Results of MOLTO, a multicenter, open label, phase II clinical trial evaluating venetoclax, atezolizumab and obinutuzumab combination in Richter syndrome.
Authors: Frustaci Anna Maria , Montillo Marco , Rossi Davide , Zinzani Pier Luigi , Motta Marina , Gaidano Gianluca , Quaresmini Giulia , Scarfo Lydia , Pietrasanta Daniela , Coscia Marta , Deodato Marina , Zamprogna Giulia , Cairoli Roberto , Stüssi Georg , Zucca Emanuele , Pileri Stefano , Zenz Thorsten , Tedeschi Alessandra 
Published: June 2023

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Background: Chemoimmunotherapy is the standard first line of patients (pts) with diffuse large B-cell lymphoma (DLBCL) variant of Richter syndrome (RS). Response rate and duration are unsatisfactory. The biology of RS (high rate of DNA damage response pathway defects, 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. MOLTO is a multicenter international ph 2 study (NCT04082897) evaluating activity and safety of atezolizumab (humanized monoclonal antibody blocking PD-L1), venetoclax (BCL2 inhibitor) and obinutuzumab (anti-CD20 MoAb) combination in untreated DLBCL-RS. Methods: Treatment consisted of 35 cycles with obinutuzumab (1000 mg C1-8), atezolizumab (1200 mg C1-18) and venetoclax (400 mg/d C1-35), q21. Primary endpoint was 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 12 colors flow cytometry and NGS on peripheral blood mononuclear cells and plasma. Results: 28 planned pts were enrolled from Oct 2019 to Oct 2022 (Table). Three were not evaluable for primary endpoint due to G5 infection (n=1) or early withdrawn (n=2). As per intention-to-treat ORR was 67.9% (19/28) thus meeting primary endpoint. CR rate was 28.6%. No clinical characteristics influenced C6-ORR. After a median follow-up of 11.6 mo, 11/19 pts (57.9%) are in continuous remission (8 on active therapy, 2 received allogenic transplant, 1 discontinued due to MDS) among them, 6 for ≥24 mo. Of the remaining 8 pts, 7 progressed after a median of 14 cycles, 1 died from sepsis at C9 in remission. Median duration of response, PFS and OS were 11.7, 16.2 and 31.6 mo, respectively. Out of the 13 patients who progressed, 4 received a salvage therapy and are alive at a median follow-up of 24.3 mo. Bulky disease and ECOG PS >1 affected PFS. Rate of unmeasurable MRD, impact of mutations and chronic lymphocytic leukemia-RS clonal relation on outcomes will be presented at the meeting. Overall 43 G3-4 adverse events (AE) were recorded in 17 pts (60.7%), mostly hematological (51.2%). Any grade immune-related AEs were reported in 6 pts (G3-4 in 2), none led to discontinuation. No tumor lysis syndrome observed. Infections ≥G3 occurred in 6 pts, including 2 G5. One pt developed MDS. Conclusions: Atezolizumab, obinutuzumab and venetoclax combination is active in pts with untreated DLBCL-RS. This regimen led to durable remissions, longer than 2 yrs in one third of responders. Clinical trial information: NCT04082897 . [Table: see text]