Gene therapy, combined with reduced-intensity conditioning, is a safe and effective treatment for SCID in patients with ADA deficiency. (ClinicalTrials.gov numbers, NCT00598481 and NCT00599781.)

and *4501, but not other alleles. Based on these findings, we developed an algorithm for prediction of nonpermissive HLA-DPB1 mismatches. Retrospective evaluation of 118 transplantations showed that the presence of nonpermissive HLA-DPB1 mismatches was correlated with significantly increased hazards of acute grade II to IV graftversus-host disease (HR ‫؍‬ 1.87, P ‫؍‬ .046) and transplantation-related mortality (HR ‫؍‬ 2.69, P ‫؍‬ .027) but not relapse (HR ‫؍‬ 0.98, P ‫؍‬ .939), as compared with the permissive group. There was also a marked but statistically not significant increase in the hazards of overall mortality (HR ‫؍‬ 1.64, P ‫؍‬ .1). These data suggest that biologic characterization of in vivo alloreactivity can be a tool for definition of clinically relevant nonpermissive HLA mismatches for unrelated HSC transplantation.

Background Intravenous-busulfan (IV-busulfan) combined with therapeutic drug monitoring to guide dosing improves outcomes after allogeneic hematopoietic cell transplantation (allo-HCT). The best method to estimate busulfan exposure and the optimal exposure in children/young adults remains unclear. We therefore evaluated three approaches to estimate IV-Bu exposure (expressed as cumulative-area-under-the-curve; AUC) and associated busulfan-AUC with clinical outcomes in children/young adults undergoing allo-HCT. Methods In this retrospective analysis, patients (0.1–30.4 years) receiving busulfan-based conditioning regimen from 15 centers were included. Cumulative AUC was calculated by numerical integration using non-linear mixed effect modeling (AUCNONMEM), non-compartmental analysis (AUC0-infinity and AUC to the end of the dose interval AUC0-tau) and by individual centers using a variety of approaches (AUCcenter). Main outcome of interest was event-free survival (EFS). Other outcomes of interest were overall survival, graft-failure, relapse, transplantation related mortality (TRM), acute toxicity (veno-occlusive disease (VOD) and/or acute graft versus-host disease (aGvHD), chronic GvHD (cGvHD) and cGVHD-free event-free survival (GEFS). Propensity score adjusted cox proportional hazard models, Weibull models, and Fine-Gray competing risk regressions were used. Results 674 patients were included (41% malignant, 59% non-malignant) Estimated 2-year EFS was 69.7%. The median busulfan AUCNONMEM was 74.4 mg*h/L (CI95% 31.1–104.6 mg*h/L). The median AUCNONMEM correlated poorly with AUCcenter (R2 = 0.254). Patients with optimal IV-busulfan AUC of 78–101 mg*h/L showed 81% EFS at 2 years compared to 66.1% and 49.5% in the low (<78 mg*h/L) and high (>101 mg*h/L) busulfan AUC group respectively (P=0.011). Graft-failure/relapse occurred more frequently in the low AUC group (HR=1.75 P<0.001). Acute toxicity, cGvHD and TRM was significantly higher in the high AUC group (HR 1.69, 2.99 and 1.30), independent of indication. Interpretation These results demonstrate that improved clinical outcomes may be achieved by targeting the busulfan-AUC to 78–101 mg*h/L using a new validated pharmacokinetic-model for all indications.

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