Histone Deactylase Inhibition in R-CHOP-Treated Double-Expressor Diffuse Large B-Cell Lymphoma

# Histone Deactylase Inhibition in R-CHOP-Treated Double-Expressor Diffuse Large B-Cell Lymphoma *Published: 2026 May 19* Tucidinostat Plus R-CHOP vs R-CHOP in MYC/BCL2 Double-Expressor Diffuse Large B-Cell Lymphoma: A Randomized Clinical Trial. Xu PP(1), Song YQ(2), Shen JZ(3), Cai QQ(4), Zhou H(5), Zhang LL(6), Xiang Y(7), Sun XH(8), Yang W(9), Yao ZH(10), Jing HM(11), Wen SJ(12), Jin J(13), Xue HW(14), Cen H(15), Ding KY(16), Jin ZM(17), Liu LH(18), Xing XJ(19), Li LF(20), Hou M(21), Liu L(22), Zhang MZ(23), Li WY(24), Bai O(25), Feng R(26), Zhu ZM(27), Wu HJ(28), Su LP(29), Gao L(30), Li F(31), Huang WR(32), Liu P(33), Yan XJ(34), Zhao Y(35), Su H(36), Zhao XL(37), Fu R(38), Liu H(39), Shi WY(39), Li HZ(40), Chen B(40), Ning ZQ(40), Zhu J(2), Zhao WL(1). Author information: (1)Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics; National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. (2)Peking University Cancer Hospital & Institute (Beijing Cancer Hospital), Beijing, China. (3)Fujian Medical University Union Hospital, Fuzhou, China. (4)Sun Yat-sen University Cancer Center, Guangzhou, China. (5)Hunan Cancer Hospital, Changsha, China. (6)Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (7)Chongqing University Cancer Hospital, Chongqing, China. (8)The Second Hospital of Dalian Medical University, Dalian, China. (9)Shengjing Hospital of China Medical University, Liaoning, China. (10)Henan Cancer Hospital, Zhengzhou, China. (11)Peking University Third Hospital, Beijing, China. (12)Xinjiang Medical University Affiliated Tumor Hospital, Wulumuqi, China. (13)The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. (14)The Affiliated Hospital of Qingdao University, Qingdao, China. (15)Guangxi Medical University Affiliated Cancer Hospital, Nanning, China. (16)The First Affiliated Hospital of USTC, Hefei, China. (17)The First Affiliated Hospital of Soochow University, Suzhou, China. (18)The Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang, China. (19)Liaoning Cancer Hospital & Institute, Shenyang, China. (20)Tianjin Medical University Cancer Institute and Hospital, Tianjin, China. (21)Qilu Hospital of Shandong University, Jinan, China. (22)The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. (23)The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. (24)Guangdong Provincial People's Hospital, Guangdong, China. (25)The First Hospital of Jilin University, Changchun, China. (26)Nanfang Hospital, Southern Medical University, Guangzhou, China. (27)Henan Provincial People's Hospital, Zhengzhou, China. (28)Hubei Cancer Center, Wuhan, China. (29)Shanxi Cancer Hospital, Taiyuan, China. (30)The Second Affiliated Hospital of Army Medical University, Chongqing, China. (31)The First Affiliated Hospital of Nanchang University, Nanchang, China. (32)The First Medical Center of Chinese PLA General Hospital, Beijing, China. (33)Zhongshan Hospital Fudan University, Shanghai, China. (34)First Hospital of China Medical University, Shenyang, China. (35)The First People's Hospital of Foshan, Foshan, China. (36)The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China. (37)Xiangya Hospital, Central South University, Changsha, China. (38)Tianjin Medical University General Hospital, Tianjin, China. (39)Affiliated Hospital of Nantong University, Nantong, China. (40)Chipscreen Biosciences Ltd, Shenzhen, China. Comment in JAMA. 2026 May 19;335(19):1669-1671. doi: 10.1001/jama.2026.4291. ## IMPORTANCE Epigenetic dysregulation is associated with the pathogenesis and progression of diffuse large B-cell lymphoma (DLBCL). MYC/BCL2 double-expressor lymphoma (DEL), a distinct population of DLBCL defined by MYC and BCL2 coexpression, refers to poor prognosis after standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) immunochemotherapy. Tucidinostat (or chidamide), an oral, selective histone deacetylase inhibitor, has shown promising activity in DEL. ## OBJECTIVE To evaluate efficacy and safety of tucidinostat plus R-CHOP vs R-CHOP alone as first-line treatment for patients with DEL. DESIGN, SETTING, AND PARTICIPANTS This randomized, double-blind, placebo-controlled phase 3 trial enrolled patients from May 21, 2020, through July 25, 2022, with follow-up to June 26, 2025. The trial was conducted at 40 study centers in China; a total of 423 eligible patients were enrolled. ## INTERVENTIONS Patients were randomly assigned in a 1:1 ratio to receive oral tucidinostat (20 mg on days 1, 4, 8, and 11 of each 21-day cycle) or matching placebo, plus 6 cycles of R-CHOP. Patients with a complete response after combination therapy received either tucidinostat or placebo maintenance up to 24 weeks. MAIN OUTCOMES AND MEASURES The primary end point was event-free survival. Secondary end points included complete response rate, progression-free survival, disease-free survival, overall survival, and tolerability. ## RESULTS Among 423 patients randomized (median age, 63 years; 47.5% male), the median follow-up duration from randomization was 41.3 months. The tucidinostat group demonstrated a 28% lower risk of disease progression, relapse after complete response, death, or initiation of new therapy for residual disease compared with the placebo group (stratified hazard ratio, 0.72 [95% CI, 0.54-0.96]; P = .02), with a 2-year event-free survival rate of 60.3% vs 50.5%, respectively. The complete response rate was 73.0% vs 61.8% (difference, 11.1% [95% CI, 2.3%-20.0%]), respectively. Increased toxicity associated with treatment was observed in the tucidinostat group but generally manageable with supportive care. CONCLUSIONS AND RELEVANCE Tucidinostat plus R-CHOP significantly improved event-free survival, with manageable toxicity in patients newly diagnosed with DEL. This trial is the first to demonstrate the benefit of an epigenetic modulator in DLBCL, offering a new first-line therapeutic approach dually targeting MYC and BCL2 oncoprotein for this high-risk population. ## TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04231448. DOI: 10.1001/jama.2026.4199 PMCID: PMC13103881 DOI: 10.1001/jama.2026.4291