Precision Dosing of Busulfan in Children Undergoing HSCT

Implementing Pharmacogenetics in the Busulfan Dosing Method for Children Undergoing Hematopoietic Stem-cell Transplantation: a Prospective, Multicentric, Randomized Clinical Trial

The objective of this clinical trial is to evaluate the personalization the conditioning regimen prior to the hematopoietic stem cell transplant (HSCT) in children and adolescents, to improve HSCT efficacy while reducing conditioning-related toxicities. Namely, we are going to compare the accuracy of two methods for determining the first dose of busulfan, one of the medicines used during the conditioning regimen. First doses will be determined based either only on anthropometric information such as age and weight or by adding a genetic factor that influences the individual ability of busulfan metabolization.

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)

This is an international study being carried out in five countries (Canada, Italy, Switzerland, France, and Denmark).

Inclusion Criteria:

• Patients must be aged from 0-18 years old on entry to the study;
• Clinical indication of allogeneic or autologous hematopoietic stem cell transplantation;
• The conditioning protocol must include IV Bu formulations, Busulfex® (Otsuka Pharmaceutical), Busilvex® (Pierre Fabre Pharma) or other European Medicines Agency (EMA) or Food and Drugs Administration (FDA) approved generic formulations regardless of the administration schedule (q6h, q12h, or q24h)
• The expected length of time from recruitment to starting the conditioning regimen must be superior to 10 days;
• Informed written consent to participate in the study signed by the participant/parent

Exclusion Criteria:

• At least one of the drugs listed below scheduled to be administered in the Bu administration days up to 24h after the last dose of Bu, whenever a washout is not possible:

• Metronidazol (required washout: 7 days)
• Nalidixic acid (required washout: 7 days)
• Phenytoin (required washout: 21 days)
• Itraconazole (required washout: 14 days)
• Ketoconazole (required washout: 7 days)
• Voriconazole (required washout: 7 days)
• Deferasirox (required washout: 7 days)