Five-Year Results of Nilotinib 400 Mg BID in Early Chronic Phase Chronic Myeloid Leukemia (CML): High Rate of Deep Molecular Response - Update of the Gimema CML WP Trial CML0307

Nilotinib is a potent and selective BCR-ABL inhibitor approved for the frontline treatment of CML based on the results of the phase 3 ENESTnd trial that demonstrated superior efficacy of nilotinib vs. imatinib, with higher and faster molecular responses and lower rates of progressions to accelerated-blastic phase (AP/BP)(3 years of follow-up). In the IRIS trial, after 5 years of follow-up, 69% of patients were still on imatinib; the event-free survival (EFS) and progression-free survival (PFS) were 83% and 93%, respectively (Druker BJ et al, NEJM 2006). In an intention-to-treat analysis of patients treated frontline with imatinib at the Hammersmith Hospital, EFS at 5 years was 63% and PFS was 83% (de Lavallade H, J Clin Oncol 2008). The long-term evaluation of the patients treated with nilotinib frontline is extremely relevant. METHODS: The GIMEMA CML WP conducted a multicentre phase 2 trial with nilotinib 400mg BID as frontline therapy (ClinicalTrials.gov.NCT00481052). Median follow-up for the present analysis was 51 months (range: 48 – 58 months); five years median follow-up data will be presented. Definitions: MR3.0 (Major Molecular Response) as a BCR-ABL/ABL ratio <0.1% IS; MR4.0, BCR-ABL/ABL ratio <0.01% with ≥10,000 ABL transcripts; failures: according to the 2009 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 CCyR at 12 months was 100%. Only 1 patient had a confirmed loss of CCyR and subsequently progressed to AP/BP (see below). Two out of 73 patients never achieved a MR3.0, 1 is the patient who progressed to AP/BP (see below), the other 1 is in stable and confirmed CCyR at 48 months. Only 3 patients had a confirmed loss of MMR due to low adherence (all 3 still on nilotinib). The overall estimated probability of MR4.0 was 82%. Twenty-five percent (18/73 patients) showed a stable MR4.0 (defined based on 3 consecutive MR4.0 samples 4 months apart). Only one patient progressed at 6 months to AP/BP and subsequently died (high Sokal risk, T315I mutation). Overall, eleven patients (15%) discontinued permanently nilotinib: 1 patient progressed to AP/BP; 3 patients had recurrent episodes of amylase and/or lipase increase (no pancreatitis); 3 patients had peripheral arterial obstructive disease (after 45, 46, and 52 months of therapy; age at nilotinib start: 65, 66, and 76 years; 2 out of 3 with at least 1 cardiovascular risk factor); 1 patient had atrial fibrillation (unrelated to study drug); 1 patient died after 32 months of mental deterioration and starvation (unrelated to study drug); 2 patients for refusal (1 patient in confirmed MR4, still off-treatment and in MR4 9 months after discontinuation); 1 patient for withdrawal of informed consent, on imatinib). The estimated probability of overall survival, progression-free survival and failure-free survival was 97% at 5 years; the estimated probability of event-free survival was 83% at 5 years. CONCLUSIONS: After a median follow-up of 5 years, the great majority of patients are still on nilotinib and, reasonably, they will continue in the next future. Even more importantly, only 1 progression so far: considering the kinetic of progression with any TKI in CML (most progressions reported during the first 2–3 years with imatinib and during the first 1–2 years with nilotinib and dasatinib), a relevant future progression incidence is very unlikely. Given the very high rate of deep molecular response, many are candidate to treatment discontinuation.