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- Title
High fludarabine exposure and relationship with treatment-related mortality after nonmyeloablative hematopoietic cell transplantation.
- Authors
Long-Boyle, J. R.; Green, K. G.; Brunstein, C. G.; Cao, Q.; Rogosheske, J.; Weisdorf, D. J.; Miller, J. S.; Wagner, J. E.; McGlave, P. B.; Jacobson, P. A.
- Abstract
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. The objective of this study was to evaluate the association between plasma F-ara-A exposure, the systemically circulating moiety of fludarabine, and engraftment, acute GVHD, TRM and OS after HCT. The preparative regimen consisted of CY 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 carried out with the first dose of fludarabine in 87 adult patients. Median (range) F-ara-A area-under-the-curve (AUC(0−∞)) was 5.0 μg h/mL (2.0-11.0), clearance 15.3 L/h (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 OS. Patients with an AUC(0−∞) greater than 6.5 μg h/mL had 4.56 greater risk of TRM and significantly lower OS. These data suggest that clinical strategies are needed to optimize dosing of fludarabine to prevent overexposure and toxicity in HCT.
- Subjects
TRANSPLANTATION of organs, tissues, etc.; TREATMENT of chronic kidney failure; FLUDARABINE; PHARMACOKINETICS; KIDNEY diseases
- Publication
Bone Marrow Transplantation, 2011, Vol 46, Issue 1, p20
- ISSN
0268-3369
- Publication type
Article
- DOI
10.1038/bmt.2010.53