Lenalidomide plus R-CHOP21 in elderly patients with untreated diffuse large B-cell lymphoma: results of the REAL07 open-label, multicentre, phase 2 trial.
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.


RESULTS
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.


CONCLUSIONS
Lenalidomide with R-CHOP21 is effective and safe in elderly patients with untreated DLBCL.


BACKGROUND
Fondazione Italiana Linfomi and Celgene.
Hematology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy. Electronic address: uvitolo@cittadellasalute.to.it.
Umberto
U
Vitolo
Hematology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy.
Annalisa
A
Chiappella
Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Azienda Ospedaliero-Universitaria Maggiore della Carità, Novara, Italy.
Silvia
S
Franceschetti
Unit of Hematology 1, Istituto di Ricovero e Cura a Carattere Scientifico Hospital and University, Istituto dei Tumori San Martino, Genoa, Italy.
Angelo Michele
AM
Carella
Unit of Biostatistics, Epidemiology and Public Health, Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy.
Ileana
I
Baldi
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.
Giorgio
G
Inghirami
Division of Medical Oncology A, Centro di Riferimento Oncologico Aviano National Cancer Institute, Aviano, Italy.
Michele
M
Spina
Unit of Hematology and Hemopoietic Stem Cell Transplantation, Ospedale Cardinale G Panico, Tricase, Italy.
Vincenzo
V
Pavone
Department of Molecular Biotechnologies and Health Sciences, University of Turin, Turin, Italy.
Marco
M
Ladetto
Università degli studi di Perugia, Azienda Ospedaliera Santa Maria, Terni, Italy.
Anna Marina
AM
Liberati
Department of Oncology and Hematology, Infermi Hospital, Rimini, Italy.
Anna Lia
AL
Molinari
Institute of Hematology Lorenzo ed Ariosto Seràgnoli, University of Bologna, Bologna, Italy.
Pierluigi
P
Zinzani
Hematology Unit, S S Antonio e Biagio e Cesare Arrigo Hospital, Alessandria, Italy.
Flavia
F
Salvi
Istituto Scientifico Romagnolo per lo studio e la Cura dei Tumori, Istituti di Ricovero e Cura a Carattere Scientifico, Meldola, Italy.
Pier Paolo
PP
Fattori
Hematology Unit, Department of Oncology and Hematology, Santa Maria delle Croci Hospital, Ravenna, Italy.
Alfonso
A
Zaccaria
Medizinische Klinik und Poliklinik III, Klinikum der Universität München, Munich, Germany.
Martin
M
Dreyling
Hematology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy.
Barbara
B
Botto
Hematology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy.
Alessia
A
Castellino
Unit of Hematology 1, Istituto di Ricovero e Cura a Carattere Scientifico Hospital and University, Istituto dei Tumori San Martino, Genoa, Italy.
Angela
A
Congiu
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.
Marcello
M
Gaudiano
Department of Molecular Biotechnologies and Health Sciences, University of Turin, Turin, Italy.
Manuela
M
Zanni
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.
Giovannino
G
Ciccone
Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Azienda Ospedaliero-Universitaria Maggiore della Carità, Novara, Italy.
Gianluca
G
Gaidano
Struttura Complessa Ematologia e Dipartimento Oncologia Medica, Spedali Civili, Brescia, Italy.
Giuseppe
G
Rossi
D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006801:Humans; D000077269:Lenalidomide; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011241:Prednisone / Q000008:administration & dosage / Q000009:adverse effects; D000069283:Rituximab; D013792:Thalidomide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D014750:Vincristine / Q000008:administration & dosage / Q000009:adverse effects
D058846:Antibodies, Monoclonal, Murine-Derived; C571759:R-CHOP protocol; D000069283:Rituximab; D013792:Thalidomide; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D000077269:Lenalidomide; D011241:Prednisone