Umbilical Cord Blood Transplantation Conditioned without Serotherapy is an Excellent Curative Alternative for Pediatric Non-Malignant Diseases

contribute to better clinical outcomes. Current therapeutic targets for exposure are however primarily based on adult studies. Therefore, this study aimed to define the optimal therapeutic target of BU in children and identify other patientspecific variables to optimize outcomes following alloHCT. Methods: This retrospective study utilized exposureresponse data available from routine pharmacokinetic analysis with or without TDM of BU levels in children and young adults treated with HCT between the years of 2000-2013 from 13 different centers. Primary endpoints were event-free survival (EFS) and overall survival (OS). Secondary endpoints included treatment-related mortality (TRM), veno-occlusive disease (VOD), acute graft-versus-host disease (aGVHD) grade IIeIV and cGVHD. A predictor analysis using Cox regression and multivariate Weibull models was performed. Results: A total of 685 subjects (range 11-116 per center) treated for a variety of malignant (n1⁄4318) and non-malignant disorders (n1⁄4367), with a median age of 5.0 years (range 0.1-28.7) were included in the analysis. The median cumulative BU area-under-the-concentration-curve (AUC) was 77mg*hr/L (range 21-160). In all patients, three-year probability of EFS, OS and graft failurewas 72%, 79%, and 5.4% respectively. BU AUC below 75 or above 100mg*hr/L (p1⁄40.03), “ex-vivo T-cell depletion” (p1⁄40.02) and “in vivo Tcell depletion using serotherapy” (ATG or alemtuzumab: p1⁄40.02) were negative predictors of EFS. A U-shaped relationship between BU AUC & EFS was observed (Figure 1). In patients with malignant disease optimal BU AUC was lower compared to non-malignant disorders (83-95mg*hr/L vs 99-111 mg*h/L, p1⁄40.04, Figure 2). Below the optimal BU target, the incidence of graft failure and relapse (malignant only) was higher (p1⁄40.01), while above the target TRM increased (p1⁄40.04). BU AUC above the median and addition of melphalan were both independently associated with the risk of aGvHD (p1⁄40.01, p1⁄40.04), and melphalan use further increased the risk of VOD (p<0.01). No association was found with cGvHD. Conclusion: BU AUC targeted to a narrow therapeutic range, which is indication dependent, (83-95 mg*h/L for malignant and 99-111mg*h/L for non-malignant diseases) was found to increase EFS andOS in children. Lower BUAUCwas associated with graft-failure and relapse and higher BU AUC with TRM. Our findings suggest that personalizing BU AUC by patientspecific factors may improve efficacy and reduce toxicity.