Background: Diffuse large B-cell (DLBCL) transformation from chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), Richter Syndrome (RS), has poor prognosis. Venetoclax, Bcl-2 inhibitor, has shown activity either in DLBCL and DLBCL-type RS. Atezolizumab is a humanized immunoglobulin monoclonal antibody (MoAb) targeting PD-L1 on tumor-infiltrating immune cells or tumor cells and prevents interaction with the PD-1 receptor and B7.1. Obinutuzumab, anti CD-20 MoAb compared to rituximab, presents a greater antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis and direct cell death. Preliminary data of atezolizumab alone or in combination with obinutuzumab showed to be safe and promising in heavily pretreated DLBCL. We present a phase II trial evaluating safety and efficacy of venetoclax, atezolizumab, obinutuzumab combination in RS. Methods: Eligible pts are: ≥18 years, ECOG PS ≤2, diagnosis of DLBCL RS from CLL/SLL. Exclusion criteria: pretreated RS, prior therapy with venetoclax or atezolizumab, CNS involvement, history of autoimmune disease. The study consists of 2 phases. In the run-in phase 9 pts will be enrolled in three cohorts of 3 subjects each. If no more than 1 pt in each of the 3 groups experiences during the first 3 cycles: treatment-related death or grade 4 non-infective/non-hematologic adverse event; the expansion phase will follow enrolling up to 31 pts. Treatment consists of 35 cycles with: obinutuzumab (1000 mg C1-8), atezolizumab (1200 mg C1-18), venetoclax (400 mg/d C1-35). Primary endpoint of the study is safety and tolerability for the run-in phase; efficacy (overall response, complete remissions, response duration, progression free and overall survival) for the expansion phase. Safety and efficacy are also secondary endpoints of each phase. Exploratory consists of MRD monitored by flow cytometry and ultra-deep NGS of disease markers; correlation between outcome and disease biomarkers. EUDRACT 2018-005028-40. Clinical trial information: 2018-005028-40.