S147: EFFICACY AND SAFETY RESULTS OF MOLTO, A MULTICENTER, OPEN LABEL, PHASE II CLINICAL TRIAL EVALUATING VENETOCLAX, ATEZOLIZUMAB AND OBINUTUZUMAB COMBINATION IN RICHTER SYNDROME

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Background: Chemoimmunotherapy is the conventional first line treatment of patients with the diffuse large B-cell lymphoma (DLBCL) variant of Richter syndrome (RS). However, the rate and duration of responses are unsatisfactory. The biology of RS (e.g., the high rate of defects of the DNA damage response pathway and the high tumor mutation burden coupled with the expression of the PD1/PDL1 axis) prompts investigation of non-chemo combinations leveraging agents that circumvent TP53 abnormalities and trigger anti-tumor immune response. Aims: MOLTO is a multicenter international phase 2 study (NCT04082897) aimed to evaluate the activity and safety of atezolizumab (humanized monoclonal antibody blocking PD-L1), venetoclax (BCL2 inhibitor) and obinutuzumab (anti-CD20 MoAb) combination in treatment naive patients with DLBCL variant of RS. Methods: Treatment consisted of 35 q21 cycles with obinutuzumab (1000 mg C1-8), atezolizumab (1200 mg C1-18) and venetoclax (400 mg/d C1-35). Primary endpoint was ORR (ORR, the study was considered positive if ORR ≥67% at C6). RS diagnosis was centrally revised. RS mutation profile was tested on pre-treatment cell free DNA. Minimal residual disease (MRD) was tested by both 8 colors flow cytometry and NGS on peripheral blood mononuclear cells and plasma. Results: Overall 28 planned patients were enrolled from Oct 2019 to Oct 2022 (Table 1). Three patients were not evaluable for primary endpoint because of G5 infection (n=1) or early withdrawn (n=2). As per intention-to-treatment ORR was 67.9% (19/28) thus meeting primary endpoint. Complete remission (CR) rate was 28.6% (8/28). None of the clinical characteristics influenced ORR achievement at C6. After a median follow-up of 11.6 months, 11/19 patients (57.9%) are in continuous remission (8 on active therapy, 2 received allogenic transplant, 1 discontinued due to MDS), among them 6 for ≥24 months. Of the remaining 8 patients, 7 progressed after a median of 14 cycles, 1 died from sepsis at C9 in remission. Median duration of response was 11.7 months, median progression free survival (PFS) was 16.2 months and median overall survival (OS) was 31.6 months. Out of the 13 patients who progressed, 4 received a salvage therapy and are alive at a median follow-up of 24.3 months. Bulky disease and ECOG PS >1 affected PFS. The rate of unmeasurable MRD and the impact of mutations and chronic lymphocytic leukemia-RS clonal relation on outcomes will be presented at the meeting. A total of 43 G3-4 adverse events (AE) were recorded in 17 patients (60.7%), mostly hematological (51.2%). Any grade immune-related AEs were reported in 6 patients (G3-4 in 2) and none led to discontinuation. Tumor lysis syndrome was not observed. Infections ≥G3 occurred in 6 patients, including two G5. One patient developed MDS. Summary/Conclusion: Atezolizumab, obinutuzumab and venetoclax combination is active in patients with previously untreated DLBCL-RS. This regimen led to durable remissions, longer than 2 years in one third of responders.Keywords: B cell chronic lymphocytic leukemia, Venetoclax, Obinutuzumab, Transformation

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