{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T22:02:24Z","timestamp":1793916144586,"version":"4.8.0"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T00:00:00Z","timestamp":1692576000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) shows poor response rates in non\u2013germinal center B cell\u2013like (non-GCB) diffuse large B-cell lymphoma (DLBCL) patients with multiple extranodal involvement. This study aims to evaluate anti-tumor activity and safety of zanubrutinib with R-CHOP (ZR-CHOP) in treatment na\u00efve non-GCB DLBCL with extranodal involvement.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this single-arm, phase 2, prospective, single-center study, patients with newly diagnosed non-GCB DLBCL with extranodal involvement enrolled between October 2020 to March 2022 received ZR-CHOP for 6 cycles followed by 2 cycles of maintenance treatment with rituximab and zanubrutinib. The primary endpoint included progression-free survival (PFS) in the intent-to-treat (ITT) population whereas the secondary endpoints included overall response rate (ORR), complete response (CR), and duration of response. Further, next-generation sequencing (NGS) was used for detection of different oncogenic mutations closely related to DLBCL pathogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>From October 2020 to March 2022, 26 patients were enrolled, and 23 of them were evaluated for efficacy after receiving 3 cycles of ZR-CHOP treatment. 1-year PFS and OS were 80.8% and 88.5% respectively while expected PFS and OS for 2-years are 74.0% and 88.5% respectively with median follow-up of 16.7 months and ORR was 91.3% (CR: 82.61%; PR: 8.70%). Oncogenic mutations closely related to DLBCL pathogenesis were assessed in 20 patients using NGS. B-cell receptor and NF-\u03baB pathway gene mutations were detected in 10 patients, which occurred in MYD88 (7\/19), CD79B (4\/19), CARD11 (5\/19), and TNFAIP3 (2\/19). Hematological adverse events (AEs) \u2265 grade 3 included neutropenia (50%), thrombocytopenia (23.1%), and anemia (7.7%) whereas non-hematological AEs \u2265 grade 3 included pulmonary infection (19.2%).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>ZR-CHOP is safe and effective for treating treatment na\u00efve non-GCB DLBCL patients with extranodal involvement.<\/jats:p><\/jats:sec><jats:sec><jats:title>Clinical Trial Registration<\/jats:title><jats:p><jats:uri>Clinicaltrials.gov<\/jats:uri>, NCT04835870<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1219167","type":"journal-article","created":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T15:54:04Z","timestamp":1692633244000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["Efficacy and safety of zanubrutinib plus R-CHOP in treatment of non-GCB DLBCL with extranodal involvement"],"prefix":"10.3389","volume":"14","author":[{"given":"Hongzhi","family":"Geng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sixun","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liangyu","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangping","family":"Zong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutong","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuangzhu","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caixia","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Depei","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,8,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3945\/an.116.012211","article-title":"World cancer report 2014. Geneva, Switzerland: World Health Organization, International agency for research on cancer, WHO press, 2015","volume":"7","author":"McGuire","year":"2016","journal-title":"Adv Nutr"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-11-536433","article-title":"Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin-embedded tissue","volume":"123","author":"Scott","year":"2014","journal-title":"Blood"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/35000501","article-title":"Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling","volume":"403","author":"Alizadeh","year":"2000","journal-title":"Nature"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2003-05-1545","article-title":"Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray","volume":"103","author":"Hans","year":"2004","journal-title":"Blood"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa012914","article-title":"The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma","volume":"346","author":"Rosenwald","year":"2002","journal-title":"N Engl J Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.60.2383","article-title":"Prognostic significance of diffuse large B-cell lymphoma cell of origin determined by digital gene expression in formalin-fixed paraffin-embedded tissue biopsies","volume":"33","author":"Scott","year":"2015","journal-title":"J Clin Oncol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"54","DOI":"10.3960\/jslrt.17029","article-title":"Clinicopathological analysis of 320 cases of diffuse large B-cell lymphoma using the hans classifier","volume":"57","author":"Ichiki","year":"2017","journal-title":"J Clin Exp Hematop"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.23638","article-title":"Sites of extranodal involvement are prognostic in patients with diffuse large B-cell lymphoma in the rituximab era: An analysis of the Surveillance, Epidemiology and End Results database","volume":"89","author":"Castillo","year":"2014","journal-title":"Am J Hematol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.27381","article-title":"Prognostic impact of extranodal involvement in diffuse large B-cell lymphoma in the rituximab era","volume":"118","author":"Takahashi","year":"2012","journal-title":"Cancer"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.2147\/OTT.S326632","article-title":"Diffuse large B-cell lymphoma (DLBCL): early patient management and emerging treatment options","volume":"15","author":"Vodicka","year":"2022","journal-title":"Onco Targets Ther"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.21147\/j.issn.1000-9604.2019.01.10","article-title":"Clinical features and outcomes of diffuse large B-cell lymphoma based on nodal or extranodal primary sites of origin: Analysis of 1,085 WHO classified cases in a single institution in China","volume":"31","author":"Shi","year":"2019","journal-title":"Chin J Cancer Res"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.221","article-title":"Influence of oncogenic mutations and tumor microenvironment alterations on extranodal invasion in diffuse large B-cell lymphoma","volume":"10","author":"Shen","year":"2020","journal-title":"Clin Transl Med"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdv304","article-title":"Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"26","author":"Tilly","year":"2015","journal-title":"Ann Oncol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.6004\/jnccn.2020.0036","article-title":"Pediatric aggressive mature B-cell lymphomas, version 2.2020, NCCN clinical practice guidelines in oncology","volume":"18","author":"Davies","year":"2020","journal-title":"J Natl Compr Canc Netw"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdu109","article-title":"Prognostic factors for diffuse large B-cell lymphoma in the R(X)CHOP era","volume":"25","author":"Vaidya","year":"2014","journal-title":"Ann Oncol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2115304","article-title":"Polatuzumab vedotin in previously untreated diffuse large B-cell lymphoma","volume":"386","author":"Tilly","year":"2022","journal-title":"N Engl J Med"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2021011330","article-title":"A phase 2 study of venetoclax plus R-CHOP as first-line treatment of patients with diffuse large B-cell lymphoma","volume":"137","author":"Morschhauser","year":"2021","journal-title":"Blood."},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.20.01366","article-title":"ROBUST: A phase III study of lenalidomide plus R-CHOP versus placebo plus R-CHOP in previously untreated patients with ABC-type diffuse large B-cell lymphoma","volume":"39","author":"Nowakowski","year":"2021","journal-title":"J Clin Oncol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.18.02403","article-title":"Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non-germinal center B-cell diffuse large B-cell lymphoma","volume":"37","author":"Younes","year":"2019","journal-title":"J Clin Oncol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2013.09.001","article-title":"B-cell receptor signaling as a driver of lymphoma development and evolution","volume":"23","author":"Niemann","year":"2013","journal-title":"Semin Cancer Biol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1514944112","article-title":"Survival of human lymphoma cells requires B-cell receptor engagement by self-antigens","volume":"112","author":"Young","year":"2015","journal-title":"Proc Natl Acad Sci USA"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2019.00107","article-title":"Dysregulation of cell survival in diffuse large B cell lymphoma: mechanisms and therapeutic targets","volume":"9","author":"Miao","year":"2019","journal-title":"Front Oncol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1801445","article-title":"Genetics and pathogenesis of diffuse large B-cell lymphoma","volume":"378","author":"Schmitz","year":"2018","journal-title":"N Engl J Med"},{"key":"B24","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1016\/j.ccell.2020.03.015","article-title":"A probabilistic classification tool for genetic subtypes of diffuse large B cell lymphoma with therapeutic implications","volume":"37","author":"Wright","year":"2020","journal-title":"Cancer Cell"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1643","DOI":"10.1016\/j.ccell.2021.10.006","article-title":"Effect of ibrutinib with R-CHOP chemotherapy in genetic subtypes of DLBCL","volume":"39","author":"Wilson","year":"2021","journal-title":"Cancer Cell"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019001160","article-title":"Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL","volume":"134","author":"Tam","year":"2019","journal-title":"Blood"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2020003698","article-title":"Zanubrutinib monotherapy for relapsed or refractory non-germinal center diffuse large B-cell lymphoma","volume":"6","author":"Yang","year":"2022","journal-title":"Blood Adv"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2013.54.8800","article-title":"Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification","volume":"32","author":"Cheson","year":"2014","journal-title":"J Clin Oncol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1186\/s13045-020-00900-7","article-title":"A randomized, open-label, Phase III study of obinutuzumab or rituximab plus CHOP in patients with previously untreated diffuse large B-Cell lymphoma: final analysis of GOYA","volume":"13","author":"Sehn","year":"2020","journal-title":"J Hematol Oncol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.jiac.2021.03.004","article-title":"Difference of preventing effects of G-CSF according to age in patients with malignant lymphoma: A nation-wide analysis in Japan","volume":"27","author":"Matsuda","year":"2021","journal-title":"J Infect Chemother"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.13155","article-title":"Double-expressor phenotype (BCL-2\/c-MYC co-expression) of diffuse large B-cell lymphoma and its clinicopathological correlation","volume":"13","author":"Hashmi","year":"2021","journal-title":"Cureus"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0172364","article-title":"Diffuse large B-cell lymphoma with concurrent high MYC and BCL2 expression shows evidence of active B-cell receptor signaling by quantitative immunofluorescence","volume":"12","author":"Bogusz","year":"2017","journal-title":"PloS One"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0000000000000799","article-title":"MYC protein-positive diffuse large B-cell lymphoma features an activated B-cell receptor signal pathway","volume":"41","author":"Wang","year":"2017","journal-title":"Am J Surg Pathol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.2147\/OTT.S154995","article-title":"Predictive value of interim PET\/CT visual interpretation in the prognosis of patients with aggressive non-Hodgkin\u2019s lymphoma","volume":"10","author":"Liao","year":"2017","journal-title":"Onco Targets Ther"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejrad.2020.109301","article-title":"Research on the midterm efficacy and prognosis of patients with diffuse large B-cell lymphoma by different evaluation methods in interim PET\/CT","volume":"133","author":"Li","year":"2020","journal-title":"Eur J Radiol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019003277","article-title":"Prognostic value of interim FDG-PET in diffuse large cell lymphoma: results from the CALGB 50303 Clinical Trial","volume":"135","author":"Sch\u00f6der","year":"2020","journal-title":"Blood"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-06-359943","article-title":"Interim 18-FDG-PET\/CT failed to predict the outcome in diffuse large B-cell lymphoma patients treated at the diagnosis with rituximab-CHOP","volume":"119","author":"Pregno","year":"2012","journal-title":"Blood"},{"key":"B38","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.critrevonc.2016.07.003","article-title":"Prognostic value of interim FDG-PET in R-CHOP-treated diffuse large B-cell lymphoma: Systematic review and meta-analysis","volume":"106","author":"Adams","year":"2016","journal-title":"Crit Rev Oncol Hematol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.2967\/jnumed.120.255034","article-title":"Interim PET in diffuse large B-cell lymphoma","volume":"62","author":"Kurch","year":"2021","journal-title":"J Nucl Med"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1007\/s00259-013-2435-6","article-title":"An international confirmatory study of the prognostic value of early PET\/CT in diffuse large B-cell lymphoma: comparison between Deauville criteria and \u0394SUVmax","volume":"40","author":"Itti","year":"2013","journal-title":"Eur J Nucl Med Mol Imaging"},{"key":"B41","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.ejca.2019.09.027","article-title":"Dynamic risk assessment based on positron emission tomography scanning in diffuse large B-cell lymphoma: Post-hoc analysis from the PETAL trial","volume":"124","author":"Schmitz","year":"2020","journal-title":"Eur J Cancer"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1219167\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T15:54:07Z","timestamp":1692633247000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1219167\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,21]]},"references-count":41,"alternative-id":["10.3389\/fimmu.2023.1219167"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2023.1219167","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,21]]},"article-number":"1219167"}}