Universiteit Leiden

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Dissertation

Individualized dosing of serotherapy in allogeneic hematopoietic cell transplantation - a delicate balance

Promotor: C.A.J. Knibbe, Co-promotor: J.J. Boelens, R.G.M. Bredius

Author
R. Admiraal
Date
15 March 2017
Links
Thesis in Leiden Repository

Anti-thymocyte globulin (ATG) and alemtuzumab are both used in hematopoietic cell transplantation (HCT) to prevent graft-versus-host-disease (GvHD) and graft failure. Main toxicities include absent or slow immune reconstitution. This thesis aims to develop evidence based dosing regimens for both agents. We found that current weight-based dosing of ATG and alemtuzumab lead to highly biased exposures across the different age groups in the pediatric population. Furthermore, ATG clearance was not found to increase with increasing body weight in patients over 50 kg (i.e. adolescents and adults). Timely CD4+ T-cell immune reconstitution after HCT is essential for reducing viral reactivations and relapse following HCT, and thereby improves survival chances. High exposure to ATG after infusion of the graft diminishes chances for CD4+ T-cell reconstitution. Therefore, exposure to ATG has a major impact on the clinical outcomes including survival following HCT in children and adults. We conclude that individualizing dosing and timing of ATG potentially makes HCT a safer and more effective treatment option, and will lead to improved survival chances. Individualized dosing regimens for ATG in children have been designed based on the results in this thesis, and are currently being evaluated in prospective clinical trials for efficacy and safety.