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ABSTRACT: Sézary syndrome (SS) is an aggressive leukemic expansion of skin-derived malignant CD4+ T cells. Drug monotherapy often results in disease relapse because of the heterogenous nature of malignant CD4+ T cells, but how therapies can be optimally combined remains unclear because of limitations in understanding the disease pathogenesis. We identified immunologic transitions that interlink mycosis fungoides with SS using single-cell transcriptome analysis in parallel with high-throughput T-cell receptor sequencing. Nascent peripheral CD4+ T cells acquired a distinct profile of transcription factors and trafficking receptors that gave rise to antigenically mature Sézary cells. The emergence of malignant CD4+ T cells coincided with the accumulation of dysfunctional monocytes with impaired fragment crystallizable γ-dependent phagocytosis, decreased responsiveness to cytokine stimulation, and limited repertoire of intercellular interactions with Sézary cells. Type I interferon supplementation when combined with a monoclonal antibody targeting the chemokine receptor type 4 (CCR4), unleashed monocyte induced phagocytosis and eradication of Sézary cells in vitro. In turn, coadministration of interferon-α with the US Food and Drug Administration-approved anti-CCR4 antibody, mogamulizumab, in patients with SS induced marked depletion of peripheral malignant CD4+ T cells. Importantly, residual CD4+ T cells after Sézary cell ablation lacked any immunologic shifts. These findings collectively unveil an auxiliary role for augmenting monocytic activity during mogamulizumab therapy in the treatment of SS and underscore the importance of targeted combination therapy in this disease.

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BACKGROUND: Mycosis fungoides (MF) and Sézary syndrome (SS) are the most prevalent cutaneous lymphomas. They were not described in a large Brazilian cohort yet. We aimed, with this single-center, retrospective cohort analysis, to describe the characteristics and outcomes of MF/SS in a tertiary public health service in Brazil. METHODS: MF/SS patients evaluated at the University of São Paulo Medical School between 1989 and 2018 were included. Data were collected at diagnosis. Demographic, clinical, histopathological, immunopathological, molecular, laboratory, and follow-up data were analyzed. RESULTS: Among 727 patients, 92.6% (673) were diagnosed with MF, 7.4% (54) with SS. There were 51.2% (372) of males, 48.8% (355) of females. The median age was 51.8 years; it was higher in erythrodermic MF (60.2) and SS (60.9). Among MF, 41.8% (281) had classic MF, 4.9% (33) folliculotropic MF, 1.8% (12) granulomatous slack skin, and 0.3% (2) pagetoid reticulosis. Common subtypes included erythrodermic (14.1%, 95), hypopigmented (10.8%, 73), and poikilodermatous MF (10.8%, 73). Extracutaneous involvement was rare. Five, 10, 20, and 30-year overall survival rates were 97.3%, 92.4%, 82.6%, and 82.6% for early-stage, and 58.6%, 42.7%, 20.8%, and 15.4% for advanced-stage disease, respectively. After multivariate analysis, SS diagnosis, folliculotropic MF, erythrodermic MF, clinical stage, age (≥60 years), increased lactate dehydrogenase, and large cell transformation conferred poorer prognosis. CONCLUSIONS: We observed a higher percentage of hypopigmented MF compared to the literature, and demographic (older age) and prognostic (poorer prognosis) similarities between erythrodermic MF and SS, suggesting a possible relationship between these erythrodermic lymphomas. Factors associated with a poorer prognosis were compatible with the literature.

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BACKGROUND: Extracorporeal photopheresis (ECP) as a part of multimodality therapy, is one of the treatments for Sézary syndrome (SS) and advanced stage mycosis fungoides (MF). This study aims to describe cutaneous and peripheral blood responses of patients with MF and SS who received multimodality therapy. METHODS: In this cross-sectional retrospective study, patients with MF or SS who received ECP treatment in combination with at least one additional systemic treatment between 2011 and 2018 were included. ECP consisted of a two-session cycle every 2 to 4 weeks. Cutaneous and blood responses were evaluated with updated criteria. RESULTS: Twenty-eight patients (11 (39%) with MF and 17 (51%) with SS) were included. Their median age at diagnosis was 63 (57-67) years. The median number of treatments before ECP was 2 (1-3). Seven out of 11 patients with MF (63%) underwent an assessment of cutaneous response. Five patients (70%) presented a partial response; 1 (15%), stable disease, and 1 (15%) progressive disease. Thirteen of the 17 patients with SS (76%) underwent evaluation. One patient (8%) presented a complete cutaneous response; 6 (46%), a partial response; 5 (38%), stable disease; and 1 (8%), progressive disease. None of them relapsed during the study period in both groups. No ECP-related adverse effects occurred during the study. CONCLUSION: Most patients with SS and MF who underwent multimodality therapy with ECP had favorable cutaneous and blood response. It is safe to combine ECP with other treatments. Studies with large numbers of patients are necessary to assess the effects of ECP on patient survival.

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Abstract Cutaneous T-cell lymphomas are a heterogeneous group of lymphoproliferative disorders, characterized by infiltration of the skin by mature malignant T cells. Mycosis fungoides is the most common form of cutaneous T-cell lymphoma, accounting for more than 60% of cases. Mycosis fungoides in the early-stage is generally an indolent disease, progressing slowly from some patches or plaques to more widespread skin involvement. However, 20% to 25% of patients progress to advanced stages, with the development of skin tumors, extracutaneous spread and poor prognosis. Treatment modalities can be divided into two groups: skin-directed therapies and systemic therapies. Therapies targeting the skin include topical agents, phototherapy and radiotherapy. Systemic therapies include biological response modifiers, immunotherapies and chemotherapeutic agents. For early-stage mycosis fungoides, skin-directed therapies are preferred, to control the disease, improve symptoms and quality of life. When refractory or in advanced-stage disease, systemic treatment is necessary. In this article, the authors present a compilation of current treatment options for mycosis fungoides and Sézary syndrome.

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Cutaneous T-cell lymphomas are a heterogeneous group of lymphoproliferative disorders, characterized by infiltration of the skin by mature malignant T cells. Mycosis fungoides is the most common form of cutaneous T-cell lymphoma, accounting for more than 60% of cases. Mycosis fungoides in the early-stage is generally an indolent disease, progressing slowly from some patches or plaques to more widespread skin involvement. However, 20% to 25% of patients progress to advanced stages, with the development of skin tumors, extracutaneous spread and poor prognosis. Treatment modalities can be divided into two groups: skin-directed therapies and systemic therapies. Therapies targeting the skin include topical agents, phototherapy and radiotherapy. Systemic therapies include biological response modifiers, immunotherapies and chemotherapeutic agents. For early-stage mycosis fungoides, skin-directed therapies are preferred, to control the disease, improve symptoms and quality of life. When refractory or in advanced-stage disease, systemic treatment is necessary. In this article, the authors present a compilation of current treatment options for mycosis fungoides and Sézary syndrome.

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BACKGROUND: Advanced-stage mycosis fungoides (MF)/Sézary syndrome (SS) patients are weighted by an unfavorable prognosis and share an unmet clinical need of effective treatments. International guidelines are available detailing treatment options for the different stages but without recommending treatments in any particular order due to lack of comparative trials. The aims of this second CLIC study were to retrospectively analyze the pattern of care worldwide for advanced-stage MF/SS patients, the distribution of treatments according to geographical areas (USA versus non-USA), and whether the heterogeneity of approaches has potential impact on survival. PATIENTS AND METHODS: This study included 853 patients from 21 specialist centers (14 European, 4 USA, 1 each Australian, Brazilian, and Japanese). RESULTS: Heterogeneity of treatment approaches was found, with up to 24 different modalities or combinations used as first-line and 36% of patients receiving four or more treatments. Stage IIB disease was most frequently treated by total-skin-electron-beam radiotherapy, bexarotene and gemcitabine; erythrodermic and SS patients by extracorporeal photochemotherapy, and stage IVA2 by polychemotherapy. Significant differences were found between USA and non-USA centers, with bexarotene, photopheresis and histone deacetylase inhibitors most frequently prescribed for first-line treatment in USA while phototherapy, interferon, chlorambucil and gemcitabine in non-USA centers. These differences did not significantly impact on survival. However, when considering death and therapy change as competing risk events and the impact of first treatment line on both events, both monochemotherapy (SHR = 2.07) and polychemotherapy (SHR = 1.69) showed elevated relative risks. CONCLUSION: This large multicenter retrospective study shows that there exist a large treatment heterogeneity in advanced MF/SS and differences between USA and non-USA centers but these were not related to survival, while our data reveal that chemotherapy as first treatment is associated with a higher risk of death and/or change of therapy and thus other therapeutic options should be preferable as first treatment approach.

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Sézary syndrome (SS) is an unusually aggressive T- cell lymphoma characterized by the triad of erythroderma, the presence of more than 1,000 Sézary cells in peripheral blood and lymphadenopathies. It is accompanied by generalized pruritus and poor quality of life. The management of SS depends on its stage, patient comorbidities, and treatment availability. Extracorporeal photopheresis (ECP) is the first line of treatment for patients with T-cell lymphomas in stage IVA1, IVA2 or SS. This treatment comprises three phases: leukapheresis, photoactivation and subsequent reinfusion of lymphocytes. As it is an immunomodulatory therapy it does not produce generalized immunosuppression. We report a 76 year-old male with SS stage IIIb initially treated with 12 sessions of ultraviolet phototherapy without response. After 10 well-tolerated sessions of ECP, itching and skin lesions eventually disappeared.

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Sézary syndrome (SS) is an unusually aggressive T- cell lymphoma characterized by the triad of erythroderma, the presence of more than 1,000 Sézary cells in peripheral blood and lymphadenopathies. It is accompanied by generalized pruritus and poor quality of life. The management of SS depends on its stage, patient comorbidities, and treatment availability. Extracorporeal photopheresis (ECP) is the first line of treatment for patients with T-cell lymphomas in stage IVA1, IVA2 or SS. This treatment comprises three phases: leukapheresis, photoactivation and subsequent reinfusion of lymphocytes. As it is an immunomodulatory therapy it does not produce generalized immunosuppression. We report a 76 year-old male with SS stage IIIb initially treated with 12 sessions of ultraviolet phototherapy without response. After 10 well-tolerated sessions of ECP, itching and skin lesions eventually disappeared.

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Los linfomas cutáneos primarios consisten en una proliferación anormal de linfocitos T o B que muestran tropismo por la piel, sin evidenciarse compromiso extra cutáneo al momento del diagnóstico. Se dividen en linfomas de células T (75 por ciento-80 por ciento) y linfomas de células B (20 por ciento-25 por ciento). La micosis fungoide es una neoplasia de estirpe T y constituye el linfoma cutáneo primario más frecuente. Su presentación clínica clásica consiste en 3 etapas: parche, placa y tumor. Sin embargo, tiene múltiples variantes y un amplio diagnóstico diferencial, por lo que para su diagnóstico se requiere una estricta correlación entre la clínica y la histopatología. El síndrome de Sézary, por su parte, es considerado la variante leucémica de los linfomas cutáneos primarios y forma parte del diagnóstico diferencial de las eritrodermias. En esta revisión profundizaremos en los principales aspectos de la clínica, histopatología, criterios diagnósticos y tratamiento de la micosis fungoide y el síndrome de Sézary.

Primary cutaneous lymphomas represent an abnormal proliferation of T or B-cells with skin-homing ability, with no evidence of extra cutaneous disease at the time of diagnosis. They are divided in T-cell lymphomas (75 percent-80 percent) and B-cell lymphomas (20 percent-25percent). Mycosis fungoides (MF) is a T-cell malignancy, being the most common lymphoma. Classic MF presents 3 clinical phases: patch, plaque and tumor stage. However, it has numerous variants and a wide range of differential diagnosis, so that precise clinicopathologic correlation is necessary for make a correct diagnosis. Sézary syndrome is an aggressive leukemic primary cutaneous T-cell lymphoma variant and it is part of the spectrum of erythroderma. In this review we will analyze the main aspects about clinical presentation, histopathology, diagnosis and treatment of mycosis fungoides and Sézary syndrome.

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La micosis fungoides y el síndrome de Sèzary constituyen el grupo más frecuente de linfomas cutáneos de células T; tienen un curso lento y progresivo y un impacto negativo en la calidad de vida del paciente. En los estadios iniciales, la curación es anecdótica y en los casos avanzados pueden comprometer la vida del paciente; con las opciones terapéuticas actuales se consigue disminuir la sintomatología y se logran remisiones temporales. Para los estadios tempranos se propone el uso de terapias dirigidas a la piel, como los esteroides tópicos, la fotoquimioterapia PUVA y la radioterapia localizada, y otros no disponibles en nuestro medio, como la quimioterapia tópica y el bexaroteno, mientras que, para los estadios más avanzados, se recomiendan terapias que combinan las dirigidas a la piel con tratamientos sistémicos, como el interferón alfa, el vorinostat y la poliquimioterapia.

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