A phase I trial of imatinib mesylate in combination with chlorambucil in previously treated chronic lymphocytic leukemia patients.

18021 Background: Treatment of chronic lymphocytic leukemia (CLL) with alkylating agents such as chlorambucil (CLB) eventually leads to resistance. One mechanism of resistance involves the repair of drug-induced DNA interstrand cross links, which is mediated, in part, by the phosphorylation of Rad51 by c-abl. Imatinib inhibits c-abl activity, and thus may sensitize CLL cells to CLB through inhibition of c-abl mediated DNA-repair pathways. In vitro studies have shown a synergistic effect of imatinib on CLB-mediated cytotoxicity in CLL lymphocytes. On this basis, a phase I clinical study was initiated combining CLB and imatinib for the treatment of relapsed and refractory CLL to determine the recommended phase II dose(RP2D) and toxicities. Preliminary efficacy was also assessed.,Patients with relapsed or refractory CLL were eligible if they met indications for treatment. Three patients were treated per dose level unless dose limiting toxicity was observed in which case the cohort was expanded to include 6 patients. Three dose levels were included corresponding to imatinib doses of 300, 400, or 600 mg/day. Chlorambucil dose was 8 mg/m in all patients. Imatinib was given on days 1-10 and CLB on days 3-7, repeated every 28 days for up to 6 cycles.,Eleven patients have been enrolled to date, 3 at dose level 1, 3 at level 2, and 5 at level 3. There has been one dose-limiting toxicity at level 3 (grade 3 thrombocytopenia), and two severe adverse events (SAEs) - one at level 2 (pneumonia with respiratory failure) and one at level 3 (disseminated herpes). At present 4 of 11 patients have completed all 6 cycles. Dose level 3 has been expanded to 6 patients. The RP2D has not yet been determined. Ten patients were assessable for efficacy. There was one complete response (CR), and 3 patients with a partial response (PR) for an overall response rate of 40%. Two responders including the CR were previously treated with fludarabine, the other two had previous treatment with CLB alone. Median follow-up is 6 months.,The combination of imatinib and CLB is well tolerated and shows evidence of efficacy. Ongoing work will clarify the RP2D with plans to move on to a phase II study. No significant financial relationships to disclose.