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

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Journal of Clinical Oncology, 2008 ASCO Annual Meeting Proceedings (Post-Meeting

Edition).

Vol 26, No 15S (May 20 Supplement), 2008: 18021

A phase I trial of imatinib mesylate in combination with chlorambucil in

previously treated chronic lymphocytic leukemia patients

J. P. Hebb, S. Assouline, C. Rousseau, R. Aloyz, P. DesJardins, S. Caplan and L.

Panasci

Sir Mortimer B Jewish General Hospital, Montreal, QC, Canada; Lady

Institute for Medical Research, Montreal, QC, Canada; Hôpital Lemoyne,

Montreal, QC, Canada

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.

Methods: 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/m2 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. Results: 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. Conclusions: 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.