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

Author(s): Long-Boyle JR, Green KG, Brunstein CG, Cao Q, Rogosheske J, Weisdorf DJ, Miller JS, Wagner JE, McGlave PB, Jacobson PA

Affiliation(s): Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA.

Publication date & source: 2011-01, Bone Marrow Transplant., 46(1):20-6. Epub 2010 Apr 12.

Publication type: Clinical Trial; Research Support, N.I.H., Extramural

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/m(2)/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-infinity))) was 5.0 mug h/mL (2.0-11.0), clearance 15.3 L/h (6.2-36.6), C(min) 55 ng/mL (17-166) and concentration on day(zero) 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-infinity)) greater than 6.5 mug 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.

Page last updated: 2011-12-09

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