Introduction

Rabbit anti-thymocyte globulin (ATG) is used in allogeneic hematopoietic cell transplantation (HCT) to prevent graft-versus-host-disease (GvHD) and graft failure (GF). Its main and unpredictable toxicity includes poor immune reconstitution associated with increased relapse, viral reactivations and subsequently higher mortality. Early (<100 days) CD4+ T-cell reconstitution has been associated with improved overall survival¹. Based on pharmacokinetic and pharmacodynamic (PKPD) studies we developed an individualized ATG dosing regimen aiming for optimal CD4+ T-cell recovery while maintaining a strong anti-GvHD effect.

Methods

We performed an open label, phase II historically controlled non-randomized prospective clinical trial investigating individualized versus fixed dosing of ATG (Thymoglobulin). Individualized dosing was based on the results from a previous validated population PKPD model^1,2 with cumulative doses varying between 2 to 10 mg/kg starting based on weight, recipient lymphocyte counts before first dose of ATG and stem cell source, starting day -9. Primary endpoint was successful CD4+ T-cell reconstitution (CD4+ >50/mm³ at 2 consecutive timepoints within 100 days after HCT¹) in patients alive without relapse or graft failure <100 days. Secondary endpoints were overall survival, event free survival, GvHD and graft failure. Results were compared to a previously described historical cohort receiving a fixed cumulative ATG dose of 10mg/kg starting day -5¹. Minimal follow-up was 1 year. Power was based on 20% effect size with α=0.05 and β=0.10. Multivariate Cox proportional hazard and Fine-Gray competing risks were used. The study was registered in the Dutch Trial Registry (NTR4960).

Results

We included 58 patients between 2015-2018, and compared to 112 historical controls (table 1). CD4+ reconstitution was significantly better in the individualized dosing group: 83% versus 54% in the fixed dosing group; HR 2.4 (95% CI 1.6-3.6), p<0.0001 (Figure 1a). The individualized group showed a trend towards improved survival (81% vs. 66%; HR 0.54 [95% CI 0.27-1.07], p = 0.078; Figure 1b) and event free survival (79% vs 61%: HR 0.52 [95% CI 0.27-1.01], p = 0.052). No differences were seen in grade 3-4 acute GvHD (7% vs.6%; HR 1.44 [95% CI 0.47-4.44], p = 0.53), and graft failure (5% vs 5%; HR 1.61 [95% CI 0.38-6.83], p = 0.52).

Conclusions

Individualized ATG dosing significantly increases the chance of rapid immune reconstitution without affecting the incidence of aGvHD and graft failure. Together, this is an important step towards predictable CD4+ T cell reconstitution and improved survival changes.

中文翻译：

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小儿同种异体造血细胞移植后个体化抗胸腺细胞球蛋白对改善T细胞重构的前瞻性开放标签II期试验：降落伞研究

介绍

兔抗胸腺细胞球蛋白（ATG）用于同种异体造血细胞移植（HCT），以预防移植物抗宿主疾病（GvHD）和移植物衰竭（GF）。其主要和不可预测的毒性包括与复发增加相关的免疫重建不良，病毒再激活以及随后更高的死亡率。早期（<100天）CD4 + T细胞重建与改善的总体生存率有关¹。基于药代动力学和药效学（PKPD）研究，我们开发了个性化ATG给药方案，旨在最佳CD4 + T细胞恢复，同时保持强大的抗GvHD作用。

方法

我们进行了一项开放标签的II期历史对照非随机前瞻性临床试验，研究了ATG（胸腺球蛋白）的个性化和固定剂量。个体化给药基于先前验证的PKPD模型^1,2的结果，累积剂量介于2到10 mg / kg之间，基于体重，ATG首次给药前的受体淋巴细胞计数和干细胞来源，从第-9天开始。主要终点是成功进行CD4 + T细胞重建（HCT ¹后100天内2个连续时间点的CD4 +> 50 / mm ^3））活着且没有复发或移植失败<100天的患者。次要终点是总体生存期，无事件生存期，GvHD和移植失败。将结果与先前描述的历史队列进行比较，该历史队列从-5 ¹开始就接受了10mg / kg的固定累积ATG剂量。最小随访时间为1年。功效基于20％的效应大小，其中α= 0.05和β= 0.10。使用多元Cox比例风险和Fine-Gray竞争风险。该研究已在荷兰试验注册中心（NTR4960）中注册。

结果

我们纳入了2015年至2018年之间的58例患者，并与112例历史对照进行了比较（表1）。个体给药组的CD4 +重构明显更好：固定给药组为83％，而固定给药组为54％；HR 2.4（95％CI 1.6-3.6），p <0.0001（图1a）。个体化组显示了生存改善的趋势（81％比66％； HR 0.54 [95％CI 0.27-1.07]，p = 0.078；图1b）和无事件生存（79％vs 61％：HR 0.52 [95] ％CI 0.27-1.01]，p = 0.052）。3-4级急性GvHD（7％vs.6％； HR 1.44 [95％CI 0.47-4.44]，p = 0.53）和移植失败（5％vs 5％; HR 1.61 [95％] CI 0.38-6.83]，p ＝ 0.52）。

结论

个性化的ATG剂量显着增加了快速免疫重建的机会，而不会影响aGvHD和移植失败的发生率。总之，这是迈向可预测的CD4 + T细胞重组和改善生存率的重要一步。