PURPOSE: The PRIMA study (ClinicalTrials.gov identifier: NCT00140582) established that 2 years of rituximab maintenance after first-line immunochemotherapy significantly improved progression-free survival (PFS) in patients with follicular lymphoma compared with observation. Here, we report the final PFS and overall survival (OS) results from the PRIMA study after 9 years of follow-up and provide a final overview of safety. METHODS: Patients (> 18 years of age) with previously untreated high-tumor-burden follicular lymphoma were nonrandomly assigned to receive one of three immunochemotherapy induction regimens. Responding patients were randomly assigned (stratified by induction regimen, response to induction treatment, treatment center, and geographic region) 1:1 to receive 2 years of rituximab maintenance (375 mg/m2, once every 8 weeks), starting 8 weeks after the last induction treatment, or observation (no additional treatment). All patients in the extended follow-up provided their written informed consent (data cutoff: December 31, 2016). RESULTS: In total, 1,018 patients completed induction treatment and were randomly assigned to rituximab maintenance (n = 505) or observation (n = 513). Consent for the extended follow-up was provided by 607 patients (59.6%) of 1,018 (rituximab maintenance, n = 309; observation, n = 298). After data cutoff, median PFS was 10.5 years in the rituximab maintenance arm compared with 4.1 years in the observation arm (hazard ratio, 0.61; 95% CI, 0.52 to 0.73; P < .001). No OS difference was seen in patients randomly assigned to rituximab maintenance or observation (hazard ratio, 1.04; 95% CI, 0.77 to 1.40; P = .7948); 10-year OS estimates were approximately 80% in both study arms. No new safety signals were observed. CONCLUSION: Rituximab maintenance after induction immunochemotherapy provides a significant long-term PFS, but not OS, benefit over observation.

Centre Henri Becquerel Rouen France

Centre Hospitalier Régional Universitaire de Nancy Université de Lorraine INSERM 1256 Nancy France

Centre Hospitalier Universitaire d'Angers Angers France

Centre Hospitalier Universitaire de Nantes Centre de Recherche en Cancérologie et Immunologie Nantes Angers INSERM Université de Nantes Nantes France

Charles University Hradec Králové Czech Republic

Chulalongkorn University Bangkok Thailand

Concord Hospital Concord University of Sydney New South Wales Australia

Department of Haematology and INSERM 1231 University Hospital F Mitterrand Dijon France

F Hoffman La Roche Basel Switzerland

Frankston Hospital and Monash University Frankston Victoria Australia

Fundaleu Buenos Aires Argentina

Ghent University Ghent Belgium

Helsinki University Hospital University of Helsinki Helsinki Finland

Herlev University Hospital Copenhagen Denmark

Hôpital de Mercy Centre Hospitalier Régional Metz Thionville Metz France

Hôpital Pitié Salpêtrière Paris France

Hôpital Saint Louis Assistance Publique Hôpitaux de Paris Paris France

Hôpitaux Universitaires Henri Mondor Université Paris Est Créteil INSERM U955 Créteil France

Hospices Civils de Lyon Université Claude Bernard Lyon 1 Institut National de la Santé et de la Recherche Médicale 1052 Pierre Bénite France

Hospital Clinic Barcelona Spain

Hospital Universitario de Salamanca Institute for Biomedical Research of Salamanca Centro de Investigación Biomédica en Red de Cáncer Salamanca Spain

Institut Curie Hôpital Rene Huguenin Saint Cloud France

Institut Paoli Calmettes Aix Marseille Université Marseille France

Institut Universitaire du Cancer de Toulouse Oncopole Toulouse France

North Shore Hospital Auckland New Zealand

Portuguese Institute of Oncology Lisbon Portugal

Queen Mary University of London London United Kingdom

Royal Melbourne Hospital and University of Melbourne Melbourne Victoria Australia

Saint Antoine Hospital Assistance Publique Hôpitaux de Paris Paris France

UCL Mont Godinne Yvoir Belgium

J Clin Oncol. 2020 Feb 10;38(5):522. doi: 10.1200/JCO.19.02019. PubMed

J Clin Oncol. 2020 Feb 10;38(5):523. doi: 10.1200/JCO.19.02689. PubMed

Zobrazit více v PubMed

Freedman A. Follicular lymphoma: 2018 update on diagnosis and management. Am J Hematol. 2018;93:296–305. PubMed

Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127:2375–2390. PubMed PMC

A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma The Non-Hodgkin’s Lymphoma Classification Project. Blood. 1997;89:3909–3918. PubMed

Marcus R, Imrie K, Belch A, et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood. 2005;105:1417–1423. PubMed

Marcus R, Imrie K, Solal-Celigny P, et al. Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisone alone in patients with previously untreated advanced follicular lymphoma. J Clin Oncol. 2008;26:4579–4586. PubMed

Salles G, Mounier N, de Guibert S, et al. Rituximab combined with chemotherapy and interferon in follicular lymphoma patients: Results of the GELA-GOELAMS FL2000 study. Blood. 2008;112:4824–4831. PubMed

Herold M, Haas A, Srock S, et al. Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: An East German Study Group Hematology and Oncology Study. J Clin Oncol. 2007;25:1986–1992. PubMed

Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: Results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2005;106:3725–3732. PubMed

van Oers MH, Klasa R, Marcus RE, et al. Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: Results of a prospective randomized phase 3 intergroup trial. Blood. 2006;108:3295–3301. PubMed

Forstpointner R, Unterhalt M, Dreyling M, et al. Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG) Blood. 2006;108:4003–4008. PubMed

van Oers MH, Van Glabbeke M, Giurgea L, et al. Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin’s lymphoma: Long-term outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol. 2010;28:2853–2858. PubMed PMC

Ghielmini M, Schmitz SF, Cogliatti SB, et al. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood. 2004;103:4416–4423. PubMed

Hainsworth JD, Litchy S, Shaffer DW, et al. Maximizing therapeutic benefit of rituximab: maintenance therapy versus re-treatment at progression in patients with indolent non-Hodgkin’s lymphoma--A randomized phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. 2005;23:1088–1095. PubMed

Pettengell R, Schmitz N, Gisselbrecht C, et al. Rituximab purging and/or maintenance in patients undergoing autologous transplantation for relapsed follicular lymphoma: A prospective randomized trial from the lymphoma working party of the European group for blood and marrow transplantation. J Clin Oncol. 2013;31:1624–1630. PubMed

Hochster H, Weller E, Gascoyne RD, et al. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: Results of the randomized phase III ECOG1496 Study. J Clin Oncol. 2009;27:1607–1614. PubMed PMC

Martinelli G, Schmitz SF, Utiger U, et al. Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J Clin Oncol. 2010;28:4480–4484. 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. 2011;377:42–51. PubMed

Salles G, Seymour JF, Feugier P, et al. Updated 6 year follow-up of the PRIMA study confirms the benefit of 2-year rituximab maintenance in follicular lymphoma patients responding to frontline immunochemotherapy. Blood. 2013;122:509.

Dreyling M, Ghielmini M, Rule S, et al. Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl_4):3109. PubMed

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

Fisher RI, LeBlanc M, Press OW, et al. New treatment options have changed the survival of patients with follicular lymphoma. J Clin Oncol. 2005;23:8447–8452. PubMed

Liu Q, Fayad L, Cabanillas F, et al. Improvement of overall and failure-free survival in stage IV follicular lymphoma: 25 years of treatment experience at The University of Texas M.D. Anderson Cancer Center. J Clin Oncol. 2006;24:1582–1589. PubMed

Luminari S, Ferrari A, Manni M, et al. Long-term results of the FOLL05 trial comparing R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage symptomatic follicular lymphoma. J Clin Oncol. 2018;36:689–696. PubMed

Rummel M, Maschmeyer G, Ganser A, et al. Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent lymphomas: Nine-year updated results from the StiL NHL1 study. J Clin Oncol. 2017;35(15_suppl; abstr 7501)

Shi Q, Flowers CR, Hiddemann W, et al. Thirty-month complete response as a surrogate end point in first-line follicular lymphoma therapy: An individual patient-level analysis of multiple randomized trials. J Clin Oncol. 2017;35:552–560. PubMed

Ciani O, Davis S, Tappenden P, et al. Validation of surrogate endpoints in advanced solid tumors: Systematic review of statistical methods, results, and implications for policy makers. Int J Technol Assess Health Care. 2014;30:312–324. PubMed

Shi Q, Schmitz N, Ou FS, et al. Progression-free survival as a surrogate end point for overall survival in first-line diffuse large B-cell lymphoma: An individual patient-level analysis of multiple randomized trials (SEAL) J Clin Oncol. 2018;36:2593–2602. PubMed PMC

Broglio KR, Berry DA. Detecting an overall survival benefit that is derived from progression-free survival. J Natl Cancer Inst. 2009;101:1642–1649. PubMed PMC

Casulo C, Byrtek M, Dawson KL, et al. Early relapse of follicular lymphoma after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone defines patients at high risk for death: An analysis from the National LymphoCare Study. J Clin Oncol. 2015;33:2516–2522. PubMed PMC

Jurinovic V, Kridel R, Staiger AM, et al. Clinicogenetic risk models predict early progression of follicular lymphoma after first-line immunochemotherapy. Blood. 2016;128:1112–1120. PubMed PMC

Launonen A, Hiddeman W, Duenzinger U, et al: Early disease progression predicts poorer survival in patients with follicular lymphoma (FL) in the GALLIUM study. Blood 130:1490, 2017.

Seymour JF, Marcus R, Davies A, et al. Association of early disease progression and very poor survival in the GALLIUM study in follicular lymphoma: Benefit of obinutuzumab in reducing the rate of early progression. Haematologica. 2019;104:1202–1208. PubMed PMC

Sarkozy C, Trneny M, Xerri L, et al. Risk factors and outcomes for patients with follicular lymphoma who had histologic transformation after response to first-line immunochemotherapy in the PRIMA trial. J Clin Oncol. 2016;34:2575–2582. PubMed

Vidal L, Gafter-Gvili A, Salles G, et al. Rituximab maintenance for the treatment of patients with follicular lymphoma: An updated systematic review and meta-analysis of randomized trials. J Natl Cancer Inst. 2011;103:1799–1806. PubMed

Carson KR, Evens AM, Richey EA, et al. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: A report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood. 2009;113:4834–4840. PubMed PMC

The EHA Research Roadmap: Malignant Lymphoid Diseases

Rituximab maintenance significantly reduces early follicular lymphoma progressions in patients treated with frontline R-CHOP

Zobrazit více v PubMed

ClinicalTrials.gov
NCT00140582