Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
JAMA Dermatol. 2021 Jan 1;157(1):90-95. doi: 10.1001/jamadermatol.2020.3958.
Sézary syndrome (SS) is an advanced form of cutaneous T-cell lymphoma with few long-term remissions observed.
To profile 3 patients with SS who have experienced long-term remission following the addition of low-dose total skin electron beam therapy (TSEBT) to systemic regimens of extracorporeal photopheresis, bexarotene, and interferon-γ.
DESIGN, SETTING, AND PARTICIPANTS: This is a retrospective case series with additional investigations of patient-donated samples to assess therapeutic response. The study was conducted at the University of Pennsylvania Cutaneous Lymphoma Clinic and follows 3 patients with stage IVA1 CD4+ SS who presented to the clinic between November 1, 2009, and November 1, 2017, and who had a history of SS that was refractory to multimodality systemic therapy prior to receiving low-dose TSEBT.
Patients were treated in a multimodality fashion with combined extracorporeal photopheresis, bexarotene, interferon-γ, and low-dose TSEBT.
To characterize treatment responses in these patients, the extent of skin disease was measured with the modified severity weighted assessment tool. Blood disease was measured with flow cytometric assessments of Sézary cell count, CD4:CD8 ratio, and high throughput sequencing of the T-cell receptors. To assess for restoration of immune function, we measured markers of immune exhaustion, including PD-1 (programmed cell death 1), TIGIT (T-cell immunoreceptor with immunoglobulin and ITIM domains), CTLA4 (cytotoxic T-lymphocyte-associated protein 4), TOX (thymocyte selection-associated high mobility group box protein), and Foxp3 (forkhead box P3) on circulating CD4 and CD8 T cells, along with production capacity of interferon-γ by lymphocytes following activation stimuli.
Following administration of low-dose TSEBT and maintenance of the other therapies, remissions ranged from 24 to 30 months, with complete responses in 2 patients ongoing. Markers of immune exhaustion including PD-1, TIGIT, CTLA4, TOX, and Foxp3 were significantly reduced from baseline following TSEBT, along with enhanced production capacity of interferon-γ by lymphocytes following activation stimuli. High throughput sequencing demonstrated near-complete eradication of the circulating clone among 2 of 3 patients with stable levels in 1.
We describe 3 patients who achieved long-term clinical and molecular remissions following low-dose TSEBT as part of a multimodality regimen for treatment of SS. As long-term remissions in SS are uncommon, this approach demonstrates promise, and clinical trials should be considered.
蕈样 （Sézary） 综合征（SS）是一种皮肤 T 细胞淋巴瘤的晚期形式，观察到的长期缓解很少。
描述 3 例 SS 患者，他们在全身光化学疗法、贝沙罗汀和干扰素-γ的系统方案中添加低剂量全身电子束治疗（TSEBT）后经历了长期缓解。
设计、地点和参与者：这是一项回顾性病例系列研究，对患者捐赠的样本进行了额外的调查，以评估治疗反应。该研究在宾夕法尼亚大学皮肤淋巴瘤诊所进行，随访了 3 例 4A1 期 CD4+SS 患者，他们于 2009 年 11 月 1 日至 2017 年 11 月 1 日就诊于该诊所，并且在接受低剂量 TSEBT 之前，他们的 SS 病史对多模式全身治疗具有抗药性。
患者以多模式方式接受联合体外光化学疗法、贝沙罗汀、干扰素-γ和低剂量 TSEBT 治疗。
为了描述这些患者的治疗反应，我们使用改良的严重程度加权评估工具测量皮肤疾病的程度。通过流式细胞术评估 Sézary 细胞计数、CD4:CD8 比值以及 T 细胞受体的高通量测序来测量血液疾病。为了评估免疫功能的恢复，我们测量了免疫衰竭的标志物，包括程序性细胞死亡蛋白 1（PD-1）、T 细胞免疫受体与免疫球蛋白和 ITIM 结构域（TIGIT）、细胞毒性 T 淋巴细胞相关蛋白 4（CTLA4）、胸腺细胞选择相关高迁移率族框蛋白（TOX）和叉头框 P3（Foxp3）在循环 CD4 和 CD8 T 细胞上，以及淋巴细胞在激活刺激后产生干扰素-γ的能力。
在给予低剂量 TSEBT 并维持其他治疗后，缓解期为 24 至 30 个月，2 例患者持续完全缓解。TSEBT 后，包括 PD-1、TIGIT、CTLA4、TOX 和 Foxp3 在内的免疫衰竭标志物从基线显著降低，淋巴细胞在激活刺激后产生干扰素-γ的能力增强。高通量测序显示，在 3 例患者中的 2 例中，循环克隆几乎完全消除，1 例稳定。
我们描述了 3 例患者，他们在全身电子束治疗作为 SS 多模式治疗方案的一部分后，实现了长期的临床和分子缓解。由于 SS 的长期缓解并不常见，因此这种方法具有前景，应考虑进行临床试验。
