淋巴瘤与EB病毒经常有关联，EB病毒阳性与某些亚型的结果较差有关。Nanatinostat是一种选择性的口服Ⅰ类组蛋白去乙酰酶（HDACi）抑制剂，在EBV阳性肿瘤细胞中诱导溶解EBV BGLF4蛋白激酶表达，通过磷酸化激活gan环鸟苷，导致肿瘤细胞凋亡。这项1b/2期研究（NCT03397706）研究了纳那替诺同瓦尔甘苷结合治疗EBV阳性淋巴瘤患者的组合疗法，这些患者经历1次或多次无可治愈的系统治疗后复发/难治。在1b期中，25名患者分为5个剂量递增队列，以确定2期扩展的推荐剂量（RP2D）。2期患者（n=30）每28天一个周期接受RP2D（纳那替诺每天20毫克，每周4天和瓦尔甘苷每天口服900毫克）的治疗。主要终点是安全性和RP2D的确定（1b期）以及总体响应率（ORR; 2期）。总共有55名患者入组（B-NHLs [n=10]，T/NK-NHLs [n=21]，经典霍奇金淋巴瘤[n=11]和免疫缺陷相关淋巴增生性疾患（IA-LPD）[n=13]）。在43名可评估患者中，ORR为40%（完全缓解率[CRR] 19% [n=8]），持续缓解时间中位数为10.4个月。对于T/NK-NHLs（n=15；所有患者均对最后一次先前治疗无反应），ORR / CRR分别为60% / 27%。最常见的不良事件（AEs）包括恶心（任何等级38%）和细胞减少（3/4级中性粒细胞减少[29%]，血小板减少[20%]和贫血[20%]）。这种新型口服方案在多个EBV阳性淋巴瘤亚型中显示出鼓舞人心的疗效，值得进一步评估；正在进行一项确证性2期研究（NCT05011058）。版权所有©2023美国血液学会。

Lymphomas are not infrequently associated with Epstein-Barr virus, with EBV-positivity linked to worse outcomes in several subtypes. Nanatinostat is a Class-I selective oral histone deacetylase inhibitor (HDACi) that induces expression of lytic EBV BGLF4 protein kinase in EBV+ tumor cells, activating ganciclovir via phosphorylation, resulting in tumor cell apoptosis. This Phase 1b/2 study (NCT03397706) investigated the combination of nanatinostat with valganciclovir in patients aged >=18 with EBV+ lymphomas relapsed/refractory to >=1 prior systemic therapies with no viable curative treatment options. In the Phase 1b part, 25 patients were enrolled into 5 dose escalation cohorts to determine the recommended Phase 2 dose (RP2D) for Phase 2 expansion. Phase 2 patients (n=30) received the RP2D (nanatinostat 20 mg daily, 4 days per week with valganciclovir 900 mg orally daily) in 28-day cycles. Primary endpoints were safety and RP2D determination (Phase 1b) and overall response rate (ORR; Phase 2). Overall, 55 patients were enrolled (B-NHLs [n=10], T/NK-NHLs [n=21], classical Hodgkin lymphoma [n=11], and immunodeficiency-associated lymphoproliferative disorders (IA-LPD) [n=13]). The ORR was 40% in 43 evaluable patients (complete response rate [CRR] 19% [n=8]) with a median duration of response of 10.4 months. For T/NK-NHLs (n=15; all refractory to last prior therapy), the ORR/CRR was 60%/27%. The most common adverse events (AEs) were nausea (38% any grade) and cytopenias (Grade 3/4 neutropenia [29%], thrombocytopenia [20%], and anemia [20%]). This novel oral regimen provided encouraging efficacy across several EBV+ lymphoma subtypes and warrants further evaluation; a confirmatory Phase 2 study (NCT05011058) is underway.Copyright © 2023 American Society of Hematology.