• James A Russell, Shahbal B Kangarloo, Tyler Williamson, M Ahsan Chaudhry, Mary Lynn Savoie, A Robert Turner, Loree Larratt, Jan Storek, Nizar J Bahlis, Mona Shafey, Christopher B Brown, Maggie Yang, Michelle Geddes, Nancy Zacarias, Ping Yue, Peter Duggan, Douglas A Stewart, and Andrew Daly.
• Departments of Medicine and Oncology, Foothills Hospital and Tom Baker Cancer Centre, Calgary, Alberta, Canada. jjamesrus@shaw.ca
• Biol. Blood Marrow Transplant. 2013 Sep 1; 19 (9): 1381-6.

AbstractA combination of fludarabine (Flu) and daily i.v. busulfan (Bu) is well tolerated and effective in patients undergoing allogeneic hematopoietic stem cell transplantation. Although there is some evidence that Bu exposures exceeding 6000 μM.min [corrected] may lead to excessive toxicity, there is little information on the effect of exposures below this level on outcomes. We studied Bu exposure, as measured by area under the concentration-time curve (AUC), in 158 patients with various hematologic malignancies in an attempt to identify an optimal range for targeted therapy. The preparative chemotherapy regimen comprised Flu 50 mg/m(2) on days -6 to -2 and i.v. Bu 3.2 mg/kg on days -5 to -2 inclusive. Graft-versus-host disease (GVHD) prophylaxis included methotrexate, cyclosporin A, and antithymocyte globulin. Patients with Bu exposures below the median AUC of 4439 μM.min [corrected] were at increased risk for acute GVHD grade II-IV (hazard ratio [HR], 2.30; 95% confidence interval [CI], 1.19 to 4.49; P = .014). Those in the highest and lowest Bu exposure quartiles (daily AUC <3814 μM.min and >4993 μM.min) [corrected] had an increased risk of nonrelapse mortality (subdistribution HR, 3.32; 95% CI, 1.46 to 7.54; P = .004), as well as worse disease-free survival (HR, 1.81; 95% CI, 1.09 to 2.99; P = .021) and overall survival (HR, 1.94; 95% CI, 1.12 to 3.37; P = .018). Bu exposures between 4440 and 4993 μM/min were accompanied by the lowest risk of both nonrelapse mortality and acute GVHD.Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

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