title: Rituximab and dose-dense chemotherapy for adults with Burkitt's lymphoma: a randomised, controlled, open-label, phase 3 trial.
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.
  
  
  CONCLUSIONS
  Addition of rituximab to a short intensive chemotherapy programme improves EFS in adults with Burkitt's leukaemia or lymphoma.
  
  
  BACKGROUND
  Gustave Roussy Cancer Campus, Roche, Chugai, Sanofi.
authors.affiliation: Department of Medicine, Gustave Roussy, Université Paris Saclay, Villejuif, France. Electronic address: vincent.ribrag@gustaveroussy.fr.
authors.forename: Vincent
authors.initials: V
authors.lastname: Ribrag
authors.affiliation: 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.
authors.forename: Serge
authors.initials: S
authors.lastname: Koscielny
authors.affiliation: Department of Biopathology, Morphology Unit, Gustave Roussy, Université Paris Saclay, Villejuif, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Bosq
authors.affiliation: Service d'hématologie clinique et thérapie cellulaire, Hôpital du Haut-Lévèque, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Leguay
authors.affiliation: Service d'hématologie Clinique, Centre Hospitalier Universitaire Dijon, Dijon, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Casasnovas
authors.affiliation: Department of Oncology and Hematology, Hôpital de Hautepierre Université de Strasbourg, Strasbourg, France.
authors.forename: Luc-Mathieu
authors.initials: LM
authors.lastname: Fornecker
authors.affiliation: Service d'Hématologie, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Recher
authors.affiliation: Onco-Hematology, Centre Léon Bérard, Université Claude Bernard Lyon 1, Lyon, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Ghesquieres
authors.affiliation: Service des Maladies du Sang, Hôpital Huriez, Université de Lille, Unité Groupe de Recherche sur les formes Injectables et les Technologies Associées, Lille, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Morschhauser
authors.affiliation: Hématologie Clinique et Thérapie Cellulaire, Centre Hospitalier Universitaire Limoges, Limoges, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Girault
authors.affiliation: 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.
authors.forename: Steven
authors.initials: S
authors.lastname: Le Gouill
authors.affiliation: Department of Hematology and Cellular Therapy Unit, Hôpital Emile Muller, Centre de Competences on Thrombotic Microangiopathies, Mulhouse, France.
authors.forename: Mario
authors.initials: M
authors.lastname: Ojeda-Uribe
authors.affiliation: Department of Haematology, Grenoble University Hospital, Grenoble, France.
authors.forename: Clara
authors.initials: C
authors.lastname: Mariette
authors.affiliation: Département d'Hématologie, Institut de Cancérologie Lucien Neuwirth, Saint-Priest en Jarez, France.
authors.forename: Jerome
authors.initials: J
authors.lastname: Cornillon
authors.affiliation: Department of Hematology, Unité Mixte de Recherche Centre national de la recherche scientifique 5235, Centre Hospitalier Universitaire Montpellier, Montpellier, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Cartron
authors.affiliation: Haematology Unit, Gustave Roussy, Université Paris Saclay, Villejuif, France.
authors.forename: Veronique
authors.initials: V
authors.lastname: Verge
authors.affiliation: Département de Biopathologie, Centre Léon Bérard, Lyon, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Chassagne-Clément
authors.affiliation: Service d'hématologie clinique, Centre Hospitalier Universitaire Paris, Groupe Hospitalier Saint-Louis, Lariboisière, Fernand-Widal, Hôpital Saint-Louis, Paris, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Dombret
authors.affiliation: Hématologie Clinique, Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Coiffier
authors.affiliation: 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.
authors.forename: Thierry
authors.initials: T
authors.lastname: Lamy
authors.affiliation: Centre Henri Becquerel, Université de Rouen, Rouen, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Tilly
authors.affiliation: Hospices Civils de Lyon, Université Lyon 1, Pierre Bénite, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Salles
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D019046:Bone Marrow Neoplasms / Q000188:drug therapy; D002051:Burkitt Lymphoma / Q000737:chemistry / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology; D016543:Central Nervous System Neoplasms / Q000188:drug therapy; D003520:Cyclophosphamide / Q000008:administration & dosage; D003561:Cytarabine / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005260:Female; D005602:France; D006801:Humans; D006854:Hydrocortisone / Q000008:administration & dosage; D007275:Injections, Intravenous; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage; D008775:Methylprednisolone / Q000008:administration & dosage; D008875:Middle Aged; D009367:Neoplasm Staging; D016017:Odds Ratio; D018579:Patient Selection; D011241:Prednisone / Q000008:administration & dosage; D016016:Proportional Hazards Models; D000069283:Rituximab / Q000008:administration & dosage*; D016896:Treatment Outcome; D014750:Vincristine / Q000008:administration & dosage
chemical_list: D014408:Biomarkers, Tumor; D003561:Cytarabine; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone; D006854:Hydrocortisone; D008775:Methylprednisolone; D008727:Methotrexate