Cerebrospinal fluid D-2-hydroxyglutarate for IDH-mutant glioma monitoring

Imaging-based glioma monitoring is confounded by treatment-related changes. D-2-hydroxyglutarate (D-2-HG), produced by the isocitrate dehydrogenase (IDH) mutation, is detectable in cerebrospinal fluid (CSF), which can be sampled from cranial or lumbar compartments. We evaluated CSF D-2-HG as a serially accessible biomarker for IDH-mutant gliomas, including the optimal compartment for longitudinal sampling.

Lumbar and cranial CSF samples were collected from patients with IDH-mutant gliomas or IDH-wild-type central nervous system pathologies via surgical field collection, lumbar punctures, and CSF access devices. CSF D-2-HG was quantified via our CLIA-certified gas chromatography mass spectrometry assay.

D-2-HG was significantly higher in cranial than lumbar CSF from IDH-mutant glioma patients. Consistent with low D-2-HG abundance in lumbar CSF, lumbar samples could not discriminate IDH-mutant gliomas from IDH-wild-type lesions. In contrast, cranial CSF D-2-HG was significantly higher in IDH-mutant gliomas than wild-type lesions, providing an adequate baseline for initial evaluations of monitoring capabilities. Across 75 samples from 7 consecutive patients with grade 4 IDH-mutant astrocytomas, serial cranial CSF D-2-HG decreased with cytoreduction, remained unchanged with stable disease, and increased with disease progression, but not pseudoprogression.

Serial cranial CSF D-2-HG shows promise as a monitoring biomarker for IDH-mutant gliomas.