Targeted‐dose of busulfan: Higher risk of sinusoidal obstructive syndrome observed with systemic exposure dose above 5000 µMol⸱min. A historically controlled clinical trial

• Published in: Hematological oncology 2020-12, Vol.38 (5), p.773-781
• Main Authors: Esteves, Iracema, Santos, Fabio Pires Souza, Ribeiro, Andreza Alice Feitosa, Seber, Adriana, Sugawara, Eduardo Kinio, Sobrinho, Jairo José do Nascimento, Barros, José Carlos, Oliveira, José Salvador Rodrigues, Fernandes, Juliana Folloni, Hamerschlak, Nelson, Andersson, Borje S., de Lima, Marcos, Kerbauy, Fabio Rodrigues
• Format: Article
• Language: English
• Subjects: acute toxicity; Administration, Intravenous; Administration, Oral; Adolescent; Area Under Curve; Busulfan; Busulfan - administration & dosage; Busulfan - adverse effects; Busulfan - pharmacokinetics; Child; Child, Preschool; Conditioning; Controlled Clinical Trials as Topic; Disease Susceptibility; Dosage; Exposure; Female; Hematologic Diseases - diagnosis; Hematologic Diseases - therapy; Hematopoietic Stem Cell Transplantation - adverse effects; Hematopoietic stem cells; hepatic sinusoidal obstructive syndrome; Hepatic Veno-Occlusive Disease - diagnosis; Hepatic Veno-Occlusive Disease - epidemiology; Hepatic Veno-Occlusive Disease - etiology; Hepatic Veno-Occlusive Disease - mortality; Humans; Incidence; Infant; Infant, Newborn; Intravenous administration; Male; Mucositis; Pharmacokinetics; Plasma levels; Prognosis; Stem cell transplantation; Stem cells; Survival; Transplantation; Transplantation Conditioning - adverse effects; Transplantation Conditioning - methods; Transplants & implants; Young Adult
• ISSN: 0278-0232; 1099-1069
• DOI: 10.1002/hon.2789

Busulfan is given in the conditioning regimens preceding hematopoietic stem cell transplantation (HSCT), and plasma levels can be monitored. A targeted, individualized systemic exposure (SE) dose can be achieved by calculating the area under the plasma concentration versus time curve (AUC). The objective of this study was to determine a cutoff value for safety for the AUC for busulfan plasma levels in patients undergoing HSCT. A total of 149 consecutive HSCT patients were studied. After an oral test dose of busulfan, we set target doses of 4000, 5000, or 6000 µMol⸱min/day, and analyzed the AUC of oral or intravenous Bu. These patients were compared with 53 historical control subjects who had received myeloablative conditioning regimen without busulfan pharmacokinetic monitoring. Using a test dose and the administration route had no impact on the sinusoidal obstructive syndrome (SOS) incidence, transplant‐related mortality or 1‐year overall survival. However, patients receiving busulfan at doses set up at AUC > 5000 had an increased risk to develop SOS after HSCT (hazard ratio 3.39, p = 0.034, 95% CI 1.09–10.52). Adjusting the busulfan dose according to SE levels target dose during conditioning is associated with lower rates of oral severe mucositis and SOS. A cutoff of 5000 µMol⸱min is safe and does not impair survival.