Deep Molecular Response to Nilotinib As First-Line Treatment of BCR-ABL+ CML in Early Chronic Phase: A Phase 3b Multicenter Study of the Gimema CML Working Party

Background: In the ENESTnd trial, nilotinib (NIL) showed a superior efficacy to imatinib (IM) with higher response rates and less frequent progression to advanced phases (ABP). Based on these results, NIL has been approved for frontline treatment of chronic myeloid leukemia (CML). The treatment-free remission (TFR) is actually considered one of the most important treatment goals in CML and a sustained deep molecular response (DMR, MR4 or better) is a pre-requisite to achieve TFR. The 5-year update from the ENESTnd trial showed a superiority of NIL over IM in terms of both MR4 and MR4.5, but differences concerning the stability of DMR have not been reported. Moreover, a significant improvement in the long-term outcome has not been demonstrated yet. Despite the efficacy, cost and safety concerns may limit the NIL use as first line treatment in CML. Independent studies are extremely relevant to confirm or to extend the results of company-sponsored trials.

Aims and Methods: To assess the efficacy of NIL frontline in terms of DMR, a phase 3b study was conducted by the GIMEMA CML WP (CML0811; NCT01535391). The primary endpoint was the rate of MR4 at 24 months. Key secondary objectives: evaluation of the kinetics of molecular response, assessment of the safety profile, analysis of the outcome. The starting NIL dose was 300 mg BID, with dose escalation to 400 mg BID in case of suboptimal response or failure according to ELN 2009 criteria, with the exception of progression to ABP and in absence of safety issues or BCR-ABL mutations insensitive to NIL. The molecular response was assessed in GIMEMA standardized molecular laboratories (LabNet network) and the results were expressed according to the International Scale. The MR4 was defined as either detectable disease ≤ 0.01% BCR-ABL or undetectable disease with ≥ 10.000 ABL copies; the MR4.5 was defined as either detectable disease ≤ 0.0032% BCR-ABL or undetectable disease with ≥ 32.000 ABL copies. Sustained MR4 or MR4.5: MR4 or MR4.5 for at least 1 year a, with at least 3 evaluable analysis. Adverse events were recorded continuously. A prospective evaluation of glucose metabolism and serum lipids was planned. All the analysis were performed according to the ITT principle.

Results: 130 CML patients in early chronic phase have been enrolled in 32 italian hematologic centers; median age, 50 years (range 18-85); high risk patients, 22%, 6% and 8% according to Sokal, Euro and EUTOS scores, respectively; clonal chromosomal abnormalities in Ph+ cells at baseline, 5%; e13a2 BCR-ABL transcript, 34%. The median follow-up is actually 21 months (all patients had at least 18 months observation; a minimum observation of 24 months will be reached by October 2014). Data with at least 24 months follow-up will be presented on site. At the last contact, the patients still on treatment with NIL were 110/130, 85% (74% with 600 mg, 7% with 300 mg or less, 4% with 800 mg daily), while 20/130 patients, 15%, permanently interrupted the study drug for the following reasons: 3% progression to ABP, 2% failure or suboptimal response (dose escalation not feasible), 1% allogeneic stem cell transplantation, 5% toxicity, 4% other reasons (including consent withdrawal and pregnancy). The complete cytogenetic response rate and the major molecular response rate at 12 months were 76% and 53%, respectively. The rates of MR4 at 3, 6, 12 and 18 months were 2%, 12%, 27% and 29%, respectively. Fifty-four patients achieved a MR4 at least once; the patients with a sustained MR4 were 18/54 (33%, or 14% of the total). The rates of MR4.5 at 3, 6, 12 and 18 months were 0, 3%, 10% and 13%, respectively. Only 3 patients achieved a sustained MR4.5. A significant increase of glycosylated hemoglobin was not observed. The total cholesterol, and both LDL and HDL cholesterol fractions significantly increased during treatment. Triglyceride concentrations had not significant variations. Six patients (5%) had a cardiovascular event, including myocardial infarction and arterial thrombosis. All the patients are still alive.

Conclusions: The molecular response rates seem to be superior to the historical data of IM. NIL 300 mg BID as frontline treatment of BCR-ABL+ CML, with dose optimization in case of non optimal response, may improve the proportion of patients able to discontinue TKI treatment. Due to the metabolic effects, a baseline selection is crucial to maximize the therapeutic benefit and to minimize the cardiovascular risks.