Sézary Syndrome Research Articles

Real-world study of pegylated interferon α-2a to treat mycosis fungoides/Sézary syndrome using time to next treatment as a measure of clinical benefit: an EORTC CLTGstudy.

Mycosis fungoides (MF) and Sézary syndrome (SS) are chronic malignant diseases that typically necessitate diverse strategies to achieve remission. Systemic interferon (IFN)-α (subtypes 2a and 2b) has been used to treat MF/SS since 1984; however, its production was recently stopped. The recombinant pegylated (PEG) form of IFN-α-2a remains the only alternative IFN treatment, although it has not been approved for use in MF/SS. To assess the effectiveness and safety of PEG-IFN-α-2a in monotherapy and in combination with other treatments using time to next treatment (TTNT) as a measure of clinical therapeutic benefit in a real-world setting. We conducted an international, multicentre retrospective study of patients with MF and SS (of any stage) treated with PEG-IFN-α-2a from July 2012 to February 2022. Patients were included across 11 centres in 10 countries. The primary endpoints were to determine the TTNT of PEG-IFN-α-2a and adverse events (AEs) in MF/SS. In total, 105 patients were included [mean (SD) age 61 (13.1) years]; 42 (40.0%) had stage IA-IIA and 63 (60.0%) had stage IIB-IVB disease. PEG-IFN-α-2a was combined with other therapies in 67 (63.8%) patients, most commonly with extracorporeal photopheresis (36%) and bexarotene (22%). Patients with stage I-IIA disease achieved an overall response rate (ORR) of 57%; the ORR in those with stage IIB-IVB disease was 51%. Combination treatment resulted in a median TTNT of 10.4 months (range 0.6-50.7) vs. 7.0 months (range 0.7-52.4) for those who received monotherapy (P < 0.01). Overall, the mean (SD) TTNT was 9.2 (10.6) months and the ORR was 53.3% (n = 56). A complete response was seen in 13% of patients and a partial response in 40%. AEs were described in 68.6% (n = 72) of patients. Flu-like symptoms (n = 28; 26.7%), lymphopenia (n = 24; 22.9%) and elevated liver function (n = 10; 9.5%) were the most frequently reported. Grade 3-4 AEs were reported in 23 (21.9%) patients, mostly related to myelosuppression. PEG-IFN-α-2a for MF/SS resulted in an ORR of 53.3% and a mean (SD) TTNT of 9.2 (10.6) months. Combination regimens were superior to monotherapy and doses of 180 µg PEG-IFN-α-2a weekly were related to a higher ORR.

Predictive and Prognostic Biomarkers in Patients With Mycosis Fungoides and Sézary Syndrome (BIO-MUSE): Protocol for a Translational Study.

Cutaneous T-cell lymphoma (CTCL) is a rare group of lymphomas that primarily affects the skin. Mycosis fungoides (MF) is the most common form of CTCL and Sézary syndrome (SS) is more infrequent. Early stages (IA-IIA) have a favorable prognosis, while advanced stages (IIB-IVB) have a worse prognosis. Around 25% of patients with early stages of the disease will progress to advanced stages. Malignant skin-infiltrating T-cells in CTCL are accompanied by infiltrates of nonmalignant T-cells and other immune cells that produce cytokines that modulate the inflammation. Skin infection, often with Staphylococcus aureus, is frequent in advanced stages and can lead to sepsis and death. S. aureus has also been reported to contribute to the progression of the disease. Previous reports indicate a shift from Th1 to Th2 cytokine production and dysfunction of the skin barrier in CTCL. Treatment response is highly variable and often unpredictable, and there is a need for new predictive and prognostic biomarkers. This prospective translational study aims to identify prognostic biomarkers in the blood and skin of patients with MF and SS. The Predictive and Prognostic Biomarkers in Patients With MF and SS (BIO-MUSE) study aims to recruit 120 adult patients with MF or SS and a control group of 20 healthy volunteers. The treatments will be given according to clinical routine. The sampling of each patient will be performed every 3 months for 3 years. The blood samples will be analyzed for lactate dehydrogenase, immunoglobulin E, interleukins, thymus and activation-regulated chemokine, and lymphocyte subpopulations. The lymphoma microenvironment will be investigated through digital spatial profiling and single-cell RNA sequencing. Microbiological sampling and analysis of skin barrier function will be performed. The life quality parameters will be evaluated. The results will be evaluated by the stage of the disease. Patient inclusion started in 2021 and is still ongoing in 2023, with 18 patients and 20 healthy controls enrolled. The publication of selected translational findings before the publication of the main results of the trial is accepted. This study aims to investigate blood and skin with a focus on immune cells and the microbiological environment to identify potential new prognostic biomarkers in MF and SS. ClinicalTrials.gov NCT04904146; https://www.clinicaltrials.gov/study/NCT04904146. DERR1-10.2196/55723.

The Role of Cytokines in Cutaneous T Cell Lymphoma: A Focus on the State of the Art and Possible Therapeutic Targets.

Cutaneous T cell lymphomas (CTCLs), encompassing mycosis fungoides (MF) and Sézary syndrome (SS), present a complex landscape influenced by cytokines and cellular responses. In this work, the intricate relationship between these inflammatory proteins and disease pathogenesis is examined, focusing on what is known at the clinical and therapeutic levels regarding the most well-known inflammatory mediators. An in-depth look is given to their possible alterations caused by novel immunomodulatory drugs and how they may alter disease progression. From this narrative review of the actual scientific landscape, Interferon-gamma (IFN-γ) emerges as a central player, demonstrating a dual role in both promoting and inhibiting cancer immunity, but the work navigates through all the major interleukins known in inflammatory environments. Immunotherapeutic perspectives are elucidated, highlighting the crucial role of the cutaneous microenvironment in shaping dysfunctional cell trafficking, antitumor immunity, and angiogenesis in MF, showcasing advancements in understanding and targeting the immune phenotype in CTCL. In summary, this manuscript aims to comprehensively explore the multifaceted aspects of CTCL, from the immunopathogenesis and cytokine dynamics centred around TNF-α and IFN-γ to evolving therapeutic modalities. Including all the major known and studied cytokines in this analysis broadens our understanding of the intricate interplay influencing CTCL, paving the way for improved management of this complex lymphoma.

Fine-Tuning Low-Dose Total Skin Electron Therapy for Optimal Management of Cutaneous T-Cell Lymphoma: A Comparative Analysis of Regimens

BackgroundLow-dose total skin electron beam therapy (TSEBT) is a proven treatment for managing cutaneous T-cell lymphoma (CTCL) and Sezary syndrome with skin burden. We performed a retrospective comparison of response rates and time to progression for patients receiving low-dose TSEBT based on dose per fractionation, total dose, and stage. MethodsOne hundred and ten patients with CTCL and Sezary syndrome were treated with 135 courses of low-dose (400-1500 cGy) TSEBT or STSEBT (subtotal skin electron therapy) at multiple centers of a single institution between 8/2003 and 6/2023. Patients were stratified according to total dose, dose per fraction, and stage. ResultsThe median follow-up was 301 days [IQR 141, 767]. The median age at treatment was 69.9 years (range 29.7 – 96.5). T-stage distribution was as follows: 3 (2.7%) T1, 74 (67.3%) T2, 16 (14.5%) T3, and 17 (15.5%) T4. AJCC 8th edition Stage distribution was as follows: 3 (2.7%) IA, 53 (48.2%) IB, 3 (2.7%) IIA, 16 (14.5%) IIB, 8 (7.3%) IIIA, 19 (17.3%) IVA, 8 (7.3%) IVB. There was no significant difference in disease distribution between patients treated with different fractionation schemes. The overall response rate was 89.6%. Forty-four courses (32.6%), 34 courses (25.2%), and 43 (31.9%) resulted in a complete, near-complete, and partial response, respectively. Fourteen courses (10.4%) resulted in no clinical response. For all patients, the median time to response was 43.0 days (IQR 23.0 – 70). The median time to skin progression for all patients was 107.5 days [IQR 67.8 – 233.5]. ConclusionsThis analysis demonstrated that CTCL patients treated with low-dose RT delivered over various fractionation schemes had similar overall response rates and median time to progression.

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.

Long term outcomes of nonmyeloablative allogeneic stem cell transplantation with TSEB TLI and ATG for Mycosis Fungoides and Sezary Syndrome

Advanced stage (IIB-IVB) Mycosis Fungoides (MF) and Sezary Syndrome (SS) have a poor prognosis with median survival <5 years. We report long-term outcomes of a non-myeloablative allogeneic stem cell transplantation regimen consisting of total skin electron beam therapy, total lymphoid irradiation and antithymocyte globulin. Our prospective cohort consisted of 41 patients with a higher proportion of MF (34MF, 7SS). Acute GVHD Grade 2 to 4 was seen in 31.7% and chronic GVHD Grade 2 to 4 in 24%. The cumulative incidence of non-relapse mortality was 9.8% at 1 year and 12.6% at 2 years. At Day +90 post-transplant 66% of patients had a complete response (CR). With a median post-transplant follow up of 5.27 years, the 5-year overall survival rate was 37.7% (MF 36.7%, SS 57.1%). The 5-year cumulative incidence of progressive disease or relapse was 52.7% in all patients but only 20.8% in those with CR at transplant compared to 70.6% in those not in CR at transplant (p = 0.006). Long term survival is possible in advanced MF and SS with non-myeloablative transplantation and outcomes are improved in patients with CR at transplant.

Extracorporeal Photopheresis in Dermatological Diseases.

Extracorporeal photopheresis (ECP) is an apheresis procedure that is conventionally used as a first-line treatment for cutaneous and leukemic subtypes of T-cell lymphoma, such as Sezary's syndrome and mycosis fungoides. Over the past three decades, its immunotherapeutic properties have been tested on a variety of autoimmune conditions, including many dermatologic diseases. There is ample evidence of ECP's ability to modify leukocytes and alter cytokine production for certain dermatologic diseases that have been refractory to first-line treatments, such as atopic dermatitis. However, the evidence on the efficacy of ECP for the treatment of these dermatologic diseases is unclear and/or lacks sufficient evidence. The purpose of this paper is to review the literature on the utilization and clinical efficacy of ECP in the treatment of several [autoimmune] dermatologic diseases and discuss its applications, guidelines, recommendations, and future implementation for dermatologic diseases.

Role of IL-4 and IL-13 in Cutaneous T Cell Lymphoma.

The interleukins IL-4 and IL-13 are increasingly recognized contributors to the pathogenesis of cutaneous T cell lymphomas (CTCLs), and their role in disease-associated pruritus is accepted. The prevailing Th2 profile in advanced CTCL underscores the significance of understanding IL-4/IL-13 expression dynamics from the early stages of disease, as a shift from Th1 to Th2 may explain CTCL progression. Targeted agents blocking key cytokines of type 2 immunity are established therapeutics in atopic disorders and have a promising therapeutic potential in CTCL, given their involvement in cutaneous symptoms and their contribution to the pathogenesis of disease. IL-4, IL-13, and IL-31 are implicated in pruritus, offering therapeutic targets with dupilumab, tralokinumab, lebrikizumab, and nemolizumab. This review analyzes current knowledge on the IL-4/IL-13 axis in mycosis fungoides and Sezary syndrome, the most common types of CTCL, examining existing literature on the pathogenetic implications with a focus on investigational treatments. Clinical trials and case reports are required to shed light on novel uses of medications in various diseases, and ongoing research into the role of IL-4/IL-13 axis blockers in CTCL therapy might not only improve the management of disease-related pruritus but also provide in-depth insights on the pathophysiologic mechanisms of CTCL.

Sezary syndrome revealed by PD‐L1 blockade for tumor stage mycosis fungoides

AbstractCutaneous T‐cell lymphomas (CTCLs) are unique non‐Hodgkin lymphomas due to the proliferation of skin‐homing T cells. Sezary syndrome (SS), a subtype of CTCL, typically presents as erythroderma with specific blood involvement and seldomly evolves from tumor‐stage mycosis fungoides (MF). The article examines the case of a 62‐year‐old female patient who developed SS while under atezolizumab treatment for tumor‐stage transformed MF. Postdiagnosis, she underwent treatments including topical corticosteroids, phototherapy, and other drug regimens, experiencing both complete responses and relapses over the years. Three years postdiagnosis, her condition deteriorated with facial tumor lesions, confirmed as MF. Despite multiple treatments, including oral drugs, radiation therapy, and a range of other therapeutic agents, her condition did not show sustained improvement. The patient was then administered atezolizumab, an antibody targeting programmed death ligand 1 (PD‐L1). Although initial results saw a disappearance of her skin tumors, the subsequent cycles led to symptoms consistent with stage IVA1 SS, coupled with an evident shift in malignant T‐cell clone dominance. Atezolizumab, a humanized monoclonal antibody, impedes the interaction of PD‐L1 with its receptor PD1, which is notably overexpressed in malignant T‐cells of SS. This case illustrates the emergence of SS during the course of atezolizumab treatment for a transformed MF condition, underlining the potential risks and complexities in using PD‐L1 inhibitors for treating CTCL.

Computational Flow Cytometry Accurately Identifies Sezary Cells Based on Simplified Aberrancy and Clonality Features

Flow cytometric identification of circulating neoplastic cells (Sezary cells) in patients with mycosis fungoides (MF) and Sezary syndrome (SS) is essential for diagnosis, staging and prognosis. While recent advances have improved the performance of this laboratory assay, the complex immunophenotype of Sezary cells and overlap with reactive T cells demand a high level of analytic expertise. We utilized machine learning to simplify this analysis using only 2 pre-defined Sezary cell-gating plots. We studied 114 samples from 59 patients with SS/MF, and 66 samples from unique patients with inflammatory dermatoses. A single dimensionality reduction plot highlighted all T-cell receptor constant β chain-restricted (clonal) CD3+/CD4+ T-cells detected by expert analysis. On receiver operator curve analysis, an aberrancy scale feature computed by comparison with controls (area under the curve = 0.98) outperformed loss of CD2 (0.76), CD3 (0.83), CD7 (0.77) and CD26 (0.82) in discriminating Sezary cells from reactive CD4+ T cells. Our results closely mirrored those obtained by exhaustive expert analysis for event classification (positive percent agreement = 100%, negative percent agreement = 99%) and Sezary cell quantitation (regression slope = 1.003, R squared = 0.9996). We demonstrate the potential of machine learning to simplify the accurate identification of Sezary cells.

Staphylococcus aureus induces drug resistance in cancer T cells in Sézary syndrome

AbstractPatients with Sézary syndrome (SS), a leukemic variant of cutaneous T-cell lymphoma (CTCL), are prone to Staphylococcus aureus infections and have a poor prognosis due to treatment resistance. Here, we report that S aureus and staphylococcal enterotoxins (SE) induce drug resistance in malignant T cells against therapeutics commonly used in CTCL. Supernatant from patient-derived, SE-producing S aureus and recombinant SE significantly inhibit cell death induced by histone deacetylase (HDAC) inhibitor romidepsin in primary malignant T cells from patients with SS. Bacterial killing by engineered, bacteriophage-derived, S aureus–specific endolysin (XZ.700) abrogates the effect of S aureus supernatant. Similarly, mutations in major histocompatibility complex (MHC) class II binding sites of SE type A (SEA) and anti-SEA antibody block induction of resistance. Importantly, SE also triggers resistance to other HDAC inhibitors (vorinostat and resminostat) and chemotherapeutic drugs (doxorubicin and etoposide). Multimodal single-cell sequencing indicates T-cell receptor (TCR), NF-κB, and JAK/STAT signaling pathways (previously associated with drug resistance) as putative mediators of SE-induced drug resistance. In support, inhibition of TCR-signaling and Protein kinase C (upstream of NF-κB) counteracts SE-induced rescue from drug-induced cell death. Inversely, SE cannot rescue from cell death induced by the proteasome/NF-κB inhibitor bortezomib. Inhibition of JAK/STAT only blocks rescue in patients whose malignant T-cell survival is dependent on SE-induced cytokines, suggesting 2 distinct ways SE can induce drug resistance. In conclusion, we show that S aureus enterotoxins induce drug resistance in primary malignant T cells. These findings suggest that S aureus enterotoxins cause clinical treatment resistance in patients with SS, and antibacterial measures may improve the outcome of cancer-directed therapy in patients harboring S aureus.

Diagnosis and management of erythroderma; a systematic review

Erythroderma, a condition characterized by diffuse erythema and scaling covering at least 90 percent of the skin\&amp;apos;s surface, poses a serious and potentially life-threatening threat. This systematic study aimed to establish diagnosis and management guidelines for erythroderma. Following PRISMA guidelines, a comprehensive review was conducted using PubMed/Medline, Scopus, and Embase databases focusing on English-language articles from 2010 to 2023. From 279 studies, seven articles were included, mainly comprising surveys and analyses of national databases. Erythroderma, as a clinical sign, can manifest as a consequence of various cutaneous and systemic diseases, drug hypersensitivity reactions, and rarely, Sezary syndrome. In pediatric patients, the clinical presentation encompasses a spectrum of acquired and inherited diseases, including infections, inflammatory skin conditions, ichthyoses, and congenital immunodeficiencies. Diagnosing erythroderma proves challenging due to its syndromatic nature, presenting with nonspecific clinical features. Dermatologists must diligently seek cause-oriented clues, employing multiple biopsies to enhance diagnostic accuracy. Initial management should include nutritional expert evaluation, assessment of fluid imbalance, skin barrier maintenance, sedative anti-histamines, and exclusion of secondary bacterial infection. Given its life-threatening potential, erythroderma might necessitate hospitalization. This study provides valuable insights into the complexities of erythroderma diagnosis and highlights essential considerations for effective management.

Varied presentations of primary cutaneous lymphoma: A case series from a tertiary care center in South India.

Recent studies indicate an upsurge of primary cutaneous lymphoma (PCL) in the Indian population. Of late, we too have come across varied presentations of PCL in relatively younger individuals. Hence, we decided to study the clinical and immunohistological profile of patients with PCL in our department. All cases diagnosed as PCL from October 2016 to October 2019 were included. Clinical details, complete blood count, peripheral smear, imaging, histopathology, and immunohistochemistry of skin specimens were analyzed. Lymph node biopsy and bone marrow studies were done in most cases. Human T lymphotropic virus-1 (HTLV1) serology was done in 10 cases. Of the 24 patients with PCL, 12 were below 50 years of age. Twenty-three patients (95.8%) had T-cell lymphoma and only one had B-cell PCL. Mycosis fungoides (MF) (n = 17; 71%) was the most common type of PCL. There were two (8.3%) cases each of adult T-cell lymphoma/leukemia (ATLL) and Sezary syndrome. MF had varied clinical morphology at presentation and variable clinical outcomes. Both cases of ATLL had features of immunosuppression in the form of infective dermatoses. We observed an increased proportion of T-cell type of PCL, with the age of onset being relatively early. HTLV-1 positivity was noted in three out of the 10 cases tested. More studies are needed to determine the factors responsible for the younger age of onset of PCL and the role of HTLV-1 infection in the development of PCL.

Flow Cytometry in Mature T- and NK-cell Neoplasms: A Retrospective Descriptive Study from a Tertiary Care Cancer Centre in Kerala, India

Introduction: Mature T- and NK-cell Neoplasms (MTNKN) constitute around 12% of all non-Hodgkin lymphomas. They have a variable clinical course, ranging from indolent to highly aggressive tumours. Flow cytometry immunophenotyping is crucial for the diagnosis, staging, and classification of MTNKN. Aim: To determine the frequency, morphologic, and immunophenotypic profile of various subtypes of MTNKN diagnosed by flow cytometry. Materials and Methods: This was a retrospective descriptive study conducted at the Department of Pathology, Regional Cancer Centre, Thiruvananthapuram, Kerala, India. All cases of MTNKN diagnosed by flow cytometry in peripheral blood, bone marrow aspirates, or body fluids from January 1, 2010 to June 30, 2020 (10.5 years duration) at the cancer centre were studied. The morphology of tumour cells and immunophenotype by flow cytometry were analysed. Clinical parameters (lymphadenopathy, hepatosplenomegaly, skin lesions, effusions, B symptoms) and follow-up details, including Progression-free Survival (PFS) and Overall Survival (OS), were also noted. Descriptive statistics for continuous variables and frequencies and percentages for categorical variables were obtained. The Kaplan-Meier method for survival plots was used. Results: Mature T- and NK-cell neoplasms constituted 83 cases. The median age of patients was 56 years. The majority of patients were males (n=49). Adult T-cell Leukaemia/Lymphoma (ATLL) (n=50) constituted the most common subtype, followed by Mycosis fungoides/Sezary syndrome (MF/SS) (n=14), T-cell Large Granular Lymphocytic Leukaemia (T-LGLL) (n=7), T-cell Prolymphocytic Leukaemia (T-PLL) (n=4), Aggressive NK-cell Leukaemia (ANKL) (n=3), Hepatosplenic T-cell Lymphoma (HSTL) (n=3), and Anaplastic Large Cell Lymphoma (ALCL) (n=2). OS and PFS at three years were 22.3% and 16.6%, respectively. Conclusion: Mature T- and NK-cell neoplasms presenting as leukaemia is rare. ATLL was the most common subtype of MTNKN. Flower cells, Sezary cells, and prolymphocytes are useful morphological clues for diagnosis. Immunophenotyping by flow cytometry, along with clinicopathologic correlation, is crucial for the diagnosis and subclassification of MTNKN. All subtypes except T-LGLL show inferior PFS and OS.

Análisis de supervivencia y factores pronósticos en una serie de 148 casos de linfomas cutáneos de células T

Background and ObjectiveCutaneous T-cell lymphomas (CTCL) such as mycosis fungoides (MF) and Sézary syndrome (SS) are rare lymphomas with varying prognoses. The aim of the study was to describe the survival of a cohort of patients with MF/SS and evaluate the prognostic factors impacting disease survival. Materials and MethodsAll cases of MF/SS diagnosed from 2008 through 2022 were retrospectively analyzed. The demographic variables, histological parameters, and analytical data were analyzed too. Progression-free survival (PFS) and disease-specific survival (DSS) were calculated. ResultsA total of 148 cases were included. A total of 121 (82%) and 27 cases were diagnosed with MF, and SS, respectively. A total of 37 patients (25%) experienced progression at some point disease progression. The median PFS and median DSS were 127 and 135 months, respectively. Age >60 years, diagnosis of SS, the presence of large cell transformation (LCT) at diagnosis, folliculotropism in early stages, high Ki-67 expression, the presence of the clonal T-cell receptor (TCR) in blood, elevated LDH and B2M levels, and advanced stages (IIB, IVA, T3, T4, N3/Nx) were associated with worse prognosis across the entire cohort. ConclusionsStage IVA and the presence of LCT at diagnosis stood out as independent factors of unfavorable prognosis. LCT was the variable that most significantly impacted the patients’ survival and was closely associated with tumor skin involvement and stage IIB.

Translated article] Cost of Treating Cutaneous T-Cell Lymphoma in Spain: Analysis of MICADOS Study Data by Disease Stage

Background and objectiveThe cost of treating cutaneous T-cell lymphoma (CTCL) in Spain is unknown. With the advent of new treatments, it is more important than ever to gain an accurate picture of the true costs involved. The MICADOS study had 2 primary objectives: 1)to evaluate the impact of CTCL on patient quality of life, and 2)to evaluate the costs associated with the disease. This article reports the results of the cost analysis. MethodsWe estimated the cost of treating CTCL over a period of 1year from the perspective of the Spanish National Health System. Twenty-three dermatologists and hematologists from 15 public hospitals analyzed data for adult patients with mycosis fungoides (MF) or Sézary syndrome (SS). ResultsA total of 141 patients (57.4% male) with a mean age of 63.6 years (95%CI: 61.4-65.7 years) were included. The mean direct annual cost of treating CTCL was €34,214 per patient. The corresponding costs by stage were €11,952.47 for stageI disease, €23,506.21 for stageII disease, €38,771.81 for stageIII disease, and €72,748.84 for stageIV disease. The total direct annual cost of treating MF/SS in public hospitals in Spain was estimated at €78,301,171; stageI disease accounted for 81% of all costs, stageII for 7%, and stagesIII andIV for 6% each. ConclusionsThe MICADOS study offers an accurate picture of the direct cost of treating CTCL in patients with MF/SS in Spain and shows that costs vary significantly according to disease stage. Patient-borne and indirect costs should be analyzed in future studies.

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.

Abstract C112: L1CAM targeting antibody-based therapy as a novel approach for L1CAM positive lymphomas

Abstract Background. L1CAM (L1 Cell Adhesion Molecule) is a glycoprotein identified as a key mediator of the metastatic process in many different tumor types. It facilitates the detachment of tumor cells from the primary tumor and their entry into the circulation. By promoting cell-cell interactions, it also directly stimulates the colonization of distant organs by circulating tumor cells. The expression and role of L1CAM in B and T cell lymphomas is poorly explored. The aim of this project was to evaluate L1CAM expression in different subtypes of lymphoma and its role as novel therapeutic target. Methods. RNA was extracted with Monarch Total RNA Miniprep Kit and qPCR performed with QuantiFast SYBR Green RT-PCR. For flow cytometry (FACS), cells were stained either with anti-L1CAM antibody or isotype control at a dilution of 1:1000. For immunohistochemistry (IHC) samples were stained for 20 minutes at a dilution of 1:100. For direct killing assay, cells were exposed six days to compounds, followed by MTT assay. Antibody dependent cellular cytotoxicity (ADCC) was performed with ADCC Reporter Bioassay (Promega). Results. L1CAM mRNA expression was assessed in 59 lymphoma cell lines. Whereas expression in most cell lines appeared low, a subgroup of cells displayed high to very high expression of L1CAM. Surface L1CAM expression was confirmed by FACS. L1CAM mRNA and protein expression levels correlated well across the cell lines and revealed that Sezary syndrome (SS) cell lines displayed the highest expression, followed by mantle cell lymphoma (MCL) and activated B cell diffuse large B cell lymphoma (ABC DLBCL) cell lines. By IHC L1CAM expression was assessed on different tissue microarrays covering multiple lymphoma subtypes; L1CAM expression was observed especially in a subset of cutaneous T-cell lymphoma and MCL. The data confirmed the findings in lymphoma cell lines. Anti-L1CAM monoclonal antibody (mAb) and four L1CAM targeting antibody drug conjugates (ADCs) (ADC1, ADC4, ADC5, ADC6), differing for the linker and payload, were tested in L1CAM positive and negative cell lines. mAB did not show any sign of direct antitumoral activity. Among ADCs, highest activity was observed with ADC6 (SG3199 payload), followed by ADC4 (MMAE payload). ADC1 and ADC5 (also containing MMAE as payload) showed limited activity. ADC6 showed the best correlation between killing activity and L1CAM expression levels, indicating a high level of target specific activity. The in vitro activity of ADC4 and ADC6 was validated in an in vivo xenograft using the MCL cell line Z138. Finally, mAb and a bispecific anti-CD3/L1CAM antibody were tested for their ability to induce ADCC. Both induced strong intracellular signaling in the reporter cell line upon co-incubation with L1CAM expressing lymphoma cells, indicative of the induction of killing activity in effector cells. Conclusions. In summary, we have demonstrated the in vitro and in vivo activity of anti-L1CAM antibody-based therapeutic approach as novel treatment for L1CAM positive lymphomas. Citation Format: Filippo Spriano, Giulio Sartori, Luca Aresu, Luciano Cascione, Elisa Civanelli, Afua A. Mensah, Chiara Tarantelli, Stefano Pileri, Flavio Mehli, Gunther Spohn, Francesco Bertoni. L1CAM targeting antibody-based therapy as a novel approach for L1CAM positive lymphomas [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C112.

Abstract B165: A pharmacologic screen identifies drugs to be combined with the non-ATP competitive PI3Kδ inhibitor roginolisib (IOA-244) for an improved anti-tumor activity in lymphoma models

Abstract Background. Despite a strong clinical activity against lymphomas, PI3Kδ inhibitors are now less used due to the risk of toxicities. Roginolisib is a non-ATP competitive PI3Kδ inhibitor (i) (Di Conza, SITC 2022; Johnson, Cancer Res Com 2023). Via a unique allosteric binding, it causes PI3Kδ inactive form stabilization without off-target effects typically seen with other PI3K inhibitors. Indeed, early clinical data show a very good safety profile (Di Giacomo, ASCO 2022; Carlo-Stella, ICML 2023). Here, we present an extensive combination study with roginolisib in lymphoma models. Methods. Cells were exposed (72h) to DMSO, 474 library compounds (5µM), single or with roginolisib (5µM), or roginolisib, followed by MTT assay. Library included 247 drugs of the Cambridge Cancer Compound Library, plus lymphoma treatment drugs or biologically relevant molecules. Hits were first validated in experiments with extended concentrations of both compounds in the same cell used in the screen. Combinations giving synergism/additivity according to Chou-Talalay algorithm were considered as beneficial. Results. A screen to identify active roginolisib-based combinations was done in two cell lines, SP-53 (mantle cell lymphoma, MCL), and HH (cutaneous T-cell lymphoma, CTCL). Combination partners identified and validated in both models included ruxolitinib (JAK1/2i), vorinostat (class I/II HDACi), venetoclax (BCL2i) BI-3802 (BCL6i), emavusertib (IRAK4i), safimaltib (MALT1i), tretinoin (all-trans-retinoic acid), and telaglenastat (glutaminase-i). Combinations with romidepsin (class I HDACi), valemetostat (EZH1/2i), diABZI (STING agonist), DNA methyltransferase i 5-azacytidine, and bromopyruvic acid (antimetabolite) were active only in the HH model. Multiple BTKi (ibrutinib, acalabrutinib, zanubrutinib, orelabrutinib, nemtabrutinib) showed increased activity when combined with roginolisib: validation was done using a 3rd generation BTK inhibitor, pirtobrutinib, observing a benefit in both cell lines. Selinexor (XPO1i) and pixantrone (chemo), with an already strong activity as single agents, showed benefit in both models. The combination of roginolisib with venetoclax or vorinostat was extended to eight more models of diffuse large B cell lymphoma (Farage, TMD8), MCL (Granta519, JVM2, SP49), chronic lymphocytic leukemia (MEC1), CTCL (MJ), NK cell lymphoma (YT), and to compounds with similar mechanism of action (class I/II HDAC i belinostat; BCL2 i S55746), and 2 MCL1i (S64315, S63845). Synergism or additivity were achieved with vorinostat, venetoclax and S63845 in 7/8 models, with belinostat and S55746 in 6/8 and with S64315 in 7/7. Roginolisib plus 5-azacytidine also achieved synergism/additivity in 5/8 cell lines. Finally, the addition of the JAK1/2i ruxolitinib to roginolisib was beneficial also in two Sezary syndrome cell lines (Hut78, H9). Conclusions. The study identified drugs that could be explored in combination with roginolisib for lymphoma patients taking advantage of the safe profile as single agent reported in clinical trials. Citation Format: Chiara Tarantelli, Elisa Civanelli, Eleonora Cannas, Filippo Spriano, Afua A. Mensah, Luciano Cascione, Alberto J Arribas, Anastasios Stathis, Karolina Niewola-Staszkowska, Giusy Di Conza, Michael Lahn, Francesco Bertoni. A pharmacologic screen identifies drugs to be combined with the non-ATP competitive PI3Kδ inhibitor roginolisib (IOA-244) for an improved anti-tumor activity in lymphoma models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B165.

Mycosis fungoides presenting as suspected allergic reaction

Mycosis Fungoides (MF) and Sezary Syndrome are the most common subtypes of cutaneous T cell lymphoma. MF is a mature T cell non-Hodgkin lymphoma with initial involvement of the skin, but as the disease progresses can involve lymph nodes, blood and viscera as illustrated in this case. Diagnosis is difficult due to the disease presenting similarly to benign allergic skin rashes. The median age of presentation for MF is between 50-60 years and affects males more than females. African Americans are more at risk although the exact reason is unknown.