Isocitrate Dehydrogenase Mutant Grade II and III Glial Neoplasms

Abstract

Mutations in isocitrate dehydrogenase (IDH) 1 or IDH2 occur in most of the adult low-grade gliomas and, less commonly, in cholangiocarcinoma, chondrosarcoma, acute myeloid leukemia, and other human malignancies. Cancer-associated mutations alter the function of the enzyme, resulting in production of R(-)-2-hydroxyglutarate and broad epigenetic dysregulation. Small molecule IDH inhibitors have received regulatory approval for the treatment of IDH mutant (mIDH) leukemia and are under development for the treatment of mIDH solid tumors. This article provides a current view of mIDH adult astrocytic and oligodendroglial tumors, including their clinical presentation and treatment, and discusses novel approaches and challenges toward improving the treatment of these tumors.

Keywords: Cancer metabolism; Isocitrate dehydrogenase (IDH); Low-grade glioma (LGG); Response assessment in neuro-oncology (RANO).

Conflict of interest statement

Disclosure I.K. Mellinghoff reports serving as a consultant for Agios Pharmaceuticals, Inc, Black Diamond, DC Europa, Debiopharm, Puma Biotechnology, and Voyager, and research grants from Amgen, Eli Lilly, and General Electric. M. van den Bent reports serving as a consultant for Agios Pharmaceuticals, Karyopharm, Cellgene, Nerviano, Carthera, and Genenta. S.M. Chang reports institutional research support from Agios Pharmaceuticals.

Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Figures

Figure 1.. “T2-FLAIR mismatch” sign.

Shown is a MRI Brain of a 35 year-old man with a histologically-confirmed mIDH 1p/19q non-codel WHO Grade II glioma. Left: T2-weighted sequence showing a hyperintensive, relatively homogeneous area; Right: FLAIR sequence with hyperintense rim surrounding a relatively hypointense central area.

Figure 2.. Low grade oligodendroglioma.

Shown are Brain MRI T2 (left image) and T1 after intravenous contrast (right image), showing inhomogeneous lesion with cortical involvement and no contrast uptake.

Figure 3.. Long-term follow-up of Progression-free survival (PFS) of RT/PCV versus RT alone in 1p/19q codel glioma patients (n=80) in EORTC 26951.