Pharmacokinetics of treosulfan in children undergoing hematopoietic stem cell transplantation

Myeloablative preparative regimens for allogeneic stem cell transplantation,
particularly when based on total body irradiation or high-dose busulfan, have a
high risk of severe early and late toxicity. Reduced toxicity conditioning
regimens may lower this risk but are accompanied by an increased rate of graft
failure, and possibly higher incidence of relapse.
Therefore, there is a need to optimize individual conditioning regimens which
combine achievement of stable donor hematopoiesis, antileukemic efficacy and
low immediate and long term treatment-related toxicity.
Treosulfan is an alkylating agent which has a suitable profile for use in
myeloablative regimens; it has high cytotoxic and also immunosuppressive
activity and relatively limited toxicity. The pharmacokinetics of treosulfan in
pediatric patients has only been studied in one small patient group before,
showing considerable inter-patient variability in drug exposure. At present,
the relation between treosulfan exposure and clinical outcome in children is
unresolved.
By further studying the pharmacokinetics of treosulfan, we hypothesize that
treosulfan based preparative regimes can be further optimized. To achieve this
goal a pharmacokinetic (PK) model will be developed and drug exposure will be
correlated with clinical outcome.

Primary Objective:
• To develop a pharmacokinetic model for treosulfan in pediatric patients
undergoing stem cell transplantation.
• To develop a limited sampling strategy, to collect samples in a patient
friendly manner, e.g. 2-3 samples instead of 6 samples per patient.
• To investigate the variability of the PK of treosulfan in pediatric patients
undergoing allogeneic stem cell transplantation

Secondary Objectives:
Phase 2: This phase will be explorative and the goal is to correlate treosulfan
exposure to clinical outcome.
• To correlate treosulfan exposure to treosulfan efficacy (95% chimerism,
engraftment rate and transfusion independency), regimen related toxicity,
relapse (if applicable), rejection, GVHD and survival
• To study in three different disease groups (hematologic malignancy, immune
deficiencies and hemoglobinopathies) the association between treosulfan
exposure and clinical outcome.

Multi-center prospective observational study.

Literature on the PK of treosulfan in children is scarce. One single study
suggests a high inter-patient variability in treosulfan exposure in pediatric
patients, which is not the case in adult patients. To characterize the PK of
treosulfan which is used routinely in pediatric patients undergoing stem cell
transplantation research specifically in the pediatric population is warranted.
To limit the burden of the patients in the future by reducing the number of
samples per patient, a limited sampling strategy will be developed. We plan to
collect so called rich curves (6 samples per patient) in approximately 20
patients which will allow us to derive a limited sampling scheme.
As all patients have permanent venous access and sampling can be performed
using this access port, the patient burden is minimized.

This study will not be directly beneficial for the patients participating in
the study. The ultimate goal of this research is to optimize individual
treosulfan exposure and further optimize patient outcome after treosulfan based
conditioning.