Hepatic adverse-event reporting after CAR T-cell therapy: a pharmacovigilance analysis of FAERS and Canada Vigilance

Hepatic adverse events after chimeric antigen receptor (CAR) T-cell therapy may reflect cytokine release syndrome (CRS), immune effector cell-associated haemophagocytic syndrome/haemophagocytic lymphohistiocytosis (IEC-HS/HLH), or immune-mediated drug-induced liver injury. We characterised product-specific hepatic adverse-event reporting and separated CRS-associated, HLH-associated, and residual patterns. We analysed deduplicated primary-suspect CAR T-cell reports in the FDA Adverse Event Reporting System (FAERS; 2016Q3-2026Q1), with directional comparison in Canada Vigilance. Hepatic events were identified using a prespecified 244-term MedDRA dictionary. The reporting odds ratio, proportional reporting ratio, information component, and empirical Bayes geometric mean were calculated for prespecified comparators. Sensitivity analyses excluded reports mentioning CRS or HLH and examined delayed-onset and hepatic phenotypes. Among 4,700,843 FAERS reports, 19,820 identified a CAR T-cell product as the primary suspect, and 734 contained hepatic events. Median onset was 5 days, with 73.5% occurring within 14 days. CRS was co-mentioned in 77.0% of hepatic reports, compared with 9.5% for HLH-spectrum terms. Excluding CRS reduced the pooled reporting odds ratio from 1.36 to 0.54, whereas excluding HLH preserved the association. Idecabtagene vicleucel showed the most consistent product-level pattern and retained a supportive pattern after excluding CRS-co-mentioned reports (ROR 2.22, 95% CI 1.38–3.57). No product retained four-method positivity beyond 14 days. Phenotype analyses identified product-specific mixed and cholestatic reporting patterns. Canada Vigilance showed a similar CRS co-mention proportion (75.0%), although the small number of hepatic adverse-event reports (n = 4) precluded meaningful product-level analysis. Hepatic adverse-event reporting after CAR T-cell therapy was predominantly early and possibly associated with CRS rather than HLH. Persistent CRS-independent reporting, particularly with idecabtagene vicleucel, warrants prospective clinical evaluation.