Effect of Nilotinib Treatment Duration on Treatment-Free Remission in CP-CML Patients Previously Treated with Imatinib: Interim Results of the ENESTPath Phase 3 Trial

In contrast to current recommendations to continue tyrosine kinase inhibitor therapy indefinitely, emerging evidence indicates that patients with sustained molecular responses (MRs) on imatinib therapy may achieve deep MRs and durable treatment-free remission (TFR) with nilotinib in patients with chronic-phase chronic myeloid leukemia (CP-CML). However, optimal duration of treatment with nilotinib to achieve the highest rate of TFR after treatment discontinuation is unknown. The ongoing randomized ENESTPath phase 3 trial evaluated the optimal duration of nilotinib therapy needed to achieve and maintain TFR upon treatment discontinuation in 620 patients with CP-CML; Rea and colleagues reported interim analysis results of the first 300 patients treated with nilotinib for ?1 years.¹

Eligible patients who achieved a complete cytogenetic response but not yet an MR⁴ after ?2 years of imatinib therapy were randomized to receive nilotinib at 300 mg twice daily for 2 years (arm 1) or 3 years (arm 2). Patients who obtained a stable MR⁴ or better for at least 12 months entered the TFR phase. The primary end point was to evaluate the proportion of patients in both arms who remained in TFR for ?1 years after nilotinib discontinuation. Median time since initial diagnosis was 58.4 months, and median duration of prior exposure to imatinib was 58.3 months. At 12 months of nilotinib treatment, cumulative incidence of newly acquired MR⁴ was 57.4% and that of MR^4.5 was 30.5%. Moreover, patients with halving time ?3 months achieved higher MR^4.5 versus those with halving time >3 months (50.7% vs 16.8%). By baseline BCR-ABL International Scale ratio, a higher proportion of patients with a ratio of >0.01% to ?0.1% achieved MR^4.0 by 12 months versus those with a ratio of >0.01% to ?1% (64.8% vs 30.8%). Adverse events (AEs) included pruritus (18.7%), headache (9.3%), skin rash (8.7%), upper abdominal pain (7.7%), and constipation (7.3%), which were mostly of grade 1/2 severity and manageable with supportive care or nilotinib dose interruption or reduction. Grade 3/4 hematologic AEs or laboratory abnormalities were uncommon. Grade 3/4 ischemic cardiovascular events were reported in 5% of patients including peripheral artery occlusive disease (1.7%) and ischemic heart disease (3.7%). Overall, 48 (16%) patients discontinued nilotinib therapy, mainly due to AEs/laboratory abnormalities. Based on these interim analysis results, switching to lower dose of nilotinib 300 mg twice daily induced deep MRs in patients who did not achieve such MRs with imatinib therapy, and was accompanied by a safety profile that was consistent with that previously described.

1. Rea D, et al. ASH 2015. Abstract 4040.