Dasatinib in Imatinib-Resistant Philadelphia Chromosome–Positive Leukemias
Moshe Talpaz, M.D., Neil P. Shah, M.D., Ph.D., Hagop Kantarjian, M.D., Nicholas Donato, Ph.D., John Nicoll, B.A., Ron Paquette, M.D., Jorge Cortes, M.D., Susan O'Brien, M.D., Claude Nicaise, M.D., Eric Bleickardt, M.D., M. Anne Blackwood-Chirchir, M.D., Vishwanath Iyer, M.S., Tai-Tsang Chen, M.Phil., Fei Huang, Ph.D., Arthur P. Decillis, M.D., and Charles L. Sawyers, M.D.
Background The BCR-ABL tyrosine kinase inhibitor imatinib iseffective in Philadelphia chromosome–positive (Ph-positive)leukemias, but relapse occurs, mainly as a result of the outgrowthof leukemic subclones with imatinib-resistant BCR-ABL mutations.We evaluated dasatinib, a BCR-ABL inhibitor that targets mostimatinib-resistant BCR-ABL mutations, in patients with chronicmyelogenous leukemia (CML) or Ph-positive acute lymphoblasticleukemia (ALL).
Methods Patients with various phases of CML or with Ph-positiveALL who could not tolerate or were resistant to imatinib wereenrolled in a phase 1 dose-escalation study. Dasatinib (15 to240 mg per day) was administered orally in four-week treatmentcycles, once or twice daily.
Results A complete hematologic response was achieved in 37 of40 patients with chronic-phase CML, and major hematologic responseswere seen in 31 of 44 patients with accelerated-phase CML, CMLwith blast crisis, or Ph-positive ALL. In these two phases,the rates of major cytogenetic response were 45 percent and25 percent, respectively. Responses were maintained in 95 percentof patients with chronic-phase disease and in 82 percent ofpatients with accelerated-phase disease, with a median follow-upmore than 12 months and 5 months, respectively. Nearly all patientswith lymphoid blast crisis and Ph-positive ALL had a relapsewithin six months. Responses occurred among all BCR-ABL genotypes,with the exception of the T315I mutation, which confers resistanceto both dasatinib and imatinib in vitro. Myelosuppression wascommon but not dose-limiting.
Conclusions Dasatinib induces hematologic and cytogenetic responsesin patients with CML or Ph-positive ALL who cannot tolerateor are resistant to imatinib. (ClinicalTrials.gov number, NCT00064233
[ClinicalTrials.gov]
.)
Source Information
From the Departments of Leukemia (M.T., H.K., J.C., S.O.) and Experimental Therapeutics (M.T., N.D.), M.D. Anderson Cancer Center, Houston; Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles (N.P.S., J.N., R.P., C.L.S.); Bristol-Myers Squibb, Wallingford, Conn. (C.N., E.B., V.I., T.-T.C., A.P.D.), and Lawrenceville, N.J. (M.A.B.-C., F.H.); and Howard Hughes Medical Institute, Chevy Chase, Md. (C.L.S.). Drs. Talpaz and Sawyers contributed equally to this article.
Address reprint requests to Dr. Sawyers at Jonsson Comprehensive Cancer Center, University of California at Los Angeles, 11-934 Factor Bldg., 10833 LeConte Ave., Los Angeles, CA 90095, or at csawyers{at}mednet.ucla.edu.
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le Coutre, P., Ottmann, O. G., Giles, F., Kim, D.-W., Cortes, J., Gattermann, N., Apperley, J. F., Larson, R. A., Abruzzese, E., O'Brien, S. G., Kuliczkowski, K., Hochhaus, A., Mahon, F.-X., Saglio, G., Gobbi, M., Kwong, Y.-L., Baccarani, M., Hughes, T., Martinelli, G., Radich, J. P., Zheng, M., Shou, Y., Kantarjian, H.
(2008). Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia. Blood
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Duncan, E. A., Goetz, C. A., Stein, S. J., Mayo, K. J., Skaggs, B. J., Ziegelbauer, K., Sawyers, C. L., Baldwin, A. S.
(2008). I{kappa}B kinase {beta} inhibition induces cell death in Imatinib-resistant and T315I Dasatinib-resistant BCR-ABL+ cells. Molecular Cancer Therapeutics
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Rix, U., Hantschel, O., Durnberger, G., Remsing Rix, L. L., Planyavsky, M., Fernbach, N. V., Kaupe, I., Bennett, K. L., Valent, P., Colinge, J., Kocher, T., Superti-Furga, G.
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