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Rituximab and dose-dense chemotherapy for adults with Burkitt's lymphoma: a randomised, controlled, open-label, phase 3 trial

Vincent Ribrag 1 Serge Koscielny 2, 3 Jacques Bosq 4 Thibaut Leguay 5 Olivier Casasnovas 6 Luc-Mathieu Fornecker 7 Christian Recher 8 Hervé Ghesquieres 9 Franck Morschhauser 10 Stéphane Girault 11 Steven Le Gouill 12 Mario Ojeda-Uribe 13 Clara Mariette 14 Jerome Cornillon 15 Guillaume Cartron 16, 17 Veronique Verge 18 Catherine Chassagne-Clément 9 Hervé Dombret 19 Bertrand Coiffier 20 Thierry Lamy 21, 22, 23 Hervé Tilly 24 Gilles Salles 20, * 
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/m2) 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, 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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Submitted on : Monday, December 19, 2016 - 3:06:48 PM
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Vincent Ribrag, Serge Koscielny, Jacques Bosq, Thibaut Leguay, Olivier Casasnovas, et al.. Rituximab and dose-dense chemotherapy for adults with Burkitt's lymphoma: a randomised, controlled, open-label, phase 3 trial. The Lancet, Elsevier, 2016, 387 (10036), pp.2402 - 2411. ⟨10.1016/S0140-6736(15)01317-3⟩. ⟨inserm-01419476⟩



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