Exploring pharmacological variability of myeloablative conditioning agents in children receiving haematopoietic stem cell transplantation

Abstract

Haematopoietic stem cell transplantation (HSCT) is a potentially curative therapeutic option for patients with a variety of life-threatening malignant and non-malignant conditions. Historically, busulfan-based chemotherapeutic conditioning has been the backbone for myeloablative conditioning in paediatric HSCT. However, its capacity to provide complete myeloablation is offset by its dose-limiting toxicities; most notably sinusoidal obstruction syndrome (SOS), which is associated with multi-organ failure and patient mortality. As such, pharmacokinetic monitoring is recommended to better target a therapeutic exposure. Development of reduced intensity conditioning regimens with treosulfan have lowered the incidence of toxicity following transplant and provided greater overall survival. Though, with less aggressive conditioning comes a higher risk of graft failure, requiring subsequent intervention with re-transplantation.

The research presented in this thesis explores the pharmacology of intravenous busulfan formulations containing N,N-dimethylacetamide (DMA) and intravenous treosulfan in paediatric patients with a broad range of malignant and non-malignant indications. The patients included in this research were representative of real-world paediatric populations that would be considered for HSCT. Through use of population pharmacokinetic modelling and pharmacodynamic assessment of post-HSCT clinical outcomes, patient-specific source of variability affecting busulfan and treosulfan pharmacology were investigated with respect to current dosing protocols.