Immune-related adverse events associated with Mogamulizumab: a comprehensive review of the literature.

INTRODUCTION: Mogamulizumab is an anti-C-C chemokine receptor 4 antibody that is increasingly being used to treat T-cell malignancies such as cutaneous T-cell lymphoma, adult T-cell leukemia-lymphoma, and peripheral T-cell lymphoma. Because CCR4 is expressed on both malignant T-cells and regulatory T-cells (Tregs), mogamulizumab can be associated with increased immune-related adverse events (irAEs). While there is abundant literature on mogamulizumab-associated rash (MAR) and graft-versus-host disease (GVHD), other reported irAEs have not been collated into a single review. AREAS COVERED: This narrative review covers irAEs associated with mogamulizumab in patients with T-cell lymphomas, focusing on events other than MAR and GVHD. We searched PubMed and Google Scholar for case reports, case series, chart reviews, and clinical trials published from inception to March 2024. Identified events include alopecia, vitiligo, arthritis, psoriasis, myocarditis, myositis/polymyositis, hepatitis, and others. EXPERT OPINION: Mogamulizumab's ability to augment the host immune response through Treg depletion adds to its efficacy but has wide-ranging implications for autoimmunity across multiple organ systems, similar to immune checkpoint inhibitor therapy. Occurrence of irAEs may be associated with improved overall clinical response, although long-term follow-up studies are needed.

Chronic Graft-versus-Host Disease-Associated Muscle Cramps: Severity and Response to Immunomodulatory Therapies.

Muscle cramps in patients with chronic graft-versus-host disease (cGVHD) are common and associated with impaired quality of life and symptom burden. Muscle cramps are not currently captured in the 2014 National Institutes of Health (NIH) response criteria, and thus characterization and response to immunomodulatory therapies are lacking. The objective of this study was to characterize muscle cramp frequency, duration, and pain level in patients with steroid-refractory cGVHD undergoing extracorporeal photopheresis (ECP). A single-center cohort of patients who underwent ECP for the indication of steroid-refractory cGVHD with muscle cramps at treatment initiation were followed from April 2021 to April 2023. Of 22 patients receiving ECP for cGVHD during the study period, 9 (41%) had muscle cramps at ECP initiation (6 males [66%]; median age, 59 years; range, 25 to 66 years). Seven of these 9 patients (78%) had multiple organs involved, and 7 (78%) had severe disease by the NIH Global Severity scale. Over a median treatment duration of 28 weeks (range, 10 to 48 weeks), 8 patients (89%) had decreased frequency of muscle cramps from a median of 5 episodes per week (range, 3 per day to 2 per week) to a median of <1 episode per week (range, 1 per month to 3 per week). The pain and duration of muscle cramps were not changed meaningfully. The NIH Global Severity score remained unchanged in 6 patients (67%) and was improved in 3 patients (33%). Muscle cramping is a morbid feature of cGVHD that may be sensitive to change with standard immunomodulatory therapies. Muscle cramp frequency should be further validated as a response measure in cGVHD.

Changes to Registered and Pivotal Clinical Trials after the 2011 Tri-Societies Guidelines for Clinical Endpoints and Response Criteria in Mycosis Fungoides and Sézary Syndrome.

Guidelines for mycosis fungoides and Sézary syndrome clinical trials were published in 2011 to standardize endpoint criteria and trial design. Our retrospective cohort study of mycosis fungoides/Sézary syndrome clinical trials registered on ClinicalTrials.gov and pivotal trials supporting drug approvals and label extensions evaluates adherence to these guidelines. Sixty-three trials met our inclusion criteria. In a subpopulation of trials, mean adherence to the guidelines was approximately 60%. When comparing trials that began in the first 6 years after their publication with those that started after, we found no difference in mean adherence (4.12 vs 3.41) (P = .15). Among the 8 pivotal trials supporting new mycosis fungoides or Sézary syndrome systemic therapies from 1990 to 2020, systemic trials published after 2011 were more likely to randomize patients (100 vs 0%, P = .036), perform superiority testing (100 vs 0%, P = .036), and use an intention-to-treat analysis (100 vs 0%, P = .036). The design of trials registered on Clinicaltrials.gov did not change significantly between the first 6 years after the publication of the guidelines and after. This demonstrates that the guidelines are still not consistently implemented across all trials. However, registrational trials were more likely to implement the recommendations.

Structural mechanism of tapasin-mediated MHC-I peptide loading in antigen presentation.

Loading of MHC-I molecules with peptide by the catalytic chaperone tapasin in the peptide loading complex plays a critical role in antigen presentation and immune recognition. Mechanistic insight has been hampered by the lack of detailed structural information concerning tapasin-MHC-I. We present here crystal structures of human tapasin complexed with the MHC-I molecule HLA-B*44:05, and with each of two anti-tapasin antibodies. The tapasin-stabilized peptide-receptive state of HLA-B*44:05 is characterized by distortion of the peptide binding groove and destabilization of the ß2-microglobulin interaction, leading to release of peptide. Movements of the membrane proximal Ig-like domains of tapasin, HLA-B*44:05, and ß2-microglobulin accompany the transition to a peptide-receptive state. Together this ensemble of crystal structures provides insights into a distinct mechanism of tapasin-mediated peptide exchange.

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.

Management of relapsed cutaneous T-Cell lymphoma following allogeneic hematopoietic stem cell transplantation: Review with representative patient case.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment option for patients with refractory cutaneous T-cell lymphoma (CTCL) through replacement of the bone marrow responsible for lymphoma cells and possibly induction of a graft-versus-lymphoma effect. However, allo-HSCT is not always curative; relapse of CTCL occurs in about half of patients post-transplant. Treatment of relapsed CTCL after allo-HSCT is challenging because post-transplant patients are at high risk of graft-versus-host disease, and this condition may be precipitated or exacerbated by standard CTCL therapies. The benefit of each potential therapy must therefore be weighed against its risk of graft versus host disease (GVHD). In this article, we review the management of relapsed CTCL after allo-HSCT. We begin with an exemplative patient whose relapsed Sezary syndrome was successfully treated without development of GVHD. We also report high-throughput T-cell receptor sequencing data obtained during the patient's disease relapse and remission. We then review general guidelines for management of relapsed CTCL and summarize all reported cases and outcomes of relapsed CTCL after transplant. We conclude by reviewing the current CTCL therapies and their risk of GVHD.

Parapsoriasis-A Diagnosis with an Identity Crisis: A Narrative Review.

Parapsoriasis is an uncommon inflammatory skin disease characterized by chronic patches that may be resistant to therapy. It was primarily introduced and classified 120 years ago, and the original classification incorporated parapsoriasis and pityriasis lichenoides under the umbrella term parapsoriasis. After a major change in classification, parapsoriasis now exclusively refers to small plaque parapsoriasis (SPP) and large plaque parapsoriasis (LPP). However, debates still frequently occur regarding various nomenclatures and classifications used by different authors. Moreover, parapsoriasis may progress to overt cutaneous lymphoma, most commonly mycosis fungoides (MF), and it is very difficult to distinguish these two conditions despite modern histologic and molecular testing techniques.As parapsoriasis is a rare disease, there is a lack of studies and clinical guidelines to assist physicians in clinical practice. In our comprehensive review, we review several aspects of parapsoriasis, from the history of nomenclature and classification, clinical characteristics, immunohistopathology, and advanced molecular techniques for the diagnosis of this condition, to the most current treatments. We also propose a scheme for distinguishing parapsoriasis from early-stage MF in this review.

Antigen identification and high-throughput interaction mapping by reprogramming viral entry.

Deciphering immune recognition is critical for understanding a broad range of diseases and for the development of effective vaccines and immunotherapies. Efforts to do so are limited by a lack of technologies capable of simultaneously capturing the complexity of adaptive immunoreceptor repertoires and the landscape of potential antigens. To address this, we present receptor-antigen pairing by targeted retroviruses, which combines viral pseudotyping and molecular engineering approaches to enable one-pot library-on-library interaction screens by displaying antigens on the surface of lentiviruses and encoding their identity in the viral genome. Antigen-specific viral infection of cell lines expressing human T or B cell receptors allows readout of both antigen and receptor identities via single-cell sequencing. The resulting system is modular, scalable and compatible with any cell type. These techniques provide a suite of tools for targeted viral entry, molecular engineering and interaction screens with broad potential applications.

Integrative medicine use in patients with cutaneous T-Cell lymphoma: A cross-sectional survey study.

OBJECTIVES: To characterize patterns of integrative medicine (IM) use and health-related quality of life (HRQoL) in patients with cutaneous T-cell lymphoma (CTCL). DESIGN: Cross-sectional, online survey, created in conjunction with the Cutaneous Lymphoma Foundation (CLF). SETTING: A link to the online survey was posted on the CLF Facebook page and emailed to the CLF listserv; 372 survey responses were received. MAIN OUTCOME MEASURES: The study outcomes were IM use, cancer symptoms, and HRQoL measured via the Skindex-16 and Functional Assessment of Cancer Therapy-General (FACT-G). RESULTS: A total of 292 patient responses (66 % female, median age 59y) were included in analysis. 87 % had mycosis fungoides and 12 % had Sézary syndrome. A majority (59 %) of patients reported using IM for their CTCL, with 48 % using IM to treat their disease and 47 % using IM to manage their symptoms. The most commonly used IM were vitamins/minerals (32 %), prayer/meditation (26 %), diet (24 %), and exercise/yoga (22 %). Higher itch scores were reported by patients using IM compared to non-users (31 (IQR 10-62) and 18 (IQR 3-46) respectively; p = 0.002). HRQoL was worse among patients who reported IM use; median Skindex-16 scores were 54 (IQR 28-72) among IM users compared to 33 (IQR 19-57) for non-IM users (p < 0.001). CONCLUSIONS: IM use is common among patients with CTCL, particularly those with worse itching and worse HRQoL. IM interventions require further study given use by CTCL patients to treat disease and ameliorate symptoms.

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.

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.

BACKGROUND: Chlormethine/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. OBJECTIVE: Our 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. METHODS: This 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. RESULTS: In 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. CONCLUSIONS: This 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.

Brentuximab Vedotin for Relapsed or Refractory Sézary Syndrome.

Importance: Treatment options for Sézary syndrome (SS) are limited and associated with low response rates. Brentuximab vedotin is a CD30-directed antibody-drug conjugate approved for refractory CD30-positive cutaneous T-cell lymphoma. However, limited data exist on its efficacy in SS, including in the pivotal phase 3 ALCANZA (A Phase 3 Trial of Brentuximab Vedotin (SGN-35) Versus Physician's Choice [Methotrexate or Bexarotene] in Participants With CD30-Positive Cutaneous T-Cell Lymphoma) trial. Objective: To assess the preliminary efficacy and tolerability of brentuximab vedotin for SS. Design, Setting, and Participants: From January 1, 2017, to July 31, 2020, a total of 13 patients with SS received brentuximab vedotin and were analyzed as part of a retrospective case series. Median follow-up was 10.4 months (range, 1.4-34.6 months). All patients were 18 years or older with a diagnosis of SS and with B2 blood involvement at the time brentuximab vedotin therapy was initiated. This single-center study was conducted at a major academic referral center. Interventions: Intravenous brentuximab vedotin administration approximately every 3 weeks. Main Outcomes and Measures: The primary end point was the global response rate. Outcomes were assessed in the skin and lymph nodes per the 2011 European Organization for Research and Treatment of Cancer-International Society of Cutaneous Lymphoma response criteria and in the blood per the 2018 Prospective Cutaneous Lymphoma International Prognostic Index revised blood response criteria. Results: The study included 13 patients (8 [62%] male; mean [SD] age, 68.2 [8.6] years). Of these 13 patients, 5 (38%) achieved a global response after a median of 6 cycles, including 1 complete response. Response rates by disease compartment were 38% in the skin, 63% in the blood, and 50% in the lymph nodes. Three of 11 patients (27%) with pruritus reported improvement. Skin CD30 positivity (>10%) was detected in 9 patients but was not associated with responses. Among responders, the median time to response was 6 weeks (range, 6-9 weeks), and the median duration of response was 5.5 months (range, 2.5-28.9 months). The median time to next treatment was 3.2 months (range, 1.5-36.7 months). Peripheral neuropathy occurred in 4 patients but resolved in 2 patients. Grade 2 adverse events were neuropathy (n = 2), constipation (n = 1), and hand-foot syndrome (n = 1). Conclusions and Relevance: In this case series, brentuximab vedotin use was associated with some efficacy in SS across multiple disease compartments and in the setting of refractory disease or low CD30 skin expression. Brentuximab vedotin may offer a manageable treatment schedule and low incidence of significant toxic effects.

Evaluating the Treatment Patterns of Chlormethine/Mechlorethamine Gel in Patients With Stage I-IIA Mycosis Fungoides: By-time Reanalysis of a Randomized Controlled Phase 2 Study.

BACKGROUND: The pivotal 201 Study investigated chlormethine/mechlorethamine gel treatment for patients with early stage disease mycosis fungoides and demonstrated the treatment was not inferior to chlormethine ointment. However, overall response rates do not provide information about response patterns. The study objective was to assess the value of by-time analysis of clinical response data in visualizing response over time. METHODS: This post hoc analysis re-evaluated chlormethine efficacy using a by-time approach that investigated the trend to treatment response and permitted assessment of response, both monthly between 1 and 6 months, and once every 2 months between 7 and 12 months, over the course of 1 year. In addition, very good partial response was redefined as a ≥ 75% response. RESULTS: By-time analyses of Composite Assessment of Index Lesion Severity (CAILS) and modified severity-weighted assessment tool (mSWAT) showed response rates at 1 month (respectively, 8.5% and 5.9%) that increased over time to peak at 10 months (78.9% and 54.4%). Early, intermittent, and late response patterns were observed. In total, 32.5% of patients experienced very good partial response over 2 consecutive visits, indicating that ∼ 33% of patients could expect to have very good to complete response within 1 year. CONCLUSION: By-time analysis for clinical response provides complementary information to traditional overall response rate data regarding response peak time and changes over time.

Low-Dose Total Skin Electron Beam Therapy as Part of a Multimodality Regimen for Treatment of Sézary Syndrome: Clinical, Immunologic, and Molecular Analysis.

Importance: Sézary syndrome (SS) is an advanced form of cutaneous T-cell lymphoma with few long-term remissions observed. Objective: To profile 3 patients with SS who have experienced long-term remission following the addition of low-dose total skin electron beam therapy (TSEBT) to systemic regimens of extracorporeal photopheresis, bexarotene, and interferon-γ. Design, Setting, and Participants: This is a retrospective case series with additional investigations of patient-donated samples to assess therapeutic response. The study was conducted at the University of Pennsylvania Cutaneous Lymphoma Clinic and follows 3 patients with stage IVA1 CD4+ SS who presented to the clinic between November 1, 2009, and November 1, 2017, and who had a history of SS that was refractory to multimodality systemic therapy prior to receiving low-dose TSEBT. Interventions: Patients were treated in a multimodality fashion with combined extracorporeal photopheresis, bexarotene, interferon-γ, and low-dose TSEBT. Main Outcomes and Measures: To characterize treatment responses in these patients, the extent of skin disease was measured with the modified severity weighted assessment tool. Blood disease was measured with flow cytometric assessments of Sézary cell count, CD4:CD8 ratio, and high throughput sequencing of the T-cell receptors. To assess for restoration of immune function, we measured markers of immune exhaustion, including PD-1 (programmed cell death 1), TIGIT (T-cell immunoreceptor with immunoglobulin and ITIM domains), CTLA4 (cytotoxic T-lymphocyte-associated protein 4), TOX (thymocyte selection-associated high mobility group box protein), and Foxp3 (forkhead box P3) on circulating CD4 and CD8 T cells, along with production capacity of interferon-γ by lymphocytes following activation stimuli. Results: Following administration of low-dose TSEBT and maintenance of the other therapies, remissions ranged from 24 to 30 months, with complete responses in 2 patients ongoing. Markers of immune exhaustion including PD-1, TIGIT, CTLA4, TOX, and Foxp3 were significantly reduced from baseline following TSEBT, along with enhanced production capacity of interferon-γ by lymphocytes following activation stimuli. High throughput sequencing demonstrated near-complete eradication of the circulating clone among 2 of 3 patients with stable levels in 1. Conclusions and Relevance: We describe 3 patients who achieved long-term clinical and molecular remissions following low-dose TSEBT as part of a multimodality regimen for treatment of SS. As long-term remissions in SS are uncommon, this approach demonstrates promise, and clinical trials should be considered.

Cutaneous T-cell lymphoma and concomitant atopic dermatitis responding to dupilumab.

Cutaneous T-cell lymphoma (CTCL) represents a diagnostic challenge because of its large symptomatic overlap with other common skin conditions such as atopic dermatitis (AD) and psoriasis. Dupilumab has offered promising results in AD treatment; however, concerns exist that its use may exacerbate undiagnosed CTCL. We present a patient with CTCL and concomitant AD who experienced improvement in both CTCL blood involvement and AD following the addition of dupilumab therapy.