Test-dose pharmacokinetics guided melphalan dose adjustment in reduced intensity conditioning allogeneic transplant for non-malignant disorders

Aims We studied melphalan pharmacokinetics (PK) and feasibility of melphalan full-dose adjustment based on test-dose PK in children and young adults with non-malignant disorders (NMD) undergoing allogeneic hematopoietic cell transplantation (HCT) using reduced intensity conditioning (RIC) containing alemtuzumab, fludarabine and melphalan. Methods Patients received test-dose melphalan (10% of planned full-dose) prior to conditioning. Blood samples for PK were obtained around test and full-dose melphalan (140 mg/m(2) or 4.7 mg/kg in patients <10 kg). Melphalan concentration was measured by liquid chromatography electrospray ionization tandem mass-spectrometry assay and data were analysed using a population-PK model and Bayesian estimation. Test and full-dose melphalan clearance estimates were evaluated by pairwise Wilcoxon test and Bland-Altman plot. Results Twenty-four patients undergoing 25 transplants were included in the final analysis. Patients received standard full-dose melphalan in 17 transplants, with median area under the concentration-time curve (AUC) of 5.5 mg*h/L (range, 3.0-9.5 mg*h/L). Patients received test-dose melphalan in 23 transplants with a test-dose PK predicted full-dose AUC range of 2.9-16.8 mg*h/L. In seven transplants where patients had baseline organ impairment, test-dose PK predicted higher exposure for standard full-dose (median AUC 13.8 mg*h/L). Melphalan full-dose was adjusted in these patients, with achievement of desired target AUC (3.6-5.4 mg*h/L) and no excess toxicity. Mean ratio of test-dose clearance to full-dose clearance was 1.03. Twenty of 22 patients (91%) were within the 95% confidence intervals of the clearance ratio. Conclusion Melphalan test-dose PK reliably predicts full-dose PK and allows for accurate adjustment of full-dose melphalan in RIC-HCT for NMD. This approach can avoid excess toxicity from increased systemic exposure, especially in patients with organ impairment.