Precision Dosing of Busulfan in Children Undergoing haematopoietic stem-cell transplantation (HSCT)- A randomised controlled study to investigate the impact and feasibility of implementing pharmacogenomics into the busulfan dosing method for children undergoing haematopoietic stem-cell transplantation on target exposure attainment following dose 1.

This study is designed as a prospective international multicentre randomised superiority clinical trial. Paediatric patients aged 0-18 years undergoing Haematopoietic Stem Cell Transplantation (HSCT) with a Busulfan (Bu)-based conditioning regimen will be randomly assigned to one of two groups. The experimental group will receive Bu dosing based on the pharmacogenetics (PG)-based personalised model. Participants will be randomly assigned (1:1 ratio, stratified by conditioning regimen - the presence of fludarabine) to receive their first dose of busulfan according to: 1) the most performing method based on age and weight - McCune's model (control arm) 2) a method that also considers a pharmacogenetic factor (variants occurring in the promoter region of the GSTA1 gene) in association with the co-administered chemotherapeutic agent fludarabine in the dose personalization (experimental arm) as per publication [Hassine K et al. 2024, Pharmacokinetic modeling and simulation with pharmacogenetic insights support the relevance of therapeutic drug monitoring for myeloablative busulfan dosing in adult HSCT, Transplantation and Cellular Therapy, Vol 30, Issue 3, P332, DOI: 10.1016/j.jtct.2023.12.003] Busulfan will be given as an intravenous infusion over a 96hour time period and can be administered either every six hours for 16 doses, every 12 hours for 8 doses or every 24 hours for 4 doses. A blood test or buccal swab is required a few weeks prior to the scheduled transplant for genotype testing which will be undertaken for Australian patients at Pathology Queensland. Sampling for busulfan plasma concentrations will be performed at several time points following the first dose and then according to standard clinical practice at the centre. Samples will be tested at local laboratories according to standard practice. The pharmacogenomic test result will be sent to a centralised service for interpretation and randomisation will occur. The centralised service will then provide the dose for initial dosing calculated for the individual according to the arm of the study. As the outcome linked to the main aim of this study is PK, the use of any drug with relevant drug-drug interaction with Bu during the days of administration of Bu up to 24h after the end of the last dose. Whenever those drugs can be stopped or replaced, a wash-out time is required prior to the first infusion of Bu. Appendix 6 contains the list of the drugs considered as presenting a relevant interaction with Bu in this study and the respective minimal wash-out time required. The child receiving treatment will be in hospital during busulfan administration as per standard of care for a paediatric patient undergoing stem cell transplant.