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Cellular Classification and Prognostic Variables

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Leukemic Cell Characteristics at Diagnosis

  1. Morphology

    In the past, ALL lymphoblasts were classified using the French-American-British (FAB) criteria as having L1 morphology, L2 morphology, or L3 morphology.[48] However, because of the lack of independent prognostic significance and the subjective nature of this classification system, it is no longer used. Most cases of ALL that show L3 morphology express surface immunoglobulin (Ig) and have a C-MYC gene translocation identical to that seen in Burkitt lymphoma (i.e., t[8;14]). Patients with this specific rare form of leukemia (mature B cell or Burkitt leukemia) should be treated according to protocols for Burkitt lymphoma. (Refer to the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for more information on the treatment of B-cell ALL and Burkitt lymphoma.)

  2. Immunophenotype

    The World Health Organization (WHO) classifies ALL as either B lymphoblastic leukemia or T lymphoblastic leukemia. B lymphoblastic leukemia is subdivided by the presence or absence of specific recurrent genetic abnormalities (t[9;22]), MLL rearrangement, t(12;21), hyperdiploidy, hypodiploidy, t(5;14), and t(1;19).[49]

    Prior to 2008, the WHO classified B lymphoblastic leukemia as precursor-B lymphoblastic leukemia, and this terminology is still frequently used in the literature of childhood ALL to distinguish it from mature B-cell ALL, now termed Burkitt leukemia, which requires different treatment than has been given for precursor B-cell ALL. The older terminology will continue to be used throughout this summary.

    • Precursor B-cell ALL (WHO B lymphoblastic leukemia): Precursor B-cell ALL, defined by the expression of cytoplasmic CD79a, CD19, HLA-DR, and other B cell-associated antigens, accounts for 80% to 85% of childhood ALL. Approximately 90% of precursor B-cell ALL cases express the CD10 (formerly known as common ALL antigen [cALLa]) surface antigen. Absence of CD10 is associated with MLL translocations, particularly t(4;11), and a poor outcome.[18,50] It is not clear whether CD10-negativity has any independent prognostic significance in the absence of an MLL gene rearrangement.[51]

      There are three major subtypes of precursor B-cell ALL as follows:

      • Pro-B ALL-CD10 negative and no surface or cytoplasmic Ig.

        Approximately 5% of patients have the pro-B immunophenotype. Pro-B is the most common immunophenotype seen in infants and is often associated with a t(4;11) translocation.

      • Common precursor B-cell ALL-CD10 positive and no surface or cytoplasmic Ig.

        Approximately three-quarters of patients with precursor B-cell ALL have the common precursor B-cell immunophenotype and have the best prognosis. Patients with favorable cytogenetics almost always show a common precursor B-cell immunophenotype.

      • Pre-B ALL presence of cytoplasmic Ig.

        The leukemic cells of patients with pre-B ALL contain cytoplasmic Ig, and 25% of patients with pre-B ALL have the t(1;19) translocation with TCF3-PBX1 (also known as E2A-PBX1) fusion (see below).[52,53]

      Approximately 3% of patients have transitional pre-B ALL with expression of surface Ig heavy chain without expression of light chain, C-MYC gene involvement, or L3 morphology. Patients with this phenotype respond well to therapy used for precursor B-cell ALL.[54]

      Approximately 2% of patients present with mature B-cell leukemia (surface Ig expression, generally with FAB L3 morphology and a translocation involving the C-MYC gene), also called Burkitt leukemia. The treatment for mature B-cell ALL is based on therapy for non-Hodgkin lymphoma and is completely different from that for precursor B-cell ALL. Rare cases of mature B-cell leukemia that lack surface Ig but have L3 morphology with C-MYC gene translocations should also be treated as mature B-cell leukemia.[54] (Refer to the PDQ summary on Childhood Non-Hodgkin's Lymphoma Treatment for more information on the treatment of children with B-cell ALL and Burkitt lymphoma.)

    • T-cell ALL: T-cell ALL is defined by expression of the T cell-associated antigens (cytoplasmic CD3, with CD7 plus CD2 or CD5) on leukemic blasts and is frequently associated with a constellation of clinical features, including male gender, older age, leukocytosis, and mediastinal mass.[8,24,44] With appropriately intensive therapy, children with T-cell ALL have an outcome similar to that of children with B-lineage ALL.[8,24,44]

      There are few commonly accepted prognostic factors for patients with T-cell ALL. There are conflicting data regarding the prognostic significance of presenting leukocyte counts in T-cell ALL.[6] The presence or absence of a mediastinal mass at diagnosis has no prognostic significance. In patients with a mediastinal mass, the rate of regression of the mass lacks prognostic significance.[55]

      A distinct subset of childhood T-cell ALL, termed early precursor T-cell ALL, was identified by gene expression profiling, flow cytometry, and single nucleotide polymorphism array analyses.[56] This subset, identified in 13% of T-cell ALL cases, is characterized by a distinctive immunophenotype (CD1a and CD8 negativity, with weak expression of stem cell or myeloid markers and weak expression of CD5). It has the same gene expression profile of normal early thymic precursor cells, a population of recent immigrants from bone marrow to the thymus, which retains multilineage differentiation potential.[56] A retrospective analysis suggested that this subset may have a poorer prognosis than other cases of T-cell ALL.[56] Another retrospective study found that the absence of biallelic deletion of the TCRgamma locus (a finding characteristic of early thymic-precursor cells), as detected by comparative genomic hybridization (CGH) and quantitative DNA polymerase chain reaction (DNA-PCR), was associated with early treatment failure in patients with T-cell ALL.[57]

      Cytogenetic abnormalities common in B-lineage ALL (e.g., hyperdiploidy) are rare in T-cell ALL.[58,59] Multiple chromosomal translocations have been identified in T-cell ALL, with many genes encoding for transcription factors (e.g., TAL1, LMO1 and LMO2, LYL1, TLX1/HOX11, and TLX3/HOX11L2) fusing to one of the T-cell receptor (TCR) loci and resulting in aberrant expression of these transcription factors in leukemia cells.[58,60,61,62,63,64] These translocations are often not apparent by examining a standard karyotype, but are identified using more sensitive screening techniques, such as fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR).[58] High expression of TLX1/HOX11 resulting from translocations involving this gene occurs in 5% to 10% of pediatric T-cell ALL cases and is associated with more favorable outcome in both adults and children with T-cell ALL.[60,61,62,64] Overexpression of TLX3/HOX11L2 resulting from the t(5;14)(q35;q32) translocation occurs in approximately 20% of pediatric T-cell ALL cases and appears to be associated with increased risk of treatment failure,[62] though not in all studies.

      NOTCH1 gene mutations occur in approximately 50% of T-cell ALL cases, but their prognostic significance has not been established.[65,66,67,68,69,70]

      A NUP214-ABL1 fusion has been noted in 4% to 6% of adults with T-cell ALL. The fusion is usually not detectable by standard cytogenetics. Tyrosine kinase inhibitors may have therapeutic benefit in this type of T-cell ALL.[71,72,73]

    • Myeloid antigen expression: Up to one-third of childhood ALL cases have leukemia cells that express myeloid-associated surface antigens. Myeloid-associated antigen expression appears to be associated with specific ALL subgroups, notably those with MLL translocations and those with the ETV6-RUNX1 gene rearrangement.[74,75] No independent adverse prognostic significance exists for myeloid-surface antigen expression.[74,75]
    • Ambiguous lineage: Less than 5% of cases of acute leukemia in children are of ambiguous lineage, expressing features of both myeloid and lymphoid lineage.[76,77,78] These cases are distinct from ALL with myeloid coexpression in that the predominant lineage cannot be determined by immunophenotypic and histochemical studies. The definition of leukemia of ambiguous lineage varies among studies, although most investigators now use criteria established by the European Group for the Immunological Characterization of Leukemias (EGIL) or the more stringent WHO criteria.[79,80,81] In the WHO classification, the presence of myeloperoxidase (MPO) is required to establish myeloid lineage. This is not the case for the EGIL classification. Leukemias of mixed phenotype comprise two groups of patients: (1) bilineal leukemias in which there are two distinct population of cells, usually one lymphoid and one myeloid, and (2) biphenotypic leukemias where individual blast cells display features of both lymphoid and myeloid lineage. Biphenotypic cases represent the majority of mixed phenotype leukemias.[76] B-myeloid biphenotypic leukemias lacking the ETV6-RUNX1 fusion have a lower rate of complete remission and a significantly worse EFS compared with patients with B-precursor ALL.[76] Some studies suggest that patients with biphenotypic leukemia may fare better with a lymphoid, as opposed to a myeloid, treatment regimen,[77,78,82] although the optimal treatment for patients remains unclear.
  3. Cytogenetics

    A number of recurrent chromosomal abnormalities have been shown to have prognostic significance, especially in B-precursor ALL. Some chromosomal abnormalities, such as high hyperdiploidy (51-65 chromosomes) and the ETV6-RUNX1 fusion, are associated with more favorable outcomes, while others, including the Philadelphia chromosome (t[9;22]), rearrangements of the MLL gene (chromosome 11q23), and intrachromosomal amplification of the AML1 gene (iAMP21), are associated with a poorer prognosis.[83]

    Prognostically significant chromosomal abnormalities in childhood ALL include the following:

    • 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.[84] Hyperdiploidy can be evaluated by measuring the DNA content of cells (DNA index) or by karyotyping. Interphase FISH may detect hidden hyperdiploidy in cases either 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 1-9 years with a low WBC count) and is itself an independent favorable prognostic factor.[84,85] Hyperdiploid leukemia cells are particularly susceptible to undergoing apoptosis and accumulate higher levels of methotrexate and its active polyglutamate metabolites,[86] which may explain the favorable outcome commonly observed for these cases.

        While the overall outcome of patients with high hyperdiploidy is considered to be favorable, factors such as age, gender, WBC count, and specific trisomies have been shown to modify its prognostic significance.[87] For instance, 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 National Cancer Institute (NCI) standard-risk ALL.[88] POG data suggest that NCI standard-risk patients with trisomies of 4 and 10, without regard to chromosome 17 status, have an excellent prognosis.[89]

        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,[90] and the outcome of these patients (treated without tyrosine kinase inhibitors) was inferior to that observed in non-Philadelphia chromosome-positive high hyperdiploid patients.

        Certain patients with hyperdiploid ALL may have a hypodiploid clone that has doubled (masked hypodiploidy).[91] 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.[91]

        Near triploidy (68 to 80 chromosomes) and near tetraploidy (>80 chromosomes) are much less common and appear to be biologically distinct from high hyperdiploidy.[92] Unlike high hyperdiploidy, a high proportion of near tetraploid cases harbors a cryptic ETV6-RUNX1 fusion.[92,93,94] 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.[92,94]

      • 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.[91] Patients with fewer than 44 chromosomes have a worse outcome than patients with 44 or 45 chromosomes in their leukemic cells.[91]
    • 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.[91] The t(12;21) occurs most commonly in children aged 2 to 9 years.[95,96] Hispanic children with ALL have a lower incidence of t(12;21) compared with white children.[97] 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 factors such as early response to treatment, NCI risk category, and treatment regimen.[98,99,100] 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.[98] There is a higher frequency of late relapses in patients with ETV6-RUNX1 fusion compared with other B-precursor ALL.[98,101] Patients with the ETV6-RUNX1 fusion who relapse seem to have a better outcome than other relapse patients.[102] 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).[103]
      • 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. This subtype of ALL is more common in older patients with precursor B-cell ALL and high WBC count. Historically, it 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 in patients in first remission.[90,104,105,106] Inhibitors of the BCR-ABL tyrosine kinase, such as imatinib, are effective in patients with Philadelphia chromosome-positive ALL. A study by the COG, which used intensive chemotherapy and concurrent imatinib 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) era.[107] 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.[50,108,109,110] The t(4;11) is the most common translocation involving the MLL gene in children with ALL and occurs in approximately 2% of cases.[108] Patients with t(4;11) 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.[18] While both infants and adults with the t(4;11) are at high risk of treatment failure, children with the t(4;11) appear to have a better outcome than either infants or adults.[50,108] 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.[50,108] Of interest, the t(11;19) occurs in approximately 1% of cases and occurs in both early B-lineage and T-cell ALL.[111] Outcome for infants with t(11;19) is poor, but outcome appears relatively favorable in older children with T-cell ALL and the t(11;19) translocation.[111]
      • 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.[52,53] The t(1;19) 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).[47] The t(1;19) translocation had been associated with inferior outcome in the context of antimetabolite-based therapy,[112] but the adverse prognostic significance was largely negated by more aggressive multi-agent therapies.[53] However, in a trial conducted by SJCRH on which all patients were treated without cranial radiation, the t(1;19) was associated with a higher risk of CNS relapse.[31]
    • 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.[113,114]

    • Other molecular genetic abnormalities

      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.[115,116,117] 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.[118]

      Overexpression of CRLF2, a cytokine receptor gene located on the pseudoautosomal regions (PAR) of the sex chromosomes, has been identified in 5% to 10% of cases of B-precursor ALL.[119,120] Chromosomal abnormalities described in cases with CRLF2 overexpression include translocations of the IgH locus (chromosome 14) to CRLF2 and interstitial PAR1 deletions resulting in a PDRY8-CRLF2 fusion.[119,120,121]CRLF2 abnormalities are strongly associated with the presence of IKZF1 deletions and JAK mutations;[120,121] they are also more common in children with Down syndrome.[120] 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.[119,120,121]

      In another retrospective study of gene expression classification in ALL, children could be classified as low, intermediate, and high risk based on a combination of gene expression and flow cytometric measures of minimal residual disease (MRD). These prognostic groups have yet to be tested in a prospective study.[122][Level of evidence: 3iiiA]

    • 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.[123,124,125] 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,[126] although such patients may also be at higher risk of developing significant treatment-related toxicities, including myelosuppression and infection.[127,128]

      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.[129] Polymorphic variants involving the reduced folate carrier have been linked to methotrexate metabolism, toxicity, and outcome.[130] 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 upon these findings will improve outcome is unknown.

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Last Updated: May 16, 2012
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