A phase 2 study of zanubrutinib in combination with rituximab and lenalidomide in de novo diffuse large B-cell lymphoma

作者：Peng-Peng Xu, Yue Zhu, Zi‐Yang Shi, Li Wang, Shu Cheng, Ying Qian, Yan Zhao, Yang He, Hongmei Yi, Binshen Ouyang, Xufeng Jiang, Biao Li, Qi Song, Rongji Mu, Weili Zhao · 发表于：Blood · 年份：2025 · DOI：10.1182/blood.2025028649 · 被引用次数：5 · 研究领域：CAR-T cell therapy research、Lymphoma Diagnosis and Treatment、Chronic Lymphocytic Leukemia Research

ABSTRACT: Older patients with diffuse large B-cell lymphoma (DLBCL) present unfavorable genetic and microenvironmental alterations. In this phase 2 trial, we assessed the efficacy and safety of zanubrutinib in combination with rituximab and lenalidomide (ZR2) in patients with de novo DLBCL aged ≥75 years. 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 a...