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Chapter 65 Clinical Manifestations and Treatment of Childhood Acute Lymphoblastic Leukemia 1021

children exposed to radiation in utero. This experience contrasts with be of therapeutic interest given the increased toxicity with standard
other reports of an increased incidence of ALL in children exposed chemotherapy in this patient population. Genome sequencing of other
to medical diagnostic radiation both in utero and in childhood. Ph-like cases identified structural alterations and mutations activating
Other evidence linking most environmental exposures to risk of kinase and cytokine receptor signaling, including EBF1-PDGFRB,
childhood ALL has largely been inconsistent. Causation pathways are NUP214-ABL1, RANBP2-ABL1, BCR-JAK2, STRN3-JAK2, and
likely to be multifactorial and it is probable that the risk of ALL from activating mutations of IL7R or FLT3. Importantly, preclinical studies
environmental exposure is influenced by germline genetic variations showed that primary leukemic cells harboring PDGFRB or ABL1
through the co-inheritance of multiple low-risk variants. fusion responded to ABL1 tyrosine kinase inhibitors, and those harbor-
ing BCR-JAK2 or mutated IL7R responded to JAK2 inhibitor, suggest-
ing that these patients would benefit from the targeted therapy. 10
PATHOBIOLOGY Historically, association studies of ALL based on the candidate
gene approach have implicated a few genes involved in the metabo-
Acute leukemias comprise a group of clonal disorders of maturation lism of carcinogens, folate metabolism, protection of DNA from
at an early phase of hematopoietic differentiation. ALL subtypes are carcinogen-induced damage, and cell-cycle regulation in the develop-
a heterogeneous group of malignancies with distinctive immunophe- ment of ALL. However, none of these genes can be confirmed by the
notype and molecular pathogenesis that result in varying clinical recent genome-wide association studies that instead have identified
characteristics and response to therapy. Accurate pathobiologic polymorphic variants in several other genes (including ARID5B,
diagnosis is not only important for prognostic stratification, but can CEBPE, GATA3, CDKN2A, BMI1-PIP4K2A, and IKZF1) that are
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also help define patient-specific therapeutic approaches. 7 associated with an increased risk of ALL or specific ALL subtypes.
Lymphoblastic leukemias can arise from either B- or T-cell mutant Rare germline mutations in PAX5 and ETV6 are linked to familial
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hematopoietic progenitor cells capable of indefinite self-renewal. ALL. In addition to identifying common, low-penetrance suscepti-
T-cell ALL can be classified into several distinct genetic subgroups bility alleles, these data provide insights into disease causation by
that correspond to specific T-cell development stages, and is frequently identifying risk variants annotating genes involved in transcriptional
associated with translocations of T-cell receptor genes on chromo- regulation and differentiation of B-cell progenitors.
some 14q11 or 7q34 with other gene partners. Early T-cell precursor
(ETP) ALL comprises 12% to 15% of T-ALL and is characterized by
immature genetic and immunophenotypic features (CD1a-negative, CLINICAL MANIFESTATIONS
CD8-negative, and CD5-weak and the coexpression of stem-cell or
myeloid markers), and gene expression reminiscent of double-negative Children with ALL present with nonspecific symptoms and signs
1 thymocyte that retains the ability to differentiate into both T-cell reflecting the degree of disruption in bone marrow (BM) function
and myeloid, but not B-cell lineages. The discovery of its mutational and the extent of extramedullary infiltration. The most common
spectrum recapitulated that of acute myeloid leukemia (AML) by presenting symptoms are fever, fatigue, pallor, petechiae, bruising,
whole genome sequencing and global transcription profile similar to bleeding from mucosal surfaces, and pain. Patients, especially young
that of normal hematopoietic stem cells, and granulocyte macrophage children, may present with bone pain, arthralgia, or refusal to walk
precursors suggest that this subtype of leukemia is a stem-cell leuke- due to leukemic infiltration of the bone or joint, or to expansion of
mia. The prevalence of mutations in genes regulating cytokine the marrow cavity by leukemic cells (Table 65.1). The evolution of
receptor and RAS signaling, and histone modification further sug-
gests that the addition of targeted therapy might improve the outcome
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of this subtype. Most B-lineage leukemias are early precursor B cells, TABLE Clinical Presentation of ALL
expressing CD19 and CD10 (or cALLa, the common acute leukemia 65.1
antigen) but lacking surface or cytoplasmic immunoglobulin. The
mature B-cell ALL, or Burkitt cell leukemia, are stratified separately Symptoms/Signs Etiology Management
and not included in this chapter. Fever Disease or infection Always conduct fever
Recent advances in global genome analysis have enabled the work up and provide
identification of recurring alterations in genes and pathways with key broad antimicrobial
roles in cell growth and tumorigenesis. Several observations suggest coverage until
that multiple lesions are acquired subsequent to founding transloca- infectious etiology
tions to induce leukemogenesis. A single nucleotide polymorphism is ruled out
(SNP) array demonstrated substantial differences in the frequency of Fatigue, pallor Anemia (ALL Packed red blood cell
copy number abnormality (CNA) among various ALL subtypes. infiltrating bone transfusion (slow if
MLL-rearranged cases had less than one CNA per case, suggesting marrow) anemia is severe,
that MLL is a potent oncogene that requires very few cooperating avoid in
lesions to induce leukemia transformation, especially in infants, while hyperleukocytosis)
other subtypes such as ETV6-RUNX1 and BCR-ABL1 leukemias have
over eight lesions per case. Petechiae, bruising, Thrombocytopenia Transfuse with
Deletion or sequence mutation of the IKZF1, a gene that encodes bleeding (ALL infiltrating platelets
the early lymphoid transcription factor IKAROS, is present in over bone marrow)
80% of Ph-positive (BCR-ABL1–positive) ALL and is common in Pain Leukemia infiltrating Establish diagnosis
Ph-like ALL that has a gene expression profile similar to that of bones/joints, or and start
Ph-positive ALL but lacks BCR-ABL1 fusion. The Ph-like ALL con- expanding marrow chemotherapy
stitutes around 10% of B-ALL in children, its prevalence increases cavity
among young adults, and it is more common in patients with Hispanic Respiratory distress/ Mediastinal mass Avoid sedation in
ethnicity and Native American genetic ancestry with germline GATA3 superior vena presence of tracheal
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polymorphism. Approximately half of the Ph-like cases have rear- cava syndrome compression.
rangements of the cytokine receptor–like factor 2 gene CRLF2, with Establish diagnosis
concomitant Janus kinase (JAK) mutations in one-third of the CRLF2- as soon as possible
rearranged cases. This genotype is associated with increased risk of and start
relapse. Remarkably, CRLF2 alterations occur in approximately 50% chemotherapy
of the cases with Down syndrome. JAK inhibitors have not yet been ALL, Acute lymphoblastic leukemia.
studied in patients with Down syndrome ALL, and could