Clinical Features, Prognostic Factors, and Pattern of Failure in H3 G34-Mutant Diffuse Hemispheric Glioma: A Multi-Institutional Experience and Meta-Analysis

Background: H3 G34-mutant diffuse hemispheric glioma (DHG) is an aggressive tumor with a poor prognosis. We investigated the relationship between patient outcomes and molecular characteristics, extent of resection, and temozolomide (TMZ) use. Additionally, we reviewed the patterns of treatment failure. Methods: Retrospective multi-institutional review of clinical, imaging, and molecular characteristics of 38 patients with newly diagnosed H3 G34-mutant DHG, supplemented by a meta-analysis. Results: The median age was 14 years (8–28 years). The median progression-free survival (PFS) was 0.6 years (95% CI 0.4–1.2 years), and the median overall survival (OS) was 1.8 years (95% CI 1.1-3.0 years). Gross total resection (GTR) was associated with improved PFS (p = 0.0078) compared to non-GTR. Twenty-two patients (57.9%) received frontline TMZ and had improved PFS compared to those without (p = 0.0034). Of the evaluable patients with progressive disease, 78% progressed within the high-dose RT field. MGMT promoter methylation was not significantly associated with PFS/OS or TMZ efficacy (33 evaluable cases, n = 19 with MGMT silencing, n = 14 without). PDGFRA amplification (n = 10) was associated with inferior OS (p = 0.0443), and CDKN2A homozygous deletion (n = 16) was associated with inferior PFS (p = 0.0204). In the meta-analysis cohort (n = 252), GTR/near-total resection had significantly better PFS (p < 0.0001) and OS (p < 0.0001), and MGMT promoter methylation was not associated with PFS/OS. Conclusions: In our cohort, MGMT promoter methylation was not a prognostic factor and was not associated with TMZ utility. The resection extent and TMZ use were associated with improved survival outcomes. As most treatment failures occurred within the high-dose RT field, extended fields are not warranted.