NILOTINIB 400 MG BID DAILY AS FRONTLINE THERAPY OF PH + CHRONIC MYELOID LEUKEMIA: DOSE DELIVERY AND SAFETY PROFILE AT 2 YEARS

Background. Nilotinib is an effective and registered treatment of chronic myeloid leukemia (CML) after imatinib failure. Its efficacy as frontline treatment has been explored in phase II trials from GIMEMA CML WP (Rosti et al., Blood 2009: results at 12 months) and MDACC (Cortes et al., J Clin Oncol 2010: median follow-up 17 months), and in a phase III trial (ENESTnd, ASH Meeting 2009: median observation 14 months). Both 300 mg and 400 mg nilotinib BID induced high and early rates of major molecular response (MMR) and complete cytogenetic response (CCgR), with a favorable tolerability profile. Aims. To present a detailed analysis of the dose delivery and the safety profile of nilotinib 400 mg BID in Ph-positive CML in early chronic phase (ECP) after the first year of treatment, with a minimum follow-up of 24 months. Methods. A multicentric phase II trial was conducted by the GIMEMA CML Working Party (ClinicalTrials.gov.NCT00481052). By March, 2010 all the patients will complete 24 months on treatment. Results. 73 patients received an initial nilotinib dose of 400 mg BID; the median age was 51 yrs; 21/73 patients (29%) were ≥ 65 year old at enrollment. The median follow-up is currently 724 days. The CCgR rate at 6,12 and 18 months was 96%. Overall, the treatment was interrupted at least once in 38 patients (52%; overall, 100 interruptions), with a median cumulative duration of drug interruption of 19 days per patient (range 3-208 days); 35 pts (48%) received the full prescribed dose. The proportion of patients with ≥1 interruption decreased during the study: 45%, 22% and 7% during the periods 0-6 months, 7-12 months and 12-18 months, respectively. During the first 12 months, the mean daily dose was 600-800 mg, 400-599 mg, and less than 400 mg in 74%, 18% and 8% of patients, respectively. During the period 13-18 months the mean daily dose was 600-800 mg, 400-599 mg, and less than 400 mg in 70%, 23% and 7% of evaluable patients, respectively. At 18 months, the last daily dose was 800 mg, 400 mg and 200 mg in 68%, 25% and 7% of evaluable patients, respectively. Four adverse events accounted for the great majority of dose interruptions: bilirubin increase, skin rash and/or pruritus, amylase and/or lipase increase, transaminases increase. Only 4 events of peripheral edema have been recorded so far (3 events grade 1; 1 event grade 2); no pleural or pericardial effusion. The transient hyperglicemia did not lead to any treatment discontinuation. The hematopoietic toxicity (grade 3-4) was negligible: only 7 events (3 neutropenias and 4 thrombocytopenias) in 5 pts (7%). Two patients went off treatment after 9 and 15 months due to recurrent episodes of amylase and/or lipase increase without pancreatitis (normal ECO scan and MRI). Both patients were in CCgR, and maintained CCgR on imatinib 400 mg daily. Conclusions. Nilotinib 400 mg BID daily is feasible and safe in ECP CML. Acknowledgements. BolognAIL, Fondazione del Monte di Bologna e Ravenna, PRIN 2005, PRIN 2007, University of Bologna, European LeukemiaNe