Phase II Pilot Study of Imatinib Mesylate Combined with Induction Chemotherapy in Blast-Phase CML and Ph+ ALL.

CML in blast crisis (BC) and Philadelphia chromosome-positive (Ph+) ALL are incurable with conventional chemotherapy and in most cases respond only transiently to the Bcr-Abl kinase inhibitor imatinib mesylate. We hypothesized that pretreatment with imatinib would overcome inherent drug resistance to induction chemotherapy mediated by Bcr-Abl, and evaluated the combination in 17 patients with Ph+ acute leukemias (5 CML in BC, 6 de-novo Ph+ ALL, 6 relapsed Ph+ ALL). All patients received a 1-week prephase of imatinib alone at 600 mg daily. In CML in BC and relapsed Ph+ ALL, imatinib was continued concomitantly with induction chemotherapy (standard-dose idarubicin/ara-C with vincristine/prednisone added for lymphoid leukemias) for an additional week. Imatinib was then ceased, but recommenced as a single agent after blood-count recovery. Patients with de-novo Ph+ ALL received the imatinib prephase and then commenced the French LALA94 protocol without concomitant imatinib. Neutrophils recovered to ≥ 1.0 x 10⁹/L at a median of day 28 (range 21–56) of induction chemotherapy. During induction, 1 patient died from sepsis and multi-organ failure, and 1 patient died on day 7 from CNS leukemia.

Subsequently, 1 patient died on day 37 from massive hemoptysis and 1 patient developed pulmonary fibrosis and died on day 144. Among 14 evaluable patients, combined imatinib and chemotherapy induction resulted in 9 (64%) complete hematological responses and there were 5 complete and 3 major cytogenetic responses. Notably, 2 out of 3 patients with CML in myeloid BC achieved major cytogenetic responses. The in-vivo effects of imatinib on Bcr-Abl activity were monitored in leukemic blasts during the imatinib-only prephase. Western blots revealed a decrease in CrkL phosphorylation to < 25% of the pretreatment level in peripheral-blood samples from 5 out of 6 evaluable cases and in marrow samples from 1 of 2 evaluable cases. Bcl-x_L expression levels revealed no consistent in-vivo responses to imatinib. However, all 7 cases evaluable for Bcl-2 protein showed strong expression levels, which were unaffected by imatinib in 5 cases and decreased in 2 cases. Imatinib potently inhibited Bcr-Abl activity in vivo in Ph+ acute leukemic blasts and its combination with induction chemotherapy was tolerable and shows promising activity.