Outcome After Cord Blood Transplantation Using Busulfan Pharmacokinetics-Targeted Myeloablative Conditioning for Hurler Syndrome

Background: Successful hematopoietic cell transplantation (HCT) provides life-long disease-modifying therapy for children with Hurler syndrome (HS). Umbilical cord blood (CB) is an important alternative stem cell source for HS children requiring HCT but lacking a suitable human leucocyte antigen (HLA)-matched, non-carrier sibling donor. This is the largest unrelated cord blood transplantation (CBT) series for HS collected from three large, experienced metabolic transplant centers. Objective: The aims of this study were to examine outcomes and performed a predictive analysis after a CBT for HS using intravenous busulfan pharmacokinetic (Bu-pk) directed myeloablative conditioning (MAC). Study design: This collaborative retrospective included 97 children with HS who received their first CBT between 2004 and 2016 at Royal Manchester Children's Hospital, University Medical Center Utrecht and University of Minnesota Children's Hospital. Outcomes of interest were overall survival (OS), engrafted survival (ES), graft failure, graft-versus-host disease (GvHD), latest donor chimerism and IDUA enzyme level. Engrafted survival (ES) was defined as the probability of being alive with ≥20% whole blood donor-cell engraftment after the first CBT. Cox proportional hazards regression modelling was used to perform univariate analysis of predictors on OS and ES. Cumulative incidence of GvHD was calculated using a competing risk analysis, considering death and graft failure as competing events. All factors associated with a p-value <0.10 by univariate analysis were included into multivariate analysis. All p-values quoted are two-sided, with a level of significance of 0.05. Statistical analyses were performed using STATA 14.2. Results: Patient and transplantation characteristics were summarised in table 1. The median age at transplant was 10.8 months (range 0.23 – 63.2 months). The median follow-up for surviving patients was 4.2 years (range, 1.0 to 12.8 years). 5-year overall survival (OS) and engrafted survival (ES) were 88% and 79%. OS was 95% after BuFluATG, 90% after BuCyATG and 74% after BuCyAlemtuzumab (p=0.02) (Figure 1a). Age, conventional HLA matching, allele level HLA matching, washed CB, cell doses were not associated with OS. ES was 84% for BuFluATG, 83% for BuCyATG and 65% for BuCyAlemtuzumab (p=0.34). Washed CB unit (p=0.03, figure 1b) and HLA ≤ 6/10 (p=0.02) were associated with significantly lower ES. The one-year cumulative incidence of graft-failure was 11% (95% CI, 6-21%). Five (5%) had grade III-IV acute GvHD. Five had limited chronic GvHD and one had extensive GvHD. The incidence of veno-occlusive disease was higher in patients conditioned with BuCy (n=10, 19%) compared to BuFlu (n=2, 5%) (p=0.03). Of the 11 patients with graft failure, 8 (73%) were aplastic and 3 (27%) autologous reconstitution. Of 11 patients with graft failure, 9 received a second transplant, and 8 (89%) survived. 89% after first CBT and all after second transplant had full donor chimerism. All had IDUA enzyme levels of above the lower limit of normal range. Conclusions: Survival after CBT for HS has improved but better strategies are needed to improve graft outcome. Mismatched ≤6/10 and washing of the cord blood graft are associated with inferior engrafted survival. Cord blood graft is associated with low risk of acute and chronic graft-versus-host disease.