EJC EUROPEAN JOURNAL OF CANCER THE OFFICIAL JOURNAL OF Volume 190S1, September 2023 ISSN 0959-8049 EORTC Cutaneous Lymphoma Tumour Group Annual Meeting 21–23 September 2023 Leiden, the Netherlands ABSTRACTS Publication of this abstract supplement is supported by the European Organisation for Research and Treatment of Cancer.
0959-8049(202308)189:C;1-M Amsterdam • Boston • London • New York • Oxford • Paris • Philadelphia • San Diego • St Louis European Journal of Cancer Editor-in-Chief Alexander M.M. Eggermont Abstracts of the EORTC Cutaneous Lymphoma Tumour Group Annual Meeting 21–23 September 2023, Leiden, the Netherlands Publication of this abstract supplement is supported by the European Organisation for Research and Treatment of Cancer.
European Journal of Cancer Editor-in-Chief: Alexander M.M. Eggermont Princess Máxima Center for Pediatric Oncology & University Medical Center Utrecht, Utrecht, Netherlands Editors: Preclinical Cancer Research: Ulrich Keilholz, Berlin, Germany Epidemiology and Prevention: Valery E.P.P. Lemmens, Utrecht, The Netherlands Tumour Immunotherapy: Aure´lien Marabelle, Villejuif, France Breast Cancer: Giuseppe Curigliano, Milan, Italy Suzette Delaloge, Villejuif, France Gastrointestinal Cancers: Volker Heinemann, Munich, Germany Michel Ducreux, Villejuif, France Genitourinary Cancers: Karim Fizazi, Villejuif, France Head and Neck Cancer: J.P. Machiels, Brussels, Belgium Hemato-Oncology: Roch Houot, Rennes, France Lung Cancer: Joachim Aerts, Rotterdam, The Netherlands Martin Schuler, Essen, Germany Gynaecological Cancers: Ignace Vergote, Leuven, Belgium Endocrine, Sarcomas and Other Rare Tumours: Hans Gelderblom, Leiden, The Netherlands Melanoma: Jessica Hassel, Heidelberg, Germany Neuro-Oncology: Martin van den Bent, Rotterdam, The Netherlands Paediatric Oncology: Rob Pieters, Utrecht, The Netherlands Digital Oncology: Titus J. Brinker, Heidelberg, Germany Founding Editor: Henri Tagnon Past Editors: Michael Peckham, London, UK; Hans-Jo¨rg Senn, St Gallen, Switzerland; John Smyth, Edinburgh, UK Editorial Office: Elsevier, The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK Tel: +44 (0) 1865 843590, Email: ejcancer@elsevier.com R. Baird (UK) N. Brünner (Denmark) R. Califano (UK) E. Calvo (Spain) F. Cardoso (Portugal) E. de Vries (The Netherlands) A. Dicker (USA) R. Dummer (Switzerland) S. Erridge (UK) H. Gelderblom (The Netherlands) B. Geoerger (France) B. Hasan (Belgium) J.C. Horiot (Switzerland) D. Jäger (Germany) A. Katz (Brazil) C. Le Tourneau (France) Y. Loriot (France) C-C. Lin (Taiwan) P. Lorigan (UK) C. Massard (France) K. McDonald (Australia) F. Meunier (Belgium) A. Miller (Canada) T. Mok (Hong Kong) D. Nam (Korea) J. Perry (Canada) J. Ringash (Canada) A. Rody (Germany) M. Schmidinger (Austria) S. Sleijfer (The Netherlands) S. Stacchiotti (Italy) C. Sternberg (Italy) A. van Akkooi (Australia) E. Van Cutsem (Belgium) G. Velikova (UK) E. Winquist (Canada) T. Yap (UK) EDITORIAL BOARD CLINICAL ONCOLOGY BASIC SCIENCE, PRECLINICAL AND TRANSLATIONAL RESEARCH P. Allavena (Italy) J. Anderson (UK) M. Broggini (Italy) C. Catapano (Switzerland) C. Caux (France) J. Carreras (Spain) E. Garattini (Italy) R. Giavazzi (Italy) J.M. Irish (USA) H.E.K. Kohrt (USA) J. Lunec (UK) A.M. Müller (USA) D. Olive (France) A.G. Papavassiliou (Greece) V. Rotter (Israel) V. Sanz-Moreno (UK) S. Singh (Canada) J. Stagg (Canada) A. Virós (UK) B. Weigelt (USA) T. Yap (UK) N. Zaffaroni (Italy) B. Armstrong (Australia) P. Autier (France) V. Bataille (UK) J.M. Borras (Spain) C. Bosetti (Italy) H. Brenner (Germany) L.E.M. Duijm (The Netherlands) J. Faivre (France) S. Franceschi (France) D. Forman (France) A. Green (Australia) K. Hemminki (Germany) C. Johansen (Denmark) L.A. Kiemeney (The Netherlands) I. Lansdorp-Vogelaar (The Netherlands) E. Lynge (Denmark) M. Maynadie´ (France) H. Møller (UK) P. Peeters (The Netherlands) S. Sanjose (Spain) M.K. Schmidt (The Netherlands) I. Soerjomataram (France) H. Storm (Denmark) L.V. van de Poll-Franse (The Netherlands) H.M. Verkooijen (The Netherlands) E. de Vries (The Netherlands) R. Zanetti (Italy) EPIDEMIOLOGY AND PREVENTION PAEDIATRIC ONCOLOGY C. Bergeron (France) A. Biondi (Italy) E. Bouffet (Canada) M. Cairo (USA) H. Caron (The Netherlands) G. Chantada (Argentina) F. Doz (France) A. Ferrari (Italy) M.A. Grootenhuis (The Netherlands) K. Pritchard-Jones (UK) L. Sung (Canada) M. van den Heuvel-Eibrink (The Netherlands) M. van Noesel (The Netherlands) Michel Ducreux, Villejuif, France Genitourinary Cancers: Karim Fizazi, Villejuif, France Head and Neck Cancer: J.P. Machiels, Brussels, Belgium Hemato-Oncology: Roch Houot, Rennes, France Lung Cancer: Joachim Aerts, Rotterdam, The Netherlands Martin Schuler, Essen, Germany Gynaecological Cancers: Ignace Vergote, Leuven, Belgium Endocrine, Sarcomas and Other Rare Tumours: Hans Gelderblom, Leiden, The Netherlands Melanoma: Jessica Hassel, Heidelberg, Germany Neuro-Oncology: Martin van den Bent, Rotterdam, The Netherlands Paediatric Oncology: Rob Pieters, Utrecht, The Netherlands Digital Oncology: Titus J. Brinker, Heidelberg, Germany Founding Editor: Henri Tagnon Past Editors: Michael Peckham, London, UK; Hans-Jo¨rg Senn, St Gallen, Switzerland; John Smyth, Edinburgh, UK Editorial Office: Elsevier, The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK Tel: +44 (0) 1865 843590, Email: ejcancer@elsevier.com R. Baird (UK) N. Brünner (Denmark) R. Califano (UK) E. Calvo (Spain) F. Cardoso (Portugal) E. de Vries (The Netherlands) A. Dicker (USA) R. Dummer (Switzerland) S. Erridge (UK) H. Gelderblom (The Netherlands) B. Geoerger (France) B. Hasan (Belgium) J.C. Horiot (Switzerland) D. Jäger (Germany) A. Katz (Brazil) C. Le Tourneau (France) Y. Loriot (France) C-C. Lin (Taiwan) P. Lorigan (UK) C. Massard (France) K. McDonald (Australia) F. Meunier (Belgium) A. Miller (Canada) T. Mok (Hong Kong) D. Nam (Korea) J. Perry (Canada) J. Ringash (Canada) A. Rody (Germany) M. Schmidinger (Austria) S. Sleijfer (The Netherlands) S. Stacchiotti (Italy) C. Sternberg (Italy) A. van Akkooi (Australia) E. Van Cutsem (Belgium) G. Velikova (UK) E. Winquist (Canada) T. Yap (UK) EDITORIAL BOARD CLINICAL ONCOLOGY BASIC SCIENCE, PRECLINICAL AND TRANSLATIONAL RESEARCH P. Allavena (Italy) J. Anderson (UK) M. Broggini (Italy) C. Catapano (Switzerland) C. Caux (France) J. Carreras (Spain) E. Garattini (Italy) R. Giavazzi (Italy) J.M. Irish (USA) H.E.K. Kohrt (USA) J. Lunec (UK) A.M. Müller (USA) D. Olive (France) A.G. Papavassiliou (Greece) V. Rotter (Israel) V. Sanz-Moreno (UK) S. Singh (Canada) J. Stagg (Canada) A. Virós (UK) B. Weigelt (USA) T. Yap (UK) N. Zaffaroni (Italy) B. Armstrong (Australia) P. Autier (France) V. Bataille (UK) J.M. Borras (Spain) C. Bosetti (Italy) H. Brenner (Germany) L.E.M. Duijm (The Netherlands) J. Faivre (France) S. Franceschi (France) D. Forman (France) A. Green (Australia) K. Hemminki (Germany) C. Johansen (Denmark) L.A. Kiemeney (The Netherlands) I. Lansdorp-Vogelaar (The Netherlands) E. Lynge (Denmark) M. Maynadie´ (France) H. Møller (UK) P. Peeters (The Netherlands) S. Sanjose (Spain) M.K. Schmidt (The Netherlands) I. Soerjomataram (France) H. Storm (Denmark) L.V. van de Poll-Franse (The Netherlands) H.M. Verkooijen (The Netherlands) E. de Vries (The Netherlands) R. Zanetti (Italy) EPIDEMIOLOGY AND PREVENTION PAEDIATRIC ONCOLOGY C. Bergeron (France) A. Biondi (Italy) E. Bouffet (Canada) M. Cairo (USA) H. Caron (The Netherlands) G. Chantada (Argentina) F. Doz (France) A. Ferrari (Italy) M.A. Grootenhuis (The Netherlands) K. Pritchard-Jones (UK) L. Sung (Canada) M. van den Heuvel-Eibrink (The Netherlands) M. van Noesel (The Netherlands)
0959-8049(202308)189:C;1-M Amsterdam • Boston • London • New York • Oxford • Paris • Philadelphia • San Diego • St Louis European Journal of Cancer Editor-in-Chief Alexander M.M. Eggermont Abstracts of the EORTC Cutaneous Lymphoma Tumour Group Annual Meeting 21–23 September 2023, Leiden, the Netherlands Table of Contents Welcome from the Chairpersons vii Oral Presentations S1 Biologic Insights 1 S1 Biologic Insights 2 S3 Clinical Studies 1 S5 Histopathology S7 CBCL S10 Clinical Studies 2 S12 Clinical Studies 3 S15 Epidemiology/QoL S17 Treatments 1 S19 Treatments 2 S22 Poster Presentations S24 Biologic Insights S24 Clinical Studies S30 Epidemiology S34 Histopathology S36 Preclinical Studies S37 Quality of Life S38 Treatments S41 Author index S51
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Dear Friends, dear Colleagues It is our great pleasure to organize the EORTC CLTG annual meeting from 21–23 September 2023 in Leiden, the Netherlands. The EORTC CLTG annual meeting has become a major event for the international scientific community dedicated to cutaneous lymphoma with high standards of scientific research while maintaining a collegial atmosphere. Presentations at this year’s meeting will include new data from (pre)clinical studies, clinical trials and translational research that will help to establish priorities for future research and ultimately improve clinical practice. At the end of this conference participants will be up-to-date in this specialist and complex field. Keynote speakers include Prof. dr. Boudewijn Lelieveldt (department of Radiology, Leiden University Medical Center, Leiden, the Netherlands) on “Seeing is discovering: visual analytics for omics data from single cell to tissue and back”, Prof. dr. Karin de Visser (the Netherlands Cancer Institute, Oncode Institute, Amsterdam, Leiden University Medical Center, Leiden, the Netherlands) on “Crosstalk between eosinophils and adaptive immune cells: a new avenue for immune checkpoint blockade in breast cancer” and Prof. dr. Pier Luigi Zinzani (Institute of Hematology “Seràgnoli”, University of Bologna, Bologna Italy) on “New Therapies in Cutaneous Lymphoma”. The scientific programme will be complemented by a social programme that will give ample time for discussion, social interaction and opportunities to meet old friends or make new friendships. On behalf of the local organising committee, we look forward to seeing you in Leiden! Julia Scarisbrick Maarten Vermeer EORTC CLTG Chair Chair of the EORTC CLTG meeting 2023 in Leiden WELCOME FROM THE CHAIRPERSONS We would like to thank the sponsors of the EORTC CLTG meeting 2123 SEPTEMBER THE NETHERLANDS VENUE Burumazaal | LUMC | Leiden DIAMOND GOLD BRONZE
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European Journal of Cancer 190S1 (2023) S1–S55 S1 EJC EUROPEAN JOURNAL OF CANCER THE OFFICIAL JOURNAL OF Volume 190S1, September 2023 ISSN 0959-8049 The EORTC Cutaneous Lymphoma Tumour Group Annual Meeting 21–23 September 2023 Leiden, the Netherlands ABSTRACTS Publication of this abstract supplement is supported by the European Organisation for Research and Treatment of Cancer. ORAL PRESENTATIONS BIOLOGIC INSIGHTS 1 O-101 Tumor necrosis factor receptor type 2 (TNFR2) may represent an alternative therapeutic target in Sézary syndrome and mycosis fungoides Asma Beldi‑Ferchiou1, Oro Saskia2, Valérie Molinier‑Frenkel1, François Lemonnier3, Allan Thiolat4, Caroline Pilon4, Jérôme Giustiniani5, Philippe Gaulard6, Marie‑Hélène Delfau‑Larue1, Nicolas Ortonne6, José L. Cohen4 1Immunobiology Department, APHP-Henri Mondor University Hospital, Creteil, France, 2Department of Dermatology, APHP-Henri Mondor University Hospital, Creteil, France, 3Hémopathies lymphoïdes, APHPHenri Mondor University Hospital, Creteil, France, 4INSERM U955, Immunoregulation and Biotherapy (I-Biot) Team, Institut Mondor de Recherche Biomédicale (IMRB), INSERM U955, Creteil, France, 5INSERM U955, Institut Mondor de Recherche Biomédicale (IMRB), INSERM U955, Creteil, France, 6Department of Pathology, APHP-Henri Mondor University Hospital, Creteil, France Introduction: Therapeutic management of mycosis fungoides (MF) and Sézary syndrome (SS) remains difficult despite the development of targeted strategies. Tumor necrosis factor (TNF) receptor type 2 (TNFR2) emerges as a promising target in some tumor context. TNFR2, highly expressed on T regulatory cells, promotes cell proliferation and survival. TNFR2 can be expressed on tumor cells and acts as a tumor growth factor. Little is known about the role of TNFR2 in lymphoproliferative malignancies. Objectives: Our objective was to depict a landscape of TNFR2 expression in a large number of peripheral T-cell lymphomas (PTCLs ), including SS and MF, in order to distinguish candidates to therapeutic TNFR2 targeting. Materials and methods: This prospective study was conducted in 43 patients with peripheral T-cell lymphomas (PTCLs): 18 SS, 3 MF, 15 angioimmunoblastic T-cell lymphomas, 3 adult T-cell leukemia/lymphomas, and 4 peripheral T-cell lymphomas not otherwise specified. All patients had detectable circulating tumor cells. TNFR2 expression was analyzed by flow cytometry (n=43) and by immunohistochemistry on paraffin embedded skin biopsies in some SS patients (n=5). Results: The SS/MF group was characterized by an enhanced TNFR2 expression on tumor cells compared to non-cutaneous PTCLs (p= 0.02). TNFR2 expression was higher on Sezary cells (SCs) than on residual normal T cells (p=0.01). TNFR2 expression was stable in SS patients with available follow-up at 6 months (n=11). Immunohistochemistry staining of skin biopsies confirmed TNFR2 expression on tumor cells. Four SS patients with high TNFR2 expression on SCs had a weak or absent KIR3DL2 expression at diagnosis. Conclusion: TNFR2 has a strong and stable expression on primary SCs. These results suggest that SS and MF may be candidates for therapeutic targeting of TNFR2, especially for patients who do not express KIR3DL2. Complementary studies are required. European Journal of Cancer 190S1 (2023) 112989 https://doi.org/10.1016/j.ejca.2023.112989 O-102 Translational data from a multicenter phase II study on dimethyl fumarate treatment in relapsed and refractory cutaneous T cell lymphoma Susanne Melchers1, Jana D. Albrecht1, Jing Zhao2, Gülow Gülow3, Christian M. Schürch2, Peter H. Krammer4, Jan P. Nicolay1 1Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Mannheim, Germany, 2Department of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tübingen, Tübingen, Germany, 3Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, University Hospital Regensburg (UKR), Regensburg, Germany, 4Department of Immunogenetics D030, German Cancer Research Center (DKFZ), Heidelberg, Germany Introduction: We performed a multicenter phase 2 clinical study on dimethyl fumarate treatment in relapsed and refractory CTCL in Germany (Publication accepted in Blood in May 2023). Dimethyl fumarate (DMF) inhibits NF-κB in the malignant T cells of CTCL patients and can specifically induce cell death [1]. Objectives: The aim of this study is to investigate the mechanism of action of DMF as well as its influence on cellular signaling and microenvironment in CTCL patients in vivo. Materials and methods: Pre- and posttreatment, Formalin-fixed-paraffin-embedded (FFPE) samples were collected, and peripheral blood mononuclear cells (PBMCs) were isolated. Immunohistochemical (IHC) and CODEX highly multiplexed tissue imaging was performed as previously described [2]. PBMCs were isolated from patient blood samples as described before [3]. Next-generation sequencing is planned at the Core Facility of the University Medical Center Mannheim. Abstracts of the EORTC CLTG Annual Meeting 2023 0959-8049/ Available online at www.sciencedirect.com journal homepage: www.ejcancer.com
S2 EORTC CLTG meeting abstract book | European Journal of Cancer 190S1 (2023) S1–S55 Results: CODEX multiplexed stainings of a responder post-treatment identified lower levels of p65 as a readout for NF-κB activity and decreased numbers of CD4+ and CD8+ T cells, whereas CD163+ macrophages increased in the dermal infiltrate. IHC stainings showed that before DMF treatment pp65 levels were significantly higher in responders, and decreased under therapy, suggesting that NF-κB activity correlates with response to therapy. Apoptotic cell numbers, reflected by cleaved caspase 3 staining, were also higher in pre-treatment responders, but the differences did not reach statistical significance. Further evaluation of the CODEX and IHC stainings is ongoing. The next-generation sequencing has not yet been completed. Conclusion: DMF is a promising new therapeutic option in CTCL that already proved effective and well-tolerable in a clinical phase II study. The first results point towards a correlation between pre-treatment NF-κB activity with response to therapy. This would allow a pre-treatment therapy stratification to better identify patients suitable for DMF therapy. References: [1] Nicolay, J.P., et al., Dimethyl fumarate restores apoptosis sensitivity and inhibits tumor growth and metastasis in CTCL by targeting NF-kappaB. Blood 2016;128(6):805–815. [2] Schurch, C.M., et al., Coordinated Cellular Neighborhoods Orchestrate Antitumoral Immunity at the Colorectal Cancer Invasive Front. Cell 2020; 183(3):838. [3] Froehlich, T.C., et al., Combined inhibition of Bcl-2 and NFkappaB synergistically induces cell death in cutaneous T-cell lymphoma. Blood 2019; 134(5):445–455. European Journal of Cancer 190S1 (2023) 112990 https://doi.org/10.1016/j.ejca.2023.112990 O-103 CD38 targeting in aggressive, treatment-refractory cutaneous T-cell lymphomas Van Anh Ta1, Maxime Battistella2, Lin Pierre Zhao1, Gabor Dobos3, Caroline Ram‑Wolff4, Isabelle Madelaine5, Jean Christophe Bories6, Olivier Tournilhac7, Jacques Rouanet8, Richard Veyrat‑Masson9, Jean‑David Bouaziz4, Anne Marie‑Cardine6, Martine Bagot4, Armand Bensussan6, Helene Moins‑Teisserenc1, Adele De Masson4 1INSERM1160, Institut de Recherche Saint-Louis, Paris, France, 2Pathology Department, Saint-Louis Hospital, Paris, France, 3Department of Dermatology, Charité Hospital, Berlin, Germany, 4Department of Dermatology, Saint-Louis Hospital, Paris, France, 5Pharmacy, Saint-Louis Hospital, Paris, France, 6INSERM976, Institut de Recherche Saint-Louis, Paris, France, 7Department of Hematology, CHU Clermont-Ferrand, Clermont-Ferrand, France, 8Department of Dermatology, CHU ClermontFerrand, Clermont-Ferrand, France, 9Hematology Laboratory, CHU Clermont-Ferrand, Clermont-Ferrand, France Introduction: Advanced-stage cutaneous T-cell lymphomas (CTCL) are rare, usually refractory and fatal diseases. The treatment of these diseases, including Sézary syndrome, the leukemic form of CTCL, remains challenging. The monoclonal antibodies mogamulizumab (anti-CCR4) and lacutamab (anti-KIR3DL2) have proven efficient in advanced-stage CTCL but are poorly effective in patients with large-cell transformation. Brentuximab vedotin, an anti-CD30 antibody-drug conjugate, improves progression-free survival in CTCL including transformed mycosis fungoides, but its use is limited by the occurrence of peripheral neuropathy. CD38 is a multifunctional ectoenzyme uniformly expressed by myeloma cells and other hematopoietic cells such as T, B and NK cells. In T cells, it functions as an adherence molecule to CD31 expressed by endothelial cells, and its ligation induces the production of different cytokines. The anti-CD38 mAbs daratumumab and isatuximab have been shown to deplete myeloma cells. They also have immunomodulatory effects on CD38+ regulatory T and myeloid-derived suppressor cells as well as on restoration of T and NK-cell mediated antitumor immune responses. Objectives: This study aimed to investigate the expression of CD38 in the skin, blood, and lymph nodes of CTCL patients. Materials and methods: We combined immunohistochemistry, multiparameter flow cytometry, and single cell RNA sequencing to characterize the expression of CD38 in skin, blood and lymph nodes of CTCL patients. In addition, we also conducted in vitro experiments using isatuximab to evaluate its cytotoxic and phagocytic effects on CTCL cells. Results: Our results show that peripheral blood Sézary cells were unequivocally CD38int, and CD38 was expressed in skin of CTCL patients with aggressive disease. Isatuximab induced in vitro CTCL cell cytotoxicity and phagocytosis. Conclusion: The potential therapeutic impact of CD38-targeting therapies in CTCL warrants further prospective investigation. European Journal of Cancer 190S1 (2023) 112991 https://doi.org/10.1016/j.ejca.2023.112991 O-104 HLA I shields tumor lymphocytes from NK cell-mediated elimination in the skin Yun‑Tsan Chang1, Susanne Kimeswenger2, Yi‑Chien Tsai1, Pacome Prompsy1, Olesya Pavlova1, Steve Pascolo3, Wolfram Hoetzenecker2, Emmanuella Guenova1 1Dermatology, Lausanne University Hospital (CHUV), Lausanne, Switzerland, 2Dermatology and Venerology, Johannes Kepler University, Linz, Austria, 3Dermatology, University Hospital of Zurich, Zurich, Switzerland Introduction: Impairment of cellular immunity in cancer is a major hurdle to therapy. With the discovery of antibodies targeting tumor cell-surface antigens we witnessed remarkable advances in blood cancer. However, many tumors of hematopoietic origin in the skin remain resistant. Objectives: In this study, we aim to identify the skin resistance mechanisms in mycosis fungoides (MF) to antibodies targeting tumor cell-surface antigens. Materials and methods: We use single-cell RNA sequencing with a clonality-supervised deep learning approach to identify cancer-predicting genes. Results: Here we use a clonality-supervised deep learning approach to identify cancer-predicting genes and the human leukocyte antigen (HLA, also known as MHC) I as a major T cell lymphoma tumor intrinsic features of cancer immune evasion in the skin. In humans, HLA-I hindered natural killer (NK) cell function and antibody dependent cellular cytotoxicity and conferred skin tumor resistance to cell-surface antigen targeted therapeutic antibodies. In mice, blockade of the H-2K (mouse MHC-I) interaction with NK cells’ inhibitory Ly49 receptors restored anti-T-cell lymphoma activity in vivo and resulted in lymphoma elimination by tumor cell-surface antigens directed treatment. Conclusion: These findings demonstrate how attenuation of HLA I-dependent tumor-driven immunosuppressive networks can revitalize NK cell antitumor activity to overcome resistance to therapy. European Journal of Cancer 190S1 (2023) 112992 https://doi.org/10.1016/j.ejca.2023.112992
EORTC CLTG meeting abstract book | European Journal of Cancer 190S1 (2023) S1–S55 S3 O-105 A novel inducible knockout mouse strain to study the impact of one-copy loss of HNRNPK in CD4 T cells as an experimental model of cutaneous lymphoma Yixin Luo1, Maarten Vermeer1, Sanne De Haan1, Frank De Gruijl1, Peter Hohenstein2, Thorbald Van Hall3, Cornelis Tensen1 1Department of Dermatology, Leiden University Medical Center, Leiden, the Netherlands, 2Department of Human genetics, Leiden University Medical Center, Leiden, the Netherlands, 3Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands Introduction: Cutaneous T cell lymphomas (CTCLs) are characterized by the infiltration of malignant T cells into the skin. Heterogeneous nuclear ribonucleoprotein K (hnRNPK) deletions and lowered expression are frequently observed in CD4+ T cells from mycosis fungoides (MF), the most common CTCL. A knockout mouse model would enable proper in vivo functional studies, but thus far, these mouse strains have proved cumbersome because of poor survival. Objectives: Here, we present a novel transgenic mouse model that is not compromised in survival, enabling in-depth investigations into the function of hnRNPK, particularly aimed at the de novo development of CTCL. Materials and methods: Using CRISPR-Cas9 technology and single-stranded oligodeoxynucleotides (ssODN), we generated hnRNPK floxed mice, which were then crossbred with CD4CreERT2 mice to generate hnRNPK flox CD4CreERT2 mice. The deletion of hnRNPK in CD4 T cells was measured using PCR analysis following the tamoxifen application. To induce hnRNPK mono-allelic deletion in CD4+ T cells in the skin, we applied hydroxy-tamoxifen to a contact allergic skin reaction. Subsequent repeated contact allergic challenges were performed to maintain prolonged skin inflammation for 20 weeks, followed by 20 weeks without further treatment. Flow cytometry and histopathological analysis were conducted on blood and skin samples collected throughout the experiment. Results: We successfully confirmed the deletion of hnRNPK in CD4 T cells after tamoxifen application. The mice exhibited no immediately obvious phenotype. After 20 weeks, the challenges were discontinued, yet the inflammation had not subsided after more than 10 weeks, in contrast to what was observed in historic hnRNPK proficient controls subjected to the same treatment regimen. This model mimicked key features of (early) CTCL, including chronic skin inflammation, infiltration of CD3+CD4+ cells, and minimal disturbances in peripheral blood. Conclusion: Hence, this mouse model provides experimental access to the complex microenvironment and immune responses involved and thus opens up opportunities for further research into the role of hnRNPK in CTCL and the development of effective therapeutic interventions for this challenging malignancy. European Journal of Cancer 190S1 (2023) 112993 https://doi.org/10.1016/j.ejca.2023.112993 BIOLOGIC INSIGHTS 2 O-106 Interstitial fluid immunophenotyping of early-stage mycosis fungoides patients after chlormethine treatment Selinde Wind1, Rianne Rijneveld2, Hendrika Grievink3, Catherine Mergen4, Koen Quint5, Maarten Vermeer5, Robert Rissmann4 1Dermatology, Centre for Human Drug Research and Leiden University Medical Center, Leiden, the Netherlands, 2Dermatology, Centre for Human Drug Research, Leiden, the Netherlands, 3Immunology, Centre for Human Drug Research, Leiden, the Netherlands, 4Dermatology, Centre for Human Drug Research and Leiden Academic Centre for Drug Research, Leiden, the Netherlands, 5Dermatology, Leiden University Medical Center, Leiden, the Netherlands Introduction: Early stages of mycosis fungoides (MF) can be treated effectively with topical chlormethine. However, insight into changes in the tumor-micro environment (TME) during treatment and how these changes contribute to therapeutic success is limited. Objectives: In this study we aimed to characterize TME of MF on a cellular level by suction blister fluid analysis. Materials and methods: In this exploratory, open-label, deep phenotyping trial a total of 21 early-stage (IA – IIA) MF patients were treated with chlormethine gel 160 µg/g QD for 16 weeks. Suction blister exudates were collected pre-treatment from lesional (LS) and non-lesional skin (NL) and after 16 weeks of treatment from LS and analyzed with flow cytometry. Here, we present preliminary data from the first 18 completers of the trial. For all statistical analyses a Wilcoxon signed-rank test was used. Results: In blister exudate pre-treatment, statistically significant more absolute cells were observed in LS compared to NL (p<0.001). Exudates from LS contained statistically significant more CD3+ cells (p<0.001), CD3+4+ T-lymphocytes (p<0.0001), activated CD4+HLA-DR+ effector T-lymphocytes (p=0.0001), CD3+8+ T-lymphocytes (p<0.0001), activated CD8+HLA-DR+ cytotoxic T-lymphocytes (p<0.001), CD14–CD16– dendritic cells (p<0.01) and CD68+macrophages (p<0.01). After 16W chlormethine gel treatment significantly less aberrant T-cells (p<0.05), CD3+8+ T-lymphocytes (p<0.05), activated CD8+HLA-DR+ cytotoxic T-lymphocytes (p<0.01) and Tregs (p<0.05) were observed compared to LS baseline. Conclusion: We show for the first time the feasibility of suction blister fluid analysis to investigate TME in MF patients. These preliminary results suggest that CD8+HLA-DR+ cytotoxic and regulatory T-lymphocytes have a prominent role in chlormethine therapy in MF. European Journal of Cancer 190S1 (2023) 112994 https://doi.org/10.1016/j.ejca.2023.112994 O-107 Modulation of immune cell polarization and PD-L1 expression by MF fibroblast exosomes: potential implications for immunotherapy in MF Lilach Moyal1, Haneen Churi2, Jamal Knaneh3, Batia Gorovitz‑Haris4, Anna Aronovich5, Maya Bal2, Iris Amitay‑Laish6, Hadas Prag Naveh5, Dafna Yaacobi7, Eric Barel7, Dean Ad‑El7, Emmilia Hodak8 1Felsenstein Medical Research Center, Rabin Medical Center and Tel Aviv University, Petach Tikva, Israel, 2Felsenstein Medical Research Center, Tel Aviv Univesity, Petach Tikva, Israel, 3Felsenstein Medical Research Center, Tel aviv university, Petach Tikva, Israel, 4Felsenstein Medical Research Center, Rabin Medical Center, Petach Tikva, Israel, 5Dermatology department, Rabin Medical Center, Petach Tikva, Israel, 6Dermatology Department, Rabin Medical Center, Petach Tikva, Israel, 7Department of Plastic and Reconstructive Surgery, Rabin Medical Center, Petach Tikva, Israel, 8Davidoff Cancer Center, Rabin Medical Center, Petach Tikva, Israel Introduction: Cancer-associated fibroblasts (CAFs) play a significant role in the tumor microenvironment (TME). Exosomes are small extracellular vesicles involved in intercellular communication secreted by various cells. In
S4 EORTC CLTG meeting abstract book | European Journal of Cancer 190S1 (2023) S1–S55 our previous study, we identified the presence of CAFs in the TME of MF skin lesions. Objectives: To investigate the impact of MF fibroblast (MF-F) exosomes compared to normal fibroblast (N-F) exosomes on immune cells. Materials and methods: Primary fibroblasts were derived from biopsies of MF patients and normal skin from healthy individuals. Exosomes were isolated from the supernatant of MF-F and N-F cells using ultracentrifugation, and their presence was confirmed by electron microscopy, Nanosight, and fluorescence-activated cell sorting (FACS). The internalization of fibroblast exosomes into peripheral blood mononuclear cells (PBMCs) and monocytes derived from healthy donors was confirmed using labeled exosomes and microscopic analysis. Immune cell characterization was performed using mass flow cytometry (CyTOF- Cytometry by time of flight) with a panel of 41 antibodies. FACS and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) were performed to assess protein markers and cytokine expression of M1 and M2 macrophages (respectively). PD-L1 expression was evaluated using FACS, and the presence of specific microRNAs was analyzed by qRT-PCR. Results: CyTOF analysis revealed that N-F exosomes increased Th1 and CD8+ cytotoxic T cells, whereas MF-F exosomes reduced Th1 cells, M1 macrophages, and Th17 cells, while increasing M2 macrophages. The polarization of M2 macrophages was further confirmed in primary monocytes incubated with MF-F exosomes compared to N-F exosomes, as evidenced by the upregulation of M2 cytokine expression. Furthermore, both MF-F and N-F exosomes increased the PD-L1 expression in M1 and M2 cells, but MF-F exosomes exhibited a higher increase. To explore the mechanism underlying the exosome-mediated upregulation of PD-L1 in monocytes, relevant specific microRNAs in MF-F and N-F exosomes were analyzed; miR-23a-3p, a positive regulator of PD-L1 and M2 polarization, was found to be more abundant in MF-F exosomes compared to N-F exosomes. Conclusion: Our findings suggest a novel mechanism by which MF-F exosomes deliver miR-23a-3p to shape an immunosuppressive microenvironment through the polarization of M2-like macrophages with high PD-L1 expression, highlighting a potential avenue for enhancing immunotherapy in MF. European Journal of Cancer 190S1 (2023) 112995 https://doi.org/10.1016/j.ejca.2023.112995 O-108 Anti-PD-L1 and lenalidomide enhance anti-tumor immunity in cutaneous T cell lymphoma through targeting PD1+M2-like tumor-associated macrophages Christiane Querfeld1, Xiwei Wu2, Hanjun Qin2, Yate‑Ching Yuan3, Chingyu Su3, Jasmine Zain3, Mingye Feng3, Steven Rosen3, Zhen Han3 1Dermatology, City of Hope National Medical Center, Beckman Rese, Duarte, United States, 2Beckman Research Institute, City of Hope National Medical Center, Beckman Rese, Duarte, United States, 3Beckman Research Institute, City of Hope National Medical Center, Duarte, United States Introduction: Cutaneous T cell lymphoma (CTCL) is an incurable and cosmetically disfiguring disease associated with microenvironmental signals. Results from our clinical phase I trial of anti-PD-L1 combined with lenalidomide in relapsed/refractory CTCL patients demonstrated promising clinical efficacy. Macrophages are important regulators in the tumor microenvironment (TME) by presenting antigens to T cells and having key roles in tumor immune surveillance and showing plasticity in producing distinct cytokines and chemokines that can influence tumor cell migration and proliferation in the TME. Objectives: We investigated the role of PD1 expression on TAMs and their impact on the CTCL TME. Moreover, we studied the therapeutic effects of antiPD-L1 alone and when combined with lenalidomide on the CTCL TME. Materials and methods: We performed transcriptional profiling, gene expression deconvolution and flow cytometry on CTCL samples and in vitro functional assays such as macrophage migration and phagocytosis assays, and T cell proliferation assays. Results: We analyzed the CTCL TME, which revealed a predominant PD1+M2-like TAM subtype with upregulated NF-κB and JAK/STAT signaling pathways and an aberrant cytokine and chemokine profile. Our in vitro studies investigated the effects of anti-PD-L1 and lenalidomide on PD1+ M2-like TAMs. The combinatorial treatment synergistically induced functional transformation of PD1+ M2-like TAMs toward a proinflammatory M1-like phenotype that gained phagocytic activity upon NF-κB and JAK/STAT inhibition, altered their migration through chemokine receptor alterations, and stimulated the effector T cell proliferation. Lenalidomide was more effective than anti-PDL1 in downregulation of the immunosuppressive IL-10, leading to decreased expression of both PD1 and PD-L1. Conclusion: Overall, PD1+M2-like TAMs play an immunosuppressive role in CTCL. Collectively, dual combination of anti-PD-L1 and lenalidomide provide a therapeutic strategy to enhance anti-tumor immunity by targeting PD1+M2-like TAMs in the CTCL TME. European Journal of Cancer 190S1 (2023) 112996 https://doi.org/10.1016/j.ejca.2023.112996 O-109 Skin infiltrating NK cells in cutaneous T-cell lymphoma are increased in number and display phenotypic alterations partially driven by the tumor Hanna Brauner1, Andrea Scheffschick1, Julia Nenonen1, Mengmeng Xiang1, Anna Winther2, Marcus Ehrström3, Marie Wahren‑Herlenius1, Liv Eidsmo4 1Medicine, Karolinska Institutet, Stockholm, Sweden, 2Dermatology, Karolinska university hospital, Stockholm, Sweden, 3Plastic surgery, Nordiska kliniken, Stockholm, Sweden, 4Immunology and Microbiology, LEO Foundation Skin Immunology Research Center and University of Copenhagen, Copenhagen, Denmark Introduction: Cutaneous T cell lymphoma (CTCL) are characterized by focal infiltration of malignant T cell clones in solitary skin lesions. Many CTCL patients experience an indolent disease, but some progress to advanced disease with high fatality. Natural killer (NK) cells are powerful cytotoxic lymphocytes that play an important role in the defense against malignancies, particularly of hematopoietic origin and are successfully used for cellular immunotherapy in several cancers. Objectives: We hypothesized that natural killer (NK) cells participate in local control of tumor growth in CTCL skin and aimed to investigate NK cell numbers, localization, phenotype and function in CTCL skin. Materials and methods: Immunohistochemistry and flow cytometry analysis was performed to assess the density, localization, phenotype and function of NK cells in twenty-nine fresh or formalin‑fixed skin biopsies from twenty-four CTCL patients and twenty-three biopsies from twenty healthy controls. Results: We found higher numbers of CD56+CD3– NK cells in CTCL skin compared to healthy skin. However, a reduced fraction of CTCL NK cells expressed the maturation marker CD57, the cytotoxic protein granzyme B and the activation marker CD69, indicating reduced tumor‑killing ability. Retained expression of immune checkpoint proteins or inhibitory proteins including PD1, TIM3, LAG3, CD73 and NKG2A and the activating receptors CD16 and NKp46 indicated maintained effector functions. Indeed, the capacity of NK
EORTC CLTG meeting abstract book | European Journal of Cancer 190S1 (2023) S1–S55 S5 cells to produce anti‑tumor acting IFNγ upon PMA + ionomycin stimulation was similar in CTCL and healthy skin. Co-cultures of primary human NK cells or the NK cell line NKL with the CTCL cell line HH resulted in reduced levels of granzyme B and CD69, furthermore indicating that close cellular interactions with CTCL cells induced the impaired functional NK cell phenotype. Conclusion: Increased numbers of NK cells are found in CTCL skin compared to healthy, and they exhibit a partially activity‑impaired phenotype. Enhancing NK cell activity with NK-activating cytokines such as IL-15 or immune checkpoint blockade therefore represents a potential immunotherapeutic approach in CTCL. European Journal of Cancer 190S1 (2023) 112997 https://doi.org/10.1016/j.ejca.2023.112997 O-110 Coexpression of natural killer cell antigens by T-cell large granular lymphocytes in hydroa vacciniforme lymphoproliferative disorder and the involvement of Vδ1+ epithelial-type γδT cells Yuki Nakagawa1, Yoji Hirai2, Keiji Iwatsuki3, Takahide Takahashi4, Tomoko Miyake2, Shogo Tanimoto2, Yoshio Kawakami2, Shin Morizane2 1Department of Dermatology, Fukuyama city hospital, Fukuyama, Japan, 2Department of Dermatology, Okayama University Graduate School of Medicine, Okayama, Japan, 3Department of Dermatology, Fukushima Rosai Hospital, Fukushima, Japan, 4Division of Medical Support, Department of Dermatology, Okayama University Graduate School of Medicine, Okayama, Japan Introduction: Hydroa vacciniforme lymphoproliferative disorder (HV-LPD) is a cutaneous variant of chronic active Epstein–Barr virus disease (CAEBV). Patients with HV-LPD are divided further into two groups: a benign subtype designated classic HV (cHV) mediated by EBV+ γδT cells, and another life-threatening subtype named systemic HV (sHV), mainly associated with EBV+ αβT or γδT cells. From therapeutic as well as prognostic points of view, it is necessary to distinguish them. Objectives: To clarify the immunophenotype of circulating EBV+ T/ NK cells of patients with HV-LPD by FCM, and the usage of TCR chains by high-throughput sequencing. Materials and methods: All the five cHV patients had increased percentages (>5%) of gdT-cell cells, whereas the sHV patients showed gdT-cell-dominant in two patients, abT-cell-dominant in two, and a mixed feature in one. Circulating CD3+ T cells expressed CD16/CD56 at 7.8–42.3% and 1.1–9.7% in sHV and cHV, respectively. The percentages of CD16/CD56+ T cells increased in the large granular lymphocyte or atypical T-cell fractions in sHV, but no TCR Va24 invariant chain characteristic of NKT cells were detected. A considerable number of CD3+ cells expressing CD56 were observed in sHV skin infiltrates. Of the circulating gdT cells tested, TCR Vd1+ cells characteristic of the epithelial type of gdT cells were dominant in two sHV cases, while Vd2+ cells were of a major cell type in cHV and healthy donors. When compared with the proportion of gdT-cells between the peripheral blood and skin infiltrates of sHV, the percentage of Vd1+ cells was higher in the skin lesion. Results: Atypical abT and gdT cells in HV-LPD frequently coexpress NK-cell antigens such as CD16 and CD56, and the Vd1+ epithelial type of gdT cells are enriched in the peripheral blood, and selectively infiltrating in the sHV skin lesions. Conclusion: Atypical abT and gdT cells in HV-LPD frequently coexpress NK-cell antigens such as CD16 and CD56, and the Vd1+ epithelial type of gdT cells are enriched in the peripheral blood, and selectively infiltrating in the sHV skin lesions. European Journal of Cancer 190S1 (2023) 112998 https://doi.org/10.1016/j.ejca.2023.112998 CLINICAL STUDIES 1 O-111 ISCL/USCLC/EORTC guidelines for the diagnosis, staging, and treatment of pediatric mycosis fungoides Emilia Hodak1, Iris Amitay‑Laish1, Martine Bagot2, Maxime Battistella3, Antonio Cozzio4, Madeleine Duvic5, Larisa Geskin6, Emmanuela Guenova7, Youn H. Kim8, Jan Nicolay9, Pablo Luis Ortiz‑Romero10, Amra Osmancevic11, Evangelia Papadavid12, Pietro Quaglino13, José A. Sanches14, Julia Scarisbrick15, Rudolf Stadler16, Franz Trautinger17, Maarten Vermeer18, Chalid Assaf19 1Dermatology, Rabin Medical Center, Tel Aviv, Israel, 2Dermatology, SaintLouis Hospital, Paris, France, 3Pathology, Saint-Louis Hospital, Paris, France, 4Dermatology, Canton Hospital St. Gallen, St. Gallen, Switzerland, 5Hematology, University of Texas, Texas, United States, 6Dermatology, Columbia University, New York, United States, 7Dermatology, University of Lausanne, Lausanne, Switzerland, 8Dermatology, Stanford University, Stanford, United States, 9Dermatology, University Medical Center Mannheim, Mannheim, Germany,10Dermatology, Hospital 12 de Octubre, Madrid, Spain, 11Dermatology, University of Gothenburg, Gothenburg, Sweden, 12Dermatology, Attikon General University Hospital, Athens, Greece, 13Dermatology, University of Turin, Turin, Italy, 14Dermatology, University of São Paulo, São Paulo, Brazil, 15Dermatology, University Hospital Birmingham, Birmingham, United Kingdom, 16Dermatology, Johannes Wesling Medical Centre, Minden, Germany, 17Dermatology, University Hospital of St. Pölten, St. Pölten, Austria, 18Dermatology, Leiden University Medical Center, Leiden, the Netherlands, 19Department of Dermatology and Venerology, Helios Hospital Krefeld, Krefeld, Germany Introduction: Although mycosis fungoides (MF) is regarded as rare in the pediatric age group, there is a wide range in the reported incidence of diagnosed cases, from as low as 0–3% of all MF cases in North America and Europe, to as high as 16–25% in the Far East. Accumulating experience indicates that compared to adult MF, almost all patients with pediatric MF are diagnosed with early-stage disease, have higher rates of atypical presentations, and the disease is characterized by an indolent course. There are no published guidelines for the staging process and treatment of pediatric MF. Objectives: To develop for the first time international guidelines, specifically designed for MF in children and adolescents. Materials and methods: The pediatric MF guidelines were developed through an international expert consensus process and in accordance with the EQUATOR Network’s recommendations for guideline development, A steering group (EH, CA) was convened online to develop questionnaires and oversee the guideline development process. Its interdisciplinary members were selected to cover a broad range of expertise and ensure a seamless integration with other existing guidelines. We conducted a modified Delphi process, with two rounds of feedback from participating experts and one hybrid consensus meeting conducted at the international EORTC CL group meeting at 14th October 2021 in Marseille. Results: A consensus was reached regarding: 1. the clinical characteristics with high rate of hypopigmented and folliculotropic variants, the extremently rare presentation of advanced stage, and the indolent course of early-stage pediatric MF 2. the staging approach which should rely on ultrasound-based imaging of the lymph nodes if indicated, and not on CT/PET-CT. 3. the first-line treatment options which includes potent topical corticosteroids, NBUVB, and
S6 EORTC CLTG meeting abstract book | European Journal of Cancer 190S1 (2023) S1–S55 in case systemic PUVA is indicated (such as in FMF), due to safety considerations and adherence issues, other UVA- based therapies should be preferred, such as topical PUVA, UVA1 or UVA+NBUVB. 4. Radiotherapy should be used only in unique instances. 5. Further recommendations are given e.g. for the use of chlormethin gel or systemic novel treatments e.g. mogamulizumab or brentuximab vedotin. Conclusion: Based on a literature analysis and discussions, recommendations were elaborated by a multidisciplinary expert panel of the three international societies, ISCL/USCLC/EORTC CLTG, presenting for the first time international guidelines for the management of pediatric MF. European Journal of Cancer 190S1 (2023) 112999 https://doi.org/10.1016/j.ejca.2023.112999 O-112 Technical alignment of standardized flow cytometry procedures among Cutaneous Lymphoma Working Groups (CLWGs) and EuroFlow centers: update on a Multicenter Study Fenna de Bie1, Alita van der Sluijs‑Gelling1, Safa Najidh1, Sanne de Haan1, Juan Flores‑Montero2, Alberto Orfao2, Jacques van Dongen3, Julia Almeida2, Maarten Vermeer1 1Dermatology, Leiden University Medical Center, Leiden, the Netherlands, 2Medicine, University of Salamanca, Salamanca, Spain, 3Immunology, Leiden University Medical Center, Leiden, the Netherlands Introduction: Cutaneous T-cell Lymphomas (CTCL) are a rare group of extra-nodal mature T-cell-derived lymphomas of which mycosis fungoides (MF) and Sézary syndrome (SS) are the most common types. Detection of circulating neoplastic cells in SS/MF mostly relies on flow cytometric (FC) assessment which is crucial for SS diagnosis, hematologic staging and immune monitoring in SS/MF. Nevertheless, current FC procedures lack standardization, which inspired the efforts to address this in a multicentric collaborative initiative between CLWGs and EuroFlow centers. Objectives: We aimed to achieve high levels of technical alignment across FC participating laboratories using uniform and newly developed 3-tube, 8-color FC panels in combination with the EuroFlow standardized protocols for instrument setup and sample preparation. Materials and methods: Each participating laboratory (n=16) measured peripheral blood samples from CTCL and healthy controls (HC) across multiple sample-inclusion rounds. All data files were centrally analyzed and compared to assess number of acquired events, scatter characteristics, and median fluorescence intensity (MedFI) values for individual markers by calculating performance scores. Results: Central data analysis allowed for the identification of technical issues among which difficulties with instrument setup and adherence to standardized protocols were most frequently observed. Targeted interventions took place to resolve these technical issues and improve data comparability including hands-on workshops, individualized meetings, and on-site visits, with an overall improvement of the results: reduced variability in MedFI values for individual markers expressed by T-cell subsets from HC, scatter characteristics of leukocytes from HC, and more homogeneous number of acquired events. Conclusion: We conclude that EuroFlow-based educational and targeted support interventions had a positive impact on data reproducibility and that high levels of inter-and intra-laboratory FC standardization are feasible even across different sites and different FC instruments. Adherence to the standardized EuroFlow protocols is critical for minimizing errors in instrument setup, sample preparation, and for increased reproducibility of the final results. European Journal of Cancer 190S1 (2023) 113000 https://doi.org/10.1016/j.ejca.2023.113000 O-113 The value of digital PCR-based quantification of DNA methylation biomarkers in diagnostic challenging early Sézary syndrome patients Willem Zoutman1, Safa Najidh1, Fenna de Bie1, Rogier Nell2, Mieke Versluis2, Pieter van der Velden2, Remco van Doorn1, Kees Tensen1, Maarten Vermeer1 1Dermatology, Leiden University Medical Center, Leiden, the Netherlands, 2Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands Introduction: Sézary syndrome (SzS) is an aggressive type of cutaneous T-cell lymphoma. Diagnosing SzS can be challenging, especially in early stages of disease. Previously, we showed that promoter methylation of PROM1, G0S2, CMTM2, PAM, GNMT and NEXN in CD4+ T-cells isolated from blood is frequently observed in patients with SzS, but is not found in healthy donors and benign erythrodermic inflammatory dermatoses (EID) patients. Objectives: We investigated the diagnostic value of promoter methylation of these biomarkers in patients suspected for SzS but that did not fulfill diagnostic criteria (early SzS). Furthermore, using flowcytometric sorted SzS cells, we assessed intra-patient tumor-specificity of these markers. Materials and methods: Promoter methylation of the selected biomarkers was analyzed in blood samples from 13 early SzS patients, 17 EID patients and 10 healthy donors. All patients with early SzS fulfilled criteria for SzS during follow-up. Quantification of biomarkers was performed by using Methylation Sensitive Restriction Enzyme – digital PCR (MSRE-dPCR) in DNA from enriched CD4+ T-cells isolated from blood. We assessed tumor-specificity in an independent cross-validation experiment using flowcytometric sorted tumor cells from blood from 4 confirmed SzS patients. Results: Blood samples from early SzS patients were positive for at least one of the markers in 12 of 13 (94.4%) of patients. Most discriminative markers were NEXN and CMTM2 (both 94.4%). In contrast, none of the markers were found positive in EID patients and healthy donors, except for CMTM2 (2 of 27 (7.4%)). Cross-validation with flowcytometric sorted SzS cells showed a high tumor-specificity. Markers CMTM2, G0S2, GNMT and PAM were found methylated in all sorted tumor cells and not in cells with a normal phenotype. Conclusion: These data show that promoter methylation of PROM1, G0S2, PAM, GNMT and NEXN is highly specific for SzS cells and can be of value in diagnostic challenging early SzS patients. In addition, the quantification of tumor cells offers a method for monitoring tumor-load, disease progression and treatment efficacy. European Journal of Cancer 190S1 (2023) 113001 https://doi.org/10.1016/j.ejca.2023.113001 O-114 Which parameters to use in flow cytometry in the diagnosis and follow up of mycosis fungoides and Sézary syndrome: a prospective study Pit Leonard Kleiner1, Rohat Cankaya2, Christian Meisel3, Tobias Sinnberg2, Rose Moritz4, Thomas Eigentler2, Max Schlaak2, Dobos Gabor2 1Skin Cancer Centre HTCC, Charité-Universitätsmedizin Berlin, Berlin, Germany, 2Skin Cancer Centre, HTCC, Charité-Universitätsmedizin Berlin, Berlin, Germany, 3Labor Berlin, Charité-Universitätsmedizin Berlin, Berlin, Germany, 4Department of Dermatology, Charité-Universitätsmedizin Berlin, Berlin, Germany Introduction: Blood involvement in mycosis fungoides (MF) and Sézary syndrome (SS) affects clinical decision-making and is generally associated with a poor prognosis. Sézary cells (SC), detected by flow cytometry (FCM) express either CD4+CD7– or CD4+CD26– by current definition and were previously measured as relative numbers. However, there was inconsistency in whether
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