Frédéric Peyrade1, Serge Bologna2, Vincent Delwail3, Jean François Emile4, Laurent Pascal5, Christophe Fermé6, Jean-Marc Schiano7, Bertrand Coiffier8, Bernadette Corront9, Hassan Farhat10, Christophe Fruchart11, Herve Ghesquieres12, Margaret Macro13, Hervé Tilly14, Bachra Choufi15, Richard Delarue16, Olivier Fitoussi17, Jean Gabarre18, Corinne Haioun19, Fabrice Jardin14. 1. Centre Antoine Lacassagne, Nice, France. Electronic address: frederic.peyrade@nice.unicancer.fr. 2. Centre Hospitalier Nancy-Brabois, Vandoeuvre, France. 3. Hematology, University Hospital, Poitiers, France. 4. Pathology Department, Hôpital Ambroise Paré, Boulogne, France. 5. Hôpital Saint-Vincent de Paul, Lille, France. 6. Institut Gustave Roussy, Villejuif, France. 7. Institut Paoli Calmettes, Marseille, France. 8. Hematology Department, Centre Hospitalier Lyon-Sud, Pierre-Benite Cedex, France. 9. Hematology, General Hospital, Annecy, France. 10. Hematology, Hôpital de Versailles, Le Chesnay, France. 11. Hematology Department, François Baclesse Cancer Center, Caen, France. 12. Onco-Hematology, Centre Léon Bérard, Lyon, France. 13. Hematology, Hôpital Côte de Nacre, CHU, Caen, France. 14. Hematology Unit, Centre Henri Becquerel, Rouen, France. 15. Centre Hospitalier de Boulogne, Boulogne, France. 16. Hematology Unit, AP-HP, Hôpital Necker, Paris, France. 17. Polyclinique Bordeaux Aquitaine, Bordeaux, France. 18. Hematology, Hôpital Pitié-Salpêtrière, Paris, France. 19. Hematology, Hôpital Henri Mondor, Créteil Cedex, France.
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/m2 of intravenous doxorubicin, 400 mg/m2 of intravenous cyclophosphamide, and 1 mg of intravenous vincristine, on day 1 of each cycle; and 40 mg/m2 of 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: The Lymphoma Study Association, GlaxoSmithKline.
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/m2 of intravenous doxorubicin, 400 mg/m2 of intravenous cyclophosphamide, and 1 mg of intravenous vincristine, on day 1 of each cycle; and 40 mg/m2 of 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: The Lymphoma Study Association, GlaxoSmithKline.
Authors: Stephen Booth; Hannah Plaschkes; Amy A Kirkwood; Adam Gibb; Patrick Horgan; Claire Higham; Joanna M Oladipo; Joe Browning; Usman Khan; Bing Tseu; Lucia Chen; John Willan; Julia Wolf; Arief Gunawan; Paul Fields; Tim Ebsworth; Robert Lown; Dominic Gordon-Walker; Nimish Shah; Kim M Linton; Graham P Collins; Jaimal Kothari; Catherine Hildyard; Toby A Eyre Journal: Blood Adv Date: 2020-09-22
Authors: Toby A Eyre; William Wilson; Amy A Kirkwood; Julia Wolf; Catherine Hildyard; Hannah Plaschkes; John Griffith; Paul Fields; Arief Gunawan; Rebecca Oliver; Stephen Booth; Jaimal Kothari; Christopher P Fox; Nicolas Martinez-Calle; Andrew McMillan; Mark Bishton; Graham P Collins; Chris S R Hatton Journal: Blood Adv Date: 2021-04-27