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).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.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.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.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.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.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.ClinicalTrials.gov Identifier: NCT02448381.
Data generated from the clinical trials, CITN-10 (NCT02243579) and CITN-13 (NCT03063632), analyzing the in vivo responses to anti-PD-1 monotherapy or anti-PD-1 interferon-gamma combination therapy in patients with advanced mycosis fungoides and sezary syndrome. Data include mass cytometry files of PBMCs, Olink serum targeted proteomics, Nanostring targeted bulk transcriptomics of tumor biopsies, CODEX imaging of tumor biopsies, and TCR sequencing from peripheral blood and tumor biopsies. Please direct correspondences to DRG or EWN.
Advanced-stage mycosis fungoides (MF; stage IIB to IV) and Sézary syndrome (SS) are aggressive lymphomas with a median survival of 1 to 5 years. Clinical management is stage based; however, there is wide range of outcome within stages. Published prognostic studies in MF/SS have been single-center trials. Because of the rarity of MF/SS, only a large collaboration would power a study to identify independent prognostic markers.
2511 Background: MRG-106 is an inhibitor of miR-155, a microRNA with a strong link to CTCL pathogenesis. The goals of this FIH study are to evaluate the safety, tolerability, PK, and efficacy of MRG-106 in mycosis fungoides (MF) patients (pts). Methods: This Ph 1 trial evaluated MRG-106 given via intralesional injection (75 mg/dose), subcutaneous or IV rapid bolus injection, or 2-hour IV infusion (300, 600 or 900 mg/dose). Pts must have MF stage I-III with plaques and/or tumors and could remain on concurrent stable CTCL therapy. Pts received 6 doses (SC/IV) in the first 26 days of the study followed by weekly or bi-weekly doses. Safety was monitored by physical exams, clinical lab tests, and reported adverse events (AEs). Efficacy was assessed by CAILS and by the modified Severity Weighted Assessment Tool (mSWAT). The effect of MRG-106 on quality of life was assessed by Skindex-29. Results: 36 subjects (20M/16F, median age 63 yrs) have been on study for up to 17 months (as of 25Jan2018). No serious AEs have been attributed to MRG-106. Most common AEs in ≥ 15% of subjects were: fatigue, neutropenia, injection site pain, nausea, pruritus, and headache. Two AEs were deemed DLTs: Gr3 worsening pruritus and Gr 3 tumor flare. MTD has not yet been reached. In the SC/IV cohorts, 26/29 evaluable subjects had improvement in mSWAT score. Skin improvements were observed as early as the first assessment (Day 17). Best improvements were after ≥ 1 month. All 8 pts (across all doses with SC or IV infusion) who achieved ≥ 50% reduction in mSWAT and received > 2 treatment cycles, maintained response for ≥ 4 months. 4/5 pts treated at the 300 mg IV infusion dose had ≥ 50% mSWAT improvement. The overall skin response in pts who received MRG-106 as monotherapy or MRG-106 with concurrent stable therapy were not significantly different. Reductions in Skindex-29 total score correlated to reductions in mSWAT score during the treatment phase. Conclusions: These preliminary results suggest that MRG-106 is well-tolerated, has clinical activity, and has potential to impact MF quality of life. These encouraging data support the continued investigation of MRG-106 in this population. The study is expanded to enroll pts with other hematologic malignancies in which miR-155 is elevated and relevant, including CLL, DLBCL, ATLL. Clinical trial information: NCT02580552.
Mogamulizumab demonstrated improved outcomes vs. vorinostat across a range of disease and patient characteristics in patients with mycosis fungoides or Sézary syndrome in the MAVORIC trial. This post-hoc analysis further examined MAVORIC data to assess factors associated with long-term response (ORR >12 months), time to next treatment (TTNT), and impact of concomitant steroid use, lymphopenia, and mogamulizumab-associated rash (MAR) on patient response. A higher proportion of patients achieved ORR lasting ≥4, 6, 8, or 12 months in the mogamulizumab vs. vorinostat arm. Long-term response was also observed in mogamulizumab-treated patients with more advanced disease (stage IVA1 [17/20], B2 blood involvement [18/20], and SS [14/20]). PFS was significantly longer (9.4 vs. 3.1 months; p < 0.0001) in mogamulizumab vs. vorinostat-treated patients taking concomitant steroids. Mogamulizumab-treated patients experienced longer TTNT vs. vorinostat. Lymphopenia and MAR were associated with response to mogamulizumab. MAVORIC demonstrated greater efficacy with mogamulizumab vs. vorinostat in relapsed/refractory patients with CTCL, including those with more advanced disease. Concomitant steroid use improved ORR and PFS but did not impact vorinostat outcomes. Overall responses occurred more frequently in mogamulizumab-treated patients that developed lymphopenia than those that did not. A higher percentage of patients with MAR had an overall response than those without MAR.
The PD-1 inhibitor pembrolizumab is effective in treating Sézary syndrome, a leukemic variant of cutaneous T-cell lymphoma. Our purpose was to investigate the effects of pembrolizumab on healthy and malignant T cells in Sézary syndrome and to discover characteristics that predict pembrolizumab response. Samples were analyzed before and after 3 weeks of pembrolizumab treatment using single-cell RNA-sequencing of 118,961 peripheral blood T cells isolated from six Sézary syndrome patients. T-cell receptor clonotyping, bulk RNA-seq signatures, and whole-exome data were integrated to classify malignant T-cells and their underlying subclonal heterogeneity. We found that responses to pembrolizumab were associated with lower KIR3DL2 expression within Sézary T cells. Pembrolizumab modulated Sézary cell gene expression of T-cell activation associated genes. The CD8 effector populations included clonally expanded populations with a strong cytotoxic profile. Expansions of CD8 terminal effector and CD8 effector memory T-cell populations were observed in responding patients after treatment. We observed intrapatient Sézary cell heterogeneity including subclonal segregation of a coding mutation and copy number variation. Our study reveals differential effects of pembrolizumab in both malignant and healthy T cells. These data support further study of KIR3DL2 expression and CD8 immune populations as predictive biomarkers of pembrolizumab response in Sézary syndrome.
8575 Background: CTCL is a heterogeneous group of non-Hodgkin lymphomas that arises in the skin (patches, plaques, tumors, and/or erythroderma) but can involve the lymph, blood, and/or viscera. Additionally, patients with cutaneous tumors or folliculotropic involvement typically have poor prognoses. Romidepsin is a histone deacetylase inhibitor approved by the US FDA for the treatment of patients with CTCL who have received ≥ 1 prior systemic therapy. Durable responses (objective response rate [ORR; complete [CR] + partial responses] of 34% and median duration of response of 15 mo) and tolerability with extended dosing have been reported. To examine responses to romidepsin in these less favorable prognostic subsets, patients with tumors or folliculotropic involvement in the pivotal study of romidepsin for the treatment of CTCL were analyzed. Methods: Patients with CTCL (N = 96) who had ≥ 1 prior systemic therapy received romidepsin 14 mg/m2on days 1, 8, and 15 every 28 days. Responses were determined by a rigorous composite endpoint that included changes in the skin, blood, and lymph. Patients with cutaneous tumors or folliculotropic involvement were identified by reviewing diagnosis and histology reports. Results: Of 96 patients with CTCL, 20 had tumors, and 10 had folliculotropic involvement (2 had both). All but 2 patients with tumors and 1 with folliculotropic involvement achieved ≥ stable disease (SD) with romidepsin (Table). Time to response and DOR ranged from 0.9-4.7 mo and 1.4-18.7+ mo, respectively, for patients with tumors and 1.0-8.3 mo and 2.1-5.0+ mo for patients with folliculotropic involvement. Discontinuation due to an adverse event occurred in 1 patient with tumors (fatigue) and 0 with folliculotropic involvement. Conclusions: In the pivotal study of romidepsin for the treatment of CTCL, patients with cutaneous tumors or folliculotropic involvement commonly responded to therapy. Additionally, despite rapid onset of response, patients with tumors rarely discontinued romidepsin due to adverse events, with the longest duration of response ongoing at 18.7 mo. Clinical trial information: NCT00106431. Best response, n (%) Tumors (n = 20) Folliculotropic involvement (n = 10) ORR 9 (45) 6 (60) CR 2 (10) 1 (10) SD 9 (45) 3 (30)
