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Chapter 65 Clinical Manifestations and Treatment of Childhood Acute Lymphoblastic Leukemia 1023

delayed for a few days to avoid undue delay in methotrexate clearance patients designated as standard-risk may relapse, and this criterion
resulting in systemic toxicity in these patients. Approximately 0.5% cannot be applied to T-cell ALL. Moreover, the prognostic impact of
of patients have hypercalcemia at diagnosis, attributable to the release age and, to a lesser extent, leukocyte count is largely due to their
of parathyroid hormone–like protein from lymphoblasts and leuke- association with specific genetic abnormalities. For example, the
mic infiltration of bone; these patients tend to be in the older age overall poor prognosis of infants less than 12 months of age can be
group and present with low blast cell count; and this complication explained by the very high frequency of MLL rearrangements (70%
generally resolves rapidly with hydration and chemotherapy. The to 80%) in this age group, and the overall favorable outcome of
chromosomal rearrangement t(17;19), observed in less than 1% of patients aged 1 to 9 years is related to the preponderance of cases
precursor B-ALL, has been associated with hypercalcemia, coagulopa- (70%) with hyperdiploidy (>50 chromosomes) or ETV6-RUNX1
thy, and dismal outcome. Liver dysfunction due to leukemic infiltra- fusion, both favorable genetic features. Thus a more reasonable
tion occurs in 10% to 20% of patients, is usually mild, and has no strategy would be to develop clinical prognostic risk categories based
prognostic consequences Because vincristine and daunorubicin are on their major immunophenotypic features and genetic characteris-
metabolized primarily through biliary excretion, modifications of the tics. As discussed below, the most important prognostic factor is the
dosage of these agents are recommended if direct bilirubin level is early response to remission induction treatment, as determined by
elevated. MRD level.
Abnormalities of the bone, such as metaphyseal banding, perios- B-ALL, lacking immunoglobulin synthesis, is the most common
teal reactions, osteolysis, osteosclerosis, or osteopenia, can be demon- form of acute leukemia in children, and can be further divided into
strated by radiographic studies in one-half of the patients, especially several subtypes based on the stage of differentiation. The high-risk
those with low presenting leukocyte counts. Routine bone surveil- features previously ascribed to pre-B ALL (presence of cytoplasmic
lance is not necessary because these findings have no clinical or IgM) are closely associated with the presence of the t(1;19) transloca-
prognostic implication. Vertebral compression fracture that can be tion with E2A (TCF3)-PBX1 fusion. Prognostic distinctions among
found in 2% of the cases in routine chest x-ray to detect mediastinal ALL immunophenotypes, including the negative prognostic impact
mass, is usually associated with low leukocyte count and hyperdip- once associated with T-cell ALL and pre-B ALL with E2A-PBX1
loidy (>50 chromosomes), and is not associated with adverse fusion, have been abolished by recent improvements in risk-directed
prognosis. 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
DIFFERENTIAL DIAGNOSIS CD13 and CD33 are expressed in cases with the ETV6-RUNX1
fusion. Once associated with a poor outcome in some studies,
Children with ALL present with a variety of nonspecific symptoms myeloid-associated antigen expression has no prognostic impact in
that may mimic other conditions. Pancytopenia and fever are also contemporary risk-directed treatment programs.
presenting symptoms for aplastic anemia. Failure of a single cell line, ALL can be classified according to modal chromosomal number
as in transient erythroblastic anemia, idiopathic thrombocytopenic (ploidy) and specific genetic abnormalities of the leukemia stem line.
purpura, and congenital or acquired neutropenia, sometimes pro- Hyperdiploidy (>50 chromosomes per cell) occurs in 25% to 30%
duces a clinical picture that is difficult to distinguish from ALL. of children with pre-B ALL and is associated with an age of 1 to 10
Routine BM aspiration is not necessary for patients with severe years, a lower median leukocyte count, increased sensitivity to anti-
thrombocytopenia and no other hematologic or physical evidence of metabolite agents, and a favorable prognosis. In contrast, a hypodip-
leukemia. However, BM aspiration should be performed to exclude loid karyotype (<44 chromosomes per cell) occurs in 2% to 3% of
leukemia in patients who require glucocorticoid treatment. Children children with pre-B ALL and predicts a poor outcome among those
with infectious mononucleosis or other acute viral illnesses may who respond poorly to remission induction. Low hypodiploidy (30
present with fever, adenopathy, splenomegaly, lymphocytosis, or to 39 chromosomes) is associated with the presence of TP53 muta-
pancytopenia. Fever, arthralgia, or a limp may frequently be confused tions that are frequently inherited, and is a manifestation of the
13
with juvenile rheumatoid arthritis, which can also be associated with Li-Fraumeni syndrome. Molecular analysis can identify prognosti-
anemia, leukocytosis, and mild splenomegaly. Children with promi- cally and therapeutically relevant subgroups that cannot be identified
nent bone pain frequently have nearly normal blood counts, a finding by karyotyping. ETV6-RUNX1, the most common specific genetic
that can contribute to a delay in diagnosis. Immunostains and rearrangement in childhood ALL, has been associated with the most
molecular studies help differentiate ALL from AML and other small favorable prognosis. With the exception of T-cell ALL with the
blue cell malignancies that invade the BM including neuroblastoma, t(11;19), 11q23/MLL rearrangements are generally associated with
rhabdomyosarcoma, Ewing sarcoma, and retinoblastoma. Infants higher risk of relapse.
may present with subcutaneous nodules (leukemia cutis) that look Genetic features do not entirely account for treatment outcome
clinically like Langerhans cell histiocytosis. and their prognostic impact also depends on the treatment efficacy.
As many as 15% of patients with hyperdiploidy >50 or ETV6-
RUNX1 fusion and poor response to induction may suffer recurrences
PROGNOSIS of their leukemia. On the other hand, 70% or more of the patients
with the t(9;22) and BCR-ABL1 fusion, once associated with dismal
Contemporary regimens have abolished the prognostic impact of prognosis, can be cured with chemotherapy and ABL tyrosine kinase
many clinical and biologic features, demonstrating that the single inhibitor without the need of allogeneic hematopoietic cell transplan-
most important prognostic factor in childhood ALL is appropriate tation if they can achieve a solid remission with no detectable
risk-directed therapy (Table 65.2). Accurate assessment of relapse MRD. 14,15 Among patients with MLL-AF4 fusion, infants and adults
hazard is an integral part of ALL therapy, so that only high-risk have a worse prognosis than children. Interindividual variability in
patients are treated aggressively, with less toxic therapy reserved for the pharmacokinetics and pharmacodynamics of many antileukemic
cases at lower risk of failure. agents also contributes to the heterogeneity in treatment response
To facilitate comparison of treatment results among different among patients with specific genetic abnormalities.
clinical trials, participants in a 1993 workshop sponsored by the The degree of reduction of the leukemic cell clone early during
United States National Cancer Institute adopted a uniform risk clas- remission induction therapy is determined by leukemic cell genetics,
sification based on age and leukocyte. Two-thirds of the patients who microenvironment, and host pharmacogenetics and pharmacody-
were 1 to 9 years old with precursor B-cell ALL and a leukocyte count namics, and has shown greater prognostic strength than any other
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less than 50 × 10 /L were considered to be at standard risk of relapse, individual biologic or host-related feature. Measurements of MRD,
while the other third were classified as high risk. This classification by flow-cytometric detection of aberrant immunophenotypes or by
proved to be of limited prognostic value because up to a third of polymerase chain reaction (PCR) of clonal antigen-receptor gene