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Forty patients were enrolled, and the primary end point was the complete response rate, which was 65.0% (95% confidence interval [CI], 48.3-78.9) at the end of induction treatment. The 2-year progression-free and overall survival rates were 67.1% (95% CI, 50.1-79.4) and 82.4% (95% CI, 66.5-91.2). The most common grades 3 and 4 hematologic adverse event (AE) was neutropenia (n = 14 [35.0%]). The most common grades 3 and 4 nonhematologic AEs were increased alanine transaminase (n = 5 [12.5%]) and aspartate transaminase levels (n = 5; 12.5%), and pulmonary infection (n = 5 [12.5%]). No events of atrial fibrillation were observed. Importantly, the efficacy of ZR2 was more dependent on tumor microenvironmental than genetic alterations, and was associated with upregulation of class I and II human leukocyte antigen and increased number and function of conventional type 1 dendritic cells. Preexisting expansion of intratumoral CD8+ T cells and treatment-induced clonal T-cell receptor (TCR) repertoire contributed to better clinical outcome. TCR sequencing of the peripheral blood mononuclear cell samples from patients with durable remission detected the expanded T-cell clones 3 years after treatment. These findings thus improve the understanding of the effect of T-cell immunological memory on ZR2-based immunotherapy, and support a paradigm shift toward mechanism-based targeted therapy of aggressive lymphoma. This trial was registered at www.clinicaltrials.gov as #NCT04460248.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2025028649","type":"journal-article","created":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T20:54:58Z","timestamp":1755636898000},"page":"2561-2573","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":10,"title":["A phase 2 study of zanubrutinib in combination with rituximab and lenalidomide in de novo diffuse large B-cell lymphoma"],"prefix":"10.1182","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8355-7343","authenticated-orcid":false,"given":"Peng-Peng","family":"Xu","sequence":"first","affiliation":[{"name":"1Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 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