Prognostic implications of breakpoint and lineage heterogeneity in Philadelphia-positive acute lymphoblastic leukemia: a review

Philadelphia-positive (Ph) acute lymphoblastic leukemia (ALL) is heterogeneous both in terms of the BCR gene breakpoints (M-bcr and m-bcr) and in the number of cell lineages carrying the Ph chromosome. The impact of these observations on the controversy surrounding Ph ALL and Ph+ chronic granulocytic leukemia (CGL) is unclear. Twenty cases of Ph ALL (four newly investigated and 16 previously published) were classified into nine stem-cell (the Ph in myeloid and lymphoid cells) and 11 lymphoid-restricted cases. Lymphoid cases had a lower leucocyte count (56 x 10(9)/l) than stem-cell cases (151 x 10(9)/l) (p < 0.01). The M-bcr and m-bcr breakpoints (in 14 cases) were found in lymphoid (four cases of each) and stem-cell (five and one cases respectively) cases. Lymphoid cases had significantly shorter event-free survival (median 4 months) than stem-cell cases (median 35 months) (p < 0.01). M-bcr cases were older (mean 41 years) than m-bcr cases (mean 36 years)(p = NS); m-bcr cases had higher leukocyte counts (mean 85 x 10(9)/l) than M-bcr cases (36 x 10(9)/l)(p < 0.01) but breakpoint had no impact on prognosis. Lineage involvement, but not breakpoint, appears to distinguish prognostically important sub-groups of Ph ALL. Paradoxically, lymphoid-restricted cases have a worse prognosis than cases arising in a pluripotent stem-cell.