Second‐line chimeric antigen receptor T‐cell therapy versus standard of care in relapsed or refractory large B‐cell lymphoma: A systematic review and meta‐analysis

BACKGROUND: CD19-directed chimeric antigen receptor (CAR)-T-cell therapy has emerged as a second-line option for relapsed/refractory large B-cell lymphoma (R/R LBCL). However, its long-term benefits over standard of care (SOC) remain a matter of debate. METHODS: A systematic review and meta-analysis was performed of three randomized controlled trials (ZUMA-7, TRANSFORM, BELINDA) and one real-world comparative study evaluating second-line CAR-T versus standard-of-care chemoimmunotherapy (±autologous stem cell transplantation) in adults with early R/R LBCL. Hazard ratios (HRs) and 95% CIs for overall survival (OS), event-free survival (EFS), and progression-free survival (PFS) were pooled. Individual patient data were reconstructed to generate pooled Kaplan-Meier survival curves. Subgroup analyses and long-term safety outcomes were also evaluated. RESULTS: A total of 1199 patients were included. Pooled analyses demonstrated a significant benefit of CAR-T over SOC in OS (HR = 0.75; 95% CI, 0.62-0.92), EFS (HR = 0.51; 95% CI, 0.33-0.78), and PFS (HR = 0.47; 95% CI, 0.39-0.58). Three-year OS and PFS estimates from reconstructed data were 53.59% and 44.08% in the CAR-T group, compared to 41.46% and 17.82% with SOC, respectively. Subgroup analyses confirmed consistent EFS across subgroups, including age, disease subtype, and relapse status. Long-term toxicities indicated more frequent hypogammaglobulinemia with CAR-T cell therapy, with no excess in secondary malignancies. CONCLUSIONS: Second-line CAR-T therapy significantly improves long-term survival and disease control in R/R LBCL, with consistent benefit across subgroups and real-world settings. These findings support early CAR-T use as a standard strategy in high-risk LBCL, while emphasizing the importance of timely delivery and long-term monitoring.