兔抗胸腺细胞球蛋白（ATG）暴露对儿童和青年患者体外 T 细胞耗竭造血细胞移植后结局的影响。
Impact of rabbit anti-thymocyte globulin (ATG) exposure on outcomes after ex vivo T-cell-depleted hematopoietic cell transplantation in pediatric and young adult patients.
机构信息
Fred Hutchinson Cancer Center, Seattle, Washington, USA; Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA.
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
出版信息
Cytotherapy. 2024 Apr;26(4):351-359. doi: 10.1016/j.jcyt.2024.01.004. Epub 2024 Feb 12.
BACKGROUND AIMS
Traditional weight-based dosing of rabbit anti-thymocyte globulin (rATG) used in allogeneic hematopoietic cell transplantation (HCT) to prevent graft-versus-host disease (GVHD) and graft rejection leads to variable exposures. High exposures induce delayed CD4+immune reconstitution (CD4+IR) and greater mortality. We sought to determine the impact of rATG exposure in children and young adults receiving various types of EX-VIVO T-cell-depleted (EX-VIVO-TCD) HCT.
METHODS
Patients receiving their first EX-VIVO-TCD HCT (CliniMACS CD34+, Isolex or soybean lectin agglutination), with removal of residual T cells by E-rosette depletion (E-) between 2008 and 2018 at Memorial Sloan Kettering Cancer Center were retrospectively analyzed. rATG exposure post-HCT was estimated (AUd/L) using a validated population pharmacokinetic model. Previously defined rATG-exposures, <30, 30-55, ≥55 AUd/L, were related with outcomes of interest. Cox proportional hazard and cause-specific models were used for analyses.
RESULTS
In total, 180 patients (median age 11 years; range 0.1-44 years) were included, malignant 124 (69%) and nonmalignant 56 (31%). Median post-HCT rATG exposure was 32 (0-104) AUd/L. Exposure <30 AUd/L was associated with a 3-fold greater probability of CD4+IR (P < 0.001); 2- to 4-fold lower risk of death (P = 0.002); and 3- to 4-fold lower risk of non-relapse mortality (NRM) (P = 0.02). Cumulative incidence of NRM was 8-fold lower in patients who attained CD4+IR compared with those who did not (P < 0.0001). There was no relation between rATG exposure and aGVHD (P = 0.33) or relapse (P = 0.23). Effect of rATG exposure on outcomes was similar in three EX-VIVO-TCD methods.
CONCLUSIONS
Individualizing rATG dosing to target a low rATG exposure post-HCT while maintaining total cumulative exposure may better predict CD4+IR, reduce NRM and increase overall survival, independent of the EX-VIVO-TCD method.
背景 目的：在异基因造血细胞移植（HCT）中，为预防移植物抗宿主病（GVHD）和移植物排斥，传统上采用基于体重的兔抗胸腺细胞球蛋白（rATG）剂量方案，但该方案会导致个体间药物暴露量存在差异。高暴露量会导致迟发性 CD4+免疫重建（CD4+IR）和更高的死亡率。我们旨在确定在接受各种类型的体外 T 细胞清除（EX-VIVO-TCD）HCT 的儿童和年轻成人中，rATG 暴露量的影响。
方法
回顾性分析了 2008 年至 2018 年期间在 Memorial Sloan Kettering 癌症中心接受首次 EX-VIVO-TCD HCT（CliniMACS CD34+、Isolex 或大豆凝集素凝集）的患者，这些患者通过 E-玫瑰花结耗竭（E-）清除残留 T 细胞。使用验证的群体药代动力学模型估算 HCT 后 rATG 的暴露量（AUd/L）。<30、30-55、≥55 AUd/L 三个 rATG 暴露组与感兴趣的结局相关。采用 Cox 比例风险和原因特异性模型进行分析。
结果
共纳入 180 例患者（中位年龄 11 岁；范围 0.1-44 岁），恶性疾病 124 例（69%），非恶性疾病 56 例（31%）。中位 HCT 后 rATG 暴露量为 32（0-104）AUd/L。暴露量<30 AUd/L 与 CD4+IR 发生的可能性增加 3 倍相关（P<0.001）；死亡风险降低 2-4 倍（P=0.002）；非复发死亡率（NRM）降低 3-4 倍（P=0.02）。与未发生 CD4+IR 的患者相比，发生 CD4+IR 的患者 NRM 累积发生率降低 8 倍（P<0.0001）。rATG 暴露与急性移植物抗宿主病（aGVHD）（P=0.33）或复发（P=0.23）无关。rATG 暴露对结局的影响在三种 EX-VIVO-TCD 方法中相似。
结论
在维持总累积暴露量的同时，将 HCT 后 rATG 剂量个体化以达到低 rATG 暴露量，可能更好地预测 CD4+IR，降低 NRM，提高总生存率，而与 EX-VIVO-TCD 方法无关。
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