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We conducted a biomarker\u2010driven phase II trial involving 123 high\u2010risk patients aged 18\u201364 with LBCL. Based on their biological risk profiles, patients received either R\u2010CHOEP\u201014 (without risk factors) or DA\u2010EPOCH\u2010R\u2010based regimens (with risk factors). Biological high\u2010risk factors included\n                    <jats:italic>C\u2010MYC<\/jats:italic>\n                    translocation,\n                    <jats:italic>C\u2010MYC<\/jats:italic>\n                    and\n                    <jats:italic>BCL2<\/jats:italic>\n                    co\u2010translocation,\n                    <jats:italic>17p\/TP53<\/jats:italic>\n                    deletion, co\u2010expression of MYC and BCL2, and P53 and\/or CD5 immunopositivity. Additionally, we evaluated circulating tumor DNA (ctDNA) kinetics during therapy. Sixty\u2010one patients (50%) were classified into biologically high\u2010risk group. Three\u2010year failure\u2010free survival and overall survival rates for the entire study population were 79% and 88%, respectively. DA\u2010EPOCH\u2010R did not improve survival compared to our previous trial, where patients with the same biological risk factor criteria received R\u2010CHOEP\u201014\u2010based therapy. High pretreatment ctDNA levels,\n                    <jats:italic>17p\/TP53<\/jats:italic>\n                    deletion, and\n                    <jats:italic>TP53<\/jats:italic>\n                    mutations were associated with worse outcomes. In contrast, ctDNA negativity at the end of therapy (EOT) was indicative of a cure and effectively addressed false residual PET positivity. The findings demonstrate promising survival for high\u2010risk LBCL patients, aside from those with\n                    <jats:italic>TP53<\/jats:italic>\n                    aberrations, high ctDNA levels, and\/or EOT ctDNA positivity.\n                  <\/jats:p>","DOI":"10.1002\/hem3.70139","type":"journal-article","created":{"date-parts":[[2025,5,12]],"date-time":"2025-05-12T04:26:29Z","timestamp":1747023989000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Biomarker\u2010adapted treatment in high\u2010risk large B\u2010cell lymphoma"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8265-511X","authenticated-orcid":false,"given":"Sirpa","family":"Lepp\u00e4","sequence":"first","affiliation":[{"name":"Department of Oncology Helsinki University Hospital Comprehensive Cancer Centre Helsinki Finland"},{"name":"Research Programs Unit and iCAN Flagship University of Helsinki 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Hematology Aarhus University Hospital Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marja\u2010Liisa","family":"Karjalainen\u2010Lindsberg","sequence":"additional","affiliation":[{"name":"Department of Pathology Helsinki University Hospital Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Beiske","sequence":"additional","affiliation":[{"name":"Department of Pathology Oslo University Hospital Oslo Norway"},{"name":"Institute of Clinical Medicine, Medical Faculty University of Oslo Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mette","family":"Pedersen","sequence":"additional","affiliation":[{"name":"Department of Pathology Zealand University Hospital Roskilde Denmark"},{"name":"Department of Clinical Medicine, Faculty of Health and Medical Sciences University of Copenhagen Copenhagen 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