Repair of the Blood Brain Barrier and Neutrophil Recovery Following HSCT in Cerebral Adrenoleukodystrophy

Abstract Cerebral leukodystrophy is an X-linked peroxisomal disease characterized by mutations in the ABCD1 gene, resulting in the lack of very long chain fatty acid (VLCFA) transport into peroxisomes. Resultant VLCFA build up in the blood and tissues leads to adrenal gland insufficiency in 95% of boys and a progressive inflammatory cerebral demyelinating process in 40% of patients, which is progressive and most often fatal (cALD). Only hematopoietic stem cell transplant (HSCT) has been shown to halt cerebral disease progression. A key clinical feature of cALD is disruption of the blood brain barrier (BBB) illustrated by gadolinium (gad) contrast enhancement on brain MRI at diagnosis and as an indicator of “active” cerebral disease. Following successful donor neutrophil recovery after HSCT, gad enhancement resolves in the majority of cases by 100 days post HSCT in our experience. A seminal question in the field is how recovery of donor-derived hematopoiesis relates to BBB repair and gad resolution. We evaluated the pre-HSCT characteristics and 1- year post-HSCT outcomes in 78 boys undergoing marrow or umbilical cord blood HSCT for cALD. The median total nucleated cell (TNC) dose was 0.8 x 108cells/kg and CD34+ cell dose was 1.27 x 106cells/kg. Pre-HSCT characteristics included: cALD on MRI quantitated using the Loes scoring system, neurologic disability using the neurologic function scale (NFS), plasma and cerebral spinal fluid (CSF) chitotriosidase level, and intensity of gadolinium on pre-HSCT MRI (gad score). We found 39 boys (59%) had gad resolution by day +28 (early) post-HSCT and 79% had gad resolution by day +100 (later) post-HSCT. Patients with gad resolution by day +28 post-HSCT had lower Loes scores at 1-year (p = 0.008), lower absolute NFS (p = 0.004), and less progression of neurologic symptoms (post-HSCT NFS - pre-HSCT NFS, p = 0.02). Graft failure had occurred in 13% of patients with early gad resolution and in 40% in those without early gad resolution (Fishers exact test p = 0.01). Interestingly, in patients without graft failure we found neutrophil recovery occurred at a mean of 16 days in the early patients compared to 20 days in those without gad resolution (p = 0.02).Factors associated with early gad resolution were: lower Loes score (p = 0.003), lower NFS (p = 0.003), lower plasma chitotriosidase (p = 0.02), lower CSF chitotriosidase (p = 0.02), day of neutrophil recovery post-HSCT (p = 0.008), and lower gad score (p = 0.02). On multivariate analysis, only the day of neutrophil recovery post-HSCT remained significant with p = 0.04). There was no significant difference in cell dose between the groups. This is the first study to link neutrophil recovery following HSCT and early repair of the BBB (gadolinium resolution). This is an important observation, as gad resolution is thought to be an indicator of cerebral disease arrest and activity of neuroinflammation. This observation may also serve as a useful biomarker as new therapies for cALD are being developed, including gene therapy and CD34 expansion. Disclosures Lund: Magenta Therapeutics: Research Funding. Miller: Sangamo Therapeutics: Employment. Orchard: Magenta Therapeutics: Research Funding.