Comparative Analysis of Mortality from Serious Adverse Events Associated with CAR-T Therapies

Chimeric Antigen Receptor T-cell (CAR-T) therapy has emerged as a promising treatment for various hematological malignancies yet the safety profile of these therapies remains a critical concern. Cordas dos Santos et al. (2024) demonstrated that infections were by far the main cause of non-relapse mortality (NRM) responsible for approximately half of NRM across all disease entities while CAR T cell-specific side effects such as Cytokine Release Syndrome (CRS), Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)/neurotoxicity and hemophagocytic lymphohistiocytosis (HLH) were only minor drivers of NRM. This study analyzed the reported Serious Adverse Events (SAEs) with fatal outcome across six approved CAR-T agents.

Methods: All SAEs associated with fatal outcome (SAWFO) reported to FDA Adverse Event Reporting System (FAERS) database through Q1 2024 for US FDA approved CAR-T therapies were extracted and analyzed across each CAR-T.

Results: The FAERS dataset revealed a total of 13,646 Adverse Events reported with CAR-T out of which 1953 (14.3%) events were associated with fatal outcome. CRS was the most common SAWFO across all CAR-T therapies ranging from 26.67% (Carvykti) to 48.94% (Breyanzi). Kymriah, Tecartus, Abecma and Yescarta showed CRS frequency of 40.99%, 46.78%, 41.27% and 35.18% respectively. ICANS was the second most common SAWFO with percentages varying from 14.23% (Kymriah) to 33.92% (Tecartus). Breyanzi, Carvykti, Abecma and Yescarta showed ICANS rates of 23.40%, 16.67%, 28.57% and 19.87%, respectively. Neurotoxicity was reported as a separate event from ICANS in some cases. Yescarta had the highest incidence at 14.98%, followed by Tecartus (13.45%), Breyanzi (12.77%), Abecma (9.52%) and Carvykti (8.33%). Hematological and Infectious Complications including sepsis, septic shock, and fungal infections were reported across multiple agents but less frequently than the CRS and ICANS. HLH observed in Carvykti (8.33%), Tecartus (6.43%), Abecma (12.7%) and Yescarta (4.99%). Cardiovascular and respiratory diagnoses were noted frequently including hypotension reported with Breyanzi (8.51%), Kymriah (12.68%), and Tecartus (5.26%) and cardiac arrest noted in Breyanzi (10.64%). Respiratory failure was observed in Carvykti (5.00%). Other notable SAWFO included hyperkalaemia (12.77%) with Breyanzi, Parkinsonism (8.33%) with Carvykti, platelet count decreased (12.96%) with Kymriah, brain oedema (5.26%) and acute kidney injury (5.26%) with Tecartus.

Conclusion: Variations in frequency and types of SAWFO across approved CAR-T therapies reflect potential differences in CAR-T mechanisms of action and patient characteristics. While some could represent early cases of CRS or ICANS and were incorrectly identified as unique observations rather than aspects of an underlying syndrome CRS and ICANS were the most prevalent SAWFOs across all agents although incidence varied. This finding is in contrast to the recently published metanalysis of other data sources but under-reporting or reporting biases are possible. Differences in patient populations, disease states, and treatment protocols were not accounted for in this analysis. These findings underscore the need for careful patient selection, close monitoring, and proactive management of SAEs in CAR-T treatment together with further research to elucidate predictors of these toxicities. Identification of predictive biomarkers for severe toxicities and optimization of CAR-T cell designs to enhance safety profiles should be prioritized in order to develop strategies to mitigate risks associated with these promising but potentially toxic therapies.