Anti-T-lymphocyte globulin exposure is associated with ac ute g ra ft-versus-host disease and relapse in pediatric acute lymphoblastic leukemia patients undergoing hematopoietic stem cell transplantation: a multinational prospective study

• Published in: Haematologica (Roma) Vol. 109; no. 9; pp. 2854 - 2863
• Main Authors: Oostenbrink, Lisa V.E., von Asmuth, Erik G.J., Jol-van der Zijde, Cornelia M., Jansen-Hoogendijk, Anja M., Vervat, Carly, Bredius, Robbert G.M., van Tol, Maarten J.D., Schilham, Marco W., Sedlacek, Petr, Ifversen, Marianne, Balduzzi, Adriana, Bader, Peter, Peters, Christina, Moes, Dirk Jan A.R., Lankester, Arjan C.
• Format: Journal Article
• Language: English
• Published: Fondazione Ferrata Storti 09.05.2024
• Subjects: Acute Lymphoblastic Leukemia
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2023.284632

Anti-T-lymphocyte globulin (ATLG) is used in hematopoietic stem cell transplantation (HSCT) to prevent graft- versus -host disease (GVHD) and graft failure. To date, insight in ATLG pharmacokinetics and -dynamics (PK/PD) is limited, and population PK (POPPK) models are lacking. In this prospective study, we describe ATLG POPPK using NONMEM ® and the impact of AT-LG exposure on clinical outcome and immune reconstitution in a homogeneous cohort of pediatric acute lymphoblastic leukemia (ALL) patients transplanted with a matched unrelated donor and receiving uniform ATLG dosing. Based on 121 patients and 812 samples for POPPK analysis, a two-compartmental model with parallel linear and non-linear clearance and bodyweight as covariate, best described the ATLG concentration-time data. The level of ATLG exposure (day active ATLG <1 AU/mL, median 16 days post-HSCT) was strongly associated with aGVHD grade II-IV, with a lower incidence in patients with prolonged active ATLG exposure (≤day 16 50% vs . >day 16 8.2%; P <0.001). When stratified for remission state, patients transplanted in complete remission (CR) 2 or 3 with prolonged ATLG exposure had a higher relapse risk, while this effect was not seen in CR1 patients ( P =0.010). High level ATLG exposure was associated with delayed CD4 T-cell recovery at 4 and 8 weeks post-HSCT, but not at 12 weeks, and overall and relapse-free survival were not influenced by CD4 recovery at 12 weeks post-HSCT. This study underlines the importance of individualized ATLG exposure with the use of model-informed precision dosing in order to optimize the HSCT outcome in pediatric ALL.