Anti-CD3/CD20 bispecific antibodies as salvage therapy after CAR-T failure in Relapsed/Refractory large B-cell lymphoma: A systematic review and meta-analysis

Abstract

Abstract Background Patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) who progress after chimeric antigen receptor T-cell (CAR-T) therapy have poor prognoses and limited treatment options. In this context, bispecific antibodies (BsAbs) have emerged as a promising salvage strategy. We conducted a meta-analysis to evaluate the efficacy and safety of BsAbs in patients with R/R LBCL following CAR-T therapy failure. Methods Following PRISMA guidelines, we systematically searched PubMed, Embase, Web of Science and the Cochrane Library through July 2025. Eligible studies are Phase I to III single-arm clinical trials designed to evaluate the efficacy of BsAbs in patients with LBCL who have relapsed or are resistant to CAR-T cell therapy after prior treatment. Outcomes analyzed included objective response rate(ORR), complete response(CR), partial response(PR) progression-free survival (PFS) and overall survival (OS). Subgroup analyses were performed using a random-effects model, and statistical heterogeneity was assessed using Cochran's Q test. Results A total of 14 studies involving 525 patients were included. The median age was 62 years (range 40–78), and 66.2% of patients were male. 62.1% of patients had an IPI score of ≥3 and 77.9% had Ann Arbor stage III-IV disease. Median number of prior therapy was 3 (range 2-7). Anti-CD3/CD20 BsAbs commonly used to treat LBCL include Glofitamab (30.9%), Odronextamab (21.5%), Epcoritamab (22.2%), and Mosunetuzumab (22.2%). The pooled ORR rate was 45% (95%CI, 37–53), including a CR rate of 30% (95% CI, 25–35) and a PR rate of 18% (95%CI, 15–22). The estimated median PFS was 4.9 months, and the median OS was 11.2 months. Subgroup analysis revealed that patients with prior CAR-T exposure had significantly lower ORR (69.0% vs 45.0%, P=0.04) and CR (45.0% vs 30.0%, P=0.01) compared to those without prior CAR-T. Among patients previously treated with CAR-T, those who responded to CAR-T (CR or PR) had a markedly higher ORR to BsAbs than non-responders (PD or SD) (52.0% vs 24.0%). Furthermore, early relapse following CAR-T (defined as < 6 months) was associated with inferior overall survival compared to late relapse (67.0% vs 21.2%). Differences in efficacy were also observed between bispecific antibody agents, with epcoritamab showing the highest ORR among agents analyzed (P=0.02). Additionally, route of administration impacted response rates, with intravenous delivery yielding a significantly higher ORR than subcutaneous administration (64% vs 41%, P=0.01). 91.9% of patients experienced any grade treatment-related adverse events (TEAEs), with grade ≥3 TEAEs occurring in 75.0% of patients. The most frequently reported toxicity was cytokine release syndrome (CRS), which occurred in 32.0% of patients, Grade ≥3 CRS was rare (1.3%). Immune effector cell-associated neurotoxicity syndrome (ICANS) was infrequently reported. Infectious adverse events were reported in 43.4% of patients (Grade ≥3: 20.6% ). Most treatment discontinuations due to infections were associated with COVID-19 or pneumonia. Hematologic toxicities were also commonly reported. Neutropenia occurred in 34.2% of patients (Grade ≥3: 22.8%), anemia in 30.0% (Grade ≥3: 13.2%), and thrombocytopenia in 23.3% (Grade ≥3: 6.5%). Conclusion BsAbs demonstrate durable efficacy and manageable safety in patients with R/R LBCL following CAR-T therapy failure. Additionally, a longer treatment interval between CAR-T and bispecific antibodies was associated with better efficacy and survival.