Early CP CML, Nilotinib 400 mg Twice Daily Frontline: Beyond 3 Years, Results Remain Excellent and Stable (A GIMEMA CML Working Party Trial)

Background: Nilotinib is a potent and selective BCR-ABL inhibitor. The phase 3 ENESTnd trial demonstrated superior efficacy nilotinib vs. imatinib, with higher and faster molecular responses. After 24 months, the rates of progression to accelerated-blastic phase (ABP) were 0.7% and 1.1% with nilotinib 300mg and 400mg BID, respectively, significantly lower compared to imatinib (4.2%). Nilotinib has been approved for the frontline treatment of Ph+ CML. With imatinib 400mg (IRIS trial), the rate of any event and of progression to ABP were higher during the first 3–4 years. Consequently, a confirmation of the durability of responses to nilotinib beyond 3 years is extremely relevant. Aims: To evaluate the long term outcome of patients treated with nilotinib 400mg BID as frontline therapy. Methods: A multicentre phase 2 trial was conducted by the GIMEMA CML WP (ClinicalTrials.gov.NCT00481052). Median 48-month follow-up data for all patients will be presented. Definitions: MR3.0 (Major Molecular Response) as a BCR-ABL/ABL ratio <0,1%IS; MR4.0, undetectable transcript levels with ≥10,000 ABL transcripts; failures: according to the revised ELN recommendations; events: failures and treatment discontinuation for any reason. All the analysis has been made according to the intention-to-treat principle. Results: 73 patients enrolled: median age 51 years; 45% low, 41% intermediate and 14% high Sokal risk. The cumulative incidence of CCgR at 12 months was 100%. CCgR at each milestone: 78%, 96%, 96%, 95%, 92% at 3, 6, 12, 18 and 24 months, respectively. The overall estimated probability of MR3.0 was 99%, while the rates of MR3.0 at 3, 6, 12, 18 and 24 months were 52%, 66%, 85%, 81% and 82%, respectively. Two out of 73 patients never achieved a MR3.0, 1 who progressed to AP/BP (see below) and 1 in stable and confirmed CCgR at 36 months. Three pts had a confirmed loss of MR3.0 due to low adherence (all 3 still on nilotinib). The overall estimated probability of MR4.0 was 79%, while the rates of MR4.0 at 12, 24 and 36 months were 12%, 27% and 25%, respectively. One third (21/73 pts) showed a stable MR4.0 (defined based on 3 consecutive MR4.0 samples 4 months apart). Only one patient progressed at 6 months to ABP and subsequently died (high Sokal risk, T315I mutation). Adverse events were mostly grade 1 or 2 and manageable with appropriate dose adaptations. During the first 12 months, the mean daily dose was 600–800mg in 74% of patients. The nilotinib last daily dose was as follows: 800mg in 46 (63%) patients, 600mg in 3 (4%) patients and 400mg in 18 (25%), 6 permanent discontinuations. Detail of discontinuation: 1 patient progressed to ABP; 3 patients had recurrent episodes of amylase and/or lipase increase (no pancreatitis); 1 patient had atrial fibrillation (unrelated to study drug) and 1 patient died after 32 months of mental deterioration and starvation (unrelated to study drug). Two patients are currently on imatinib second-line and 2 on dasatinib third-line. With a median follow-up of 39 months, the estimated probability of overall survival, progression-free survival and failure-free survival was 97%, the estimated probability of event-free survival was 91%. Conclusions: The rate of failures was very low during the first 3 years. Responses remain stable. The high rates of responses achieved during the first 12–18 months are being translated into optimal outcome for most of patients.