Nilotinib in Chronic Myeloid Leukemia Patients in Accelerated Phase (CML-AP) with Imatinib Resistance or Intolerance: 2-Year Follow-up Results of a Phase 2 Study

Background: Nilotinib is a rationally designed, potent and highly selective BCR-ABL kinase inhibitor, and binds to ABL with higher affinity and improved topological fit compared to imatinib. Nilotinib is approved for the treatment of patients (pts) with Philadelphia chromosome-positive chronic myeloid leukemia pts in chronic (CML-CP) or accelerated phase (CML-AP) resistant or intolerant to prior therapy including imatinib. Methods: This open-label, single-arm, phase 2 study was designed to evaluate the efficacy and safety of nilotinib in CML-AP pts who are resistant or intolerant to imatinib. Nilotinib was dosed at 400 mg twice daily with the option to dose escalate to 600 mg twice daily for lack of response. The primary endpoint was confirmed hematologic response (HR). Complete hematologic response (CHR) was defined as meeting all of the following criteria: myeloblast count <5% in bone marrow, no myeloblast in peripheral blood, neutrophil count ≥1.5 × 109/L, platelet count ≥100×109/L, basophils <5%, no evidence of extramedullary involvement. Secondary endpoints included major cytogenetic response (MCyR), time to progression, overall survival, and safety. Results: A total of 138 CML-AP pts (80% imatinib resistant; 20% imatinib intolerant) who received at least 1 dose of nilotinib were included in the analysis. Median age was 57 years (range, 22–82 years); median duration of prior imatinib treatment was 28 months. Seventy-nine percent of pts received prior imatinib doses ≥600 mg/day; overall, 45% received ≥800 mg/day imatinib. Median dose intensity of nilotinib was near planned dose at 775 mg/day with a median duration of exposure of 253 days (8.4 months). Of 134 pts with at least 6 months of follow-up included in the efficacy analysis, 56% had confirmed HR and 30% had CHR. Responses were rapid, with a median time to first HR of 1 month. Hematologic responses were durable at 1 year, with 78% of pts who achieved HR maintaining their response. MCyR and complete cytogenetic response (CCyR) occurred in 32% and 19% of pts, respectively. Cytogenetic responses were also durable, with 69% of pts maintaining MCyR at 18 months. Median time to progression was 16 months in this population of pts with advanced disease. Progression was defined as any of the following: investigator’s evaluation as progression, development of CML-AP or blast crisis, loss of CHR, loss of MCyR. Estimated overall survival at 1 year is 82%. Longer follow-up has not significantly changed the safety profile of nilotinib. The most frequently reported grade 3/4 laboratory abnormalities were thrombocytopenia (40%), neutropenia (40%), anemia (25%), elevated serum lipase (17%), and hypophosphatemia (12%). Grade 3/4 non-hematologic adverse events were uncommon (<1%) and included rash, nausea, fatigue, and diarrhea. Brief dose interruptions were sufficient to manage most adverse events. Conclusions: The long-term follow-up results of this phase 2 study confirm that nilotinib induces rapid and durable responses in pts with CML-AP who failed prior imatinib therapy due to intolerance or resistance, with a favorable toxicity profile.