title: Combination of ofatumumab and reduced-dose CHOP for diffuse large B-cell lymphomas in patients aged 80 years or older: an open-label, multicentre, single-arm, phase 2 trial from the LYSA group.
abstract: BACKGROUND
  In 2011 we reported a rituximab plus miniCHOP (reduced-dose cyclophosphamide, doxorubicin, vincristine, and prednisone) combination for patients older than 80 years with diffuse large B-cell lymphoma (DLBCL). The 2-year overall survival was 59% (95% CI 49-67) with an excess of early toxicity. To improve those results we tested the same chemotherapy protocol in combination with ofatumumab and a pre-phase treatment.
  
  
  METHODS
  For this open-label, multicentre, single-group, phase 2 trial, we recruited patients older than 80 years with untreated histologically-proven CD20-positive DLBCL, Ann Arbor stage I to IV, from 41 academic and hospital centres in France and Belgium. Patients received a pre-phase with oral vincristine (1 mg total dose 1 week before cycle 1 [day -7]) and oral prednisone (60 mg total dose starting 1 week before cycle 1, for 4 days [day -7 to day -4]) before the first cycle of the ofatumumab plus miniCHOP regimen. The regimen consisted of 1000 mg total dose of intravenous ofatumumab, 25 mg/m2of intravenous doxorubicin, 400 mg/m2of intravenous cyclophosphamide, and 1 mg of intravenous vincristine, on day 1 of each cycle; and 40 mg/m2of oral prednisone on days 1-5. Ofatumumab was administered with 1000 mg of paracetamol and 50 mg of diphenhydramine. The primary endpoint was overall survival in the intention-to-treat population. The statistical analysis has been done on an intention-to-treat principle. This study was registered with ClinicalTrials.gov, number NCT01195714.
  
  
  RESULTS
  Between June 2, 2010, and Nov 4, 2011, we enrolled 120 patients. Age-adjusted International Prognostic Index was 2-3 in 68 (57%) of them. The median follow-up time was 26·8 months (IQR 24·5-30·1). The 2-year overall survival was 64·7% (95% CI 55·3-72·7) and median overall survival was not reached (95% CI 30·2-not reached). 45 patients died during the treatment, of whom 28 (62%) died due to lymphoma. The most common side-effect was haematological toxicity. Among the 120 patients, grade 3-4 neutropenia was reported in 24 (21%) patients and thrombocytopenia in two (2%), during the treatment period. Grade 3-4 anaemia was reported in six (5%) patients; seven (6%) patients had one episode of febrile neutropenia. 17 (15%) of 115 patients in the modified intention-to-treat population had red blood cell transfusions and three (3%) had platelet transfusions.
  
  
  CONCLUSIONS
  Our result suggest that, in patients older than 80 years with DLBCL, ofatumumab and pre-phase treatment seem to improve overall survival compared with the previously reported data. The combination of pre-phase treatment, a monoclonal antibody against CD20, and miniCHOP can be considered a new treatment platform for use in randomised clinical trial design for DLBCL treatment in patients older than 80 years.
  
  
  BACKGROUND
  The Lymphoma Study Association, GlaxoSmithKline.
authors.affiliation: Centre Antoine Lacassagne, Nice, France. Electronic address: frederic.peyrade@nice.unicancer.fr.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Peyrade
authors.affiliation: Centre Hospitalier Nancy-Brabois, Vandoeuvre, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Bologna
authors.affiliation: Hematology, University Hospital, Poitiers, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Delwail
authors.affiliation: Pathology Department, Hôpital Ambroise Paré, Boulogne, France.
authors.forename: Jean François
authors.initials: JF
authors.lastname: Emile
authors.affiliation: Hôpital Saint-Vincent de Paul, Lille, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Pascal
authors.affiliation: Institut Gustave Roussy, Villejuif, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Fermé
authors.affiliation: Institut Paoli Calmettes, Marseille, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Schiano
authors.affiliation: Hematology Department, Centre Hospitalier Lyon-Sud, Pierre-Benite Cedex, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Coiffier
authors.affiliation: Hematology, General Hospital, Annecy, France.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Corront
authors.affiliation: Hematology, Hôpital de Versailles, Le Chesnay, France.
authors.forename: Hassan
authors.initials: H
authors.lastname: Farhat
authors.affiliation: Hematology Department, François Baclesse Cancer Center, Caen, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Fruchart
authors.affiliation: Onco-Hematology, Centre Léon Bérard, Lyon, France.
authors.forename: Herve
authors.initials: H
authors.lastname: Ghesquieres
authors.affiliation: Hematology, Hôpital Côte de Nacre, CHU, Caen, France.
authors.forename: Margaret
authors.initials: M
authors.lastname: Macro
authors.affiliation: Hematology Unit, Centre Henri Becquerel, Rouen, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Tilly
authors.affiliation: Centre Hospitalier de Boulogne, Boulogne, France.
authors.forename: Bachra
authors.initials: B
authors.lastname: Choufi
authors.affiliation: Hematology Unit, AP-HP, Hôpital Necker, Paris, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Delarue
authors.affiliation: Polyclinique Bordeaux Aquitaine, Bordeaux, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Fitoussi
authors.affiliation: Hematology, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Gabarre
authors.affiliation: Hematology, Hôpital Henri Mondor, Créteil Cedex, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Haioun
authors.affiliation: Hematology Unit, Centre Henri Becquerel, Rouen, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Jardin
mesh_terms: D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D005260:Female; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy*; D008297:Male; D011241:Prednisone / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000037:antagonists & inhibitors; D016896:Treatment Outcome; D014750:Vincristine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; C497867:CD22 protein, human; D051918:Sialic Acid Binding Ig-like Lectin 2; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; C527517:ofatumumab; D011241:Prednisone