The presence and degree of peripheral blood involvement in patients with cutaneous T-cell lymphoma (CTCL) portend a worse clinical outcome. Available systemic therapies for CTCL may variably decrease tumor burden and improve quality of life, but offer limited effects on survival; thus, novel approaches to the treatment of advanced stages of this non-Hodgkin lymphoma are clearly warranted. Mutational analyses of CTCL patient peripheral blood malignant cell samples suggested the antiapoptotic mediator B-cell lymphoma 2 (BCL2) as a potential therapeutic target. To test this, we developed a screening assay for evaluating the sensitivity of CTCL cells to targeted molecular agents, and compared a novel BCL2 inhibitor, venetoclax, alone and in combination with a histone deacetylase (HDAC) inhibitor, vorinostat or romidepsin. Peripheral blood CTCL malignant cells were isolated from 25 patients and exposed ex vivo to the 3 drugs alone and in combination, and comparisons were made to 4 CTCL cell lines (Hut78, Sez4, HH, MyLa). The majority of CTCL patient samples were sensitive to venetoclax, and BCL2 expression levels were negatively correlated (r = −0.52; P = .018) to 50% inhibitory concentration values. Furthermore, this anti-BCL2 effect was markedly potentiated by concurrent HDAC inhibition with 93% of samples treated with venetoclax and vorinostat and 73% of samples treated with venetoclax and romidepsin showing synergistic effects. These data strongly suggest that concurrent BCL2 and HDAC inhibition may offer synergy in the treatment of patients with advanced CTCL. By using combination therapies and correlating response to gene expression in this way, we hope to achieve more effective and personalized treatments for CTCL.

皮肤T细胞淋巴瘤（CTCL）患者的外周血受累程度和临床预后较差。CTCL可用的全身疗法可能会不同程度地降低肿瘤负担并改善生活质量，但对存活率的作用有限；因此，显然需要新颖的方法来治疗这种非霍奇金淋巴瘤的晚期。CTCL患者外周血恶性细胞样品的突变分析表明，抗凋亡介质B细胞淋巴瘤2（BCL2）作为潜在的治疗靶点。为了测试这一点，我们开发了一种筛选测定法，用于评估CTCL细胞对靶向分子试剂的敏感性，并比较了新型BCL2抑制剂，venetoclax（单独使用或与组蛋白脱乙酰基酶（HDAC）抑制剂，伏立诺他或罗米地辛联用）。从25例患者中分离出外周血CTCL恶性细胞，并单独和联合使用三种药物进行离体暴露，并对4种CTCL细胞系（Hut78，Sez4，HH，MyLa）进行了比较。大多数CTCL患者样本对Venetoclax敏感，并且BCL2表达水平与50％抑制浓度值呈负相关（r = -0.52; P = .018）。此外，通过同时进行HDAC抑制，这种抗BCL2的作用显着增强，其中93％的患者接受Venetoclax和vorinostat治疗，73％的患者接受Venetoclax和Romidepsin治疗，表现出协同作用。这些数据强烈表明，同时抑制BCL2和HDAC可能在晚期CTCL患者的治疗中提供协同作用。通过使用组合疗法并以这种方式将对基因表达的反应相关联，我们希望为CTCL实现更有效和个性化的治疗。