Abstract
Busulfan has been used as a conditioning regimen in allogeneic hematopoietic cell stem transplantation (HSCT). Owing to a large inter-individual variation in pharmacokinetics, therapeutic drug monitoring (TDM)-guided busulfan dosing is necessary to reduce graft failure and relapse rate. As there exists no TDM of busulfan administration for HCT in Taiwan, we conducted a pilot study to assess the TDM-dosing of busulfan in the Taiwanese population; Seven patients with HCT from The Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan, received conditioning regimens consisting of intravenous busulfan and other chemotherapies. After the initial busulfan dose, blood samples were collected for busulfan TDM at 5 min, 1 h, 2 h, and 3 h. Busulfan was extracted and detected by performing stable-isotope dilution LC–MS/MS. Plasma busulfan concentration was quantified and used for dose adjustment. Potential adverse effects of busulfan, such as mucositis and hepatic veno-occlusive disease (VOD), were also evaluated; The LC–MS/MS method was validated with an analyte recovery of 88–99%, within-run and between-run precision of <15%, and linearity ranging from 10 to 10,000 ng/mL. Using TDM-guided busulfan dosing, dose adjustment was necessary and performed in six out of seven patients (86%) with successful engraftments in all patients (100%). Mild mucositis was observed, and VOD was diagnosed in only one patient; This single-center study in Taiwan demonstrated the importance of busulfan TDM in increasing the success rate of HCT transplantation. It is also necessary to further investigate the optimal busulfan target value in the Taiwanese population in the future.
Highlights
We demonstrated that busulfan pharmacokinetics differed between patients, and most patients were subjected to dose adjustment using therapeutic drug monitoring (TDM) data obtained from the analysis of the first dose of busulfan
Several LC–MS/MS methods have been reported for the quantitation of busulfan in biological fluids [27,28,29,30,31,32]
The busulfan target cumulative under the tion–time curve (cAUC) of 90 mg × h/L used in this study was originally intended for children and young adults in Western populations [25,42], we found that hematopoietic cell transplantation (HCT) engraftments were successful in all patients receiving this target value (Table 4)
Summary
Allogeneic hematopoietic cell transplantation (HCT) is a therapeutic approach used for managing several hematopoietic or genetic diseases [1]. HCTs have been reported in the treatment of malignancies, such as acute myeloid leukemia (AML) [2], neuroblastoma [3,4], and inborn genetic errors such as adrenoleukodystrophy (ALD) [5] and Lesch–Nyhan syndrome (LNS) [6,7]. Before HCT is conducted in recipients, conditioning regimens are administered to reduce the occurrence of tumors and immune ablation. A high dose of total body irradiation has been used for HCT conditioning; patients usually present with immediate or delayed toxicities [1].
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