Hematopoietic Cell Transplantation for Mucopolysaccharidosis Patients Is Safe and Effective: Results after Implementation of International Guidelines

Abstract

Allogeneic hematopoietic cell transplantation (HCT) is the only treatment able to prevent progressive neurodegenerative disease in a selected group of mucopolysaccharidosis (MPS) disorders. However, its use was historically limited by the high risk of graft failure and transplantation-related morbidity and mortality. Therefore, since 2005 new international HCT guidelines for MPS disorders were proposed. The survival and graft outcomes of MPS patients receiving HCT according to these guidelines in 2 European centers of expertise were evaluated. Two consecutive conditioning regimens were used, busulfan/cyclophosphamide or fludarabine/busulfan-based, both with exposure-targeted i.v. busulfan. A noncarrier matched sibling donor (MSD), matched unrelated cord blood (UCB), or matched unrelated donor (MUD) were considered to be preferred donors. If not available, a mismatched UCB donor was used. Participants were 62 MPS patients (56 MPS type I-Hurler, 2 MPS type II, 2 MPS type III, and 2 MPS type VI) receiving HCT at median age 13.5 months (range, 3 to 44). Forty-one patients received a UCB donor, 17 MSD, and 4 MUD. High overall survival (95.2%) and event-free survival (90.3%) were achieved with only low toxicity: 13.3% acute graft-versus-host disease aGVHD) grades II to IV and 14.8% chronic GVHD (1.9% extensive). A mismatched donor predicted for lower event-free survival (P = .04). A higher age at HCT was a predictor for both aGVHD (P = .001) and chronic GVHD (P = .01). The use of a mismatched donor was a predictor for aGVHD (P = .01). Higher rates of full-donor chimerism were achieved in successfully transplanted UCB recipients compared with MSD/MUD (P = .002). If complying with the international HCT guidelines, HCT in MPS patients results in high safety and efficacy. This allows extension of HCT to more attenuated MPS types. Because a younger age at HCT is associated with reduction of HCT-related toxicity, newborn screening may further increase safety.

Hematopoietic Stem Cell Transplantation for Patients with Mucopolysaccharidosis II

“…Although three of 27 new cases of MPS II patients treated with HSCT showed GVHD, all patients have survived the treatment and shown clinical improvements. To date, more than 900 patients with various forms of MPS have been treated with HSCT, showing an increase in acceptance of this therapy [3,10,13,22,37–44]. HSCT guidelines highly indicate HSCT for patients with MPS I when the procedure is made at an early stage [11,24,38,39,45].…”

“…The international HSCT guidelines recommend that to achieve high overall survival and event-free survival with low toxicity, a non-carrier matched sibling donor, matched unrelated UCB, and matched unrelated donor are preferred donors. Complying with these guidelines in HSCT for MPS II patients should result in improved safety and efficacy, allowing extension of HSCT to more attenuated MPS types [22]. Since a younger age at HSCT correlates with reduction of HSCT-related toxicity and increase of therapeutic efficacy, newborn screening for MPS II will improve safety and treatment outcomes.…”

“…Furthermore, a recent study suggested improvements in speech and neurological impairments for MPS II patients treated with HSCT [21]. Thus, HSCT for MPS II became a therapeutic option for patients in Japan although survival rates depend on the clinical condition of the patient, the donor type, and the skills of trained staffs [3,18,19,22]. In this study, we evaluated the efficacy of HSCT for MPS II by investigating clinical, biochemical, and radiological findings in 27 new cases of HSCT, 51 new cases of ERT, and 15 untreated cases from Japan and comparing outcomes with 119 reported cases of HSCT.…”

Cognitive outcomes and age of detection of severe mucopolysaccharidosis type 1

“…These restrictions are based on the expected benefits of HCT on long-term outcomes and overall posttransplant event-free survival, which is estimated to be 90%. 5 …”

Mucopolysaccharidosis Type I Newborn Screening: Best Practices for Diagnosis and Management

“…2 Available disease modifying therapies include hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT) with laronidase. 4 Because early intervention with HSCT has been demonstrated to stabilize neurocognitive function in MPS I, [5][6][7] it is currently recommended as standard for patients who are predicted to have severe disease. 4,6 ERT with laronidase is used for treating nondirect CNS manifestations of MPS I.…”