MURANO: Final 7 Year Follow Up and Retreatment Analysis in Venetoclax‐rituximab (venr)‐treated Patients with Relapsed/refractory Chronic Lymphocytic Leukemia (R/R CLL)

Introduction: Fixed-duration (FD) VenR treatment (tx) in patients (pts) with R/R CLL in the Phase 3 MURANO trial (NCT02005471) resulted in superior progression-free survival (PFS) and overall survival (OS), versus bendamustine (B)R. This was sustained at 5 years (y) median (m) follow up (FU): PFS, 53.6 months [mo] with VenR versus 17.0 mo with BR; 5 y OS rates, 82.1% with VenR versus 62.2% with BR; p < 0.0001 for both. We report the final analyses of MURANO at 7 y mFU: specifically, updated PFS and OS, with minimal residual disease (MRD) evaluation, in pts treated in the main study, and in VenR-retreated pts in the substudy. Methods: Pts with R/R CLL were randomized to VenR (Ven 400 mg daily for 2 y + monthly R for the first 6 mo) or BR (6 mo). In the substudy (2018 onwards), pts with progressive disease (PD) received VenR (to the main study regimen) as re-tx or as crossover from BR. PFS was investigator assessed. Peripheral blood MRD was measured centrally by ASO-PCR and/or flow cytometry. Undetectable (u)MRD was defined as <10–4. Results: Baseline characteristics are shown in the Table. At the final data cut (3 August 2022), mPFS (95% confidence interval [CI]) in VenR-treated pts (n = 194) was 54.7 mo (52.3, 59.9) versus 17.0 mo (15.5, 21.7) in BR-treated pts (n = 195; hazard ratio [HR] 0.25). Seven y PFS rates (95% CI) were 23.0% (16.1, 29.9) with VenR (no BR-treated pts were progression free at this time point); 7 y OS rates (95% CI) were 69.6% (62.8, 76.5) with VenR and 51.0% (43.3, 58.7) with BR (HR 0.53). M time to next tx with VenR was 63.0 mo versus 24.0 mo with BR (HR 0.30); 37.1% of VenR-treated pts have not had further anti-CLL tx. Among VenR-treated pts who had uMRD at end of tx (EOT) without PD (n = 83/118; 70.3%), mPFS (95% CI) from EOT was 52.5 mo (44.5, 61.5) versus 18.0 mo (8.5, 29.3; p < 0.0001) in pts who were MRD+ at EOT (n = 35; 29.7%). At 7 y FU, 14 (16.9%) pts had no PD nor confirmed MRD conversion; in the 63 (75.9%) pts with MRD conversion, m time to conversion (95% CI) was 19.4 mo (8.7, 28.0). Among 63 pts who converted, 39 subsequently had PD or died; m time from conversion to PD (95% CI) was 28.3 mo (23.2, 35.0). In the substudy (n = 34), 25 pts received VenR re-tx (Table), 92.0% of whom had ≥1 of the following high-risk features: IGHV-unmutated disease, genomic complexity, del(17p) and/or TP53 mutations; despite this, 14/25 (56.0%) achieved uMRD at EOT in the main study. Best overall response rate (ORR) to re-tx was 72.0% and mPFS (95% CI) was 23.3 mo (15.6, 24.3). M (range) time from the last Ven dose in the main study to Ven ramp-up in the substudy was 2.3 y (1.2–3.1). Eight (32.0%) pts achieved uMRD at the re-tx end of combination tx, but no pts retained uMRD at the re-tx EOT. No new safety findings were observed. Conclusions: PFS and OS benefits for VenR versus BR were sustained and uMRD was associated with prolonged PFS. In the high risk VenR-retreated pts, ORR was high and uMRD was attainable. These data support FD VenR in R/R CLL, and suggest that VenR re-tx is a viable option for pre-treated pts. Encore Abstract - previously submitted to EHA 2023 The research was funded by: MURANO was sponsored by F. Hoffmann-La Roche Ltd and AbbVie, Inc. Third-party medical writing and editorial assistance, under the direction of the authors was provided by Roisin Weaver, MSc, and Alex Maksymowych, MSc, of Ashfield MedComms, an Inizio company, and was funded by F. Hoffmann-La Roche Ltd. The authors would also like to thank Jenny Qun Wu, Genentech Inc, and Anne-Marie van der Kevie-Kersemaekers, Amsterdam University Medical Centers, for their contributions to the study. Keywords: Chronic Lymphocytic Leukemia (CLL), Combination Therapies Conflicts of interests pertinent to the abstract A. P. Kater Employment or leadership position: Amsterdam University Medical Centers, University of Amsterdam Consultant or advisory role: Abbvie, AstraZeneca, BMS, Janssen, Genmab, LAVA, Roche/Genentech Research funding: Abbvie, AstraZeneca, BMS, Janssen, Genmab, LAVA, Roche/Genentech Educational grants: Abbvie, AstraZeneca, Janssen, Roche/Genentech Other remuneration: Leadership- HOVON: President of executive board, chairman of the CLL working group; Amsterdam UMC: Chairman Good Research Practice committee; EHA: Chairman Scientific Working group on CLL; ERIC: member executive board; Speaker’s Bureau - Abbvie, Janssen R. Harrup Consultant or advisory role: AstraZeneca 20 July 2021 T. J. Kipps Consultant or advisory role: Ascerta/AstraZeneca; Celgene; Genentech/Roche; Gilead; Janssen; Loxo Oncology; TG Therapeutics; Verastem; Pharmacyclics/AbbVie; Breast Cancer Research Foundation; Md Anderson Cancer Center; Oncternal Therapeutics, Inc.; Specialized Center of Research [SCOR] - The Leukemia and Lymphoma Society [LLS]; California Institute for Regenerative Medicine [CIRM]; National Cancer Institute/NIH; VelosBio, Inc. – Research Agreement Honoraria: Pharmacyclics/AbbVie, Genentech/Roche, Janssen, Gilead, National Cancer Institute/NIH, Celgene, European Research Initiative on CLL [ERIC], Dava Oncology, Breast Cancer Research Foundation, iwNHL, NCCN CLL/SLL Hairy Cell Leukemia Panel Meeting, OncLive Research funding: Ascerta/AstraZeneca; Celgene; Genentech/Roche; Gilead; Janssen; Loxo Oncology; TG Therapeutics; Verastem; Pharmacyclics/AbbVie; Breast Cancer Research Foundation; Md Anderson Cancer Center; Oncternal Therapeutics, Inc.; Specialized Center of Research [SCOR] - The Leukemia and Lymphoma Society [LLS]; California Institute for Regenerative Medicine [CIRM]; National Cancer Institute/NIH; VelosBio, Inc. – Research Agreement Educational grants: Pharmacyclics/AbbVie, Genentech/Roche, Janssen, Gilead, National Cancer Institute/NIH, Celgene, European Research Initiative on CLL [ERIC], Dava Oncology, Breast Cancer Research Foundation, iwNHL, NCCN CLL/SLL Hairy Cell Leukemia Panel Meeting, OncLive Other remuneration: Patents, royalties or other intellectual property - Cirmtuzumab was developed by TJK in the TJK laboratory and licensed by the University of California to Oncternal Therapeutics, Inc., which provided stock options and research funding to the TJK laboratory B. Eichhorst Employment or leadership position: University Hospital Cologne, Faculty of Medicine; Ended employment in the past 24 months - University Hospital Cologne, Faculty of Medicine Consultant or advisory role: Janssen, AbbVie, Gilead, AstraZeneca, BeiGene, MSD, Lilly Honoraria: Roche, AbbVie, BeiGene, AstraZeneca, MSD Research funding: Janssen, Gilead, Roche, AbbVie, BeiGene, AstraZeneca Educational grants: BeiGene Other remuneration: Leadership - Director Prof. Michael Hallek; Speaker’s Bureau - Roche, AbbVie, BeiGene, AstraZeneca, MSD C. J. Owen Honoraria: AbbVie, AstraZeneca, BeiGene, Janssen, Merck, Incyte, Novartis, Seattle Genetics, Roche S. Assouline Consultant or advisory role: Abbvie, Roche, AstraZeneca, BMS, Paladin, Novartis, Pfizer, Janssen Honoraria: Abbvie, Roche, AstraZeneca, BMS, Paladin, Novartis, Pfizer, Janssen Research funding: Novartis N. Lamanna Consultant or advisory role: Abbvie, AstraZeneca, BeiGene, Eli Lilly/Loxo, Genentech, Janssen, Pharmacyclics Research funding: Abbvie, AstraZeneca, BeiGene, Eli Lilly/Loxo, Genentech, MingSight, Octapharma, Oncternal, TG Therapeutics T. Robak Employment or leadership position: Medical University of Lodz, Copernicus Memorial Hospital, Lodz, Poland Consultant or advisory role: AstraZeneca, BeiGene Honoraria: Abbvie, Janssen, AstraZeneca, BeiGene, Regeneron, Octapharma Research funding: Abbvie, Janssen, AstraZeneca, BeiGene, Regeneron, Octapharma Educational grants: Janssen, AstraZeneca U. Jaeger Honoraria: Roche G. Cartron Consultant or advisory role: Roche, Celgene, Mabqi, MedxCell Honoraria: Gilead Sciences, Janssen, Celgene, Roche, AbbVie, Novartis Educational grants: Roche M. Montillo Employment or leadership position: Consultant in Haematology Honoraria: Abbvie, Janssen C. Mellink Employment or leadership position: Cytogeneticist, Human Genetics, AUMC Amsterdam Research funding: Financing for array-analysis Murano sample B. Chyla Employment or leadership position: AbbVie Stock ownership: AbbVie M. Thadani-Mulero Employment or leadership position: Roche Stock ownership: Roche M. Lefebure Employment or leadership position: Roche Stock ownership: Roche Y. Jiang Employment or leadership position: Roche/GNE Stock ownership: Roche/GNE R. Millen Employment or leadership position: Roche; Ended employment in the past 24 months- Hubrecht Institute Honoraria: Hubrecht Institute Research funding: Oncode Institute M. Boyer Employment or leadership position: Roche Stock ownership: Roche Honoraria: Roche J. F. Seymour Consultant or advisory role: AbbVie, AstraZeneca, BeiGene, BMS, Genor Bio, Gilead, Janssen, Roche, TG Therapeutics Honoraria: AbbVie, AstraZeneca, BeiGene, BMS, Gilead, Janssen, Roche Research funding: AbbVie, BMS, Janssen, Roche Educational grants: AbbVie, AstraZeneca, Roche Other remuneration: Speaker’s Bureau- AbbVie, AstraZeneca, Roche; Patents, royalties, other intellectual property- AbbVie; Expert testimony- BMS, TG Therapeutics