title: Single Daily Busulfan Dosing for Infants with Nonmalignant Diseases Undergoing Reduced-Intensity Conditioning for Allogeneic Hematopoietic Progenitor Cell Transplantation.
abstract: Busulfan (Bu) is widely used in conditioning regimens for infants undergoing allogeneic hematopoietic progenitor cell transplantation (HPCT), but the best approach to administer Bu in this population is still unknown. Here, we report a single-center experience of the use of a test dose to guide dose adjustment of intravenous (i.v.) Bu therapy in infants. Between 2004 and 2013, 33 infants younger than 1 year with nonmalignant conditions received allogeneic peripheral blood or cord blood HPCT after a reduced-intensity conditioning (RIC) regimen consisting of fludarabine, antithymocyte globulin, and 2 single daily doses of i.v. Bu. Pharmacokinetic results of a test dose of i.v. Bu (.8 mg/kg) were used to determine the dose of 2 single daily i.v. Bu regimen doses, adjusted to target an area under the curve (AUC) of 4000 μMol*minute per day in a first cohort (n = 12) and 5000 μMol*minute in a second cohort (n = 21). The mean Bu clearance in our infant patients was found to be 3.67 ± 1.03 mL/minute/kg, and the test dose clearance was highly predictive of the regimen dose clearance. The mean AUC achieved after the first single daily regimen dose was 3951 ± 1239 in the AUC 4000 cohort and 4884 ± 766 for the AUC 5000 cohort. No patient in either cohort developed hepatic sinusoidal obstructive syndrome or seizures attributable to Bu. Primary graft failure occurred in 4 patients and secondary graft failure occurred in 3, predominantly in the AUC 4000 cohort (6 of 7). Among the engrafted patients (n = 28), 16 achieved full donor chimerism and 9 patients attained stable mixed chimerism. Overall survival of patients at 6 years after transplantation was 59.5% for the AUC 4000 cohort and 85.4% for the AUC 5000 cohort, with primary graft failure in the first cohort being a major contributor to morbidity. Logistic regression analysis showed that the risk of graft failure increased significantly if cord blood hematopoietic progenitor cells were used or if total Bu exposure was below 4000 μMol*minute per day for 2 days. The difference in clinical outcomes between the 2 cohorts supports the conclusion that targeting a higher Bu AUC of 5000 μMol*minute per day for 2 days improves donor engraftment in infants with nonmalignant conditions undergoing RIC HPCT without increasing toxicity. Measuring i.v. Bu pharmokinetics using a test dose allows timely adjustment of single daily regimen doses and optimization of total Bu exposure, resulting in an effective and safe regimen for these infants.
authors.affiliation: Stem Cell Transplant Program, Division of Hematology-Oncology-Transplant, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Jessica
authors.initials: J
authors.lastname: Ward
authors.affiliation: Stem Cell Transplant Program, Division of Hematology-Oncology-Transplant, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Electronic address: kletzel@att.net.
authors.forename: Morris
authors.initials: M
authors.lastname: Kletzel
authors.affiliation: Stem Cell Transplant Program, Division of Hematology-Oncology-Transplant, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Reggie
authors.initials: R
authors.lastname: Duerst
authors.affiliation: Division of Allergy and Immunology, Ann & Robert H. Lurie Children's Hospital of Chicago, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Ramsay
authors.initials: R
authors.lastname: Fuleihan
authors.affiliation: Stem Cell Transplant Program, Division of Hematology-Oncology-Transplant, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Sonali
authors.initials: S
authors.lastname: Chaudhury
authors.affiliation: Stem Cell Transplant Program, Division of Hematology-Oncology-Transplant, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Schneiderman
authors.affiliation: Stem Cell Transplant Program, Division of Hematology-Oncology-Transplant, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: William T
authors.initials: WT
authors.lastname: Tse
mesh_terms: D064591:Allografts; D002066:Busulfan / Q000008:administration & dosage* / Q000009:adverse effects; D036101:Cord Blood Stem Cell Transplantation; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D015996:Survival Rate; D019172:Transplantation Conditioning
chemical_list: D002066:Busulfan
keywords: Busulfan/fludarabine; Hematopoietic progenitor cell transplantation; Infants; Pediatrics; Pharmacokinetics; Single-dose daily regimen