Hematopoietic cell transplantation in Hurler syndrome. Optimizing the safety and efficacy

Abstract

Hurler syndrome is a severe inherited metabolic disorder caused by a deficiency of the lysosomal enzyme alpha-L-iduronidase (IDUA). Without treatment, all Hurler syndrome patients will inevitably follow a clinical course characterized by a progressive and ultimately fatal multisystem deterioration. At present, this fatal course can be halted only with allogeneic hematopoietic-cell transplantation (HCT). Nevertheless, the success of HCT in Hurler syndrome has historically been limited by high rates of graft failure and HCT-related morbidity and mortality as well as significant residual disease burden despite successful engraftment. Through international collaboration we identified important risk factors for graft failure and transplantation-related morbidity and mortality regarding HCT in Hurler syndrome patients. A lower age at HCT, a fully ablative conditioning regimen with personalized medicine using therapeutic drug monitoring, and the use of a well-matched unrelated cord blood (UCB) or matched sibling donor predicted for higher safety and efficacy. Adjusting the international HCT guidelines according to these risk factors has already resulted in a significant improvement of engrafted survival rates in Hurler syndrome patients to more than 95 percent in HCT-centers of expertise. Furthermore, we describe the largest cohort assembled to date addressing the long-term outcomes of Hurler syndrome patients receiving HCT. Residual disease burden was observed in many of the patients, often requiring medical interventions despite HCT. Interestingly, in a subgroup of the patients a strikingly superior course was noticed. Both a younger age at HCT and a normal IDUA enzyme level obtained post-HCT were found to be highly important predictors for a better long-term prognosis. This thesis further provides an overview of the recommended evaluations in Hurler syndrome patients at baseline and during follow-up after HCT in order to timely recognize the potential complications. Also, we demonstrate that dried blood spots are an alternative highly reliable tool to monitor metabolic correction in transplanted Hurler syndrome patients. Based on our findings the following recommendations are made to improve the safety en efficacy of HCT in Hurler syndrome patients: 1) Perform HCT as early in life as possible. This will not only improve the chance of survival and engraftment but could also result in a significantly superior long-term clinical prognosis, including a maximal chance of preserving cognitive function. 2) Strive for at least normal IDUA enzyme levels post-transplant. Only non-carrier donors and approaches to achieve full-donor chimerism should be used. As an UCB donor is readily available, with maximal engrafted survival rates and highest chance of obtaining normal IDUA levels post-transplant, this stem cell source is particularly attractive. 3) Stick to the international guidelines. Great achievements concerning the survival and engraftment rates of Hurler syndrome patients have already been made based on the implementation of recent international HCT guidelines. Finally, we advice that future studies should focus on strategies to identify patients at an early age such as newborn screening as well as therapies providing enhanced enzyme delivery to the more refractory organ systems, including gene therapy.