Primary cutaneous T cell lymphomas (CTCL) are characterized by high relapse rates to initially highly effective therapies. Combination therapies have proven beneficial, particularly if they incorporate extracorporeal photopheresis (ECP). The NF-κB inhibitor dimethyl fumarate (DMF) has proven a new, effective drug in CTCL in a clinical phase II study. In vitro experiments with patient-derived SS cells and the CTCL cell lines HH, HuT 78, and SeAx revealed a synergistic effect of DMF and ECP on cell death induction in CTCL cells. Furthermore, an additional increase in the capacity to inhibit NF-κB in CTCL was detected for the combination treatment compared to DMF monotherapy. The same synergistic effects could be measured for ROS production via decreased Thioredoxin reductase activity and glutathione levels. Consequently, a cell death inhibitor screen indicated that the DMF/ECP combination treatment induces a variety of cell death mechanisms in CTCL. As a first step into clinical translation, 4 patients were already treated with the DMF/ECP combination therapy with an overall response rate of 100% and a time to next treatment in skin and blood of up to 57 months. Therefore, our study introduces the combination treatment of DMF and ECP as a highly effective and long-lasting CTCL therapy.

原发性皮肤 T 细胞淋巴瘤 （CTCL） 的特点是初始高效治疗的高复发率。联合疗法已被证明是有益的，特别是如果它们结合了体外光分离法 （ECP）。NF-κB 抑制剂富马酸二甲酯 （DMF） 已在临床 II 期研究中证明是一种治疗 CTCL 的新型有效药物。患者来源的 SS 细胞和 CTCL 细胞系 HH、HuT 78 和 SeAx 的体外实验揭示了 DMF 和 ECP 对 CTCL 细胞死亡诱导的协同作用。此外，与 DMF 单一疗法相比，检测到联合治疗对 CTCL 中 NF-κB 的抑制能力额外增加。通过降低硫氧还蛋白还原酶活性和谷胱甘肽水平，可以测量对 ROS 产生的相同协同效应。因此，细胞死亡抑制剂筛选表明 DMF/ECP 联合治疗在 CTCL 中诱导多种细胞死亡机制。作为临床转化的第一步，4 名患者已经接受了 DMF/ECP 联合治疗，总体反应率为 100%，皮肤和血液下一次治疗的时间长达 57 个月。因此，我们的研究引入了 DMF 和 ECP 的联合治疗作为一种高效且持久的 CTCL 疗法。