Lenalidomide in combination with <scp>R‐ESHAP</scp> in patients with relapsed or refractory diffuse large <scp>B</scp>‐cell lymphoma: A phase 2 study from the Spanish group <scp>GELTAMO</scp> (2017)

Introduction: Diffuse large B-cell lymphoma (DLBCL) patients with relapsed or refractory disease after rituximab-containing therapy have poor outcomes with current salvage regimens. We conducted a phase 1b/2 trial to analyze the safety and efficacy of adding lenalidomide to R-ESHAP regimen (LR-ESHAP). The phase 1b part of the trial has been completed, and lenalidomide 10 mg/day was identified as the maximum tolerated dose (Br J Haematol 2016; 173: 245-52). Here we present the preliminary results of the phase 2 part (ClinicalTrials.gov Identifier: NCT02340936). Methods: Eligible patients must have relapsed or refractory DLBCL after first-line treatment with rituximab combined with an anthracycline-containing regimen. Subjects received 3 cycles of lenalidomide 10 mg given on days 1 to 14 of every 21-day cycle, in combination with R-ESHAP at standard doses. Responding patients received BEAM conditioning followed by autologous stem-cell transplantation (ASCT). The primary end point was overall response rate (ORR) after 3 cycles of therapy. Secondary end points were complete remission (CR) rate, stem-cell mobilization activity, progression-free survival (PFS), overall survival (OS), and toxicity. Results: A total of 46 patients (median age 58 [23-69] years, 56.5% male) were included (January 2012-November 2015). Evaluable population per-protocol consisted of 44 patients. Forty-two serious adverse events were reported during 128 cycles of LR-ESHAP, including 14 episodes of febrile neutropenia (11%), 12 infections (9%), 2 renal disorders, 3 cardiac disorders, 3 thrombosis, and 8 other toxicities, all of them recovered except 1 case of colon adenocarcinoma. There were no treatment-related deaths. Forty out of 44 patients (91%) received the planned 3 cycles of treatment (2 without lenalidomide in the third cycle). ORR to LR-ESHAP was 68% (41% CR). Patients with relapsed disease had significantly better ORR and CR rates (87% and 67%, respectively) than patients in PR after first-line (77% and 31%) or with primary refractory disease (<PR) (37% and 25%) (p = 0.004 and 0.02, respectively). Evaluation of response according to cell of origin (COO) is ongoing. So far, 30 and 21 patients, respectively, have been analyzed according to Hans' algorithm (ORR of 62% and 44% in germinal-center B-cell-like [GCB] [n = 21] and non-GCB [n = 9] groups, respectively, p > 0.1) and gene expression profiling (ORR of 71%, and 75% in GCB [n = 14], and activated B-cell-like [ABC] [n = 4] groups, respectively, p > 0.1). Thirty-nine out of 42 patients (93%) were successfully mobilized after one (n = 32) or 2 (n = 7) mobilization procedures, and 28 (64% of evaluable patients) underwent ASCT according to protocol, one of them after bone-marrow harvest. With a median follow-up of 15 months (11-53), the estimated 2-year PFS and OS were 54% and 52%, respectively. Conclusions: LR-ESHAP is safe, feasible, and associated with high-response rates in rituximab-pretreated relapsed or refractory DLBCL patients. Efficacy analysis according to COO and other biological factors is ongoing. Keywords: diffuse large B-cell lymphoma (DLBCL); lenalidomide; salvage treatment