14800-DvRappard

77 Efficacy of hematopoietic cell transplantation in metachromatic leukodystrophy 5 Metachromatic leukodystrophy (MLD) is a neurodegenerative disorder caused by deficiency of arylsulfatase A, 1 leading to sulfatide accumulation and subsequent demyelination of the central and peripheral nervous system. 2,3 MLD is divided into 3 subtypes, based on the age of onset, late-infantile (< 30 months), juvenile (2.5-16 years) and adult (>16 years). With early disease onset, progression is fast andmotor signs areprominent, in contrast to later formswith insidious onset of cognitive deterioration. 6 Eventually, all acquired skills are lost and patients die. Hematopoietic cell transplantation (HCT) is a possible treatment, but systematic outcome data are lacking, due to the use of different eligibility criteria and protocols worldwide. 6-12 In order to assess HCT efficacy, we evaluated all 35 consecutive MLD patients presenting between 2004 and 2015 in our department, the Dutch Leukodystrophy Referral Center (Figure 1A). Patients with a total intelligence quotient (IQ) above 70 and without gross neurological signs (i.e. ambulation without support, no dysphagia) were considered HCT candidates (Tables 1 and 2). HCT was performed at the University Medical Center Utrecht (UMCU; Blood and Marrow Transplantation Program) according to international protocols. 13 Patients received HCT from either a HLA identical sibling (n=3; noncarrier) or from an unrelated umbilical cord blood (n=10) donor (with a minimum match of 4 out of 6 HLA-loci) after fludarabine (160mg/m2) + busulfan (targeted to cumulative exposure of 90mg*h/L); thymoglobuline was added in cord blood recipients. For details, see supplemental Methods (available on the Blood Web site). Transplanted patients were followed for a mean duration of 4.7 years, assessments including neurological examination, cognitive function, brain magnetic resonance imaging (MRI) rated by the MLD-Loes score, 14 measurement of arylsulfatase A activity, and assessment of nerve conduction velocity. Gross motor function (GMF) was scored according to a classification developed for MLD. 15 After 5 years, follow-up intervals were adapted to clinical status. Follow-up of nontransplanted patients (mean, 4.6 years) consisted of neurological examination, in some cases, assessment of nerve conduction velocity, and MRI, the intervals depending on clinical condition. Two composite survival endpoints were analysed; intervention- free survival (IFS) and activities of daily living-compromise free survival (AFS). There was no transplantation-related mortality. All patients engrafted and achieved full donor chimerism. Three symptomatic patients (23%; 1 late-infantile,1 juvenile,1 adult) died due to disease progression, all within 1 year after HCT. Eight nontransplanted