Tucidinostat Plus R-CHOP vs R-CHOP in MYC/BCL2 Double-Expressor Diffuse Large B-Cell Lymphoma: A Randomized Clinical Trial

Clinical Snapshot

Key Findings

• P Value: P = 0.02

• Effect Size: 28% reduction in risk of disease progression, relapse, death, or new therapy initiation

• Primary Outcome: Event-free survival significantly improved with tucidinostat plus R-CHOP

• Nnt Or Sensitivity: Number needed to treat approximately 10 patients to prevent one additional event at 2 years (based on 10% absolute risk reduction)

• Confidence Interval: Hazard ratio 0.72 (95% CI: 0.54-0.96)

Clinical Application

Requires access to tucidinostat and expertise in managing HDAC inhibitor toxicity alongside R-CHOP Tucidinostat not currently TGA-approved; would require Special Access Scheme. DLBCL management aligns with current Australian guidelines, but this specific subtype targeting represents novel approach not yet in RACGP or haematology society recommendations Adults with newly diagnosed MYC/BCL2 double-expressor DLBCL suitable for intensive chemotherapy

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.

References

1. 1.Xu, P. P., Song, Y. Q., Shen, J. Z., Cai, Q. Q., Zhou, H., Zhang, L. L., Xiang, Y., Sun, X. H., Yang, W., Yao, Z. H., Jing, H. M., Wen, S. J., Jin, J., Xue, H. W., Cen, H., Ding, K. Y., Jin, Z. M., Liu, L. H., Xing, X. J., Li, L. F., Hou, M., Liu, L., Zhang, M. Z., Li, W. Y., Bai, O., Feng, R., Zhu, Z. M., Wu, H. J., Su, L. P., Gao, L., Li, F., Huang, W. R., Liu, P., Yan, X. J., Zhao, Y., Su, H., Zhao, X. L., Fu, R., Liu, H., Shi, W. Y., Li, H. Z., Chen, B., Ning, Z. Q., Zhu, J., & Zhao, W. L. (2026). Tucidinostat Plus R-CHOP vs R-CHOP in MYC/BCL2 Double-Expressor Diffuse Large B-Cell Lymphoma: A Randomized Clinical Trial. *JAMA*. https://doi.org/10.3389/fmed.2023.1096529