Minimal Cross-Intolerance Between Nilotinib and Imatinib in Patients with Imatinib-Intolerant Chronic Myeloid Leukemia in Chronic Phase (CML-CP) or Accelerated Phase (CML-AP)

Background: Nilotinib is a rationally designed, potent and highly selective BCR-ABL kinase inhibitor with significant clinical efficacy in the treatment of patients with Philadelphia chromosome-positive chronic myeloid leukemia patients in chronic (CML-CP) or accelerated phase (CML-AP) who are resistant or intolerant to prior therapy including imatinib. This subanalysis of the phase 2 registration study of nilotinib was designed to examine the occurrence of cross-intolerance to nilotinib in patients with prior intolerance to imatinib. Methods: Imatinib intolerance was defined as discontinuation of imatinib due to grade 3/4 adverse events (AEs) or persistent (>1 month) or recurrent (recurred >3 times) grade 2 AEs despite optimal supportive care. Additionally, patients with major cytogenetic response (MCyR) at baseline were excluded from the trial. Cross-intolerance between nilotinib and imatinib was defined as treatment with nilotinib and occurrence (regardless of causality) of grade 3/4, or persistence or recurrent grade 2, of the same AE(s) that previously led to discontinuation of imatinib therapy. Nilotinib was dosed at 400mg twice daily with the option to escalate to 600 mg twice daily for lack of response. Results: Ninety-five of 321 (30%) CML-CP patients and 27 of 138 (20%) CML-AP patients were included in this subanalysis of cross-intolerance following imatinib intolerance. Patients experiencing multiple reasons for imatinib intolerance were counted for each AE category and these included patients (8 CML-CP, 3 CML-AP) with unusual symptoms during imatinib therapy, none of these patients discontinued nilotinib due to the same AE. Median dose intensity for nilotinib (CML-CP 688mg/day, range 151–800; CML-AP 769mg/day range 184–1149) closely approximated the planned dose of 800mg/day. Among these patients, 64% of CML-CP and 52% of CML-AP patients experienced dose interruptions, however, the median cumulative duration of dose interruptions were short (CML-CP 24 days, range 1–301; CML-AP 17 days, range 4–234). Of the 72 patients (57 CML-CP, 15 CML-AP) who discontinued imatinib due to non-hematologic AEs, 3/72 (4%) experienced same persistent grade 2 AEs, only 1 patient (1%) experienced a recurrence of same grade 3/4 AE during nilotinib therapy, and none discontinued nilotinib due to cross intolerance. Approximately one-third of patients were imatinib intolerant due to hematologic AEs. Of 39 patients (30 CML-CP, 9 CML-AP) with hematologic intolerance to imatinib, 3/39 (8%) experienced same persistent grade 2 hematologic AEs, 20/39 (51%) of patients experienced a recurrence of same grade 3/4 AEs during nilotinib therapy, however, only 7 (18%) discontinued nilotinib and all occurred in CML-CP patients due to thrombocytopenia. Nilotinib therapy exhibited significant efficacy in imatinib-intolerant patients. Among the imatinib-intolerant patients included in this subanalysis who did not have complete hematologic response (CHR) at baseline, 90% of patients with CML-CP and 37% with CML-AP achieved a CHR on nilotinib therapy. Among all imatinib-intolerant patients included in this subanalysis, MCyR was achieved by 63% and 32% of patients with CML-CP and CML-AP, respectively; CCyR was achieved by 49% of CML-CP and 19% of CML-AP patients. Conclusions: These results confirm that there is minimal cross-intolerance with nilotinib in imatinib-intolerant CML-CP and CML-AP patients. Thrombocytopenia was the only laboratory abnormality leading to imatinib intolerance that has recurred with any significant frequency during nilotinib therapy.