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1746 Impact of Broad-Spectrum Antibiotic Exposure on CAR-T Therapy Outcomes in B-Cell Lymphoma: A Multicenter International Study

Program: Oral and Poster Abstracts
Session: 628. Aggressive Lymphomas: Cellular Therapies: Poster I
Hematology Disease Topics & Pathways:
Research, Clinical Practice (Health Services and Quality), Lymphomas, Non-Hodgkin lymphoma, Clinical Research, Health outcomes research, Diseases, Real-world evidence, Aggressive lymphoma, Lymphoid Malignancies
Saturday, December 7, 2024, 5:30 PM-7:30 PM

Roni Shouval, MD, PhD1,2, Teng Fei, PhD3*, Giulia Gabrielli, MD4,5,6*, Natalie Grier Smith, BA7,8*, Guido Ghilardi, MD5,9,10*, John Slingerland8*, Jonathan U. Peled, MD, PhD11,12,13, Ying Taur, MD13,14*, Sunita D. Nasta, MD10,15,16, Alejandro Luna, MD, PhD2*, Magdalena Corona, MD, PhD2*, Kai Rejeski, MD17,18, Sophia Stock, MD19,20,21*, Ronit Marcus, MD22*, Noa Golan Accav23*, Ofrat Beyar-Katz, MD, PhD24*, Hazim Khatib25*, Sandeep S. Raj, MD2, Alexander P. Boardman, MD13,26,27*, Parastoo B Dahi, MD11,13,26*, Richard J. Lin, MD, PhD13,18,26, Michael Scordo, MD11,13,26, Lorenzo Falchi, MD13,28, Jakub Svoboda, MD10,29,30, Elise A. Chong, MD5,10,31, Stefan K. Barta, MD10,32,33, Daniel J. Landsburg, MD10,31,34, Avichai Shimoni, MD23*, Arnon Nagler, MD23, Gunjan L. Shah, MD11,13,26, Maria Lia Palomba, MD26,35,36, Gilles Salles, MD, PhD26,36,37, Jae H. Park, MD1,26, Stephen J. Schuster, MD5,10,16, Tsila Zuckerman, MD38, Marion Subklewe, MD39, Abraham Avigdor, MD40, Miguel Angel Perales, MD2,41, Marcel R.M. van den Brink42,43* and Marco Ruella, MD5,9,10

1Department of Medicine, Weill Cornell Medicine, New York, NY
2Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
3Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
4Division of Hematology and Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA
5Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
6Lymphoma Program, Abramson Cancer Center, Hospital of the University of Pennsylvania, Philadelphia, PA
7Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY
8City of Hope National Medical Center, Duarte, CA
9Division of Hematology-Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA
10Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
11Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY
12Department of Medicine, Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY
13Department of Medicine, Weill Cornell Medical College, New York, NY
14Department of Medicine, Infectious Disease Service, Memorial Sloan-Kettering Cancer Center, New York, NY
15Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
16Division of Hematology/Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA
17Hematology/Oncology, LMU University Hospital, Department of Medicine III, Munich, Germany
18Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY
19Department of Medicine III, LMU University Hospital, LMU Munich, Munich, Germany
20Division of Clinical Pharmacology, University Hospital, LMU Munich, Munich, Germany
21German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
22Division of Hematology and Bone Marrow Transplantation, The Chaim Sheba Medical Center, Ramat Gan, Israel
23Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel Aviv, Israel
24Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus; The Ruth and Bruce Rappaport Faculty of Medicine, Haifa, Israel
25Department of Hematology and Bone Marrow Transplantation,, Rambam Health Care Campus, Haifa, Israel
26Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
27Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY
28Memorial Sloan Kettering Cancer Center, New York, NY
29Abramson Cancer Center, Department of Medicine, Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, PA
30Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania,, Philadelphia, PA
31Department of Medicine, Division of Hematology/Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA
32Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA
33School of Medicine, Division of Hematology/Oncology, University of Pennsylvania, Philadelphia, PA
34Center for Cellular Immunotherapies,, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
35Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
36Department of Medicine, Weill Cornell Medical College, New York
37Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York
38Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Moshav Ein Ayalla, Israel
39Department of Medicine III, LMU University Hospital, Munich, Germany
40Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Ramat Gan, Israel
41Weill Cornell Medical College, New York, NY
42Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY
43City of Hope National Medical Center, Duarte

Background: Previous studies by us and others have shown that broad-spectrum antibiotic exposure, particularly with PIM (piperacillin-tazobactam, imipenem, and meropenem), before CD19-chimeric antigen receptor T-cell (CAR-T) therapy is associated with poor outcomes in B-cell malignancies. Larger studies are needed to clarify the impact of antibiotics administered after CAR-T infusion, especially in the context of cytokine release syndrome (CRS), where fevers and subsequent antibiotic use are common. Additionally, a more detailed understanding of the effects of specific antibiotics given before and after CAR-T therapy is necessary. This study aims to elucidate the influence of commonly used broad-spectrum antibiotics, including 4th generation cephalosporins (CS, e.g., Cefepime) and PIM, on the efficacy of CAR-T therapy.

Methods: This multicenter international observational study included adult patients treated with autologous CD19 CAR-T cells for large B-cell lymphoma (LBCL). We documented all antibiotic exposures from lymphodepletion initiation to 30 days post-infusion. Exposure between the start of lymphodepletion and the day preceding infusion was defined as pre-CAR-T, while exposure from the day of infusion to 30 days post-infusion was defined as post-CAR-T. Patients exposed to CS or PIM pre-CAR-T were excluded from the post-CAR-T analysis. We constructed multivariable logistic regression and Cox regression models to evaluate response and survival-related outcomes, respectively. All antibiotic exposure models were adjusted for age, pre-lymphodepletion LDH levels, bridging therapy, CAR-T product, and center. Post-CAR-T models were landmarked at day 30 post-infusion and adjusted for the occurrence of CRS.

Results: Among the 956 patients, the median age was 63 (IQR 52-70). Most patients (60%) were treated in US centers, with the remainder in European centers. Bridging therapy was administered to 69% of patients. Axi-cel was the most common CAR-T product (40%), followed by tisa-cel (35%), liso-cel (12%), and a CD19-point-of-care academic product (13%).

In the pre-CAR-T period, 12% of patients were exposed to broad-spectrum antibiotics (PIM and/or CS); 10% to PIM and 2.5% to CS, with 7 patients exposed to both. Post-CAR-T, 75% of patients experienced CRS. Additionally, 67% of patients were exposed to broad-spectrum antibiotics, with significant variation across centers. PIM was used in 56% of patients, with center-specific rates ranging from 10% to 90%. CS were used in 16% of patients, with rates ranging from 0% to 41%. The median duration of post-CAR-T broad-spectrum antibiotic exposure was 9 days (IQR 6-12). Post-CAR-T bloodstream infections were rarely identified, and antibiotic treatment was predominantly empiric.

In multivariable regression models, pre-CAR-T exposure to either PIM and/or CS was associated with a decreased likelihood of complete response (CR) (OR 0.50 [95% CI 0.30-0.82]), shorter overall survival (OS) (HR 2.12 [1.57-2.85]), and progression-free survival (PFS) (HR 1.66 [1.24-2.22]). When considered independently, both PIM and CS maintained a detrimental association with OS.

After multivariable adjustment, post-CAR-T exposure to either PIM and/or CS was not associated with CR, OS, or PFS. However, when PIM was considered independently, it was associated with shorter OS compared to non-exposed patients (HR 1.49 [1.00-2.11]). In multivariable Cox regression models, patients with post-CAR-T exposure to either PIM and/or CS for 10 days or more had shorter OS (HR 1.55 [1.01-2.37]), but not inferior PFS or CR, compared to those with no exposure. Notably, patients with exposure >10 days had higher pre-CAR-T LDH and more severe CRS and ICANS. Shorter exposure (<10 days) was not associated with lower OS or PFS or lower CR rates compared to no exposure.

Conclusions and Perspectives: In this large international multicenter study, two-thirds of patients were exposed to broad-spectrum antibiotics after CAR-T cell infusion, often for durations exceeding a week. Importantly, initiation of broad-spectrum antibiotics after CAR-T infusion with an exposure of less than 10 days did not appear to compromise anti-lymphoma treatment efficacy. These findings may help guide antibiotic use in patients undergoing CAR-T therapy.

Disclosures: Ghilardi: Vittoria Biotherapeutics: Honoraria. Peled: Seres Therapeutics: Patents & Royalties, Research Funding; Crestone Inc: Consultancy; CSL Behring: Consultancy; DaVolterra: Consultancy; Postbiotics Plus Research: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Canaccord Genuity, Inc: Consultancy; MaaT Pharma: Consultancy; Prodigy Biosciences: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Nasta: MERCK: Other: DSMB; Acrotech: Membership on an entity's Board of Directors or advisory committees; ADCT: Membership on an entity's Board of Directors or advisory committees; GenMab: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Takeda: Research Funding; Pharmacyclics: Research Funding; Loxo/Lilly: Research Funding; FortySeven/Gilead: Research Funding; ATAEA: Research Funding; ASTEX: Research Funding; ONO therapeutics: Research Funding; Caribou Biosciences: Research Funding. Rejeski: BMS/celgene: Consultancy, Honoraria; Pierre-Fabre: Other: Travel support; novartis: Honoraria; kite/gilead: Consultancy, Honoraria, Other: Travel support, Research Funding. Boardman: Bristol Myers Squibb: Consultancy; OncLive: Honoraria; Cancer Study Group, LLC: Consultancy. Scordo: Miltenyi Biotec: Consultancy; Sanofi: Research Funding; Kite - A Gilead Company: Consultancy; Angiocrine Biosciences, Inc.: Research Funding; MJH Life Sciences (Cancer Network): Honoraria; IDEOlogy: Honoraria; Medscape: Honoraria; Amgen: Research Funding; Omeros Corporation: Consultancy, Research Funding. Falchi: Genentech, Roche, Genmab, AbbVie, Innate, BeiGene: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; EvolveImmune: Consultancy; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Taylor Francis: Other: Journal Editor; Genmab: Consultancy, Research Funding; Genentech, Roche, Genmab, Abbvie, Sanofi, EvolveImmune: Honoraria; Kaplan: Other: CME Presentation: Projects in Knowledge; Roche: Consultancy, Research Funding; Memorial Sloan Kettering Cancer Center: Current Employment; AbbVie, Genentech, ADC Therapeutics, Seagen, Ipsen: Membership on an entity's Board of Directors or advisory committees. Svoboda: TG Therapeutics: Honoraria; Adaptive: Honoraria, Research Funding; Merck: Honoraria; Abbvie: Honoraria; Atara: Honoraria; BMS: Honoraria; Incyte: Research Funding; Seagen: Honoraria; GenMab: Honoraria. Chong: Nurix: Research Funding; CARGO: Research Funding; Genentech/Roche: Research Funding; AbbVie: Research Funding; AstraZeneca: Consultancy, Research Funding; Beigene: Consultancy; Genmab: Research Funding. Barta: Kyowa Kirin: Consultancy; BMS: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees; Acrotech: Consultancy; Daiichi Sankyo: Consultancy. Landsburg: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GenMab: Honoraria; Calithera: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Shah: Janssen, Amgen, Beyond Spring, BMS, GPCR, DSMB with ArcellX.: Research Funding. Palomba: Bristo Meyer Squibb: Consultancy; Synthekine: Consultancy; Novartis: Consultancy; Cellectar: Consultancy. Salles: BMS/Celgene: Consultancy; Genentech/Roche: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Kite/Gilead: Consultancy; Incyte: Consultancy; Genmab: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Merck: Consultancy; Ipsen: Consultancy, Research Funding; BeiGene: Consultancy; Molecular Partners: Consultancy; Nurix: Research Funding. Park: Takeda: Consultancy; Autolus, Fate Therapeutics, Genentech, InCyte, Servier, Sobi, Takeda (Institution): Research Funding; Curocell: Current equity holder in publicly-traded company; Adaptive Biotechnologies, Affyimmune, Allogene, Amgen, Artiva Biotherapeutics, Autolus, Bright Pharmaceutical Services, BMS, Caribou Biosciences, Curocell, Galapagos, Gilead Sciences, Intellia, In8Bio, Kite, Novartis, Pfizer, Servier, Sobi, Synthekine: Consultancy. Schuster: viTToria biotherapeutics: Consultancy; Pharmacyclics: Consultancy, Research Funding; Gilead: Research Funding; Acerta: Consultancy; Nordic Nanovector: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Legend Biotech: Consultancy, Honoraria; Kite Pharmaceuticals: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Genmab: Consultancy; AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Consultancy, Honoraria, Research Funding; Celgene/Juno Therapeutics: Consultancy, Honoraria, Research Funding; Caribou Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioNTech: Consultancy; BeiGene: Consultancy, Honoraria. Subklewe: Amgen, BMS/Celgene, Gilead/Kite, Janssen, Miltenyi Biotec, Molecular Partners, Novartis, Roche, Seagen, Takeda: Research Funding; AbbVie, Amgen, Autolus, AvenCell, BMS, CanCell Therapeutics, Genmab US, Gilead, Ichnos Sciences, Incyte Biosciences, Interius BioTherapeutics, Janssen, Miltenyi Biomedicine, Molecular Partners, Nektar Therapeutics, Novartis, Orbital Therapeutics, Pfizer,: Honoraria; AstraZeneca, BMS, Gilead/Kite, GSK, Janssen, LAWG, Novartis, Pfizer, Roche, Springer Healthcare: Speakers Bureau. Avigdor: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; BeiGene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Speakers Bureau; Ascentage: Consultancy, Honoraria, 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; Karyospharm: Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, 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; 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. Perales: Adicet: Consultancy; Caribou Biosciences: Consultancy; Allogene: Consultancy, Research Funding; VectivBio AG: Consultancy; NexImmune: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Omeros: Current equity holder in publicly-traded company; OrcaBio: Current equity holder in publicly-traded company; ImmPACT Bio: Consultancy; Karyopharm: Consultancy; Merck: Consultancy; OrcaBio: Consultancy; Miltenyi Biotec Incorporated: Consultancy; Kite Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy; Sanofi S.A.: Consultancy; Nektar Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Jazz Pharmaceuticals: Consultancy; Miltenyi Biotec: Consultancy, Research Funding; Sellas Life Sciences: Research Funding; Incyte: Consultancy, Research Funding; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy. Ruella: Vittoria Biotherapeutics: Current equity holder in private company, Patents & Royalties; AbClon Inc.: Other: Consultancy, Research Funding.

*signifies non-member of ASH