Umberto Vitolo1, Annalisa Chiappella2, Silvia Franceschetti3, Angelo Michele Carella4, Ileana Baldi5, Giorgio Inghirami6, Michele Spina7, Vincenzo Pavone8, Marco Ladetto9, Anna Marina Liberati10, Anna Lia Molinari11, Pierluigi Zinzani12, Flavia Salvi13, Pier Paolo Fattori14, Alfonso Zaccaria15, Martin Dreyling16, Barbara Botto2, Alessia Castellino2, Angela Congiu4, Marcello Gaudiano6, Manuela Zanni9, Giovannino Ciccone17, Gianluca Gaidano3, Giuseppe Rossi18. 1. Hematology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy. Electronic address: uvitolo@cittadellasalute.to.it. 2. Hematology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy. 3. Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Azienda Ospedaliero-Universitaria Maggiore della Carità, Novara, Italy. 4. Unit of Hematology 1, Istituto di Ricovero e Cura a Carattere Scientifico Hospital and University, Istituto dei Tumori San Martino, Genoa, Italy. 5. Unit of Biostatistics, Epidemiology and Public Health, Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy. 6. Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies, University of Turin, Turin, Italy; Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA. 7. Division of Medical Oncology A, Centro di Riferimento Oncologico Aviano National Cancer Institute, Aviano, Italy. 8. Unit of Hematology and Hemopoietic Stem Cell Transplantation, Ospedale Cardinale G Panico, Tricase, Italy. 9. Department of Molecular Biotechnologies and Health Sciences, University of Turin, Turin, Italy. 10. Università degli studi di Perugia, Azienda Ospedaliera Santa Maria, Terni, Italy. 11. Department of Oncology and Hematology, Infermi Hospital, Rimini, Italy. 12. Institute of Hematology Lorenzo ed Ariosto Seràgnoli, University of Bologna, Bologna, Italy. 13. Hematology Unit, S S Antonio e Biagio e Cesare Arrigo Hospital, Alessandria, Italy. 14. Istituto Scientifico Romagnolo per lo studio e la Cura dei Tumori, Istituti di Ricovero e Cura a Carattere Scientifico, Meldola, Italy. 15. Hematology Unit, Department of Oncology and Hematology, Santa Maria delle Croci Hospital, Ravenna, Italy. 16. Medizinische Klinik und Poliklinik III, Klinikum der Universität München, Munich, Germany. 17. Unit of Clinical Epidemiology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino and Centro di Riferimento per l'Epidemiologia e la Prevenzione Oncologica in Piemonte, Turin, Italy. 18. Struttura Complessa Ematologia e Dipartimento Oncologia Medica, Spedali Civili, Brescia, Italy.
Abstract
BACKGROUND: Up to 40% of elderly patients with untreated diffuse large B-cell lymphoma (DLBCL) given a regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone every 21 days (R-CHOP21) relapse or develop refractory disease. Lenalidomide has high activity in relapsed or refractory aggressive B-cell lymphomas. In phase 2 of the REAL07 trial, we aimed to establish the safety and efficacy of the combination of lenalidomide and R-CHOP21 in elderly patients with untreated DLBCL. METHODS: REAL07 was an open-label, multicentre trial that was done in 13 centres in Italy and one in Germany. Eligible patients were aged 60-80 years; had newly diagnosed, untreated, CD20-positive, Ann Arbor stage II-IV DLBCL or grade 3b follicular lymphoma; had an Eastern Cooperative Oncology Group performance status of 0-2; had an International Prognostic Index (IPI) risk of low-intermediate, intermediate-high, or high; and were fit according to comprehensive geriatric assessment. Participants were to receive 15 mg oral lenalidomide on days 1-14 of six 21-day cycles, and standard doses of R-CHOP21 chemotherapy (375 mg/m(2) intravenous rituximab, 750 mg/m(2) intravenous cyclophosphamide, 50 mg/m(2) intravenous doxorubicin, and 1·4 mg/m(2) intravenous vincristine on day 1, and 40 mg/m(2) oral prednisone on days 1-5). The primary endpoint was frequency of overall response (complete response [CR] and partial response [PR]), which was assessed by (18)F-fluorodeoxyglucose ((18)F-FDG) PET at the end of the treatment. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00907348. FINDINGS: 49 patients were included in phase 2: nine had been enrolled into phase 1 between Oct 23, 2008, and June 4, 2009, and had received the maximum tolerated dose of 15 mg lenalidomide; and 40 were enrolled into phase 2 between April 28, 2010, and June 3, 2011. 45 patients (92%, 95% CI 81-97) achieved a response (42 [86%] CR; three [6%] PR). Three patients (6%) did not respond and one (2%) died for reasons unrelated to treatment or disease. 277 (94%) of 294 planned cycles of lenalidomide and R-CHOP21 were completed. Grade 3-4 neutropenia was reported in 87 cycles (31%), grade 3-4 leukopenia in 77 (28%), and grade 3-4 thrombocytopenia in 35 (13%). No grade 4 non-haematological adverse events were reported. No patients died during the study as a result of toxic effects. INTERPRETATION: Lenalidomide with R-CHOP21 is effective and safe in elderly patients with untreated DLBCL. FUNDING: Fondazione Italiana Linfomi and Celgene.
BACKGROUND: Up to 40% of elderly patients with untreated diffuse large B-cell lymphoma (DLBCL) given a regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone every 21 days (R-CHOP21) relapse or develop refractory disease. Lenalidomide has high activity in relapsed or refractory aggressive B-cell lymphomas. In phase 2 of the REAL07 trial, we aimed to establish the safety and efficacy of the combination of lenalidomide and R-CHOP21 in elderly patients with untreated DLBCL. METHODS: REAL07 was an open-label, multicentre trial that was done in 13 centres in Italy and one in Germany. Eligible patients were aged 60-80 years; had newly diagnosed, untreated, CD20-positive, Ann Arbor stage II-IV DLBCL or grade 3b follicular lymphoma; had an Eastern Cooperative Oncology Group performance status of 0-2; had an International Prognostic Index (IPI) risk of low-intermediate, intermediate-high, or high; and were fit according to comprehensive geriatric assessment. Participants were to receive 15 mg oral lenalidomide on days 1-14 of six 21-day cycles, and standard doses of R-CHOP21 chemotherapy (375 mg/m(2) intravenous rituximab, 750 mg/m(2) intravenous cyclophosphamide, 50 mg/m(2) intravenous doxorubicin, and 1·4 mg/m(2) intravenous vincristine on day 1, and 40 mg/m(2) oral prednisone on days 1-5). The primary endpoint was frequency of overall response (complete response [CR] and partial response [PR]), which was assessed by (18)F-fluorodeoxyglucose ((18)F-FDG) PET at the end of the treatment. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00907348. FINDINGS: 49 patients were included in phase 2: nine had been enrolled into phase 1 between Oct 23, 2008, and June 4, 2009, and had received the maximum tolerated dose of 15 mg lenalidomide; and 40 were enrolled into phase 2 between April 28, 2010, and June 3, 2011. 45 patients (92%, 95% CI 81-97) achieved a response (42 [86%] CR; three [6%] PR). Three patients (6%) did not respond and one (2%) died for reasons unrelated to treatment or disease. 277 (94%) of 294 planned cycles of lenalidomide and R-CHOP21 were completed. Grade 3-4 neutropenia was reported in 87 cycles (31%), grade 3-4 leukopenia in 77 (28%), and grade 3-4 thrombocytopenia in 35 (13%). No grade 4 non-haematological adverse events were reported. No patients died during the study as a result of toxic effects. INTERPRETATION:Lenalidomide with R-CHOP21 is effective and safe in elderly patients with untreated DLBCL. FUNDING: Fondazione Italiana Linfomi and Celgene.
Authors: Grzegorz S Nowakowski; Annalisa Chiappella; Thomas E Witzig; David W Scott; Michele Spina; Randy D Gascoyne; Lei Zhang; Jacqueline Russo; Janet Kang; Jingshan Zhang; Yingyong Xu; Umberto Vitolo Journal: Haematologica Date: 2020-01-31 Impact factor: 9.941
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