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



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).[88]

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.[89] Hyperdiploidy can be evaluated by measuring the DNA content of cells (DNA index) or by karyotyping. Interphase FISH may detect hidden hyperdiploidy in cases with a normal karyotype or in which standard cytogenetic analysis was unsuccessful. 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.[89,90] Hyperdiploid leukemia cells are particularly susceptible to undergoing apoptosis and accumulate higher levels of methotrexate and its active polyglutamate metabolites,[91] 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, the following factors have been shown to modify its prognostic significance:[92]

      • Age.
      • Gender.
      • WBC count.
      • Specific trisomies.

      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.[93] POG data suggest that NCI standard-risk patients with trisomies of 4 and 10, without regard to chromosome 17 status, have an excellent prognosis.[94]

      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,[95] 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).[96] 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.[96]

      Near triploidy (68–80 chromosomes) and near tetraploidy (>80 chromosomes) are much less common and appear to be biologically distinct from high hyperdiploidy.[97] Unlike high hyperdiploidy, a high proportion of near tetraploid cases harbor a cryptic ETV6-RUNX1 fusion.[97,98,99] 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.[97,99]

    • Hypodiploidy (<44 chromosomes)

      A significant trend is observed for a progressively worse outcome with a decreasing chromosome number. Cases with 24 to 28 chromosomes (near haploidy) have the worst outcome.[96] Patients with fewer than 44 chromosomes have a worse outcome than patients with 44 or 45 chromosomes in their leukemic cells.[96]

  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.[96] The t(12;21) occurs most commonly in children aged 2 to 9 years.[100,101] Hispanic children with ALL have a lower incidence of t(12;21) than white children.[102]

      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: [103,104,105]

      • Early response to treatment.
      • NCI risk category.
      • 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.[103] There is a higher frequency of late relapses in patients with ETV6-RUNX1 fusion compared with other B-precursor ALL.[103,106] Patients with the ETV6-RUNX1 fusion who relapse seem to have a better outcome than other relapse patients.[107] 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).[108]

    • 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 stem cell transplantation (SCT) in patients in first remission.[95,109,110,111] Inhibitors of the BCR-ABL tyrosine kinase, such as imatinib mesylate, are effective in patients with Ph+ ALL. 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.[112] 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.[54,113,114,115] 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.[113]

      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.[54,113] Irrespective of the type of 11q23 abnormality, infants with leukemia cells that have 11q23 abnormalities have a worse treatment outcome than older patients whose leukemia cells have an 11q23 abnormality.[54,113]

      Of interest, the t(11;19) translocation occurs in approximately 1% of cases and occurs in both early B-lineage and T-cell ALL.[116] 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.[116]

    • 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.[56,57] 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).[51]

      The t(1;19) translocation had been associated with inferior outcome in the context of antimetabolite-based therapy,[117] but the adverse prognostic significance was largely negated by more aggressive multi-agent therapies.[57] However, in a trial conducted by SJCRH on which all patients were treated without cranial radiation, the t(1;19) translocation was associated with a higher risk of CNS relapse.[34]

  3. Other genetic abnormalities
    • 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.[118,119]
    • IKZF1 deletions: Recent application of microarray-based genome-wide analysis of gene expression and DNA copy number, complemented by transcriptional profiling, resequencing, and epigenetic approaches, has identified a specific subset of patients with high-risk B-precursor ALL with a very poor prognosis. These patients have a gene-expression signature similar to patients with BCR-ABL-positive ALL, but lack that translocation. IKZF1 deletions were identified in about 30% of high-risk B-precursor ALL and were significantly associated with a very poor outcome.[120,121,122] A subset of patients with IKZF1 deletions were found to have JAK kinase mutations (about 10% of all high-risk cases), suggesting a possible future therapeutic target.[123]
    • CRLF2 and JAK mutation: Overexpression of CRLF2, a cytokine receptor gene located on the pseudoautosomal regions of the sex chromosomes, has been identified in 5% to 10% of cases of B-precursor ALL.[124,125] Chromosomal abnormalities described in cases with 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 PDRY8-CRLF2 fusion.[124,125,126]CRLF2 abnormalities are strongly associated with the presence of IKZF1 deletions and JAK mutations;[125,126] they are also more common in children with Down syndrome.[125] The results of several retrospective studies suggest that CRLF2 abnormalities may have adverse prognostic significance, although none have established it as an independent predictor of outcome.[124,125,126]
  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.[127,128,129] 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,[130] although such patients may also be at higher risk of developing significant treatment-related toxicities, including myelosuppression and infection.[131,132]

    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.[133] Polymorphic variants involving the reduced folate carrier have been linked to methotrexate metabolism, toxicity, and outcome.[134] 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.


WebMD Public Information from the National Cancer Institute

Last Updated: February 25, 2014
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