The classic Philadelphia chromosome giving rise to Bcr-Abl is associated with a certain additional cytogenetic abnormality in a significant minority of patients. A number of groups have previously investigated the significance of large deletions adjacent to the translocation breakpoints in patients with chronic myeloid leukemia (CML). These deletions have been reported in between 10% to 15% of patients; they typically span the translocation breakpoint and often involve both chromosomes 9 and 22. The deletions can be many megabases in length and are presumably formed at the time of the Philadelphia translocation. Such deletions are associated with a poor prognosis in terms of shorter length of chronic phase, earlier disease transformation, and shorter survival. Previous analyses were largely confined to patients who had been treated with interferon-alpha (IFN-α), although interestingly the effect was still evident in patients treated by allogeneic transplantation. However, does the “poor-prognosis” effect still stand up in imatinib-treated patients?
In this edition of Blood, Huntly and colleagues (page 2205) present new data addressing the question of whether therapy with imatinib overrides the deletion effect. The answer seems to be that deletions still seem to confer a somewhat poorer prognosis in certain settings but that the effect is clearly “diluted” by the use of imatinib in comparison to groups of patients treated with IFN. For example, in 122 chronicphase patients, significant differences in progression-free survival, but not overall survival, were seen among patients with (n = 15) and without (n = 107) deletions. In successive cohorts of analyzed patients it seems evident that as there is a greater proportion treated with imatinib so the prognostic impact of deletions diminishes.
Finally, why these deletions should confer a poor prognosis remains far from clear. The data presented in this article would suggest that the molecular abnormalities present in patients with deletions in some way cooperate with, but are not entirely dependent upon, Bcr-Abl. It would seem that this evolving story is far from complete: the prospective analysis of deletions in future clinical studies will not only allow confirmation of the initial observations of this study, but will also allow a long-term analysis of the true impact on survival. Furthermore, it is not inconceivable that elucidation of the molecular aberrations underlying this effect may allow further improvements in the therapy of CML in due course.
