TY - JOUR
T1 - Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia
T2 - A randomised, open-label, phase 3 trial
AU - Hallek, Michael
AU - Fischer, K.
AU - Fingerle-Rowson, Gunter
AU - Fink, A.M.
AU - Busch, Raymonde
AU - Mayer, J.
AU - Hensel, M.
AU - Hopfinger, Georg
AU - Hess, G D
AU - Von Grünhagen, U.
AU - Bergmann, Matthias
AU - Catalano, J.
AU - Zinzani, Pier L.
AU - Caligaris-Cappio, Federico
AU - Seymour, J. F.
AU - Berrebi, A.
AU - Jäger, U.
AU - Cazin, Bruno
AU - Trneny, Marek
AU - Westermann, A.
AU - Wendtner, Clemens M.
AU - Eichhorst, B. F.
AU - Staib, P.
AU - Bühler, A.
AU - Winkler, D.
AU - Zenz, T.
AU - Böttcher, S.
AU - Ritgen, Matthias
AU - Mendila, Myriam
AU - Kneba, Michael
AU - Döhner, Hartmut
AU - Stilgenbauer, Stephan
PY - 2010/10/2
Y1 - 2010/10/2
N2 - 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/m2 per day) and cyclophosphamide (250 mg/m2 per day) for the first 3 days of each 28-day treatment course with or without rituximab (375 mg/m2 on day 0 of first course, and 500 mg/m2 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. Findings 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. Interpretation 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. Funding F Hoffmann-La Roche.
AB - 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/m2 per day) and cyclophosphamide (250 mg/m2 per day) for the first 3 days of each 28-day treatment course with or without rituximab (375 mg/m2 on day 0 of first course, and 500 mg/m2 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. Findings 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. Interpretation 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. Funding F Hoffmann-La Roche.
UR - http://www.scopus.com/inward/record.url?scp=77957664665&partnerID=8YFLogxK
U2 - 10.1016/S0140-6736(10)61381-5
DO - 10.1016/S0140-6736(10)61381-5
M3 - Article
C2 - 20888994
AN - SCOPUS:77957664665
SN - 0140-6736
VL - 376
SP - 1164
EP - 1174
JO - The Lancet
JF - The Lancet
IS - 9747
ER -