Chimeric antigen receptor T-cell (CAR-T) treatment has revolutionized the therapeutic approach for relapsed or refractory hematologic malignancies. But its unique toxicity profile, particularly immune-mediated adverse events, is a significant question in comparison with other high-intensity therapy strategies. Systematic, comparative, specific assessment of CAR-T–associated toxicities are essential to guide clinical practice and institutional preparedness.

We conducted a systematic review and meta-analysis comparing the incidence and management of significant toxicities associated with CAR‐T therapy versus standard treatment approaches, including conventional chemotherapy‐based regimens, intensive monoclonal antibody–based therapies, and allogeneic hematopoietic stem cell transplantation (allo‐HSCT). The primary outcomes looked for were cytokine release syndrome (CRS), immune effector cell–associated neurotoxicity syndrome (ICANS), prolonged cytopenias, serious infections, and treatment-related mortality (TRM). Random-effects analysis was performed using random-effects models. Subgroup analyses were planned according to comparator type, sensitivity analyses excluding CRS and ICANS, temporal toxicity analyses, and clinical heterogeneity assessments.

CAR-T therapy was associated with significantly elevated risks of severe CRS and ICANS (relative risks [RRs] > 8) in relation to conventional chemotherapy, and that they might be mechanistically at baseline, suggesting fundamental differences in the underlying mechanism. These risks were reduced, though they stayed significant, when compared with the intensive monoclonal antibody–based therapies and allo-HSCT. In stark contrast, differences in prolonged cytopenia and serious infections were more modest and comparator dependent. In sensitivity analyses limited to hematologic and infectious toxicities, CAR-T therapy remained associated with increased risk of prolonged cytopenias (RR 3.10; 95% CI, 2.43–3.95) and serious infections (RR 2.00; 95% CI, 1.53–2.62), reinforcing the robustness of the findings beyond immune-mediated events. TRM was not significantly different from most comparisons. Temporal analyses showed a biphasic relationship of toxicity with early immune-mediated and intermediate/late hematologic and infectious events. The observed heterogeneity was attributed to the CAR-T construct, disease burden, prior treatment exposure, and institutional management practices.

CAR-T therapy results in a unique, temporally concentrated toxicity phenotype as opposed to a uniformly higher toxicity burden than alternative high-intensity therapies. Although immune-mediated toxicities differentiate CAR-T therapy, hematologic and infectious risks overlap significantly with those of other advanced modalities, particularly allo-HSCT. The study emphasizes the imperative need for CAR-T therapy delivered in high-therapeutic-demand settings and in well-equipped centers with standardized toxicity management strategies, consistent with balanced, individualized treatment selection.