ID #532 Targeted Therapy in Diffuse Midline Glioma H3K27-Altered: Clinical Impact and Survival Outcomes

Abstract Background Diffuse midline glioma (DMG) H3K27-altered is a lethal tumor with a median overall survival (OS) 12 months. Given the dismal prognosis with current treatment, targeted therapies (TT) are increasingly explored, although their real-world impact remains unclear. Materials and Methods We performed a single-centre retrospective study including 77 patients (median age 7.1 years, range 2.0-31.0) with DMG treated at Bambino Gesù Children’s Hospital (Rome, Italy) between 2009 and 2025. Histology was available for most patients, with additional immunohistochemical and molecular analyses. OS was compared among patients receiving 1st-line TT, ≥2-line TT, or no TT. Progression-free survival (PFS) was compared between patients treated with or without the addition of TT to conventional treatment. Adverse events and the impact of recurrent molecular alterations and copy number alterations (CNA) were also analysed. Results Molecular analyses identified recurrent alterations consistent with known DMG biology, including activation of the PI3K/AKT/mTOR pathway and frequent co-mutations of TP53, particularly in non-pontine DMG. No significant correlations between co-mutations and survival were found; however, the presence of CNAs was associated with a numerically shorter OS (11.31 vs 21.63 months, p = 0.3). Median OS and PFS were longer in patients treated with TT, regardless of location. No significant OS/PFS differences were observed between mTOR inhibitors and other TT. Conversely, stratification by treatment line showed longer OS in patients receiving 1st or ≥ 2-line TT compared with no TT (median OS: 17.6 vs 16.4 vs 14.4 months, p = 0.0069). In multivariable analysis, TT was independently associated with a reduced risk of death, while re-irradiation showed a significant OS benefit only on univariable analysis. TT was generally well tolerated, with a maximum toxicity grade 3, reversible, and mostly mucocutaneous. Conclusions TT was associated with a trend toward longer survival in patients with DMG, which should be explored in prospective studies.