C H A P T E R 64
CLINICAL MANIFESTATIONS AND TREATMENT OF ACUTE
LYMPHOBLASTIC LEUKEMIA IN CHILDREN
Serial risk-directed clinical trials have optimized the combination of
chemotherapeutic agents and, along with advances in supportive care,
have led to current cure rates of childhood acute lymphoblastic leuke-
mia (ALL) exceeding 85% compared with long-term survival less than
10% in the 1960s.1 However, because ALL is the most common
cancer in children, relapsed ALL remains the leading cause of death
from a disease in this age group. Over the past decade, minimal
residual disease (MRD) has become a major determinant in risk strati-
fication, cranial irradiation has been successfully omitted from some
frontline protocols, and the tyrosine kinase inhibitor (TKI) imatinib
has revolutionized the treatment of patients with BCR-ABL1 rear-
rangement. Our understanding of the immunology and molecular
pathways involved in ALL is improving at a rapid pace, and several
targeted therapies are showing promise in early clinical trials. The
challenge is to successfully incorporate targeted therapy into personal-
ized ALL regimens aiming at improving cure rates and reducing
toxicity.2
EPIDEMIOLOGY
Acute lymphoblastic leukemia accounts for approximately 75% of all
cases of childhood leukemia and is the most common pediatric cancer
in developed countries, representing 23% of cancer diagnoses among
children younger than 15 years of age. About 2400 children and
adolescents are diagnosed with ALL each year in the United States,
an annual rate of 30 to 40 per million. The peak incidence of ALL
occurs around 4 years of age. This young age peak historically has
appeared at different times in different countries and has been associ-
ated with major periods of industrialization, suggesting a causative
role for environmental carcinogens. ALL occurs more frequently in
boys than in girls at all ages.3
Acquired and inherited genetic factors play an essential role in ALL
as supported by the demonstration of genetic abnormalities in leuke-
mic cells of children with ALL as well as by clinical observations.
Children with the constitutional chromosomal abnormality trisomy
21 (Down syndrome) are up to 15 times more likely to develop leu-
kemia than children without Down syndrome. Genetic instability and
DNA repair disorders (e.g., Bloom syndrome, ataxia telangiectasia,
Fanconi anemia) are also associated with an increased risk of develop-
ing ALL.4 Among identical twins, if one is diagnosed with ALL during
the first year of life, the risk that the other twin will develop ALL is
more than 70%, approaching 100% in twins with a single monocho-
rionic placenta. Highest in infancy, this risk diminishes with increas-
ing age at diagnosis in the first twin to about one in 10 in older
children. If the first twin develops ALL by 5 to 7 years of age, the risk
to the second twin is at least twice that in the general population,
regardless of zygosity.5 After the age of 7 years, the risk to the unaf-
fected twin is similar to that for persons in the general population. The
extraordinarily high concordance rate in monozygotic infants twins
compared with dizygotic infant twins or nontwinned siblings results
from the metastasis of leukemic cells from one twin to the other
through shared placental circulation. The majority of infants with
ALL have a chromosome translocation that results in the fusion of the
Sima Jeha and Ching-Hon Pui
MLL gene at 11q23 with a variety of partner genes but principally
AF4. Identical twin infant pairs with concordant ALL share the same
acquired MLL gene rearrangements.
The most common chromosome translocation in childhood ALL,
t(12;21), results in ETV6(TEL)-RUNX1(AML1) fusion. In contrast
to MLL-rearranged ALL, ETV6-RUNX1 leukemias present after
infancy and have a concordance rate of only 10% in identical twins.
ETV6-RUNX1 fusion can be found in as many as 1% of cord blood
samples of normal newborn babies, a frequency 100 times higher
than the prevalence of this subtype of leukemia, suggesting that
additional postnatal mutations are necessary for malignant transfor-
mation. Analysis of Guthrie cards of 2- to 6-year old children with
ALL showed that most did have detectable, clonotypic ETV6-RUNX1
sequences at birth. In addition, identical ETV6 and RUNX1 break-
points were present in each of twin pairs with a very asynchronous
diagnosis, supporting the requirement for one or more additional
postnatal events after in utero initiation. This interpretation suggests
that ETV6-RUNX1 initiates leukemogenesis but is insufficient for
overt disease, and further genetic alterations are required. ETV6 dele-
tions on chromosome 12p, the most frequent additional genetic
abnormalities described in cases of ALL with ETV6-RUNX1, appear
to be subclonal in fluorescence in situ hybridization (FISH) analysis
of leukemic cells from nontwin patients. These findings indicate that
ETV6 deletion is a secondary or later event in leukemogenesis and
suggest that leukemia might be initiated in utero but requires an
essential second postnatal event (two hits).6
Several genetic, dietary, and environmental factors have been pro-
posed to modify the risk of leukemia initiation. Children with various
congenital immunodeficiency diseases, including Wiskott-Aldrich
syndrome, congenital hypogammaglobulinemia, and ataxia telangiec-
tasia, have an increased risk of developing lymphoid malignancies, as
do patients under chronic treatment with immunosuppressive drugs.
The loss of cellular immune surveillance capability for tumor antigens
and the inability to self-regulate lymphoproliferative processes may
contribute to malignant transformation in these patients. Absence of
exposure to common infections in the first year of life is associated
with a higher risk of developing ETV6-RUNX1positive or hyperdip-
loid ALL in older children. A possible explanation is that in the
absence of infection-driven modulation of the naive immune network
in infants, subsequent infectious exposures could result in a highly
dysregulated response to infections in older children, contributing to
leukemogenesis. Exposure to ionizing radiation and certain toxic
chemicals could also facilitate the development of acute leukemia. The
high incidence of leukemia among survivors of atomic bomb explo-
sions in Japan during World War II is well documented. Among sur-
vivors of the atomic bomb, there was no increase in the incidence of
leukemia in children exposed to radiation in utero. This experience
contrasts with other reports of an increased incidence of ALL in chil-
dren exposed to medical diagnostic radiation both in utero and in
childhood. Other evidence linking most environmental exposures to
risk of childhood ALL has largely been inconsistent. Causation path-
ways are likely to be multifactorial, and it is probable that the risk of
ALL from environmental exposure is influenced by genetic variation
through the coinheritance of multiple low-risk variants.
951
 952 Part VII Hematologic Malignancies

PATHOBIOLOGY These patients probably would require more intensive therapy because
this genotype was associated with poor outcome in the reported
Acute leukemias comprise a group of clonal disorders of maturation series, albeit not independently significant in one.13
at an early phase of hematopoietic differentiation. ALL subtypes are Experimental models have established that cooperative mutations
a heterogeneous group of malignancies with distinctive immunophe- are necessary to induce leukemia and contribute to the development
notype and molecular pathogenesis that result in varying clinical of drug resistance. Association studies of ALL based on the candidate
characteristics and response to therapy. Accurate pathobiologic diag- gene approach have evaluated a restricted number of polymorphisms
nosis is not only important for prognostic stratification but can also in genes implicated in the metabolism of carcinogens, folate metabo-
help define patient-specific therapeutic approaches.7 lism, protection of DNA from carcinogen-induced damage, and cell
Lymphoblastic leukemias can arise from either B- or T-cell mutant cycle regulation. Such studies highlight difficulties in conducting
hematopoietic cells capable of indefinite self-renewal. T-cell ALL statistically and methodologically rigorous investigations into ALL
can be classified into several distinct genetic subgroups that corre- risk. Genome-wide association studies of childhood ALL have
spond to specific T-cell development stages and is frequently recently demonstrated that common variation at four genetic loci
associated with translocations of T-cell receptor genes on chromo- [7p12.2 (IKZF1), 9p12 (CDKN2A/CDKN2B), 10q21.2 (ARID5B)
some 14q11 or 7q34 with other gene partners. Recent studies have and 14q11.2 (CEBPE)] confers a modest increase in risk, establishing
identified a novel high-risk immature T-cell subtype termed early a role for genetic susceptibility in the development of ALL. In addi-
T-cell precursor (ETP) ALL with immunologic markers and gene tion to identifying common, low-penetrance susceptibility alleles,
expression reminiscent of double-negative 1 thymocyte that retains these data provide insights into disease causation by identifying risk
the ability to differentiate into both T-cell and myeloid, but not variants and annotating genes involved in transcriptional regulation
B-cell, lineages.8 The discovery of its mutational spectrum recapitu- and differentiation of B-cell progenitors.
lated that of acute myeloid leukemia (AML) by whole-genome
sequencing and a global transcription profile similar to that of normal
hematopoietic stem cells (HSCs) and granulocyte macrophage CLINICAL MANIFESTATIONS
precursors suggests that this subtype of leukemia is a stem cell leuke-
mia. The prevalence of mutations in genes regulating cytokine recep- Children with ALL present with nonspecific symptoms and signs
tor and Ras signaling, and histone modification further suggests reflecting the degree of disruption in bone marrow (BM) function
that the addition of myeloid-directed therapy might improve and the extent of extramedullary infiltration. The most common
the outcome of this subtype.9 Most B-lineage leukemias are early presenting symptoms are fever, fatigue, pallor, petechiae, bruising,
precursor B cell, expressing CD19 and CD10 (or cALLa, the common bleeding from mucosal surfaces, and pain (Table 64-1). Patients,
acute leukemia antigen) but lacking surface or cytoplasmic immuno- especially young children, may present with bone pain, arthralgia,
globulin. The mature B-cell ALLs, or Burkitt-cell leukemia, are strati- or refusal to walk because of leukemic infiltration of the bone or
fied separately and are not included in this chapter (see Chapters 81 joint or because of expansion of the BM cavity by leukemic cells.
and 83). The evolution of symptoms may proceed over a few days, weeks,
Recent advances in global genome analysis have enabled the or months. Less common presenting symptoms include headache,
identification of recurring alterations in genes and pathways with key visual complaints, vomiting, respiratory distress, oliguria, and anuria.
roles in cell growth and tumorigenesis. Several observations suggest Occasionally, patients present with life-threatening infection or
that multiple lesions are acquired subsequent to founding transloca- bleeding.
tions to induce leukemogenesis. Single nucleotide polymorphism On physical examination, fever, pallor, petechiae, and ecchymoses
(SNP) array analysis demonstrated substantial differences in the fre- may be present. The lymphoproliferative nature of the disease may
quency of copy number abnormality (CNA) among various ALL
subtypes. MLL-rearranged cases had less than one CNA per case,
suggesting that MLL is a potent oncogene that requires very few Table 64-1 Clinical Presentation of Acute Lymphoblastic Leukemia
cooperating lesions to induce leukemia transformation, but ETV6-
RUNX1 and BCR-ABL1 leukemias have more than six lesions Symptoms and Signs Etiology Management
per case.
Fever Disease or infection Always conduct fever
Deletion or sequence mutation of the IKZF1, a gene that encodes
workup and provide
the early lymphoid transcription factor IKAROS, is present in more
broad antimicrobial
than 80% of BCR-ABL1positive ALL and in a novel high-risk sub-
coverage until infectious
group of BCR-ABL1negative ALL that has a gene expression profile
etiology is ruled out
significantly similar to that of BCR-ABL1-positive ALL.10 The BCR-
ABL1-like ALL occurs in as many as 7% to 9% of children with Fatigue, pallor Anemia (ALL RBC transfusion (slow if
ALL. Approximately half of the BCR-ABL1like cases have rearrange- infiltrating BM) anemia is severe; avoid
ments of the lymphoid cytokine receptor gene CRLF2, with con- in hyperleukocytosis)
comitant Janus kinases (JAKs) mutations in one-third of the Petechiae, bruising, Thrombocytopenia Transfuse with platelets
CRLF2-rearranged cases.11 This genotype is associated with high risk bleeding (ALL infiltrating
of relapse, independent of age, leukocyte count at diagnosis, cytoge- BM)
netics, and levels of MRD after remission induction. A recent tran-
scriptome sequencing study of 12 cases of BCR-ABL1like cases (with Pain Leukemia infiltrating Establish diagnosis and
whole-genome sequencing in two of them) identified structural bones or joints or start chemotherapy
alterations and mutations activating kinase and cytokine receptor expanding BM
signaling in all cases, including EBF1-PDGFRB, NUP214-ABL1, cavity
RANBP2-ABL1, BCR-JAK2, STRN3-JAK2, and activating mutations Respiratory distress, Mediastinal mass Avoid sedation in the
of IL7R or FLT3. Importantly, preclinical studies showed that primary superior vena presence of tracheal
leukemic cells harboring PDGFRB or ABL1 fusion responded to cava syndrome compression; establish
ABL1 TKIs, and those harboring BCR-JAK2 or mutated IL7R diagnosis as soon as
responded to JAK2 inhibitor, suggesting that these patients would possible and start
benefit from the targeted therapy.12 Another novel subtype of B-cell chemotherapy
precursor ALL, characterized by CRLF2 alterations (PAR1 deletion
and IGH-CRLF2), occurs in 5% to 7% of children with ALL and, ALL, Acute lymphoblastic leukemia; BM, bone marrow; RBC, red blood cell.
remarkably, in approximately 50% of the cases with Down syndrome.
 Chapter 64 Clinical Manifestations and Treatment of Acute Lymphoblastic Leukemia in Children 953

be manifested as lymphadenopathy, splenomegaly, or less commonly
hepatomegaly. Central nervous system (CNS) involvement is uncom-
mon at presentation and in most instances is detected by screening
lumbar puncture in high-risk patients who are asymptomatic at the
time of the puncture (Fig. 64-1, A and B). Papilledema, retinal hem-
orrhages, and cranial nerve palsies should be ruled out on examina-
tion. CNS involvement usually is restricted to leptomeninges, and
parenchymal mass lesions are uncommon. Epidural spinal cord com-
pression is a rare but serious presenting finding and requires immedi-
ate chemotherapy and high-dose glucocorticoid therapy. Laminectomy
or radiotherapy is generally not necessary because leukemias are very
sensitive to chemotherapy at diagnosis. Overt testicular involvement
occurs in only 2% of boys and usually presents as painless, asym-
metric enlargement that can be distinguished from hydrocele by
ultrasonography (Fig. 64-1, C and D). Less common presenting
features include ocular involvement, subcutaneous nodules (leukemia
cutis) (see Fig. 64-1, E and F) and enlarged salivary glands (Mikulicz
syndrome). Approximately 55% of T-cell cases present with an ante-
rior mediastinal mass. A bulky mediastinal mass can compresses the
great vessels and trachea, resulting in superior vena cava syndrome
and respiratory distress. Patients with a large mediastinal mass gener-
ally present with cough, dyspnea, orthopnea, dysphagia, stridor, cya-
nosis, facial edema, increased intracranial pressure, and sometimes
syncope. When significant tracheal compression is present, general
anesthesia should be avoided and procedures should be performed
under local anesthesia. Immediate diagnosis and initiation of steroids
and chemotherapy is essential to prevent respiratory failure.
Clinical laboratory data often reveal a broad spectrum of abnormal
findings. Various degrees of anemia and thrombocytopenia are usually
present at diagnosis. The presenting leukocyte counts range widely
from 0.1 to 1500 109/L. Leukemic blasts may or may not be seen
on peripheral smear. Approximately 45% of children have leukocyte
counts less than 10 109/L, and 15% present with hyperleukocytosis
(>100 109/L). Patients with hyperleukocytosis are at increased risk
of CNS disease, tumor lysis syndrome, and leukostasis. Leukostasis
may manifest as dyspnea, chest pain, alterations in mental status,
cranial nerve palsies, or priapism. The majority of childhood ALL are
B cell in derivation with approximately 12% to 15% of children with
ALL having a T-cell immunophenotype. T-cell ALL usually occurs in
patients older than 9 years of age with elevated leukocyte counts and
is associated with CNS involvement. Coagulopathy, usually mild, can
occur in T-cell ALL and is only rarely associated with severe bleeding.
Elevated serum uric acid and lactate dehydrogenase levels are common
in patients with a large leukemic cell burden. Patients with massive
renal involvement can have increased levels of creatinine, urea nitro-
gen, uric acid, and phosphorus. Approximately 0.5% of patients have
hypercalcemia at diagnosis, attributable to the release of parathyroid
hormone-like protein from lymphoblasts and leukemic infiltration of
bone; these patients tend to be in the older age group and present with
low blast cell counts. This complication generally resolves rapidly with
hydration and chemotherapy. Liver dysfunction caused by leukemic
infiltration occurs in 10% to 20% of patients, is usually mild, and has
no prognostic consequences. Because vincristine and daunorubicin
are metabolized primarily through biliary excretion, modifications of
the dosage of these agents are recommended if the direct bilirubin level
is elevated.
Abnormalities of the bone, such as metaphyseal banding, perios-
teal reactions, osteolysis, osteosclerosis, or osteopenia, can be

A C E

B D F
Figure 64-1 CENTRAL NERVOUS SYSTEM (CNS), TESTICULAR, AND SUBCUTANEOUS INVOLVEMENT
IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA (ALL). CNS disease identified in the cerebrospinal
fluid (CSF) by screening lumbar puncture at the time of diagnosis in a 12-year-old boy with high-risk precursor B-cell
ALL. The total count of the CSF specimen was 6131/L with 6076 white blood cells/L and 98% blasts. A and B,
The cytospin preparation shows mostly blasts, slightly altered morphologically by the preparation. In B, there is a small
lymphocyte (middle) for comparison with the blasts. C and D, Testicular disease noted at relapse in a 13-year-old boy
with precursor B-cell ALL. Note the infiltrate of blasts in the parenchyma of the testes, surrounding the seminiferous
tubules. Immunostaining (not shown) demonstrated that the blasts were CD19+, CD10+, and TdT+. E and F, Cutane-
ous disease at diagnosis. The patient was an 8-year-old boy with a scalp lesion for 2 months that was initially treated
with antibiotics. On biopsy, there was much crush artifact, but deep in the specimen, there was an infiltrate of blasts
separating fibers (F) shown to be B-cell lineage. Interestingly, the patient had a normal complete blood count, but bone
marrow was packed with blasts that had a precursor B-cell phenotype and a hyperdiploid karyotype.
 954 Part VII Hematologic Malignancies
demonstrated by radiographic studies in half of patients, especially
those with low presenting leukocyte counts. Vertebral compression
fracture can be detected in 2% of the cases, usually with low leukocyte
count and hyperdiploidy (>50 chromosomes), and is not associated
with adverse prognosis.
DIFFERENTIAL DIAGNOSIS
Children with ALL present with a variety of nonspecific symptoms
that may mimic other conditions. Pancytopenia and fever are also
presenting symptoms for aplastic anemia. Failure of a single cell line,
as in transient erythroblastic anemia, idiopathic thrombocytopenic
purpura, and congenital or acquired neutropenia, sometime produces
a clinical picture that is difficult to distinguish from ALL. Routine
BM aspiration is not necessary for patients with severe thrombocy-
topenia and no other hematologic or physical evidence of leukemia.
However, BM aspiration should be performed to exclude leukemia
in patients who require glucocorticoid treatment. Children with
infectious mononucleosis or other acute viral illnesses may present
with fever, adenopathy, splenomegaly, lymphocytosis, or pancytope-
nia. Fever, arthralgias, or a limp may frequently be confused with
juvenile rheumatoid arthritis, which can also be associated with
anemia, leukocytosis, and mild splenomegaly. Children with promi-
nent bone pain frequently have nearly normal blood counts, a finding
that can contribute to a delay in diagnosis. Immunostains and molec-
ular studies help differentiate ALL from AML and other small blue
cell malignancies that invade the BM, including neuroblastoma,
rhabdomyosarcoma, Ewing sarcoma, and retinoblastoma. Infants
may present with subcutaneous nodules (leukemia cutis) that look
clinically like Langerhans cell histiocytosis.
PROGNOSIS
Contemporary regimens have abolished the prognostic impact of
many clinical and biologic features, demonstrating that the single
most important prognostic factor in childhood ALL is appropriate
risk-directed therapy (Table 64-2). Accurate assessment of relapse
hazard is an integral part of ALL therapy, so that only high-risk
patients are treated aggressively, with less toxic therapy reserved for
cases at lower risk of failure.
To facilitate comparison of treatment results among different
clinical trials, participants in a 1993 workshop sponsored by the
United States National Cancer Institute adopted a uniform risk clas-
sification based on age and leukocyte count. Two-thirds of the
patients who were 1 to 9 years old with precursor B-cell ALL and a
leukocyte count less than 50 109/L were considered to be at stan-
dard risk of relapse; the other third was classified as high risk. This
classification proved to be of limited prognostic value because up to
one-third of patients designated as standard risk may relapse, and
these criteria cannot be applied to T-cell ALL. Moreover, the prog-
nostic impact of age and, to a lesser extent, leukocyte count is largely
attributable to their association with specific genetic abnormalities.
For example, the overall poor prognosis of infants younger than 12
months of age can be explained by the very high frequency of MLL
rearrangements (70%80%) in this age group,14 and the overall favor-
able outcome of patients ages 1 to 9 years is related to the preponder-
ance of cases (70%) with hyperdiploidy (>50 chromosomes) or
ETV6-RUNX1 (also known as TEL-AML1) fusion, which are both
favorable genetic features. Thus a more reasonable strategy is to
develop clinical prognostic risk categories based on their major
immunophenotypic features and genetic characteristics.
Early pre-B ALL, lacking immunoglobulin synthesis, is the most
common form of acute leukemia in children. The high-risk features
previously ascribed to pre-B ALL (presence of cytoplasmic immuno-
globulin M) are closely associated with the presence of the t(1;19)
translocation and E2APBX1 fusion. Prognostic distinctions among
ALL immunophenotypes, including the negative prognostic impact
once associated with T-cell ALL and pre-B ALL with E2A-PBX1
fusion, have been abolished by recent improvements in risk-directed
treatment. Aberrant expression of myeloid-associated antigens has
been observed with certain genetic subtypes. CD15, CD33, and
CD65 are expressed in ALL cases with a rearranged MLL gene, and
CD13 and CD33 are expressed in cases with the ETV6-RUNX1
fusion. Once associated with a poor outcome in some studies,
myeloid-associated antigen expression has no prognostic impact
in contemporary risk-directed treatment programs. The recently
identified ETP ALL subtype is characterized by immature genetic
and immunophenotypic features (CD1a negative, CD8 negative, and
CD5 weak and the expression of stem cell or myeloid markers) and
a dismal prognosis with conventional therapy.9
Acute lymphoblastic leukemia can be classified according to
modal chromosomal number (ploidy) and specific genetic abnormali-
ties of the leukemia stem line. Hyperdiploidy (>50 chromosomes per
cell) is associated with an age of 1 to 10 years, a lower median leu-
kocyte count, increased sensitivity to antimetabolite agents, and a
favorable prognosis. A hypodiploid karyotype (<44 chromosomes per
cell), by contrast, predicts a poor outcome. Molecular analysis can
identify prognostically and therapeutically relevant subgroups that
cannot be identified by karyotyping. ETV6-RUNX1, the most
common specific genetic rearrangement in childhood ALL, has been
associated with a good prognosis. With the exception of T-cell ALL
with the t(11;19), the prognosis of cases with 11q23/MLL rearrange-
ments is generally poor.
Genetic features do not entirely account for treatment outcome,
and their prognostic impact also depends on the treatment efficacy.
Although up to 15% of patients with hyperdiploidy greater than 50
chromosomes per cell or ETV6RUNX1 fusion have recurrences of
their leukemia, a substantial proportion of the patients with the
t(9;22) and BCR-ABL1 fusion who are 1 to 9 years old and have low
leukocyte counts at diagnosis may be cured with intensive chemo-
therapy alone.15 Among patients with MLLAF4 fusion, infants and
adults have a worse prognosis than children. Interindividual vari-
ability in the pharmacokinetics and pharmacodynamics of many
antileukemic agents also contributes to the heterogeneity in treatment
response among patients with specific genetic abnormalities.16
The degree of reduction of the leukemic cell clone early during
remission induction therapy is determined by both leukemic
cell genetics and host pharmacogenetics and has shown greater prog-
nostic strength than any other individual biologic or host-related
feature.17 Measurements of MRD by flow-cytometric detection
of aberrant immunophenotypes or by polymerase chain reaction
(PCR) of clonal antigenreceptor gene rearrangements provides a
level of sensitivity and specificity that cannot be attained by tradi-
tional morphologic assessment of early treatment response. Patients
who achieve an immunologic or molecular remission, defined as
leukemic involvement of less than 104 nucleated BM cells on
Minimal Residual Disease
The rapidity of response to induction therapy is an important
independent predictor of outcome. There is strong concordance
between the assessment of MRD by flow cytometry and by PCR
methods. We (the authors) monitor MRD using primarily flow
cytometry methods, which are simple and rapid, and we reserve
PCR methods for the few patients (<5%) whose leukemic cells
lack a suitable immunophenotype. About half of all patients show
a disease reduction to 104 or lower after only 2 weeks of remis-
sion induction, and these patients appear to have an exception-
ally good treatment outcome. Persistence of MRD of 104 or more
at 4 months from diagnosis is associated with an especially
dismal outcome. The adverse prognosis of high-risk slow early
responders can be improved with intensification of induction and
consolidation. Standard-risk cases may be spared the increased
risk of early morbidity and mortality from intensive induction,
provided that they receive postinduction intensification therapy.
 Chapter 64 Clinical Manifestations and Treatment of Acute Lymphoblastic Leukemia in Children 955

Table 64-2 Prognostic Factors in Acute Lymphoblastic Leukemia

Factor Prognosis Clinical Application

Age
<1yr MLL+ (70%80% infants): Poor outcome MLL: Do well on standard ALL therapy
MLL : Same outcome as for older children Potential role for FLT3 inhibitor for MLL+
19yr Standard risk ALL biology may change risk
>9yr Higher risk ALL biology may change risk
White Blood Cell Count
<50 109/L Standard risk ALL biology may change risk
50 109/L Higher risk ALL biology may change risk
Central Nervous System
CNS3 Higher risk Therapy intensification
CNS2 Higher risk of CNS relapse CNS-directed therapy intensification
Traumatic lumbar puncture with blasts
Testicular Higher risk Therapy intensification
Immunophenotype
T cell Higher risk Poor outcome abolished with current therapy
PreB cell (cIgM+) Higher risk Poor outcome abolished with current therapy
Early preB cell Standard risk Genetics may change risk
ETP Dismal prognosis Ongoing studies exploring effective therapies
Ploidy
>50 (DI >1.16) Low risk Good response to antimetabolites
<44 Higher risk Therapy intensification
Genetic Alterations
t(9;22)/BCR-ABL1 Higher risk BCR-ABL inhibitors
t(4;11)/MLL-AF4 Higher risk Potential role for FLT3 inhibitors and hypomethylating agents
t(1;19)/E2A-PBX1 Higher risk Poor outcome cancelled on current therapy
t(12;21)/ETV6-RUNX1 Low risk
IKZF1 Poor prognosis. Present in 80% BCR-ABL1+ and Potential role for TKI, JAK inhibitors
also in BCR-ABL1 like
NUP214-ABL1 High risk Potential benefits from TKI
CRLF2 In 1/3 BCR-ABL1like, associated with Hispanic or Potential role for JAK inhibitors
Latino ethnicity and poor outcome
CREBBP Associated with drug resistance and relapse Potential benefit from histone deacetylase inhibitors
Minimal Residual Disease
Day 15 <0.01% Excellent outcome No benefit from second delayed intensification
Slow early responders Higher MRD = Higher risk of relapse Benefit from augmented delayed intensification
EOI >1% Dismal prognosis HSCT in first CR
4mo >0.1% Dismal outcome HSCT in first CR

CNS, Central nervous system; CR, complete remission; DI, DNA index; EOI, end of induction; HSCT, hematopoietic stem cell transplantation; MRD, minimal residual
disease; JAK, Janus kinase; TKI, tyrosine kinase inhibitor.

completion of remission induction, have a much more favorable
prognosis than do those who do not achieve this status. Patients
who are in morphologic remission but have a postinduction
MRD level of 1% or more fare as poorly as those who do not achieve
clinical remission by conventional criteria (5% blasts). About half
of all patients show a disease reduction to 104 or lower after only 2
weeks of remission induction, and they appear to have an exception-
ally good treatment outcome. The persistence of MRD (0.01%)
beyond 4 months from diagnosis was associated with an estimated
70% cumulative risk of relapse. Patients with 0.1% MRD or more
at 4 months had an especially dismal outcome. Most contemporary
clinical trials have incorporated MRD detection into the risk classi-
fication system. Although MRD positivity is strongly associated with
known presenting risk features, it has independent prognostic strength
and is increasingly used in risk stratification of ALL in contemporary
regimens.18
Currently, pediatric ALL patients are typically classified into three
risk groupslow-, intermediate-, and high-risk (also referred to as
standard-, high-, and very high-risk)which are categories based on
age, leukocyte count at diagnosis, blast cell immunophenotype, and
genotype, as well as early treatment response. More recently, gene
expression profiling of leukemic cells by the DNA microarray method
 956 Part VII Hematologic Malignancies
has proved useful in identifying previously unrecognized genes whose
expression may have prognostic significance. The predictive power of
these newly identified expression signatures requires validation in
prospective clinical trials.
THERAPY, INCLUDING STEM CELL TRANSPLANTATION
With the exception of patients with mature B-cell ALL, who are
treated with short-term intensive chemotherapy, therapy for patients
with ALL is administered over 2 to 3 years. Treatment starts with
a 4- to 6-week remission-induction phase aimed at eradicating the
initial leukemic cell burden and restoring normal hematopoiesis. The
induction phase typically includes the administration of a glucocor-
ticoid (prednisone or dexamethasone), vincristine, and at least a third
drug (asparaginase, anthracycline, or both). A three-drug induction
regimen appears sufficient for most standard-risk cases, provided they
receive intensified postremission therapy. The benefit in long-term
survival of using four or more drugs during induction is widely
accepted in higher risk patients but less clear in lower risk patients.
With this approach, 98% to 99% of patients can attain remission, as
defined by fewer than 5% blasts in the BM and a return of neutrophil
and platelet counts to near normal levels. Intrathecal chemotherapy
is usually initiated at the start of treatment.
After remission induction, consolidation (or intensification) is
given to eradicate drug-resistant residual leukemic cells. Therapy is
tailored to the leukemia subtype and risk group. All patients benefit
from a delayed intensification (or delayed reinduction), consisting of
using drugs similar to those used in remission induction therapy after
a 3-month period of a less intensive, interim maintenance chemo-
therapy. Double-delayed intensification with a second reinduction at
week 32 of treatment improves outcome in patients with intermediate-
risk leukemia but does not benefit patients with rapid early response.
An augmented intensification regimen consisting of the administra-
tion of additional doses of vincristine and asparaginase during the
myelosuppression period after delayed intensification and sequential
escalating-dose parental methotrexate followed by asparaginase
improved the outcome of high-risk patients whose disease had
responded slowly to initial multiagent induction therapy.
After completion of induction and consolidation, patients receive
a 2- to 2.5-year continuation (or maintenance) phase consisting of
low-intensity metronomic chemotherapy designed to eradicate any
residual leukemic cell burden. Weekly low-dose methotrexate and
daily oral mercaptopurine form the backbone of most continuation
regimens. Many groups add regular pulses of vincristine and
Consolidation Therapy
The importance of a consolidation phase after remission induc-
tion is undisputed, but the treatment regimen and duration vary
in the different childhood ALL studies. Commonly used strategies
include high-dose methotrexate plus mercaptopurine, frequent
pulses of vincristine and corticosteroid plus high-dose asparagi-
nase for 20 to 30 weeks, and reinduction treatment with the
same agents given during initial remission induction. Reinduction
treatment has become an integral component of contemporary
protocols. In one randomized study, double reinduction further
improved treatment outcome in patients with intermediate-risk
ALL, but additional pulses of vincristine and prednisone after a
single reinduction course were not beneficial, suggesting that the
increased dose intensity of other drugs, such as asparaginase,
was responsible for the observed improvement. An augmented
regimen including Capizzi methotrexate (escalating-dose intrave-
nous methotrexate with no rescue followed by asparaginase) and
additional doses of vincristine and asparaginase during periods
of myelosuppression improved the outcome of patients with a
slow early response to therapy.
corticosteroids to this regimen, although the benefit of these pulses
and their optimal duration and frequency of administration in the
context of contemporary therapy has not been established.19 Adjust-
ing chemotherapy doses to maintain a white cell count between 2 to
3 109/L and neutrophil counts between 0.5 and 1.5 109/L has
been associated with a better clinical outcome. Overzealous use of
mercaptopurine, to the extent that neutropenia necessitates chemo-
therapy interruption, reduces overall dose intensity and is counter-
productive. The optimal duration of therapy remains unknown.
Attempts to shorten therapy duration from 24 months to 12 or 18
months have resulted in a significant increase in relapses. Several
studies showed no advantage to prolonging treatment beyond 3 years.
A small number of patients with particularly poor prognostic features
may undergo BM transplantation during first remission.
Radiation therapy was the first modality that was successfully used
to prevent CNS relapse. The effectiveness of cranial radiation as
preventive therapy was offset by substantial late effects in long-term
survivors, including learning disabilities, multiple endocrinopathies,
and an increased risk of second malignancies. Subsequent trials dem-
onstrated that in the context of optimal systemic and intrathecal
therapy, cranial irradiation can be reduced or even omitted altogether.
Patients with high-risk genetic features, large leukemic cell burden,
T-lineage ALL, and leukemic cells in the cerebrospinal fluid, even
from iatrogenic introduction from a traumatic lumbar puncture at
diagnosis, are at increased risk of CNS relapse and require more
intense CNS-directed therapy.20 Studies have successfully used triple
intrathecal therapy with methotrexate, hydrocortisone, and cytara-
bine or intrathecal methotrexate alone. Systematically administered
agents, including high-dose methotrexate, dexamethasone, and aspar-
aginase, also contribute to prevention of extramedullary relapse.
Based on reports of more potent in vitro antileukemic activity and
better CNS penetration, dexamethasone has replaced prednisone in
many continuation regimens. Prednisone remains the preferred gluco-
corticoid during induction because of the relative increased toxicity
associated with dexamethasone use.21 Polyethylene glycolconjugated
asparaginase, a long-acting and less allergenic form, is progressively
replacing the native Escherichia coli and is being increasingly adminis-
tered intravenously instead of intramuscularly. Asparaginase derived
from Erwinia chrysanthemi has a short half-life, and its use is currently
limited to patients who are allergic to the E. coli formulations. The
dose schedule for asparaginase should take into account the variability
in the pharmacokinetic profile and potency among the different
preparations.22 Intensifying asparaginase therapy during the early
phase of treatment benefits high-risk patients, particularly those with
T-cell disease. Significant improvement was also reported in the
outcome of patients receiving early intensification consisting of inter-
mediate- or high-dose antimetabolite therapy.23 The optimal dose of
methotrexate depends on the leukemic cell genotype and phenotype,
as well as host pharmacogenetic and pharmacokinetic parameters.
Methotrexate at 2.5g/m2 is adequate for most patients with standard-
risk B-cell precursor ALL, but a higher dose (5g/m2) may benefit those
with T-cell or high-risk B-cell precursor ALL. This observation is
consistent with the finding that T-lineage blast cells accumulate meth-
otrexate polyglutamates less avidly than do B-lineage blast cells. The
increased ability of hyperdiploid ALL blasts cells to accumulate meth-
otrexate polyglutamate could partially explain the excellent outcome
High-Risk Central Nervous System Relapse
Patients with the following characteristics are at increased risk
of CNS relapse and require more intense CNS-directed therapy:
1. Patients with high-risk genetic features
2. Large leukemic cell burden
3. T-lineage ALL
4. CNS-3 status (>5 WBC/L CSF with presence of
lymphoblasts on Cytospin)
5. CNS-2 status (<5 WBC/L CSF with lymphoblasts)
6. Traumatic CSF with blasts
 Chapter 64 Clinical Manifestations and Treatment of Acute Lymphoblastic Leukemia in Children
of children with hyperdiploid greater than 50 chromosomes per cell
ALL treated on low-intensity antimetabolite-based regimens. Leu-
covorin rescue is necessary after treatment with high-dose methotrex-
ate; however, overzealous rescue might counteract the antileukemic
activity of methotrexate. Although the intensive asparaginase and
high-dose methotrexate treatment has significantly improved the
outcome for patients with T-cell ALL, the emergence of specific
therapy such as the purine nucleoside analog nelarabine will likely
increase the tendency to assign patients with T-cell ALL to a specific
treatment protocol or strata.
It is generally recommended to give mercaptopurine at bedtime to
patients with an empty stomach and to avoid taking it together with
milk or milk products that contain xanthine oxidase, an enzyme that
can degrade the drug. About 10% of the population inherit one wild-
type gene encoding thiopurine methyltransferase (TPMT) and one
nonfunctional variant allele, resulting in intermediate enzyme activity,
but one in 300 people inherits two nonfunctional variant alleles and
are completely deficient of this enzyme that catalyses the S-methylation
of mercaptopurine to its inactive metabolite. Patients with heterozy-
gous and especially homozygous deficiency of TPMT are at high risk
of severe myelosuppression. Identification of these patients allows
physicians to selectively guide reductions in mercaptopurine dosage
without modifying the dose of methotrexate. Substituting thiogua-
nine for mercaptopurine during continuation therapy was associated
with a high incidence of profound thrombocytopenia and hepatic
venoocclusive disease. Thioguanine use has therefore been limited to
short pulses administered during consolidation therapy in some trials;
mercaptopurine is selected for prolonged administration.
Because optimizing the administration of existing therapies is
reaching its limit, further improvements in outcome will require the
development of therapeutic approaches directed against rational
therapeutic targets. An example is the significant improvement in the
outcome of Philadelphia chromosomepositive (Ph+) ALL with the
advent of TKIs targeting the constitutively active BCR-ABL1 TKI in
ALL subset. Ph+ ALL has historically had an extremely poor outcome,
but recent studies have demonstrated dramatic improvements in
treatment outcome with incorporation of BCR-ABL1 inhibitors into
Ph+ ALL treatment.24 Recent identification of novel chimeric fusions
involving kinases in ALL (e.g., NUP214ABL1 and STRN3JAK2)
suggests that additional high-risk cases may benefit from targeted
therapies directed at kinase signaling.
The expanded understanding of the biologic, immunologic, and
genetic heterogeneity of ALL has enabled development of several
novel therapeutic strategies.25 Various monoclonal antibodies are
showing promise in early clinical trials and may be incorporated into
ALL regimens in the future.
Autologous transplantation has failed to improve outcome in
ALL. Comparisons between allogeneic HSC transplantation (HSCT)
and intensive chemotherapy have yielded inconsistent results because
of the small numbers of patients studied and differences in case selec-
tion criteria. It is generally accepted that allogeneic HSCT is a treat-
ment modality for patients with ALL who are predicted to respond
poorly to intensive chemotherapy.26 At present, patients with
Dose Schedule
The biologically equivalent doses among the different formula-
tions of corticosteroids, thiopurines, and asparaginase are not
clear. Trials comparing such agents should be cautiously inter-
preted, taking into account the dose schedule used and the effect
of variability in the pharmacokinetic profile and potency among
the agents involved. Simple modification of the dose or schedule
may result in significant differences in efficacy and toxicity. Also,
when comparing regimens containing high-dose intravenous
methotrexate, the dose schedule of leucovorin rescue should not
be ignored because it plays a crucial role in modulating the activ-
ity and toxicity of methotrexate.
957
refractory leukemia (failure to enter morphologic remission after 46
weeks of induction therapy), high level of MRD (>1%) after remis-
sion induction, persistent MRD after consolidation treatment, and
early hematologic relapse are candidates for allogeneic transplanta-
tion. It is crucial to reduce residual disease to, or close to, undetect-
able levels as outcome is superior if MRD is undetectable before
HSCT and worsens with increasing MRD levels at the time of
HSCT. Treatment approaches for adolescents and young adults with
ALL have evolved considerably with the widespread adoption of
pediatric-based protocols, which appears to have significantly
improved survival and decreased the need for HSCT in this age
group. The benefit of allogeneic HSCT in infants with t(4;11) ALL
remains controversial and should be evaluated in the context of
emerging molecular therapies such as FLT3 inhibitors and DNA
methyltransferase inhibitors. Patients with the recently identified
ETP ALL have a dismal prognosis (event-free survival of 22%), even
though half of the patients received transplantation because of high
MRD levels after remission induction. The therapeutic role of HSCT
in this group of patients remains to be determined by studying a
larger number of patients. Matched unrelated-donor or cord blood
transplantation has yielded outcomes comparable to those obtained
with matched related-donor HSCT and should be considered reason-
able alternatives if a matched donor is not available. Many advances
have been made in stem cell transplantation, such as prevention of
graft-versus-host disease (GVHD), expansion of the pool of suitable
unrelated or related donors, donor selection and tissue typing, accel-
eration of engraftment, enhancement of the graft-versus-leukemia
effect, and supportive care. Because improvements in transplantation
tend to parallel those in chemotherapy, the indications for transplan-
tation in newly diagnosed and relapsed patients should be reevaluated
periodically. For example, the presence of Philadelphia chromosome
is no longer a clear indication for transplantation with the advent of
TKIs.
ACUTE LYMPHOBLASTIC LEUKEMIA RELAPSE
Most relapses occur during treatment or within the first 2 years after
its completion, although relapses have been reported as late as 10
years after initial ALL diagnosis. The most common site of relapse is
the BM.27 Relapse in extramedullary sites, such as the CNS and testes,
has decreased to less than 5% and 2% respectively. Leukemia relapse
occasionally occurs at other sites, including the eye, ovary, uterus,
bone, muscle, tonsil, kidney, mediastinum, pleura, and paranasal
sinus. Extramedullary relapse in children with ALL frequently pres-
ents as an isolated clinical finding. However, in studies that included
MRD assays, many extramedullary recurrences were associated with
MRD in the BM. A small fraction of patients experience a recurrence
of acute leukemia with an immunophenotype different from that
determined at diagnosis. Some of the cases represent relapse of origi-
nal leukemic clones with a shift in immunophenotype, but others are
secondary malignancies caused by the mutagenic effects of leukemia
treatment, especially from epipodophyllotoxin. Patients with isolated
BM relapse generally fare worse than those with isolated extramedul-
lary relapse.28 Factors indicating an especially poor prognosis are a
short initial remission and a T-cell immunophenotype. Other adverse
factors include t(9;22). The presence of MRD at the end of second
remission induction is also a strong adverse prognostic indicator.
Although chemotherapy may secure a prolonged second remission in
children with ALL who experience late relapse (defined as >6 months
after cessation of therapy), allogeneic HSCT is the treatment of
choice for patients who experience hematologic relapse during
therapy or shortly thereafter and for those with T-cell ALL. Patients
with late-onset isolated CNS relapse who had not received cranial
irradiation as initial CNS-directed therapy have a very high remission
retrieval rate, with a long-term prognosis approaching that of newly
diagnosed patients in those who had a long initial remission before
the CNS event.
Genome-wide studies using matched diagnosis and relapse samples
from the same patients are exploring the genetic basis of relapse.
 958 Part VII Hematologic Malignancies
Although 90% of the patients exhibit differential gaining or losing
genetic lesions from diagnosis to relapse, most relapse samples are
clonally related to diagnosis samples. Relapse clones could be present
as minor populations at diagnosis and selected during treatment to
emerge as the predominant clone at relapse displaying alterations of
genes that have been implicated in treatment resistance. Almost 20%
of relapsed cases have sequence or deletion mutations of CREBBP,
which impair histone acetylation and transcriptional regulation of
CREBBP targets, suggesting that the mutations may confer drug
resistance and raising the possibility of using drugs to reverse the
aberrant epigenetic programs, such as histone deacetylase inhibitors.29
The next generation of deep sequencing technologies promises to
unravel many more if not the full repertoire of genetic alterations in
leukemia. Parallel gene expression studies, which have identified a
proliferative gene signature that emerges at relapse and consistent
upregulation of genes such as survivin, provide attractive targets for
novel therapeutic intervention.
SUPPORTIVE CARE
Stringent supportive care significantly contributes to a favorable ALL
outcome and should be initiated at diagnosis because remission
induction is associated with an increased risk from cardiovascular,
metabolic, and infectious complications. All febrile patients with or
without documented infection should be given broad-spectrum intra-
venous antibiotics until an infectious disease can be excluded. Rapid
turnover of leukemia cells before and immediately after the initiation
of chemotherapy leads to metabolic disturbances, including hyperka-
lemia, hyperuricemia, hyperphosphatemia, and hypocalcemia.
Patients with high levels of uric acid are at risk for the development
of acute renal failure secondary to uric acid deposition in the kidneys.
All patients require intravenous hydration to prevent or treat hyper-
uricemia and hyperphosphatemia. Allopurinol, a xanthine oxidase
inhibitor, can prevent uric acid formation. Rasburicase, a recombi-
nant urate oxidase that breaks down uric acid to allantoin (a readily
excretable metabolite with five- to 10-fold higher solubility than uric
acid), is more effective than allopurinol but is associated with met-
hemoglobinemia or hemolytic anemia in patients with glucose-6-
phosphate dehydrogenase deficiency because hydrogen peroxide is a
byproduct of the uric acid breakdown.30 Phosphate binders should
also be used to prevent or treat hyperphosphatemia. Transfusions
should be administered slowly in patients with severe anemia to
prevent congestive heart failure. In patients with extreme hyperleu-
kocytosis, packed red blood cell transfusion should be delayed until
after leukocyte count is decreased to prevent complications of
leukostasis. All blood products should be irradiated in patients
who are receiving immunosuppressive therapy to prevent GVHD.
Patients should avoid foods that may be contaminated with patho-
gens and reduce salt intake, which could induce hypertension and
resultant seizure in patients receiving glucocorticoids during induc-
tion. Adolescents, obese individuals, and individuals with
Drug Interactions
We have not yet reached a full understanding of the contribution
of genetic polymorphisms to interindividual differences in drug
effects to allow us to translate this new knowledge into clinical
practice. However, by simply avoiding drug interactions, one can
prevent increased toxicity or reduced efficacy of chemotherapy.
Phenytoin and phenobarbital induce the activity of cytochrome
P450 enzymes, significantly increasing the systemic clearance of
several antileukemic agents that may adversely affect treatment
outcome. We substitute these anticonvulsants with gabapentin or
Keppra in patients receiving antileukemic therapy. On the other
hand, azole compounds (e.g., fluconazole, itraconazole, ketocon-
azole) can inhibit cytochrome P450 enzymes and increase the
toxicities of various antileukemic agents, especially vincristine.
Down syndrome are at increased risk of hyperglycemia and other
complications. Prophylactic use of trimethoprimsulfamethoxazole
(or pentamidine or atovaquone in patients with poor tolerance to
trimethoprimsulfamethoxazole) successfully prevents Pneumocystis
jiroveci (formerly carinii) pneumonia. Dental evaluation at diagnosis
and meticulous oral hygiene during chemotherapy minimize the oral
complications of leukemia and its treatment. It is important to dis-
tinguish between herpes simplex viral infection and chemotherapy-
induced oral mucositis. Occasionally, patients have nausea and
substantial pain on swallowing caused by esophageal herpes simplex
viral infection, candidiasis, or both. Oral candidiasis occurs fre-
quently, especially in young children. Azole compounds (e.g., fluco-
nazole, itraconazole, ketoconazole) are frequently used to treat fungal
infections. It should be recognized that they can inhibit cytochrome
P450 enzymes and increase the toxicities of various antileukemic
agents, especially vincristine. On the other hand, concomitant
administration of anticonvulsants that induce cytochrome P450
enzymes (e.g., phenytoin, phenobarbital, carbamazepine) increases
the systemic clearance of several antileukemic agents and may
adversely affect treatment outcome. Anticonvulsants that are less
likely to induce the activity of cytochrome P450 enzymes (e.g.,
Keppra) are recommended in patients receiving chemotherapy. Pho-
tosensitive skin rash can occur during antimetabolite therapy. The
rashes are erythematous, maculopapular, similar to atopic eczema,
and most prominent on the face. Topical administration of simple
emollients or a weak steroid preparation and avoidance of external
exposure to sunlight should improve the skin condition. Patients with
Down syndrome tolerate methotrexate poorly; appropriate dose
adjustment is indicated. During each clinic visit, a thorough review
of all drugs should be undertaken because of potential adverse inter-
actions among them. In fact, chemotherapy can also interact with
various food (e.g., grapefruit) and supplements (e.g., St. Johns wort,
folic acid).31
LATE EFFECTS OF TREATMENT
The most problematic late effects of contemporary ALL therapy
include neuropsychological impairments, bone morbidity, and
obesity. Although neuropsychologic deficits are well-recognized side
effects of cranial irradiation, intrathecal and systemic chemotherapy
(especially methotrexate) can also cause brain atrophy and spinal cord
dysfunction and contribute to the development of neurocognitive
toxicities. Severe CNS toxicity has been attributed to cranial irradia-
tion at doses of 2400 cGy or higher, but lower doses have also been
associated with long-term neuropsychological impairments, espe-
cially in younger children. Obesity, which is most prevalent among
female survivors of childhood ALL, may be related to cranial radia-
tion and corticosteroids. Osteopenia, fractures, and osteonecrosis
have been observed in up to 30% of survivors of childhood ALL.
Osteonecrosis, which can lead to significant pain, loss of function,
and total joint replacement, has been reported in approximately 8%
of children with ALL, with the highest frequency observed in those
diagnosed in adolescence. Ovarian and testicular function are rela-
tively unaffected by most antileukemic therapy. Offspring of patients
successfully treated for childhood ALL are expected to be as normal
as the general population. Second malignant neoplasms, including
malignant gliomas, meningiomas, and AML, occur with increased
frequency in patients treated on regimens that include irradiation,
epipodophyllotoxins, or alkylating agents.
FUTURE DIRECTIONS
As the cure rate approaches 90%, treatment response assessed by
MRD measurements of submicroscopic leukemia has emerged as a
powerful and independent prognostic indicator for gauging the
intensity of ALL therapy. Children at high risk of relapse may now
benefit from early intensification of therapy. The next goal is to
reduce the intensity of therapy in children at very low risk of relapse,
 Chapter 64 Clinical Manifestations and Treatment of Acute Lymphoblastic Leukemia in Children
hence avoiding undue toxicity. The successful elimination of preven-
tive cranial irradiation indicates that treatment reduction is feasible
if done with caution and appropriate substitution with less toxic
alternatives. Global genome analysis, in addition to refining leukemia
classification, is helping identify potential molecular targets for
therapy. Expanding the application of pharmacogenomics, a science
that aims to define the genetic determinants of drug effects, will allow
further personalized therapy in the future.
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 Chapter 64 Clinical Manifestations and Treatment of Acute Lymphoblastic Leukemia in Children 959.e1

Key Words
Acute lymphoblastic leukemia
Acute lymphoblastic leukemia (ALL) epidemiology
Acute lymphoblastic leukemia (ALL) pathobiology
Chemotherapy
Central nervous system (CNS)
Concordant acute lymphoblastic leukemia (ALL)
Molecular targets
Minimal residual disease (MRD)
Risk classification