lunes, 8 de abril de 2019

Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®) 1/5 —Health Professional Version - National Cancer Institute

Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®)—Health Professional Version - National Cancer Institute

National Cancer Institute



Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®)–Health Professional Version

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General Information About Childhood Acute Lymphoblastic Leukemia (ALL)

Cancer in children and adolescents is rare, although the overall incidence of childhood cancer, including ALL, has been slowly increasing since 1975.[1] Dramatic improvements in survival have been achieved in children and adolescents with cancer.[1-3] Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[1-3] For ALL, the 5-year survival rate has increased over the same time from 60% to approximately 90% for children younger than 15 years and from 28% to more than 75% for adolescents aged 15 to 19 years.[4] Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Incidence

ALL is the most common cancer diagnosed in children and represents approximately 25% of cancer diagnoses among children younger than 15 years.[2,3] In the United States, ALL occurs at an annual rate of approximately 41 cases per 1 million people aged 0 to 14 years and approximately 17 cases per 1 million people aged 15 to 19 years.[4] There are approximately 3,100 children and adolescents younger than 20 years diagnosed with ALL each year in the United States.[5] Since 1975, there has been a gradual increase in the incidence of ALL.[4,6]
A sharp peak in ALL incidence is observed among children aged 2 to 3 years (>90 cases per 1 million per year), with rates decreasing to fewer than 30 cases per 1 million by age 8 years.[2,3] The incidence of ALL among children aged 2 to 3 years is approximately fourfold greater than that for infants and is likewise fourfold to fivefold greater than that for children aged 10 years and older.[2,3]
The incidence of ALL appears to be highest in Hispanic children (43 cases per 1 million).[2,3,7,8] The incidence is substantially higher in white children than in black children, with a nearly threefold higher incidence of ALL from age 2 to 3 years in white children than in black children.[2,3,7]

Anatomy

Childhood ALL originates in the T and B lymphoblasts in the bone marrow (refer to Figure 1).
ENLARGEBlood cell development; drawing shows the steps a blood stem cell goes through to become a red blood cell, platelet, or white blood cell. A myeloid stem cell becomes a red blood cell, a platelet, or a myeloblast, which then becomes a granulocyte (the types of granulocytes are eosinophils, basophils, and neutrophils). A lymphoid stem cell becomes a lymphoblast and then becomes a B-lymphocyte, T-lymphocyte, or natural killer cell.
Figure 1. Blood cell development. Different blood and immune cell lineages, including T and B lymphocytes, differentiate from a common blood stem cell.
Marrow involvement of acute leukemia as seen by light microscopy is defined as follows:
  • M1: Fewer than 5% blast cells.
  • M2: 5% to 25% blast cells.
  • M3: Greater than 25% blast cells.
Almost all patients with ALL present with an M3 marrow.

Risk Factors for Developing ALL

Few factors associated with an increased risk of ALL have been identified. The primary accepted risk factors for ALL and associated genes (when relevant) include the following:
  • Prenatal exposure to x-rays.
  • Postnatal exposure to high doses of radiation (e.g., therapeutic radiation as previously used for conditions such as tinea capitis and thymus enlargement).
  • Previous treatment with chemotherapy.
  • Genetic conditions that include the following:
    • Down syndrome. (Refer to the Down syndrome section of this summary for more information.)
    • Neurofibromatosis (NF1).[9]
    • Bloom syndrome (BLM).[10]
    • Fanconi anemia (multiple genes; ALL is observed much less frequently than acute myeloid leukemia [AML]).[11]
    • Ataxia telangiectasia (ATM).[12]
    • Li-Fraumeni syndrome (TP53).[13-15]
    • Constitutional mismatch repair deficiency (biallelic mutation of MLH1, MSH2, MSH6, and PMS2).[16,17]
  • Low- and high-penetrance inherited genetic variants.[18] (Refer to the Low- and high-penetrance inherited genetic variants section of this summary for more information.)
  • Carriers of a constitutional Robertsonian translocation that involves chromosomes 15 and 21 are specifically and highly predisposed to developing iAMP21 ALL.[19]

Down syndrome

Children with Down syndrome have an increased risk of developing both ALL and AML,[20,21] with a cumulative risk of developing leukemia of approximately 2.1% by age 5 years and 2.7% by age 30 years.[20,21]
Approximately one-half to two-thirds of cases of acute leukemia in children with Down syndrome are ALL, and about 2% to 3% of childhood ALL cases occur in children with Down syndrome.[22-24] While the vast majority of cases of AML in children with Down syndrome occur before the age of 4 years (median age, 1 year),[25] ALL in children with Down syndrome has an age distribution similar to that of ALL in non–Down syndrome children, with a median age of 3 to 4 years.[22,23]
Patients with ALL and Down syndrome have a lower incidence of both favorable (t(12;21)(p13;q22)/ETV6-RUNX1 [TEL-AML1]) and hyperdiploidy [51–65 chromosomes]) and unfavorable (t(9;22)(q34;q11.2)) or t(4;11)(q21;q23) and hypodiploidy [<44 chromosomes]) cytogenetic findings and a near absence of T-cell phenotype.[22-26]
Approximately 50% to 60% of cases of ALL in children with Down syndrome have genomic alterations affecting CRLF2 that generally result in overexpression of the protein produced by this gene, which dimerizes with the interleukin-7 receptor alpha to form the receptor for the cytokine thymic stromal lymphopoietin.[27-29] CRLF2 genomic alterations are observed at a much lower frequency (<10%) in children with precursor B-cell ALL who do not have Down syndrome.[29-31] Based on the relatively small number of published series, it does not appear that genomic CRLF2 aberrations in patients with Down syndrome and ALL have prognostic relevance.[26,28] However, IKZF1 gene deletions, observed in up to 35% of patients with Down syndrome and ALL, have been associated with a significantly worse outcome in this group of patients.[28,32]
Approximately 20% of ALL cases arising in children with Down syndrome have somatically acquired JAK2 mutations,[27,28,33-35] a finding that is uncommon among younger children with ALL but that is observed in a subset of primarily older children and adolescents with high-risk precursor B-cell ALL.[36] Almost all Down syndrome ALL cases with JAK2mutations also have CRLF2 genomic alterations.[27-29] Preliminary evidence suggests no correlation between JAK2 mutation status and 5-year event-free survival in children with Down syndrome and ALL,[28,34] but more study is needed to address this issue, as well as the prognostic significance of CRLF2 alterations and IKZF1 gene deletions in this patient population.

Low- and high-penetrance inherited genetic variants

Genetic predisposition to ALL can be divided into several broad categories, as follows:
  • Association with genetic syndromes. Increased risk can be associated with the genetic syndromes listed above in which ALL is observed, although it is not the primary manifestation of the condition.
  • Common alleles. Another category for genetic predisposition includes common alleles with relatively small effect sizes that are identified by genome-wide association studies. Genome-wide association studies have identified a number of germline (inherited) genetic polymorphisms that are associated with the development of childhood ALL.[18] For example, the risk alleles of ARID5B are associated with the development of hyperdiploid (51–65 chromosomes) precursor B-cell ALL. ARID5B is a gene that encodes a transcriptional factor important in embryonic development, cell type–specific gene expression, and cell growth regulation.[37,38] Other genes with polymorphisms associated with increased risk of ALL include GATA3,[39] IKZF1,[37,38,40] CDKN2A,[41] CDKN2B,[40,41] CEBPE,[37] PIP4K2A,[39,42] and TP63.[43]
  • Rare germline variants with high penetrance. A germline variant in PAX5 that substitutes serine for glycine at amino acid 183 and that reduces PAX5 activity has been identified in several families that experienced multiple cases of ALL.[44,45] Similarly, several germline ETV6 variants that lead to loss of ETV6 function have been identified in kindreds affected by both thrombocytopenia and ALL.[46-48] Sequencing of ETV6 in remission (i.e., germline) specimens identified variants that were potentially related to ALL in approximately 1% of children with ALL that were evaluated.[46] This suggests a previously unrecognized contribution to ALL risk that will need to be assessed in future studies.[46-48]
    Rare, pathogenic germline TP53 variants are associated with an increased risk of ALL.[49] A study of 3,801 children with ALL observed that 26 patients (0.7%) had a pathogenic TP53 germline variant, with an associated odds ratio of 5.2 for ALL development.[49] Compared with ALL in children with TP53 wild-type status or TP53variants of unknown significance, ALL in children with pathogenic germline TP53variants was associated with older age at diagnosis (15.5 years vs. 7.3 years), hypodiploidy (65% vs. 1%), inferior event-free survival and overall survival, and a higher risk of second cancers.

Prenatal origin of childhood ALL

Development of ALL is in most cases a multistep process, with more than one genomic alteration required for frank leukemia to develop. In at least some cases of childhood ALL, the initial genomic alteration appears to occur in utero. Evidence to support this comes from the observation that the immunoglobulin or T-cell receptor antigen rearrangements that are unique to each patient’s leukemia cells can be detected in blood samples obtained at birth.[50,51] Similarly, in ALL characterized by specific chromosomal abnormalities, some patients have blood cells that carry at least one leukemic genomic abnormality at the time of birth, with additional cooperative genomic changes acquired postnatally.[50-52] Genomic studies of identical twins with concordant leukemia further support the prenatal origin of some leukemias.[50,53]
Evidence also exists that some children who never develop ALL are born with very rare blood cells carrying a genomic alteration associated with ALL. For example, in one study, 1% of neonatal blood spots (Guthrie cards) tested positive for the ETV6-RUNX1translocation, far exceeding the number of cases of ETV6-RUNX1 ALL in children.[54] Other reports confirm [55] or do not confirm [56,57] this finding, and methodological issues related to fluorescence in situ hybridization testing complicate interpretation of the initial 1% estimate.[58]

Clinical Presentation

The typical and atypical symptoms and clinical findings of childhood ALL have been published.[59-61]

Diagnosis

The diagnostic evaluation needed to definitively diagnose childhood ALL has been published.[59-62]

Overall Outcome for ALL

Among children with ALL, approximately 98% attain remission, and approximately 85% of patients aged 1 to 18 years with newly diagnosed ALL treated on current regimens are expected to be long-term event-free survivors, with over 90% surviving at 5 years.[63-66]
Despite the treatment advances in childhood ALL, numerous important biologic and therapeutic questions remain to be answered before the goal of curing every child with ALL with the least associated toxicity can be achieved. The systematic investigation of these issues requires large clinical trials, and the opportunity to participate in these trials is offered to most patients and families.
Clinical trials for children and adolescents with ALL are generally designed to compare therapy that is currently accepted as standard with investigational regimens that seek to improve cure rates and/or decrease toxicity. In certain trials in which the cure rate for the patient group is very high, therapy reduction questions may be asked. Much of the progress made in identifying curative therapies for childhood ALL and other childhood cancers has been achieved through investigator-driven discovery and tested in carefully randomized, controlled, multi-institutional clinical trials. Information about ongoing clinical trials is available from the NCI website.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
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World Health Organization (WHO) Classification System for Childhood ALL

The 2016 revision to the WHO classification of tumors of the hematopoietic and lymphoid tissues lists the following entities for acute lymphoid leukemias:[1]

2016 WHO Classification of B-Lymphoblastic Leukemia/Lymphoma

  • B-lymphoblastic leukemia/lymphoma, not otherwise specified (NOS).
  • B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities.
  • B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2); BCR-ABL1.
  • B-lymphoblastic leukemia/lymphoma with t(v;11q23.3); KMT2A rearranged.
  • B-lymphoblastic leukemia/lymphoma with t(12;21)(p13.2;q22.1); ETV6-RUNX1.
  • B-lymphoblastic leukemia/lymphoma with hyperdiploidy.
  • B-lymphoblastic leukemia/lymphoma with hypodiploidy.
  • B-lymphoblastic leukemia/lymphoma with t(5;14)(q31.1;q32.3); IL3-IGH.
  • B-lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3); TCF3-PBX1.
  • Provisional entity: B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like.
  • Provisional entity: B-lymphoblastic leukemia/lymphoma with iAMP21.

2016 WHO Classification of T-Lymphoblastic Leukemia/Lymphoma

  • Provisional entity: Early T-cell precursor lymphoblastic leukemia.

2016 WHO Classification of Acute Leukemias of Ambiguous Lineage

For acute leukemias of ambiguous lineage, the group of acute leukemias that have characteristics of both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), the WHO classification system is summarized in Table 1.[2,3] The criteria for lineage assignment for a diagnosis of mixed phenotype acute leukemia (MPAL) are provided in Table 2.[1]
Table 1. Acute Leukemias of Ambiguous Lineage According to the World Health Organization Classification of Tumors of Hematopoietic and Lymphoid Tissuesa
ConditionDefinition
NOS = not otherwise specified.
aBéné MC: Biphenotypic, bilineal, ambiguous or mixed lineage: strange leukemias! Haematologica 94 (7): 891-3, 2009.[2] Obtained from Haematologica/the Hematology Journal website http://www.haematologica.org.
Acute undifferentiated leukemiaAcute leukemia that does not express any marker considered specific for either lymphoid or myeloid lineage
Mixed phenotype acute leukemia with t(9;22)(q34;q11.2); BCR-ABL1Acute leukemia meeting the diagnostic criteria for mixed phenotype acute leukemia in which the blasts also have the (9;22) translocation or the BCR-ABL1 rearrangement
Mixed phenotype acute leukemia with t(v;11q23); KMT2A (MLL) rearrangedAcute leukemia meeting the diagnostic criteria for mixed phenotype acute leukemia in which the blasts also have a translocation involving the KMT2A gene
Mixed phenotype acute leukemia, B/myeloid, NOSAcute leukemia meeting the diagnostic criteria for assignment to both B and myeloid lineage, in which the blasts lack genetic abnormalities involving BCR-ABL1 or KMT2A
Mixed phenotype acute leukemia, T/myeloid, NOSAcute leukemia meeting the diagnostic criteria for assignment to both T and myeloid lineage, in which the blasts lack genetic abnormalities involving BCR-ABL1 or KMT2A
Mixed phenotype acute leukemia, B/myeloid, NOS—rare typesAcute leukemia meeting the diagnostic criteria for assignment to both B and T lineage
Other ambiguous lineage leukemiasNatural killer–cell lymphoblastic leukemia/lymphoma
Table 2. Lineage Assignment Criteria for Mixed Phenotype Acute Leukemia According to the 2016 Revision to the World Health Organization Classification of Myeloid Neoplasms and Acute Leukemiaa
LineageCriteria
aAdapted from Arber et al.[1]
bStrong defined as equal to or brighter than the normal B or T cells in the sample.
Myeloid lineageMyeloperoxidase (flow cytometry, immunohistochemistry, or cytochemistry); ormonocytic differentiation (at least two of the following: nonspecific esterase cytochemistry, CD11c, CD14, CD64, lysozyme)
T lineageStrongb cytoplasmic CD3 (with antibodies to CD3 epsilon chain); or surface CD3
B lineageStrongb CD19 with at least one of the following strongly expressed: CD79a, cytoplasmic CD22, or CD10; or weak CD19 with at least two of the following strongly expressed: CD79a, cytoplasmic CD22, or CD10
Leukemias of mixed phenotype may be seen in various presentations, including the following:
  1. Bilineal leukemias in which there are two distinct populations of cells, usually one lymphoid and one myeloid.
  2. Biphenotypic leukemias in which individual blast cells display features of both lymphoid and myeloid lineage.
Biphenotypic cases represent the majority of mixed phenotype leukemias.[4] Patients with B-myeloid biphenotypic leukemias lacking the TEL-AML1 fusion have lower rates of complete remission (CR) and significantly worse event-free survival (EFS) rates compared with patients with precursor B-cell ALL.[4] Some studies suggest that patients with biphenotypic leukemia may fare better with a lymphoid, as opposed to a myeloid, treatment regimen.[5-8] A large retrospective study from the international Berlin-Frankfurt-Münster (BFM) group demonstrated that initial therapy with an ALL-type regimen was associated with a superior outcome compared with AML-type or combined ALL/AML regimens, particularly in cases with CD19 positivity or other lymphoid antigen expression. In this study, hematopoietic stem cell transplantation (HSCT) in first CR was not beneficial, with the possible exception of cases with morphologic evidence of persistent marrow disease (≥5% blasts) after the first month of treatment.[8]
Key clinical and biological characteristics, as well as the prognostic significance for these entities, are discussed in the Cytogenetics/Genomics of Childhood ALL section of this summary.
References
  1. Arber DA, Orazi A, Hasserjian R, et al.: The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127 (20): 2391-405, 2016. [PUBMED Abstract]
  2. Béné MC: Biphenotypic, bilineal, ambiguous or mixed lineage: strange leukemias! Haematologica 94 (7): 891-3, 2009. [PUBMED Abstract]
  3. Borowitz MJ, Béné MC, Harris NL: Acute leukaemias of ambiguous lineage. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer, 2008, pp 150-5.
  4. Gerr H, Zimmermann M, Schrappe M, et al.: Acute leukaemias of ambiguous lineage in children: characterization, prognosis and therapy recommendations. Br J Haematol 149 (1): 84-92, 2010. [PUBMED Abstract]
  5. Rubnitz JE, Onciu M, Pounds S, et al.: Acute mixed lineage leukemia in children: the experience of St Jude Children's Research Hospital. Blood 113 (21): 5083-9, 2009. [PUBMED Abstract]
  6. Al-Seraihy AS, Owaidah TM, Ayas M, et al.: Clinical characteristics and outcome of children with biphenotypic acute leukemia. Haematologica 94 (12): 1682-90, 2009. [PUBMED Abstract]
  7. Matutes E, Pickl WF, Van't Veer M, et al.: Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification. Blood 117 (11): 3163-71, 2011. [PUBMED Abstract]
  8. Hrusak O, De Haas V, Stancikova J, et al.: International cooperative study identifies treatment strategy in childhood ambiguous lineage leukemia. Blood : , 2018. [PUBMED Abstract]

Cytogenetics/Genomics of Childhood ALL

The genomics of childhood ALL has been extensively investigated and multiple distinctive subtypes based on cytogenetic and molecular characterizations have been defined, each with its own pattern of clinical and prognostic characteristics.[1] Figure 2 illustrates the distribution of ALL cases by cytogenetic/molecular subtype.[1]
ENLARGEPie chart showing subclassification of childhood ALL.
Figure 2. Subclassification of childhood ALL. Blue wedges refer to B-progenitor ALL, yellow to recently identified subtypes of B-ALL, and red wedges to T-lineage ALL. Reprinted from Seminars in Hematology, Volume 50, Charles G. Mullighan, Genomic Characterization of Childhood Acute Lymphoblastic Leukemia, Pages 314–324, Copyright (2013), with permission from Elsevier.
The genomic landscape of precursor B-cell ALL is typified by a range of genomic alterations that disrupt normal B-cell development and in some cases by mutations in genes that provide a proliferation signal (e.g., activating mutations in RAS family genes or mutations/translocations leading to kinase pathway signaling). Genomic alterations leading to blockage of B-cell development include translocations (e.g., TCF3-PBX1 and ETV6-RUNX1), point mutations (e.g., IKZF1 and PAX5), and intragenic/intergenic deletions (e.g., IKZF1, PAX5, EBF, and ERG).[2]
The genomic alterations in precursor B-cell ALL tend not to occur at random, but rather to cluster within subtypes that can be delineated by biological characteristics such as their gene expression profiles. Cases with recurring chromosomal translocations (e.g., TCF3-PBX1 and ETV6-RUNX1, and MLL (KMT2A)-rearranged ALL) have distinctive biological features and illustrate this point, as do the examples below of specific genomic alterations within distinctive biological subtypes:
  • IKZF1 deletions and mutations are most commonly observed within cases of Philadelphia chromosome–positive (Ph+) ALL and Ph-like ALL.[3,4]
  • Intragenic ERG deletions occur within a distinctive subtype characterized by this alteration and lacking other recurring cytogenetic alterations associated with pediatric precursor B-cell ALL.[5-7]
  • TP53 mutations occur at high frequency in patients with low hypodiploid ALL with 32 to 39 chromosomes, and the TP53 mutations in these patients are often germline.[8] TP53mutations are uncommon in other patients with precursor B-cell ALL.
Activating point mutations in kinase genes are uncommon in high-risk precursor B-cell ALL, and JAK genes are the primary kinases that are found to be mutated. These mutations are generally observed in patients with Ph-like ALL that have CRLF2 abnormalities, although JAK2 mutations are also observed in approximately 15% of children with Down syndrome ALL.[4,9,10] Several kinase genes and cytokine receptor genes are activated by translocation as described below in the discussion of Ph-positive ALL and Ph-like ALL. FLT3mutations occur in a minority of cases (approximately 10%) of hyperdiploid ALL and MLL(KMT2A)-rearranged ALL, and are rare in other subtypes.[11]
Understanding of the genomics of precursor B-cell ALL at relapse is less advanced than understanding of ALL genomics at diagnosis. Childhood ALL is often polyclonal at diagnosis and under the selective influence of therapy, some clones may be extinguished and new clones with distinctive genomic profiles may arise.[12] Of particular importance are new mutations that arise at relapse that may be selected by specific components of therapy. As an example, mutations in NT5C2 are not found at diagnosis whereas specific mutations in NT5C2 were observed in 7 of 44 (16%) and 9 of 20 (45%) cases of precursor B-cell ALL with early relapse that were evaluated for this mutation.[12,13] NT5C2 mutations are uncommon in patients with late relapse, and they appear to induce resistance to mercaptopurine and thioguanine.[13] Another gene that is found mutated only at relapse is PRSP1, a gene involved purine biosynthesis.[14] Mutations were observed in 13.0% of a Chinese cohort and 2.7% of a German cohort, and were observed in patients with on-treatment relapses. The PRSP1 mutations observed in relapsed cases induce resistance to thiopurines in leukemia cell lines. CREBBP mutations are also enriched at relapse and appear to be associated with increased resistance to glucocorticoids.[12,15] With increased understanding of the genomics of relapse, it may be possible to tailor upfront therapy to avoid relapse or detect resistance-inducing mutations early and intervene before a frank relapse.
Specific genomic and chromosomal alterations are described below, with a focus on their prognostic significance.
T-cell ALL is characterized by genomic alterations leading to activation of transcriptional programs related to T-cell development and by a high frequency of cases (approximately 60%) with mutations in NOTCH1 and/or FBXW7 that result in activation of the NOTCH1 pathway.[16] In contrast to B-cell ALL, the prognostic significance of T-cell ALL genomic alterations is less well-defined. Cytogenetic abnormalities common in B-lineage ALL (e.g., hyperdiploidy, 51–65 chromosomes) are rare in T-cell ALL.[17,18]

B-cell ALL cytogenetics/genomics

A number of recurrent chromosomal abnormalities have been shown to have prognostic significance, especially in precursor B-cell ALL. Some chromosomal alterations are associated with more favorable outcomes, such as high hyperdiploidy (51–65 chromosomes) and the ETV6-RUNX1 fusion. Others historically have been associated with a poorer prognosis, including the Philadelphia chromosome (t(9;22)(q34;q11.2)), rearrangements of the MLL (KMT2A) gene, hypodiploidy, and intrachromosomal amplification of the AML1 gene (iAMP21).[19]
In recognition of the clinical significance of many of these genomic alterations, the 2016 revision of the World Health Organization classification of tumors of the hematopoietic and lymphoid tissues lists the following entities for precursor B-cell ALL:[20]
  • B-lymphoblastic leukemia/lymphoma, not otherwise specified (NOS).
  • B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities.
  • B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2); BCR-ABL1.
  • B-lymphoblastic leukemia/lymphoma with t(v;11q23.3); KMT2A rearranged.
  • B-lymphoblastic leukemia/lymphoma with t(12;21)(p13.2;q22.1); ETV6-RUNX1.
  • B-lymphoblastic leukemia/lymphoma with hyperdiploidy.
  • B-lymphoblastic leukemia/lymphoma with hypodiploidy.
  • B-lymphoblastic leukemia/lymphoma with t(5;14)(q31.1;q32.3); IL3-IGH.
  • B-lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3); TCF3-PBX1.
  • Provisional entity: B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like.
  • Provisional entity: B-lymphoblastic leukemia/lymphoma with iAMP21.
These and other chromosomal and genomic abnormalities for childhood ALL are described below.
  1. Chromosome number
    • High hyperdiploidy (51–65 chromosomes)
      High hyperdiploidy, defined as 51 to 65 chromosomes per cell or a DNA index greater than 1.16, occurs in 20% to 25% of cases of precursor B-cell ALL, but very rarely in cases of T-cell ALL.[21] Hyperdiploidy can be evaluated by measuring the DNA content of cells (DNA index) or by karyotyping. In cases with a normal karyotype or in which standard cytogenetic analysis was unsuccessful, interphase fluorescence in situ hybridization (FISH) may detect hidden hyperdiploidy. High hyperdiploidy generally occurs in cases with clinically favorable prognostic factors (patients aged 1 to <10 years with a low white blood cell [WBC] count) and is itself an independent favorable prognostic factor.[21-23] Within the hyperdiploid range of 51 to 65 chromosomes, patients with higher modal numbers (58–66) appeared to have a better prognosis in one study.[23] Hyperdiploid leukemia cells are particularly susceptible to undergoing apoptosis and accumulate higher levels of methotrexate and its active polyglutamate metabolites,[24] which may explain the favorable outcome commonly observed in these cases.
      While the overall outcome of patients with high hyperdiploidy is considered to be favorable, factors such as age, WBC count, specific trisomies, and early response to treatment have been shown to modify its prognostic significance.[25,26]
      Patients with trisomies of chromosomes 4, 10, and 17 (triple trisomies) have been shown to have a particularly favorable outcome as demonstrated by both Pediatric Oncology Group (POG) and Children's Cancer Group analyses of National Cancer Institute (NCI) standard-risk ALL.[27] POG data suggest that NCI standard-risk patients with trisomies of 4 and 10, without regard to chromosome 17 status, have an excellent prognosis.[28]
      Chromosomal translocations may be seen with high hyperdiploidy, and in those cases, patients are more appropriately risk-classified based on the prognostic significance of the translocation. For instance, in one study, 8% of patients with the Philadelphia chromosome (t(9;22)(q34;q11.2)) also had high hyperdiploidy,[29] and the outcome of these patients (treated without tyrosine kinase inhibitors) was inferior to that observed in non-Philadelphia chromosome–positive (Ph+) high hyperdiploid patients.
      Certain patients with hyperdiploid ALL may have a hypodiploid clone that has doubled (masked hypodiploidy).[30] These cases may be interpretable based on the pattern of gains and losses of specific chromosomes. These patients have an unfavorable outcome, similar to those with hypodiploidy.[30]
      Near triploidy (68–80 chromosomes) and near tetraploidy (>80 chromosomes) are much less common and appear to be biologically distinct from high hyperdiploidy.[31] Unlike high hyperdiploidy, a high proportion of near tetraploid cases harbor a cryptic ETV6-RUNX1 fusion.[31-33] Near triploidy and tetraploidy were previously thought to be associated with an unfavorable prognosis, but later studies suggest that this may not be the case.[31,33]
      The genomic landscape of hyperdiploid ALL is represented by mutations in genes of the receptor tyrosine kinase (RTK)/RAS pathway in approximately one-half of cases. Genes encoding histone modifiers are also present in a recurring manner in a minority of cases. Analysis of mutation profiles demonstrates that chromosomal gains are early events in the pathogenesis of hyperdiploid ALL.[34]
    • Hypodiploidy (<44 chromosomes)
      Precursor B-cell ALL cases with fewer than the normal number of chromosomes have been subdivided in various ways, with one report stratifying based on modal chromosome number into the following four groups:[30]
      • Near-haploid: 24 to 29 chromosomes (n = 46).
      • Low-hypodiploid: 33 to 39 chromosomes (n = 26).
      • High-hypodiploid: 40 to 43 chromosomes (n = 13).
      • Near-diploid: 44 chromosomes (n = 54).
      Most patients with hypodiploidy are in the near-haploid and low-hypodiploid groups, and both of these groups have an elevated risk of treatment failure compared with nonhypodiploid cases.[30,35] Patients with fewer than 44 chromosomes have a worse outcome than do patients with 44 or 45 chromosomes in their leukemic cells.[30] One study of 20 patients with near-haploid or low-hypodiploid ALL indicated that minimal residual disease (MRD) may have prognostic significance in the hypodiploid population.[36]
      The recurring genomic alterations of near-haploid and low-hypodiploid ALL appear to be distinctive from each other and from other types of ALL.[8] In near-haploid ALL, alterations targeting RTK signaling, RAS signaling, and IKZF3are common.[37] In low-hypodiploid ALL, genetic alterations involving TP53, RB1, and IKZF2 are common. Importantly, the TP53 alterations observed in low-hypodiploid ALL are also present in nontumor cells in approximately 40% of cases, suggesting that these mutations are germline and that low-hypodiploid ALL represents, in some cases, a manifestation of Li-Fraumeni syndrome.[8]
      Approximately two-thirds of patients with ALL and germline pathogenic TP53variants have hypodiploid ALL.[38]
  2. Chromosomal translocations and gains/deletions of chromosomal segments
    • t(12;21)(p13.2;q22.1); ETV6-RUNX1 (formerly known as TEL-AML1)
      Fusion of the ETV6 gene on chromosome 12 to the RUNX1 gene on chromosome 21 is present in 20% to 25% of cases of precursor B-cell ALL but is rarely observed in T-cell ALL.[32] The t(12;21)(p12;q22) produces a cryptic translocation that is detected by methods such as FISH, rather than conventional cytogenetics, and it occurs most commonly in children aged 2 to 9 years.[39,40] Hispanic children with ALL have a lower incidence of t(12;21)(p13;q22) than do white children.[41]
      Reports generally indicate favorable event-free survival (EFS) and overall survival (OS) in children with the ETV6-RUNX1 fusion; however, the prognostic impact of this genetic feature is modified by the following factors:[42-46]
      • Early response to treatment.
      • NCI risk category (age and WBC count at diagnosis).
      • Treatment regimen.
      In one study of the treatment of newly diagnosed children with ALL, multivariate analysis of prognostic factors found age and leukocyte count, but not ETV6-RUNX1, to be independent prognostic factors.[42] It does not appear that the presence of secondary cytogenetic abnormalities, such as deletion of ETV6 (12p) or CDKN2A/B (9p), impacts the outcome of patients with the ETV6-RUNX1 fusion.[46,47] There is a higher frequency of late relapses in patients with ETV6-RUNX1 fusion compared with other precursor B-cell ALL.[42,48] Patients with the ETV6-RUNX1 fusion who relapse seem to have a better outcome than other relapse patients,[49] with an especially favorable prognosis for patients who relapse more than 36 months from diagnosis.[50] Some relapses in patients with t(12;21)(p13;q22) may represent a new independent second hit in a persistent preleukemic clone (with the first hit being the ETV6-RUNX1 translocation).[51,52]
    • t(9;22)(q34.1;q11.2); BCR-ABL1 (Ph+)
      The Philadelphia chromosome t(9;22)(q34;q11.2) is present in approximately 3% of children with ALL and leads to production of a BCR-ABL1 fusion protein with tyrosine kinase activity (refer to Figure 3).
      ENLARGEPhiladelphia chromosome; three-panel drawing shows a piece of chromosome 9 and a piece of chromosome 22 breaking off and trading places, creating a changed chromosome 22 called the Philadelphia chromosome. In the left panel, the drawing shows a normal chromosome 9 with the ABL gene and a normal chromosome 22 with the BCR gene. In the center panel, the drawing shows chromosome 9 breaking apart in the ABL gene and chromosome 22 breaking apart below the BCR gene. In the right panel, the drawing shows chromosome 9 with the piece from chromosome 22 attached and chromosome 22 with the piece from chromosome 9 containing part of the ABL gene attached. The changed chromosome 22 with the BCR-ABLgene is called the Philadelphia chromosome.
      Figure 3. The Philadelphia chromosome is a translocation between the ABL-1 oncogene (on the long arm of chromosome 9) and the breakpoint cluster region (BCR) (on the long arm of chromosome 22), resulting in the fusion gene BCR-ABL1. BCR-ABL1 encodes an oncogenic protein with tyrosine kinase activity.
      This subtype of ALL is more common in older children with precursor B-cell ALL and high WBC count, with the incidence of the t(9;22)(q34;q11.2) increasing to about 25% in young adults with ALL.
      Historically, the Philadelphia chromosome t(9;22)(q34;q11.2) was associated with an extremely poor prognosis (especially in those who presented with a high WBC count or had a slow early response to initial therapy), and its presence had been considered an indication for allogeneic hematopoietic stem cell transplantation (HSCT) in patients in first remission.[29,53-55] Inhibitors of the BCR-ABL1 tyrosine kinase, such as imatinib mesylate, are effective in patients with Ph+ ALL.[56] A study by the Children's Oncology Group (COG), which used intensive chemotherapy and concurrent imatinib mesylate given daily, demonstrated a 5-year EFS rate of 70% ± 12%, which was superior to the EFS rate of historical controls in the pre-tyrosine kinase inhibitor (imatinib mesylate) era.[57,58]
    • t(v;11q23.3); MLL (KMT2A)-rearranged
      Rearrangements involving the MLL (KMT2A) gene occur in approximately 5% of childhood ALL cases overall, but in up to 80% of infants with ALL. These rearrangements are generally associated with an increased risk of treatment failure.[59-62] The t(4;11)(q21;q23) is the most common rearrangement involving the MLL gene in children with ALL and occurs in approximately 1% to 2% of childhood ALL.[60,63]
      Patients with the t(4;11)(q21;q23) are usually infants with high WBC counts; they are more likely than other children with ALL to have central nervous system (CNS) disease and to have a poor response to initial therapy.[64] While both infants and adults with the t(4;11)(q21;q23) are at high risk of treatment failure, children with the t(4;11)(q21;q23) appear to have a better outcome than either infants or adults.[59,60] Irrespective of the type of MLL (KMT2A) gene rearrangement, infants with leukemia cells that have MLL gene rearrangements have a worse treatment outcome than older patients whose leukemia cells have an MLL gene rearrangement.[59,60] Whole-genome sequencing has determined that cases of infant ALL with MLL gene rearrangements have few additional genomic alterations, none of which have clear clinical significance.[11] Deletion of the MLL gene has not been associated with an adverse prognosis.[65]
      Of interest, the t(11;19)(q23;p13.3) involving MLL (KMT2A) and MLLT1/ENLoccurs in approximately 1% of ALL cases and occurs in both early B-lineage and T-cell ALL.[66] Outcome for infants with the t(11;19) is poor, but outcome appears relatively favorable in older children with T-cell ALL and the t(11;19).[66]
    • t(1;19)(q23;p13.3); TCF3-PBX1 and t(17;19)(q22;p13); TCF3-HLF
      The t(1;19) occurs in approximately 5% of childhood ALL cases and involves fusion of the TCF3 gene on chromosome 19 to the PBX1 gene on chromosome 1.[67,68] The t(1;19) may occur as either a balanced translocation or as an unbalanced translocation and is the primary recurring genomic alteration of the pre-B ALL immunophenotype (cytoplasmic Ig positive).[69] Black children are relatively more likely than white children to have pre-B ALL with the t(1;19).[70]
      The t(1;19) had been associated with inferior outcome in the context of antimetabolite-based therapy,[71] but the adverse prognostic significance was largely negated by more aggressive multiagent therapies.[68,72] However, in a trial conducted by St. Jude Children's Research Hospital (SJCRH) on which all patients were treated without cranial radiation, patients with the t(1;19) had an overall outcome comparable to children lacking this translocation, with a higher risk of CNS relapse and a lower rate of bone marrow relapse, suggesting that more intensive CNS therapy may be needed for these patients.[73,74]
      The t(17;19) resulting in the TCF3-HLF fusion occurs in less than 1% of pediatric ALL cases. ALL with the TCF3-HLF fusion is associated at diagnosis with disseminated intravascular coagulation and with hypercalcemia. Outcome is very poor for children with the t(17;19), with a literature review noting mortality for 20 of 21 cases reported.[75] In addition to the TCF3-HLF fusion, the genomic landscape of this ALL subtype was characterized by deletions in genes involved in B-cell development (PAX5, BTG1, and VPREB1) and by mutations in RAS pathway genes (NRAS, KRAS, and PTPN11).[69]
    • DUX4-rearranged ALL with frequent ERG deletions
      Approximately 5% of standard-risk and 10% of high-risk pediatric precursor B-cell ALL patients have a rearrangement involving DUX4 that leads to its overexpression.[76,77] The frequency in older adolescents (aged >15 years) is approximately 10%. The most common rearrangement produces IGH-DUX4fusions, with ERG-DUX4 fusions also observed. Approximately 50% of DUX4-rearranged cases have focal intragenic deletions involving ERG that are not observed in other ALL subtypes,[76,77] and DUX4-rearranged cases show a distinctive gene expression pattern that was initially identified as being associated with these focal deletions in ERG.[5-7] IKZF1 alterations are observed in 35% to 40% of DUX4-rearranged ALL.[76,77] ERG deletion connotes an excellent prognosis, with OS exceeding 90%; even when the IZKF1 deletion is present, prognosis remains highly favorable.[5-7] Patients with DUX4rearrangements who lack ERG deletion also appear to have favorable prognosis.[77]
    • MEF2D-rearranged ALL
      Gene fusions involving MEF2D, a transcription factor that is expressed during B-cell development, are observed in approximately 4% of childhood ALL cases.[78,79] Although multiple fusion partners may occur, most cases involve BCL9, which is located on chromosome 1q21, as is MEF2D.[78,80] The interstitial deletion producing the MEF2D-BCL9 fusion is too small to be detected by conventional cytogenetic methods. Cases with MEF2D gene fusions show a distinctive gene expression profile, except for rare cases with MEF2D-CSFR1 that have a Philadelphia chromosome (Ph)–like gene expression profile.[78,81] The median age at diagnosis for cases of MEF2D-rearranged ALL in studies that included both adult and pediatric patients was 12 to 14 years.[78,79] For 22 children with MEF2D-rearranged ALL enrolled in a high-risk ALL clinical trial, the 5-year EFS was 72% (standard error, ±10%), which was inferior to that for other patients.[78]
    • ZNF384-rearranged ALL
      ZNF384 is a transcription factor that is rearranged in approximately 4% to 5% of pediatric B-cell ALL cases.[78,82,83] Multiple fusion partners for ZNF384 have been reported, including ARID1B, CREBBP, EP300, SMARCA2, TAF15, and TCF3. Regardless of the fusion partner, ZNF384-rearranged ALL cases show a distinctive gene expression profile.[78,82,83] ZNF384 rearrangement does not appear to confer independent prognostic significance.[78,82,83] The immunophenotype of B-cell ALL with ZNF384 rearrangement is characterized by weak or negative CD10 expression, with expression of CD13 and/or CD33 commonly observed.[82,83] Cases of mixed phenotype B/myeloid acute leukemia that have ZNF384 gene fusions have been reported, but it is unclear whether the clinical behavior of these cases is the same as that of ZNF384-rearranged B-cell ALL.[84,85]
    • t(5;14)(q31.1;q32.3); IL3-IGH
      This entity is included in the 2016 revision of the WHO classification of tumors of the hematopoietic and lymphoid tissues.[20] The finding of t(5;14)(q31.1;q32.3) in patients with ALL and hypereosinophilia in the 1980s was followed by the identification of the IL3-IGH fusion as the underlying genetic basis for the condition.[86,87] The joining of the IGH locus to the promoter region of the interleukin-3 gene (IL3) leads to dysregulation of IL3 expression.[88] Cytogenetic abnormalities in children with ALL and eosinophilia are variable, with only a subset resulting from the IL3-IGH fusion.[89]
      The number of cases of IL3-IGH ALL described in the published literature is too small to assess the prognostic significance of the IL3-IGH fusion.
    • Intrachromosomal amplification of chromosome 21 (iAMP21)
      iAMP21 with multiple extra copies of the RUNX1 (AML1) gene at 21q22 occurs in approximately 2% of precursor B-cell ALL cases and is associated with older age (median, approximately 10 years), presenting WBC of less than 50 × 109/L, a slight female preponderance, and high end-induction MRD.[90-92]
      The United Kingdom (UK)–ALL clinical trials group initially reported that the presence of iAMP21 conferred a poor prognosis in patients treated in the MRC ALL 97/99 trial (5-year EFS, 29%).[19] In their subsequent trial (UKALL2003 [NCT00222612]), patients with iAMP21 were assigned to a more intensive chemotherapy regimen and had a markedly better outcome (5-year EFS, 78%).[91] Similarly, the COG has reported that iAMP21 was associated with a significantly inferior outcome in NCI standard-risk patients (4-year EFS, 73% for iAMP21 vs. 92% in others), but not in NCI high-risk patients (4-year EFS, 73% vs. 80%).[90] On multivariate analysis, iAMP21 was an independent predictor of inferior outcome only in NCI standard-risk patients.[90] The results of the UKALL2003 and COG studies suggest that treatment of iAMP21 patients with high-risk chemotherapy regimens abrogates its adverse prognostic significance and obviates the need for SCT in first remission.[92]
    • Amplification of PAX5
      PAX5 amplification was identified in approximately 1% of B-cell ALL cases, and it was usually detected in cases lacking known leukemia-driver genomic alterations.[93] Cases with PAX5 amplification show male predominance (66%), with most (55%) having NCI high-risk status. For a cohort of patients with PAX5amplification diagnosed between 1993 and 2015, the 5-year EFS rate was 49% (95% confidence interval [CI], 36%–61%), and the OS rate was 67% (95% CI, 54%–77%), suggesting a relatively poor prognosis for this B-cell ALL subtype.
    • BCR-ABL1–like (Ph-like)
      BCR-ABL1–negative patients with a gene expression profile similar to BCR-ABL1–positive patients have been referred to as BCR-ABL1–like.[94-96] This occurs in 10% to 20% of pediatric ALL patients, increasing in frequency with age, and has been associated with IKZF1 deletion or mutation.[9,94,95,97,98]
      Retrospective analyses have indicated that patients with BCR-ABL1–like ALL have a poor prognosis.[4,94] In one series, the 5-year EFS for NCI high-risk children and adolescents with BCR-ABL1–like ALL was 58% and 41%, respectively.[4] While it is more frequent in older and higher-risk patients, the BCR-ABL1–like subtype has also been identified in NCI standard-risk patients. In a COG study, 13.6% of 1,023 NCI standard-risk B-cell ALL patients were found to have BCR-ABL1–like ALL; these patients had an inferior EFS compared with non-BCR-ABL1–like standard-risk patients (82% vs. 91%), although no difference in overall survival (93% vs. 96%) was noted.[99] In one study of 40 BCR-ABL1–like patients, the adverse prognostic significance of this subtype appeared to be abrogated when patients were treated with risk-directed therapy on the basis of MRD levels.[100]
      The hallmark of BCR-ABL1–like ALL is activated kinase signaling, with 50% containing CRLF2 genomic alterations [96,101] and half of those cases containing concomitant JAK mutations.[102] Additional information about BCR-ABL1–like ALL cases with CRLF2 genomic alterations is provided below.
      Many of the remaining cases of BCR-ABL1–like ALL have been noted to have a series of translocations with a common theme of involvement of kinases, including ABL1, ABL2, CSF1R, JAK2, and PDGFRB.[4,97] Fusion proteins from these gene combinations have been noted in some cases to be transformative and have responded to tyrosine kinase inhibitors both in vitro and in vivo,[97] suggesting potential therapeutic strategies for these patients. The prevalence of targetable kinase fusions in BCR-ABL1–like ALL is lower in NCI standard-risk patients (3.5%) than in NCI high-risk patients (approximately 30%).[99] Point mutations in kinase genes, aside from those in JAK1 and JAK2, are uncommon in Ph-like ALL cases.[9]
      Genomic alterations in CRLF2, a cytokine receptor gene located on the pseudoautosomal regions of the sex chromosomes, have been identified in 5% to 10% of cases of precursor B-cell ALL; they represent approximately 50% of cases of BCR-ABL1–like ALL.[103-105] The chromosomal abnormalities that commonly lead to CRLF2 overexpression include translocations of the IgH locus (chromosome 14) to CRLF2 and interstitial deletions in pseudoautosomal regions of the sex chromosomes, resulting in a P2RY8-CRLF2 fusion.[9,101,103,104] CRLF2 abnormalities are strongly associated with the presence of IKZF1 deletions and JAK mutations;[9,101,102,104,106] they are also more common in children with Down syndrome.[104] Point mutations in tyrosine kinase genes other than JAK1 and JAK2 are uncommon in CRLF2-overexpressing cases.[9]
      Although the results of several retrospective studies suggest that CRLF2abnormalities may have adverse prognostic significance on univariate analyses, most do not find this abnormality to be an independent predictor of outcome.[101,103,104,107,108] For example, in a large European study, increased expression of CRLF2 was not associated with unfavorable outcome in multivariate analysis, while IKZF1 deletion and BCR-ABL1–like expression signatures were associated with unfavorable outcome.[98] Controversy exists about whether the prognostic significance of CRLF2 abnormalities should be analyzed based on CRLF2 overexpression or on the presence of CRLF2 genomic alterations.[107,108]
      Approximately 9% of BCR-ABL1–like ALL cases result from rearrangements that lead to overexpression of a truncated erythropoietin receptor (EPOR).[109] The C-terminal region of the receptor that is lost is the region that is mutated in primary familial congenital polycythemia and that controls stability of the EPOR. The portion of the EPOR remaining is sufficient for JAK-STAT activation and for driving leukemia development.
    • IKZF1 deletions
      IKZF1 deletions, including deletions of the entire gene and deletions of specific exons, are present in approximately 15% of precursor B-cell ALL cases. Less commonly, IKZF1 can be inactivated by deleterious point mutations.[95] Cases with IKZF1 deletions tend to occur in older children, have a higher WBC count at diagnosis, and are therefore, more common in NCI high-risk patients than in NCI standard-risk patients.[2,95,106,110] A high proportion of BCR-ABL1 cases have a deletion of IKZF1,[3,106] and ALL arising in children with Down syndrome appears to have elevated rates of IKZF1 deletions.[111] IKZF1deletions are also common in cases with CRLF2 genomic alterations and in Ph-like (BCR-ABL1–like) ALL (see above).[5,94,106]
      Multiple reports have documented the adverse prognostic significance of an IKZF1 deletion, and most studies have reported that this deletion is an independent predictor of poor outcome on multivariate analyses.[5,94,95,98,106,112-116]; [117][Level of evidence: 2Di] However, the prognostic significance of IKZF1 may not apply equally across ALL biological subtypes, as illustrated by the apparent lack of prognostic significance in patients with ERGdeletion.[7] The Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP)–Berlin-Frankfurt-Münster (BFM) group reported that IKZF1 deletions were significant adverse prognostic factors only in B-cell ALL patients with high end-induction MRD and in whom co-occurrence of deletions of CDKN2A, CDKN2B, PAX5, or PAR1 (in the absence of ERG deletion) were identified.[118]
      There are few published results of changing therapy on the basis of IKZF1 gene status. The Malaysia-Singapore group published results of two consecutive trials. In the first trial (MS2003), IKZF1 status was not considered in risk stratification, while in the subsequent trial (MS2010), IKZF1-deleted patients were excluded from the standard-risk group. Thus, more IKZF1-deleted patients in the MS2010 trial received intensified therapy. Patients with IKZF1-deleted ALL had improved outcomes in MS2010 compared with patients in MS2003, but interpretation of this observation is limited by other changes in risk stratification and therapeutic differences between the two trials.[119][Level of evidence: 2A]

T-cell ALL cytogenetics/genomics

Multiple chromosomal translocations have been identified in T-cell ALL that lead to deregulated expression of the target genes. These chromosome rearrangements fuse genes encoding transcription factors (e.g., TAL1/TAL2, LMO1 and LMO2, LYL1, TLX1, TLX3, NKX2-I, HOXA, and MYB) to one of the T-cell receptor loci (or to other genes) and result in deregulated expression of these transcription factors in leukemia cells.[16,17,120-124] These translocations are often not apparent by examining a standard karyotype, but can be identified using more sensitive screening techniques, including fluorescence in situhybridization (FISH) or polymerase chain reaction (PCR).[17] Mutations in a noncoding region near the TAL1 gene that produce a super-enhancer upstream of TAL1 represent nontranslocation genomic alterations that can also activate TAL1 transcription to induce T-cell ALL.[125]
Translocations resulting in chimeric fusion proteins are also observed in T-cell ALL.[126]
  • A NUP214-ABL1 fusion has been noted in 4% to 6% of T-cell ALL cases and is observed in both adults and children, with a male predominance.[127-129] The fusion is cytogenetically cryptic and is seen in FISH on amplified episomes or, more rarely, as a small homogeneous staining region.[129] T-cell ALL may also uncommonly show ABL1 fusion proteins with other gene partners (e.g., ETV6, BCR, and EML1).[129] ABL tyrosine kinase inhibitors, such as imatinib or dasatinib, may demonstrate therapeutic benefits in this T-cell ALL subtype,[127,128,130] although clinical experience with this strategy is very limited.[131-133]
  • Gene fusions involving SPI1 (encoding the transcription factor PU.1) were reported in 4% of Japanese children with T-cell ALL.[134] Fusion partners included STMN1 and TCF7. T-cell ALL cases with SPI1 fusions had a particularly poor prognosis; six of seven affected individuals died within 3 years of diagnosis of early relapse.
  • Other recurring gene fusions in T-cell ALL patients include those involving MLLT10, KMT2A, and NUP98.[16]
Notch pathway signaling is commonly activated by NOTCH1 and FBXW7 gene mutations in T-cell ALL, and these are the most commonly mutated genes in pediatric T-cell ALL.[16,135] NOTCH1-activating gene mutations occur in approximately 50% to 60% of T-cell ALL cases, and FBXW7-inactivating gene mutations occur in approximately 15% of cases, with the result that approximately 60% of cases have Notch pathway activation by mutations in at least one of these genes.[136]
The prognostic significance of NOTCH1/FBXW7 mutations may be modulated by genomic alterations in RAS and PTEN. The French Acute Lymphoblastic Leukaemia Study Group (FRALLE) and the Group for Research on Adult Acute Lymphoblastic Leukemia groups reported that patients having mutated NOTCH1/FBXW7 and wild-type PTEN/RAS constituted a favorable-risk group while patients with PTEN or RAS mutations, regardless of NOTCH1/FBXW7 status, have a significantly higher risk of treatment failure.[126,137] In the FRALLE study, 5-year cumulative incidence of relapse and disease-free survival (DFS) were 50% and 46% for patients with mutated NOTCH1/FBXW7 and mutated PTEN/RAS versus 13% and 87% for patients with mutated NOTCH1/FBXW7 and wild-type PTEN/RAS.[126] The overall 5-year DFS in the FRALLE study was 73%, and additional research is needed to determine whether the same prognostic significance for NOTCH1/FBXW7 and PTEN/RASmutations will apply to current treatment regimens, which produce overall 5-year DFS rates that approach 90%.

Early T-cell precursor ALL

Detailed molecular characterization of early T-cell precursor ALL showed this entity to be highly heterogeneous at the molecular level, with no single gene affected by mutation or copy number alteration in more than one-third of cases.[138] Compared with other T-cell ALL cases, the early T-cell precursor group had a lower rate of NOTCH1 mutations and significantly higher frequencies of alterations in genes regulating cytokine receptors and RAS signaling, hematopoietic development, and histone modification. The transcriptional profile of early T-cell precursor ALL shows similarities to that of normal hematopoietic stem cells and myeloid leukemia stem cells.[138]
Studies have found that the absence of biallelic deletion of the TCRgamma locus (ABGD), as detected by comparative genomic hybridization and/or quantitative DNA-PCR, was associated with early treatment failure in patients with T-cell ALL.[139,140] ABGD is characteristic of early thymic precursor cells, and many of the T-cell ALL patients with ABGD have an immunophenotype consistent with the diagnosis of early T-cell precursor phenotype.

Gene polymorphisms in drug metabolic pathways

A number of polymorphisms of genes involved in the metabolism of chemotherapeutic agents have been reported to have prognostic significance in childhood ALL.[141-143] For example, patients with mutant phenotypes of thiopurine methyltransferase (TPMT, a gene involved in the metabolism of thiopurines, such as mercaptopurine [6-MP]), appear to have more favorable outcomes,[144] although such patients may also be at higher risk of developing significant treatment-related toxicities, including myelosuppression and infection.[145,146] Patients with homozygosity for TPMT variants associated with low enzymatic activity tolerate only very low doses of mercaptopurine (approximately 10% of the standard dose) and are treated with reduced doses of mercaptopurine to avoid excessive toxicity. Patients who are heterozygous for this mutant enzyme gene generally tolerate mercaptopurine without serious toxicity, but they do require more frequent dose reductions for hematologic toxicity than do patients who are homozygous for the normal allele.[147,148]
Germline variants in nucleoside diphosphate–linked moiety X-type motif 15 (NUDT15) that reduce or abolish activity of this enzyme also lead to diminished tolerance to thiopurines.[147,149] The variants are most common in East Asians and Hispanics, and they are rare in Europeans and Africans. Patients homozygous for the risk variants tolerate only very low doses of mercaptopurine, while patients heterozygous for the risk alleles tolerate lower doses than do patients homozygous for the wild-type allele (approximately 25% dose reduction on average), but there is broad overlap in tolerated doses between the two groups.[147,150]
Gene polymorphisms may also affect the expression of proteins that play central roles in the cellular effects of anticancer drugs. As an example, patients who are homozygous for a polymorphism in the promoter region of CEP72 (a centrosomal protein involved in microtubule formation) are at increased risk of vincristine neurotoxicity.[151]
Genome-wide polymorphism analysis has identified specific single nucleotide polymorphisms associated with high end-induction MRD and risk of relapse. Polymorphisms of IL-15, as well as genes associated with the metabolism of etoposide and methotrexate, were significantly associated with treatment response in two large cohorts of ALL patients treated on SJCRH and COG protocols.[152] Polymorphic variants involving the reduced folate carrier and methotrexate metabolism have been linked to toxicity and outcome.[153,154] While these associations suggest that individual variations in drug metabolism can affect outcome, few studies have attempted to adjust for these variations; it is unknown whether individualized dose modification on the basis of these findings will improve outcome.
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