Initial results of a multicenter phase 2 study of venetoclax in combination with R‐CHOP (VR‐CHOP) for patients with Richter Syndrome

Abstract

Introduction: We previously reported promising efficacy for venetoclax (V) plus da-R-EPOCH (VR-EPOCH) for 26 patients (pts) with CLL who developed Richter Syndrome (RS), with a CR rate of 50% and median OS of 19.6 mo.; however, hematologic and infectious complications were common (Davids et al., Blood, 2022). We hypothesized that de-intensifying the chemoimmunotherapy backbone while keeping the venetoclax could potentially preserve efficacy while mitigating the toxicities observed with this approach. Here, we report for the first time on an ongoing study of VR-CHOP in RS. Methods: This is a single-arm, phase 2, investigator sponsored trial of VR-CHOP for RS (NCT03054896) open at 3 US sites. We treated pts with CLL and biopsy-confirmed DLBCL with R-CHOP for 1 cycle, then after count recovery with accelerated inpatient daily V ramp-up (20/50/100/200/400 mg), then VR-CHOP outpatient for up to 5 additional 21d cycles (V 400 mg qd, d1–10 of each cycle) with mandatory G-CSF support. Responders could then receive daily V 400 mg qd maintenance in 28d cycles or elect to come off study for alloHCT. Response was by Lugano criteria with PET/CT, toxicity by CTCAE v4.03. Results: As of 24 Feb 2023, 27 pts have started study treatment. Median age: 72 yrs (range 42–80), 37% had del(17p) or TP53 mut, 26% had NOTCH1 mut. Median # prior CLL treatments was 1 (range 1–9), including 44% post-BTKi and 17% post-V; 4 pts (15%) had prior treatment for RS. Median # of VR-CHOP cycles to date in this ongoing study is 4 (range 1–6). ≥Gr 3 heme toxicity included: neutropenia (36%), anemia (32%), thrombocytopenia (40%). Additional ≥Gr 3 toxicities in ≥10% of pts included: febrile neutropenia (32%) and peripheral neuropathy (12%). No TLS occurred with daily V ramp-up after 1 cycle of R-CHOP. Two pts on active treatment have not yet reached the first response eval. In the remaining 25 pts, ORR: 68% (17/25), CR: 48% (12/25). 7 pts have died: 4 due to PD (including 2 prior to starting V) and 3 due to infection (n = 2 sepsis, n = 1 COVID-19). 8 pts with initial CLL marrow involvement had re-staging marrows, and 88% (7/8) were uMRD for CLL by flow at 10–4. 7 pts in remission electively went to alloHCT. With a median follow-up of 6.1 mo (range 0.1–21.4), median PFS is 7.2 mo (Figure A), median OS is 19.5 mo (Figure B). The research was funded by: Genentech Keywords: Chemotherapy, Chronic Lymphocytic Leukemia (CLL), Combination Therapies Conflicts of interests pertinent to the abstract. M. S. Davids Consultant or advisory role: AbbVie, Adaptive Biotechnologies, Ascentage Pharma, AstraZeneca, BeiGene, Bristol-Myers Squibb, Eli Lilly, Genentech, Genmab, Janssen, Merck, Mingsight Pharmaceuticals, Ono Pharmaceuticals, Secura Bio, Takeda, and TG Therapeutics Honoraria: Aptitude Health, AXIS Medical Education, BioAscend, Curio Science, Medscape Education, PeerView Institute for Medical Education, Physician’s Education Resource, PlatformQ Health Education, Plexus Communications, and Research to Practice Research funding: AbbVie, Ascentage Pharma, AstraZeneca, Genentech, Novartis, Secura Bio, and TG Therapeutics K. A. Rogers Consultant or advisory role: AbbVie, AstraZeneca, Genentech, Pharmacyclics, Janssen, Beigene, LOXO/Lilly Honoraria: AstraZeneca, Janssen Research funding: Genentech, AbbVie, Janssen, and Novartis Educational grants: AstraZeneca N. Jain Consultant or advisory role: Pharmacyclics, Janssen, AbbVie, Genentech, AstraZeneca, BMS, Adaptive Biotechnologies, Kite/Gilead, Precision Biosciences, Beigene, Cellectis, MEI Pharma, Ipsen, CareDX, MingSight, Novalgen Research funding: Pharmacyclics, AbbVie, Genentech, AstraZeneca, BMS, Pfizer, ADC Therapeutics, Cellectis, Adaptive Biotechnologies, Precision Biosciences, Fate Therapeutics, Kite/Gilead, Mingsight, Takeda, Medisix, Loxo Oncology, Novalgen, Dialectic Therapeutics, Newave, TransThera Sciences, Novartis, Carna Biosciences, Sana Biotechnology, Kisoji Biotechnology J. R. Brown Consultant or advisory role: Abbvie, Acerta/Astra-Zeneca, BeiGene, Genentech/Roche, Grifols Worldwide Operations, Hutchmed, iOnctura, Janssen, Kite, Loxo/Lilly, MEI Pharma, Numab Therapeutics, Pfizer, Pharmacyclics Research funding: BeiGene, Gilead, iOnctura, Loxo/Lilly, MEI Pharma, TG Therapeutics P. A. Thompson Consultant or advisory role: Janssen, AbbVie, Adaptive Biotechnologies, Beigene, Lilly, Genentech Research funding: AbbVie, Pharmacyclics, Lilly and Adaptive Biotechnologies