Association of incidence and severity of neurotoxicity with six FDA-approved chimeric receptor T-cell therapies: A meta-analysis of 61 studies including 8,376 patients.

Abstract

e23351 Background: Immune effector cell-associated neurotoxicity syndrome (ICANS) is a significant and serious side effect of chimeric antigen receptor-T (CAR-T)-cell therapies, with incidence varying widely across different CAR-T products. The true overall risk and product-specific rates of ICANS have not been fully quantified. We conducted a meta-analysis to determine the pooled incidence of ICANS, including severe ICANS (grade ≥3), across six FDA-approved CAR-T cell therapies. Methods: We conducted a systematic review of the published literature for clinical trials and observational studies reporting ICANS rates with six FDA-approved CAR-T products [axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), lisocabtagene maraleucel (liso-cel), brexucabtagene autoleucel (brexu-cel), idecabtagene vicleucel (ide-cel), ciltacabtagene autoleucel (cilta-cel)]. The primary endpoint was incidence of any grade ICANS; secondary endpoint was incidence of severe ICANS (grade ≥3). Pooled incidence proportions of any grade ICANS and grade ≥3 ICANS were estimated using a random-effects model. Between-study heterogeneity was assessed (I² statistic, Cochran Q). Results: We analyzed 61 studies encompassing 8,376 patients treated with CAR-T. Overall, the pooled incidence of any grade ICANS was 28.3% (95% confidence interval [CI] 23.6–33.6), and severe ICANS (grade ≥3) occurred in 9.4% (95% CI 7.5–11.8). Between-study heterogeneity was high (I² = 95%, p < 0.001), reflecting broad variability across products and settings. ICANS rates differed markedly by product. Any grade ICANS incidence ranged from 9.3% with cilta-cel (targeting BCMA for myeloma patients) to 60.9% with brexu-cel (targeting CD19 for lymphoma patients), with intermediate incidences for ide-cel (19.0%), tisa-cel (15.8%), liso-cel (26.5%), and axi-cel (53.3%). Similarly, grade ≥3 ICANS ranged from 3.5% with cilta-cel to 28.9% with brexu-cel, with ide-cel 3.9%, tisa-cel 4.1%, liso-cel 8.9%, and axi-cel 18.3%. Differences across products were statistically significant ( p < 0.001). Conclusions: Approximately 28% of CAR-T recipients develop ICANS, but risk varies substantially by each CAR-T product. CD28-costimulatory CD19 CAR-T therapies (axi-cel, brexu-cel) carry the highest neurotoxicity risk, whereas 4-1BB-based CD19 and BCMA-targeted CAR-T products have much lower rates. The overall risk for severe ICANS is roughly 1 in 10 patients. These findings underscore the significance of product-specific risk stratification for not only patient counseling, and strategies for monitoring and early intervention, but also providing benchmarks for developing safer next-generation CAR-T therapies.