Simple SummaryDiffuse midline glioma,H3 K27-altered are central nervous system tumors that primarily affect the pediatric population. Currently, there are no curative therapies, with several completed and on-going clinical trials exploring many different therapeutic options. In this systematic review, we utilized individual participant data from published clinical trials to assess the effect of treatment options, molecular makeup and clinical characteristics on overall survival. These findings are intended to provide guidance for future interventions along with indicate the need to continue to assess results from clinical trials as they become available at a larger scale.AbstractDiffuse midline glioma (DMG),H3 K27-altered are highly aggressive, incurable central nervous system (CNS) tumors. The current standard palliative treatment is radiotherapy, with most children succumbing to the disease in less than one year from the time of diagnosis. Over the past decade, there have been significant advancements in our understanding of these heterogeneous tumors at the molecular level. As a result, most of the newer clinical trials offered utilize more targeted approaches with information derived from the tumor biopsy. In this systematic review, we used individual participant data from seven recent clinical trials published over the past five years that met our inclusion and exclusion criteria to analyze factors that influence overall survival (OS). We found that the most prominent genetic alterations H3.3 (H3F3A) andTP53were associated with worse OS and that ACVR had a protective effect. In addition, re-irradiation was the only statistically significant treatment modality that showed any survival benefit. Our findings highlight some important characteristics of DMG,H3 K27-altered and their effects on OS along with the importance of continuing to review clinical trial data to improve our therapies for these fatal tumors.