Allogeneic hematopoietic cell transplantation for adult metachromatic leukodystrophy: a case series

Abstract

Metachromatic leukodystrophy (MLD) is a rare genetic disorder caused by pathogenic variants of the ARSA gene, leading to a deficiency of the arylsulfatase A enzyme (ARSA) and consecutive accumulation of galactosylceramide-3-0-sulfate in the nervous system. The condition leads to severe neurological deficits and subsequently results in profound intellectual and motoric disability. Especially, the adult form of MLD, which occurs in individuals over the age of 16 years, poses significant challenges for treating physicians due to the rarity of cases, limited therapeutic options and different allogeneic hematopoietic cell transplantation (allo-HCT) protocols worldwide. Here we report the results of allo-HCT treatment in four patients with a confirmed adult MLD diagnosis. Bone marrow or mobilized peripheral progenitor cells were infused after a reduced intensity conditioning regime consisting of Fludarabine and Treosulfan. In 3 patients allo-HCT was followed by an infusion of mesenchymal cells to further consolidate ARSA production. We observed a good tolerability and an increase in ARSA levels up to normal range values in all patients. A full donor chimerism was detected in 3 patients within the first 12 months. In a one-year follow-up, patients with complete donor chimerism showed a neurological stable condition. Only one patient with an increasing autologous chimerism showed neurological deterioration and a decline in ARSA levels in the first year. In summary, allo-HCT offers a therapeutic option for reconstituting ARSA enzyme levels in adult MLD patients with tolerable side effects.