Jelicic, Jelena (56180044800)Jelena (56180044800)JelicicJuul-Jensen, Karen (57218352166)Karen (57218352166)Juul-JensenBukumiric, Zoran (36600111200)Zoran (36600111200)BukumiricRunason Simonsen, Mikkel (59177988400)Mikkel (59177988400)Runason SimonsenRoost Clausen, Michael (58039350000)Michael (58039350000)Roost ClausenLudvigsen Al-Mashhadi, Ahmed (57189056494)Ahmed (57189056494)Ludvigsen Al-MashhadiSchou Pedersen, Robert (59178141900)Robert (59178141900)Schou PedersenBjørn Poulsen, Christian (59177988500)Christian (59177988500)Bjørn PoulsenOrtved Gang, Anne (58039201900)Anne (58039201900)Ortved GangBrown, Peter (56437846200)Peter (56437846200)BrownEl-Galaly, Tarec Christoffer (22634515900)Tarec Christoffer (22634515900)El-GalalyStauffer Larsen, Thomas (35405235400)Thomas (35405235400)Stauffer Larsen2025-06-122025-06-122025https://doi.org/10.1111/ejh.14301https://www.scopus.com/inward/record.uri?eid=2-s2.0-85203535420&doi=10.1111%2fejh.14301&partnerID=40&md5=15661206531647ac6254417fa4687bd5https://remedy.med.bg.ac.rs/handle/123456789/707Objectives: Recent front-line clinical trials used the International Prognostic Index (IPI) to identify trial-eligible patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). However, many IPI-like variants with improved accuracy have been developed over the years for rituximab-treated patients. Methods: We assessed the impact of International Prognostic Indices on patient enrolment in clinical trials, aiming to exclude low-risk IPI patients based on POLARIX/EPCORE DLBCL-2 trial criteria. Results: We identified 2877 patients in the Danish Lymphoma Registry who would have been eligible for the POLARIX trial if patients with IPI 0–1 scores were included. IPI and NCCN-IPI assigned 33.3% and 11.9% of patients to the low-risk group, respectively. Shorter 5-year overall survival (91.4% vs. 97.5%), higher relapse rate (9.9% vs. 4.4%), and more deaths (16.1% vs. 4.4%) occurred in the low-risk IPI group compared with low-risk NCCN-IPI group. Analyzed models failed to identify true high-risk patients with poor prognosis. Similar results were found in the confirmatory cohort developed based on EPCORE DLBCL-2 trial eligibility criteria. Conclusion: True low-risk patients are more optimal identified by NCCN-IPI and should be excluded from front-line clinical trials due to their excellent prognosis. However, additional high-risk factors besides clinical prognostic models need to be considered when selecting trial-eligible patients. © 2024 The Author(s). European Journal of Haematology published by John Wiley & Sons Ltd.clinical trialdiffuse large B cell lymphomaprognostic modelsselection criteria