Activity of a Specific Inhibitor of the BCR-ABL Tyrosine Kinase in the Blast Crisis of Chronic Myeloid Leukemia and Acute Lymphoblastic Leukemia with the Philadelphia Chromosome
Brian J. Druker, M.D., Charles L. Sawyers, M.D., Hagop Kantarjian, M.D., Debra J. Resta, R.N., Sofia Fernandes Reese, M.D., John M. Ford, M.D., Renaud Capdeville, M.D., and Moshe Talpaz, M.D.
Background BCR-ABL, a constitutively activated tyrosine kinase,is the product of the Philadelphia (Ph) chromosome. This enzymeis present in virtually all cases of chronic myeloid leukemia(CML) throughout the course of the disease, and in 20 percentof cases of acute lymphoblastic leukemia (ALL). On the basisof the substantial activity of the inhibitor in patients inthe chronic phase, we evaluated STI571 (formerly known as CGP57148B), a specific inhibitor of the BCR-ABL tyrosine kinase,in patients who had CML in blast crisis and in patients withPh-chromosome–positive ALL.
Methods In this dose-escalating pilot study, 58 patients weretreated with STI571; 38 patients had myeloid blast crisis and20 had ALL or lymphoid blast crisis. Treatment was given orallyat daily doses ranging from 300 to 1000 mg.
Results Responses occurred in 21 of 38 patients (55 percent)with a myeloid-blast-crisis phenotype; 4 of these 21 patientshad a complete hematologic response. Of 20 patients with lymphoidblast crisis or ALL, 14 (70 percent) had a response, including4 who had complete responses. Seven patients with myeloid blastcrisis continue to receive treatment and remain in remissionfrom 101 to 349 days after starting the treatment. All but onepatient with lymphoid blast crisis or ALL has relapsed. Themost frequent adverse effects were nausea, vomiting, edema,thrombocytopenia, and neutropenia.
Conclusions The BCR-ABL tyrosine kinase inhibitor STI571 iswell tolerated and has substantial activity in the blast crisesof CML and in Ph-chromosome–positive ALL.
Source Information
From the Division of Hematology and Medical Oncology, Oregon Health Sciences University, Portland (B.J.D.); the Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles (C.L.S.); the Departments of Leukemia (H.K.) and Bioimmunotherapy (M.T.), University of Texas M.D. Anderson Cancer Center, Houston; and the Department of Oncology Clinical Research, Novartis Pharmaceuticals, East Hanover, N.J. (D.R.J.), and Basel, Switzerland (S.F.R., J.M.F., R.C.).
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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A correction has been published: N Engl J Med 2001;345(3):232.
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