Safety and efficacy of CAR T-cell therapy in CNS lymphoma: A meta-analysis

Background: The efficacy and safety of Chimeric Antigen Receptor T-cell (CART) therapy in Central Nervous System Lymphoma (CNSL) remain uncertain, given the limited representation of CNS involvement in pivotal CAR T-cell trials. This meta-analysis synthesized data from studies evaluating outcomes in both primary (PCNSL) and secondary CNS lymphoma (SCNSL) cohorts treated with CART. Methods: A comprehensive search was performed across PubMed, Scopus, Web of Science, and clinical registries up to June 2025. Studies reporting efficacy or toxicity outcomes in CNSL following CART therapy were included. Proportions were stabilized using the Freeman-Tukey double arcsine transformation and pooled using inverse variance weighting. Between-study heterogeneity was estimated with the DerSimonian-Laird method, and τ² confidence intervals were calculated via the Jackson approach. Random- or fixed-effects models were applied based on I² ≥ 50% or < 50%, respectively. Publication bias was assessed using Egger's regression. Subgroup and multiple meta-regression analyses evaluated moderators including CNS category (PCNSL, SCNSL, or Both) and publication year. Results: Data from thirty-nine studies encompassing 1,457 participants were meta-analyzed. The pooled overall response rate (ORR) was 0.75 [95% CI: 0.70-0.79; I² = 52.2%]. Complete response (CR) rate was 0.52 [95% CI: 0.46-0.58; I² = 63.0%], and partial response (PR) rate 0.18 [95% CI: 0.14-0.22; I² = 50.40%]. No significant publication bias was detected. Meta-regression indicated no significant effect of publication year or CNS category on ORR. Cytokine Release Syndrome (CRS) occurred in 83.8% [95% CI: 79.1-88.2; I² = 71.4%], with grade ≥3 CRS in 5.74% [95% CI: 3.21-8.76; I² = 62.1%]. Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) was reported in 44.4% [95% CI: 35.9-53.1; I² = 86.5%], with severe (grade ≥3) events in 16.8% [95% CI: 11.9-22.4; I² = 74.3%]. Conclusions: CART therapy achieves robust response rates in CNS lymphoma, with efficacy comparable between PCNSL and SCNSL. Neurotoxicity remains frequent but manageable, and severe CRS events are infrequent.