Abstract
Background: Chimeric antigen receptor (CAR) T-cell therapies have transformed the therapeutic landscape for relapsed or refractory B-cell malignancies in heavily pretreated populations. Six CAR T-cell products have been approved by the U.S. Food and Drug Administration (FDA) to date: tisagenlecleucel (Tisa-cel), axicabtagene ciloleucel (Axi-cel), brexucabtagene autoleucel (Brexu-cel), lisocabtagene maraleucel (Liso-cel), ciltacabtagene autoleucel (Cilta-cel), and idecabtagene vicleucel (Ida-cel), for pediatric and adult B-cell acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), multiple myeloma, follicular lymphoma and mantle cell lymphoma. While clinical trials have established the efficacy and safety of CAR T-cell therapies, long-term real-world data on secondary malignancies and recurrence/relapse patterns are limited. In January 2024, the FDA highlighted the serious risk of T-cell malignancies in the Black Box warning of the products. We conducted a comprehensive FAERS-based analysis to characterize secondary malignancies, recurrent disease, and unique neoplasms reported after CAR T-cell therapy, aiming to identify product-specific patterns that may inform surveillance strategies, regulatory oversight, and risk mitigation.
Methods: A retrospective pharmacovigilance analysis was performed using FAERS reports from initial product approval through Q1 2025 for Tisa-cel, Axi-cel, Brexu-cel, and Liso-cel. Data was filtered to capture only post-CAR T-cell events and reports listing “Neoplasms Benign, Malignant and Unspecified” after CAR T-cell therapy were included. Demographics, malignancy subtypes, and serious outcomes were descriptively analyzed.
Results: Of 13,685 adverse events reported in the FAERS database, 2,722 (19.9%) were neoplasm-related, including 1,226 linked to Axi-cel (45.1%), 1,169 to Tisa-cel (42.9%), 258 to Brexu-cel (9.5%), and 69 to Liso-cel (2.5%). Males accounted for 55.3% of reports, females 30.5%, and 14.1% were unspecified. The majority of cases occurred in adults aged 18–85, with Tisa-cel being the only product with meaningful pediatric representation. Estimated mean ages were 52.8 years (Axi-cel), 60.0 years (Brexu-cel), 60.7 years (Liso-cel), and 40.6 years (Tisa-cel).
Event patterns differed by product.
Tisa-cel: Malignant neoplasm progression (n=444, 38.0%), recurrent ALL (n=310, 26.5%), DLBCL (n=239, 20.4%), relapsed/refractory DLBCL (n=201, 17.2%), second primary malignancy (SPM) (n=114, 9.8%), ALL (n=84, 7.2%), and myelodysplastic syndrome (MDS) (n=56, 4.8%).
Axi-cel: MDS (n=235, 19.2%), DLBCL (n=234, 19.1%), acute myeloid leukemia (AML) (n=91, 7.4%), recurrent DLBCL (n=62, 5.1%), squamous cell carcinoma of the skin (n=60, 4.9%), lymphoma (n=58, 4.7%), and B-cell lymphoma (n=37, 3.0%).
Brexu-cel: MDS (n=41, 15.9%), squamous cell carcinoma of the skin (n=35, 13.6%), basal cell carcinoma (n=30, 11.6%), recurrent mantle cell lymphoma (n=29, 11.2%), mantle cell lymphoma (n=22, 8.5%), AML (n=12, 4.7%), and recurrent ALL (n=12, 4.7%).
Liso-cel: Malignant neoplasm progression (n=18, 26.1%), MDS (n=11, 15.9%), tumor pseudoprogression (n=6, 8.7%), DLBCL (n=5, 7.2%), AML (n=5, 7.2%), peripheral T-cell lymphoma, unspecified (n=4, 5.8%), and basal cell carcinoma (n=3, 4.3%).
Rare and unique malignancies (≤1.5% per product) were identified across therapies. Tisa-cel was linked to single cases of glioblastoma multiforme, sarcoma, pharyngeal cancer, and pancreatic adenocarcinoma.Axi-celwas associated with 4 cases of Kaposi's sarcoma and single cases of lung carcinoid tumor, leiomyosarcoma, neuroendocrine carcinoma of the skin, and ocular neoplasm. Brexu-cel was linked to alveolar rhabdomyosarcoma (2 cases) and single cases of laryngeal squamous cell carcinoma, glioneuronal tumor, and leukemia cutis. Liso-cel was associated with angiocentric lymphoma, gastric cancer, pancreatic carcinoma, and metastatic adenocarcinoma.
Mortality was reported in 41.4% of Tisa-cel, 40.2% of Axi-cel, 36.2% of Liso-cel, and 23.3% of Brexu-cel cases, while hospitalizations ranged from 11.6% to 24.5%, and permanent disability occurred in up to 2.1% of cases.
Conclusion: Our FAERS analysis reveals distinct patterns of secondary primary malignancies and relapsed diseases following CAR T-cell therapy in real-world settings. The identification of myelodysplastic syndromes, cutaneous neoplasms, and rare T-cell or solid tumors highlights the need for vigilant post-therapy surveillance.
