Background: Nilotinib and dasatinib are the next generation of tyrosine kinase inhibitors (TKIs) which have been developed for use in the treatment of imatinib-resistant/intolerant CML. Few therapeutic options are available for patients (pts) with CML who fail to benefit from or to tolerate first, imatinib, and then, a second generation TKI such as dasatinib and nilotinib. This phase II open-label study was designed to evaluate the safety and efficacy of nilotinib in such pts who either failed or were intolerant to imatinib and dasatinib.

Methods: Nilotinib was administered at a dose of 400 mg twice daily (BID) to pts with CML-CP, -AP, and -BC who previously received and either failed or were intolerant to imatinib and dasatinib. Pts who had inadequate hematologic and/or cytogenetic responses at 28 days or who had disease progression could be escalated to 600 mg BID in the absence of safety concerns.

Results: A total of 67 evaluable pts are reported with CML-CP (27), -AP (15), and -BC (25 total; 15 myeloid, 8 lymphoid). Overall, 25% of pts had extramedullary disease at baseline (14 spleen, 6 liver). For all pts, median time from first diagnosis was 20 (<1–266) months. The median duration of nilotinib exposure was 85 (2–542) days with median dose intensity of 800 (211–1093) mg/day. A total of 22 (33%) pts with dasatinib failure remained on nilotinib and 45 (67%) discontinued (8 for adverse events, 27 for disease progression). Of 17 pts with CML-CP who did not have a complete hematologic response (CHR) at baseline, 11 (65%) achieved a CHR at 4-month follow-up. Of all 22 pts with CML-CP at 4-month follow-up, 7 (32%) had a major cytogenetic response (3 complete, 4 partial). Disease progression occurred in only 2 pts with CML-CP, both of whom had CHR at baseline. Of 13 evaluable pts with CML-AP, 3 (23%) demonstrated no evidence of leukemia and 3 (23%) had a return to chronic phase (RTC) after 4 months of nilotinib therapy. No pts with CML-AP had disease progression at 4 months. Of 20 evaluable pts with CML-BC, 3 (15%) achieved CHR, 1 (5%) had RTC, and 6 (30%) had disease progression. For all pts (N=67), the most common grade 3/4 hematologic adverse events reported were neutropenia (51%), thrombocytopenia (44%), and anemia (21%). The most frequent grade 3/4 nonhematologic adverse events reported were pyrexia (8%), anorexia and headache (3%), and diarrhea, asthenia, constipation, fatigue, and myalgia (2% each). 3 pts had pleural effusion and 1 had pericardial effusion during nilotinib therapy.

Conclusion: Nilotinib has impressive clinical activity in these heavily pretreated pts with CML-CP, -AP, or -BC in whom both imatinib and dasatinib have failed. In addition, nilotinib tolerability and safety profile in this subset of pts was similar to that reported for pts who failed only imatinib.

Author notes

Disclosure:Employment: Gallagher, Haque--Novartis. Research Funding: Giles, le Coutre, Kantarjian - Novartis Honoraria Information: le Coutre - Novartis Membership Information: le Coutre - Novartis advisory board. Off Label Use: At the time of submission, nilotinib is not FDA approved for use in the United States.