Clinical Outcomes of COVID-19 in Mycosis Fungoides and Sezary Syndrome.

INTRODUCTION: Haemato-oncologic patients are more susceptible to severe infections with SARS-CoV-2. We aimed to assess the clinical outcomes of SARS-CoV-2 infection among patients with Mycosis Fungoides and Sezary Syndrome (MF/SS). METHODS: The data were retrieved from anonymized electronic medical records of Maccabi Healthcare Services (MHS), the second-largest healthcare organization in Israel. Patients diagnosed with MF/SS were included in the study. COVID-19 PCR test results together with sociodemographic and clinical data were extracted and analyzed to evaluate the association of COVID-19 with clinical outcomes. RESULTS: In the period of 2020-2022, 1,472 MF/SS patients were included in the study. Among them, 768 (52%) had SARS-CoV-2 infection. The hospitalization rate was 2.9% and infection by the Delta variant was associated with the highest hospitalization rate (7.7%). The hospitalization rate was lower among fully vaccinated patients (p = 0.032) but higher for patients older than 65 (p < 0.001) and patients with SS (vs. MF) (p < 0.001) or COPD (p = 0.024) diagnosis. There was a tendency for decreased hospitalization among patients treated with nirmatrelvir + ritonavir within 5 days of infection, with a 79% risk reduction, although it was not statistically significant (p = 0.164). CONCLUSION: Patients with MF/SS do not necessarily have worse COVID-19 outcomes compared to the general population.

[A patient with erythroderma and pruritus: Sézary syndrome]. / Een man met jeuk en roodheid van de huid.

BACKGROUND: Erythroderma could be the first sign of a cutaneous T-cell lymphoma (CTCL), such as Sézary syndrome. Causes of erythroderma include inflammatory dermatosis, toxicoderma, paraneoplastic erytroderma, and CTCL. Hence, diagnosing Sézary syndrome can be difficult. Sézary syndrome is a rare, aggressive disease characterized by erythroderma, generalized lymphadenopathy and the presence of clonally related neoplastic T-cells in skin, peripheral blood, and lymph nodes. Treatment consists of photochemotherapy (PUVA), radiotherapy, immunomodulatory agents, low dose cytotoxic agents, and intensive chemotherapy. Immunotherapy directed against CCR4 and PD1 are new, promising developments. CASE DESCRIPTION: A 51-year-old man presented with a 1-year history of progressive, itchy erythroderma and lymphocytosis. After extensive cytomorphological, histopathological and molecular examination the diagnosis of Sézary syndrome could be established. Combination treatment of interferon and photochemotherapy (PUVA) was started. CONCLUSION: Diagnostic delay in Sézary syndrome is common. Integrated cytomorphological, immunological, and molecular evaluation of peripheral blood in patients with unexplained erythroderma non-responsive to (topical) treatment is warranted.

Brentuximab-induced splinter nail haemorrhages in a patient with Sézary syndrome: A case report.

Sézary syndrome is a systemic variant of cutaneous T-cell lymphoma characterized by erythroderma, lymphadenopathy and circulating atypical lymphocytes (Sézary cells). It may present with nonspecific lesions on multiple digits. We describe an atypical case of brentuximab-induced splinter nail haemorrhages in a patient with Sézary syndrome, associated with a poor prognosis during follow-up. Concomitantly with the appearance of nail lesions, significant lymphocytosis was detected as well as infiltration of bone marrow and nail matrices. The lesions followed a precise sequence, which can be traced back to the monthly application of brentuximab and its direct cytotoxic effect on CD30+ T lymphocytes in the nail matrix. Brentuximab-induced nail lesions might be associated with decreased efficacy of brentuximab in this patient with advanced cutaneous T-cell lymphoma.

[Minimal change nephropathy and IgA deposits associated with a Sezary syndrome]. / Néphropathie à IgA et LGM au cours d'un syndrome de Sézary.

INTRODUCTION: The Sézary syndrome (SS) is an aggressive form of cutaneous T-cell lymphoma (CTCL) requiring a rapid diagnosis due to its poor prognosis. CASE REPORT: We report the first case of an eighty-nine-year-old woman who presented with concomitant Sezary syndrome and anasarca, revealing a nephrotic syndrome caused by a minimal change nephropathy associated with immunoglobulin A (IgA) deposits. Scarce literature described rare cases associating these two entities (nephrotic syndrome and nephropathy). However, the nephrotic syndrome was delayed from disease onset, secondary to immunosuppressive treatment of SS, or due to the weaning of SS therapy. Thus, the direct link between the glomerular lesion and the cutaneous lymphoma was difficult to establish. However, the synchronous occurrence of both SS and glomerulopathy in our patient, along with Sezary cells in both urines (urinary cytology) and biopsy, and resolution of nephropathy after treatment of SS, support the likely attributability of SS in glomerulopathy. CONCLUSION: Practitioners must acknowledge the possible occurrence of glomerular involvement in SS.

Erythroderma: psoriasis or lymphoma? A diagnostic challenge and therapeutic pitfall.

BACKGROUND: Psoriasis and lymphoma risk is widely debated, but few is known about misdiagnosis risk between erythrodermic psoriasis and lymphoma. In fact, erythroderma might represent a clinical presentation of psoriasis, cutaneous T-cell lymphomas and skin dissemination of systemic lymphomas. METHODS: All patients referred to psoriasis outpatient service with a diagnosis of erythrodermic psoriasis were re-examined. Among them, all the patients with a subsequent lymphoma diagnosis were included. For each patient data concerning age, gender, age at erythroderma onset, age at lymphoma diagnosis, immune-suppressive therapy, type of lymphoma and relative stage, lymphoma treatment and outcome were obtained. RESULTS: Twenty-five patients (15 females and 10 males) with a diagnosis of erythrodermic psoriasis were retrieved. Among them, 9 patients (5 males and 4 females) were affected by erythrodermic lymphoma, including 4 patients with Sèzary Syndrome, 3 with mycosis fungoides, and 2 with peripheral T-cell lymphoma not otherwise specified. Prior to lymphoma diagnosis all the patients (9/9) received cyclosporine, two (2/9) of them methotrexate, one (1/9) azatioprine, and two (2/9) systemic corticosteroids. The prognosis of our patients was poor, due to immune-suppressive drugs administration in patients with undiagnosed lymphoma. The only exception was one (1/9) patient with Sèzary Syndrome still alive with disease after 120 months of follow-up. CONCLUSIONS: In case of patients with erythroderma, multiple skin biopsies and specific peripheral blood studies like flow cytometry and T-cell receptor gene rearrangement analysis are required in order to avoid misdiagnosis risk between psoriasis and lymphoma.

Primary cutaneous lymphomas in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): A series of 12 cases.

BACKGROUND: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is associated with an increased risk of a second malignancy. METHODS: We conducted a retrospective clinicopathologic review of 12 patients with CLL/SLL who developed a second lymphoma in the skin. Demographic data, clinical information, and histopathology from 31 biopsies were recorded. Cases of secondary cutaneous involvement by CLL/SLL (leukemia cutis) and non-primary cutaneous lymphomas were excluded. RESULTS: A wide variety of primary cutaneous lymphomas was identified, including classic mycosis fungoides (3), cutaneous marginal zone lymphoma (2), primary cutaneous peripheral T-cell lymphoma unspecified (2), folliculotropic mycosis fungoides (1), Sézary syndrome (1), cutaneous gamma-delta T-cell lymphoma (1), cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (1), and cutaneous anaplastic large cell lymphoma (1). A male predominance was observed, and the average age was 74.1 years. In all patients, CLL/SLL predated the development of the second lymphoma, which was aggressive in the majority of cases (58%). Aggressive cytotoxic T-cell lymphomas, generally rare neoplasms, were relatively common (30%). CONCLUSIONS: CLL/SLL patients may develop a second lymphoma in the skin, which may be aggressive. Atypical cutaneous lymphoid infiltrates in this patient population should not be assumed to represent secondary CLL/SLL involvement and require thorough immunohistochemical analysis.

Acute and sub-acute toxicity profile of ultra-hypofractionated low-dose total skin electron beam with two 4 Gy fractions for cutaneous T cell lymphoma.

PURPOSE: Low-dose total skin electron beam therapy (TSEBT) over 3 weeks has proved to be a safe and effective treatment for cutaneous T cell lymphomas (CTCL). In this prospective trial, we examined the feasibility of ultra-hypofractionated low-dose TSEBT regimen in two fractions with 4 Gy combined with systemic therapy to minimize the number of visits to radiation centers. PATIENTS AND METHODS: Six patients with mycosis fungoides (MF) or Sézary syndrome (SS) received TSEBT with a total radiation dose of 8 Gy in two fractions between April 2020 and June 2020. Patient and treatment characteristics, tumor burden, the impact on the quality of life using Skindex-29 questionnaires, and acute toxicities were analyzed. RESULTS: During TSEBT, all patients developed grade 1 toxicities while two patients developed grade 2 toxicities. One patient experienced sepsis. The most common adverse effects were erythema and edema. All grade 2 toxicities regressed after 4 weeks following TSEBT. Based on the reported symptoms measured by Skindex-29, we detected a significant reduction in total Skindex-29 score after 8 weeks of radiation (P = 0.03), particularly in the symptoms (P = 0.01) and emotional domains (P = 0.04). CONCLUSION: Ultra-hypofractionated low-dose TSEBT followed by systemic therapy seems to be a safe and feasible alternative to conventional fractionated TSEBT for patients with MF/SS. The skin tumor burden and the health-related quality of life have been significantly improved within 8 weeks following radiotherapy.

Rapid and sustained control of itch and reduction in Th2 bias by dupilumab in a patient with Sézary syndrome.

BACKGROUND: Sézary syndrome is a leukaemic variant of cutaneous T-cell lymphoma with poor prognosis. With the exception of stem cell transplantation, current treatments for SS are not curative. Rather, they aim at reducing disease burden and improving quality of life. Yet, pruritus - the major cause for impaired quality of life in these patients - is notoriously difficult to treat. Thus, supportive treatments addressing agonizing pruritus are urgently needed. OBJECTIVES: To explore the clinical and immunological effects of type 2 cytokine blockade with dupilumab as supportive treatment in Sézary syndrome. METHODS: A Sézary syndrome patient with stable disease but intractable pruritus was treated with dupilumab in combination with continued extracorporeal photopheresis. Close clinical and immunological monitoring on blood and skin samples from the patient was performed over 44 weeks. In vitro assays with patient's lymphoma cells were performed to address effects of dupilumab on Sézary cell's response to Th2 cytokines. RESULTS: Clinically, dupilumab treatment induced rapid and sustained reduction in itch and improvement of skin and lymph node involvement. In both blood and skin, a reduction in Th2 bias was observed. Intriguingly, lymphocyte counts and Sézary cells in blood increased and later stabilized under dupilumab treatment. In vitro, dupilumab abrogated the anti-apoptotic and activating effects of Th2 cytokines on Sézary cells. CONCLUSIONS: In this Sézary patient, inhibition of IL-4 and IL-13 signalling was associated with striking clinical benefit in terms of quality of life, pruritus and use of topical corticosteroids. While safety remains an important concern, our data support the future exploration of Th2 modulation for supportive care in Sézary Syndrome.

Quality of Life Effect of the Anti-CCR4 Monoclonal Antibody Mogamulizumab Versus Vorinostat in Patients With Cutaneous T-cell Lymphoma.

BACKGROUND: Sézary syndrome (SS) and mycosis fungoides (MF), 2 types of cutaneous T-cell lymphoma, cause significant morbidity and adversely affect patients' quality of life (QoL). The present study assessed the QoL measurement changes in patients receiving mogamulizumab versus vorinostat. PATIENTS AND METHODS: A multicenter phase III trial was conducted of patients with stage IB-IV MF/SS with ≥ 1 failed systemic therapy. The QoL measures included Skindex-29 and the Functional Assessment of Cancer Therapy-General. The symptoms, function, and QoL subdomains were longitudinally modeled using mixed models with prespecified covariates. Meaningful change thresholds (MCTs) were defined using distribution-based methods. The categorical changes by group over time and the time to clinically meaningful worsening were analyzed. RESULTS: Of the 372 randomized patients, mogamulizumab demonstrated improvement in Skindex-29 symptoms (cycles 3, 5, and 7; P < .05) and functional (cycles 3 and 5; P < .05) scales. A significantly greater proportion of mogamulizumab-treated patients improved by MCTs or more from baseline in the Skindex-29 symptoms domain (cycles 3, 5, 7, and 11) and functioning domain (cycle 5). Significant differences in the Functional Assessment of Cancer Therapy-General physical well-being (cycles 1, 3, and 5; P < .05) were observed in favor of mogamulizumab and a greater proportion of patients had declined by MCTs or more at cycles 1, 3, 5, and 7 with vorinostat treatment. The median time to symptom worsening using Skindex-29 was 27.4 months for mogamulizumab versus 6.6 months for vorinostat. In the patients with SS, the time to worsening favored mogamulizumab (P < .005) for all Skindex-29 domains. The time to worsening was similar for the 2 MF treatment arms. CONCLUSION: The symptoms, function, and overall QoL of patients with MF/SS favored mogamulizumab over vorinostat across all time points. Patients with the greatest symptom burden and functional impairment derived the most QoL benefit from mogamulizumab.

Adult T-cell leukemia/lymphoma clinically confused with viral/drug skin eruptions and pathologically misinterpreted as mycosis fungoides/Sézary syndrome.

Adult T-cell leukemia/lymphoma (ATLL) is a lymphoproliferative disorder of mature CD4-positive T-cell lymphoid cells associated with retrovirus human T-lymphotropic virus type-1 (HTLV-1) with a wide clinical and pathologic spectrum. We report a case of a 53-year-old African man who presented with fever and skin eruptions on the trunk composed of non-itchy erythematous reticulated macules and papules initially suspected for viral exanthem or drug rash. Skin punch biopsy showed a dermal T-cell lymphoid infiltrate with epidermotropism. The patient developed generalized lymphadenopathy and his peripheral blood showed lymphocytosis with atypical lymphocytes with convoluted nuclei. Our initial diagnosis was mycosis fungoides with Sézary syndrome. However, some clinical and histopathologic features were unusual. The acute onset, lack of previous skin lesions, the histomorphologic features of the dermal, nodal and peripheral blood lymphocytes and the geographic origin of the patient raised the suspicion of other T-cell lymphomas, particularly ATLL. This was confirmed by a positive anti-HTLV-1 serology. Our final diagnosis was acute variant ATLL. Different T-cell lymphomas can involve the skin with overlapping clinical, histomorphologic and immunohistochemical features. Some clinical and pathologic features should alarm dermatologists and pathologists to the possibility of ATLL particularly in patients from HTLV-1 endemic geographic areas.

Pénfigo paraneoplásico secundario a síndrome de Sézary: presentación de un caso / No disponible

No disponible

Reduction of T Lymphoma Cells and Immunological Invigoration in a Patient Concurrently Affected by Melanoma and Sezary Syndrome Treated With Nivolumab.

Despite the recent availability of several new drugs in hemato-oncology, T-cell lymphomas are still incurable and PD-1 blockade could represent a therapeutic chance for selected patients affected by these malignancies, although further studies are required to understand the biological effects of anti-PD-1 mAbs on neoplastic T-cells and to identify biomarkers for predicting and/or monitoring patients' response to therapy. Sezary Syndrome (SS) represents a rare and aggressive variant of cutaneous T cell lymphoma (CTCL) with a life expectancy of less than 5 years, characterized by the co-presence of neoplastic lymphocytes mainly in the blood, lymph nodes and skin. In this study we analyzed longitudinal blood samples and lesional skin biopsies of a patient concurrently affected by SS and melanoma who underwent 22 nivolumab administrations. In blood, we observed a progressive reduction of SS cell number and a raise in the percentage of normal CD4+ and CD8+ T cells and NK cells over total leukocytes. Eight weeks from the start of nivolumab, these immune cell subsets showed an increase of Ki67 proliferation index that positively correlated with their PD-1 expression. Conversely, SS cells displayed a strong reduction of Ki67 positivity despite their high PD-1 expression. On skin biopsies we observed a marked reduction of SS cells which were no more detectable at the end of therapy. We also found an increase in the percentage of normal CD4+ T cells with a concomitant decrease of that of CD8+ and CD4+ CD8+ T cells, two cell subsets that, however, acquired a cytotoxic phenotype. In summary, our study demonstrated that nivolumab marked reduced SS tumor burden and invigorated immune responses in our patient. Our data also suggest, for the first time, that Ki67 expression in circulating neoplastic and immune cell subsets, as well as an enrichment in T cells with a cytotoxic phenotype in lesional skin could be valuable markers to assess early on treatment SS patients' response to PD-1 blockade, a therapeutic strategy under clinical investigation in CTCL (ClinicalTrials.gov NCT03385226, NCT04118868).

A case of bullous Sézary syndrome.

Sézary syndrome is a rare leukemic subtype of cutaneous T cell lymphoma that is characterized by erythroderma, lymphadenopathy, and malignant T cells in the peripheral blood. Poor prognostic factors of Sézary syndrome include advanced disease stage, older age at onset, and large cell transformation. Presentation with bullous lesions, though rare, has been reported in a few patients. We present an elderly woman with bullous Sézary syndrome who presented with a two-month history of progressive rash. Upon admission, the patient had pruritic, erythematous, edematous plaques with overlying flaccid bullae and erosions involving the scalp, neck, torso, and extremities. Despite treatment, the patient died two months after presentation. Although rare, bullous lesions associated with Sézary syndrome may indicate poor prognosis.

Staphylococcus aureus enterotoxins induce FOXP3 in neoplastic T cells in Sézary syndrome.

Sézary syndrome (SS) is a heterogeneous leukemic subtype of cutaneous T-cell lymphoma (CTCL) with generalized erythroderma, lymphadenopathy, and a poor prognosis. Advanced disease is invariably associated with severe immune dysregulation and the majority of patients die from infectious complications caused by microorganisms such as, Staphylococcus aureus, rather than from the lymphoma per se. Here, we examined if staphylococcal enterotoxins (SE) may shape the phenotype of malignant SS cells, including expression of the regulatory T-cell-associated marker FOXP3. Our studies with primary and cultured malignant cells show that SE induce expression of FOXP3 in malignant cells when exposed to nonmalignant cells. Mutations in the MHC class II binding domain of SE-A (SEA) largely block the effect indicating that the response relies at least in part on the MHC class II-mediated antigen presentation. Transwell experiments show that the effect is induced by soluble factors, partly blocked by anti-IL-2 antibody, and depends on STAT5 activation in malignant cells. Collectively, these findings show that SE stimulate nonmalignant cells to induce FOXP3 expression in malignant cells. Thus, differences in exposure to environmental factors, such as bacterial toxins may explain the heterogeneous FOXP3 expression in malignant cells in SS.