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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. [ABSTRACT FROM AUTHOR]

Childhood obesity has more than tripled in the past 30 years. The prevalence of overweight and obese children has also increased in the pediatric cancer setting, causing substantial concern over proper chemotherapeutic dosing in this population. The purpose of this study was to determine if children with an increased body mass index (BMI) have an alteration in busulfan pharmacokinetics during hematopoietic stem cell transplant (HSCT) conditioning. We retrospectively reviewed data on busulfan pharmacokinetics (PK) on HSCT subjects (subjects were part of a prospective study previously reported by our group at Children’s Memorial Hospital) to determine appropriateness of dosing. Subjects were divided into appropriate BMI categories (<25th percentile, 25th-85th percentile, ≥85th percentile) and busulfan PK dosing was analyzed (test dose, regimen dose, area under the curve [AUC], and clearance). The dosing based on PK test dose data of children with BMI ≥85% was compared against the package insert dosing recommendations of using adjusted ideal body weight (AIBW) in obese patients to determine which dosing schema was most accurate. Children with high BMIs had higher AUCs when dosing on actual weight then their normal or low BMI counterparts. This indicates that children with a high BMI require less drug (2.9 mg/kg using actual body weight) to achieve the same AUC as children with normal BMI (4.0 mg/kg) or low BMI (3.6 mg/kg). Using the recommended AIBW dosing schema, 53% of the patients with high BMIs would have had regimen dose AUCs ≥20% over/under the target; whereas with the PK test dose method, only 16% of the patients with high BMIs had regimen dose AUCs ≥20% over/under the target. PK testing continues to be the gold standard for busulfan dosing in children. Particular vigilance should be paid to PK monitoring in high BMI categories because of the potential risk of imprecise dosing when using the AIBW schema. [ABSTRACT FROM AUTHOR]

Myeloablative conditioning (MAC) regimens decrease the risk of relapse in pediatric patients undergoing hematopoietic stem cell transplant (HCT) but cause significant toxicities: transplant-related mortality (TRM) and late effects. Therefore, a MAC regimen that decreases toxicity has the potential to improve overall survival (OS). Busulfan (Bu), fludarabine (Flu), anti-thymocyte globulin (ATG) and 400 cGy of total body irradiation (TBI), a reduced toxicity, MAC regimen was used in pediatric patients. To evaluate the safety and toxicity of this regimen. Secondary objectives included determining OS at 2 and 5 years, and incidence of relapse and GVHD. We prospectively evaluated 40 patients ≤21 years of age undergoing HCT for high-risk leukemias who received dose-adjusted Bu, Flu, ATG and TBI. Bu pharmacokinetics were measured after a test dose and regimen dose 1 to target AUC of 4000-5000 uMol*min/day. Patients were treated between October 2008 and June 2018 (Table 1). OS was 67% and 51% at 2 and 5 years post-HCT, respectively. OS at 2 and 5 years was 70% and 55% for patients with myeloid disease versus 56% and 37% for patients with lymphoid disease, respectively (p=0.18) (Figure 1). Relapse occurred in 11 (28%) at a median of 7 months. TRM was 8% and 13% at 100 days and 1 year post-HCT, respectively. All patients engrafted. >Grade II acute GVHD was seen in 9 (23%); chronic GVHD was seen in 16 (40%). There was no significant impact of age, disease type, donor source or type on HCT outcomes. Long-term toxicities noted were ovarian insufficiency in 8, and short stature, hypothyroidism and learning disabilities in 2 each. Evaluation of Bu AUCs and multivariate analyses are still ongoing. Reduced toxicity, MAC regimen was well tolerated with a low incidence of TRM. This regimen shows a trend toward better efficacy in patients with myeloid disease, however larger studies are needed. [ABSTRACT FROM AUTHOR]