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.
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.
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. (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. 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.
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. 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. A retrospective analysis suggested that this subset may have a poorer prognosis than other cases of T-cell ALL. 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.
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). 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, 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]