Tucidinostat Plus R-CHOP vs R-CHOP in MYC/BCL2 Double-Expressor Diffuse Large B-Cell Lymphoma

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.

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Journal
JAMA
Published
2026-04-22
DOI
https://doi.org/10.1001/jama.2026.4199
Citations
1
Primary Topic
Lymphoma Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
21.53
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article

Tucidinostat Plus R-CHOP vs R-CHOP in MYC/BCL2 Double-Expressor Diffuse Large B-Cell Lymphoma

M Zhang, Zhengming Jin, Xiaojing Xing, F Li et al.
1 citations
JAMA
Lymphoma Diagnosis and Treatment
21.53
article

Tucidinostat Plus R-CHOP vs R-CHOP in MYC/BCL2 Double-Expressor Diffuse Large B-Cell Lymphoma

M Zhang, Zhengming Jin, Xiaojing Xing, F Li, Wen‐Yu Li, Hongmei Jing, Lu Liu, Hong‐Wei Xue, Shujuan Wen, Kaiyang Ding, Ming Hou, Xielan Zhao, Yan X, W R Huang, Zhiqiang Ning, Lan-Fang Li, Li-Ping Su, L Gao, Zun-Min Zhu, Qing-Qing Cai, Rong Fu, Hui Zhou, Ying Xiang, Ru Feng, Wei Yang, Jian-Zhen Shen, Hong Cen, Wen-Yu Shi, Zhi-Hua Yao, Peng-Peng Xu, Hang Su, Yu-Qin Song, Xiu-Hua Sun, Li-Ling Zhang, Hong Liu, Bo Chen, Jun Zhu, Ying Zhao, Jie Jin, Wei-Li Zhao, Hui-Jing Wu, Ou Bai, Hui-Zhi Li, Peng Liu
article en
1 citations

Abstract

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.

JAMA
Qingdao University (CN), Hebei Medical University (CN), Fujian Medical University (CN), Central South University (CN), Nanchang University (CN), Army Medical University (CN), Xinjiang Medical University (CN), Sun Yat-sen University (CN), Chongqing University (CN), Guangxi Medical University (CN), Dalian Medical University (CN), Jilin University (CN), Nantong University (CN), Peking University (CN), Fudan University (CN), Ruijin Hospital (CN), Tianjin Medical University General Hospital (CN), Tianjin Medical University Cancer Institute and Hospital (CN), Chinese PLA General Hospital (CN), Soochow University (CN), Affiliated Hospital of Nantong University (CN), Peking University Cancer Hospital (CN), Second Affiliated Hospital of Chongqing Medical University (CN), Second Affiliated Hospital of Dalian Medical University (CN), Tumor Hospital of Xinjiang Medical University (CN), Shanxi Provincial Cancer Hospital (CN), Nanfang Hospital (CN), First People's Hospital of Foshan (CN), Fourth Hospital of Hebei Medical University (CN), Hunan Cancer Hospital (CN), Affiliated Hospital of Qingdao University (CN), First Hospital of Jilin University (CN), Zhongshan Hospital (CN), The First Affiliated Hospital, Sun Yat-sen University (CN), Wuhan Union Hospital (CN), The Affiliated Yongchuan Hospital of Chongqing Medical University (CN), Henan Provincial People's Hospital (CN), First Hospital of China Medical University (CN), Peking University Third Hospital (CN), Henan Cancer Hospital (CN), Sun Yat-sen University Cancer Center (CN), Shanghai Institute of Hematology (CN), First Affiliated Hospital of Soochow University (CN), Guangdong Provincial People's Hospital (CN), Chongqing Cancer Hospital (CN), First Affiliated Hospital of Zhengzhou University (CN), Xiangya Hospital Central South University (CN), Hubei Cancer Hospital (CN), Liaoning Cancer Hospital & Institute (CN), Qilu Hospital of Shandong University (CN), Union Hospital (CN), First Affiliated Hospital of Nanchang University (CN), First Affiliated Hospital Zhejiang University (CN), Shenzhen Chipscreen Biosciences Co., Southern Medical University (CN), Chongqing Medical University (CN), China Medical University (CN)
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