Allogeneic HSCT for adult-onset leukoencephalopathy with spheroids and pigmented glia

Abstract

Adult-onset leukoencephalopathy with spheroids and pigmented glia (ALSP) is an autosomal dominant leukoencephalopathy caused by mutations in colony stimulating factor 1 receptor (CSF1R). Here we report clinical and imaging outcomes following allogeneic haematopoietic stem cell transplantation (HSCT) in two patients with ALSP at the University of California, San Francisco between January 2016 and December 2017. Patient 1 proceeded to transplantation at age 53 with a haplo-identical sibling donor. Patient 2, whose sister and mother had died of the disease, proceeded to transplantation at age 49 with a 12/12 human leukocyte antigen-matched unrelated donor. Both patients received reduced intensity conditioning regimens. At 28 and 26 months post-HSCT, respectively, both patients were alive, without evidence of graft-versus-host disease, with major infection at 1 year in one and new-onset seizures in the other. In both cases, neurological worsening continued post-HSCT; however, the progression in cognitive deficits, overall functional status and gait impairment gradually stabilized. There was continued progression of parkinsonism in both patients. On brain MRI, within 1 year there was stabilization of T2/FLAIR abnormalities, and after 2 years there was complete resolution of abnormal multifocal reduced diffusion. In summary, after >2 years of follow-up, allogeneic HSCT in ALSP led to interval resolution of diffusion MRI abnormalities, stabilization of T2/FLAIR MRI abnormalities, and partial clinical stabilization, supportive of treatment response. Allogeneic HSCT may be beneficial in ALSP by providing a supply of bone marrow-derived brain-engrafting myeloid cells with donor wild-type CSF1R to repopulate the microglial niche.

Microglial replacement therapy: a potential therapeutic strategy for incurable CSF1R-related leukoencephalopathy

“…This meaningful finding is further supported by a recent study convincingly showing the effectiveness of HSCT from human leukocyte antigen-matched wild-type CSF1R gene donors in two CSF1R-related leukoencephalopathy patients [95]. These patients did not show any signs of acute or chronic graft-versus-host disease after HSCT, but experienced worsened neurological symptoms such as parkinsonism after transplantation [95]. During the follow-up period one patient developed pneumonia and the other suffered from new localization-related seizures.…”

“…A previous study reported an affected individual who underwent HSCT from her sibling remained stable for more than 15 years [96]. This meaningful finding is further supported by a recent study convincingly showing the effectiveness of HSCT from human leukocyte antigen-matched wild-type CSF1R gene donors in two CSF1R-related leukoencephalopathy patients [95]. These patients did not show any signs of acute or chronic graft-versus-host disease after HSCT, but experienced worsened neurological symptoms such as parkinsonism after transplantation [95].…”

“…Empiric trials of glucocorticoids did not show obvious clinical improvements in reported CSF1R-related leukoencephalopathy cases [95]. Hematopoietic stem cell transplantation (HSCT) offers a potential regenerative strategy for patients in order to halt disease progression and improve survival (Fig.…”

“…During the follow-up period one patient developed pneumonia and the other suffered from new localization-related seizures. Reducing intensity-conditioning regimens is required in order to minimize potential toxicity during HSCT [95]. More importantly, the progression of cognitive decline, overall clinical outcomes and gait impairment gradually stabilized in 9 and 6 years post-HSCT for each patient [95].…”

“…Reducing intensity-conditioning regimens is required in order to minimize potential toxicity during HSCT [95]. More importantly, the progression of cognitive decline, overall clinical outcomes and gait impairment gradually stabilized in 9 and 6 years post-HSCT for each patient [95]. Furthermore, in brain MRIs the T2 lesions and fluid-attenuated inversion recovery abnormalities were gradually reduced, and there was a significant resolution of abnormal multifocal reduced diffusion as measured by MRI after 2 years [95].…”