H3K27-altered diffuse midline glioma (DMG) has been recognized primarily as a pediatric entity. Little is understood about clinical characteristics and response to conventional therapies, such as radiation therapy (RT) and chemotherapy, in adolescent and young adult (AYA) patients with DMG. 

This is a retrospective study of AYA patients (age 15–39 years; median age 21.5 years) diagnosed with DMG seen at Memorial Sloan Kettering Cancer (MSKCC) between 1/2012-3/2023. Histone mutations (H3K27M) were identified by immunohistochemistry (IHC) and/or next-generation sequencing (NGS). 

 Twenty patients were identified with midline-located gliomas: thalamus in 10 patients, spinal cord in 4, brainstem in 3, and the cerebellum, pineal gland, and midline intraventricular location in one patient each. 11/20 (55%) patients were male. Histone H3 mutations were identified in 16/20 patients with IHC and 15/20 patients with NGS. The one non-canonical H3-3B mutation in our study was identified by NGS only. The MGMT promoter was hypomethylated in all 10 patients for whom this testing was completed. All patients received focal RT. 15/20 (75%) patients received temozolomide (TMZ). Four (20%) patients received treatment with pediatric neuro-oncologists, with none receiving TMZ. 10/20 patients (50%) were enrolled in a clinical trial during their disease journeys; 5/10 patients were enrolled before date of first progression. 3/20 (15%) patients were alive at time of last follow-up with MSKCC.

NGS may be helpful in identifying non-canonical histone H3 mutations, as the IHC antibody only recognizes H3K27M. The MGMT promoter was unmethylated in all patients tested for it, querying if this prognostic marker is useful in this cohort. It remains unclear if temozolomide renders meaningful survival benefit for these patients. Larger studies are needed to form consensus treatment guidelines for adolescents and young adults with DMG.