title: Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial.
abstract: BACKGROUND
  Rituximab plus chemotherapy, most often CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), is the first-line standard of care for patients with advanced indolent lymphoma, and for elderly patients with mantle-cell lymphoma. Bendamustine plus rituximab is effective for relapsed or refractory disease. We compared bendamustine plus rituximab with CHOP plus rituximab (R-CHOP) as first-line treatment for patients with indolent and mantle-cell lymphomas.
  
  
  METHODS
  We did a prospective, multicentre, randomised, open-label, non-inferiority trial at 81 centres in Germany between Sept 1, 2003, and Aug 31, 2008. Patients aged 18 years or older with a WHO performance status of 2 or less were eligible if they had newly diagnosed stage III or IV indolent or mantle-cell lymphoma. Patients were stratified by histological lymphoma subtype, then randomly assigned according to a prespecified randomisation list to receive either intravenous bendamustine (90 mg/m(2) on days 1 and 2 of a 4-week cycle) or CHOP (cycles every 3 weeks of cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), and vincristine 1.4 mg/m(2) on day 1, and prednisone 100 mg/day for 5 days) for a maximum of six cycles. Patients in both groups received rituximab 375 mg/m(2) on day 1 of each cycle. Patients and treating physicians were not masked to treatment allocation. The primary endpoint was progression-free survival, with a non-inferiority margin of 10%. Analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00991211, and the Federal Institute for Drugs and Medical Devices of Germany, BfArM 4021335.
  
  
  RESULTS
  274 patients were assigned to bendamustine plus rituximab (261 assessed) and 275 to R-CHOP (253 assessed). At median follow-up of 45 months (IQR 25-57), median progression-free survival was significantly longer in the bendamustine plus rituximab group than in the R-CHOP group (69.5 months [26.1 to not yet reached] vs 31.2 months [15.2-65.7]; hazard ratio 0.58, 95% CI 0.44-0.74; p<0.0001). Bendamustine plus rituximab was better tolerated than R-CHOP, with lower rates of alopecia (0 patients vs 245 (100%) of 245 patients who recieved ≥3 cycles; p<0.0001), haematological toxicity (77 [30%] vs 173 [68%]; p<0.0001), infections (96 [37%] vs 127 [50%]); p=0.0025), peripheral neuropathy (18 [7%] vs 73 [29%]; p<0.0001), and stomatitis (16 [6%] vs 47 [19%]; p<0.0001). Erythematous skin reactions were more common in patients in the bendamustine plus rituximab group than in those in the R-CHOP group (42 [16%] vs 23 [9%]; p=0.024).
  
  
  CONCLUSIONS
  In patients with previously untreated indolent lymphoma, bendamustine plus rituximab can be considered as a preferred first-line treatment approach to R-CHOP because of increased progression-free survival and fewer toxic effects.
  
  
  BACKGROUND
  Roche Pharma AG, Ribosepharm/Mundipharma GmbH.
authors: Medizinische Klinik IV, Hospital of the Justus-Liebig-University, Giessen, Germany. mathias.rummel@innere.med.uni-giessen.de
authors: Mathias J
authors: MJ
authors: Rummel
authors: Norbert
authors: N
authors: Niederle
authors: Georg
authors: G
authors: Maschmeyer
authors: G Andre
authors: GA
authors: Banat
authors: Ulrich
authors: U
authors: von Grünhagen
authors: Christoph
authors: C
authors: Losem
authors: Dorothea
authors: D
authors: Kofahl-Krause
authors: Gerhard
authors: G
authors: Heil
authors: Manfred
authors: M
authors: Welslau
authors: Christina
authors: C
authors: Balser
authors: Ulrich
authors: U
authors: Kaiser
authors: Eckhart
authors: E
authors: Weidmann
authors: Heinz
authors: H
authors: Dürk
authors: Harald
authors: H
authors: Ballo
authors: Martina
authors: M
authors: Stauch
authors: Fritz
authors: F
authors: Roller
authors: Juergen
authors: J
authors: Barth
authors: Dieter
authors: D
authors: Hoelzer
authors: Axel
authors: A
authors: Hinke
authors: Wolfram
authors: W
authors: Brugger
mesh_terms: D000328:Adult; D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000069461:Bendamustine Hydrochloride; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D007262:Infusions, Intravenous; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy*; D008875:Middle Aged; D009588:Nitrogen Mustard Compounds / Q000008:administration & dosage / Q000009:adverse effects; D011241:Prednisone / Q000008:administration & dosage / Q000009:adverse effects; D011446:Prospective Studies; D000069283:Rituximab; D016896:Treatment Outcome; D014750:Vincristine / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D009588:Nitrogen Mustard Compounds; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D000069461:Bendamustine Hydrochloride; D011241:Prednisone