title: Long-term outcomes after allogeneic hematopoietic stem cell transplantation for metachromatic leukodystrophy: the largest single-institution cohort report.
abstract: BACKGROUND
  Metachromatic Leukodystrophy (MLD) is a rare, fatal demyelinating disorder with limited treatment options. Published outcomes after hematopoietic stem cell transplantation (HSCT) are scant and mixed. We report survival and function following HSCT for a large, single-center MLD cohort.
  
  
  METHODS
  Transplant-related data, survival and serial measures (brain MRI, nerve conduction velocity (NCV), neurologic and neuropsychology evaluations) were reviewed. When possible, parental interviews informed current neurologic status, quality-of-life, and adaptive functioning. Gross motor and expressive functions for late-infantile (LI-MLD) and juvenile (J-MLD) patients were described using previously reported, MLD-specific scales.
  
  
  RESULTS
  Forty patients with confirmed MLD have undergone HSCT at our center. Twenty-one (53 %) survive at a median 12 years post-HSCT. Most deaths (n = 17) were treatment-related; two died from disease progression. Survival did not depend upon MLD subtype or symptom status at transplant. LI-MLD patients survive beyond reported life expectancy in untreated disease. Abnormal brain MRI and peripheral nerve conduction velocities (NCV) were common before HSCT. Following transplant, fewer patients experienced MRI progression compared to NCV deterioration. Sixteen LI-MLD and J-MLD survivors were evaluable for long-term gross motor and/or expressive language functioning using existing MLD clinical scoring systems. While most J-MLD patients regressed, the aggregate cohort demonstrated superior retention of function compared to published natural history. Seventeen LI-MLD, J-MLD and adult subtype (A-MLD) survivors were evaluable for long-term adaptive functioning, activities of daily living, and/or cognition. Relative cognitive sparing was observed despite overall global decline. Five sibling pairs (one LI-MLD and four J-MLD), in which at least one underwent transplant in our cohort, were evaluable. Within each familial dyad, survival or function was superior for the treated sibling, or if both siblings were transplanted, for the pre-symptomatic sibling.
  
  
  CONCLUSIONS
  HSCT is a viable treatment option for MLD, but has significant limitations. Later-onset phenotypes may benefit most from early, pre-symptomatic transplant. Until superior, novel treatment strategies are demonstrated, MLD patients should be carefully considered for HSCT.
authors.affiliation: Department of Internal Medicine and Pediatrics, University of Minnesota, Minneapolis, MN, 55455, USA. bouch070@umn.edu.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Boucher
authors.affiliation: Division of Pediatric Blood and Marrow Transplantation, 420 Delaware Street SE, MMC 484, Minneapolis, MN, 55455, USA. mill4991@umn.edu.
authors.forename: Weston
authors.initials: W
authors.lastname: Miller
authors.affiliation: Biostatistics Core, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, USA. shan0219@umn.edu.
authors.forename: Ryan
authors.initials: R
authors.lastname: Shanley
authors.affiliation: Division of Pediatric Clinical Neurosciences, University of Minnesota, Minneapolis, MN, 55455, USA. ziegl002@umn.edu.
authors.forename: Richard
authors.initials: R
authors.lastname: Ziegler
authors.affiliation: Division of Pediatric Blood and Marrow Transplantation, 420 Delaware Street SE, MMC 484, Minneapolis, MN, 55455, USA. lundx072@umn.edu.
authors.forename: Troy
authors.initials: T
authors.lastname: Lund
authors.affiliation: Division of Pediatric Clinical Neurosciences, University of Minnesota, Minneapolis, MN, 55455, USA. gvraymon@umn.edu.
authors.forename: Gerald
authors.initials: G
authors.lastname: Raymond
authors.affiliation: Division of Pediatric Blood and Marrow Transplantation, 420 Delaware Street SE, MMC 484, Minneapolis, MN, 55455, USA. orcha001@umn.edu.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Orchard
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D007966:Leukodystrophy, Metachromatic / Q000473:pathology / Q000523:psychology / Q000628:therapy*; D008279:Magnetic Resonance Imaging; D008297:Male; D009483:Neuropsychological Tests; D011788:Quality of Life; D014184:Transplantation, Homologous; D055815:Young Adult