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    Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®): Treatment - Health Professional Information [NCI] - Risk-based Treatment Assignment


    Cytogenetics/genomic alterations

    A number of recurrent chromosomal abnormalities have been shown to have prognostic significance, especially in B-precursor ALL. Some chromosomal abnormalities are associated with more favorable outcomes, such as high hyperdiploidy (51-65 chromosomes) and the ETV6-RUNX1 fusion. Others are associated with a poorer prognosis, including the Philadelphia chromosome (t(9;22)), rearrangements of the MLL gene (chromosome 11q23), and intrachromosomal amplification of the AML1 gene (iAMP21).[112]

    Prognostically significant chromosomal abnormalities in childhood ALL include the following:

    1. Chromosome number
      • High hyperdiploidy

        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.[113] 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 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 WBC count) and is itself an independent favorable prognostic factor.[19,113,114] Within the hyperdiploid range of 51 to 66 chromosomes, patients with higher modal numbers (58-66) appeared to have a better prognosis in one study.[19] Hyperdiploid leukemia cells are particularly susceptible to undergoing apoptosis and accumulate higher levels of methotrexate and its active polyglutamate metabolites,[115] 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.[116]

        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 (CCG) analyses of NCI standard-risk ALL.[117] POG data suggest that NCI standard-risk patients with trisomies of 4 and 10, without regard to chromosome 17 status, have an excellent prognosis.[118]

        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)) also had high hyperdiploidy,[119] 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).[120] 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.[120]

        Near triploidy (68-80 chromosomes) and near tetraploidy (>80 chromosomes) are much less common and appear to be biologically distinct from high hyperdiploidy.[121] Unlike high hyperdiploidy, a high proportion of near tetraploid cases harbor a cryptic ETV6-RUNX1 fusion.[121,122,123] 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.[121,123]

      • 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:[120]

        • 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.[120,124] Patients with fewer than 44 chromosomes have a worse outcome than do patients with 44 or 45 chromosomes in their leukemic cells.[120]

        The recurring genomic alterations of near-haploid and low-hypodiploid ALL appear to be distinctive from each other and from other types of ALL.[125] In near-haploid ALL, alterations targeting receptor tyrosine kinase signaling, Ras signaling, and IKZF3 are common. 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.[125]

    2. Chromosomal translocations
      • ETV6-RUNX1 (t(12;21) cryptic translocation, formerly known as TEL-AML1)

        Fusion of the ETV6 gene on chromosome 12 to the RUNX1 gene on chromosome 21 can be detected in 20% to 25% of cases of B-precursor ALL but is rarely observed in T-cell ALL.[122] The t(12;21) occurs most commonly in children aged 2 to 9 years.[126,127] Hispanic children with ALL have a lower incidence of t(12;21) than do white children.[128]

        Reports generally indicate favorable EFS and OS in children with the ETV6-RUNX1 fusion; however, the prognostic impact of this genetic feature is modified by the following factors: [129,130,131,132]

        • 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.[129] There is a higher frequency of late relapses in patients with ETV6-RUNX1 fusion compared with other B-precursor ALL.[129,133] Patients with the ETV6-RUNX1 fusion who relapse seem to have a better outcome than other relapse patients,[134] with an especially favorable prognosis for patients who relapse more than 36 months from diagnosis.[135] Some relapses in patients with t(12;21) may represent a new independent second hit in a persistent preleukemic clone (with the first hit being the ETV6-RUNX1 translocation).[136,137]

      • Philadelphia chromosome (t(9;22) translocation)

        The Philadelphia chromosome t(9;22) is present in approximately 3% of children with ALL and leads to production of a BCR-ABL1 fusion protein with tyrosine kinase activity (see Figure 2).

        Figure 2. 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-ABL. BCR-ABL 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.

        Historically, the Philadelphia chromosome t(9;22) 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.[119,138,139,140] Inhibitors of the BCR-ABL tyrosine kinase, such as imatinib mesylate, are effective in patients with Ph+ ALL.[141] A study by the COG, which used intensive chemotherapy and concurrent imatinib mesylate given daily, demonstrated a 3-year EFS rate of 80.5%, which was superior to the EFS rate of historical controls in the pre-tyrosine kinase inhibitor (imatinib mesylate) era.[141,142] Longer follow-up is necessary to determine whether this treatment improves the cure rate or merely prolongs DFS.

      • MLL translocations

        Translocations involving the MLL (11q23) gene occur in up to 5% of childhood ALL cases and are generally associated with an increased risk of treatment failure.[71,143,144,145] The t(4;11) translocation is the most common translocation involving the MLL gene in children with ALL and occurs in approximately 2% of cases.[143]

        Patients with the t(4;11) translocation are usually infants with high WBC counts; they are more likely than other children with ALL to have CNS disease and to have a poor response to initial therapy.[10] While both infants and adults with the t(4;11) translocation are at high risk of treatment failure, children with the t(4;11) translocation appear to have a better outcome than either infants or adults.[71,143] Irrespective of the type of MLL 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.[71,143] Deletion of the MLL gene has not been associated with an adverse prognosis.[146]

        Of interest, the t(11;19) translocation involving MLL and MLLT1/ENL occurs in approximately 1% of ALL cases and occurs in both early B-lineage and T-cell ALL.[147] Outcome for infants with the t(11;19) translocation is poor, but outcome appears relatively favorable in older children with T-cell ALL and the t(11;19) translocation.[147]

      • TCF3-PBX1 (E2A-PBX1; t(1;19) translocation)

        The t(1;19) translocation occurs in approximately 5% of childhood ALL cases and involves fusion of the E2A gene on chromosome 19 to the PBX1 gene on chromosome 1.[73,74] The t(1;19) translocation may occur as either a balanced translocation or as an unbalanced translocation and is primarily associated with pre-B ALL immunophenotype (cytoplasmic Ig positive). Black children are more likely than white children to have pre-B ALL with the t(1;19).[148]

        The t(1;19) translocation had been associated with inferior outcome in the context of antimetabolite-based therapy,[149] but the adverse prognostic significance was largely negated by more aggressive multiagent therapies.[74,150] However, in a trial conducted by SJCRH on which all patients were treated without cranial radiation, patients with the t(1;19) translocation 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.[44,151]

    3. Other genomic alterations

      Numerous new genetic lesions have been discovered by various array comparative hybridization and next-generation sequencing methods. Appreciation of these submicroscopic genomic abnormalities and mutations is redefining the subclassification of ALL:[152,153,154,155,156,157,158]

      • Intrachromosomal amplification of chromosome 21 (iAMP21): iAMP21 with multiple extra copies of the RUNX1 (AML1) gene occurs in 1% to 2% of precursor B-cell ALL cases and may be associated with an inferior outcome.[112,159,160]
      • 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. Cases with IKZF1 deletions tend to occur in older children, have a higher WBC count at diagnosis, and are therefore, more common among NCI high-risk patients compared with NCI standard-risk patients.[161,162] A high proportion of BCR-ABL1 cases have a deletion of IKZF1,[162,163] and ALL arising in children with Down syndrome appears to have elevated rates of IKZF1 deletions.[58]IKZF1 deletions are also common in cases with CRLF2 genomic alterations and in Philadelphia chromosome-like (Ph-like) ALL (see below).[152,162,164]

        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.[152,162,164,165,166,167,168,169]

      • CRLF2 and JAK mutations: 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 B-precursor ALL.[170,171] 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.[170,171,172,173]CRLF2 abnormalities are strongly associated with the presence of IKZF1 deletions and JAK mutations;[54,162,171,172,173] they are also more common in children with Down syndrome.[171] Point mutations in kinase genes other than JAK1 and JAK2 are uncommon in CRLF2-overexpressing cases.[173]

        Although the results of several retrospective studies suggest that CRLF2 abnormalities may have adverse prognostic significance on univariate analyses, most do not find this abnormality to be an independent predictor of outcome.[155,170,171,172,174] 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-ABL-like expression signatures were associated with unfavorable outcome.[169] There is also controversy about whether the prognostic significance of CRLF2 abnormalities should be analyzed based on CRLF2 overexpression or on the presence of CRLF2 genomic alterations.[155,174]

      • Ph-like ALL: BCR-ABL1-negative patients with a gene expression profile similar to BCR-ABL1-positive patients have been referred to as Ph-like ALL.[164,165] This occurs in 10% to 15% of pediatric ALL patients, increasing in frequency with age, and is associated with a poor prognosis and with IKZF1 deletion/mutation.[157,164,165,169,173] The hallmark of this entity is activated kinase signaling, with 50% containing CRLF2 genomic alterations [172] and 25% concomitant JAK mutations.[54] Many of the remaining cases have been noted to have a series of translocations with a common theme of involvement of either ABL1, JAK2, PDGFRB, or EPOR.[157] 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,[157] suggesting potential therapeutic strategies for these patients. Point mutations in kinase genes, aside from those in JAK1 and JAK2, are uncommon in Ph-like ALL cases.[173]
    4. 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.[175,176,177] For example, patients with mutant phenotypes of thiopurine methyltransferase (a gene involved in the metabolism of thiopurines, such as 6-mercaptopurine), appear to have more favorable outcomes,[178] although such patients may also be at higher risk of developing significant treatment-related toxicities, including myelosuppression and infection.[179,180]

      Genome-wide polymorphism analysis has identified specific single nucleotide polymorphisms associated with high end-induction minimal residual disease (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.[181] Polymorphic variants involving the reduced folate carrier and methotrexate metabolism have been linked to toxicity and outcome.[182,183] While these associations suggest that individual variations in drug metabolism can affect outcome, few studies have attempted to adjust for these variations; whether individualized dose modification based on these findings will improve outcome is unknown.

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