Outcomes of hematopoietic stem cell transplantation for Hurler's syndrome in Europe: a risk factor analysis for graft failure

Abstract

Hurler's syndrome (HS), the most severe form of mucopolysaccharidosis type-I, causes progressive deterioration of the central nervous system and death in childhood. Allogeneic stem cell transplantation (SCT) before the age of 2 years halts disease progression. Graft failure limits the success of SCT. We analyzed data on HS patients transplanted in Europe to identify the risk factors for graft failure. We compared outcomes in 146 HS patients transplanted with various conditioning regimens and grafts. Patients were transplanted between 1994 and 2004 and registered to the European Blood and Marrow Transplantation database. Risk factor analysis was performed using logistic regression. 'Survival' and 'alive and engrafted'-rate after first SCT was 85 and 56%, respectively. In multivariable analysis, T-cell depletion (odds ratio (OR) 0.18; 95% confidence interval (CI) 0.04-0.71; P=0.02) and reduced-intensity conditioning (OR 0.08; 95% CI 0.02-0.39; P=0.002) were the risk factors for graft failure. Busulfan targeting protected against graft failure (OR 5.76; 95% CI 1.20-27.54; P=0.028). No difference was noted between cell sources used (bone marrow, peripheral blood stem cells or cord blood (CB)); however, significantly more patients who received CB transplants had full-donor chimerism (OR 9.31; 95% CI 1.06-82.03; P=0.044). These outcomes may impact the safety/efficacy of SCT for 'inborn-errors of metabolism' at large. CB increased the likelihood of sustained engraftment associated with normal enzyme levels and could therefore be considered as a preferential cell source in SCT for 'inborn errors of metabolism'.

Figure 1

Kaplan–Meier curves for being ‘alive and engrafted’. Influence of (a) conditioning, (b) TCD and (c) cell source are shown. A&E, alive and engrafted; BM, bone marrow; Flud-MA=fludarabine-based myeloablative; PBSC, peripheral blood stem cell; RIC=reduced-intensity conditioning; TCD, T-cell depletion.

Figure 2

Multivariate predictors of being ‘alive and engrafted’ after first SCT. In the Flud-MA group: Bu/Cy/Flud was successful in 4/9 cases, Bu/Flud in 4/4 (of whom three patients received successful DLI because of progressive mixed chimerism) and Bu/Me/Cy in 4/4 cases. Without the three patients patients receiving successful DLI Flud-MA is no longer a predictor for a higher rate of being ‘alive and engrafted’. Bu/Cy^hi=busulfan/cyclophosphamide-high dose (either 240 or 260 mg/kg); Bu-target=doses adjusted busulfan; Flud-MA=fludarabine-based myeloablative conditioning; matching=matched donor vs mismatched donor (Id-donor denotes identical donor); OR=odds ratio; TCR=T-cell depletion; 95% CI=95% confidence interval.