LAUSR

Primary CNS lymphoma (PCNSL) is a rare, infiltrative disease. High-dose methotrexate (HD-MTX) is the backbone of induction regimens for PCNSL. While MTX-associated white matter changes are well-described, treatment-related brain volume loss is much less understood, especially in radiotherapy-naïve cohorts. Here, we aimed to longitudinally quantify the rates of brain volume loss in PCNSL patients treated with HD-MTX. We included 12 radiotherapy-naïve patients (age mean±SD 61±15y, range 37-84y, 9F) with histopathologically confirmed PCNSL who received HD-MTX induction (mean±SD 12±4 cycles, range 8-18) +/-rituximab. MRIs were collected from within 1 month of HD-MTX initiation until the end of follow-up (mean±SD: 3.7±2.9y). Longitudinal whole-brain segmentation was performed on FLAIR images using the Sequence Adaptive Multimodal Segmentation tool of FreeSurfer. Brain volumes were normalized to the initial scan, white matter lesion volumes were normalized to cerebral volume (nWML). The average rate of cerebral volume change was -2.1±1.9%/year. Half of patients showed marked cerebral volume loss in the first year (-5.6±1.4% vs. -2.0±1.4%; n=10; p=0.003) with the most prominent change occurring within 6-months of treatment initiation (-4.2±1.7% vs. -0.5±1.6; n=12; p=0.004). Cerebral volume loss reached a plateau after the 1-year mark in both groups (0.3±0.8%/year vs. 1.4±3.3%/year; n=8; p=0.4). Patients younger than 61 years exhibited markedly higher rates of cerebral volume loss (-6.2±1.1%/year vs. 2.4±1.5%/year p=0.003), which was corroborated by strong inverse correlation between age and cerebral volume loss (Pearson’s r=-0.82, p=0.004). Neither the cerebellar volume, nor the nWML load correlated with age. In the present cohort, brain volume loss was approximately four-fold higher than what is described in the healthy aging. Younger patients treated with HD-MTX exhibited more severe cerebral volume loss, which may be due to higher initial brain volume reserve. Detailed analyses of a larger sample are underway.