Subtype Of Cutaneous T-cell Lymphoma Research Articles

Update on primary cutaneous T-cell lymphomas rare subtypes

Rare subtypes of cutaneous T-cell lymphomas (CTCL) include four entities, primary cutaneous γδ T-cell lymphoma, primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma, and primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorders, primary cutaneous acral CD8+ T-cell lymphoma, which were previously considered provisional and are now included in the new 5th World Health Organization classification of hematolymphoid tumors as distinct entities. An updated summary of the clinical, histological, and genomic characteristics of these uncommon CTCL subtypes is given in this review, with a focus on the growing body of knowledge regarding their classification and possible treatment strategies.

Abstract 813: Primary cutaneous gamma-delta T-Cell lymphoma in the United States: A nationwide analysis of demographics and survival outcomes among the Hispanic population

Abstract BACKGROUND: Primary Cutaneous Gamma-Delta T-Cell Lymphoma (PCGDTCL) is a rare subtype of cutaneous T-cell lymphoma (CTCL) that, despite comprising <1% of cutaneous lymphomas, has gained recognition in recent years as an entity separate from other rare CTCLs. (LeukemiaPMID 35732829) A 5 year survival of 11% demonstrates a low response to current available therapies. (BloodPMID 30635287, Clin Hematol Int.PMID 35950208) Due to lack of consistency in behavior between CTCLs, there exists a need for studies of demographic, clinical, and survival disparities, including between Hispanics (HI) vs. non-Hispanics (NH). METHODS: Data were analyzed on PCGDTCL patients in the United States reported to the National Cancer Database (NCDB) between 2004-2019. Demographic and treatment characteristics were compared between ethnic groups. Kaplan-Meier and Cox regression analyses were used to compare OS between populations. Multivariate analysis and propensity score matching was performed with adjustment for age, stage, co-morbidity score, and insurance status, type of facility and great circle distance. RESULTS: Among 132 PCGDTCL patients studied (5% HI, 92% NH), the HI group was younger at diagnosis than NH (49.5y vs. 60y) (p=0.384); The majority of HI (50%) was diagnosed between 2010-2012 vs 2017-2019 for NH (45%) (p=0.673). Most of HI and NH were white (67% vs 79%). Private insurance was the most prevalent type in HI (67%) vs government sponsored for NH (49%). The most non-Insured group was NH (3%) vs HI (0%). The most prevalent bracket for Census Median Income (2008-2012) was $63,000+ for both HI (50%) and NH (31%). 17% HI vs 13%. NH had median income <$38,000. For Charlson-Deyo Score (comorbidities score), HI had 0% =/> 2 score, vs NH 6%. NCI-designated comprehensive cancer centers were the most prevalent type of facility providing care for HI (100%) and NH (56%) Survival probability (OS) at 2, 5 and 10y (HI vs NH) were (80% vs 48%), (80% vs 44%), and (80% vs 26%), respectively. Median survival time (MS) was not reached for HI vs 1.9 years for NH. Overall survival (OS) difference favored HI (p=0.13) On multivariate analysis, there was no independent variable associated with better or worse OS. Interestingly, the propensity matched analysis demonstrated significant MS difference between HI vs NH (median not reached vs. 1.35 years). CONCLUSION: There was no significant difference in OS between groups; however, the weighed MS favored the HI cohort, likely in part due to the difference in numbers between cohorts. The drastically low survival in all demographics is consistent with prior studies. These results demonstrate an unmet need for more comprehensive studies with the potential inclusion of correlatives looking at intrinsic biologic characteristics that may offer insight into druggable targets, aiming for improvement in survival outcomes for this rare lymphoma. Citation Format: Katherine Thiel, Rosa White, Qianqian Liu, Joel Michalek, Adolfo Enrique Diaz Duque. Primary cutaneous gamma-delta T-Cell lymphoma in the United States: A nationwide analysis of demographics and survival outcomes among the Hispanic population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 813.

JAK Inhibitors in Cutaneous T-Cell Lymphoma: Friend or Foe? A Systematic Review of the Published Literature.

Cutaneous T-cell lymphomas (CTCLs) are a group of lymphoid neoplasms with high relapse rates and no curative treatment other than allogeneic stem cell transplantation (allo-SCT). CTCL is significantly influenced by disruption of JAK/STAT signaling. Therefore, Janus kinase (JAK) inhibitors may be promising for CTCL treatment. This study is a systematic review aiming to investigate the role of JAK inhibitors in the treatment of CTCL, including their efficacy and safety. Out of 438 initially searched articles, we present 13 eligible ones. The overall response rate (ORR) in the treatment with JAK inhibitors in clinical trials was 11-35%, although different subtypes of CTCL showed different ORRs. Mycosis fungoides showed an ORR of 14-45%, while subcutaneous-panniculitis-like T-cell lymphoma (SPTCL) displayed an ORR ranging from 75% to 100%. Five cases were reported having a relapse/incident of CTCL after using JAK inhibitors; of these, three cases were de novo CTCLs in patients under treatment with a JAK inhibitor due to refractory arthritis, and two cases were relapsed disease after graft-versus-host disease treatment following allo-SCT. In conclusion, using JAK inhibitors for CTCL treatment seems promising with acceptable side effects, especially in patients with SPTCL. Some biomarkers, like pS6, showed an association with better responses. Caution should be taken when treating patients with an underlying autoimmune disease and prior immunosuppression.

The Battle of Cutaneous T Cell Lymphomas: Mycosis Fungoides Vs. Sezary Syndrome

Introduction: Mycosis Fungoides (MF) & Sezary Syndrome (SS) are two distinct extra-nodal Cutaneous T Cell Lymphomas (CTCL), which are a subtype of Non-Hodgkin's Lymphoma (NHL). Although belonging to the same entity, its presentation varies drastically. Early stage of MF is limited to the skin and whereas advanced-stage disease can involve lymph nodes, blood, & visceral organs, whereas SS involves the blood, lymph nodes, and skin. The aim of this retrospective analysis is to study the variance in the epidemiology and prognosis of MF and SS. Method: The data was collected from Surveillance, Epidemiology and End Result database Research Plus Data, 17 Registries, Nov 2022 Sub (2000-2020). We extracted Mycosis Fungoides and Sezary Syndrome cases diagnosed after 20 years of age, with Lymphoid neoplasm recode 2(b)2.1.1 and 2(b)2.1.2. The analysis was stratified based on age, sex, racial incidence rates, & survival curves based were compared, using the Log-rank test (GraphPad Prism). Results: 8853 cases of MF were identified between 2000-2020. The median age of diagnosis was 60 years. Of the affected individuals, 57.59% were males and 42.40% were females. The incidence of MF, per 1,000,000 population, in 2000 was 6.1 & 6.05 in 2020. 62.45% were whites, 13.75% were blacks, 6.98% were Asians/Pacific Islanders, 0.42% were American Indians/Alaskan Natives, & 11.64% were Hispanics. 5.2% of patients had localized disease, 8.38% patients had regionall disease, & 1.34% had the evidence of distant metastasis. vs. 307 cases of SS were identified between 2000-2020. The median age of diagnosis was 71 years. Of the affected individuals, 56.35% were males and 43.64 were females. The incidence rate of SS, per 1,000,000 population, in 2000 was 0.17 & 0.28 in 2020. 69.70% were whites, 14.00% were blacks, 2.28% were Asians/Pacific Islanders, 0.65% were American Indians/Alaskan Natives, & 12.70% were Hispanics. 46.24% of patients had localized disease, 38.11% patients had regional disease, & 16.61% had the evidence of distant metastasis. Survival analyses were compared for the general population & further stratified based on races, between MF & SS. The median of survival (mOS) was 238 months for MF & 39 months for SS ( p<0.0001, Hazard Ratio (HR) 0.2215, Confidence Interval (CI) 0.1649 to 0.2975.) Conclusion: When the subtypes of CTCLs, MF & SS, were compared, prevalence of MF was significantly more than SS. Incidence of MF somewhat stayed the same in 20 years vs SS showed an uptrend. Median age for diagnosis was higher SS (71 years) vs. SS(60 years). Both showed a strong predilection towards males. The most commonly affected race for both, was seen in Whites & the least was for American Indians/Alaskan Natives. Survival for MF(238 months) was significantly higher than SS (39 months). Although rarer of the two CTCL, SS has a poorer prognosis. With this retrospective study, our aim was to understand the epidemiology of the two CTCLs, as with the newer treatment options for these diseases like Romidepsin and Brentuximab Vedotin, it would be interesting to do a follow-up study on the epidemiological variability & survival, for these rare hematological malignancies.

Health-Related Quality of Life (HRQL) in Cutaneous T-Cell Lymphoma: Psychological Burden and Influencing Factors from Mycosis Fungoides and Sézary Syndrome Patients in China

Introduction: Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of cutaneous T-cell lymphomas (CTCL). However, beyond the clinical and economic burden, psychological burden from CTCL patients in China has not been reported and requires further evaluation. Methods: The analysis used data from adults (≥18 years) clinically diagnosed with MF or SS, and have been receiving or have received disease-related treatment in the past year. MF patients with stage IA-IIA, patch or plaque phase were categorized into early stage, while stage IIB-IVA, tumor phase were late stage. All SS patients are late stage. HRQL data from the EQ-5D-5L, Skindex-29 and Functional Assessment of Cancer Therapy - General (FACT-G) were analysed at the item level and scored according to instrument guidelines. Multivariate analyses were used to identify factors associated with poor HRQL. Results: Data were collected from a quantitative survey of 56 MF patients and 5 SS patients residing in 38 cities of 21 provinces across China: 56% were male, with a mean (SD) age of 39 (13) years (median was 38, ranged 19 to 74 years old). 51% were late stage. Based on emotional domain questions of Skindex-29, among all patients, 39% always or often worried about the disease progression, while 45% of late-stage patients were always and often worried. 36% of all patients often or always felt CTCL was annoying. Based on FACT-G, in physical well-being domain, 39% of all patients, and 48% of late-stage patients felt they were ill in “quite a bit” or “very much” scale, respectively. In social well-being domain, 35% of all, and 39% of early-stage patients felt “not at all” or only “a little bit” satisfied with their sex life. In emotional well-being domain, 38% of all patients were “not at all” or “a little bit” satisfied with their coping with the disease, while 36% of all patients “quite a bit” or “very much” worried about the condition getting worse. In the functional well-being domain, 29% of all patients felt they were “not at all” or “a little bit” able to work. In multivariate analysis, regression on EQ-5D-5L score showed that younger patients were more likely to report severe anxiety and depression. Skindex-29 score showed that female patients worried more that the disease get more serious and causing scars on their skin. Conclusions: In China, psychological burden with MF and SS, included anxiety, depression, worrying about disease progression, unable to work, and unsatisfied sex life. Younger patients and female patients reported greater psychological impact of the disease. Optimal medical management of MF and SS should address psychological impacts of the disease.

The Overlap of Skin and Blood T-Cell Clones in Early-Stage Mycosis Fungoides

Introduction: Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma that initially starts in the skin but can progress to involve blood with significant mortality in late stages. Even in early stages and in the absence of blood involvement, changes in blood T-cell receptor (TCR) repertoire have been observed in MF patients. While prior work has explored the significance of dominant blood T-cell clones in the prognosis of early MF, the relationship between TCR sequences and T-cell repertoires of blood and skin in early-stage MF patients has not been characterized. Objectives: To determine the relationship of blood and skin T-cell repertories and to reassess the impact of dominant blood T-cell clones on selected outcome endpoints in early-stage MF. Materials and Methods: We used high-throughput sequencing to interrogate TCR sequences in blood and skin of MF patients without blood involvement at the Jefferson Cutaneous Lymphoma Clinic (Adaptive Biotechnologies). ImmunoSEQ Analyzer provided T-cell repertoire overlap metric (Morisita's index) and diversity measure (Simpson's clonality score). Time to systemic treatment (TTST) was calculated as the time from initial diagnosis to initiation of first systemic therapy. Results: 60 MF patients with no blood involvement were enrolled. 28% had a dominant clone in blood; of these, 18% were identical to dominant skin clones and 82% were distinct from the dominant clones identified in skin. We found that MF patients with discordant dominant T-cell clones in blood and skin had a longer TTST when compared to the identical clone cohort (P=0.0057) (Figure 1A). Furthermore, patients with discordant dominant clones had a lower degree of T-cell repertoire overlap between blood and skin (P<0.0001) and higher blood T-cell repertoire diversity scores (P=0.013) when compared to the identical clone group (Figure 1B). In all patients, the degree of T-cell overlap in blood and skin did not significantly change over a period of months to years or among skin biopsies obtained from different anatomical locations. Finally, in a subset of patients with discordant clones, the dominant skin clone did not appear to be detected in blood even at low frequencies. Conclusion: Our data highlight the importance of establishing clonal associations between dominant T-cell clones of the skin and blood in MF. We propose that early-stage MF patients with dominant clones in blood segregate into two cohorts with distinct prognoses and T-cell repertoires based on the identity of their peripheral T-cell clones. In addition, our findings suggest that not all MF patients have reservoirs of malignant T-cell clones readily available in peripheral circulation to seed new lesions in skin. Figure 1: A: Kaplan-Meier analyses of time to systemic treatment (TTST) in skin-limited mycosis fungoides (MF) patients with an identical dominant T-cell clone in blood and skin, a discordant dominant T-cell clone in blood and skin, and no dominant blood clones. NS- not significant (P =0.5274), ** (P =0.0057), *** (P <0.0003). B: Average Morisita's index for blood and skin overlap for patients in indicated groups of I: identical dominant clones in blood and skin, D: discordant dominant clones in blood and skin, and N: no dominant clone in blood. **** (P <0.0001).

Health-Related Quality of Life (HRQL) in Cutaneous T-Cell Lymphoma: A Post Hoc Analysis Examining Disease Burden and Patient Characteristics from the Phase 3 Mavoric Trial in Mycosis Fungoides and Sézary Syndrome

The MAVORIC phase 3 study (NCT01728805) evaluated the efficacy of mogamulizumab compared with vorinostat in patients with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) - the most common subtypes of cutaneous T-cell lymphoma (CTCL). This retrospective analysis of baseline (pre-treatment) data from the large well-defined population in the MAVORIC study describes the burden of CTCL on HRQL and identifies characteristics that are associated with poorer HRQL. The MAVORIC study enrolled patients with stage IB-IVB relapsed or refractory MF/SS that had failed to respond to one or more systemic therapies. HRQL data from the Skindex-29, ItchyQOL, and Functional Assessment of Cancer Therapy - General (FACT-G) were analysed at the item level and scored according to instrument guidelines. Bivariate analysis was used to identify factors associated with relatively poorer HRQL and guided selection of variables for the multivariate analysis. 372 participants were enrolled, 55% with MF and 45% with SS; 77% had advanced (stage IIB-IV) disease. The mean (SD) age was 63 (13.0) years and 42% were female. Disease involved the skin in all participants, blood in 66%, nodes in 66%, viscera in 2%, and other sites in 5%. ECOG performance status was 0, 1, and 2 in 56%, 43%, and 1%, respectively. The domains and total scores for Skindex-29, ItchyQoL and FACT-G are shown in table 1 For individual items, the greatest impairments were seen in skin itch, skin sensitivity, worry of worsening, annoyed by skin condition, sleep, and need to buy special soaps. In bivariate analysis, worse total score across all three HRQL measures was related to being younger, female, having moderate or severe itch, ECOG performance status 1 or 2, and higher Modified Severity-Weighted Assessment Tool (mSWAT) scores. On the Skindex-29 and ItchyQol, worse total scores were also related to Black/African American ethnicity, having disease involving nodes, and higher affected body surface area (BSA). Worse Emotional domain scores across all three HRQL measures was related to being female and having severe itch; worse Functional domain scores were related to disease involving nodes, ECOG performance status 1 or 2, higher mSWAT score, higher affected BSA, and moderate or severe itch. Worse Symptom domain scores (Skindex-29 and ItchyQol) were related to being female, ECOG performance status 1 or 2, higher mSWAT score, higher affected BSA, and severe itch. Differences across HRQL measures will also be reported. In multivariate analysis, worse HRQL was associated with being younger, female, or Black/African American, and with moderate or worse itch and ECOG stage 1 or 2 but was not generally associated with disease stage. In participants with advanced MF/SS, HRQL was most impacted by symptoms with the impact varying by patient characteristics rather than disease stage. Assessing patients' individual disease concerns may inform treatment goals and therapeutic choice.

CD84 (SLAMF5) As a Potential Target for Immunomodulation in Cutaneous T-Cell Lymphoma (CTCL)

Background: Cutaneous T-cell lymphoma (CTCL) develops from clonally expanded, skin-homing CD4 + T cells within a background of chronic inflammation. Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of CTCLs. Patients with advanced-stage MF/SS experience progressively worsening disease and decreased overall survival (Scarisbrick et al., 2015). Immune cells and immune checkpoints (ICs) are essential factors for tumor growth and the host immune response in CTCL. Tumor-associated macrophages (TAMs [M2-like]) play a key role in CTCL growth, and neoplastic T cells escape immune surveillance via the PD-L1/PD1 axis (Wu et al., 2014). However, the approach of ICs inhibition with monoclonal antibodies (mAbs) in CTCL has been challenged due to modest efficacy and remaining immunosuppression. Hence, novel therapeutic strategies are needed to improve anti-tumor immunity in CTCL. We previously characterized CD84 (SLAMF5) as one of the key players in the tumor microenvironment (TME) by regulating multiple ICs, including PD-L1 and PD1, and modulating myeloid cell fractions and T cells in our preclinical MM models. Our CD84 targeting strategy using anti-CD84 mAb significantly reduced PD1 on effector CD8 + T cells and PD-L1 on the tumor and myeloid cells, decreased tumor burden, and increased the survival of the mice with myeloma (Lewinsky and Gunes et al., 2021). The role of CD84 in ICs regulation and anti-tumor immunity in CTCL remains to be explored. Methods and Results: In this study, we evaluated the role of CD84 in CTCL and, for the first time, reported CD84 as a potential target to reduce immunosuppression through the PD-L1/PD1 axis in CTCL. We found upregulated CD84 CD274 (PD-L1) , and PDCD1 (PD1) gene expressions in CTCL patients (n=5) compared to healthy individuals (n=4). We also noted higher CD84 geneexpression in SS patients (n=8) than in MF patients (n=6). We next evaluated CD84 expression on the formalin-fixed paraffin-embedded (FFPE) tumor sections derived from SS patients' skin lesions. We noted that CD84 is highly expressed in the TME and co-expressed in Ki67 + Sézary cells. We further evaluated the CD84 expression in immune cell clusters in SS patients and healthy individuals using publicly available single-cell RNA sequencing (scRNA-seq) datasets. We noted a profound CD84 expression in CD4 + T cells and CD163 + M2-like macrophages in SS patients. We also noted a strong correlation between CD84 and CD274 (p=0.0086) and CD84 and PDCD1 (p=0.0002) in SS patients. We next assessed the expressions of CD84, PD-L1 on CD163 + M2-like macrophages, and PD1 on T cell subsets in a coculturing setting with human SS cell line, Hut78, to determine the impact of Sézary cells on these cell compartments in the TME. We observed a significant increase in the percentages of CD163 + M2-like macrophages and CD4 + T cells and elevated CD84, PD-L1, and PD1 expressions on these cells following the coculturing of peripheral blood mononuclear cells (PBMCs) derived from healthy donors (HDs) with Hut78 cells (n=3, *P < 0.05, **P < 0.01). While the percentages of CD8 + T cells were slightly reduced, CD84 and PD1 expressions were elevated in these cells following the coculturing with Hut78 cells (n=3, *P < 0.05, ***P < 0.001). Dysregulation of STAT proteins, particularly STAT3, has been shown in MF/SS (Olszewska et al., 2020). To explore whether Sézary cells regulate STAT3 in CD163 + M2-like macrophages, we assessed pSTAT3 levels in CD163 + M2-like macrophages following the coculturing of HDs PBMCs with Hut78 cells. We found that Hut78 cellssignificantly increased intracellular pSTAT3 levels inCD163 + M2-like macrophages (n=3, *P < 0.05). Furthermore, we noted the inhibition of STAT signalingusing a pan-STAT inhibitor decreased PD-L1 and PD1 expression onCD163 + M2-like macrophages and T-cell subsets, respectively. Notably, we found the stimulation of CD84 signaling with an agonist anti-CD84 mAb enhanced pSTAT3 levels in CD163 + M2-like macrophages, suggesting the STAT pathway might regulate PD-L1 expression in immunosuppressive CD163 + M2-like macrophages through CD84 signaling in SS. Conclusion: Our preliminary data from this exploratory study indicate that CD84 may be a potential target to reduce immunosuppression in CTCL. Further studies are needed to explore the functions of CD84 as an immune receptor in CTCL TME and its therapeutic potential in CTCL.

A Retrospective Study of Extracorporeal Photopheresis (ECP) in Treatment of Cutaneous T-Cell Lymphoma (CTCL) Evaluating Global, Skin and Blood Responses

Introduction: Cutaneous T-cell lymphoma (CTCL) is a rare form of T-cell lymphoma involving the skin in early stage, and blood, lymph nodes, and viscera in more advanced stages. Mycosis fungoides (MF) and Sezary syndrome (SS) are the most common subtypes of CTCL. Patients (pts) with advanced stage (AS)-MF and SS can have severe symptoms including erythroderma, pruritus, desquamation, and have a poor quality of life. Extracorporeal Photopheresis (ECP) was approved by FDA for CTCL in 1988. It is the recommended frontline therapy for SS and is also often used in AS-MF. ECP works by immunomodulatory mechanisms and has minimum side effects. However updated data is lacking on the efficacy of contemporary ECP. Most of the studies were published years ago and did not stage pts and evaluate responses using the current criteria. Blood response was not evaluated in most studies. Besides, ECP techniques including the administration of methoxsalen have changed. Seeking to understand the efficacy of ECP in current practice, we conducted a retrospective study including CTCL pts treated with ECP at Moffitt Cancer Center (MCC), FL, USA in the past 13 years. Methods: Pts with MF or SS who started ECP at MCC after Jan. 2010 were included. In our practice, pts are typically started on ECP alone. A systemic therapy is added in ~ 3 months when a pt does not respond. Response in blood and skin were evaluated every 3 months. Results: A total of 39 pts were included. 23 (59%) were male; 31 (82%) were Caucasian, 4 (11%) were African-American. When starting ECP, 33 (89%) had stage III/IV disease; 30 (77%) had erythroderma; 10.3%, 33.3% and 56.4% of pts had B0, B1 and B2 disease, respectively (Table 1). 18 (46.2%) pts achieved a best global response of complete response (CR), and 12 (30.8%) achieved partial response (PR). The median time to first global response was 6.5 months (range 3.2-19.8 months). At 3 months 28 pts were on ECP alone and 11 were on concurrent systemic therapy including: Interferon (4), retinoid acid (3), romidepsin (3), and pralatrexate (1). At 6 months 20 pts were on ECP alone and 19 were on concurrent systemic therapy including interferon (7), retinoid acid (4), Romidepsin (4), and 1 patient for each of mogamulizumab, vorinostat, methotrexate and interferon + retinoid acid. When evaluated at 3 months, the overall response rate (ORR) in skin was 8/39 (20.5%) in the entire cohort, and 5/28 (17.9%) in pts not on concurrent systemic treatment. When evaluate at 6 months the skin response rates were 16 (41.0%) and 9 (45.0%) in pts with and without concurrent systemic treatment, respectively. The ORR in blood at 3 months was 19/39 (48.7%) in the entire cohort and 13/28 (46.4%) in pts on ECP alone; at 6 months, the ORRs in blood were 25/39 (64.1%) and 13/20 (65%), respectively. With a median followup of 43 months, the median PFS was not reached (NR). The 5-year PFS rate was 58%. At the last followup, 7 pts who were on ECP alone were in CR, and 3 in PR. The response rates at 3 months, 6 months and the best response rates were not associated with baseline characteristics including blood stage (B0 vs B1 vs B2), global stage (I/II vs III/IV), and concurrent systemic therapy (p>0.1 for all, table 1, part of the data was not shown). Discussion: Our results showed the contemporary ECP therapy had excellent efficacy in SS and AS-MF (ORR 77%). Many pts achieved durable remission (5-year PFS 58%). However, it took a median of 6.5 months to achieve an objective response. Pts with AS-MF and SS have significant symptoms and poor quality of life. Research is needed to identify treatment combinations with ECP to induce a quicker response. One limitation of our study is, some pts received systemic therapy concurrently with ECP, thus making it difficult to isolate the treatment effect of ECP. As a sensitivity analysis, we evaluated responses of pts on ECP alone in the first 6 months, and in this way decreased the confounding effect. Our study is also limited by the retrospective nature and the limited sample size. Future prospective studies in larger scale are needed to confirm our results.

Spatial transcriptomics reveals heterogeneity of macrophages in the tumor microenvironment of granulomatous slack skin.

Granulomatous slack skin (GSS) is an extremely rare subtype of cutaneous T-cell lymphoma accompanied by an abundant number of macrophages and is clinically characterized by the development of pendulous skin folds. However, the characteristics of these macrophages in GSS remain unclear. Here, we conducted a spatial transcriptomic study on one frozen GSS sample and drew transcriptomic maps of GSS for the first time. Gene expression analysis revealed the enrichment of three clusters with macrophage transcripts, each exhibiting distinct characteristics suggesting that their primary composition consists of different subpopulations of macrophages. The CD163+ /CD206+ cluster showed a tumor-associated macrophage (TAM) M2-like phenotype and highly expressed ZFP36, CCL2, TNFAIP6, and KLF2, which are known to be involved in T-cell interaction and tumor progression. The APOC1+ /APOE+ cluster presented a non-M1 or -M2 phenotype and may be related to lipid metabolism. The CD11c+ /LYZ+ cluster exhibited an M1-like phenotype. Notably, these cells strongly expressed MMP9, MMP12, CHI3L1, CHIT1, COL1A1, TIMP1, and SPP1, which are responsible for extracellular matrix (ECM) degradation and tissue remodeling. This may partially explain the symptoms of cutaneous relaxation in GSS. Further immunohistochemistry on four GSS cases demonstrated that CD11c predominantly marked granulomas and multinucleated giant cells, whereas CD163 was mainly expressed on scattered macrophages, appearing as a mutually exclusive pattern. The expression pattern of MMP9 overlapped with that of CD11c, implying that CD11c+ macrophages may be a source of MMP9. Our data shed light on the characteristics of macrophages in the GSS microenvironment and provide a theoretical basis for the application of MMP9 inhibitors to prevent cutaneous relaxation of GSS. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Involvement of cutavirus in a subset of patients with cutaneous T-cell lymphoma with an unfavorable outcome

European studies suggest an association between cutavirus (CuV) and cutaneous T-cell lymphoma (CTCL); however, the worldwide prevalence of CuV in patients with CTCL and its prognostic impact remain unknown.We investigated the prevalence and viral loads of CuV DNA using biopsy specimens from the lesional skins of 141 Japanese patients with cutaneous malignancies, including 55 patients with various types of CTCL.CuV DNA was detected significantly more frequently in biopsies from patients with mycosis fungoides (MF) (38% [13/34]; the most common subtype of CTCL) than in those from patients with other cutaneous malignancies (6% [6/107]; P<0.001). The viral-load range in patients with CuV DNA-positive MF was 23-3922 copies/103 cells and 8-65 copies/μg of DNA. A phylogenetic analysis using the partial sequences of the CuV viral capsid protein 1 (VP1)/VP2 genes revealed that the CuV sequences identified here were clustered in a Japanese-specific clade distinct from that comprising CuV sequences from European patients with MF. Kaplan-Meier curves and a log-rank test showed that CuV positivity was associated with a shorter disease-specific survival in patients with MF (P = 0.031), whereas no significant difference in overall survival was observed (P = 0.275). No significant correlation was observed between CuV DNA load and survival in patients with CuV-positive MF.Our results suggest that CuV is associated with MF in a subset of Japanese patients. Large-scale prospective studies are warranted to clarify the role of CuV status, especially regarding the viral genotype, on adverse outcomes in patients with CuV-positive MF.

Accessibility and readability of online patient education on cutaneous lymphomas

Patients facing a cutaneous lymphoma diagnosis frequently turn to the internet for information but finding patient-accessible education may be a challenge. To investigate accessibility and readability of patient-oriented online education on cutaneous lymphomas, including cutaneous T-cell and B-cell lymphoma subtypes. This study queried a search engine for 11 cutaneous lymphoma terms, resulting in 1083 webpages. Webpages were screened using defined inclusion/exclusion criteria; literature directed to physicians and scientists was excluded. Webpages were stratified by academic/nonacademic and dermatology/nondermatology hosts and assessed by order of appearance. Readability, including text complexity, was analyzed for grade level understanding using 5 established calculators. Overall readability was assessed by Flesch-Kincaid Reading Ease. Academic webpages had earlier order of appearance. There was a dearth in dermatology-hosted webpages. Rarer cutaneous lymphomas yielded fewer patient-accessible results. Search term readability significantly exceeded the American Medical Association-recommended sixth grade level (P<.001∗), with higher grade levels for cutaneous T-cell lymphoma subtype webpages than cutaneous B-cell lymphoma subtypes. Webpage quality, accuracy, and language were not assessed. Current online education for cutaneous lymphomas exceeds the American Medical Association's maximum readability recommendation. There is a need for more patient-accessible education amidst predominance of scientific literature, greater dermatology host websites, and enhanced readability of existing online education.

Primary cutaneous lymphomas: exploration of 10-year data from supraregional mutlidisciplinary team meetings in Glasgow, UK.

Primary cutaneous lymphomas (PCLs) are non-Hodgkin lymphomas, presenting in the skin. They are classified into cutaneous B-cell lymphomas (CBCLs) or cutaneous T-cell lymphomas (CTCLs). The most common CTCL subtypes are mycosis fungoides (MF) and Sézary syndrome (SS). All patient's cases should be discussed at a specialist multidisciplinary team (MDT) meeting. This is the first published review, to our knowledge, of PCL MDT case discussion in the UK. Patient cases between 2008 and 2019 were reviewed to assess: frequency of PCL subtype, documentation of CTCL staging and management of MF/SS. Of 356, 103 (29%) were CBCLs and the majority (n = 200, 56%) were CTCLs. MF/SS was the diagnosis in 120 (34%). Staging was documented in 44% (n = 53) of patients with MF/SS. Management largely followed guidelines for MF/SS, topical corticosteroids were the most common treatment (n = 93, 78%). Frequency of PCL subtype is largely comparable with previously published data. Documentation of CTCL staging is low, but higher than other reports. Our work begins to address the gap in real-world data on CTCLs. A standardized approach to data collection would inform clinical practice.

Clinical and biological analysis of Sézary syndrome: A report of four cases

Background: Sézary syndrome (SS) is a rare and aggressive type of cutaneous T cell lymphoma characterized by an intensely pruritic, exfoliative rash, known as erythroderma, with cutaneous and systemic dissemination of clonal CD4+ T cells into the blood and lymph nodes. We report through a series of 4 cases, the experience of the hematology laboratory in the diagnosis of the syndrome of Sézary. Methods: Four patients with SS were identified retrospectively among patients with cutaneous T-cell lymphoma followed up in the dermatology department and diagnosed in the hematology laboratory of the Avicenne military hospital in Marrakesh. Results: Four patients with SS were described: three men and one woman, mean age at diagnosis 62 years (55-71). All the patients showed generalized dry erythroderma, pruritus and lymphadenopathy. Palmo-plantar hyperkeratosis, nail lesions and alopecia were also present. The white blood cell count was elevated (&gt;10,000 WBC/ mm3) in all 4 patients with a mean value of 17,276 and one patient among these showed an elevation of eosinophils (&gt; 500/ µl). The blood smear showed the presence of 65% of small to medium-sized cells with a high nucleocytoplasmic ratio and cerebriform nuclei typical of Sézary cells and suggests the diagnosis of SS. Conclusion: Sézary syndrome is a rare subtype of cutaneous T-cell lymphoma characterized by erythroderma, circulating neoplastic T cells, and poor prognosis. Microscopic findings must be correlated with the clinical presentation to make the diagnosis.

QuPath Analysis for CD30+ Cutaneous T-Cell Lymphoma.

Mycosis fungoides is the most common subtype of cutaneous T-cell lymphoma, in which the expression of cluster of differentiation 30 (CD30)+ subtype can now be treated with the CD30 antibody conjugate brentuximab vedotin. Diagnostic methods are based on immunohistochemical (IHC) staining followed by manual assessment by pathologists, which is always a subjective calculation. QuPath, an open-source software for digital pathology image analysis, satisfies the requirements of objective approaches. Ten samples from mycosis fungoides patients with CD30 expression at different stages were stained for CD3 and CD30 by IHC staining, scanned, and quantitative analysis was performed using QuPath (version 2.1). Each slide was independently assessed by 3 board-certified dermatopathologists. Individual estimates for CD30+/CD3+ cells varied among the individual histopathologists (mean coefficient of variation, 0.46; range, 0-0.78). QuPath analysis showed excellent separation between the positively stained cells for CD3 and CD30 IHC and other cells and tissue structures, although the results correlated strongly with the respective mean estimates of the 3 histopathologists (Pearson-R 0.93). The results show a high interobserver variability evaluation of IHC markers, although quantitative image analysis offer a significant advantage for comparison. This is not only relevant for clinical routine but also especially critical in therapeutic studies addressing targeted molecules.

Two women with primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder during pregnancy.

Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder (PCSM-TCLPD) is a rare subtype of cutaneous T-cell lymphomas of unknown origin. We report for the first time, to the best of our knowledge, on an association of PCSM-TCLPD with pregnancy and briefly discuss the possible pathogenetic link.

Primary Cutaneous CD8+ Aggressive Epidermotropic Cytotoxic T-Cell Lymphoma (PCAECTCL) Descriptors and Clinicopathologic Determinants of Survival: Analysis of a Pooled Database

Introduction: Primary Cutaneous CD8+ Aggressive Epidermotropic Cytotoxic T-cell lymphoma (PCAECTCL) is a rare provisional clinical entity and a subtype of cutaneous T-cell lymphoma. It is characterized by cytotoxic T-cells that primarily involve the epidermis causing rapidly progressive epidermal necrosis and extensive skin ulcers. PCAECTCL is often resistant to conventional chemotherapy and is usually associated with a poor prognosis. We conducted this pooled database analysis to delineate key disease characteristics and clinicopathologic determinants of survival in this rare provisional cutaneous T-cell lymphoma. Methods: To study the demographic characteristics, molecular and immunohistochemical signatures, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 128 cases. Kaplan-Meier survival curves were constructed. Cox proportional hazards model and Log-rank tests were used to assessing the influence of demographic and clinicopathologic factors on overall survival (OS). Results: A total of 128 patients with confirmed PCAECTCL were identified. The median age was 62, with a peak incidence between 60 and 75 years. There was a male predominance with M:F ratio of 1.9. The median duration of symptoms prior to diagnosis was 6 months. Most of the patients presented with stage IIB (75%), followed by IB (13%), IA(7%), IVB(3%), and IIA(1%). Constitutional symptoms (CS), hemophagocytic syndrome, and ulceration/necrosis were present in 6%, 33%, 1.5%, and 45%, respectively. PCAECTCL widely metastasized in 62% of the cases, mainly to mucocutaneous tissues and visceral organs (83%), which included testicles (11%) and CNS (22%). PCAECTCL immunophenotype consisted of: CD2(37%), CD3(99%), CD5(40%), CD7(66%), CD30(16%), CD45RA(77%), CD56(6%), Granzyme B(72%), TIA-1(100%), and a median Ki-67 score of 70%. The median OS of the whole group was 20 months. OS was significantly impacted as age increased from <40 to 40-59 and > 60 (34 vs. 27 vs. 12 months, p=0.0003). Combination chemotherapy and stem cell transplant were statistically superior to no treatment, with a median OS of 17, 50, and 1 months, respectively (p=0.0002). Males tended to have shorter OS than females (13 vs. 24 months). Similarly, the presence of CS tended to have a shorter OS (6 vs. 21 months). OS was not impacted by stage or immunohistochemical features. Conclusions: This study presents updated clinicopathologic data from a pooled cohort of patients with PCAECTCL. It details the features of this rare provisional entity and identifies the clinical, immunohistochemical, and treatment modalities that are major determinants of OS.

HDACi Promotes the Occurrence of Ferroptosis in CTCL

Cutaneous T-cell lymphoma (CTCL) is a type of extranodal non-Hodgkin's lymphoma (NHL), a disease caused by clonal proliferation of T-lymphocytes originating in the skin. CHOP is the classic first-line treatment regimen for PTCL, working best for ALK-positive ALCL, while chemotherapy regimens are not very friendly for CTCL and other subtypes of PTCL. Currently, second-line treatment regimens have shown encouraging results with HDAC inhibitors in PTCL, and the anti-tumor mechanisms of HDAC inhibitors are being explored, including induction of apoptosis, cell cycle arrest inhibition of tumor angiogenesis, and so on. Ferroptosis is a new mode of cell death, which was mainly manifested by mitochondrial membrane lipid peroxidation, ferritin phagocytosis, the release of ferrous ions. And ferrous ions further leads to cellular lipid peroxidation, resulting in cell death. Our study shows that HDACi can significantly enhance ferroptosis inducer-mediated ferroptosis. WB and qPCR showed that ferroptosis-related molecules were significantly downregulated. In the case of HDACi combined with ferroptosis inducer, HDACi significantly enhanced the intensity of ferroptosis, and mitochondrial shrinkage and increased membrane density could be observed under electron microscopy. Intracellular iron content was detected by PGSK probe and detected by co Focused microscopy revealed that the fluorescence signal was significantly attenuated in the combination group. Reactive oxygen species assay indicated a significant increase in intracellular reactive oxygen species level, where we found the presence of ferroptosis in PTCL for the first time. In addition, we found that HDACi combined with ferroptosis inducer could enhance the apoptosis level of lymphoma cells, and the combination group significantly downregulated BCL-2, Caspase3,and significantly upregulated p-H2AX expression compared with the single drug.In terms of cycle arrest, CyclinD1 was significantly down-regulated in the combination group, and flow cytometry results were consistent with the above, while CCK8 and Edu showed significant down-regulation of cell viability and proliferation. SD rat transplantation tumor models showed a significant reduction in tumor volume in the combination group compared to the single agent and control groups, suggesting that HDACI combined with ferroptosis inducer is a promising therapeutic strategy.

40. Clonal evolution of Cutaneous T Cell Lymphoma (CTCL) revealed at single cell resolution

Patients with CTCL subtypes Mycosis Fungoides and Sézary Syndrome (MF/SS) frequently progress to advanced stage disease, which has a 20% 5-year survival. The molecular factors that drive MF/SS progression remain undefined. To address this, we subjected 41 longitudinal tumor samples (peripheral blood, skin and lymph node biopsies, 49-1050 days apart) and matched, purified non-malignant cells from 10 MF/SS patients to single-cell (sc)RNA-seq and exome+whole genome sequencing (eWGS). and patient-specific TCR clonotype assignment (scRepertoire). Clustering and cell type inference of scRNAseq (UMAP/Seurat/singleR) showed canonical CTCL marker genes and high clonal proportions (1-100%) of patient-specific TCR clonotypes. Somatic genome copy number variants (CNV) from scRNAseq (copykat) and eWGS (cnvkit), and deleterious/damaging single nucleotide variants (SNV) (eWGS, GATK/Mutect2) were identified in CTCL versus matched, non-malignant cells. To segregate early genomic events from progression-associated, we developed an integrative analysis pipeline to prioritize somatic CNV/SNV in genes with altered expression in >=30% of patients. This novel approach revealed alterations in NF-KB and T-cell receptor pathways (NFKB2, STAT3/5, TOX) as early events that were maintained in subsequent CTCL samples. We demonstrate gain-of-function activity in a novel-to-CTCL mutation in STAT3. Losses of some chromatin-modifying enzymes (DNMT3A, KDM6B) are early events, while gains of others (EZH2) are acquired with progression. Strikingly, progression-associated mutations were enriched in cell metabolism, growth, and motility genes, some of which are new to MF/SS: HIF1A, ITPR3, GTPase/RAS (IQGAP1/2, RASA1), and PI kinase (AKT1, MTOR, PIK3R1). These findings represent new insights into MF/SS progression and identify new precision medicine targets for currently available therapies.

Genetics Abnormalities with Clinical Impact in Primary Cutaneous Lymphomas.

Simple SummaryThe genetic landscape of cutaneous T-cell lymphomas analyzed by sequencing high throughput techniques shows a heterogeneous somatic mutational profile and genomic copy number variations in the TCR signaling effectors, the NF-κB elements, DNA damage/repair elements, JAK/STAT pathway elements and epigenetic modifiers. A mutational and genomic stratification of these patients provides new opportunities for the development or repurposing of (personalized) therapeutic strategies. The genetic heterogeneity in cutaneous B-cell lymphoma parallels with the specific subtype. Damaging mutations in primary cutaneous diffuse large B-cell lymphoma of the leg type, involving MYD88 gene, or BCL6 and MYC translocations or CDKN2A deletions are useful for diagnostic purposes. The more indolent forms, as the primary cutaneous lymphoma of follicle center cell (somatic mutations in TNFRSF14 and 1p36 deletions) and the cutaneous lymphoproliferative disorder of the marginal zone cells (FAS gene), present with a more restricted pattern of genetic alterations.Primary cutaneous lymphomas comprise a heterogeneous group of extranodal non-Hodgkin lymphomas (NHL) that arise from skin resident lymphoid cells and are manifested by specific lymphomatous cutaneous lesions with no evidence of extracutaneous disease at the time of diagnosis. They may originate from mature T-lymphocytes (70% of all cases), mature B-lymphocytes (25–30%) or, rarely, NK cells. Cutaneous T-cell lymphomas (CTCL) comprise a heterogeneous group of T-cell malignancies including Mycosis Fungoides (MF) the most frequent subtype, accounting for approximately half of CTCL, and Sézary syndrome (SS), which is an erythrodermic and leukemic subtype characterized by significant blood involvement. The mutational landscape of MF and SS by NGS include recurrent genomic alterations in the TCR signaling effectors (i.e., PLCG1), the NF-κB elements (i.e., CARD11), DNA damage/repair elements (TP53 or ATM), JAK/STAT pathway elements or epigenetic modifiers (DNMT3). Genomic copy number variations appeared to be more prevalent than somatic mutations. Other CTCL subtypes such as primary cutaneous anaplastic large cell lymphoma also harbor genetic alterations of the JAK/STAT pathway in up to 50% of cases. Recently, primary cutaneous aggressive epidermotropic T-cell lymphoma, a rare fatal subtype, was found to contain a specific profile of JAK2 rearrangements. Other aggressive cytotoxic CTCL (primary cutaneous γδ T-cell lymphomas) also show genetic alterations in the JAK/STAT pathway in a large proportion of patients. Thus, CTCL patients have a heterogeneous genetic/transcriptional and epigenetic background, and there is no uniform treatment for these patients. In this scenario, a pathway-based personalized management is required. Cutaneous B-cell lymphoma (CBCL) subtypes present a variable genetic profile. The genetic heterogeneity parallels the multiple types of specialized B-cells and their specific tissue distribution. Particularly, many recurrent hotspot and damaging mutations in primary cutaneous diffuse large B-cell lymphoma of the leg type, involving MYD88 gene, or BCL6 and MYC translocations and BLIMP1 or CDKN2A deletions are useful for diagnostic and prognostic purposes for this aggressive subtype from other indolent CBCL forms.