Type Of Cutaneous T-cell Lymphoma Research Articles

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.

The Role of the Immune Phenotype in Tumor Progression and Prognosis of Patients with Mycosis Fungoides: A Quantitative Immunohistology Whole Slide Approach.

Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphomas, characterized by mature, skin-tropic CD4+ T-helper cells. In order to study the immune tumor microenvironment in MF patients, we performed immunohistochemical stains on MF biopsies, digitized whole-slide tissue sections, and performed quantitative analysis of the different immune cell subsets to correlate tissue parameters with the clinical data of patients, such as progression-free survival or overall survival. Overall, 35 patients who were treated between 2009 and 2019 and for whom one or more paraffin tissue blocks were available have been included in the present study (58 tissue specimens in total). Conventional immunohistochemistry stains for CD3, CD4, CD8, CD20 and CD30 were used for the analysis of the immune phenotype, and quantitative analysis was performed using QuPath as a quantitative digital pathology tool for bioimage analysis of whole slides. Analysis of tissue parameters for prognostic significance revealed that patients with a stronger infiltration by CD8+ lymphocytes within the tumor cell compartment had a higher risk of disease progression (p = 0.031) and showed a shorter progress-free survival (p = 0.038). Furthermore, a significant association of the percentage of CD30+ cells (median: 7.8%) with the risk of disease progression (p = 0.023) and progression-free survival (p = 0.023) was found. In relation to the clinical features of our patient cohort, a higher risk of disease progression (p = 0.015) and a shorter progression-free survival (p = 0.032) for older patients (>61 years) were observed. Our results demonstrated the prognostic relevance of large-cell transformation in mycosis fungoides and its strong association with the presence of CD30+ lymphocytes. Unlike previous reports, our study suggests an adverse prognostic role for CD8+ T cells in patients with mycosis fungoides. Moreover, our data indicate that the immune phenotype within the tumor microenvironment shows strong temporal heterogeneity and is altered in the course of tumor progression.

Mechlorethamine Hydrochloride Gel in the Treatment of Mycosis Fungoides-Type Cutaneous T-Cell Lymphoma (MF-CTCL): A Focus on Patient Selection and Special Considerations.

Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma (CTCL) and often has an indolent course, particularly for patients presenting with early-stage (patch/plaque) disease. Early-stage MF is primarily managed with skin-directed therapies. Topical mechlorethamine hydrochloride (nitrogen mustard [NM]) gel has increased tolerability compared to prior NM formulations, though contact dermatitis remains a common side effect. The addition of topical steroids can improve tolerability while maintaining the efficacy of NM gel. Real-world experience supports that NM gel also has a role in combination therapy and as adjunctive therapy in advanced-stage disease. Here we review factors that may influence patient selection for use of NM gel, including MF variants, special patient populations, cost effectiveness, and impact on quality of life for patients with MF.

TCL-458 Real-World Treatment Patterns in Patients With Sézary Syndrome in the United States and the Impact of Covid-19.

Sézary syndrome (SS) is an aggressive type of cutaneous T-cell lymphomas (CTCL). Due to its low prevalence, there are limited data on real-world treatment patterns of available SS therapies. Furthermore, recent approvals of new agents for patients with CTCL as well as COVID-19 likely impacted real-world treatment patterns. To examine real-world treatment patterns and the impact of COVID-19 among SS patients treated in 2018-2020 in the United States. Patients in the 2018-2020 Symphony Health Solutions database were classified into 3 groups: ≥1 diagnosis of SS (ICD-10-CM code: C84.1x) in 2018, 2019, and 2020, respectively. Patient characteristics and treatment patterns for National Comprehensive Cancer Network guideline 2.2021 recommended therapies were examined: systemic therapy (e.g., extracorporeal photopheresis (ECP), parenteral, oral agents), skin-directed therapy (SDT, e.g., topical, local radiation, total skin electron beam therapy, phototherapy) and bone marrow transplant. The impact of COVID-19 was assessed using quarterly analysis. The analyses included 869, 882, and 853 SS patients in 2018, 2019, and 2020, respectively (mean age: 66.3, 66.9 and 67.3 years; male: 54.4%, 54.8%, and 55.6%). Overall, systemic therapy increased from 2018-2020 (41.8% to 46.5%), with increased parenteral (20.7% to 28.7%) but decreased ECP (17.0% to 13.5%) usage. SDT increased from 2018-2020 (48.9% to 52.9%), with increased topical (42.3% to 48.3%) but decreased phototherapy (6.3% to 4.1%) usage. ECP, mogamulizumab, and bexarotene were the most prescribed systemic therapies in 2019-2020, with mogamulizumab being the only one with increased usage over time. Quarterly analysis showed decreasing ECP from Q1 to Q4 within each year, with a notable drop in Q2 2020. For parental systemics, there was an increasing trend in 2019 and 2020, but lower utilization in Q4 2020 than in Q3 2020. For oral systemic, there was a notable drop in Q2 2020 but an increased trend in Q3-Q4 2020. This claims analysis indicated increased use in systemic and SDT among SS patients in 2018-2020. The quarterly analysis indicated that the drop in ECP and oral systemic usage in Q2 2020 coincided with the onset of the pandemic, but there was a stable use of parenteral systemic during 2020.

CD8+ T Lymphocytes in Hypopigmented Mycosis Fungoides: Malignant Cells or Reactive Clone?

Hypopigmented mycosis fungoides (HMF) is the most common type of cutaneous T-cell lymphoma in children (Amorim et al., 2018). HMF has a benign course and rarely progresses past localized disease, a striking difference from classic MF, which sometimes progresses from patches to tumors in an average of 12.4 years. On the basis of the identification of dominant clonal T-cell populations, classic MF is seen as a malignancy of CD4+ skin-resident memory cells, whereas HMF is considered to be a malignancy of CD8+ T cells (El-Shabrawi-Caelen et al., 2002).

Skin Tape Strip Proteomics in Mycosis Fungoides Identifies Tumor-Associated Biomarkers

Mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma (CTCL), manifests as patches, plaques, and tumors, representing cutaneous infiltration with skin-homing malignant T-cells. The gold standard for MF diagnosis and disease monitoring is histological examination via punch biopsy. Tape strips (TS) are an emerging, non-invasive approach for exploring biomarkers in skin diseases including atopic dermatitis and psoriasis, with limited exploration in MF (He et al., 2021, He et al., 2020).

859 Skin tape strip proteomics in mycosis fungoides identifies tumor associated biomarkers

Mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma (CTCL), is characterized by malignant T-cell skin infiltration that leads to inflammation and skin barrier defects. Identifying reproducible biomarkers in MF skin is important for monitoring disease activity. Skin tape-stripping is gaining recognition as a non-invasive, easy method for tracking disease biomarkers. Tape strips from lesional (L) and non-lesional (NL) skin of 42 MF patients and matched sites of 21 healthy controls (HC) were analyzed with a proximity extension assay of 183 proteins relevant to oncology and inflammation.

TOX Expression in Mycosis Fungoides and Sezary Syndrome

Mycosis fungoides (MF) and Sezary syndrome (SS) are the two most common type of cutaneous T-cell lymphoma (CTCL). Currently, no markers can be clearly related to prognosis or to differential diagnosis between early stages and inflammatory benign diseases (IBD). The thymocyte selection-associated high mobility group box factor (TOX), has been proposed as a possible marker in differential diagnosis between early CTCL stages and IBD. Recently TOX has been related to prognosis. We aimed to investigate whether TOX may be a diagnostic or prognostic marker. MF and SS biopsies between 2010 and 2020 were retrieved. New tissues slides were stained with an anti-TOX antibody, (Clone NAN448B). On each slide, 5 fields were examined at high magnification (400×), to evaluate the percentage of marker-positivity in a quantitative way. Thirty-six patients (12 females and 24 males) and 48 biopsies were collected. Nine patients had multiple biopsies. TOX expression in MF/SS cases showed an increase from early to advanced phases. TOX was not regarded as a prognostic marker due to the absence of significant changes by comparing early MF cases with reactive conditions. TOX statistical significance increased in patients alive with disease and in those dead of disease (p = 0.013 and = 0.0005, respectively) as compared with patients in complete remission. Our results show that TOX should be regarded more as a prognostic than a diagnostic marker.

Real-world treatment patterns in patients with Sézary syndrome in the United States and the impact of Covid-19.

e19578 Background: Sézary syndrome (SS) is an aggressive type of cutaneous T-cell lymphomas (CTCL). Due to its low prevalence, there are limited data on real-world treatment patterns of currently available SS therapies. Furthermore, recent approvals of new agents for patients with CTCL as well as COVID-19 likely impacted real-world treatment patterns. Objective: To examine real-world treatment patterns and the impact of COVID-19 among SS patients treated in 2018-2020 in the US. Methods: Patients with public or private insurance in the 2018-2020 Symphony Health Solutions database were classified into 3 groups: ≥1 diagnosis of SS (ICD-10-CM code: C84.1x) in 2018, 2019, and 2020, respectively. Patient characteristics and treatment patterns for all therapies recommended by the National Comprehensive Cancer Network guidelines version 2.2021 were examined: systemic therapy (e.g., extracorporeal photopheresis (ECP), parenteral, or oral agents), skin-directed therapy (SDT, e.g., topical, local radiation, total skin electron beam therapy, or phototherapy) and bone marrow transplant. The impact of COVID-19 was assessed via quarterly analysis. National drug codes, current procedural terminology and healthcare common procedure coding system codes were used to identify all treatments. Results: The analyses included 869, 882, and 853 SS patients in 2018, 2019, and 2020, respectively (mean age: 66.3, 66.9 and 67.3 years; male: 54.4%, 54.8%, and 55.6%). Overall, systemic therapy increased from 2018 to 2020 (41.8% to 46.5%), with increased parenteral (20.7% to 28.7%) but decreased ECP (17.0% to 13.5%) usage. SDT increased from 2018 to 2020 (48.9% to 52.9%), with increased topical (42.3% to 48.3%) but decreased phototherapy (6.3% to 4.1%) usage. ECP, mogamulizumab, and bexarotene were the most prescribed systemic therapies in 2019-2020, with mogamulizumab being the only one with increased usage over time. Quarterly analysis showed a decreasing ECP from Q1 to Q4 within each year, with a notable drop in Q2 2020. For parental systemics, there was an increasing trend in 2019 and 2020, but utilization in Q4 2020 was lower than that of Q3 2020. For oral systemic, there was a notable drop in Q2 2020 but an increased trend in Q3-Q4 2020. Conclusions: This claims analysis indicated increased use in systemic and SDT among SS patients in 2018-2020. The quarterly analysis indicated that the drop in ECP and oral systemic usage in Q2 2020 coincided with the onset of the pandemic, but there was a stable use of parenteral systemic during 2020.

Single-Cell RNA Sequencing Unveils the Clonal and Transcriptional Landscape of Cutaneous T-Cell Lymphomas.

Clonal malignant T lymphocytes constitute only a fraction of T cells in mycosis fungoides skin tumors and in the leukemic blood of Sézary syndrome, the classic types of cutaneous T-cell lymphomas. However, lack of markers specific for malignant lymphocytes prevents distinguishing them from benign T cells, thus delaying diagnosis and the development of targeted treatments. Here we applied single-cell methods to assess the transcriptional profiles of both malignant T-cell clones and reactive T lymphocytes directly in mycosis fungoides/Sézary syndrome patient samples. Single-cell RNA sequencing was used to profile the T-cell immune repertoire simultaneously with gene expression in CD3+ lymphocytes from mycosis fungoides and healthy skin biopsies as well as from Sézary syndrome and control blood samples. Transcriptional data were validated in additional advanced-stage mycosis fungoides/Sézary syndrome skin and blood samples by immunofluorescence microscopy. Several nonoverlapping clonotypes are expanded in the skin and blood of individual advanced-stage mycosis fungoides/Sézary syndrome patient samples, including a dominant malignant clone as well as additional minor malignant and reactive clones. While we detected upregulation of patient-specific as well as mycosis fungoides- and Sézary syndrome-specific oncogenic pathways within individual malignant clones, we also detected upregulation of several common pathways that included genes associated with cancer cell metabolism, cell-cycle regulation, de novo nucleotide biosynthesis, and invasion. Our analysis unveils new insights into mycosis fungoides/Sézary syndrome pathogenesis by providing an unprecedented report of the transcriptional profile of malignant T-cell clones in the skin and blood of individual patients and offers novel prospective targets for personalized therapy.

Primary cutaneous lymphoma: the 2018 update of the WHO-EORTC classification

Primary cutaneous lymphomas are a heterogeneous group of cutaneous T-cell lymphomas (CTCL) and cutaneous B-cell lymphomas (CBCL) that present in the skin with no evidence of extracutaneous disease at the time of diagnosis. In the last decade the 2005 WHO-EORTC consensus classification has served as a golden standard for the diagnosis and classification of these conditions. Recently, an updated version of the WHO-EORTC was published. This classification contains several new entities, including primary cutaneous acral CD8+ T-cell lymphoma and EBV-positive mucocutaneous ulcer, while other conditions were slightly modified. Herein, the characteristic features of the different types of CTCL and CBCL are presented, differences with previous classification schemes discussed and the results of more recent molecular studies with clinical implications for these conditions reviewed. In addition, an update of the frequency and survival of the different types of primary cutaneous lymphomas is provided.

Tissue levels of suppressor of cytokine signaling-3 (SOCS-3) in mycosis fungoides

Mycosis fungoides (MF) is a type of cutaneous T-cell lymphoma with proposed multifactorial etiology. Suppressor of cytokine signaling-3 (SOCS-3) is one of the proteins expressed in MF. Its exact role in disease pathogenesis has not yet been thoroughly investigated. This study aimed to assess the expression of SOCS-3 in patients’ skin with mycosis fungoides to elucidate their possible role in the pathogenesis in MF. 30 patients with mycosis fungoides and 30 age and sex-matched healthy controls were included. After clinical examination, tissue levels of SOCS-3 were measured by ELISA. The level of expression of SOCS-3 was significantly upregulated in the lesional tissue compared to perilesional SOCS-3 level in patients’ group (P < 0.001), and both levels were higher than the SOCS-3 level in control group (P < 0.001). In addition, there was a statistically significant positive correlation between lesional SOCS-3 level and itching in patients’ group (P < 0.001). Regarding lesional and perilesional SOCS-3 levels in each stage, there was a significant increase in lesional SOCS-3 levels in comparison to perilesional level whether in stage Ia, Ib, and IIa; (P < 0.001), (P < 0.001) and (P < 0.001), respectively. Increased tissue levels of SOCS-3 patients with mycosis fungoides point to a role that SOCS-3 could play in its pathogenesis. Also, high levels of SOCS-3 in MF patients with itching suggest a role in the pathogenesis of this symptom. These findings may prove helpful in formulating a new treatment modality in addition to the current treatment of MF.

Mycosis fungoides in pediatric population: comprehensive review on epidemiology, clinical presentation, and management.

Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma. However, it is rare in pediatric population. Most of the cases of pediatric MF present with hypopigmented patches and/or various other forms, which may often mimic common childhood dermatoses, thereby causing a delay in the diagnosis. There are no established treatment guidelines for pediatric MF. As the progression of childhood MF is extremely rare and it has an indolent course, it is usually diagnosed at an early stage (IA, IB, IIA), and hence phototherapy with a response rate of >80% is a well-established effective treatment in children. However, as recurrences are frequently seen on stopping the therapies, a maintenance regimen and long-term follow-up is equally important. This article reviews the epidemiological factors, clinical presentations, diagnosis, and various treatment modalities used in pediatric MF. We analyzed and compared the data of almost 616 childhood MF cases from various studies undertaken from 1988 to 2021.

The Role of microRNA in Pathogenesis, Diagnosis, Different Variants, Treatment and Prognosis of Mycosis Fungoides.

Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma (CTCL), accounting for approximately 50% of all CTCLs. Although various molecular changes in MF have been described in existing studies, no obvious disease-specific changes have been found thus far. microRNAs (miRs) are short, noncoding RNA molecules that play roles in the post-transcriptional regulation of oncogenes and tumor suppressor genes in various diseases. Recently, there has been rapidly expanding experimental evidence for the role of miRs in the progression, early diagnosis, prognosis prediction for MF. Efforts to improve early diagnosis and develop personalized therapy options have become more important in recent years. Here, we provide an overview and update of recent advances regarding miRs associated with MF. Furthermore, we provide insights into future opportunities for miR-based therapies.

Folliculotropic mycosis fungoides: Clinicopathological features

Folliculotropic variant of mycosis fungoides (MF) is a rare type of cutaneous T-cell lymphoma, detected in less than 10% of patients with MF. It occurs mostly in elderly adults, and usually involves the head, neck region, and upper trunk. The diagnosis of this disease is based on a combination of clinical presentation, histology, and T-cell monoclonality. Identification of this variant of disease is important because it may imply worse prognosis and require more intensive treatment.

Increased Chlormethine-Induced DNA Double-Stranded Breaks in Malignant T Cells from Mycosis Fungoides Skin Lesions

Mycosis fungoides (MF) is a type of cutaneous T-cell lymphoma. Chlormethine (CL) is recommended as first-line therapy for MF, with a major purpose to kill tumor cells through DNA alkylation. To study the extent of treatment susceptibility and tumor specificity, we investigated the gene expression of different DNA repair pathways, DNA double-stranded breaks, and tumor cell proliferation of clonal TCR Vβ+ tumor cell populations in cutaneous T-cell lymphoma skin cells on direct exposure to CL. Healthy human T cells were less susceptible to CL exposure than two T-lymphoma cell lines, resulting in higher proportions of viable cells. Interestingly, in T cells from MF lesions, we observed a downregulation of several important DNA repair pathways, even complete silencing of RAD51AP1, FANC1, and BRCA2 involved in homologous recombination repair. In the presence of CL, the double-stranded DNA breaks in malignant MF skin T cells increased significantly as well as the expression of the apoptotic gene CASP3. These data point toward an important effect of targeting CL on MF skin tumor T cells, which support CL use as an early cutaneous lymphoma treatment and can be of synergistic use, especially beneficial in the setting of combination skin-directed therapies for cutaneous T-cell lymphoma.

Roles of OX40 and OX40 Ligand in Mycosis Fungoides and Sézary Syndrome.

Mycosis fungoides (MF) and Sézary syndrome (SS), the most common types of cutaneous T-cell lymphoma (CTCL), are characterized by proliferation of mature CD4+ T-helper cells. Patients with advanced-stage MF and SS have poor prognosis, with 5-year survival rates of 52%. Although a variety of systemic therapies are currently available, there are no curative options for such patients except for stem cell transplantation, and thus the treatment of advanced MF and SS still remains challenging. Therefore, elucidation of the pathophysiology of MF/SS and development of medical treatments are desired. In this study, we focused on a molecule called OX40. We examined OX40 and OX40L expression and function using clinical samples of MF and SS and CTCL cell lines. OX40 and OX40L were co-expressed on tumor cells of MF and SS. OX40 and OX40L expression was increased and correlated with disease severity markers in MF/SS patients. Anti-OX40 antibody and anti-OX40L antibody suppressed the proliferation of CTCL cell lines both in vitro and in vivo. These results suggest that OX40–OX40L interactions could contribute to the proliferation of MF/SS tumor cells and that the disruption of OX40–OX40L interactions could become a new therapeutic strategy for the treatment of MF/SS.

Hypopigmented Mycosis Fungoides in Younger Patients: A Mimicker of Common Hypopigmented Inflammatory Rashes

Hypopigmented mycosis fungoides (HMF) is a rare type of cutaneous T-cell lymphoma (CTCL), a non-classic variant among up to 50 variants of mycosis fungoides (MF), that typically affects younger individuals in the second to fourth decades of life of darker skin types. The presenting cutaneous findings of HMF can be mistaken for and mimic other commonly seen hypopigmented skin disorders and misdiagnosed by an untrained eye in the dermatologic and general practice settings. MF has many different variants, and affects both children and adults. For the purpose of this article, the discussion will be limited to HMF specifically presenting in younger patients. With limited literature on HMF commonly affecting the younger generations, knowledge of how to diagnose and treat this cutaneous malignancy is lacking among clinicians. The goal of this CME article is to provide more awareness to clinicians on this rare form of CTCL, thus improving patient care through early detection and treatment in this patient population.

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

Importance: Sézary syndrome (SS) is a rare, leukemic type of cutaneous T-cell lymphoma (CTCL), which can be successfully controlled with extracorporeal photopheresis (ECP). Reliable biomarkers to objectively monitor the response to ECP in patients with SS are missing. Objective: 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 address the question if the magnitude of the effect can be associated with the treatment response to ECP in SS patients. Materials and Methods: We collected blood samples before starting therapy and after an average of 9 months of uninterrupted ECP treatment from a case-series of 13 SS patients (8 women, 5 men). This is a single-centre study. All patients were diagnosed according to EORTC-WHO criteria and gave written informed consent to the use of their material and data for research purposes. Blood from healthy volunteers was obtained anonymously from a blood bank. Number of NK cells by flow cytometry, ADCC activity by LDH release assay and flow cytometry, treatment response based on blood tumour staging. Results: NK cell numbers were reduced in SS patients compared to healthy individuals and showed a tendency of recovery after long-term ECP treatment, independent of the response to treatment. Patients with marginal increase (≤1.5 AU-fold) or lack of increase in ADCC activity failed to respond to treatment, while an increase in ADCC efficacy paralleled a positive response to ECP. Conclusions and Relevance: NK-mediated ADCC is selectively enhanced and can serve as a reliable biomarker to objectively monitor response to ECP in patients with SS.

Bio-O2-04 - 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. We assessed numbers of NK cells, ADCC activity, and treatment response based on blood tumor staging in a cohort of 13 SS patients (8 women, 5 men) treated with ECP as a first-line therapy. Blood samples were collected before treatment start and after an average of 9 months of uninterrupted ECP treatment. NK cell numbers were reduced in SS patients compared to healthy individuals and showed a tendency of recovery after long-term ECP treatment, independent of the clinical response to treatment. Patients with marginal increase (≤1.5 AU-fold) or lack of increase in ADCC activity failed to respond clinically to treatment, while patients with an increased ADCC activity showed a reduction in blood tumor burden. NK-mediated ADCC is selectively enhanced and might be a mechanism underlying the effect of ECP while in addition it can possibly serve as a reliable biomarker to objectively monitor response to ECP in patients with SS.