Efficacy and Safety of Topical Hypericin Photodynamic Therapy for Early-Stage Cutaneous T-Cell Lymphoma (Mycosis Fungoides)

Abstract

ImportanceGiven 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).ObjectivesTo 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 ParticipantsThis 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.InterventionsIn 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 MeasuresThe 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.ResultsThe 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 RelevanceThe 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 RegistrationClinicalTrials.gov Identifier: NCT02448381

A Review of the Dermatologic Clinical Applications of Topical Photodynamic Therapy

“…Patients that received two and three 6-week hypericin-PDT treatment cycles had further improvements in index lesion response rates compared to a single treatment cycle of hypericin-PDT (49% after 3 cycles and 40% after 2 cycles vs 16% after 1 cycle; P < .001). 146 In phone interviews of patients treated with MAL-PDT for Stage 1A or 1B MF refractory to topical chemotherapies, patients reported a higher mean satisfaction score for MAL-PDT compared to topical chemotherapies (6.8 vs 4.8; P = .0271). 147 In addition, the study found that if patients were given a choice, 82% preferred MAL-PDT to topical chemotherapy.…”

An Update on Recent Advances of Photodynamic Therapy for Primary Cutaneous Lymphomas

“…Rook et al conducted a dose escalation of hypericin, showing that 0.25% yielded the best therapeutic response [ 66 ]. The FLASH phase 3 randomized controlled trial (NCT02448381) showed significant efficacy after 6 weeks of treatment in early-stage MF/CTCL [ 67 ]. The study engaged 39 academic and community centers and included 196 patients aged 18 years and older with stage IA, IB, or IIA MF.…”

“…There was a 40% increase in TLRR in patients who received two cycles of the treatment ( p < 0.001). The most-common treatment-related adverse events (AEs) were mild local skin reactions, and no drug-related serious AEs were reported [ 67 ]. NCT05380635 further explored the safety of the HyBryte™ (0.25% hypericin) ointment by monitoring the blood level and changes of the electrocardiograms, for which the result was not posted on the website.…”

Hypericin as a promising natural bioactive naphthodianthrone: A review of its pharmacology, pharmacokinetics, toxicity, and safety

“…In a FLASH phase 3 randomized clinical trial, a synthetic hypericin ointment (0.25%) obtained a favorable safety profile, and it exhibited satisfying efficiency in early‐stage patch and plaque mycosis fungoides‐cutaneous T‐cell lymphoma (Kim et al, 2022).…”