ID #405 IDH mutated low grade glioma in childhood and the impact of early inhibitor use: an international registry study
Juhi Mehrotra, Marina Caballero Bellon, Vivek Pai, Ian Burns, Adrian Levine, Yoshiko Nakano, Abitha Suthakaran, Sheradan Doherty, Amanda Li, Tara McKeown, Siya Verma, Craig Erker, Chantel Cacciotti, Shayna Zelcer, Annette Weiser, Ana Sofia, Guerreiro Stücklin, Hamza Gorsi, Anthony Pak, Yin Liu, Eric Bouffet, Anita Villani, David Malkin, Abhaya Kulkarni, Jennifer Quon, Peter Dirks, Cynthia Hawkins, Uri Tabori, Julie Bennett, Anirban DasAbstract
Background
Vorasidenib has changed the therapeutic landscape for low-grade gliomas (LGG) with IDH1/IDH2 mutations in adults. IDH mutant (mIDH)-LGG are rare in children and pediatric data for inhibitor use is lacking. We aimed to investigate the prevalence and profile of pediatric mIDH LGG and report our early experience using vorasidenib in children.
Methods
Using a dual approach, we performed a retrospective population-based analysis of IDH1/IDH2 mutations in all pediatric LGG diagnosed between 1986-2025 and initiated a prospective international registry-based follow-up for children (12-18 years) on vorasidenib.
Results
IDH1/IDH2 mutations were detected in 2.4% (n = 30/1255) of pediatric LGG. Median age was 15-years (range: 8.8-18), with predominance of IDH1 mutation (93.4%, vs IDH2: 6.7%), and relative frequency of astrocytoma (56.6%) over oligodendroglioma (1p/19q codeletion: 43.4%). ATRX and TP53 mutations were noted in 20% of pediatric mIDH astrocytoma. 13.4% had syndromic associations (Li Fraumeni, Olliers, ANDP, biallelic MBD4-deficiency). While complete resection (23.3%) was the primary goal, diffuse infiltrative/multifocal disease resulted in subtotal resection (30%) or biopsy (46.7%) followed by neuroimaging surveillance in the majority. Ten children received vorasidenib following radiological progression, with a median follow-up of 16.9 (range: 16.4–17.3 months) months on drug. Common adverse effects (≥15%) included fatigue, headache, dizziness, and nausea. Grade 3 transaminitis persisted or recurred, mandating dose-reduction in 40% of patients. Weight gain (n = 2/10) was reported. Importantly, serial reduction in tumor growth-rate and radiological stabilization was observed in n = 9/10 on vorasidenib. None received radiation. Improved seizure-control was reported in 50% with this presenting symptom. Biomarker and CSF ctDNA analyses are ongoing.
Conclusions
We highlight the impact and challenges of using vorasidenib in mIDH low grade glioma in childhood. Pediatric safety and pharmacokinetic studies are being developed. Combined surveillance and biomarker analyses will continue over the next decade to investigate whether treatment in childhood can impact the natural history and mitigate transformation risk, allowing mIDH-glioma interception.