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Cutaneous T-cell lymphomas (CTCL) are a diverse group of malignant blood disorders characterized by initial skin infiltration, and sometimes, tumor spreading to lymph nodes, blood, and viscera. Mycosis fungoides is the most common form. Sézary syndrome is a distinctive form of CTCL marked by a significant presence of circulating tumor cells in peripheral blood. These diseases are characterized by the plasticity and heterogeneity of the tumor cells in the different tissue compartments, and a difficulty in identifying these tumor cells for diagnostic purposes and therapeutic monitoring. Progress has been made in the understanding of the pathophysiology of these diseases in recent years, and we provide here a review of these advancements., Competing Interests: Declaration of competing interest Caroline Ram-Wolff : Innate Pharma Adele de Masson, Martine Bagot, Maxime Battistella: Innate Pharma, Takeda, Recordati, Kyowa Kirin Helene Moins-Teisserenc, Armand Bensussan, Jerome Giustiniani, Ingrid Lazaridou: none, (Copyright © 2024 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)

Background: IPH4102 is a first-in-class monoclonal antibody targeting KIR3DL2, a cell surface protein that is expressed in cutaneous T-cell lymphoma, and predominantly in its leukaemic form, Sézary syndrome. We aimed to assess the safety and activity of IPH4102 in cutaneous T-cell lymphoma.Methods: We did an international, first-in-human, open-label, phase 1 clinical trial with dose-escalation and cohort-expansion parts in five academic hospitals in the USA, France, the UK, and the Netherlands. Eligible patients had histologically confirmed relapsed or refractory primary cutaneous T-cell lymphoma, an Eastern Cooperative Oncology group performance score of 2 or less, were aged 18 years or older, and had received at least two previous systemic therapies. Ten dose levels of IPH4102, administered as an intravenous infusion, ranging from 0·0001 mg/kg to 10 mg/kg, were assessed using an accelerated 3 + 3 design. The primary endpoint was the occurrence of dose-limiting toxicities during the first 2 weeks of treatment, defined as toxicity grade 3 or worse lasting for 8 or more days, except for lymphopenia. Global overall response by cutaneous T-cell lymphoma subtype was a secondary endpoint. Safety and activity analyses were done in the per-protocol population. The study is ongoing and recruitment is complete. This trial is registered with ClinicalTrials.gov, number NCT02593045.Findings: Between Nov 4, 2015, and Nov 20, 2017, 44 patients were enrolled. 35 (80%) patients had Sézary syndrome, eight (18%) had mycosis fungoides, and one (2%) had primary cutaneous T-cell lymphoma, not otherwise specified. In the dose-escalation part, no dose limiting toxicity was reported and the trial's safety committee recommended a flat dose of 750 mg for the cohort-expansion, corresponding to the maximum administered dose. The most common adverse events were peripheral oedema (12 [27%] of 44 patients) and fatigue (nine [20%]), all of which were grade 1-2. Lymphopenia was the most common grade 3 or worse adverse event (three [7%]). One patient developed possibly treatment-related fulminant hepatitis 6 weeks after IPH4102 discontinuation and subsequently died. However, the patient had evidence of human herpes virus-6B infection. Median follow-up was 14·1 months (IQR 11·3-20·5). A confirmed global overall response was achieved in 16 (36·4% [95% CI 23·8-51·1]) of 44 patients, and of those, 15 responses were observed in 35 patients with Sézary syndrome (43% [28·0-59·1]).Interpretation: IPH4102 is safe and shows encouraging clinical activity in patients with relapsed or refractory cutaneous T-cell lymphoma, particularly those with Sézary syndrome. If confirmed in future trials, IPH4102 could become a novel treatment option for these patients. A multi-cohort, phase 2 trial (TELLOMAK) is underway to confirm the activity in patients with Sézary syndrome and explore the role of IPH4102 in other subtypes of T-cell lymphomas that express KIR3DL2.Funding: Innate Pharma. [ABSTRACT FROM AUTHOR]

Mogamulizumab is a defucosylated monoclonal antibody targeting the C-C chemokine receptor 4 (CCR4) and approved for the treatment of adult patients with mycosis fungoides (MF) and Sézary syndrome (SS) who have received at least one prior systemic therapy. The efficacy of mogamulizumab was demonstrated in the open-label, phase 3 MAVORIC clinical trial comparing mogamulizumab to vorinostat. This retrospective observational study was conducted in 14 French centres to further assess efficacy and safety of mogamulizumab in a real-life setting. Data collected from medical records of MF and SS patients treated with mogamulizumab between February 2014 and March 2020 in the participating centres were analysed. Patients treated with mogamulizumab in the MAVORIC trial and still alive at the end of the trial were also included (n=20 pts). The primary endpoint was efficacy based on the percentage of patients achieving complete (CR) or partial (PR) response according to the Global Response Score for MF/SS, at mogamulizumab best response (overall response - ORR). Safety was also evaluated on the number and type of adverse events. A total of 124 patients aged 69.3±11.8 (mean ± standard deviation [SD]) years, treated with mogamulizumab were included. Patients (MF: n=55, SS: n=69) had an average disease duration of 4.8±3.4 and 2.8±3.1 (mean ± SD) years, respectively. Prior to mogamulizumab, patients had received a median of 3 systemic treatments lines. The stage of the disease at mogamulizumab initiation was IA – 1.7%; IB – 13.4%; IIA – 6.7%; IIB – 5.9%; IIIA – 6.7%; IIIB 7.6%; IVA1 – 49.6%; IVA2 – 6.7%; IVB – 1.7%. 81 patients had blood involvement at mogamulizumab initiation (B1: n=16; B2: n=65). The average duration of treatment with mogamulizumab was 7.6±11.6 (mean ± SD) months. The ORR was 58.6% [95% CI: 48.8–67.8] in the total population vs 47.1% [95% CI: 32.9–61.5] and 68.3% [95% CI: 55–79.7] in MF and SS subsets, respectively. The response in the blood compartment was 55% [95% CI: 45.2–64.4] in the total population vs 71.7% [95% CI: 58.6–82.5] in SS patients. Side effects related to treatment were recorded in 54% of the patients. Skin adverse reactions were the most common adverse events, with 45 recorded instances occurring in 26 patients; over half (55.6%) of all instances were mild-to-moderate in severity. Infusion-related reactions were recorded in 12.1% of patients and were limited to the first (88%) or second (12%) infusion; only 3 patients had a Grade 3 reaction, but none led to treatment discontinuation. Overall, 7 patients passed away, 5 owing to disease progression (1 stage IIB, 3 stage IVA1, 1 stage IVA2) and 2 to sepsis; neither case of sepsis was considered treatment related. This real-life- survey shows both a significant ORR and a favourable safety profile in MF and SS patients treated with mogamulizumab. The shown data are consistent with those observed in MAVORIC study. [ABSTRACT FROM AUTHOR]

Patients with primary cutaneous lymphoma receive immunosuppressive therapy for long term disease control. Both cutaneous lymphoma and immunosuppressive treatment can contribute to the development of more severe COVID-19 complications. The real challenge during the COVID-19 pandemic remains the management of the advanced and aggressive forms of cutaneous lymphomas, including late-stage mycosis fungoides (MF) and Sézary syndrome (SS). Extracorporeal photopheresis (ECP) is one of those treatments. ECP is considered high risk therapy according to the United States Cutaneous Lymphoma Consortium recommendations for treatment of cutaneous lymphomas during the COVID-19 pandemic because it may require travel to the clinic or hospital. In this cross-sectional retrospective study, data of patients with MF or SS who received ECP treatment were collected. ECP consisted of a two-session cycle every two to four weeks. In our group we did not carry out prophylactic interruption of the therapy, once started. In patients with stable disease (SD) or partial response (PR), ECP was administered every 4 weeks, until a 6-week maximum interval was reached, and the response maintained. During the study period, the frequency of treatments was decreased, especially for patients with severe comorbidities and/or older age. The associated therapy was considered individually, depending on the extension of the disease, comorbidities, and adverse effects of each agent. 16 patients with cutaneous lymphoma received ECP (9 (56%) with SS and 7 (44%) with MF). Their median age at diagnosis was 63 (57–67) years. The median number of treatments before ECP was 2 (1–3), which was typically either phototherapy or systemic corticosteroids. Regarding the associated treatment during ECP and pandemic, INF and retinoids were the first-choice treatments. In the MF group 3 patients (2 PR and 1 relapse) required additional therapy with acitretin and topic corticosteroids. In the SS group 5 patients (1 PR, 3 progressive disease and 1 relapse) received concomitant t treatment with INF alfa 2b, bexarotene and electron beam; the relapsed patient underwent mono chemotherapy. Three patients were infected with SARS-CoV-2, all of them were from the SS group, the contagion was outside the hospital environment. Two of the patients who developed COVID infection died. For patients with advanced forms of LCCT, who usually have multiple risk factors for a severe course of SARS-CoV-2 infection therapy. The critical patient subset includes those with advanced disease, who require treatment with polychemotherapy, ECP and checkpoint inhibitors. Treatment decisions should be made on an individual basis. In our experience, the continuous use of ECP during the pandemic did not increase the risk of contagion. [ABSTRACT FROM AUTHOR]

Patients with advanced CTCL disease ((stage IIB–IVB) mycosis fungoides (MF) or Sézary syndrome (SS)) have a poor prognosis and suffer from profound symptom burden. These patients require systemic treatment. However, it is still a key challenge to achieve durable remissions with the available treatment options. CTCL is characterized by the presence of malignant clonal T-cells in the skin and/or blood, lymph nodes or visceral organs. Epigenetic alterations in malignant T cells are known to play a key role in the pathogenesis of the disease. Resminostat is an orally available HDAC-inhibitor, which induces changes in gene expression resulting in growth inhibition, modified cell differentiation and enhanced tumor immunogenicity. The purpose of the RESMAIN study is to investigate resminostat as maintenance treatment for patients with advanced stage mycosis fungoides (MF) or Sézary syndrome (SS) that have achieved disease control with systemic therapy. The RESMAIN study is a multicenter, double blind randomized, placebo controlled, prospective efficacy trial. Patients are randomized 1:1 to the resminostat and the placebo arm. Furthermore, patients are stratified according to their remission status and their disease stage immediately prior to the last systemic therapy. Patients will be treated until disease progression. Patients of the placebo arm have the option to receive resminostat treatment. In addition, exploratory biomarker analyses will be performed. The study is conducted in 11 European countries at 51 sites and at 5 sites in Japan. The first patient was enrolled in January 2017. Recruitment was impacted by the COVID-19 pandemic but continued slowly in 2020 and is now in its final stage. The independent data safety monitoring committee (DSMB) recommended continuation of the ongoing RESMAIN study without modification after a pre-specified review of cumulative safety data of the first 50, 100, ,150 and 175 patients which had completed at least one treatment cycle. The poster will present an actual status update of the RESMAIN study. The primary objective is to determine if maintenance treatment with resminostat increases progression free survival (PFS) compared to placebo. As a key secondary end point the effect of resminostat on time to symptom worsening (TTSW) of pruritus compared to placebo will be assessed. Further secondary endpoints are TTP, TTNT, ORR, OS and HrQoL among others. To our knowledge, this is the first randomized study that investigates the potential of an HDAC inhibitor as maintenance therapy in advanced CTCL. [ABSTRACT FROM AUTHOR]

Sézary syndrome (SS) is a cutaneous T cell lymphoma (CTLC) with poor prognosis which can present de novo or secondary to mycosis fungoides (MF). We report our experience treating patients with SS with mogamulizumab (n=3). A 76-year-old woman presented with an 8-year history of refractory erythroderma. Skin biopsy showed dermal lymphocytic infiltrate with aberrant phenotype. Blood flow cytometric analysis detected 77% pathologic T-lymphocytes (TL) with SS phenotype and positive T-cell receptor (TCR) ϒ gene rearrangement. Lymph node biopsy showed SS infiltration. She was diagnosed with stage IVA1 SS (T4N1M0B2). Due to disease progression after treatment with bexarotene, mogamulizumab was started following the usual protocol. Patient achieved complete clinical response (CR) since the 2nd infusion in skin, blood and lymph nodes. She presented grade IV neutropenia after the 6th infusion which resolved with filgastrim, and a grade II lymphopenia after the 5th infusion which resolved with posology spaced to every 6 weeks. Patient continues disease-free after 12 months of treatment. A 66-year-old woman presented with a 1-year history of erythroderma. Skin biopsies were consistent with MF. Blood flow cytometric analysis detected 59.2% of pathological TL with SS phenotype and positive TCR ϒ gene rearrangement. Lymph node biopsy showed SS infiltration. Diagnosis of stage IVA2 SS (T4N3M0B2) was stablished. She was treated with extracorporeal photopheresis, interferon α-2B, bexarotene and gemcitabine with partial response. Treatment with mogamulizumab was started with complete CR after the 4th infusion in skin, lymph nodes, and blood with good tolerability. She received an allogeneic bone marrow transplant after the 5th cycle and continues disease-free after 100 days post-transplant. CASE 3 A 36-year-old man presented with follicular infiltrated papules and alopecia affecting most of the body surface. Blood flow cytometric analysis showed 93% of pathological TL and positive TCR ϒ gene rearrangement. Skin biopsy was consistent with MF. Lymph nodes showed SS infiltration. Patient was diagnosed with Stage IVA2 SS (T2N3M0B2). He was treated with bexarotene and brentuximab with initial CR but disease progression after 10 cycles. Treatment with mogamulizumab was started with initial improvement but failure after 6 months. Mogamulizumab is a monoclonal antibody that selectively binds to CCR4 present on atypical TL. To date, only a series of 13 patients with CTCL treated with mogamulizumab in clinical practice has been reported, with good tolerability and CR in blood and skin. In our series 2 out of 3 patients presented an impressive CR in all aspects of the disease. One patient developed neutropenia and lymphopenia in relation to mogamulizumab, which resolved after specific treatment. This series supports the use of mogamulizumab in patients with refractory SS. Larger series are needed to evaluate the use mogamulizumab for CTCL in routine clinical practice. [ABSTRACT FROM AUTHOR]

Mycosis fungoides (MF) is the most prevalent form of primary cutaneous T-cell lymphoma. Patients frequently present with early-stage disease typically associated with a favourable prognosis, but over 25% may progress to advanced disease and 30% present with the advanced stages with a median survival <4 years and of just 13 months in those with lymphomatous nodal effacement. An international study from 2015 in advanced MF found age >60 years, large cell transformation in skin, stage IV and raised LDH all to be associated with a worse prognosis and developed the CLIC prognostic index which stratified patients into low (0–1 factor) medium (2 factors) or high risk (3–4 factors) for poor survival [ 1 ]. In order to prospectively investigate prognostic factors in mycosis fungoides and Sézary syndrome the PROCLIPI International Study was launched in 2015 collecting predefined data [ 2 ]. We tested the prognostic index developed on a retrospective group of advanced MF/SS patients on a prospective group of advanced MF/SS patients from the PROCLIPI study. In PROCLIPI 1862 patients have been recruited at 51 sites, from 20 countries across 6 continents. 1442 early-stage patients (male:female ratio 1.7:1) and 420 advanced (male:female ratio 1.7:1). 297 patients from the advanced cohort had sufficient data to stratify according to the CLIC Prognostic Index to include n=112 low, n=118 medium and n=67 high risk patients. Applying this index found that low risk advanced MF/SS patients had a significantly better prognosis then high-risk advanced patients p<0.001 as did the medium risk versus high-risk p=0.005. Each group contained a variety of stages and 30% of the high-risk patients were stages IIB-IVA1. This is important as comparing median survival between stages IIB, IIIA, IIIB and IVA1 did not identify any significant difference although the survival of this group versus stage IVA2 patients was significantly better (p=0.002). Identifying prognostic factors at diagnosis may allow better management and improve survival and the development of a prognostic index could help identify patients at risk of progression. On Behalf of the Cutaneous Lymphoma international Consortium (CLIC): Julia Scarisbrick, Pietro Quaglino, Miles Prince, Maarten Vermeer, Evangelina Papadavid, Emilia Hodak, Sean Whittaker, Martine Bagot, Christina Querfeld, Oleg Akilov, Octavio Servitje, Emilio Berti, Pablo Ortiz-Romero, Rudolf Stadler, Constanze Jonak, Robert Knobler, Christina Mitteldorf, Teresa Estrach, Marta Marschalko, Emmanuella Guenova, Nicola Pimpinelli, Marie Beylot-Barry, Marion Wobser, Ulrike Wehkamp, Richard Cowan, Liisa Vakeva, Anne-Marie Buschots, Rubeta Matin, Felicity Evison, Lorenzo Cerroni, Werner Kempf, Ale Gru, Maxime Battistella, Rein Willemze and Youn Kim. [ABSTRACT FROM AUTHOR]

Erythroderma is a diagnostic challenge for dermatologists and pathologists. We aimed to identify clinical, histological and immunohistochemical markers that can be used to improve erythroderma diagnosis. This single-centre retrospective study included patients with erythroderma. To be included, erythroderma cases needed an accurate final diagnosis, at minimum one year of follow-up, available pictures and available skin biopsies to be reviewed. The demographic, clinical, biological (lactate deshydrogenase, eosinophilia, immunophenotype) and molecular features (T-cell clone in blood and skin) were recorded. All skin biopsies were reviewed for the following features: psoriasiform hyperplasia, parakeratosis, neutrophil microabscess, spongiosis, eosinophil infiltrate, lichenoid lesion, necrotic keratinocytes, epidermotropism, atypical lymphocytes, as well as routine immunostainings (CD3, CD4, CD8). Additional T follicular helper markers (PD1, ICOS and CXCL13), CD7 loss and Ki-67 proliferation index were also studied. For PD1 expression, percentage of positive lymphocytes as well as staining intensity (+ to +++) were recorded, all together combined in the semi-quantitative H score= [0 × (% cells 0) + 1 × (% cells 1+) + 2 × (% cells 2+) + 3 × (% cells 3+)]. Among 91 patients included with erythroderma, 21 were diagnosed as eczema, 17 as psoriasis, 20 as drug-induced erythroderma (DE), 13 as erythrodermic mycosis fungoides (E-MF) and 20 as Sézary syndrome (SS). Nail alterations, ear involvement and severe scaling were associated with psoriasis (p=0.044). Fever and hypereosinophilia were associated with DE diagnosis (p=0.044 and p=0.0003). Atypical lymphocytes in the skin were more frequent in E-MF and SS (p=0.044), as well as an abnormal blood immunophenotype and identical skin and blood T-cell clone. In SS, PD1 expression by T cells was significantly higher than in other aetiologies, as percentage of positive lymphocytes and intensity. PD1 H-score >50 was associated with SS (p<0.001, Se=75%; Sp=92%), with good reproducibility between observers, kappa coefficient of 0.66 (95% CI 0.33–1.00). CXCL13 expression was also associated with SS (p=0.044); CD7 loss was more frequent in E-MF and SS (p=0.022), and Ki-67 index was higher in SS and DE (p=0.041). In this large series erythroderma, we report the PD1 expression, and specifically the PD1 H-score combining percentage and intensity scoring, as a tool for differential diagnosis between SS and other aetiologies including E-MF. Interdisciplinary expertise combining clinical, pathological, and molecular data remain essential for erythroderma diagnosis. [ABSTRACT FROM AUTHOR]

A novel monoclonal antibody therapy termed mogamulizumab is currently seeking approval for treatment of mycosis fungoides and Sézary syndrome. Mogamulizumab is a humanized IgG1 κ monoclonal antibody which targets C-C chemokine receptor type 4 (CCR4), a transmembrane chemokine receptor which promotes T cell migration to the skin and is expressed at high levels on the surface of the malignant cells which drive cutaneous lymphomas. We performed a multi-centre clinical audit using data from 16 patients who have received mogamulizumab through a patient access programme at The Christie (8) and University Hospitals Birmingham (8) NHS Foundation Trusts. Our cohort had a median age of 68.1 (57.1–71.5) years at initiation of treatment, with a male to female sex ratio of 1.67 and varied diagnoses including Sézary syndrome (62.5%), classical mycosis fungoides (18.8%) and folliculotropic mycosis fungoides (12.5%). We assessed objective measures of disease response in the skin (mSWAT scores) and blood (flow cytometry), progression free survival (PFS) and the incidence of adverse events with the aim to further assess the efficacy and safety of mogamulizumab in this setting. The patients in our cohort showed significant responses to mogamulizumab with median mSWAT score falling from 108 (53.8–139.1) to 23.1 (8.8–75.0) at peak response which was achieved at a median of 202 (115.5–328) days. 31.3% of our patients achieved a complete skin response whilst 37.5% achieved a partial skin response. The flow cytometry results of our cohort showed a marked improvement after initiation of mogamulizumab with median CD4/CD8 ratio, median number of circulating CD4+CD7– and CD4+CD26–being reduced by 89.0%, 96.8% and 95.8% respectively with median time to peak response being 193 (139.75–305.25) days. 62.5% of patients achieved a complete blood response with a further 25% achieving a partial blood response. Mogamulizumab was generally well tolerated with a median number of CTCAE events of 1.5 (0–4.25), which were predominantly grade 1 (62.9%) followed by grade 2 (22.9%) and grade 3 (14.3%) with no higher-grade adverse events being reported by any of the patients who had received mogamulizumab. One patient did discontinue treatment due to toxicity. Progression was only seen in 2 of the 16 with a medium follow up of 267 days (194.3–462.8) The median PFS has not been reached. 3 of the 16 patients have died, causes of death were CTCL (1), squamous cell carcinoma (1) and upper gastrointestinal haemorrhage (1). Mogamulizumab treatment resulted in marked improvements in skin and blood disease activity for patients across both centres whilst being generally well tolerated. The median PFS has not been reached after a median FU of 8.9 months. This compares favourably with the PFS of 7.7 months seen in the MAVORIC study. This observational study confirmed a high response rate in blood and skin in this group of diseases. [ABSTRACT FROM AUTHOR]

Advanced stage mycosis fungoides/Sézary syndrome (MF/SS) are difficult to treat and associated with an inferior prognosis. Brentuximab vedotin (BV) is a frequently used agent in higher stages, particularly in cases with a high expression of CD30. The ALCANZA trial, which included MF patients with a CD30 expression >10%, demonstrated high response rates and a good tolerability. However, its effectiveness in advanced stage MF/SS syndrome with low CD30-expression (<10%) still has to be systematically evaluated. Therefore, the question is whether an equally good response with BV is achievable in these CTCL cases. Between 2018 - 2020, 32 patients in 11 centres with predominantly advanced MF/SS and low CD-30 expression (<10%) were treated with BV in the recommended dosage, retrospective evaluation of therapy response was done according to the EORTC-ISCL criteria. In all patients (n=32) at least one other systemic therapy preceded BV treatment. The median number of previous treatments was 3. Thirty patients suffering from MF (IB: 2; IIA: 1; IIB: n=18; III: 1; IV: 9; total ≥IIB: 27) and 2 SS patients were analyzed. As a result, 17 of 31 patients (OR: 54.8%) responded to therapy (CR n=4/31 12.9%, PR n=13/31 41.9%) after 6 cycles. The median progression-free interval among patients with OR was 6.4 months (range: 0.5–15.5 months, mean ± SD: 6.4±3.8, n=16). In 37.5% (n=12) the CD-30 Expression was 5-9% and in 62.5% (n=20) CD-30-Expression was <5%. In conclusion, with 54.8% OR, BV in MF/SS with low CD-30 expression (<10%) shows a comparable response rate compared to CTCL with CD-30 expression ≥10% (56-73%) and CR (12.9% vs. 3–35%) but with a lower PFS (6.4 vs. 11 months). In summary, based on this data the treatment of MF/SS with low CD-30 expression with BV seems to be an effective therapeutical option and justifies its use in challenging cases independent of the degree of CD30 positivity. [ABSTRACT FROM AUTHOR]

Sézary syndrome (SS) is a primary cutaneous T-cell lymphoma characterized by measurable levels of malignant lymphocytes in the blood, and progressive impairment of the immune response. Among the mechanisms of immune modulation, adenosine can impair anti-tumor immunity, through the attenuation of protective effector cells, including T and NK cells, and by enhancing the suppressive capacity of T regulatory cells. CD39 and CD73 nucleotide-metabolizing enzymes are involved in the adenosine-generating pathway: CD39 cleaves ATP and ADP down into AMP, which is converted into adenosine by CD73. The extracellular adenosine deaminase/CD26 complex catalyzes the deamination of adenosine to inosine, thus reducing the adenosine levels. The objective of this study were: to investigate the expression of the of CD39 and CD73 nucleotide-metabolizing ectoenzymes in peripheral blood from SS patients; to define the contribution of the CD39/CD73 adenosinergic immunosuppressive pathway to tumor escape from immune response and immune dysfunctions in patients with SS. CD39 and CD73 expression analyzed in whole blood with multiparametric flow-cytometry from SS patients (n=10) and healthy donors (HD, n=11) revealed altered expression of CD39 and CD73 in SS patients compared to HD. Two subgroups of patients can be identified based on the mutually exclusive overexpression of CD39 or CD73 in CD4+ T cells. Indeed, 7 out of 10 patients had high CD39, while 3 had high CD73. CD4+T cells with high CD39 have low CD73, vice versa those with high CD73 have low CD39. To define whether CD39 and CD73 were biologically active, we compared the ability of peripheral blood CD4+T cells from SS patients and HD to hydrolyze ATP and to convert AMP into adenosine, in vitro. Briefly, CD4+ Tcells from SS/HD were seeded in 48-well plates in HBSS, pretreated or not with specific inhibitors for 1h and then incubated with exogenous (e) eATP (patients with high CD39) or eAMP (patients with high CD73) at 37°C. After 1 h incubation, analyses of the supernatant were performed with an RP-HPLC. Results indicated that CD4+ T cells from SS patients with high levels of CD39 showed an increased ability to hydrolyze ATP with increased generation of AMP compared to normal control cells. In parallel, CD4+ T cells with high levels of CD73 showed increased conversion of AMP into ADO, respect to normal control cells. The aberrant expression of CD39 and CD73 along with loss of CD26 expression in circulating Sézary cells suggest that the sequential activity of CD39 and CD73 ectoenzymes scavenges ATP and generates immunosuppressive adenosine in the tumor microenvironment contributing to tumor immune escape. The results inferred from this study are the starting point for more comprehensive studies towards the development of new therapies targeting the CD39/CD73 adenosinergic axis in order to overcome tumor immunosuppression, allowing the induction of effective anti-tumor immune response. [ABSTRACT FROM AUTHOR]

Targeted therapies for cutaneous T-cell lymphoma (CTCL) are limited and curative approaches are still lacking. Relapses and drug-induced side effects are major challenges in the therapeutic management of CTCL patients, resulting in an urgent need for new, effective therapies. Expression of CD30 receptor is usually restricted to a small population of activated B- and T-cells, but is also found in hematologic malignancies, such as CTCL. In mycosis fungoides (MF) its expression seems to be associated with advanced disease stage and large-cell transformation. However, the functional role of CD30 in CTCL remains unknown. Consequently, this study aims to determine 1) CD30 and CD30 ligand (CD30L) expression in CTCL cell lines and primary CD4-positive cells from CTCL patients, 2) the dynamics of CD30 expression over time and after treatment, 3) CD30 function in vitro , ex vivo and in vivo , 4) mechanisms involved in CD30 signaling. The CTCL cell lines HH, SeAx and HUT-78 were used for in vitro experiments. For ex vivo analysis, primary CD4-positive T-cells isolated from fresh blood samples of patients with Sézary syndrome were used. Cells were challenged with dimethyl fumarate for 24 hours. CD30 was stimulated via its natural ligand. Methods used for expression and pathway analysis were FACS, western blot, PCR and luciferase assay. For in vivo experiments, CTCL cells were suspended in PBS/Matrigel (1:1, vol/vol) and injected intradermally into the right flank of female NOD/SCID/Il2Rg null (NSG) mice. After development of tumors, CD30L was injected into the lesions. We found that CD30 activation can influence viability of CTCL cells in vitro , which is currently under investigation in an in vivo setting. Involved mechanisms include the MEK/ERK and NF-κB pathway. The highest CD30 expression was detected in the HH cell line. The primary CD4-positive cells analyzed so far were negative for CD30 surface expression. However, intracellular CD30 protein was detectable via western blot. CD30 levels were influenced by cell culture conditions in HH cells and significantly reduced upon therapeutic NFκB inhibition in HH, SeAx and HUT-78 cells. Our results indicate a therapeutic potential of CD30 receptor stimulation as a new targeted therapy in CD30-positive MF in vitro , which has to be proven in vivo. Furthermore, we found a dynamic nature of CD30 expression in CTCL, which might account for the described effectiveness of the antibody-drug conjugate brentuximab vedotin directed to CD30 also in patients diagnosed as CD30 low-expressing. [ABSTRACT FROM AUTHOR]

Sézary syndrome (SS) is an aggressive leukemic variant of cutaneous T-cell lymphomas (CTCL) for which current available treatments do not provide long-term responses. Two epigenetic-modulating agents belonging to the family of histone deacetylase inhibitors (HDACi), vorinostat and romidepsin are FDA approved for advanced stage CTCL. However, the rationale for using such therapies in SS and their biological impact are not well defined. The majority of cancer cells achieve proliferative immortality by activating or upregulating the normally silent human Telomerase Reverse Transcriptase (hTERT) gene. Sezary cells do not escape to this phenomenon. As the hTERT promoter is rich in CpG, we investigated the contribution of epigenetic mechanisms in its re-expression. We analyzed hTERT -promoter methylation status in CTCL cells compared to healthy cells. Nine CTCL cell lines including, five SS cell lines were experimentally investigated (HuT78, the unique commercial SS cell line and four newly developed SS cell lines from our laboratory (PMID: 33106625). Gene-specific methylation analyses revealed a common promotor hypermethylation pattern exclusively observed in tumor cells. We explored hTERT promoter methylation status under the pressure of a demethylating agent approved for the treatment of several hematological disorders (5-azacytidine) by comparison with clinically approved HDACi (romidespin and vorinostat). Surprisingly, romidespin, vorinostat or 5-azacytidine could each reduce hTERT expression level without altering the methylation status of hTERT promoter. To go further, we analyzed the functional effect of the aforementioned epidrugs on the clonogenic capacities of Sézary cells using the soft agar assay. Our data revealed that, besides hTERT downregulation, epidrugs reduced the proliferative and the tumor formation capacities in Sézary cells in vitro. Our first report on hTERT promotor methylation status in CTCL suggests that hTERT promotor methylation status is a hallmark of neoplastic CTCL cells. Our results also provide evidence for functional consequences of epidrugs treatments on tumor formation capacities in Sézary cells in vitro. Indeed, the present investigation states that Sézary cells' clonogenic capacity correlates well with hTERT expression level under epigenetic drugs pressure. The present findings represent a step forward towards a better understanding of the relationship between targeting epigenetic modifiers in a cell-context–dependent manner and the response generated at the cellular levels. [ABSTRACT FROM AUTHOR]

In cancer, the lack of early diagnostic biomarkers is a challenge, results in delayed diagnosis, and can seriously affect treatment and prognosis. Therefore, defining accurate methods for early identification of rare malignant cells is of pivotal importance. We explore the potential of artificial intelligence (AI) to uncover tumor-defining cells in Sézary syndrome (SS), a rare type of skin lymphoma. We established a 37-antibody mass cytometry panel to generate single-cell data from peripheral blood and trained an AI model, called CellCNN, on the datasets. CellCNN is a supervised machine learning algorithm that trains a convolutional neural network with a single layer using labelled single-cell data as inputs. Our study included a discovery cohort of 60 individuals (20 Sézary syndrome patients and as comparators 20 healthy donors and 20 atopic dermatitis patients) and a validation cohort of 33 individuals, containing 11 individuals of each group. Algorithm performance was assessed with area under the curve (AUC), specificity, sensitivity, and F1 score (weighted average of sensitivity and specificity). We discovered a combination of cell surface markers by mass cytometry to sensitively and specifically identify tumor-defining SS cells in blood and validated our results in a blinded setting with zero false positives and only one false negative prediction (AUC of 0.98, sensitivity of 0.91, specificity of 1.0, F1 score of 0.95). To allow easy implementation into routine diagnostics, we further reduced the number of markers to 15 to be used in standard FACS assays. Diagnostic predictions with those FACS settings still achieved very high sensitivity of 1.0 and specificity of 0.91 (AUC of 0.94, F1 score of 0.95). Furthermore, we could show that our model can even classify blood samples from SS patients at an early stage of initial clinical manifestation, which is currently a grand challenge, with a high accuracy (AUC of 0.93, sensitivity of 1.0, specificity of 0.91, F1 score of 0.95). This study reports the successful validation and performance of an AI-based algorithm to detect rare tumor-defining cells in lymphoma blood samples. Furthermore, our model allows to accurately distinguish tumor samples at initial clinical suspicion and in advanced disease from its benign mimicker. Our findings pave the way for an easy-to-implement and sensitive diagnostic approach to facilitate early diagnosis of Sézary syndrome, and other tumors with blood involvement as well. [ABSTRACT FROM AUTHOR]

Linked Article: Roelens et al. Br J Dermatol 2022; 186:1010–1025. Sézary syndrome (SS) is a rare form of skin cancer (T‐cell lymphoma) arising in the skin from white blood cells. Management involves many successive treatments, as disease relapse and lack of response to treatment often occur. Also, patients with SS experience immunodeficiency as their disease progresses, this means their immune system is less able, or completely unable, to fight infectious diseases and cancer. Mogamulizumab therapy has been shown to increase progression‐free survival in patients with SS. It is a monoclonal antibody treatment. This study from France included 26 patients with hard‐to‐treat SS that had not responded to at least one systemic treatment (given by mouth or injection). The authors wanted to find out more about how mogamulizumab might improve patients' long‐term clinical response. They undertook various investigations including using a process called multicolour flow cytometry. Both malignant and non‐malignant T‐cells were monitored. They found that mogamulizumab not only eradicates malignant cells but also potentially contributes to the restoration of efficient immunity. In conclusion, this study provides new insights that will help with the management of this condition. Linked Article: Roelens et al. Br J Dermatol 2022; 186:1010–1025. [ABSTRACT FROM AUTHOR]

A severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread worldwide during 2020, was declared as a public health emergency and potentially life-threatening. Patients with hematologic malignancies may have an increased risk of severe COVID-19, due to immunosuppression related to the underlying disease and its treatment. In the absence of specific data, potential risk factors for severe events of COVID-19 should be considered as for other community acquired respiratory virus (CARV) infections: >60 years, severe immunodeficiency, chemotherapy treatment. We present three patients with Sézary syndrome (SS) and COVID-19 infection. We aim to report the outcome of COVID-19 in patients with SS treated at the department of Dermatology of the Hospital Italiano de Buenos Aires. Patients with SS who were diagnosed positive for COVID19 infection, during worldwide pandemic in 2020. We collected retrospectively clinical data, SS evolution and treatment response. A 58-year-old male with hypertension was diagnosed with SS stage IVA1 in July 2014, he received multiple systemic treatments such as extracorporeal photopheresis (ECP), IFN 2b, bexarotene, with partial response (PR) and eventually stable disease. In August 2020, he was hospitalized due to fever, dry cough and progressive cutaneous disease. SARS-CoV2 was confirmed, requiring invasive mechanical ventilatory (IMV) in the ICU and systemic corticosteroids. The clinical course improved with complete response (CR) of cutaneous disease and persistence of hematologic involvement. He was discharged 3 months later with no SARS-CoV-2 sequels. A 66-year-old female with breast cancer in 2002 treated with RT and tamoxifeno was diagnosed with SS stage IVA1 in March 2012. She was treated with IFN 2b, TSEB, vorinostat and ECP with CR, relapse and then PR. In November 2020 she started chemotherapy due to cutaneous and nodal progression. A month later, she required hospitalisation and IMV due to dry cough and respiratory distress, SARS-CoV-2 was confirmed. She died 7 days later due to progression of respiratory distress. An 86-year-old male with arterial hypertension was diagnosed with SS stage IVA1 in March 2017. He received ECP, methotrexate, with PR. In February 2021 he was hospitalized due to dry cough, headache with cutaneous disease relapse. Laboratory parameters showed pre-existing lymphopenia. SARS CoV-2 was confirmed. He was admitted to the ICU requiring IMV due to respiratory distress, and died 15 days after. Among our patients, two had several associated comorbidities and risk factors for a severe event of COVID-19, besides case 3 presented pre-existing lymphopenia at presentation. Case 1, despite his comorbidities and IMV, developed a favorable clinical course. To our knowledge there are many unknown factors and limited published studies, describing COVID-19 outcomes in patients with SS, most of them based on case reports. [ABSTRACT FROM AUTHOR]

Mycosis fungoides (MF) and Sézary syndrome (SS) are forms of primary cutaneous T-cell lymphomas. The clinical aspects and symptoms vary greatly depending on the stage of disease. These are rare diseases which remain incurable, but there is a wide variety of treatment options. Few studies have been performed on this topic in Sweden and there is an emerging need for descriptive studies and research in this field. The aim of this study is to describe and analyze diagnostic criteria for patients with MF/SS and to describe treatment modalities and evaluate treatment response of this patient-group. This is a descriptive retrospective study based on the data collected in the Primary Cutaneous Lymphoma quality register at the department of Dermatology and Venerology at Sahlgrenska University Hospital between 1997-2021. Eighty-two patients, median age 55.9 years (range 8.6–91.7) at diagnosis, with MF (n=70) or SS (n=12) were included. Male to female ratio was 1.7:1. From the onset of skin symptoms until initial diagnosis took on average 2.7 years (median, range 0.1–42.4 years). The subtypes of MF were folliculotropic (n=9), syringotropic (n=4), hypopigmented (n=1) and hyperpigmented (n=1). The majority of the patients (n=63) were diagnosed at early-stage disease (IA-IIA) while 18 patients were diagnosed with advanced stage disease (IIB–IVB). Overall disease progression was seen in 10% (n=8) of the patients. Eight (10%) patients were deceased out of which three (3.8%) deaths were associated with MF/ SS related causes. The most common co-morbidities in our study population were overweight 31%, hypertension (29%), obesity (18%), hyperlipidaemia (16%), diabetes mellitus (15%), and dermatitis (11%). The most common malignancies were basal cell carcinoma (16%), haematological malignancies (7%), malignant melanoma (6%) and prostate cancer (6%). Topical corticosteroids (96.3%), UVB (57.3%) and PUVA (47.6%) were common choices of treatment in all patients, along with acitretin in those with advanced stage disease. No significant difference in overall response was detected between patients with early-stage disease and advanced stage disease for any treatment. This study contributes to knowledge on epidemiological and clinical features in addition to diagnostic findings in patients with MF and SS diagnosed and/or followed up for a long period of time in Western Sweden. We observed increased risk of cardiovascular disease and higher risk of developing other malignancies. This study suggests that treatment for these patients have been adequately adjusted for stage and highlights the importance of topical corticosteroids as an integrated part of the treatment. UVB and PUVA are beneficial treatments for patients with early-stage disease, but could also be valuable for patients with advanced disease along with acitretin. Hopefully this study will inspire to and be integrated in future research ahead. [ABSTRACT FROM AUTHOR]

Cutaneous T-cell lymphomas (CTCL) are a rare, heterogenous group of T-cell lymphomas that primarily manifest in the skin. Mycosis fungoides (MF) and Sézary syndrome (SS) are considered the classic types of CTCL. The diverse manifestation of CTCL results in a wide range of symptoms with a possible mild to severe impact on quality of life (QoL) depending on the disease stage. Previous studies on QoL in CTCL patients report diverse patient populations and use many different QoL instruments. In the current literature a clear overview on the influence of the different stages of disease (early MF, late-stage MF/SS or total group) on the QoL is lacking. Therefore, a systematic search of the literature was conducted using the PubMed, Embase, PsycINFO, and Web of Science databases. Studies were included if they described QoL in patients with MF and SS retrieved by 14 standardized instruments or qualitative interviews. In total 24 studies were included using 18 different questionnaires to report on dermatology-specific, cancer-specific, and generic QoL. The effect on QoL was found to be greater in patients with late-stage disease as compared to early-stage disease, with significant impairments on functional, emotional, and physical domains. Nonetheless, even in patients with limited disease, QoL was mildly to moderately affected. Overall, pruritus was the most frequent reported and most bothersome symptom. Significant influence of the disease on daily life activities were found, not only in patients but also on caregivers and family. This broad, structured overview on QoL in MF and SS patients underlines the influence of disease stage on QoL, and therefore recommends future studies to distinguish between disease stages when reporting results. Furthermore, this overview can inform clinicians in clinical practice by creating awareness of QoL deficits according to disease stage. [ABSTRACT FROM AUTHOR]

Mycosis fungoides (MF) and Sézary syndrome (SS) are rare and chronic non-Hodgkin lymphomas that present in skin and can progress to involve extracutaneous sites. For many patients, skin lesions are disfiguring with an intractable itch. Other symptoms can include difficulty regulating body temperature and sleep disturbance. Symptomatic MF and SS can have a negative impact on health-related quality of life (HRQL). Mogamulizumab is approved in Europe for the treatment of adult patients with MF or SS after at least one prior systemic therapy based on the efficacy and safety demonstrated in the phase 3 MAVORIC trial (NCT01728805). To capture personal descriptions from patients and their spouses of the burden of MF and SS before starting mogamulizumab treatment and their early treatment experience. Five patients and three spouses were recruited at two hospital clinics in the UK. Following informed consent, 1:1 semi-structured, 60-minute telephone interviews were conducted. Participants were asked about their experience of symptoms and impact of their condition on domains of HRQL prior to starting treatment with mogamulizumab, and any changes during the first six months of treatment. Spouses were also asked about any impact on their role as a carer since mogamulizumab treatment was initiated. Interviews were transcribed, responses coded, and narrative summary provided. Prior to treatment with mogamulizumab, patients and their spouses reported moderate-to-severe problems with all skin-related symptoms and regulating their body temperature. The majority described fatigue and sleep problems, with spouses also reporting patients' moderate-to-severe problems with those symptoms. On starting mogamulizumab, both patients and their spouses described rapid improvement in itching, with gradual improvement in skin flaking, redness, and pain/discomfort. Similarly, body temperature regulation, fatigue and sleep quality gradually improved in the first six months of treatment. There was a wide distribution in the reported level of disease impact on HRQL domains prior to treatment with mogamulizumab including emotional well-being, ability to self-care, activities of daily living, social well-being, and family relationships. Symptom presentation on hands and feet was associated with greater impact on these QoL domains. For those with moderate-to-severe problems pre-treatment, patients and spouses described a meaningful reduction in the level of impairment, sometimes within the first few months of treatment. Spouses reported that their everyday life as a carer had positively changed since their partner had received treatment with mogamulizumab. Participants described multiple symptoms and the detrimental impact on their HRQL prior to treatment with mogamulizumab. There was a rapid improvement in itching with improvement in other symptoms and overall HRQL in the first six months of mogamulizumab treatment. [ABSTRACT FROM AUTHOR]

Mogamulizumab is an anti-CC chemokine receptor 4 (CCR4) monoclonal antibody that has been approved for the treatment of adult patients with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) who have been treated with at least 1 prior line of therapy. We present the case of a 76-year-old woman diagnosed with SS refractory to all prior lines of therapies, who presented a prolonged response to Mogamulizumab in the peripheral blood, skin, and lymph nodes. However, after almost 1 year of treatment, the patient developed psoriasis-like patches (confirmed by histology), and arthritis mainly in the shoulder girdle, hip and cervical region diagnosed by MRI and ultrasonography as a polymyalgia rheumatica-like. After consensus between hematologists, dermatologists and rheumatologists, the patient was treated with low-dose prednisone (5–10 mg) daily and mogamulizumab was tapered (dose widening to every two months), with great control of side effects and maintenance of complete response of her SS (skin, peripheral blood, and lymph nodes) until now. Mogamulizumab has been shown to be an effective and well tolerated therapy for patients with relapsed and refractory MF/SS with excellent activity in the circulating component of the disease. Common adverse events include infusion reactions and drug eruptions and increase of the risk of immune-mediated complications such as autoimmune disease and acute graft-versus-host disease following transplantation. However, we still must be aware of new drug eruptions and side effects that require prompt diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Mycosis fungoides (MF) and Sézary syndrome (SS) are the most frequent cutaneous T-cell lymphomas. These tumors have a chronic progradient course. Hitherto there is no evidence of effective therapy, particularly of the late-stage of the diseases. About 30% of the patients are not effected by interferon, radiotherapy and combined treatment regimens. Patients' age (median age 62 years) limits therapy options. Several lines of previous treatment could lead to tumor resistance and higher accumulated toxicity. Thus, use of potentially effective chemotherapeutic agents in lower doses will reduce myelotoxicity and expand the cohort of patients. Gemcitabine is an effective medication in treatment of MF/SS. Its efficacy is preserved in small doses with prolonged duration of infusion and allows to decrease myelotoxicity. It was firstly discovered in therapy of solid tumors. In current study 14 patients were involved with resistant forms of MF/SS (10 patients with MF, 3 with SS, and 1 case of MF with transformation into large cell lymphoma). We used 6-hour infusion of gemcitabine at dosage of 250 mg/m2. 86% of patients achieved a general response: 29% complete remission, 50% partial remission, 21% stabilization of disease, 14% (2 patients) progression. Present study showed promising results in treatment of patients with advanced stages of MF/SS which had at least two preceding lines of therapy without an effect. Common response (PR/CR) was received in high percent of cases. This treatment protocol is reproducible in elderly patients. For long-term conclusions further studies are required. [ABSTRACT FROM AUTHOR]

Mogamulizumab is a novel defucosylated monoclonal antibody targeting C-C chemokine receptor 4 (CCR4) that eradicates Sézary cells via antibody-dependent cellular cytotoxicity. Treatment of Sézary syndrome with mogamulizumab has recently shown an increase in progression-free survival compared to vorinostat in previously treated cutaneous T-cell lymphoma. To investigate immune side effects of mogamulizumab in Sézary syndrome patients. Three cases of Sézary syndrome patients treated with mogamulizumab who developed clinically confirmed vitiligo were reported. Case 1 was a 66-year-old woman from Tunisia. Seven months after the administration of mogamulizumab,she developed vitiligo on her face and hands while still in complete remission of Sézary syndrome. Case 2 was a 72-year-old woman from Martinique, with no history of autoimmune disease, who was diagnosed with stage IVA1 Sézary syndrome. The patient received multiple lines of treatment with no improvement. After six months of mogamulizumab treatment, while still on treatment, the patient progressively developed well-demarcated depigmented patches on the scalp, upper limbs, and trunk, consistent with vitiligo. Case 3 was a 38-year-old woman from France, who was diagnosed with Sézary syndrome in October 2019. Mogamulizumab therapy was started in December 2019. Eight months later, she developed histologically confirmed vitiligo on her legs. Vitiligo can be another autoimmune manifestation associated with mogamulizumab, and the occurrence of vitiligo could be a favorable predictive factor for response to treatment. [ABSTRACT FROM AUTHOR]

Sézary syndrome (SS), the leukemic variant of cutaneous T cell lymphoma (CTCL), shows high relapse rates and poor prognosis, which complicates the clinical course as well as the treatment. The circulating atypical T cells known as Sézary cells (SC) display a CD4+/CD8–T helper cell phenotype. A diagnostic marker profile of SC is defined by loss of CD7 and/or CD26 and increased CD158k expressions. Due to frequent relapses and treatment-related side effects of current therapies as well as progressive therapy resistance of SS, there is an urgent need for the development of effective and well-tolerated therapeutic options. Dimethyl fumarate (DMF) is a potent NFκB inhibitor and is being used in a clinical phase 2 study for CTCL patients. Our group has shown that DMF induces apoptosis, specifically in malignant CTCL cells while sparing the healthy T cells. Extracorporeal photopheresis (ECP) is an established standard treatment for erythrodermic CTCL such as SS. We found in 3 SS patients that the new targeted combination therapy of DMF and ECP (in part with interferon-alpha) decreased the SC count drastically. All of these patients had received ECP and DMF separately as monotherapies before receiving the combination therapy, but had developed a resistance. However, with the combination therapy approach patients had long-term complete remissions in the blood and the interval between therapies, a parameter for the efficacy and tolerability of the treatment, was at least 3 times higher than for all other CTCL therapies. In light of these interesting clinical findings, our aim is to investigate ECP and DMF as a novel combined therapy in CTCL cell lines and patient derived CD4+ T cells and understand their synergistic effects based on immunomodulation and cell death. Hence, the underlying cellular and molecular mechanisms of this new therapeutic approach will be identified. CD4+ T cells isolated from peripheral blood monocytes of SS patients as well as the CTCL cell lines SeAx, HH and Hut-78 were treated ex vivo with UVA to mimic ECP therapy in combination with DMF treatment. SS patient cells show different cell death responses to the combination treatment depending on the previous therapies that the patients received. Additionally, in CTCL cell lines combination treatment led to distinctive cell death patterns as consequence of different signaling pathways and alterations that they represent. We will further study the synergistic mechanism of the combination treatment and unveil involved pathways by performing single cell RNA sequencing analysis of CTCL patient cells and RNA sequencing analysis in cell lines. Furthermore, activity of NFKB subunits and the cytokine profile present in the serum of patients will be investigated before and after the combination treatment. In addition, we aim to study this combinatory effect also in vivo in a CTCL mouse model in order to eventually translate it into a clinical study. [ABSTRACT FROM AUTHOR]

Sézary syndrome (SS) is an aggressive form of cutaneous T-cell lymphoma with a diverse set of mutated genes. Using previously published datasets, we reanalyzed the copy number landscape of SS and detected whole genome amplifications in 20% of all SS samples. Furthermore, we determined the molecular time of copy number occurrence and could show that single chromosome amplifications are extremely early events in the tumorigenesis. Contrastingly, whole genome duplications are extremely late events. Taken together, our results provide initial cornerstones for building a model of SS tumorigenesis based solely on genomic data. [ABSTRACT FROM AUTHOR]

Black patients can face a higher incidence and poorer prognosis from cutaneous T-cell lymphoma (CTCL) compared to their white counterparts yet race is not a known factor in the treatment of CTCL. The significance of race, particularly in the treatment of early-stage CTCL using extracorporeal photopheresis (ECP), is not well understood. To characterize race-based and stage- based differences in ECP utilization and response among adults with mycosis fungoides and Sézary syndrome. A 10-year retrospective chart review was performed at a single tertiary referral center institution. Among total 42 qualifying CTCL patients that received, 57.1% were female, 47.6% identified as black, and 54.7% presented with early-stage CTCL (Stage IA–IIA). There were no race-based differences in the number of systemic therapies trialed before ECP (p=0.8), use of ECP as 1st-line treatment (p=0.5), number of ECP treatments (p=0.4965), or use of concomitant medications (e.g. interferon, oral retinoids). White patients began ECP sooner than black patients following CTCL diagnosis (median 16 vs 4 months; p=0.08). Black patients were significantly more likely to face progressive disease following ECP (p=0.04) and had a shorter duration of response (16.1 vs 36.5 months; p=0.0455). This was a retrospective study. There are race-based differences in ECP use and disease progression among adults with CTCL. Future research may investigate the source of these disparities, be they attributable to biologic differences in disease or differential treatment prescription. [ABSTRACT FROM AUTHOR]

Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of non-Hodgkin lymphomas that differ greatly in clinical presentation and prognosis. Mycosis fungoides (MF) is the most frequent subtype. Sézary syndrome (SS) is less prevalent but has a much more unfavourable prognosis. Previous studies have shown that the incidence of CTCL has tripled between 1970 and 2000 but since then has stabilized. However, data on the incidence of MF and SS in the Netherlands have never been published. The aim of the present study was to estimate the changes in incidence of newly diagnosed MF and SS in the Netherlands over the last 20 years. Annual incidence rates were retrieved from the Dutch Cutaneous Lymphoma Registry (DCLR) between January 2000 and December 2019. In all cases, the diagnosis was based on the clinicopathological criteria of the World Health Organization European Organisation for Research and Treatment of Cancer classification and confirmed by an expert panel of dermatologists and pathologists at a periodical meeting of the Dutch Cutaneous Lymphoma Working Group. We calculated the number of registered patients with MF and SS per 100 000 persons, corrected for the size of the Dutch population. 1044 patients with MF, including 238 patients with folliculotropic MF (FMF), and 93 patients with SS were included. In 2000, the corrected number of cases of MF was 0.19 per 100 000 persons, while this was 0.35 per 100 000 in 2010 and 0.46 per 100 000 persons in 2019. This means that a 2.42-fold increase, corrected for Dutch population growth, was seen between 2000 and 2019 for the incidence of MF in the Netherlands. In 2000, 2010 and 2019 the corrected incidences for SS were 0.013, 0.018 and 0.075 per 100 000 persons, respectively. The overall increase for SS was 6.0-fold corrected for the Dutch population between 2000 and 2019. In summary, a significant increase of patients with classical MF, FMF and SS included in the DCLR was seen over the past 20 years. In contrast to previous studies that suggest a stabilization since 2000, this study shows that the incidence of patients with MF and SS in the Netherlands increased 2.42-fold over the past two decades. [ABSTRACT FROM AUTHOR]

Illness perception describes patients' internal beliefs about their illness and their resulting psychosocial impact. This concept is important because it can give healthcare providers a tool to identify issues that may need to be addressed with their patients, but few studies have investigated illness perception in cutaneous T-cell lymphomas (CTCLs). CTCL is a chronic and often debilitating group of malignancies that can have an indolent but remitting course. Treatment options may also be burdensome to the patient; therefore, it is important to gain an understanding of CTCL patients' beliefs about their disease and how those beliefs impact their quality of life (QOL). Moreover, the COVID-19 pandemic offers a unique opportunity to investigate how significant disruptions in access to healthcare have impacted illness perception and QOL. The objectives of this study are to identify disease understanding in patients with CTCL, investigate the impact additional education modalities have on disease understanding, and whether disparities exist between specific groups of patients. This study also aims to determine how the COVID-19 pandemic impacted healthcare-related QOL in this population. CTCL patients of the Johns Hopkins Hospital above the age of 18 are recruited for this study. Patients are given an electronic survey containing the Illness Perception Questionnaire-Revised (IPQ-R), Skindex-29, FACT-G7, and selected questions based on the Household Pulse survey to assess COVID impact on QOL. Patients are then randomly selected to view an educational PowerPoint with educational material on CTCL, in addition to verbal education routinely given during their visit. Follow-up responses to these questions will be collected at 2 and 6 months after the initial survey. In this ongoing study, we anticipate a total sample size of 100 patients. Thus far, initial survey responses have been collected from 39 patients, 60% who identified as male and 40% who identified as female. 44% of patients identified as "White," 36% identified as "Black/African American," 10% as "Hispanic/Latino," 8% as "Asian," and 2% as "Other." 34% of patients were Stage 1B at time of survey. Most patients (22.99 + 4.2) perceived their diseases to be chronic but endorsed a high sense of personal control (21.61 + 4.2) and therapeutic control (18.98 + 2.6) over their conditions. Patients between 40-59 demonstrated higher disease consequence, as did patients within the Black/African American patient group. Illness coherence was also significantly higher for White patients when compared to Black/African American patients. Therefore, it appears that patients 40-59 may be more emotionally and practically affected by their disease, potentially because these patients are at the highest level of work and life productivity. Further, these results indicate that a gap may exist within the Black/African American community that may negatively affect these patients' QOL. The outcomes from additional initial and follow-up surveys from this ongoing study will provide insight into the use of additional educational modalities to improve patient understanding of CTCL, with the goal of addressing common patient misconceptions about the disease, improving educational resources, and identifying actionable paths to diminish the inequities identified by this study. [ABSTRACT FROM AUTHOR]

Mogamulizumab, an anti-CCR4 monoclonal antibody, has shown to increase progression-free survival in cutaneous T-cell lymphoma. We hypothesized that, besides the targeted depletion of Sézary cells (SCs), mogamulizumab may contribute to immunological changes, improving clinical response. We also explored potential phenotypic changes of SCs during treatment, potentially resulting in resistance/tumor escape to therapy. We have prospectively followed 26 SS patients with B2 stage before mogamulizumab initiation. We performed extended phenotypic characterization of malignant and benign compartments, using KIR3DL2, TCRVb and/or CD26 markers, every month, up to one year. Prior to mogamulizumab, the non-malignant (benign) subset of CD4+ T-cells displayed exhausted phenotypes. When comparing SCs, benign and controls CD4+ T cells, our data showed a gradient of PD1, TIGIT, DNAM, CD27, CD28 and CD70 expression. All patients presented SCs with heterogeneous surface phenotypes and differential expression of individual markers were found within distinct malignant subsets. An early complete blood response was observed in 17/26 patients and was associated to a higher baseline CCR4 expression on SCs. A drastic decrease in benign T-cells and activated Treg absolute counts was observed during the first 4 weeks. Long-term follow-up revealed the emergence of an immune restoration involving CD8+ and naive and TSCM CD4+ subsets, concomitant with almost complete disappearance of exhausted T lymphocytes. Finally, the development of resistance/tumor escape to mogamulizumab therapy allowed us to longitudinally follow phenotypic characteristics of SCs and revealed the emergence of CCR4–SCs displaying significant changes in their heterogeneity patterns. In conclusion, mogamulizumab is not only aimed at eradicating malignant-cells but is likely contributing to the restoration of an efficient immunity. This is of importance as a competent immune status is required for effective anti-infectious and anti-tumoral responses as well as for the efficacy of further immunotherapies. [ABSTRACT FROM AUTHOR]

The prognosis of Sézary syndrome (SS) and mycosis fungoides (MF) depends on lymph node (LN) involvement. The usefulness of LN image-guided core-needle biopsies (CNBs), instead of surgical sampling, has been poorly evaluated. To determine the prognostic value of LN CNB in MF/SS. A retrospective search was conducted to identify all LN biopsy specimens of MF/SS between 2008 and 2019. Biopsies were staged according to the International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer (ISCL/EORTC) criteria. We performed immunolabelling and determined the tumour clone frequency (TCF) by high-throughput sequencing of the T-cell receptor beta locus. We included 119 consecutive biopsies from 100 patients, 45 with MF and 55 with SS. N1, N2 and N3 stages were diagnosed in 34 (29%), 26 (22%) and 59 (49%) cases, respectively. The TCF, Ki67 index, and percentage of cells positive for thymocyte selection-associated high mobility group box protein (TOX), programmed cell death protein 1 (PD1), killer cell immunoglobulin-like receptor 3DL2 (KIR3DL2) and cluster of differentiation (CD)30 were all positively correlated with the N stage. Median overall survival (OS) for N1/N2 vs. N3 patients was 42 months (range 26–not reached) vs. 14 months (range 5–30), respectively (p<0.001). In univariate analyses, an age >75 years, LN short-axis diameter >15 mm, N3 stage, presence of large-cell transformation, TOX >60%, PD1 >25%, Ki67 >30%, KIR3DL2 >15%, CD30 >10% and TCF >25% were identified as adverse prognostic factors. In multivariate analyses, only an age >75 years and Ki67 index >30% were associated with reduced OS. We developed a new prognostic index associating the N stage and the Ki67 index, which better discriminates N3 patients with poor prognosis. CNB allows an objective assessment of the LN involvement in MF/SS, relevant for staging and prognosis. [ABSTRACT FROM AUTHOR]

Prolonged complete remissions (CRs) are rare in advanced-stage cutaneous T-cell lymphomas (CTCLs). Ifosfamide + etoposide (I+E) have been used to treat lymphomas, combined with platinum-based agents in Hodgkin disease or non-Hodgkin lymphomas including peripheral T-cell lymphomas. Monoclonal antibodies have induced long-term remissions in CTCL but are usually poorly effective in transformed disease Allogeneic haematopoietic stem cell transplantation (alloHSCT) holds a potential for cure but relies on the existence of a pretransplant CR, which may require the use of chemotherapeutic regimens. To our knowledge, to date there are no published data on I+E efficacy and tolerance in advanced refractory CTCL. We performed a retrospective monocentre study on 28 patients with mycosis fungoides (MF, n=15) or Sézary syndrome (SS, n=13) treated with I+E between 2012 and 2019. In this study, I+E showed antitumor activity in these heavily pretreated patients with CTCL, with an ORR of 43%, and no significant difference between the full-dose and reduced-dose regimens in terms of ORR or SAE frequencies, indicating that the reduced regimen may be a suitable option in fragile patients. In conclusion, I+E is a valuable therapeutic option in patients with advanced, refractory CTCL. [ABSTRACT FROM AUTHOR]

Despite increasing availability of therapeutic agents, Sézary syndrome (SS) remains associated with a generally poor prognosis. Typically, patients endure multi-line treatment, frequently with disappointingly short durations of clinical benefit. Time to next treatment (TTNT) measures the interval from the date of commencement of one therapy to the date of initiation of the next line of therapy, and provides a simple and reliable surrogate for duration of clinical benefit outside of clinical trials [ 1 ]. In this multi-centre collaborative study, we review the clinical outcomes of patients with SS/ mycosis fungoides (MF) with B1-2 blood involvement, and compare the treatment efficacy of the currently available systemic therapies using TTNT. In this retrospective analysis, eligible patients were identified from University Hospital Birmingham, Birmingham, Peter MacCallum Cancer Centre, Melbourne, and Hôpital Saint Louis, Paris. Strict eligibility required biopsy-proven MF/SS, with B1-2 blood involvement, newly diagnosed during 1/1/2012 to 31/12/2020. Studied treatment groups include monotherapy and combination therapies of interferon, methotrexate, ECP, HDAC inhibitors, retinoids, monoclonal antibodies, biologicals, chemotherapy, allogeneic stem cell transplant, and best supportive care. The primary endpoint was TTNT, with the aim to compare the efficacy of these systemic therapies. 178 patients were eligible. 77 (43%) were female, median age was 66 (17–94) years. At diagnosis, 35 (20%) patients had Stage IIIB, 131 (74%) Stage IVA and 12 (7%) Stage IVB MF/SS. Large cell transformation was present in 35 (20%) patients at time of diagnosis. A total of 802 treatment lines were delivered, of which 711 were systemic therapies and were included for analysis. Of the 178 patients, 168 received systemic therapy first-line: the most commonly delivered first-line systemic treatments were ECP-containing regimens in 42 (25%) patients (ECP-monotherapy, 17, ECP-based combination therapy, 25), retinoid monotherapy in 34 (19%), interferon monotherapy in 25 (14%) and methotrexate monotherapy in 25 (14%) patients. TTNT and overall survival data will be presented. As a surrogate for duration of clinical benefit, TTNT is a useful endpoint to retrospectively compare the treatment efficacy of currently available systemic therapies for SS/MF with B1-2 blood involvement. Long-term disease control with durable clinical benefit remains the ultimate goal for patients with SS/MF with blood involvement. [ABSTRACT FROM AUTHOR]

Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common types of cutaneous T-cell lymphomas (CTCL). The assessment of skin involvement is critical for the correct TNMB classification, however, prone to intra- and interobserver variability. The aim of this project was an automated identification of skin lesions with artificial intelligence on clinical images of CTCL patients to reduce subjectivity in the evaluation of skin lesions. The analysis included two datasets. The first set included 50 standard photographic clinical images of three CTCL patients with multilocular disease. These images were manually segmented by a dermatologist to obtain binary masks used as ground truth. The second set included 50 lesional images with a calibration marker of 15 patients retrieved with mobile devices (iPhone, iPad) and manually marked for lesional areas on the device. For both cohorts, all images were split with a ratio of 80:20 into training and validation set and analyzed using a convolutional neural network (CNN) created in cooperation by the imito AG, Zürich, the department of informatics of the University Hospital and Institute of Medical Informatics at Luebeck University. Overall, 15 CTCL patients (11 M, 4 F; M:F 2.75), median age seventy (41-80 years) were included. 13 patients were diagnosed with MF, stages IA (3), IB (5), IIB (4), IIIA (1) and two patients with SS. The median mSWAT was 8 (ranges 1–85). Due to the large image size, all images were split into smaller pixel sizes, so that the final image set included 931 images for the standard photographs and 1123 images in the mobile device cohort. The CNN was created as a UNet and trained with a Google OpenImages dataset. Several analyses were performed and the finally used variant chosen based on the test accuracy (F-score and Jaccard index). Within the first set of images, lesional areas were correctly identified in 79.8% and non-lesional in 89.2%, compared to 19.8% and 96.8% in the second set. The lesional areas were digitally calculated in the second set. The image classification in the first set was considered very convincing. However, the discrepancy between the results of the analysis of the first and second set appear striking with a much better classification and correct identification of lesional areas in the first set. Both approaches were based on trained algorithms as explained. Therefore, we presume that the inferior recognition in the mobile cohort is most likely due to a less exact mark-up of the lesions on the device and the restriction that only one lesion could be marked as a lesion. Overall, we consider that the standardized assessment of cutaneous involvement in CTCL may be helpful in the evaluation of skin lesions in daily practice and in clinical trials. With further development, an automated full-body skin lesion recognition and calculation of involved areas might be feasible. [ABSTRACT FROM AUTHOR]

Sézary syndrome (SS) is a rare, aggressive leukemic form of cutaneous T-cell lymphoma characterized by generalized erythroderma, lymphadenopathy and circulating malignant CD4+ T cells (Sézary cells). Sézary syndrome evolves very quickly, patients are severely immunocompromised and their quality of life is drastically impaired. SS prognosis remains dismal despite recent therapeutic advances. AAC-11 (Anti-Apoptosis Clone 11, also known as Api5) is a survival scaffold protein that is widely expressed in cancer cells. Recent data indicate that AAC-11 might to be one of the central molecules involved in cancer cell progression and survival. Therefore, its inactivation might constitute an attractive approach for developing novel cancer therapeutics. AAC-11 contains a heptad leucine repeat domain that constitutes a protein-protein interaction motif, allowing its interaction with several apoptosis regulatory proteins. Loss-of-function mutations of the heptad leucine repeat motif are responsible for a defect in the interaction with its binding partners and associated with an abolition of the survival properties of AAC-11. We have recently described cell penetrating peptides based on the fusion of penetratin and a portion of the heptad leucine repeat region of AAC-11 that can induce cancer cells death. This effect is not observed in normal cells, suggesting high therapeutic indices. Here we evaluated the anti-tumor effect of a novel AAC-11-derived peptide, termed RT39, in the context of Sézary syndrome. Our results demonstrate that RT39 exerts an efficient and specific cytotoxic activity towards Sézary cells, while sparring the other immune cell populations, both ex vivo on primary patient cells and in vivo in preclinical Sézary syndrome murine models. Mechanistic studies revealed that RT39 induces membranolysis of Sézary cells by means of binding to p21-activated kinase 1 (PAK1) in the context of Sézary cells plasma membrane, where PAK1 is overexpressed. Preliminary pharmacokinetic studies in mice indicated that, after intravenous, subcutaneous or intraperitoneal administration, the half-life of the peptide is of the order of 30 minutes, but the elimination phase is very prolonged with high AUCs, indicative of durable exposure. Along with excellent tolerability in mice, our preclinical results support the development of RT39 as a new therapeutic strategy in Sézary syndrome. [ABSTRACT FROM AUTHOR]

Sézary syndrome (SS) is a rare and aggressive epidermotropic cutaneous T-cell lymphoma (CTCL) defined by erythroderma, pruritis and a circulating atypical CD4+ T-cell clonal population. The diversity of Sézary cells (SC) phenotype and genotype possibly reflects either plasticity or heterogeneity that is difficult to assess, as SC are difficult to expand with very few cell lines available. Therefore, we developed six new defined culture conditions allowing the amplification of SC defined by their immunophenotype and monoclonality in 4 of 7 patients. The SC expansion in response to different culture conditions by addition of several cytokines and stromal cells is heterogeneous between patients. This shows the importance of tumor microenvironment for tumor SC growth. Engraftment of SC into immunodeficient NOD.Cg-Prkdc(scid)Il2rg(tm1Wjll)/SzJ (NSG) mice was achieved in 2 of 14 cases. Secondary xenograft by subcutaneous injection mimicked several clinical features of SS with dermal infiltration, epidermotropism and blood spreading. Such models permitted to assess the intra-individual heterogeneity of patient SC. Such subclones sharing the same TCR gene rearrangement evolved independently according to culture condition and/or after xenografting. This clonal selection was associated with phenotypic differences and limited genomic evolution both in vitro and in vivo. The long-term amplification of SC allowed the development of eight new SC lines derived from four different patients. They represent the cell of origin diversity of SC cells and new tools to evaluate their functional properties. Indeed, SC lines demonstrate differential responses to therapies (romidepsin, doxorubicin and vorinostat) according to the cells of origin of SC. The new in vivo model we developed mimicking both skin and blood involvement of SS represents a new preclinical model to test therapeutic agents as well as the mechanisms regulating the balance between blood and skin compartments of SC cells. [ABSTRACT FROM AUTHOR]

Mogamulizumab (moga), a monoclonal humanized anti-CCR4 antibody, is an effective and well-tolerated treatment for patients with mycosis fungoides and Sézary syndrome. Despite almost universal expression of CCR4 in CTCL, most patients will eventually develop resistance to moga. The mechanisms of resistance to mogamulizumab have not been characterized. An understanding of the resistance mechanisms will shed light on the disease biology and inform selection of next line therapies and the development of future CCR4-directed treatments. We identified 19 patients with mycosis fungoides or Sézary syndrome in whom mogamulizumab had been discontinued due to disease progression. Seven patients had developed resistance after an initial period of response, while 12 patients were refractory to therapy. We performed immune phenotyping and targeted next generation sequencing at the time of disease progression. We identified loss of CCR4 expression by immunohistochemistry and flow cytometry in 8 patients post treatment. Three patients were found to harbor previously undescribed, emergent CCR4 mutations targeting the N-terminal and transmembrane domains at the time of disease progression. Emerging CCR4 copy number loss was detected in 2 patients concurrent with CCR4 mutations. Acquisition of CCR4 genomic alterations corresponded with loss of CCR4 expression by immunohistochemistry. In conclusion, our study indicates that resistance to mogamulizumab in CTCL is frequently associated with loss of CCR4 expression and the emergence of CCR4 genomic alterations. This finding has important implications for management and monitoring of CTCL patients on mogamulizumab and the development of CCR4 therapies in cutaneous T-cell lymphomas. [ABSTRACT FROM AUTHOR]

Sézary syndrome (SS) is a rare, leukemic type of cutaneous T-cell lymphoma (CTCL), for which extracorporeal photopheresis (ECP) is a first-line therapy. Reliable biomarkers to objectively monitor the response to ECP in patients with SS are missing. We examined the quantitative and qualitative impact of ECP on natural killer (NK) cell activity in SS patients, and especially their functional ability for antibody-dependent cell-mediated cytotoxicity (ADCC). Further, we addressed the question whether the magnitude of the effect on ADCC can be associated with the anti-cancer efficacy of ECP in SS patients. We assessed numbers of NK cells, ADCC activity, and treatment response based on blood tumor staging in a cohort of 13 SS patients (8 women, 5 men) treated with ECP as a first-line therapy. Blood samples were collected before treatment start and after an average of 9 months of uninterrupted ECP treatment. NK cell numbers were reduced in SS patients compared to healthy individuals and showed a tendency of recovery after long-term ECP treatment, independent of the clinical response to treatment. Patients with marginal increase (≤1.5 AU-fold) or lack of increase in ADCC activity failed to respond clinically to treatment, while patients with an increased ADCC activity showed a reduction in blood tumor burden. NK-mediated ADCC is selectively enhanced and might be a mechanism underlying the effect of ECP while in addition it can possibly serve as a reliable biomarker to objectively monitor response to ECP in patients with SS. [ABSTRACT FROM AUTHOR]

Sézary syndrome (SS) is an aggressive leukemic form of cutaneous T-cell lymphoma with neoplastic CD4+ T cells present in skin, lymph nodes, and blood. The detection of these so-called Sézary cells and the assessment of tumor burden in blood mostly relies on the recognition of immunophenotypic aberrancies by flow cytometry (FC). Nevertheless, despite the extensive use in research and widespread implementation in clinical practice, FC protocols lack standardization and is further hampered by the profound diversity in Sézary cell immunophenotypic characteristics. Exploring heterogeneity is critical for the overall knowledge of SS pathogenesis, tumor evolution, and resistance to therapy. In turn, this is essential for the discovery of Sézary-specific targets and biomarkers. We applied highly sensitive and standardized EuroFlow-based multiparameter FC (MFC) methods and tools on 37 SS samples for the in-depth immunophenotypic characterization and classification of Sézary cells according to their T-helper differentiation and maturation profiles. We combined MFC with fluorescence-activated cell sorting (FACS) and RNA sequencing (RNA-seq) on purified immunophenotypically distinct Sézary and matched normal CD4+ T-cell subsets of the same patients and healthy controls. With this approach, we aimed to determine the clonality status of FACS-cell sorted populations, study the transcriptome of immunophenotypically distinct Sézary cell subsets, and discover novel Sézary-specific markers using gene expression data. By applying MFC, we accurately identified, quantified, and characterized Sézary cells in all SS samples. Comparative immunophenotypic analyses between Sézary cells and their normal CD4+ T-cell counterpart revealed substantial inter-and intra-patient heterogeneity in the expression of different markers and immunophenotypic changes over time. Sézary cells exhibited phenotypes corresponding with classical and non-classical T-helper subsets with different maturation phenotypes. Our RNA-seq data confirmed pure mono-clonality of isolated immunophenotypically aberrant CD4+ T-cell subsets and revealed the transcriptional profiles of different FACS-sorted CD4+ T-cell populations thereby identifying novel Sézary-specific signature genes that were consistently and exclusively perturbed across Sézary cell subsets. Our in-depth analyses provided a thorough overview of the immunophenotypic and transcriptional profiles in SS and further unraveled the heterogeneity of Sézary cell subpopulations between and within patients. Incorporating additional resolutive SS-specific markers could prove diagnostic and prognostic utility. Together, these new data will support improved diagnosis, disease monitoring, therapy, and prognosis. [ABSTRACT FROM AUTHOR]

Background: Sézary syndrome is a cutaneous T-cell lymphoma characterized by erythroderma and leukemic involvement., Objective: We sought to define the clinical, biologic, and histopathologic features of Sézary syndrome without erythroderma., Methods: Features of patients with Sézary syndrome and normal-appearing skin or stage-T1 patches, fulfilling Sézary syndrome hematologic criteria and with histologically documented disease in normal-appearing skin were collected. Expression of Sézary syndrome molecular biomarkers in peripheral blood and skin lymphocytes were studied., Results: Five women and 1 man (median age: 71 years) were all referred for generalized pruritus. Four had no specific lesions; 2 had T1-stage patches. Histologic examination of normal-appearing skin from all patients showed lesions compatible with Sézary syndrome. Peripheral blood lymphocytes from 3 of 4 patients tested strongly expressed PLS3, Twist-1, and KIR3DL2. All normal-appearing skin biopsy specimens expressed programmed death-1. Median follow-up was 9 years. Although no patient developed erythroderma, tumors, or abnormal lymph nodes, specific skin lesions appeared in all patients during follow-up. Only 1 death, unrelated to Sézary syndrome, occurred., Limitations: Retrospective design and small sample size are limitations., Conclusion: Sézary syndrome without erythroderma is a rare entity that may have a better prognosis than classic Sézary syndrome., (Copyright © 2014 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)