Lineage ALL Subtypes

Although the nomenclature for B-lineage ALL subtypes varies among published reports, the major subtypes and their characteristic antigenic features show enough overlap and inherent heterogeneity to justify a coherent presentation (Table 15-3).

The most immature subtype of B-lineage ALL (termed ProB, Pre-Pre-B, CD10- Early Pre-B, Null-Cell, Early-Early-B, early B-precursor ALL, or B1 Subtype) is recognized as such on the basis of cytoplasmic CD22 (cCD22) and/or cytoplasmic CD79a and/or surface CD19 expression in the absence of other lymphoid or myeloid antigens. Both cCD22+CD19- and cCD22-CD19+ cases have been seen. Typically, these cells are CD34+ HLA-DR+CD117- and often express CD133 (Paietta E, unpublished observation); CD24 may or may not be found. Approximately 10 percent of adult ALL patients present with this immunophenotype. In children, there is the preponderance of this immature leukemia in infants, with the incidence higher the younger the age.313,314 This is the immunophenotype associated with the (4;11)(q21;q23) cytogenetic abnormality or with the presence of MLL-AF4 transcripts, the molecular consequence of this translocation.199,313-317 Expression of the myeloid antigens CD65(s) and/or CD15(s) is much more common in this subtype than in more mature B-lineage ALL, whereas the incidence of CD33 and/or CD13 expression is lower.194,199,318 In terms of outcome, the prognosis of adult patients with this immunophenotype appears to have improved with intensification of therapy.199,317 In infants, event-free survival of CD10- ALL is significantly worse than that of CD10+ ALL,314,319 possibly owing to an observed resistance of CD10-B-cell precursor cells to prednisone and L-asparaginase.314 In children, absence of CD10 is commonly associated with poor prognostic features, such as hyperleukocytosis and pseudo-diploidy. However, the poor prognostic impact of CD10 negativity is lost when infants are excluded from the analysis.320

Early Pre-B ALL, also termed CD10- Early Pre-B or Common ALL or ALL of B2 Subtype, is characterized by the expression of CD10 in the absence of cytoplasmic or surface immunoglobulin HC or LC expression. The intracellular presence of surrogate LCs (^5/VpreB) has been documented for this maturation stage.266 This is the most common immunophenotype in children over the age of 1 year and in adults. CD10+ CD34+ B-lineage ALL is the typical immunophenotype associated with the Philadelphia chromosome (Ph), t(9;22)(q34;q11), and its molecular equivalent, the BCR/ABL fusion transcripts, found in less than 5 percent of children but in up to 25 percent of adults and associated with a poor prognosis.317,321,322 Expression of CD25, the a chain of the IL-2 receptor, can serve as a surrogate marker for BCR/ABL transcription in Ph+ ALL.19 In children, CD10 and CD34 are otherwise often accompanied by good prognostic features, such as hyperdiploidy, low incidence of cerebrospinal involvement, and lower leukocyte counts at presentation.30,140,322 Acute lymphocytic leukemia with TEL/AML1 rearrangement, which results from a cryptic (12;21)(p12;q22) translocation, expresses CD10.20 In fact, lym-phoblasts containing t(12;21) express CD10 with higher fluorescence intensity than is found in t(12;21)-negative cases.21 High-level expression of CD10 combined with low-level expression of CD20, CD45, and CD34 may thus provide a surrogate marker profile for this genotype.20,21 Although infrequent in adults,323,324 TEL/AML1 positivity is the most common molecular finding in children with ALL325 and is associated with favorable outcome.324,326 In adults, the CD10+, cytoplasmic HC- immunophenotype carries a superior prognosis among B-lineage ALL subtypes in most studies. CD2+CD19+CD10+ ALL may be related to a normal bipotential lymphoid precursor, which seems to be programmed more toward the B- than the T-cell lineage, as evidenced by in vitro differentiation to the stage of Pre-B cells283 and by clinical features (e.g., lack of mediasti-

Table 15-3.

Subclassification of B-Lineage ALL

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