Optimizing Nilotinib Dose in CML Could Yield Higher Response Rates

Dose optimization of nilotinib is feasible and may help patients with chronic myeloid leukemia (CML) in the chronic phase achieve molecular responses, according to final results of a new study. Dose escalation for efficacy, and re-escalation after adverse events, were both effective strategies.

“There are data to suggest that nilotinib dose escalations or reductions, as necessary, can be beneficial for some patients, maximizing both efficacy and tolerability,” wrote study authors led by Timothy P. Hughes, MD, of the South Australian Health and Medical Research Institute, in Adelaide. Earlier studies showing nilotinib’s efficacy, however, did not allow for dose adjustments for optimization purposes.

The ENESTxtnd trial was an open-label, prospective phase III study, including 421 patients with CML in 18 countries. It allowed dose escalation of nilotinib from 300 to 400 mg twice daily in the case of suboptimal response or treatment failure, and dose re-escalation in those who required a reduction due to adverse events. The 2-year results of the trial were published online ahead of print in the British Journal of Haematology.

The median age of patients was 48 years, and 53.7% of patients were male; the median time on treatment was 23.7 months. In total, 144 patients (34.2%) received a reduced a nilotinib dose during the study; of those, 74 were due to adverse events, 36 were due to dosing errors, 27 were due to scheduling conflicts, 11 were due to dose reductions per the study protocol, and 3 were due to dispensing errors. Eighty-four patients received a dose re-escalation to a dose lower than prescribed.

Among the 144 with reduced doses, 106 patients (73.6%) attempted to re-escalate to 300 mg twice daily, and 92 of those successfully re-escalated. In the patients with reductions due to adverse events, 85.1% attempted to re-escalate to 300 mg twice daily, and 54 did so successfully.

Another 88 patients (20.9%) escalated their nilotinib dose to 400 mg twice daily due to a lack of efficacy; 83 of those 88 patients remained on the higher dose at the end of treatment.

The cumulative rate of major molecular response (MMR) at 12 months was 70.8%; by 24 months, the MMR rate was 81%. Of the 88 patients with escalated dosing due to a lack of efficacy, 56 (63.6%) achieved MMR by 24 months. Among the 144 with dose reductions for any reason, 109 (75.7%) achieved MMR by 24 months, including 84.8% of those who successfully re-escalated the dose. No new safety signals with nilotinib emerged during the study.

The study “demonstrate[s] the feasibility and potential benefits of nilotinib dose optimization,” the authors wrote. Compared with historical rates, this study had higher MMR rates, which may in part be due to higher overall dose intensity. That higher intensity may in turn be due to the dose optimization strategies, suggesting these may be useful in clinical practice.