Background: Treatment with high dose chemotherapy followed by autologous stem cell transplantation (ASCT) is considered the standard of care (SOC) second line treatment for relapsed or refractory (R/R) large B-cell lymphoma (LBCL) in patients responding to salvage therapy. However, more than half of the patients will not proceed to ASCT due to progressive disease. Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 has revolutionized the treatment of R/R LBCL. With unprecedented overall response rates of 50-80% and durable responses of 30-40% at 4-5y, CAR T-cell therapy is now considered SOC for patients with R/R LBCL after 2 or more lines of therapy. Randomized prospective studies have recently examined whether earlier admission of CAR T-cell therapy after failure of 1 line of therapy could improve outcomes.
Aims: The aim of present meta-analysis was to compare the efficacy and safety of CAR-T vs. high dose chemotherapy followed by ASCT as second line treatment for R/R LBCL.
Methods: Systematic review and meta-analysis of randomized controlled trials including patients with R/R LBCL, comparing second line treatment with high dose chemotherapy followed by ASCT to CAR-T cell therapy. Cochrane Library, PubMed, conference proceedings and references were searched until January 2022. Two reviewers appraised the quality of trials and extracted data. Primary outcome was overall survival (OS). Secondary outcomes included overall response rate (ORR), complete response (CR) rate, event free survival (EFS), progression free survival (PFS) and safety.
Results: Our search yielded 3 trials conducted between the years 2018 and 2021, including 865 patients (one abstract, and two published in peer review journals). Age of patients enrolled ranged between 19 to 81 years. Each trial tested one of the three FDA approved anti-CD19 CAR-T products: Axicabtagene Ciloleucel (Axi-cel, “ZUMA-7”), Tisagenlecleucel (Tisa-cel, “BELINDA”) and Lisocabtagene Maraleucel (Liso-cel, “TRANSFORM”). All trials included LBCL patients either refractory to frontline therapy or relapsed within 12 months. OS was significantly improved with CAR-T as compared to SOC, HR 0.77, [95% confidence interval (CI) 0.60-0.98, 865 patients, 3 trials] (figure 1). CAR-T therapy was associated with significantly better ORR and CR rate, RR 1.55 [95% CI 1.12-2.13, 865 patients, 3 trials] and RR 1.49 [95% CI 1.09-2.05, 865 patients, 3 trials]) respectively. EFS and PFS were significantly improved as compared to SOC, HR 0.57 [95% CI 0.49-0.68, 865 patients, 3 trials] and HR 0.47 [95% CI 0.37-0.60, 543 patients, 2 trials] respectively. Regarding safety, all trials reported grade 3 or 4 adverse events (N=739). The risk of any grade 3 or 4 adverse event was comparable between the two arms, RR=1.03 [95% CI 0.93–1.14, 865 patients].
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Summary/Conclusion: This systematic review and meta-analysis shows that CAR-T therapy has superior outcomes compared to SOC in LBCL refractory to frontline therapy or relapsing within 12 months, without excess toxicity. CAR-T therapy was associated with statistically significant improved ORR and CR rates and longer EFS and PFS, translating into improved OS. However, results are quite preliminary with median follow up of trials ranging between 6-24 months. Longer follow-up is needed to confirm these results and determine the optimal sequencing of CAR T-cell therapy in the management of R/R LBCL.