{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T18:06:21Z","timestamp":1779473181943,"version":"3.53.1"},"reference-count":42,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Lymphoma Research Fund of China Anti-Cancer Association","award":["NA"],"award-info":[{"award-number":["NA"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To compare the safety and efficacy of first-line dose-adjusted EPOCH-R (DA-EPOCH-R) versus R-CHOP treatment in diffuse large B-cell lymphoma (DLBCL) patients with high Ki67 expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A retrospective analysis of DLBCL patients receiving R-CHOP determined the threshold of high Ki67 expression predicting 2-year progression-free survival (PFS) events using receiver operating characteristic (ROC) curve. Then we initiated a prospective, observational study evaluating DA-EPOCH-R therapy for DLBCL with high Ki67 expression, and selected a retrospective R-CHOP cohort to perform a propensity score-matched (PSM) analysis. Primary endpoints were PFS and overall survival (OS).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>A Ki67 threshold of 82.5% was determined using ROC in the retrospective analysis of 376 DLBCL cases, thus the threshold was ultimately set at 80%. A total of 29 patients receiving DA-EPOCH-R were enrolled in the prospective study, the enrollment was terminated due to the conditional power and a slow accrual. Following 1:1 PSM, no PFS (HR 0.93, 95% CI: 0.47\u20131.84, p\u2009=\u20090.83) and OS (HR 1.28, 95% CI: 0.42\u20133.83, p\u2009=\u20090.66) benefit of DA-EPOCH-R versus R-CHOP was observed, with a nearly significantly higher frequency of grade\u2009\u2265\u20093 hematological adverse events (AEs) observed in the DA-EPOCH-R group (p\u2009=\u20090.052). Notably, only 37.9% (11\/29) of patients executed dose escalation, which indicated a worse tolerance to this intensified regimen of the East Asians.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>No significant survival benefit from DA-EPOCH-R treatment was observed for DLBCL with high Ki67 expression, which may be attributed to the poorer tolerance in the East Asian population.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0350024","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T17:35:14Z","timestamp":1779471314000},"page":"e0350024","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Comparison of dose-adjusted EPOCH-R and R-CHOP in diffuse large B-cell lymphoma with high Ki67 expression: Results from a prospective observational study"],"prefix":"10.1371","volume":"21","author":[{"given":"Wenxin","family":"Jiang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3768-2994","authenticated-orcid":true,"given":"Peng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,5,22]]},"reference":[{"issue":"6","key":"pone.0350024.ref001","first-page":"443","article-title":"2016 US lymphoid malignancy statistics by World Health Organization subtypes","volume":"66","author":"LR Teras","year":"2016","journal-title":"CA Cancer J Clin"},{"issue":"2","key":"pone.0350024.ref002","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1200\/JCO.2010.30.0368","article-title":"Immunohistochemical methods for predicting cell of origin and survival in patients with diffuse large B-cell lymphoma treated with 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Hashmi","year":"2021","journal-title":"Cureus"},{"issue":"3","key":"pone.0350024.ref030","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1517\/17425250902800153","article-title":"Ethnic differences in drug metabolism and toxicity from chemotherapy","volume":"5","author":"VH Phan","year":"2009","journal-title":"Expert Opin Drug Metab Toxicol"},{"issue":"15","key":"pone.0350024.ref031","doi-asserted-by":"crossref","first-page":"4806","DOI":"10.1158\/1078-0432.CCR-09-0344","article-title":"Cancer pharmacoethnicity: ethnic differences in susceptibility to the effects of chemotherapy","volume":"15","author":"PH O\u2019Donnell","year":"2009","journal-title":"Clin Cancer Res"},{"issue":"11","key":"pone.0350024.ref032","doi-asserted-by":"crossref","first-page":"1881","DOI":"10.1097\/JTO.0b013e31822722b6","article-title":"Ethnic difference in hematological toxicity in patients with non-small cell lung cancer treated with chemotherapy: a pooled analysis on Asian versus non-Asian in 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R\u00e9cher","year":"2011","journal-title":"Lancet"},{"issue":"17","key":"pone.0350024.ref035","doi-asserted-by":"crossref","first-page":"2307","DOI":"10.1182\/blood.2020008750","article-title":"Obinutuzumab vs rituximab for advanced DLBCL: a PET-guided and randomized phase 3 study by LYSA","volume":"137","author":"S Le Gouill","year":"2021","journal-title":"Blood"},{"issue":"12","key":"pone.0350024.ref036","doi-asserted-by":"crossref","first-page":"2845","DOI":"10.1038\/s41375-022-01713-y","article-title":"Interim FDG-PET analysis to identify patients with aggressive non-Hodgkin lymphoma who benefit from treatment intensification: a post-hoc analysis of the PETAL trial","volume":"36","author":"R Seifert","year":"2022","journal-title":"Leukemia"},{"issue":"15","key":"pone.0350024.ref037","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1200\/JCO.18.02403","article-title":"Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, 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