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

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Blank A phase I study of imatinib mesylate in combination with chlorambucil in

previously treated chronic lymphocytic leukemia patients.

J Hebb, S Assouline, C Rousseau, P Desjardins, S Caplan, MJ Egorin, L Amrein, R

Aloyz, and L Panasci

Cancer Chemother Pharmacol, December 1, 2010;

Lady Institute for Medical Research, Sir Mortimer B -Jewish General

Hospital, Montreal, QC, Canada.

PURPOSE: The tyrosine kinase inhibitor, imatinib, has the potential to

indirectly inhibit DNA repair. This mechanism of action has been shown to

mediate sensitization to chlorambucil in chronic lymphocytic leukemia (CLL). To

evaluate this effect in vivo, we performed a phase I study of chlorambucil

combined with imatinib in relapsed CLL patients. METHODS: The three dose levels

studied included imatinib at 300, 400, or 600?mg/day. Imatinib was given on days

1-10, and chlorambucil (8?mg/m(2) daily) was given on days 3-7 of a 28-day cycle

(up to 6?cycles). RESULTS: Eleven patients participated in this study. Low-grade

gastrointestinal toxicities were observed in a dose-dependent manner. Forty-five

percent of patients responded (two unconfirmed CRs and three PRs). Two

responding patients were fludarabine refractory. The in vitro IC(50) of

chlorambucil alone or in the presence of 5??M imatinib in CLL lymphocytes

correlated with the decrease in lymphocyte counts on day 15. Imatinib plasma

concentrations achieved in patients were in the range of those effective in in

vitro sensitization studies. CONCLUSION: The combination of chlorambucil and

imatinib in patients with previously treated CLL was well tolerated and showed

evidence of clinical efficacy. Based on our results, we recommend the 400 mg

daily dose of imatinib on days 1-10 with 8 mg/m(3) chlorambucil on days 3-7

every 28 days as the phase II dose. This represents the first clinical trial

examining the potential synergy between a tyrosine kinase inhibitor and a

conventional alkylating agent for the treatment of CLL.

PMID: 21120481