Efficacy of Nilotinib Versus High-Dose Imatinib in Early Chronic Phase CML Patients Who Have Suboptimal Molecular Responses to Standard-Dose Imatinib (RE-NICE Multicenter Study)

Abstract 2765

In CML, achievement of major molecular response (MMR) is a significant prognostic factor as it has been shown to be associated with longer duration of complete cytogenetic response (CCyR) and long-term progression-free survival. In IRIS study, patients who achieved both CCyR and MMR showed higher progression-free survival rates, compared to those who had CCyR without MMR. Higher doses of imatinib are expected to yield higher CCyR and MMR rates, compared to standard dose of imatinib, and second-generation tyrosine kinase inhibitor, nilotinib also produces high CCyR and MMR rates in patients with CP CML who are resistant to imatinib. In this prospective study, the efficacy of nilotinib and high-dose imatinib was investigated in suboptimal molecular responders who received standard-dose imatinib as first-line therapy. Early CP CML patients who have achieved CCyR but no MMR after at least 18 months and up to 24 months (≥ 18 to ≤ 24 months) on first-line imatinib therapy at a daily dose of 400 mg were enrolled in this clinical trial, and informed consents were obtained from all patients prior to participation. In nilotinib arm, patients received oral dose of 400 mg BID (800 mg/day), and patients received 800 mg/day administrated as 400 mg BID in imatinib dose-escalation arm. To assess the drug efficacy, cytogenetics and RQ-PCR analysis were performed at regular intervals, and baseline mutational analysis was conducted for every patient with subsequent mutational analyses performed in patients demonstrating either lack of response or disease progression. Primary endpoint is to evaluate the cumulative MMR rates by 12 months, and secondary endpoints are to evaluate the cumulative CMR rates and time to and duration of MMR and CMR during further 24 month follow-up. Progression-free survival and safety profiles will also be assessed as secondary endpoints. Patients showing lack of response (lack of complete hematologic response (CHR) at 6 months, increasing WBC, no major cytogenetic response (MCyR) at 24 months), loss of response (loss of CHR or MCyR) or severe intolerance to treatment were allowed to crossover to the alternative treatment arm. With a data cut-off date of 18 Jul 2011, a total of 30 patients were randomized into nilotinib arm (n =13) or imatinib arm (n = 17), and 6 patients have crossed-over to nilotinib arm due to lack of response. With a median follow-up of 11 months (range, 0.2–28 mos), all patients have maintained CCyR without progression to advanced disease, and progressive decrease in BCR-ABL transcript levels was observed in all patients. Cumulative MMR rates at 20 months were significantly higher in nilotinib arm compared to imatinib dose-escalation arm (59.00% vs. 27.40%, P = 0.047), and patients treated with nilotinib also showed faster molecular response rates, with 5 patients achieving MMR within 3 months of nilotinib therapy. At the last follow-up, 7/13 (53.85%) and 2/11 (18.18%) patients achieved MMR in nilotinib arm and in high-dose imatinib arm, respectively, with 1 patient in nilotinib arm achieving 4-log reduction of BCR-ABL transcripts. Although toxicity was observed more frequently in imatinib dose-escalation arm, all patients currently maintain the initial dose (except 1 patient who interrupted imatinib therapy due to neurosurgical operation), and based on the toxicity data, no additional or serious adverse events were developed except for pre-existing toxicities before randomization. These preliminary results demonstrate that early intervention using nilotinib or dose escalation of imatinib could be recommended in suboptimal molecular responders, with nilotinib being more preferable. Through further clinical investigation on a large patient population and longer period of observation, efficacy and safety of early intervention of suboptimal molecular response using nilotinib or dose escalation of imatinib will be assessed. Updated data with longer follow-up duration will be presented in the meeting.