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

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Morphology

In the past, ALL lymphoblasts were classified using the French-American-British (FAB) criteria as having L1 morphology, L2 morphology, or L3 morphology.[69] 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 about the treatment of B-cell ALL and Burkitt lymphoma.)

Immunophenotype

The World Health Organization (WHO) classifies ALL as either:[70]

  • B lymphoblastic leukemia.
  • T lymphoblastic leukemia.

Either B or T lymphoblastic leukemia can coexpress myeloid antigens. These cases need to be distinguished from leukemia of ambiguous lineage.

  1. Precursor B-cell ALL (WHO B lymphoblastic leukemia)

    Before 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. Mature B-cell ALL is now termed Burkitt leukemia and 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, 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 surface antigen (formerly known as common ALL antigen [cALLa]). Absence of CD10 is associated with MLL translocations, particularly t(4;11), and a poor outcome.[10,71] It is not clear whether CD10-negativity has any independent prognostic significance in the absence of an MLL gene rearrangement.[72]

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

    • 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.

    • 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 MLL gene rearrangements.

    • 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).[73,74]

      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.[75]

      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.[75] (Refer to the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for more information about the treatment of children with B-cell ALL and Burkitt lymphoma.)

  2. 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. T-cell ALL is frequently associated with a constellation of clinical features, including the following:[17,29,62]

    • Male gender.
    • Older age.
    • Leukocytosis.
    • Mediastinal mass.

    With appropriately intensive therapy, children with T-cell ALL have an outcome approaching that of children with B-lineage ALL.[17,29,32,33,62]

    There are few commonly accepted prognostic factors for patients with T-cell ALL. Conflicting data exist regarding the prognostic significance of presenting leukocyte counts in T-cell ALL.[6,29,30,31,32,33,34,35] 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.[76]

    Cytogenetic abnormalities common in B-lineage ALL (e.g., hyperdiploidy) are rare in T-cell ALL.[77,78]

    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 loci and resulting in aberrant expression of these transcription factors in leukemia cells.[77,79,80,81,82,83] 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).[77] 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.[79,80,81,83] Overexpression of TLX3/HOX11L2 resulting from the cryptic 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,[81] although not in all studies.

    Notch pathway signaling is commonly activated by NOTCH1 and FBXW7 gene mutations in T-cell ALL.[84]NOTCH1-activating gene mutations occur in approximately 50% of T-cell ALL cases, and FBXW7 inactivating gene mutations occur in approximately 15% of cases, with the result that approximately 60% of cases having Notch pathway activation by mutations in at least one of these genes. The prognostic significance of Notch pathway activation by NOTCH1 and FBXW7 mutations in pediatric T-cell ALL is not clear, as some studies have shown a favorable prognosis for mutated cases,[85,86,87] while other studies have not shown prognostic significance for the presence of NOTCH1 and/or FBXW7 mutations.[88,89,90]

    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.[91,92,93] The fusion is cytogenetically cryptic and is seen in FISH on amplified episomes or more rarely, as a small homogeneous staining region.[93] T-cell ALL may also uncommonly show ABL1 fusion proteins with other gene partners (e.g., ETV6, BCR, and EML1).[93]ABL tyrosine kinase inhibitors, such as imatinib or dasatinib, may have therapeutic benefit in this T-cell ALL subtype,[91,92,94] although clinical experience with this strategy is very limited.[95,96,97]

    Early T-cell precursor ALL

    Early T-cell precursor ALL, a distinct subset of childhood T-cell ALL, was initially defined by identifying T-cell ALL cases with gene expression profiles highly related to expression profiles for normal early T-cell precursors.[36] The subset of T-cell ALL cases, identified by these analyses represented 13% of all cases and they were characterized by a distinctive immunophenotype (CD1a and CD8 negativity, with weak expression of CD5 and coexpression of stem cell or myeloid markers). 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.[98] Compared with other T-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.[98] Retrospective analyses have suggested that this subset has a poorer prognosis than other cases of T-cell ALL.[36,99,100] However, further study in larger patient cohorts is needed.

    Studies have found that the absence of biallelic deletion of the TCRgamma locus (ABGD), as detected by comparative genomic hybridization and/or quantitative DNA-PCRn, was associated with early treatment failure in patients with T-cell ALL.[101,102] 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.

  3. 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.[103,104] No independent adverse prognostic significance exists for myeloid-surface antigen expression.[103,104]

    Leukemia of ambiguous lineage

    Less than 5% of cases of acute leukemia in children are of ambiguous lineage, expressing features of both myeloid and lymphoid lineage.[105,106,107] 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. However, most investigators now use criteria established by the European Group for the Immunological Characterization of Leukemias (EGIL) or the more stringent WHO criteria.[108,109,110] In the WHO classification, the presence of myeloperoxidase is required to establish myeloid lineage. This is not the case for the EGIL classification.

    Leukemias of mixed phenotype comprise the following two groups:[105]

    • Bilineal leukemias in which there are two distinct populations of cells, usually one lymphoid and one myeloid.
    • Biphenotypic leukemias in which individual blast cells display features of both lymphoid and myeloid lineage. Biphenotypic cases represent the majority of mixed phenotype leukemias.[105] Patients with B-myeloid biphenotypic leukemias lacking the ETV6-RUNX1 fusion have a lower rate of complete remission and a significantly worse EFS than do patients with B-precursor ALL. Some studies suggest that patients with biphenotypic leukemia may fare better with a lymphoid, as opposed to a myeloid, treatment regimen,[106,107,111] although the optimal treatment for patients remains unclear.
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