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Cutaneous T-cell lymphomas are rare non-Hodgkin lymphomas with substantial morbidity and mortality in advanced disease stages. We compared the efficacy of mogamulizumab, a novel monoclonal antibody directed against C-C chemokine receptor 4, with vorinostat in patients with previously treated cutaneous T-cell lymphoma. In this open-label, international, phase 3, randomised controlled trial, we recruited patients with relapsed or refractory mycosis fungoides or Sézary syndrome at 61 medical centres in the USA, Denmark, France, Italy, Germany, the Netherlands, Spain, Switzerland, the UK, Japan, and Australia. Eligible patients were aged at least 18 years (in Japan, ≥20 years), had failed (for progression or toxicity as assessed by the principal investigator) at least one previous systemic therapy, and had an Eastern Cooperative Oncology Group performance score of 1 or less and adequate haematological, hepatic, and renal function. Patients were randomly assigned (1:1) using an interactive voice web response system to mogamulizumab (1·0 mg/kg intravenously on a weekly basis for the first 28-day cycle, then on days 1 and 15 of subsequent cycles) or vorinostat (400 mg daily). Stratification was by cutaneous T-cell lymphoma subtype (mycosis fungoides vs Sézary syndrome) and disease stage (IB–II vs III–IV). Since this study was open label, patients and investigators were not masked to treatment assignment. The primary endpoint was progression-free survival by investigator assessment in the intention-to-treat population. Patients who received one or more doses of study drug were included in the safety analyses. This study is ongoing, and enrolment is complete. This trial was registered with ClinicalTrials.gov, number NCT01728805. Between Dec 12, 2012, and Jan 29, 2016, 372 eligible patients were randomly assigned to receive mogamulizumab (n=186) or vorinostat (n=186), comprising the intention-to-treat population. Two patients randomly assigned to mogamulizumab withdrew consent before receiving study treatment; thus, 370 patients were included in the safety population. Mogamulizumab therapy resulted in superior investigator-assessed progression-free survival compared with vorinostat therapy (median 7·7 months [95% CI 5·7–10·3] in the mogamulizumab group vs 3·1 months [2·9–4·1] in the vorinostat group; hazard ratio 0·53, 95% CI 0·41–0·69; stratified log-rank p<0·0001). Grade 3–4 adverse events of any cause were reported in 75 (41%) of 184 patients in the mogamulizumab group and 76 (41%) of 186 patients in the vorinostat group. The most common serious adverse events of any cause were pyrexia in eight (4%) patients and cellulitis in five (3%) patients in the mogamulizumab group; and cellulitis in six (3%) patients, pulmonary embolism in six (3%) patients, and sepsis in five (3%) patients in the vorinostat group. Two (67%) of three on-treatment deaths with mogamulizumab (due to sepsis and polymyositis) and three (33%) of nine on-treatment deaths with vorinostat (two due to pulmonary embolism and one due to bronchopneumonia) were considered treatment-related. Mogamulizumab significantly prolonged progression-free survival compared with vorinostat, and could provide a new, effective treatment for patients with mycosis fungoides and, importantly, for Sézary syndrome, a subtype that represents a major therapeutic challenge in cutaneous T-cell lymphoma. Kyowa Kirin.

Mycosis fungoides (MF) is a rare primary cutaneous T-cell lymphoma (pCTCL) that generally has an indolent course with a favorable prognosis. However, numerous clinical variants have been described that differ substantially from classic Alibert–Bazin MF, resulting in altered prognosis, treatment response, and patient outcomes. This narrative review considers rare MF variants—bullous, ichthyosiform, hypopigmented, folliculotropic, poikilodermatous, granulomatous, granulomatous slack skin, pagetoid reticulosis and syringotropic MF—with emphasis on practical diagnostic approaches for clinicians. Given that MF can mimic more than 50 different dermatoses and is frequently associated with prolonged diagnostic delay, we provided detailed clinical and dermoscopic features that should raise diagnostic suspicion and guide biopsy decisions. We discussed extensive differential diagnoses for each variant and highlighted MF’s status as dermatology’s “great imitator.” Additionally, we addressed the risk of second primary malignancy in patients with MF, as well as the genetic and microenvironmental factors proposed to contribute to its clinical heterogeneity. Furthermore, we evaluated existing classification systems and suggested future directions that integrate molecular data and tumor biology to improve prognostic assessment and guide therapeutic decision-making.

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of T-cell lymphomas characterized with the presence of clonal malignant T cells. Mycosis fungoides (MF) is the most common type of CTCL. However, the pathogenesis of MF and the role of the tumor microenvironment (TME) remain unclear. We performed single-cell RNA sequencing on tumor and adjacent normal tissues and peripheral blood mononuclear cell (PBMC) from patients with advanced MF and healthy control (HC). We compared skin lesions in different stages within the same patient to overcome inter-individual variability. The malignant clones displayed dual phenotypes characterized with tissue-resident memory T cells (TRMs) and central memory T cells (TCMs). We supposed that the tumor cells transformed from TRM-dominant phenotype to TCM-dominant phenotype during MF progressed from early-stage to advanced-stage. The cancer-associated fibroblasts (CAFs) showed active role in TME. The occurrence of inflammatory CAFs (iCAFs) may represent the advanced-stage MF. There may be mutual positive feedback of the crosstalk between tumor cells and CAFs during the MF development. Tumor cells promote CAF generation, and the CAFs, in turn, improve the invasiveness and metastasis of the malignant T cells through the IL-6/JAK2/STAT3/SOX4 or IL-6/HIF-1α/SOX4 pathway. SOX4 may be a critical regulatory gene of this positive feedback loop. Target SOX4 may disrupt the interactions between tumor cells and CAFs. Our study revealed the origin and evolution trajectory of MF and uncovered the intercellular interactions between malignant T cells and CAFs, providing new insights into the novel treatment targets of MF.

While most patients with early-stage mycosis fungoides (MF) follow an indolent course, patients with advanced-stage MF/Sézary syndrome (SS) have a poor prognosis with a median survival of less than 5 years. Although there are a number of treatments currently available, achieving and maintaining a durable response remain challenging, especially in advanced-stage MF/SS. The choice of frontline therapy is dependent on the stage of disease. For early-stage MF, the treatment concept is to control skin lesions mainly by skin-directed therapies, such as topical therapies, phototherapies, and radiotherapies. For advanced-stage MF/SS, systemic treatments by biological or targeted therapies including bexarotene and interferon either alone or in combination are tried first, with more immunosuppressive chemotherapies being reserved for refractory or rapidly progressive disease. Recent improvements in biological or targeted therapies include brentuximab vedotin and mogamulizumab. When biopsy samples have 10% or more CD30-positive malignant cells, brentuximab vedotin, an anti-CD30 antibody conjugated to monomethyl auristin E, can be a desirable treatment option. For cases with blood involvement, mogamulizumab, an antibody binding to C-C chemokine receptor 4, is effective with high response rates. In the refractory setting, alemtuzumab, histone deacetylase inhibitors, pralatrexate, gemcitabine, and doxorubicin are considered as the treatment option. Because only allogeneic hematopoietic stem cell transplantation can offer a chance of cure with durable complete remission, advanced-stage patients with a markedly short life expectancy should be evaluated for eligibility. Given that there are few randomized controlled studies in the literature, it is necessary to investigate which therapy is preferable for each patient with MF/SS by comparative prospective trials.

Advanced-stage cutaneous T-cell lymphomas (CTCLs) are rare, usually refractory, and fatal diseases. Case series have suggested that allogeneic haematopoietic stem cell transplantation (HSCT) might improve the prognosis of advanced-stage CTCLs. The objective of this study was to investigate the effect of allogeneic HSCT compared with non-HSCT therapy on the outcome of individuals with advanced-stage CTCLs. In this prospective, multicentre, matched controlled trial, conducted at 30 hospitals, participants with advanced CTCLs were allocated treatment: if they had an available compatible related donor they were assigned to allogeneic HSCT, or if not they were allocated to non-allogeneic HSCT therapy. Key inclusion criteria were participants aged 18–70 years, with advanced stage mycosis fungoides or Sézary syndrome, and at least one poor prognostic criteria. Participants were excluded if they were not in complete or partial remission of the disease. Propensity score 1:1 matching with replacement (ie, that each participant treated with HSCT was matched to the participant with the closest propensity score treated with non-HSCT therapy, even if they had already been matched) was used to handle confounding factors, with the balance of covariate distribution between HSCT and non-HSCT groups assessed using standardised mean differences. The primary endpoint was progression-free survival in the matched intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02520908), and is currently active but not recruiting. From June 1, 2016, to March 3, 2022, total of 99 participants were enrolled at 17 centres in France. Participants with a sibling or matched unrelated donor were assigned to allogeneic HSCT (HSCT group, n=55 [56%]) and participants without a donor were assigned to non-allogeneic HSCT treatment (non-HSCT group, n=44 [44%]). The median follow-up among survivors was 12·6 months (IQR 11·0–35·2). In the HSCT group, 51 participants (93%) were 1:1 matched to participants from the non-HSCT group. In the intention-to-treat analysis, median progression-free survival was significantly longer in the HSCT group (9·0 months [95% CI 6·6–30·5]) than in the non-HSCT group (3·0 months [2·0–6·3]), with a hazard ratio of 0·38 (95% CI 0·21–0·69; p<0·0001). In the per-protocol population, 40 participants (78%) in the HSCT group had 101 serious events and 29 participants (67%) in the non-HSCT group had 70 serious adverse events. The most common serious adverse event other than graft-versus-host disease in both groups was infections, occurring in 30 participants (59%) in the HSCT group and in 19 participants (44%) in the non-HSCT group. Allogeneic HSCT was associated with significantly longer progression-free survival in participants with advanced-stage CTCLs. These results indicate that allogeneic HSCT treatment should be made available to individuals with high-risk, advanced-stage mycosis fungoides or Sézary syndrome who achieve pre-transplant disease remission. French Ministry of Health, National Cancer Institute, Programme Hospitalier de Recherche Clinique en Cancérologie.

Background and Objective Classical mycosis fungoides (CMF), the most common form of primary cutaneous T‐cell lymphoma, shows marked heterogeneity in disease progression and prognosis, while reliable molecular prognostic markers remain scarce. This study aimed to evaluate the prognostic significance of GATA‐binding protein 3 (GATA3) expression in early‐stage CMF. Methods We retrospectively analyzed 106 patients with early‐stage CMF diagnosed at West China Hospital, Sichuan University, between 2009 and 2021. Immunohistochemistry (IHC) was performed to assess GATA3 expression in dermal tumor cells. Associations with progression‐free survival (PFS) and overall survival (OS) were examined using Cox regression models adjusted by inverse probability of treatment weighting (IPTW). Receiver operating characteristic (ROC) curve analysis was conducted to evaluate predictive performance. Results High GATA3 expression (≥ 60%) was detected in 92.5% of cases. Elevated GATA3 levels were significantly associated with reduced PFS and OS. IPTW‐adjusted Cox regression confirmed high GATA3 expression as an independent adverse prognostic factor. ROC curve analysis demonstrated strong predictive performance for CMF progression (AUC = 0.867), with an optimal cutoff of 57.5% (sensitivity 73.7%, specificity 94.3%). For clinical applicability, a 60% threshold was adopted. Conclusion High GATA3 expression is an independent adverse prognostic biomarker in early‐stage CMF. Incorporating GATA3 into risk stratification models may improve prognostic accuracy and guide personalized treatment strategies.

Background We investigated mental health diagnoses (MHDs) in mycosis fungoides (MF) patients compared to the general population, evaluated risk factors, and studied survival outcomes in a large population database. Methods MF patients from the Utah Cancer Registry diagnosed from 2001 to 2014 were matched with up to five general population individuals from the Utah Population Database. MHDs were retrospectively tracked in both populations (median follow‐up = 6.67 years). Risk factors for new MHDs among MF patients were studied using the Cox proportional hazards model. Overall survival (OS) and disease‐specific survival (DSS) were assessed using Kaplan–Meier analysis. Results The incidence of anxiety disorders (HR = 1.99, 95% CI [1.16, 3.42]) and delirium/dementia disorders (HR = 2.43, 95% CI [1.05, 5.63]) was higher among MF patients than the matched general population. Among MF patients, Charlson Comorbidity Index (CCI) ≥ 2 and BMI < 18 kg/m2 were risk factors for new anxiety disorders. Radiation therapy, CCI ≥ 2, and female gender were risk factors for new delirium/dementia disorders. The 15‐year OS was worse for MF patients with versus without an MHD (36% vs. 81%, HR 2.62, 95%CI [1.24, 5.65]). The 15‐year DSS also worsened for MF patients with versus without an MHD (63% vs. 97%, HR 6.55, 95%CI [1.64, 26.2]). Conclusions MF patients developed anxiety and delirium/dementia disorders at rates above the general population, and MHDs correlated with worse DSS and OS. Careful mental health monitoring may be an actionable step towards improving health‐related quality of life in this population.

Background Atopic dermatitis (AD) is a chronic, pruritic, and inflammatory dermatosis seen in individuals with an atopic predisposition. This study aimed to examine the immunoreactivity of spexin and TRPM2 in skin samples from patients with AD and MF lesions using immunohistochemical methods. Materials and methods The study utilized a total of 60 skin samples, comprising 20 from AD patients, 20 from MF patients, and 20 from control subjects. Skin samples from patients diagnosed with other dermatological diseases, malignancies, and diabetes mellitus were excluded from the study. During staining, the prevalence (0.1: <25%, 0.4: 26–50%, 0.6: 51–75%, 0.9: 76–100%) and intensity (0: none, + 0.5: very low, + 1: low, + 2: moderate, + 3: intense) of immunoreactivity were used as criteria to establish a histo-score. Calculations employed the formula histo-score = prevalence x intensity. Results Statistically significant higher spexin histoscores were observed in both the AD and MF patient groups compared to the control group (1.30 ± 0.46, 1.04 ± 0.29, and 0.20 ± 0.07, respectively; p  = 0.000). Similarly, TRPM2 histoscores were significantly higher in the AD and MF patient groups compared to the control group (1.12 ± 0.28, 1.02 ± 0.30, and 0.20 ± 0.07, respectively; p  = 0.000). Conclusion It is hypothesized that the increase in the neuropeptide spexin in both AD and MF is triggered by inflammation and contributes to itching mechanisms via galanin receptors. TRPM2, an ion channel, is speculated to be a marker of Reactive Oxygen Species (ROS) in chronic inflammatory dermatoses like AD, but it may not serve as a potential biomarker for distinguishing chronic inflammatory dermatoses from MF.

Short-chain fatty acids (SCFAs) are critical metabolites produced by gut microbiota that play a key role in modulating inflammation and regulating systemic immunity, including against cancer. Decreases in SCFAs can foster a permissive tumor immune environment. Recent studies have shown that cutaneous T-cell lymphoma (CTCL) patients exhibit increasing gut dysbiosis and loss of bacteria predicted to produce SCFAs with increasing disease severity. To investigate this functional connection, we collected stool swab samples from 15 individuals– 8 mycosis fungoides (MF) patients and 7 matched healthy controls (HC)– and quantified concentrations of four SCFAs (acetate, propionate, isovalerate, butyrate) via liquid chromatography-mass spectrometry. Our results demonstrated significantly reduced acetate and propionate concentrations in MF patients when compared to HC (both p  = 0.027). Total measured SCFA concentrations were on average lower in MF versus HC, but did not achieve statistical significance ( p  = 0.063). Both propionate and acetate have been previously demonstrated to promote tumor apoptosis, inhibit tumor proliferation, and enhance antitumor immunity. Thus, dysbiosis-associated reductions in SCFAs may be another contributive factor in the immune dysfunction observed in CTCL. Our pilot findings add to the growing body of knowledge implicating the gut microbiota-SCFA axis in CTCL pathogenesis and offer potential new avenues for therapeutic intervention.