Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
Department of Dermatology, MD Anderson Cancer Center, Houston, USA.
Ann Oncol. 2014 Sep;25(9):1807-1812. doi: 10.1093/annonc/mdu231. Epub 2014 Jun 19.
Forodesine is a potent inhibitor of purine nucleoside phosphorylase (PNP) that leads to intracellular accumulation of deoxyguanosine triphosphate (dGTP) in T and B cells, resulting in apoptosis. Forodesine has demonstrated impressive antitumor activity in early phase clinical trials in cutaneous T-cell lymphoma (CTCL).
In this phase II study, patients with CTCL who had already failed three or more systemic therapies were recruited. We investigated the response rate, safety and tolerability of oral forodesine treatment in subjects with cutaneous manifestations of CTCL, stages IB, IIA, IIB, III and IVA. The safety population encompassing all stages was used for analysis of accountability, demographics and safety. The efficacy population differed from the safety population by exclusion of stage IB and IIA patients.
All 144 patients had performance status 0-2. The median duration of CTCL from diagnosis was 53 months (5-516 months). The median number of pretreatments was 4 (range: 3-15). No complete remissions were observed. In the efficacy group of patients, 11% achieved partial remission and 50% had stable disease. The median time to response was 56 days and the median duration of response was 191 days. A total of 96% of all treated patients reported one or more adverse events (AEs) and 33% reported a serious AE. The majority of AEs were classified as mild or moderate in severity. The most commonly reported AEs (>10%) were peripheral edema, fatigue, insomnia, pruritus, diarrhea, headache and nausea. Overall eight patients died during the study: five due to sepsis and infections, one due to a second malignancy (esophageal cancer), one due to disease progression and one due to liver failure.
Oral forodesine at a dose of 200 mg daily is feasible and shows partial efficacy in this highly selected CTCL population and some durable responses.
氟达拉滨是一种强效的嘌呤核苷磷酸化酶（PNP）抑制剂，可导致 T 和 B 细胞内脱氧鸟苷三磷酸（dGTP）蓄积，从而诱导细胞凋亡。氟达拉滨在早期临床试验中已显示出对皮肤 T 细胞淋巴瘤（CTCL）具有显著的抗肿瘤活性。
本研究为 II 期临床试验，纳入了已接受过三种或以上全身治疗失败的 CTCL 患者。我们评估了口服氟达拉滨治疗皮肤 CTCL 患者（分期为 IB、IIA、IIB、III 和 IVA）的疗效、安全性和耐受性。安全性人群包括所有分期，用于分析病例报告、人口统计学和安全性。疗效人群与安全性人群的不同之处在于排除了 IB 和 IIA 期患者。
所有 144 例患者的体能状态均为 0-2 级。从确诊 CTCL 到研究入组的中位时间为 53 个月（5-516 个月）。中位预处理次数为 4 次（范围：3-15 次）。未观察到完全缓解。在疗效人群中，11%的患者达到部分缓解，50%的患者疾病稳定。中位起效时间为 56 天，中位缓解持续时间为 191 天。所有接受治疗的患者中，96%报告了 1 次或多次不良事件（AE），33%报告了严重 AE。大多数 AE 的严重程度为轻度或中度。报告发生率>10%的 AE 包括外周水肿、疲劳、失眠、瘙痒、腹泻、头痛和恶心。研究期间共有 8 例患者死亡：5 例因脓毒症和感染，1 例因第二恶性肿瘤（食管癌），1 例因疾病进展，1 例因肝功能衰竭。
每日 200mg 口服氟达拉滨在该高度选择的 CTCL 人群中是可行的，并显示出部分疗效和一些持久缓解。
