Hurler Syndrome: II. Outcome of HLA-Genotypically Identical Sibling and HLA-Haploidentical Related Donor Bone Marrow Transplantation in Fifty-Four Children

Abstract

Untreated patients with Hurler syndrome (MPSIH) experience progressive neurologic deterioration and early death. Allogeneic bone marrow transplantation (BMT) ameliorates or halts this course. The Storage Disease Collaborative Study Group was formed to evaluate the effectiveness and toxicity of BMT. Effectiveness was defined as engrafted survival with continuing cognitive development. Fifty-four patients deficient in leukocyte α-l-iduronidase enzyme activity (median age, 1.8 years; range, 0.4 to 7.9) received high-dose chemotherapy with or without irradiation and BMT from HLA-genotypically identical sibling (GIS) or HLA-haploidentical related (HIR) donors between September 16, 1983 and July 14, 1995; all children were included in this report. Thirty-nine of 54 patients (72%) engrafted following the first BMT. The probability of grade II to IV acute graft-versus-host disease (GVHD) at 100 days was 32% for GIS and 55% for HIR patients. The probability of extensive chronic GVHD was 0% for GIS and 24% for HIR patients. The actuarial probability of survival at 5 years was 64% for all patients, 75% for GIS patients, 53% for HIR patients, and 53% for patients with donor marrow engraftment. The baseline Mental Developmental Index (MDI) was examined both for children less than and greater than 24 months of age at BMT. Children transplanted before 24 months had a mean baseline MDI of 78, while those transplanted after 24 months had a mean baseline MDI of 63 (P = .0002). Both baseline and post-BMT neuropsychologic data were available for 26 of 30 engrafted survivors. Of 14 patients transplanted before 24 months of age, nine demonstrated developmental trajectories that were normal or somewhat slower than normal. In contrast, of 12 patients transplanted after 24 months of age, only three showed developmental trajectories that were normal or somewhat slower than normal (P = .01). For children with a baseline MDI greater than 70, there was a significant correlation between the MDI at follow-up study and leukocyte α-l-iduronidase enzyme activity (P = .02). Children were more likely to maintain normal cognitive development if they were fully engrafted following BMT from a donor with homozygous normal leukocyte α-l-iduronidase enzyme activity. Children who developed acute GVHD of grade II or worse had significantly poorer cognitive outcomes (P < .009). No difference in the post-BMT MDI was observed between patients whose preparative therapies did (n = 10; radiation dose, 300 to 1,400 cGy) or did not (n = 16) include radiation. We conclude that MPSIH patients, particularly those less than 24 months of age with a baseline MDI greater than 70, can achieve a favorable long-term outcome with continuing cognitive development and prolonged survival after successful BMT from a related donor with homozygous normal enzyme activity.

Mortality after hematopoietic stem cell transplantation for severe mucopolysaccharidosis type I: the 30‐year University of Minnesota experience

“…This study also confirms the findings of others ( Finally, this study suggests that females undergoing HSCT for MPS IH may have increased mortality. The earliest reports of survival after HSCT for MPS IH included a large international study , showing a 5-year actuarial probability of survival of 64% for all patients (75% for those receiving a genetically identical sibling marrow, 53% for those receiving an HLA haplo-identical related marrow) (Peters et al 1996(Peters et al , 1998. The survival curves suggested that there were few, if any, deaths more than 2-3 years post-HSCT.…”

“…Causes of death most frequently identified in the literature were transplant-related (within the first year), including viral infection, pulmonary hemorrhage (idiopathic pulmonary syndrome/diffuse alveolar hemorrhage), and graft-versus-host disease (GvHD) (Vellodi et al 1997;Souillet et al 2003;Boelens et al 2007Boelens et al , 2013Mitchelletal 2013). Most studies of 5-year survival probability report the predicted survival curve to have an extended plateau (no deaths) following the initial peri-transplant period (Peters et al 1998;Souillet et al 2003;Boelens et al 2013;Mitchell et al 2013).…”

Current and potential therapeutic strategies for mucopolysaccharidoses

“…63,64 Notably, HSCT has been shown to preserve cognition and increase survival in patients with Hurler syndrome if performed before the age of 2 years and before the onset of serious mental involvement. 51,[67][68][69] Clinical experience with HSCT is very limited for other MPSs. In MPS II, controversy still prevails surrounding the efficacy of HSCT in altering the course of the neurological decline despite observed somatic improvements.…”

Combined enzyme replacement and haematopoietic stem cell transplantation in Hurler syndrome

“…4 HSCT, introduced in 1981, restores endogenous production of the inherently deficient enzyme, and is most beneficial if performed prior to onset of cognitive decline (usually by 24 months of age) by arresting the neurodegenerative process. 5 The morbidity and mortality associated with HSCT alone are considerable and discouraging for parents (see Table 2). 6 Combined ERT-HSCT is being evaluated for benefit in ameliorating the high transplant-related morbidity and mortality in MPS I 7,8 (see Table 2 for comparison showing a significant decrease in overall mortality).…”