BACKGROUND The calcineurin pathway is often activated in mycosis fungoides. We aimed to assess the activity and safety of topical pimecrolimus, a calcineurin inhibitor, in patients with early mycosis fungoides. METHODS PimTo-MF was a single-arm, multicentre, phase 2 trial done at six medical centres in Spain. Patients (aged ≥18 years) had histologically confirmed early mycosis fungoides (stages IA-IIA) and an Eastern Cooperative Oncology Group performance status of 0-1. Key exclusion criteria included the use of concurrent treatments for mycosis fungoides, including sunbathing, topical or systemic corticosteroids, and other calcineurin inhibitors. Patients applied topical pimecrolimus 1% cream on their skin lesions twice daily for 16 weeks (1 g per 2% of body surface), with subsequent follow-up of 12 months. Dosage modifications were not allowed. To evaluate adherence to the treatment, patients were instructed to return all empty tubes to the hospital (as per drug accountability protocols). The primary endpoint was the overall response ratein the intention-to-treat population. PimTo-MF is registered with EudraCT, 2014-001377-14, and is complete. FINDINGS Between March 1, 2015, and Sept 30, 2016, 39 patients were enrolled. All patients were assessable, with a median age of 51·5 years (IQR 45-62), and the population was predominantly male (24 male [62%], 15 female [38%]). Median follow-up after baseline was 5·7 years (IQR 5·7-6·2). 22 (56%) of 39 patients had an overall response (one complete response, 21 partial responses). Responses were observed across IA (14 [54%] of 26 patients) and IB (eight [73%] of 11 patients) clinical stages, but not IIA. Topical pimecrolimus was well tolerated and no patient required a dose reduction or discontinued treatment because of unacceptable drug-related toxicity. No patients were lost to follow-up or discontinued treatment. 13 (33%) of 39 patients reported adverse events; transitory mild burning or pruritus (grade 1) was the most common, seen in eight (21%) patients. In three (8%) of these patients, the burning or pruritus was considered related to treatment. No grade 4 or 5 adverse events were observed. INTERPRETATION Pimecrolimus 1% cream seems active and safe in patients with early stage mycosis fungoides. Our findings should be taken with caution until long-term follow-up data are obtained that confirm the safety of this treatment. Further controlled clinical trials are warranted to confirm these results. FUNDING Instituto de Salud Carlos III and the European Regional Development Fund. TRANSLATION For the Spanish translation of the abstract see Supplementary Materials section.

中文翻译：

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局部吡美莫司治疗早期蕈样肉芽肿 (PimTo-MF) 患者的活性和安全性：一项单臂、多中心、2 期试验。

背景技术 钙调神经磷酸酶途径通常在蕈样肉芽肿中被激活。我们旨在评估外用吡美莫司（一种钙调神经磷酸酶抑制剂）在早期蕈样肉芽肿患者中的活性和安全性。方法 PimTo-MF 是一项单臂、多中心、2 期试验，在西班牙的六个医疗中心进行。患者（年龄≥18 岁）组织学证实为早期蕈样肉芽肿（IA-IIA 期），东部肿瘤协作组体能状态为 0-1。关键的排除标准包括对蕈样肉芽肿的同时治疗，包括日光浴、局部或全身性皮质类固醇和其他钙调神经磷酸酶抑制剂。患者每天两次在皮肤损伤处局部涂抹 1% 吡美莫司乳膏，持续 16 周（每 2% 体表 1 克），随后随访 12 个月。不允许修改剂量。为了评估对治疗的依从性，指示患者将所有空管送回医院（根据药物问责协议）。主要终点是意向治疗人群的总体反应率。PimTo-MF 已在 EudraCT 注册，2014-001377-14，并且已完成。结果 2015 年 3 月 1 日至 2016 年 9 月 30 日期间，共有 39 名患者入组。所有患者均可评估，中位年龄为 51·5 岁（IQR 45-62），人群主要为男性（24 名男性 [62%]，15 名女性 [38%]）。基线后的中位随访时间为 5·7 年（IQR 5·7-6·2）。39 名患者中有 22 名（56%）有总体反应（1 名完全反应，21 名部分反应）。在 IA（26 名患者中的 14 名 [54%]）和 IB（11 名患者中的 8 名 [73%]）临床阶段中观察到反应，但在 IIA 中没有观察到反应。局部吡美莫司耐受性良好，没有患者因为不可接受的药物相关毒性而需要减少剂量或停止治疗。没有患者失访或停止治疗。39 名患者中有 13 名（33%）报告了不良事件；暂时性轻度灼热或瘙痒（1 级）是最常见的，见于 8 名 (21%) 患者。在这些患者中的三名（8%）中，烧灼感或瘙痒被认为与治疗有关。未观察到 4 级或 5 级不良事件。解释 1% 吡美莫司乳膏似乎对早期蕈样真菌病患者有效且安全。在获得证实这种治疗安全性的长期随访数据之前，应谨慎对待我们的研究结果。需要进一步的对照临床试验来证实这些结果。资助 Instituto de Salud Carlos III 和欧洲区域发展基金。翻译 有关摘要的西班牙语翻译，请参阅补充材料部分。