First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial.

BACKGROUND: Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab is the standard therapy for physically fit patients with advanced chronic lymphocytic leukaemia. This international phase 3 study compared the efficacy and tolerance of the standard therapy with a potentially less toxic combination consisting of bendamustine and rituximab. METHODS: Treatment-naive fit patients with chronic lymphocytic leukaemia (aged 33-81 years) without del(17p) were enrolled after undergoing a central screening process. Patients were randomly assigned (1:1) with a computer-generated randomisation list using randomly permuted blocks with a block size of eight and were stratified according to participating country and Binet stage. Patients were allocated to receive six cycles of intravenous fludarabine (25 mg/m(2) per day) and cyclophosphamide (250 mg/m(2) per day) for the first 3 days or to intravenous bendamustine (90 mg/m(2) per day) for the first 2 days of each cycle. Rituximab 375 mg/m(2) was given intravenously in both groups on day 0 of cycle 1 and subsequently was given at 500 mg/m(2) during the next five cycles on day 1. The primary endpoint was progression-free survival with the objective to assess non-inferiority of bendamustine and rituximab to the standard therapy. We aimed to show that the 2-year progression-free survival with bendamustine and rituximab was not 67·5% or less with a corresponding non-inferiority margin of 1·388 for the hazard ratio (HR) based on the 90·4% CI. The final analysis was done by intention to treat. The study is registered with ClinicalTrials.gov, number NCT%2000769522. FINDINGS: 688 patients were recruited between Oct 2, 2008, and July 11, 2011, of which 564 patients who met inclusion criteria were randomly assigned. 561 patients were included in the intention-to-treat population: 282 patients in the fludarabine, cyclophosphamide, and rituximab group and 279 in the bendamustine and rituximab group. After a median observation time of 37·1 months (IQR 31·0-45·5) median progression-free survival was 41·7 months (95% CI 34·9-45·3) with bendamustine and rituximab and 55·2 months (95% CI not evaluable) with fludarabine, cyclophosphamide, and rituximab (HR 1·643, 90·4% CI 1·308-2·064). As the upper limit of the 90·4% CI was greater than 1·388 the null hypothesis for the corresponding non-inferiority hypothesis was not rejected. Severe neutropenia and infections were more frequently observed with fludarabine, cyclophosphamide, and rituximab (235 [84%] of 279 vs 164 [59%] of 278, and 109 [39%] vs 69 [25%], respectively) during the study. The increased frequency of infectious complications with fludarabine, cyclophosphamide, and rituximab was more pronounced in patients older than 65 years. INTERPRETATION: The combination of fludarabine, cyclophosphamide, and rituximab remains the standard front-line therapy in fit patients with chronic lymphocytic leukaemia, but bendamustine and rituximab is associated with less toxic effects. FUNDING: Roche Pharma AG, Mundipharma, German Federal Ministry of Education and Research.

Long Term Follow-up Data and Health-Related Quality of Life in Frontline Therapy of Fit Patients Treated With FCR Versus BR (CLL10 Trial of the GCLLSG).

Fludarabine, cyclophosphamide and rituximab (FCR) was compared to bendamustine and rituximab (BR) in an international, randomized, open label, phase 3 trial in 561 previously untreated, fit patients with chronic lymphocytic leukemia (CLL) without del (17p). Primary endpoint was progression free survival (PFS). The final primary endpoint analysis after 37.1 months median follow up failed to show the non-inferiority of BR as compared with FCR. With extended median follow up of 58.2 months, median PFS was 42.3 months in BR-treated patients versus 57.6 months for FCR-treated patients (Hazard Ratio [HR] 1.593; 95% CI 1.271-1.996; p < 0.0001). For patients > 65 years, median PFS was 48.5 months with BR versus 57.9 months with FCR without reaching statistical significance (HR 1.352; 95% CI 0.912-2.006; p = 0.134). Median OS was not reached for both arms with 5-year OS rates of 80.1% vs 80.9%, respectively (HR 1.108; 95% CI 0.755-1.627; p = 0.599). No statistically significant difference was found in the time to secondary malignancy between the 2 groups (at 5 years, 86.6% free from secondary malignancies in the BR group vs 83.8% in the FCR group [HR 0.801; 95% CI 0.507-1.267; p = 0.344]). In patients >65 years secondary neoplasia occurred more frequently after FCR treatment [28 of 86 (32.6%) patients] as compared with BR [18 of 107 (16.8%) patients; p = 0.011]. Health-related quality of life was similar in both treatments. Despite the improved PFS for FCR, OS did not differ. These results also suggest an increase in secondary neoplasia associated with FCR in elderly fit CLL patients.