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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 P 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

The CCR4-directed monoclonal antibody mogamulizumab has been shown to significantly improve progression-free survival and overall response rate compared with vorinostat in adults with relapsed/refractory mycosis fungoides (MF) and Sezary syndrome (SS). One of the most common adverse events seen with mogamulizumab in MF/SS patients is rash. Because of the protean nature of MF/SS and the variable clinical and histopathological features of mogamulizumab-associated rash, healthcare providers may have difficulty distinguishing rash from disease, and may not be aware of appropriate treatment strategies for this generally manageable adverse event. The objective of this report was to combine results from published literature with experiences and recommendations from multiple investigators and institutions into clinical best practice recommendations to assist healthcare providers in identifying and managing mogamulizumab-associated rash. Optimal management, which includes biopsy confirmation and steroid treatment, requires a multidisciplinary approach among oncology, dermatology, and pathology practitioners. INFOGRAPHIC.

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.

Background Tissue culture and histopathology are the conventional diagnostic modalities for skin and soft tissue infections (SSTIs), but few studies have investigated their concordance. Objective Determine concordance between histopathology and tissue culture in the diagnosis of suspected SSTIs. Methods Single-center retrospective study of 355 cases with suspected SSTIs identified from the dermatology inpatient consultation log January 2014-July 2017. Results Overall concordance between histopathology testing and tissue culture results was high (76.1%). Concordance was high for cases defined as no evidence of infection, fungal infection and mycobacterial infection by histopathology (77.8%, 74.2%, and 80.0%) and tissue culture (92.1%, 67.7%, and 83.3%). Concordance was lower for suspected SSTIs with bacterial infection by histopathology (61.9%) and tissue culture (28.4%). Concordance rates were not significantly affected by age, sex, race, antimicrobial agent use, immunologic status, or biopsy size. Limitations Retrospective and single-institution nature of the study. Conclusion This study demonstrated a high concordance between histopathology and tissue culture in SSTIs with no clinical evidence of infection and suspected fungal and mycobacterial SSTIs, though concordance was lower for suspected SSTIs with evidence of bacterial infection. Clinicians should not be deterred from relying on initial histopathological results based on patients’ immunosuppressed status, antimicrobial agent use, age, or biopsy tissue size.

BACKGROUND Given the severe symptom burden and chronic nature of mycosis fungoides (MF) and Sezary syndrome (SS), effective assessment of quality of life (QoL) is essential to guiding patient-centred care in this population. In this study, we aim to provide a comprehensive assessment of QoL in early- and advanced-stage MF/SS and to assess the correlation of traditional measures of clinical severity with QoL measures. METHODS Between July 2017 and April 2019, outpatients at an academic medical centre with either MF/SS (n = 115) or general dermatology concerns (n = 115) completed generic and dermatology-specific QoL instruments [Health Utilities Index Mark 3 (HUI3), RAND 36-Item Short-Form Health Survey (SF-36), Skindex-29, visual analogue scale for itch (VAS itch) and 5-D pruritus scale]. The mean scores of MF/SS patients were compared to that of controls using multivariable regression models adjusted for demographics and medical comorbidities. Cluster analysis of the QoL instruments and clinical severity measures (e.g. stage and body-surface-area involvement) was performed. RESULTS Patients with MF/SS scored significantly worse than controls on all QoL instruments used, with advanced-stage (IIB-IVB) disease having the worst QoL impairment. Early-stage (IA-IIA) and advanced-stage MF/SS patients had significantly reduced overall health status (HUI3; P

Background Although it is relatively common after hematopoietic cell transplant (HCT), graft-vs-host disease (GVHD) is a rare complication following solid organ transplantation (SOT). Methods This study evaluated skin biopsy specimens from five cases of SOT GVHD, 15 cases of HCT GVHD, and 15 cases of cutaneous drug eruption. Immunohistochemical staining for CD3, CD4, CD8, T-bet, and GATA-3 was performed to examine the density and immune phenotype of skin-infiltrating lymphocytes. Results Similar to HCT GVHD, the predominant histopathologic findings in skin biopsy specimens of SOT GVHD were widespread vacuolar interface dermatitis with scattered necrotic keratinocytes. However, the density of dermal inflammation was considerably higher in SOT GVHD. Features that were more predictive of a cutaneous drug eruption over GVHD included spongiosis, confluent parakeratosis, and many eosinophils. Involvement of the hair follicle epithelium was seen in all three disorders. Both forms of cutaneous GVHD showed a predominance of Th1 (CD3+/T-bet+) lymphocytes within the inflammatory infiltrates. This shift was more pronounced in SOT GVHD, particularly among intraepidermal T-cells. Conclusions SOT GVHD shares many histopathologic features with HCT GVHD. However, SOT GVHD has a greater tendency to develop brisk lichenoid inflammation.

Background: Treatment for Cutaneous T Cell Lymphoma (CTCL) is generally not curative. Therefore, selecting a therapy that is both effective and tolerable is critical to clinical decision-making. Histone deacetylase inhibitors (HDACi), epigenetic modifier drugs, are commonly used but effective in only ~30% of patients. There are no predictive markers of HDACi response and the histone acetylation landscape in CTCL remains unmapped. We sought to identify pre-treatment molecular markers of resistance in CTCL that progressed on HDACi therapy. Methods: Purified T cells from 39 pre/post-treatment peripheral blood samples and skin biopsies from 20 patients were subjected to RNA-seq and ChIP-seq for histone acetylation marks (H3K14/9ac, H3K27ac). We correlated significant differences in histone acetylation with gene expression in HDACi-resistant/sensitive CTCL. We extended these findings in additional CTCL patient cohorts (RNA-seq, microarray), and using ELISA in matched CTCL patient plasma. Findings: Resistant CTCL exhibited high levels of histone acetylation, which correlated with increased expression of 338 genes (FC≥2, FDR

High-risk skin cancer is a rare, but severe, complication associated with discoid lupus erythematosus (DLE). Chronic scar, inflammation, ultraviolet radiation and immunosuppressive medications are proposed explanations for this heightened skin cancer risk; however, the exact mechanism driving skin carcinogenesis in DLE is unknown. The distinct co-localization of multiple independent skin cancers with areas of active inflammation in two DLE patients followed over eight years strongly suggested that lupus inflammation promotes skin carcinogenesis in DLE. To investigate this clinical observation, we subjected lupus-prone MRL/lpr and control (MRL/n) mice to a skin carcinogenesis protocol. Skin tumors developed preferentially within the cutaneous lupus inflammation without scarring in MRL/lpr mice (p < 0.01). The inflammation in MRL/lpr skin was characterized by the accumulation of T regulatory cells, mast cells, M2 macrophages, and markedly elevated TGF-β1 and interleukin (IL)-6 levels, which have been linked to tumor promotion. Importantly, tacrolimus treatment reduced skin inflammation and blocked cancer development in MRL/lpr mice (p = 0.0195). A similar tumor- promoting immune environment was detected in SCCs and the perilesional skin of cancer-prone DLE patients. Therefore, discoid lupus inflammation promotes skin cancer in high-risk DLE patients and blocking the inflammation may be critical for preventing this life-threatening complication of DLE.

RC is a consultant for Kyowa Kirin and served on an advisory board for Helsinn. JJS is a consultant for Kyowa Kirin, Takeda, Recordat, 4SC, Innate Pharma and Helsinn. She received a 1-year educational grant from Kyowa Kirin for work on quality of life in CTCL. She also has membership on an entity’s Board of Directors or advisory committees for Kyowa Kirin, Takeda, 4SC, Innate Pharma, Miragen and Helsinn. PLZ has received honoraria from MSD, Celltrion, Gilead, Janssen-Cilag, BMS and TG Therapeutics. He is also a consultant for MSD, EUSA Pharma, Sanofi and Verastem. He also has membership on an entity’s Board of Directors or advisory committees for MSD, Eusa Pharma, Celltrion, Gilead, Janssen-Cilag, BMS, Servier, Sandoz, Immune Design, Celgene, Portola, Roche, Kyowa Kirin, TG Therapeutics, and Verastem. He has also been on a Speakers Bureau for MSD, EUSA Pharma, Celltrion, Gilead, Janssen-Cilag, BMS, Servier, Immune Design, Celgene, Portola, Roche, Kyowa Kirin and Verastem. JPN has received honoraria from Pharmaceutical Industries, TEVA, Novartis AG, Biogen GmbH, Almirall Hermal AG, Actelion Pharmaceuticals, UCB Pharma, LaRoche Posay, Takeda Pharmaceuticals and Kyowa Kirin. He is also a consultant for Novartis AG, Biogen GmbH, Almirall Hermal AG, Actelion Pharmaceuticals, Innate Pharma, Kyowa Kirin and Takeda Pharmaceuticals. He has also received grants and personal fees from Pharmaceutical Industries outside of the submitted work. LS is a consultant for Dren Bio and served on an advisory board for Kyowa Kirin, Kymera Therapeutics and EUSA Pharma. LP-B has been an advisory board for Epizyme, Morphosys, Helsinn, Verastem and Actelion. She is also a consultant for Acrotech. PQ has received honoraria from Actelion, Innate Pharma, Takeda, Kyowa Kirin, Helsinn and Therakos. He also been on an advisory board for Actelion, Innate Pharma, Takeda, Kyowa Kirin, Helsinn and Therakos. LI has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by AbbVie, Almirall, Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Centocor, Eli Lilly, Janssen-Cilag, Kyowa Kirin, LEO Pharma, MSD, Novartis, Pfizer, Sun Pharma and UCB. RD is a consultant for Merck Sharp & Dohme, Novartis, Bristol-Myers Squibb, Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym and Second Genome. AM is an investigator for Menlo, Soligenix, Pfizer, Elorac and miRagen. She has also received honoraria from Kyowa Kirin. She also has a membership on an entity’s Board of Directors or advisory committees for Helsinn. FF has received honoraria from Seagen, Mallinckrodt and Kyowa Kirin. She is also a consultant for Miragen. She had also served on a Data Safety Monitoring Board for Celgene. She was also the President of the US Cutaneous Lymphoma Consortium. TI is an employee of Kyowa Kirin, Inc. J-PR is an employee of Kyowa Kirin, Inc. MCM is an employee of Kyowa Kirin, Inc.

Psoriasis is a chronic inflammatory condition that affects patients of all skin colors. Biologic therapies, first approved for psoriasis in the early 2000s, have ushered in a new era of treatments for moderate to severe psoriasis and psoriatic arthritis. Non-Caucasian patients have a lower prevalence of psoriasis (1.9% in Blacks, 1.6% in Hispanics, and 1.4% in other races) compared to Caucasians (3.6%),1 but often present with worse disease severity.2 Yet, little is known about the utilization of biologic therapies versus traditional therapies in patients of color. To address this gap in knowledge, we sought to determine rates of biologic medication use in Black and other minority races compared to Caucasians.

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.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.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.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.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.

As an academic clinician, keeping abreast of the fast-changing world of science is a great challenge. This challenge is more acute for those of us who teach medical students and dermatology residents. The prospect of delving into the primary scientific literature is daunting, and in the setting of a busy clinical practice, nearly impossible. Science changes fast, and it can be embarrassing to present outdated explanations of scientific techniques to audiences that are likely to notice. Thus, access to concise, accurate, and updated descriptions of scientific methodology is critical for teaching. Research Techniques Made Simple (RTMS) helps immensely with this process. I routinely use content from RTMS in my educational lectures because it helps me to stay informed, gives me confidence that my lecture is accurate and updated, and provides my audience with a background on scientific topics that they need to fully understand my lectures.

BACKGROUND Cutaneous T-cell lymphoma (CTCL) negatively impacts quality of life (QoL), but existing QoL questionnaires may not comprehensively reflect patients' experience. OBJECTIVES To identify the aspects of QoL that are most meaningful to patients with CTCL and to evaluate existing QoL instruments in this context. METHODS Semistructured interviews were conducted between May and June 2019 using purposive sampling of patients with CTCL. Data were analysed by an inductive thematic approach using Dedoose Version 8.0.35. RESULTS One-on-one interviews lasting a median of 43 min were completed by 18 patients [median age 62 years (interquartile range 52-70); 39% advanced-stage (IIB-IV)]. Itch was the most common clinical symptom reported (16 of 18 patients), followed by pain (12 of 18), skin breaks (11 of 18) and skin flaking (10 of 18). Eleven patients reported that their symptoms interfered with sleep, which impacted daily functioning. Patients also noted a lack of understanding of the disease in the community and felt uncertain (12 of 18), depressed (11 of 18), suicidal (four of 18) and hopeless (nine of 18). Nearly all patients (17 of 18) reported a sense of 'otherness' (not feeling 'normal' or 'like themselves'), and most patients (16 of 18) specifically mentioned concern about their physical appearance. Patients also noted substantial treatment burden. Salient patient concerns, including individual clinical symptoms, concern about appearance and problems with sleep, were not adequately or consistently represented in generic, skin-specific or CTCL-specific QoL measures. CONCLUSIONS Incorporating the concerns and priorities that distinguish patients with CTCL from other patient populations will be of paramount importance in developing a comprehensive CTCL-specific measure of QoL that adequately captures patients' experience.

Importance Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a spectrum of severe mucocutaneous drug reaction associated with significant morbidity and mortality. A previously developed SJS/TEN-specific severity-of-illness model (Score of Toxic Epidermal Necrolysis [SCORTEN]) has been reported to overestimate and underestimate SJS/TEN-related in-hospital mortality in various populations. Objective To derive a risk prediction model for in-hospital mortality among patients with SJS/TEN and to compare prognostic accuracy with the SCORTEN model in a multi-institutional cohort of patients in the United States. Design, Setting, and Participants Data from a multicenter cohort of patients 18 years and older treated for SJS/TEN between January 1, 2000, and June 1, 2015, were obtained from inpatient consult databases and electronic medical record systems at 18 medical centers in the United States as part of the Society for Dermatology Hospitalists. A risk model was derived based on data from 370 of these patients. Model discrimination (calculated as area under the receiver operating characteristic curve [AUC]) and calibration (calculated as predicted vs observed mortality, and examined using the Hosmer-Lemeshow goodness-of-fit statistic) were assessed, and the predictive accuracy was compared with that of SCORTEN. All analysis took place between December 2016 and April 2018. Main Outcomes and Measures In-hospital mortality. Results Among 370 patients (mean [SD] age 49.0 [19.1] years; 195 [52.7%] women), 54 (15.14%) did not survive to hospital discharge. Five covariates, measured at the time of admission, were independent predictors of in-hospital mortality: age in years (odds ratio [OR], 1.05; 95% CI, 1.02-1.07), body surface area (BSA) in percentage of epidermal detachment (OR, 1.02; 95% CI, 1.01-1.04), serum bicarbonate level below 20 mmol/L (OR, 2.90; 95% CI, 1.43-5.88), active cancer (OR, 4.40; 95% CI, 1.82-10.61), and dialysis prior to admission (OR, 15.94; 95% CI, 3.38-66.30). A severity-of-illness score was calculated by taking the sum of 1 point each for age 50 years or older, epidermal detachment greater than 10% of BSA, and serum bicarbonate level below 20 mmol/L; 2 points for the presence of active cancer; and 3 points for dialysis prior to admission. The score was named ABCD-10 (age, bicarbonate, cancer, dialysis, 10% BSA). The ABCD-10 model showed good discrimination (AUC, 0.816; 95% CI, 0.759-0.872) and calibration (Hosmer-Lemeshow goodness of fit test, P = .30). For SCORTEN, on admission, the AUC was 0.827 (95% CI, 0.774-0.879) and was not significantly different from that of the ABCD-10 model (P = .72). Conclusions and Relevance In this cohort of patients with SJS/TEN, ABCD-10 accurately predicted in-hospital mortality, with discrimination that was not significantly different from SCORTEN. Additional research is needed to validate ABCD-10 in other populations. Future use of a new mortality prediction model may provide improved prognostic information for contemporary patients, including those enrolled in observational studies and therapeutic trials.

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a rare, severe mucocutaneous reaction with few large cohorts reported. This multicenter retrospective study included patients with SJS/TEN seen by inpatient consultative dermatologists at 18 academic medical centers in the United States. A total of 377 adult patients with SJS/TEN between January 1, 2000 and June 1, 2015 were entered, including 260 of 377 (69%) from 2010 onward. The most frequent cause of SJS/TEN was medication reaction in 338 of 377 (89.7%), most often to trimethoprim/sulfamethoxazole (89/338; 26.3%). Most patients were managed in an intensive care (100/368; 27.2%) or burn unit (151/368; 41.0%). Most received pharmacologic therapy (266/376; 70.7%) versus supportive care alone (110/376; 29.3%)-typically corticosteroids (113/266; 42.5%), intravenous immunoglobulin (94/266; 35.3%), or both therapies (54/266; 20.3%). Based on day 1 SCORTEN predicted mortality, approximately 78 in-hospital deaths were expected (77.7/368; 21%), but the observed mortality of 54 patients (54/368; 14.7%) was significantly lower (standardized mortality ratio = 0.70; 95% confidence interval = 0.58-0.79). Stratified by therapy received, the standardized mortality ratio was lowest among those receiving both steroids and intravenous immunoglobulin (standardized mortality ratio = 0.52; 95% confidence interval 0.21-0.79). This large cohort provides contemporary information regarding US patients with SJS/TEN. Mortality, although substantial, was significantly lower than predicted. Although the precise role of pharmacotherapy remains unclear, co-administration of corticosteroids and intravenous immunoglobulin, among other therapies, may warrant further study.

Granulomatous dermatitis (GD) describes disorders in which mixed inflammatory infiltrates composed primarily of histiocytes invade the skin. The pathogenesis of GD is unknown; however, GD has been noted to occur in areas previously affected by trauma, sun damage, or infection.1 When GD presents at the same site of a healed, unrelated skin disease, it falls within the category of a Wolf's isotopic response.2 The regional restriction of a Wolf's isotopic response is proposed to occur due to an area of localized immunocompromise known as an immunocompromised district.3 This immunocompromised district is believed to result from various types of cutaneous damage that hinder lymph circulation, like chronic regional lymphedema or prior herpes virus infection (eg, varicella zoster virus [VZV] and herpes simplex virus [HSV]).3 Postherpetic isotopic response (PHIR) is the most commonly reported isotopic response, and more cases of PHIR-GD have been reported than any other type of isotopic response.3 It can occur within the same dermatomal distribution either immediately after primary lesion resolution (VZV>HSV) or many years later.3 Persistent VZV DNA has been detected in PHIR lesions within 4 weeks after an acute episode4, 5 but not after 7 weeks.6, 7 The presence of viral DNA in some lesions has led to the proposal that VZV glycoproteins (gpI/II) may still be expressed at a sufficient level to initiate granuloma formation.8 Since the first report of granuloma annulare (GA) as an isotopic response,9 38% of the 32 cases have been reported in the setting of immunocompromise.10 We now add 5 unreported cases and 16 literature cases (not reviewed in prior meta-analyses) of immunocompromised PHIR-GD. Our review of the literature has also added 23 cases of nonimmunocompromised PHIR-GD. Our analysis of 33 immunocompromised and 43 immunocompetent cases highlights PHIR-GD associations with immunocompromise, chronic lymphocytic leukemia (CLL), and male sex.

Background Cutaneous squamous cell carcinoma (cSCC) is not uncommon in association with indolent malignancies that were treated with prior radiotherapy and after allogenic bone marrow transplantation. On the other hand, cutaneous T-cell lymphoma (CTCL) is a subtype of non-Hodgkin’s lymphoma which is characterized by an indolent course, with relative refractoriness to conventional chemotherapies and radiotherapy, and occasionally referred for allogeneic hematopoietic cell transplantation (allo-HCT). Recently, the use of immune checkpoint inhibitors has gained attention in the treatment of both cutaneous squamous cell carcinoma and hematological malignancies. However, many patients with hematological malignancies eventually undergo allo-HCT, raising the concern of potential adverse events (graft versus host disease) due to manipulation of the immune system with use of checkpoint inhibitors. Case presentation We describe a patient with relapsed refractory CTCL (Sézary Syndrome) who underwent allo-HCT with persistence of disease post-transplant. The patient additionally developed a progressively worsening lesion on the right shoulder which was biopsied and showed poorly differentiated carcinoma (cSCC). Pembrolizumab was started for the treatment of cSCC. After second cycle of treatment, the cSCC lesion responded dramatically to the use of immune checkpoint inhibitor. Also, the patient experienced significant resolution of pruritus and generalized erythema. During 24 months of follow up after initial treatment with checkpoint inhibition immunotherapy, the patient showed durable response of both cSCC and CTCL, as well as restoration of full donor chimerism, without obvious worsening of graft versus host disease (GVHD). Conclusion This is the first case to our knowledge of rapid and durable response of both cSCC and CTCL to immune checkpoint inhibition after allo-HCT. Although this report highlights the potential for significant response to this class of medication, further studies are required to confirm the efficacy and safety of this approach in patients with CTCL after allo-HCT given the potential concern of GVHD.

Background MAVORIC was a phase 3, open-label, multi-center, randomized controlled trial that evaluated the safety and efficacy of mogamulizumab compared with vorinostat in patients with relapsed/refractory mycosis fungoides (MF) or Sézary syndrome (SS) (NCT01728805). Mogamulizumab-associated rash was the second most common TEAE of any cause or grade in the mogamulizumab treatment arm and the most common TEAE leading to treatment discontinuation, resulting in a discontinuation rate of 7% (13/184). Grade 1-2 and 3 drug rashes occurred in 20% (36/184) and 4% (8/184) of mogamulizumab-treated patients, respectively. The objectives of this analysis were to describe histopathological and other characteristics of drug rash in patients who received mogamulizumab in MAVORIC. Methods In MAVORIC, 372 patients were randomized 1:1 to receive either intravenous mogamulizumab at 1.0 mg/kg once weekly for Cycle 1 (28 days) and then on days 1 and 15 of subsequent cycles or oral vorinostat at 400 mg daily. Confirmed overall response rate (ORR; complete response + partial response) was based on a global composite response involving all four disease compartments and verified at two consecutive visits. Guidance to investigators was provided in the protocol for evaluation and management of new drug rash on mogamulizumab treatment. Patients with an initial Grade 1 drug rash were allowed to continue treatment with use of topical steroids as needed. For patients with Grade ≥2 drug rash, mogamulizumab was temporarily stopped, and treatment of the drug rash with topical steroids was advised. Use of systemic steroids was prohibited during the study. Treatment could resume if the drug rash resolved to Grade ≤1 within 2 weeks. Biopsies were evaluated by an on-site pathologist, and a central blinded review was also conducted. Results This analysis included 44 patients who were treated with mogamulizumab and experienced drug rash during MAVORIC. Pathologically, central review assessed rashes as granulomatous, histiocytic spongiotic, lichenoid, eosinophilic, psoriasiform, or a combination of these patterns with no clear predominant histological pattern. Among the 44 patients with drug rash, 59.1% (26/44) were ≥65 years of age, and more patients with SS [56.8 (25/44)] than MF [43.2% (19/44]) experienced drug rash. Median (Q1, Q3) exposure among patients with drug rash was 344 days (162, 652) in patients with SS and 185 days (85, 463) in patients with MF. Mogamulizumab did not result in any cases of anaphylaxis or SJS/toxic epidermal necrolysis (TEN). Concomitant or immediate prior CTCL therapies that may make patients prone to drug rash were examined, and no trend toward increased incidence of drug rash was observed with any particular agent or class. The proportion of SS responders with drug rash was significantly higher than responders without rash (P=0.02; Figure 1); the proportion of MF responders with drug rash did not differ from responders without rash (P=0.21). Overall, the median (Q1, Q3) time to onset of drug rash was 106 days (36, 254). Initial drug rash occurred after response to mogamulizumab in 70% (14/20) of patients who experienced both. Thirty-five patients (80%) in the drug rash cohort resumed treatment with mogamulizumab upon resolution of initial drug rash per-protocol. After these patients resumed treatment, the median (Q1, Q3) duration of exposure to mogamulizumab was 183 days (58, 332). Conclusions Mogamulizumab-associated rashes displayed heterogeneous histopathology without one predominant feature; therefore, close correlation of suspected drug rash with clinical features is advised to differentiate it from disease progression. A trend toward higher rate of drug rash was observed in patients with SS, the group more likely to respond to mogamulizumab. Therefore, drug rash may be attributable to increased exposure, but rash may also involve underlying disease characteristics or treatment-induced immune alterations; further investigations are warranted. Nevertheless, the observation that 80% of patients on trial were able to continue mogamulizumab for >6 months following resolution of their initial rash suggests that appropriate evaluation, identification, and management of these reactions may prevent premature discontinuation. Disclosures Musiek: Kyowa Kirin: Honoraria; Helsinn: Honoraria; miRagen: Other: Investigator; Elorac: Other: Investigator; Soligenix: Other: Investigator. Horwitz:ASTEX: Consultancy; Affirmed: Consultancy; Vividion Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Corvus: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Portola: Consultancy, Research Funding; Beigene: Consultancy; C4 Therapeutics: Consultancy; Daiichi Sankyo: Research Funding; GlaxoSmithKline: Consultancy; Janssen: Consultancy; ADCT Therapeutics: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Kura Oncology: Consultancy; Miragen: Consultancy; Myeloid Therapeutics: Consultancy; Aileron: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Bagot:Helsinn/Recordati: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Huen:Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Galderma: Other: Travel expense reimbursement, Research Funding; miRagen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Helsinn: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Research Funding; Rhizen: Consultancy, Research Funding. Fisher:Dana-Farber Cancer Institute: Current Employment; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees. Haun:Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Karger, Inc.: Patents & Royalties: Textbook royalties. Vermeer:Kyowa Kirin: Consultancy, Research Funding; Takeda: Research Funding; PIQUR: Research Funding; Innate Pharma: Consultancy. Ito:Kyowa Kirin Pharmaceutical Development, Inc.: Current Employment. Dwyer:Kyowa Kirin Pharmaceutical Development, Inc.: Current Employment. Herr:Kyowa Kirin, Inc.: Current Employment. Kim:Elorac: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Corvus: Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Kyowa-Kirin Pharma: Research Funding; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Research Funding; Galderma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon Pharma: Consultancy, Research Funding; miRagen: Research Funding; Merck: Research Funding; Solingenix: Research Funding; Trillium: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Neumedicine: Consultancy, Research Funding; Portola: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Context: Topical steroids are a mainstay of treatment for patients with mycosis fungoides (MF) and Sezary syndrome (SS). Because patients undergoing mogamulizumab treatment likely also receive steroids, a thorough understanding of the safety/efficacy of their concomitant use is beneficial for physician decision-making. This post hoc analysis was designed to determine how many MAVORIC patients were treated with steroids and their impact on the safety/efficacy of mogamulizumab therapy. Design: MAVORIC ( NCT01728805 ) was an open-label, phase 3 trial in which patients with previously treated MF/SS were randomized 1:1 to mogamulizumab (1.0 mg/kg weekly for the first 28-day cycle, then Days 1 and 15 of subsequent cycles) or vorinostat (400 mg daily). Patients on a stable, low dose of corticosteroids could continue use, and investigators attempted tapering to the lowest tolerable dosage. Results: Steroid use occurred in the majority of patients (intent-to-treat [ITT] population: 67%, 249/372; mogamulizumab arm: 68%, 127/186; vorinostat arm: 66%, 122/186). Similar numbers of patients were treated with low-/intermediate-potency and high-potency steroids in each arm (mogamulizumab: 24% and 44%; vorinostat: 23% and 43%). Patients receiving mogamulizumab with concomitant steroids had longer median progression-free survival (PFS) relative to the ITT population (9.4 vs 7.7 months); however, in the vorinostat group, PFS was similar between groups (3.1 vs 3.1 months). Mogamulizumab also resulted in a higher overall response rate (ORR, confirmed complete response + partial response) in patients receiving concomitant steroids relative to those in the ITT population (37% vs 28%), whereas vorinostat ORR was similar between groups (3% vs 5%). For most disease stages, ORR was better in mogamulizumab-treated patients receiving concomitant steroids relative to those in the ITT population. Differences were also noted between mogamulizumab-treated patients receiving concomitant steroids and the ITT population within the skin (54% vs 42%) and blood compartments (73% vs 68%). No unexpected differences were reported in the AE profiles of patients with steroid use vs patients without steroid use and the ITT population. Conclusions: Concomitant steroid therapy, which likely mirrors regular clinical practice for patients with MF/SS, may be associated with increased patient benefit for mogamulizumab-treated but not vorinostat-treated patients. Funding: Kyowa Kirin.

Cutaneous T-cell lymphoma (CTCL) has been associated with considerable physical, psychological and financial burden. However, its impact on health-related quality of life (QoL) and economic costs are not well studied.To measure the QoL impact and financial burden of CTCL.A cross-sectional survey of 67 patients with CTCL was conducted using the Ontario Health Utilities Index Mark 3 (HUI3) questionnaire. Normative population data (n = 3310) were obtained from the 2002-2003 Joint Canada/United States Survey of Health. Economic cost was estimated using quality-adjusted life-year (QALY) loss derived from HUI3 scores.Patients with CTCL had significantly lower aggregate HUI3 scores than the general population (0·68 vs. 0·87, P 0·001). Multivariable regression analysis adjusting for demographics and comorbidities showed CTCL was associated with significantly poorer performance overall (-0·13, 95% CI -0·21 to -0·06, P 0·001) and in domains of speech (-0·03, 95% CI -0·05 to -0·01, P = 0·01), ambulation (-0·04, 95% CI -0·08 to 0·00, P = 0·03), emotion (-0·07, 95% CI -0·12 to -0·02, P = 0·01), and pain (-0·07, 95% CI -0·13 to -0·01, P = 0·03). These health utility decrements yielded an average loss of 1·48 QALYs per patient. Using a $50 000 per QALY willingness-to-pay threshold, CTCL was associated with an individual lifetime burden of $73 889 and U.S. societal burden of $2·86 billion.These findings suggest CTCL has a pervasive impact on QoL, comparable with debilitating conditions such as end-stage renal disease. The substantial economic burden of CTCL underscores the potential societal benefit of prompt diagnosis and effective management. What's already known about this topic? Cutaneous T-cell lymphoma is associated with physical, psychological and financial burden. What does this study add? The overall quality-of-life impact of cutaneous T-cell lymphoma has not previously been measured using a generic health utility instrument. In this study, we compare the overall quality-of-life burden of patients with cutaneous T-cell lymphoma with that of other populations and calculate the economic burden of the disease.

Neuro-Sweet disease (NSD) should be considered in the differential diagnosis of recurrent aseptic meningoencephalitis; a thorough skin examination and early skin biopsy can facilitate diagnosis and early treatment for this steroid-responsive condition.

Context: MAVORIC was an open-label, multicenter, randomized phase 3 study evaluating the safety and efficacy of mogamulizumab compared to vorinostat in patients with previously treated mycosis fungoides (MF) or Sezary syndrome (SS) ( NCT01728805 ). Primary results have been reported based on a data cutoff date of December 31, 2016 (Kim Y, et al. Lancet Oncol 2018). The most common treatment-emergent adverse events (TEAEs) of any cause reported in patients randomized to mogamulizumab were infusion-related reaction (33.2%), drug eruption (23.9%), diarrhea (23.4%), and fatigue (23.4%). This report provides final safety results as of January 3, 2019. Design: Patients were randomized 1:1 to mogamulizumab 1.0 mg/kg administered intravenously on Days 1, 8, 15, and 22 of the first cycle and on Days 1 and 15 of subsequent cycles or to vorinostat 400 mg administered orally once daily. Patients receiving vorinostat could cross over to mogamulizumab upon progression or intolerable toxicity. Results: In total, 372 patients were randomized (mogamulizumab, 186; vorinostat, 186), and 370 received study drug and were included in the safety analysis (mogamulizumab, 184; vorinostat, 186). Median duration of follow-up was 34.5 months (range, 0.13-70.0) in the randomized part of the study. The type and frequency of all-cause TEAEs in both groups were consistent with those reported in the primary analysis. TEAEs that occurred at a higher frequency in the mogamulizumab vs vorinostat arm included infusion-related reaction (33.2% [61/184] vs 0.5% [1/186], respectively) and drug eruption (25.0% [46/184] vs 1.1% [2/186]); the majority (>80%) of these events were grade 1 or 2. Rates of discontinuation due to AEs were similar between treatment arms and in crossover patients (mogamulizumab, 21.7% [40/184]; vorinostat, 23.7% [44/186]; crossover, 25.9% [35/135]). The median [95% CI] overall survival was similar across treatment groups (57.17 months [43.2, -] for mogamulizumab and 58.37 [45.6, -] for vorinostat, not adjusted for crossover). Conclusions: This final safety analysis from the MAVORIC study in patients with previously treated MF and SS demonstrated that mogamulizumab was generally well tolerated. Longer follow-up and treatment exposure did not identify any new safety signals. Funding: Kyowa Kirin.

Cutaneous T-cell lymphomas (CTCL) are cancers of mature skin-homing T lymphocytes, but the molecular drivers remain poorly understood. We performed whole genome, exome, epigenome, bulk and single cell (sc) transcriptome analyses of serial peripheral blood, skin, and lymph node biopsies from 20 CTCL patients. Initial studies defined markers of therapy resistance and disease progression in pathways that mediate cell migration, cytokine signaling, and epigenetic regulation. Several were novel to CTCL, including BIRC5 (anti-apoptotic); RRM2 (cell cycle); CXCR4 and LAIR2 (migration). On average 7413 cells from 16 serial samples (>100,000 cells total) passed quality thresholds for scRNA- + TCR-seq. We used Seurat, dittoSeq, and SingleR for quality control, dimensionality reduction (TSNE/UMAP), clustering, marker detection, cell type inference, and visualizations, and confirmed the therapy-resistant expression patterns we previously identified, including LAIR2. TCR clonotypes confirmed patient-specific malignant cell populations and defined clonal changes in serial samples. Pseudotime analysis of serial samples with Slingshot identified significant changes in expression related to changes in therapy, particularly in chemokine, TNF, and NFKB signaling. We identified mutations in STAT3&5 in 3/10 and in epigenetic modifiers (KMT2C/D and DNMT3A) in 6/10 patients. Loss of DNMT3A perturbs T cell differentiation and causes leukemia/lymphoma in mouse models. DNMT3A deficiency and additional epigenetic alterations may be previously unrecognized “drivers” of CTCL. These studies define mechanisms of therapy resistance, map clonal evolution, and reveal novel mechanisms of pathogenesis and progression in CTCL.

Hematopoietic stem cell transplants (HSCTs) are used to treat a variety of conditions, including hematologic malignancies, bone marrow failure syndromes, and immunodeficiencies. Over 60,000 HSCTs are performed annually worldwide, and the numbers continue to increase. Indeed, as new conditioning regimens develop, more and more individuals, including those of older age, will be eligible for transplants. Nevertheless, although HSCTs are clearly a life-saving and necessary treatment for thousands of patients per year, there is still substantial morbidity and mortality associated with the procedure. Of note, skin eruptions in the post-HSCT period are frequent and often significantly reduce quality of life in recipients. Moreover, these cutaneous findings sometimes herald an underlying systemic condition, presenting possible opportunities for timelier intervention. Dermatologists therefore play a vital role in distinguishing life-threatening conditions from benign issues and prompting recognition of critical complications earlier in their course. This article aims to review the major dermatologic conditions occurring in the early post-HSCT period.

We present the case of a 65-year-old man with severe headaches and unilateral facial weakness, seen in consultation by the dermatology service to rule out primary cutaneous melanoma after brain imaging identified an enlarging mass within the right trigeminal (Meckel's) cave. Examination revealed only a pair of erythematous papules on the scalp, for which biopsy demonstrated metastatic papillary thyroid carcinoma. Further evaluation and subsequent thyroidectomy confirmed the origin of widespread internal disease, followed by definitive excision of scalp lesions and multimodal management of systemic involvement. Whereas presentation of metastasis to the skin is highly variable, a low threshold for biopsy may allow for histological identification of internal disease not otherwise considered in the clinical differential.

Cutaneous T-cell lymphomas are rare non-Hodgkin lymphomas with substantial morbidity and mortality in advanced disease stages. We compared the efficacy of mogamulizumab, a novel monoclonal antibody directed against C-C chemokine receptor 4, with vorinostat in patients with previously treated cutaneous T-cell lymphoma.In this open-label, international, phase 3, randomised controlled trial, we recruited patients with relapsed or refractory mycosis fungoides or Sézary syndrome at 61 medical centres in the USA, Denmark, France, Italy, Germany, the Netherlands, Spain, Switzerland, the UK, Japan, and Australia. Eligible patients were aged at least 18 years (in Japan, ≥20 years), had failed (for progression or toxicity as assessed by the principal investigator) at least one previous systemic therapy, and had an Eastern Cooperative Oncology Group performance score of 1 or less and adequate haematological, hepatic, and renal function. Patients were randomly assigned (1:1) using an interactive voice web response system to mogamulizumab (1·0 mg/kg intravenously on a weekly basis for the first 28-day cycle, then on days 1 and 15 of subsequent cycles) or vorinostat (400 mg daily). Stratification was by cutaneous T-cell lymphoma subtype (mycosis fungoides vs Sézary syndrome) and disease stage (IB-II vs III-IV). Since this study was open label, patients and investigators were not masked to treatment assignment. The primary endpoint was progression-free survival by investigator assessment in the intention-to-treat population. Patients who received one or more doses of study drug were included in the safety analyses. This study is ongoing, and enrolment is complete. This trial was registered with ClinicalTrials.gov, number NCT01728805.Between Dec 12, 2012, and Jan 29, 2016, 372 eligible patients were randomly assigned to receive mogamulizumab (n=186) or vorinostat (n=186), comprising the intention-to-treat population. Two patients randomly assigned to mogamulizumab withdrew consent before receiving study treatment; thus, 370 patients were included in the safety population. Mogamulizumab therapy resulted in superior investigator-assessed progression-free survival compared with vorinostat therapy (median 7·7 months [95% CI 5·7-10·3] in the mogamulizumab group vs 3·1 months [2·9-4·1] in the vorinostat group; hazard ratio 0·53, 95% CI 0·41-0·69; stratified log-rank p0·0001). Grade 3-4 adverse events of any cause were reported in 75 (41%) of 184 patients in the mogamulizumab group and 76 (41%) of 186 patients in the vorinostat group. The most common serious adverse events of any cause were pyrexia in eight (4%) patients and cellulitis in five (3%) patients in the mogamulizumab group; and cellulitis in six (3%) patients, pulmonary embolism in six (3%) patients, and sepsis in five (3%) patients in the vorinostat group. Two (67%) of three on-treatment deaths with mogamulizumab (due to sepsis and polymyositis) and three (33%) of nine on-treatment deaths with vorinostat (two due to pulmonary embolism and one due to bronchopneumonia) were considered treatment-related.Mogamulizumab significantly prolonged progression-free survival compared with vorinostat, and could provide a new, effective treatment for patients with mycosis fungoides and, importantly, for Sézary syndrome, a subtype that represents a major therapeutic challenge in cutaneous T-cell lymphoma.Kyowa Kirin.