ALBERT

Description: Background. T-cell depletion is often used to reduce graft-vs-host disease in haploidentical donor hematopoietic cell transplantation (HCT). However, the absence of adoptively transferred T-cells may increase graft failure, relapse, and infection. Novel methods have been developed to more selectively deplete naïve T cells and preserve memory T cells. Depletion of CD45RA+ cells can provide robust early recovery of diverse memory T-cell populations in haploidentical donor transplantation, and may provide increased immunity against viral infections. Likewise, the provision of additional donor NK cells may reduce viral complications. Patients and Methods. Sixty-seven patients received initial allogeneic HCT on 3 consecutive IRB approved haploidentical donor HCT trials at St. Jude Children's Research Hospital from 2005 to 2015. CD3-depletion was used in 41 recipients, and CD45RA-depletion was used in 26. All patients received similar preparative doses of fludarabine, thiotepa, and melphalan. Patients with CD3-depleted grafts received OKT3 (n=20) or Campath (n=21), and all 41 received rituximab on Day 0 as EBV prophylaxis. Patients with CD45RA-depleted grafts (n=26) did not receive antibody therapy, but instead received total lymphoid irradiation and a dose of cyclophosphamide added to the preparative backbone. Donor NK cells were given Day +6. Peripheral blood was tested for CMV, EBV, and adenovirus using quantitative PCR at least weekly until day +100, and then as indicated. The first 180 days post-HCT were evaluated. Fisher's exact test was used to compare two proportions. Results. Patients with CD3-depletion received a median 0.04 (range: 0.01 - 0.15) x 106 CD3+ cells/kg, and patients with CD45RA-depletion received a median 80.07 (range: 16.08 - 528.52) x 106 CD3+ cells/kg. CMV reactivation occurred in 23 of 41 patients (56.1%) with CD3-depletion and 5 of 26 patients (19.2%) with CD45RA-depletion (p=0.005). Differences occurred predominantly in those CMV seropositive recipients who received grafts from CMV seropositive donors, as CMV was detected in 22 of 24 (91.7%) +/+ patients with CD3-depletion and 4 of 11 (36.4%) +/+ patients with CD45RA-depletion (p=0.001). Of the 23 patients with CMV after CD3-depletion, the peak viral load was a median 4.49 log10 copies/mL blood (range:

Description: Background : Serious morbidity and mortality in sickle cell anemia (SCA) begins early in life during the physiologic decline of fetal hemoglobin (HbF) and its replacement with sickle hemoglobin (HbSS). In older children (〉5 years), hydroxyurea (HU) is safe and provides similar laboratory benefits as in adults when escalated to a mean (standard deviation, SD) maximal tolerated dose (MTD) of 25.6 ± 6.2 mg/kg/day (Kinney, Blood 1999). In infants, a fixed-dose of 20 mg/kg/day is safe, improves hematologic parameters and provides substantial clinical benefits (Wang, Lancet 2011). However, the hematologic benefits of intensifying HU to MTD in young children have not been evaluated. We aimed to describe the initial and long-term hematologic changes provided by initiation of HU and escalation to MTD in young children (

Description: Introduction: Hydroxyurea (HU) reduces vaso-occlusive complications, hospitalizations and transfusion requirements in children with sickle cell anemia (SCA; HbSS and HbSβ0thalassemia). Despite linear pharmacokinetics (PK) and apparent dose dependency for HU effect, there remains unexplained large inter-individual variability in drug response. To better understand this variability, we conducted a PK study of HU to assess: 1) effect of multiple dosing on PK of HU, and 2) explore the utility of using a single post-dose HU plasma concentration as a basis for therapeutic drug monitoring. Methods: Data from two prospective trials, "Pharmacokinetics of Liquid Hydroxyurea in Pediatric Patients with Sickle Cell Anemia" (NCT01506544) and "Single-Dose (SD) and Steady-State (SS) Pharmacokinetics of Hydroxyurea in Children and Adolescents with Sickle Cell Disease", were utilized for this analysis. Participants were children (≤18 years) with HgbSS and HbSβ0 thalassemia from 8 medical centers in the U.S. One cohort of patients had never been treated with HU and the second cohort had been treated with HU for at least ≥3 months at a stable dose. All participants received a single oral dose of HU and plasma PK samples were collected pre-dose, then at 15, 30, 45, and 60 minutes, and 1.5, 2, 4, 6, and 8 hours after study drug was administered under direct supervision. HU was quantitated from plasma and urine using a validated HPLC method. PK parameters for HU were determined from each patient using a standard model-independent approach (apparent Cmax observed from plasma concentration vs time data; AUC determined via a log-linear approach). PK parameters were compared using parametric (two-sample t-test) or nonparametric (Wilcoxon Rank Sum test) as appropriate based on normality of distribution. The coefficient of determination was used to determine the most predictive relationship between post-peak HU plasma concentrations and systemic exposure (AUC). The significance limit accepted for all statistical analyses was a = 0.05. Results: A complete plasma HU PK profile was obtained for 59 children. Participants with PK after the first dose (n=7, HUfirst) group received an average dose of 17.9 ±2.6 mg/Kg of HU whereas those with PK after multiple doses (n=52, HUchronic group) received an average dose of 23.8 ±5.1 mg/Kg (p 〈 0.01). Absorption of HU was rapid in both groups with a time to maximal plasma concentration (Tmax) of 0.9 ±0.58 hours in the HUfirst group and 0.8 ±0.47 hours in the HUchronic group (p=0.68). The mean dose/weight- normalized Cmax in the HUfirst group (2.0 mg/L per 1 mg/kg dose) was 1.4 fold higher than in the HUchronic (1.4 mg/L per 1 mg/kg) (p=0.03). A similar relationship was observed in mean dose/weight-normalized AUCinf, where the HUfirst group was 1.3 fold higher than in the HUchronic group (5.9 vs 4.6 mg/L*hr per 1 mg/kg; p=0.002). Weight-normalized mean apparent oral clearance (Cl/F) was significantly lower in the HUfirst cohort (0.17 L/hr/kg) as compared to the HUchronic (0.23 L/hr/kg) (p