Cerebrospinal fluid D-2-hydroxyglutarate for IDH-mutant glioma: utility for detection versus monitoring

BACKGROUNDImaging-based monitoring of gliomas is limited by treatment-related changes. D-2-hydroxyglutarate (D-2-HG), produced by the isocitrate dehydrogenase (IDH) mutation, is detectable in cerebrospinal fluid (CSF) that can be accessed from various anatomic compartments. We evaluated CSF D-2-HG as a serially accessible biomarker for IDH-mutant gliomas. METHODSA CLIA-approved gas chromatography mass spectrometry assay was developed for CSF D- and L-2-HG. Lumbar and cranial CSF samples were collected from patients with IDH-mutant gliomas or IDH-wild-type brain tumors and non-tumor pathologies via surgical field collection, lumbar punctures, Ommaya reservoirs, and ventriculoperitoneal shunts. RESULTSCSF D-2-HG was significantly higher in cranial than lumbar samples from IDH-mutant glioma patients (median lumbar=0.20 M, cranial = 1.72 M; p<0.0001). Cranial, but not lumbar, CSF D-2-HG distinguished primary IDH-mutant gliomas from IDH-wild type lesions (cranial AUC= 0.89, 95% confidence interval (CI)= 0.80-0.97); lumbar AUC= 0.52, 95% CI=0.28-0.76). When evaluated in recurrent lesions as a separate validation cohort, this finding was also reproduced in this group (cranial AUC=0.97, 95% CI= 0.94-1.00; lumbar AUC=0.60, 95% CI=0.38-0.83). Cranial CSF D-2-HG levels decreased to 0.54x of baseline with resection in seventeen patients (p=0.0129) but did not decrease significantly with chemoradiation in five patients (p=0.6250). Longitudinal anatomical changes, such as cavity collapse, influenced serial sample interpretation. In grade 4 IDH-mutant astrocytomas, serial cranial CSF D-2-HG increased with disease progression and differentiated stability from pseudoprogression when tumor-CSF contact was sufficient. CONCLUSIONSSerial cranial CSF D-2-HG shows promise as a monitoring biomarker in patients with IDH-mutant gliomas when anatomic variables remain constant. KEY POINTSO_LICranial CSF D-2-HG levels exceed that of lumbar CSF in patients with IDH-mutant gliomas. C_LIO_LICranial CSF D-2-HG may discriminate disease stability vs. treatment effects, although post-resection anatomical changes can impact monitoring. C_LI IMPORTANCE OF THE STUDYImproved glioma monitoring is needed due to challenges distinguishing disease progression from treatment-related changes on imaging. Toward this goal, we evaluated CSF D-2-HG as a biomarker of IDH-mutant gliomas using a CLIA-approved assay. This study answers whether D-2-HG can identify IDH-mutant gliomas via either cranial or lumbar CSF. Importantly, in seventeen patients, we demonstrate that CSF D-2-HG is responsive to cytoreduction via resection, but not chemoradiation in five patients. This is also the first study to demonstrate that longitudinal anatomical changes can impact evaluation of CSF D-2-HG as a monitoring biomarker. Finally, the study demonstrates that serial CSF D-2-HG can increase with disease progression, but not pseudoprogression or stable disease, in five patients with grade 4 IDH-mutant astrocytomas. These findings support the potential of CSF D-2-HG as a monitoring biomarker in patients with IDH-mutant gliomas, particularly when there are minimal changes to the anatomy of the resection cavity.