Research Unit for Photodermatology, Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria.
Department of Dermatology, Medical University of Vienna, Vienna, Austria.
JAMA Dermatol. 2019 May 1;155(5):538-547. doi: 10.1001/jamadermatol.2018.5905.
Psoralen-UV-A (PUVA) photochemotherapy is standard first-line treatment for skin-limited, early-stage mycosis fungoides capable of producing high initial complete response (CR) rates. However, much remains unknown about PUVA's therapeutic mechanisms, optimal duration and frequency of treatment, dose escalation, or use as maintenance therapy.
To evaluate low-dose, low-frequency PUVA, and whether maintenance treatment extends disease-free remission in patients with mycosis fungoides.
DESIGN, SETTING, AND PARTICIPANTS: This prospective randomized clinical trial with defined PUVA dosing regimen was carried out in 5 centers (Graz, Vienna, Hietzing, Innsbruck, and Salzburg) across Austria. Patients with stage IA to IIA mycosis fungoides (n = 27) were enrolled in the study beginning March 13, 2013, with the last patient enrolled March 21, 2016. These patients were treated with oral 8-methoxypsoralen followed by UV-A exposure 2 times per week for 12 to 24 weeks until CR. Patients with CR were randomized to PUVA maintenance for 9 months (14 total exposures) or no maintenance. The study was conducted from April 27, 2012, to July 27, 2018. Data analysis of the primary end point was of the intention-to-treat population, and the secondary end point analysis was of the evaluable population.
Efficacy of the PUVA regimen was determined by the rate of CR as defined by a modified severity-weighted assessment tool (mSWAT) score reduction to 0. Levels of proinflammatory molecules in serum and histologic features and percentage of clonal T cells in skin were assessed to search for biomarkers of clinical response.
In 27 patients with mycosis fungoides, 19 (70%) were male with mean (range) age 61 (30-80) years. At baseline, patients with CR had a mean (range) mSWAT score of 18.6 (1-66) compared with 16.8 (3-46) in patients with partial response. The 12- to 24-week PUVA induction regimen reduced the mSWAT score in all patients and led to CR in 19 (70%) of 27 patients and a low mean cumulative UV-A dose of 78.5 J/cm2. The subsequent standardized 9-month PUVA maintenance phase prolonged median (range) disease-free remission from 4 (1-20) months to 15 (1-54) months (P = .02). High density of histologic infiltrate and high percentage of clonal TCR sequences in skin biopsy specimens at baseline were inversely associated with therapeutic response. No severe adverse effects were seen during the PUVA induction or maintenance phase.
This proof-of-concept study identifies potential biomarkers for therapeutic response to PUVA in mycosis fungoides; it also demonstrates that low-dose, low-frequency PUVA appears to be highly effective, and maintenance treatment may extend disease-free remission.
ClinicalTrials.gov identifier: NCT01686594.
补骨脂素-紫外线 A（PUVA）光化学疗法是治疗局限性早期蕈样真菌病的标准一线治疗方法，能够产生高初始完全缓解（CR）率。然而，PUVA 的治疗机制、最佳治疗持续时间和频率、剂量递增或维持治疗的作用仍有许多未知之处。
评估低剂量、低频率的 PUVA，以及维持治疗是否延长蕈样真菌病患者的无病缓解期。
设计、地点和参与者：这项前瞻性随机临床试验在奥地利的 5 个中心（格拉茨、维也纳、海茨宁、因斯布鲁克和萨尔茨堡）进行，有明确的 PUVA 剂量方案。2013 年 3 月 13 日开始招募患有 IA 期至 IIA 期蕈样真菌病（n=27）的患者，最后一名患者于 2016 年 3 月 21 日入组。这些患者接受口服 8-甲氧基补骨脂素，然后每周接受 2 次紫外线 A 照射，持续 12 至 24 周，直到 CR。CR 患者随机分为接受 PUVA 维持治疗 9 个月（共 14 次照射）或不接受维持治疗。研究于 2012 年 4 月 27 日至 2018 年 7 月 27 日进行。主要终点的数据分析是意向治疗人群，次要终点的分析是可评估人群。
PUVA 方案的疗效通过改良严重程度加权评估工具（mSWAT）评分降低到 0 来确定 CR 率。评估血清中促炎分子的水平以及组织学特征和皮肤中克隆性 T 细胞的百分比，以寻找临床反应的生物标志物。
在 27 例蕈样真菌病患者中，19 例（70%）为男性，平均（范围）年龄为 61（30-80）岁。在基线时，CR 患者的 mSWAT 评分平均（范围）为 18.6（1-66），而部分反应患者的评分平均为 16.8（3-46）。12 至 24 周的 PUVA 诱导方案降低了所有患者的 mSWAT 评分，导致 27 例患者中的 19 例（70%）达到 CR，并使累积紫外线 A 剂量达到低平均 78.5 J/cm2。随后标准化的 9 个月 PUVA 维持阶段将无病缓解期的中位数（范围）从 4（1-20）个月延长至 15（1-54）个月（P=0.02）。基线时组织学浸润密度高和皮肤活检标本中克隆性 TCR 序列百分比高与治疗反应呈负相关。在 PUVA 诱导或维持阶段未观察到严重不良反应。
这项概念验证研究确定了 PUVA 治疗蕈样真菌病的潜在治疗反应生物标志物；它还表明，低剂量、低频率的 PUVA 似乎非常有效，维持治疗可能延长无病缓解期。
ClinicalTrials.gov 标识符：NCT01686594。
