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

  1. Cecile Riviere-Cazaux
  2. Yuta Suzuki
  3. Zain Kizilbash
  4. William J. Laxen
  5. Jean M. Lacey
  6. Tamara M. Wipplinger
  7. Arthur E. Warrington
  8. Michael B. Keough
  9. Lionel Fotso Kamga
  10. Katherine M. Andersen
  11. Nicholas Canaday
  12. Matthew L. Kosel
  13. Silvia Tortorelli
  14. Ugur Sener
  15. Michael W. Ruff
  16. Paul A. Decker
  17. Jeanette E. Eckel-Passow
  18. Sani H. Kizilbash
  19. Timothy J. Kaufmann
  20. Terry C. Burns
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Abstract

BACKGROUND

Imaging-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.

METHODS

A 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.

RESULTS

CSF D-2-HG was significantly higher in cranial than lumbar samples from IDH-mutant glioma patients (median lumbar=0.20 μM, cranial = 1.72 μM; 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.

CONCLUSIONS

Serial cranial CSF D-2-HG shows promise as a monitoring biomarker in patients with IDH-mutant gliomas when anatomic variables remain constant.

KEY POINTS

  • Cranial CSF D-2-HG levels exceed that of lumbar CSF in patients with IDH-mutant gliomas.

  • Cranial CSF D-2-HG may discriminate disease stability vs. treatment effects, although post-resection anatomical changes can impact monitoring.

    • IMPORTANCE OF THE STUDY

    Improved 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.

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    1. Version published to 10.1101/2025.04.08.25325500v1 on medRxiv