Efficacy and Safety of Topical Hypericin Photodynamic Therapy for Early-Stage Cutaneous T-Cell Lymphoma (Mycosis Fungoides): The FLASH Phase 3 Randomized Clinical Trial.

Importance: Given that mycosis fungoides-cutaneous T-cell lymphoma (MF/CTCL) is chronic, there is a need for additional therapies with minimal short- and long-term adverse effects. Topical synthetic hypericin ointment, 0.25%, activated with visible light is a novel, nonmutagenic photodynamic therapy (PDT). Objectives: To determine the efficacy and safety of topical synthetic hypericin ointment, 0.25%, activated with visible light as a nonmutagenic PDT in early-stage MF/CTCL. Design, Settings, and Participants: This was a multicenter, placebo-controlled, double-blinded, phase 3 randomized clinical trial (FLASH study) conducted from December 2015 to November 2020 at 39 academic and community-based US medical centers. Participants were adults (≥18 years) with early-stage (IA-IIA) MF/CTCL. Interventions: In cycle 1, patients were randomized 2:1 to receive hypericin or placebo to 3 index lesions twice weekly for 6 weeks. In cycle 2, all patients received the active drug for 6 weeks to index lesions. In cycle 3 (optional), both index and additional lesions received active drug for 6 weeks. Main Outcomes and Measures: The primary end point was index lesion response rate (ILRR), defined as 50% or greater improvement in modified Composite Assessment of Index Lesion Severity (mCAILS) score from baseline after 6 weeks of therapy for cycle 1. For cycles 2 and 3, open label response rates were secondary end points. Adverse events (AEs) were assessed at each treatment visit, after each cycle, and then monthly for 6 months. Data analyses were performed on December 21, 2020. Results: The study population comprised 169 patients (mean [SD] age, 58.4 [16.0] years; 96 [57.8%] men; 120 [72.3%] White individuals) with early-stage MF/CTCL. After 6 weeks of treatment, hypericin PDT was more effective than placebo (cycle 1 ILRR, 16% vs 4%; P = .04). The ILRR increased to 40% in patients who received 2 cycles of hypericin PDT (P < .001 vs cycle 1 hypericin) and to 49% after 3 cycles (P < .001 vs cycle 1 hypericin). Significant clinical responses were observed in both patch and plaque type lesions and were similar regardless of age, sex, race, stage IA vs IB, time since diagnosis, and number of prior therapies. The most common treatment-related AEs were mild local skin (13.5%-17.3% across cycles 1-3 vs 10.5% for placebo in cycle 1) and application-site reactions (3.2%-6.9% across cycles 1-3 vs 4% for placebo in cycle 1). No drug-related serious AEs occurred. Conclusion and Relevance: The findings of this randomized clinical trial indicate that synthetic hypericin PDT is effective in early-stage patch and plaque MF/CTCL and has a favorable safety profile. Trial Registration: ClinicalTrials.gov Identifier: NCT02448381.

The efficacy of laser therapy in wound repair: a meta-analysis of the literature.

OBJECTIVE: We determined the overall effects of laser therapy on tissue healing by aggregating the literature and subjecting studies meeting the inclusion and exclusion criteria to statistical meta-analysis. BACKGROUND DATA: Low-level laser therapy (LLLT) devices have been in use since the mid sixties, but their therapeutic value remains doubtful, as the literature seems replete with conflicting findings. MATERIALS AND METHODS: Pertinent original research papers were gathered from library sources, online databases and secondary sources. The papers were screened and coded; those meeting every inclusion and exclusion criterion were subjected to meta-analysis, using Cohen's d. statistic to determine the treatment effect size of each study. RESULTS: Twenty-four studies with 31 effect sizes met the stringent inclusion and exclusion criteria. The overall mean effect of laser therapy on wound healing was highly significant (d = +2.22). Sub-analyses of the data revealed significant positive effects on wound healing in animal experiments (d = +1.97) as well as human clinical studies (d = +0.54). The analysis further revealed significant positive effects on specific indices of healing, for example, acceleration of inflammation (d = +4.45); augmentation of collagen synthesis (d = +1.80); increased tensile strength (d = +2.37), reduced healing time (d = +3.24); and diminution of wound size (d = +0.55). The Fail-Safe number associated with the overall effect of laser therapy was 509; a high number representing the number of additional studies-in which laser therapy has negative or no effect on wound healing-required to negate the overall large effect size of +2.22. The corresponding Fail-Safe number for clinical studies was 22. CONCLUSION: We conclude that laser therapy is an effective tool for promoting wound repair.