Meyer Cancer Center, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY.
Memorial Sloan Kettering Cancer Center, New York, NY.
Blood. 2023 May 4;141(18):2194-2205. doi: 10.1182/blood.2022018254.
Peripheral T-cell lymphomas (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) plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) as initial treatment for PTCL. CC-486 at 300 mg daily was administered for 7 days before C1 of CHOP, and for 14 days before CHOP C2-6. The primary end point was end-of-treatment complete response (CR). Secondary end points included safety and survival. Correlative studies assessed mutations, gene expression, and methylation in tumor samples. Grade 3 to 4 hematologic toxicities were mostly neutropenia (71%), with febrile neutropenia uncommon (14%). Nonhematologic toxicities included fatigue (14%) and gastrointestinal symptoms (5%). In 20 evaluable patients, CR was 75%, including 88.2% for PTCL-TFH (n = 17). The 2-year progression-free survival (PFS) was 65.8% for all and 69.2% for PTCL-TFH, whereas 2-year overall survival (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 = .007), favorable PFS (P = .004) and OS (P = .015), and DNMT3A mutations associated with adverse PFS (P = .016). CC-486 priming contributed to the reprograming of the tumor microenvironment by upregulation of genes related to apoptosis (P < .01) and inflammation (P < .01). DNA methylation did not show significant shift. This safe and active regimen is being further evaluated in the ALLIANCE randomized study A051902 in CD30-negative PTCL. This trial was registered at www.clinicaltrials.gov as #NCT03542266.
外周 T 细胞淋巴瘤（PTCL）伴 T 滤泡辅助表型（PTCL-TFH）存在影响表观遗传调节剂的复发性突变，这可能导致异常的 DNA 甲基化和化疗耐药。这项 2 期研究评估了口服阿扎胞苷（CC-486）联合环磷酰胺、多柔比星、长春新碱和泼尼松（CHOP）作为 PTCL 的初始治疗。CC-486 每天 300mg，在 CHOP 的 C1 前用 7 天，在 CHOP C2-6 前用 14 天。主要终点是治疗结束时的完全缓解（CR）。次要终点包括安全性和生存。相关研究评估了肿瘤样本中的突变、基因表达和甲基化。3 级至 4 级血液学毒性主要为中性粒细胞减少症（71%），发热性中性粒细胞减少症少见（14%）。非血液学毒性包括疲劳（14%）和胃肠道症状（5%）。在 20 例可评估的患者中，CR 为 75%，其中 PTCL-TFH 为 88.2%（n=17）。所有患者的 2 年无进展生存率（PFS）为 65.8%，PTCL-TFH 为 69.2%，所有患者的 2 年总生存率（OS）为 68.4%，PTCL-TFH 为 76.1%。TET2、RHOA、DNMT3A 和 IDH2 突变的频率分别为 76.5%、41.1%、23.5%和 23.5%，TET2 突变与 CR（P=0.007）、有利的 PFS（P=0.004）和 OS（P=0.015）显著相关，DNMT3A 突变与不良的 PFS（P=0.016）相关。CC-486 引发可通过上调与凋亡（P<0.01）和炎症（P<0.01）相关的基因，对肿瘤微环境进行重编程。DNA 甲基化没有明显变化。在 CD30 阴性 PTCL 的 ALLIANCE 随机研究 A051902 中，正在进一步评估这种安全有效的方案。该试验在 www.clinicaltrials.gov 上注册为#NCT03542266。
