Biological effect of azacitidine (CC-486) on peripheral T-cell lymphoma

TCL 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 and prioritized enrollment for PTCL-TFH (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% for all and 75.6% 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 upregulated genes related to apoptosis (p<0.01) and inflammation (p<0.01), with a decrease in TFH proliferation based on gene expression and cell-type deconvolution analysis. 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. RNA and DNA methylation profiles of PTCL tissue samples pre (C1D-6) and post (C1D1) CC-486 treatment were generated by Illumina sequencing

伴滤泡辅助T细胞（T-follicular helper, TFH）表型的外周T细胞淋巴瘤（Peripheral T-Cell Lymphoma, PTCL-TFH）存在复发性突变累及表观遗传调控因子，这可能介导异常DNA甲基化与化疗耐药。本项II期临床试验评估了口服DNA甲基转移酶抑制剂阿扎胞苷（azacitidine, CC-486）联合CHOP方案作为外周T细胞淋巴瘤的初始治疗方案，并优先纳入PTCL-TFH患者（ClinicalTrials.gov平台注册号：NCT03542266）。CC-486以每日300mg的剂量，在CHOP第1周期前连续给药7天，在CHOP第2至6周期前连续给药14天。该试验的主要终点为治疗结束时的完全缓解（Complete Response, CR）率，次要终点包括客观缓解率（Objective Response Rate, ORR）、安全性及生存结局。相关性研究对肿瘤样本中的突变、基因表达与甲基化水平进行了检测。3-4级血液学毒性以中性粒细胞减少最为常见（71%），发热性中性粒细胞减少发生率较低（14%）；非血液学毒性包括疲乏（14%）与胃肠道症状（5%）。在20例可评估患者中，总体CR率为75%，其中PTCL-TFH患者的CR率达88.2%（n=17）。中位随访21个月时，所有入组患者的2年无进展生存期（Progression-Free Survival, PFS）为65.8%，PTCL-TFH亚组患者为69.2%；所有患者的2年总生存期（Overall Survival, OS）为68%，PTCL-TFH亚组患者为75.6%。TET2、RHOA、DNMT3A与IDH2的突变频率分别为76.5%、41.1%、23.5%与23.5%；其中TET2突变与CR（p=0.007）、良好的PFS（p=0.004）及OS（p=0.015）显著相关，而DNMT3A突变与不良PFS相关（p=0.016）。CC-486预处理可上调与细胞凋亡（p<0.01）及炎症反应（p<0.01）相关的基因，通过基因表达与细胞类型反卷积分析发现滤泡辅助T细胞增殖受到抑制；DNA甲基化水平未出现显著变化。该安全且具有抗肿瘤活性的初始治疗方案，目前正在ALLIANCE随机对照试验A051902中针对CD30阴性的外周T细胞淋巴瘤患者开展进一步评估。本研究通过Illumina测序技术，获取了PTCL组织样本在CC-486治疗前（C1D-6，即CHOP第1周期第-6天）与治疗后（C1D1，即CHOP第1周期第1天）的RNA与DNA甲基化谱。