Rituximab maintenance for patients with aggressive B-cell lymphoma in first remission: results of the randomized NHL13 trial
Ulrich Jaeger,
Marek Trneny,
Helen Melzer,
Michael Praxmarer,
Weerasak Nawarawong,
Dina Ben Yehuda,
David Goldstein,
Bilijana Mihaljevic,
Osman Ilhan,
Veronika Ballova,
Michael Hedenus,
Liang-Tsai Hsiao,
Wing-Yan Au,
Sonja Burgstaller,
Gerhard Weidinger,
Felix Keil,
Christian Dittrich,
Cathrin Skrabs,
Anton Klingler,
Andreas Chott,
Michael A. Fridrik,
Richard Greil
Affiliations
Ulrich Jaeger
Medical University of Vienna, Dept. of Medicine I, Division of Hematology and Hemostaseology, Comprehensive Cancer Center, Vienna, Austria;Arbeitsgemeinschaft Medikamentöse Tumortherapie, AGMT, Salzburg, Austria
Marek Trneny
Institute of Hematology and Blood Transfusion, 1st Dept. of Medicine, 1st Faculty of Medicine, Charles University, General Hospital, Czech Lymphoma Study Group, Praha, Czech Republic
Helen Melzer
Medical University of Vienna, Dept. of Medicine I, Division of Hematology and Hemostaseology, Comprehensive Cancer Center, Vienna, Austria;Arbeitsgemeinschaft Medikamentöse Tumortherapie, AGMT, Salzburg, Austria
Michael Praxmarer
Assign Data Management and Biostatistics GmbH Assign Group, Innsbruck, Austria;Arbeitsgemeinschaft Medikamentöse Tumortherapie, AGMT, Salzburg, Austria
Weerasak Nawarawong
Dept. of Internal Medicine, Faculty of Medicine, Chiang Mai University, Thailand
Dina Ben Yehuda
Dept. of Hematology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
David Goldstein
Australasian Leukaemia & Lymphoma Group, East Melbourne, Australia
Bilijana Mihaljevic
Clinic for Hematology, Clinical Center Serbia, Belgrade, Serbia
Osman Ilhan
Ankara University School of Medicine, Dept. of Hematology, Ankara, Turkey
Veronika Ballova
NOU, Klenova Bratislava, Slovakia
Michael Hedenus
Dept. of Internal Medicine, Sundsvall Hospital, Sweden
Liang-Tsai Hsiao
Division of Hematology and Oncology, Dept. of Medicine, Taipei Veterans General Hospital, and National Yang-Ming University, Taipei, Taiwan
Wing-Yan Au
University Medical Unit, Queen Mary Hospital, Hong Kong, China
Sonja Burgstaller
Dept. of Internal Medicine IV, Wels-Grieskirchen Hospital, Wels, Austria;Arbeitsgemeinschaft Medikamentöse Tumortherapie, AGMT, Salzburg, Austria
Gerhard Weidinger
1st Medical Dept., Landesklinikum Wiener Neustadt, Austria;Arbeitsgemeinschaft Medikamentöse Tumortherapie, AGMT, Salzburg, Austria
Felix Keil
3rd Medical Dept., Hanusch Hospital, Vienna, Austria;Arbeitsgemeinschaft Medikamentöse Tumortherapie, AGMT, Salzburg, Austria
Christian Dittrich
LBI-ACR & ACR-ITR Vienna, Kaiser Franz Josef-Spital, Vienna, Austria;Arbeitsgemeinschaft Medikamentöse Tumortherapie, AGMT, Salzburg, Austria
Cathrin Skrabs
Medical University of Vienna, Dept. of Medicine I, Division of Hematology and Hemostaseology, Comprehensive Cancer Center, Vienna, Austria;Arbeitsgemeinschaft Medikamentöse Tumortherapie, AGMT, Salzburg, Austria
Anton Klingler
Assign Data Management and Biostatistics GmbH Assign Group, Innsbruck, Austria;Arbeitsgemeinschaft Medikamentöse Tumortherapie, AGMT, Salzburg, Austria
Andreas Chott
Institute of Pathology and Microbiology, Wilhelminenspital, Vienna, Austria
Michael A. Fridrik
3rd Dept. of Medicine, AKH-Linz, Austria;Arbeitsgemeinschaft Medikamentöse Tumortherapie, AGMT, Salzburg, Austria
Richard Greil
Dept. of Internal Medicine III, Private Medical University of Salzburg, Austria;Arbeitsgemeinschaft Medikamentöse Tumortherapie, AGMT, Salzburg, Austria
We investigated rituximab maintenance therapy in patients with diffuse large B-cell lymphoma (n=662) or follicular lymphoma grade 3b (n=21) in first complete remission. Patients were randomized to rituximab maintenance (n=338) or observation (n=345). At a median follow-up of 45 months, the event-free survival rate (the primary endpoint) at 3 years was 80.1% for rituximab maintenance versus 76.5% for observation. This difference was not statistically significant for the intent-to-treat population (likelihood ratio P=0.0670). The hazard ratio by treatment arm was 0.79 (95% confidence interval 0.57–1.08; P=0.1433). The secondary endpoint, progression-free survival was also not met for the whole statistical model (likelihood ratio P=0.3646). Of note, rituximab maintenance was superior to observation when treatment arms only were compared (hazard ratio: 0.62; 95% confidence interval 0.43–0.90; P=0.0120). Overall survival remained unchanged (92.0 versus 90.3%). In subgroup analysis male patients benefited from rituximab maintenance with regards to both event-free survival (84.1% versus 74.4%) (hazard ratio: 0.58; 95% confidence interval 0.36–0.94; P=0.0267) and progression-free survival (89.0% versus 77.6%) (hazard ratio: 0.45; 95% confidence interval 0.25–0.79; P=0.0058). Women had more grade 3/4 adverse events (P=0.0297) and infections (P=0.0341). Men with a low International Prognostic Index treated with rituximab had the best outcome. In summary, rituximab maintenance in first remission after R-CHOP-like treatment did not prolong event-free, progression-free or overall survival of patients with aggressive B-non-Hodgkin lymphoma. The significantly better outcome of men warrants further studies prior to the routine use of rituximab maintenance in men with low International Prognostic Index. This trial is registered under EUDRACT #2005-005187-90 and www.clinicaltrials.gov as #NCT00400478.
