title: 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.
abstract: 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 < or = 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.
authors: Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77230-1402, USA. hkantarj@mdanderson.org
authors: Hagop M
authors: HM
authors: Kantarjian
authors: Francis
authors: F
authors: Giles
authors: Norbert
authors: N
authors: Gattermann
authors: Kapil
authors: K
authors: Bhalla
authors: Giuliana
authors: G
authors: Alimena
authors: Francesca
authors: F
authors: Palandri
authors: Gert J
authors: GJ
authors: Ossenkoppele
authors: Franck-Emmanuel
authors: FE
authors: Nicolini
authors: Stephen G
authors: SG
authors: O'Brien
authors: Mark
authors: M
authors: Litzow
authors: Ravi
authors: R
authors: Bhatia
authors: Francisco
authors: F
authors: Cervantes
authors: Ariful
authors: A
authors: Haque
authors: Yaping
authors: Y
authors: Shou
authors: Debra J
authors: DJ
authors: Resta
authors: Aaron
authors: A
authors: Weitzman
authors: Andreas
authors: A
authors: Hochhaus
authors: Philipp
authors: P
authors: le Coutre
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D001549:Benzamides; D002908:Chronic Disease; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000009:adverse effects* / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib