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 preclinical 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 followup 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. (Blood. 2007;110: [3540][3541][3542][3543][3544][3545][3546]

Activity and tolerability of nilotinib

“…Our results reinforce the efficacy and safety of nilotinib shown in previous reports [5][6][7][8] and recent updates. 8,[16][17][18] CHR was newly achieved in 66% and major cytogenetic response in 43%.…”

“…Nilotinib is active in Philadelphia-positive CML both in vitro 3,4 and in clinical studies of imatinib-resistant or -intolerant patients in chronic phase, accelerated phase (AP), and blast crisis (BC) CML. [5][6][7][8] It was recently approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of imatinib-resistant or -intolerant CML patients 9 in chronic and accelerated phases. Additional information regarding the efficacy and safety of nilotinib can be gained from expanded access trials that incorporate in their design aspects learned from the initial phase 2 trials, and are aimed at treating broader populations.…”

Optimizing therapy for patients with chronic myelogenous leukemia in chronic phase

“…57 Nilotinib was associated with very low rates of pleural or pericardial effusions (approximately 1; none have been grade 3/4). 58 The most common grade 3/4 AEs associated with nilotinib therapy were thrombocytopenia (20%-33%), neutropenia (13%-31%), elevated bilirubin (7%), and elevated serum lipase (5%-15%). 57,58,61 Food increases the bioavailability of nilotinib, 62 and no food should be taken at least 2 hours before and at least 1 hour after nilotinib is taken.…”

“…58 The most common grade 3/4 AEs associated with nilotinib therapy were thrombocytopenia (20%-33%), neutropenia (13%-31%), elevated bilirubin (7%), and elevated serum lipase (5%-15%). 57,58,61 Food increases the bioavailability of nilotinib, 62 and no food should be taken at least 2 hours before and at least 1 hour after nilotinib is taken. Grapefruit products and other foods that are known to inhibit hepatic metabolic pathways like CYP3A4 should be avoided.…”

“…Among patients with CML-CP (N ¼ 321; 71% imatinib resistant and 29% imatinib intolerant), 58,59 158 of 206 patients (77%) who did not have a CHR at baseline achieved a CHR during nilotinib therapy. An MCyR was noted in 186 patients (59%), and 44% achieved a CCyR.…”