High fludarabine exposure and relationship with treatment-related mortality after nonmyeloablative hematopoietic cell transplantation

摘要

Despite its common use in nonmyeloablative preparative regimens, the pharmacokinetics of fludarabine are poorly characterized in hematopoietic cell transplantation (HCT) recipients and exposure-response relationships remain undefined. Our objective of this study was to evaluate the association between plasma F-ara-A exposure, the systemically circulating moiety of fludarabine, and engraftment, acute graft vs host disease (GVHD), treatment-related mortality (TRM) and survival after HCT. The preparative regimen consisted of cyclophosphamide 50 mg/kg/day i.v. day −6; plus fludarabine 30-40 mg/m²/day i.v. on days −6 to −2 and TBI 200 cGy on day −1. F-ara-A pharmacokinetics were performed with the first dose of fludarabine in 87 adult patients. Median (range) F-ara-A AUC (0-∞) was 5.0 ug*hr/mL (2.0-11.0), clearance 15.3 L/hour (6.2-36.6), Cmin 55 ng/mL (17-166), and concentration on dayzero 16.0 ng/mL (0.1-144.1). Despite dose reductions, patients with renal insufficiency had higher F-ara-A exposures. There was strong association between high plasma concentrations of F-ara-A and increased risk of TRM and reduced overall survival. Patients with an AUC(0-∞) greater than 6.5 ug*hr/mL had 4.56 greater risk of TRM and significantly lower survival. These data suggest that clinical strategies are needed to optimize dosing of fludarabine to prevent overexposure and toxicity in HCT.