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 ATLG 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.

Department of Clinical Pharmacy and Toxicology Leiden University Medical Center Leiden

Dept of children and adolescents medicine Copenhagen University Hospital Rigshospitalet Copenhagen

Motol University Hospital Prague Czech Republic

Pediatric Hematopoietic Stem Cell Transplant Unit Fondazione IRCCS San Gerardo dei Tintori; School of Medicine and Surgery Milano Bicocca University Monza

St Anna Children's Hospital Children's Cancer Research Institute Vienna

University Hospital Frankfurt Frankfurt am Main

Willem Alexander Children's Hospital Leiden University Medical Center Leiden

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Mohty M. Mechanisms of action of antithymocyte globulin: T-cell depletion and beyond. Leukemia. 2007;21(7):1387-1394. PubMed

Penack O, Fischer L, Gentilini C. The type of ATG matters -natural killer cells are influenced differentially by thymoglobulin, lymphoglobulin and ATG-Fresenius. Transpl Immunol. 2007;18(2):85-87. PubMed

Popow I, Leitner J, Grabmeier-Pfistershammer K, et al. . A comprehensive and quantitative analysis of the major specificities in rabbit antithymocyte globulin preparations. Am J Transplant. 2013;13(12):3103-3113. PubMed

Waller E, Langston A, Lonial S. Pharmacokinetics and pharmacodynamics of anti-thymocyte globulin in recipients of partially HLA-matched blood haematopoietic progenitor cell transplantation. Biol Blood Marrow Transplant. 2003;9(7):460-471. PubMed

Locatelli F, Bernardo ME, Bertaina A, et al. . Efficacy of two different doses of rabbit anti-T-lymphocyte globulin to prevent graft-versus-host disease in children with haematological malignancies transplanted from an unrelated donor: a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18(8):1126-1136. PubMed

Kang HM, Kim SK, Lee JW, Chung NG, Cho B. Efficacy of low dose antithymocyte globulin on overall survival, relapse rate, and infectious complications following allogeneic peripheral blood stem cell transplantation for leukemia in children. Bone Marrow Transplant. 2021;56(4):890-899. PubMed

Willemsen L, Jol-van der Zijde CM, Admiraal R, et al. . Impact of serotherapy on immune reconstitution and survival outcomes after stem cell transplantations in children: thymoglobulin versus alemtuzumab. Biol Blood Marrow Transplant. 2015;21(3):473-482. PubMed

Call S, Kasow K, Barfield R. Total and active rabbit antithymocyte globulin (rATG; Thymoglobulin®) pharmacokinetics in pediatric patients undergoing unrelated donor bone marrow transplantation. Biol Blood Marrow Transplant. 2009;15(2):274-278. PubMed PMC

Admiraal R, van Kesteren C, Jol-van der Zijde CM, et al. . Population pharmacokinetic modeling of thymoglobulin in children receiving allogeneic-haematopoietic cell transplantation (HCT): towards individualized dosing to improve survival. Biol Blood Marrow Transplant. 2014;20:S96-S98.

Admiraal R, Lindemans CA, van Kesteren C, et al. . Excellent T-cell reconstitution and survival depend on low ATG exposure after pediatric cord blood transplantation. Blood. 2016;128(23):2734-2741. PubMed

Admiraal R, van Kesteren C, Jol-van der Zijde CM, et al. . Association between anti-thymocyte globulin exposure and CD4+ immune reconstitution in paediatric haemopoietic cell transplantation: a multicentre, retrospective pharmacodynamic cohort analysis. Lancet Haematol. 2015;2(5):e194-203 PubMed

Admiraal R, van Kesteren C, Jol-van der Zijde CM, et al. . Population pharmacokinetic modeling of Thymoglobulin® in children receiving allogeneic-haematopoietic cell transplantation: towards improved survival through individualized dosing. Clin Pharmacokinet. 2015;54(4):435-446. PubMed

Admiraal R, Nierkens S, Bierings MB, et al. . Individualised dosing of anti-thymocyte globulin in paediatric unrelated allogeneic haematopoietic stem-cell transplantation (PARACHUTE): a single-arm, phase 2 clinical trial. Lancet Haematol. 2022;9(2):e111-120. PubMed

Oostenbrink LVE, Jol-van der Zijde CM, Kielsen K, et al. . Differential elimination of anti-thymocyte globulin of Fresenius and genzyme impacts T-cell reconstitution after haematopoietic stem cell transplantation. Front Immunol. 2019;10:315. PubMed PMC

Vogelsang V, Kruchen A, Wustrau K, Spohn M, Müller I. Influence of anti-thymocyte globulin plasma levels on outcome parameters in stem cell transplanted children. Int Immunopharmacol. 2020;83:106371. PubMed

Peters C, Dalle JH, Locatelli F, et al. . Total body irradiation or chemotherapy conditioning in childhood all: a multinational, randomized, noninferiority phase III study. J Clin Oncol. 2021;39(4):295-307. PubMed PMC

Jol-van der Zijde CM, Bredius RGM, Jansen-Hoogendijk AM, et al. . IgG antibodies to ATG early after pediatric haematopoietic SCT increase the risk of acute GVHD. Bone Marrow Transplant. 2012;47(3):360-368. PubMed

Therneau TM. A Package for Survival Analysis in R. 2022. version 3.5-7. https://cran.r-project.org/package=survival. Accessed 01 November 2023.

Storci G, Barbato F, Ricci F, et al. . Pre-transplant CD69+ extracellular vesicles are negatively correlated with active ATLG serum levels and associate with the onset of GVHD in allogeneic HSCT patients. Front Immunol. 2023;13:1058739. PubMed PMC

Atay D, Akcay A, Yenigurbuz FD, et al. . Clinical study of graft-versus-host disease prophylaxis in unrelated haematopoietic stem cell transplantation for pediatric nonmalignant diseases with different doses anti-human T-lymphocyte immunoglobulin. Pediatr Transplant. 2021;25(8):e14098. PubMed

Bonifazi F, Rubio MT, Bacigalupo A, et al. . Rabbit ATG/ATLG in preventing graft-versus-host disease after allogeneic stem cell transplantation: consensus-based recommendations by an international expert panel. Bone Marrow Transplant. 2020;55(6):1093-1102. PubMed PMC

Gagelmann N, Ayuk F, Wolschke C, Kröger N. Comparison of different rabbit anti-thymocyte globulin formulations in allogeneic stem cell transplantation: systematic literature review and network meta-analysis. Biol Blood Marrow Transplant. 2017;23(12):2184-2191. PubMed

Kumar A, Reljic T, Hamadani M, Mohty M, Kharfan-Dabaja MA. Antithymocyte globulin for graft-versus-host disease prophylaxis: an updated systematic review and meta-analysis. Bone Marrow Transplant. 2019;54(7):1094-1106. PubMed

Soiffer RJ, Kim HT, McGuirk J, et al. . A prospective randomized double blind phase 3 clinical trial of anti- T lymphocyte globulin (ATLG) to assess impact on chronic graft-versus-host disease (cGVHD) free survival in patients undergoing HLA matched unrelated myeloablative haematopoietic cell transplantation (HCT). J Clin Oncol. 2017;35(36):4003-4011. PubMed PMC

Finke J, Bethge WA, Schmoor C, et al. . Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial. Lancet Oncol. 2009;10(9):855-864. PubMed

Massoud R, Klyuchnikov E, Gagelmann N, et al. . Impact of anti-T-lymphocyte globulin dosing on GVHD and Immune reconstitution in matched unrelated myeloablative peripheral blood stem cell transplantation. Bone Marrow Transplant. 2022;57(10):1548-1555. PubMed PMC

Bosch M, Dhadda M, Hoegh-Petersen M, et al. . Immune reconstitution after anti-thymocyte globulin-conditioned haematopoietic cell transplantation. Cytotherapy. 2012;14(10):1258-1275 PubMed PMC

Duval M, Pédron B, Rohrlich P, et al. . Immune reconstitution after haematopoietic transplantation with two different doses of pre-graft antithymocyte globulin. Bone Marrow Transplant. 2002;30(7):421-426. PubMed

Lugthart G, Goedhart M, van Leeuwen MM, et al. . Expansion of cytotoxic CD56bright natural killer cells during T-cell deficiency after allogeneic haematopoietic stem cell transplantation. J Allergy Clin Immunol. 2017;140(5):1466-1469. PubMed

de Koning C, Prockop S, van Roessel I, et al. . CD4+ T-cell reconstitution predicts survival outcomes after acute graft-versus-host-disease: a dual-center validation. Blood. 2021;137(6):848-855. PubMed PMC