Dupilumab is highly effective for moderate-to-severe atopic dermatitis (AD). Increasing reports of cutaneous T-cell lymphoma (CTCL) diagnosed during or after dupilumab therapy have raised concern, although a causal relationship remains unproven. Interpretation of the available evidence is limited by its retrospective, observational nature, diagnostic overlap between AD and early CTCL, and detection and surveillance bias. These clinical consensus recommendations, developed through expert consensus among European CTCL specialists, primarily address dupilumab receipt in patients initially diagnosed with AD in whom CTCL is suspected, while briefly considering selective IL-13 inhibitors for which evidence remains limited. Clinical, epidemiologic, and mechanistic evidence is synthesized to develop practice-oriented recommendations. Dupilumab remains an appropriate treatment for moderate-to-severe AD but should be avoided if mycosis fungoides or Sézary syndrome is suspected or confirmed. In atypical or treatment-refractory disease, particularly adult-onset AD without atopic history, clinicians should maintain a high index of suspicion for CTCL, with a low threshold for skin biopsy, clinicopathologic correlation, and T-cell clonality assessment. Lack of response, disease worsening, or emerging atypical features during therapy should prompt reassessment. These recommendations reflect expert consensus that is based on available evidence and highlight the need for prospective studies to better define risk profiles and guide patient selection.

Abstract Early-stage cutaneous T-cell lymphoma (CTCL) is an indolent lymphoma of the skin. It has a high symptom burden and causes reduced quality of life from painful, itchy and unsightly lesions. The primary objective of this phase III study is to evaluate the ability of an 18-week course of HyBryte™ (research name SGX301), activated by visible light, to induce a treatment response in patients with patch- or plaque-phase CTCL compared with patients receiving placebo and visible light. HyBryte is a novel, first-in-class, photodynamic therapy utilizing safe, visible light for activation. The active ingredient in HyBryte™ is synthetic hypericin, a potent photosensitizer that is topically applied to skin lesions and is taken up by the malignant T cells, and then activated by safe, visible light approximately 24 h later. Treatment response is defined as an improvement of ≥ 50% in the mCAILS score (Modified Composite Assessment of Index Lesion Severity) summed over the three to five index lesions compared with the patient’s baseline evaluation. FLASH2 is a randomized, double-blind, placebo-controlled, multicentre study that is enrolling approximately 80 patients with early-­stage CTCL. The independent study data monitoring committee (DMC) is empowered to conduct one formal interim analysis when approximately 60% (n = 48) of the total patients have completed the primary endpoint evaluation (i.e. week 18 or before). As this enrolment has been reached, the DMC meeting will be at the end of April 2026. Efficacy and safety results from this meeting will be presented. One DMC meeting was conducted already on safety data alone. It concluded that there are no safety concerns with the ongoing phase III study and that HyBryte has an acceptable safety profile that remains consistent with the safety data from all prior clinical studies.

Mogamulizumab (MOGA), an anti-CCR4 monoclonal antibody, improves progression-free survival (PFS) and overall survival in Sézary syndrome (SS). Recently, a multicentre retrospective study conducted by the French Cutaneous Lymphoma study group assessed PFS in 52 patients with SS (median age 73 years, 56% female sex, 75% stage IVA1) who discontinued MOGA for reasons other than disease progression (Moga-stop Study). We report data from an extended follow-up of this cohort, along with comparative PFS outcomes from a parallel SS cohort with continuous MOGA treatment until progression.

BACKGROUND:In advanced-stage cutaneous T-cell lymphoma (CTCL), current therapeutic options rarely provide long-lasting responses. We aimed to evaluate the efficacy and safety of a histone deacetylase inhibitor, resminostat, as maintenance therapy in patients with advanced-stage mycosis fungoides or Sézary syndrome, in whom disease control had been previously met. METHODS:We conducted a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial (RESMAIN) at 55 medical centres in Austria, Belgium, France, Germany, Greece, Italy, the Netherlands, Poland, Spain, Switzerland, the UK, and Japan. Adult patients (aged ≥18 years) with histologically confirmed, stage IIB-IVB mycosis fungoides or Sézary syndrome; an Eastern Cooperative Oncology Group performance status score of 0-2; and disease control after at least one previous systemic therapy or total skin electron beam were eligible for inclusion. Patients were randomly assigned to receive either oral resminostat (600 mg) or matching oral placebo once daily for 5 days, followed by a treatment-free period of 9 days, within a 14-day treatment cycle. Randomisation was stratified by disease stage (IIB-IVA1 vs IVA2-IVB) and remission status following previous therapy (complete or partial response vs stable disease) by use of a dynamic block allocation process (block size 100 patients). Participants, investigators, site staff, and study personnel involved in outcome assessment and data analysis were masked to group assignment. Patients with disease progression during masked treatment were unmasked; patients on placebo were offered open-label resminostat. Treatment was continued until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, defined as the time from randomisation to disease progression or death from any cause (whichever occurred first), analysed by intention to treat. This trial is registered with ClincalTrials.gov (NCT02953301) and has been completed. FINDINGS:Between Jan 9, 2017, and May 11, 2022, 234 patients were screened for eligibility, of whom 201 (86%) patients were randomly assigned: 100 (50%) to resminostat and 101 (50%) to placebo. 123 (61%) participants were men and 78 (39%) were women, with a median age of 64 years (range 30-87). Most participants (173 [86%]) were White, 19 (9%) were Asian (mainly Japanese), two (1%) were Black, and seven (3%) were either another race or ethnicity, or did not disclose these data. Median progression-free survival was 8·3 months (95% CI 4·2-15·7) in the resminostat group and 4·2 months (2·8-6·4) in the placebo group (HR 0·62 [95% CI 0·42-0·92]; p=0·015). Median follow-up time for progression-free survival was 11·2 months (95% CI 5·6-19·6) in the resminostat group and 17·0 months (13·9-30·5) in the placebo group. Adverse events were reported in 96 (96%) patients receiving resminostat and in 81 (80%) patients receiving placebo. Serious adverse events occurred in 19 (19%) patients in the resminostat group, 11 (11%) of which were considered related to treatment, and in 12 (12%) in the placebo group, of which one (1%) was considered to be treatment-related. Adverse events of grade 3 or above occurred in 38 (38%) patients in the resminostat group and in 15 (15%) patients in the placebo group. The most common treatment-related adverse events were nausea (68 [68%] in the resminostat group vs six [6%] in the placebo group), diarrhoea (44 [44%] vs nine [9%]), vomiting (32 [32%] vs one [1%]), and fatigue (29 [29%] vs 14 [14%]). There were no treatment-related deaths. INTERPRETATION:These findings support the beneficial effect of resminostat maintenance therapy in patients with advanced CTCL. The overall safety profile of resminostat was acceptable, with gastrointestinal side-effects occurring most frequently. Anti-emetic prophylaxis should be considered in the future to manage side-effects and to improve tolerability and adherence to maintenance therapy. FUNDING:4SC AG.

Abstract The PROspective Cutaneous Lymphoma International Prognostic Index Study ‘PROCLIPI’ (ClinicalTrials.Gov ID: NCT02848274) opened in 2015 at > 50 international expert centres for mycosis fungoides (MF) and Sézary syndrome (SS). The aim of the study was to determine a prognostic index to better stratify patients for survival. A prognostic index for advanced MF and SS has recently been published that stratifies patients with advanced MF/SS into risk groups with significantly different 5-year overall survival. A CLIPI for early-stage MF is urgently needed to allow dermatologists to identify patients at risk of progression to advanced stage and subsequently select treatments for improved survival, as PROCLIPI shows that 5-year overall survival varies between 72.4% and 95.4% in early-stage MF and SS. Prospectively collected predefined datasets were analysed, including clinical, pathological, genotypic, treatment and quality-of-life data, in patients with newly diagnosed MF or SS. In total, 2004 patients with early-stage disease (IA, n = 921; IB, n = 853; IIA, n = 154) were recruited across 52 sites, presenting at a median age of 57 years (interquartile range 43–68). In multivariate analysis, the presence of cutaneous plaques (P < 0.001), nodal enlargement (Nx–N2) (P < 0.001), age > 60 years (P = 0.02) and large cell transformation in skin (P < 0.001) were significant factors for progression and overall survival. Notably, plaques have a high correlation with disease progression and poor overall survival (83.2% 5-year survival) compared with patients with patch-only disease (94.9% 5-year survival). Early-stage MF is typically reported as a low-grade lymphoma, but data from PROCLIPI have found low 5-year survival rates coupled with a median age of diagnosis of 57 years. Thus there is a marked reduction in life expectancy for some patients. However, 5-year survival rates for patients with patch-only disease are comparable with those of the average 57-year-old individual in Europe. In addition to plaques, PROCLIPI has identified other significant factors associated with poor survival, enabling the identification of at-risk patients using markers such as nodal enlargement and large cell transformation in the skin. The data highlight the need for better stratification of patients with early-stage MF and SS to allow improved management.

Abstract Brentuximab vedotin (BV), a CD30+ antibody conjugate, was approved for CD30+ cutaneous T-cell lymphoma in 2018. Mogamulizumab, an anti-CCR4 monoclonal antibody was approved for refractory mycosis fungoides and Sézary syndrome. The overall survival (OS) benefit and optimal sequencing of these therapies remain unclear in relation to traditional systemic therapies – bexarotene and extracorporeal photopheresis (ECP) – used in advanced-stage disease. The PROCLIPI study (NCT02848274) was interrogated for patients with advanced-stage disease (2015–2025) receiving mogamulizumab, BV, bexarotene or ECP. Of 593 patients, 566 had recorded systemic therapy. Treatment groups overlapped because most had more than one modality. Extracted data included stage, treatment line, OS and best response [either complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD)]. Mogamulizumab was given to 72 patients with 52 completed courses. Rates of CR, PR, SD and PD were 31%, 37%, 15% and 17%, respectively, and the median OS was 64 months. BV was given to 83 patients with 69 completed courses. The rates of CR, PR, SD and PD were 12%, 35%, 41%, and 13%, respectively, and the median OS was 28 months. Bexarotene was used in 178 patients (CR, PR, SD and PD in 8%, 37%, 42% and 13%; median OS 48.5 months) and ECP in 153 (CR, PR, SD and PD in 3%, 40%, 46% and 11%; median OS 41 months). In survival analyses (n = 370), OS improved if a patient received mogamulizumab for any line vs. those who received other systemic (P = 0.008). Data for BV did not reach statistical significance. Monoclonal exposure improved OS (P = 0.04). B2 stage favoured mogamulizumab (P = 0.001). Treatment groups were not mutually exclusive. Mogamulizumab demonstrated the highest objective response. Patients receiving mogamulizumab for any line had longer OS, favouring its use in blood-dominant Sézary syndrome. BV produced durable responses, supporting its role in CD30+ large-cell transformation. Shorter OS in BV any line may reflect inadequacies in current staging, as tumour disease (IIB) had worse outcomes than erythrodermic disease (stage III/IV). Bexarotene and ECP remain important systemic therapies. These data inform phenotype-directed sequencing and underscore the need for prospective comparative studies.

ABSTRACT Primary cutaneous gamma‐delta T‐cell lymphoma has been described as an aggressive entity with a poor prognosis. However, gamma‐delta T‐cell receptor expression has been described in various types of skin lymphoproliferations. Paediatric cases of LyP are increasingly recognized, but paediatric LyP with a gamma‐delta phenotype have been rarely described. We report three paediatric patients with indolent gamma‐delta lymphoproliferation, with a relapsing‐remitting course evoking LyP. These three cases emphasize that TCR gamma‐delta expression in a lymphoproliferation is not a synonym of gamma‐delta lymphoma. Indeed, these cases raise the question of a paediatric variant of CD30‐negative lymphomatoid papulosis with histological features of atypical gamma‐delta‐positive T‐cell lymphoproliferation and underline the necessity of cautious clinico‐histological correlation when facing a gamma‐delta lymphoproliferation to avoid overtreatment.

Cutaneous T-cell lymphoma (CTCL), characterized by malignant T-cell proliferation primarily in the skin, includes subtypes such as mycosis fungoides (MF) and Sézary syndrome (SS). The tumor microenvironment (TME) is central to their pathogenesis, with flow cytometry and histology being the gold standards for detecting malignant T cells within the TME. Alongside emerging molecular markers, particularly clonality analysis, these tools are indispensable for accurate diagnosis and treatment planning. Of note, adenosine signaling within the TME has been shown to suppress immune responses, affecting various cell types. The expression of CD39, CD73, and CD38, enzymes involved in adenosine production, can be elevated in MF and SS, contributing to immune suppression. Conversely, the expression of CD26, part of the adenosine deaminase/CD26 complex, that degrades adenosine, is often lost by circulating tumoral cells. Flow cytometry has demonstrated increased levels of CD39 and CD73 on Sézary cells, correlating with disease progression and prognosis, while CD38 shows a variable expression, with its prognostic significance remaining under investigation. Understanding these markers’ roles in the complexity of TME-mediated immune evasion mechanisms might enhance diagnostic precision and offer new therapeutic targets in CTCL.

2522 Background: Sézary syndrome (SS) is a rare and aggressive cutaneous T-cell lymphoma, which commonly expresses KIR3DL2, a killer immunoglobulin-like receptor, reported in ≥ 85% of patients. SS is characterized by erythroderma, significant blood involvement, lymphadenopathy and poor prognosis (10-20% 5-year survival). Lacutamab is a first-in-class monoclonal antibody designed to specifically deplete KIR3DL2-expressing cells via antibody-dependent cell-cytotoxicity and phagocytosis. Methods: TELLOMAK is an international, Phase 2 trial with multiple cohorts (NCT03902184). We report here long term follow-up results from Cohort 1, evaluating lacutamab in patients with relapsed/refractory (R/R) SS after at least 2 prior systemic therapies including mogamulizumab. Lacutamab 750 mg is administered until progression or unacceptable toxicity. Primary endpoint was Objective Response Rate (ORR) based on the evaluation of 4 compartments: skin, blood, lymph nodes and viscera according to the International Consensus criteria Olsen 2011. Secondary endpoints included but were not limited to duration of response (DOR), progression free survival (PFS), safety, and quality of life assessments. Results: As of October 17, 2024, recruitment was completed with 63 SS patients enrolled. Median age was 69 years (range: 42-86), the median prior lines of systemic therapies were 5.0 (range: 2-13), 65.1% and 34.9 % patients had stage IVA1 and stage IVA2 at baseline respectively, all patients had blood involvement (B2), 63.5% had confluence of erythema covering ≥ 80% body surface area (T4), 34.9% had lymph node lymphoma involvement (N3). Median follow-up was 25.1 months (95% CI 21.0-29.4). Global confirmed ORR was 42.9% (CI 31.4-55.1) including 6 (9.5%) CRs who are all still in CR; with a median time to response of 2.8 months (range 1-10) and a median duration of response of 25.6 months (CI 11.0, NE). According to each compartment, ORR in skin was 52.4% (CI 40.3-64.2) including 9 (14.3%) CRs, ORR in blood was 50.8% (CI 38.8-62.7) including 21 (33.3) CRs, and ORR in lymph nodes was 28.8% (CI 18.3-42.3) including 9 (17.3) CRs. Median PFS was 8.3 months (CI 5.1-18.7). Grade ≥ 3 related Treatment-Emergent Adverse Events (TEAEs) were observed in 20.6% patients. Serious related TEAEs were observed in 9.5% patients and related TEAEs leading to study drug discontinuation in 6.3% patients. Data from additional key endpoints will be presented. Conclusions: The long term follow-up data from TELLOMAK study in a R/R SS population previously treated with 2 or more prior systemic therapies including mogamulizumab, confirm that lacutamab shows promising clinical activity with ORR 42.9% (95% CI 31.4-55.1) and median duration of response of 25.6 months (11.0, NE) and an overall favourable safety profile. These data support the further development of lacutamab in an effort to bring improved treatments to patients with SS. Clinical trial information: NCT03902184 // EU CT number: 2023-507777-18-00.

Cutaneous T-cell lymphomas (CTCLs) are rare, usually refractory, and sometimes fatal diseases. Patients presenting with advanced-stage CTCL usually exhibit poor long-term survival outcomes. Only very few treatments have improved progression-free survival (PFS) in advanced CTCL, and no treatment has increased overall survival (OS). In 2023, the results of the CUTALLO trial supported the hypothesis that hematopoietic stem-cell transplantation (HSCT) was associated with significantly longer PFS as compared with standard-of-care treatment among advanced-stage patients although HSCT did not significantly affect OS. We provide herein the final OS data pertaining to the same patient population after a longer median follow-up of 38.9 months. Of the 99 patients included in the analysis, 55 (56%) were assigned to the HSCT group, whereas 44 (44%) were allocated to the non-HSCT group. The updated survival analysis reported that 16 of 55 patients (29%) in the HSCT group and 22 of 44 patients (50%) in the non-HSCT group died. The median OS was not reached in the HSCT group and 51.5 months (95% CI, 26.9 to 51.5) in the non-HSCT group (hazard ratio, 0.40 [95% CI, 0.20 to 0.80]). Compared with the standard of care for advanced CTCL, after extended follow-up, allogeneic HSCT was associated with significantly longer OS.

In recent classifications several cutaneous lymphomas were reclassified as lymphoproliferative disorder (LPDs). These include primary cutaneous CD4+ small/medium T-cell LPD (PCSM-TCLPD), primary cutaneous acral CD8+ T-cell LPD (acral CD8+ TCLPD) and primary cutaneous marginal zone lymphoma/LPD (PCMZL/LPD). The latter is still classified as primary cutaneous marginal zone lymphoma (PCMZL) in the 5th edition of the World Health Organization classification. A survey was previously carried out among 30 cutaneous lymphoma centres on the effects of this new terminology on clinical management. The results revealed considerable heterogeneity and emphasized the need to develop uniform recommendations for management and treatment of these disorders. Our objective was to develop consensus recommendations for staging, treatment and follow-up in PCSM-TCLPD, acral CD8+ TCLPD and PCMZL/LPD. Two surveys with questions regarding staging, treatment and follow-up of cutaneous LPDs were distributed among 30 cutaneous lymphoma expert centres collaborating within the EORTC-CLTG, USCLC and ISCL. Consensus recommendations were formulated based on these surveys, an extensive literature search, two rounds of feedback and a final consensus meeting. Important changes compared with current practice and literature are as follows. (i) Staging examinations, other than thorough clinical examination of skin and peripheral lymph nodes, are not required in typical cases of PCSM-TCLPD and acral CD8+ TCLPD. (ii) Low-dose radiotherapy (4-8 Gy) can be used rather than dose ≥ 20 Gy for PCSM-TCLPD and acral CD8+ TCLPD, and 4 Gy can be used for PCMZL/LPD. The dose can be escalated to 20-24 Gy in the case of local failure. (iii) Intralesional corticosteroids are also recommended as initial treatment in all three LPDs. (iv) A limited follow-up period (2 years) is acceptable in PCSM-TCLPD and acral CD8+ TCLPD LPD. These EORTC/USCLC/ISCL consensus recommendations reflect the state-of-the-art management and treatment as agreed upon by major cutaneous lymphoma centres. They may contribute to uniform staging, treatment and follow-up policy in patients with cutaneous LPDs.

Purpose: Mogamulizumab demonstrated improved outcomes vs. vorinostat across a range of disease and patient characteristics in patients with mycosis fungoides or Sezary syndrome in the MAVORIC trial. Materials and methods: This post-hoc analysis further examined MAVORIC data to assess factors associated with long-term response (ORR >12 months), time to next treatment (TTNT), and impact of concomitant steroid use, lymphopenia, and mogamulizumab-associated rash (MAR) on patient response. Results: A higher proportion of patients achieved ORR lasting >= 4, 6, 8, or 12 months in the mogamulizumab vs. vorinostat arm. Long-term response was also observed in mogamulizumab-treated patients with more advanced disease (stage IVA1 [17/20], B2 blood involvement [18/20], and SS [14/20]). PFS was significantly longer (9.4 vs. 3.1 months; p < 0.0001) in mogamulizumab vs. vorinostat-treated patients taking concomitant steroids. Mogamulizumab-treated patients experienced longer TTNT vs. vorinostat. Lymphopenia and MAR were associated with response to mogamulizumab. Conclusions: MAVORIC demonstrated greater efficacy with mogamulizumab vs. vorinostat in relapsed/refractory patients with CTCL, including those with more advanced disease. Concomitant steroid use improved ORR and PFS but did not impact vorinostat outcomes. Overall responses occurred more frequently in mogamulizumab-treated patients that developed lymphopenia than those that did not. A higher percentage of patients with MAR had an overall response than those without MAR.

INTRODUCTION:Treatment of advanced mycosis fungoides (MF) and Sézary syndrome (SS) is a challenge. In this international, multicenter, open-label phase II trial, we assessed the efficacy and safety of anti-PD-L1 atezolizumab in stage IIB-IV refractory/relapsed MF and SS. MATERIALS AND METHODS:Patients received atezolizumab 1200 mg IV Q3w for up to 1 year unless progression or withdrawal. The main study endpoints were overall response rate (ORR), progression-free survival (PFS), time to next systemic treatment (TTNT), and overall survival (OS). RESULTS:A total of 26 patients were enrolled from seven countries. Seventeen patients met the inclusion criteria. At a median follow-up of 36.6 months, the ORR was 15.4 % in the intention to treat (ITT) and 17.6 % in the per protocol (PP) population, respectively. In the PP group, 58.8 % of patients, and in the ITT group, 53.9 % of patients achieved partial response or stable disease as their best outcome. One complete response was observed after 1 year. Median PFS was 3 months (95 % CI 1.4-4.9) in PP and 3.1 months (95 % CI 2.4-4.0) in ITT. Median OS was not reached for PP and was 22.3 months (20.0-NE) for ITT. Median TTNT was 5.9 months (2.8-NE) in PP and 6.2 months (3.1-14.8) in ITT. The most common grade ≥ 3 adverse events were fatigue (23.1 %) and infections (15.4 %), with two sepsis-related deaths. Atezolizumab was primarily discontinued due to disease progression (50 %). CONCLUSIONS:Atezolizumab shows moderate activity in pretreated refractory/relapsed MF and SS. Further studies are needed to identify reliable predictors of safety and treatment response.