RARE DISEASE
Sézary syndrome
Sézary syndrome
Sézary syndrome
Synonyms: Sézary lymphoma
Synonyms: Sézary lymphoma
Synonyms: Sézary lymphoma
Drug discovery
0
drugs
With orphan designations
Overview
Sézary syndrome is an aggressive leukemic variant of cutaneous T-cell lymphoma characterized by erythroderma, lymphadenopathy, and circulating malignant Sézary cells (CD4+ T-cells with cerebriform nuclei). It progresses rapidly, often causing severe pruritus, alopecia, and palmoplantar keratoderma. Diagnosis requires blood involvement (≥1,000 Sézary cells/μL) and clonal T-cell receptor rearrangement in skin, blood, or lymph nodes [1][5][16].
Burden
Health-related quality of life: Severe pruritus (75% of patients), anxiety/depression (38–44%), and financial strain from chronic care [4][9][16].
5-year survival: ~24–30%, influenced by stage, blood involvement, and racial disparities [6][16].
High healthcare utilization: Frequent infections, hospitalizations, and multidisciplinary management needs [4][18].
Therapies
Skin-directed therapies: Phototherapy (PUVA/UVB), topical corticosteroids, radiation (total skin electron beam) [1][8].
Systemic agents: Immunotherapy (extracorporeal photopheresis), targeted therapies (brentuximab vedotin, mogamulizumab), histone deacetylase inhibitors [1][3][13].
Palliative approaches: Low-dose chemotherapy, allogeneic stem cell transplant for high-risk cases, and clinical trials (e.g., immune checkpoint inhibitors) [3][8][13].
Categories: rare hematological diseases, rare neoplastic diseases, rare skin diseases, rare transplant-related disorders
Research Papers
1,496 drug discovery papers about Sézary syndrome, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,496 drug discovery papers about Sézary syndrome, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-06 | Cellular and molecular aberrations generating new immunotherapeutic approaches in mycosis fungoides and Sézary syndrome: a comprehensive review of literature.
Recent advances in molecular and immunologic profiling have substantially refined the understanding of mycosis fungoides (MF) and Sézary syndrome (SS), the two most prominent subtypes of cutaneous T-cell lymphomas (CTCL). CTCL comprise a heterogeneous group of lymphoid malignancies characterized by clonal proliferation of malignant T-cell with cutaneous tropism. The pathogenesis of MF and SS appears to be driven by convergent oncogenic programs involving dysregulated JAK/STAT, NF-κB, PI3K/AKT/mTOR, and MAPK signaling, epigenetic reprogramming, apoptosis resistance, immune escape, and microenvironmental support. In parallel, altered surface phenotypes and chemokine receptor programs shape tissue tropism across skin, blood, and lymph nodes, while the tumor microenvironment promotes tumor persistence and Th2-skewed immune polarization. These insights have translated into novel targeted and immune-based therapies. This review summarizes current insights into the cell-intrinsic and microenvironmental biology of MF and SS and discusses emerging approaches aimed at achieving more durable and personalized disease control.
2026-08-01 | A Six-year Response to Belinostat in a Highly Probable Case of Relapsed/Refractory MF/SS Initially Classified as PTCL-NOS: A Case Report
Abstract: Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of hematological malignancies, whose diagnosis is often delayed and requires highly individualized therapeutic strategies. We report an unusual case of a highly probable r/r MF/SS in a 66-year-old male initially diagnosed with peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), based on an atypical leukemic presentation without skin involvement. Cutaneous lesions developed during the disease course, prompting then for a retrospective diagnostic reassessment. Expression of KIR3DL2 on circulating malignant cells, along with a clonal TCR-gamma rearrangement present in both the blood and the skin, and a TP53 nonsense variant, led to a revision of the diagnosis to mycosis fungoides (MF) and Sézary syndrome (SS). MF/SS are the most prevalent CTCL subtypes and are associated with a poor prognosis in advanced stages, largely due to the lack of effective treatments that can achieve sustained remission. Therapeutic options for patients with relapsed/refractory (r/r) MF/SS remain limited and long-term disease control is uncommon. After failure of two treatment lines, including CHOEP-based chemotherapy and bendamustine-brentuximab vedotin (B-BV), the patient received belinostat, a histone deacetylase inhibitor (HDACi). Following three cycles of belinostat, complete cutaneous remission and a partial hematological response were achieved and have been maintained for more than six years (79 cycles to date). Treatment was well tolerated, with only mild anemia. This case highlights the potential role of belinostat in the management of advanced MF/SS and suggests that durable disease control may be achievable in selected r/r patients. Further investigations are warranted to better identify the patients most likely to benefit from belinostat therapy. Keywords: HDAC inhibitor, belinostat, MF/SS, CTCL
2026-07-21 | WEE1 Inhibition as a Novel Therapeutic Strategy in Cutaneous T-Cell Lymphoma
Background/Objectives: Cutaneous T-cell lymphomas (CTCL), most commonly mycosis fungoides and Sézary syndrome, are rare non-Hodgkin lymphomas. Advanced disease responds poorly to current treatments, highlighting the need for new molecularly tar-geted therapies. WEE1 is a central regulator of the G2/M checkpoint and S-phase progression and has emerged as a therapeutic target in several malignancies, yet it has not been systematically explored in CTCL. Methods: We screened a library of more than 2,200 kinase inhibitors in CTCL cell lines and selected adavosertib for further study. Its effects were tested in four CTCL lines, in primary keratinocytes and fibroblasts, in patient-derived malignant CD4⁺ T cells and healthy donor CD4⁺ T cells, and in a MyLa xenograft model, using viability, apoptosis, cell-cycle, western blot, and phospho-protein array assays. Results: Adavosertib reduced viability at submicromolar IC₅₀ values (0.26–0.56 µM) across all four CTCL lines while largely sparing primary skin cells and was more active in malignant than in healthy donor CD4⁺ T cells. It induced apoptosis and cell-line-specific S-phase and/or G2/M accumulation, lowered WEE1 and phospho-CDK1 (Tyr15), and increased phospho-H2A.X. A phospho-protein array showed activation of checkpoint and stress signalling. In vivo, adavosertib slowed MyLa xenograft growth. Conclusions: These preclinical data identify WEE1 as a therapeutic target in CTCL and support further preclinical and early-phase clinical evaluation of adavosertib in this disease.
2026-06-13 | Comment on ‘Context, not class, may be the key signal in systemic Janus kinase inhibitor exposure in mycosis fungoides/Sézary syndrome’: reply from authors
The effects of systemic JAKi exposure in MF/SS appear context-dependent and should not be interpreted as a homogeneous entity. Although disease worsening was observed in several patients initially diagnosed with presumed inflammatory dermatoses, causality cannot necessarily be inferred and may reflect, among other factors, underlying MF/SS biology, referral bias or concurrent immunosuppressive influences. In patients with post-transplant MF/SS receiving JAKi for graft-versus-host disease, MF/SS progression may reflect impaired immune surveillance or other disease-related factors rather than a direct effect of JAKi. These findings underscore the complexity of interpreting JAKi exposure in MF/SS and highlight the need for prospective studies to better define risks across clinical settings.
2026-06-01 | LY06 Golidocitinib-based therapy in relapsed or refractory mycosis fungoides and Sézary syndrome: a real-world retrospective analysis
Abstract Cutaneous T-cell lymphoma (CTCL), primarily mycosis fungoides (MF) and Sézary syndrome (SS), is an incurable malignancy characterized by skin-tropic malignant CD4+ T cells. Current therapies for relapsed or refractory disease exhibit limited efficacy, and patients with transformed disease face dismal outcomes. Somatic Janus kinase (JAK)1 and JAK3 mutations often drive constitutive JAK–signal transducer and activator of transcription activation in CTCL, promoting oncogenesis and resistance. Golidocitinib, a potent and selective JAK1 inhibitor, has previously demonstrated antitumour activity in relapsed or refractory peripheral T-cell lymphoma. This study aims to evaluate the real-world clinical benefit, efficacy and safety of golidocitinib-based therapy – administered either as monotherapy or in combination regimens – for the treatment of patients with relapsed or refractory MF or SS. A real-world retrospective analysis was conducted with a data cutoff of 22 July 2025. Ten patients received at least one cycle of golidocitinib. The cohort had a median age of 57.4 years and a median of 2 prior systemic therapies. The majority of patients (n = 9, 90%) received combination therapy, all incorporating brentuximab vedotin (BV), while one patient received monotherapy. Most patients presented with advanced disease features, including large cell transformation and high CLIPI scores. The best overall response rate and skin response rate were both 80% (8 of 10), comprising 8 partial responses. One patient maintained stable disease, and one experienced progression. Notably, four patients who had previously relapsed or not responded to BV therapy responded to the golidocitinib–BV combination. The median time to response was 31.5 days. Regarding safety, treatment-related adverse events (TRAEs) occurred in six patients, primarily cytomegalovirus infection (50%) and thrombocytopenia (30%). This pioneering real-world study demonstrates that golidocitinib-based regimens offer favourable clinical efficacy in patients with relapsed or refractory MF or SS, including those refractory to prior BV. Subsequent prospective trials are warranted to further validate these combination strategies.
cell therapies
2026-06-08 | Cutaneous Lymphomas and Lymphoproliferative Disorders Associated With SARS-CoV-2 Vaccination: A Systematic Review.
Cutaneous lymphomas (CLs) are rare neoplastic skin disorders, primarily of T-cell origin. Since the widespread rollout of SARS-CoV-2 vaccines, several cases of CLs and non-neoplastic lymphoproliferative disorders (nn-LPDs) temporally associated with vaccination have been reported, raising concerns about a potential immunologic link. To systematically review the literature on cases of CLs and related nn-LPDs occurring after COVID-19 vaccination, focusing on clinical features, subtype distribution, latency to onset, and proposed pathophysiological mechanisms. A systematic review was conducted according to PRISMA guidelines. Case reports and series describing new-onset or relapsed CLs or nn-LPDs temporally following SARS-CoV-2 vaccination were included. Demographic, clinical, histological, therapeutic and temporal data were extracted and analysed. Fifteen manuscripts encompassing 35 cases met the inclusion criteria. Eighteen (51.4%) were histologically confirmed CLs, most commonly lymphomatoid papulosis (n = 9), followed by Sézary syndrome (n = 3) and mycosis fungoides (n = 2). The remaining 17 cases (48.6%) were classified as nn-LPDs, including cutaneous lymphoid hyperplasia, lymphomatoid reactions and CD4+ small/medium T-cell lymphoproliferative disorders. CD30 positivity was noted in 76.2% of the cases with available immunophenotyping. Most patients (80%) received the BNT162b2 (Pfizer-BioNTech) vaccine. In the 17 new-onset CLs, time to onset ranged from 3 to 42 days, with most cases clustering within 14 days. Most of the cases were low-grade T-cell CLs and nn-LPDs. Although a causal relationship cannot be established, the short latency observed in many new-onset cases raises the possibility that some patients may have harboured an undiagnosed disease, with vaccination acting as a trigger for clinical manifestation or for raised awareness. These findings support indeed the need for continued pharmacovigilance among clinicians, especially in patients with prior or latent lymphoproliferative conditions. Nevertheless, these extremely rare and indolent events should not alter the overall favourable risk-benefit profile of COVID-19 vaccination.
2026-01-30 | Sézary syndrome arising from cutaneous epitheliotropic T-cell lymphoma, resembling human folliculotropic mycosis fungoides, in a dog.
A 9-year-old neutered male Pug dog presented with a history of chronic dermatitis. Dermatological examination revealed skin thickening with keratin fronds, erythematous macules and generalized lymphadenopathy. Haematology revealed leucocytosis with lymphocytosis and medium to large neoplastic lymphocytes having cerebriform nuclei (Sézary cells). Fine-needle aspirate samples from the skin and the superficial lymph nodes contained pleomorphic medium-sized lymphocytes and a cytological diagnosis of lymphoma was made. The dog was euthanized. In addition to the cutaneous lesions, post-mortem examination revealed lymphadenomegaly, splenomegaly and hepatomegaly. Histological examination of the skin revealed a neoplastic proliferation of large lymphocytes infiltrating the deep dermis and surrounding the hair follicles. Similar neoplastic cells were present in the lymph nodes, spleen, liver and bone marrow. Neoplastic cells were immunoreactive for CD3 and not for PAX-5. The final diagnosis was Sézary syndrome arising from cutaneous epitheliotropic T-cell lymphoma resembling human folliculotropic mycosis fungoides.
2025-11-19 | Extracorporeal Photopheresis for the Inpatient Dermatologist
Abstract Purpose of Review Extracorporeal photopheresis (ECP) is an immunomodulatory treatment in which an apheresis machine isolates mononuclear cells from whole blood that are then treated with psoralen and ultraviolet-A light and reinfused into the patient. ECP has been approved for use in cutaneous T-cell lymphoma (CTCL) for 30 years; it has also been shown to be effective for graft-versus-host disease, solid organ transplant rejection, and various autoimmune diseases. Nonetheless, ECP is relatively underutilized, perhaps due to knowledge gaps and resource limitations. Here, we review ECP indications and techniques, as well as the data supporting its use in clinical settings. Recent Finding Recent clinical studies have emphasized the durability of ECP in CTCL, both as monotherapy and in combination with topical and other systemic CTCL treatment modalities. New insights into the mechanism of action underlying ECP have illuminated its effects on both cellular and humoral immunity. Specific clinical and laboratory findings have been identified as potential predictors of ECP response. Summary ECP is a well-tolerated and effective treatment option for a growing list of indications. In CTCL, ECP can achieve durable responses with longer treatment courses and should be considered as a first-line option for erythrodermic disease and Sézary syndrome.
2025-11-03 | Racial disparities in mycosis fungoides - from self-reported race to genetic ancestry analysis
Abstract Introduction: Racial disparities in mycosis fungoides (MF) and Sezary syndrome (SS) are well-documented, with self-identified Black patients being diagnosed younger, with more advanced disease, and worse survival. (Su C et al. J Am Acad Dermatol. 2017; Wilson LD et al. Clin Lymphoma Myeloma Leuk. 2012). Our previous work showed that these disparities persist after adjusting for socioeconomic factors (Gandham AR et al. Clin Lymphoma Myeloma Leuk. 2024) suggesting genetic ancestry may contribute. We compared clinical characteristics and outcome of MF/SS patients stratified by self-reported race versus genetic ancestry. Methods: Patients with confirmed MF/SS were consented for genetic profiling via Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT). Genetic ancestry was inferred using ADMIXTURE and single nucleotide polymorphisms (SNPs) captured by MSK-IMPACT (Arora K et al. Cancer discovery. 2022). Patients with ancestral fraction of >0.8 for any single population were assigned that population label; otherwise, they were considered admixed. Results: Genetic ancestry analysis of 161 MF/SS patients (104 self-reported White race, 30 Black, 7 Asian, 20 Other/Unknown) identified 74 as European (EUR), 21 Ashkenazi Jewish (ASJ), 23 African (AFR), 5 East/South Asian, 1 Native American and 37 as admixed. AFR patients were diagnosed 10 years younger than EUR/ASJ (p=0.01) and were less likely to present with stage IA disease compared to EUR/ASJ patients (0% vs 23.2%, p=0.01). Trends towards higher female dominance (52% vs. 35%, p=0.1), higher disease-related mortality (22% vs 12%, p=0.2) and worse progression-free survival (PFS, p=0.11) were observed in AFR patients. ASJ patients showed a trend toward improved PFS compared to EUR patients (p=0.08). Conclusions: Our novel ancestry-based stratification of MF/SS patients confirms disparities seen in self-reported race groups, supporting the need to further investigate specific genetic and non-genetic contributors to disparities in MF/SS patients.
2025-10-02 | Allogeneic hematopoietic cell transplant in cutaneous T-cell lymphomas: recommendations from the EBMT PH&G Committee.
This manuscript provides expert recommendations on the role of allogeneic hematopoietic cell transplantation (allo-HCT) for cutaneous T-cell lymphoma (CTCL), specifically Mycosis Fungoides (MF) and Sezary Syndrome (SS). Critical aspects such as patient selection, timing, and bridging therapy are addressed, as well as donor source, conditioning regimens and post-transplant management. These consensus guidelines are based on a thorough literature review and discussions among leading dermatologists and hematologists. These recommendations aim to harmonise clinical practice towards improving patient outcomes in these rare but aggressive lymphomas. It is of critical importance to consider allo-HCT early in the management of eligible patients with high-risk disease. Advanced stage, large-cell transformation, relapsed or refractory disease following systemic treatment, and N3-stage lymph node involvement are indicators that should trigger consultation with a transplant hematologist in parallel with a donor search. Early interaction between dermatologists and transplant hematologists is vital to avoiding delays, which can significantly impact post-transplant outcomes and survival. This EBMT Practice Harmonisation & Guidelines Committee consensus provides practical recommendations for the selection, timing, and conduct of allogeneic transplantation in advanced-stage mycosis fungoides and Sézary syndrome, aiming to optimize outcomes through early multidisciplinary collaboration and evidence-based decision making.
antibodies
2026-07-28 | Sézary Syndrome Biomarker, T Cell Transcription Factors and Cytokine Genes Provide Novel Insight into Response During Mogamulizumab Treatment.
Background: Novel Sézary syndrome (SS) biomarker genes identified previously through transcription profiling were examined for changes in expression after mogamulizumab treatment. Incorporating new biomarkers for measuring response to disease would improve clinical care. Objective: To assess novel SS biomarker and cytokine genes in patients treated with mogamulizumab with clinical response, blood response, and immunologic parameters. Methods: We performed a real-world case-control and case-case study analyzing the expression of SS biomarker genes in peripheral blood mononuclear cells (PBMCs) from six SS patients treated with mogamulizumab using qRT-PCR. Results: We demonstrated a reduced expression of SS biomarker genes in PBMCs of SS patients following mogamulizumab therapy. In our cohort, five of the SS biomarker genes (PLS3, TWIST1, KCNK1, DNM3 and TOX) showed statistically consistent high expression compared to normal PBMCs at baseline. After treatment with mogamalizumab, these five SS biomarkers showed significant correlations with skin response (p < 0.05) and three (TOX, TCRL3 and DNM3) with blood response (p < 0.05). A decrease in GATA3 expression correlated to an improvement in skin severity, and STAT4 inversely correlated to Sézary cell decrease (p < 0.05). Two cytokine genes, IL4 and IFNG, reflective of an immune response that is abnormal in SS, showed a trend to normalized expression with IL-4 decreasing and IFNG increasing after treatment. Limitations: This was a real-world study of patients who failed prior treatments, with a small sample size and variable timing between patient sample collection. Conclusions: Unique SS biomarker, cytokine and T cell transcription factor genes are valuable in assessing molecular and immune responses following treatment.
2026-07-28 | Dissecting Immune Determinants in Lesional Skin of Cutaneous T-Cell Lymphoma During Mogamulizumab Therapy.
Background: Mycosis fungoides (MF) and Sézary syndrome (SS) are the predominant cutaneous T-cell lymphomas. Although malignant T cells in MF/SS overexpress CCR4 and respond to the anti-CCR4 antibody mogamulizumab, skin response rates vary. We hypothesized that immune components within the tumor microenvironment contribute to differential outcomes. Methods: Imaging mass cytometry with a 37-antibody panel was used to characterize immune and structural elements in FFPE tissues from sixteen MF/SS patients (6 MF, 10 SS) treated with Mogamulizumab, including seven skin responders and nine non-responders. Single-cell phenotyping and spatial analyses were performed using the Visiopharm® Phenoplex™ platform, with supervision. Results: We identified 68,974 cells pre-treatment and 58,852 cells post-treatment. Malignant CD4+ T cells showed reduced baseline CD27, CD103, CD25, and ICOS expression compared with non-malignant CD4+ cells. Baseline MF lesions were enriched for IL-13+ and CD103+ malignant T cells, whereas SS lesions contained higher proportions of CD27+ and LAG3+ cells. IL 13+ malignant cells decreased after treatment, most prominently in MF. Myeloid profiles differed by disease and response: MF lesions exhibited baseline enrichment of M1-like macrophages (CD86+, HLA-DR+), while SS lesions were predominantly M2-polarized macrophages (CD163+, CD206+). Responders showed increased M1-like macrophages, whereas non-responders displayed reduced M1-features. An increase in DC3-like cells was observed in non-responders following treatment. Conclusions: This single-cell spatial atlas reveals shared and subtype-specific immune features in MF/SS. Th2-skewed malignant T-cell status and myeloid polarization correlate with clinical response, supporting their potential as spatial biomarkers for patient stratification in mogamulizumab therapy.
2026-07-23 | Final results of UK NCRI phase II trial of pembrolizumab and radiotherapy in cutaneous T cell lymphoma.
The outlook for patients with advanced cutaneous T-cell lymphomas (CTCL); mycosis fungoides (MF) and Sézary syndrome (SS) remains poor and most systemic treatments provide short-lived remissions. Immunotherapy has provided a major cancer breakthrough, and the PORT trial was designed to investigate the efficacy of Pembrolizumab and whether the addition of Radiotherapy (RT) could further enhance systemic "abscopal" anti-tumour immune responses. Pembrolizumab followed by 12Gy in 3 fractions RT to a localized lesion was investigated in a single-arm, multicentre phase II trial for relapsed/refractory CTCL. Primary endpoint was overall response rate (ORR), secondary endpoints included duration of response (DOR), abscopal response, progression-free survival (PFS), overall survival (OS). 46 patients (41 MF, 5 SS) were registered, median age 63 (24-83), 24% stage IV. Median follow-up was 24.8 months. 24% of patients remained on treatment for >1 year whilst 57% received.
2026-07-22 | Durable remission with no survival reduction after mogamulizumab discontinuation in Sézary syndrome
Mogamulizumab (MOGA), an anti-CCR4 monoclonal antibody, improves progression-free survival (PFS) and overall survival in Sézary syndrome (SS). Recently, a multicentre retrospective study conducted by the French Cutaneous Lymphoma study group assessed PFS in 52 patients with SS (median age 73 years, 56% female sex, 75% stage IVA1) who discontinued MOGA for reasons other than disease progression (Moga-stop Study). We report data from an extended follow-up of this cohort, along with comparative PFS outcomes from a parallel SS cohort with continuous MOGA treatment until progression.
2026-06-18 | Mogamulizumab as Bridge to Thiotepa-Based Allogeneic Haematopoietic Stem Cell Transplantation in Sézary Syndrome: A Single-Centre Experience.
Sézary syndrome (SS) is an aggressive cutaneous T-cell lymphoma for which allogeneic haematopoietic stem cell transplantation (allo-HSCT) represents the only potentially curative treatment. We report a single-centre series of three consecutive SS patients treated with mogamulizumab as bridging therapy to allo-HSCT using thiotepa-based reduced-intensity conditioning. Mogamulizumab induced rapid clearance of circulating Sézary cells and significant clinical improvement. All patients achieved early and stable full donor chimerism and complete remission. Post-transplant GVHD occurred but was manageable with standard therapy. Early use of mogamulizumab may provide effective disease control and facilitate successful allo-HSCT in SS. The authors have confirmed clinical trial registration is not needed for this submission.
proteins
2026-05-19 | Flow Cytometry for Diagnosing Sézary Syndrome When Skin Biopsies Are Inconclusive: A Case Report.
Sézary syndrome (SS) is a rare leukemic variant of cutaneous T-cell lymphomas, accounting for a small proportion of cases, estimated at less than 5% of all cutaneous T-cell lymphomas, characterized by pruritic erythroderma, lymphadenopathy, and circulating clonal T lymphocytes. Diagnosis can be challenging when skin biopsies are non-diagnostic, potentially delaying treatment. Peripheral blood flow cytometry (FC) is essential for detecting aberrant T-cells, assessing clonality, which may be supported in selected cases by T-cell receptor beta-chain constant region 1 (TRBC1) expression analysis, quantifying tumor burden, and guiding tumor-node-metastasis-blood (TNMB) staging and follow-up. A 58-year-old man presented with diffuse pruritic erythroderma and lesions refractory to topical corticosteroids, systemic corticosteroids, methotrexate, and emollients. Repeated skin biopsies showed spongiotic or psoriasiform changes without evidence of malignancy. Peripheral blood smear revealed 5-7% Sézary cells. FC identified an aberrant cluster of differentiation (CD)4+ T-cell population representing 90% of lymphocytes, with CD7+, CD26-, and 97% TRBC1 positivity, confirming a clonal malignant population. Lymph node biopsy was consistent with T-cell lymphoma. TNMB classification was T4N3M0B2 (stage IVA2). The patient received peginterferon alfa-2a with topical corticosteroids and supportive care, leading to clinical and laboratory improvement. This case underscores the critical role of FC when skin biopsies are inconclusive. Comprehensive immunophenotyping, including TRBC1, confirms monoclonality, informs TNMB staging, and guides targeted therapy. Quantitative assessment of circulating malignant cells allows dynamic monitoring of treatment response. Early integration of peripheral blood FC in suspected SS improves diagnostic accuracy, reduces delays, and enables rapid initiation of targeted therapy, ultimately optimizing patient outcomes.
2025-06-27 | P159 Use of Besremi® (pegylated interferon-alfa-2b) in the treatment of cutaneous T-cell lymphoma
Abstract Interferon-alfa has been used to treat mycosis fungoides (MM) and Sézary syndrome (SS) since the 1980s. Type 1 interferons (IFN-alfa and IFN-beta) have antiviral, antitumour, immunomodulatory and antiproliferative properties. The initial marketed product, IFN-alfa-2b (Intron®), was licensed and approved for the treatment of cutaneous T-cell lymphoma in Europe and the USA. Due to the supplier’s financial considerations, Intron® was withdrawn from the market; patients were moved onto IFN-alfa-2a (Roferon®). Roferon was subsequently withdrawn and patients switched to pegylated IFN-alfa-2a (Pegasys®). Peg-IFN-alfa-2a is recommended in the 2023 European Organisation for Research and Treatment of Cancer guidelines for the treatment of MF/SS. Pegasys has the benefit of once-weekly dosing (compared with three times per week for nonpegylated IFNs) and demonstrates similar efficacy. Due to manufacturing issues, there is currently an international shortage of Pegasys. We report our response to this including use of a novel alternative IFN. From our hospital pharmacy records, we identified 21 patients taking Pegasys when forthcoming shortages were announced. Initially, the frequency of administration was reduced from weekly to fortnightly. Initiation of new patients was paused and alternative treatment options considered. Ropeginterferon-alfa-2b (Besremi®), a newer pegylated interferon with similar pharmacokinetics to Pegasys, was identified as the only interferon-alfa product available in England. Besremi is licensed and commissioned in England to treat myeloproliferative neoplasms. It is administered subcutaneously once per fortnight using a prefilled, reusable pen. Besremi 250 μg is therapeutically equivalent to Pegasys 180 μg, and has a National Health Service list price 2.8 times that of Pegasys. Of our 21 patients taking Pegasys, 12 had stage 1B disease, four stage 2B, two stage 3A and two stage 3B, and one had cutaneous lymphoid hyperplasia. All 21 patients initially dose reduced to fortnightly administration; 9 reported a deterioration in their skin. Six (to date) have subsequently switched to Besremi, with seven further switches pending. Four patients moved from Pegasys directly to other therapies due to disease progression or lack of control (two brentuximab, one bexarotene and one total skin electron beam). Four patients have died: two from unrelated causes and two of disease. To date, six patients have been taking Besremi for 6–8 weeks. Early observations indicate that Besremi is at least as effective as Pegasys, with reversal of disease deterioration triggered by dose reduction of Pegasys. Three patients report their skin is stable, and two report an improvement in skin and mood on Besremi. One patient developed a serious adverse event, 5 days after administration of the first dose of Besremi. Symptoms included fever, shortness of breath, cough, skin rash and palpitations, requiring inpatient admission. She has tolerated subsequent doses well, suggesting that this event was unrelated. However, we highlight that palpitations are reported as a common side-effect of Besremi in the product literature. We report ongoing results from the use of Besremi in MF/SS, discussing dosing, efficacy, safety and monitoring.
2025-06-23 | A phase 1 study of interleukin-15 in combination with mogamulizumab in relapsed and refractory T-cell malignancies.
Recombinant human interleukin-15 (rhIL-15) is an immunotherapeutic agent that enhances natural killer (NK) cells to augment the antibody-dependent cellular cytotoxicity (ADCC) of monoclonal antibodies. Mogamulizumab is a CC chemokine receptor 4-directed monoclonal antibody that exerts cytotoxicity through ADCC and depletes regulatory T cells within the tumor microenvironment. We conducted a phase 1 clinical trial of rhIL-15 in combination with mogamulizumab. Patients with relapsed or refractory adult T-cell leukemia/lymphoma (ATLL), mycosis fungoides (MF), and Sezary syndrome (SS) received a fixed dose mogamulizumab, combined with escalating doses of rhIL-15 to identify the maximum tolerated dose (MTD). Six patients were enrolled, 4 with ATLL and 2 with MF/SS. The most common adverse events were rash, infection, and fever (67% of all). Two patients (33%) had grade 4 acute kidney injury, and in 25% of cycles, grade 3 or higher anemia was present. The MTD was dose level 1. One patient with ATLL had a partial response despite receiving only 4 cycles because of grade 4 myositis. Circulating NK cells were increased in all patients during the first cycle and a rapid reduction in tumor cells within the peripheral circulation was noted. Ex vivo assessment demonstrated increased NK cell activation and increased cell lysis in the presence of monoclonal antibodies after only 5 days. Our small study suggests that rhIL-15, in combination with mogamulizumab, leads to effector NK cell activation and regulatory T-cell depletion but has an unfavorable safety profile. Future development of combinations of immunotherapy that target the microenvironment in relapsed or refractory T-cell lymphomas remains rational. This trial was registered at www.ClinicalTrials.gov as #NCT04185220.
2025-06-10 | An evaluation of denileukin diftitox for the treatment of relapsed or refractory cutaneous T-cell lymphoma.
Denileukin difitox (DD), a recombinant cytotoxic fusion protein composed of full-length human interleukin-2 (IL-2) conjugated to diphtheria toxin's A and B subunits, has shown activity in patients with relapsed and refractory (R/R) mycosis fungoides and the Sezary Syndrome (MF/SS) whose tumor cells expressed CD25, with response rates of 30-44% in advanced and earlier (Stage I-III) stage patients, respectively. Recently, a newer version of DD with improved purity and bioactivity (DD-cxdl) was developed. A registrational trial of D-cxdl showed similar response rates in R/R MF/SS. The purpose of this review is to describe efficacy and safety data surrounding these medications and highlight the equivalency of these two drugs. Both DD and DD-cxdl demonstrate activity in R/R MF/SS with higher response rate in tumor and plaque stage disease. Adverse events grade ≥3 included infusion reactions in 8%, elevated hepatic transaminases in 22%, and capillary leak syndrome in 8%. In addition to direct targeting of CD25 expressing tumor cells, both drugs are also capable of depleting immunoregulatory T-cells. A clinical trial of DD-cxdl in Japan showed that responses were independent of CD25 expression, suggesting multiple mechanisms of action for DD-cxdl in MF/SS and potentially other malignancies.
2025-03-25 | Therapeutic advances for cutaneous T-cell lymphoma.
Cutaneous T-cell lymphomas (CTCLs) are a group of rare and heterogenous diseases. There is currently no curative treatment for patients with advanced mycosis fungoides (MF) and Sézary syndrome (SS). The European Organisation for Research and Treatment of Cancer consensus recommendations for the treatment of MF/SS have been updated and focus on recently available treatments. Peginterferon, a new form of interferon, has a favourable risk-benefit profile for the treatment of patients with CTCL. Recently approved monoclonal antibodies (mABs) have completely modified the treatment algorithm of advanced CTCL treatment. Brentuximab vedotin is very efficient for tumours and transformed MF. Mogamulizumab can induce long-term remission in patients with SS. An international trial of lacutamab has recently been completed, for both SS and MF. Numerous novel targets have been identified, and several new mABs have been shown to be able to enhance specific immune responses and to induce targeted antibody-dependent cytotoxicity and cytophagocytosis. These new antibodies warrant further evaluation in controlled trials. Kinase inhibitors and chimeric antigen receptor T-cell therapy are promising new treatments. Finally, recent studies have demonstrated that allogeneic haematopoietic stem-cell transplantation can increase survival and quality of life in patients with advanced CTCL.
other
2025-06-01 | 382 | GENE COPY NUMBER ALTERATIONS IDENTIFY SUBSET OF SEZARY SYNDROME PATIENTS WITH WORSE SURVIVAL OUTCOMES
A. Kiwan, M. Girardi, M. Xu, and A. Siddon equally contributing author. Background: Sezary syndrome (SS) is an aggressive primary cutaneous T-cell lymphoma (CTCL) characterized by erythroderma and leukemic involvement of peripheral blood. In this study, we investigated the effect of specific GCNAs and clinical features on survival outcomes among pts with SS in attempt to obtain better insight on risk stratification and molecular-clinical correlation reflecting the underpinning pathophysiology. Methods: We identified 125 pts with SS, 85 of whom had a validated FISH panel at diagnosis. FISH probes designed to capture 97.5% of GCNAs in pts with CTCL and SS included probes for TP53, MYC, RB1, CDKN2A, ATM, STAT3, STAT5B, ARID1A, ZEB1, FAS, CARD11, and DNMT3A genes. Overall survival (OS) analysis was conducted using the Kaplan-Meier method to estimate survival probabilities and the log-rank test to compare survival distributions between different groups. Results: Of 85 pts who had FISH at diagnosis, 54% exhibited GCNAs. Deletions were identified in ATM (11q22.3) in 14%, DNMT3A (2p23) in 17%, TP53 (17p13.1) in 40%, ZEB1 (10p11.2) in 18%, RB1 (11q14.2) in 13%, ARID1A (1p35.3) in 13%, and CDKN2A (9p21.3) in 15% of all pts. Amplifications were observed in STAT3 (17q21.31) in 26%, MYC (8q24.21) in 37%, and CARD11 (7p22) in 11% of all pts. The median OS of all pts was 54 months (95% CI: 33–84). Univariate Cox regression analysis identified several significant prognostic factors for OS, including age, elevated ALC (hazard ratios [HR] = 1.1, p < 0.001), WBC (HR = 1.02, p < 0.001), LDH (HR = 1.001, p < 0.000) and ANC (HR = 1.2, p = 0.016. The presence of ARID1A deletion (HR = 3.3, p = 0.001) and ZEB1 deletion (HR = 2.05, p = 0.04) were strongly associated with poorer OS. None of amplifications of STAT3 (HR = 1.4, p = 0.3), MYC (HR = 1.2, p = 0.5), or CARD11 (HR = 1.3, p = 0.6), were significantly associated with poorer OS. A total number of 78 pts had full data and were included in the multivariate CPH model. Among GCNAs, ZEB1 deletion (HR = 5.8, p = 0.008), ARID1A deletion (HR = 5.7, p = 0.009), or ATM deletion (HR = 5.5, p = 0.01) were all significantly associated with poorer OS. Clinical variables including male gender (HR = 7.3, p < 0.001), higher ANC (HR = 1.3, p = 0.05) and lower Hgb (HR = 0.6, p < 0.000) were all significant predictors. GCNAs were documented in 50% of alive pts (vs 58% of deceased pts, p = 0.5). The median OS (months, 95%CI) for pts with ZEB1 deletion (34, 14-NA) was significantly lower compared to wild-type ZEB1 (86, 46-NA). Pts with ATM deletion (39, 20-NA) and AIRD1A deletion (21, 19-NA) had significantly lower OS compared to wild type cases (93 and 94, respectively). Summary: In summary, we identified novel molecular prognostic markers for pts with SS. In conjunction with clinical data, our results will help identify high risk pts with specific GCNAs alteration who will benefit from intensive treatment approaches. Research funding declaration: none Encore Abstract: Regional or national meetings with up to 1000 attendees Keywords: cutaneous non-Hodgkin lymphoma No potential sources of conflict of interest.
2024-02-20 | The Complex Role of Infectious Agents in Human Cutaneous T-Cell Lymphoma Pathogenesis: From Candidate Etiological Factors to Potential Therapeutics
Cutaneous T-cell lymphoma (CTCL) is a devastating, potentially fatal T-lymphocyte malignancy affecting the skin. Despite all efforts, the etiology of this disease remains unknown. Infectious agents have long been suspected as factors or co-factors in CTCL pathogenesis. This review deals with the panel of bacterial and viral pathogens that have been investigated so far in an attempt to establish a potential link between infection/carriage and CTCL development. A special focus is given to a recently discovered human protoparvovirus, namely the cutavirus (CutaV), which has emerged as a plausible CTCL etiological agent. Available evidence in support of this hypothesis as well as alternative interpretations and uncertainties raised by some conflicting data are discussed. The complexity and multifacetedness of the Parvoviridae family of viruses are illustrated by presenting another protoparvovirus, the rat H-1 parvovirus (H-1PV). H-1PV belongs to the same genus as the CutaV but carries considerable potential for therapeutic applications in cutaneous lymphoma.
2024-01-15 | The Multifaceted Role of Protoparvoviruses in Human Cutaneous T Cell Lymphoma: From Candidate Causative Agents to Potential Oncolytic Virus Therapeutics
Cutaneous T cell lymphoma (CTCL) is a devastating, potentially fatal T lymphocyte malignancy affecting the skin. Despite all efforts, the etiology of the disease remains unknown. Infectious agents have long been suspected as factors or co-factors in CTCL pathogenesis. This review deals with the panel of bacterial and viral pathogens that have been investigated so far in an attempt to establish a potential link between infection/carriage and CTCL development. A special focus is given to a recently discovered human protoparvovirus, namely the cutavirus (CutaV), which has emerged as a plausible CTCL etiological agent. Available evidence in support of this hypothesis as well as alternative interpretations and uncertainties raised by some conflicting data are discussed. The complexity and the multifacetedness of the Parvoviridae family of viruses are illustrated by presenting another protoparvovirus, the rat H-1 parvovirus (H-1PV). H-1PV belongs to the same genus as the CutaV but carries a considerable potential for therapeutic applications in cutaneous lymphoma.
2023-09-29 | New JAK3-INSL3 Fusion Transcript—An Oncogenic Event in Cutaneous T-Cell Lymphoma
Constitutively activated tyrosine kinase JAK3 is implicated in the pathogenesis of cutaneous T-cell lymphomas (CTCL). The mechanisms of constitutive JAK3 activation are unknown although a JAK3 mutation was reported in a small portion of CTCL patients. In this study, we assessed the oncogenic roles of a newly identified JAK3-INSL3 fusion transcript in CTCL. Total RNA from malignant T-cells in 33 patients with Sézary syndrome (SS), a leukemic form of CTCL, was examined for the new JAK3-INSL3 fusion transcript by RT-PCR followed by Sanger sequencing. The expression levels were assessed by qPCR and correlated with patient survivals. Knockdown and/or knockout assays were conducted in two CTCL cell lines (MJ cells and HH cells) by RNA interference and/or CRISPR/Cas9 gene editing. SS patients expressed heterogeneous levels of a new JAK3-INSL3 fusion transcript. Patients with high-level expression of JAK3-INSL3 showed poorer 5-year survival (n = 19, 42.1%) than patients with low-level expression (n = 14, 78.6%). CTCL cells transduced with specific shRNAs or sgRNAs had decreased new JAK3-INSL3 fusion transcript expression, reduced cell proliferation, and decreased colony formation. In NSG xenograft mice, smaller tumor sizes were observed in MJ cells transduced with specific shRNAs than cells transduced with controls. Our results suggest that the newly identified JAK3-INSL3 fusion transcript confers an oncogenic event in CTCL.
2023-09-04 | Non-coding RNAs in the epigenetic landscape of cutaneous T-cell lymphoma.
Cutaneous T-cell lymphoma (CTCL) is a type of cancer that affects skin, and is characterized by abnormal T-cells in the skin. Epigenetic changes have been found to play a significant role in the development and progression of CTCL. Recently, non-coding RNAs (ncRNAs), such as microRNAs and long non-coding RNAs, have been identified as key players in the regulation of gene expression in CTCL. These ncRNAs can alter the expression of genes involved in cell growth, differentiation, and apoptosis, leading to the development and progression of CTCL. In this review, we summarize the current understanding of the role of ncRNAs in CTCL, including their involvement in DNA methylation, and other biological processes. We also discuss the types of ncRNAs, their role as oncogenic or tumor suppressive, and their putative use as diagnostic and prognostic biomarkers, based on the emerging evidence from laboratory-based as well as patients-based studies. Moreover, we also present the potential targets and pathways affected by ncRNAs. A better understanding of the complex epigenetic landscape of CTCL, including the role of ncRNAs, has the potential to lead to the development of novel targeted therapies for this disease.
small molecules
2026-08-06 | Cellular and molecular aberrations generating new immunotherapeutic approaches in mycosis fungoides and Sézary syndrome: a comprehensive review of literature.
Recent advances in molecular and immunologic profiling have substantially refined the understanding of mycosis fungoides (MF) and Sézary syndrome (SS), the two most prominent subtypes of cutaneous T-cell lymphomas (CTCL). CTCL comprise a heterogeneous group of lymphoid malignancies characterized by clonal proliferation of malignant T-cell with cutaneous tropism. The pathogenesis of MF and SS appears to be driven by convergent oncogenic programs involving dysregulated JAK/STAT, NF-κB, PI3K/AKT/mTOR, and MAPK signaling, epigenetic reprogramming, apoptosis resistance, immune escape, and microenvironmental support. In parallel, altered surface phenotypes and chemokine receptor programs shape tissue tropism across skin, blood, and lymph nodes, while the tumor microenvironment promotes tumor persistence and Th2-skewed immune polarization. These insights have translated into novel targeted and immune-based therapies. This review summarizes current insights into the cell-intrinsic and microenvironmental biology of MF and SS and discusses emerging approaches aimed at achieving more durable and personalized disease control.
2026-08-01 | A Six-year Response to Belinostat in a Highly Probable Case of Relapsed/Refractory MF/SS Initially Classified as PTCL-NOS: A Case Report
Abstract: Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of hematological malignancies, whose diagnosis is often delayed and requires highly individualized therapeutic strategies. We report an unusual case of a highly probable r/r MF/SS in a 66-year-old male initially diagnosed with peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), based on an atypical leukemic presentation without skin involvement. Cutaneous lesions developed during the disease course, prompting then for a retrospective diagnostic reassessment. Expression of KIR3DL2 on circulating malignant cells, along with a clonal TCR-gamma rearrangement present in both the blood and the skin, and a TP53 nonsense variant, led to a revision of the diagnosis to mycosis fungoides (MF) and Sézary syndrome (SS). MF/SS are the most prevalent CTCL subtypes and are associated with a poor prognosis in advanced stages, largely due to the lack of effective treatments that can achieve sustained remission. Therapeutic options for patients with relapsed/refractory (r/r) MF/SS remain limited and long-term disease control is uncommon. After failure of two treatment lines, including CHOEP-based chemotherapy and bendamustine-brentuximab vedotin (B-BV), the patient received belinostat, a histone deacetylase inhibitor (HDACi). Following three cycles of belinostat, complete cutaneous remission and a partial hematological response were achieved and have been maintained for more than six years (79 cycles to date). Treatment was well tolerated, with only mild anemia. This case highlights the potential role of belinostat in the management of advanced MF/SS and suggests that durable disease control may be achievable in selected r/r patients. Further investigations are warranted to better identify the patients most likely to benefit from belinostat therapy. Keywords: HDAC inhibitor, belinostat, MF/SS, CTCL
2026-07-21 | WEE1 Inhibition as a Novel Therapeutic Strategy in Cutaneous T-Cell Lymphoma
Background/Objectives: Cutaneous T-cell lymphomas (CTCL), most commonly mycosis fungoides and Sézary syndrome, are rare non-Hodgkin lymphomas. Advanced disease responds poorly to current treatments, highlighting the need for new molecularly tar-geted therapies. WEE1 is a central regulator of the G2/M checkpoint and S-phase progression and has emerged as a therapeutic target in several malignancies, yet it has not been systematically explored in CTCL. Methods: We screened a library of more than 2,200 kinase inhibitors in CTCL cell lines and selected adavosertib for further study. Its effects were tested in four CTCL lines, in primary keratinocytes and fibroblasts, in patient-derived malignant CD4⁺ T cells and healthy donor CD4⁺ T cells, and in a MyLa xenograft model, using viability, apoptosis, cell-cycle, western blot, and phospho-protein array assays. Results: Adavosertib reduced viability at submicromolar IC₅₀ values (0.26–0.56 µM) across all four CTCL lines while largely sparing primary skin cells and was more active in malignant than in healthy donor CD4⁺ T cells. It induced apoptosis and cell-line-specific S-phase and/or G2/M accumulation, lowered WEE1 and phospho-CDK1 (Tyr15), and increased phospho-H2A.X. A phospho-protein array showed activation of checkpoint and stress signalling. In vivo, adavosertib slowed MyLa xenograft growth. Conclusions: These preclinical data identify WEE1 as a therapeutic target in CTCL and support further preclinical and early-phase clinical evaluation of adavosertib in this disease.
2026-06-13 | Comment on ‘Context, not class, may be the key signal in systemic Janus kinase inhibitor exposure in mycosis fungoides/Sézary syndrome’: reply from authors
The effects of systemic JAKi exposure in MF/SS appear context-dependent and should not be interpreted as a homogeneous entity. Although disease worsening was observed in several patients initially diagnosed with presumed inflammatory dermatoses, causality cannot necessarily be inferred and may reflect, among other factors, underlying MF/SS biology, referral bias or concurrent immunosuppressive influences. In patients with post-transplant MF/SS receiving JAKi for graft-versus-host disease, MF/SS progression may reflect impaired immune surveillance or other disease-related factors rather than a direct effect of JAKi. These findings underscore the complexity of interpreting JAKi exposure in MF/SS and highlight the need for prospective studies to better define risks across clinical settings.
2026-06-01 | LY06 Golidocitinib-based therapy in relapsed or refractory mycosis fungoides and Sézary syndrome: a real-world retrospective analysis
Abstract Cutaneous T-cell lymphoma (CTCL), primarily mycosis fungoides (MF) and Sézary syndrome (SS), is an incurable malignancy characterized by skin-tropic malignant CD4+ T cells. Current therapies for relapsed or refractory disease exhibit limited efficacy, and patients with transformed disease face dismal outcomes. Somatic Janus kinase (JAK)1 and JAK3 mutations often drive constitutive JAK–signal transducer and activator of transcription activation in CTCL, promoting oncogenesis and resistance. Golidocitinib, a potent and selective JAK1 inhibitor, has previously demonstrated antitumour activity in relapsed or refractory peripheral T-cell lymphoma. This study aims to evaluate the real-world clinical benefit, efficacy and safety of golidocitinib-based therapy – administered either as monotherapy or in combination regimens – for the treatment of patients with relapsed or refractory MF or SS. A real-world retrospective analysis was conducted with a data cutoff of 22 July 2025. Ten patients received at least one cycle of golidocitinib. The cohort had a median age of 57.4 years and a median of 2 prior systemic therapies. The majority of patients (n = 9, 90%) received combination therapy, all incorporating brentuximab vedotin (BV), while one patient received monotherapy. Most patients presented with advanced disease features, including large cell transformation and high CLIPI scores. The best overall response rate and skin response rate were both 80% (8 of 10), comprising 8 partial responses. One patient maintained stable disease, and one experienced progression. Notably, four patients who had previously relapsed or not responded to BV therapy responded to the golidocitinib–BV combination. The median time to response was 31.5 days. Regarding safety, treatment-related adverse events (TRAEs) occurred in six patients, primarily cytomegalovirus infection (50%) and thrombocytopenia (30%). This pioneering real-world study demonstrates that golidocitinib-based regimens offer favourable clinical efficacy in patients with relapsed or refractory MF or SS, including those refractory to prior BV. Subsequent prospective trials are warranted to further validate these combination strategies.
cell therapies
2026-06-08 | Cutaneous Lymphomas and Lymphoproliferative Disorders Associated With SARS-CoV-2 Vaccination: A Systematic Review.
Cutaneous lymphomas (CLs) are rare neoplastic skin disorders, primarily of T-cell origin. Since the widespread rollout of SARS-CoV-2 vaccines, several cases of CLs and non-neoplastic lymphoproliferative disorders (nn-LPDs) temporally associated with vaccination have been reported, raising concerns about a potential immunologic link. To systematically review the literature on cases of CLs and related nn-LPDs occurring after COVID-19 vaccination, focusing on clinical features, subtype distribution, latency to onset, and proposed pathophysiological mechanisms. A systematic review was conducted according to PRISMA guidelines. Case reports and series describing new-onset or relapsed CLs or nn-LPDs temporally following SARS-CoV-2 vaccination were included. Demographic, clinical, histological, therapeutic and temporal data were extracted and analysed. Fifteen manuscripts encompassing 35 cases met the inclusion criteria. Eighteen (51.4%) were histologically confirmed CLs, most commonly lymphomatoid papulosis (n = 9), followed by Sézary syndrome (n = 3) and mycosis fungoides (n = 2). The remaining 17 cases (48.6%) were classified as nn-LPDs, including cutaneous lymphoid hyperplasia, lymphomatoid reactions and CD4+ small/medium T-cell lymphoproliferative disorders. CD30 positivity was noted in 76.2% of the cases with available immunophenotyping. Most patients (80%) received the BNT162b2 (Pfizer-BioNTech) vaccine. In the 17 new-onset CLs, time to onset ranged from 3 to 42 days, with most cases clustering within 14 days. Most of the cases were low-grade T-cell CLs and nn-LPDs. Although a causal relationship cannot be established, the short latency observed in many new-onset cases raises the possibility that some patients may have harboured an undiagnosed disease, with vaccination acting as a trigger for clinical manifestation or for raised awareness. These findings support indeed the need for continued pharmacovigilance among clinicians, especially in patients with prior or latent lymphoproliferative conditions. Nevertheless, these extremely rare and indolent events should not alter the overall favourable risk-benefit profile of COVID-19 vaccination.
2026-01-30 | Sézary syndrome arising from cutaneous epitheliotropic T-cell lymphoma, resembling human folliculotropic mycosis fungoides, in a dog.
A 9-year-old neutered male Pug dog presented with a history of chronic dermatitis. Dermatological examination revealed skin thickening with keratin fronds, erythematous macules and generalized lymphadenopathy. Haematology revealed leucocytosis with lymphocytosis and medium to large neoplastic lymphocytes having cerebriform nuclei (Sézary cells). Fine-needle aspirate samples from the skin and the superficial lymph nodes contained pleomorphic medium-sized lymphocytes and a cytological diagnosis of lymphoma was made. The dog was euthanized. In addition to the cutaneous lesions, post-mortem examination revealed lymphadenomegaly, splenomegaly and hepatomegaly. Histological examination of the skin revealed a neoplastic proliferation of large lymphocytes infiltrating the deep dermis and surrounding the hair follicles. Similar neoplastic cells were present in the lymph nodes, spleen, liver and bone marrow. Neoplastic cells were immunoreactive for CD3 and not for PAX-5. The final diagnosis was Sézary syndrome arising from cutaneous epitheliotropic T-cell lymphoma resembling human folliculotropic mycosis fungoides.
2025-11-19 | Extracorporeal Photopheresis for the Inpatient Dermatologist
Abstract Purpose of Review Extracorporeal photopheresis (ECP) is an immunomodulatory treatment in which an apheresis machine isolates mononuclear cells from whole blood that are then treated with psoralen and ultraviolet-A light and reinfused into the patient. ECP has been approved for use in cutaneous T-cell lymphoma (CTCL) for 30 years; it has also been shown to be effective for graft-versus-host disease, solid organ transplant rejection, and various autoimmune diseases. Nonetheless, ECP is relatively underutilized, perhaps due to knowledge gaps and resource limitations. Here, we review ECP indications and techniques, as well as the data supporting its use in clinical settings. Recent Finding Recent clinical studies have emphasized the durability of ECP in CTCL, both as monotherapy and in combination with topical and other systemic CTCL treatment modalities. New insights into the mechanism of action underlying ECP have illuminated its effects on both cellular and humoral immunity. Specific clinical and laboratory findings have been identified as potential predictors of ECP response. Summary ECP is a well-tolerated and effective treatment option for a growing list of indications. In CTCL, ECP can achieve durable responses with longer treatment courses and should be considered as a first-line option for erythrodermic disease and Sézary syndrome.
2025-11-03 | Racial disparities in mycosis fungoides - from self-reported race to genetic ancestry analysis
Abstract Introduction: Racial disparities in mycosis fungoides (MF) and Sezary syndrome (SS) are well-documented, with self-identified Black patients being diagnosed younger, with more advanced disease, and worse survival. (Su C et al. J Am Acad Dermatol. 2017; Wilson LD et al. Clin Lymphoma Myeloma Leuk. 2012). Our previous work showed that these disparities persist after adjusting for socioeconomic factors (Gandham AR et al. Clin Lymphoma Myeloma Leuk. 2024) suggesting genetic ancestry may contribute. We compared clinical characteristics and outcome of MF/SS patients stratified by self-reported race versus genetic ancestry. Methods: Patients with confirmed MF/SS were consented for genetic profiling via Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT). Genetic ancestry was inferred using ADMIXTURE and single nucleotide polymorphisms (SNPs) captured by MSK-IMPACT (Arora K et al. Cancer discovery. 2022). Patients with ancestral fraction of >0.8 for any single population were assigned that population label; otherwise, they were considered admixed. Results: Genetic ancestry analysis of 161 MF/SS patients (104 self-reported White race, 30 Black, 7 Asian, 20 Other/Unknown) identified 74 as European (EUR), 21 Ashkenazi Jewish (ASJ), 23 African (AFR), 5 East/South Asian, 1 Native American and 37 as admixed. AFR patients were diagnosed 10 years younger than EUR/ASJ (p=0.01) and were less likely to present with stage IA disease compared to EUR/ASJ patients (0% vs 23.2%, p=0.01). Trends towards higher female dominance (52% vs. 35%, p=0.1), higher disease-related mortality (22% vs 12%, p=0.2) and worse progression-free survival (PFS, p=0.11) were observed in AFR patients. ASJ patients showed a trend toward improved PFS compared to EUR patients (p=0.08). Conclusions: Our novel ancestry-based stratification of MF/SS patients confirms disparities seen in self-reported race groups, supporting the need to further investigate specific genetic and non-genetic contributors to disparities in MF/SS patients.
2025-10-02 | Allogeneic hematopoietic cell transplant in cutaneous T-cell lymphomas: recommendations from the EBMT PH&G Committee.
This manuscript provides expert recommendations on the role of allogeneic hematopoietic cell transplantation (allo-HCT) for cutaneous T-cell lymphoma (CTCL), specifically Mycosis Fungoides (MF) and Sezary Syndrome (SS). Critical aspects such as patient selection, timing, and bridging therapy are addressed, as well as donor source, conditioning regimens and post-transplant management. These consensus guidelines are based on a thorough literature review and discussions among leading dermatologists and hematologists. These recommendations aim to harmonise clinical practice towards improving patient outcomes in these rare but aggressive lymphomas. It is of critical importance to consider allo-HCT early in the management of eligible patients with high-risk disease. Advanced stage, large-cell transformation, relapsed or refractory disease following systemic treatment, and N3-stage lymph node involvement are indicators that should trigger consultation with a transplant hematologist in parallel with a donor search. Early interaction between dermatologists and transplant hematologists is vital to avoiding delays, which can significantly impact post-transplant outcomes and survival. This EBMT Practice Harmonisation & Guidelines Committee consensus provides practical recommendations for the selection, timing, and conduct of allogeneic transplantation in advanced-stage mycosis fungoides and Sézary syndrome, aiming to optimize outcomes through early multidisciplinary collaboration and evidence-based decision making.
antibodies
2026-07-28 | Sézary Syndrome Biomarker, T Cell Transcription Factors and Cytokine Genes Provide Novel Insight into Response During Mogamulizumab Treatment.
Background: Novel Sézary syndrome (SS) biomarker genes identified previously through transcription profiling were examined for changes in expression after mogamulizumab treatment. Incorporating new biomarkers for measuring response to disease would improve clinical care. Objective: To assess novel SS biomarker and cytokine genes in patients treated with mogamulizumab with clinical response, blood response, and immunologic parameters. Methods: We performed a real-world case-control and case-case study analyzing the expression of SS biomarker genes in peripheral blood mononuclear cells (PBMCs) from six SS patients treated with mogamulizumab using qRT-PCR. Results: We demonstrated a reduced expression of SS biomarker genes in PBMCs of SS patients following mogamulizumab therapy. In our cohort, five of the SS biomarker genes (PLS3, TWIST1, KCNK1, DNM3 and TOX) showed statistically consistent high expression compared to normal PBMCs at baseline. After treatment with mogamalizumab, these five SS biomarkers showed significant correlations with skin response (p < 0.05) and three (TOX, TCRL3 and DNM3) with blood response (p < 0.05). A decrease in GATA3 expression correlated to an improvement in skin severity, and STAT4 inversely correlated to Sézary cell decrease (p < 0.05). Two cytokine genes, IL4 and IFNG, reflective of an immune response that is abnormal in SS, showed a trend to normalized expression with IL-4 decreasing and IFNG increasing after treatment. Limitations: This was a real-world study of patients who failed prior treatments, with a small sample size and variable timing between patient sample collection. Conclusions: Unique SS biomarker, cytokine and T cell transcription factor genes are valuable in assessing molecular and immune responses following treatment.
2026-07-28 | Dissecting Immune Determinants in Lesional Skin of Cutaneous T-Cell Lymphoma During Mogamulizumab Therapy.
Background: Mycosis fungoides (MF) and Sézary syndrome (SS) are the predominant cutaneous T-cell lymphomas. Although malignant T cells in MF/SS overexpress CCR4 and respond to the anti-CCR4 antibody mogamulizumab, skin response rates vary. We hypothesized that immune components within the tumor microenvironment contribute to differential outcomes. Methods: Imaging mass cytometry with a 37-antibody panel was used to characterize immune and structural elements in FFPE tissues from sixteen MF/SS patients (6 MF, 10 SS) treated with Mogamulizumab, including seven skin responders and nine non-responders. Single-cell phenotyping and spatial analyses were performed using the Visiopharm® Phenoplex™ platform, with supervision. Results: We identified 68,974 cells pre-treatment and 58,852 cells post-treatment. Malignant CD4+ T cells showed reduced baseline CD27, CD103, CD25, and ICOS expression compared with non-malignant CD4+ cells. Baseline MF lesions were enriched for IL-13+ and CD103+ malignant T cells, whereas SS lesions contained higher proportions of CD27+ and LAG3+ cells. IL 13+ malignant cells decreased after treatment, most prominently in MF. Myeloid profiles differed by disease and response: MF lesions exhibited baseline enrichment of M1-like macrophages (CD86+, HLA-DR+), while SS lesions were predominantly M2-polarized macrophages (CD163+, CD206+). Responders showed increased M1-like macrophages, whereas non-responders displayed reduced M1-features. An increase in DC3-like cells was observed in non-responders following treatment. Conclusions: This single-cell spatial atlas reveals shared and subtype-specific immune features in MF/SS. Th2-skewed malignant T-cell status and myeloid polarization correlate with clinical response, supporting their potential as spatial biomarkers for patient stratification in mogamulizumab therapy.
2026-07-23 | Final results of UK NCRI phase II trial of pembrolizumab and radiotherapy in cutaneous T cell lymphoma.
The outlook for patients with advanced cutaneous T-cell lymphomas (CTCL); mycosis fungoides (MF) and Sézary syndrome (SS) remains poor and most systemic treatments provide short-lived remissions. Immunotherapy has provided a major cancer breakthrough, and the PORT trial was designed to investigate the efficacy of Pembrolizumab and whether the addition of Radiotherapy (RT) could further enhance systemic "abscopal" anti-tumour immune responses. Pembrolizumab followed by 12Gy in 3 fractions RT to a localized lesion was investigated in a single-arm, multicentre phase II trial for relapsed/refractory CTCL. Primary endpoint was overall response rate (ORR), secondary endpoints included duration of response (DOR), abscopal response, progression-free survival (PFS), overall survival (OS). 46 patients (41 MF, 5 SS) were registered, median age 63 (24-83), 24% stage IV. Median follow-up was 24.8 months. 24% of patients remained on treatment for >1 year whilst 57% received.
2026-07-22 | Durable remission with no survival reduction after mogamulizumab discontinuation in Sézary syndrome
Mogamulizumab (MOGA), an anti-CCR4 monoclonal antibody, improves progression-free survival (PFS) and overall survival in Sézary syndrome (SS). Recently, a multicentre retrospective study conducted by the French Cutaneous Lymphoma study group assessed PFS in 52 patients with SS (median age 73 years, 56% female sex, 75% stage IVA1) who discontinued MOGA for reasons other than disease progression (Moga-stop Study). We report data from an extended follow-up of this cohort, along with comparative PFS outcomes from a parallel SS cohort with continuous MOGA treatment until progression.
2026-06-18 | Mogamulizumab as Bridge to Thiotepa-Based Allogeneic Haematopoietic Stem Cell Transplantation in Sézary Syndrome: A Single-Centre Experience.
Sézary syndrome (SS) is an aggressive cutaneous T-cell lymphoma for which allogeneic haematopoietic stem cell transplantation (allo-HSCT) represents the only potentially curative treatment. We report a single-centre series of three consecutive SS patients treated with mogamulizumab as bridging therapy to allo-HSCT using thiotepa-based reduced-intensity conditioning. Mogamulizumab induced rapid clearance of circulating Sézary cells and significant clinical improvement. All patients achieved early and stable full donor chimerism and complete remission. Post-transplant GVHD occurred but was manageable with standard therapy. Early use of mogamulizumab may provide effective disease control and facilitate successful allo-HSCT in SS. The authors have confirmed clinical trial registration is not needed for this submission.
proteins
2026-05-19 | Flow Cytometry for Diagnosing Sézary Syndrome When Skin Biopsies Are Inconclusive: A Case Report.
Sézary syndrome (SS) is a rare leukemic variant of cutaneous T-cell lymphomas, accounting for a small proportion of cases, estimated at less than 5% of all cutaneous T-cell lymphomas, characterized by pruritic erythroderma, lymphadenopathy, and circulating clonal T lymphocytes. Diagnosis can be challenging when skin biopsies are non-diagnostic, potentially delaying treatment. Peripheral blood flow cytometry (FC) is essential for detecting aberrant T-cells, assessing clonality, which may be supported in selected cases by T-cell receptor beta-chain constant region 1 (TRBC1) expression analysis, quantifying tumor burden, and guiding tumor-node-metastasis-blood (TNMB) staging and follow-up. A 58-year-old man presented with diffuse pruritic erythroderma and lesions refractory to topical corticosteroids, systemic corticosteroids, methotrexate, and emollients. Repeated skin biopsies showed spongiotic or psoriasiform changes without evidence of malignancy. Peripheral blood smear revealed 5-7% Sézary cells. FC identified an aberrant cluster of differentiation (CD)4+ T-cell population representing 90% of lymphocytes, with CD7+, CD26-, and 97% TRBC1 positivity, confirming a clonal malignant population. Lymph node biopsy was consistent with T-cell lymphoma. TNMB classification was T4N3M0B2 (stage IVA2). The patient received peginterferon alfa-2a with topical corticosteroids and supportive care, leading to clinical and laboratory improvement. This case underscores the critical role of FC when skin biopsies are inconclusive. Comprehensive immunophenotyping, including TRBC1, confirms monoclonality, informs TNMB staging, and guides targeted therapy. Quantitative assessment of circulating malignant cells allows dynamic monitoring of treatment response. Early integration of peripheral blood FC in suspected SS improves diagnostic accuracy, reduces delays, and enables rapid initiation of targeted therapy, ultimately optimizing patient outcomes.
2025-06-27 | P159 Use of Besremi® (pegylated interferon-alfa-2b) in the treatment of cutaneous T-cell lymphoma
Abstract Interferon-alfa has been used to treat mycosis fungoides (MM) and Sézary syndrome (SS) since the 1980s. Type 1 interferons (IFN-alfa and IFN-beta) have antiviral, antitumour, immunomodulatory and antiproliferative properties. The initial marketed product, IFN-alfa-2b (Intron®), was licensed and approved for the treatment of cutaneous T-cell lymphoma in Europe and the USA. Due to the supplier’s financial considerations, Intron® was withdrawn from the market; patients were moved onto IFN-alfa-2a (Roferon®). Roferon was subsequently withdrawn and patients switched to pegylated IFN-alfa-2a (Pegasys®). Peg-IFN-alfa-2a is recommended in the 2023 European Organisation for Research and Treatment of Cancer guidelines for the treatment of MF/SS. Pegasys has the benefit of once-weekly dosing (compared with three times per week for nonpegylated IFNs) and demonstrates similar efficacy. Due to manufacturing issues, there is currently an international shortage of Pegasys. We report our response to this including use of a novel alternative IFN. From our hospital pharmacy records, we identified 21 patients taking Pegasys when forthcoming shortages were announced. Initially, the frequency of administration was reduced from weekly to fortnightly. Initiation of new patients was paused and alternative treatment options considered. Ropeginterferon-alfa-2b (Besremi®), a newer pegylated interferon with similar pharmacokinetics to Pegasys, was identified as the only interferon-alfa product available in England. Besremi is licensed and commissioned in England to treat myeloproliferative neoplasms. It is administered subcutaneously once per fortnight using a prefilled, reusable pen. Besremi 250 μg is therapeutically equivalent to Pegasys 180 μg, and has a National Health Service list price 2.8 times that of Pegasys. Of our 21 patients taking Pegasys, 12 had stage 1B disease, four stage 2B, two stage 3A and two stage 3B, and one had cutaneous lymphoid hyperplasia. All 21 patients initially dose reduced to fortnightly administration; 9 reported a deterioration in their skin. Six (to date) have subsequently switched to Besremi, with seven further switches pending. Four patients moved from Pegasys directly to other therapies due to disease progression or lack of control (two brentuximab, one bexarotene and one total skin electron beam). Four patients have died: two from unrelated causes and two of disease. To date, six patients have been taking Besremi for 6–8 weeks. Early observations indicate that Besremi is at least as effective as Pegasys, with reversal of disease deterioration triggered by dose reduction of Pegasys. Three patients report their skin is stable, and two report an improvement in skin and mood on Besremi. One patient developed a serious adverse event, 5 days after administration of the first dose of Besremi. Symptoms included fever, shortness of breath, cough, skin rash and palpitations, requiring inpatient admission. She has tolerated subsequent doses well, suggesting that this event was unrelated. However, we highlight that palpitations are reported as a common side-effect of Besremi in the product literature. We report ongoing results from the use of Besremi in MF/SS, discussing dosing, efficacy, safety and monitoring.
2025-06-23 | A phase 1 study of interleukin-15 in combination with mogamulizumab in relapsed and refractory T-cell malignancies.
Recombinant human interleukin-15 (rhIL-15) is an immunotherapeutic agent that enhances natural killer (NK) cells to augment the antibody-dependent cellular cytotoxicity (ADCC) of monoclonal antibodies. Mogamulizumab is a CC chemokine receptor 4-directed monoclonal antibody that exerts cytotoxicity through ADCC and depletes regulatory T cells within the tumor microenvironment. We conducted a phase 1 clinical trial of rhIL-15 in combination with mogamulizumab. Patients with relapsed or refractory adult T-cell leukemia/lymphoma (ATLL), mycosis fungoides (MF), and Sezary syndrome (SS) received a fixed dose mogamulizumab, combined with escalating doses of rhIL-15 to identify the maximum tolerated dose (MTD). Six patients were enrolled, 4 with ATLL and 2 with MF/SS. The most common adverse events were rash, infection, and fever (67% of all). Two patients (33%) had grade 4 acute kidney injury, and in 25% of cycles, grade 3 or higher anemia was present. The MTD was dose level 1. One patient with ATLL had a partial response despite receiving only 4 cycles because of grade 4 myositis. Circulating NK cells were increased in all patients during the first cycle and a rapid reduction in tumor cells within the peripheral circulation was noted. Ex vivo assessment demonstrated increased NK cell activation and increased cell lysis in the presence of monoclonal antibodies after only 5 days. Our small study suggests that rhIL-15, in combination with mogamulizumab, leads to effector NK cell activation and regulatory T-cell depletion but has an unfavorable safety profile. Future development of combinations of immunotherapy that target the microenvironment in relapsed or refractory T-cell lymphomas remains rational. This trial was registered at www.ClinicalTrials.gov as #NCT04185220.
2025-06-10 | An evaluation of denileukin diftitox for the treatment of relapsed or refractory cutaneous T-cell lymphoma.
Denileukin difitox (DD), a recombinant cytotoxic fusion protein composed of full-length human interleukin-2 (IL-2) conjugated to diphtheria toxin's A and B subunits, has shown activity in patients with relapsed and refractory (R/R) mycosis fungoides and the Sezary Syndrome (MF/SS) whose tumor cells expressed CD25, with response rates of 30-44% in advanced and earlier (Stage I-III) stage patients, respectively. Recently, a newer version of DD with improved purity and bioactivity (DD-cxdl) was developed. A registrational trial of D-cxdl showed similar response rates in R/R MF/SS. The purpose of this review is to describe efficacy and safety data surrounding these medications and highlight the equivalency of these two drugs. Both DD and DD-cxdl demonstrate activity in R/R MF/SS with higher response rate in tumor and plaque stage disease. Adverse events grade ≥3 included infusion reactions in 8%, elevated hepatic transaminases in 22%, and capillary leak syndrome in 8%. In addition to direct targeting of CD25 expressing tumor cells, both drugs are also capable of depleting immunoregulatory T-cells. A clinical trial of DD-cxdl in Japan showed that responses were independent of CD25 expression, suggesting multiple mechanisms of action for DD-cxdl in MF/SS and potentially other malignancies.
2025-03-25 | Therapeutic advances for cutaneous T-cell lymphoma.
Cutaneous T-cell lymphomas (CTCLs) are a group of rare and heterogenous diseases. There is currently no curative treatment for patients with advanced mycosis fungoides (MF) and Sézary syndrome (SS). The European Organisation for Research and Treatment of Cancer consensus recommendations for the treatment of MF/SS have been updated and focus on recently available treatments. Peginterferon, a new form of interferon, has a favourable risk-benefit profile for the treatment of patients with CTCL. Recently approved monoclonal antibodies (mABs) have completely modified the treatment algorithm of advanced CTCL treatment. Brentuximab vedotin is very efficient for tumours and transformed MF. Mogamulizumab can induce long-term remission in patients with SS. An international trial of lacutamab has recently been completed, for both SS and MF. Numerous novel targets have been identified, and several new mABs have been shown to be able to enhance specific immune responses and to induce targeted antibody-dependent cytotoxicity and cytophagocytosis. These new antibodies warrant further evaluation in controlled trials. Kinase inhibitors and chimeric antigen receptor T-cell therapy are promising new treatments. Finally, recent studies have demonstrated that allogeneic haematopoietic stem-cell transplantation can increase survival and quality of life in patients with advanced CTCL.
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2025-06-01 | 382 | GENE COPY NUMBER ALTERATIONS IDENTIFY SUBSET OF SEZARY SYNDROME PATIENTS WITH WORSE SURVIVAL OUTCOMES
A. Kiwan, M. Girardi, M. Xu, and A. Siddon equally contributing author. Background: Sezary syndrome (SS) is an aggressive primary cutaneous T-cell lymphoma (CTCL) characterized by erythroderma and leukemic involvement of peripheral blood. In this study, we investigated the effect of specific GCNAs and clinical features on survival outcomes among pts with SS in attempt to obtain better insight on risk stratification and molecular-clinical correlation reflecting the underpinning pathophysiology. Methods: We identified 125 pts with SS, 85 of whom had a validated FISH panel at diagnosis. FISH probes designed to capture 97.5% of GCNAs in pts with CTCL and SS included probes for TP53, MYC, RB1, CDKN2A, ATM, STAT3, STAT5B, ARID1A, ZEB1, FAS, CARD11, and DNMT3A genes. Overall survival (OS) analysis was conducted using the Kaplan-Meier method to estimate survival probabilities and the log-rank test to compare survival distributions between different groups. Results: Of 85 pts who had FISH at diagnosis, 54% exhibited GCNAs. Deletions were identified in ATM (11q22.3) in 14%, DNMT3A (2p23) in 17%, TP53 (17p13.1) in 40%, ZEB1 (10p11.2) in 18%, RB1 (11q14.2) in 13%, ARID1A (1p35.3) in 13%, and CDKN2A (9p21.3) in 15% of all pts. Amplifications were observed in STAT3 (17q21.31) in 26%, MYC (8q24.21) in 37%, and CARD11 (7p22) in 11% of all pts. The median OS of all pts was 54 months (95% CI: 33–84). Univariate Cox regression analysis identified several significant prognostic factors for OS, including age, elevated ALC (hazard ratios [HR] = 1.1, p < 0.001), WBC (HR = 1.02, p < 0.001), LDH (HR = 1.001, p < 0.000) and ANC (HR = 1.2, p = 0.016. The presence of ARID1A deletion (HR = 3.3, p = 0.001) and ZEB1 deletion (HR = 2.05, p = 0.04) were strongly associated with poorer OS. None of amplifications of STAT3 (HR = 1.4, p = 0.3), MYC (HR = 1.2, p = 0.5), or CARD11 (HR = 1.3, p = 0.6), were significantly associated with poorer OS. A total number of 78 pts had full data and were included in the multivariate CPH model. Among GCNAs, ZEB1 deletion (HR = 5.8, p = 0.008), ARID1A deletion (HR = 5.7, p = 0.009), or ATM deletion (HR = 5.5, p = 0.01) were all significantly associated with poorer OS. Clinical variables including male gender (HR = 7.3, p < 0.001), higher ANC (HR = 1.3, p = 0.05) and lower Hgb (HR = 0.6, p < 0.000) were all significant predictors. GCNAs were documented in 50% of alive pts (vs 58% of deceased pts, p = 0.5). The median OS (months, 95%CI) for pts with ZEB1 deletion (34, 14-NA) was significantly lower compared to wild-type ZEB1 (86, 46-NA). Pts with ATM deletion (39, 20-NA) and AIRD1A deletion (21, 19-NA) had significantly lower OS compared to wild type cases (93 and 94, respectively). Summary: In summary, we identified novel molecular prognostic markers for pts with SS. In conjunction with clinical data, our results will help identify high risk pts with specific GCNAs alteration who will benefit from intensive treatment approaches. Research funding declaration: none Encore Abstract: Regional or national meetings with up to 1000 attendees Keywords: cutaneous non-Hodgkin lymphoma No potential sources of conflict of interest.
2024-02-20 | The Complex Role of Infectious Agents in Human Cutaneous T-Cell Lymphoma Pathogenesis: From Candidate Etiological Factors to Potential Therapeutics
Cutaneous T-cell lymphoma (CTCL) is a devastating, potentially fatal T-lymphocyte malignancy affecting the skin. Despite all efforts, the etiology of this disease remains unknown. Infectious agents have long been suspected as factors or co-factors in CTCL pathogenesis. This review deals with the panel of bacterial and viral pathogens that have been investigated so far in an attempt to establish a potential link between infection/carriage and CTCL development. A special focus is given to a recently discovered human protoparvovirus, namely the cutavirus (CutaV), which has emerged as a plausible CTCL etiological agent. Available evidence in support of this hypothesis as well as alternative interpretations and uncertainties raised by some conflicting data are discussed. The complexity and multifacetedness of the Parvoviridae family of viruses are illustrated by presenting another protoparvovirus, the rat H-1 parvovirus (H-1PV). H-1PV belongs to the same genus as the CutaV but carries considerable potential for therapeutic applications in cutaneous lymphoma.
2024-01-15 | The Multifaceted Role of Protoparvoviruses in Human Cutaneous T Cell Lymphoma: From Candidate Causative Agents to Potential Oncolytic Virus Therapeutics
Cutaneous T cell lymphoma (CTCL) is a devastating, potentially fatal T lymphocyte malignancy affecting the skin. Despite all efforts, the etiology of the disease remains unknown. Infectious agents have long been suspected as factors or co-factors in CTCL pathogenesis. This review deals with the panel of bacterial and viral pathogens that have been investigated so far in an attempt to establish a potential link between infection/carriage and CTCL development. A special focus is given to a recently discovered human protoparvovirus, namely the cutavirus (CutaV), which has emerged as a plausible CTCL etiological agent. Available evidence in support of this hypothesis as well as alternative interpretations and uncertainties raised by some conflicting data are discussed. The complexity and the multifacetedness of the Parvoviridae family of viruses are illustrated by presenting another protoparvovirus, the rat H-1 parvovirus (H-1PV). H-1PV belongs to the same genus as the CutaV but carries a considerable potential for therapeutic applications in cutaneous lymphoma.
2023-09-29 | New JAK3-INSL3 Fusion Transcript—An Oncogenic Event in Cutaneous T-Cell Lymphoma
Constitutively activated tyrosine kinase JAK3 is implicated in the pathogenesis of cutaneous T-cell lymphomas (CTCL). The mechanisms of constitutive JAK3 activation are unknown although a JAK3 mutation was reported in a small portion of CTCL patients. In this study, we assessed the oncogenic roles of a newly identified JAK3-INSL3 fusion transcript in CTCL. Total RNA from malignant T-cells in 33 patients with Sézary syndrome (SS), a leukemic form of CTCL, was examined for the new JAK3-INSL3 fusion transcript by RT-PCR followed by Sanger sequencing. The expression levels were assessed by qPCR and correlated with patient survivals. Knockdown and/or knockout assays were conducted in two CTCL cell lines (MJ cells and HH cells) by RNA interference and/or CRISPR/Cas9 gene editing. SS patients expressed heterogeneous levels of a new JAK3-INSL3 fusion transcript. Patients with high-level expression of JAK3-INSL3 showed poorer 5-year survival (n = 19, 42.1%) than patients with low-level expression (n = 14, 78.6%). CTCL cells transduced with specific shRNAs or sgRNAs had decreased new JAK3-INSL3 fusion transcript expression, reduced cell proliferation, and decreased colony formation. In NSG xenograft mice, smaller tumor sizes were observed in MJ cells transduced with specific shRNAs than cells transduced with controls. Our results suggest that the newly identified JAK3-INSL3 fusion transcript confers an oncogenic event in CTCL.
2023-09-04 | Non-coding RNAs in the epigenetic landscape of cutaneous T-cell lymphoma.
Cutaneous T-cell lymphoma (CTCL) is a type of cancer that affects skin, and is characterized by abnormal T-cells in the skin. Epigenetic changes have been found to play a significant role in the development and progression of CTCL. Recently, non-coding RNAs (ncRNAs), such as microRNAs and long non-coding RNAs, have been identified as key players in the regulation of gene expression in CTCL. These ncRNAs can alter the expression of genes involved in cell growth, differentiation, and apoptosis, leading to the development and progression of CTCL. In this review, we summarize the current understanding of the role of ncRNAs in CTCL, including their involvement in DNA methylation, and other biological processes. We also discuss the types of ncRNAs, their role as oncogenic or tumor suppressive, and their putative use as diagnostic and prognostic biomarkers, based on the emerging evidence from laboratory-based as well as patients-based studies. Moreover, we also present the potential targets and pathways affected by ncRNAs. A better understanding of the complex epigenetic landscape of CTCL, including the role of ncRNAs, has the potential to lead to the development of novel targeted therapies for this disease.
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