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 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 treatment-free remission after treatment discontinuation is unknown.
The ongoing randomized ENESTPath phase 3 trial evaluated the optimal duration of nilotinib therapy needed to achieve and maintain treatment-free remission upon treatment discontinuation in 620 patients with CP-CML; Delphine Rea, MD, PhD, Adult Hematology Department, Hopital Saint-Louis, APHP, Paris, France, 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 an MR4 after ≥2 years of imatinib therapy were randomized to receive nilotinib 300 mg twice daily for 2 years (arm 1) or 3 years (arm 2). Patients who obtained a stable MR4 or better for ≥12 months entered the treatment-free remission phase. The primary end point was to evaluate the proportion of patients in both arms who remained in treatment-free remission 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 MR4.5 was 30.5%. Moreover, patients with halving time ≤3 months achieved higher MR4.5 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 MR4 by 12 months versus those with a ratio of >0.01% to ≤1% (64.8% vs 30.8%).
Adverse events 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 adverse events 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 because of adverse events/laboratory abnormalities.
Based on these interim analysis results, switching to a lower dose of nilotinib 300 mg twice daily induced deep MRs in patients who did not achieve such MR levels with imatinib therapy, and was accompanied by a safety profile that was consistent with that previously described.
1. Rea D, Rosti G, Cross NCP, et al. Enestpath: a phase III study to assess the effect of nilotinib treatment duration on treatment-free remission (TFR) in chronic phase-chronic myeloid leukemia (CP-CML) patients (pts) previously treated with imatinib: interim analysis from the first year of induction phase. Blood. 2015;126:4040.