Early increase in apparent diffusion coefficient predicts favorable response to dordaviprone (ONC201) therapy in H3K27M-mutant diffuse midline glioma
Abstract
Background: Dordaviprone (ONC201) is the first FDA-approved therapy for H3K27M-mutant diffuse midline glioma (DMG). However, therapeutic response varies among patients, and no imaging biomarkers currently predict long-term benefit. Diffusion-weighted MRI and apparent diffusion coefficient (ADC) obtained during standard clinical imaging reflect tissue cellularity and necrosis, offering potential as an early response indicator.
Methods: Clinical and imaging data from patients treated with dordaviprone (n = 83) on completed studies underwent centralized neuroradiology review, ADC histogram analysis, and functional diffusion mapping (fDM), which were compared and correlated to CSF tumor DNA (tDNA) and metabolomics when available. Final analysis included 38 patients receiving standardized dordaviprone dosing and treatment schedule.
Results: In the pre-progression cohort, early changes in volumetric or cross-sectional RAPNO criteria were not predictive of overall (OS) or progression-free survival (PFS). Importantly, in patients treated pre-progression with dordaviprone post-radiation, tumors with increased diffusion ADC (reduced cellularity) at cycle 3 demonstrated median OS of 732 versus 360 days for those with decreased ADC (increased cellularity, P = .0149); with corresponding PFS of 334 versus 110 days (P = .0132). fDM analysis of spatio-temporal changes of ADC did not correlate with outcomes in a sub-cohort analysis but demonstrated predictive patterns in individual patient time course series. CSF metabolomics stratified by ADC change revealed differences in reductive stress metabolites among dordaviprone responders, linking ADC elevation to dordaviprone-driven metabolic effects.
Conclusion: Early increase in ADC correlates with improved response to dordaviprone in H3K27M-DMG and correlates with CSF metabolic changes, suggesting ADC warrants prospective validation as a biomarker.
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BibTeX
@article{lau2026early,
title = {{Early increase in apparent diffusion coefficient predicts favorable response to dordaviprone (ONC201) therapy in H3K27M-mutant diffuse midline glioma}},
author = {Benison C Lau and Diala P Ajaero and Benjamin A Hoff and Ashley Pearson and Peter Sajjakulnukit and Jack Wadden and Tiffany Adam and Sunjong Ji and Adam L Green and Ali Nabavizadeh and Yue Cao and Madhava Aryal and Santhosh Upadhyaya and Andrea T Franson and Stefanie Galban and Sriram Venneti and Bryan Federowicz and Mark A Shapiro and Timothy J Stuhlmiller and Costas A Lyssiotis and Craig J Galban and Hemant A Parmar and Mohannad Ibrahim and Carl Koschmann},
journal = {Neuro-Oncology},
year = {2026},
month = jul,
doi = {10.1093/neuonc/noag164},
url = {https://doi.org/10.1093/neuonc/noag164},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Early increase in apparent diffusion coefficient predicts favorable response to dordaviprone (ONC201) therapy in H3K27M-mutant diffuse midline glioma
AU - Benison C Lau
AU - Diala P Ajaero
AU - Benjamin A Hoff
AU - Ashley Pearson
AU - Peter Sajjakulnukit
AU - Jack Wadden
AU - Tiffany Adam
AU - Sunjong Ji
AU - Adam L Green
AU - Ali Nabavizadeh
AU - Yue Cao
AU - Madhava Aryal
AU - Santhosh Upadhyaya
AU - Andrea T Franson
AU - Stefanie Galban
AU - Sriram Venneti
AU - Bryan Federowicz
AU - Mark A Shapiro
AU - Timothy J Stuhlmiller
AU - Costas A Lyssiotis
AU - Craig J Galban
AU - Hemant A Parmar
AU - Mohannad Ibrahim
AU - Carl Koschmann
PY - 2026
DA - 2026/07/21
JO - Neuro-Oncology
DO - 10.1093/neuonc/noag164
UR - https://doi.org/10.1093/neuonc/noag164
AB - Background: Dordaviprone (ONC201) is the first FDA-approved therapy for H3K27M-mutant diffuse midline glioma (DMG). However, therapeutic response varies among patients, and no imaging biomarkers currently predict long-term benefit. Diffusion-weighted MRI and apparent diffusion coefficient (ADC) obtained during standard clinical imaging reflect tissue cellularity and necrosis, offering potential as an early response indicator. Methods: Clinical and imaging data from patients treated with dordaviprone (n = 83) on completed studies underwent centralized neuroradiology review, ADC histogram analysis, and functional diffusion mapping (fDM), which were compared and correlated to CSF tumor DNA (tDNA) and metabolomics when available. Final analysis included 38 patients receiving standardized dordaviprone dosing and treatment schedule. Results: In the pre-progression cohort, early changes in volumetric or cross-sectional RAPNO criteria were not predictive of overall (OS) or progression-free survival (PFS). Importantly, in patients treated pre-progression with dordaviprone post-radiation, tumors with increased diffusion ADC (reduced cellularity) at cycle 3 demonstrated median OS of 732 versus 360 days for those with decreased ADC (increased cellularity, P = .0149); with corresponding PFS of 334 versus 110 days (P = .0132). fDM analysis of spatio-temporal changes of ADC did not correlate with outcomes in a sub-cohort analysis but demonstrated predictive patterns in individual patient time course series. CSF metabolomics stratified by ADC change revealed differences in reductive stress metabolites among dordaviprone responders, linking ADC elevation to dordaviprone-driven metabolic effects. Conclusion: Early increase in ADC correlates with improved response to dordaviprone in H3K27M-DMG and correlates with CSF metabolic changes, suggesting ADC warrants prospective validation as a biomarker.
SN - 1522-8517
SN - 1523-5866
ER -