-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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4393 Tumor Determinants of Response to CAR-T Therapy in Relapsed or Refractory Mantle Cell Lymphoma

Program: Oral and Poster Abstracts
Session: 623. Mantle Cell, Follicular, Waldenstrom’s, and Other Indolent B Cell Lymphomas: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Research, Adult, Translational Research, Lymphomas, Non-Hodgkin lymphoma, Elderly, Clinical Research, B Cell lymphoma, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Diseases, Real-world evidence, Treatment Considerations, Biological therapies, Lymphoid Malignancies, Study Population, Human
Monday, December 9, 2024, 6:00 PM-8:00 PM

Zachary D. Epstein-Peterson, MD1,2, Christine E. Ryan, MD3, Sean M. Devlin, PhD4*, Noa Golan Accav5*, Abraham Avigdor, MD6, Magdalena Corona, MD, PhD7*, Ivetta Danylesko, MD8*, Jamie Dela Cruz9*, Andre Goy, MD, MS10,11, Caron A. Jacobson, MD, MMSc3, Ofrat Beyar Katz12, Hazim Khatib, MD12*, Anita Kumar, MD13, Lori A. Leslie, MD14, Alejandro Luna, MD, PhD15*, Ronit Marcus, MD16*, Reid W. Merryman, MD17, Miguel Angel Perales, MD18,19, Alfredo Rivas-Delgado, MD, PhD2, Gilles Salles, MD, PhD1,20, Michael Scordo, MD1,21, Inbal Sdayoor, BSc22*, Gunjan L. Shah, MD1,23, Noga Shem-Tov, MD22*, Avichai Shimoni, MD24*, Nataly Vahaba12*, Ronit Yerushalmi, MD22, Andrew D. Zelenetz, MD, PhD2, Maria Lia Palomba, MD2,18, Andrew Ip, MD, MSc10 and Roni Shouval, MD, PhD7,25

1Department of Medicine, Weill Cornell Medical College, New York, NY
2Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
4Department of Biostatistics and Epidemiology, Memorial Sloan Kettering Cancer Center, New York, NY
5Institute of Hematology, Sheba Medical Center, Ramat Gan, Israel
6Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Ramat Gan, Israel
7Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
8Division of Hematology and Bone Marrow Transplantation, Sheba Medical Center, Ramat Gan, Israel
9Dana Farber Cancer Institute, Boston, MA
10Lymphoma Division, John Theurer Cancer Center, Hackensack Meridian Health, Hackensack, NJ
11John Theurer Cancer Center, Hackensack, NJ
12Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel
13Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, Short Hills, NJ
14Lymphoma Division, John Theurer Cancer Center, Hackensack Meridian School of Medicine, Hackensack, NJ
15Unidad de trasplante y terapia celular, Hospital Universitario Ramon y Cajal, Madrid, Spain
16School of Medicine, Faculty of Medical and health Sciences,Aviv University, Tel Aviv, Israel
17Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
18Department of Medicine, Weill Cornell Medical College, New York
19Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
20Lymphoma Service Chief, Memorial Sloan Kettering Cancer Center, New York, NY
21Transplant and Cellular Therapy Services, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY
22Division of Hematology and Bone Marrow Transplantation, The Chaim Sheba Medical Center, Ramat Gan, Israel
23Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY
24Division of Hematology and Bone Marrow Transplantation Department, Chaim Sheba Medical Center, Tel-Aviv, Israel
25Department of Medicine, Weill Cornell Medicine, New York, NY

Background: While complete response rates to CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy in relapsed or refractory (R/R) mantle cell lymphoma (MCL) exceed 70%, a substantial proportion of patients’ (pts) disease will ultimately relapse. Biomarkers are urgently needed to inform resistance mechanisms and identify pts at risk for poor outcomes in this setting. It remains unclear whether traditional histological, cytogenetic, and genomic features that predict outcomes with frontline chemoimmunotherapy and other agents in MCL can serve as informative biomarkers in the CAR-T setting. Therefore, we conducted a multicenter retrospective analysis to evaluate molecular and patient-level factors influencing response and survival in pts with R/R MCL receiving CD19 CAR-T.

Methods: In this international multicenter retrospective study, we included pts with R/R MCL treated with autologous CD19-directed CAR-T therapies. Comprehensive patient-, disease-, and treatment-related data were collected. Pre-CAR-T tumor genomic data gathered from targeted next-generation sequencing panels were available for a subset of pts. We evaluated the association between tumor features (histology, cytogenetics, and genomics) and CAR-T response using univariable logistic regression models. We used Cox regression models to analyze the relationship between predictive features and overall survival (OS) and progression-free survival (PFS) and Fisher's exact test between TP53 mutations and response.

Results: We included 88 pts from 5 international centers with a median age at infusion of 66 years (range 36-86). Brexu-cel was the predominant product (N=57) followed by liso-cel (N=21) and a point-of-care CD19 CAR-T product (N=10) with a CD28 costimulatory domain (Kedmi et al., JTCT 2022). Most pts (58%) received ≤3 lines of therapy prior to CAR-T.

High-risk disease features were frequent in the population; 46% had blastoid/pleomorphic morphology, 68% had K67 ≥50%, and 54% had high risk MIPIb (54%) at apheresis. Deletion 17p was observed in 19/60 (32%) pts and P53 was detected by immunohistochemistry in 32/56 (57%) pts. Among pts with available pre-CAR-T tumor NGS testing, the most frequent mutations were TP53 (28/52, 54%) and ATM (13/50, 26%). CDKN2A alterations were detected in 5/52 pts.

Our cohort had high overall response (86%) and CR rates (82%), comparable to results in the pivotal CAR-T MCL clinical trials. Grade ≥3 cytokine release syndrome and neurotoxicity occurred in 10% and 19% of patients, respectively.

With a median follow-up of 18 months (IQR 7.8-28.1), 1-year OS and PFS were 64% (95% CI: 54-77%) and 59% (95% CI: 48-72%), respectively. Blastoid/pleomorphic morphology, Ki67 > median of 60%, P53 expression (any percentage), SOX11 expression, deletion(17p), MIBIb group at apheresis, and LDH before lymphodepletion were not associated with OS or PFS from time of infusion.

In the subset of pts with NGS testing, TP53 and ATM alterations lacked significant association with these outcomes. For example, 2-year PFS differed by TP53 mutation status (52% vs. 39%), but this difference was not statistically significant. Of the features evaluated, only receipt of bridging therapy (66% of pts) was associated with inferior PFS (HR 2.39, 95% CI: 1.12-5.03) and OS (HR 2.16, 95% CI: 1.01-4.63). Additionally, TP53-mutated MCL was associated with a lower CR rate that did not meet statistical significance (96% vs. 74%, P = 0.053).

Discussion: In this comprehensive, multicenter/multinational dataset derived predominantly from pts treated in non-trial settings, molecular features traditionally associated with inferior outcomes in MCL did not significantly influence response or survival in pts with R/R MCL treated with CD19-CAR-T. Our findings, which warrant confirmation in larger genomically characterized cohorts, highlight the utility of CAR-T even in pts with high-risk MCL features. These data also underscore the pressing need for identifying novel biomarkers to inform on resistance mechanisms and predict treatment success. Data from additional patients will be incorporated if this work is selected for presentation at the meeting.

Disclosures: Epstein-Peterson: Kymera: Research Funding; OncLive: Honoraria; Genmab: Consultancy; Viracta: Research Funding; Amgen: Research Funding. Ryan: Genentech: Other: Institutional research funding; AstraZeneca: Honoraria. Avigdor: Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Speakers Bureau; BeiGene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Speakers Bureau; TG Therapeutics: Consultancy; Karyospharm: Research Funding; Ascentage: Consultancy, Honoraria, Speakers Bureau; 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; Janssen: 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; 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; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau. Jacobson: ADC Therapeutics: Consultancy; Pfizer: Research Funding; MorphoSys: Consultancy; ImmPACT Bio: Consultancy; Bristol Myers Squibb/Celgene: Consultancy; Miltenyi: Consultancy; Instil Bio: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Synthekine: Consultancy; Novartis: Consultancy; Daiichi Sankyo: Consultancy; Caribou Biosciences: Consultancy; Ipsen: Consultancy; Abintus Bio: Consultancy; AbbVie: Consultancy. Kumar: Astra Zeneca: Honoraria, Research Funding; Seattle Genetics: Research Funding; Kite Pharmaceuticals, Janssen: Honoraria; Loxo Oncology/Lily Pharmaceuticals: Honoraria, Research Funding; BridgeBio Pharmaceuticals: Current equity holder in publicly-traded company; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Adaptive Biotechnologies, Celgene, Pharmacyclics: Research Funding; Abbvie Pharmaceuticals: Research Funding. Leslie: TG Therapeutics: Speakers Bureau; Seagen: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Merck: Consultancy; , Janssen/Johnson & Johnson: Consultancy, Speakers Bureau; Epizyme: Consultancy, Speakers Bureau; Eli Lily: Consultancy, Speakers Bureau; BeiGene: Consultancy, Speakers Bureau; ADC Therapeutics: Consultancy; AstraZeneca: Consultancy, Speakers Bureau; Genmab: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Kite Pharma: Consultancy, Speakers Bureau. Merryman: Genmab: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; DG Medicine: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Merck: Research Funding. Perales: OrcaBio: Consultancy, Current holder of stock options in a privately-held company; VectivBio AG: Consultancy, Research Funding; Omeros: Consultancy, Current equity holder in publicly-traded company; Astellas: Honoraria; Celgene: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria, Research Funding; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Sellas: Other: DSMB member; Caribou Biosciences: Consultancy; Sanofi: Consultancy; Cidara Therapeutics: Other: DSMB member; Vor Biopharma: Consultancy; Allogene: Consultancy, Research Funding; AbbVie: Honoraria; Merck: Consultancy, Research Funding; Syncopation: Consultancy; Nektar Therapeutics: Consultancy, Honoraria, Research Funding; Allovir: Consultancy; Adicet: Consultancy; Karyopharm: Honoraria; MorphoSys: Honoraria; Takeda: Honoraria; Medigene: Other: DSMB member; Servier: Other: DSMB member. Salles: Janssen: Consultancy, Research Funding; Kite/Gilead: Consultancy; Merck: Consultancy; BMS/Celgene: Consultancy; BeiGene: Consultancy; AbbVie: Consultancy, Research Funding; Incyte: Consultancy; Genmab: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; Ipsen: Consultancy, Research Funding; Molecular Partners: Consultancy; Nurix: Research Funding. Scordo: Miltenyi Biotec: Consultancy; Medscape: Honoraria; MJH Life Sciences (Cancer Network): Honoraria; Amgen: Research Funding; Sanofi: Research Funding; IDEOlogy: Honoraria; Kite - A Gilead Company: Consultancy; Angiocrine Biosciences, Inc.: Research Funding; Omeros Corporation: Consultancy, Research Funding. Shah: Janssen, Amgen, Beyond Spring, BMS, GPCR, DSMB with ArcellX.: Research Funding. Zelenetz: MEI Pharma: Consultancy, Research Funding; Janssen: Consultancy; Novartis: Consultancy; Adaptive Biotechnology: Consultancy; Abbvie: Consultancy; Gilead/Kite: Consultancy; BMS/Celgene/Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; MorphoSys: Consultancy; Genentech/Roche: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding. Palomba: Cellectar: Consultancy; Synthekine: Consultancy; Novartis: Consultancy; Bristo Meyer Squibb: Consultancy.

*signifies non-member of ASH