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Blood, 15 November 2007, Vol. 110, No. 10, pp. 3540-3546.
Prepublished online as a Blood First Edition Paper on August 22, 2007; DOI 10.1182/blood-2007-03-080689.
 Previous Article | Table of Contents | Next Article 
CLINICAL TRIALS AND OBSERVATIONS
Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome–positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance
Hagop M. Kantarjian1,
Francis Giles1,
Norbert Gattermann2,
Kapil Bhalla3,
Giuliana Alimena4,
Francesca Palandri5,
Gert J. Ossenkoppele6,
Franck-Emmanuel Nicolini7,
Stephen G. O'Brien8,
Mark Litzow9,
Ravi Bhatia10,
Francisco Cervantes11,
Ariful Haque12,
Yaping Shou12,
Debra J. Resta12,
Aaron Weitzman12,
Andreas Hochhaus13, and
Philipp le Coutre14
1 M. D. Anderson Cancer Center, Houston, TX;
2 Universitaetsklinikum Duesseldorf, Duesseldorf, Germany;
3 H. Lee Moffitt Cancer Center, Tampa, FL;
4 Azienda Policlinico Umberto I–Universita La Sapienza, Rome, Italy;
5 S. Orsola–Malpighi University Hospital, University of Bologna, Bologna, Italy;
6 Vrije University (VU) Medisch Centrum, Amsterdam, the Netherlands;
7 Hópital Edouard Herriot, Lyon, France;
8 Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom;
9 Mayo Clinic, College of Medicine, Rochester, MN;
10 City of Hope National Medical Center, Duarte, CA;
11 Hospital Clinic, Barcelona, Spain;
12 Novartis Pharmaceuticals, Florham Park, NJ;
13 III Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg, Mannheim, Germany; and
14 Campus Virchow Klinikum, Charité, Humboldt-Universität, Berlin, Germany
Nilotinib, an orally bioavailable, selective Bcr-Abl tyrosine kinase inhibitor, is 30-fold more potent than imatinib in pre-clinical models, and overcomes most imatinib resistant BCR-ABL mutations. In this phase 2 open-label study, 400 mg nilotinib was administered orally twice daily to 280 patients with Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) after imatinib failure or intolerance. Patients had at least 6 months of follow-up and were evaluated for hematologic and cytogenetic responses, as well as for safety and overall survival. At 6 months, the rate of major cytogenetic response (Ph  35%) was 48%: complete (Ph = 0%) in 31%, and partial (Ph = 1%-35%) in 16%. The estimated survival at 12 months was 95%. Nilotinib was effective in patients harboring BCR-ABL mutations associated with imatinib resistance (except T315I), and also in patients with a resistance mechanism independent of BCR-ABL mutations. Adverse events were mostly mild to moderate, and there was minimal cross-intolerance with imatinib. Grades 3 to 4 neutropenia and thrombocytopenia were observed in 29% of patients; pleural or pericardial effusions were observed in 1% (none were severe). In summary, nilotinib is highly active and safe in patients with CML-CP after imatinib failure or intolerance. This clinical trial is registered at http://clinicaltrials.gov as ID no. NCT00109707
[ClinicalTrials.gov]
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