Clinical Pearls & Morning Reports
Published August 16, 2023
Mellinghoff et al. conducted a randomized, placebo-controlled phase 3 trial that evaluated the efficacy of vorasidenib, a dual inhibitor of the mutant isocitrate dehydrogenase (IDH)1 and IDH2 enzymes, in patients with residual or recurrent IDH-mutant grade 2 gliomas who had undergone surgery as their only previous treatment. Read the NEJM Original Article here.
Q: How common are mutations in the genes encoding IDH1 or IDH2 in grade 2 diffuse gliomas in adults?
A: Mutations in the genes encoding the metabolic enzymes IDH1 or IDH2 are present in nearly all grade 2 diffuse gliomas in adults. The mutant enzyme produces the metabolite 2-hydroxyglutarate, which accumulates in glioma tissue and competitively inhibits various α-ketoglutarate–dependent enzymes, resulting in a broad range of changes in DNA hydroxymethylation, gene expression, cellular differentiation, and the tumor microenvironment.
Q: Are IDH-mutant grade 2 gliomas indolent?
A: Gliomas that have a mutation in IDH1 or IDH2 and an unbalanced translocation between chromosomes 1 and 19 (1p/19q-codeleted) are defined as oligodendrogliomas, whereas IDH-mutant gliomas without 1p/19q codeletion (1p/19q–non-codeleted) are defined as astrocytomas. IDH-mutant grade 2 oligodendrogliomas and astrocytomas grow continuously (albeit slowly), infiltrate normal brain tissue, and eventually become aggressive tumors with accelerated tumor growth and neovascularization, which is reflected by the appearance of enhancement on magnetic resonance imaging (MRI).
A: The combination of radiation therapy and chemotherapy has become the standard care for the postoperative treatment of patients with IDH-mutant grade 3 gliomas and for patients with IDH-mutant grade 2 gliomas who are considered to be at high risk for early disease progression. Although adjuvant chemoradiotherapy can result in long-lasting disease remission, treatment is not curative and is associated with radiation-induced neurocognitive dysfunction, chemotherapy-associated DNA hypermutation, and other toxic effects. To delay these potential long-term toxic effects, many patients with IDH-mutant grade 2 gliomas do not receive immediate adjuvant chemoradiotherapy after their initial diagnosis and are instead monitored with serial MRI scans of the head.
A: The results of the prespecified second interim analysis showed that treatment with vorasidenib significantly improved both imaging-based progression-free survival according to blinded independent review and the time to the next intervention, as compared with placebo, among patients who were considered to be candidates for a watch-and-wait approach. On the basis of these results, the trial was unblinded, and all the patients in the placebo group were subsequently offered crossover to the vorasidenib group. Overall, vorasidenib was associated with mainly low-grade toxic effects. The most common adverse event of grade 3 or higher was an increased alanine aminotransferase level (in 9.6% of the patients who received vorasidenib and in none of those who received placebo). Additional end points, including the effect of vorasidenib or placebo on seizures, health-related quality of life, and neurocognition, are not reported here. Follow-up for overall survival is ongoing.