Clinical, molecular, and immunologic determinants of survival in WHO-defined IDH-wildtype glioblastoma treated with radiotherapy: a large real-world cohort study

Glioblastoma (WHO grade 4), defined by IDH-wildtype status and associated molecular features, carries poor prognosis, and real-world survival models incorporating molecular and immunologic variables remain limited. Severe radiation-induced lymphopenia (sRIL) is a proposed prognostic factor, but its independent effect in molecularly defined glioblastoma has not been established in the modern era. We retrospectively identified 832 adults with glioblastoma, defined as WHO 2021 grade 4 IDH-wildtype diffuse glioma treated with maximal safe resection and adjuvant radiotherapy (RT) with or without chemotherapy between 2014 and 2024. A trial-eligible subgroup was defined using Stupp criteria. Clinical, molecular, and hematologic variables were analyzed. sRIL was defined as CTCAE grade ≥ 3 lymphopenia within 4 months of RT. Multivariable Cox models incorporated LASSO for variable selection and spline regression for non-linearity. Median overall survival (OS) was 13.0 months. On multivariable analysis, sRIL (HR 1.37, 95% CI 1.16–1.63) remained an independent predictor of worse OS after adjustment for MGMT status, age, resection extent, and treatment factors. MGMT methylation predicted benefit from concurrent TMZ (pinteraction<0.001), and trial-eligible patients had longer OS across MGMT subgroups. Age and post-RT lymphocyte nadir were non-linearly associated with survival. Proton therapy was associated with a favorable but non-significant OS estimate (HR 0.87, p = 0.11), with no benefit in the trial-eligible cohort. In this large, real-world cohort, sRIL remained a strong independent prognostic factor. MGMT methylation predicted TMZ benefit, and trial eligibility conferred favorable outcomes. These findings underscore the prognostic relevance of post-treatment lymphopenia and support prospective evaluation of lymphocyte-sparing treatment strategies. • Severe post-RT lymphopenia is independently associated with worse survival in IDH-wt glioblastoma. • MGMT methylation predicts temozolomide benefit; trial-eligible patients have superior outcomes. • No survival advantage was observed for proton versus photon therapy in adjusted analyses.