Journal
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
Volume 14, Issue 2, Pages 220-228Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.bbmt.2007.10.028
Keywords
hematopoietic stem cell transplantation; transplantation conditioning; drug toxicity; busulfan; pharmacokinetics; therapeutic drug monitoring
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Low plasma busulfan (Bu) area under the concentration-time curve (AUC) is associated with graft failure and relapsed leukemias, and high AUC with toxicities when Bu is used orally or i.v. 4 times daily combined with cyclophosphamide in myeloablative hematopoietic stem cell transplantation (SCT) conditioning regimens. We report Bu AUC and its association with clinical outcomes in 130 patients with hematologic malignancies given a once-daily i.v. Bu (3.2 mg/kg days -5 to -2) and fludarabine (Flu, 50 mg/m(2) days -6 to -2) regimen. Total-body irradiation (TBI) 200 cGy x 2 was added for 51 patients with acute leukemias. Plasma AUC varied 3.6-fold (2184-7794 mu M - min, median 4699 mu M - min). Patients with an AUC > 6000 mu M - min had lower overall survival (OS) than those with AUC : 6000 AM - min at 12 months (38% versus 74%) and 3 6 months (23% versus 68%, P < .001). This effect was apparent in patients with standard-risk and high-risk disease, and persisted when potential confounders were considered (hazard ratio 3.2, 95% confidence interval 1.7-6.3). Nonrelapse mortality (NRM) at 100 days (6% versus 19%) and progression free survival (PFS; 58% versus 16%) at 3 years were better with AUC <= 6000 mu M center dot min. These data support a role for therapeutic dose monitoring and dose adjustment with daily i.v. busulfan. (c) 2008 American Society for Blood and Marrow Transplantation.
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