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.

1st Department of Medicine Charles University General Hospital Prague Czech Republic

Department 1 for Internal Medicine and Centre of Integrated Oncology University of Cologne Cologne Germany

Department 1 for Internal Medicine and Centre of Integrated Oncology University of Cologne Cologne Germany; Cluster of Excellence on Cellular Stress Responses in Aging University of Cologne Cologne Germany

Department 1 of Internal Medicine Klinikum Schwabing Munich Germany

Department for Haematology and Oncology University Hospital Tübingen Tübingen Germany

Department of Haematology Luzerner Kantonsspital Lucerne Switzerland

Department of Haematology Section of Internal Medicine Vejle Hospital Vejle Denmark

Department of Internal Medicine 1 Klinikum Frankfurt Oder Frankfurt Germany

Department of Internal Medicine 2 University Hospital of Schleswig Holstein Campus Kiel Kiel Germany

Department of Internal Medicine 3 University of Ulm Ulm Germany

Evangelisches Krankenhaus Hamm Germany

Haematopathology Section and Lymph Node Registry Department of Pathology University of Kiel Kiel Germany

Private oncology practice Koblenz Germany

Private oncology practice Landshut Germany

Private oncology practice Mannheim Germany

Private oncology practice Villingen Schwenningen Germany

Private oncology practice Würzburg Germany

Technical University Institute for Medical Statistics and Epidemiology Munich Germany

Comment In

Lancet Oncol. 2016 Jul;17(7):852-854. doi: 10.1016/S1470-2045(16)30118-8. PubMed

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