Pharmacokinetics and Pharmacodynamics of Treosulfan in Patients With Thalassemia Major Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.

A treosulfan (Treo)-based conditioning regimen prior to hematopoietic stem cell transplantation (HSCT) has been successfully used in treating hematological malignant and nonmalignant diseases. We report Treo pharmacokinetics (PK) in patients with thalassemia major undergoing HSCT (n = 87), receiving Treo at a dose of 14 g/m2 /day. Median Treo AUC and clearance (CL) was 1,326 mg*h/L and 10.8 L/h/m2 , respectively. There was wide interindividual variability in Treo AUC and CL (64 and 68%) which was not explained by any of the variables tested. None of the Treo PK parameters were significantly associated with graft rejection or toxicity; however, Treo CL <7.97 L/h/m2 was significantly associated with poor overall (hazard ratio (HR) 2.7, confidence interval (CI) (1.09-6.76), P = 0.032) and event-free survival (HR 2.4, CI (0.98-5.73), P = 0.055). Further studies in a larger cohort are warranted to identify the factors explaining the variation in Treo PK as well as to establish a therapeutic range of Treo for targeted dose adjustment to improve HSCT outcome.