Efficacy and Safety of a Specific Inhibitor of the BCR-ABL Tyrosine Kinase in Chronic Myeloid Leukemia

doi:10.1056/NEJM200104053441401

Volume 344:1031-1037		April 5, 2001		Number 14

Efficacy and Safety of a Specific Inhibitor of the BCR-ABL Tyrosine Kinase in Chronic Myeloid Leukemia

Brian J. Druker, M.D., Moshe Talpaz, M.D., Debra J. Resta, R.N., Bin Peng, Ph.D., Elisabeth Buchdunger, Ph.D., John M. Ford, M.D., Nicholas B. Lydon, Ph.D., Hagop Kantarjian, M.D., Renaud Capdeville, M.D., Sayuri Ohno-Jones, B.S., and Charles L. Sawyers, M.D.

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ABSTRACT

Background BCR-ABL is a constitutively activated tyrosine kinasethat causes chronic myeloid leukemia (CML). Since tyrosine kinaseactivity is essential to the transforming function of BCR-ABL,an inhibitor of the kinase could be an effective treatment forCML.

Methods We conducted a phase 1, dose-escalating trial of STI571(formerly known as CGP 57148B), a specific inhibitor of theBCR-ABL tyrosine kinase. STI571 was administered orally to 83patients with CML in the chronic phase in whom treatment withinterferon alfa had failed. Patients were successively assignedto 1 of 14 doses ranging from 25 to 1000 mg per day.

Results Adverse effects of STI571 were minimal; the most commonwere nausea, myalgias, edema, and diarrhea. A maximal tolerateddose was not identified. Complete hematologic responses wereobserved in 53 of 54 patients treated with daily doses of 300mg or more and typically occurred in the first four weeks oftherapy. Of the 54 patients treated with doses of 300 mg ormore, cytogenetic responses occurred in 29, including 17 (31percent of the 54 patients who received this dose) with majorresponses (0 to 35 percent of cells in metaphase positive forthe Philadelphia chromosome); 7 of these patients had completecytogenetic remissions.

Conclusions STI571 is well tolerated and has significant antileukemicactivity in patients with CML in whom treatment with interferonalfa had failed. Our results provide evidence of the essentialrole of BCR-ABL tyrosine kinase activity in CML and demonstratethe potential for the development of anticancer drugs basedon the specific molecular abnormality present in a human cancer.

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From the Division of Hematology and Medical Oncology, Oregon Health Sciences University, Portland (B.J.D., S.O.-J.); the Departments of Bioimmunotherapy (M.T.) and Leukemia (H.K.), University of Texas M.D. Anderson Cancer Center, Houston; the Department of Oncology Clinical Research, Novartis Pharmaceuticals, East Hanover, N.J. (D.J.R.), and Basel, Switzerland (B.P., E.B., J.M.F., N.B.L., R.C.); and the Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles (C.L.S.).

Address reprint requests to Dr. Druker at Oregon Health Sciences University, L592, 3181 SW Sam Jackson Park Rd., Portland, OR 97201, or at drukerb{at}ohsu.edu.

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