Efficacy and safety of chimeric antigen receptor (CAR) T-cell therapy in richter transformation: A systematic review and meta-analysis

Abstract Introduction: Richter transformation (RT) is an aggressive transformation of chronic lymphocytic leukemia (CLL) into diffuse large b cell lymphoma (DLBCL) or less frequent, hodgkin lymphoma. The advent of chimeric antigen receptor (CAR) T-cell therapy has improved survival outcomes in relapsed/refractory LBCL. However, patients with RT, who experience majorly poor outcomes, were largely excluded from the trials. Given the limited and heterogeneous data available, we pooled the existing data evaluating efficacy and safety of CAR T-cell therapy in RT. Methodology: We performed a systematic search of PubMed, Embase, and Cochrane databases to identify studies evaluating the outcomes of CAR T-cell therapy in RT transformed LBCL patients. The primary outcomes were overall response rate (ORR) and complete response rate (CRR). Secondary outcomes included 1-year progression-free survival (PFS) and overall survival (OS) and rates of grade >3 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Meta-analyses of pooled proportions were conducted using random-effects model. Statistical heterogeneity was assessed using the I² statistic. Analyses were performed in R version 4.4.2 Results: Four studies including 124 patients with RT were identified. The pooled ORR was 68% [95% CI: 56% – 73.58%](I² = 6.8%) and CRR was 48.3% [95% CI: 39.19% – 57.49%](I² = 0%). At 1 year of follow-up, PFS was 43.7% [95% CI: 23.88 – 63.47%](I2>60%), while the OS was 52.5% [95% CI: 35.26% – 69.53%](I² > 60%). The incidence of grade >3, CRS was 14.5% [95% CI: 8.4 – 21.86](I² = 0%), and ICANS was 22% [95% CI: 9.38 – 38.4](I² = 65.8%). Conclusion: CAR T-cell therapy demonstrates encouraging efficacy in RT patients with manageable safety profiles. However, findings are limited by small sample size and heterogeneity. Larger prospective trials with standardized reporting and comparisons to novo DLBCL are needed optimize CAR T-therapy utilization in RT patients.