiation in patients with
dose of 450 mg/m 2 of doxorubicin (or its equivalent), the ALL always results in azoospermia. Exposure to moderate
occurrence of cardiac toxicity has been greatly decreased. or high doses of cyclophosphamide or ifosfamide causes
Cardiac complications occur primarily because of the oligospermia and azoospermia, whereas regimens using
use of anthracyclines. The long-term cardiac effects of both agents cause azoospermia in almost all patients. Sperm
anthracyclines are a major complication of childhood cryopreservation is very successful in patients who pursue
cancer therapy, and their consequences can greatly affect this option; however, because spermarche occurs around
the patients quality of life. age 13, sperm banking is not an option for young children.
The cardiotoxicity is thought to be caused by depressed Although sperm and oocyte banking provides patients the
cardiac contractility from loss of cardiac myocytes, resulting option of conceiving a child in the future, this method of
in left ventricular dysfunction and, subsequently, congestive fertility preservation is not considered by everyone because
heart failure. Patients with cardiovascular complications it is expensive.
can be divided in two categories: those with subclinical
Obesity
cardiotoxicity who are usually asymptomatic (thought
Obesity is more commonly reported in survivors of ALL
to occur in as much as 56% of patients having received
than AML and has been reported in as many as 57% of ALL
anthracyclines) and those with clinical cardiotoxicity who survivors. Recent studies suggest there might be an age
are symptomatic (with an incidence of 9.8% at 20 years association with the development of obesity: the younger
in patients who have received cumulative doses greater the age at diagnosis, the more likely the patient will become
than 300 mg/m2). Risk factors for the development of obese. To date, both sexes seem to be equally affected with
cardiotoxicity include age younger than 4 years at the time this endocrinopathy. Some researchers have suggested that
of administration of the anthracycline agent, female sex, and prolonged exposure to high doses of corticosteroids during
higher cumulative doses. Administration of doxorubicin at ALL therapy is responsible for pituitary dysfunction, causing
dosages greater than 45 mg/m 2/week has also been associated growth hormone deficiency and decreased sensitivity to
with an increased risk of the development of heart failure. leptin. One way to manage this complication is to treat
Contrary to previous assumptions, continuous infusion patients with growth hormone because it has lipolytic
of anthracyclines does not have a cardioprotective benefit properties.
compared with bolus administration. Patients who develop
congestive heart failure are usually treated with digoxin and Skeletal Abnormalities
should be managed by a cardiologist. High doses of corticosteroids (especially dexamethasone),
cranial radiation, and the use of MTX and cyclophosphamide
have all been associated with the occurrence of osteopenia
Endocrinopathies
and osteoporosis in pediatric survivors of leukemias. All
Thyroid Dysfunction patients should be vigilantly screened for any signs of bone
Hypothyroidism is a complication that occurs when demineralization to prevent and reduce the risk of fractures
patients receive head and neck radiation. It is thought that and other complications of osteoporosis. Avascular necrosis
there is a larger number of undiagnosed subclinical thyroid is a complication of prolonged exposure to high-dose
disorders than overt primary thyroidism cases. This number steroids; it is manifested by severe bone pain and has been
is expected to drop in the future because cranial radiation is reported to have a 3-year cumulative incidence of 9.3%. The
no longer routinely performed in patients with leukemia. incidence of avascular necrosis is higher in patients who

Pediatric Leukemias 114 Pharmacotherapy Self-Assessment Program, 6th Edition

are white, older than 10 years (14.2% vs. 0.9% for younger 2. Roden DM, Altman RB, Benowitz NL, Flockhart DA,
patients), and of the female sex, and it is directly related to Giacomini KM, Johnson JA, et al. Pharmacogenomics:
the duration of exposure to dexamethasone. In advanced challenges and opportunities. Ann Intern Med 2006;145:749
57.
cases, patients require joint replacement surgery.
Drug therapy has often been known to have an unpredictable
outcome. In addition to having a beneficial effect, the
Secondary Malignancies
effect of drug therapy can range from lack of efficacy to
The occurrence of secondary malignancies after toxicity, sometimes serious. Some of the variability of effect
leukemia is estimated to be lower than solid tumors. can be explained with or through pharmacogenetics and
Central nervous system and thyroid cancers are the most pharmacogenomics. The authors of this article describe
commonly observed malignancies in long-term survivors of various mechanisms for the variable responses of drugs
acute leukemias. The most common types of brain tumors based on pharmacokinetics and pharmacodynamics. The
reported are high-grade gliomas, followed by peripheral authors next discuss the challenges that must be overcome
neuroectodermal tumors, ependymomas, and meningiomas. to apply the information obtained with genetic testing.
Only if the challenges that pharmacogenetics presents are
High-grade gliomas have a dismal prognosis, whereas overcome can improvements be made in drug development
meningiomas are curable. Secondary AML after ALL and individualized therapy be accomplished.
therapy is reported mostly in patients who have received
etoposide or teniposide (average onset is 33 months). The 3. Evans WE. Pharmacogenetics of thiopurine
incidence of this secondary malignancy is likely to decrease S-methyltransferase and thiopurine therapy. Ther Drug
because this class of drugs is no longer used in the initial Monit 2004;26:18691.
management of patients with ALL. The use of intermittent The efficacy and toxicity of drugs vary widely among
granulocyte colony-stimulating factors is also implicated patients. Pharmacogenetics is an emerging field of study
in the occurrence of secondary AML. Independent risk looking at genetic differences that may predict efficacy
factors for the development of secondary malignancies as well as toxicity in individuals receiving certain drugs.
include previous craniospinal radiation, relapsed disease, The genetic polymorphism associated with thiopurine
S-methyltransferase is one of the best-described examples of
and female sex. pharmacogenetics. Most people (90%) inherit high activity;
10% have intermediate activity because of heterozygosity;

The Role of the Pharmacist and 0.3% have low or no detectable enzyme activity because
they inherit two nonfunctional alleles. Knowing the patients
thiopurine S-methyltransferase activity before initiating
Clinical pharmacists play an integral role in managing mercaptopurine therapy can reduce the incidence of toxicity,
pediatric patients with malignancies. The pharmacist because patients who inherit two nonfunctional alleles
must know all the different protocols that patients receive require significant decreases in mercaptopurine (to 5% to
10% of standard dosages) to prevent toxicity.
and how to manage adverse effects of therapy to provide
patients with a better quality of life. Supportive care issues
4. Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll
in treating patients with malignancies are often left to AJ, Carroll WL, et al. Clinical significance of minimal
the pharmacist to manage, so it is important to know the residual disease in childhood acute lymphoblastic leukemia
short- and long-term complications of anticancer agents. and its relationship to other prognostic factors: a Childrens
Monitoring adherence to oral chemotherapy drugs is also Oncology Group study. Blood 2008;111:547785.
important to prevent resistance and relapse. With the advent It was previously determined that MRD is a predictor of
of pharmacogenetics, the role of the pharmacist in drug relapse in patients with ALL. This prognostic factor had
dosing will become even more critical. not been studied in relation to other variables that predict
outcome. The Childrens Oncology Group studied 2143
patients with precursor B-cell ALL and assessed MRD in
Annotated Bibliography the peripheral blood at day 8 of induction and in the bone
marrow at the end of induction and the end of consolidation.
Across all risk groups, patients who were MRD positive had
1. Pui CH, Evans WE. Treatment of acute lymphoblastic a lower event-free survival. Patients who still had detectable
leukemia. N Engl J Med 2006;354:16678. disease noted by the presence of MRD in the marrow at the
The authors of this article review in depth the treatment end of consolidation had a very poor response. The authors
of ALL, the most common malignancy affecting pediatric concluded that more intensive therapy might be necessary
patients. Factors predicting clinical outcome are discussed, for patients with positive MRD at the end of induction. This
including clinical features of the patient, genetics of more intensive therapy will need to increase survival, without
the leukemic cells, and host pharmacodynamics and increasing toxicity.
pharmacogenetic features. Included in the discussion are
risk factors that may predispose the patient to therapy-related 5. Larson RA. Three new drugs for acute lymphoblastic
adverse events. Current treatment strategies are discussed, leukemia: nelarabine, clofarabine and forodesine. Semin
focusing on the different courses of therapy and the goals Oncol 2007;34(6 Suppl 5):S13S20.
of each course. With a cure rate approaching 90%, future Current treatment strategies for pediatric ALL have cure
directions are discussed that focus on novel agents that may rates approaching 90%. New therapies should be developed
further improve outcomes. Studies are needed with these to continue to improve outcomes and decrease the toxicity
newer agents to improve the cure rate without increasing associated with current therapies. Three purine nucleoside
toxicity. analogs (i.e., nelarabine, clofarabine, and forodesine) have

Pharmacotherapy Self-Assessment Program, 6th Edition 115 Pediatric Leukemias

 been developed that show activity in patients with relapsed with a better quality of life during treatment. Finally, the use
or refractory ALL. Nelarabine has shown activity against of these agents is limited to patients with AML who have
T-cell leukemia. Clofarabine is effective for the treatment FLT3 mutations, so patients will have to be checked for this
of relapsed ALL and may be effective for the treatment of mutation.
AML. Forodesine is the newest agent with activity against
B- and T-cell leukemias. More studies are needed to further 9. Harousseau JL, Lancet JE, Reiffers J, Lowenberg B, Thomas X,
assess the activity and toxicity of these agents when used Huguet F, et al. A phase 2 study of the oral farnesyltransferase
with traditional treatment or as single-agent therapy as part inhibitor tipifarnib in patients with refractory or relapsed
of salvage regimens. acute myeloid leukemia. Blood 2007;109:51516.
The authors of this article conducted an open-label Phase II
6. Rocha JC, Cheng C, Liu W, Kishi S, Das S, Cook EH, et trial to assess the effectiveness of tipifarnib in adult patients
al. Pharmacogenetics of outcome in children with acute with refractory or relapsed AML. Tipifarnib inhibits the
lymphoblastic leukemia. Blood 2005;105:47528. ras proteinsignaling pathway leading to inhibition of cell
The outcomes of 246 children with ALL were studied to proliferation. Some 252 patients received tipifarnib at a
identify relationships of 16 genetic polymorphisms that affect dose of 600 mg orally twice daily for 21 days of a 28-day
the pharmacodynamics of antileukemic agents. If high-risk cycle. Complete remission was achieved in 4% of patients,
patients had the glutathione S-transferase nonnull genotype, and disease stabilization occurred in 5% of patients.
they had a greater risk of hematologic relapse (p=0.03). Pharmacokinetic analyses were performed in 17 patients
This outcome was increased by the thymidylate synthase after administration of tipifarnib. An advantage of this
3/3 genotype (p=0.03). For low-risk patients, no genotype study is that it was conducted in North America, Europe, and
was predictive of relapse. The vitamin D receptor start site Asia, which eliminates patient selection bias because many
(p=0.02) and the intron 8 genotype (p=0.04) were predictive of people from different ethnic backgrounds were treated with
CNS relapse in the high-risk group. For low-risk patients, the the same regimen. An advantage of tipifarnib is that it is an
thymidylate synthase 3/3 genotype (p=0.04) was predictive of oral drug, and because the prognosis of patients with relapsed
CNS relapse. The authors conclude that these genotypes are and refractory AML is not good, it provides them with a
predictive, based on the specific treatment patients received, better quality of life than if they were receiving intravenous
and that additional studies of host genetic features should be chemotherapy. There are no published trials about the use of
undertaken. Pharmacogenetic testing should be undertaken tipifarnib in pediatric patients.
to maximize therapy while minimizing toxicity.
10. Arceci RJ, Sande J, Lange B, Shannon K, Franklin J,
7. Oeffinger KC, Mertens AC, Sklar CA, Kawashima T, Hudson Hutchinson R, et al. Safety and efficacy of gemtuzumab
MM, Meadows AT, et al. Chronic health conditions in adult ozogamicin in pediatric patients with advanced CD33+ acute
survivors of childhood cancer. N Engl J Med 2006;355:1572 myeloid leukemia. Blood 2005;106:11838.
82. This is the first reported study to use gemtuzumab
The Childhood Cancer Survivor Study Group conducted ozogamicin in pediatric patients with AML. The authors
this study to estimate the overall incidence of chronic health report their experience with 29 patients in this Phase I
conditions faced by long-term survivors of childhood cancer. open-label study. Gemtuzumab ozogamicin was given at
It retrospectively compared patients with their siblings, a starting dose of 6 mg/m 2 intravenously every 14 days for
which is a very good way of comparing two groups because two doses with a planned dose escalation to 9 mg/m 2. Eight
the cohorts are matched for ethnicity and socioeconomic patients (28%) achieved CR (four of them had CR except for
status (among other factors). Compared with their siblings, full recovery of their platelets). The authors concluded that
survivors have an 8.2-fold (95% confidence interval [CI], the 6-mg/m 2 dosage was tolerated in most patients and that
6.99.7) greater chance of developing a severe to life- additional pediatric studies should use this dose as their
threatening and disabling condition. For example, the starting point. This was a pivotal trial because it served as
relative risk of a childhood cancer survivor requiring major a stepping-stone from which many other groups have used
joint replacement surgery was 54 times higher (95% CI, 7.6 gemtuzumab ozogamicin in combination with standard AML
386.3). An advantage of this study is that it is one of the largest therapies to treat both patients with de novo and relapsed or
observational trials to be published about long-term follow- refractory AML.
up survivors of childhood malignancies (10,397 survivors and
3034 siblings). This article shows that survivors of childhood 11. Hijiya N, Hudson MM, Lensing S, Zacher M, Onciu M,
malignancies must be monitored by a physician very closely Behm F, et al. Cumulative incidence of secondary neoplasms
because they are more prone to suffer from chronic health as a first event after childhood acute lymphoblastic leukemia.
conditions. JAMA 2007;297:120715.
This article retrospectively assessed the incidence of
8. Illmer T, Ehninger G. FLT3 kinase inhibitors in the secondary neoplasms in 2169 patients with ALL treated at
management of acute myeloid leukemia. Clin Lymphoma St. Jude Childrens Research Hospital. Some 123 patients
Myeloma 2007;8(Suppl 1):S24S34. developed a second malignancy after they went into
This article provides a good overview of the FLT3 kinase remission, with AML being reported in 37 cases (30%) and
inhibitors currently undergoing evaluation as treatment CNS malignancies (mainly meningiomas) occurring in 38
options for patients with AML. Although this article cases (31%). Compared with the general population, patients
mainly discusses the successful use of these agents in adult who had ALL were at a 13.5% (95% CI, 10.916.8) overall
patients with AML, most of these agents are currently increased risk of developing a second malignancy. Those who
being investigated for use in pediatric patients with AML. received craniospinal or cranial radiation had a 45.8% (95%
The advantage of these FLT3 kinase inhibitors (sunitinib, CI, 2664.2) increase in overall risk of developing a CNS
sorafenib, and lestaurtinib [CEP701]) is that they are orally malignancy. The authors of this article reviewed the medical
bioavailable and thus have the potential of providing patients records of a large number of long-term survivors of ALL for

Pediatric Leukemias 116 Pharmacotherapy Self-Assessment Program, 6th Edition

 an extended period and give the reader good insight into the
different neoplasms that can develop. One limitation of this
study is that patients were followed up for 10 years after their
diagnosis or until they reached their 18th birthday (whichever
came later), so those who developed malignancies after that
period were not accounted for.

12. Lange BJ, Smith FO, Feusner J, Barnard DR, Dinndorf P,

Feig S, et al. Outcomes in CCG-2961, a Childrens Oncology
Group phase 3 trial for untreated pediatric acute myeloid
leukemia (AML): a report from the Childrens Oncology
Group. Blood 2008;111:104453.
This article relates the results of the latest AML trial
performed by the Childrens Oncology Group. The
anthracycline agent used in this trial for both induction and
consolidation was mostly idarubicin. Patients were also
randomized to receive fludarabine during consolidation
therapy, and some of them received aldesleukin. The goal of
this study was to assess the survival and response rates of
patients with AML treated with fludarabine and idarubicin.
Some 901 patients with de novo AML were enrolled in the
study; overall survival was 52% 4%, whereas event-free
survival was 42% 3%, which is similar to results of other
studies performed in patients with AML by other cooperative
groups. The authors conclude that aldesleukin is not an
effective agent against AML and that additional studies of
this agent in this disease are not warranted. The authors
also compared the idarubicin-treated group with a historical
cohort of patients treated with daunorubicin; both cohorts
achieved similar remission rates.

13. Long-term follow-up guidelines for survivors of childhood,

adolescent, and young adult cancers. Available at www.
survivorshipguidelines.org. Accessed February 24, 2009.
This Web site, set up by the Childrens Oncology Group,
is an excellent resource for anyone interested in setting
up a program to monitor long-term survivors of pediatric
malignancies. It provides information on how often patients
should be followed up depending on the treatment modality
they received. It also provides a detailed summary of the
specific health conditions that survivors are at risk of
developing based on the drugs they received. This Web site is
useful for all health care professionals wanting to learn about
the types and severity of chronic health conditions cancer
survivors face.

Pharmacotherapy Self-Assessment Program, 6th Edition 117 Pediatric Leukemias

Pediatric Leukemias 118 Pharmacotherapy Self-Assessment Program, 6th Edition
Self-Assessment Questions
Questions 13 refer to the following case. A. Continue the same mercaptopurine dose.
Z.P. is a 2-year-old white girl given a diagnosis of precursor B. Increase the mercaptopurine.
B-cell acute lymphocytic leukemia (ALL). Her original C. Decrease the mercaptopurine.
complete blood cell count revealed a white blood cell (WBC) D. Discontinue the mercaptopurine.
count of 28 103 cells/mm3; hemoglobin 6.5 mg/dL; and
platelet count 55,000 cells/mm3. All her blood chemistry 6. M.P. presents to the clinic with redness and pain at his
test results were within normal limits. Z.P.s initial lumbar injection site the morning after receiving his third dose
puncture was negative; her DNA index was 1.22. of asparaginase. His thigh on the side of the injection
is swollen. Which one of the following is the best
1. In addition to prednisone and intrathecal therapy, which adjustment to M.P.s therapy?
one of the following is the best therapy to initiate for A. Continue asparaginase but decrease the dose.
Z.P.? B. Change to pegaspargase.
A. Cyclophosphamide, doxorubicin, C. Continue asparaginase but premedicate M.P. next
and mercaptopurine. time.
B. Vincristine, daunorubicin, and asparaginase. D. Give no additional asparaginase.
C. Cytarabine, daunorubicin, and asparaginase.
D. Cytarabine, cyclophosphamide, 7. C.D. is a 1-year-old white girl with Down syndrome
and mercaptopurine. and a diagnosis of ALL. The patient is due for high-
dose methotrexate (MTX). Which one of the following
2. Based on the toxicity profile of chemotherapeutic agents changes in drug dosage is best for C.D.?
commonly used in induction, which baseline studies are A. No dosage modification is necessary.
best performed before the initiation of therapy in Z.P.? B. The dose should not be higher than 500 mg/m 2.
A. Chest radiograph and computed tomography of the C. No dosage modification is needed as long as
chest. aggressive leucovorin rescue is administered.
B. 24-hour urine collection and liver enzymes. D. C.D. should not receive high-dose MTX.
C. Echocardiogram, direct bilirubin, and liver
enzymes. 8. Z.C. is a 7-year-old boy with relapsed ALL. He
D. Thyroid studies and echocardiography. originally relapsed 18 months after therapy was
discontinued. After receiving front-line therapy for
3. At the end of induction, Z.P. has less than 0.01% minimal relapsed ALL, Z.C. still has persistent disease. The
residual disease (MRD) in her bone marrow. Which one decision is made to treat Z.C. with a combination of
of the following best describes how this will affect her clofarabine, cyclophosphamide, and etoposide. Which
risk classification? one of the following adverse events should be lessened
A. Does not change her risk classification. by clofarabine?
B. Changes her to standard risk. A. Nephrotoxicity.
C. Changes her to high risk. B. Hepatotoxicity.
D. Changes her to very high risk. C. Pulmonary toxicity.
D. Neurotoxicity.
Questions 4 and 5 refer to the following case.
T.V., a 6-year-old white boy receiving maintenance therapy Questions 9 and 10 refer to the following case.
for ALL, presents to the clinic with persistently low platelet, A.Y. is a 20-month-old girl with acute myeloid leukemia
WBC, and red blood cell counts. The patient is neutropenic (AML). She has received two courses of induction therapy
without lymphoblasts on his blood smear. with cytarabine, etoposide, and daunorubicin. She is now
undergoing disease evaluation, and her MRD is 6%. She has
4. Which one of the following genetic tests is best to tolerated her previous therapy except for some mild liver
perform on T.V.? dysfunction.
A. Thymidylate synthase.
B. Thiopurine S-methyltransferase. 9. Which one of the following options is the best treatment
C. Glutathione S-transferase. for A.Y. at this time?
D. Dihydrofolate reductase. A. Gemtuzumab ozogamicin.
B. Hematopoietic stem cell transplantation (HSCT).
5. T.V.s family is administering mercaptopurine correctly. C. Cytarabine, etoposide, and daunorubicin.
The genetic test used to determine mercaptopurine D. Tipifarnib.
metabolism confirms that T.V. is heterozygous for that
polymorphism. Which one of the following is the best
recommendation for T.V.?

Pharmacotherapy Self-Assessment Program, 6th Edition 119 Pediatric Leukemias

10. Assuming A.Y. does not require HSCT, which of the following drugs are most likely to have contributed to
following long-term complications is A.Y. at greatest his secondary AML?
risk of developing once she reaches adulthood? A. Daunorubicin and MTX.
A. Congestive heart failure, second malignant B. Cyclophosphamide and etoposide.
neoplasm, and hypothyroidism. C. Vincristine and cyclophosphamide.
B. Renal failure, hearing loss, and cardiac D. Asparaginase and MTX.
arrhythmias.
C. Second malignant neoplasm, congestive heart 16. G.H. is a 16-year-old boy receiving induction therapy
failure, and cardiac arrhythmias. for AML. His induction regimen consists of cytarabine,
D. Hearing loss, avascular necrosis, and ovarian daunorubicin, and etoposide. Which one of the following
failure. drugs is best while G.H. is receiving his induction
therapy?
Questions 11 and 12 refer to the following case. A. Dexamethasone eye drops with cytarabine.
N.F., a 7-year-old patient with newly diagnosed AML, B. Dexrazoxane to be given before daunorubicin.
is currently undergoing induction therapy. This patient C. A fluid bolus to be given before etoposide.
is expected to be immunosuppressed for the duration of D. Digoxin to be given before daunorubicin.
induction therapy.
17. A.P., a 3-year-old boy, recently received a diagnosis of
11. Which one of the following antimicrobial regimens is AML. His cytogenetics show that he has inv(16) AML.
best for N.F.? Based on the current classifications of this disease,
A. Meropenem, vancomycin, and caspofungin. which one of the following AML subtypes is A.P. most
B. Voriconazole, oxacillin, and palivizumab. likely to have and what is his prognosis?
C. Voriconazole, vancomycin, and ciprofloxacin. A. AML M1 with a poor prognosis.
D. Amphotericin B, metronidazole, and levofloxacin. B. AML M5 with a good prognosis.
C. AML M2 with a very poor prognosis.
12. Which one of the following pathogens would most D. AML M4Eo with a good prognosis.
likely cause infections in N.F.s case?
A. Gram-negative bacilli. 18. B.T. is a 17-year-old male patient who was treated for
B. A fungal organism. ALL at the age of 3 years. His treatment consisted
C. Gram-positive cocci. of conventional chemotherapy together with cranial
D. Parasites. radiation for CNS prophylaxis. Which one of the
following long-term complications is B.T. most likely
Questions 13 and 14 refer to the following case. to have because of his cranial radiation?
A.L. is a 2-year-old white girl given a diagnosis of AML A. Hypothyroidism and secondary brain tumor.
(M4). Her original complete blood count was WBC count B. Hypothyroidism and congestive heart failure.
20 103 cells/mm3, hemoglobin 5 mg/dL, and platelets 7 C. Azoospermia and obesity.
103 cells/mm3. Cytogenetics show that she has the inv(16) D. Secondary brain tumors and osteoporosis.
translocation.
19. S.R. is a 6-year-old boy who now has relapsed refractory
13. Which one of the following combinations of findings and AML. He has already completed four different treatment
symptoms did A.L. most likely have on presentation? regimens. His parents still want him to receive curative
A. Mediastinal mass, gum bleeding, and pallor. chemotherapy, so the oncologist is going to enroll him
B. Fever, splenomegaly, and hyperuricemia. in an investigational study. Which one of the following
C. Chloroma, gum bleeding, and pallor. classes of chemotherapy agents is S.R. most likely to
D. Chloroma, fatigue, and bone marrow blasts less benefit from?
than 20%. A. DNA topoisomerase I inhibitor.
B. Nitrogen mustard alkylating agent.
14. Which one of the following is the best therapy for A.L. C. Farnesyltransferase inhibitor.
after induction therapy? D. Tyrosine kinase inhibitor.
A. HSCT and maintenance therapy.
B. Consolidation therapy and radiation therapy. 20. E.T. is a 4-year-old white girl who presents with a normal
C. Maintenance therapy and radiation therapy. WBC count, decreased hemoglobin, and decreased
D. Central nervous system (CNS) prophylaxis and platelet count. She is given a diagnosis of precursor
consolidation therapy. B-cell ALL. Standard induction therapy is initiated
while awaiting cytogenetics. Based on E.T.s age and
15. A 19-year-old patient who is now 6 years off therapy for diagnosis, which one of the following translocations is
ALL presents with low platelet and red blood cell counts she most likely to have?
and fatigue. On further examination, he is found to have A. TEL-AML1.
secondary AML. His therapy for ALL included MTX, B. MLL gene rearrangement.
cyclophosphamide, daunorubicin, mercaptopurine, C. E2A-PBX1.
etoposide, vincristine, and asparaginase. Which of the D. BCR-ABL.

Pediatric Leukemias 120 Pharmacotherapy Self-Assessment Program, 6th Edition