Transplant Cell Ther. 2024 May 18:S2666-6367(24)00412-3. doi: 10.1016/j.jtct.2024.05.015. Online ahead of print.
ABSTRACT
BACKGROUND: In αβ T-cell/CD19 B-cell depleted hematopoietic stem cell transplantation (αβhaplo-HSCT) recipients, anti–thymocyte globulin (ATG, Thymoglobulin®) is used for preventing graft rejection and graft-versus-host disease (GvHD). However, optimal dosing has yet to be established. Here, we present the first comparative analysis of three different ATG dosing strategies and their impact on immune reconstitution and GvHD.
OBJECTIVE(S): Our study aims to evaluate the effects of three distinct dosing strategies of ATG on engraftment success, αβ+ and γδ+ T-cells immune reconstitution, and the incidence and severity of acute GvHD in recipients of αβhaplo-HSCT.
STUDY DESIGN: This comparative analysis includes three cohorts of pediatric patients with malignant (36) or non-malignant diseases (8). Cohorts 1 and 2 were given fixed ATG doses, while cohort 3 received doses via a new nomogram, based on absolute lymphocyte count (ALC) and body weight (BW).
RESULTS: Cohort 3 showed 0% incidence of Day-100 grade II-IV acute GvHD, as opposed to 48% and 27% in cohort 1 and 2, respectively. Further, cohort 3 (the ALC/BW-based cohort) had a significant increase in CD4+ and CD8+ naïve T-cells by Day 90 (P=0.04; P=0.03). Additionally, we found that the reconstitution and maturation of γδ+ T-cells post-HSCT was not impacted across all three cohorts. Cumulative ATG exposure in all cohorts was lower than previously reported in T-cell replete settings, with a lower pre-HSCT exposure (<40 AU*day/mL) correlating with engraftment failure (p=0.007). Conversely, a post-HSCT ATG exposure between 10-15 AU*day/mL was optimal for improving Day-100 CD4+ (p= 0.058) and CD8+ (p=0.03) immune reconstitution, without increasing relapse or non-relapse mortality risks.
CONCLUSION(S): This study represents the first comparative analysis of ATG Thymoglobulin® exposure in αβhaplo-HSCT recipients. Our findings indicate that i) a 1-2-fold ATG to ATLG bioequivalence is more effective than previously established standards, and ii) ATG exposure post-HSCT does not adversely affect γδ+ T-cell immune reconstitution. Furthermore, a model-based ATG dosing strategy effectively reduces graft rejection and Day-100 acute GvHD while also promoting early CD4+/CD8+ immune reconstitution. These insights suggest that further optimization, including more distal administration of higher ATG doses within an ALC/BW-based strategy, will yield even greater improvements in outcomes.
PMID:38768907 | DOI:10.1016/j.jtct.2024.05.015
