Hess G, Bunjes D, Siegert W, et al. Sustained complete molecular remissions after treatment with imatinib-mesylate in patients with failure after allogeneic stem cell transplantation for chronic myelogenous leukemia: results of a prospective phase II open-label multicenter study. J Clin Oncol 2005;23:7583-93.

While imatinib mesylate (IM) has become the frontline treatment for most patients with chronic myelogenous leukemia (CML), it does not represent a cure. Even patients with complete molecular remission (CMR) relapse rapidly upon discontinuation of the drug. Allogeneic stem cell transplantation (SCT) remains the only potentially curative treatment for CML - the putative mechanism is induction of an effective graft-versus-leukemia (GVL) immune response. Still, 5-20 percent of CML patients relapse after SCT. While an effective treatment is donor lymphocyte infusion (DLI), this is associated with substantial risk of graft-versus-host disease (GVHD). Thus, IM represents an attractive alternative treatment for relapsed CML post-SCT. The questions then are: Is IM effective in relapsed CML post-SCT? Is it simply a bridging measure? What should be done next? In a prospective multicenter trial by Hess et al., the investigators followed 44 CML patients who relapsed (18 molecular relapses and 19 cytogenetic relapses) post-SCT and were treated with IM. Subjects were analyzed with quantitative PCR for bcr-abl to monitor molecular responses. Immunosuppression was generally tapered prior to enrollment, and the initial IM dose of 400 mg/day was escalated to 600-800 mg/day for patients who did not achieve at least a major molecular response after three months. Eventually 77 percent of patients achieved CMR (defined as negative nested PCR for bcr-abl in three consecutive samples after an initial positive PCR). As part of this trial, patients could be taken off IM after at least six months if they remained in CMR at three consecutive time points within a period of three months. By these criteria, 10 patients discontinued IM. Intriguingly, four of these 10 patients (40 percent) maintained durable CMR off IM with a median follow-up of 494 days. This is distinctly different from CML patients treated up front with IM (without SCT), who invariably relapse within 90 days.

These results demonstrate that IM is indeed an effective treatment for relapsed CML post-SCT. Given the significant risk for GVHD with DLI, IM is an attractive alternative that carries fewer side effects. Even more importantly, IM may represent a possible cure in a subset of these patients. Suppression of the relapsed CML population by IM may somehow lead to re-emergence of an effective GVL response in transplanted patients that may ultimately lead to eradication of residual CML stem cells or their sustained immunological control. If so, understanding the biology of residual CML cells (if any) and anti-leukemia immune responses in these patients may shed important insights that could lead to novel combinations of IM with immune therapy. Of note, patients with sustained CMR off IM tended to be treated longer (median treatment duration 269 days) than those who lost CMR (median 151 days). This argues that discontinuation of IM in CMR should not be attempted too early. Understanding the host immune responses that lead to sustained CMR could also facilitate selection of patients for IM discontinuation. The complex interplay between cancer cell suppression by targeted therapy and the immune response offers promising opportunities for novel treatment strategies and research.

Competing Interests

Dr. Lee indicated no relevant conflicts of interest.