移植相关血栓性微血管病（TA-TMA）是造血细胞移植（HCT）的一种并发症，与内皮损伤相关，导致严重的终末器官损伤、急性和长期发病率和死亡率。清髓性调节是一个已知的危险因素，但具体的致病因素尚未确定。我们假设环磷酰胺和噻替派 (CY TT) 的组合对内皮细胞具有特别的毒性，使患者面临 TA-TMA 的较高风险。我们对 2012 年期间接受条件自体和同种异体 HCT 的儿童和年轻成人患者进行了回顾性审查以及 2023 年 8 月在旧金山加州大学旧金山分校贝尼奥夫儿童医院。我们排除了接受基因治疗或三重串联脑肿瘤移植的患者。神经母细胞瘤串联移植被分类为单次移植发生。从2016年12月至2019年5月和2022年5月至2023年8月，高剂量N-乙酰半胱氨酸（NAC）预防被纳入机构护理标准。根据机构指南，对被认为患有正弦阻塞综合征（SOS）高风险的患者预防性给予去纤苷或用于 SOS 预防的临床试验 NCT#02851407 或用于 TA-TMA 预防的 NCT#03384693。 Kaplan-Meier 分析用于估计 TA-TMA 的 1 年累积发生率。使用对数秩检验对每个感兴趣的潜在风险因素进行单变量分析，并使用向后选择的 Cox 回归模型进行双变量分析，并使用同种异体 HCT 的单变量 p 值 <0.2 的所有协变量建立风险比。 SPSS (v29) 用于估计所有汇总统计数据、累积发生率以及单变量和双变量分析。总共对 43 名发生 TA-TMA 的患者进行了 558 次移植，1 年累积发生率为 8.6%（同种异体和自体 HCT 分别为 95% CI，5.9-11.3%）和 7.2%（95% CI，2.9-11.5%）（p=0.62）。在同种异体受者 (n=417) 中，以 CY TT 作为调节一部分的 TA-TMA 1 年累积发生率为 35.7% (95% CI, 15.7-55.7%)，而 11.7% (95% CI, 7.2-单独使用 CY 或 TT 时为 16.2%），如果预处理方案中未包含任何药物，则为 1.2%（95% CI，0-2.8%）（p<0.001）。使用 CY 或 TT（HR=10.14；p=0.002）或 CY TT（HR=35.93；p<0.001）、病毒感染（HR=4.3；p=0.017）和真菌感染（HR=2.98；p=0.027） ）是导致 TA-TMA 风险增加的重要因素。在接受自体 HCT 的受试者中 (n=141)，TA-TMA 与 CY TT 的 1 年累积发生率为 19.6% (95% CI，8.8-30.6%)，而接受 CY 或 TT 治疗的患者中未发生 TA-TMA单独使用 TT 或两者都不包含时 (p<0.001)。 TA-TMA 仅发生在接受 CY TT 作为调理一部分的神经母细胞瘤患者中。对于接受 CY TT 的自体患者，HCT 时 CMV 血清阴性的患者 TA-TMA 的发生率为 6.7%（95% CI，0.1-15.7%），而 TA-TMA 的发生率为 38.1%（95% CI，35-41.2）。 %) 对于那些 CMV 血清阳性的患者 (p=0.007)。这些数据表明，CY 或 TT 单独或组合作为 HCT 之前移植前调理的一部分会增加 TA-TMA 的发生率。应尽可能考虑排除 CY TT 组合的替代调理，以限制 TA-TMA 的发展。版权所有 © 2024。由 Elsevier Inc. 出版。

Transplant associated thrombotic microangiopathy (TA-TMA) is a complication of hematopoietic cell transplant (HCT) associated with endothelial injury resulting in severe end organ damage, acute and long-term morbidity, and mortality. Myeloablative conditioning is a known risk factor, though specific causative agents have not been identified. We hypothesized that the combination of cyclophosphamide and thiotepa (CY+TT) is particularly toxic to the endothelium, placing patients at elevated risk for TA-TMA.We conducted a retrospective review of pediatric and young adult patients who received conditioned autologous and allogeneic HCT between 2012 and August 2023 at UCSF Benioff Children's Hospital, San Francisco. We excluded patients undergoing gene therapy or triple tandem transplants for brain tumors. Neuroblastoma tandem transplants were classified a single transplant occurrence. High dose N-acetylcysteine (NAC) prophylaxis was incorporated into the institutional standard of care from December 2016-May 2019 and May 2022-August 2023. Defibrotide was given prophylactically to patients deemed high-risk for sinusoidal obstruction syndrome (SOS) per institutional guidelines or on clinical trial NCT#02851407 for SOS prophylaxis or NCT#03384693 for TA-TMA prophylaxis. Kaplan-Meier analysis was used to estimate the 1-year cumulative incidence of TA-TMA. Univariate analysis was performed for each of the potential risk factors of interest using log-rank tests and bivariate analysis with Cox regression models using backward selection and hazard ratios were built using all covariates with a univariate p-value <0.2 for allogeneic HCT. SPSS (v29) was used to estimate all summary statistics, cumulative incidences, and uni- and bi-variate analyses.A total of 558 transplants were performed with 43 patients developing TA-TMA, for a 1-year cumulative incidence of 8.6% (95% CI, 5.9-11.3%) and 7.2% (95% CI, 2.9-11.5%) in allogeneic and autologous HCTs, respectively (p=0.62). In allogeneic recipients (n=417), the 1-year cumulative incidence of TA-TMA with CY+TT as part of conditioning was 35.7% (95% CI, 15.7-55.7%) compared to 11.7% (95% CI, 7.2-16.2%) with either CY or TT alone, and 1.2% (95% CI, 0-2.8%) if neither agent was included in the conditioning regimen (p<0.001). Use of either CY or TT (HR=10.14; p=0.002) or CY+TT (HR=35.93; p<0.001), viral infections (HR=4.3; p=0.017) and fungal infections (HR=2.98; p=0.027) were significant factors resulting in increased risk for developing TA-TMA. In subjects undergoing autologous HCT (n=141), the 1-year cumulative incidence of TA-TMA with CY+TT was 19.6% (95% CI, 8.8-30.6%) while TA-TMA did not occur in patients receiving either CY or TT alone or when neither were included (p<0.001). TA-TMA occurred only in patients with neuroblastoma receiving CY+TT as part of their conditioning. For autologous patients who received CY+TT, those who were CMV seronegative at the time of HCT had an incidence of TA-TMA of 6.7% (95% CI, 0.1-15.7%) compared to 38.1% (95% CI, 35-41.2%) for those CMV seropositive (p=0.007).These data show that CY or TT alone or in combination as part of pre-transplant conditioning prior to HCT increase the incidence of TA-TMA. Alternative conditioning excluding the combination of CY+TT should be considered whenever possible to limit the development of TA-TMA.Copyright © 2024. Published by Elsevier Inc.