title: 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.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Roche Pharma AG, Mundipharma, German Federal Ministry of Education and Research.
authors.affiliation: Department I for Internal Medicine and Centre of Integrated Oncology, University of Cologne, Cologne, Germany. Electronic address: barbara.eichhorst@uk-koeln.de.
authors.forename: Barbara
authors.initials: B
authors.lastname: Eichhorst
authors.affiliation: Department I for Internal Medicine and Centre of Integrated Oncology, University of Cologne, Cologne, Germany.
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Fink
authors.affiliation: Department I for Internal Medicine and Centre of Integrated Oncology, University of Cologne, Cologne, Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Bahlo
authors.affiliation: Technical University, Institute for Medical Statistics and Epidemiology, Munich, Germany.
authors.forename: Raymonde
authors.initials: R
authors.lastname: Busch
authors.affiliation: Department I for Internal Medicine and Centre of Integrated Oncology, University of Cologne, Cologne, Germany.
authors.forename: Gabor
authors.initials: G
authors.lastname: Kovacs
authors.affiliation: Department I for Internal Medicine and Centre of Integrated Oncology, University of Cologne, Cologne, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Maurer
authors.affiliation: Evangelisches Krankenhaus, Hamm, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Lange
authors.affiliation: Private oncology practice, Koblenz, Germany.
authors.forename: Hubert
authors.initials: H
authors.lastname: Köppler
authors.affiliation: Department of Internal Medicine I, Klinikum Frankfurt/Oder, Frankfurt, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kiehl
authors.affiliation: Department for Haematology and Oncology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Sökler
authors.affiliation: Private oncology practice, Würzburg, Germany.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Schlag
authors.affiliation: Private oncology practice, Landshut, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Vehling-Kaiser
authors.affiliation: Private oncology practice, Villingen-Schwenningen, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Köchling
authors.affiliation: Private oncology practice, Mannheim, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Plöger
authors.affiliation: Department of Haematology, Luzerner Kantonsspital, Lucerne, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Gregor
authors.affiliation: Department of Haematology, Section of Internal Medicine, Vejle Hospital, Vejle, Denmark.
authors.forename: Torben
authors.initials: T
authors.lastname: Plesner
authors.affiliation: First Department of Medicine, Charles University General Hospital, Prague, Czech Republic.
authors.forename: Marek
authors.initials: M
authors.lastname: Trneny
authors.affiliation: Department I for Internal Medicine and Centre of Integrated Oncology, University of Cologne, Cologne, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Fischer
authors.affiliation: Department of Internal Medicine III, University of Ulm, Ulm, Germany.
authors.forename: Harmut
authors.initials: H
authors.lastname: Döhner
authors.affiliation: Department of Internal Medicine II, University Hospital of Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kneba
authors.affiliation: Department I of Internal Medicine, Klinikum Schwabing, Munich, Germany.
authors.forename: Clemens-Martin
authors.initials: CM
authors.lastname: Wendtner
authors.affiliation: Haematopathology Section and Lymph Node Registry, Department of Pathology, University of Kiel, Kiel, Germany.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Klapper
authors.affiliation: Department I for Internal Medicine and Centre of Integrated Oncology, University of Cologne, Cologne, Germany.
authors.forename: Karl-Anton
authors.initials: KA
authors.lastname: Kreuzer
authors.affiliation: Department of Internal Medicine III, University of Ulm, Ulm, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Stilgenbauer
authors.affiliation: Department of Internal Medicine II, University Hospital of Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Böttcher
authors.affiliation: Department I for Internal Medicine and Centre of Integrated Oncology, University of Cologne, Cologne, Germany; Cluster of Excellence on Cellular Stress Responses in Aging (CECAD), University of Cologne, Cologne, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hallek
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000069461:Bendamustine Hydrochloride / Q000008:administration & dosage; D003520:Cyclophosphamide / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007167:Immunotherapy; D007390:International Agencies; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D000069283:Rituximab / Q000008:administration & dosage; D015996:Survival Rate; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D000069283:Rituximab; D003520:Cyclophosphamide; D000069461:Bendamustine Hydrochloride; D014740:Vidarabine; C024352:fludarabine