RARE DISEASE
Sézary syndrome
Sézary syndrome
Sézary syndrome
Synonyms: Sézary lymphoma
Synonyms: Sézary lymphoma
Synonyms: Sézary lymphoma
Drug discovery
1,505
papers
On emerging therapies
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
1,505 drug discovery papers about Sézary syndrome, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,505 drug discovery papers about Sézary syndrome, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-26 | Cutaneous T Cell Lymphoma: Targeting the Survival Network in Mycosis Fungoides and Sézary Syndrome.
Cutaneous T cell lymphoma (CTCL) comprises a heterogeneous group of skin-homing T cell malignancies, with mycosis fungoides (MF) and Sézary Syndrome representing the most frequent and clinically relevant entities. Their clinical behavior differs substantially: MF often follows an indolent course over years, whereas Sézary Syndrome is a distinct clinicopathological entity that is typically characterized by erythroderma, a high burden of circulating malignant T cells and frequent lymph node involvement. Early-stage MF can often be controlled with skin-directed therapies, but advanced, relapsed or refractory CTCL remains therapeutically challenging. Established treatments are selected primarily according to disease stage, disease compartment and surface-target expression, whereas most pathway-directed, redox-modulating and apoptosis-sensitizing approaches remain investigational. Increasing evidence indicates that malignant T cells are maintained by an interconnected survival network rather than by a single dominant oncogenic pathway. This network includes constitutive inflammatory signaling, nuclear factor kappa B (NF-κB) activation, apoptosis resistance, altered redox homeostasis, mitochondrial and metabolic adaptation, rat sarcoma viral oncogene homolog (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase kinase (MEK) signaling and epigenetic regulation. These mechanisms cooperate to promote malignant T cell survival, therapy resistance, and disease progression, but they also create opportunities for targeted therapeutic intervention. Particular emphasis is placed on redox-regulated cell death, nuclear factor kappa B (NF-κB)-dependent survival, B-cell lymphoma 2 (BCL-2) family proteins, RAS pathway alterations, epigenetic sensitization and mechanism-informed treatment strategies. Integrating clinicopathological staging with molecular profiling and functional vulnerability screens may support more rational combination therapies and improve patient stratification in CTCL.
2026-08-22 | Patient and care partner burden in cutaneous T-cell lymphoma using disease-specific measures of symptoms and health-related quality of life
Patients with mycosis fungoides (MF) or Sézary syndrome (SS) may experience visible lesions, severe itch, sleep disturbance, body temperature dysregulation and depression. In this international study, 73 patients completed a symptom diary and questionnaires relating to fatigue and health-related quality of life [HRQoL: the MF/SS-cutaneous T-cell lymphoma QoL measure (MF/SS-CTCL QoL)]; 24 care partners also completed an HRQoL questionnaire. Patients reported a high symptom burden that differed between MF and SS, with a moderate impact on HRQoL. This is the first study to identify which symptoms of MF/SS compromise different aspects of both patients’ and care partners’ HRQoL. Addressing specific skin symptoms may improve patients’ fatigue, sleep and overall HRQoL and care partners’ HRQoL.
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.
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.
2025-10-17 | Erythroderma Part I. Erythrodermic form of cutaneous T-cell lymphoma (CTCL)
Erythrodermic cutaneous T-cell lymphoma (E-CTCL) includes erythrodermic (E) mycosis fungoides (E-MF) and Sézary syndrome (SS), considered to be two distinct clinical entities, although related. Clinical characteristics of E-MF and SS are similar, with a hallmark of erythroderma and varying numbers of Sézary cells in the blood. Distinguishing between E-MF and SS relies on determining the degree of blood involvement, based on the expanded criteria for B classification from the ISCL-EORTC. Epidermotropic infiltrate of atypical, monoclonal, CD4+ lymphoid cells can be present in both dise ases with minor differences in the quantity of the infiltrating cells, in dermal changes, and in the presence of nonspecific histology. Clinicopathologic findings can be subtle and may mimic benign dermatoses. Thus, immunohistochemistry, molecular analysis, and blood flow cytome try are essential for accurate diagnosis.
antibodies
2026-09-24 | Real-World Experience With Mogamulizumab for Mycosis Fungoides and Sézary Syndrome.
Mogamulizumab is an established treatment option for relapsed/refractory mycosis fungoides (MF) and Sézary syndrome (SS); however, large-scale real-world outcome data remain limited. We conducted a retrospective cohort study on patients with MF or SS who received treatment with mogamulizumab using TriNetX. A total of 394 patients were included (182 [46.2%] MF, 212 [53.8%] SS). The median follow-up was 31.5 months. The 1- and 3-year OS rates were 85.7% and 73.4%, respectively. Corresponding rates among MF and SS patients were 82.0% versus 88.2% and 69.3% versus 76.7%. In univariable analyses, SS was associated with improved OS (Hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.57-0.98; P = .032), whereas nodal involvement predicted inferior survival (HR 1.36, 95% CI 1.01-1.93; P = .043). Following adjustment, both associations were attenuated to non-significant trends (SS: aHR = 0.70, 95% CI: 0.47-1.03, P = .067; nodal involvement: aHR 1.40, 95% CI 0.95-2.06; P = .089). Overall, 154 patients (39.1%) required subsequent systemic therapy, with the 1- and 3-year cumulative incidence being 31.1% (95% CI: 25.7%-35.7%) and 41.0% (95% CI: 35.1%-46.9%), respectively. Elevated LDH independently predicted shorter TTNT (acsHR 1.62, 95% CI 1.29-2.03; P < .001). The 12-month incidences of infection, sepsis, hospitalization, and emergency department visits were 39.8%, 13.5%, 34.3%, and 20.6%, respectively, with similar incidences between MF and SS. In this large real-world cohort, mogamulizumab was associated with durable survival, prolonged treatment-free intervals, and the outcomes observed were consistent with the pattern seen in the MAVORIC trial.
2026-09-15 | Immune Dysregulation, Compartment-Specific Biology, and Therapeutic Biomarkers in Mycosis Fungoides and Sézary Syndrome.
Cutaneous T-cell lymphoma (CTCL), including mycosis fungoides (MF) and Sézary syndrome (SS), is defined by malignant CD4+ T-cell clones that evolve within and remodel the skin and systemic immune compartments. For disease biology and immune remodeling, we prioritize evidence from human primary samples; for therapeutic implications, we integrate clinical-trial and translational biomarker studies. We organize evidence by compartment (skin vs. blood) and, within skin, by stage (patch/plaque vs. tumor). Early patch/plaque MF often shows features consistent with constrained inflammation: skin-resident memory T-cell (TRM)-like malignant clones are in a Th1-leaning microenvironment with relatively preserved cytotoxic surveillance. Progression to tumor-stage MF (and/or large-cell transformation) is frequently associated with clonal dominance, Th2 cytokine polarization, upregulation of checkpoint pathways, and remodeling of myeloid/fibroblast populations. SS is typically associated with leukemic clonal dominance, systemic Th2 skewing, and broad impairment of cytotoxic immune control. These trajectories support an interpretive framework that aligns immune-directed therapies with compartment- and stage-associated biology; these include strategies that (i) deplete malignant clones (e.g., CCR4, CD30, KIR3DL2 targeting), (ii) re-engage exhausted effectors (PD-1/PD-L1 axis), (iii) reprogram cytokine balance (IFN-γ, IL-12, extracorporeal photopheresis), or (iv) suppress malignant signaling programs with secondary immune effects (JAK/STAT inhibition). We highlight potential candidate predictive biomarkers at varying levels of maturity, most of which require prospective validation, including antigen density, compartmental tumor burden, tumor cell fraction, effector-cell substrate, and interferon/cytokine signatures.
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.
proteins
2026-09-02 | Ropeginterferon-α2b in mycosis fungoides and Sézary syndrome: Safety and efficacy in 41 patients.
Pegylated interferon-α2a became the off-label alternative for treating mycosis fungoides/Sézary syndrome (MF/SS) after non-pegylated interferons were withdrawn. This study aimed to evaluate the safety and efficacy of ropeginterferon-α2b in MF/SS. We performed a retrospective multicenter analysis at 5 Austrian centers and 1 Dutch center, including 41 patients with MF or SS who were treated with ropeginterferon-α2b between October 2024 and September 2025. We included 38 MF (early-stage n = 16, advanced-stage n = 22) and 3 SS patients. In 70.7 % of cases (29/41), ropeginterferon-α2b was administered as part of a combination treatment with a mean dose of 100 µg every 2 weeks. We observed an overall response rate of 48.8 % over a median treatment duration of 6 months (range 1-11 months). Treatment was discontinued in 16 patients (39.0 %) after a median of 4 months because of progressive disease (n = 9), adverse events (n = 4), or other reasons (n = 3). Most frequent AEs were fatigue/flu-like symptoms (32.5 %), anemia (15 %), neutropenia (15 %), lymphopenia (10 %), and elevated liver enzymes (10 %), classified as grade 1 or 2. Conclusions: This study provides initial evidence that ropeginterferon-α2b may be effective and well tolerated in patients with CTCL. Although interpretation is limited by the small retrospective cohort and short follow-up, the observed outcomes appear comparable to those previously reported for other interferon-α formulations.
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.
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
2026-09-26 | Cutaneous T Cell Lymphoma: Targeting the Survival Network in Mycosis Fungoides and Sézary Syndrome.
Cutaneous T cell lymphoma (CTCL) comprises a heterogeneous group of skin-homing T cell malignancies, with mycosis fungoides (MF) and Sézary Syndrome representing the most frequent and clinically relevant entities. Their clinical behavior differs substantially: MF often follows an indolent course over years, whereas Sézary Syndrome is a distinct clinicopathological entity that is typically characterized by erythroderma, a high burden of circulating malignant T cells and frequent lymph node involvement. Early-stage MF can often be controlled with skin-directed therapies, but advanced, relapsed or refractory CTCL remains therapeutically challenging. Established treatments are selected primarily according to disease stage, disease compartment and surface-target expression, whereas most pathway-directed, redox-modulating and apoptosis-sensitizing approaches remain investigational. Increasing evidence indicates that malignant T cells are maintained by an interconnected survival network rather than by a single dominant oncogenic pathway. This network includes constitutive inflammatory signaling, nuclear factor kappa B (NF-κB) activation, apoptosis resistance, altered redox homeostasis, mitochondrial and metabolic adaptation, rat sarcoma viral oncogene homolog (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase kinase (MEK) signaling and epigenetic regulation. These mechanisms cooperate to promote malignant T cell survival, therapy resistance, and disease progression, but they also create opportunities for targeted therapeutic intervention. Particular emphasis is placed on redox-regulated cell death, nuclear factor kappa B (NF-κB)-dependent survival, B-cell lymphoma 2 (BCL-2) family proteins, RAS pathway alterations, epigenetic sensitization and mechanism-informed treatment strategies. Integrating clinicopathological staging with molecular profiling and functional vulnerability screens may support more rational combination therapies and improve patient stratification in CTCL.
2026-08-22 | Patient and care partner burden in cutaneous T-cell lymphoma using disease-specific measures of symptoms and health-related quality of life
Patients with mycosis fungoides (MF) or Sézary syndrome (SS) may experience visible lesions, severe itch, sleep disturbance, body temperature dysregulation and depression. In this international study, 73 patients completed a symptom diary and questionnaires relating to fatigue and health-related quality of life [HRQoL: the MF/SS-cutaneous T-cell lymphoma QoL measure (MF/SS-CTCL QoL)]; 24 care partners also completed an HRQoL questionnaire. Patients reported a high symptom burden that differed between MF and SS, with a moderate impact on HRQoL. This is the first study to identify which symptoms of MF/SS compromise different aspects of both patients’ and care partners’ HRQoL. Addressing specific skin symptoms may improve patients’ fatigue, sleep and overall HRQoL and care partners’ HRQoL.
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.
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.
2025-10-17 | Erythroderma Part I. Erythrodermic form of cutaneous T-cell lymphoma (CTCL)
Erythrodermic cutaneous T-cell lymphoma (E-CTCL) includes erythrodermic (E) mycosis fungoides (E-MF) and Sézary syndrome (SS), considered to be two distinct clinical entities, although related. Clinical characteristics of E-MF and SS are similar, with a hallmark of erythroderma and varying numbers of Sézary cells in the blood. Distinguishing between E-MF and SS relies on determining the degree of blood involvement, based on the expanded criteria for B classification from the ISCL-EORTC. Epidermotropic infiltrate of atypical, monoclonal, CD4+ lymphoid cells can be present in both dise ases with minor differences in the quantity of the infiltrating cells, in dermal changes, and in the presence of nonspecific histology. Clinicopathologic findings can be subtle and may mimic benign dermatoses. Thus, immunohistochemistry, molecular analysis, and blood flow cytome try are essential for accurate diagnosis.
antibodies
2026-09-24 | Real-World Experience With Mogamulizumab for Mycosis Fungoides and Sézary Syndrome.
Mogamulizumab is an established treatment option for relapsed/refractory mycosis fungoides (MF) and Sézary syndrome (SS); however, large-scale real-world outcome data remain limited. We conducted a retrospective cohort study on patients with MF or SS who received treatment with mogamulizumab using TriNetX. A total of 394 patients were included (182 [46.2%] MF, 212 [53.8%] SS). The median follow-up was 31.5 months. The 1- and 3-year OS rates were 85.7% and 73.4%, respectively. Corresponding rates among MF and SS patients were 82.0% versus 88.2% and 69.3% versus 76.7%. In univariable analyses, SS was associated with improved OS (Hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.57-0.98; P = .032), whereas nodal involvement predicted inferior survival (HR 1.36, 95% CI 1.01-1.93; P = .043). Following adjustment, both associations were attenuated to non-significant trends (SS: aHR = 0.70, 95% CI: 0.47-1.03, P = .067; nodal involvement: aHR 1.40, 95% CI 0.95-2.06; P = .089). Overall, 154 patients (39.1%) required subsequent systemic therapy, with the 1- and 3-year cumulative incidence being 31.1% (95% CI: 25.7%-35.7%) and 41.0% (95% CI: 35.1%-46.9%), respectively. Elevated LDH independently predicted shorter TTNT (acsHR 1.62, 95% CI 1.29-2.03; P < .001). The 12-month incidences of infection, sepsis, hospitalization, and emergency department visits were 39.8%, 13.5%, 34.3%, and 20.6%, respectively, with similar incidences between MF and SS. In this large real-world cohort, mogamulizumab was associated with durable survival, prolonged treatment-free intervals, and the outcomes observed were consistent with the pattern seen in the MAVORIC trial.
2026-09-15 | Immune Dysregulation, Compartment-Specific Biology, and Therapeutic Biomarkers in Mycosis Fungoides and Sézary Syndrome.
Cutaneous T-cell lymphoma (CTCL), including mycosis fungoides (MF) and Sézary syndrome (SS), is defined by malignant CD4+ T-cell clones that evolve within and remodel the skin and systemic immune compartments. For disease biology and immune remodeling, we prioritize evidence from human primary samples; for therapeutic implications, we integrate clinical-trial and translational biomarker studies. We organize evidence by compartment (skin vs. blood) and, within skin, by stage (patch/plaque vs. tumor). Early patch/plaque MF often shows features consistent with constrained inflammation: skin-resident memory T-cell (TRM)-like malignant clones are in a Th1-leaning microenvironment with relatively preserved cytotoxic surveillance. Progression to tumor-stage MF (and/or large-cell transformation) is frequently associated with clonal dominance, Th2 cytokine polarization, upregulation of checkpoint pathways, and remodeling of myeloid/fibroblast populations. SS is typically associated with leukemic clonal dominance, systemic Th2 skewing, and broad impairment of cytotoxic immune control. These trajectories support an interpretive framework that aligns immune-directed therapies with compartment- and stage-associated biology; these include strategies that (i) deplete malignant clones (e.g., CCR4, CD30, KIR3DL2 targeting), (ii) re-engage exhausted effectors (PD-1/PD-L1 axis), (iii) reprogram cytokine balance (IFN-γ, IL-12, extracorporeal photopheresis), or (iv) suppress malignant signaling programs with secondary immune effects (JAK/STAT inhibition). We highlight potential candidate predictive biomarkers at varying levels of maturity, most of which require prospective validation, including antigen density, compartmental tumor burden, tumor cell fraction, effector-cell substrate, and interferon/cytokine signatures.
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.
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2026-09-02 | Ropeginterferon-α2b in mycosis fungoides and Sézary syndrome: Safety and efficacy in 41 patients.
Pegylated interferon-α2a became the off-label alternative for treating mycosis fungoides/Sézary syndrome (MF/SS) after non-pegylated interferons were withdrawn. This study aimed to evaluate the safety and efficacy of ropeginterferon-α2b in MF/SS. We performed a retrospective multicenter analysis at 5 Austrian centers and 1 Dutch center, including 41 patients with MF or SS who were treated with ropeginterferon-α2b between October 2024 and September 2025. We included 38 MF (early-stage n = 16, advanced-stage n = 22) and 3 SS patients. In 70.7 % of cases (29/41), ropeginterferon-α2b was administered as part of a combination treatment with a mean dose of 100 µg every 2 weeks. We observed an overall response rate of 48.8 % over a median treatment duration of 6 months (range 1-11 months). Treatment was discontinued in 16 patients (39.0 %) after a median of 4 months because of progressive disease (n = 9), adverse events (n = 4), or other reasons (n = 3). Most frequent AEs were fatigue/flu-like symptoms (32.5 %), anemia (15 %), neutropenia (15 %), lymphopenia (10 %), and elevated liver enzymes (10 %), classified as grade 1 or 2. Conclusions: This study provides initial evidence that ropeginterferon-α2b may be effective and well tolerated in patients with CTCL. Although interpretation is limited by the small retrospective cohort and short follow-up, the observed outcomes appear comparable to those previously reported for other interferon-α formulations.
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.
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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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