Tucidinostat Plus R-CHOP vs R-CHOP in MYC/BCL2 Double-Expressor Diffuse Large B-Cell Lymphoma: A Randomized Clinical Trial
Mené en Chine sur 423 patients atteints d'un lymphome diffus à grandes cellules B exprimant les gènes MYC et BCL2 (âge médian : 63 ans ; durée médiane de suivi : 41,3 mois), cet essai randomisé de phase III évalue l'efficacité, du point de vue de la survie sans événement, et la toxicité de l'ajout du tucidinostat (un inhibiteur d'histone désacétylase) à une immunochimiothérapie de première ligne de type R-CHOP
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.
JAMA , résumé, 2026