Abstract：
Anti-thymocyte globulin (ATG) is widely used in allogeneic hematopoietic stem cell transplantation to prevent severe graft-versus-host disease (GVHD) and graft failure. However, overexposure to ATG may increase cytomegalovirus (CMV), Epstein-Barr virus (EBV) reactivation, non-relapse mortality, and disease recurrence. To investigate the optimal dosing of ATG, we established a targeted dosing strategy based on ATG concentration monitoring for haploidentical peripheral blood stem cell transplantation (haplo-PBSCT). The aim of this phase 2 trial is to evaluate the safety and efficacy of the ATG-targeted dosing strategy in adult unmanipulated haplo-PBSCT. ATG was administered for 4 days (-5 days to -2 days) during conditioning. The ATG doses on -3 days and -2 days were adjusted by our dosing strategy to achieve the optimal ATG exposure. The primary endpoint was CMV reactivation on +180 days. Between December 2020 and January 2022, 66 haplo-PBSCT patients were enrolled and 63 of them were evaluable with a median follow-up of 632 days. The cumulative incidence of CMV reactivation was 36.7% and that of EBV was 58.7%. The 1-year disease-free survival was 82.5%, overall survival was 92.1%, and CD4+ T-cell reconstruction on +100 days was 76.8%. The most common severe regimen-associated toxicities (> grade 3) were infections (51.5%) and gastrointestinal toxicity (25.5%). A total of 102 haplo-PBSCT patients who received the conventional fixed ATG dose (cumulative 10 mg/kg) comprised historical control. The outcomes in historical control were inferior to those of phase 2 trial cohort (CMV reactivation: 70.8%, p < .001; EBV reactivation: 76.0%, p = .024; CD4 + T-cell reconstruction: 54.1%, p = .040). In conclusion, ATG-targeted dosing strategy reduced CMV/EBV reactivation and improved survival without increasing GVHD after haplo-PBSCT. These advantages may be associated with accelerated immune reconstitution.
摘要：
抗胸腺细胞球蛋白(ATG)广泛用于异基因造血干细胞移植,以预防严重的移植物抗宿主病(GVHD)和移植物衰竭。然而,过度暴露于ATG可能会增加巨细胞病毒（CMV），EB病毒（EBV）重新激活，非复发死亡率，和疾病复发。为了研究ATG的最佳剂量，我们针对单倍体相合外周血干细胞移植(haplo-PBSCT)建立了基于ATG浓度监测的靶向给药策略.这项2期试验的目的是评估ATG靶向给药策略在成人未操作的haplo-PBSCT中的安全性和有效性。在调节期间施用ATG4天(-5天至-2天)。通过我们的给药策略调整-3天和-2天的ATG剂量以达到最佳的ATG暴露。主要终点是+180天的CMV再激活。在2020年12月至2022年1月之间，纳入了66例haplo-PBSCT患者，其中63例患者可评估，中位随访时间为632天。CMV再激活的累积发生率为36.7％，EBV的累积发生率为58.7％。1年无病生存率为82.5%,总生存率为92.1%,+100天CD4+T细胞重建率为76.8%。最常见的严重方案相关毒性（>3级）是感染（51.5%）和胃肠道毒性（25.5%）。总共102名接受常规固定ATG剂量(累积10mg/kg)的haplo-PBSCT患者包括历史对照。历史对照的结果低于2期试验队列的结果（CMV再激活：70.8％，p<.001；EBV再激活：76.0%，p=.024；CD4+T细胞重建：54.1%，p=.040）。总之,ATG靶向给药策略减少CMV/EBV再激活并改善生存率而不增加haplo-PBSCT后GVHD。这些优点可能与加速的免疫重建有关。
