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

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.

MYC/BCL2双表达淋巴瘤（DEL），这是一种由MYC和BCL2共同表达定义的DLBCL独特群体，在接受标准的利妥昔单抗联合环磷酰胺、多柔比星、长春新碱和泼尼松（R-CHOP）免疫化疗后预后较差。

Tucidinostat (or chidamide), an oral, selective histone deacetylase inhibitor, has shown promising activity in DEL.

Tucidinostat（或称chidamide），一种口服的选择性组蛋白去乙酰化酶抑制剂，在DEL中显示出有希望的活性。

Background

To evaluate efficacy and safety of tucidinostat plus R-CHOP vs R-CHOP alone as first-line treatment for patients with DEL.

评估tucidinostat联合R-CHOP与单独使用R-CHOP作为DEL患者一线治疗的有效性和安全性。

DESIGN, SETTING, AND PARTICIPANTS: This randomized, double-blind, placebo-controlledphase 3 trial enrolled patients from May 21, 2020, through July 25, 2022, with follow-up to June 26, 2025.

设计、设置和参与者：这项随机、双盲、安慰剂对照的III期试验从2020年5月21日开始，至2022年7月25日结束，随访至2025年6月26日。

The trial was conducted at 40 study centers in China; a total of 423 eligible patients were enrolled.

该试验在中国的40个研究中心进行；共招募了423名符合条件的患者。

Methods

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.

患者按照1:1的比例随机分配接受口服曲替诺司他（每21天周期的第1、4、8和11天口服20毫克）或匹配安慰剂，加上6个周期的R-CHOP治疗。

Patients with a complete response after combination therapy received either tucidinostat or placebo maintenance up to 24 weeks.

在联合治疗后达到完全缓解的患者，接受曲替诺司他或安慰剂维持治疗，持续时间最多为24周。

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.

主要终点是无事件生存。次要终点包括完全缓解率、无进展生存、无病生存、总生存和耐受性。

Results

Among 423 patients randomized (median age, 63 years; 47.5% male), the median follow-up duration from randomization was 41.3 months.

在随机分配的423名患者中（中位年龄63岁；47.5%为男性），从随机分配开始的中位随访时间为41.3个月。

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.

与安慰剂组相比，曲替利珠单抗组在疾病进展、完全缓解后的复发、死亡或开始新治疗的风险降低了28%（分层风险比为0.72 [95% 置信区间, 0.54-0.96]；P = .02），2年无事件生存率分别为60.3%和50.5%。

The complete response rate was 73.0% vs 61.8% (difference, 11.1% [95% CI, 2.3%-20.0%]), respectively.

完全缓解率分别为73.0%和61.8%（差异为11.1% [95% 置信区间, 2.3%-20.0%]）。

Increased toxicity associated with treatment was observed in the tucidinostat group but generally manageable with supportive care.

在tucidinostat组中观察到与治疗相关的毒性增加，但通常可以通过支持性护理进行管理。

conclusions_and_relevance

Tucidinostat plus R-CHOP significantly improved event-free survival, with manageable toxicity in patients newly diagnosed with DEL.

Tucidinostat联合R-CHOP显著改善了新诊断为DEL患者的无事件生存率，毒性可控。

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.

这项试验首次证明了表观遗传调节剂在弥漫性大B细胞淋巴瘤（DLBCL）中的益处，为这一高风险人群提供了一种新的双重靶向MYC和BCL2癌蛋白的一线治疗方法。

trial_registration

ClinicalTrials.gov Identifier: NCT04231448.

ClinicalTrials.gov注册号：NCT04231448。