Nilotinib Therapy after Dasatinib Failure in Patients with Imatinib-Resistant or -Intolerant Chronic Myeloid Leukemia (CML) in Chronic Phase (CP), Accelerated Phase (AP) or Blast Crisis (BC).

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.