Insights from pre-clinical studies for new combination treatment regimens with the Bcr-Abl kinase inhibitor imatinib mesylate (Gleevec/Glivec) in chronic myelogenous leukemia: a translational perspective

Clinical phase I/II studies with the Abl kinase inhibitor imatinib mesylate (Gleevec/Glivec, formerly STI571) for the treatment for chronic myelogenous leukemia (CML) demonstrated the safety and the remarkable efficacy of this molecularly targeted agent. However, a significant proportion of patients treated in the chronic phase of the disease after having failed interferon alpha (IFN) remain predominantly Philadelphia chromosome positive (Ph+), suggesting a risk of later relapses. Furthermore, results in blast crisis patients revealed a high frequency of relapses or resistance to imatinib. To circumvent resistance, improve response rates, or prolong survival, pre-clinical evaluations of combinations of imatinib with other agents have been pursued. Some of these have already been translated into clinical studies. Here, we first summarize evidence from pre-clinical studies on new combination regimens with imatinib in the treatment of CML. Second, we analyze preliminary clinical data of ongoing combination studies. Finally, we provide a summary of approaches that use novel antileukemic agents with molecularly characterized modes of action.