Maarten H. Vermeer

The tumour microenvironment (TME) plays a pivotal role in the progression of mycosis fungoides (MF), characterised by a shift in the immune response from a T helper (Th) 1 cell (Th1) to a Th2 cell profile. While this framework captures key features of disease progression, recent single-cell and spatial transcriptomic studies have further illuminated diverse malignant T-cell states, immune trajectories and spatial niches that extend beyond cytokine polarity alone. Skin-directed and systemic therapies for MF affect both malignant T-cells and the surrounding TME. The therapeutic response begins with biological changes in the TME, including tumour T-cell elimination via tumour cell killing and apoptosis, along with modification of the inflammatory milieu. Because these biological changes take time, early signs of clinical improvement may be subtle. Skin-related treatment-related adverse events, including inflammation, may occur and can be difficult to distinguish from ongoing disease. Given this overlap, careful clinical evaluation is warranted before changes to therapy are considered. It is therefore important to distinguish biological responses in the skin TME from clinical responses on the skin. In this article, we review data on biological and clinical responses to treatment in patients with MF and highlight the lack of biomarkers correlating with skin responses. Finally, we explore emerging tools and consider their potential to improve clinical decision-making when differentiating between biological and clinical responses.

Advanced mycosis fungoides (MF) and Sézary syndrome (SS) are the most aggressive forms of cutaneous T‐cell lymphoma and remain associated with a poor prognosis and heterogeneous therapeutic approaches. Recent advances, including targeted therapies and improved transplant strategies, have substantially expanded treatment options, highlighting the need for updated international guidance integrating dermatologic, hematologic, and transplant perspectives. An international multidisciplinary panel convened by the European Hematology Association (EHA), the EORTC Cutaneous Lymphoma Tumours Group (EORTC‐CLTG), the International Society for Cutaneous Lymphoma (ISCL), and the EBMT Lymphoma Working Party reviewed the available evidence and developed consensus recommendations for the management of advanced MF and SS. Thirty international experts participated in the process. Recommendations address diagnostic work‐up, systemic therapies, treatment sequencing, combination strategies, and indications for allogeneic hematopoietic cell transplantation (allo‐HCT). The consensus supports a stage‐adapted and compartment‐oriented therapeutic approach. Immunomodulatory strategies remain central in advanced CTCL: extracorporeal photopheresis is commonly used as first‐line therapy in SS and in patients with significant blood involvement, while interferon‐α and retinoids are widely used in MF, often in combination with skin‐directed therapies. Mogamulizumab and brentuximab vedotin represent key options after prior systemic therapy, with differential activity across skin, blood, and nodal compartments. Combination approaches integrating systemic and skin‐directed treatments may improve response depth and durability. Practical treatment algorithms for advanced MF and SS are proposed to support therapeutic sequencing and multidisciplinary management. Allo‐HCT remains the only potentially curative treatment and should be considered early in selected patients with high‐risk disease features.

Summary: Sézary syndrome (SS) is an aggressive cutaneous T‐cell lymphoma, characterized by erythroderma, lymphadenopathy and circulating malignant CD4 ⁺ T cells. Despite therapeutic advances, SS remains an incurable disease. Early diagnosis is therefore essential for timely therapeutic intervention; however, reliable biomarkers to identify circulating SS cells are still lacking. Recent studies highlighted dysregulation of the ectoenzymes CD39, CD73 and CD38 in SS, suggesting a potential role for these molecules in the disease. Thirty‐three patients were enrolled in this study, and CD39/CD73/CD38 expression was analysed on circulating CD4 ⁺ T cells by multiparametric flow cytometry, enabling discrimination between malignant and non‐malignant T‐cell subsets. SS cells exhibited marked CD39 or CD73 overexpression together with consistent CD38 downregulation, a pattern also confirmed in paired skin biopsy, whereas non‐malignant CD4 ⁺ T cells largely maintained expression profiles comparable to healthy controls. Genotyping further identified ENTPD1 single nucleotide polymorphism rs10748643 as a contributor to CD39 dysregulation, defining a CD39‐permissive subgroup characterized by CD39 ⁺ SS cells. In conclusion, the combined overexpression of CD39 or CD73 and loss of CD38 defines a distinct tumour‐restricted immunophenotypic signature in SS. Integrating these ectoenzymes into flow cytometry panels may improve detection of malignant CD4 ⁺ T cells across blood and skin, eventually strengthening diagnostic accuracy.

Background: The Dutch flagship project Next Generation ImmunoDermatology (NGID) aims to profile five chronic immune‐mediated inflammatory skin diseases: atopic dermatitis (AD), plaque psoriasis (PSO), hidradenitis suppurativa (HS), chronic spontaneous urticaria (CSU) and cutaneous lupus erythematosus (CLE) in comparison with cutaneous T‐cell lymphoma subtype mycosis fungoides (MF) and healthy volunteers. Within NGID, a clinical study entitled: ‘SKIN disease profiling by an Exploratory, pRospective, biomarker study in dermatoloGY practice (SKINERGY)’ will be conducted as a multicentre, parallel‐cohort, open‐label, observational, longitudinal basket study. Objectives: Objectives include evaluation of disease‐related characteristics in comparison to those of healthy volunteers and evaluation of biomarkers for disease stratification and (targeted) treatment response in patients in a real‐world clinical setting. Additionally, differences and similarities in disease characteristics between diseases, changes over time, and profiles of responders versus non‐responders will be evaluated. Methods: Patients with AD ( N = 120), PSO ( N = 160), HS ( N = 80), CSU (N = 120) and CLE (N = 120) will be enrolled in groups of N ≤ 40 patients per treatment. Matched healthy volunteers (N = 120) and the MF cohort (N = 120) will serve as control groups. Assessments include blood sampling, skin punch biopsies, tape stripping, skin swabs, (multimodal) imaging, tele‐health and patient‐ and physician‐reported outcomes. This manuscript describes the study protocol prior to data collection and its strategic evaluation of multi‐omics profiling. Patient advocacy groups co‐defined the research agenda and contributed to study design and informed consent document development, ensuring alignment with patients' needs and real‐world relevance. Results: SKINERGY will generate a machine learning‐ready dataset with information about changes in various biomarkers over time, including histology, metabolomics, spatial proteomics, transcriptomics, lipidomics, microbiomics, imaging biomarkers, tele‐health, patient‐reported outcome measures (PROMs) and clinical parameters. Conclusion: Identified biomarker profiles within SKINERGY may guide targeted treatment selection, enhance targeted therapeutic response in clinical practice and improve understanding of disease pathology in chronic immune‐mediated skin diseases.

Advanced mycosis fungoides (MF) and Sézary syndrome (SS) have a poor overall survival (OS) of 60 years (P < .001), raised serum lactate dehydrogenase (P = .005), and large-cell transformation in skin (P = .006). Modeling these 4 independent risk factors into a CLIPI found that there was a worse OS in high- vs low-risk (P < .001), high- vs intermediate-risk (P = .002) and intermediate- vs low-risk (P = .010) groups. Five-year OS was 63.3%, 44.7%, and 18.3% in the low-, intermediate-, and high-risk groups, respectively. In this advanced stage cohort there was a low 5-year survival and increasing stage was not associated with worsening survival. The use of CLIPI to stratify patients into risk groups has the potential to improve outcomes and aid optimal treatment selection. This trial was registered at www.ClinicalTrials.gov as #NCT02848274.