Efficacy and Tolerability of Nilotinib in Chronic Myeloid Leukemia Patients in Chronic Phase (CML-CP) Who Failed Prior Imatinib and Dasatinib Therapy: Updated Results of a Phase 2 Study

Background: Treatment options are limited for patients with Philadelphia chromosome-positive (Ph+) CML who are resistant or intolerant to both imatinib and dasatinib. Nilotinib is a potent and highly selective BCR-ABL kinase inhibitor approved for the treatment of Ph+ CML patients in chronic (CML-CP) or accelerated phase (CML-AP) who are resistant or intolerant to prior therapy including imatinib. Here we report the updated results evaluating the safety and efficacy of nilotinib in patients with CML-CP who were either resistant or intolerant to both imatinib and dasatinib therapy.

Methods: Nilotinib was dosed at 400 mg twice daily with an option to dose escalate to 600 mg twice daily in patients with inadequate hematologic and/or cytogenetic responses or disease progression.

Results: A total of 37 patients (median age 62 years) with CML-CP were included in the analysis. The median time since first diagnosis of CML was 86 months. The median duration of prior imatinib therapy was 40.6 months with 84% being imatinib-resistant and 16% imatinib-intolerant. The median duration of prior dasatinib therapy was 6.6 months, with the majority of patients (65%) being intolerant to dasatinib therapy and 32% of patients were dasatinib resistant. Approximately half (51%) of the patients discontinued dasatinib due to grade 3/4 laboratory abnormalities or adverse events (AEs) and 32% discontinued due to disease progression. The median duration of nilotinib exposure was 218 days (7.3 months; range 43–723 days) and 65% of patients remained on nilotinib at the time of data cut-off. In total, only 4 (11%) patients discontinued nilotinib due to AEs and 9 (24%) discontinued due to disease progression. For CML-CP patients without complete hematologic response (CHR) at baseline, 81% achieved CHR with nilotinib treatment. The median time to first CHR for patients with confirmed HR was 1 month. Major cytogenetic response (MCyR) was achieved in 38% of patients with median time to first MCyR being 1 month and median duration of MCyR being 9.7 months. Complete cytogenetic response (CCyR) was achieved in 18% of patients. Estimated 1-year overall survival was 97%. The most frequent drug-related non-hematologic AEs on nilotinib were rash (22%), nausea (16%), and pruritus (14%). Newly occurring or worsening grade 3/4 hematologic laboratory abnormalities included neutropenia (38%), thrombocytopenia (24%), and anemia (5%). Other common grade 3/4 biochemical laboratory abnormalities included elevated lipase (24%), hyperglycemia (11%), elevated alanine aminotransferase (8%), and hypophosphatemia (8%). Brief dose interruptions were sufficient to manage most adverse events.

Conclusions: Nilotinib is highly active in heavily pretreated CML-CP patients who failed both prior imatinib and dasatinib therapy. Importantly, most patients in this study were previously intolerant to dasatinib, and discontinuation of nilotinib in this study was uncommon. These results support nilotinib’s significant efficacy and favorable tolerability profile demonstrated in earlier trials with nilotinib as second-line therapy for the treatment of CML-CP. The frequency of adverse events among these heavily pretreated patients is low and similar to patients who failed imatinib only.