Long-term outcomes of systemic therapies for Hurler syndrome: an international multicenter comparison

Julie B Eisengart, Kyle D Rudser, Yong Xue, Paul Orchard, Weston Miller, Troy Lund, Ans Van der Ploeg, Jean Mercer, Simon Jones, Karl Eugen Mengel, Seyfullah Gökce, Nathalie Guffon, Roberto Giugliani, Carolina F M de Souza, Elsa G Shapiro, Chester B Whitley, Julie B Eisengart, Kyle D Rudser, Yong Xue, Paul Orchard, Weston Miller, Troy Lund, Ans Van der Ploeg, Jean Mercer, Simon Jones, Karl Eugen Mengel, Seyfullah Gökce, Nathalie Guffon, Roberto Giugliani, Carolina F M de Souza, Elsa G Shapiro, Chester B Whitley

Abstract

Purpose: Early treatment is critical for mucopolysaccharidosis type I (MPS I), justifying its incorporation into newborn screening. Enzyme replacement therapy (ERT) treats MPS I, yet presumptions that ERT cannot penetrate the blood-brain barrier (BBB) support recommendations that hematopoietic cell transplantation (HCT) treat the severe, neurodegenerative form (Hurler syndrome). Ethics precludes randomized comparison of ERT with HCT, but insight into this comparison is presented with an international cohort of patients with Hurler syndrome who received long-term ERT from a young age.

Methods: Long-term survival and neurologic outcomes were compared among three groups of patients with Hurler syndrome: 18 treated with ERT monotherapy (ERT group), 54 who underwent HCT (HCT group), and 23 who received no therapy (Untreated). All were followed starting before age 5 years. A sensitivity analysis restricted age of treatment below 3 years.

Results: Survival was worse when comparing ERT versus HCT, and Untreated versus ERT. The cumulative incidences of hydrocephalus and cervical spinal cord compression were greater in ERT versus HCT. Findings persisted in the sensitivity analysis.

Conclusion: As newborn screening widens treatment opportunity for Hurler syndrome, this examination of early treatment quantifies some ERT benefit, supports presumptions about BBB impenetrability, and aligns with current guidelines to treat with HCT.

Keywords: enzyme replacement therapy; hematopoietic cell transplantation; mucopolysaccharidosis; neurodegenerative; newborn screening.

Conflict of interest statement

Conflicts of Interest: Julie Eisengart has received honoraria, consulting fees, and/or research support from ArmaGen, Regenexbio, Sangamo, and Sanofi Genzyme, and has done contract work for Shapiro Neuropsychology Consulting, LLC; Yong Xue is an employee of Sanofi Genzyme; Paul Orchard has received research support and honoraria from Sanofi Genzyme; Weston Miller will be employed by Sangamo Therapeutics in January 2018; Troy Lund has received research support from Sanofi Genzyme; Simon Jones has received research support and consulting fees from Sanofi Genzyme; SeyfullahGökce has received travel support from Alexion, Sanofi Genzyme, and Shire. Nathalie Guffon has received research support from Sanofi Genzyme and Biomarin, and consulting fees from Sanofi Genzyme; Roberto Giugliani has received speaker honoraria, travel grants and investigator fees from ArmaGen, BioMarin and Sanofi Genzyme; Carolina F. M. Souza has received speaker honoraria, travel grants and investigator fees from BioMarin and Sanofi Genzyme; Elsa Shapiro is a Partner in Shapiro Neuropsychology Consulting, LLC; and Chester B. Whitley has received consulting fees and research support from ArmaGen, Sangamo, BioMarin and Sanofi Genzyme. The other authors have no conflicts of interest to disclose.

Figures

Figure 1
Figure 1
Survival in Hurler syndrome. Survival curves depict differences in clinical course for patients with Hurler syndrome who received HCT (HCT), ERT monotherapy (ERT), or no systemic therapy (Untreated).
Figure 2
Figure 2
Cumulative incidence of hydrocephalus in Hurler syndrome. Cumulative incidence functions show differences in development of hydrocephalus for patients with Hurler syndrome who received HCT (HCT) or ERT monotherapy (ERT). As no patients who underwent HCT developed this symptom, the function is flat.
Figure 3
Figure 3
Cumulative incidence of cervical cord compression in Hurler syndrome. Cumulative incidence functions show differences in development of cervical cord compression for patients with Hurler syndrome who received HCT (HCT) or ERT monotherapy (ERT).

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