Oral busulfan pharmacokinetics and engraftment in children with Hurler syndrome and other inherited metabolic storage diseases undergoing hematopoietic cell transplantation

Allogeneic hematopoietic cell transplantation (HCT) is the only treatment for selected inherited metabolic storage diseases (IMSD); a significant shortcoming is failure to achieve donor-derived engraftment. This study was undertaken to determine whether busulfan pharmacokinetics (BU PK) are altered in children with IMSD and whether BU concentrations are important in achieving engraftment. BU samples were obtained from 39 IMSD children, including 20 children with Hurler syndrome, undergoing HCT. Patients received oral BU (40 mg/m²/dose × 8 doses), cyclophosphamide (60 mg/kg/day × 2 doses) and TBI (750 cGy in one fraction) as a preparative regimen. Median (range) oral clearance corrected for bioavailability (Cl/F in ml/min/kg), area under the curve (AUC in ng min/ml) and BU plasma concentration (Cp in ng/ml) with the fourth dose were 5.2 (2.1-11.4), 318 294 (112 893-640 995) and 950 (314-1780), respectively. Children <3 years of age had lower AUC and Cp but higher Cl/F (P ≤ 0.03). BU Cp (P = 0.06) or marrow cell dose (P = 0.32) was not different in Hurler syndrome compared to other IMSD. A median BU Cp of 959 and 831 ng/ml was achieved in children with full and failed early engraftment, respectively. There was no difference in early and late engraftment between children with Hurler and other IMSD. In conclusion, we found no significant association between engraftment, marrow cell dose and BU exposure when combined with CY and TBI in children with IMSD.