Low-incidence adverse events (AEs): An emerging challenge in chimeric antigen receptor T-cell (CAR-T) therapy

Chimeric antigen receptor T-cell (CAR-T) therapy is a significant breakthrough in oncology; however, its use is limited by a range of distinctive toxicities. Besides well-known acute adverse events (AEs) such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), clinical experience has revealed a series of low-incidence yet potentially severe and long-term safety concerns, including delayed or chronic toxicities. This review describes the spectrum of these low-incidence AEs affecting multiple organ systems, including CAR-T-associated hemophagocytic lymphohistiocytosis/macrophage activation syndrome, respiratory complications, neurological complications beyond ICANS, cardiovascular complications, coagulopathies, secondary malignancies, and rare AEs involving other systems. These toxicities can be classified based on mechanistic analysis into four categories: CRS-extension type, on-target/off-tumor type, immune exhaustion/secondary type, and therapy-related malignancy type. The underlying pathophysiology is multifaceted, involving systemic inflammation, on-target/off-tumor effects, profound immune dysregulation, and interactions with patient-specific factors including pre-existing comorbidities, prior treatments, and genetic predispositions. Management remains challenging due to a paucity of prospective studies, incomplete mechanistic understanding, and a lack of validated predictive biomarkers and standardized diagnostic or treatment protocols. Future studies should prioritize mechanistic research, prospective validation of predictive tools, development of preventive strategies, next-generation CAR engineering, and establishment of international registries for long-term surveillance. Increasing awareness, ongoing clinical vigilance, and personalized management strategies are essential to maximize the long-term benefits of CAR-T therapy while minimizing its risks.