Adjustment of low-dose ATG exposure improves outcomes in allogeneic hematopoietic stem cell transplantation: a prospective multicenter study.

Abstract

Antithymocyte globulin (ATG) has been used to prevent the incidence of graft-versus-host disease (GVHD) in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Low-dose ATG can suppress GVHD without increasing the risk of infectious complications. However, the relationship between ATG exposure and transplant outcomes in low-dose settings remains unclear, particularly in terms of the effect of absolute lymphocyte count (ALC) on its pharmacokinetics. This study aimed to explore the relationship between ATG exposure and transplant outcomes, with a focus on immune reconstitution and GVHD prevention, and to examine whether the pre-ATG ALC could predict ATG exposure in the low-dose setting. This prospective, multicenter, observational study included 71 patients with hematologic malignancies who underwent peripheral blood stem cell transplantation at six centers between May 2019 and March 2023. The serum concentration of ATG was measured over time. The area under the curve (AUC) was determined, and the correlations with the incidence of GVHD, post-transplant immune recovery, and survival were examined. Fifty-three of the 71 patients received ATG; the remaining 18 did not. Three distinct patterns of ATG administration were observed: standard (total 2.5 mg/kg: 1.25 mg/kg administered on days-2 and -1), early standard (total 2.5 mg/kg administered before day-2), and early reduced (total 1.25 mg/kg: single dose administered before day-2). Successful immune reconstitution (CD4 ≥ 120/μL at day 60) exhibited correlations with improved relapse-free survival (78.9% vs 47.7%, P = 0.034) and lower relapse rates (4.9% vs 37.2%, P = 0.003). Lower post-transplant AUC (≤ 250 μg/mL/day) exhibited an independent association with successful immune reconstitution (OR = 6.59 [95% CI, 1.23-35.40], P = 0.028). The post-transplant ATG exposure in the early reduced group was lower than those in the standard (P < 0.001) and early standard groups (P = 0.004). The ATG/ALC ratio was strongly correlated with the post-transplant AUC in the early administration groups (Spearman's correlation coefficient = 0.71, P < 0.001). The incidences of grade II-IV acute GVHD (17.1% vs. 39.4%, P = 0.013) and moderate-to-severe chronic GVHD (19.6% vs. 49.4%, P = 0.029) were significantly lower in the ATG group compared to the non-ATG group. The administration methods and ATG exposure levels had no effect on the incidence of GVHD in the ATG group. Early administration of reduced-dose ATG prevents the incidence of GVHD; furthermore, it potentially optimizes immune reconstitution by lowering post-transplant ATG exposure. The strong correlation between pre-ATG ALC and ATG exposure indicates that ALC-based dosing strategies may be beneficial even in low-dose settings. The ATG/ALC ratio is a practical tool for individualizing ATG dosing during early administration.