Neurotoxicity and Rare Adverse Events in BCMA-Directed CAR T Cell Therapy: A Comprehensive Analysis of Real-World FAERS Data

Moataz Ellithi; Magdi Elsallab; Matthew A Lunning; Sarah A Holstein; Smriti Sharma; Jonathan Q Trinh; Jihyun Ma; Marcela V Maus; Matthew J Frigault; Christopher R D'Angelo

doi:10.1016/j.jtct.2024.12.002

Neurotoxicity and Rare Adverse Events in BCMA-Directed CAR T Cell Therapy: A Comprehensive Analysis of Real-World FAERS Data

Transplant Cell Ther. 2024 Dec 12:S2666-6367(24)00803-0. doi: 10.1016/j.jtct.2024.12.002. Online ahead of print.

Authors

Affiliations

¹ Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska; Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, New York.
² Harvard-MIT Center for Regulatory Science, Harvard Medical School, Boston, Massachusetts; Cellular Immunotherapy Program, Mass General Cancer Center, and Department of Medicine, Harvard Medical School, Boston, Massachusetts. Electronic address: melsallab@mgh.harvard.edu.
³ Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
⁴ Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
⁵ Department of Biostatistics, University of Nebraska Medical Center, Omaha, Nebraska.
⁶ Cellular Immunotherapy Program, Mass General Cancer Center, and Department of Medicine, Harvard Medical School, Boston, Massachusetts.

PMID: 39672542
DOI: 10.1016/j.jtct.2024.12.002

Abstract

Chimeric antigen receptor T (CAR T) cell therapies have emerged as a valuable treatment modality for patients with plasma cell disorders. As the population of patients receiving CAR T therapies grows, the identification and management of associated rare toxicities become increasingly crucial. This study aims to identify safety signals associated with commercial anti-B-cell maturation antigen (BCMA) CAR T therapies using the Food and Drug Administration Adverse Event Reporting System (FAERS). We performed a cross-sectional analysis of the adverse events (AE) reports associated with ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel), submitted to FAERS between January 2021 and December 2023. AE frequencies were summarized using descriptive statistics, and safety signals were explored by measuring the reporting odds ratio (ROR) compared to control groups. Among 4,472,782 unique FAERS reports, 1,496 involved BCMA-directed CAR-T therapies. AEs reported more frequently included immune-associated conditions and neurological disorders. Neurotoxicity associated with cilta-cel predominantly manifested as cranial nerve palsies, Parkinson's disease and parkinsonism, and acute and chronic polyneuropathies, while ide-cel neurotoxicity presented as confusion, disorientation, seizures, balance disturbances, and tremors. In cilta-cel reports, other safety signals included Guillain-Barre syndrome (ROR: 17.1, 95% CI 6.1 to 47.5), intracranial hemorrhage and cerebrovascular accidents (ROR: 2.9, 95% CI 1.8 to 4.8), Haemophilus infections (ROR: 34.2, 95% CI 11.8 to 98.9) and cytomegalovirus infections (ROR: 3.9, 95% CI 1.6 to 9.5). For ide-cel, new signals included parkinsonism (ROR: 13.7, 95% CI 5.5 to 34.5), acute and chronic sarcoidosis (ROR: 197.1, 95% CI 32.9 to 1180.1), ventricular arrhythmias, and cardiac arrest (ROR: 3.9, 95% CI 2.1 to 7.3). This analysis provides a comprehensive insight into the safety profiles of the commercial BCMA-directed CAR T therapies, underscoring the importance of vigilant post-marketing surveillance to mitigate potential risks.

Keywords: CAR T; FDA; Myeloma; Neurotoxicity; Postmarketing; Safety.