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.

1st Medical Dept Landesklinikum Wiener Neustadt Austria Arbeitsgemeinschaft Medikamentöse Tumortherapie AGMT Salzburg Austria

3rd Dept of Medicine AKH Linz Austria Arbeitsgemeinschaft Medikamentöse Tumortherapie AGMT Salzburg Austria

3rd Medical Dept Hanusch Hospital Vienna Austria Arbeitsgemeinschaft Medikamentöse Tumortherapie AGMT Salzburg Austria

Ankara University School of Medicine Dept of Hematology Ankara Turkey

Assign Data Management and Biostatistics GmbH Assign Group Innsbruck Austria Arbeitsgemeinschaft Medikamentöse Tumortherapie AGMT Salzburg Austria

Australasian Leukaemia and Lymphoma Group East Melbourne Australia

Clinic for Hematology Clinical Center Serbia Belgrade Serbia

Dept of Hematology Hadassah Hebrew University Medical Center Jerusalem Israel

Dept of Internal Medicine 3 Private Medical University of Salzburg Austria Arbeitsgemeinschaft Medikamentöse Tumortherapie AGMT Salzburg Austria

Dept of Internal Medicine 4 Wels Grieskirchen Hospital Wels Austria Arbeitsgemeinschaft Medikamentöse Tumortherapie AGMT Salzburg Austria

Dept of Internal Medicine Faculty of Medicine Chiang Mai University Thailand

Dept of Internal Medicine Sundsvall Hospital Sweden

Division of Hematology and Oncology Dept of Medicine Taipei Veterans General Hospital and National Yang Ming University Taipei Taiwan

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

Institute of Pathology and Microbiology Wilhelminenspital Vienna Austria

LBI ACR and ACR ITR Vienna Kaiser Franz Josef Spital Vienna Austria Arbeitsgemeinschaft Medikamentöse Tumortherapie AGMT Salzburg Austria

Medical University of Vienna Dept of Medicine 1 Division of Hematology and Hemostaseology Comprehensive Cancer Center Vienna Austria Arbeitsgemeinschaft Medikamentöse Tumortherapie AGMT Salzburg Austria

NOU Klenova Bratislava Slovakia

University Medical Unit Queen Mary Hospital Hong Kong China

Haematologica. 2015 Nov;100(11):e480-1. doi: 10.3324/haematol.2015.133223. PubMed

Haematologica. 2015 Nov;100(11):e482. doi: 10.3324/haematol.2015.134288. PubMed

Zobrazit více v PubMed

Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346(4):235–242. PubMed

Sehn LH, Donaldson J, Chhanabhai M, et al. Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia. J Clin Oncol. 2005;23(22): 5027–5033. PubMed

Vidal L, Gafter-Gvili A, Leibovici L, et al. Rituximab maintenance for the treatment of patients with follicular lymphoma: systematic review and meta-analysis of randomized trials. J Natl Cancer Inst. 2009;101(4): 248–255. PubMed

Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 377(9759): 42–51. PubMed

Ghielmini M, Vitolo U, Kimby E, et al. ESMO guidelines consensus conference on malignant lymphoma 2011 part 1: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL). Ann Oncol. 2012;24(3): 561–576. PubMed PMC

Armitage J. My treatment approach to patients with diffuse large B-cell lymphoma. Mayo Clin Proc. 2012;87(2):161–171. PubMed PMC

Ganti AK, Weisenburger DD, Smith LM, et al. Patients with grade 3 follicular lymphoma have prolonged relapse-free survival following anthracycline-based chemotherapy: the Nebraska Lymphoma Study Group Experience. Ann Oncol. 2006;17(6):920–927. PubMed

Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood. 2011;117(19):5019–5032. PubMed PMC

Habermann TM, Weller EA, Morrison VA, et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol. 2006;24(19):3121–3127. PubMed

Huang BT, Zeng QC, Yu J, et al. How to determine post-RCHOP therapy for risk-tailored adult patients with diffuse large B-cell lymphoma, addition of maintenance rituximab or observation: multicenter experience. J Cancer Res Clin Oncol. 2012;138(1): 125–132. PubMed PMC

Haioun C, Mounier N, Emile JF, et al. Rituximab versus observation after high-dose consolidative first-line chemotherapy with autologous stem-cell transplantation in patients with poor-risk diffuse large B-cell lymphoma. Ann Oncol. 2009;20(12):1985–1992. PubMed

Gisselbrecht C, Schmitz N, Mounier N, et al. Rituximab maintenance therapy after autologous stem-cell transplantation in patients with relapsed CD20+ diffuse large B-cell lymphoma: final analysis of the collaborative trial in relapse aggressive lymphoma. J Clin Oncol. 2012;30(36):4462–4469. PubMed PMC

Advani R, Hong F, Habermann TM, et al. Improved risk stratification with addition of male sex to the elderly international prognostic index for DLBCL patients > 60 years treated with R-CHOP: an international collaboration of the US Intergroup, German High-grade Non-Hodgkin Lymphoma Study Group and Groupe d’Etude De Lymphome d’Adultes [abstract]. Blood. 2013;122(21): 3045a. PubMed

Müller C, Murawski N, Wiesen MH, et al. The role of sex and weight on rituximab clearance and serum elimination half-life in elderly patients with DLBCL. Blood. 2012;119(14):3276–3284. PubMed

Jäger U, Fridrik M, Zeitlinger M, et al. Rituximab serum concentrations during immuno-chemotherapy of follicular lymphoma correlate with patient gender, bone marrow infiltration and clinical response. Haematologica. 2012;97(9):1431–1438. PubMed PMC

Cheson BD, Horning SJ, Coiffier B, et al. Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. J Clin Oncol. 1999;17(4): 1244. PubMed

The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med. 1993;329(14):987–994. PubMed

Maurer MJ, Ghesquieres H, Jais JP, et al. Event-free survival at 24 months is a robust end point for disease-related outcome in diffuse large B-cell lymphoma treated with immunochemotherapy. J Clin Oncol. 2014;32(10):1066–1073. PubMed PMC

Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med. 1995;333(23):1540–1545. PubMed

Pfreundschuh M, Müller C, Zeynalova S, et al. Suboptimal dosing of rituximab in male and female patients with DLBCL. Blood. 2014;123(5):640–646. PubMed

Pfreundschuh M, Schubert J, Ziepert M, et al. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol. 2008;9(2): 105–116. PubMed

Pfreundschuh M, Held G, Zeynalova S, et al. Increased rituximab (R) doses and effect on risk of elderly male patients with aggressive CD20+ B-cell lymphomas: results from the SEXIE-R-CHOP-14 trial of the DSHNHL. J Clin Oncol 32:5s, 2014. (suppl; abstr 8501) PubMed

Carson KR, Bartlett NL, McDonald JR, et al. Increased Body Mass Index is associated with improved survival in United States veterans with diffuse large B-cell lymphoma. J Clin Oncol. 2012;30(26):3217–3222. PubMed PMC

Pfreundschuh M, Trümper L, Osterborg A, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. 2006;7(5):379–391. PubMed

Pfreundschuh M, Kuhnt E, Trümper L, et al. CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group. Lancet Oncol. 2011;12(11): 1013–1022. PubMed

Armitage JO, Weisenburger DD. New approach to classifying non-Hodgkin’s lymphomas: clinical features of the major histologic subtypes. J Clin Oncol. 1998;16(8): 2780–2795. PubMed

Phan J, Mazloom A, Medeiros LJ, et al. Benefit of consolidative radiation therapy in patients with diffuse large B-cell lymphoma treated with R-CHOP chemotherapy. J Clin Oncol. 2010;28(27):4170–4176 PubMed

Held G, Murawski N, Ziepert M, et al. Role of radiotherapy to bulky disease in elderly patients with aggressive B-cell lymphoma. J Clin Oncol. 2014;32(11):1112–1118. PubMed

Campbell BA, Connors JM, Gascoyne RD, Morris WJ, Pickles T, Sehn LH. Limited-stage diffuse large B-cell lymphoma treated with abbreviated systemic therapy and consolidation radiotherapy. Cancer. 2012;118(17):4156–4165. PubMed

Pfreundschuh M, Ho AD, Cavallin-Stahl E, et al. Prognostic significance of maximum tumour (bulk) diameter in young patients with good-prognosis diffuse large-B-cell lymphoma treated with CHOP-like chemotherapy with or without rituximab: an exploratory analysis of the MabThera International Trial Group (MInT) study. Lancet Oncol. 2008;9(5):435–444. PubMed

Murawski N, Pfreundschuh M, Zeynalova S, et al. Optimization of rituximab for the treatment of DLBCL (I): dose-dense rituximab in the DENSE-R-CHOP-14 trial of the DSHNHL. Ann Oncol. 2014;25(9):1800–1806. PubMed

Pfreundschuh M, Poeschel V, Zeynalova S, et al. Optimization of rituximab for the treatment of diffuse large B-cell lymphoma (II): extended rituximab exposure time in the SMARTE-R-CHOP-14 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group. J Clin Oncol. 2014;32(36): 4127–4133. PubMed

Shustik J, Quinn M, Connors JM, Gascoyne RD, Skinnider B, Sehn LH. Follicular non-Hodgkin lymphoma grades 3A and 3B have a similar outcome and appear incurable with anthracycline-based therapy. Ann Oncol. 2011;22(5):1164–1169. PubMed

Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059–3068. PubMed PMC

Crump M, Leppä S, Fayad LE, et al. A phase III study of enzastaurin in patients with high-risk diffuse large B cell lymphoma following response to primary treatment: the prelude trial. Blood. 121 (suppl; abstr. 371), 2013.

Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma

Rituximab maintenance overcomes the negative prognostic factor of obesity in CLL: Subgroup analysis of the international randomized AGMT CLL-8a mabtenance trial

Zobrazit více v PubMed

EudraCT
2005-005187-90

ClinicalTrials.gov
NCT00400478