Prediction of initial cytogenetic response for subsequent major and complete cytogenetic response to imatinib mesylate therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia.

Abstract

In a recent article published in Cancer, Kantarjian et al. describe the predictive power of the initial cytogenetic response of patients with chronic myeloid leukemia (CML) to imatinib mesylate (IM).1 They report a lack of cytogenetic response at ≥ 6 months to be a good indicator of failure to achieve a subsequent complete cytogenetic response (CCR). Conversely, a minor cytogenetic response at 3–12 months was associated with a 35–54% chance of achieving a CCR. They conclude by stating that allogeneic stem cell transplantation (alloSCT) should be used only in patients who fail to achieve a cytogenetic response at 6 months, with all other patients continuing to receive imatinib monotherapy. These somewhat didactic conclusions are difficult to justify based on this study and other published data concerning imatinib. First, the study was conducted in patients with established chronic phase (CP) CML, all of whom had failed treatment with interferon. Although no median duration of disease was given, many of these patients will almost certainly have been in the “late” CP. This patient group is likely to have relatively poor-risk disease, as evidenced by the considerably lower incidence of CCR (57%) noted at a median follow-up of 29 months compared with that already published for newly diagnosed patients (a 76% CCR rate predicted at 18 months according to the IRIS study2). Therefore, it is difficult to relate these data to the situation of patients with newly diagnosed CP CML, which is precisely the group the authors' advice regarding transplantation is targeted to. Second, the incidence of complete molecular remission (i.e., negative sensitive Q-RT-PCR on 2 occasions that are > 1 month apart) is rare with imatinib monotherapy3, 4 compared with alloSCT with a successful outcome. The term “operational cure” has been proposed for IM treated patients with low-level MRD; nevertheless, much longer follow-up clearly is needed before its true significance can be determined. Third, and taking the previous two points into account, no acknowledgement is given to patient preference; in the absence of evidence for IM-induced cure, patients still should be be informed that alloSCT remains the only curative measure available to them. Some individuals, in our experience, may then elect to undergo transplantation at the outset rather than live with low levels of CML. Indeed, this may be the preferred option if a deletion of the derivative chromosome 9 is detected, in which the incidence of cytogenetic responses and time to disease progression with imatinib appear to be reduced significantly.5 Finally, such advice does not take into account recent (and impressive) data regarding the utility of nonmyeloablative alloSCT in patients with CP CML.6 In an ideal world, one would advocate a randomized trial between IM therapy and alloSCT so that patients could be advised properly. Although we acknowledge that this is unlikely to happen, concluding statements such as those expressed in the study by Kantarjian et al.1 make it even less likely. In a currently ongoing study, we are performing nonmyeloablative alloSCT in patients who achieve a CCR with IM monotherapy. To say therefore that transplantation and IM therapy have to be mutually exclusive at the outset of CML therapy is a somewhat narrow approach. It is indeed early days with regard to IM therapy, but that is precisely why some caution should be exercised.