PTCL-TFH表现型（T细胞亚型滤泡辅助性）具有反复发生的影响表观遗传调控因子的突变，这可能有助于非正常的DNA甲基化和化疗耐药性。本二期研究评估了口服异环鞘氨苷（CC-486），一种DNA甲基转移酶抑制剂，加CHOP作为PTCL的初始治疗（ClinicalTrials.gov - NCT03542266）。CC-486每天300毫克给药，连续7天在CHOP的C1前，连续14天在CHOP C2-6前。主要终点是治疗结束时的完全缓解。次要终点包括总有效率、安全性和生存率。相关研究评估了肿瘤样本中的突变、基因表达和甲基化。3-4级造血毒性主要是中性粒细胞减少症（71％），高热中性粒细胞减少症不太常见（14％）。非血液学的不良反应包括疲劳（14％）和胃肠症状（5％）。在20名可评估患者中，完全缓解率为75％，其中PTCL-TFH为88.2％（n = 17）。在中位随访21个月后，所有病例2年PFS为65.8％，PTCL-TFH为69.2％，而2年总生存率分别为68.4％和76.1％。TET2、RHOA、DNMT3A和IDH2突变的频率分别为76.5％、41.1％、23.5％和23.5％，其中TET2突变与CR（p = 0.007）、有利的PFS（p = 0.004）和OS（p = 0.015）显着相关，而DNMT3A突变与不良PFS（p = 0.016）相关。CC-486的预处理有助于通过调节与凋亡（p<0.01）和炎症（p<0.01）相关的基因来重构肿瘤微环境。DNA甲基化没有显示出明显的变化。这种安全且有效的初始治疗方案正在ALLIANCE随机研究A051902中进一步评估，适用于CD30阴性的PTCL。版权所有©2023年美国血液学会。

PTCL with T-follicular helper phenotype (PTCL-TFH) has recurrent mutations affecting epigenetic regulators, which may contribute to aberrant DNA methylation and chemoresistance. This phase 2 study evaluated oral azacitidine (CC-486), a DNA methyltransferase inhibitor, plus CHOP as initial treatment for PTCL (ClinicalTrials.gov - NCT03542266). CC-486 at 300 mg daily was administered for 7 days prior to C1 of CHOP, and for 14 days before CHOP C2-6. The primary endpoint was end-of-treatment CR. Secondary endpoints included ORR, safety and survival. Correlative studies assessed mutations, gene expression and methylation in tumor samples. Grade 3-4 hematologic toxicities were mostly neutropenia (71%), with febrile neutropenia uncommon (14%). Non-hematologic toxicities included fatigue (14%) and GI symptoms (5%). In 20 evaluable patients, CR was 75%, including 88.2% for PTCL-TFH (n=17). At a median follow-up of 21 months, 2-yr PFS was 65.8% for all and 69.2% for PTCL-TFH, while 2-yr OS was 68.4% for all and 76.1% for PTCL-TFH. The frequencies of the TET2, RHOA, DNMT3A, and IDH2 mutations were 76.5%, 41.1%, 23.5% and 23.5%, respectively, with TET2 mutations significantly associated with CR (p=0.007), favorable PFS (p=0.004) and OS (p=0.015), and DNMT3A mutations associated with adverse PFS (p=0.016). CC-486 priming contributed to the reprograming of the tumor microenvironment by upregulation of genes related to apoptosis (p<0.01) and inflammation (p<0.01). DNA methylation did not show significant shift. This safe and active initial therapy regimen is being further evaluated in the ALLIANCE randomized study A051902 in CD30-negative PTCL.Copyright © 2023 American Society of Hematology.