Background: Lenalidomide is an immunomodulatory drug that could reverse rituximab refractoriness in lymphoma patients (pts). We conducted an open label multicenter phase 2 trial testing the efficacy and toxicity of a combination of lenalidomide and rituximab (R2) plus GDP schedule (R2-GDP) in Relapsed/Refractory Diffuse Large B Cell Lymphoma (R/R DLBCL) pts, not suitable for autologous stem cell transplant (ASCT). Methods: Patients with R/R DLBCL previously treated with at least 1 prior line of immunochemotherapy including rituximab, and not candidates for ASCT, were eligible. After a run-in phase period, treatment consisted of an induction phase with lenalidomide (LEN) 10 mg po d1-14, rituximab 375 mg/m2 iv d1, cisplatin 60 mg/m2 iv d1, gemcitabine 750 mg/m2 iv d1 and d8 and dexamethasone 20 mg d1-3, up to a maximum of 6 cycles. Pts without disease progression (DP) entered into a maintenance phase with LEN 10 mg, or last LEN dose received in the induction phase, d1-21 in cycles every 28 days. Primary endpoint was overall response rate (ORR) by investigator assessment. Secondary endpoints included disease free survival (DFS), event free survival (EFS), overall survival (OS), safety and response by cell of origin (COO), type of DLBCL (double-triple hit) and other microenvironment and genomic biomarkers. Results: 79 pts were enrolled between April 2015 and September 2018. Median age was 70 years (range 23-86), 48,7% women. 78 pts were considered for efficacy and safety in the intention to treat (ITT) analysis. With a median follow-up of 13 months at the time of cut-off (November 2019), ORRwas 59.0%, with 32.1% complete responses (CR) and 26.9% partial responses (PR). In the primary refractory population (n = 33), ORR was 45.5%, with 21.2% CR and 24.3% PR. There were no statistically significant differences in ORR with respect to COO. In Double-Hit R/R DLBCL (n = 16), ORR was 37.5% with 25% CR. Median OS was 12.0 months (6.9-17.0). Most common grade 3/4 (G3/4) adverse events were thrombocytopenia (60.2%), neutropenia (60.2%) and anemia (26.9%). Febrile neutropenia occurred in 14.1% pts. Most frequent non-hematologic G3/4 events were asthenia (19.2%), infection (15.3%) and renal insufficiency (6.4%). There were 4 toxic deaths related to the R2-GDP schedule. Conclusions: LEN with Rituximab and GDP (R2-GDP) is feasible and active in R/R DLBCL. Results in the primary refractory DLBCL population are particularly promising. Analysis of COO did not revealed differences in response rates. Immune biomarkers results will be showed at the meeting. Clinical trial information: EudraCT 2014-001620-29.