Real-world cohort study of clinical, molecular, and immunologic determinants of survival in IDH-wildtype glioblastoma

Glioblastoma (GBM; WHO grade 4), defined by IDH-wildtype status and associated molecular features, carries a poor prognosis, and realt-world survival models incorporating molecular and immunologic variables remain limited. A retrospective cohort study at University of Pennsylvania (Philadelphia) evaluated clinical, molecular, and immunologic determinants of survival in 832 adult IDH-wildtype GBM patients treated with maximal safe resection and adjuvant radiotherapy (RT) with or without chemotherapy between 2014 and 2024. A trial-eligible subgroup (n=495) was defined using Stupp criteria (age ≤ 70 years, ECOG performance status ≤ 2; baseline absolute neutrophil count ≥1.5 x 10⁹/L,and platelet count ≥ 100 x 10⁹/L). The median overall survival (OS) was 13.0 months. On multivariable analysis, severe radiation-induced lymphopenia (sRIL; grade ≥ 3 lymphopenia within 4 months of RT) remained an independent predictor of worse OS (HR 1.37; 95% CI 1.16-1.63) after adjustment for MGMT status, age, resection extent, and treatment factors. MGMT methylation predicted benefit from concurrent temozolomide (p_interaction <0.001), and trial-eligible patients had had longer OS compared with trial-ineligible patients. The authors conclude that these findings underscore the prognostic relevance of post-treatment lymphopenia and support prospective evaluation of lymphocyte-sparing treatment strategies.