Individualized Dosing and Therapeutic Drug Monitoring for Anti-Thymocyte Globulin to Improve Outcome following Cord Blood Transplantation: Proof of Concept

  • Admiraal R
  • van Kesteren C
  • Nierkens S
  • et al.
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Introduction: Survival following cord blood transplantation (CBT) may be influenced by rapid and robust T-cell immune reconstitution (IR), which is hampered by too high exposure of anti-thymocyte globulin (ATG) to the graft1. Still, in-vivo lymphodepletion is required to reduce graft-versus-host-disease (GvHD) and graft failure (GF), warranting a high exposure to ATG before infusion of the graft1. In this study, we describe our experience in individualized dosing and therapeutic drug monitoring (TDM) of ATG, aiming for optimal ATG exposure both before and after CBT. Methods: From early 2014, patients receiving a CBT in the University Medical Center in Utrecht, the Netherlands, and were at high risk for GF or had ongoing infections and fast IR was essential, received individualized ATG dosing. High risk for graft failure was defined as having increased inflammation with intact T-cell function, hemoglobulinopathies, and osteo-petrosis. From early 2015, we amended the protocol by adding TDM for patient with high GF-risk. Dosage and timing of ATG was calculated with a validated population PK-model so that post-CBT exposure was very low (<10 AU*day/mL), while pre-HCT AUC was targeted at 40 AU*day/mL (80 AU*day/mL for TDM-patients)1,2. In TDM-patients, doses were adjusted according to individual pharmacokinetics if necessary. Results: Thus far, 13 patients have been treated according to this protocol, of which 5 received TDM. Mean cumulative dose of ATG (Thymoglobulin) was 11.8 mg/kg (range 3-30 mg/kg), starting at a mean of 11.6 days before HCT (range 7-17). In all TDM-patients, both measured pre-HCT AUC (mean 104, range 73-140) and post-HCT AUC (3.4, 0.1-6) were well within the target (fig. 1). Immune reconstitution was significantly improved compared to historical controls, and comparable to patients not receiving ATG. No GF occurred, 1 patient experience mild GvHD. Two patients experienced a transient viral reactivation of CMV/Adenovirus. Although follow-up is relatively short, survival is encouraging with 1 death. Conclusions: Individualized dosing, with added TDM for patients with a high risk for GF, may yield improved outcome in pediatric CBT. Since June 2015, a phase-II study (PARACHUTE-trial) has started in the Netherlands investigating individualized dosing, results are expected in 2018.




Admiraal, R., van Kesteren, C., Nierkens, S., Boelens, J.-J., Lacna, A. M., & Raaij, L. E. (2016). Individualized Dosing and Therapeutic Drug Monitoring for Anti-Thymocyte Globulin to Improve Outcome following Cord Blood Transplantation: Proof of Concept. Biology of Blood and Marrow Transplantation, 22(3), S116.

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