Data Sheet 2_Navigating the risks: a systematic review of immune checkpoint inhibitor therapy before liver transplant for hepatocellular carcinoma and its impact on allograft rejection and survival outcomes.docx

BackgroundThe administration of immune checkpoint inhibitors (ICIs) prior to liver transplantation (LT) for hepatocellular carcinoma (HCC) has been reported. Several studies suggest that ICIs may elevate the risk of allograft rejection (AR) and influence other clinical outcomes. This meta-analysis aimed to assess the efficacy and safety of pre-LT ICI treatment in HCC patients.
MethodsA systematic literature search was conducted in PubMed, Embase, Cochrane, and Web of Science for retrospective studies and randomized controlled trials (RCTs) examining pre-LT ICI therapies in HCC patients. Random-effects models were employed to evaluate treatment effects on allograft rejection (AR), complete recovery rate among patients with AR, graft loss, HCC recurrence, and progression-free survival (PFS). Common-effects models were used to assess overall mortality and AR-related mortality. Study quality was evaluated using the JBI critical appraisal tools. The review was registered with PROSPERO (CRD42024616267).
ResultsStudies involving HCC patients receiving pre-LT ICIs for downstaging or bridging were included. After screening databases from inception to 31 December 2024, eight studies (n = 229 patients) were included. The studies had diverse designs and were primarily from China and the US. The pooled post-LT AR rate across all eight studies was 19% (95% CI: 12%–30%). The incidence of AR was 24% in the PD-L1 inhibitor group, 18% in the PD-1 inhibitor group, and 20% in the bispecific/combination therapies group. The complete recovery rate among patients with AR was 78% (95% CI: 59%–97%), and graft loss occurred in 4% (95% CI: 1%–7%). The HCC recurrence rate across six studies was 24% (95% CI: 12%–36%). The pooled median recurrence-free survival (RFS) was 17.63 months (95% CI: 11.57–23.69 months). Overall mortality was 8% (95% CI: 4%–12%), and AR-related mortality was 2% (95% CI: 0%–5%). Sensitivity analysis supported the robustness of the results, while funnel plots indicated potential publication bias for several outcomes. This meta-analysis offers a comprehensive synthesis of the impact of pre-LT ICIs on post-transplantation outcomes.
ConclusionThe use of ICIs as bridging or downstaging therapy prior to liver transplantation in HCC patients appears feasible.
Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42024616267.

研究背景
针对肝细胞癌（hepatocellular carcinoma，HCC）患者在肝移植（liver transplantation，LT）术前应用免疫检查点抑制剂（immune checkpoint inhibitors，ICIs）的相关报道已见诸文献。多项研究提示，免疫检查点抑制剂可能升高移植物排斥反应（allograft rejection，AR）风险，并对其他临床结局产生影响。本荟萃分析旨在评估肝细胞癌患者肝移植术前接受免疫检查点抑制剂治疗的疗效与安全性。

研究方法
本研究于PubMed、Embase、Cochrane及Web of Science数据库中开展系统性文献检索，筛选针对肝细胞癌患者肝移植术前免疫检查点抑制剂治疗的回顾性研究与随机对照试验（randomized controlled trials，RCTs）。采用随机效应模型评估治疗对移植物排斥反应、移植物排斥反应患者的完全恢复率、移植物丢失、肝细胞癌复发及无进展生存期（progression-free survival，PFS）的影响；采用固定效应模型评估总死亡率与移植物排斥反应相关死亡率。采用JBI关键评价工具对研究质量进行评估。本系统评价已在PROSPERO平台注册（注册号：CRD42024616267）。

研究结果
本研究纳入了接受肝移植术前免疫检查点抑制剂降期或桥接治疗的肝细胞癌患者相关研究。从建库至2024年12月31日对各数据库进行筛选后，最终纳入8项研究，共包含229例患者。纳入研究的研究设计存在异质性，且主要来自中国与美国。8项研究合并后的肝移植术后移植物排斥反应发生率为19%（95%置信区间：12%~30%）；其中PD-L1抑制剂组移植物排斥反应发生率为24%，PD-1抑制剂组为18%，双特异性/联合治疗组为20%。移植物排斥反应患者的完全恢复率为78%（95%置信区间：59%~97%），移植物丢失发生率为4%（95%置信区间：1%~7%）。6项研究合并后的肝细胞癌复发率为24%（95%置信区间：12%~36%），合并后的无复发生存期（recurrence-free survival，RFS）中位值为17.63个月（95%置信区间：11.57~23.69个月）。总死亡率为8%（95%置信区间：4%~12%），移植物排斥反应相关死亡率为2%（95%置信区间：0%~5%）。敏感性分析证实研究结果具有稳健性，而漏斗图分析提示部分结局指标存在潜在发表偏倚。本荟萃分析全面整合了肝移植术前免疫检查点抑制剂应用对移植术后结局的影响。

研究结论
肝细胞癌患者肝移植术前应用免疫检查点抑制剂作为桥接或降期治疗方案，似乎具有可行性。
系统评价注册信息：https://www.crd.york.ac.uk/prospero/，注册号：CRD42024616267。