Pharmacokinetics-guided ATG targeted dosing strategy in unmanipulated haploidentical haematopoietic stem cell transplantation: A randomized, multicenter, phase 3 clinical trial

Abstract Purpose:Fixed dosing of 10 mg/kg anti-thymocyte globulin (ATG) has been a standard prophylaxis for graft-versus-host disease (GVHD) in unmanipulated haploidentical haematopoietic stem cell transplantation (haplo-HSCT). However, the pharmacokinetics of ATG in vivo vary significantly, and fixed dosing may not optimize efficacy while minimizing toxicity. This study aimed to evaluate the clinical results of a pharmacokinetics-guided, dose-optimized ATG strategy in haplo-HSCT recipients. Methods: In this multicenter, randomized, phase 3 trial, patients with haematological malignancies were randomly assigned in a 1:1 ratio to receive either a targeted dose of ATG or a fixed dose of 10 mg/kg from day -5 to day -2. The primary endpoint was cytomegalovirus (CMV) reactivation within 180 days post-transplant. This trial was registered at ClinicalTrials.gov (identifier: NCT05166967). Results: Between January 2022 and January 2024, 204 patients from three transplant centers were enrolled, with 102 patients in each group. The cumulative incidence of CMV reactivation at day 180 was significantly lower in the targeted dose group (30.7%; 95% confidence interval [CI], 22.0 to 39.9) compared with the fixed dose group (54.9%; 95% CI, 44.7 to 64.0; P = 0.0003). The 365-day graft-versus-host disease-free, relapse-free survival (GRFS) was higher in the targeted dose group (63.7%) than in the fixed dose group (48.0%; hazard ratio [HR], 0.5958; 95% CI, 0.4071 to 0.8719; P = 0.007). Fewer infections were reported in the targeted dose group (56.9%) than in the fixed dose group (97.1%; P < 0.001). More patients in the targeted dose group achieved optimal ATG exposure (P = 0.007) and superior CD4⁺ T-cell reconstitution (P = 0.002). Conclusion: Our findings suggest that pharmacokinetics guided ATG targeted dosing significantly reduces CMV reactivation, enhances immune reconstitution, and improves GRFS, without increasing GVHD or graft failure.