Combined oral 5-azacytidine and romidepsin are highly effective in patients with PTCL: a multicenter phase 2 study
Combined oral 5-azacytidine and romidepsin are highly effective in patients with PTCL: a multicenter phase 2 study
复制标题
DOI：
10.1182/blood.2020009004
复制
发表时间：
2021-04-22
期刊：
影响因子：
20.3
通讯作者：
O'Connor, Owen A.
中科院分区：
文献类型：
--
作者：
Falchi, Lorenzo;Ma, Helen;O'Connor, Owen A.
外周T细胞淋巴瘤（PTCL）是唯一易受表观遗传修饰剂。我们在T细胞淋巴瘤的临床前模型中证明了组蛋白去乙酰化酶抑制剂和DNA甲基转移酶抑制剂之间的体外协同作用。在1期试验中，我们发现口服5-氮杂胞苷和罗米地辛是安全有效的，在复发/难治性（R/R）PTCL患者中具有谱系选择性活性。初治或R/R PTCL患者在第1 - 14天接受氮杂胞苷300 mg每日一次，在第8、15和22天接受罗米地辛14 mg/m2，每35天一次。主要目标是总体缓解率（ORR）。对肿瘤样本进行靶向下一代测序，以关联突变谱和应答。在25例入组患者中，ORR和完全缓解率分别为61%和48%。然而，具有T-滤泡辅助细胞（tTFH）表型的患者表现出更高的ORR（80%）和完全缓解率（67%）。最常见的3 - 4级不良事件为血小板减少（48%）、中性粒细胞减少（40%）、淋巴细胞减少（32%）和贫血（16%）。中位随访时间为13.5个月，中位无进展生存期、缓解持续时间和总生存期分别为8.0个月、20.3个月和未达到。R/R疾病患者的中位无进展生存期和总生存期分别为8.0个月和20.6个月。tTFH患者的中位生存期特别长（未达到中位生存期）。应答者在涉及DNA甲基化和组蛋白去乙酰化的基因中具有较高的平均突变数。氮杂胞苷和罗米地辛联合治疗PTCL患者具有高度活性，可以作为治疗这种疾病的新方案的平台。
Peripheral T-cell lymphomas (PTCLs) are uniquely vulnerable to epigenetic modifiers. We demonstrated in vitro synergism between histone deacetylase inhibitors and DNA methyltransferase inhibitors in preclinical models of T-cell lymphoma. In a phase 1 trial, we found oral 5-azacytidine and romidepsin to be safe and effective, with lineage-selective activity among patients with relapsed/refractory (R/R) PTCL. Patients who were treatment naive or who had R/R PTCL received azacytidine 300 mg once per day on days 1 to 14, and romidepsin 14 mg/m(2) on days 8, 15, and 22 every 35 days. The primary objective was overall response rate (ORR). Targeted next-generation sequencing was performed on tumor samples to correlate mutational profiles and response. Among 25 enrolled patients, the ORR and complete response rates were 61% and 48%, respectively. However, patients with T-follicular helper cell (tTFH) phenotype exhibited higher ORR (80%) and complete remission rate (67%). The most frequent grade 3 to 4 adverse events were thrombocytopenia (48%), neutropenia (40%), lymphopenia (32%), and anemia (16%). At a median follow-up of 13.5 months, the median progression-free survival, duration of response, and overall survival were 8.0 months, 20.3 months, and not reached, respectively. The median progression-free survival and overall survival were 8.0 months and 20.6 months, respectively, in patients with R/R disease. Patients with tTFH enjoyed a particularly long median survival (median not reached). Responders harbored a higher average number of mutations in genes involved in DNA methylation and histone deacetylation. Combined azacytidine and romidepsin are highly active in PTCL patients and could serve as a platform for novel regimens in this disease.