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Multicenter Study
. 2025 Jan;171(2):373-381.
doi: 10.1007/s11060-024-04852-7. Epub 2024 Oct 21.

A multi-center, clinical analysis of IDH-mutant gliomas, WHO Grade 4: implications for prognosis and clinical trial design

Ethan A Wetzel #  1 , Amin I Nohman #  2   3 , Annie L Hsieh  4 , David Reuss  5   6 , Andreas W Unterberg  2   3 , Ilker Y Eyüpoglu  7 , Lingyang Hua  8 , Gilbert Youssef  9 , Patrick Y Wen  9 , Daniel P Cahill  1 , Christine Jungk #  2   3 , Tareq A Juratli #  1   7 , Julie J Miller #  10   11
Affiliations
Multicenter Study

A multi-center, clinical analysis of IDH-mutant gliomas, WHO Grade 4: implications for prognosis and clinical trial design

Ethan A Wetzel et al. J Neurooncol. 2025 Jan.

Abstract

Purpose: Mutations in the Isocitrate Dehydrogenase (IDH) genes, IDH1 or IDH2, define a group of adult diffuse gliomas associated with a younger age at diagnosis and better prognosis than IDH wild-type glioblastoma. Within IDH mutant gliomas, a small fraction of astrocytic tumors present with grade 4 histologic features and poor prognosis. In molecular studies, homozygous deletion of CDKN2A/B is independently predictive of poor prognosis and short survival. As a consequence, 2021 WHO classification now also recognizes this molecular feature, CDKN2A/B deletion, as sufficient for classifying an astrocytoma as IDH-mutant, WHO Grade 4, regardless of histological grading. Here, we investigate outcomes of patients with WHO Grade 4 IDH-mutant astrocytoma both with and without CDKN2A/B deletion, to compare these groups and evaluate clinical and radiographic factors that contribute to survival.

Methods: We retrospectively identified 79 patients with IDH-mutant astrocytoma with CDKN2A/B deletion detected at initial diagnosis across five international institutions as well as a comparison group of 51 patients with IDH-mutant, astrocytoma, histologically Grade 4 without detectable CDKN2A/B deletion. We assembled clinical and radiographic features for all patients.

Results: We find that CDKN2A/B deletion was associated with significantly worse overall survival (OS; p = 0.0004) and progression-free survival (PFS; p = 0.0026), with median OS of 5.0 years and PFS of 3.0 years, compared to 10.1 and 5.0 years for tumors with a grade 4 designation based only on histologic criteria. Multivariate analysis confirmed CDKN2A/B deletion as a strong negative prognosticator for both OS (HR = 3.51, p < 0.0001) and PFS (HR = 2.35, p = 0.00095). In addition, in tumors with CDKN2A/B deletion, preoperative contrast enhancement is a significant predictor of worse OS (HR 2.19, 95% CI 1.22-3.93, p = 0.0090) and PFS (HR = 1.74, 95% CI = 1.02-2.97, p = 0.0420).

Conclusions: These findings underscore the severe prognostic impact of CDKN2A/B deletion in IDH-mutant astrocytomas and highlight the need for further refinement of tumor prognostic categorization. Our results provide a key benchmark of baseline patient outcomes for therapeutic trials, underscoring the importance of CDKN2A/B status assessment, in addition to histologic grading, in clinical trial design and therapeutic decision-making for IDH-mutant astrocytoma patients.

Keywords: CDKN2A/B homozygous deletion; Astrocytoma; Glioma; Isocitrate dehydrogenase (IDH); WHO grade 4.

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Conflict of interest statement

Declarations. Competing interests: D. P. C reports grants from NIH and Tawingo Fund during the conduct ofthe study; financial compensation from Servier, Boston Scientific and Pyramid Biosciences for advisory input. PYW reports research support from Astra Zeneca, Black Diamond, Bristol Meyers Squibb, Celgene, Chimerix, Eli Lily, Erasca, Genentech/ Roche, Kazia, MediciNova, Merck, Novartis, Nuvation Bio, Servier, Vascular Biogenics, VBI Vaccines; personal fees from Astra Zeneca, Black Diamond, Celularity, Chimerix, Day One Bio, Genenta, Glaxo Smith Kline, Merck, Mundipharma, Novartis, Novocure, Nuvation Bio, Prelude Therapeutics, Sapience, Servier, Sagimet, Vascular Biogenics, VBI Vaccines. T.A.J. received honoraria from CSL Behring. J.J.M. reports grants from the National Institute of Neurological Diseases and Stroke, American Cancer Society, Seeman Family Funds, National Cancer Institute, and MGH Transformative Scholar Award during the conduct of the study; personal fees from Servier.

Figures

Fig. 1
Fig. 1
Kaplan-Meier curves of the effect of CDKN2A/B homozygous deletion on (A) overall survival and (B) progression-free survival. P-values represent significance level as determined by log-rank test
Fig. 2
Fig. 2
Kaplan-Meier curves of the effect of CDKN2A/B homozygous deletion in patients who received adjuvant radiation and chemotherapy on (A) overall survival and (B) progression-free survival. P-values represent significance level as determined by log-rank test
Fig. 3
Fig. 3
Kaplan-Meier curves of the effect of pre-operative contrast enhancement on survival outcomes of patients with tumors with CDKN2A/B deletion (A / B) and comparision cohort with grade 4 determination made on histologic grounds (C / D). P-values represent significance level as determined by log-rank test
See this image and copyright information in PMC

References

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