Outcomes after Hematopoietic Cell Transplantation for Hurler Syndrome after Implementation Newborn Screening in US and Europe

Background Hurler syndrome (HS), the most severe phenotype in the spectrum of Mucopolysaccharidosis type I, is caused by a severe 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. At present, hematopoietic cell transplantation (HCT) is the only treatment able to prevent central nervous system deterioration and therefore considered the treatment of choice in HS. In large intercontinental cohorts, predictors for outcomes (short and long-term) were found to be age at HCT and enzyme levels after HCT. Newborn screening (NBS) and early HCT could therefore potentially impact outcomes. In several States in the US and Europe NBS has been implemented over the last couple years. We were interested in the age at HCT and outcome of HS patients diagnosed by NBS. Methods All HS patients transplanted in 3 centers in states with NBS were included; Minneapolis, New York (United States) and Utrecht (The Netherlands). The main outcomes of interest were (engrafted)-survival, Graft-versus-Host Disease, auto-immune cytopenia (AIC), sinusoidal obstructive syndrome (SOS) and donor chimerism. Because of the recent implementation of NBS for HS, long-term outcomes are unevaluable. Results 13 patients with concordant HS genotype and phenotype were included; all were identified by genotype matching the HS clinical phenotype. One patient received a non-carrier matched sibling donor and 12 an unrelated cord blood donor (five 8/8, four 7/8 and three 6/8 match). All patients received a busulfan-based myeloablative conditioning (cumulative Bu exposure of 90mg*h/L) combined with either Fludarabine 160mg/m2 (n=12), or Clofarabine (120mg/m2)/Fludarabine (40mg/m2) (n=1). In 6 patients rituximab (day -10, 28) and in 2 cyclophosphamide (50mg/kg) was added as AIC prophylaxis. Patients had a median age of 3.5 (2.4-6) months at HCT. All patients (100%) are engrafted and alive at a median follow-up of 2.9 (0.3-4.8) years. One patient (8%), who was enrolled on an expanded CB trial, experienced a late graft failure (at 1 year), but was successfully retransplanted (and now 3 years after 2nd HCT). One patient (8%) experienced moderate/severe acute GvHD (grade 3) and one patient experienced SOS (8%). No chronic GvHD, no auto-immune cytopenia events or CNS deterioration were noted. At the latest follow-up timepoint, all patients are full donor chimeric (>95%) and have IDUA levels in the normal range. Conclusion NBS facilitates curative HCT for HS patients very early in life. HCT for HS in the first months of life is safe and effective. Longer-term follow-up is needed to study the impact on residual disease burden.