Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study

Abstract

The single-arm, phase 2 ENESTfreedom trial assessed the potential for treatment-free remission (TFR; i.e., the ability to maintain a molecular response after stopping therapy) following frontline nilotinib treatment. Patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase with MR4.5 (BCR-ABL1⩽0.0032% on the International Scale (BCR-ABL1IS)) and ⩾2 years of frontline nilotinib therapy were enrolled. Patients with sustained deep molecular response during the 1-year nilotinib consolidation phase were eligible to stop treatment and enter the TFR phase. Patients with loss of major molecular response (MMR; BCR-ABL1IS⩽0.1%) during the TFR phase reinitiated nilotinib. In total, 215 patients entered the consolidation phase, of whom 190 entered the TFR phase. The median duration of nilotinib before stopping treatment was 43.5 months. At 48 weeks after stopping nilotinib, 98 patients (51.6%; 95% confidence interval, 44.2-58.9%) remained in MMR or better (primary end point). Of the 86 patients who restarted nilotinib in the treatment reinitiation phase after loss of MMR, 98.8% and 88.4%, respectively, regained MMR and MR4.5 by the data cutoff date. Consistent with prior reports of imatinib-treated patients, musculoskeletal pain-related events were reported in 24.7% of patients in the TFR phase (consolidation phase, 16.3%).

Conflict of interest statement

The authors declare the following relationships: A Hochhaus: reports honoraria from Novartis, BMS, ARIAD and Pfizer; consulting or advisory role for Novartis, BMS, ARIAD and Pfizer; research funding from Novartis, BMS, ARIAD, Pfizer and MSD; travel, accommodation or other expenses paid or reimbursed by Novartis and BMS; T Masszi: reports honoraria from Novartis, Takeda, Janssen-Cilag and BMS; consulting or advisory role for Novartis, Takeda, Janssen-Cilag and BMS; FJ Giles: reports honoraria from Novartis; consulting or advisory role for Novartis; research funding from Novartis; JP Radich: reports consulting or advisory role for Novartis, ARIAD, BMS and Gilead; research funding from Novartis; DM Ross: reports honoraria from Novartis and BMS; consulting or advisory role for Novartis; research funding from Novartis and Celgene; MT Gómez Casares: reports honoraria from BMS, Novarti, and ARIAD; consulting or advisory role for BMS, Novartis and ARIAD; travel, accommodation or other expenses paid or reimbursed by BMS, Novartis and ARIAD; A Hellmann: reports honoraria from Novartis, BMS and ARIAD; travel, accommodation, or other expenses paid or reimbursed by Novartis, Orphan, Servier and BMD; J Stentoft: reports research funding from Novartis, BMS, Pfizer and ARIAD; E Conneally: reports honoraria from Novartis, BMS, Pfizer and Gilead; consulting or advisory role for Novartis, BMS, Pfizer and Gilead; research funding from BMS and Pfizer; V García-Gutiérrez: reports honoraria from Novartis, BMS, Pfizer and ARIAD; consulting or advisory role for Novartis, BMS, Pfizer and ARIAD; research funding from Novartis, BMS, Pfizer and ARIAD; travel, accommodation, or other expenses paid or reimbursed by Novartis, BMS, Pfizer and ARIAD; N Gattermann: reports honoraria, research funding and travel, accommodation, or other expenses paid or reimbursed by Novartis; W Wiktor-Jedrzejczak: reports consulting or advisory role for Roche, Janssen-Cilag, Onconova, Celgene, Sandoz and Angelini; research funding from Amgen, BMS, Novartis and AbbVie; expert testimony for Celgene; travel, accommodation or other expenses paid or reimbursed by Pierre Fabre, Novartis, Roche and Sanofi; PD le Coutre: reports participation in a speakers bureau for Novartis, BMS, Pfizer and ARIAD; B Martino: has nothing to disclose; S Saussele: reports honoraria from Novartis, BMS, Pfizer and ARIAD; consulting or advisory role for Novartis, BMS, Pfizer and ARIAD; research funding from Novartis and BMS; travel, accommodation or other expenses paid or reimbursed by Novartis and BMS; HD Menssen: is employed by, and owns stock in, Novartis Pharma AG; W Deng: is employed by Novartis Pharmaceuticals Corporation; N Krunic: is employed by, and owns stock in, Novartis Institute for Biomedical Research; V Bedoucha: is employed by Novartis Pharma AG; G Saglio: reports consulting or advisory role for Novartis, BMS, ARIAD, and Pfizer.

Figures

Figure 1

ENESTfreedom study design.aDefined as (in the last 4 quarterly RQ-PCR assessments) MR4.5 in the last assessment, no assessment worse than MR4 and ⩽2 assessments between MR4 and MR4.5.

Figure 2

Patient disposition. aThree of these patients were still in the continuation phase at the data cutoff date. Of the 10 patients who completed the continuation phase, 8 were in the TFR-2 phase and 2 remained on nilotinib therapy at the data cutoff date.

Figure 3

Kaplan–Meier estimate of TFS among all patients who entered the TFR phase. TFS was defined as the time from the start of TFR until the earliest of any of the following: loss of MMR, reinitiation of nilotinib for any reason, progression to AP/BC or death because of any cause.

Figure 4

Cumulative incidence of (a) MMR and (b) MR4.5 regained after nilotinib reinitiation.