title: Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial.
abstract: BACKGROUND
  On the basis of promising results that were reported in several phase 2 trials, we investigated whether the addition of the monoclonal antibody rituximab to first-line chemotherapy with fludarabine and cyclophosphamide would improve the outcome of patients with chronic lymphocytic leukaemia.
  
  
  METHODS
  Treatment-naive, physically fit patients (aged 30-81 years) with CD20-positive chronic lymphocytic leukaemia were randomly assigned in a one-to-one ratio to receive six courses of intravenous fludarabine (25 mg/m(2) per day) and cyclophosphamide (250 mg/m(2) per day) for the first 3 days of each 28-day treatment course with or without rituximab (375 mg/m(2) on day 0 of first course, and 500 mg/m(2) on day 1 of second to sixth courses) in 190 centres in 11 countries. Investigators and patients were not masked to the computer-generated treatment assignment. The primary endpoint was progression-free survival (PFS). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00281918.
  
  
  RESULTS
  408 patients were assigned to fludarabine, cyclophosphamide, and rituximab (chemoimmunotherapy group) and 409 to fludarabine and cyclophosphamide (chemotherapy group); all patients were analysed. At 3 years after randomisation, 65% of patients in the chemoimmunotherapy group were free of progression compared with 45% in the chemotherapy group (hazard ratio 0·56 [95% CI 0·46-0·69], p<0·0001); 87% were alive versus 83%, respectively (0·67 [0·48-0·92]; p=0·01). Chemoimmunotherapy was more frequently associated with grade 3 and 4 neutropenia (136 [34%] of 404 vs 83 [21%] of 396; p<0·0001) and leucocytopenia (97 [24%] vs 48 [12%]; p<0·0001). Other side-effects, including severe infections, were not increased. There were eight (2%) treatment-related deaths in the chemoimmunotherapy group compared with ten (3%) in the chemotherapy group.
  
  
  CONCLUSIONS
  Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab improves progression-free survival and overall survival in patients with chronic lymphocytic leukaemia. Moreover, the results suggest that the choice of a specific first-line treatment changes the natural course of chronic lymphocytic leukaemia.
  
  
  BACKGROUND
  F Hoffmann-La Roche.
authors.affiliation: Department I of Internal Medicine and Centre for Integrated Oncology, University of Cologne, Cologne, Germany. michael.hallek@uni-koeln.de
authors.forename: M
authors.initials: M
authors.lastname: Hallek
authors.forename: K
authors.initials: K
authors.lastname: Fischer
authors.forename: G
authors.initials: G
authors.lastname: Fingerle-Rowson
authors.forename: A M
authors.initials: AM
authors.lastname: Fink
authors.forename: R
authors.initials: R
authors.lastname: Busch
authors.forename: J
authors.initials: J
authors.lastname: Mayer
authors.forename: M
authors.initials: M
authors.lastname: Hensel
authors.forename: G
authors.initials: G
authors.lastname: Hopfinger
authors.forename: G
authors.initials: G
authors.lastname: Hess
authors.forename: U
authors.initials: U
authors.lastname: von Grünhagen
authors.forename: M
authors.initials: M
authors.lastname: Bergmann
authors.forename: J
authors.initials: J
authors.lastname: Catalano
authors.forename: P L
authors.initials: PL
authors.lastname: Zinzani
authors.forename: F
authors.initials: F
authors.lastname: Caligaris-Cappio
authors.forename: J F
authors.initials: JF
authors.lastname: Seymour
authors.forename: A
authors.initials: A
authors.lastname: Berrebi
authors.forename: U
authors.initials: U
authors.lastname: Jäger
authors.forename: B
authors.initials: B
authors.lastname: Cazin
authors.forename: M
authors.initials: M
authors.lastname: Trneny
authors.forename: A
authors.initials: A
authors.lastname: Westermann
authors.forename: C M
authors.initials: CM
authors.lastname: Wendtner
authors.forename: B F
authors.initials: BF
authors.lastname: Eichhorst
authors.forename: P
authors.initials: P
authors.lastname: Staib
authors.forename: A
authors.initials: A
authors.lastname: Bühler
authors.forename: D
authors.initials: D
authors.lastname: Winkler
authors.forename: T
authors.initials: T
authors.lastname: Zenz
authors.forename: S
authors.initials: S
authors.lastname: Böttcher
authors.forename: M
authors.initials: M
authors.lastname: Ritgen
authors.forename: M
authors.initials: M
authors.lastname: Mendila
authors.forename: M
authors.initials: M
authors.lastname: Kneba
authors.forename: H
authors.initials: H
authors.lastname: Döhner
authors.forename: S
authors.initials: S
authors.lastname: Stilgenbauer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000008:administration & dosage; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage; D015994:Incidence; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000401:mortality; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D000069283:Rituximab; D012720:Severity of Illness Index; D016896:Treatment Outcome; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D007155:Immunologic Factors; D000069283:Rituximab; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine