Chimeric antigen receptor T-cell therapy and bispecific antibody sequence for large B-cell lymphoma: a systematic review and meta-analysis.

BACKGROUND: The optimal treatment sequence for large B-cell lymphoma is unknown. We aimed to assess through meta-analysis the comparative effectiveness of bispecific antibodies (BsAb) after chimeric antigen receptor T-cell therapy (CAR-T) or CAR-T after BsAb. METHODS: We performed a systematic review and meta-analysis by searching MEDLINE and Embase from Jan 1, 2010, until Sept 16, 2025, and haematological conferences in 2024 and 2025 for studies assessing effectiveness of BsAb monotherapy or combination therapy after CAR-T and CAR-T after BsAb. We assessed summary data from published studies and abstracts for survival endpoints, response outcomes, and adverse events (cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome). We performed an indirect comparison of pooled estimates from separate studies (retrospective studies and single-arm clinical trials) by an inverse variance random-effects meta-analysis. We used the Joanna Briggs Institute and Methodological Index for Non-Randomised Studies checklists for bias assessment. This study is registered with PROSPERO (CRD420251071424). FINDINGS: 2122 patients were included across 15 clinical trials and 15 retrospective studies, drawn from 14 haematology conference abstracts and 19 full text articles. Five studies represented 113 patients for CAR-T after BsAb, 20 studies represented 737 patients for BsAb after CAR-T, and five studies included BsAb combination treatments after CAR-T with 125 patients. In studies that reported demographic information (27 of 28 studies), the mean or median age ranged from 48 to 73 years. We found a pooled complete response rate for CAR-T after BsAb of 53·7% (95% CI 39·8-67·0; I2 =38·0%; four studies [n=101]) compared with 29·4% (25·1-34·0; 34·8%; 18 studies [n=680]; p=0·0008) for BsAb after CAR-T. When excluding abstracts from conferences the pooled complete response rate for BsAb after CAR-T was 28·1% (95% CI 23·3-33·4 I2 =33·3%, 12 studies [n=511]). The pooled complete response rate for BsAb combination after CAR-T was 46·4% (37·9-55·2; I2 =0·0%; five studies [n=125]) compared with 29·4% (25·1-34·0; I2 =34·8%; 18 studies [n=680]; p=0·0005) for BsAb monotherapy after CAR-T. Finally, we found an improved objective response rate in patients treated with CAR-T after BsAb compared with patients treated with CAR-T without previous BsAb exposure (pooled risk ratio of 1·62 [95% CI 1·24-2·11]; two studies [n=57, n=64]; p=0·0004). INTERPRETATION: Based on current evidence, our meta-analysis suggests that BsAb therapy before CAR-T could improve future CAR-T effectiveness for large B-cell lymphoma, although our conclusions are limited by small sample sizes. Nonetheless, our findings have important implications for the design of randomised controlled trials to identify the optimal treatment sequence of CAR-T and BsAb. FUNDING: None.