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.
Bibliographical noteFunding Information:
reported grants from Innate Pharma and Galderma; consulting/advisory fees from Almirall, Galderma, and Helsinn; and honoraria from Ology and UpToDate, all outside the submitted work. Dr Mangold reported grants from Crispr Therapeutics, Elorac, Kyowa Hakko Kirin, and Sun Pharmaceuticals; consulting/advisory fees from UCB, Eli Lilly, Regeneron, PHLEC, Corbus, Incyte, Pfizer, Novartis, Jansen, Argenx, Akari, and Castle Biosciences, all outside the submitted work. Dr Seminario-Vidal reported grants from Kyowa Kirin, and personal fees from Kyowa Kirin, Novartis, Boehringer Ingelheim, Helsinn, Regeneron, Blueprint, Eli Lilly, Soligenix, Helsinn, Eisai, AbbVie, Bristol Myers Squibb, Celgene, Glenmark, Amgen, AnaptysBio, and Innate Pharma outside the submitted work; and being a faculty member at the University of South Florida during the conduct of the study. Dr Guitart reported personal fees from Kirin Kyowa and Elorac outside the submitted work. Dr Korman reported consulting and advisory fees from AbbVie, Amgen, Argenx, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, ChemoCentryx, Dermavant, Dermira, Eli Lilly, Galderma, Genentech, GlaxoSmithKline, Immune, Janssen, Kyowa Hakko Kirin Pharma, Leo Pharma, Menlo Therapeutics, Novartis, Pfizer, Principia, Prothena, Regeneron, Rhizen, Soligenix, Sun Pharma, Syntimmune, Trevi Therapeutics, UCB, Valeant, and XBiotech, outside the submitted work. Dr Zeitouni reported grants from Sun Pharma, Biofrontera, and speaking honoraria from Biofrontera outside the submitted work. Dr Nikbakht reported consulting fees and serving as a member of Helsinn Advisory Board. Dr Shinohara reported grants from Elorac, Cabaletta Bio, and Astex, and serving on the board of the US Cutaneous Lymphoma Consortium outside the submitted work. Dr Piette reported a grant through Rush Medical University from Soligenix outside the submitted work. Dr Kuzel reported grants from Eisai and speaker’s honoraria from Kyowa Kirin. Dr Musiek reported personal fees and grants from Kyowa, Elorac, UpToDate, ADD Board Prep Plus Author, Pfizer, Bristol Myers Squibb, and Aristea Therapeutics, all outside the submitted work. Dr Pariser reported consulting fees from Biofrontera, Dermira, Novartis, Regeneron, Bickel Biotechnology, and Sanofi; and serving as a DSMB member of Bristol Myers Squibb, on the advisory board for Pfizer, and a researcher for Almirall, Amgen, AOBiome, Asana Biosciences, Bickel Biotech, Celgene, Dermira, Eli Lilly, Leo Pharma, Menlo Therapeutics, Novartis, Novo Nordisk, Ortho Dermatologics, Pfizer, and Regeneron, all outside the submitted work. Dr Olsen reports receiving consulting fees from Kyowa Kirin, UpToDate, Molecular Biotech, Helsinn, Soligenix and served on data safety monitoring board for Affimed. Dr Boh reported grants through the Tulane School of Medicine during the conduct of the study. Dr Duvic reported serving on the Soligenix scientific advisory board during the conduct of the study; and personal fees from Eisai, Bionz Consulting, and Bausch scientific advisory board outside the submitted work. Dr Huen reported grants from Kyowa Kirin, Trillium, Galderma, Innate, Eisai, and Seattle Genetics; and personal fees from Kyowa Kirin, Rhizen, Stemline, Helsinn, all outside the submitted work. Dr Querfeld reported advisory board fees from Helsinn, Kyowa Kirin, Mallinckrodt, Stemline, Helsinn, Celgene, and speaking fees from Helsinn, all outside the submitted work. Dr Wood reported serving on the scientific advisory board of Soligenix. Dr Rumage reported equity in Soligenix and a grant from the US National Cancer Institute (NCI), outside the submitted work. Dr Schaber reported a grant from NCI during the conduct of the study and being the co-investor and holding a patent for the hypericin process. Dr Straube reported a grant from NCI during the conduct of the study. Dr Pullion reported personal fees from Soligenix outside the submitted work. Dr Rook reported serving on the scientific advisory board of Soligenix and speaking fees from Mallinckrodt. No other disclosures were reported.
Funding/Support: The research was sponsored
© 2022 American Medical Association. All rights reserved.
- Lymphoma, T-Cell, Cutaneous/drug therapy
- Middle Aged
- Mycosis Fungoides/pathology
- Ointments/therapeutic use
- Perylene/analogs & derivatives
- Photochemotherapy/adverse effects
- Photosensitizing Agents/adverse effects
- Skin Neoplasms/pathology
- Treatment Outcome
PubMed: MeSH publication types
- Research Support, Non-U.S. Gov't
- Randomized Controlled Trial
- Multicenter Study
- Clinical Trial, Phase III
- Journal Article