Hematologic and Cytogenetic Responses to Imatinib Mesylate in Chronic Myelogenous Leukemia
Hagop Kantarjian, M.D., Charles Sawyers, M.D., Andreas Hochhaus, M.D., Francois Guilhot, M.D., Charles Schiffer, M.D., Carlo Gambacorti-Passerini, M.D., Dietger Niederwieser, M.D., Debra Resta, R.N., Renaud Capdeville, M.D., Ulrike Zoellner, M.Sc., Moshe Talpaz, M.D., Brian Druker, M.D., for the International STI571 CML Study Group
Background Chronic myelogenous leukemia (CML) is caused by theBCR-ABL tyrosine kinase, the product of the Philadelphia chromosome.Imatinib mesylate, formerly STI571, is a selective inhibitorof this kinase.
Methods A total of 532 patients with late–chronic-phaseCML in whom previous therapy with interferon alfa had failedwere treated with 400 mg of oral imatinib daily. Patients wereevaluated for cytogenetic and hematologic responses. Time toprogression, survival, and toxic effects were also evaluated.
Results Imatinib induced major cytogenetic responses in 60 percentof the 454 patients with confirmed chronic-phase CML and completehematologic responses in 95 percent. After a median follow-upof 18 months, CML had not progressed to the accelerated or blastphases in an estimated 89 percent of patients, and 95 percentof the patients were alive. Grade 3 or 4 nonhematologic toxiceffects were infrequent, and hematologic toxic effects weremanageable. Only 2 percent of patients discontinued treatmentbecause of drug-related adverse events, and no treatment-relateddeaths occurred.
Conclusions Imatinib induced high rates of cytogenetic and hematologicresponses in patients with chronic-phase CML in whom previousinterferon therapy had failed.
Source Information
From the M.D. Anderson Cancer Center, Houston (H.K., M.T.); the University of California at Los Angeles, Los Angeles (C Sawyers); Universitätsklinikum Mannheim der Universität Heidelberg, Mannheim, Germany (A.H.); Centre Hospitalier Universitaire de Poitiers, Poitiers, France (F.G.); Wayne State University, Detroit (C Schiffer); San Gerardo Hospital and National Cancer Institute, Milan, Italy (C.G.-P.); University of Leipzig, Leipzig, Germany (D.N.); Novartis Pharmaceuticals, East Hanover, N.J., and Basel, Switzerland (D.R., R.C., U.Z.); and Oregon Health Sciences University, Portland (B.D.).
Address reprint requests to Dr. Kantarjian at the Department of Leukemia, Box 428, M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, or at hkantarj{at}mdanderson.org.
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Druker, B. J., Guilhot, F., O'Brien, S. G., Gathmann, I., Kantarjian, H., Gattermann, N., Deininger, M. W.N., Silver, R. T., Goldman, J. M., Stone, R. M., Cervantes, F., Hochhaus, A., Powell, B. L., Gabrilove, J. L., Rousselot, P., Reiffers, J., Cornelissen, J. J., Hughes, T., Agis, H., Fischer, T., Verhoef, G., Shepherd, J., Saglio, G., Gratwohl, A., Nielsen, J. L., Radich, J. P., Simonsson, B., Taylor, K., Baccarani, M., So, C., Letvak, L., Larson, R. A., the IRIS Investigators,
(2006). Five-Year Follow-up of Patients Receiving Imatinib for Chronic Myeloid Leukemia. NEJM
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Luo, F. R., Yang, Z., Camuso, A., Smykla, R., McGlinchey, K., Fager, K., Flefleh, C., Castaneda, S., Inigo, I., Kan, D., Wen, M.-L., Kramer, R., Blackwood-Chirchir, A., Lee, F. Y.
(2006). Dasatinib (BMS-354825) Pharmacokinetics and Pharmacodynamic Biomarkers in Animal Models Predict Optimal Clinical Exposure. Clin. Cancer Res.
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Puttini, M., Coluccia, A. M. L., Boschelli, F., Cleris, L., Marchesi, E., Donella-Deana, A., Ahmed, S., Redaelli, S., Piazza, R., Magistroni, V., Andreoni, F., Scapozza, L., Formelli, F., Gambacorti-Passerini, C.
(2006). In vitro and In vivo Activity of SKI-606, a Novel Src-Abl Inhibitor, against Imatinib-Resistant Bcr-Abl+ Neoplastic Cells. Cancer Res.
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(2006). Phase 1 clinical results with tandutinib (MLN518), a novel FLT3 antagonist, in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome: safety, pharmacokinetics, and pharmacodynamics. Blood
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Tikkanen, J. M., Hollmen, M., Nykanen, A. I., Wood, J., Koskinen, P. K., Lemstrom, K. B.
(2006). Role of Platelet-derived Growth Factor and Vascular Endothelial Growth Factor in Obliterative Airway Disease. Am. J. Respir. Crit. Care Med.
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(2006). Impact and Perceptions of Mandatory Tumor Biopsies for Correlative Studies in Clinical Trials of Novel Anticancer Agents. JCO
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Kometani, K., Aoki, M., Kawamata, S., Shinozuka, Y., Era, T., Taniwaki, M., Hattori, M., Minato, N.
(2006). Role of SPA-1 in Phenotypes of Chronic Myelogenous Leukemia Induced by BCR-ABL-Expressing Hematopoietic Progenitors in a Mouse Model.. Cancer Res.
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Mologni, L., Sala, E., Cazzaniga, S., Rostagno, R., Kuoni, T., Puttini, M., Bain, J., Cleris, L., Redaelli, S., Riva, B., Formelli, F., Scapozza, L., Gambacorti-Passerini, C.
(2006). Inhibition of RET tyrosine kinase by SU5416.. J Mol Endocrinol
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Baccarani, M., Saglio, G., Goldman, J., Hochhaus, A., Simonsson, B., Appelbaum, F., Apperley, J., Cervantes, F., Cortes, J., Deininger, M., Gratwohl, A., Guilhot, F., Horowitz, M., Hughes, T., Kantarjian, H., Larson, R., Niederwieser, D., Silver, R., Hehlmann, R.
(2006). Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood
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(2006). Advances in the Therapy of Chronic Idiopathic Myelofibrosis. The Oncologist
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Roy, L., Guilhot, J., Krahnke, T., Guerci-Bresler, A., Druker, B. J., Larson, R. A., O'Brien, S., So, C., Massimini, G., Guilhot, F.
(2006). Survival advantage from imatinib compared with the combination interferon-{alpha} plus cytarabine in chronic-phase chronic myelogenous leukemia: historical comparison between two phase 3 trials. Blood
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(2006). Leukemogenesis induced by wild-type and STI571-resistant BCR/ABL is potently suppressed by C/EBP{alpha}. Blood
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(2006). Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias.. NEJM
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Kantarjian, H., Giles, F., Wunderle, L., Bhalla, K., O'Brien, S., Wassmann, B., Tanaka, C., Manley, P., Rae, P., Mietlowski, W., Bochinski, K., Hochhaus, A., Griffin, J. D., Hoelzer, D., Albitar, M., Dugan, M., Cortes, J., Alland, L., Ottmann, O. G.
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Ault, P., Kantarjian, H., O'Brien, S., Faderl, S., Beran, M., Rios, M. B., Koller, C., Giles, F., Keating, M., Talpaz, M., Cortes, J.
(2006). Pregnancy Among Patients With Chronic Myeloid Leukemia Treated With Imatinib. JCO
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A correction has been published: N Engl J Med 2002;346(24):1923.
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