Long-term clinical and biomarker observations following rituximab exposure in two siblings with CSF1R-related leukoencephalopathy: a preliminary familial case series

Abstract

Colony-stimulating factor 1 receptor (CSF1R)-related leukoencephalopathy (CRL) is a rare microgliopathy, characterized by progressive neurodegeneration. Impaired STAT3 signaling reduces microglial numbers and limits their ability to clear cellular debris, leading to persistent inflammation and brain tissue damage that activates peripheral CD20⁺ B cells. These cells migrate into the CNS and secrete interleukin-6 (IL-6), amplifying inflammation and further disrupting STAT3 signaling in a self-reinforcing cycle that drives white-matter injury. We describe two siblings from a single family, both carrying the same heterozygous CSF1R variant (c.2562 T > A, p.Asn854Lys), who received four infusions of rituximab (RTX;500 mg) on a compassionate, off-label basis between 2014-2017. The long-term disease trajectory was evaluated using standardized clinical rating scales and brain magnetic resonance imaging (MRI). As a secondary biomarker outcome, serum and CSF neurofilament light chain (NfL) concentrations were assessed. In both siblings, RTX exposure was followed by EDSS stability at 6.5 and 7.0, respectively, over 5 years, with mixed trajectories in other functional and cognitive domains. Over the 23-year MRI follow-up period, patients developed cerebral atrophy. During the post-treatment period, no new focal lesions were observed on brain MRI, and levels of CSF-NfL and CSF-CXCL13 were normalized. In this preliminary familial case series of two siblings carrying the same CSF1R variant, RTX exposure was followed by long-term clinical stability and favorable biomarker trajectories. Patient 1 had a pre-treatment disease course of approximately 13 years, indicating an inherently slow disease progression that cannot be entirely separated from the treatment effect in an uncontrolled observation. CSF1R-related leukoencephalopathy (CRL) is a rare inherited brain disorder that gradually affects movement, thinking, and behavior by damaging brain tissue. Research suggests that certain immune cells may contribute to inflammation in the brain. We report the experiences of two sisters with CRL who carried the same disease-causing change in the CSF1R gene. They received four infusions of rituximab, a treatment that reduces the number of these immune cells, and were followed for several years with neurological assessments, brain scans, and blood tests. After treatment, their symptoms remained stable or improved, no new areas of brain damage were seen on scans, and blood test results improved. Larger studies involving more people with CRL are needed to determine whether this treatment could benefit others with the condition.