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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

Keywords: CTCL classifications; CTCL, cutaneous T-cell lymphoma; LDH, lactate dehydrogenase; MF, mycosis fungoides; SS, Sezary syndrome; Sezary syndrome; T cell; WBC, white blood cell; clinical cases; leukemic progression; lymphoma; medical dermatology; mycosis fungoides. Conflict of interest statement Dr Dummer reports intermittent, project-focused consulting and/or advisory relationships with Novartis, Merck Sharp and Dhome, Bristol-Myers Squibb, Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, and Alligator outside the submitted work. Dr Ramelyte reports intermittent, project-focused consulting and/or advisory relationships with Amgen, Novartis, Sanofi, Pierre Fabre, and Sun Pharma outside the submitted work. Dr Kim reports grants and personal fees from Actelion and 10.13039/501100009754Galderma; personal fees from Helsinn and Almirall; and grants from 10.13039/501100004628MedImmune, Kyowa Kirin, and Soligenix outside the submitted work. Drs Maredia, Cozzio, and Rozati have no conflicts of interest to declare.

The number of patients with primary cutaneous lymphoma (PCL) relative to other non-Hodgkin lymphomas (NHLs) is small and the number of subtypes large. Although clinical trial guidelines have been published for mycosis fungoides/Sézary syndrome, the most common type of PCL, none exist for the other PCLs. In addition, staging of the PCLs has been evolving based on new data on potential prognostic factors, diagnosis, and assessment methods of both skin and extracutaneous disease and a desire to align the latter with the Lugano guidelines for all NHLs. The International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous LymphomaConsortium (USCLC), and the Cutaneous Lymphoma Task Force of the European Organization for the Research and Treatment of Cancer (EORTC) now propose updated staging and guidelines for the study design, assessment, endpoints, and response criteria in clinical trials for all the PCLs in alignment with that of the Lugano guidelines. These recommendations provide standardized methodology that should facilitate planning and regulatory approval of new treatments for these lymphomas worldwide, encourage cooperative investigator-initiated trials, and help to assess the comparative efficacy of therapeutic agents tested across sites and studies.

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.

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.

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.

Background: Chlormethine gel (also known as mechlorethamine) is a skin-directed therapy approved for the treatment of early-stage mycosis fungoides-type cutaneous T-cell lymphoma (MF-CTCL). In previously published data, topical steroids and phototherapy were found to be commonly used by patients treated with chlormethine gel. Post-hoc analyses on the PROVe study were carried out to describe the specific treatment sequence and timing of these concomitant therapies and chlormethine gel in a real-world setting among MF-CTCL patients. Methods: Data analyzed derives from the observational PROVe study using US-based registry of MF-CTCL patients treated with chlormethine gel and enrolled across 46 centers between March 2015 and October 2018. Patients were followed for up to 2 years after chlormethine gel initiation. Due to the observational nature of the study, patients had visits at irregular intervals. Information on patient demographics, medical history, clinical characteristics, ongoing treatments for MF-CTCL and response were collected. Concomitant use of chlormethine gel with topical steroids or phototherapy were assessed using treatment start and stop dates recorded in the registry, and descriptive statistics were calculated. Results: A total of 298 eligible patients were analyzed with a mean ± standard deviation (SD) age of 61±13 years. Approximately 60% were males, 69% had Stage IA/IB and their duration of MF-CTCL was 4.8±6.5 years at chlormethine gel initiation. A total of 186 (85%) reported concomitant use of topical steroids with chlormethine gel during the study period. Of these 186 patients, 138 (74%) patients were already using steroids prior to chlormethine gel initiation, 14 (8%) started chlormethine gel and steroids on same day and the remaining 34 (18%) added steroids later. A total of 81 (27%) reported concomitant use of phototherapy with chlormethine gel during the study period. Of these 81 patients, 67 (83%) patients were already on phototherapy prior to chlormethine gel initiation and the remaining 14 (17%) initiated phototherapy later. Conclusions: Among the patients with concomitant therapies, the majority had started steroids or phototherapy and then added chlormethine gel. These observations suggest that in real life settings, combination treatments are standard practice as physicians expect improved outcomes with an acceptable tolerability profile.

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.

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.

Background: Chlormethine gel is a skin-directed therapy approved in US for daily treatment of stage IA/IB mycosis fungoides-type cutaneous T-cell lymphoma (MF-CTCL). Based on a previous study it has been observed that the alternative treatment schedules and the schedule changes may benefit patients by improving tolerability and response to treatment [ 1 ]. This study was carried out to better understand schedule changes before and after achieving partial response (PR) and effect of maintenance therapy i.e., continuing treatment with chlormethine gel after achieving PR, in a real-world setting among MF-CTCL patients. Methods: Data is derived from the observational PROVe study using US-based registry of MF-CTCL patients treated with chlormethine gel in combination with other treatments between March 2015 and October 2018. Patients were enrolled across 46 centers and were followed for up to 2 years. Information on patient demographics, clinical characteristics, treatments received for MF-CTCL (including chlormethine gel, topical steroids, phototherapy, radiation therapy, chemotherapy, retinoids and other topical). Responses were collected at enrollment and ongoing visits with no specific visit schedules or clinical assessments due to expected variability in practice patterns. Episodes of treatments with chlormethine gel with start date, stop date and schedule changes were recorded and analyzed. Partial response (PR) was defined as either ≥50% improvement in body surface area (BSA) at least once from gel initiation to the end of study participation or based on the clinical assessment of the physician. For those who achieved PR and following the date of PR, deepening response was defined as achieving either ≥10% additional improvement in BSA (i.e., 60% or more improvement in BSA after achieving 50% improvement at the time of PR) or achieving complete response based on the clinical assessment by physician. Descriptive statistics were reported for schedule changes and maintenance therapy with chlormethine gel. Results: Of 298 eligible patients with mean age 61±13 years, 60% were males, and 69% had clinical stage IA/IB. A total of 222 (75%) patients achieved PR following chlormethine gel initiation and during study period. Of these 222, 81% patients did not change their schedule prior to achieving PR and 61% were on a daily schedule immediately prior to PR. Of 203 patients receiving maintenance chlormethine gel post PR, 153 (75%) maintained, 29 (14%) reduced and 24 (12%) increased their dosing schedule in the post-PR period as compared to their schedule prior to PR. Of these 203, 53 (26%) later achieved deepening response. Conclusions: 75% of the patients received maintenance therapy with chlormethine gel in combination with other therapies and continued with the same schedule after PR. The study results suggest that continuing maintenance therapy and adjusting chlormethine gel dosing schedule may contribute to deepen treatment responses.

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 Sezary 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 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.

Diagnosis and management of mycosis fungoides and Sézary syndrome (MF/SS) require accurate clinicopathological correlation and a multidisciplinary approach. We reviewed major advances in the field regarding diagnostic and prognostic tools as well as skin-directed therapies (SDTs) and systemic agents for MF/SS published in the past 2 years.Improved technology (T-cell receptor high-throughput sequencing) and increased multicenter collaboration (Cutaneous Lymphoma International Consortium) have led to diagnostic/prognostic advances. Concurrently, numerous genomic studies have enhanced understanding of disease pathogenesis. Advances in SDTs include topical resiquimod, a novel potent Toll-like receptor (TLR) agonist; consensus CTCL phototherapy guidelines; and use of low-dose radiation therapy. Novel systemic therapies for advanced disease of note include targeted antibody drug conjugates (brentuximab vedotin), immune checkpoint inhibitors, and allogeneic hematopoietic stem cell transplantation (HSCT). Our "toolbox" to diagnose and treat the spectrum of MF/SS continues to expand. Further characterization of genomic data going forward will enable a rational approach to selecting and combining therapies to improve patient care.

Loss of CD26 surface expression on the circulating malignant T-cell is the most widely accepted diagnostic marker in patients with leukemic cutaneous T-cell lymphoma (CTCL). CTCL cases with reemergence of CD7 and/or CD26 surface expression are unusual and of uncertain prognosis. We report the case of an erythrodermic leukemic mycosis fungoides patient who had achieved temporary remission after several months on multimodality immunotherapy and extracorporeal photopheresis, but who relapsed with aggressive disease phenotypically characterized by CD4+ T-cells with high CD26 expression. Polymerase chain reaction studies and high-throughput sequencing analyses from peripheral blood mononuclear cells at presentation and relapse consistently showed an identical clonal T-cell receptor suggesting evolution of her original malignant clone which lacked CD26 expression. Interestingly, quantitative expression of the sialomucin, CD164, mirrored her clinical picture, thus favoring its reliability as a novel biomarker in CTCL.

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.

Retinoids are natural and synthetic vitamin A analogs with effects on cell proliferation, differentiation, and apoptosis. They have significant activity in hematologic malignancies and have been studied extensively in cutaneous T-cell lymphoma. Retinoids bind to nuclear receptors and exert their effects through moderation of gene expression. Retinoic acid receptor and retinoic X receptor exert regulatory activity in vivo, binding to distinct ligands. Studies investigating systemic retinoids as monotherapy and in combination with other agents active against cutaneous lymphoma are reviewed. Side effects associated with retinoids include teratogenicity, dyslipidemias, and hypothyroidism, which should be carefully monitored in patients receiving treatment.

Purpose Brentuxiumab vedotin (BV) is an anti-CD30 monoclonal antibody-drug conjugate approved in 2011 for treating anaplastic large cell and Hodgkin lymphomas. The product label indicates that three BV-treated patients developed progressive multifocal leukoencephalopathy (PML), a frequently fatal JC-virus induced central nervous system infection. Prior immunosuppressive therapy and compromised immune systems were postulated risk factors. We report 5 patients who developed BV-associated PML, including two immunocompetent patients.

Although more common with advanced age, the entire spectrum of benign and malignant cutaneous lymphoproliferative disorders can present in the pediatric population. Nevertheless, these conditions are often mistaken for other more common, benign dermatoses, resulting in delayed diagnosis. Standardized management of these conditions is also lacking. The purpose of this review is to provide an update on the most common benign and malignant cutaneous lymphoproliferative disorders in children: pityriasis lichenoides and mycosis fungoides. The presentation, evaluation and management of each of these conditions are discussed.

Mycosis fungoides (MF) and Sezary syndrome (SS) comprise the majority of cutaneous T-cell lymphomas (CTCLs). Despite the rarity of these diseases, new insights into the epidemiology and pathophysiology of MF/SS are rapidly emerging that should lead to improved diagnosis and treatment. Here we discuss updates on MF/SS incidence, prognosis and survival, clinical variants, disease biomarkers, pathophysiology, genetics, and disease progression.

Amaral and Garbe discuss the impressive developments in targeted therapy for non-melanoma skin cancers (NMSCs) such as basal cell carcinoma and squamous cell carcinoma [1]. Systemic targeted therap...

Folliculotropic mycosis fungoides (MF) is a rare variant of cutaneous T-cell lymphoma with distinct clinical and histological features that is less responsive to therapy than the classic epidermotropic subtype of MF (1, 2). At any given stage, the folliculotropic variant has a worse prognosis than the epidermotropic variant. Due to the (peri) follicular nature of the neoplastic cells in folliculotropic MF, the T-cell infiltrate is thought to be too deep for penetration of many skin-directed treatments. Topical monotherapy is not currently recommended in the current National Comprehensive Cancer Network (NCCN) (3) guidelines as a mainstay treatment option even in patients with a low burden of disease. There is limited evidence that carmustine topical therapy (also known as bis-chlorethylnitrosourea or BCNU) may be beneficial in the treatment of folliculotropic MF. In this study, we hypothesized that topical carmustine would be a safe and effective treatment option for patients with stages I–III folliculotropic MF.

Cutaneous T-cell lymphomas most commonly have a CD4(+) memory T-cell phenotype with relatively indolent course, but may in rare cases present with a CD8(+) cytotoxic phenotype exhibiting strikingly more aggressive clinical behavior. We present two cases of the clinically aggressive subtype of primary cutaneous epidermotropic CD8(+) cutaneous T-cell lymphoma and review the current literature, clinical behavior, and recommendations for treatment distinct from that of more common CD4(+) variants of cutaneous T-cell lymphoma.

PURPOSE OF REVIEW Cutaneous T-cell lymphomas (CTCLs) are a heterogenous group of non-Hodgkin's lymphomas characterized by atypical, skin-homing T lymphocytes and have varying prognoses depending on subtype and disease stage. Numerous therapeutic options exist; however, many patients experience refractory disease and novel treatments are needed. RECENT FINDINGS This review will highlight selected advances in CTCL treatment over the past year (2007-2008). Discoveries regarding the pathophysiology of mycosis fungoides and Sezary syndrome, the two most common CTCL types, have led to an expansion of new treatments and an increase in experience with multimodality therapy continues to increase. A number of reports have examined both combination regimens of currently available CTCL therapies as well as treatments approved for other dermatologic or oncologic conditions. Also, several novel skin-directed treatments and systemic compounds have been studied in all CTCL stages as well as in treatment-refractory disease. SUMMARY There remains a continued impetus to develop and amass experience with new therapeutic options for CTCL, particularly for patients with advanced stage and treatment-refractory disease.

Cutaneous T cell lymphomas (CTCLs) are a heterogenous group of lymphoproliferative disorders caused by clonally derived, skin-invasive T cells. Mycosis fungoides (MF) and Sezary syndrome (SS) are the most common types of CTCLs and are characterized by malignant CD4(+)/CLA(+)/CCR4(+) T cells that also lack the usual T cell surface markers CD7 and/or CD26. As MF/SS advances, the clonal dominance of the malignant cells results in the expression of predominantly Th2 cytokines, progressive immune dysregulation in patients, and further tumor cell growth. This review summarizes recent insights into the pathogenesis and immunobiology of MF/SS and how these have shaped current therapeutic approaches, in particular the growing emphasis on enhancement of host antitumor immune responses as the key to successful therapy.

Progressive multifocal leukoencephalopathy is a central nervous system disease due to reactivation of the human polyoma JC virus in immunocompromised patients. Advanced mycosis fungoides patients are intrinsically immunosuppressed and susceptible to infections, but only rarely have been reported to develop progressive multifocal leukoencephalopathy. We report a case of progressive multifocal leukoencephalopathy developing in an advanced mycosis fungoides patient without prior history of immunosuppressive therapy.

To evaluate the efficacy and safety of a novel mechlorethamine hydrochloride, 0.02%, gel in mycosis fungoides. DESIGN Randomized, controlled, observer-blinded, multicenter trial comparing mechlorethamine, 0.02%, gel with mechlorethamine, 0.02%, compounded ointment. Mechlorethamine was applied once daily for up to 12 months. Tumor response and adverse events were assessed every month between months 1 and 6 and every 2 months between months 7 and 12. Serum drug levels were evaluated in a subset of patients.Academic medical or cancer centers.In total, 260 patients with stage IA to IIA mycosis fungoides who had not used topical mechlorethamine within 2 years and were naive to prior use of topical carmustine therapy.Response rates of all the patients based on a primary clinical end point (Composite Assessment of Index Lesion Severity) and secondary clinical end points (Modified Severity-Weighted Assessment Tool and time-to-response analyses).Response rates for mechlorethamine gel vs ointment were 58.5% vs 47.7% by the Composite Assessment of Index Lesion Severity and 46.9% vs 46.2% by the Modified Severity-Weighted Assessment Tool. By the Composite Assessment of Index Lesion Severity, the ratio of gel response rate to ointment response rate was 1.23 (95% CI, 0.97-1.55), which met the prespecified criterion for noninferiority. Time-to-response analyses demonstrated superiority of mechlorethamine gel to ointment (P.01). No drug-related serious adverse events were seen. Approximately 20.3% of enrolled patients in the gel treatment arm and 17.3% of enrolled patients in the ointment treatment arm withdrew because of drug-related skin irritation. No systemic absorption of the study medication was detected.The use of a novel mechlorethamine, 0.02%, gel in the treatment of patients with mycosis fungoides is effective and safe.clinicaltrials.gov Identifier:NCT00168064.

Background There is a paucity of effective therapies for patients with Sezary syndrome and advanced mycosis fungoides with peripheral blood involvement. Total skin electron beam (TSEB) radiation therapy is an extremely effective skin-directed therapy for these patients, but, until recently, it was thought not to signifcantly affect the peripheral blood malignant T-cell population. Objective We conducted this study to determine if TSEB has therapeutic effect on the peripheral blood in patients with advanced mycosis fungoides and Sezary syndrome. Methods All patients on stable medication regimens seen in our photopheresis facility who received TSEB therapy between January 2008 and October 2011 at Temple University Hospital, Philadelphia, PA, were analyzed retrospectively for improvement in the peripheral blood, as documented by flow cytometry. Results Six of 11 patients achieved 50% or greater decrease in their peripheral blood malignant T-cell population after TSEB therapy, for an overall response rate of 55%. Within the group of patients who had a response in the skin, 67% also had a response in the peripheral blood. Limitations This analysis is limited in 3 ways. First, the sample described is small. Second, the results may be confounded by the fact that each patient was on other systemic therapies in addition to TSEB, albeit stable pre-existing regimens. The time interval between completion of TSEB therapy and repetition of flow cytometry was not standardized among patients, which may result in an underestimation of the overall response to TSEB therapy. Conclusion In patients with advanced mycosis fungoides and Sezary syndrome, the peripheral blood tumor burden may improve after treatment with TSEB.

Background: Patients (pts) with cutaneous T-cell lymphoma (CTCL) are at increased risk of developing second primary malignancies. Intrinsic or treatment-related immune dysregulation in this population may contribute to pathogenesis and impact prognosis and pathological features of CTCL-associated malignancies. We investigated characteristics of a large institutional cohort of CTCL pts to identify those with second primary malignancies, with a specific focus on classical Hodgkin lymphoma (HL). Methods: We performed aretrospective review of CTCL patients seen at our institution from January 2000 through December 2014 with ≥1 additional malignancy. Pts with CTCL including Mycosis Fungoides (MF) and Sezary Syndrome (SS) were identified by querying our institutional database using ICD codes. Second malignancies were determined through chart review with confirmation by diagnostic pathology and clinical history. For pts with concurrent CTCL and HL, CTCL presentation was defined as symptom onset per patient self-report or clinical history. Incidence of HL in the general population was obtained from the SEER Cancer Statistics Review. Pt characteristics and clinical outcomes are reported through July 2015. Results: In our cohort of 1,995 CTCL pts, we identified 192 (10%) pts with second malignancies [66 (3%) second hematologic malignancies, 107 (5%) second epithelial malignancies, and 30 (2%) second dermatologic malignancies excluding basal cell and squamous cell carcinoma of the skin]. Ten (1%) pts had third primary malignancies. Of those with second malignancies, 46 (24%) had B-cell malignancies including 31 with non-Hodgkin B-cell lymphomas and 4 with multiple myeloma. Twelve CTCL pts (0.6 % of the total CTCL cohort) developed HL, an incidence 3 times higher than the general population. Of pts with concurrent HL and CTCL, 11 (92%) had MF, 1 (8%) had SS, 8 (67%) were male and 9 (75%) were Caucasian. Nine (75%) were diagnosed with HL after CTCL presentation and 2 (17%) were diagnosed with CTCL within one year after HL diagnosis. Only 1 patient (8%) had a distant history of HL prior to CTCL presentation. Median age at HL diagnosis was 60 years (range 33-82). Six (50%) pts had nodular sclerosing subtype, 2 (17%) had mixed cellularity, and 4 (33%) were not specified. In the 8 patients who had EBV staining performed on HL biopsies, 2 (25%) were EBV positive. Two (17%) pts had single nodal involvement by both CTCL and HL. At presentation, 2 (17%) pts had B symptoms and 1 pt had advanced (Ann Arbor stage III) HL. Only one pt had received immunosuppressive CTCL-directed chemotherapy (pentostatin) prior to HL diagnosis, while 3 (25%) pts had phototherapy, and 1 had local radiation. In all pts, HL was treated with standard anthracycline-based chemotherapy with 8 (67%) pts receiving consolidative radiotherapy. Two (17%) pts required salvage therapy for progressive HL. There were no unique complications of HL therapy reported and all pts ultimately achieved complete remission of their HL. Six of 12 pts with HL expired (Figure, median follow up 51 months), with no deaths attributable to HL. Four (33%) pts died of CTCL or complications of therapy. While the course of CTCL varied in this cohort, any CTCL response to HL-directed therapy was transient and 8 pts (67%) had active CTCL at time of last follow-up. Three (25%) pts with HL had a third primary cancer during their lifetime (malignant melanoma, therapy-related acute myeloid leukemia, esophageal adenocarcinoma). Conclusions: In this large institutional cohort, we identified 12 cases of concurrent CTCL and HL. We demonstrated an increased incidence of HL in the CTCL population. Compared to HL pts in the general population, those with concomitant CTCL appear to present in older age and with limited stage disease. Although the sample is small, our cohort tolerated HL therapy without unexpected toxicities and had excellent HL outcomes. Since most pts presented with HL prior to requiring systemic CTCL treatment, we conclude the etiology of CTCL-associated HL is more likely related to intrinsic vs. treatment-related immune dysregulation. Better understanding of HL features in relation to CTCL may guide clinical management for this complex population. The potential role of underlying T-cell biology will be studied in subsequent investigations. Figure 1. Figure 1. Disclosures Mato: Genentech: Consultancy; Pharmacyclics: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; TG Therapeutics: Research Funding; Pronai Pharmaceuticals: Research Funding; Gilead: Consultancy, Research Funding. Nasta:Seattle Genetics: Research Funding; BMS: Research Funding. Schuster:Phamacyclics: Consultancy, Research Funding; Novartis: Research Funding; Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Hoffman-LaRoche: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Genentech: Consultancy. Svoboda:Celldex: Research Funding; Immunomedics: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding.

Although Sezary syndrome (SS) represents an advanced stage of cutaneous T-cell lymphoma, this diagnosis presents a challenge even for the most experienced dermatologic clinicians. SS is characterized clinically by erythroderma, but can also be identified in the presence of specific histologic and peripheral blood findings. Erythrodermic cutaneous T-cell lymphoma can mimic a number of nonmalignant disorders with erythroderma, including pityriasis rubra pilaris, psoriasis, atopic dermatitis, and graft-versus-host disease. The diagnosis is made even more challenging because the histology of SS is often nonspecific and rarely pathognomonic. As a result, peripheral blood studies in patients with erythroderma are frequently informative in the diagnosis of SS. Peripheral blood abnormalities including elevated CD4/CD8 ratio, aberrant CD26, CD27 and CD7 expression, and T-cell clonality can all be used to help arrive at a diagnosis. This review evaluates current data on the usefulness and limitations of specific peripheral blood markers detected by flow cytometry and T-cell receptor gene rearrangement polymerase chain reaction.

Sezary syndrome (SS) has a poor prognosis and few guidelines for optimizing therapy. The US Cutaneous Lymphoma Consortium, to improve clinical care of patients with SS and encourage controlled clinical trials of promising treatments, undertook a review of the published literature on therapeutic options for SS. An overview of the immunopathogenesis and standardized review of potential current treatment options for SS including metabolism, mechanism of action, overall efficacy in mycosis fungoides and SS, and common or concerning adverse effects is first discussed. The specific efficacy of each treatment for SS, both as monotherapy and combination therapy, is then reported using standardized criteria for both SS and response to therapy with the type of study defined by a modification of the US Preventive Services guidelines for evidence-based medicine. Finally, guidelines for the treatment of SS and suggestions for adjuvant treatment are noted.

Background There is a need for standardized quantitative disease assessment measures in mycosis fungoides/Sezary syndrome. In 2005, a cutaneous T-cell lymphoma (CTCL)-severity index (SI) that not only measures disease extent (on a scale of 0-75) independent of the classic TNM(B) staging system but can also be used to estimate individual 5-year survival (SR5) was reported. Objective We sought to assess the generalizability of the CTCL-SI/SR5 equation (SR5 equation) to predict prognosis in our cohort of patients with advanced mycosis fungoides/Sezary syndrome (n = 50, photopheresis service, 1984-2001). Methods TNM(B) staging, CTCL-SI score (based on skin involvement, presence of tumors, lymph node/visceral/blood involvement), and SR5 (SR5 equation = 124 – 2 × [CTCL-SI]%) at initial diagnosis were calculated retrospectively and compared with overall survival by the Kaplan-Meier method. The prognostic significance of TNM(B) staging versus the CTCL-SI was determined by Cox proportional hazards models and Brier scores. Results Patients had stage IIA to IVA disease with a median actuarial overall survival of 58 months. By disease stage, the overall 5-year survival was 70% (stage IIA), 48% (stage IIB-IIIB), and 36% (stage IVA). In our cohort, the CTCL-SI itself was predictive of overall survival ( P = .028) but the SR5 equation was not predictive of survival (Brier score of 0.29). Limitations Small sample size, single academic center population, and retrospective design are limitations. Conclusions The CTCL-SI is a relatively simple-to-use quantitative tool that measures disease activity in all compartments (skin, nodes, blood, viscera) and has prognostic significance in multivariate analysis. The CTCL-SI may be a useful adjunct to the TNM(B) staging for tracking disease activity quantitatively in all disease compartments (skin, nodes, blood, viscera) in clinical practice and trials, but the predictive ability of the SR5 equation needs further validation at other centers in larger groups of patients.

Long-term prognosis for advanced stages of cutaneous T-cell lymphoma may be beneficially altered with the use of multimodality therapy. However, refractory disease exists in which current therapeutic options fail to halt the progression of disease. We present 3 cases of refractory Sezary syndrome in which the combination of vorinostat and interferon gamma was well tolerated and produced significant clinical improvement. The potential immunologic basis for this is discussed.

Cutaneous T-cell lymphomas are a type of indolent non-Hodgkin's lymphoma where patients with limited skin disease can be successfully treated with a variety of skin-directed, systemic, and immunomodulating therapies, whereas durable remissions are difficult to achieve in patients with tumor, erythrodermic, or systemic disease. We describe a patient with cutaneous T-cell lymphoma and malignant cells constituting 99% of her peripheral blood lymphocytes who had a sustained complete response after an HLA-matched sibling allogeneic stem cell transplantation. We also review the current literature regarding both autologous and allogeneic stem cell transplantations for advanced stages of cutaneous T-cell lymphoma, discuss the importance of the graft-versus-tumor immunomodulatory effect in successful transplantations, and suggest that allogeneic stem cell transplantation deserves further consideration and study as a potential treatment for selected patients who are younger and at high risk.

Mycosis fungoides (MF), and the associated leukemic variant Sezary Syndrome (SS), are the most common group of cutaneous T-cell lymphomas. MF/SS is a non-Hodgkin's lymphoma of mature, skin-homing, clonal, malignant T lymphocytes that initially presents in the skin as patches, plaques, tumors, or generalized erythema (erythroderma) and can involve the lymph nodes and peripheral blood. Much progress has been made in recent years in understanding the origin of the malignant T cell in MF/SS and the pathophysiology and immunology of the disease. This recent work has made a great impact on diagnosis, prognostication, and treatment. In this review, we survey the MF/SS published literature over the past year and highlight some of the important advances.

In this issue of Blood , Kim and colleagues demonstrate that zanolimumab offers promise for treating refractory early- and advanced-stage mycosis fungoides and Sezary syndrome. Cutaneous T-cell lymphomas (CTCLs) are malignancies of skin-homing T cells with the most common subtype, mycosis