Lenalidomide plus cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab is safe and effective in untreated, elderly patients with diffuse large B-cell lymphoma: a phase I study by the Fondazione Italiana Linfomi
Annalisa Chiappella,
Alessandra Tucci,
Alessia Castellino,
Vincenzo Pavone,
Ileana Baldi,
Angelo Michele Carella,
Lorella Orsucci,
Manuela Zanni,
Flavia Salvi,
Anna Marina Liberati,
Gianluca Gaidano,
Chiara Bottelli,
Bernardo Rossini,
Sonia Perticone,
Pasqualina De Masi,
Marco Ladetto,
Giovannino Ciccone,
Antonio Palumbo,
Giuseppe Rossi,
Umberto Vitolo
Affiliations
Annalisa Chiappella
Hematology 2, Città della Salute e della Scienza, Hospital and University, Torino, Italy
Alessandra Tucci
Hematology Unit, Spedali Civili Hospital and University, Brescia, Italy
Alessia Castellino
Hematology 2, Città della Salute e della Scienza, Hospital and University, Torino, Italy
Vincenzo Pavone
Hematology and Transfusional Department, Cardinal Panico Hospital, Tricase-Lecce, Italy
Ileana Baldi
Unit of Biostatistics, Epidemiology and Public Health, Department of Cardiac, Thoracic and Vascular Sciences, University of Padova, Genova, Italy
Angelo Michele Carella
Hematology Unit, San Martino Hospital and University, Genova, Italy
Lorella Orsucci
Hematology 2, Città della Salute e della Scienza, Hospital and University, Torino, Italy
Manuela Zanni
Hematology 1 and Molecular Biology, Città della Salute e della Scienza Hospital and University, Torino, Italy
Flavia Salvi
Hematology Unit, SS. Antonio e Biagio e Cesare Arrigo Hospital, Alessandria, Italy
Anna Marina Liberati
Hematology Unit, Santa Maria Hospital, Terni, Italy
Gianluca Gaidano
Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
Chiara Bottelli
Hematology Unit, Spedali Civili Hospital and University, Brescia, Italy
Bernardo Rossini
Hematology and Transfusional Department, Cardinal Panico Hospital, Tricase-Lecce, Italy
Sonia Perticone
Fondazione Italiana Linfomi Secretary, Alessandria, Italy
Pasqualina De Masi
Hematology 2, Città della Salute e della Scienza, Hospital and University, Torino, Italy
Marco Ladetto
Hematology 1 and Molecular Biology, Città della Salute e della Scienza Hospital and University, Torino, Italy
Giovannino Ciccone
Unit of Cancer Epidemiology, University and CPO Piemonte, Torino, Italy
Antonio Palumbo
Hematology 1 and Molecular Biology, Città della Salute e della Scienza Hospital and University, Torino, Italy
Giuseppe Rossi
Hematology Unit, Spedali Civili Hospital and University, Brescia, Italy
Umberto Vitolo
Hematology 2, Città della Salute e della Scienza, Hospital and University, Torino, Italy
Despite improvements in standard therapy with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone for patients with untreated, diffuse large B-cell lymphoma, up to 40% of these patients relapse. Lenalidomide alone or in combination with rituximab has been shown to be active in relapsed/refractory aggressive lymphomas. In this phase I study we determined the maximum tolerated dose of lenalidomide plus rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone in untreated, elderly (median age 68 years) patients with diffuse large B-cell lymphoma. Four lenalidomide doses (5, 10, 15, and 20 mg/day on days 1–14) allocated using the continual reassessment method were planned to be administered for 14 days in combination with each course of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone for a total of six courses. Seven cohorts of patients (n=3 in each cohort) were treated (total n=21) at 10, 20, 15, 15, 15, 10, and 10 mg of lenalidomide. Dose-limiting toxicities occurred in seven patients during the first three courses of treatment. The third dose-level of lenalidomide (15 mg/day) was selected as the maximum tolerated dose, with an estimated probability of dose-limiting toxicities of 0.345 (95% credibility interval 0.164–0.553). Grade 3–4 hematologic adverse events were: neutropenia in 28% of the courses, thrombocytopenia in 9%, and anemia in 3%. Non-hematologic toxicities were moderate: grade 4 increase of creatinine phosphokinase (n=1), grade 3 cardiac (n=2), grade 3 neurological (n=3), and grade 3 gastrointestinal (n=1). In this phase I study, the overall response rate was 90%, with 81% achieving complete remission. This combination regimen appears safe in elderly patients with diffuse large B-cell lymphoma and its efficacy will be assessed in the ongoing phase II trial. This trial was registered at www.clinicaltrials.gov as NCT00907348.
