Background Chimeric antigen receptor (CAR) T-cell therapy has been compared with established non-CAR T treatments in several hematological malignancies, but the magnitude and consistency of benefit across diseases and comparators remain unclear. We conducted a systematic review and meta-analysis of comparative studies in non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), and multiple myeloma (MM). Methods 71 comparative studies evaluating CAR T-cell therapy versus standard chemoimmunotherapy (SOC), targeted therapy (TAT), transplantation, chemotherapy or donor lymphocyte infusion (DLI) comparators were included. Outcomes were analyzed separately by disease entity. Treatment effects were summarized using odds ratios (ORs) for response and hazard ratios (HRs) for survival with random-effects models. Results In NHL, largely driven by large B-cell lymphoma (LBCL), CAR T-cell therapy increased response compared with SOC (OR=2.48, 95% CI=1.35–4.57) and improved overall survival (OS) (HR=0.61, 95% CI=0.48–0.78). Progression-free survival (PFS) was longer with CAR T-cells therapy than SOC in second-line LBCL, whereas no clinical advantage was observed over TAT or transplantation. In follicular lymphoma, CAR T-cells prolonged PFS versus SOC, while OS differences varied across comparators. In MM, CAR T-cells increased PFS compared with SOC or TAT (HR=0.30, 95% CI=0.11–0.77) and OS favored CAR T-cell infused patients. In ALL, OS favored CAR T-cell versus chemotherapy or DLI (HR 0.30, 95% CI=0.25–0.36) and was associated with fewer graft-versus-host disease events after transplantation. Conclusions CAR T-cell therapy provides disease- and comparator-specific efficacy advantages without increased overall toxicity. Benefits are most consistent for PFS in LBCL and MM, however, in ALL, further comparator-specific evidence is needed.
