Admiraal Rick, Nierkens Stefan, Bierings Marc B, Belderbos Mirjam E, Huitema Alwin D, Bredius Robbert G M, Jiang Yilin, Curran Kevin J, Scaradavou Andromachi, Cancio Maria I, Klein Elizabeth, Kollen Wouter J, Bresters Dorine, Calkoen Friso G J, Versluijs A Birgitta, Zwaan C Michel, Boelens Jaap Jan, Lindemans Caroline A
Pediatric Blood and Marrow Transplantation Program, Princess Máxima Centre for Pediatric Oncology, Utrecht, The Netherlands.
Centre for Translational Immunology, University Medical Centre, Utrecht, The Netherlands.
Blood Adv. 2025 May 13;9(9):2344-2353. doi: 10.1182/bloodadvances.2024014836.
Antithymocyte globulin (ATG) is used in pediatric allogeneic hematopoietic cell transplantation (HCT) to prevent graft-versus-host disease (GVHD) and graft failure (GF). Poor T-cell recovery, associated with increased mortality, is the main toxicity of ATG. Model-based precision dosing of ATG (MBD-ATG) minimizes toxicity while maintaining efficacy. We report updated results of the single-arm phase 2 PARACHUTE trial investigating MBD-ATG, combined with real-world experience using identical MBD-ATG. Consecutive patients receiving a first T-cell-replete HCT for any indication were evaluated. Results were compared with historical patients receiving conventional fixed ATG dosing (FIX-ATG). Primary outcome was overall survival (OS). The MBD-ATG group consisted of 214 patients (58 trial patients; 156 real-world patients); 100 patients received FIX-ATG. MBD-ATG led to superior OS compared with FIX-ATG (hazard ratio [HR] for death, 0.56; 95% confidence interval [CI], 0.34-0.93; P = .026), and lower treatment-related mortality (TRM; HR, 0.51; 95% CI, 0.29-0.92; P = .025). Successful T-cell reconstitution (>0.05 × 109/L CD4+ T cells twice within 100 after HCT) was improved in MBD-ATG vs FIX-ATG (87% ± 2% vs 47% ± 5%; P < .0001). The improved T-cell reconstitution led to lower TRM (HR, 0.19; 95% CI, 0.09-0.36; P < .0001). Incidence of grade 2-4 acute GVHD was comparable, whereas chronic GVHD (HR, 0.35; 95% CI, 0.17-0.72; P = .004) and GF (HR, 0.36; 95% CI, 0.13-0.97; P = .044) were both less frequent in MBD-ATG compared with FIX-ATG. MBD-ATG results in improved OS and reduced TRM, while reducing chronic GVHD and GF. This easy-to-implement approach improves outcomes after pediatric HCT, confirmatory studies are needed. The PARACHUTE trial is registered with the Dutch Trial Register as #NL4836.
抗胸腺细胞球蛋白（ATG）用于儿科异基因造血细胞移植（HCT），以预防移植物抗宿主病（GVHD）和移植物衰竭（GF）。与死亡率增加相关的T细胞恢复不良是ATG的主要毒性。基于模型的ATG精准给药（MBD-ATG）在维持疗效的同时将毒性降至最低。我们报告了单臂2期降落伞试验研究MBD-ATG的最新结果，并结合了使用相同MBD-ATG的真实世界经验。对因任何适应症接受首次T细胞充足的HCT的连续患者进行了评估。将结果与接受传统固定ATG给药（FIX-ATG）的历史患者进行比较。主要结局是总生存期（OS）。MBD-ATG组由214名患者组成（58名试验患者；156名真实世界患者）；100名患者接受FIX-ATG。与FIX-ATG相比，MBD-ATG导致更好的OS（死亡风险比[HR]为0.56；95%置信区间[CI]，0.34-0.93；P = 0.026），以及更低的治疗相关死亡率（TRM；HR，0.51；95%CI，0.29-0.92；P = 0.025）。与FIX-ATG相比，MBD-ATG组成功的T细胞重建（HCT后100天内两次CD4+T细胞>0.05×109/L）得到改善（87%±2%对47%±5%；P < 0.0001）。改善的T细胞重建导致更低的TRM（HR，0.19；95%CI，0.09-0.36；P < 0.0001）。2-4级急性GVHD的发生率相当，而慢性GVHD（HR，0.35；95%CI，0.17-0.72；P = 0.004）和GF（HR，0.36；95%CI，从0.13-0.97；P = 0.044）在MBD-ATG组中比FIX-ATG组更少见。MBD-ATG可改善OS并降低TRM，同时减少慢性GVHD和GF。这种易于实施的方法可改善儿科HCT后的结局，仍需要进行验证性研究。降落伞试验已在荷兰试验注册中心注册，编号为#NL4836。
