Outcome of Allogenic Hematopoietic Stem Cell Transplantation in Leukodystrophies: A Single-Center Experience over 15 Years

Background: Leukodystrophies are a heterogenous group of inborn errors of metabolism characterized by progressive demyelination. While gene therapy has shown promising results, allogenic hematopoietic stem cell transplantation (HSCT) remains the standard curative treatment. Due to the rarity of these diseases, reports on transplantation outcomes are limited, and detailed treatment guidelines have not been established.

Methods: We retrospectively analyzed 23 patients diagnosed with leukodystrophy through either enzyme assay or genetic analysis who underwent HSCT at Seoul National University Children's Hospital from January 2009 to December 2023.

Results: The median age at diagnosis and at the time of HSCT were 5.2-year-old (range 0.1-24.1) and 5.4-year-old (range 2.0-24.5), respectively. The median interval between diagnosis and HSCT was 5.8 months (range 1.9-65.7). Twelve patients had adrenoleukodystrophy (ALD) (52.2%), eight had Krabbe disease (34.8%), and three had metachromatic leukodystrophy (13.0%). All patients underwent busulfan-based myeloablative conditioning. In the case of haploidentical transplantation, graft-versus-host disease (GvHD) prophylaxis was performed with post-transplantation cyclophosphamide. One (4.3%) received a transplant from a matched family donor, seven (30.4%) from matched unrelated donors, three (13.0%) from HLA-1-mismatched unrelated donors, and twelve (52.2%) from haploidentical donors. The stem cell source was cord blood in one patient (4.3%), bone marrow in one patient (4.3%), and peripheral blood in the remaining 21 patients (91.3%).

Fourteen patients (60.9%) had neurological regression before HSCT, while nine patients (39.1%) underwent HSCT at asymptomatic state. Asymptomatic patients were detected through screening tests due to family history or newborn screening programs. Cognitive decline, gait abnormality, seizures, and neuropsychiatric symptoms were observed in 10 (43.5%), 11 (47.8%), 4 (17.4%), and 9 (39.1%) patients, respectively. Among the nine asymptomatic patients, eight developed normally and one patient had mild developmental delay. Of the 14 patients with regression, 8 patients (8/14, 57.1%) had further regression and became a bed-ridden state, and 6 patients (6/14, 42.9%) remained neurologically stable.

The 5-year overall survival was 85.9% at a median follow-up of 77.0 months (range 2.4-135.4). Four patients died: the cause of death was disease progression in two patients and treatment-related mortality (TRM) in two patients (one case of adenovirus pneumonia following secondary graftment failure, and one case of liver failure due to acute GvHD). All patients achieved primary engraftment. Four patients (17.4%) showed mixed chimerism (range 1.3-1.91%) on day 28 post-transplantation, while the others (82.6%) had complete donor chimerism. All patients developed febrile neutropenia; however, except for the one patient who died from adenovirus pneumonia, there were no severe infections or identified pathogens. Grade 3 or higher liver toxicity occurred in eight patients (34.8%), veno-occlusive disease in six patients (26.1%), and CMV viremia in sixteen patients (69.6%). Grade II-IV acute GvHD occurred in nine patients (39.1%), and moderate to severe chronic GvHD occurred in one patient (4.3%). Other than the TRM cases, these toxicities were reversible with medication.

Conclusions: Neurological regression before HSCT is a significant factor in determining post-transplant neurological outcomes. Overall toxicity was tolerable regardless of donor type, and considering the accessibility of haploidentical donors, haploidentical HSCT could be a feasible treatment option for leukodystrophies. In South Korea, the very long-chain fatty acid analysis, a screening test for ALD, has recently been included in the newborn screening program. As the early detection rate increases, more effective treatment guidelines need to be established.

Kang:GPCR: Other: Research funding to my institution; Takeda: Other: Travel/Accommodations/Expenses; Takeda, Handok Teva, Recordati, Novartis, MSD: Consultancy.