Safety and efficacy of switching to nilotinib 400 mg twice daily for patients with chronic myeloid leukemia in chronic phase with suboptimal response or failure on front-line imatinib or nilotinib 300 mg twice daily

Abstract

In a randomized, phase III trial of nilotinib versus imatinib in patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia in chronic phase, more patients had suboptimal response or treatment failure on front-line imatinib than on nilotinib. Patients with suboptimal response/treatment failure on imatinib 400 mg once or twice daily or nilotinib 300 mg twice daily could enter an extension study to receive nilotinib 400 mg twice daily. After a 19-month median follow up, the safety profile of nilotinib 400 mg twice daily in patients switching from imatinib (n=35) was consistent with previous reports, and few new adverse events occurred in patients escalating from nilotinib 300 mg twice daily (n=19). Of patients previously treated with imatinib or nilotinib 300 mg twice daily, respectively, 15 of 26 (58%) and 2 of 6 (33%) without complete cytogenetic response at extension study entry, and 11 of 34 (32%) and 7 of 18 (39%) without major molecular response at extension study entry, achieved these responses at any time on nilotinib 400 mg twice daily. Estimated 18-month rates of freedom from progression and overall survival after entering the extension study were lower for patients switched from imatinib (85% and 87%, respectively) versus nilotinib 300 mg twice daily (95% and 94%, respectively). Nilotinib dose escalation was generally well tolerated and improved responses in about one-third of patients with suboptimal response/treatment failure. Switch to nilotinib improved responses in some patients with suboptimal response/treatment failure on imatinib, but many did not achieve complete cytogenetic response (clinicaltrials.gov identifiers: 00718263, 00471497 - extension).

Trial registration: ClinicalTrials.gov NCT00471497 NCT00718263.

Figure 1.

Cumulative incidence of suboptimal response (A) and treatment failure (B) in the ENESTnd core study by 6, 12, and 18 months. Key criteria for suboptimal response/treatment failure at 6, 12, and 18 months are shown in parentheses on the x-axis. Suboptimal response also included loss of major molecular response (MMR) at any time. Treatment failure also included loss of complete hematologic response (CHR), loss of partial cytogenetic response/complete cytogenetic response (PCyR/CCyR), or progression to accelerated phase/blast crisis at any time. Patients satisfying criteria for both suboptimal response and treatment failure were considered to have treatment failure. Only a patient’s worst response at or before each time point was counted.

Figure 2.

Cumulative incidence of complete cytogenetic response (CCyR) and major molecular response (MMR) on extension study treatment (nilotinib 400 mg twice daily) in patients previously treated with (A) imatinib or (B) nilotinib 300 mg twice daily. Shown from left to right are rates of CCyR at any time (from date of extension study entry to data cut-off date; median follow up of 19 months) in patients without CCyR at extension study entry, rates of MMR at any time and by 12 months in patients without MMR at extension study entry, and rates of MMR by 12 months in patients without MMR but with CCyR at extension study entry.