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This study is a multicenter, prospective, single\u2010arm, phase 2 clinical study initiated by investigators to evaluate the efficacy and safety of combined zanubrutinib with R\u2010CHOP, which includes rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone for patients with DEL (stage II or more), as well as to explore factors related to efficacy preliminarily.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>From November 2020 to July 2022, 48 newly diagnosed patients were enrolled. All patients received twice\u2010daily oral zanubrutinib (160 mg) for 6 months and standardized R\u2010CHOP regimen for six to eight cycles.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The objective response rate (ORR) was 89.6%, with a complete response rate (CRR) of 83.3%. The median follow\u2010up was 29.3 months. The median progression\u2010free survival (PFS) and overall survival (OS) were not reached. The PFS and OS were 81.25% and 93.75% at 2 years, respectively. Grade \u22653 adverse events (AEs) were reported in 23 of 48 (47.9%) patients. Next\u2010generation sequencing (NGS) results of 33 patients showed that <jats:italic>TP53<\/jats:italic>, <jats:italic>MYD88<\/jats:italic>, and <jats:italic>PIM1<\/jats:italic> were the most common mutated gene. Multivariate analysis revealed that <jats:italic>BCL\u20106<\/jats:italic> gene rearrangement was an adverse prognostic factor for both PFS (hazard ratio [HR], 0.247; 95% confidence article [CI], 0.068\u20130.9; <jats:italic>p<\/jats:italic>\u00a0=\u00a0.034) and OS (HR, 0.057; 95% CI, 0.006\u20130.591; <jats:italic>p<\/jats:italic> =\u00a0.016), whereas the number of extranodal involvements also significantly influenced OS (HR, 15.12; 95% CI, 1.07\u2013213.65; <jats:italic>p<\/jats:italic>\u00a0=\u00a0.044).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Zanubrutinib in combination with R\u2010CHOP is an effective option for DEL patients, and the toxicity of zanubrutinib is entirely acceptable for patients.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cncr.35697","type":"journal-article","created":{"date-parts":[[2025,1,3]],"date-time":"2025-01-03T03:29:10Z","timestamp":1735874950000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Zanubrutinib plus R\u2010CHOP for the treatment of newly diagnosed double\u2010expressor lymphoma: A phase 2 clinical study"],"prefix":"10.1002","volume":"131","author":[{"given":"Xia","family":"Yin","sequence":"first","affiliation":[{"name":"Department of Lymphoma Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences  Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"He","sequence":"additional","affiliation":[{"name":"Department of Lymphoma Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences  Jinan Shandong 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