Pirtobrutinib, venetoclax, and obinutuzumab for patients with richter transformation: A phase 2 trial

Nitin Jain; Niranjan Khaire; Mahesh Swaminathan; Alessandra Ferrajoli; Jan Burger; Vishruth Shah; Kelly Chien; Gautam Borthakur; Koichi Takahashi; Naveen Pemmaraju; Prithviraj Bose; Jo Ishizawa; Beenu Thakral; Naveen Garg; Hyunsoo Hwang; Wei Qiao; Cameron Garcia; Anna Evangelio; Ana Ayala; Guillermo Garcia-Manero; Deepa Sampath; Varsha Gandhi; Michael Keating; Hagop Kantarjian; William Wierda

doi:10.1182/blood-2025-89

Background: Richter transformation (RT) represents transformation of chronic lymphocytic leukemia (CLL) to an aggressive lymphoma histology, most commonly DLBCL. Traditionally, RT is treated with DLBCL-directed chemoimmunotherapy regimens such as R-CHOP, and more recently, clinical trials have reported efficacy of targeted therapies including BTK, PD-1, and BCL2 inhibitors. We report first results of an investigator-initiated Phase II trial of combined therapy with pirtobrutinib, a non-covalent BTKi, venetoclax, and obinutuzumab as treatment for patients (pts) with RT (NCT05536349). Methods: Pts with previously untreated or relapsed/refractory RT (DLBCL histology) arising from CLL were enrolled. Previously untreated RT were required to have received prior therapy for CLL. Pts received pirtobrutinib 200mg daily starting Cycle 1 Day 1 (C1D1) continuously daily. Obinutuzumab was given as standard 6 cycles starting C1D1. Venetoclax standard ramp-up was initiated C2D1 to the target dose of 400mg daily. Combined pirtobrutinib and venetoclax was given until end of C25. Pts in ongoing response (PR or better) after cycle 25, could continue pirtobrutinib for an additional 12 cycles. Each cycle was 28 days. Response evaluations by Lugano criteria were done by PET/CT imaging and bone marrow (BM) assessment at the end of C1, C4, C7, C10, C13, C19 and C25. Results: Between February 2023 and April 2025, 12 pts (male, n=9; female, n=3) were enrolled. Median age was 70 years (range, 48-81 years). 8/9 (89%) pts with available data had IGHV-unmutated CLL. 7/10 (70%) had del(17p)/TP53 mutated CLL. Median prior lines of therapy for CLL and RT were 2 (range, 1-4); median prior lines of treatment for CLL were 1 (range, 0-2) and for RT were 1 (range, 0-4). Prior therapy for CLL (4 pts had no prior therapy for CLL) included BTKi (n=6), BCL2i (n=2), CD20 antibody (n=3), and conventional chemotherapy (n=1). Prior therapy for RT included conventional chemotherapy (n=9), BCL2i (n=5), CD20 antibody (n=8), checkpoint inhibitor (n=4), allo-SCT (n=1), and CD19 CAR T (n=1). Three pts were previously untreated for RT (all 3 had received prior CLL therapy). Median time from CLL diagnosis to treatment was 58 months (range, 24-211) and from RT diagnosis to treatment was 6 months (range, 0.3-28). The median follow-up is 15.3 months (range, 1.8-26.8). Seven out of 12 pts achieved complete metabolic response (CMR) and 1/12 achieved partial metabolic response (PMR) giving an ORR of 8/12 (67%). One pt has stable disease after 4 cycles of therapy and remains on treatment. Three pts had no response (1 pt with previously untreated RT who received venetoclax + obinutuzumab for CLL; 1 pt with prior BR and Ibrutinib + obinutuzumab for CLL, and prior atezolizumab + venetoclax + obinutuzumab, and R-CHOP + venetoclax for RT; 1 pt with no prior CLL therapy and R-EPOCH for RT). Two of the responding pts underwent consolidative allo-SCT. 1 pt with 4 prior therapies for RT in PMR after C6; pt is alive in remission 17.5 months post allo-SCT. 1 pt who previously received R-CHOP + venetoclax followed by allo-SCT and then had relapsed RT prior to enrollment on the current trial; pt went to second allo-SCT in CMR after C12 on the trial but died 5.3 months after the second allo-SCT from transplant-related complications. Among the 3 previously untreated RT, 2 achieved a CMR and are continuing to receive treatment 13.9 and 14.7 months since treatment initiation; 1 pt had worsening disease while receiving venetoclax dose escalation in C2 and elected to go to hospice. Among the 8 responding pts, 1 pt went to allo-SCT in C6. Among the remaining 7 pts who reached end of C7, 6/7 achieved U-MRD4 remission in BM by flow-cytometry. 6 pts reached end of C13 (1 pt went to allo-SCT in C12); all 6 were U-MRD4 in BM by flow-cytometry. The 12-month EFS and OS for the whole cohort (n=12) was 73% and 82%, respectively. The 12-month EFS and OS for the R/R RT (n=9) was 75% and 88%, respectively. There have been no relapses among the responders to date. There were 4 deaths which included 3 non-responders and 1 death in a pt in remission with post-transplant complications. Conclusions: We report results of combined pirtobrutinib, venetoclax, and obinutuzumab in pts with untreated or R/R RT. We observed an ORR rate of 67% and a 12-month EFS and OS rates of 73% and 82%, respectively. Jain:AbbVie: Consultancy (Includes expert testimony); Honoraria; Research Funding Adaptive Biotechnologies: Consultancy (Includes expert testimony); Honoraria; Research Funding ADC Therapeutics: Research Funding AstraZeneca: Consultancy (Includes expert testimony); Honoraria; Research Funding Autolus: Consultancy (Includes expert testimony); Honoraria Beigene: Consultancy (Includes expert testimony); Honoraria; Research Funding BMS: Consultancy (Includes expert testimony); Honoraria; Research Funding Carna Biosciences: Research Funding Cellectis: Consultancy (Includes expert testimony); Honoraria; Research Funding Fate Therapeutics: Research Funding Genentech: Consultancy (Includes expert testimony); Honoraria; Research Funding Janssen: Consultancy (Includes expert testimony); Honoraria Kisoji Biotechnology: Research Funding Kite/Gilead: Consultancy (Includes expert testimony); Honoraria; Research Funding Lilly: Consultancy (Includes expert testimony); Honoraria; Research Funding Mingsight: Research Funding Newave: Research Funding Novalgen: Consultancy (Includes expert testimony); Honoraria Novartis: Research Funding Nurix: Consultancy (Includes expert testimony); Honoraria Pharmacyclics: Consultancy (Includes expert testimony); Honoraria; Research Funding Precision Biosciences: Consultancy (Includes expert testimony); Honoraria; Research Funding Sana Biotechnology: Research Funding Takeda: Research Funding Triarm Therapeutics: Research Funding Swaminathan:Astrazeneca: Consultancy (Includes expert testimony); Honoraria Intellisphere: Consultancy (Includes expert testimony) Sobi: Consultancy (Includes expert testimony) Ferrajoli:AstraZeneca: Consultancy (Includes expert testimony) BeOne Medicines Ltd: Consultancy (Includes expert testimony) Eli Lilly: Research Funding Genetech: Consultancy (Includes expert testimony); Research Funding GenMab: Research Funding Janssen: Consultancy (Includes expert testimony) Burger:AbbVie: Research Funding AstraZeneca: Consultancy (Includes expert testimony); Research Funding BeOne: Research Funding Johnson and Johnson: Honoraria Pharmacyclics: Consultancy (Includes expert testimony); Research Funding Borthakur:AbbVie: Consultancy (Includes expert testimony) Aptevo: Research Funding ASTEX Pharmaceuticals: Research Funding Epigentix: Research Funding Lava Therapeutics: Consultancy (Includes expert testimony) Nkarta: Research Funding PPD Development: Consultancy (Includes expert testimony) Treadwell Therapeutics: Research Funding Pemmaraju:AbbVie: Consultancy (Includes expert testimony); Honoraria Affymetrix/Thermo Fisher Scientific: Research Funding Aplastic Anemia & MDS International Foundation, CancerNet, Celgene, Cimeio Therapeutics AG, ClearView Healthcare Partners, CTI BioPharma, Curio Science, EUSA Pharma, Harborside Press, Imedex, Immunogen, Intellisphere, Karyopharm Therapeutics, Magdalen Medical Publishing, Medscape, Menarini Group, Morphosys, OncLive, Pacylex, Patient Power, PeerView Institute for Medical Education, PharmaEssentia, and Physician Education Resource (PER): Honoraria Aplastic Anemia & MDS International Foundation, CancerNet, Celgene, Cimeio Therapeutics AG, ClearView Healthcare Partners, Curio Science, Dava Oncology, EUSA Pharma, Harborside Press, Imedex, Immunogen, Intellisphere, Karyopharm Therapeutics, Magdalen Medical Publishing, Medscape, Menarini Group, Morphosys, OncLive, Pacylex, Patient Power, PeerView Institute for Medical Education, PharmaEssentia, and Physician Education Resource (PER): Consultancy (Includes expert testimony) Aptitude Health: Consultancy (Includes expert testimony); Honoraria Astellas Pharma: Consultancy (Includes expert testimony) Astellas Pharma US: Consultancy (Includes expert testimony); Honoraria Blueprint Medicines: Consultancy (Includes expert testimony); Honoraria Bristol Myers Squibb: Consultancy (Includes expert testimony); Honoraria CareDx: Consultancy (Includes expert testimony); Honoraria Celgene: Honoraria Cellectis: Research Funding Clearview Healthcare Partners: Consultancy (Includes expert testimony) CTI BioPharma Corporation: Consultancy (Includes expert testimony) Daiichi Sankyo: Research Funding DAVA Oncology: Honoraria DAVA Pharmaceuticals: Honoraria Immunogen: Consultancy (Includes expert testimony) Incyte: Honoraria Karger Publishers: Patents & Royalties LFB Biotechnologies: Honoraria Mustang Bio: Honoraria; Research Funding National Institutes of Health/National Cancer Institute (NIH/NCI) and U.S. Department of Defense (DOD): Research Funding Neopharm: Consultancy (Includes expert testimony); Honoraria Novartis: Consultancy (Includes expert testimony); Honoraria Pacylex: Consultancy (Includes expert testimony) Plexxikon: Research Funding Protagonist Therapeutics: Consultancy (Includes expert testimony) Roche Molecular Diagnostics: Honoraria Samus Therapeutics: Research Funding Springer Science + Business Media LLC: Honoraria Stemline Therapeutics: Honoraria; Research Funding Triptych Health Partners: Consultancy (Includes expert testimony) Bose:Abbvie: Consultancy (Includes expert testimony); Honoraria Astellas: Research Funding Blueprint Medicines, a Sanofi Company: Consultancy (Includes expert testimony); Honoraria; Research Funding BMS: Consultancy (Includes expert testimony); Honoraria; Research Funding Cogent Biosciences: Consultancy (Includes expert testimony); Honoraria; Research Funding CTI BioPharma (now Sobi): Consultancy (Includes expert testimony); Honoraria; Research Funding Disc Medicine: Consultancy (Includes expert testimony); Research Funding Geron: Consultancy (Includes expert testimony);

Pirtobrutinib, venetoclax, and obinutuzumab for patients with richter transformation: A phase 2 trial

View Online

Abstract

Details

Metrics