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

• Published in: Bone marrow transplantation (Basingstoke) Vol. 46; no. 1; pp. 20 - 26
• Main 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2011; Nature Publishing Group
• Subjects: 631/154/436/1729; 692/700/565/545/576/1955; Adult; Aged; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Biological and medical sciences; Bone marrow transplantation; Bone marrow, stem cells transplantation. Graft versus host reaction; Cancer; Care and treatment; Cell Biology; Complications and side effects; Data processing; Dosage and administration; Dose-response effects; Drug Monitoring; Female; Fludarabine; Graft Survival - drug effects; Graft vs Host Disease - epidemiology; Graft-versus-host reaction; Hematology; Hematopoietic Stem Cell Transplantation - mortality; Hematopoietic stem cells; Hemopoiesis; Humans; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - adverse effects; Immunosuppressive Agents - blood; Immunosuppressive Agents - pharmacokinetics; Incidence; Internal Medicine; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Clearance Rate; Middle Aged; Mortality; Neutrophil Infiltration - drug effects; original-article; Patient outcomes; Pharmacokinetics; Prodrugs - adverse effects; Prodrugs - pharmacokinetics; Prodrugs - therapeutic use; Public Health; Renal insufficiency; Renal Insufficiency - complications; Renal Insufficiency - metabolism; Risk Factors; Stem cell transplantation; Stem Cells; Survival Analysis; Toxicity; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Transplantation; Transplantation Conditioning; Vidarabine - analogs & derivatives; Vidarabine - blood; Vidarabine Phosphate - adverse effects; Vidarabine Phosphate - analogs & derivatives; Vidarabine Phosphate - pharmacokinetics; Vidarabine Phosphate - therapeutic use; Young Adult; United States; fludarabine; pharmacokinetics; nonmyeloablative; TRM; F-ara-A; Antineoplastic agent; Purine nucleotide; Hematology; Stem cell; Mortality; Hematopoietic cell; Exposure; Nucleotide analog; Non myeloablative treatment; Fludarabine; Treatment; Antimetabolic; Graft; Fluorine Organic compounds; Pharmacokinetics
• ISSN: 0268-3369; 1476-5365
• DOI: 10.1038/bmt.2010.53

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−∞) ) was 5.0 μg 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−∞) 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.