Background Resistance to imatinib mesylate can occur in chronicmyelogenous leukemia (CML). Preclinical in vitro studies haveshown that nilotinib (AMN107), a new BCR-ABL tyrosine kinaseinhibitor, is more potent than imatinib against CML cells bya factor of 20 to 50.
Methods In a phase 1 dose-escalation study, we assigned 119patients with imatinib-resistant CML or acute lymphoblasticleukemia (ALL) to receive nilotinib orally at doses of 50 mg,100 mg, 200 mg, 400 mg, 600 mg, 800 mg, and 1200 mg once dailyand at 400 mg and 600 mg twice daily.
Results Common adverse events were myelosuppression, transientindirect hyperbilirubinemia, and rashes. Of 33 patients withthe blastic phase of disease, 13 had a hematologic responseand 9 had a cytogenetic response; of 46 patients with the acceleratedphase, 33 had a hematologic response and 22 had a cytogeneticresponse; 11 of 12 patients with the chronic phase had a completehematologic remission.
Conclusions Nilotinib has a relatively favorable safety profileand is active in imatinib-resistant CML. (ClinicalTrials.govnumber, NCT00109707
[ClinicalTrials.gov]
.)
Source Information
From the Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston (H.K., F.G., S.O., J.C.); J.W. Goethe Universität, Frankfurt, Germany (L.W., B.W., D.H., O.G.O.); Moffitt Cancer Center, Tampa, Fla. (K.B.); Novartis Pharmaceuticals, East Hanover, N.J. (C.T., P.M., P.R., W.M., K.B., M.D., L.A.); Quest Diagnostics, San Juan Capistrano, Calif. (M.A.); Fakultät fur Klinische Medizin Mannheim, Universität Heidelberg, Mannheim, Germany (A.H.); and the Department of Medical Oncology, Dana–Farber Cancer Institute, Boston (J.D.G.). Drs. Kantarjian and Giles contributed equally to this article.
Address reprint requests to Dr. Kantarjian at the Department of Leukemia, Unit 428, University of Texas M.D. Anderson Cancer Center, P.O. Box 301402, Houston, TX 77230-1402, or at hkantarj{at}mdanderson.org.
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Rowe, J. M.
(2007). Closing the gap in CML. Blood
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(2007). Resistance to c-KIT kinase inhibitors conferred by V654A mutation. Molecular Cancer Therapeutics
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Weisberg, E., Catley, L., Wright, R. D., Moreno, D., Banerji, L., Ray, A., Manley, P. W., Mestan, J., Fabbro, D., Jiang, J., Hall-Meyers, E., Callahan, L., DellaGatta, J. L., Kung, A. L., Griffin, J. D.
(2007). Beneficial effects of combining nilotinib and imatinib in preclinical models of BCR-ABL+ leukemias. Blood
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Wang, Y., Cai, D., Brendel, C., Barett, C., Erben, P., Manley, P. W., Hochhaus, A., Neubauer, A., Burchert, A.
(2007). Adaptive secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) mediates imatinib and nilotinib resistance in BCR/ABL+ progenitors via JAK-2/STAT-5 pathway activation. Blood
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Bozulic, L., Morin, P. J., Hunter, T., Hemmings, B. A.
(2007). Meeting Report: Targeting the Kinome--20 Years of Tyrosine Kinase Inhibitor Research in Basel. Sci Signal
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Kantarjian, H. M., Giles, F., Quintas-Cardama, A., Cortes, J.
(2007). Important Therapeutic Targets in Chronic Myelogenous Leukemia. Clin. Cancer Res.
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Lerma, E. I., Nguyen, V.-A., Wang, T., Tipping, A., Melo, J. V., Kufe, D., Austin, D. J., Deisseroth, A.
(2007). Novel compounds with antiproliferative activity against imatinib-resistant cell lines. Molecular Cancer Therapeutics
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Martinelli, G., Soverini, S., Iacobucci, I., Baccarani, M.
(2007). MK-0457: a light at the end of the tunnel?. Blood
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Giles, F. J., Cortes, J., Jones, D., Bergstrom, D., Kantarjian, H., Freedman, S. J.
(2007). MK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphocytic leukemia with the T315I BCR-ABL mutation. Blood
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Radich, J. P.
(2007). The Biology of CML Blast Crisis. ASH Education Book
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Thomas, D. A.
(2007). Philadelphia Chromosome Positive Acute Lymphocytic Leukemia: A New Era of Challenges. ASH Education Book
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Kantarjian, H. M., Talpaz, M., Giles, F., O'Brien, S., Cortes, J.
(2006). New Insights into the Pathophysiology of Chronic Myeloid Leukemia and Imatinib Resistance. ANN INTERN MED
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Soverini, S., Colarossi, S., Gnani, A., Rosti, G., Castagnetti, F., Poerio, A., Iacobucci, I., Amabile, M., Abruzzese, E., Orlandi, E., Radaelli, F., Ciccone, F., Tiribelli, M., di Lorenzo, R., Caracciolo, C., Izzo, B., Pane, F., Saglio, G., Baccarani, M., Martinelli, G., on behalf of the GIMEMA Working Party on Chronic M,
(2006). Contribution of ABL Kinase Domain Mutations to Imatinib Resistance in Different Subsets of Philadelphia-Positive Patients: By the GIMEMA Working Party on Chronic Myeloid Leukemia. Clin. Cancer Res.
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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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Fausel, C. A.
(2006). Novel treatment strategies for chronic myeloid leukemia.. Am J Health Syst Pharm
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Talpaz, M., Shah, N. P., Kantarjian, H., Donato, N., Nicoll, J., Paquette, R., Cortes, J., O'Brien, S., Nicaise, C., Bleickardt, E., Blackwood-Chirchir, M. A., Iyer, V., Chen, T.-T., Huang, F., Decillis, A. P., Sawyers, C. L.
(2006). Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias.. NEJM
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Druker, B. J.
(2006). Circumventing resistance to kinase-inhibitor therapy.. NEJM
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