Cutaneous T-cell Lymphoma Mycosis Fungoides Research Articles

Prevalence, tropism, and activity of cutavirus in circulating blood lymphocytes, stool, and skin biopsy specimens of patients with cutaneous T-cell lymphoma and parapsoriasis en plaques.

A significant association has been established between a newly emerging human parvovirus, cutavirus (CuV), and cutaneous T-cell lymphoma/mycosis fungoides (CTCL/MF) and its precursor parapsoriasis en plaques (PP). CTCL is a heterogeneous group of skin malignancies of T cells, the cause of which remains unknown. This study aimed to determine the activity, spread, and cell tropism of the skin-persistent CuV. CuV DNA was detected in both skin biopsies (6/20, 30%) and peripheral blood mononuclear cells (PBMCs) (4/29, 13.8%) from 49 CTCL/MF or PP patients, while none from 33 patients with any other type of skin disease or healthy subjects harbored CuV DNA. CuV DNA persisted in the skin or PBMCs for up to 15 years, despite circulating CuV-specific IgG. Spliced CuV mRNA was expressed in skin, indicating viral activity. Also, both of two available stool samples contained encapsidated CuV genomes, suggesting that the patients excrete infectious virus into the environment. Finally, CuV was observed to target circulating and skin-resident CD4 + T cells and some skin keratinocytes and macrophages. This is especially intriguing as malignant T cells in CTCL develop from CD4 + T cells. Hence, CuV should be further investigated for the overall role it plays in the complex tumor microenvironment of CTCL/MF.

P-190 - Evaluating the impact of a novel multidisciplinary mycosis fungoides cutaneous T-cell lymphoma clinic day on patient care

P-190 - Evaluating the impact of a novel multidisciplinary mycosis fungoides cutaneous T-cell lymphoma clinic day on patient care

Chlormethine Gel for the Treatment of Mycosis Fungoides Cutaneous T-Cell Lymphoma: In Vitro Release and Permeation Testing.

IntroductionThe DNA-alkylating agent chlormethine (CL, or mechlorethamine) is approved in several countries worldwide as a 0.016% w/w topical CL gel formulation, to treat mycosis fungoides cutaneous T-cell lymphoma, with a positive benefit/risk ratio.MethodsRelease profiles of CL from the gel and a compounded ointment-based 0.016% CL formulation were compared via in vitro release testing (IVRT), utilizing static diffusion cells, a pseudo-infinite dose, and polytetrafluoroethylene membranes, over 5 h. The percutaneous absorption profile of CL gel in ex vivo human skin was also examined, using in vitro permeation testing (IVPT) with flow-through diffusion cells, dermatomed skin (epidermis plus dermis) and epidermal membranes, a finite dose, over 24 h.ResultsIn IVRT experiments, the mean ± SD CL release rate was significantly higher for the gel versus the ointment (5.70 ± 0.73 versus 2.38 ± 1.03 μg/cm2/√h); the formulations were inequivalent per the US Food and Drug Administration scale-up and postapproval changes for nonsterile semisolid dosage forms (FDA SUPAC-SS) criteria. Mean IVPT cumulative CL (gel) permeating through epidermal membrane was higher than for dermatomed skin (4.6% versus 2.5% of applied dose). Mean residual CL on the epidermal membrane surface was 1.3% of the applied dose.ConclusionsCL gel (0.016%) and ointment were inequivalent, with an optimized release profile, suggesting minimal passage of CL gel through human epidermal tissue to the dermis.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13555-022-00813-y.

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

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.

Feasibility of Deriving Health State Utilities in Mycosis Fungoides Cutaneous T-Cell Lymphoma Using Mapping Algorithms.

BackgroundA prospective, observational, US-based study (PROVe) used three questionnaires (Pruritus-VAS, Skindex-29, MF/SS-CTCL QoL) to assess quality of life in patients diagnosed with mycosis fungoides cutaneous T-cell lymphoma (MF-CTCL); however, none of these studies was provided with a preference-based algorithm yielding health state utility values (HSUVs).ObjectiveThis study aimed to assess the feasibility of deriving HSUVs from published mapping algorithms by comparing mapped utilities with the HSUVs reported in the MF-CTCL literature.MethodsWe searched PubMed, the School of Health and Related Research Health Utility Database (ScHARRHUD), and the Health Economics Research Centre (HERC) database of mapping studies (version 7.0) to identify any studies mapping Pruritus-VAS, Skindex-29, or MF/SS-CTCL QoL to a preference-based instrument (ideally, EQ-5D), and any studies assessing HSUVs in MF-CTCL. Two algorithms from a recent study that mapped Pruritus-VAS onto EQ-5D-3L were applied to the PROVe patient-level data. We performed multiple imputation to handle missing VAS data, calculated average mapped utilities in the whole sample, and compared them with relevant factors using the t-test and one-way analysis of variance (ANOVA).ResultsOverall, 298 patients provided 1441 Pruritus-VAS scores over a 2-year follow-up (1–21 visits per patient). The average mapped HSUVs ranged between 0.950 and 0.999 depending on the algorithm applied and imputation of missing data. In subgroup analysis, significant differences (p < 0.05) were observed according to age, race, and cancer stage. A few previous studies that collected HSUVs from MF-CTCL patients reported mean values of between 0.82 and 0.87 using time trade-off, 0.63 and 0.83 using EQ-5D, and 0.51 and 0.69 using the HUI3.ConclusionsThe HSUVs derived by applying published mapping algorithms to PROVe Pruritus-VAS data appeared largely overestimated if compared with the existing literature. More research is required to understand the applicability of existing mapping algorithms and to develop new mapping algorithms in MF-CTCL.Supplementary InformationThe online version contains supplementary material available at 10.1007/s41669-022-00326-6.

Roles of OX40 and OX40 Ligand in Mycosis Fungoides and Sézary Syndrome.

Mycosis fungoides (MF) and Sézary syndrome (SS), the most common types of cutaneous T-cell lymphoma (CTCL), are characterized by proliferation of mature CD4+ T-helper cells. Patients with advanced-stage MF and SS have poor prognosis, with 5-year survival rates of 52%. Although a variety of systemic therapies are currently available, there are no curative options for such patients except for stem cell transplantation, and thus the treatment of advanced MF and SS still remains challenging. Therefore, elucidation of the pathophysiology of MF/SS and development of medical treatments are desired. In this study, we focused on a molecule called OX40. We examined OX40 and OX40L expression and function using clinical samples of MF and SS and CTCL cell lines. OX40 and OX40L were co-expressed on tumor cells of MF and SS. OX40 and OX40L expression was increased and correlated with disease severity markers in MF/SS patients. Anti-OX40 antibody and anti-OX40L antibody suppressed the proliferation of CTCL cell lines both in vitro and in vivo. These results suggest that OX40–OX40L interactions could contribute to the proliferation of MF/SS tumor cells and that the disruption of OX40–OX40L interactions could become a new therapeutic strategy for the treatment of MF/SS.

134 Percutaneous Absorption of Chlormethine Gel in Human Skin: In Vitro Permeation Testing

The synthetic DNA-alkylating agent chlormethine (CL, or mechlorethamine) is commercially available as 0.016% CL gel purposely developed and indicated to treat mycosis fungoides cutaneous T-cell lymphoma, with a positive benefit/risk ratio. This study evaluated the permeation of CL from gel formulation via in-vitro permeation testing (IVPT) using ex vivo human skin (dermatomed and epidermal membrane) mounted on flow-through cells. Healthy barrier-competent skin, harvested from elective abdominal surgeries, was either dermatomed to a thickness of 500μm (real skin ∼2000μm) or separated into epidermal membranes. Skin samples were mounted on to flow-through diffusion cells designed to mimic physiological/anatomical skin in situ. CL gel was applied to the surface at 10mg/cm2 and receptor solution samples were automatically collected every 2h postdose for 24h. Liquid chromatography-tandem mass spectrometry was used to quantify mean cumulative CL (ng/cm2), CL flux rates (ng/cm2/h) and residual CL from skin surface (ng). In dermatomed skin (1 donor; 7 replicates) and epidermal membrane (3 donors; 7 replicates), CL in receptor solution rose from 2h postdose to plateau at ∼8–10h. Mean cumulative CL that permeated through dermatomed skin and epidermal membrane were 40ng/cm2 (2.5% of applied dose) and 73ng/cm2 (4.6% of applied dose), respectively after 24h. Mean CL flux through dermatomed skin and epidermal membranes was 5.2ng/cm2/h peaking at ∼4h and 10.8ng/cm2/h peaking at ∼2h, respectively. Mean residual CL from the skin surface of epidermal membranes at 24h was 21ng (1.3% of applied dose). No residual CL was detectable from the dermatomed skin surface. This IVPT demonstrates CL 0.016% gel permeation profiles were similar for dermatomed skin and epidermal membrane. However, CL gel appeared to deliver more CL with a higher CL flux in epidermal membrane than dermatomed skin, suggesting that minimal CL levels pass through epidermal tissue and reach dermal tissue.

A Little Experience Goes a Long Way: Chlormethine/Mechlorethamine Treatment Duration as a Function of Clinician-Level Patient Volume for Mycosis Fungoides Cutaneous T-Cell Lymphoma (MF-CTCL)-A Retrospective Cohort Study.

Topical chlormethine yields high response rates in mycosis fungoides cutaneous T-cell lymphoma with early discontinuation often attributed to skin reactions. We evaluated over 4,000 patients and found an association of clinician case volume with treatment duration and early discontinuation of chlormethine gel. The minority of clinicians with high patient volume markedly outperformed clinicians with only few patients on both outcome parameters, yet case volume as low as five patients seemed to mark a threshold for avoiding early discontinuation of treatment regimen.

Chlormethine Gel for the Treatment of Skin Lesions in All Stages of Mycosis Fungoides Cutaneous T-Cell Lymphoma: A Narrative Review and International Experience.

Mycosis fungoides (MF), the most common form of primary cutaneous T-cell lymphoma, is a disease typically with an indolent course that is initially characterized by localized patches and plaques. In the early stages of the disease, treatment involves skin-directed therapies (SDTs) such as topical corticosteroids and retinoids. Chlormethine gel (also known as mechlorethamine) was the first SDT purposely developed to treat MF and is currently endorsed by international guidelines for the treatment of adult patients with MF as a first-line therapy. While chlormethine is an efficacious therapy, its usage may be complicated by the development of cutaneous reactions at the sites of application. Herein, we discuss the supportive guidelines for MF and the suitability of chlormethine as a therapeutic option in patients with MF. In addition, we present real-world experience on the use of chlormethine gel from clinics in the USA, Israel, and France with the aim of demonstrating the efficacy of chlormethine gel in routine clinical practice and outlining strategies that are being used to manage emergent cutaneous reactions.Infographic

The PROVe Study: US Real-World Experience with Chlormethine/Mechlorethamine Gel in Combination with Other Therapies for Patients with Mycosis Fungoides Cutaneous T-Cell Lymphoma

BackgroundChlormethine/mechlorethamine gel is a skin-directed therapy for patients with mycosis fungoides cutaneous T-cell lymphoma. Currently, real-world data on chlormethine gel are lacking.ObjectiveOur objective was to analyze the effect of chlormethine gel in combination with other therapies on efficacy, safety, and health-related quality of life in a real-world setting.MethodsThis prospective, observational study enrolled adult patients actively using chlormethine gel. Patients were monitored for up to 2 years during standard-of-care clinic visits. No specific visit schedules or clinical assessments, with the exception of patient-completed questionnaires, were mandated because of the expected variability in practice patterns. The primary efficacy endpoint was the proportion of patients with stage IA–IB disease receiving chlormethine + topical corticosteroids + other with ≥ 50% decrease in body surface area from baseline to 12 months. Response was assessed at each visit using by-time analysis, which investigates the trend to treatment response and allows assessment of response over time. Health-related quality of life was assessed with the Skindex-29 questionnaire.ResultsIn total, 298 patients were monitored. At 12 months post-treatment initiation, 44.4% (chlormethine + topical corticosteroids + other) and 45.1% (patients receiving chlormethine + other treatment) of efficacy-evaluable patients were responders. By-time analysis demonstrated that peak response occurred (chlormethine + other; 66.7%) at 18 months. There was a significant correlation between responder status and lower post-baseline Skindex-29 scores.ConclusionsThis real-world study confirmed that chlormethine gel is an important therapeutic option for patients with mycosis fungoides and contributes to reducing the severity of skin lesions and improving health-related quality of life.Infographic

Lack of Systemic Absorption of Topical Mechlorethamine Gel in Patients with Mycosis Fungoides Cutaneous T-Cell Lymphoma

Lack of Systemic Absorption of Topical Mechlorethamine Gel in Patients with Mycosis Fungoides Cutaneous T-Cell Lymphoma

Single Institutional Experience on Cutaneous Manifestation of Adult T-cell Leukemia/Lymphoma - Potential Diagnostic Pitfall

Abstract Introduction/Objective Adult T-cell Leukemia/Lymphoma (ATLL) is an aggressive peripheral T-cell neoplasm caused by the human T-cell lymphotropic virus-1 (HTLV1). Approximately half of the patients diagnosed with ATLL have heterogeneous cutaneous manifestations and 1/3 of those patients have skin changes e.g. rashes, papules, and nodules at initial presentation. There is clinical and morphologic overlap between ATLL and other cutaneous T-cell neoplasms such as Cutaneous T-Cell Lymphoma/mycosis fungoides (CTCL/MF) which could pose a potential diagnostic challenge. Methods A retrospective study was conducted using PathNet system to search for HTLV1 positive ATLL patients. Clinicopathologic features of the patients with cutaneous involvement were analyzed. Results Total 31 patients with ATLL were identified. Nine patients (29%, median 54.5 years, range 47-67 years, male: female ratio 2:7) showed skin manifestations, and the cutaneous involvement with ATLL was confirmed by skin biopsy. Five (55.5%, 5/9) cases were initially misdiagnosed as CTCL/MF. Among the 5 patients, 2 presented with skin rash or diffuse erythematous patch/plaque before developing generalized lymphadenopathy or overt circulating atypical lymphocytosis; 2 developed severe pruritic rash with erythematous skin changes resembling Sezary syndrome; and 1 patient had folliculotrophic MF diagnosed 12 years before. Notably, atypical lymphocytosis (0.46- 41.19/µL) occurred in 3 of the 4 remaining cases. In addition, eight of the 9 patients displayed a variable level of CD3+/CD4+/ CD25strong+ abnormal T-cells on flow cytometry. A low-level bone marrow involvement (2-10%) was found in 8 of 9 cases. Elevated calcium levels were identified in 3 of 9 cases (33%). There were 7 of 8 patients (87.5%) who developed generalized lymphadenopathy when diagnosis of ATLL was rendered. Conclusion In patients with cutaneous manifestations, features including hypercalcemia, atypical lymphocytosis, lymphadenopathy, CD3/CD4/strong CD25 coexpression, and bone marrow involvement should prompt a test for HTLV1. Early diagnosis of ATLL can initiate proper treatment and improve patient clinical outcomes.

833 No detectable systemic absorption of topically applied 0.02% and 0.04% chlormethine (CL) gel in patients with mycosis-fungoides cutaneous T-cell lymphoma (MF-CTCL)

833 No detectable systemic absorption of topically applied 0.02% and 0.04% chlormethine (CL) gel in patients with mycosis-fungoides cutaneous T-cell lymphoma (MF-CTCL)

REACH: Study to Determine the Aetiology of Chlormethine Gel Induced-skin Drug Reaction in Early Stage Mycosis Fungoides Cutaneous T Cell Lymphoma (MF-CTCL)

REACH: Study to Determine the Aetiology of Chlormethine Gel Induced-skin Drug Reaction in Early Stage Mycosis Fungoides Cutaneous T Cell Lymphoma (MF-CTCL)

Successful Treatment of CNS Involvement in Cutaneous T-Cell Lymphoma Mycosis Fungoides (P2.6-009)

Successful Treatment of CNS Involvement in Cutaneous T-Cell Lymphoma Mycosis Fungoides (P2.6-009)

Prognostic Significance of Serum Copper in Patients With Cutaneous T-cell Lymphoma

BackgroundSerum copper has been reported to be increased in various cancers, including lymphoma. The purpose of the present study was to investigate the clinical and prognostic importance of serum copper levels in patients with cutaneous T-cell lymphoma (CTCL). Patients and MethodsSerum copper was measured in 60 men and 38 women with mycosis fungoides (MF) and 14 men and 3 women with erythrodermic CTCL (6 with Sézary syndrome) consecutively evaluated from July 1980 to June 1985. ResultsA greater than normal copper level was present in nearly 20% of patients and was associated with an increased risk of disease progression and shortened disease-specific survival for patients with patch or plaque phase MF, but not for those with tumor phase MF or erythrodermic CTCL. In contrast, the serum lactate dehydrogenase level and neutrophil/lymphocyte ratio were not significantly associated with prognosis in our patient cohort. ConclusionThe reason for the association between the high serum copper levels and adverse prognosis is unknown. We hypothesized that interleukin-6 is secreted primarily by non-neoplastic cells at MF skin sites, leading to release of copper by the liver. Local production of interleukin-6 at the lesion sites might conceivably also promote neoplastic cell progression by stimulation of the STAT3 pathway. Further studies on the relationship between activated tumor-associated macrophages, serum copper levels, interleukin-6, or C-reactive protein and prognosis might be informative.

108 - Efficacy and quality of life (QoL) in patients with mycosis fungoides cutaneous T-cell lymphoma (MF-CTCL) treated with chlormethine gel and other therapies: results from the PROVe study

108 - Efficacy and quality of life (QoL) in patients with mycosis fungoides cutaneous T-cell lymphoma (MF-CTCL) treated with chlormethine gel and other therapies: results from the PROVe study

021 - Clinician-level variation in mechlorethamine treatment duration in mycosis fungoides cutaneous T-cell lymphoma (MF-CTCL)

021 - Clinician-level variation in mechlorethamine treatment duration in mycosis fungoides cutaneous T-cell lymphoma (MF-CTCL)

082 - Efficacy of chlormethine gel in patients with stage I–IIA mycosis fungoides cutaneous T-cell lymphoma (MF-CTCL): re-analysis of a randomized phase 2 study

082 - Efficacy of chlormethine gel in patients with stage I–IIA mycosis fungoides cutaneous T-cell lymphoma (MF-CTCL): re-analysis of a randomized phase 2 study

Phase 1 Trial of Cobomarsen, an Inhibitor of Mir-155, in Cutaneous T Cell Lymphoma

Background:Cobomarsen (MRG-106) is an inhibitor of miR-155, a microRNA with a strong link to cutaneous T cell lymphoma (CTCL) pathogenesis. The goals of this first in human study are to evaluate the safety, tolerability, pharmacokinetics, and efficacy of cobomarsen in mycosis fungoides (MF) patients.Methods:This Phase 1 trial evaluated cobomarsen given via intralesional injection (75 mg/dose), subcutaneous (SC), IV rapid bolus injection, or 2-hour IV infusion (300, 600 or 900 mg/dose). Patients must have MF stage I-III with plaques and/or tumors and could remain on concurrent stable CTCL therapy. Patients received 6 doses, either subcutaneous or intravenous, in the first 26 days of the study followed by weekly or bi-monthly 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 cobomarsen on quality of life was assessed by Skindex-29.Results:38 subjects receiving IV or SC treatment (25 male/13 female, median age 59 years) have been on study for up to 22 months. As of the data cut off, no serious AEs have been attributed to cobomarsen. The most common AEs reported in greater than 15% of subjects were: fatigue, neutropenia, injection site pain, nausea, pruritus, and headache. Two AEs were deemed dose limiting toxicities (DLTs): Grade 3 worsening pruritus and Grade 3 tumor flare. The maximum tolerated dose (MTD) has not yet been reached.In the subcutaneous and IV cohorts, 29 out of 32 (91%) evaluable subjects had improvement in mSWAT score. Skin improvements were observed as early as the first assessment (Day 17). The best improvements were observed after more than 1 month of treatment. Eleven out of twenty-one (52%) patients receiving more than one month of dosing (6 doses) achieved greater than 50% reduction in mSWAT score. The mean duration of response (n=11) was 213 days, as of data cut off. Eight patients achieved a partial response meeting the criteria for ORR4, an objective response rate lasting at least four months in duration.The overall skin response in patients who received cobomarsen as monotherapy or cobomarsen with concurrent stable therapy were not significantly different. Improvement in quality of life (QOL), as measured by the Skindex-29 total score, correlated with reductions in mSWAT score during the treatment phase.Conclusions:These results demonstrate that cobomarsen is well-tolerated, has clinical activity, and has the potential to impact MF quality of life. These encouraging data support the continued investigation of cobomarsen in the CTCL population. The study is expanded to enroll patients with other hematologic malignancies in which miR-155 is elevated and relevant, including chronic lymphocytic leukemia (CLL), diffuse large B cell lymphoma (DLBCL), and adult T cell lymphoma/leukemia (ATLL). Final safety and efficacy data on CTCL mycosis fungoides will be presented. DisclosuresFoss:Seattle genetics: Consultancy; Miragen: Consultancy, Speakers Bureau; Spectrum: Consultancy; Mallinkrodt: Consultancy.