Abstract：
Chimeric antigen receptor T cell (CAR-T) therapies, including axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel), are innovative treatments for patients with relapsed or refractory (r/r) large B cell lymphoma (LBCL). Following initial regulatory approvals, real-world evidence (RWE) of clinical outcomes with these therapies has been accumulating rapidly. Notably, several large registry studies have been published recently. Here we comprehensively describe clinical outcomes with approved CAR-T therapies in patients with r/r LBCL using available RWE. We systematically searched Embase, MEDLINE, and 15 conference proceedings to identify studies published between 2017 and July 2022 that included ≥10 patients with r/r LBCL treated with commercially available CAR-T therapies. Eligible study designs were retrospective or prospective observational studies. Key outcomes of interest were objective response rate (ORR), complete response (CR) rate, overall survival (OS), progression-free survival (PFS), cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS). Random-effects meta-analyses were used to compare real-world outcomes with those of pivotal clinical trials and to compare clinical outcomes associated with axi-cel and tisa-cel. Study cohort mapping was conducted to avoid including patients more than once. Of 76 cohorts we identified, 46 reported patients treated specifically with either axi-cel or tisa-cel, with 39 cohorts (n = 2754 patients) including axi-cel and 20 (n = 1649) including tisa-cel. No studies of liso-cel that met the inclusion criteria were identified during the search period. One-half of the tisa-cel cohorts were European, compared with 33% of the axi-cel cohorts. Among studies with available data, axi-cel had a significantly shorter median time from apheresis to CAR-T infusion than tisa-cel. Despite including broader patient populations, real-world effectiveness and safety of both axi-cel and tisa-cel were consistent with data from the pivotal clinical trials. Comparative meta-analysis of axi-cel versus tisa-cel demonstrated adjusted hazard ratios for OS and PFS of .60 (95% confidence interval [CI], .47 to .77) and .67 (95% CI, .57 to .78), respectively, both in favor of axi-cel. Odds ratios (ORs) for ORR and CR rate, both favoring axi-cel over tisa-cel, were 2.05 (95% CI, 1.76 to 2.40) and 1.70 (95% CI, 1.46 to 1.96), respectively. The probability of grade ≥3 CRS was comparable with axi-cel and tisa-cel, whereas axi-cel was associated with a higher incidence of grade ≥3 ICANS (OR, 3.95; 95% CI, 3.05 to 5.11). Our meta-analysis indicates that CAR-T therapies have manageable safety profiles and are effective in a wide range of patients with r/r LBCL, and that axi-cel is associated with improved OS and PFS and increased risk of grade ≥3 ICANS compared with tisa-cel. Limitations of this study include nonrandomized treatments, potential unknown prognostic factors, and the lack of available real-world data for liso-cel.
摘要：
背景：嵌合抗原受体（CAR）T细胞疗法，包括axicabtageneciloleucel（axi-cel）和tisagenlecleucel（tisa-cel），是复发性或难治性（r/r）大B细胞淋巴瘤（LBCL）患者的创新治疗方法。在获得初步监管批准后，这些疗法的临床结果的真实世界证据(RWE)正在迅速积累.值得注意的是,最近发表了几项大型注册研究。
目标：这里，我们使用现有的RWE全面描述了在r/rLBCL患者中获得批准的CART细胞疗法的临床结局.
方法：我们系统地搜索了EMBASE，MEDLINE,和15个会议记录，以确定2017年至2022年9月之间发表的研究，其中包括≥10例接受市售CART细胞疗法治疗的r/rLBCL患者。符合条件的研究设计是回顾性或前瞻性观察性研究。感兴趣的关键结果是客观反应率(ORR)，完全反应（CR）率，总生存期（OS），无进展生存期（PFS），细胞因子释放综合征（CRS），和免疫效应细胞相关神经毒性综合征（ICANS）。随机效应荟萃分析用于比较真实世界结果与关键临床试验的结果，并比较axi-cel与tisa-cel的临床结果。进行研究队列定位以避免将患者纳入不止一次。
结果：在我们确定的76个队列中，46例报告了用axi-cel或tisa-cel治疗的患者，包括axi-cel在内的39个队列（n=2,754）和包括tisa-cel在内的20个队列（n=1,649）。在搜索期间，没有发现符合纳入标准的干细胞研究。tisa-cel队列中有一半是欧洲人，而欧洲队列占axi-cel队列的33%。在有可用数据的研究中，与tisa-cel相比，axi-cel从单采到CAR-T细胞输注的中位时间明显更短。尽管包括更广泛的患者人群，axi-cel和tisa-cel的实际有效性和安全性与关键临床试验一致.axi-cel与tisa-cel的比较荟萃分析显示，OS和PFS的调整风险比为0.60(95%置信区间[CI]，0.47-0.77)和0.67(95%CI，0.57-0.78)，分别,都赞成axi-cel.ORR和CR率的赔率比，都赞成axi-cel而不是tisa-cel，分别为2.05(95%CI，1.76-2.40)和1.70(95%CI，1.46-1.96)，分别。≥3级CRS与axi-cel或tisa-cel的概率相当，而axi-cel与≥3级ICANS的较高发生率相关(比值比:3.95;95%CI,3.05-5.11).
结论：我们的荟萃分析表明，CAR-T细胞疗法具有可控的安全性，并且在许多r/rLBCL患者中有效，与tisa-cel相比，axi-cel与OS和PFS改善以及≥3级ICANS风险增加相关。这项研究的局限性包括非随机治疗，潜在的未知预后因素，以及缺乏可用的实时数据。
目标：这里，我们使用现有的RWE全面描述了在r/rLBCL患者中获得批准的CART细胞疗法的临床结局.
方法：我们系统地搜索了EMBASE，MEDLINE,和15个会议记录，以确定2017年至2022年9月之间发表的研究，其中包括≥10例接受市售CART细胞疗法治疗的r/rLBCL患者。符合条件的研究设计是回顾性或前瞻性观察性研究。感兴趣的关键结果是客观反应率(ORR)，完全反应（CR）率，总生存期（OS），无进展生存期（PFS），细胞因子释放综合征（CRS），和免疫效应细胞相关神经毒性综合征（ICANS）。随机效应荟萃分析用于比较真实世界结果与关键临床试验的结果，并比较axi-cel与tisa-cel的临床结果。进行研究队列定位以避免将患者纳入不止一次。
结果：在我们确定的76个队列中，46例报告了用axi-cel或tisa-cel治疗的患者，包括axi-cel在内的39个队列（n=2,754）和包括tisa-cel在内的20个队列（n=1,649）。在搜索期间，没有发现符合纳入标准的干细胞研究。tisa-cel队列中有一半是欧洲人，而欧洲队列占axi-cel队列的33%。在有可用数据的研究中，与tisa-cel相比，axi-cel从单采到CAR-T细胞输注的中位时间明显更短。尽管包括更广泛的患者人群，axi-cel和tisa-cel的实际有效性和安全性与关键临床试验一致.axi-cel与tisa-cel的比较荟萃分析显示，OS和PFS的调整风险比为0.60(95%置信区间[CI]，0.47-0.77)和0.67(95%CI，0.57-0.78)，分别,都赞成axi-cel.ORR和CR率的赔率比，都赞成axi-cel而不是tisa-cel，分别为2.05(95%CI，1.76-2.40)和1.70(95%CI，1.46-1.96)，分别。≥3级CRS与axi-cel或tisa-cel的概率相当，而axi-cel与≥3级ICANS的较高发生率相关(比值比:3.95;95%CI,3.05-5.11).
结论：我们的荟萃分析表明，CAR-T细胞疗法具有可控的安全性，并且在许多r/rLBCL患者中有效，与tisa-cel相比，axi-cel与OS和PFS改善以及≥3级ICANS风险增加相关。这项研究的局限性包括非随机治疗，潜在的未知预后因素，以及缺乏可用的实时数据。
