Predictors of Long-Term Clinical Outcome in Hurler Syndrome Patients after Successful Hematopoietic Cell Transplantation: An International Study

Objectives     Hurler syndrome (HS), the most severe phenotype of Mucopolysaccharidosis type I, is caused by a deficiency of the lysosomal enzyme alpha-L-iduronidase (IDUA). HS is clinically characterized by a progressive and ultimately fatal multi-system deterioration with involvement of the central nervous system (CNS). At present, hematopoietic cell transplantation (HCT) is the only treatment able to prevent disease progression in the CNS and therefore considered the treatment of choice in HS. However, there is a lack of long-term follow-up data on successfully transplanted HS patients as well as the factors influencing them. Therefore, this international multicenter study was initiated to identify predictors of the long-term outcome of successfully transplanted HS patients worldwide.

Methods        Alive and engrafted HS patients with at least 3 years follow-up after HCT were retrospectively evaluated. The main endpoint included the neurodevelopmental outcome; secondary endpoints included the growth, neurologic, orthopedic, cardiac, respiratory, ophthalmologic, audiologic and endocrinologic outcome. The influence of patient, donor, and transplantation-related variables on these endpoints was analyzed using multivariate Cox proportional hazards, logistic regression, and linear mixed models.

Results          197 HS patients from 10 transplantation centers within Europe and the United States were included. This is estimated to represent about 70% of the HS patients successfully transplanted worldwide till 2008. Patients had a median age of 16 (2-80) months at transplantation with a median follow-up of 8.9 (3-22.6) years after last HCT. Post-transplant leukocyte IDUA enzyme levels below the lower reference were seen in 25% of patients due to mixed-chimerism or the use of a carrier donor. Following successful HCT, the clinical course of HS patients is strikingly improved, evident in all organ systems. Residual disease burden is present in the majority of the patients with high variability between patients. A better cognitive status at HCT was a major predictor for superior cognitive development after HCT (figure 1). Significant predictors for superior long-term outcome in all organ systems were the presence of “normal IDUA enzyme levels obtained after HCT” and a “younger age at transplantation”. See the association between the leukocyte IDUA enzyme level obtained after HCT and surgical intervention for cord compression and growth, in figure 2 and 3 respectively.

Conclusion    Although HCT significantly improved the clinical course in HS patients, residual disease burden was observed in the majority of transplanted HS patients. Using exclusively non-carrier donors and accepting only full donor-chimerism will improve the prognosis of HS patients. Reducing the age at HCT through newborn screening could further improve the outcomes of HS patients after HCT.