Outcomes Following Allogeneic Hematopoietic Stem Cell Transplantation For Metachromatic Leukodystrophy

Metachromatic Leukodystrophy (MLD) is a rare demyelinating disease caused by deficient lysosomal arylsulfatase-A (ARSA) activity and resulting pathologic sulfatide excess. Signs and symptoms vary with the age of disease onset. In early phenotypes (“late infantile” and “early juvenile”; onset < 6 years; E-MLD) rapid neurologic regression and death are observed. In late disease (“late juvenile” and “adult”; onset ≥ 6 years; L-MLD) a neuropsychiatric prodrome often precedes frank neurologic decline. For over 30 years, allogeneic hematopoietic stem cell transplantation (HSCT) has been used to halt or curb MLD progression. Yet published outcome data are scant and mixed. We report characteristics of and outcomes for 42 MLD patients following HSCT at the University of Minnesota, the largest such report to our knowledge.

From 1984 to 2008, 17 E-MLD and 25 L-MLD patients were transplanted. The median age at HSCT in the E-MLD group was 5 years (range, 0 – 8 years); the median age at transplant in the L-MLD group was 20 years (range, 6 – 44 years). Twelve (29%) patients were male. Preparative regimens varied. Twenty-seven (64%) patients received myeloablative busulfan/cyclophosphamide conditioning; 11 (26%) received a cyclophosphamide/TBI regimen; 4 (10%) underwent reduced-intensity conditioning. Allograft sources also varied. 10 (24%) patients received an HLA-matched sibling marrow graft; 16 (38%) had an unrelated marrow donor (HLA-mismatched = 6); 16 (38%) received UCB grafts (HLA-mismatched = 14).

Thirty-three (79%) patients were symptomatic at HSCT. The median time from symptom onset to diagnosis was 17 months in E-MLD and 50 months in L-MLD patients. Pre-HSCT brain MRI data was available for 37 patients; 36 (97%) demonstrated white-matter abnormalities. Of 40 patients with evaluable pre-HSCT nerve conduction velocity (NCV) studies, 37 (93%) had measurable peripheral neuropathy. Non-neuropsychological clinical involvement was scored per a neurologic function scale (NFS, 0 = no neurologic findings, 25 = maximal neurologic findings) spanning the domains of auditory processing, vision, motor, swallowing, incontinence, and seizures. Of 40 patients evaluable for pre-HSCT NFS, 25 (63%) had a non-zero score (range, 1 - 4) and 15 (37%) a zero score.

Five-year survival was 58%. Greatest survival (70%) was seen in recipients of HLA-matched, sibling marrow. Among alternative graft recipients (n = 32), favorable survival followed UCB transplantation compared to unrelated marrow (62% versus 47%). Ten patients (24%) died of transplant-related causes by day 180 (3 from hepatic veno-occulsive disease; 2 each from graft-versus-host disease (GvHD) and sepsis; 1 each from graft failure, thrombotic thrombocytopenic purpura, and multiple organ failure syndrome). Four additional patients died within 1 year of transplant, all from infection. Four patients (all E-MLD) died from disease progression (range, 1.5 – 7.1 years post-HSCT). Fourteen patients (33%) developed grade II-IV acute GvHD; 6 (14%) developed chronic GvHD.

The median survivor follow-up was 10 years; 74% demonstrated ≥ 80% donor engraftment at most recent observation. Of 30 evaluable patients, only 9 (31%) demonstrated progression of white-matter disease at median MRI follow-up of 1.26 years. For 22 patients with post-HSCT NCV studies, 17 (77%) evidenced worsening peripheral neuropathy at median follow-up 2.9 years. Twenty-four patients had evaluable post-transplant NFS scores. In E-MLD, the median increase in NFS score was 9 (range, 1 - 10) at median follow-up of 3.4 years. In L-MLD, the median increase was 3 (range, 0 - 22) at median follow-up of 3 years. Symptom status (present versus absent) at the time of HSCT neither impacted survival nor post-transplant NFS. Of 15 L-MLD patients surviving past one year, 7 had an evaluable verbal IQ (VIQ, average range 80 - 120) on both pre- and post-HSCT neuropsychological evaluations. In this subgroup, the mean pre- and post-HSCT VIQ were 83 and 75, respectively; mean follow up was 4.1 years post-HSCT.

In summary, we report outcomes following HSCT for a large MLD cohort. Preliminary analysis suggests favorable clinical neurologic and neuropsychological performance following transplant for L-MLD. Ongoing analysis of the entire cohort, including comparisons against untreated siblings, aims to further define the neurological and neuropsychological benefit of HSCT for MLD.