Pediatric H3 G34-mutant diffuse hemispheric glioma: clinical, imaging and molecular prognostic factors, MGMT expression, and temozolomide response

Previous studies have demonstrated poor outcomes in pediatric patients with H3 G34-mutant diffuse hemispheric glioma (DHG). However, the biological basis for this therapeutic resistance remains poorly understood. Furthermore, the effectiveness of temozolomide (TMZ) and the role of surgery in pediatric patients remain uncertain. Therefore, we performed a multi-institutional retrospective analysis of the clinical, imaging, and molecular characteristics of 36 pediatric (≤ 18 years) patients with newly diagnosed H3 G34-mutant DHG. The median age of the cohort was 14 years (8-18 years). The median progression-free survival (PFS) was 0.7 years (95% CI 0.4-1.2 years), and the median overall survival (OS) was 1.8 years (95% CI 1.1-3.2 years). Gross total resection (GTR) was associated with improved PFS (p = 0.0046). Infiltration of three or more brain lobes (gliomatosis cerebri) was noted in 22.6% (7/31) of patients at presentation. Twenty-one patients (58.3%) received frontline TMZ and had improved PFS (p = 0.0049) compared to those who did not. Low MGMT expression was associated with better PFS (p = 0.0039) and better OS (p < 0.0001). In pediatric DHG, gene body/intronic CpG methylation, rather than promoter methylation, correlated with MGMT expression (p < 0.0001). MGMT promoter methylation was not significantly associated with PFS or OS. PDGFRA alterations (n = 13) were associated with inferior OS (p = 0.0035). Post-radiation local (± distant) recurrence occurred in 81.0% (17/21) of patients. Our findings reaffirm the dismal outcomes of pediatric H3 G34-mutant DHG, which exhibits radiation resistance, frequent widespread disease, and a novel mechanism of MGMT regulation. Our data support the use of frontline TMZ in pediatric patients and underscore the importance of GTR when feasible.