Safety and efficacy of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in relapsed or refractory B-cell lymphomas: A systematic review and meta-analysis

Abstract Introduction: Relapsed or refractory B-cell lymphomas occur in approximately 30–40% of patients with large B-cell lymphoma, with nearly one-third relapsing within two years of first-line chemo-immunotherapy. The feasibility of chimeric antigen receptor (CAR) T-cell therapies is tested as a second-line treatment in this setting. This review compares CART T Cell therapies with conventional salvage regimens to assess long-term overall survival and real-world safety outcomes. Methodology: This meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We included randomized controlled trials (RCTs) and observational studies evaluating CAR-T cell therapy compared to standard of care in relapsed or refractory B-cell lymphomas. A systematic search was conducted across five databases; PubMed, Cochrane Library, ClinicalTrials.gov, Embase, and Scopus; using Medical Subject Headings (MeSH) and relevant keywords. CAR-T therapies included were lisocabtagene maraleucel, axicabtagene ciloleucel (axi-cel), and tisagenlecleucel. The meta-analysis was performed using fixed- or random-effects models based on heterogeneity (I² threshold of 50%). Dichotomous outcomes were reported as risk ratios (RRs), and continuous outcomes as mean differences (MDs). Results: A total of seven studies (including four RCTs), were included in the final synthesis, comprising 692 patients receiving CAR-T therapy and 834 receiving standard of care (SOC). Regarding treatment response, CAR-T therapy was associated with improved outcomes. The objective response rate (ORR), pooled from six studies, favored CAR-T over SOC (RR = 1.31, 95% CI: 1.09–1.58; I² = 68%; p = 0.004). Similarly, the complete response rate (CRR) was significantly higher in the CAR-T group (RR = 1.48, 95% CI: 1.09–2.00; I² = 73%; p = 0.01). Partial response (PR), based on four studies, showed no significant difference (RR = 1.26, 95% CI: 0.94–1.70; I² = 0%). In terms of survival outcomes, CAR-T therapy was associated with significantly inferior overall survival (OS) compared to SOC, based on four studies (RR = 0.69, 95% CI: 0.59–0.80; I² = 0%; p = 0.001). The pooled hazard ratio (HR) for OS was 0.89 (95% CI: 0.44–1.77), with moderate heterogeneity (I² = 69.1%), which dropped to 8.4% upon exclusion of Avivi I et al., 2022. Similarly, progression-free survival (PFS) was lower in the CAR-T group (RR = 0.75, 95% CI: 0.57–0.99; I² = 61%), with heterogeneity eliminated (I² = 0%) after excluding the same study. The pooled HR for PFS was 0.42 (95% CI: 0.31–0.57; I² = 0%). For event-free survival (EFS), the pooled RR was 0.77 (95% CI: 0.58–1.02; I² = 78%) and HR was 0.76 (95% CI: 0.17–3.39). In terms of safety, the incidence of any adverse event was similar between groups (RR = 1.00, 95% CI: 0.98–1.02; I² = 0%). Serious adverse events were less frequent in the CAR-T group (RR = 0.51, 95% CI: 0.17–1.54; I² = 73%), with heterogeneity eliminated after excluding Westin J et al., 2019. Grade 3 adverse events showed no significant difference (RR = 0.96, 95% CI: 0.73–1.25; I² = 83%). Notably, adverse events leading to death were significantly lower in the CAR-T group (RR = 0.59, 95% CI: 0.35–0.99; I² = 8%; p = 0.04). Conclusion: CAR-T therapy showed higher objective and complete response rates compared to standard of care (SOC), but this did not translate into improved overall or progression-free survival. As an established second-line option for relapsed or refractory disease, CAR-T remains an important treatment strategy, with fewer treatment-related deaths in the CAR-T group.