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.
La Rosée
P
P
Oregon Health and Science University, Division of Hematology and Medical Oncology, Portland 97201, USA.
O'Dwyer
M E
ME
Druker
B J
BJ
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D016903:Drug Monitoring; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome
D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl