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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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\u2009\u2265\u20093 lymphopenia within 4 months of RT. Multivariable Cox models incorporated LASSO for variable selection and spline regression for non-linearity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Median overall survival (OS) was 13.0 months. On multivariable analysis, sRIL (HR 1.37, 95% CI 1.16\u20131.63) 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 (p\n                      <jats:sub>interaction<\/jats:sub>\n                      &lt;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,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.11), with no benefit in the trial-eligible cohort.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s11060-026-05572-w","type":"journal-article","created":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T08:26:57Z","timestamp":1777105617000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Clinical, molecular, and immunologic determinants of survival in WHO-defined IDH-wildtype glioblastoma treated with radiotherapy: a large real-world cohort study"],"prefix":"10.1007","volume":"177","author":[{"given":"Cole","family":"Friedes","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Berger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren","family":"Linkowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Casey","family":"Hollawell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harper","family":"Hubbeling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Alexander","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Goldie","family":"Kurtz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Lustig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay F.","family":"Dorsey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arati S.","family":"Desai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard E.","family":"Phillips","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Brem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christos","family":"Davatzikos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"MacLean","family":"Nasrallah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald M.","family":"O\u2019Rourke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Jackson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nduka M.","family":"Amankulor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Alonso-Basanta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suyash","family":"Mohan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen J.","family":"Bagley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily S.","family":"Lebow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,25]]},"reference":[{"key":"5572_CR1","doi-asserted-by":"publisher","first-page":"12","DOI":"10.3322\/caac.21820","volume":"74","author":"RL Siegel","year":"2024","unstructured":"Siegel RL, Giaquinto AN, Jemal A (2024) Cancer statistics, 2024. 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