-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

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4504 CD19 CAR-T Cell Therapy Is Effective in Richter Transformation: A Multicenter Retrospective Analysis By the European Research Initiative on Chronic Lymphocytic LeukemiaClinically Relevant Abstract

Program: Oral and Poster Abstracts
Session: 628. Aggressive Lymphomas: Cellular Therapies: Poster III
Hematology Disease Topics & Pathways:
Research, Clinical Research, Real-world evidence
Monday, December 9, 2024, 6:00 PM-8:00 PM

Ofrat Beyar-Katz, MD, PhD1,2*, Ohad Benjamini, MD3*, Julio Delgado, MD, PhD4*, Marco Ruella, MD5, Ron Ram6*, Sigal Grisariu, MD7,8*, Andrea Visentin, MD, PhD9*, Elisabeth Vandenberghe, MD, PhD10,11*, Massimo Gentile, MD12,13*, Abraham Avigdor, MD14,15, Avichai Shimoni, MD14*, Roni Shouval, MD, PhD16,17, Ronit Marcus, MD18,19*, Stephen J. Schuster, MD5,20, Valentin Ortiz-Maldonado, MD, PhD, MSc21, Guido Ghilardi, MD22*, Luca Paruzzo, MD22*, Tsila Zuckerman, MD1,23, Tamar Tadmor, MD24*, Riva Fineman, MD25*, Odelia Amit, MD26*, Nuria Martinez-Cibrian27*, Giulia Gabrielli, MD28*, Batia Avni, MD7,8*, Eva Minga29*, Noga Shem-Tov, MD14,18*, Lydia Scarfo, MD30, Ronit Yerushalmi, MD3,15*, Arnon Nagler, MD14,31, Ronit Leiba32*, Ivetta Danylesko, MD3,15*, Kostas Stamatopoulos29*, Thomas Chatzikonstantinou, MD29*, Paolo Ghia, MD, PhD33 and Yair Herishanu, MD34,35*

1Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
2Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus; The Ruth and Bruce Rappaport Faculty of Medicine, Haifa, Israel
3Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
4Oncoimmunotherapy Unit, Department of Hematology, Hospital Clínic de Barcelona, Barcelona, Spain
5Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
6Bone Marrow Transplant Unit, Tel Aviv Sourasky Medical Center and Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
7Faculty of Medicine, The Hebrew University, Jerusalem, Israel
8Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah Medical Center, Jerusalem, Israel
9Hematology unit, Department of Medicine, University of Padova, Padova, Italy
10Department of Haematology, St. James's Hospital, Dublin, Ireland
11Trinity College Dublin, Dublin, Ireland
12Department of Pharmacy, Health and Nutritional Science, University of Calabria, Rende, Italy
13Hematology Unit, Azienda Ospedaliera di Cosenza, Cosenza, Italy
14Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
15Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Ramat Gan, Israel
16Department of Medicine, Weill Cornell Medicine, New York, NY
17Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
18Division of Hematology and Bone Marrow Transplantation, The Chaim Sheba Medical Center, Ramat Gan, Israel
19School of Medicine, Faculty of Medical and health Sciences,Aviv University, Tel Aviv, Israel
20Center for Cellular Therapy, University of Pennsylvania, Philadelphia, PA
21Hematology Department, Hospital Clínic Barcelona, Barcelona, Spain, Seattle, WA
22Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
23Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Moshav Ein Ayalla, Israel
24Hematology Unit, Bnai Zion Medical Center, Haifa, Israel
25Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel
26BMT Unit, Tel Aviv Sourasky Medical Center and Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
27Hospital Clínic de Barcelona, Barcelona, Spain
28Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA
29Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece
30Division of Experimental Oncology, IRCCS Ospedale San Raffaele Milan Italy., Milano, Italy
31Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel Aviv, Israel
32Department of Statistics, Rambam Health Care Campus, Haifa, Israel
33Università Vita-Salute San Raffaele, Milano, Italy
34Bone Marrow Transplantation Unit, Tel Aviv Sourasky Medical Center, Tel Aviv-Yafo, Israel
35Sackler School of Medicine, Tel Aviv University, Tel Aviv-Yafo, Israel

Introduction: Richter transformation (RT) is a devastating complication of chronic lymphocytic leukemia (CLL), associated with poor outcomes. While the progressively expanding use of CAR-T cells in the setting of large B-cell lymphoma (LBCL) is yielding encouraging results, findings regarding the response of patients with RT to this therapy are inconclusive and the need for further consolidation with allogeneic stem cell transplantation (allo SCT) has not been determined yet. Additionally, the issue of CAR-T cell treatment-related toxicity in this patient population remains unclear. The current study aimed to analyze clinical response and survival rates among patients with RT treated with CD19 targeting CAR-T cells.

Methods: This retrospective multicenter study, conducted across Europe and the USA by the European Research Initiative on CLL (ERIC) group, included all consecutive patients with RT who received CAR-T cells targeting CD19 in the participating centers between 06/2018 and 01/2024. Response rates, progression-free survival (PFS) and overall survival (OS) were assessed from the day of CAR-T infusion. CAR-T related toxicities were reported by ASTCT criteria.

Results: The study included 54 patients with RT treated with anti-CD19 CAR-T cells (investigational products: n=29, 54%; tisagenlecleucel: n=20, 37%; axicabtagene ciloleucel: n=4, 7%; lisocabtagene maraleucel: n=1, 2%). The median age at CAR-T cell product infusion was 62.6 (range 41-82) years. The ECOG performance status (PS) prior to lymphodepletion was 0-1 in 39 (72%) and 2-3 in 15 (28%) patients. Mean prior lines of CLL treatment were 2 (range, 0-8). The majority of patients (35/52, 67%) had previously received Bruton tyrosine kinase inhibitors. Bridging therapy was administered to most patients (n=36, 67%). Lymphodepletion consisted of fludarabine with cyclophosphamide in 46/52(85%) and bendamustine in 8 (15%) patients. The overall and grade 3-4 cytokine release syndrome (CRS) were documented in 47 (87%) and 10 (21%) patients, respectively. Immune effector cell-associated neurotoxicity syndrome (ICANS) of any grade was diagnosed in 12 (22%) patients, with high-grade ICANS found in 5 (42%) of them. Among the infections identified in a total of 22 patients (41%), bacterial infections were most common (71%). Seven patients (13%) underwent allo SCT following CAR-T cell infusion. Among these, four patients (57%) died, with 3/4 due to transplant-related toxicities and 1/4 due to progressive disease. The overall response rate was 65%, with complete response (CR) achieved in 46% of patients at 1 month and in 50% at 3 months following CAR-T cell infusion. With a median follow-up of 20.2 (range, 2-57) months, median OS was 14.4 months (95% CI = 8.8-19.2). PFS rates at 6 and 12 months were 56% (95% CI = 42%–70%) and 41% (95% CI = 27%-56%), respectively. The median PFS was 24.6 months (95%CI=16 - 32) for patients achieving any response (CR+PR) compared with 1.2 months (95% CI= 0.92 - 1.6) for patients with stable disease/progressive disease.

In the univariable analysis, mortality was found to be significantly associated with high ECOG PS (2-3) at the time of CAR-T cell infusion (p <0.001), the development of ICANS (p = 0.027) and lack of response 1 month following CAR-T cell infusion (p=0.001). Multivariable analysis revealed that the two latter factors remained statistically significant. There was no significant difference in response rates among patients harboring genetic aberrations such as deletion 17p, 13q, 11q, trisomy 12, TP53 mutations or IGHV mutational status. CAR-T cell related toxicity was more frequently observed in patients with a high disease burden, defined according to the lactate dehydrogenase (LDH) level prior to CAR-T cell infusion [150 (131-193) vs 274 (222-359) mU/ml, p <0.001].

Conclusions: The current study demonstrates clinically significant response rates and manageable toxicity in patients with RT treated with investigational as well as commercially available CAR-T cell products. These findings could potentially pave the way for new treatment paradigms in the management of this high-risk and challenging patient population.

Disclosures: Ruella: Vittoria Biotherapeutics: Current equity holder in private company, Patents & Royalties; AbClon Inc.: Other: Consultancy, Research Funding. Grisariu: Gilead, Medison, MSD, Novartis, Sanofi, Takeda: Consultancy. Visentin: Beigene: Consultancy, Research Funding, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; J&J: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; AstraZenca SpA: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Avigdor: Karyospharm: Research Funding; Ascentage: Consultancy, Honoraria, Speakers Bureau; BeiGene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Eli Lilly: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Speakers Bureau; TG Therapeutics: Consultancy; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau. Ortiz-Maldonado: Pfizer: Honoraria; Kite/Gilead: Honoraria, Other: Travel grants; Miltenyi: Honoraria; Hospital Clínic de Barcelona: Current Employment; Janssen: Honoraria, Other: Travel grants; Celgene-BMS: Honoraria, Other: Travel grants; Novartis: Honoraria. Ghilardi: Vittoria Biotherapeutics: Honoraria. Tadmor: Janssen, roche, abbvie, astra, takeda, novartis, beigene, medison: Consultancy, Research Funding. Avni: Sanofi: Consultancy; Johnson and Johnson: Consultancy; Novartis: Consultancy; MSD: Consultancy; Takeda: Consultancy; Medison: Consultancy. Scarfo: Janssen: Honoraria; Lilly: Honoraria; BeiGene: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Octapharma: Honoraria. Stamatopoulos: AstraZeneca: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Research Funding; Roche: Research Funding; Bristol Myers Squibb: Honoraria; AbbVie: Honoraria, Research Funding; Lilly: Honoraria. Ghia: Loxo@Lilly: Consultancy; Galapagos: Consultancy; Johnson&Johnson: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; BeiGen: Consultancy; AstraZeneca: Consultancy, Research Funding; AbbvVie: Consultancy, Research Funding; MSD: Consultancy; Galapagos: Consultancy; Roche: Consultancy.

*signifies non-member of ASH