Background: CAR-T cell therapies have revolutionized cancer therapeutics with durable responses in hematologic malignancies. However, toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) are well-established off-target effects of CAR-T therapy. Immune effector cell (IEC) therapy can result in hemophagocytic lymphohistiocytosis (HLH)-like events, which are now understood as separate entities. Rare and fatal, HLH is characterized by abnormal activation of natural killer (NK) cells, macrophages, and cytotoxic T-lymphocytes; this leads to supraphysiologic production of cytokines and immune-mediated organ system damage. Expert consensus review defines IEC-HS as the development of pathologic features of HLH/macrophage activation independent from CRS and ICANS attributed to IEC therapy, including new onset or worsening cytopenia, hyperferritinemia (>2 times the upper limit of normal), coagulopathy with hypofibrinogenemia, and elevated transaminases. Few clinical studies have shown IEC-HS in Acute Lymphocytic Leukemia (ALL), especially in the pediatric and adolescent populations. However, the incidence and risk of IEC-HS exposure to CD19 and BCMA CAR-T are yet to be determined in B-cell lymphomas and Myelomas. The FDA Adverse Event Reporting System (FAERS) contains circumstantial case reports and serious post-CAR-T therapy IEC-HS. This retrospective analysis from the FAERS aims to address these questions and estimate the risk of IEC-HS with CAR-T cell therapies.

Methods: FAERS is a publicly accessible database of adverse event reports associated with various therapies, including CAR-T cell therapies. To estimate the risk of HLH-like syndrome associated with CAR-T treatment, we analyzed the reporting of four CD19 CAR-T therapies (Axicabtagene Ciloleucel, Brexucabtagene Autoleucel, Tisagenlecleucel, and Lisocabtagene Maraleucel) and BCMA CAR-T (Idecabtagene Vicleucel) from the database between 2016 and 2023. Statistical analysis involved a disproportionality analysis using a reported odds ratio (ROR). OpenVigil, a software package used to analyze pharmacovigilance data, enabled the calculation of the ROR with a 95% confidence interval (CI). ROR greater than one, p<0.05, and a confidence interval not including one was considered significant.

Results: Between 2016 and April 2023, the FAERS database recorded 8,302 CD19 CAR-T therapies (axicabtagene ciloleucel, n = 4,496; brexucabtagene autoleucel, n = 713; tisagenlecleucel n = 27,51; lisocabtagene maraleucel; n = 342) and 472 BCMA CAR-T therapies, Idecabtagene Vicleucel. We identified 177 reported HLH events as the primary events in patients receiving CAR-T therapies (CD19 CAR-T n = 165; BCMA n = 12). Thirty-six (20.3%) were reported as single IEC-HS, 96 (54.2%) as combined IEC-HS and CRS, 9 (5.1%) as combined IEC-HS and ICANS, and 36 (20.3%) as having all three IEC-related toxicities. The median age was 57 (4-89) years, and males > females at a ratio of 2:1. The study's limitation is that medical personnel reported most of the adverse events (n = 166 of 177 [94%]), and it is unclear if the diagnosis of IEC-HS followed current diagnostic criteria. The CD19 CAR-T was primarily associated with B-cell lymphomas (n = 104, 60.0%), followed by R/R ALL (n= 39, 22.0%) and Chronic Lymphocytic Leukemia, CLL (n = 3, 1.7%). Their combined elevated risk for IEC-HS was greater than that of patients in the database who had not been exposed [ROR, 63.6; 95% CI 54.7-74.1] [p<0.001]. In addition, we conducted a stratified analysis for each drug. Tisagenlecleucel had the highest risk for IEC-HS among the CD19 CAR-T drugs [ROR, 82.3; 95% CI 65.5-104.0] [p<0.001]. The risk was also significant with Idecabtagene Vicleucel [ROR, 73.5; 95% CI 41.4-130.5]. Overall, the results of the study indicate a strong association between CAR-T cell therapy exposure and IEC-HS.

Conclusion: CAR-T cell therapy poses a risk for rare IEC-HS, CRS, and ICANS, necessitating early detection to minimize morbidity and mortality. The study's results will be compared to the institutional patient cohort for annual meeting. Understanding factors contributing to this rare complication is crucial for optimizing patient outcomes and ensuring safe CAR T cell therapy use.

Strati:Astrazeneca Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; ALX Oncology: Research Funding; Roche Genentech: Consultancy; Hutchinson MedoPharma: Consultancy; Kite Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sobi: Membership on an entity's Board of Directors or advisory committees, Research Funding. Srour:Orca Bio: Research Funding. Wang:BeiGene: Consultancy, Honoraria, Research Funding; Scripps: Honoraria; Eastern Virginia Medical School: Honoraria; Dava Oncology: Honoraria, Other: Travel; CAHON: Honoraria; Molecular Templates: Research Funding; Vincerx: Research Funding; Anticancer Association: Honoraria; Loxo Oncology: Consultancy, Research Funding; Juno Therapeutics: Research Funding; Celgene: Other: Travel, Research Funding; Genentech: Consultancy, Research Funding; WebMD: Honoraria; Deciphera: Consultancy; Genentech: Consultancy, Research Funding; InnoCare: Consultancy, Research Funding; Amphista Therapeutics Limited: Consultancy; Pharmacyclics: Consultancy, Honoraria, Research Funding; Oncternal: Consultancy, Research Funding; Parexel: Consultancy; Pepromene Bio: Consultancy; Milken Institute: Consultancy; Miltenyi Biomedicine: Consultancy; Genmab: Honoraria, Research Funding; i3Health: Honoraria; IDEOlogy Health: Honoraria; Medscape: Honoraria; VelosBio: Consultancy, Research Funding; Bantam Pharmaceutical: Honoraria; Studio ER Congressi: Honoraria; AstraZeneca: Consultancy, Honoraria, Other: Travel, Research Funding; Be Biopharma: Consultancy; Bristol Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel, Research Funding; Leukemia & Lymphoma Society: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Eli Lilly and Company: Consultancy, Research Funding; Merck: Consultancy, Honoraria; ADC Therapeutics America: Consultancy; Acerta Pharma: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Meeting Minds Experts: Honoraria; MD Education: Honoraria; MJH Life Sciences: Honoraria; Moffit Cancer Center: Honoraria; NIH: Honoraria; Nurix: Honoraria; Oncology Specialty Group: Honoraria; OncLive: Honoraria; Physicians Education Resources (PER): Honoraria, Other: Travel; Practice Point Communications (PPC): Honoraria; BioInvent: Consultancy, Honoraria, Research Funding; DTRM Biopharma (Cayman) Limited: Consultancy; Hebei Cancer Prevention Federation: Honoraria; BGICS: Honoraria; Clinical Care Options: Honoraria; Epizyme: Consultancy, Honoraria; CSTone: Consultancy; Practice Point Communications: Honoraria; Physicians Education Resources: Honoraria; Pharmacyclics: Honoraria; OMI: Honoraria; Mumbai Hematology Group: Honoraria; TS Oncology: Honoraria; Imedex: Honoraria. Jain:AstraZeneca: Consultancy, Honoraria. Shpall:Navan: Membership on an entity's Board of Directors or advisory committees; Syena: Other: License agreement; Takeda: Other: License agreement; Affimed: Other: License agreement; Fibrobiologics: Membership on an entity's Board of Directors or advisory committees; Axio: Membership on an entity's Board of Directors or advisory committees; Celaid Therapeutics: Membership on an entity's Board of Directors or advisory committees; Adaptimmune: Membership on an entity's Board of Directors or advisory committees; NY Blood Center: Membership on an entity's Board of Directors or advisory committees. Neelapu:Precision Biosciences: Research Funding; Kite, A Gilead Company: Consultancy, Other: Advisory Board Member, Research Funding; N/A: Patents & Royalties: Related to cell therapy and the safety switch described (intellectual property); Longbow Immunotherapy: Current holder of stock options in a privately-held company; Carsgen: Consultancy; Orna Therapeutics: Consultancy, Other: Advisory board member; Takeda: Consultancy, Other: Advisory board member; Synthekine: Consultancy, Other: Advisory board member; Morphosys: Consultancy, Other: Advisory board member; Janssen: Consultancy, Other: Advisory board member; Sana Biotechnology: Consultancy, Other: Advisory board member, Research Funding; Caribou: Consultancy, Other: Advisory board member; Astellas Pharma: Consultancy, Other: Advisory board member; Chimagen: Consultancy, Other: Advisory board member; Bluebird Bio: Consultancy, Other: Advisory board member; Fosun Kite: Consultancy, Other: Advisory board member; Immunoadoptive Cell Therapy Private Limited: Consultancy, Other: Scientific Advisory Board; Bristol Myers Squibb: Consultancy, Other: Advisory Board Member, Research Funding; Adicet Bio: Consultancy, Other: Advisory board member, Research Funding; Incyte: Consultancy, Other: Advisory board member; Athenex: Consultancy, Other: Advisory board member; Allogene: Consultancy, Other: Advisory board member, Research Funding; Sellas Life Sciences: Consultancy, Other: Advisory board member; Merck: Consultancy, Other: Advisory Board Member. Patel:Takeda: Consultancy; AbbVie; Allogene Therapeutics, Inc.; Arcellx; Bristol Myers Squibb/Celgene Corporation; Cellectis; Janssen Pharmaceuticals, Inc.; Nektar Therapeutic; Poseida Therapeutics; Precision BioSciences, Inc.; and Takeda Pharmaceuticals U.S.A., Inc.: Research Funding; AbbVie; Arcellx, AstraZeneca; Bristol Myers Squibb/Celgene Corporation; Caribou Science; Cellectis; Curio Bioscience; Genentech; Janssen Pharmaceuticals, Inc.; Karyopharm; Legend Biotech; Merck & Co., Inc.; Oncopeptides; Pfizer; Precision BioSciences: Consultancy. Iyer:Salarius: Consultancy; Pfizer: Research Funding; Ono: Research Funding; Astra Zeneca: Research Funding; Legend: Research Funding; Acrotech: Consultancy, Research Funding; Innate: Research Funding; CRISPR: Consultancy, Research Funding; Seagen: Consultancy, Research Funding; Merck: Research Funding; Drenbio: Research Funding; Yingli: Consultancy, Research Funding; CuraBio: Speakers Bureau; American Society of Hematology: Speakers Bureau; American Society of Transplant and Cellular Therapy: Speakers Bureau.

Figure 1
Figure 1
View largeDownload slide
This content is only available as a PDF.
2023
Sign in via your Institution