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Clinical Cancer Research Vol. 8, 2167-2176, July 2002
© 2002 American Association for Cancer Research

Clinical Trials

Treatment of Philadelphia Chromosome-positive, Accelerated-phase Chronic Myelogenous Leukemia with Imatinib Mesylate1

Hagop M. Kantarjian2, Susan O’Brien, Jorge E. Cortes3, Terry L. Smith, Mary Beth Rios, Jianqin Shan, Ying Yang, Francis J. Giles, Deborah A. Thomas, Stefan Faderl, Guillermo Garcia-Manero, Sima Jeha, William Wierda, Jean-Pierre J. Issa, Steven M. Kornblau, Michael Keating, Debra Resta, Renaud Capdeville and Moshe Talpaz

Departments of Leukemia [H. M. K., S. O., J. E. C., M. B. R., J. S., F. J. G., D. A. T., S. F., G. G-M., S. J., W. W., J-P. J. I., S. M. K., M. K.], Biostatistics [T. L. S., Y. Y.], and Bioimmunotherapy [M. T.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas, and Novartis Pharmaceutical, Basel, Switzerland [D. R., R. C.]

Purpose: Imatinib mesylate, a specific Bcr-Abl tyrosine kinase inhibitor, has shown encouraging activity in chronic myelogenous leukemia (CML).

Experimental Design: We treated 237 patients (median age, 50 years; age range, 18–82 years) with Philadelphia chromosome (Ph)-positive accelerated-phase CML with oral imatinib mesylate at daily doses of 400 mg (26 patients) or 600 mg (211 patients) and evaluated response and survival characteristics in univariate and multivariate analyses.

Results: Among the 200 patients with accelerated-phase CML for whom follow-up was 3 months or more, rates of complete and partial hematological response were 80% and 10%. Cytogenetic responses were evident in 90 patients [45%; complete response in 47 patients (24%) and partial response (Ph 1–34%) in 21 patients (11%)]. The estimated 18-month survival rate was 73%. The estimated complete hematological response rate at 18 months was 68%; that for cytogenetic response was 82%. In multivariate analyses, a diagnosis-to-treatment interval of 3 years or more, splenomegaly, and peripheral blasts predicted poor major cytogenetic response; age >60 years, marrow basophilia, and clonal evolution predicted poor survival. The 600-mg drug dose was associated with better cytogenetic response and survival in univariate analysis (P < 0.01) but not in multivariate analysis. Landmark analysis showed that achieving a cytogenetic response at 3 months or a major cytogenetic response (Ph < 35%) at 6 months was associated with better long-term survival. Seven of 15 patients who were in a second chronic phase achieved major cytogenetic response. The incidence of severe nonhematological toxic effects was 23%; drug discontinuation for severe toxicity was needed in 3% of patients.

Conclusions: Imatinib mesylate was active against Ph-positive, accelerated-phase CML, and the prognostic factors identified in this study could aid in tailoring treatment strategies to specific risk groups.




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Copyright © 2002 by the American Association for Cancer Research.