NILOTINIB 400 MG BID FRONTLINE: WITH A FOLLOW-UP OF 3 YEARS, RESULTS REMAIN EXCELLENT AND STABLE. (A GIMEMA CML WP PHASE 2 TRIAL)

Nilotinib is a potent and selective BCR-ABL inhibitor. The phase 3 ENESTnd trial demonstrated superior efficacy of nilotinib vs imatinib, with higher and faster molecular responses. After a median of 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 years. Consequently, a confirmation of the durability of responses to nilotinib beyond 3 years is extremely important. Aims. To evaluate the response and the outcome of patients treated for 3 years with nilotinib 400mg BID as frontline therapy. Methods. A multicentre phase 2 trial was conducted by the GIMEMA CML WP (ClinicalTrials.gov.NCT00481052). Minimum 36-month follow-up data for all patients will be presented. Definitions: Major Molecular Response (MMR): BCR-ABL/ABL ratio <0,1%IS; Complete Molecular Response (CMR): 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-totreat principle. Results. 73 patients enrolled: median age 51 years; 45% low, 41% intermediate and 14% high Sokal risk. The cumulative incidence of CCgR by 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 MMR was 97%, while the rates of MMR at 3, 6, 12, 18 and 24 months were 52%, 66%, 85%, 81% and 82%, respectively. The overall estimated probability of CMR was 79% at 30 months, while the rates of CMR at 12 and 24 months were 12% and 27%, respectively. No patient achieving a MMR progressed to ABP. Over 3 years of observation, only one patient progressed to ABP, at 6 months, and subsequently died (high Sokal risk, T315I mutation). AEs 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. Nilotinib last daily dose was as follows: 800mg in 46 (63%) patients, 600mg in 3 (4%) patients and 400mg in 18 (25%). Six permanent discontinuations: 2/6 deaths (1:ABP, 1: mental deterioration and starvation, unrelated to study drug). 3/6, recurrent episodes of amylase and/or lipase increase (no pancreatitis) and 1/6, atrial fibrillation (other epysodes before nilotinib): 2 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 months are being translated into optimal outcome for most of patients.