Vincent Ribrag1, Serge Koscielny2, Jacques Bosq3, Thibaut Leguay4, Olivier Casasnovas5, Luc-Mathieu Fornecker6, Christian Recher7, Hervé Ghesquieres8, Franck Morschhauser9, Stéphane Girault10, Steven Le Gouill11, Mario Ojeda-Uribe12, Clara Mariette13, Jerome Cornillon14, Guillaume Cartron15, Veronique Verge16, Catherine Chassagne-Clément17, Hervé Dombret18, Bertrand Coiffier19, Thierry Lamy20, Hervé Tilly21, Gilles Salles22. 1. Department of Medicine, Gustave Roussy, Université Paris Saclay, Villejuif, France. Electronic address: vincent.ribrag@gustaveroussy.fr. 2. Biostatistics and Epidemiology Unit, Gustave Roussy, Université Paris Saclay, Villejuif, France; Centre for Research in Epidemiology and Population Health, Institut national de la santé et de la recherche médicale U1018, Université Paris-Sud, Villejuif, France. 3. Department of Biopathology, Morphology Unit, Gustave Roussy, Université Paris Saclay, Villejuif, France. 4. Service d'hématologie clinique et thérapie cellulaire, Hôpital du Haut-Lévèque, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France. 5. Service d'hématologie Clinique, Centre Hospitalier Universitaire Dijon, Dijon, France. 6. Department of Oncology and Hematology, Hôpital de Hautepierre Université de Strasbourg, Strasbourg, France. 7. Service d'Hématologie, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France. 8. Onco-Hematology, Centre Léon Bérard, Université Claude Bernard Lyon 1, Lyon, France. 9. Service des Maladies du Sang, Hôpital Huriez, Université de Lille, Unité Groupe de Recherche sur les formes Injectables et les Technologies Associées, Lille, France. 10. Hématologie Clinique et Thérapie Cellulaire, Centre Hospitalier Universitaire Limoges, Limoges, France. 11. Department of Hematology, Institut national de la santé et de la recherche médicale, Unité Mixte de Recherche 892, Equipe 10, Nantes Institut national de la santé et de la recherche médicale, Centre d'Investigation Clinique 004, Nantes University Hospital, Nantes, France. 12. Department of Hematology and Cellular Therapy Unit, Hôpital Emile Muller, Centre de Competences on Thrombotic Microangiopathies, Mulhouse, France. 13. Department of Haematology, Grenoble University Hospital, Grenoble, France. 14. Département d'Hématologie, Institut de Cancérologie Lucien Neuwirth, Saint-Priest en Jarez, France. 15. Department of Hematology, Unité Mixte de Recherche Centre national de la recherche scientifique 5235, Centre Hospitalier Universitaire Montpellier, Montpellier, France. 16. Haematology Unit, Gustave Roussy, Université Paris Saclay, Villejuif, France. 17. Département de Biopathologie, Centre Léon Bérard, Lyon, France. 18. Service d'hématologie clinique, Centre Hospitalier Universitaire Paris, Groupe Hospitalier Saint-Louis, Lariboisière, Fernand-Widal, Hôpital Saint-Louis, Paris, France. 19. Hématologie Clinique, Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France. 20. Department of Clinical Hematology, Rennes University Hospital, Rennes, France; Institut national de la santé et de la recherche médicale Unité Mixte de Recherche 917, Faculté de médecine, Université Rennes 1, Rennes Department of Clinical Investigation, Rennes University Hospital, Rennes, France. 21. Centre Henri Becquerel, Université de Rouen, Rouen, France. 22. Hospices Civils de Lyon, Université Lyon 1, Pierre Bénite, France.
Abstract
BACKGROUND:Short intensive chemotherapy is the standard of care for adult patients with Burkitt's leukaemia or lymphoma. Findings from single-arm studies suggest that addition of rituximab to these regimens could improve patient outcomes. Our objective was to test this possibility in a randomised trial. METHODS: In this randomised, controlled, open-label, phase 3 trial, we recruited patients older than 18 years with untreated HIV-negative Burkitt's lymphoma (including Burkitt's leukaemia) from 45 haematological centres in France. Exclusion criteria were contraindications to any drug included in the chemotherapy regimens, any serious comorbidity, poor renal (creatinine concentration >150 μmol/L) or hepatic (cirrhosis or previous hepatitis B or C) function, pregnancy, and any history of cancer except for non-melanoma skin tumours or stage 0 (in situ) cervical carcinoma. Patients were stratified into two groups based on disease extension (absence [group B] or presence [group C] of bone marrow or central nervous system involvement). Patients were further stratified in group C according to age (<40 years, 40-60 years, and >60 years) and central nervous system involvement. Participants were randomly assigned in each group to either intravenous rituximab injections and chemotherapy (lymphome malin B [LMB]) or chemotherapy alone by the Groupe d'Etude des Lymphomes de l'Adulte datacentre. Randomisation was stratified by treatment group and centre using computer-assisted permuted-block randomisation (block size of four; allocation ratio 1:1). We gave rituximab (375 mg/m(2)) on day 1 and day 6 during the first two courses of chemotherapy (total of four infusions). The primary endpoint is 3 year event-free survival (EFS). We analysed all patients who had data available according to their originally assigned group. This trial is registered with ClinicalTrials.gov, number NCT00180882. RESULTS: Between Oct 14, 2004, and Sept 7, 2010, we randomly allocated 260 patients to rituximab or no rituximab (group B 124 patients [64 no rituximab; 60 rituximab]; group C 136 patients [66 no rituximab; 70 rituximab]). With a median follow-up of 38 months (IQR 24-59), patients in the rituximab group achieved better 3 year EFS (75% [95% CI 66-82]) than did those in the no rituximab group (62% [53-70]; log-rank p stratified by treatment group=0·024). The hazard ratio estimated with a Cox model stratified by treatment group, assuming proportionality, was 0·59 for EFS (95% CI 0·38-0·94; p=0·025). Adverse events did not differ between the two treatment groups. The most common adverse events were infectious (grade 3-4 in 137 [17%] treatment cycles in the rituximab group vs 115 [15%] in the no rituximab group) and haematological (mean duration of grade 4 neutropenia of 3·31 days per cycle [95% CI 3·01-3·61] vs 3·38 days per cycle [3·05-3·70]) events. INTERPRETATION: Addition of rituximab to a short intensive chemotherapy programme improves EFS in adults with Burkitt's leukaemia or lymphoma. FUNDING: Gustave Roussy Cancer Campus, Roche, Chugai, Sanofi.
RCT Entities:
BACKGROUND: Short intensive chemotherapy is the standard of care for adult patients with Burkitt's leukaemia or lymphoma. Findings from single-arm studies suggest that addition of rituximab to these regimens could improve patient outcomes. Our objective was to test this possibility in a randomised trial. METHODS: In this randomised, controlled, open-label, phase 3 trial, we recruited patients older than 18 years with untreated HIV-negative Burkitt's lymphoma (including Burkitt's leukaemia) from 45 haematological centres in France. Exclusion criteria were contraindications to any drug included in the chemotherapy regimens, any serious comorbidity, poor renal (creatinine concentration >150 μmol/L) or hepatic (cirrhosis or previous hepatitis B or C) function, pregnancy, and any history of cancer except for non-melanoma skin tumours or stage 0 (in situ) cervical carcinoma. Patients were stratified into two groups based on disease extension (absence [group B] or presence [group C] of bone marrow or central nervous system involvement). Patients were further stratified in group C according to age (<40 years, 40-60 years, and >60 years) and central nervous system involvement. Participants were randomly assigned in each group to either intravenous rituximab injections and chemotherapy (lymphome malin B [LMB]) or chemotherapy alone by the Groupe d'Etude des Lymphomes de l'Adulte datacentre. Randomisation was stratified by treatment group and centre using computer-assisted permuted-block randomisation (block size of four; allocation ratio 1:1). We gave rituximab (375 mg/m(2)) on day 1 and day 6 during the first two courses of chemotherapy (total of four infusions). The primary endpoint is 3 year event-free survival (EFS). We analysed all patients who had data available according to their originally assigned group. This trial is registered with ClinicalTrials.gov, number NCT00180882. RESULTS: Between Oct 14, 2004, and Sept 7, 2010, we randomly allocated 260 patients to rituximab or no rituximab (group B 124 patients [64 no rituximab; 60 rituximab]; group C 136 patients [66 no rituximab; 70 rituximab]). With a median follow-up of 38 months (IQR 24-59), patients in the rituximab group achieved better 3 year EFS (75% [95% CI 66-82]) than did those in the no rituximab group (62% [53-70]; log-rank p stratified by treatment group=0·024). The hazard ratio estimated with a Cox model stratified by treatment group, assuming proportionality, was 0·59 for EFS (95% CI 0·38-0·94; p=0·025). Adverse events did not differ between the two treatment groups. The most common adverse events were infectious (grade 3-4 in 137 [17%] treatment cycles in the rituximab group vs 115 [15%] in the no rituximab group) and haematological (mean duration of grade 4 neutropenia of 3·31 days per cycle [95% CI 3·01-3·61] vs 3·38 days per cycle [3·05-3·70]) events. INTERPRETATION: Addition of rituximab to a short intensive chemotherapy programme improves EFS in adults with Burkitt's leukaemia or lymphoma. FUNDING: Gustave Roussy Cancer Campus, Roche, Chugai, Sanofi.
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