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


CONCLUSIONS
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.
Lady Davis Institute for Medical Research, Sir Mortimer B Davis-Jewish General Hospital, Montreal, QC, Canada.
Jonathan
J
Hebb
Sarit
S
Assouline
Caroline
C
Rousseau
Pierre
P
Desjardins
Stephen
S
Caplan
Merrill J
MJ
Egorin
Lilian
L
Amrein
Raquel
R
Aloyz
Lawrence
L
Panasci
D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001549:Benzamides; D002699:Chlorambucil / Q000008:administration & dosage; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000008:administration & dosage; D051135:Rad51 Recombinase / Q000037:antagonists & inhibitors; D011995:Recombination, Genetic; D016896:Treatment Outcome; D014740:Vidarabine / Q000031:analogs & derivatives / Q000627:therapeutic use
D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D002699:Chlorambucil; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl; D051135:Rad51 Recombinase; D014740:Vidarabine; C024352:fludarabine