Sézary Syndrome Patients Research Articles

A Retrospective Cohort Study to Determine Real-World Treatment Patterns in Patients with Sézary Syndrome in the United States.

Sézary syndrome (SS) is a rare leukemic cutaneous T cell lymphoma. This study was conducted to examine the real-world treatment patterns among patients with SS in the USA from 2018 to 2020. This was a retrospective cohort study using the Symphony Health Solutions claims database. Adult patients with ≥ 1 diagnosis code for SS were classified into three non-mutually exclusive cohorts: 2018, 2019, and 2020. Patient characteristics and treatment patterns were examined across the 3years of study and reported descriptively for each year. Annual treatment patterns were also described for the five states with the highest proportions of SS patients in 2020. Overall, 869, 882, and 853 SS patients were identified in 2018, 2019, and 2020, respectively (median age: 70years for each year; male: 54.4%, 54.8%, and 55.6%, respectively). The use of any systemic and parenteral systemic treatments increased over time. While utilization rates for many specific systemic therapies decreased over the study period, mogamulizumab use increased, making it the most commonly used systemic treatment in 2020 (29.2%) among patients with any systemic treatment. The five states with the highest proportions of SS patients in 2020 were Florida, New York, California, Texas, and Pennsylvania. Systemic treatment patterns varied considerably by state. Some systemic therapies showed decreased usage over time while a few showed increased utilization, with mogamulizumab showing the largest increase. Treatment patterns for SS varied by region. Further research is needed to examine the factors that drive treatment selection for patients with SS.

Evaluation of Sézary cell marker expression and cell death behaviour upon invitro treatment by flow cytometry in Sézary syndrome patients.

The diagnosis of Sézary syndrome (SS) relies on the identification of blood Sézary cells (SC) by different markers via flow cytometry. Treatment of SS is challenging since its pathogenesis is characterized by cell death resistance rather than hyperproliferation. In this study, we establish an integrated approach that considers both the expression of SC markers and sensitivity to cell death both spontaneously and upon invitro treatment. Peripheral blood mononuclear cells were isolated from 20 SS patients and analysed for the SC markers CD7 and CD26 loss as well as CD158k and PD1 gain. The cells were then treated with different established and experimental therapies invitro and cell death was measured. Spontaneous and therapeutically induced cell death were measured and correlated to cellular marker profiles. In the marker-positive cells, spontaneous cell death sensitivity was reduced. Different treatments invitro managed to specifically induce cell death in the putative CTCL cell populations. Interestingly, a repeated analysis after 3 months of treatment revealed the CTCL cell death sensitivity to be restored by therapy. We propose this novel integrated approach comprising the evaluation of SC marker expression and analysis of cell death sensitivity upon treatment that can also enable a better therapy stratification.

Development and psychometric properties of the Functional Assessment of Cancer Therapy-Cutaneous T-Cell Lymphoma (FACT-CTCL).

Patients with Mycosis Fungoides (MF)/Sézary Syndrome (SS) can experience impacted health-related quality of life (HRQoL). To validate the CTCL-S, a novel subscale of the Functional Assessment of Cancer Therapy - General (FACT-G), in patients with MF/SS. Qualitative interviews were conducted with expert clinicians and MF/SS patients. Thematic analysis identified the most common concerns, and 19 items were selected.MF/SS patients were recruited from a single center. FACT-G, CTCL-S (collectively "FACT-CTCL"), Skindex29, and Visual Analogue Scale-Pruritis (VAS itch) were administered. A subset repeated FACT-CTCL and VAS itch after ≈2 weeks. Patient demographics and clinical characteristics were obtained via review of the electronic medical record.Psychometric properties were assessed. Internal consistency was estimated using Cronbach's alpha (α). Convergent and discriminant validity were assessed by comparing CTCL-S to disease stage, age, VAS itch, FACT-G, and SkinDex29. Exploratory factor analysis (EFA) was used to preliminarily assess CTCL-S dimensionality. Test-retest repeatability was summarized using intraclass correlation coefficient (ICC), within-subject standard deviation (wSD), and within-subject coefficient of variation. Seventy-two patients completed the initial survey, and 35 repeated the FACT-CTCL and VAS itch after ≈2 weeks. Two-thirds were male, most were white (78%). The majority (85%) had MF, 15% SS, and 75% early (stage IA-IIA) and 25% advanced (≥ stage IIB) disease. Preliminary EFA found a single predominant factor, supporting a hypothesis of unidimensionality of the CTCL-S. Internal consistency of the CTCL-S was high (α: 0.95 [95% CI: 0.93-0.96]). There was no significant change in CTCL-S average test-retest scores (ICC of 0.93 (p = 0.63)). CTCL-S was significantly lower in advanced vs early stage disease (median[IQR]: 34[26, 48] vs. 59[44, 68], p < 0.001) and strongly correlated with VAS itch (Spearman's r (rs): -0.70, 95% CI: -0.81, -0.55), FACT-G (rs: 0.77, 95% CI: 0.65, 0.85), and Skindex29 (rs: -0.90, 95% CI: -0.94, -0.84), supporting convergent validity. CTCL-S scores had little correlation with age (rs: 0.19, 95% CI: -0.05, 0.41, p = 0.12), supporting discriminant validity. The FACT-CTCL is a disease specific instrument for assessing HRQoL with high reproducibility and good performance in a cohort of patients with MF/SS.

On the Way to Curing Advanced-Stage Mycosis Fungoides/Sézary Syndrome

Advanced-stage mycosis fungoides (MF) and Sézary syndrome (SS) have poor prognosis with median survivals of less than 5 years. Although a variety of treatments are approved for MF/SS patients, durable complete remissions (CR) are rare. Advanced-stage MF or SS patients who achieved CR and maintained in CR or stage IA for more than 10 years were identified by a retrospective search of the principal investigator's database. Of 2266 patients diagnosed with MF or SS, 23 patients with advanced-stage MF/SS (6 IIB, 1 IIIB, 5 IVA1, 3 IVA2, 8 IVB) who achieved CR and maintained in CR or stage IA for ≥ 10 years were identified. As final/curative treatment, 11 patients underwent allogeneic stem cell transplantation (SCT). Most patients presented at young age, underwent SCT with reduced intensity conditioning regimen, had matched related donors, and controllable post-transplant graft versus host disease. Eleven patients were treated with TSEB as part of combined modality protocol in 2 patients and debulking therapy before allogeneic SCT in 9 patients. Five stage IIB patients achieved CR with radiotherapy. Four patients with blood involvement were treated with extracorporeal photopheresis (ECP) in combination with long-term antibiotics and immunomodulatory agents. Long-term antibiotics were given to 14 patients. TSEB followed by allogeneic SCT, radiotherapy, ECP plus long-term antibiotics and immunomodulatory agents were the most common curative/final treatments found in our patients. We are reporting the details of our long-term complete responders' treatment course in the hopes of obtaining more cure responses in the future.

Abstract 5171: CD39, CD73 and CD38 as potential biomarkers for monitoring the response to mogamulizumab in Sézary syndrome

Abstract We demonstrated aberrant expression of CD39 or CD73 and low expression of CD38 in circulating and skin-homing CD4+ T cells in patients with Sézary syndrome (SS), an erythrodermic cutaneous T-cell lymphoma (CTCL) with a leukemic component. The anti-CCR4 monoclonal antibody Mogamulizumab (Moga) has been shown to increase progression-free survival in patients with advanced SS. Here, we longitudinally explored the modulation of the expression of CD39, CD73 and CD38 in circulating CD4+ T cells from SS patients under treatment with Moga. Eight patients with relapsed/refractory SS were included in the study and prospectively followed up for two years (median duration of treatment 9,5 months, range 5-28 months). Seven out of eight (87,5%) patients showed early complete response in the blood and partial (5/7, 71,4%) or near complete response (2/7, 28,6%) in the skin. One patient (12,5%) showed no blood or skin response to the treatment. Flow cytometry analysis highlighted that the clinical response was accompanied by a rapid and remarkable increase in CD38 expression in the residual circulating CD4+ T cells, as well as in CD8+ T cells. Moreover, in six patients carrying the homozygous G/G or heterozygous A/G ENTPD1 SNP rs10748643 genotypes, permissive to CD39 overexpression in T cells, the increased CD38 expression was paralleled by rapid reduction/loss of CD39. Notably, in one patient carrying the A/A genotype, characterized by low CD39 and high CD73 expression at the baseline, response to treatment was characterized by reduction of CD73 expression. The only one patient with A/A genotype who didn’t respond to Moga showed no modulation of CD38 or CD39 expression, while CD73 expression increased. Noteworthy, Moga increases the expression of CD38 in responding patients, and influences the expression of CD39 only in patients with the permissive CD39 genotypes (G/G; A/G), but not in those with the A/A genotype. Two patients showing initial response to Moga experienced skin progression during treatment, which was associated with a significant increase of CD39 and simultaneous decrease of CD38 in residual circulating CD4+ T cells, although there was no evidence of blood relapse. These preliminary results suggest that partial or complete responses to Moga is paralleled by reduced CD39 and/or CD73 expression and increased CD38 expression. Instead, an opposite modulation of these markers is associated with disease progression hinting at the potential clinical utility of CD38, CD39 and CD73 as markers to monitor patients' response to Moga therapy. Citation Format: Yuliya Yakymiv, Sara Marchisio, Erika Ortolan, Verdiana Pullano, Chiara Leso, Rebecca Senetta, Lorenzo Marega, Gabriele Roccuzzo, Pietro Quaglino, Ada Funaro. CD39, CD73 and CD38 as potential biomarkers for monitoring the response to mogamulizumab in Sézary syndrome [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 5171.

High-throughput RNA sequencing of the T cell receptor alpha and beta chains for simultaneous clonality and biological analyses in Sezary syndrome.

Previous investigations pointed out a role for antigen stimulation in Sezary syndrome (SS). High-throughput sequencing of the T cell receptor (TR) offers several applications beyond diagnostic purposes, including the study of T cell pathogenesis. We performed high-throughput RNA sequencing of the TR alpha (TRA) and beta (TRB) genes focusing on the complementarity-determining region 3 (CDR3) in 11 SS and one erythrodermic mycosis fungoides (MF) patients. Five psoriasis patients were employed as controls. Peripheral blood CD4+ cells were isolated and RNA sequenced (HiSeq2500). High-resolution HLA typing was performed in neoplastic patients. Highly expanded predominant TRA and TRB CDR3 were only found in SS patients (median frequency: 94.4% and 93.7%). No remarkable CDR3 expansions were observed in psoriasis patients (median frequency of predominant TRA and TRB CDR3: 0.87% and 0.69%, p < 0.001 compared to SS). CDR3 almost identical to the predominant were identified within each SS patient and were exponentially correlated with frequencies of the predominant CDR3 (R2 = 0.918, p < 0.001). Forty-six different CDR3 were shared between SS patients displaying HLA similarities, including predominant TRA and TRB CDR3 in one patient that were found in other three patients. Additionally, 351 antigen matches were detected (Cytomegalovirus, Epstein-Barr, Influenza virus, and self-antigens), and the predominant CDR3 of two different SS patients matched CDR3 with specificity for Influenza and Epstein-Barr viruses. Besides detecting clonality, these findings shed light on the nature of SS-related antigens, pointing to RNA sequencing as a useful tool for simultaneous clonality and biological analysis in SS.

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.

Lacutamab in Patients with Relapsed and Refractory Sèzary Syndrome: Results from the Tellomak Phase 2 Trial

Introduction Cutaneous T-cell lymphoma (CTCL) is a rare form of non-Hodgkin lymphoma. Sézary syndrome (SS) is a rare, aggressive and advanced type of CTCL. It has a unique biology, with high expression of KIR3DL2, a killer immunoglobulin-like receptor, reported in more than 85% of patients. SS is characterized by erythroderma, significant blood involvement with malignant SS cells, and lymphadenopathy. These patients suffer from debilitating itching and recurrent skin infections, often affecting quality of life (QoL). SS is distinguished by its poor prognosis, as the median survival of patients is approximately 5 years. 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, open-label, Phase 2 trial with multiple cohorts (NCT03902184). We report here results from Cohort 1, designed to evaluate safety and efficacy of single agent lacutamab in patients with relapsed/refractory (R/R) SS after at least 2 prior systemic therapies including mogamulizumab. Patients had blood stage B2 (≥1000 circulating Sézary cells/mm 3) at screening based on central evaluation by flow cytometry. Patients with evidence of large cell transformation were excluded. Lacutamab 750 mg is administered as an intravenous infusion weekly × 5 weeks (w), every 2 w × 10, then every 4 w until progression or unacceptable toxicity. Primary endpoint was Objective Response Rate (ORR) by global response score based on the evaluation of 4 compartments: skin, blood, lymph nodes and viscera according to International Consensus criteria (Olsen 2011). Secondary endpoints included but not limited to additional efficacy endpoints, safety, QoL assessments. Results At the data cut-off of May 1, 2023, 56 SS patients were enrolled treated and evaluated in Cohort 1. Median age was 69 years (range: 42-86), the median prior lines of systemic therapies was 6.0 (range: 2-15), 60.7 % (n=34) had stage IVA1, 32.1 % (n=18) had stage IVA2 and 7.1% (n=4) had stage IVB disease at baseline, all patients (100%) had blood involvement (B2), 67.9% (n=38) had confluence of erythema covering ≥ 80% body surface area (T4), 35.7% (n=20) had lymph node lymphoma involvement (N3). Median follow-up was 14.4 months (95% CI 9.0-18.4). In the ITT population (n=56), Global confirmed ORR was 37.5% (n=21; 95% CI 26.0-50.6) including 2 CRs, with a median time to response of 2.8 months (range 1-9; Figure 1). Confirmed ORR in skin was 46.4% (n=26; 95% CI 34.0-59.3) including 5 CRs. Confirmed ORR in blood was 48.2% (n=27; 95% CI 35.7-61.0) including 15 CRs. Clinical Benefit Rate (CBR, defined as CR+PR+SD) was 87.5 % (n=49; 95% CI 76.4-93.8). Median PFS was 8.0 months (95% CI 4.7-21.2). Grade ≥ 3 Treatment-related (TR) Treatment-Emergent Adverse events (TEAEs) were observed in 10/56 (17.9%) pts, Serious TR TEAEs were observed in 4/56 (7.1%) and 3/56 (5.4%) pts discontinued study drug due to TR TEAE. Data from additional key endpoints will be presented. Conclusion In this SS cohort from the TELLOMAK study, our data confirm that lacutamab monotherapy shows promising clinical activity in a R/R population previously treated with 2 or more prior systemic therapies including mogamulizumab, and an overall favourable safety profile. Continued evaluation of this new targeted treatment option for patients with SS is warranted.

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 &amp;lt; 0.05, **P &amp;lt; 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 &amp;lt; 0.05, ***P &amp;lt; 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 &amp;lt; 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.

New JAK3-INSL3 Fusion Transcript-An Oncogenic Event in Cutaneous T-Cell Lymphoma.

Constitutively activated tyrosine kinase JAK3 is implicated in the pathogenesis of cutaneous T-cell lymphomas (CTCL). The mechanisms of constitutive JAK3 activation are unknown although a JAK3 mutation was reported in a small portion of CTCL patients. In this study, we assessed the oncogenic roles of a newly identified JAK3-INSL3 fusion transcript in CTCL. Total RNA from malignant T-cells in 33 patients with Sézary syndrome (SS), a leukemic form of CTCL, was examined for the new JAK3-INSL3 fusion transcript by RT-PCR followed by Sanger sequencing. The expression levels were assessed by qPCR and correlated with patient survivals. Knockdown and/or knockout assays were conducted in two CTCL cell lines (MJ cells and HH cells) by RNA interference and/or CRISPR/Cas9 gene editing. SS patients expressed heterogeneous levels of a new JAK3-INSL3 fusion transcript. Patients with high-level expression of JAK3-INSL3 showed poorer 5-year survival (n = 19, 42.1%) than patients with low-level expression (n = 14, 78.6%). CTCL cells transduced with specific shRNAs or sgRNAs had decreased new JAK3-INSL3 fusion transcript expression, reduced cell proliferation, and decreased colony formation. In NSG xenograft mice, smaller tumor sizes were observed in MJ cells transduced with specific shRNAs than cells transduced with controls. Our results suggest that the newly identified JAK3-INSL3 fusion transcript confers an oncogenic event in CTCL.

PD-1 Overexpression in Sézary Syndrome Is Epigenetically Regulated

PD-1 Overexpression in Sézary Syndrome Is Epigenetically Regulated

Health-related quality of life and economic burden in Chinese patients with cutaneous T-cell lymphoma.

e19533 Background: Cutaneous T-cell lymphoma (CTCL) is a rare type of non-Hodgkin lymphoma. As described in European Organization for Research and Treatment of Cancer Consensus, the subtypes of mycosis fungoides (MF) and Sézary Syndrome (SS) comprised roughly 55% and 5% of CTCL, respectively. The clinical presentations of MF and SS include skin lesion, tumors, ulcerations, systemic involvements and even death. This study aimed to measure the overall HRQoL and economic burden of MF and SS patients in China. Methods: A cross-sectional survey was conducted from 21 July 2022 to 24 October 2022. Eligible adult participants with a pathologically confirmed diagnosis of either MF or SS were recruited from specialty or general hospitals across China. All participants were asked to complete a questionnaire that assessed HRQoL and annual economic burden. Validated instruments in Chinese, specifically the EuroQoL Group’s five-level QoL five-dimensional questionnaire (EQ-5D-5L), Functional Assessment of Cancer Therapy-General (FACT-G), and Skindex-29, were used to assess general, cancer and skin-related HRQoL. All HRQoL outcomes were calculated using the scoring system provided by the institutions, and EQ-5D utility scores were mapped using the China time trade-off value sets. As for economic burden, it was investigated from the societal perspective, as the direct medical costs, direct non-medical costs, and productivity loss were all calculated. Results: A total of 61 patients were recruited and completed the survey. Patients resided in 38 cities of 21 provinces across China. 56 patients (92%) were diagnosed with MF and 5 (8%) with SS. 56% were male, with a mean age of 39 years. Half of the patients had early-stage disease (defined as less than stage IIB, patch or plaque), with the remainder having late-stage disease. Among the recruited patients, 43 (70%) received skin-directed therapy, and 55 (90%) received systemic therapy. As for HRQoL measures, EQ-5D utility score was 0.79 (±0.18), FACT-G score was 61.3 (±12.4), and the Skindex-29 score was 43.4 (±24.2). Comparison between patients with early-stage disease and late-stage is presented in the table. As for economic burden, the annual per capita cost for MF and SS patients was CNY 86,729 (USD 12,428), which greatly exceeded the annual disposable income in 2022 (CNY 36,883, equals USD 5,440). Conclusions: This was the first study investigating economic burden and HRQoL using patient-reported outcomes conducted in mainland China. The findings suggested that MF and SS has significantly compromised patients’ HRQoL and posed substantial economic burden. [Table: see text]

Identifying racial and ethnic disparities in patients diagnosed with mycosis fungoides/Sezary syndrome in the United States: A contemporary SEER analysis.

7544 Background: Mycosis fungoides (MF) and Sezary syndrome (SS) are rare cutaneous T-cell lymphomas. In this study, we compare demographics, treatment, and survival patterns in Hispanic (HI) vs. Non-Hispanic (NH) patients diagnosed with MF and SS. Methods: Data were analyzed on MF and SS patients in the US reported to SEER 18 database between 2000 and 2018. SEER 18 contains the most comprehensive population-based cancer information in the US, covering approximately 27% of the total US population, and up to 36% of HI. Racial groups analyzed included NH whites, HI whites, blacks, and Asians/Pacific Islanders. Patient characteristics, age-adjusted incidence rate, and survival rate were compared across ethnic groups, HI vs NH. Stratification by age, gender, and stage at diagnosis were considered. Kaplan-Meier and Cox regression analyses were used to compare overall survival (OS) between HI and NH. Multivariate analysis and propensity score matching were performed with adjustment for age, stage, and B-symptoms. Results: 8578 patients with MF and 275 patients with SS were identified. Of patients with MF, 11% were HI and 89% were NH; of patients with SS, 12% were HI and 88% were NH. In NH patients with MF, most patients were male (58%); for HI patients with MF, a male predominance was not observed (p &lt; 0.001). In patients with SS, most patients were male in both NH and HI (56% NH, 56% HI; p = 0.989). In both MF and SS, HI were diagnosed at younger ages compared to NH, 49 y.o vs 60 y.o (p &lt; 0.001) and 59 y.o vs 71 y.o (p = 0.009) respectively. Most HI and NH with MF and SS did not receive radiotherapy (91% of NH and 92% of HI for MF; 92% of NH and 91% of HI for SS; p values 0.166 and 0.760, respectively). On survival analysis, for patients with MF, the survival probability (SP) at 2, 5, and 10 years for HI vs NH were 94%, 87%, and 77% vs. 91%, 81%, and 69%, respectively. The survival difference observed favored HI (p &lt; 0.001). For patients with SS, there was no statistically significant survival difference between HI and NH with 2, 5, and 10 year SP at 65%, 42%, and 17% for HI and 62%, 36%, and 16% for NH, respectively (p = 0.99). In patients with SS, the median survival time in years was 3.3 and 3.2 in NH and HI patients, respectively. In patients with MF, the median survival time was not reached. On multivariate analysis, when adjusted for age, those patients with MF and SS who were older than 80 y.o and between 60 to 80 y.o, had worse OS compared to those younger than 60 y.o, with HR 17.6 (95%: 13.8 – 22.3 ) and 4.2 (95 % CI: 3.6 – 5) respectively for MF; and HR 1.8 (95% CI: 0.9 – 3.7) and 1.64 (CI 95% 1 – 2.8) respectively for SS. Conclusions: We identified ethnic differences in incidence, age at diagnosis, sex, and survival outcomes in patients with MF and SS. Notably, we identified a survival advantage in patients with MF that favored HI. In patients with SS, there was no ethnic difference in survival.

Complete Response to tenalisib and romidepsin with long-term maintenance using tenalisib monotherapy in a patient with relapsed and refractory sézary syndrome.

Mycosis fungoides (MF) and Sézary Syndrome (SS) are the most common subtypes of cutaneous T cell lymphomas (CTCL). Advanced-stage MF/SS have poor prognoses and may be refractory to multiple systemic treatments. These cases can be difficult to achieve and maintain complete response and there is a need for novel therapeutics. Inhibition of the phosphatidylinositol 3-kinase (PI3K) pathway by Tenalisib presents one such emerging drug. We report a relapsed/refractory SS patient achieving complete remission using the combination of Tenalisib and Romidepsin and subsequently maintaining long-duration CR with Tenalisib monotherapy.

Imbalanced IL-1B and IL-18 Expression in Sézary Syndrome.

Sézary syndrome (SS) is a rare and aggressive type of cutaneous T-cell lymphoma, with an abnormal inflammatory response in affected skin. The cytokines IL-1B and IL-18, as key signaling molecules in the immune system, are produced in an inactive form and cleave to the active form by inflammasomes. In this study, we assessed the skin, serum, peripheral mononuclear blood cell (PBMC) and lymph-node samples of SS patients and control groups (healthy donors (HDs) and idiopathic erythroderma (IE) nodes) to investigate the inflammatory markers IL-1B and IL-18 at the protein and transcript expression levels, as potential markers of inflammasome activation. Our findings showed increased IL-1B and decreased IL-18 protein expression in the epidermis of SS patients; however, in the dermis layer, we detected increased IL-18 protein expression. In the lymph nodes of SS patients at advanced stages of the disease (N2/N3), we also detected an enhancement of IL-18 and a downregulation of IL-1B at the protein level. Moreover, the transcriptomic analysis of the SS and IE nodes confirmed the decreased expression of IL1B and NLRP3, whereas the pathway analysis indicated a further downregulation of IL1B-associated genes. Overall, the present findings showed compartmentalized expressions of IL-1B and IL-18 and provided the first evidence of their imbalance in patients with Sézary syndrome.

460 Enhancement of antibody-dependent cellular cytotoxicity is associated with treatment response to extracorporeal photopheresis in Sézary syndrome

Sézary syndrome (SS) is a rare, leukemic type of cutaneous T-cell lymphoma (CTCL), for which extracorporeal photopheresis (ECP) is a first-line therapy. Reliable biomarkers to objectively monitor the response to ECP in patients with SS are missing. We examined the quantitative and qualitative impact of ECP on natural killer (NK) cell activity in SS patients, and especially their functional ability for antibody-dependent cell-mediated cytotoxicity (ADCC). Further, we addressed the question whether the magnitude of the effect on ADCC can be associated with the anti-cancer efficacy of ECP in SS patients.

Single-cell analyses reveal novel molecular signatures and pathogenesis in cutaneous T cell lymphoma

Sézary syndrome (SS) is a rare and aggressive type of cutaneous T cell lymphoma (CTCL) with a poor prognosis. Intra-tumoral heterogeneity caused by different disease compartments (e.g., skin, blood) and poor understanding of the pathogenesis has created obstacles to the precise diagnosis and targeted treatment of the disease. Here we performed a comprehensive analysis by integrating single-cell transcriptomic data of 40,333 peripheral blood mononuclear cells (PBMCs) and 41,580 skin cells, as well as single-cell chromatin accessibility data of 11,058 PBMCs from an SS patient and matched healthy controls (HCs). Validation and functional investigation were carried out in an independent cohort consisting of SS patients, mycosis fungoides (MF) patients, psoriatic erythroderma patients, and HCs, as well as multiple cell lines. The analysis revealed that skin-derived Sézary cells (SCs) had a shifting trend to more advanced mature phenotypes compared to blood-derived SCs. A series of specific marker genes (TOX, DNM3, KLHL42, PGM2L1, and SESN3) shared in blood- and skin-derived SCs were identified, facilitating the diagnosis and prognosis of MF/SS. Moreover, luciferase reporter assays and gene knockdown assays were used to verify that KLHL42 was transcriptionally activated by GATA3 in SS. Functional assays indicated that KLHL42 silencing significantly inhibited aggressive CTCL cell proliferation and promoted its apoptosis. Therefore, targeting inhibition KLHL42 might serve as a promising therapeutic approach in CTCL.

Predictors of large cell transformation in patients with Sezary Syndrome-A retrospective analysis.

Large cell transformation (LCT) of Sezary Syndrome (SS) is a rare phenomenon. To date, there are no rigorous studies identifying risk factors for its development. Here, we seek to characterize the clinicopathologic risk factors that predispose patients with SS to develop LCT. We retrospectively evaluated all SS patient records available in the Michigan Medicine Cancer Registry from 2010-2021. Clinical and pathologic variables were compared between groups. The Kaplan-Meier method and log-rank test were used to assess overall survival. Of 28 SS patients identified, eight patients experienced LCT, and 20 did not (NLCT). Peak lactate dehydrogenase (LDH) before LCT (p = 0.0012), maximum total body surface area (TBSA) involvement before LCT (p = 0.0114), absolute CD8+ cell count measured on flow cytometry at diagnosis of SS (p = 0.0455) and at the most recent blood draw (p = 0.00736), and ulceration on biopsy (p = 0.0034) were significant clinicopathologic variables identified between the SS patients that developed LCT versus those that did not. Maximum TBSA involvement, peak LDH, presence of ulceration, and decreased levels of CD8+ cells in the peripheral blood may predict the development of LCT in patients with SS.

Allogeneic Hematopoietic Cell Transplantation in Advanced Phase Mycosis Fungoides and Sézary Syndrome: A Retrospective Analysis of 57 Consecutive Patients

Background: Advanced stage Mycosis Fungoides (MF) and Sézary Syndrome (SS) are cutaneous T-cell lymphomas (CTCL) associated to dismal prognosis, with 5-year survival rates ranging from 47% for stage IIB to 18% for stage IVA2-IVB and with a high tendency to relapse. Allogeneic hematopoietic stem cell transplantation (allo-HCT) is considered the only curative treatment option. Recently, allo-HCT from haploidentical donor (Haplo-HCT) has been increasingly used also in MF/SS patients. We hereby report an update on long-term outcome of MF/SS patients who underwent allo-HCT at our Center from 2001 to 2022, currently including a larger population with an increased proportion of Haplo-HCT. Methods: We retrospectively collected clinical data of all consecutive patients with MF/SS transplanted at our Center between September 2001 and May 2022. Conditioning was based on reduced intensity (RIC) regimens, including flaudarabine/cyclophosphamide/TBI200, pentostatin/TBI200, and fludarabine/melphalan in transplants from HLA-identical sibling and unrelated donor (UD), and the thiotepa/fludarabine/cyclophosphamide/TBI200 regimen in Haplo setting. GvHD prophylaxis consisted of CsA, MMF and ATG. Post-transplant cyclophosphamide was added in Haplo-HCT. Results: As of August 2022, 57 CTCL patients underwent allo-HCT at our Institution: 22 (38.5%) from a HLA-identical sibling, 13 (23%) from a 10/10 matched UD, 12 (21%) from a 9/10 or 8/10 matched UD, 1 (1.8%) from cord blood, and 9 (15.7%) from a Haplo donor. Median age at transplant was 55 years (range 20-67). Indication for allo-HCT was MF in 36 patients (63%) and SS in 21 patients (37%). Median number of previous treatment lines was 6 (range 2-11) with a median time from diagnosis to transplantation of 46 months (10-274). Disease status at transplant was complete remission (CR) in 14 cases (24.5%), partial remission (PR) in 35 (61.5%) and progressive disease (PD) in 8 (14%). Stem cell source was peripheral blood in 53 patients (92.9%), bone marrow in 3 (5.2%) and cord blood in 1 (1.8%). After a median follow up of 81 months, 30 patients (52%) were alive, of whom 23 (76%) in CR. Acute GvHD occurred in 29 patients (51%; grade III-IV in 13, 23%), while chronic GvHD in 19 (33%; moderate/severe in 10 patients, 17%). Cause of death was disease progression in 17 patients (62.5%), acute GvHD in 4 (15%), infection in 2 (7.5%) and other in 4 (15%). In the whole cohort, 5-yr overall survival (OS) and disease-free survival (DFS) were respectively 57.6% (95% CI 44-71) and 37.9% (95% CI 25-51). According to donor type, 5-yr OS was 69%, 39% and 89% and DFS 57%, 19% and 57% for HLA-identical sibling, UD and Haplo, respectively (Figure 1). 5-yr OS was significantly higher in SS versus MF patients (78% vs 47%, p=0.03) and in patients who were in CR at the time of transplant (100% vs 43.5%, p<0.001). In the Haplo setting,.disease status at transplant was CR in 1 pt and PR in 8. After a median follow-up of 26 months, 7 out of 9 patients (78%) were still alive and in CR. Acute GvHD occurred in 6 patients (66%), grade III-IV in 2 (22%), while chronic GvHD occurred in 3 patients (33%), moderate/severe in 1 (11%). Two patients relapsed at +5 and +2 months, of whom the latter died 157 days after HCT. Conclusions: After a median follow up of more than 9 years for alive patients, we confirm that RIC allo-HSCT is a powerful therapeutic strategy in selected patients with advanced CTCL, and particularly in SS. With the limitation of a shorter follow-up, transplant outcomes following allo-HCT from haploidentical donor appear to be associated with very low toxicity, excellent OS and DFS comparable to HLA-identical sibling transplants. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

TCL-456 Real-World Use of Mogamulizumab among Patients With Mycosis Fungoides and Sézary Syndrome Before and During COVID-19 in the United States.

Per label, mogamulizumab (Moga) is administered on days 1, 8, 15, and 22 of the first 28-day cycle (loading) and on days 1 and 15 of each subsequent cycle (maintenance) for adult patients with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) after ≥1 prior systemic therapy. During the COVID-19 pandemic, professional organizations suggested dosing intervals for systemic cancer therapies be extended to limit in-person visits. This study examined the real-world use of Moga before and during the COVID-19 pandemic in the United States. Using the Symphony Health Solutions database, adults with ≥1 diagnosis of MF or SS (ICD-10 CM: C84.0x or C84.1x) and ≥1 Moga claim during 10/1/2018-5/6/2021 were identified. Within the MF (no SS diagnosis) and SS (any SS diagnosis) cohorts, patients were divided into 2 subgroups based on their Moga initiation date: 10/1/2018-3/31/2020 (pre COVID-19) and 4/1/2020-5/6/2021 (COVID-19). Patient characteristics and dosing intervals between Moga doses 1-4 (loading) and between subsequent doses (maintenance) were examined. Overall, 154 MF and 204 SS patients initiated Moga during the study period (mean age: 66.8 and 69.2 years; male: 64% and 55%, respectively). In the MF cohort, 98 and 56 patients were in the pre COVID-19 and COVID-19 subgroups. The mean dosing interval was shorter among patients in the COVID-19 subgroup for both the loading (9.1 vs. 13.2 days) and maintenance doses (15.2 vs. 16.1 days). In the SS cohort, 121 and 83 patients were in the pre COVID-19 and COVID-19 subgroups. Mean loading (9.0 vs. 11.1 days) and maintenance (15.0 vs. 16.8 days) dosing intervals were shorter for patients included in the COVID-19 subgroup. For both MF and SS patients, the COVID-19 subgroup had a higher proportion of patients with ≤10 days between loading doses and ≤21 days between maintenance doses compared to the pre COVID-19 subgroup. Among MF and SS patients, dosing intervals for Moga in loading and maintenance were not extended during the 1st year of the COVID-19 pandemic compared to pre COVID-19. There was a trend towards closer concordance with the label during COVID-19.