Evaluation of Low-Dose, Low-Frequency Oral Psoralen-UV-A Treatment With or Without Maintenance on Early-Stage Mycosis Fungoides: A Randomized Clinical Trial

Abstract

Importance: 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.

Objectives: 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.

Main outcomes and measures: 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.

Results: 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.

Conclusions and relevance: 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.

Trial registration: ClinicalTrials.gov identifier: NCT01686594.

Figure 1.. Patient Flowchart

PUVA indicates psoralen–UV-A.

Figure 2.. Clinical, Histologic, and Clonal Response of Patients With Psoralen–UV-A (PUVA) Treatment

Representative cases of patients with complete response (CR) and partial response (PR). Baseline evaluation of clinical presentation, histologic features and high-throughput T-cell receptor sequencing results from skin biopsy specimens of patients 5 (A) and 22 (C) are shown. Respective reevaluation of these parameters after 16 (B) or 24 (D) weeks of PUVA induction treatment are depicted. The box in the clinical photographs indicates area of biopsy. Imaging of hematoxylin-eosin staining (original magnification ×20) was performed, and the infiltration density score (IDS) for each patient is shown. Plots of clonality analyses show the total count of T-cell receptor (TCR) reads per TCRBJ family. The malignant clone is annotated, and associated amino acid sequence and percentage of clonal TCR reads are shown.

Figure 3.. Effect of Psoralen–UV-A (PUVA) Maintenance on Disease-Free Remission Time

A, Score on the modified severity-weighted assessment tool (mSWAT) was monitored throughout the duration (3-6 months) of the PUVA induction phase until randomization (month 0). Reduction of the mSWAT score to a value of 0 was defined in the trial protocol as complete response (n = 19). A substantial reduction of mSWAT values occurred also in patients who showed partial response (n = 8). B, This swimmer plot of the treatment course of each patient shows the length of the PUVA induction phase (dark blue), maintenance treatment (medium blue), and time in remission (light blue). The arrowheads indicate patients who had not yet relapsed (n = 2) at study termination. C, This Kaplan-Meier plot of disease-free remission shows a statistically significant (P = .02; calculated using log-rank test) difference between patients randomized to either PUVA maintenance or to no PUVA maintenance. PL indicates plaque; PT, patch.

Figure 4.. Baseline Serum Levels of Proinflammatory Mediators and Clinical Outcome After Psoralen–UV-A (PUVA) Treatment

Multivariate comparison of serum levels of proinflammatory mediators at baseline between patients with partial response (PR) and patients with complete response (CR). A, Hierarchical cluster analysis is shown with association coefficient (ibs) of chemotactic mediator levels. Mediators negatively associated with CR are shown in dark blue; mediators positively associated with CR are shown in light blue. Dashed line indicates a threshold of P < .05. B, Comparison of baseline levels of CXCL9, CXCL11, CXCL12, CXCL13, TNFSF13, and TWEAK in patients with CR and those with PR is shown. Mean (SEM) is plotted, Mann-Whitney test was used to evaluate statistical significance (P values are shown).