Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinasein chronic myeloid leukemia.

Background: BCR-ABL is a constitutively activated tyrosine kinase that caus es chronic myeloid leukemia (CML). Since tyrosine kinase activity is essent ial to the transforming function of BCR-ABL, an inhibitor of the kinase cou ld be an effective treatment for CML. Methods: We conducted a phase 1, dose-escalating trial of STI571 (formerly known as CGP 57148B), a specific inhibitor of the BCR-ABL tyrosine kinase. STI571 was administered orally to 83 patients with CML in the chronic phase in whom treatment with interferon alfa had failed. Patients were successiv ely assigned to 1 of 14 doses ranging from 25 to 1000 mg per day. Results: Adverse effects of STI571 were minimal; the most common were nause a, myalgias, edema, and diarrhea. A maximal tolerated dose was not identifi ed. Complete hematologic responses were observed in 53 of 54 patients treat ed with daily doses of 300 mg or more and typically occurred in the first f our weeks of therapy. Of the 54 patients treated with doses of 300 mg or mo re, cytogenetic responses occurred in 29, including 17 (31 percent of the 5 4 patients who received this dose) with major responses (0 to 35 percent of cells in metaphase positive for the Philadelphia chromosome); 7 of these p atients had complete cytogenetic remissions. Conclusions: STI571 is well tolerated and has significant antileukemic acti vity in patients with CML in whom treatment with interferon alfa had failed . Our results provide evidence of the essential role of BCR-ABL tyrosine ki nase activity in CML and demonstrate the potential for the development of a nticancer drugs based on the specific molecular abnormality present in a hu man cancer. (N Engl J Med 2001;344:1031-7.) Copyright (C) 2001 Massachusett s Medical Society.