Louise Evans ¹ Sarah Trinder ^2,3 Andrew Dodgshun ⁴ David D. Eisenstat ^5,6,7 James R Whittle ^10,8,9 Jordan Robert Hansford ^1,11,12* Santosh Valvi ^13,14,15*

• ¹ Women's and Children's Hospital, Adelaide, Australia
• ² Sydney Children's Hospital, Sydney, New South Wales, Australia
• ³ Children's Cancer Institute Australia, Randwick, New South Wales, Australia
• ⁴ Department of Paediatrics, University of Otago, Christchurch, Christchurch, Canterbury, New Zealand
• ⁵ Children's Cancer Centre, Royal Children's Hospital, Parkville, Victoria, Australia
• ⁶ Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia
• ⁷ Departments of Paediatrics and Critical Care, University of Melbourne, Parkville, Victoria, Australia
• ⁸ Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
• ⁹ Walter and Eliza Hall Institute of Medical Research, The University of Melbourne, Parkville, Victoria, Australia
• ¹⁰ Department of Medical Biology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia
• ¹¹ South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia
• ¹² South Australian Immunogenomics Cancer Institute, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia
• ¹³ Telethon Kids Institute, University of Western Australia, Nedlands, Western Australia, Australia
• ¹⁴ Division of Paediatrics, School of Medicine, University of Western Australia, Perth, Western Australia, Australia
• ¹⁵ Perth Children's Hospital, Perth, Western Australia, Australia

Gliomas account for nearly 30% of all primary central nervous system (CNS) tumors in children and adolescents and young adults (AYA), contributing to significant morbidity and mortality. The updated molecular classification of gliomas defines molecularly diverse subtypes with a spectrum of tumors associated with age-distinct incidence. In adults, gliomas are characterized by the presence or absence of mutations in isocitrate dehydrogenase (IDH), with mutated IDH (mIDH) gliomas providing favorable outcomes and avenues for targeted therapy with the emergence of mIDH inhibitors. Despite their rarity, IDH mutations have been reported in 5-15% of pediatric glioma cases. Those with primary mismatchrepair deficient mIDH astrocytomas (PMMRDIA) have a particularly poor prognosis. Here, we describe the biology of mIDH gliomas and review the literature regarding the emergence of mIDH inhibitors, including clinical trials in adults. Given the paucity of clinical trial data from pediatric patients with mIDH glioma, we propose guidelines for the inclusion of pediatric and AYA patients with gliomas onto prospective trials and expanded access programs as well as the potential of combined mIDH inhibition and immunotherapy in the treatment of patients with PMMRDIA at high risk of progression.