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We performed a retrospective analysis of 35 patients with R\/R DE-DLBCL treated at two hematology centers from June 2021 to June 2024. All patients received zanubrutinib combined with one of several salvage regimens, including zR-MINE, zR-DHAP, zR-GemOx, or zR2. Endpoints included objective response rate (ORR), complete response rate (CRR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs). The median age was 60 years, and 91.4% of patients had the non-germinal center B-cell (non-GCB) subtype. At the end of therapy, the ORR and CRR were 45.7% (16\/35) and 42.9% (15\/35), respectively. After a median follow-up of 33.0 months, median PFS and OS were 8.0 and 12.0 months, respectively. Relapsed patients achieved a significantly higher CRR than refractory patients (56.5% vs. 16.7%,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.034). On multivariate analysis, longer duration of response to prior therapy was an independent protective factor for OS (HR 0.88, 95% CI 0.77\u20130.99;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.041). Grade 3\u20134 hematologic AEs were mainly neutropenia (42.8%) and thrombocytopenia (14.3%). Pulmonary infection was the most common non-hematologic AE (34.3%), and overall toxicity was manageable. Zanubrutinib combined with salvage chemotherapy demonstrates clinically meaningful activity with a manageable safety profile in patients with R\/R DE-DLBCL and may represent a therapeutic option for this high-risk population. Sensitivity analysis confirmed the robustness of the observed survival benefit.\n                  <\/jats:p>","DOI":"10.1007\/s00277-026-06974-6","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T01:22:19Z","timestamp":1776216139000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Real-world effectiveness of zanubrutinib plus salvage chemotherapy in relapsed or refractory double-expressor DLBCL"],"prefix":"10.1007","volume":"105","author":[{"given":"Jinbo","family":"Lu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujie","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingru","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuyan","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ran","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyi","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jvjuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hailing","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuexin","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haorui","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanmei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,15]]},"reference":[{"issue":"16","key":"6974_CR1","doi-asserted-by":"publisher","first-page":"1800","DOI":"10.1182\/blood-2017-03-769620","volume":"130","author":"M Crump","year":"2017","unstructured":"Crump M, Neelapu SS, Farooq U, Van Den Neste E, Kuruvilla J, Westin J, Link BK, Hay A, Cerhan JR, Zhu L et al (2017) Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. 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