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912 CAR-Tography: Longitudinal Mapping of CAR-T Toxicities across B-Cell Malignancies Reveals Biologically Distinct and Prognostically Relevant Toxicity Phenotypes

Program: Oral and Poster Abstracts
Type: Oral
Session: 702. CAR-T Cell Therapies: Basic and Translational: Acute and Late Toxicities Following CAR-T Cell Therapy
Hematology Disease Topics & Pathways:
Research, Translational Research, Lymphomas, Non-Hodgkin lymphoma, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Diseases, Aggressive lymphoma, Treatment Considerations, Biological therapies, Lymphoid Malignancies, Adverse Events
Monday, December 9, 2024: 4:00 PM

Kai Rejeski, MD1,2, Teng Fei, PhD3*, Alejandro Luna, MD, PhD1*, Mohammad Alhomoud, MD1, Yannis K. Valtis, MD4, Noriko Nishimura, MD5, Marina Gomez-Llobell, MD1*, Noa Golan Accav6*, Ofrat Beyar-Katz, MD, PhD7*, Sandeep S. Raj, MD1, Magdalena Corona, MD, PhD1*, Alfredo Rivas-Delgado, MD, PhD4, Hamza Sloan Hashmi, MD5*, Sridevi Rajeeve, MD5, Efrat Luttwak, MD8, Michael Scordo, MD9, Gunjan L. Shah, MD10, Maria Lia Palomba, MD8, Michael von Bergwelt-Baildon, MD, PhD11*, Marion Subklewe, MD12, Abraham Avigdor, MD6, Ronit Marcus, MD13*, Avichai Shimoni, MD6*, Arnon Nagler, MD6, Tsila Zuckerman, MD14, Jabour Halloun, MD15*, Uri Greenbaum, MD16, Sham Mailankody, MD, MBBS5, Saad Z. Usmani, MD5, Gilles Salles, MD, PhD17, Jae H. Park, MD18, Miguel Angel Perales, MD4 and Roni Shouval, MD, PhD1

1Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
2Department of Medicine III, LMU University Hospital, LMU Munich, Munich, Germany
3Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
4Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
5Myeloma Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
6Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel Aviv, Israel
7Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus; The Ruth and Bruce Rappaport Faculty of Medicine, Haifa, Israel
8Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
9Transplant and Cellular Therapy Services, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY
10Transplant and Cellular Therapy Services, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
11Department of Medicine III, University Hospital, LMU Munich, Munich, Germany
12Department of Medicine III, LMU University Hospital, Munich, Germany
13Division of Hematology and Bone Marrow Transplantation, The Chaim Sheba Medical Center, Ramat Gan, Israel
14Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Moshav Ein Ayalla, Israel
15Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel
16Department of Hematology, Soroka University Medical Center, Beer Sheva, Israel
17Lymphoma Service Chief, Memorial Sloan Kettering Cancer Center, New York, NY
18Cell Therapy Service and Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY

Background: CAR T-cell therapy (CAR-T) results in a unique spectrum of toxicities, affecting morbidity, mortality, and quality of life. Traditionally, immunotoxicities like cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are studied independently. However, the overall toxicity landscape of CAR-T is complex and interdependent, with patterns that remain incompletely understood. To address this, we mapped early CAR-T toxicities day-by-day across multiple dimensions to understand their biological and clinical implications.

Study Design: This international multicenter observational study included 558 adult patients treated with standard-of-care CD19 or BCMA CAR-T therapies for relapsed/refractory B-cell malignancies (77% B-NHL, 7% B-ALL, 16% multiple myeloma). The product breakdown was: axi-cel (39%), tisa-cel (22%), liso-cel (17%), cilta-cel (9%), ide-cel (7%), brexu-cel (6%). A team of trained investigators evaluated four major toxicity domains daily, from lymphodepletion until 30 days post-infusion. CRS (1) and ICANS (2) were graded according to ASTCT criteria. Infections (3) were clinically or microbiologically defined and graded per Hill et al., Blood 2018. Hematotoxicity grades (4) were derived computationally using serial neutrophil counts (EHA/EBMT ICAHT grading).

Results: We comprehensively reviewed over 20,000 patient days, resulting in 80,352 unique toxicity datapoints. To quantify the overall burden of toxicity at a patient-level, we first devised a cumulative toxicity index (CTI) reflecting the aggregated severity and duration of the four major toxicity domains. Across all patients, the median CTI was 23 (IQR 10-51). We identified product-specific variations of CTI. Among CD19 CAR-T products, brexu-cel had the highest CTI, followed by axi-cel, tisa-cel and liso-cel (45 vs. 27 vs. 24 vs. 18, p=0.003). For BCMA CAR-T products, cilta-cel and ide-cel had a comparable CTI (17 vs. 14, p=0.6).

Next, we employed a topographical imaging approach to visualize patient-level toxicity profiles across four dimensions of toxicity and time. Visual inspection revealed complex interactions between these five elements, which are challenging to interpret directly. To elucidate these complexities, we applied an unsupervised learning technique—latent trajectory class analysis (Hart & Fei et al., Biometrics 2020)—to the longitudinal toxicity data, focusing on the large B-cell lymphoma cohort (n=384).

We identified three distinct toxicity phenotypes: low-tox (LT), mid-tox (MT), and high-tox (HT). The LT phenotype (n=175) was characterized by mild-to-moderate CRS, short duration of cytopenias, rare and mild ICANS, and notably, the absence of infectious complications. The MT phenotype (n=134) exhibited similar rates of CRS and ICANS, but showed longer and deeper cytopenias, and an increased infection signal throughout the first 30 days. The hallmark of the HT phenotype (n=75) was protracted and severe toxicity across all four domains. In terms of CTI, we noted a gradual increase with each phenotype (L/M/HT: 10 vs. 37 vs. 85, p<0.001). Cytokine profiling revealed divergent inflammatory signatures among the toxicity phenotypes, with the HT phenotype showing upregulation of IL-6, IL-10, and TNF-α.

The newly defined phenotypes were strongly linked to morbidity and mortality. HT patients were hospitalized longer (L/M/HT: 12 vs. 15 vs. 22 days, p<0.001), required more ICU admissions (4% vs. 5% vs. 47%, p<0.001), and had increased non-relapse mortality (1-year NRM: 3.7% vs. 4.4% vs. 12.6%, p=0.003). Notably, HT patients showed inferior PFS (1-year PFS 53% vs. 47% vs. 30%, p<0.001) and OS (1-year OS, 78% vs. 70% vs. 52%, p<0.001). In a multivariable Cox regression model accounting for age, pre-lymphodepletion LDH levels and product, the toxicity phenotype was independently associated with both PFS (HT vs. LT: HR 2.0, p=0.003) and OS (HT vs. LT: HR 1.7, p=0.007).

Conclusions: Leveraging over 80,000 longitudinal data points from a large, deeply annotated international cohort, we developed a new metric, the Cumulative Toxicity Index (CTI), to quantify the main toxicity burden in CAR-T patients. Additionally, employing an unsupervised approach, we defined biologically distinct and prognostically relevant toxicity phenotypes, underlining that CAR-T toxicities should be understood as more than the sum of their parts.

Disclosures: Rejeski: Novartis: Honoraria; BMS/CELGENE: Consultancy, Honoraria; Pierre-Fabre: Other: Travel Support; Kite/Gilead: Consultancy, Honoraria, Other: Travel Support, Research Funding. Valtis: EastRx: Consultancy. Hashmi: Karyopharm: Consultancy; Amgen: Consultancy; Janssen: Consultancy. Scordo: Sanofi: Research Funding; IDEOlogy: Honoraria; Miltenyi Biotec: Consultancy; Angiocrine Biosciences, Inc.: Research Funding; Amgen: Research Funding; Medscape: Honoraria; Kite - A Gilead Company: Consultancy; MJH Life Sciences (Cancer Network): Honoraria; Omeros Corporation: Consultancy, Research Funding. Shah: Janssen, Amgen, Beyond Spring, BMS, GPCR, DSMB with ArcellX.: Research Funding. Palomba: Cellectar: Consultancy; Synthekine: Consultancy; Novartis: Consultancy; Bristo Meyer Squibb: Consultancy, Patents & Royalties: immediate family member. von Bergwelt-Baildon: TABBY: Membership on an entity's Board of Directors or advisory committees; AMGEN, Astellas, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, KITE/Gilead Mologen, Miltenyi, MSD Sharp + Dohme, Novartis, Priothera, Roche, TABBY: Consultancy, Honoraria, Research Funding, Speakers Bureau. Subklewe: AstraZeneca, BMS, Gilead/Kite, GSK, Janssen, LAWG, Novartis, Pfizer, Roche, Springer Healthcare: Speakers Bureau; 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. Avigdor: 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; 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; 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. Mailankody: BMS, J&J, GSK, Springworks Therapeutics: Research Funding. Usmani: Bristol-Myers Squibb: Consultancy, Research Funding; Gilead: Research Funding; Amgen: Consultancy, Research Funding; Array Biopharma: Research Funding; Pharmacyclics: Research Funding; SecuraBio: Consultancy; SeaGen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Genentech: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy, Research Funding; Gracell: Consultancy; Bristol-Myers Squibb - Celgene:: Consultancy, Research Funding; Merck: Research Funding; Oncopeptides: Consultancy; Abbvie: Consultancy, Research Funding; GSK: Consultancy, Research Funding; EdoPharma: Consultancy; TeneoBio: Consultancy; SkylineDX: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Bristol-Myers Squibb - Celgene: Consultancy, Research Funding; Johnson & Johnson - Janssen: Consultancy, Research Funding. Salles: AbbVie: Consultancy, Research Funding; Molecular Partners: Consultancy; Merck: Consultancy; Incyte: Consultancy; Kite/Gilead: Consultancy; BMS/Celgene: Consultancy; Genmab: Consultancy, Research Funding; Ipsen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; BeiGene: Consultancy; Genentech/Roche: Consultancy, Research Funding; Nurix: Research Funding. Park: Curocell: Current equity holder in publicly-traded company; Autolus, Fate Therapeutics, Genentech, InCyte, Servier, Sobi, Takeda (Institution): Research Funding; 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; Takeda: Consultancy. Perales: Adicet: Consultancy; Allogene: Consultancy, Research Funding; Allovir: Consultancy; Caribou Biosciences: Consultancy; Celgene: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; OrcaBio: Consultancy, Current holder of stock options in a privately-held company; Cidara Therapeutics: Other: DSMB member; Syncopation: Consultancy; Merck: Consultancy, Research Funding; VectivBio AG: Consultancy, Research Funding; Kite/Gilead: Consultancy, Honoraria, Research Funding; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Nektar Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Vor Biopharma: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria; AbbVie: Honoraria; Sellas: Other: DSMB member; Omeros: Consultancy, Current equity holder in publicly-traded company; Sanofi: Consultancy; Astellas: Honoraria; Karyopharm: Honoraria; MorphoSys: Honoraria; Takeda: Honoraria; Medigene: Other: DSMB member; Servier: Other: DSMB member.

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