ABSTRACTS BOOK

TABLE OF CONTENTS

COMMITTEES 4

ACKNOWLEDGMENT OF PARTNERS SPONSORS 5

DISCLOSURES 6

ORAL PRESENTATIONS 11

> SESSION B Clinicopathological Correlation > SESSION C Prognotic Factors In CTCL > SESSION D Epidemiology > SESSION E Immunology I > SESSION F Immunology II > SESSION G Pathogenesis Of Cutaneous Lymphomas > SESSION H Biomarkers I > SESSION I Biomarkers II > SESSION J Genetic Pathogenesis > SESSION K Epigenetic Abnormalities > SESSION L Genomic Insights > SESSION M Molecular Characterization Of Rare Cutaneous Lymphomas I > SESSION N Molecular Characterization Of Rare Cutaneous Lymphomas II > SESSION O Cutaneous B-Cell Lymphomas > SESSION P Quality Of Life > SESSION R Preclinical Development Of Personalized Therapies I > SESSION S Preclinical Development Of Personalized Therapies II > SESSION T Novel Therapeutics > SESSION U Stem Cell Transplant > SESSION V Therapeutics I > SESSION W Therapeutics & Clinical Trials II > SESSION X Observations And Perspectives > SESSION Y Topical Chemotherapy > SESSION Z1 Clinical Observations I > SESSION Z2 Clinical Observations II > SESSION Z3 Clinical Observations III > SESSION Z4 Clinical Observations IV

POSTERS PRESENTATIONS 77

> Primary Cutaneous Lymphoma, Clinical & Pathological - Mycosis Fungoides > Primary Cutaneous Lymphoma, Clinical & Pathological - CD30+ Lymphoproliferative Disorders > Primary Cutaneous Lymphoma, Clinical & Pathological - Primary Cutaneous B-Cell . Lymphomas, Including Follicle Center Lymphoma, Marginal Zone, And Diffuse Large B-Cell Lymphoma > Primary Cutaneous Lymphoma, Clinical & Pathological - Uncommon Primary Cutaneous Lymphomas > Basic Research - Etiology And Pathomechanisms - Genomics, Genetics And Epigenetics > Basic Research - Etiology And Pathomechanisms - Molecular Pathways > Basic Research - Etiology And Pathomechanisms - Immunology, Host Response And Tumor Microenvironment > Translational And Clinical Research - Biomarkers & Pathogenesis > Translational And Clinical Research - New Targets In The Treatment Of Cutaneous Lymphomas > Translational And Clinical Research - Combination Therapies: Prospects And Problems > Translational And Clinical Research - Clinical Trials > Translational And Clinical Research - Multinational Collaborative Studies > Patient Care In Cutaneous Lymphoma - Personalized Medicine > Patient Care In Cutaneous Lymphoma - Guidelines > Patient Care In Cutaneous Lymphoma Available Therapies - New Targets > Patient Care In Cutaneous Lymphoma - Quality Of Life/Supportive Therapies > Patient Care In Cutaneous Lymphoma - Difficult To Treat/Rare Lymphomas

INDEX OF AUTHORS 114 COMMITTEES

SCIENTIFIC PLANNING COMMITTEE ISCL HEADQUARTERS > Ramón M. Pujol, Co-Chair | Spain 1932 S. Halsted St., Suite 413 > Larisa Geskin, Co-Chair | USA Chicago, IL 60608 USA > Martine Bagot | France +1-630-578-3991 > Francine Foss | USA EXECUTIVE DIRECTOR: Victoria Ceh, MPA > Joan Guitart | USA [email protected] > Emmilia Hodak | Israel cutaneouslymphoma.org/default.aspx > Chris McCormack | Australia > José Antonio Sanches | Brazil EORTC CUTANEOUS LYMPHOMA TASK > Julia Scarisbrick | U.K. > Makoto Sugaya | Japan FORCE CHAIR: Julia Scarisbrick, MBChB, MD | U.K. LOCAL ORGANIZING COMMITTEE SECRETARY: Antonio Cozzio, MD, PhD | Switzerland TREASURER: Evangelia Papadavid, MD | Greece > Ramón M. Pujol > Fernando Gallardo > Teresa Estrach EORTC HEADQUARTERS > Octavio Servitje Avenue Emmanuel Mounier 83/11 > Pablo Ortiz Romero 1200 Brussels, Belgium > Ricardo Fernández de Misa www.eortc.org/research_field/cutaneous-lymphoma/

4WCCL WORK GROUP UNITED STATES CUTANEOUS LYMPHOMA > Ramón M. Pujol, Co-Chair CONSORTIUM (USCLC) BOARD OF > Larisa Geskin, Co-Chair DIRECTORS > Fernando Gallardo PRESIDENT: Francine Foss, MD > Joan Guitart SECRETARY-TREASURER: Madeleine Duvic, MD > Emmilia Hodak IMM PAST PRESIDENT: John Zic, MD > Julia Scarisbrick > Victoria Ceh, ISCL Executive Director > Wei Ai, MD > Melanie Stancampiano, ISCL Program Manager > Oleg Akilov, MD, PhD > Maria Sanmiguel, Congress Secretariat/Grupo Pacífico > Joi Carter, MD > Larisa Geskin, MD ISCL BOARD OF DIRECTORS > Michael Girardi, MD > Alejandro Gru, MD PRESIDENT: Larisa Geskin, MD | USA > Ellen Kim, MD SECRETARY: Emmilia Hodak, MD | Israel > Stefan Schieke, MD TREASURER: Julia Scarisbrick, MBChB, MD | U.K. > Jasmine Zain, MD IMM PAST PRESIDENT: Joan Guitart, MD | USA REGISTRY CHAIR: Elise Olsen, MD > Martine Bagot, MD, PhD | France > Antonio Cozzio, MD, PhD | Switzerland USCLC HEADQUARTERS > Jade Cury Martins, MD, PhD | Brazil > Paula A. Enz, MD | Argentina 6134 Poplar Bluff Circle, Suite 101 > Steven M. Horwitz, MD | USA Norcross, GA 30092 USA > Michael Khodadoust, MD | USA +1-770-613-0932 > Ivan Litvinov, MD, PhD, FRCPL | Canada EXECUTIVE DIRECTOR: Alyson Conley > Christopher McCormack, MBBS | Australia [email protected] > Montserrat Molgo, MD | Chile http://www.usclc.org/ > Pablo L. Ortiz-Romero, MD, PhD | Spain > Evangelia Papadavid, MD | Greece > Lauren C. Pinter-Brown, MD | USA > Ramon M. Pujol, MD, PhD | Spain > Christiane Querfeld, MD, PhD | USA > Alain H. Rook, MD | USA > Yoshiki Tokura, MD, PhD | Japan > Yang Wang, MD, PhD | China FOUNDING MEMBER: Günter Burg, MD FOUNDING MEMBER: Peter Heald, MD FOUNDING MEMBER: Eric C. Vonderheid, MD

4 ACKNOWLEDGMENT OF PARTNERS SPONSORS

GOLD SPONSOR

SILVER SPONSOR

BRONZE SPONSOR

BASIC SPONSOR

5 DISCLOSURES

Relevant Financial Relationship Disclosures

Abdulla, Farah M-03 Consulting Fees: Mallinkcrodt, Inc Akilov, Oleg E-03 Contracted Research: Pfizer, Trillium, Kyowa Akilov, Oleg R-06 Consulting Fees: Trillium Therapeutics. Contracted Research: Pfizer, Trillium Therapeutics Akilov, Oleg W-01 Contracted Research: Pfizer, Trillium, Kyowa Amitay-Laish, Iris Z-29 Receipt of Intellectual Property Rights/Patent Holder: None Bagot, Martine 077 Consulting Fees: Takeda, Innate Pharma, Kyowa Kirin, Galderma Borgmann, Matthias 069 Salary: 4SC AG Chebly, Alain K-02 Salary: Saint Joseph University Beirut, Lebanon. Grant/ Schoolarship: Hubert Curlen Partnership PHC CEDRE Di Raimondo, Cosimo K-04 Salary: Residency University of Roma Tor Vergata Enciso Olivera, Leonardo J. 076 Consulting Fees: Therakos Flanagan, Charlotte E. R-04 Other: Charity funded PhD Foss, Francine M. U-04 Consulting Fees: Seattle Genetics, Acrotech,Miragen. Fees received for promotional services: Seattle Genetics Foss, Francine M. 071 Consulting Fees: Seattle Genetics, Acrotech,Miragen, Kuva. Gilmore, Elain S. Y-04 Contracted Research: Helsinn Therapeutics Inc Giza, Agnieszka P-01 Consulting Fees: Takeda Giza, Agnieszka Z-19 Consulting Fees: Takeda Gru, Alejandro B-02 Salary: Seattle Genetics / Innate Pharma . Consulting Fees: Seattle Genetics / Innate Pharma. Fees received for promotional services: Seattle Genetics / Stemline. Contracted Research: Innate Pharma / Stemline Guenova, Emmanuella 073 Consulting Fees: Therakos, Takeda, Helsinn, Recordati, Kyowa Guitart, Joan B-05 Consulting fees: Miragen, Kirin, Helsinn. Contracted research: Galderma, Elacon, Soligenix Hwang, Sam S-01 Receipt of Intellectual Property Rights/Patent Holder: Inventor on specific therapeutic use of the ChemoCentryx agent evaluated in this study Kim, Ellen Y-03 Consulting Fees: Helsinn. Contracted Reseach: Galderma, Helsinn, Kyowa Kirin, MedImmune, Soligenix Noor, Sarah Z-04 Consulting Fees: Advisory Board, Kyowa Kirin Noor, Sarah 037 Consulting Fees: Advisory Board, Kyowa Kirin Phillips, Scott 070 Salary: Elorac, Inc. Ownership interest: Elorac, Inc Poligone, Brian Z-03 Fees received for promotional services: Helsinn, Regeneron, Stemline, Mallinckrodt . Contracted Research: Helsinn Therapeutics, Astex, Bioniz, Innate Pharmaceuticals, Kyowa-Kirin, Miragen, Soligenix, Replimmune Poligone, Brian 026 Fees received for promotional services: Helsinn, Regeneron, Stemline, Mallinckrodt . Contracted Research: Helsinn Therapeutics, Astex, Bioniz, Innate Pharmaceuticals, Kyowa-Kirin, Miragen, Soligenix, Replimmune Prag Naveh, Hadas Y-01 Advisory boards: RAFA Quaglino, Pietro X-01 Consulting Fees: Takeda, 4SC, Therakos, Kyowa, Helsinn

6 DISCLOSURES

Querfeld, Christiane S-06 Consulting Fees: Helsinn, Miragen, Kyowa Kirin. . Contracted Research: Celgene, Helsinn, Miragen, Bioniz . Reseach grant: Celgene Querfeld, Christiane Y-02 Consulting Fees: Helsinn, Miragen, Kyowa Kirin. . Contracted Research: Celgene, Helsinn, Miragen, Bioniz . Reseach grant: Celgene Ramelyte, Egle T-04 Consulting Fees: None Scarisbrick, Julia C-01 Consulting Fees: Therakos, Takeda, Helsinn, Recordati, Kyowa Scarisbrick, Julia V-05 Consulting Fees: Takeda, Kyowa, Helsinn, Recordati, 4SC, Innate Pharma, Therakos Schrader, Anne M.R. O-04 Salary: LUMC, Leiden, The Netherlands Sokołowska-Wojdyło, T-02 Salary: Roche, Takeda . Consulting Fees: Takeda, Helsinn Healthcare Malgorzata Stadler, Rudolf Z-17 Consulting Fees: Kyowa Kirin, Takeda, 4SC Stadler, Rudolf 072 Consulting Fees: Kyowa Kirin, Takeda, 4SC Streubel, Gundula S-05 Salary: 4SC AG Wong, Henry K. E-02 Consulting Fees: Helsinn, Kyowa Kirin . Contracted Research: Soligenix, Eisai Wong, Henry K. L-03 Consulting Fees: Helsinn, Kyowa Kirin . Contracted Research: Soligenix, Eisai Wong, Henry K. 060 Consulting Fees: Helsinn, Kyowa Kirin . Contracted Research: Soligenix, Eisai Zic, John B-01 Royalty: UpToDate, Inc

7 DISCLOSURES

None Disclosure

Andrade Campos, Marcio V-01 Gainza Apraiz, Isabel 010 Aranguren-López, Iñigo 050 Gallardo, Fernando R-01 Audrey, Gros O-03 Gallardo, Fernando 053 Bagot, Martine T-01 Geller, Shamir C-03 Bakr, Farrah S-02 Geller, Shamir I-02 Bastidas Torres, Armando N-03 Gonzalez Romero, Nerea 034 Beksac, Burcu J-04 Goyal, Amrita D-06 Bhat, Trisha P-02 Goyal, Amrita X-03 Bhat, Trisha P-03 Goyal, Amrita Z-23 Bhat, Trisha P-05 Goyal, Amrita 011 Blanco, Gonzalo L-04 Grandi, Vieri 075 Braun, Jana Dorothea 001 Grekova, Ekaterina I-03 Brunner, Patrick M. J-01 Grekova, Ekaterina 012 Buelens, Odette Z-25 Gunes, E. Gulsen E-01 Cayrol, Maria Florencia S-04 Hirotsu, Kelsey E. X-06 Choi, Jaehyuk L-01 Ibrahim, Mona Abdel-Halim Z-20 Christoph, Blazejak 002 Ibrahim, Mona Abdel-Halim Z-22 Colomo, Luis M-05 Ibrahim, Mona Abdel-Halim Z-28 Combalia, Andrea 003 Ibrahim, Mona Abdel-Halim 013 Coolman, Tyler 078 Iriondo, June Z-07 Csányi, Ildikó Z-05 Iyer, Aishwarya 014 Daniels, Jay N-01 Iyer, Aishwarya 015 Davis, Michael 032 Iznardo, Helena 016 De Freire Cassia, Flavia 004 Iżykowska, Katarzyna K-01 De Freire Cassia, Flavia 005 Jan P., Nicolay H-01 De Freire Cassia, Flavia 006 Jean-Philippe, Merlio O-02 De Freire Cassia, Flavia 007 Jeroen , Pyl 061 De la Torre Gomar, Francisco Javier 033 Johnson, Amy Z-01 De la Torre Gomar, Francisco Javier 051 Johnson, Amy Z-18 De Masson, Adèle I-01 Johnson, Courtney D-03 De Masson, Adèle 008 Jones, Christine G-04 Del Guzzo, Christina 009 Jones, Christine H-02 Dimitriou, Florentia O-06 Jost, Marion 054 D'Incan, Michel 036 Jo-Velasco, Margarita O-05 Doss, Gowardhanan X-05 Kamijo, Hiroaki 066 Enz, Paula D-05 Khalid, Amina 074 Espinosa, Maria L. Z-02 Kim, Youn H. W-03 Eve , Maubec 041 Koralov, Sergei G-02 Fornons, Rosa Z-06 Koralov, Sergei L-02 Fujii, Kazuyasu 052 Laggis, Caroline 017 Gabor, Dobos D-01 Lastrucci, Irene 042 Gabor, Dobos J-03 Lewis, Daniel V-06

8 DISCLOSURES

Litvinov, Ivan 018 Riera Monroig, Josep 039 Lobato Izagirre, Ane 019 Rodriguez Pinilla, Socorro Maria H-03 Lopes Iori, Nathalia Z-12 Rodriguez Pinilla, Socorro Maria M-04 López Aventín, Daniel 020 Rook, Alain H. W-02 Lopez-Lerma, Ingrid 055 Rooke, Bethanie X-02 Machan, Salma M-01 Rosell-Diaz, Angel Manuel 056 Martí Laborda, Rosa Maria 043 Rosenthal, Jaclyn M. 080 Martinez, Xochiquetzal P-04 Rosés Gibert, Pau 057 Martinez, Xochiquetzal 082 Rovira-López, Roger 046 Massuda, Juliana Yumi Z-10 Rytenband, Fernanda 040 Mccormack, Christopher M-02 Saenz Aguirre, Amaia 047 Mccormack, Christopher 035 Secamilli, Elisa Nunes Z-16 Melchers, Rutger X-04 Seffens, Angelina G-01 Melchers, Rutger Z-08 Shimauchi, Takatoshi F-04 Meruelo Ruano, Mikel 021 Sim, Van Ren T-03 Michel, Mirna Z-14 Suga, Hiraku 027 Michelena, Miren Josune 022 Suzuki, Natalia Z-24 Mirza, Fatima N. D-02 Suzuki, Natalia Naomi 028 Mirza, Fatima N. R-05 Szakonyi, József 058 Miyagaki, Tomomitsu 067 Szakonyi, József 059 Miyashiro, Denis C-04 Takahashi-Shishido, Naomi G-05 Miyashiro, Denis V-03 Torres-Cabala, Carlos B-06 Molgó, Montserrat Z-11 Trager, Megan Z-09 Molgó, Montserrat Z-15 Trager, Megan 029 Morris, Stephen U-03 Urigoitia Ugalde, Peru 030 Moyal, Lilach K-03 Vakeva, Liisa 081 Najidh, Safa G-03 Van Santen, Suzanne B-03 Nakagawa, Yuki 044 Walker, Christina J. B-04 Nieto Benito, Lula María 068 Walker, Christina J. 049 O'donnell, Megan V-02 Wang, Erica J-02 Ødum, Niels 062 Wang, Jennifer Y. X-07 Onida, Francesco U-02 Wang, Yang F-01 Palomero, Teresa R-03 Wehkamp, Ulrike G-06 Papadavid, Evangelia 064 Wehkamp, Ulrike Z-27 Papaleo, Natalia 023 Wehkamp, Ulrike 063 Papathemeli, Despoina F-03 Weng, Wen-Kai U-01 Parente Almeida, Isabella Z-26 William, Basem V-04 Patsatsi, Aikaterini 024 Yoo, Jinah C-02 Pileri, Alessandro 025 Yumeen, Sara R-02 Pileri, Alessandro 065 Yumeen, Sara Z-13 Prieto Torres, Lucia 045 Zhou, Xiaolong O-01 Pulido-Perez, Ana 079 Zhou, Xiaolong Z-21 Pulitzer, Melissa N-02 Reyes-Baraona, Francisco D-04 Riera Monroig, Josep 038

9 DISCLOSURES

Off Label Disclosures

Akilov, Oleg E-03

Akilov, Oleg R-06

Akilov, Oleg W-01

Bagot, Martine T-01

Chebly, Alain K-02

Combalia, Andrea 003

Espinosa, Maria L. Z-02

Ibrahim, Mona Abdel-Halim Z-20

Johnson, Amy Z-01

Johnson, Amy Z-18

Laggis, Caroline 017

Lewis, Daniel V-06

Mirza, Fatima N. D-02

Mirza, Fatima N. R-05

Palomero, Teresa R-03

Pulido-Perez, Ana 079

Ramelyte, Egle T-04

Rodriguez Pinilla, Socorro Maria H-03

Rodriguez Pinilla, Socorro Maria M-04

Rosenthal, Jaclyn M. 080

Sokołowska-Wojdyło, Malgorzata T-02

Trager, Megan Z-09

Trager, Megan 029

Weng, Wen-Kai U-01

William, Basem V-04

10 ORAL PRESENTATIONS ORAL PRESENTATIONS

SESSION B - CLINICOPATHOLOGICAL CORRELATION

B-01 CLINICOPATHOLOGIC CORRELATION AND SHORT-TERM OUTCOME ANALYSIS OF A HIGHLY CURATED COHORT OF FOLLICULOTROPIC MYCOSIS FUNGOIDES: AN INTERNATIONAL VIRTUAL STUDY

Hodak, E.1; Zic, J.2; Bagot, M.3; Gru, A.4; Battistella, M.5; Mitteldorf, C.6; Cozzio, A.7; Guenova-Hotzenecker, E.8; Guitart, J.9; Geskin, L.10; Knobler, R.11; Ortiz, P.12; Papadavid, L.13; Querfeld, C.14; Quaglino, P.15; Rooke, B.16; Stadler, R.17; Sanchez, J.A.18; Duvic, M.19; Junkins-Hopkins, J.20; Pulitzer, M.M.21; Kempf, W.8; Haun, P.22; Torres-Cabala, C.23; Robson, A.24; Beltraminelli, H.25; Subtil, A.26; Kim, Y.27; Scarisbrick, J.16

1Dermatology, Rabin Medical Center, Tel Aviv University, Israel; 2Dermatology, Vanderbilt University, Nashville, United States; 3Dermatology, Hospital St. Louis, Paris, France; 4Pathology & Dermatology, University of Virginia, Charlottesville, United States; 5Pathology & Dermatology, Hospital St. Louis, Paris, France; 6Dermatology, University of Goettingen, Goettingen, Germany; 7Dermatology, University of St. Gallen, St. Gallen, Switzerland; 8Dermatology, University of Zurich, Zurich, Switzerland; 9Pathology & Dermatology, Northwestern University, Chicago, United States; 10Dermatology, Columbia University, New York, United States; 11Dermatology, University of Vienna, Vienna, Austria; 12Dermatology, University of Madrid, Madrid, Spain; 13Dermatology, Attikon University Hospital, Athens, Greece; 14Dermatology, City of Hope Medical Center, Duarte, United States; 15Dermatology, University of Torino, Turin, Italy; 16Dermatology, University Hospitals Birmingham, Birmingham, United Kingdom; 17Dermatology, University of Minden, Minden, Germany; 18Dermatology, University of Sao Paulo, Sao Paulo, Brazil; 19Dermatology, MD Anderson Cancer Center, Houston, United States; 20Dermatology, Geissinger Medical Center, Danville, United States; 21Pathology, Memorial Sloan-Kettering Cancer Center, New York, United States; 22Dermatology, University of Pennsylvania, Philadelphia, United States; 23Pathology, MD Anderson Cancer Center, Houston, United States; 24Dermatopathology, St. John's Institute of Dermatology, London, United Kingdom; 25Dermatology, University of Bern, Bern, Switzerland; 26Pathology, Royal-Jubilee Hospital, Victoria, Canada; 27Dermatology, Stanford University, Palo Alto, United States.

Introduction: The concept of 2 distinct patterns of clinicopathologic features of folliculotropic mycosis fungoides (FMF), representing early-stage (patch/thin plaque) and advanced-stage (thick plaque/tumor), reported by two single-center studies requires international validation.

Material and Methods: Clinical photos of patients with FMF from international experts were centrally scanned and virtually reviewed using REDCap (Research Electronic database Capture, Vanderbilt University).

The REDCap survey contained clinical images and questions to capture expert opinion on clinical FMF phenotype. Lesions were scored as early; patch/thin plaque (including follicular papules, keratosis pilaris-like lesions or milia) or advanced; thick plaque/tumor, if >65% of the participants agreed. A separate, blinded, virtual pathological review was performed on corresponding histologic slides by a panel of expert dermatopathologists who graded severity of the perifollicular infiltrate (1,2,3).

Following separate clinical and pathological virtual review, participants met for clinicopathological real-time review of each case (12.6.2019). Clinicopathologic correlation was quantified and additional clinical outcome data analyzed.

Results: 83 biopsy sites from 71 patients were evaluated in this training set. Based on the REDCap survey, in 72% there was clinical agreement of early/advanced lesion-type, and in 69% of cases agreement on early/advanced FMF. Agreement was highest in the limb (86%) and trunk (79%), followed by face (65%), and lowest from the scalp (38%). A high correlation was found between grade-1 perifollicular infiltrate and early lesions, with lower correlation between grade-2 and early lesions, and grade-3 and advanced lesions. There were no overall survival differences comparing cases with clinical agreement of early to advanced FMF (median follow-up= 27 months; range 0-227 months). In contrast, comparison of overall survival of patients with grade-1 pathology to grade-3 pathology was statistically significant (p=0.038, log rank test).

Conclusion: This virtual international study confirms 2 clinicopathologic subgroups of FMF. Pathologic grade may play more than a diagnostic role in FMF management.

B-02 FOLLICULOTROPIC MYCOSIS FUNGOIDES – RESULTS OF AN INTERNATIONAL CONSENSUS HISTOPATHOLOGIC REVIEW

Gru, A.1; Climent Esteller, F.2; Mitteldorff, C.3; Pulitzer, M.4; Hodak, E.5; Zic, J.6; Kempf, W.7; Guenova, E.7; Haun, P.8; Torres Cabala, C.9; Robson, A.10; Querfeld, C.11; Junkins Hopkins, J.12; Cozzio, A.13; Papadavid, E.14; Quaglino, P.15; Beltraminelli, H.16; Knobler, R.17; Stadler, R.18; Geskin, L.19; Bagot, M.20; Subtil, A.21; Sanches Jr, J.A.22; Guitart, J.23; Rook, B.24; Duvic, M.25; Ortiz Romero, P.26; Kim, Y.27; Scarisbrick, J.24; Battistella, M.28

1Pathology & Dermatology, University of Virginia, Charlottesville., United States; 2Pathology, Hospital Universitari de Bellvitge, L´Hospitalet de Llobregat, Spain; 3Dermatology, University of Goettingen, Göttingen, Germany; 4Pathology, Memorial Sloan Kettering Cancer Center, New York, United States; 5Dermatology, Rabin Medical Center, Petah Tikva, Israel; 6Dermatology, Vanderbilt University, Nashville, United States; 7Dermatology, University of Zurich, Zurich, Switzerland; 8Dermatology, University of Pennsylvania, Philadelphia, United States; 9Pathology, MD Anderson Cancer Center, Houston, United States; 10Pathology, St. John's Institute, London, United Kingdom; 11Dermatology, City of Hope, Duarte, United States; 12Dermatology, Geisinger, Danville, United States; 13Dermatology, University of Saint Gallen, Saint Gallen, Switzerland; 14Dermatology, University of Athens, Athens, Greece; 15Dermatology, University of Torino, Torino, Italy; 16Dermatology, University of Bern, Bern, Switzerland; 17Dermatology, University of Vienna, Vienna, Austria; 18Dermatology, University of Minden, Minden, Germany; 19Dermatology, Columbia University, New York, United States; 20Dermatology,

12 ORAL PRESENTATIONS

Hospital St. Louis, Paris, France; 21Pathology, Royal-Jubilee, Victoria, Canada; 22Dermatology, University of Sao Paulo, Sao Paulo, Brazil; 23Dermatology, Northwestern University, Chicago, United States; 24Dermatology, University Hospitals Birmingham, Birmingham, United Kingdom; 25Dermatology, MD Anderson Cancer Center, Houston, United States; 26Dermatology, Hospital Universitario 12 de Octubre, Madrid, Spain; 27Dermatology, Stanford University, Palo Alto, United States; 28Pathology & Dermatology, Hospital St. Louis, Paris, France.

Introduction/Aim: The current study evaluated the histopathologic characteristics of folliculotropic mycosis fungoides (FMF) using centralized pathology review in an international, multi-institutional approach.

Material and Methods: Patients with clinical and histopathologic diagnosis of FMF were included in this study. All histopathologic slides were referred for digital slide scanning. A panel of expert dermatopathologists first reviewed all digitized slides and had consensus conferences to discuss diagnostic discrepancies. The histopathologic criteria included: density/ intensity of perifollicular infiltrate and folliculotropism, depth of infiltrate, presence of follicular mucinosis, epidermotropism, granulomatous elements, syringotropism, large cell transformation, and CD30/Ki67 expression (when available). The pathologists were blinded to the type of lesion biopsied and the clinical staging of the disease. A consensus agreement was established when ≥67% agreement was reached among the reviewers.

Results: A total of 83 patients were enrolled in this training set, with 105 biopsies independently scored by the reviewers. 5 biopsies were excluded due to insufficient histologic quality. The perifollicular infiltrate pathologic grading included 30% of cases with grade 1, 47% grade 2, and 19% grade 3. Consensus grading was achieved in 75% of grade 1, 67% of grade 2, and 85% of grade 3. Only 6 cases lacked consensus agreement in grading. The overall consensus agreement across all grades was 74%. The interobserver agreement for the grading system used was 0.58 (moderate agreement) in the training set. A validation cohort of 81 patient samples will be used for assessment of interobserver agreement improvement (for a total of 164 patients being analyzed).

Conclusions: Appropriate consensus histopathologic agreement can be established in most cases of FMF using strict criteria for grading. Perifollicular infiltrate grades 1 and 3 show very good correlation with the type of clinical lesion being biopsied.

B-03 PLAQUE STAGE FOLLICULOTROPIC MYCOSIS FUNGOIDES: HISTOPATHOLOGIC FEATURES AND PROGNOSTIC FACTORS IN A SERIES OF 40 PATIENTS

Van Santen, S.1; Jansen, P.2; Quint, K.1; Vermeer, M.1; Willemze, R.1

1Dermatology, Leiden University Medical Center, Leiden, Netherlands; 2Clinical Pathology, Leiden University Medical Center, Leiden, Netherlands.

Introduction & Objectives: Folliculotropic mycosis fungoides (FMF) is a distinct variant of mycosis fungoides. Recent studies recognized indolent and aggressive subgroups of FMF, but there is controversy how patients presenting with plaques should be classified. The present study describes the histopathologic features of 40 FMF plaques. The aim of the study was to identify risk factors for disease progression and poor outcome in this group.

Materials & Methods: Clinical, histopathological and immunophenotypical data from 40 patients with plaque stage FMF were reviewed and analysed for risk factors for disease progression and survival.

Results: After a median follow-up of 80 months disease progression occurred in 20 of 40 patients. Percentage of atypical cells, cell size, percentage of Ki-67+ cells and co-existent interfollicular epidermotropism, but not the extent of perifollicular infiltrates, were associated with disease progression and reduced survival, while extensive follicular mucinosis was associated with increased survival.

Conclusions: This study underlines that FMF patients presenting with plaques represent a heterogeneous group and that a subgroup of these patients may have an indolent clinical course. It furthers shows that histological hallmarks are a valuable tool to differentiate between indolent and aggressive disease.

B-04 ADNEXOTROPISM: AN UNDER-RECOGNIZED HISTOPATHOLOGICAL FINDING IN AGGRESSIVE CYTOTOXIC CUTANEOUS LYMPHOMAS

Walker, C.J.; Martinez-Escala, E.; Espinosa, M.L.; Tan, T.; Guitart, J.

Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, United States.

Introduction and Objectives: Primary cutaneous gamma-delta T-cell lymphoma (PCGDTCL) and primary cutaneous aggressive epidermotropic T cell lymphomas (PCAETCL) are rare aggressive cytotoxic cutaneous lymphomas (CyCL) often difficult to diagnose. Adnexotropism, including folliculotropism and syringotropism, are usually associated with mycosis fungoides and its occurrence in CyCL has been rarely described. Our aim is to evaluate histopathological adnexotropism in CyCL with clinical correlation.

Material and Methods: Retrospective single-center review of medical records, clinical photographs and histopathological material from CyCL patients with pathological annotation of adnexotropism.

13 ORAL PRESENTATIONS

Results: We reviewed 109 skin biopsies of 39 patients (median age 73 years; 32M:7F) diagnosed with PCAETCL (16), PCGDTCL (15) and cytotoxic CTCL, unspecified (8) with notable adnexotropism. Clinically, most patients had extensive patches/plaques (92%) and ulcerated tumors (41%) occupying a mean body surface area of 20%. Patches of alopecia (36%) often associated with follicular prominence (31%) were noted in 13 cases, mostly correlating with extensive adnexotropism. Palmoplantar involvement was associated with syringotropism in 7 cases. The pathological pattern was primarily epidermotropic (83%) or dermal (17%) without predominantly panniculitic lymphomas. Folliculotropism (75%) was observed more frequently than syringotropism (54%) and combined adnexotropism was noted in 46% of cases. Follicular mucinosis (3), hyperplasia of the eccrine unit (2) and disruption of the follicular epithelium with granulomatous reaction (1) were rarely observed. Eosinophils were abundant in 28% of biopsies.

Conclusions: We estimate that the majority of epidermotropic CyCL demonstrate adnexotropism, which in some cases may be the salient location of the tumor infiltrate. This histological finding is rarely accompanied by clinical signs of adnexotropism. Raising awareness of this phenomenon is important for a timely diagnosis of these aggressive lymphomas.

B-05 SUBCUTANEOUS PANNICULITIS-LIKE T-CELL LYMPHOMA (SPTCL): A LARGE US CASE SERIES REVEALS A LYMPHOMA WITH LIMITED GROWTH POTENTIAL IN NEED OF DIAGNOSTIC AND THERAPEUTIC GUIDELINES

Guitart, J.1; Walker, C.J.1; Martinez-Escala, E.1; Comfere, N.I.2; Pulitzer, M.3; Rieger, K.4; Torres Cabala, C.A.5; Pincus, L.6; Duvic, M.7; Park, K.E.7; Espinosa, M.L.1; Kumar, E.S.8; Horwitz, S.9; Kim, Y.H.10; Mangold, A.R.11

1Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, United States; 2Department of Dermatology, Mayo Clinic, Rochester, United States; 3Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States; 4Department of Dermatopathology, Stanford University, Palo Alto, United States; 5Department of Pathology, MD Anderson Cancer Center, Houston, United States; 6Department of Dermatology, University of California San Francisco, San Francisco, United States; 7Department of Dermatology, MD Anderson Cancer Center, Houston, United States; 8Department of Pathology, Pathology Laboratory Associates/Regional Medical Laboratory, Tulsa, United States; 9Oncology, Memorial Sloan Kettering Cancer Center, New York, United States; 10Department of Dermatology, Stanford University, Stanford, United States; 11Department of Dermatology, Mayo Clinic, Phoenix, United States.

Introduction & Objectives: The knowledge of SPTCL is limited by the lack of multicenter large cohort data. We aimed to review the collaborative experience of 6 US academic centers.

Materials & Methods: Retrospective clinic-pathological review of 95 cases during 2workshops.

Results: We identified a spectrum of cases including atypical lymphocytic lobular panniculitis (ALLP) characterized bymixed lymphohistiocytic infiltrate with T-cell clonality, subtle atypia and indolent chronic course (20 cases) preceding SPTCL in 2 cases. We also identified 75 SPTCL cases (mean age 39; F:M ratio: 2.7) fulfilling rigorous clinic-pathological criteria. Most patients had multiple deep painful nodules (85%) involving legs (66%)> arms (53%) with 15% unilesional cases. Lesional and/or non-lesional lipoatrophy was observed in 31% of the cases and a personal (26%) or family history (13%) of autoimmunity was recognized. While fever and other B-symptoms were common (75%) only 17% were reported to have HLH (mean 3.4 criteria). An abnormal bone marrow biopsy was reported in 30%, including HLH 11, SPTCL 4. Most abnormal PET/CT involved the subcutaneous tissue with 2 PET-avid nodal cases with negative biopsy. With a mean follow up of 54 months 66.6% achieved CR with 3 median cumulative therapies. Relapse was common (61%) with a gradual decrease in recurrence after each subsequent treatment. None of our patients died of disease progression or HLH.

Conclusions: This is the largest reported series of SPTCL to date demonstrating no evidence of systemic tumoral progression beyond the subcutaneous fat. Rare involvement of marrow adipose tissue or perinodal fat does not seem to imply systemic progression. Clonal ALLP poses a diagnostic challenge and may precede SPTCL. Our data shows favorable responses with a variety of treatments from immune- suppression to polychemotherapy with morbidity mostly related to HLH. Our observations highlight the need for consensus guidelines for the diagnosis and treatment of SPTCL.

B-06 GRANULOMATOUS MYCOSIS FUNGOIDES: A CLINICOPATHOLOGICAL STUDY OF 41 CASES FROM A TERTIARY CANCER CENTER

Alani, A.1; Navarrete-Viveros, J.2; Aung, P.2; Nagarajan, P.2; Tetzlaff, M.2; Curry, J.2; Prieto, V.2; Huen, A.3; Miranda, R.2; Duvic, M.3; Torres-Cabala, C.2

1Pathology, Baylor College of Medicine, Houston, United States; 2Pathology, The University of Texas MD Anderson Cancer Center, Houston, United States; 3Dermatology, The University of Texas MD Anderson Cancer Center, Houston, United States.

Introduction & Objectives: Our current knowledge of the clinicopathological features of granulomatous mycosis fungoides (GMF) is very limited. We aimed to evaluate a large series of GMF in order to elucidate histopathological features and their impact on prognosis.

Material & Methods: 47 skin biopsies from 41 GMF patients seen at our institution between 2010 and 2019 were evaluated. Medical records and skin biopsies were examined. Clinical and pathological findings were recorded.

Results: The median age of our patients (28 Caucasian, 11 African American, 2 Hispanic) was 63 years. M:F was 1.4:1. Biopsies were taken from upper extremities (34%), lower extremities including hip (22%), head & neck (20%), back (15%), and chest and abdomen (9%). Most

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of the lesions were plaques (79%) and tumors (18%) with moderate to high cell density (92%) and nodular/diffuse pattern of infiltration (95%). Epidermotropism was common (95%) but predominantly mild (77%). Folliculotropism was frequent (74%); syringotropism was detected in 34% of the cases. Four cases (10%) showed large cell transformation. The granulomatous component of the lesions showed: poorly formed granulomas (74%), well-formed granulomas (26%), multinucleated giant cells (68%), elastophagocytosis (36%), and emperipolesis (21%). Immunophenotype of the tumors was: CD4+CD8- (89%), CD4-CD8+ (2%), CD4+CD8+ (at least a subset, 7%), and CD4-CD8- (at least a subset 2%). All the tested cases showed alpha/beta phenotype. 41.5% of our GMF patients were dead on a median follow up of 67.2 months. All the large cell transformation patients were alive at last follow up. Histopathological features that appeared to be associated with survival were: presence of well-formed granulomas (80% patients alive), elastophagocytosis (79%), and emperipolesis (100%).

Conclusions: GMF frequently occurs on upper and lower extremities. Folliculotropism is frequently seen and syringotropism is not uncommon. Cases showing well-formed granulomas, elastophagocytosis, and emperipolesis on biopsy examination may be associated with a better survival.

SESSION C - PROGNOSTIC FACTORS IN CTCL

C-01 PROGNOSTIC FACTORS FOR STAGE PROGRESSION AND SURVIVAL IN MYCOSIS FUNGOIDES AND SEZARY SYNDROME: THE PROCLIPI STUDY

Scarisbrick, J.1; Quaglino, P.2; Prince, M.3; Papadavid, E.4; Hodak, E.5; Whittaker, S.6; Bagot, M.7; Querfeld, C.8; Akilov, O.9; Servitje, O.10; Berti, E.11; Ortiz, P.12; Stadler, R.13; Knobler, R.14; Mitteldorf, C.15; Estrach, T.16; Marschalko, M.17; Guenova, E.18; Pimpinelli, N.19; Beylot-Barrie, M.20; Wobser, M.21; Wehkemp, U.22; Cowan, R.23; Vakeva, L.24; Busschots, A.M.25; Matin, R.26; Evison, F.27; Hong, E.28; Cerroni, L.29; Kempf, W.30; Gru, A.31; Battistella, M.32; Vermeer, M.33; Willemze, R.33; Kim, Y.28

1Dermatology, University Hospital Birmingham, Birmingham, United Kingdom; 2Dermatology, Turin, Turin, Italy; 3Haematology, PeterMac, Melbourne, Australia; 4Dermatology, Athens, Athens, Greece; 5Dermatology, Rabin, Tel Aviv, Israel; 6Dermatology, GSTT, London, United Kingdom; 7Dermatology, St Louis, Paris, France; 8Dermatology, City of Hope, Los Angeles, United States; 9Dermatology, Pittsburgh, Pittsburgh, United States; 10Dermatology, Barcelona, Barcelona, Spain; 11Dermatology, Milan, Milan, Italy; 12Dermatology, Madrid, Madrid, United Kingdom; 13Dermatology, Minden, Minden, Germany; 14Dermatology, Vienna, Vienna, Austria; 15Dermatology, Hildesheim, Hildesheim, Germany; 16Dermartology, Barcelona, Barcelona, Spain; 17Dermatology, Semmelweis, Semmelweis, Hungary; 18Dermatology, Zurich, Zurich, Switzerland; 19Dermatology, Florence, Florence, Italy; 20Dermatology, Bordeaux, Bordeaux, France; 21Dermatology, Wuerzburg, Wuerzburg, Germany; 22Dermatology, Kiel, Kiel, Germany; 23Oncology, Manchester, Manchester, United Kingdom; 24Dermatology, Helsinki, Helsinki, Finland; 25Dermatology, Leuven, Leuven, Belgium; 26Dermatology, Oxford, Oxford, United Kingdom; 27Statistician, University Hospital Birmingham, Birmingham, United Kingdom; 28Dermatology, Stanford, Stanford, United States; 29Histopathology, Graz, Graz, Austria; 30Histopathology, Zurich, Zurich, Switzerland; 31Dermatology, Virginia, Virginia, United States; 32Histopathology, St Louis, Paris, France; 33Dermatology, Leiden, Leiden, Netherlands.

Introduction & Objectives: In order to investigate prognostic factors in mycosis fungoides and Sezary syndrome the PROCLIPI Study; a prospective international study was launched in 2015.

Materials & Methods: This study collects pre-defined clinical, haematological, radiological, immunohistochemical, genotypic and treatment data.

Results: 1519 patients have been recruited at 47 sites, from 18 countries across 6 continents, with a median follow-up of 13 months. 1157 early-stage patients (male:female ratio=1.7:1) and 362 advanced (male;female ratio 1.7:1). Early-stage includes IA;n=590, IB;n=481, IIA;n=85 with median age=58years. Blood involvement (B1) was present in 8% and 16% had an identical clone in blood to skin. 443 patients (40%) had imaging and 67 patients (15%) had lymph nodes ≥1.5cm. Only 20 had a LN biopsy which was N1;n=16 and N2;n=3. Factors associated with progression to advanced disease (n=66) included higher mSWAT;p<0.001, raised LDH;p=0.020, LCT skin;p<0.001 but not age>60yrs;p=0.075 or B1;p=0.115 or identical blood clone;p=0.131. Stage IIA patients had a higher mSWAT;p=0.0012 but were not more likely to be B1 than IB patients;p=0.434. 362 advanced stage patients are recruited stage IIB;n=116,IIIA;n=43,IIIB;n=41,IVA1;n=114, IVA2;n=34,IVB;n=14. The median age=66yrs (significantly higher than early-stage cohort at 58yrs p<0.0001). In advanced stages disease- specific deaths were more frequent with LCT skin;p=0.044 and N3;p<0.001 but not raised LDH;p=0.183 or age>60yrs;p=0.409.

Conclusions PROCLIPI is the first international prospective study recording pre-defined prognostic parameters in MF/SS. In early stage progression to advanced disease is associated with higher mSWAT, raised LDH and LCT in skin but not age>60yrs. In advanced disease poor survival was also associated with raised LCT in skin but not raised LDH, age or mSWAT. N3 nodes were also a poor prognostic marker for survival. Identifying prognostic markers may help select patients for more aggressive treatment options and better management and survival.

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C-02 REVIEW OF THE MEASUREMENTS OF ABNORMAL LYMPH NODES ON IMAGING AND THE CORRELATION WITH N CLASS FROM THE PROSPECTIVE CUTANEOUS LYMPHOMA INTERNATIONAL PROGNOSTIC INDEX STUDY

Yoo, J.1; Bagot, M.2; Hodak, E.2; Servitige, O.2; Pujol, R.2; Marschalko, M.2; Papadavid, E.2; Cowan, R.2; Mitteldorf, C.2; Jonak, C.2; Querfeld, C.3; Busschots, A.2; Martin, R.2; Wehkamp, U.2; Hong, E.3; Battistella, M.2; Evison, F.4; Kim, Y.3; Scarisbrick, J.2

1Department of Dermatology, University Hospitals Birmingham, Birmingham, United Kingdom; 2Cutaneous Lymphoma Task Force EORTC, Belgium; 3Cutaneous Lymphoma International Consortium, United States; 4University Hospitals Birmingham, Birmingham, United Kingdom.

Introduction & Objectives: Current skin lymphoma guideline defines abnormal node as long axis ≥15mm on imaging which requires further histological investigation. However, this is based on systemic lymphoma guidelines which does not reflect the presence of dermatopathic lymph nodes(LNs). Therefore, we reviewed measurements on imaging to make a correlation with histological N-class.

Materials & Methods: We reviewed PROCLIPI database to identify patients who had LN biopsy following imaging and reviewed measurements of the biopsied LN on imaging.

Results: 82 patients had LN biopsy following imaging. Gender was 56 males:26 females(2:1). Median age at diagnosis was 58 yrs(IQR=50-70yrs). Stage at diagnosis was IB=5,IIA=20,IIB=8,IIIA=4,IIIB=8,IVA1=9,IVA2=25 & IVB=3. In 74(85%) this was a biopsy at diagnosis. Median time from diagnosis to biopsy was 1 month(IQR=0-4months). The N-class of the biopsied node was N1=37(43%), N2=17(20%), N3=33(38%). Imaging was USS; n=6(7%), CT; n=63(72%) and PET/CT; n=15(17%). 68/82 (83%) had the biopsied node with long axis ≥15mm on imaging. Comparing LN imaging of the biopsied node with histological N-class (N1/2vsN3) the median long-axis was 23mm(IQR=19-27mm) in N1/2 and 30mm(IQR=24-40mm) in N3(p=0.0011), the short-axis was 12mm(IQR=11-15mm) in N1/2 and 18.5mm(IQR=14.5-20mm) in N3(p=0.0006), the median Product of Dimension(PD) was 291mm²(IQR=228-378mm²) in N1/N2 and 522mm²(IQR=400-805mm²) in N3(p=0.0001) and the Sum of Product of Dimension(SPD) of the scan was 751mm2(IQR=479-1129 mm2) in N1/2 and 1300 mm2(IQR=800-1900 mm2) in N3(p=0.0062). Median number of LN sites with enlarged LN (total-nodal-score) was 3 in both N1/2 and 4 in N3(p=0.1190). mSWAT was significantly higher in N3 at 93(IQR=68-110) compared with 68(IQR=31-90) in N1/2(p=0.0051).

Conclusions: Our study showed that PD is the better predictor for N3 node than any single axis measurement. As current guideline on imaging is based on systemic lymphomas, developing specific imaging guideline for skin lymphomas will better identify LN suspicious for N3 and thereby improve LN selection for biopsy and our diagnosis and avoid unnecessary LN biopsies.

C-03 T-CELL MONOCLONALITY IN BLOOD AND SKIN CORRELATES WITH POOR RESPONSE TO TREATMENT IN MYCOSIS FUNGOIDES

Geller, S.1; Fajnerman Tel-Dan, S.1; Solar, I.2; Sprecher, E.1; Goldberg, I.1

1Department of Dermatology, Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 2Department of Pathology, Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Introduction & Objectives: The prognostic value of T-cell receptor (TCR) clonality in the blood and skin in mycosis fungoides (MF) is a matter of debate. We aimed at ascertaining the relation between the presence of a monoclonal T-cell population in the skin and circulation and the response to treatment in a large cohort of MF patients.

Materials & Methods: We identified 94 adult patients with MF who had polymerase chain reaction (PCR) results for TCR-gamma gene rearrangement in both the skin and the blood and were followed by the cutaneous lymphoma clinic at Tel Aviv Sourasky Medical Center for at least three years. Data including age, sex, stage at diagnosis and response to treatment were retrospectively collected.

Results: TCR clonality was assessed in 84 patients with a diagnosis of early-stage MF and in 10 patients with advanced-stage disease. T-cell monoclonality was detected in the skin, blood or both tissues in 32%, 13% and 6% of all cases, respectively. 64 patients achieved complete clinical response (CR, 68%), 13 - partial response (PR, 14%), 10 had stable disease (SD, 11%) and 7 had progression of disease (PD, 7%). T-cell polyclonality in the circulation was associated with higher rates of CR (P=0.006). The presence of a monoclonal T-cell population in skin (P=0.009), blood (P=0.002) and in both tissues (P<0.001) were found to be statistically associated with lack of response to treatment (SD and PD) and this correlation was found to be statistically significant also after adjusting for age, sex and disease stage in a multivariate analysis.

Conclusions: T-cell monoclonality in the circulation and the skin correlates with poorer response to therapy in MF. Assessment of skin and blood T-cell clonality should be considered as part of the routine initial workup in patients with early-stage disease.

C-04 ERYTHRODERMA: ANALYSIS OF SÉZARY SYNDROME CRITERIA IN 309 ERYTHRODERMIC PATIENTS

Miyashiro, D.1; Cury-Martins, J.1; Abdo, A.2; Pereira, J.2; Sanches, J.A.1

1Dermatology, University of São Paulo Medical School, São Paulo, Brazil; 2Hematology, University of São Paulo Medical School, São Paulo, Brazil.

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Introduction & Objectives: Distinction between Sézary syndrome (SS) and benign inflammatory erythroderma (BIE) is difficult, and many cases remain idiopathic. Our objective was to analyze SS criteria and compare with BIE and idiopathic cases.

Materials & Methods: Data of 292 erythrodermic patients was collected in a single center from 2007 to 2018.

Results: There were 39 (13.4%) SS, 200 (68.5%) BIE, and 53 (18.1%) idiopathic. SS and idiopathic were older (median 64y and 68y, respectively) than BIE (53y) (p=0.0027). SS had higher levels of leukocytes (median 13.575/mm3 vs 9.570/mm3 BIE, 9.555/mm3 idiopathic, p=0.0019), lymphocytes (median 4.400/mm3 vs 1.800/mm3 BIE, 1.585/mm3 idiopathic, p=0.0001), Sézary cells (median 248/mm3 vs 0/ mm3 BIE and idiopathic, p=0.0001). Increased LDH was more frequent in SS (76.3%) and idiopathic (76.5%) than BIE (58.7%, p=0.018). SS had higher CD3 (92% vs 78% BIE, 78% idiopathic, p=0.0001), absolute CD4 (2.697/mm3 vs 770/mm3 BIE, 803/mm3 idiopathic, p=0.0001), CD4/CD8 (18.25 vs 1.97 BIE, 2.9 idiopathic, p=0.0001), CD4+CD7- (45% vs 8% BIE, p=0.0173; 45% vs 11.5% idiopathic, p=0.1825), absolute CD4+CD7- (1.34/mm34 vs 154/mm3 BIE, p=0.0059; 1.344/mm3 vs 179/mm3 idiopathic, p=0.0499), CD4+CD26- (76.5% vs 16% BIE, 17% idiopathic, p<0.0001), absolute CD4+CD26- (2.776/mm3 vs 225/mm3 BIE, 271/mm3 idiopathic, p=0.0001); but had lower CD8 count (240/mm3 vs 351/mm3 BIE, 319/mm3 idiopathic, p=0.0194). TCR clonality was obviously more frequent in SS in blood, skin, and lymph- nodes (90.9%, 75.9%, 88.2%, respectively); but positivity was observed in some cases of BIE (7.5%, 8.4%, 0%) and idiopathic (12.2%, 6.8%, 0%) (p<0.001). Sensitivity/specificity were: 65.8%/99.0% for CD4/CD8 ratio≥10; 57.1%/77.5% for CD4+CD7-≥40%; 92.9%/86.9% for CD4+CD26-≥30%; 32%/100% for Sézary cells≥1.000/mm3; 56%/100% for Sézary cells≥100/mm3.

Conclusions: Erythroderma is a challenging syndrome. We described laboratory, immunophenotypic, and molecular differences between SS, BIE, and idiopathic cases, and highlight the importance in standardizing laboratory techniques to facilitate the diagnosis and management of erythrodermic patients.

SESSION D - EPIDEMIOLOGY

D-01 GLOBAL EPIDEMIOLOGY OF PRIMARY CUTANEOUS LYMPHOMAS: A SYSTEMATIC REVIEW OF RELATIVE FREQUENCIES AND META-ANALYSIS

Dobos, G.; Ram-Wolff, C.; Bagot, M.; De Masson, A.

Department of Dermatology, Hopital Saint-Louis, APHP, Paris, France.

Cutaneous lymphomas (CL) are a heterogenous group of lymphomas primary affecting the skin. There is strong evidence supporting geographic inequalities in the epidemiology of other frequent skin cancers. However, there was no comparison in the epidemiology of cutaneous lymphomas among different geographic regions.

A systematic literature review and meta-analysis were conducted to compare the relative frequencies of CLs in different countries. Based on a previously registered protocol standardized searches were performed in Medline and the Cochrane Library. Peer-reviewed articles reporting at least 100 patients were included if detailing at least 3 CLs according to the WHO, EORTC or WHO-EORTC classifications. Publications before 1999 were excluded. We extracted study characteristics, reporting quality and relative frequencies of CLs. References of included articles were screened for additional records.

Altogether 3,752 records were identified, after removal of duplicates 501 remained, of which 92 were screened in full text for eligibility. Twenty-five publications were included in the meta-analysis. The articles reported 120-4,551 patients. The majority of thestudies reported on European populations. More than half of them presented survival data. The reporting quality of the studies improved over time, most authors used the WHO-EORTC 2005 classification. Only one study compared the different classification systems. Cutaneous T-cell lymphomas (CTCL) compared to the CLs was stable and varied between 63-98%. The group of mycosis fungoides and Sézary syndrome made up 52-93% of CTCLs. CD30-positive CTCLs represented 3.5-40%. The relative frequencies of subcutaneous panniculitis- like lymphomas and NK/T-cell lymphomas varied the most, being more frequent in Asians. The proportion of marginal zone B-cell lymphomas compared to CBCLs was 8-54%, whereas follicle center lymphomas varied between 5-73%.

CTCLs make up approximately two thirds of cutaneous lymphomas, seeming to be stable around the world. MF-SS account for almost two third of CTCLs. Rare CTCLs seem to be more frequent in Asia.

D-02 EPIDEMIOLOGY OF PRIMARY CUTANEOUS CD8+ T CELL LYMPHOMA: A UNITED STATES POPULATION-BASED COHORT ANALYSIS USING THE SURVEILLANCE, EPIDEMIOLOGY, AND END RESULTS DATABASE

Mirza, F.N.; Yumeen, S.; Girardi, M.

Department of Dermatology, Yale School of Medicine, New Haven, United States.

Introduction and Objectives: While the most common immunophenotype of primary cutaneous T cell lymphoma (CTCL) is CD4+, CD8+ CTCL variants have also been described. Recent epidemiologic studies have identified African-American race, advancing age, and male

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gender as risk factors for CTCL, but little is known about the epidemiology of CD8+ CTCLs; thus, we sought to characterize demographic and baseline characteristics of patients diagnosed with CD8+ variants (e.g. aggressive primary cutaneous epidermotropic cytotoxic, acral CD8+ T-cell lymphoma, indolent cutaneous CD8+ lymphoid proliferation), independent of specific subtype.

Materials and Methods: A population-based cohort analysis was conducted in the Surveillance, Epidemiology, and End Results (SEER) database, 2010-2016, for all patients diagnosed with CD8+ CTCL, ICD-9 9709, removing historic cases, death certificate only, and pathology-only cases. Cases coded with a primary skin site (C440-449) were included; age <18 years were excluded.

Results: CD8+ CTCLs were diagnosed and reported in 1271 patients during the 6-year period studied, revealing a slight predominance in males (55.9%), and with lesion location on the face (21%), trunk (20.5%), and extremities (24%). The incidence rate increased with age, with 63 as the median age of diagnosis. Staging data was limited to 9% of cases, all localized to the skin. Highest incidence was in individuals of Caucasian race (75.7%) followed by African-Americans (15.4%). Patients received surgical management for their diagnosis in 28.8% of cases. Since 2010, 264 (20.7%) died of their disease, with mean time to death in these cases as 55.6 months.

Conclusions: Higher incidences of primary CD8+ CTCLs are found with Caucasian race, male gender, and increasing age, and lesions are found generally distributed across skin sites. While our study presents population-level data on CD8+ CTCL collectively, the SEER database does not allow for such analysis across each CD8+ variant.

D-03 RACIAL AND AGE DISPARITIES IN CARDIOVASCULAR EVENTS MAY EXIST IN PATIENTS WITH CUTANEOUS T-CELL LYMPHOMAS

Johnson, C.; Rozati, S.

Dermatology, Johns Hopkins School of Medicine, Baltimore, United States.

Introduction & Objectives: Racial disparities exist in cutaneous T-cell lymphomas (CTCL) with possibly higher incidence rates and at times more advanced disease among African American than white individuals in the US. Moreover, non-whites tend to have more cardiovascular risk factors and higher rates of mortality from cardiovascular disease (CVD). In this retrospective study, we seek to investigate the extent of CVD in non-white patients with CTCL as compared to white patients with CTCL.

Materials & Methods: The prevalence and odds ratio of CVD in non-white patients as compared to white patients with CTCL was assessed from within the Johns Hopkins Health System medical database from January 2011 to June 2019.

Results: Our preliminary data shows the prevalence of CVD in the CTCL population as compared to the control population was slightly increased (p=0.036) with a similar result in all racial groups. CTCL patients had a 16% increased association (95% CI 1.012-1.330, p=0.034) of CVD with a similar result in all racial groups. However, by age stratification, the young population of non-white CTCL patients had a significantly increased association (OR 1.32, 95% CI 1.008-1.733, p=0.043) of CV events; whereas the older white population, hada significantly decreased association of CV events (OR 0.770, 95% CI 0.618-0.959, p=0.019). When accounting for CV risk factors, the total population and the younger population in all racial groups showed significant increased association for CVD with young non-white patients having the highest association of 70% (95% CI 1.213-2.384, p=0.0022).

Conclusions: The increased association of CVD in young non-white CTCL patients is being confirmed by further analysis and may present an opportunity for targeted preventative therapies. Furthermore, the difference in CV events by race and age may reflect a unique immunosuppressive role of the malignant T-cell clones requiring further studies to elucidate relevant markers and pathways.

D-04 MYCOSIS FUNGOIDES IN THE CHILEAN PEDIATRIC POPULATION: A RETROSPECTIVE EPIDEMIOLOGICAL AND CLINICAL- PATHOLOGICAL STUDY IN A CHILEAN REFERRAL CENTER

Molgó, M.; Reyes-Baraona, F.; Downey, C.; Giordano, M.C.; Acle, R.; González, S.

Dermatology, Pontificia Universidad Católica de Chile, Santiago, Chile.

Introduction: Mycosis fungoides (MF) is the most common primary cutaneous T-cell lymphoma. Hypopigmented MF is the most prevalent variant in children and adolescents. However, clinical presentation, prognosis and response to treatment are poorly described in this population. Hypopigmented MF diagnosis is usually delayed due to its similarity with other common childhood hypopigmented diseases. Childhood MF treatment has scarce evidence and there are no treatment guidelines made specially for this population. Despite having a good prognosis, its relapse rate is high, which requires long-term follow-up. This paper reports the largest number of cases of MF in our country’s pediatric population.

Objectives: To describe the epidemiological, clinical-pathological characteristics, therapeutic response and prognosis of MF in pediatric population.

Materials and methods: A retrospective review of patients under 18 years-old diagnosed with MF between 1986 and 2019 was performed in a tertiary medical center.

Results: Twenty-three pediatric patients diagnosed with MF were included. The distribution by sex was F:M (1:2). The most frequent

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clinical variant was hypopigmented MF (n = 21, 91.3%), 1 case of classical MF and 1 case of folliculotropic MF were reported. Mean age at diagnosis was 10 years-old (range: 4 to 18 years-old inclusive) and the time between star of clinical symptoms to diagnosis was an average of 27 months. Narrow-band UVB (nbUVB) phototherapy was the treatment of choice in all patients. No patient had any extra cutaneous involvement. Response to phototherapy was favorable in 14 out of 23 patients, of which 9 had recurrence of lesions, only with skin involvement. Five of the twenty three patients continue in treatment and follow-up.

Conclusions: Hypopigmented MF was the most common variant of MF, as described in the literature. Showing good prognosis as all cases, despite the frequent occurrence of relapses, had only cutaneous involvement.

D-05 MYCOSIS FUNGOIDES IN CHILDREN

Bruey, S.1; Angles, V.1; Andrade, A.1; Volonteri, V.2; Enz, P.1

1Dermatologia, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina, 2Anatomía patológica, Hospital Italiano, Buenos Aires, Argentina.

Mycosis fungoides (MF) is the most common a type of cutaneous T-cell lymphoma in adults and children. However, in pediatric population, MF are less frequent than in adults. We present five children with hypopigmented MF confirmed by biopsy and tratments.

Case 1: An 11 years old boy who started with generalized hypopigmented lesions 1 year ago. He was diagnosed in another center as vitiligo and received treatment with topical corticosteroids. After MF diagnosis he was treated with nbUVB (60 sessions) with good response. Case 2: A 9 year old girl, who started with hipopigmented macules in the abdomen, buttocks and legs, 2 months ago. She started treatment with UVB 30 sessions and topical corticosteroids. Case 3: A 15 year old girl, who began 7 years ago with skin lesions diagnosed as chronic lichenoide pytiriasis, then hypopigmented macules appeared , MF was diagnosed and she was treated with 32 sessions of PUVA, with good evolution. Case 4: A 18 year old girl, with diagnosis of Atopic dermatitis started with hypopigmented macules , 2 months ago. 50 sessions of PUVA improved her condition. Case 5: A 6 year old boy, who started 2 years ago with hypopigmented macules on the trunk, and limbs. With MF diagnosis the patient will receive nbUVB, since it is a recent diagnosis.

We present a rare pathology in pediatrics population with good evolution to phototherapy treatment and good prognosis. However, relapses are frequent, so follw-up is for life.

D-06 THE EPIDEMIOLOGY OF PRIMARY CUTANEOUS GAMMA/DELTA T-CELL LYMPHOMA: A SEER-18 ANALYSIS

Goyal, A.; Pearson, D.; Bohjanen, K.

Dermatology, University of Minnesota, Minneapolis, United States.

Introducion & Objectives: Primary cutaneous gamma-delta T-cell lymphoma (pcGDTCL) and subcutaneous panniculitis-like T-cell lymphoma (SPTCL) are two very rare primary cutaneous lymphomas that present with multifocal subcutaneous nodules.

Materials & Methods: We use Surveillance, Epidemiology, and End Results 18 (SEER-18) data to compare the incidence, demographics, and survival of these two lymphomas.

Results: We identified 37 cases of pcGDTCL and 132 of SPTCL diagnosed between 2006-2015. The cumulative incidence of pcGDTCL, 0.40 per 10 million (95% CI 0.28-0.56 per 10 million), was significantly lower than that of SPTCL at 1.51 per 10 million (95% CI 1.26-1.80 per 10 million; p<0.05). Patients with pcGDTCL were significantly older than those with SPTCL (median 63 years vs. 45 years; p<0.001) and more likely to be male (p<0.013). Cox proportional hazards modeling revealed that patients with pcGDTCL were at significantly higher risk of death than patients with SPTCL (HR 5.00, 95% confidence interval [CI] 1.8-14.3, p=0.005). Increasing age (HR 1.31 per 10 years, 95% CI 1.0- 1.7, p=0.04) and stage (HR 1.52, 95% CI 1.05-2.1, p=0.023) were also significant factors.

Limitations: Limitations of sample size, classification, and the SEER-18 database may underestimate the aggressive nature of pcGDTCL in this report.

Conclusions: pcGDTCL has a markedly worse prognosis than SPTCL.

19 ORAL PRESENTATIONS

SESSION E - IMMUNOLOGY I

E-01 PROINFLAMMATORY AND IMMUNOSUPPRESSIVE CYTOKINES POLARIZE THE MICROENVIRONMENT IN CUTANEOUS T CELL LYMPHOMA AND REGULATE PD-L1 EXPRESSION

Gunes, E.G.1; Rosen, S.T.2; Querfeld, C.3

1Beckman Research Institute, City of Hope National Medical Center, Duarte, United States; 2Hematology and Beckman Research Institute, City of Hope National Medical Center, Duarte, United States; 3Div. of Dermatology and Beckman Research Institute, City of Hope National Medical Center, Duarte, United States.

Background: Macrophages play key roles in tumor surveillance. Cytokines determine the fate of macrophages into inflammatory or immunosuppressive macrophages within the tumor microenvironment (TME). Tumor‐associated macrophages (TAMs) exhibit a CD163+ (M2‐like) phenotype and represent the most abundant cell type in lesions of MF patients. In addition, neoplastic T cells escape immune surveillance via immune checkpoint signaling such as PD1/PD-L1 axis. It remains unknown how cytokines promote tumor-growth and polarize the TME.

Methods and results: Multiplex imaging and flow cytometry in skin and blood revealed that PD-L1 is differently expressed depending on the environment in MF/SS and when compared to healthy control. CD163+ M2 are high in PD-L1 expression in skin lesions. PBMCs incubated with supernatant from 2 CTCL cell lines showed PD-L1 upregulation compared to PBMCs cultured with media alone, demonstrating that secreted factors from CTCL cells regulate PD-L1 expression. We conducted cytokine stimulation, STAT pathway inhibition and antibody blocking studies by adding recombinant human IL-6, IL-10, INF- and TNF- , pan-STAT inhibitor and/or anti- human IFN- , IL-6, IL-10 or TNF- antibodies to the in vitro culture, respectively. We observed 1) PD-L1 expression is regulated by STAT and NFkB signaling and 2) polarization of monocyte/macrophage subsets depending on the TMEγ cytokineα milieu. In addition, we confirmed IFN- and TNF-γ mRNA is upregulatedα in CTCL skin lesions by mRNAseq analysis and correlates with skin burden.

Conclusions:γ Theα CTCL cytokine profile bias PD-L1 expression and polarizes towards CD163+ M2 macrophages to potentiate Tcell exhaustion in the TME.

E-02 NORMAL FIBROBLASTS PROMOTE TH1 CYTOKINE EXPRESSION IN MYLA CELLS BY SUPPRESSING TWIST1 EXPRESSION

Mehdi, S.J.; Moerman-Herzog, A.; Wong, H.K.

Dermatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States.

Introduction & Objectives: The interaction of tumor cells with fibroblasts serves an important role in tumor cell biology, and normal fibroblasts can exert suppressive functions against cancer initiating and metastatic cells. The role of fibroblasts in mycosis fungoides (MF) tumorigenesis is largely unknown. The aim of this study is to decipher the effect of fibroblasts on MF cells, and identify pathways that mediate these effects.

Materials & Methods: Fibroblasts were isolated from normal skin using collagenase. Myla cells were cultured either alone or with normal fibroblasts for 5 days, trypsinized and replated, followed by serial washing to collect floating Myla cells. Myla were subjected to RT-PCR for MF biomarkers (TWIST1 and TOX), Th1 subtype (IFN), and Th2 subtype (GATA3, IL-5). Western blot was performed to detect TWIST1 expression in Myla cells.

Results: Myla cells have high TWIST1 expression which is significantly suppressed after co-culturing with normal fibroblasts (p < 0.0001), suggesting that fibroblasts promote Th1 cell transcriptional network in Myla cells. Since TWIST1 limits IFN expression in Th1 cells, we found that IFN expression was increased in Myla cells after co-culture (p < 0.0001), suggesting that IFN increased expression is related to TWIST1 suppression. GATA3 deletion allows the appearance of IFN producing cells, we found that normal fibroblasts modulates Th2 cells gene expression in Myla cells by suppressing GATA3 expression (p < 0.0001). TOX expression was suppressed in Myla cells after co- culture (p< 0.0001), suggesting that fibroblasts might regulate T cells exhaustion during the disease progression.

Conclusions: We conclude that normal fibroblasts promote Th1 cell transcriptional network via TWIST1-GATA3 axis. Fibroblasts are crucial components of the tumor microenvironment, and normal fibroblasts can promote Th1 cytokine expression by attenuating Th2 processes. Increased expression of IFN producing Th1 cells might enhance immune responses against the tumor cells.

20 ORAL PRESENTATIONS

E-03 ANTI-CD47 IMMUNOTHERAPY IS MEDIATED BY CYTOTOXIC CD107A+IFN-Γ- NK CELLS AND CAN BE POTENTIATED BY INTERFERON-Α IN CUTANEOUS LYMPHOMA

Kruglov, O.1; Johnson, L.2; Uger, R.2; Wong, M.2; Wu, X.3; Hwang, S.3; Akilov, O.1

1Dermatology, University of Pittsburgh, Pittsburgh, United States; 2Immunotherapy, Trillium Therapeutics, Mississauga, Canada; 3Dermatology, University of California Davis, Davis, United States.

Introduction and Objectives: CD47 has been identified as a “do-not-eat” signal which is frequently overexpressed on tumor cells and is an attractive therapeutic target. The mechanism by which anti-CD47 immunotherapy eliminates cutaneous lymphoma has not been explored.

Material and Methods: We utilized depletion of NK cells and mice genetically deficient in IFN- to elucidate the mechanism of anti- CD47 therapy in the murine MBL2 model of cutaneous T-cell lymphoma. γ Results: After intraepidermal inoculation of MBL2 cells, treatment with anti-CD47 led to significant reduction of the thickness of the tumors as early as four days after the first treatment, which was accompanied by an increase in the number of cytotoxic NK cells at the tumor site. While depletion of NK cells resulted in marked attenuation of the anti-tumor effect of anti-CD47, IFN- was not required. An improved therapeutic effect was observed when anti-CD47 therapy was combined with IFN- . An increased number of cytotoxic CD107a+IFN- - NK1.1 cells and intermediate CD62L+ NKG2a- NK1.1 cells was observed during anti-CD47+IFN- therapy γin comparison with either treatment as a monotherapy. α γ α Conclusions: CD47 blockade is an effective therapy for cutaneous lymphoma via engagement of cytotoxic NK cells rather than IFN- - producing NK cells, and this effect can be potentiated by IFN- . γ α

SESSION F - IMMUNOLOGY II

F-01 MAC-1/MAC-2A CELLS REPRESENT A POTENTIAL MODEL TO STUDY IL-13 SIGNALING IN SATB1 POSITIVE CUTANEOUS ALCL

Kadin, M.E.1; Kouttab, N.1; Morgan, J.1; Xu, H.1; Wang, Y.2

1Dermatology, Boston University, Boston. Roger Williams Medical Center, Providence, United States; 2Dermatology and Venerology, Peking University First Hospital, Beijing, China.

Introduction & Objectives: SATB1, a thymocyte specific chromatin organizer, and IL-13 play a role in the pathogenesis of Sezary Syndrome and Mycosis Fungoides, but IL-13 activity has not been described in CD30+ cutaneous lymphoproliferative disorders (CLPD). We reported that CD30+ CLPD with a SATB1 positive phenotype have a Th17 profile but also upregulation of gene transcripts for IL-13, IL-13Ra1, IL-4Ra and pSTAT6. (JID, 2018) Here we investigated protein expression of SATB1, IL-13 and downstream target pSTAT6 in cell lines and clinical samples of CD30+ CLPD.

Methods and Materials: Mac-2A and Mac-1 cell lines derived from progression of lymphomatoid papulosis (LyP) to ALCL were studied for IL-13, IL-4, their receptors and pSTAT6 by flow cytometry and immunohistochemistry. Effects of silencing SATB1 in Mac-1 cells with small hairpin RNAs were investigated. Clinical samples of cutaneous ALCL and LyP were studied by immunohistochemistry for SATB1, IL-13, IL-4, pSTAT6 and GATA3.

Results: Mac-2A cells produced IL-13 and expressed IL-4R, IL-13Ra1, IL-13Ra2, and pSTAT6. Immunohistochemistry of original skin tumors confirmed tumor cell expression of SATB1, pSTAT6 and IL-13 as well as IL-4, IL-17F and GATA3. Three primary LyP cases showed similar results. Mac-1 cells did not produce IL-13 but did produce IL-4, expressed IL-4Ra, IL-13Ra, IL-13Ra2 and IL-17F. Silencing SATB1 in Mac-1 cells suppressed IL-17F and up-regulated IFNg.

Conclusions: (1) These studies show expression of IL-13, IL-13Ra1, IL-4, IL-4Ra and their downstream target pSTAT6 in CD30+ CLPD, consistent with our reported high correlation of IL-13 and IL-13Ra1 transcripts with SATB1 positivity. (2) pSTAT6 appears to be a biomarker of SATB1+ CLPD and may explain the frequent presence of eosinophils and elevated serum IgE. (3) Mac-1/Mac-2A cell lines represent a potential model to study IL-13 signaling in SATB1+ CLPD; further studies defining the role of IL-13 in autocrine/paracrine growth of cutaneous ALCL are in progress.

21 ORAL PRESENTATIONS

F-03 PROTEIN AND MRNA EXPRESSION LEVELS OF IL-17A, IL-17F AND IL-22 IN PATIENTS WITH MYCOSIS FUNGOIDES

Papathemeli, D.1; Patsatsi, A.1; Koletsa, T.2; Pikou, O.1; Lazaridou, E.1; Georgiou, E.3

12nd Department of Dermatology and Venereology, Cutaneous Lymphoma Outpatient Clinic, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece; 2Department of Pathology, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece; 3Laboratory of Biological Chemistry, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Introduction & Objectives: It is well known that IL-17A, IL-17F and IL-22 play a crucial role in psoriasis and other inflammatory diseases. The aim of this study is to elucidate the possible role of IL-17A, IL-17F and IL-22 in mycosis fungoides.

Patients & Methods: The peripheral blood protein and mRNA levels of IL-17A, IL-17F and IL-22 were examined in 49 MF patients and 50 healthy controls. Among patients, 38 (77,5%) had early-stage disease (IA-IIA) and 11 had advanced stage disease (IIB-IV). Also 19 patients were newly diagnosed and had received no previous treatment for MF and 30 had a previous history of MF and were under treatment, having active disease. The protein level was evaluated in the serum using ELISA and the mRNA levels were evaluated in peripheral blood by quantitative real-time PCR. Mean expression levels in patients were compared to controls by unpaired Student’s t-test.

Results: Protein levels did not differ significantly among patients and controls for IL-17A, IL-17F and IL-22 (p: 0,301, 0,219 and0,178, respectively). Likewise, mRNA relative quantities were not found significantly different between patients and controls (p: 0,303, 0,804 and 0,264 respectively). Also protein expression levels did not differ significantly among early and advanced stage patients. Interestingly, significantly higher IL-22 mRNA expression levels were detected in early stage patients (p=0,025), a finding which must be further confirmed. In general, protein and mRNA expression levels of the examined interleukins in peripheral blood were extremely low, with few exceptions.

Conclusions: No significant differences in circulating IL-17A, IL-17F and IL-22 were found. Increased IL-22 mRNA expression levelsin early stage MF remains to be interpreted. The interplay among cytokines in mycosis fungoides and the similarities or differences in immunological pathways among early MF and psoriasis or eczema may be important for therapeutic or prognostic purposes, although still blurr.

F-04 INDUCTION OF ANTI-TUMOR EFFECT BY CD8+ T-CELLS VIA CADM1/CRTAM INTERACTION IN PATIENTS WITH ADULT T-CELL LEUKEMIA LYMPHOMA

Tatsuno, K.; Shimauchi, T.; Tokura, Y.

Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan.

Introduction & Objective: Adult T cell leukemia/lymphoma (ATL) cells express CADM1 (Cell Adhesion Molecule 1), and its expression is increased upon disease progression. CRTAM (Class I Restricted T-cell Associated Molecule), a CADM1 ligand, is expressed on activated CD8+ T-cells, and CRTAM-CADM1 interaction leads to increased IFN- production and cell lytic function against CADM1 expressing target cells. However, CADM1-expressing ATL cells seem to cunningly evade the host immunity against itself. The aim of study is to explore the association of CADM1 and CRTAM interaction in ATL patients. Materials & Methods: Activated PBMCs from ATL patients (n=6) were evaluated for CRTAM expression on CD8+ T-cells with or without autologous CD4+ ATL cells by flow cytometry. Isolated CD8+ T-cells were co-cultured with autologous CD4+ ATL cells in transmembrane co-culture system and analyzed again (n=4). Isolated and pre-activated CD8+ CRTAM+ T-cells were co-cultured with autologous CD4+ ATL cells with or without anti-CADM1 blocking antibody, and then, casepase-3 activity on tumor cells were analyzed by flow cytometry (n=5).

Results: We found that CRTAM expression on CD8+ T-cells in ATL patients were significantly suppressed compared to normal subjects. Interestingly, depletion of ATL cells lead to the recovery of CRTAM expression on CD8+ T-cells. Co-culture of ATL cells and CD8+ T-cells using transmembrane culture device did not suppress the CRTAM expression. Furthermore, casepase-3 expression on CD4+ ATL cells was induced by co-culture with autologous CRTAM+ CD8+ T-cells, which was efficiently hampered by pretreatment with anti-CADM1 blocking antibody.

Conclusions: These observations underscore the importance of CRTAM in host defense against ATL cells, and it’s down-modulation by direct cell-cell contact with tumor cells. Thus, the control of CRTAM expression on CD8+ T-cells suggests high therapeutic potential for the treatment of ATL.

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SESSION G - PATHOGENESIS OF CUTANEOUS LYMPHOMAS

G-01 ROLE OF TOX1 AND STAT3 PATHWAYS IN THE PATHOGENESIS OF CUTANEOUS T-CELL LYMPHOMA

Seffens, A.1; Koralov, S.2; Geskin, L.3

1Dermatology, Columbia University Vagelos College of Physicians and Surgeons, New York, United States; 2Pathology, New York University School of Medicine, New York, United States; 3Dermatology, Columbia University Irving Medical Center, New York, United States.

Introduction: Thymocyte selection associated high mobility group box 1 (Tox1), a transcription factor that is required to establish the CD4+ lineage, is overexpressed in malignant cells found in the skin and blood of patients with CTCL. Another gene which is consistently overexpressed in patient samples is signal transducers and activators of transcription 3 (Stat3), a transcription factor critical for the differentiation of Th17 and follicular helper T cells. The Koralov lab has developed a mouse model which constitutively expresses a hyperactive STAT3 allele, STAT3C, that recapitulates several key features of MF. I hypothesize that both TOX and STAT3 genes are involved in CTCL pathogenesis, and that their upregulation contributes to the ability of malignant cells to survive, proliferate, migrate, and invade tissues. Overexpression of both of these genes which are known to contribute to T-cell lymphomagenesis will likely enhance malignant transformation in a transgenic mouse model.

Materials and Methods: To evaluate the contribution of TOX1 overexpression to CTCL pathogenesis, we have introduced Tox1 cDNA downstream of a floxed stop cassette into the ubiquitously expressed Rosa26 locus of C57Bl/6J embryonic stem (ES) cells.

Results and Conclusions: We have generated R26Tox1stopfl mice using tetraploid complementation to generate 100% ES cell derived animals and genotyped these animals to ensure that they express TOX1 cDNA. They have been crossed to CD4Cre and CD4Cre STAT3Cstopfl strains, thus enabling us to study the contribution of TOX1 overexpression to T cell lymphomagenesis and giving us an opportunity to examine synergy between TOX1 overexpression and hyperactive JAK/STAT signaling in CTCL. We have taken peripheral blood from CD4 Cre Tox1stopfl mice and STAT3Cstopfl Tox1stopflCD4Cre mice and have seen a 13-fold upregulation of TOX1 cDNA in mutant mice. We hope that the newly generated mice will pave the way to a better understanding of this enigmatic malignancy.

G-02 PROBING THE CAUSATIVE LINK BETWEEN MICROBIAL TRIGGERS AND CTCL PROGRESSION

Herrera, A.1; Seffens, A.2; Tegla, C.3; Fanok, M.1; Fulmer, Y.4; Laird, M.5; Dean, G.6; Podkowik, M.7; Odum, N.8; Segal, L.7; Scher, J.7; Latkowski, J.A.5; Torres, V.9; Hymes, K.7; Kadin, M.6; Geskin, L.2; Shopsin, B.7; Koralov, S.1

1Pathology, NYU School of Medicine, New York, United States; 2Dermatology, Columbia University, New York, United States; 3Cancer Center, NYU School of Medicine, New York, United States; 4Medicine, Roger Williams Medical Center, New York, United States; 5Dermatology, NYU School of Medicine, New York, United States; 6Pathology, Roger Williams Medical Center, Providence, United States; 7Medicine, NYU School of Medicine, New York, United States; 8Dermatology, University of Copenhagen, Copenhagen, Denmark; 9Microbiology, NYU School of Medicine, New York, United States.

Introduction: The skin of CTCL patients is frequently colonized with Staphylococcus aureus (S. aureus) strains and infections are a frequent cause of morbidity and mortality among patients with advanced CTCL. Here we provide a comprehensive analysis of the association between CTCL and S. aureus colonization, and use our unique pre-clinical animal model of CTCL to determine the cause- effect relationship between skin-associated S. aureus and CTCL progression.

Materials and Methods: We collected skin swabs from active lesions, unaffected skin and nares of CTCL patients to perform S. aureus cultures and 16S rRNA gene sequencing. We used our mouse model of CTCL housed under specific-pathogen-free (SPF) conditions and in germ free (GF) isolators to interrogate the causal relationship between bacteria and CTCL progression. Results: Colonization rates correlated positively with the disease stage. Unbiased, 16s sequencing-based analysis of the skin microbiome from advanced CTCL patients revealed that the overall skin microbiome of these patients is distinct from that of healthy individuals and patients with psoriasis. A lower phylogenetic diversity and significantly higher relative abundance ofStaphylococcus species was found in CTCL patients. The CD4CreSTAT3stopfl/+ mice express a hyperactive STAT3C mutant protein selectively in T lymphocytes. Virtually all mutant mice develop T cell infiltration in the epidermis causing skin lesions resembling CTCL with age. In contrast to the SPF housed animals, GF mice remained disease free or developed only a mild phenotype. We examined the role of TCR signaling in mediating T cell transformation using mice in which TCR signaling is compromised.

Conclusions: We demonstrate a strong correlation between CTCL staging and rates of S. aureus colonization. Our study supports a cause-effect relationship between skin flora and CTCL oncogenesis. We propose that CTCL represents an antigen driven malignancy. Further gnotobiotic studies are needed to further interrogate the role of specific bacteria.

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G-03 STANDARDIZED FLOW CYTOMETRY (EUROFLOW) DEMONSTRATES HETEROGENEOUS T-CELL ORIGIN OF SÉZARY LYMPHOMA CELLS

Najidh, S.1; Van Der Sluijs-Gelling, A.2; Zoutman, W.H.1; Tensen, C.P.1; Van Hall, T.3; Almeida, J.4; Van Dongen, J.2; Vermeer, M.H.1

1Dermatology, Leiden University Medical Center, Leiden, Netherlands; 2Immunology, Leiden University Medical Center, Leiden, Netherlands; 3Oncology, Leiden University Medical Center, Leiden, Netherlands; 4Immunology, Centro de Investigación del Cáncer, Salamanca, Spain.

Introduction&Objectives Sézary syndrome (SS) is generally considered as a T-helper central memory (TCM) cell of T-helper (Th)2-subset. However, Sézary cells (SCs) remain incompletely characterized and sensitive monitoring tools are lacking for their identification. Therefore, our goal was to identify the immunophenotypic profiles of SS and to investigate expression of characteristic T-helper subset markers by SCs to increase our general understanding of SS.

Material&Methods We applied fully standardized flow cytometric protocols as developed by EuroFlow Consortium on freshly isolated SCs from 15 patients (and additional follow-up samples) using immunophenotypic markers included in the Lymphoid Screening Tube (LST) and T-cell Lymphoproliferative Disease (T-CLPD) antibody panels. Moreover, T-cell origin of SCs was investigated using a recently developed EuroFlow CD4+ T-cell characterization Tube including a variety of chemokine receptor, activation and maturation markers.

Results Dim expression of CD3 and lack of CD26 surface marker were the most commonly observed immunophenotypic aberrancies, followed by CD7-/dim and CD2-/dim. Atypical cells were then re-defined in the CD4+ T-cell Tube based on their patient-specific phenotypic profile in the LST and T-CLPD panels. Markers CD45RA, CD27, and CD62L then allowed for different maturation stages to be defined. Subsequently, functionally distinct T-helper subsets were discriminated using chemokine receptors CXCR3, CCR4, CCR6, and CCR10. SCs

were mostly of TCM origin and shared overexpression of chemokine receptor CCR4 which is preferentially expressed on Th2 differentiated CD4+ T cells. Nevertheless, some samples showed surface phenotypes resembling Th17 (CCR4+CCR6+), Th22 (CCR4+CCR6+CCR10+) or other T-helper functional subsets. Interestingly, we observed overlapping but sometimes diverse phenotypic profiles within one patient, showing intra-patient dynamics in SC differentiation. Furthermore, SCs from follow-up samples showed a phenotypic shift over time. Conclusions Here, we demonstrated distinct phenotypic profiles in SS reflecting SC heterogeneity which is suggestive of a more inter- and intratumor heterogeneous nature of the disease than previously appreciated.

G-04 MUTATIONAL SIGNATURE ANALYSIS REVEALS A KEY ROLE FOR UV RADIATION IN THE ACCUMULATION OF MUTATIONS IN CUTANEOUS T-CELL LYMPHOMA

Jones, C.1; Degasperi, A.2; Grandi, V.1; Mitchell, T.1; Nik-Zainal, S.2; Whittaker, S.1

1St. John's Institute of Dermatology, King's College London, London, United Kingdom; 2MRC Cancer Unit, University of Cambridge, Cambridge, United Kingdom.

Introduction & Objectives: T-cell lymphomas, including Mycosis Fungoides and Sezary Syndrome, develop following transformation of tissue resident T-cells. Although a diverse set of driver gene mutations contribute to constitutive TCR signalling and evasion of apoptosis, little is understood about the underlying mechanisms driving these mutations.

Materials & Methods: We performed a meta-analysis of mutational catalogues derived from whole exome sequencing data from 403 patients with eight subtypes of T-cell lymphoma to identify mutational signatures and recurrent gene mutations associated with specific causal peaks within these signatures.

Results: Signature 1, indicative of age-related deamination, was prevalent across all T-cell lymphoma subtypes, reflecting the derivation of these malignancies from memory T- cell subsets. Signature 7, implicating UV exposure as a potential initiating factor was uniquely identified in cutaneous T-cell lymphoma, contributing 52% of the mutational burden in Mycosis Fungoides and 23% in Sezary Syndrome. Importantly whilst the Mycosis Fungoides samples were obtained from skin biopsies, in Sezary Syndrome the UV signature was observed in tumour enriched T-cells isolated from blood.

Conclusions: Our analysis identifies UV exposure as a key contributor to the mutational burden in cutaneous T-cell lymphoma. The identification of this signature in tumour enriched T-cells isolated from blood indicates prolonged exposure of these T-cells to UV during re-circulation through or residence in the skin.

G-05 EPIDERMAL FATTY ACID-BINDING PROTEIN IS NOT EXPRESSED BY TUMOR CELLS IN ADVANCED MYCOSIS FUNGOIDES

Takahashi-Shishido, N.1; Morimura, S.1; Suga, H.2; Oka, T.2; Kamijo, H.2; Miyagaki, T.2; Sato, S.2; Sugaya, M.1

1Dermatology, International University of Health and Welfare, Chiba, Japan; 2Dermatology, the University of Tokyo Graduate School of Medicine, Tokyo, Japan.

Introduction & Objectives: Epidermal fatty acid-binding protein (E-FABP) is predominantly expressed by keratinocytes, contributing to their differentiation. It is also expressed by immune cells like macrophages. The importance of E-FABP in the maintenance of skin- resident memory CD8+ T cells was recently reported. Mycosis fungoides (MF) is regarded as malignancy of skin-resident T cells and it is important to know whether or not tumor cells in MF express E-FABP. In this study, we investigated E-FABP expression in psoriasis vulgaris (PV), atopic dermatitis (AD), MF, and Sézary syndrome (SS).

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Materials & Methods: Messenger RNA (mRNA) levels of E-FABP were examined by quantitative RT-PCR. Skin samples were collected from 23 patients with MF/SS, five patients with PVF, 12 patients with AD and eight healthy control subjects. We also performed immunohistochemical staining using skin samples from 28 patients with MF/SS, 10 patients with PV, five patients with AD and 11 healthy subjects.

Results: E-FABP mRNA levels were increased in lesional skin of PV, AD, and MF/SS, compared to those of normal skin. While E-FABP mRNA levels in patch, plaque, and erythrodermic MF/SS were significantly higher than normal skin, those in MF tumor lesions were not elevated. Immunohistochemical staining showed that E-FABP was strongly positive in the suprabasal epidermal layers of PV skin. Epidermis of AD and MF/SS skin was slightly positive. Dermal cells such as macrophages and endothelial cells also expressed E-FABP in these skin diseases. In MF/SS, some lymphocytes infiltrating into the epidermis were positive, suggesting that a part of tumor cells expressed this protein. In tumor MF lesions, however, most dermal atypical lymphocytes were negative for E-FABP.

Conclusions: E-FABP is expressed by some tumor cells and surrounding inflammatory cells in early MF and SS. In advanced MF, tumor cells do not express E-FABP, suggesting that this protein cannot be a therapeutic target.

G-06 PATCH LESIONS OF MYCOSIS FUNGOIDES PATIENTS HAVE A SIMILAR SKIN MICROBIOME PROFILE COMPARED TO NON- LESIONAL AND HEALTHY SKIN

Ulrike, W.1; Britt M, H.2; Marion, J.1; John F, B.3; Jürgen, H.1

1Department of Dermatology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany; 2Evolutionary Genomics, Max Planck Institute for Evolutionary Biology,, Plön, Germany; 3Institute for Experimental Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

Staphylococci are known to play a role in cutaneous T-cell lymphoma. Previously, it has been shown that staphylococcal enterotoxin- producing bacteria may promote activation of the oncogenic pathway via STAT3 in the malignant T-cell population. In addition, many patients in advanced disease stages decease due to septic complications often mediated by S. aureus. The here presented study aimed to characterize the microbiome profile in patch lesions of mycosis fungoides (MF) patients. The skin microbiome was investigated compared to non-lesional and healthy skin by 16S amplicon sequencing. Skin washing solutions were retrieved from MF patch lesions and non-lesional skin of the same patient at 5 cm distance to the lesion in the same area. Age-, localization- and sex-matched healthy individuals were used as controls. 8 MF patients were analyzed, with 7 of 8 in early disease stage (IA, IB). The relatively most abundant genera across the samples were Staphylococcus, Bacteroidales spec., and Erysipeloptrichaceae spec. No significant differences between the patch lesions, non-lesional MF and healthy control skin were detected. Interestingly, lesional and non-lesional skin of MF patients displayed a consistent intraindividual microbiome profile. Further analysis including plaque and tumor lesions of patients are necessary to gain insight whether a shift in the microbiome might be present in more infiltrated skin lesions or more advanced disease stage, hereby potentially promoting or triggering disease progression.

SESSION H - BIOMARKERS I

H-01 EVALUATION OF BLOOD SÉZARY MARKERS BY MEANS OF CORRELATION WITH APOPTOSIS RESISTANCE AND CLONALITY

Sven, S.1; Chalid, A.2; Max, S.3; Rudolf, S.4; Rene, S.4; Ulrike, W.5; Marion, W.6; Jana, B.7; Sergij, G.7; Jan, N.7

1Clinical Chemistry, University Medical Center Mannheim, Mannheim, Germany; 2Dermatology, HELIOS Klinikum Krefeld, Krefeld, Germany; 3Dermatology, University Hospital Munich, Munich, Germany; 4Dermatology, University Hospital Minden, Minden, Germany; 5Dermatology, University Hospital Kiel, Kiel, Germany; 6Dermatology, University Hospital Würzburg, Würzburg, Germany; 7Dermatology, University Medical Center Mannheim, Mannheim, Germany.

Introduction and objectives: To date, the diagnosis of Sézary syndrome (SS) is often impaired by the distinct lack of unique diagnostic blood markers that clearly allow the identification of the malignant T cell population in the blood. Several markers are known and characterized, such as CD7 and CD26 loss as well as gain of PD-1 and CD158k. Nevertheless, it is yet to be clarified which of these markers characterize the malignant population best and how these markers correlate with T cell receptor (TCR) clonality, the defining feature of the malignant Sézary cells. In addition, the correlation of these markers with the distinct apoptosis resistance described for Sézary cells is still not sufficiently clarified.

Materials and methods: We isolated CD4+ T cells from the peripheral blood of Sézary patients. These cells were separated into different populations according to their positivity for CD7, CD26, PD-1 and CD158k by flow-cytometry. Cell death was measured in these populations following different conditions as well as apoptotic and therapeutic stimuli. In addition, we determined TCR clonality by flow cytometry or TCR sequencing to further correlate marker expression within the populations with TCR clonality.

Results: We found significant intra-individual differences in cell death sensitivity and correlation with clonality between the different marker-positive T cell populations. For example, our data confirm the preferred clonal expansion of specific TCR chains in different

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patients. In addition, apoptosis sensitivity significantly correlates with CD7 and CD26 loss. The exact and final results will be presented at the WCCL 2020.

Conclusions: The established Sézary cell markers vary in specificity and sensitivity and can only be used in combination. Correlation of surface markers with clonality and apoptosis increases the sensitivity of flow cytometry in SS. This underlines the need to establish novel unique markers and highly standardized panels.

H-02 THE A ALLELE OF RS7096317 IS PERMISSIVE FOR CD39 EXPRESSION IN CTCL AND IS A NEGATIVE PROGNOSTIC FACTOR IN OLDER PATIENTS

Jones, C.; Devaney, A.; Grandi, V.; Samuel, S.; Whittaker, S.; Mitchell, T.

St. John's Institute of Dermatology, King's College London, London, United Kingdom.

Introduction & Objectives: CD39 overexpression has been observed in a proportion of patients with cutaneous T-cell lympyhoma. GWAS analysis of immune traits has shown that expression of CD39 is strongly associated with the genotype of the rs7096317 SNP in healthy T-cells. As the rate-limiting enzyme in the generation of immunosuppressive adenosine, overexpression of CD39 could be influential in in the tumour microenvironment in CTCL.

Materials & Methods: We performed flow cytometry and genotyping on CD4+ T-cells from 46 CTCL patients to examine the relationship between cell surface expression of CD39 and genotype at the rs7096317 SNP in CTCL. Subsequently we performed genotyping on a cohort of 543 CTCL patients to investigate whether rs7096317 genotype had any influence on survival. Results: A substantially increased proportion of CD39+ cells was observed within the CD4+ T-cell population of CTCL patients with the A/A or A/G genotype at rs7096317 but not in those with the G/G genotype. Within the 543 patient cohort the allele frequency for A was 0.53, which is in agreement with the allele frequency reported in dbSNP. Overall survival was reduced in patients harbouring an A allele and analyses of clinically relevant subsets revealed that an A allele confers significantly worse survival in patients who present aged 60 or above. This difference was independent of gender, disease, or staging at diagnosis.

Conclusions: We confirm that CD39 overexpression is frequent in CTCL patients and is genetically regulated. The genotype permissive for CD39 expression is a negative prognostic factor in patients who present over the age of 60 suggesting that CD39 expression is playing a pathogenic role. In addition to the prognostic potential, this data could be of value in the targeting of anti-CD39 antibody therapy to the subgroup of patients likely to see the greatest benefit.

H-03 NEXT GENERATION SEQUENCING OF TCRBETA GENE COULD BE USEFULL IN DIFFERENTIATING TUMORAL STAGES OF MYCOSIS FUNGOIDES FROM CD30 LYMPHOPROLIFERATIVE DISORDERS OVER MF PLAQUES

Palomar Moreno, C.I.1; Machan, S.2; Borregon, J.1; Perez, N.1; Cereceda, L.1; Piris, M.A.1; Rodriguez Pinilla, S.M.1; Manso, R.1

1Pathology, Fundación Jiménez Díaz, Madrid, Spain; 2Dermatology, Fundación Jiménez Díaz, Madrid, Spain.

Introduction: Primary cutaneous lymphomas represent a broad group of diseases with different clinical, histopathological, phenotypic, molecular and prognostic characteristics. The most frequent are mycosis fungoides (MF) and positive CD30 lymphoproliferative processes (CD30-LP) such as anaplastic large cell lymphoma and Lymphomatoid Papulosis. Sometimes, both MF and CD30-LP take place in the same patient and usually share the same TCR clone. The differential diagnosis between CD30-positive tumoral MF and CD30-LP is not usually easy and has important prognostic and therapeutic implications. We take advantage of new generation sequencing methods (NGS) of both TCRBETA and GAMMA genes in an attempt to help solving this problem.

Material and methods: Samples of 4 patients with MF at different stages of disease including tumoral phases and 3 patients with CD30- LP associated to MF have been analyzed with both NGS and conventional multiplex PCR methods using biomed primers analyzed by capillary electrophoresis (CE).

Results: On one hand, it has been observed that NGS is more sensible than conventional multiplex PCR methods in the identification of dominant clones. On the other hand, MF and CD30-LP samples in the same patients exhibit coinciding TCRGAMMA rearrangements, albeit the VAF was lower in the CD30-LP lesions. But the most striking finding was the absence of TCRBETA rearrangements in the CD30-LP lesions when compared with MF lesions in the same patients, thus implying that the clinical presentation is reflecting not only changes in the tumour stroma, but also in the genetic background of the neoplastic cells. In contrast, tumoral MF samples showed matching TCRGAMMA and TCRBETA rearrangements when compared with initial MF samples.

Conclussion: NGS analysis of TCRGAMMA and TCRBETA genes could be useful in differentiating tumoral stages of MF from CD30-LP associated with early stage MF. An ampler series of cases is being evaluated to confirm this data.

26 ORAL PRESENTATIONS

SESSION I - BIOMARKERS II

I-01 IDENTIFICATION OF CD39 AS A POTENTIAL THERAPEUTIC TARGET IN SEZARY SYNDROME

De Masson, A.1; Battistella, M.2; Sonigo, G.1; Janela, B.3; Thonnart, N.4; Musette, P.4; Ginhoux, F.3; Bensussan, A.4; Bagot, M.1; Marie-Cardine, A.5

1Dermatology, Université de Paris, INSERM U976, Team 1, Onco-Dermatology and Therapies, Saint-Louis Hospital, Paris, France; 2Pathology, Université de Paris, INSERM U976, Team 1, Onco-Dermatology and Therapies, Saint-Louis Hospital, Paris, France; 3Skin Research Institute of Singapore (, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore; 4INSERM U976, Team 1, Onco-Dermatology and Therapies, Saint-Louis Hospital, Paris, France; 5Université de Paris, INSERM U976, Team 1, Onco-Dermatology and Therapies, Saint-Louis Hospital, Paris, France.

Introduction and objectives: Sezary syndrome (SS) is a cutaneous T-cell lymphoma characterized by the presence of malignant CD4+ T-cells that accumulate mainly in the skin and peripheral blood. Flow cytometry is now the method of choice for evaluating blood tumor burden in SS. Some years ago, we identified KIR3DL2 as a unique and specific positive marker for Sezary cells, expressed in 90% of SS patients. CD39 is an ectonucleotidase involved in ATP/ADP hydrolysis, leading to the generation of adenosine. Its expression by tumor cells in cancer patients was recently correlated to their ability to inhibit T-cell proliferation and generation of cytotoxic effector CD8+ T-cells in an adenosine-dependent manner. We aimed to investigate CD39 expression in SS.

Material and methods: CyTOF phenotyping was conducted on peripheral blood mononuclear cells from SS patients (n=2) and healthy donors (HDs) (n=5). Flow cytometry was performed on blood from HDs (n=30) and SS patients (n=30). CD39 expression was studied by immunohistochemistry in lesional skin of 36 SS patients.

Results: Most CD4+ T cells of SS patients segregated in a single cluster by CyTOF, corresponding to the malignant T-cell clone (as confirmed by its high expression levels of KIR3DL2 and CCR4) that co-expressed CD39. CD39 expression was detected by immunohistochemistry in lesional skin of 34 out of 36 studied SS patients (mean % of positive cells:45%;range:5-90%). Classical flow cytometry analysis confirmed CD39 over-expression on SS patients malignant CD4+ T-cells. Moreover, an unusual percentage of CD39-positive cells was also detected in normal CD4+ and CD8+ T cell and NK cell populations when compared to HDs.

Conclusions: These findings support the possibility of using CD39 as a diagnostic marker of SS but also as a promising therapeutic target with the current development of CD39-blocking antibodies that may restore efficient antitumor responses.

I-02 THE CORRELATION OF FLOW CYTOMETRY ANALYSIS ON SKIN TISSUE WITH IMMUNOHISTOCHEMISTRY IN CUTANEOUS T-CELL LYMPHOMA

Geller, S.1; Ho, C.2; Noor, S.3; Roshal, M.2; Myskowski, P.3; Moskowitz, A.4; Horwitz, S.4; Pulitzer, M.2

1Department of Dermatology, Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 2Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States; 3Department of Dermatology, Memorial Sloan Kettering Cancer Center, New York, United States; 4Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, United States.

Introduction & Objectives: Flow cytometric analysis (FC) of fresh skin specimens is infrequently used to diagnose and manage cutaneous T-cell lymphoma (CTCL). Our goal was to compare objective and interpretive characteristics of contemporaneous formalin-fixed paraffin- embedded (FFPE) and FC skin biopsies in CTCL.

Materials & Method: Flow plots from 31 consecutive skin samples from 25 WHO/EORTC-classified CTCL patients with 27/31 concomitant H&E and immunohistochemically stained tissue sections were retrospectively identified and reviewed. Histology, clonality, flow sample quality, cell yield, skin lesion and procedure type were analyzed for association with identification of an abnormal population. Antibodies employed and immunophenotypic interpretation of abnormal lymphocytes on FC and FFPE were compared.

Results: FC specimens included 23 punch biopsies, 6 shave biopsies and two excisions. Cell counts varied (70-180,000, mean 14,215) and correlated with procedure type (p=0.01). FC identified an abnormal T-cell population in 71% of cases. Identification of an abnormal population by FC was associated with lesion type (p<.001) and not with CTCL classification (p=.09), histological localization (p=0.4) or monoclonality (p=0.1). FC did not detect an abnormal population in 9 cases; three with no or histologically equivocal lymphoma, three with sparse diagnostic infiltrates, and one with necrosis. Comparison of aberrant cells between FC and FFPE skin samples showed differences in CD4 or CD8 labeling/interpretation (5/17 cases), and in pan-T-cell markers (CD3/CD5/CD7, 10/18 cases) but not in CD2. In 2 patients FC identified immunophenotypically identical populations in temporo-spacially distinct skin. In 8 patients, FC of extracutaneous tissue showed the same abnormal phenotype as in skin.

Conclusions: FC detects abnormal T-cell populations in CTCL tissues with small numbers of analyzed cells and can identify immunophenotypically similar populations in temporo-spacially distinct biopsies, and extracutaneous sites, with diagnostically insignificant differences in individual marker labeling/interpretation. The implementation of skin FC with FFPE should be considered routinely for patient management.

27 ORAL PRESENTATIONS

I-03 OVEREXPRESSION OF STAT4 AT EARLY STAGES OF MYCOSIS FUNGOIDES: COINCIDENCE OR NOT?

Olisova, O.1; Grekova, E.1; Zaletaev, D.2; Alekseeva, E.2

1V.A. Rakhmanov Department of Skin and Venereal Diseases, I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation; 2Laboratory of Medical Genetics, I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation.

Introduction: Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphomas (CTCL) accounting for approximately 65-85% of all CTCL. Early diagnosis of MF is challenging due to the existence of different clinical forms and absence of definitive diagnostic criteria. STAT4 is essential for T-helper (Th) 1 differentiation. The objective of this study was to investigate the expression levels of STAT4 at different stages of MF and inflammatory skin disorders (ISDs).

Material and Methods: The study included patients with early MF (stages I-IIA; n=19), advanced MF (stages IIB-IV; n=10), ISDs that may mimic CTCL (atopic dermatitis, chronic eczema, psoriasis) (n=13) and healthy controls (n=10). MF was diagnosed using clinical examination and skin biopsies for histological, immunohistochemical and molecular tests. Molecular tests entailed detection of TCR gene rearrangement by PCR. RNA expression of STAT4 was evaluated by quantitative real-time PCR (qPCR) using FAM-labeled hydrolysis probes (Bio-Rad, USA). γ To normalize the level of STAT4 gene expression in each individual sample, B2M and ACTB reference genes with stable expression during cell activity were used as endogenous control. A p value of 0.05 was chosen as a threshold for statistical significance.

Results:As demonstrated in Fig.1, STAT4 was significantly elevated in early MF lesional skin compared to healthy skin, as well as ISDs skin samples (p=0.0075). Our study showed that STAT4 expression, which is essential for Th1 differentiation, is decreased at advanced stages, where the disease shifts to the Th2 phenotype and produces malignant T-cells. This finding is consistent with previous reports.

Conclusions: Thus, the STAT signaling pathway appears to play a crucial role in malignant phenotype switching. Further studies may fully assess the usefulness of STAT4 in early diagnosis of MF and help develop effective treatment options.

28 ORAL PRESENTATIONS

SESSION J - GENETIC PATHOGENESIS J-01 COMPARISON OF EARLY WITH ADVANCED MYCOSIS FUNGOIDES LESIONS ON A SINGLE CELL LEVEL TO ASSESS POTENTIAL MEDIATORS OF DISEASE PROGRESSION

Farlik, M.1; Bauer, W.1; Shaw, L.1; Porkert, S.1; Halbritter, F.2; Jonak, C.1; Brunner, P.M.1

1Department of Dermatology, Medical University of Vienna, Vienna, Austria; 2Children’s Cancer Research Institute, Children’s Cancer Research Institute, Vienna, Austria.

Introduction & Objectives: Mycosis fungoides (MF) has been identified as a malignancy of tissue resident memory T-cells, but mechanisms associated with stable vs. progressive disease are still only incompletely understood. We sought to characterize MF-cells and their skin microenvironment, comparing longstanding stable patches with rapidly growing tumors.

Materials & Methods: We investigated skin cells from patch and tumor lesions of early and advanced MF, respectively, by using single cell RNA sequencing.

Results: MF-cells were CD3+, CD4+ and TOX+ in all stages, while benign bystander T-cells were mostly TOX- and displayed distinct clustering in UMAP plots. MF-cells expressed high levels of the activation marker NKG7 and were hyperproliferative as indicated by broad MKI67 upregulation. In line with published literature, we detected high levels of IL13 and IL26 in MF-cells (but not in bystander T-cells), paralleled by upregulated IL13RA1 in nearly all other identified cell populations. Higher numbers of malignant T-cells in tumors were paralleled by relative increases in macrophage, dendritic cell and endothelial cell counts, but a decrease in benign T-cells. Differential gene expression analysis of MF-cells identified increases in GZMB and GNLY in advanced disease, with concomitant decreases in CCL5 and CD7. In parallel, myeloid cells acquired fatty-acid binding protein 5 (FABP5) and S100A9 in tumor vs. patch stage. FABP5 is a negative regulator of IL-12 production in dendritic cells, and S100A9, despite its general role as a pro-inflammatory antimicrobial, has been shown to attenuate inflammatory capabilities of dendritic cells. Thus, these two markers might reflect dendritic cell exhaustion. We also found fibroblasts and endothelial cells to upregulate the tissue inhibitor of metalloproteinases TIMP1 in tumors vs. patches, likely impacting on extracellular matrix remodeling with progressive disease.

Conclusions: Single-cell transcriptomics shed a new light on interactions between MF-cells and their skin microenvironment, revealing novel potential regulatory mechanisms facilitating disease progression.

J-02 CHARACTERIZATION OF TUMOR EVOLUTION OF PRIMARY T-CELL LYMPHOMA USING TARGETED NEXT-GENERATION SEQUENCING PANEL

Wang, E.1; Kim, Y.H.1; Stehr, H.2; Khodadoust, M.S.2

1Dermatology, Stanford University, Stanford, United States; 2Medicine, Stanford University, Stanford, United States.

Introduction & Background: T-cell lymphomas (TCL) often evolve clinically over time, but it is unclear whether these changes correspond to acquired genomic events. Next-generation sequencing (NGS) with targeted panels has the potential to both inform therapy selection and to reveal genomic alterations that may emerge in the context of treatment failure.

Methods & Materials: We applied a novel targeted hematolymphoid NGS panel enriched for common TCL alterations to FFPE tissue or peripheral blood from patients with TCL. Repeated sequencing was performed on a subsequent biopsy for patients with a substantial change in clinical disease features and/or after disease progression with targeted therapy.

Results: We analyzed samples from 89 patients with TCL including mycosis fungoides, Sézary syndrome, primary cutaneous gamma/ delta TCL, adult T-cell leukemia/lymphoma, T-cell prolymphocytic leukemia, and subcutaneous panniculitis-like TCL. We detected at least one genetic alteration in over 90% of sequenced samples. Translocations and copy number variations were detected in a subset of cases. Results of NGS contributed to the selection of targeted agents in 15 patients. In a subset of 14 patients with repeated sequencing, we discovered new emerging mutations. These included mutations in genes downstream to targeted agents, including mutations in STAT3 and PLCG1. We found that JAK3 mutations in the pseudokinase domain may be associated with response to JAK inhibition whereas acquired mutations in JAK1 after initiation of targeted therapy suggests possible mechanism for resistance.

Conclusions: Using a targeted NGS panel, we identified actionable targets that guided prioritization of treatment and demonstrated the importance of reassessment with disease progression. Our findings suggest that changes in genetic alterations may account for resistance or variations in tumor response to treatment. Monitoring of genetic mutations across time points may be helpful in understanding tumor heterogeneity, evolution, and resistance to treatment.

29 ORAL PRESENTATIONS

J-03 GENIC SIGNATURE OF CUTANEOUS T CELL LYMPHOMA-ASSOCIATED FIBROBLASTS FROM MYCOSIS FUNGOIDES AND SEZARY SYNDROME

Habib, Z.1; Gabor, D.2; Adèle, D.M.3; Sophie, L.K.S.2; Christophe, B.4; Anne, B.5; Martine, B.3; Armand, B.2; Jean-François, D.5; Laurence, M.2

1Fondation Jean Dausset-CEPH, CEA, PARIS, France; 2Dermatology, INSERM U976, PARIS, France; 3Dermatology, AP-HP, PARIS, France; 4UMR 1036, CEA, Grenoble, France; 5Centre National de Recherche en Génomique Humaine, CEA, Evry, France.

Background: Cancer-associated fibroblasts (CAFs), a component of tumor microenvironment, play a key role in oncogenesis and promote growth, invasion, metastasis and resistance to chemo-prevention of tumor cells. Here, we aimed to determine the contribution of skin microenvironment in cutaneous T-cell lymphoma (CTCL) tumor lesions by characterizing the gene expression profile of dermal fibroblasts obtained from skin lesions.

Materials and methods: Stranded RNA-sequencing (RNA-seq) was performed on non-activated fibroblast primary cultures from skin biopsies of 8 Mycosis fungoides (MF) and 6 Sezary syndrome (SS) versus 15 normal fibroblasts (NF) from healthy mammary skin controls (age-paired). RNA-seq was performed using Illumina TruSeq V3 reagents. Quantification of expression level used DESeq2 and the identification of statistically differentially expressed genes (DEG) in CTCL versus controls was performed with DESeq2 (adjusted p-value padj<0.05). DEGs with log2FoldChange ≤-1 were considered down-regulated and ≥1, up-regulated. The functional analyzes of DEGs were carried out to define their biological significance by "Gene Set Enrichment Analysis" (GSEA) and "Ingenuity Pathway Analysis" (IPA®).

Results: We found 1044 DEGs between CTCL-associated fibroblasts and NF, with 542 under-expressed and 502 over-expressed genes, 1345 genes in MF-associated fibroblasts versus NF, 457 genes in SS versus NF and only 45 genes in SS- versus MF-associated fibroblasts. GSEA of all CTCL-associated fibroblasts and NF data against the "hallmark gene sets" (h.all.v6.2 containing 50 gene-sets) identified 3 enriched signaling pathways (NES≥1.5): "IFN RESPONSE", "IFN RESPONSE", "MYC TARGETS". The IPA® transcription factor analysis highlighted 25 networks and several pathway-associated gene-sets including “Inhibition of Matrix Metalloproteases” or “Leukocyte Extravasation Signaling”. Validation of main genes of interest is underγ current investigation by qRT-PCR.

Conclusion. The present data demonstrate the alteration of gene expression in CTCL-associated dermal fibroblasts, suggesting the involvement of mesenchymal cells on the behavior of CTCL.

J-04 THE EFFECT OF EXTRACELLULAR MATRIX AND FIBROBLASTS ON PROLIFERATION AND SURVIVAL OF MALIGNANT CELLS IN MYCOSIS FUNGOIDES

Beksac, B.1; Baik, S.2; O'donnell, M.2; Porcu, P.3; Nikbakht, N.2

1Dermatology, University of Health Sciences Gulhane Research and Training Hospital, Ankara, Turkey; 2Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, United States; 3Medical Oncology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, United States.

Introduction & Objectives: It is not known how cancer-associated fibroblasts (CAFs) and the extracellular matrix (ECM) affect malignant T cell survival and proliferation in mycosis fungoides (MF). Our aim was to investigate the effects of dermal fibroblasts and fibronectin, a major dysregulated component of ECM in malignancy, on the proliferation and survival of lymphocytes from MF lesions and MF cell lines.

Materials and Methods: CAFs and skin-derived lymphocytes (SDL) were obtained through explant method from MF skin biopsies. Fibroblasts were also obtained from normal skin. Proliferation assays were performed using CFSE dye dilution, and cell survival, with and without doxorubicin, was assessed via annexin V assay.

Results: Co-cultures with fibroblasts increased proliferation rates of SDL and HUT-78 cells while dramatically suppressing the growth of peripheral blood CD4+ T cells activated with anti-CD3/28 microbeads. CAF co-cultures also rescued MyLa, but not HUT-78 cells and SDL from doxorubicin-induced cell death. Interestingly, HUT-78 cells and SDL, but not MyLa, co-cultured with fibroblasts exhibited lower survival than their counterparts cultured alone. The fibronectin-binding integrin receptors were present on all cell types we analyzed including HUT-78, MyLa, SDL, and pooled blood CD4+ T cells. While exposure to fibronectin slightly increased the proliferation rate of MyLa cells, it decreased that of HUT-78 cells and SDL. Overall, fibronectin did not provide a survival advantage to MF cells with or without doxorubicin.

Conclusions: Co-cultures with CAFs appear to provide a proliferative advantage to MF cells but do not effectively rescue MF cells from chemotherapy. Fibronectin binding to its receptors, integrins, produced variable effects on MF cells in our cultures unlike the previous results reported for leukemic Jurkat cells. Further studies are warranted to investigate the effects of fibroblasts and ECM on the pathogenesis of MF.

30 ORAL PRESENTATIONS

SESSION K - EPIGENETIC ABNORMALITIES K-01 HYPOMETHYLATION-MEDIATED ACTIVATION OF TMEM244 GENE IN SÉZARY CELLS

Iżykowska, K.1; Rassek, K.1; Żurawek, M.1; Nowica, K.1; Paczkowska, J.2; Olek-Hrab, K.3; Giefing, M.2; Przybylski, G.1

1Department of Molecular Pathology, Institute of Human Genetics PAS, Poznań, Poland; 2Department of Cancer Genetics, Institute of Human Genetics PAS, Poznań, Poland; 3Department of Dermatology, University of Medical Sciences, Poznań, Poland.

Introduction & Objectives: Sézary syndrome (SS) is characterized by many complex changes in genome, transcriptome and epigenome, although, it is still unclear, which changes are the drivers that cause the disease, and which are the passengers that occur during the disease progression. Our previous studies confirmed the role of known tumor suppressors (TP53, FAS), epigenetic modifiers (NCOR1, DNMT3A) and dysregulated signaling pathways in the pathogenesis of this disease. In addition, we have shown for the first time ectopic expression of TMEM244 gene, with unknown biological function, in SS patients. This aberrantly activated expression was detected by RNAseq in nine SS patients and confirmed by qRT-PCR (n=13). To determine the mechanism behind this transcriptional activation the DNA methylation status of TMEM244 promoter region was analyzed.

Materials & Methods: DNA and RNA were isolated from 5 SS patients, 5 healthy donors and 5 established T-cell lines (SeAx, Hut78, HH, Jurkat, HDLM2). TMEM244 expression was analyzed by qRT-PCR (TaqMan expression assay) and DNA methylation level was analyzed at three CG dinucleotides (genomic position: chr6:130,182,479-130,182,514; GRCh37/hg19) by bisulfite pyrosequencing.

Results: TMEM244 expression was detected in all SS patients, SS derived cell lines: SeAx, Hut78, HH and T-cell derived Hodgkin lymphoma HDLM2 cell line. In contrast, there was no TMEM244 expression in mononuclear cells from healthy donors and T-ALL Jurkat cell line. Bisulfite sequencing revealed 85-89% (MV=86%) methylation of promoter in all samples without TMEM244 expression and hypomethylation, 2-68% (MV=28%), in samples expressing TMEM244. The percentage of promoter DNA methylation was inversely proportional to the level of TMEM244 expression (Pearson correlation coefficient r=-.58; p<.02).

Conclusions: Our study shows that in normal T-cells TMEM244 promoter is methylated and its hypomethylation in Sézary cells drives aberrant TMEM244 expression.

K-02 EPIGENETIC INVOLVEMENT IN CUTANEOUS T-CELL LYMPHOMA LYMPHOMAGENESIS

Chebly, A.1; Ropio, J.1; Baldasseroni, L.1; Prochazkova-Carlotti, M.1; Idrissi, Y.1; Ferrer, J.1; Poglio, S.1; Pham-Ledard, A.1; Beylot-Barry, M.1; Merlio, J.P.1; Tomb, R.2; Soares, P.3; Chevret, E.1

1INSERM U1053 BaRITon, University of Bordeaux, Bordeaux (University of Bordeaux), France; 2Dermatology, Saint Joseph University, Saint Joseph University, Lebanon; 3Pathology, University of Porto, Porto (i3s/ipatimup), Portugal.

Telomeres and telomerase (hTERT), considered as biomarkers of cancer cells, were found implicated in cutaneous T-cell lymphomagenesis. Epigenetic changes play a role in the increased expression of biomarkers in Mycosis Fungoides (MF) and Sézary Syndrome (SS). This is supported by the efficacy of evolving therapeutic strategies, such as histone deacetylase inhibitors (HDACi) and methylation inhibitors in the treatment of cutaneous T-cell lymphoma (CTCL).

In this study, we investigated the implication of epigenetic events in telomere biology, focusing on hTERT gene promoter methylation status and the transcription of subtelomeric regions towards chromosome ends into long non-coding RNAs (TERRA). Bisulfite sanger sequencing was performed to evaluate hTERT promoter methylation and RT-qPCR was used to assess the expression of TERRA in 7 CTCL cell lines, 6 SS patients and 28 healthy lymphocytes (CD4+ TCRv + and TCRv - cells as well as CD34+ cells) samples. Comparing with normal cells, we observed the implication of hTERT Hypermethylated Oncological Region (THOR) in CTCL. This hypermethylation is responsible for TERT expression, and offersβ importantβ insights that may be used for diagnosis, prognosis, and treatment monitoring.

We also found that besides enriched in heterochromatic marks, telomeres are transcribed from multiple chromosome ends (1q, 9p, 10q, 11q, 15q, 16p and XpYp). This TERRA expression correlates with telomere length and allows distinguishing different CTCL subtypes. Moreover, one TERRA emerges to be implicated in CTCL lymphomagenesis. However, the molecular details of TERRA functions remain to be elucidated.

In this work we unveiled the mechanism behind the activation of telomerase and we identified a potential new biomarker valuable in CTCL lymphomagenesis.

K-03 MYCOSIS FUNGOIDES CELL LINE – DERIVED EXOSOMES SHOW A DISTINCT SIGNATURE OF ELEVATED EXPRESSION OF MIR-155, MIR-1246, AND OX40 TO PROMOTE TUMOR PROGRESSION

Moyal, L.; Arkin, C.; Gorovitz, B.; Knaneh, J.; Hodak, E.

Dermatology, Rabin Medical Center and Tel Aviv University, Petah Tikva, Israel.

31 ORAL PRESENTATIONS

Introduction & Objectives- Exosomes are endosome-derived nano-sized extra-cellular vesicles that mediate intercellular communication by transferring biological information into the recipient cells. Cancer exosomes create a favorable tumor microenvironment and promote tumor progression. We have previously shown that cutaneous T-cell lymphoma (CTCL) cell lines secrete exosomes with oncogenic cargo known to be involved in CTCL. Herein, we extend our in-vitro study to explore the functional oncogenic role of exosomes in CTCL.

Material & Methods- Exosomes were isolated from CTCL cell lines by differential ultracentrifugation, with further confirmation by electron microscopy, nanoparticle tracking analysis and FACS analysis for CD81 (exosome surface marker). The exosomes were profiled for miR content by Affymetrix microarray (followed by qPCR for specific miRs), and for protein content by proteomic mass spectrometry. Exosome internalization was monitored by fluorescence microscopy and FACS analysis of PKH26, exosomal miR uptake- by qPCR, and protein uptake- by immunofluorescence. Survival assay was done by MTT and cell migration by transwell migration assay.

Results- Mycosis fungoides (MF) cell lines (MJ and MyLa) were characterized by abundant exosomal miRs and proteins, with an overlap signature. miR-155 and miR-1246 had the highest expression, both known as exosomal oncomiRs in hematologic and solid neoplasms, respectively. In contrast, Sezary (Hut78) and aggressive CTCL cell lines (HH) had low content exosomes. MJ cell- derived exosomes were internalized into MyLa cells, which in turn increased the cellular expression of miR-155 and miR-1246, protected from doxorubicin- induced cell death, and enhanced cell motility. In addition, exosomes derived from MF cell lines were found to carry OX40 protein (member of the TNF superfamily) which activates the suppression activity of Treg in the tumor microenvironment.

Conclusions- Our results support an important role of exosomal miRs and proteins in regulating MF progression, which highlights their potential for target therapies.

K-04 TRANSFORMED MYCOSIS FUNGOIDES SHOWS DISTINCT MIRNA AND MRNA EXPRESSION PROFILES COMPARED TO CLASSIC MYCOSIS FUNGOIDES

Di Raimondo, C.1; Wu, X.2; Zain, J.3; Abdulla, F.4; Rosen, S.T.3; Querfeld, C.4

1Dermatology, City of Hope Medical Center/University of Rome Tor Vergata, Duarte, United States; 2Molecular and Cellular Biology, City of Hope Medical Center, Duarte, CA, United States; 3Hematology and Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, CA, United States; 4Dermatology, City of Hope Medical Center, Duarte, CA, United States.

Introduction and Objectives:Mycosis Fungoides (MF) is the most common primary cutaneous T cell lymphoma (CTCL).Large cell transformation of MF (MF-LCT) occurs in 20–50% of advanced MF, and is generally associated with poor response to treatment regimens and dismal prognosis. The objective of our study was to identify differences in microRNA (miR) and gene expression profiles of MF-LCT when compared to classic MF using high-throughput sequencing. In addition, we analyzed clinical data and 5-year overall survival of MF-LCT vs classic MF.

Materials and Methods:Total RNA from 56 FFPE lesional skin from 43 MF patients, stages IA-IV was extracted with miRNAeasy FFPE kit (Quiagen) that included5 plaques and 10 tumors with LCT. Total RNA, which includes miRNA, was extracted from CTCL (MF and MF-LCT) samples. Library preparation and high-throughput next generation sequencingwas performed on an IlluminaHiseq 2500. Differences in miR and RNA expression between MF and MF-LCT cases were measured. Gene ontology (GO) term enrichment analysis and Kyoto Encyclopedia of genes and genomes (KEGG) pathway analysis, based on R software, were applied for the identification of pathways in which differentially expressed genes (DEGs) significantly enriched.

Results:Our analysis revealed a distinct miR expression profile for MF-LCT when compared to classic MF. 27 upregulated miRs correlated with MF-LCT; the highest ranked miRs included miR330, miR130b, miR146, miR1246 and miR21-3p/5p. Downregulated miRs included miR203 and 205. KEGG pathway analysis identified DEGs significantly enriched in 10 pathways including T cell receptor signaling, NF- kappa B, Chemokine, NK cell-mediated cytotoxicity signaling pathways. When compared with clinical course the 5-year OS for classic MF was 95% compared to 50% in patients with MF-LCT.

Conclusions:We identified key miRs and gene signaling pathways in MF-LCT that provide insight into pathogenesis and mayshow promise for therapeutic targets.

SESSION L - GENOMIC INSIGHTS

L-01 WHOLE GENOME SEQUENCING ANALYSIS OF CUTANEOUS T CELL LYMPHOMA

Park, J.1; Daniels, J.1; Ringbloom, K.G.1; Martinez-Escala, M.E.1; Choi, S.1; Thomas, J.J.1; Altunbulakli, C.1; Doukas, P.G.1; Yang, J.1; Zhang, Y.1; Conran, C.1; Tegtmeyer, K.1; Pease, D.R.1; Jothishankar, B.2; Shih, D.J.3; Kwok, P.Y.4; Sahni, N.3; Abdulla, F.5; Pro, B.6; Louissaint Jr., A.7; Boggon, T.J.8; Guitart, J.1; Rao, D.9; Choi, J.1

1Department of Dermatology, Northwestern University, Chicago, United States; 2Department of Dermatology, University of Chicago, Chicago, United States; 3Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, United States;

32 ORAL PRESENTATIONS

4Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States; 5Division of Dermatology, City of Hope, Duarte, United States; 6Medicine (Hematology/Oncology), Northwestern University, Chicago, United States; 7Department of Pathology, Massachussets General Hospital, Boston, United States; 8Department of Molecular Biology and Biophysics, Yale University, New Haven, United States; 9Department of Medicine, Brigham and Women's Hospital, Boston, United States.

Introduction and Objectives: Previous efforts have shown that somatic copy number variants are the major mechanism for mutagenesis in cutaneous T cell lymphoma (CTCL). Because the breakpoints typically occur in non-coding regions, whole genome sequencing data is critical to precisely characterize these.

Materials and Methods: To elucidate the genomic map of CTCL, we have analyzed 70 samples of CTCL by whole genome sequencing. We leveraged the improved sensitivity and specificity of whole genome sequencing to comprehensively identify structural variants, non- coding mutations, and somatic copy number variants. We utilized multiple orthogonal analyses to identify genes which are mutated more often than expected by chance.

Results: Collectively, we identified >30 novel putative driver genes. These genes affect previously underappreciated signaling pathways. We have used sgRNA-CRISPR screens to functionally validate our findings.

Conclusions and Future Directions: We have comprehensively identified putative driver genes in CTCL. As a future step, we will evaluate these genetic lesions to identify potential modifiers of disease phenotypesin vitro and in vivo.

L-02 NOVEL MULTI-LAYERED SINGLE-CELL PROTEOGENOMIC ANALYSIS OF PATIENT BIOSPECIMENS PROVIDES UNPRECEDENTED INSIGHT INTO CELLULAR AND MOLECULAR LANDSCAPE OF CTCL

Herrera, A.1; Cheng, A.2; Mimitou, E.3; Seffens, A.4; Buus, T.5; Tegla, C.6; Bar-Natan, M.1; Sun, A.1; Dean, G.7; Odum, N.5; Latkowski, J.A.8; Hymes, K.9; Kadin, M.7; Ouyang, Z.10; Geskin, L.11; Smibert, P.3; Koralov, S.1

1Pathology, NYU School of Medicine, New York, United States; 2Genetics and Genome Sciences, University of Connecticut, Farmington, United States; 3Technology Innovation Lab, New York Genome Center, New York, United States; 4College of Physicians and Surgeons, Columbia University, New York, United States; 5Microbiology, University of Copenhagen, Copenhagen, Denmark; 6Hematology/ Oncology, NYU School of Medicine, New York, United States; 7Pathology, Roger Williams Medical Center, Providence, United States; 8Dermatology, NYU School of Medicine, New York, United States; 9Medicine, NYU School of Medicine, New York, United States; 10Biostatistics, UMass, Amherst, United States; 11Dermatology, Columbia University, New York, United States.

Introduction: Among lymphomas, CTCL is unique in its heterogeneity and the striking dermal tropism of transformed cells. Both the microenvironment of the CTCL skin lesions and the molecular heterogeneity of the malignant lymphocytes remain poorly understood.

Materials and Methods: To explore the tumor microenvironment and molecular heterogeneity and clonal evolution of malignant disease in CTCL we used the recently optimized ECCITE-Seq (Expanded CRISPR-compatible Cellular Indexing of Transcriptomes and Epitopes by Sequencing) protocol. ECCITE-Seq enables simultaneous evaluation of transcriptome and surface proteins of single cells in a high-throughput manner, along with analysis of the antigen receptor repertoire of lymphocytes. Immunophenotyping is made possible by use of oligo-linked antibodies, allowing us to pair characterization of cellular phenotypes with unbiased transcriptome profiling and TCR clonality assessment. Additionally, use of oligo-labeled antibodies allows for “hashing” of samples, thereby enabling combining of multiple samples in a single experiment.

Results: Concurrent analysis of patient skin biopsies and blood using the ECCITE-Seq platform enabled us to track the evolution of the malignant clone across these two tissues. Detailed molecular analysis of the transcriptome of individual cells permitted tracing of clonal disease progression using pseudotime and “real-time” algorithms. Joint visualization of surface phenotypes using >50 antibody-derived epitope tags and transcriptome enabled unprecedented insight into the tumor-microenvironment of the skin lesions – providing insight into changes in the stroma and immune compartment associated with CTCL.

Conclusions: Analysis of 6+ individual patient biospecimens (along with healthy and benign controls) revealed a significant molecular heterogeneity within individual malignant cell clones and notable variability in clonal disease trajectory between individual cases. The highly adaptable ECCITE-Seq platform provides unprecedented insight into the cellular landscape of the tumor microenvironment and molecular etiology of CTCL. We are now applying this platform to examine the impact of environmental triggers and therapeutics on TME in CTCL.

L-03 FUNCTIONAL BIOLOGICAL CLASSIFICATION OF DIFFERENTIAL GENE EXPRESSION IN SÉZARY SYNDROME

Moerman-Herzog, A.1; Acheampong, D.1; Rahmatallah, Y.2; Glazko, G.2; Medhi, S.J.1; Wong, H.K.1

1Dermatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States; 2Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States.

Introduction & objectives: T cell lymphomas are a heterogenous subset of lymphoid malignancies with highly variable clinical course. Thus, diagnosis of erythrodermic skin diseases can be a challenge. We previously identified gene expression abnormalities unique to Sézary syndrome (SS) CD4+CD45RO+ T cells by excluding gene expression shared by a novel disease control, lymphocytic- variant hypereosinophilic syndrome, a benign T-lymphoproliferation with clinical findings similar to SS [Moerman-Herzog, et al. (2019)

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Oncotarget 10:5052]. Here, we sought to validate this gene expression signature in an independent cohort of SS cases, and gain insight from the genes assigned to biological function classifications. Materials & methods: Transcriptome-wide RNA sequencing was conducted on purified T cells from 6 SS cases (CD4+ or CD4+CD45RO+) and 6 normal donors (CD4+CD45RO+). The microarray-derived, SS-unique gene expression signature was compared to differential gene expression detected by RNA sequencing, and concordant gene expression abnormalities were identified. The Molecular Signatures Database was queried to identify enriched Gene Ontology (GO) processes.

Results: A validated SS-unique gene expression signature of 79 upregulated and 67 downregulated genes was identified, including increased expression of FCRL3, HDAC9, NEDD4L, TIGIT and TOX, and decreased expression of DPP4 and STAT4. GO results for all 146 genes included “Regulation of Cell Population Proliferation” and “Negative Regulation of Cytokine Production.” When analyzed separately, upregulated genes were enriched in 12 categories for morphogenesis- and development-related processes. Downregulated genes were enriched in 2 proliferation and 16 immune-related categories.

Conclusions: These results suggest that abnormal gene expression contributes to proliferative processes in SS. Up- and down-regulated genes were associated with different GO processes. Elevated ectopic gene expression may contribute to or reflect altered cell fate specification in SS, while reduced expression of genes normally expressed in memory T cells may contribute to dysregulated immune phenotypes in SS.

L-04 HIGH-THROUGHPUT SEQUENCING REVEALS T-CELL REPERTOIRE RESTRICTION IN SÉZARY SYNDROME AND MYCOSIS FUNGOIDES

Blanco, G.1; López-Aventín, D.2; Pujol, R.M.2; Gómez-Llonín, A.1; Puiggros, A.3; López-Sánchez, M.4; Estrach, T.5; Garcia-Muret, M.P.6; Lopez- Lerma, I.7; Servitje, O.8; Muro, M.4; Espinet, B.3; Rabionet, R.9; Gallardo, F.2

1IMIM - Cancer Research Programme, Hospital del Mar, Barcelona, Spain; 2Servei de Dermatologia, Hospital del Mar, Barcelona, Spain; 3Servei de Patologia, Hospital del Mar, Barcelona, Spain; 4Servicio de Inmunología, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain; 5Servei de Dermatologia, Hospital Clínic de Barcelona, Barcelona, Spain; 6Servei de Dermatologia, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 7Servei de Dermatologia, Hospital Universitari Vall d´Hebrón, Barcelona, Spain; 8Servei de Dermatologia, Hospital Universitari de Bellvitge, L´Hospitalet de Llobregat, Spain; 9Departament de Genètica, Microbiologia i Estadística, Universitat de Barcelona, Barcelona, Spain.

Introduction and Objectives. Prior studies suggested a role for antigen stimulation in Sézary syndrome (SS) and mycosis fungoides (MF) pathogenesis. We aimed to characterize the T-cell Receptor Alfa (TRA) and Beta (TRB) CDR3 repertoire of CD4+ T-cells and the HLA haplotypes in SS/MF.

Materials and Methods. Peripheral blood CD4+ cells were isolated in 11 SS and one MF patients. mRNA was sequenced on a HiSeq2500 (Illumina). Sequencing data was QC’d with FastQC and aligned to reference genome with STAR. High-resolution HLA typing was performed employing PCR-SSO on microbeads array (One Lambda). CDR3 amino acid regions were obtained using IMGT/V-QUEST, and those almost identical to the predominant (CDR3-AIP) were defined as having identical length and one different amino acid. Antigen matches (AgM) were identified employing VDJdb.

Results. Overall, 82216 CDR3 sequences were obtained. An important restriction of the CD4+ T-cell repertoire was observed in SS, with a median frequency of the predominant CDR3 (CDR3-P) of 94.4% for TRA and 93.7% for TRB. Both parameters strongly correlated (r=0.832, P=0.002). CDR3-P and CDR3-AIP frequencies in the same SS patient were exponentially correlated (R2=0.918, P<0.001). Identical CDR3 were frequently detected among different SS/MF patients. VDJdb analysis considering CDR3 with ≥3 reads revealed 21 AgM, including CMV, EBV and self- antigens. CDR3 regions shared by SS/MF patients showed increased frequency of AgM compared to unique CDR3 (TRA: 15.7% vs. 1.4%, P<0.001; TRB: 11.8% vs. 0.6%, P=0.005; respectively). HLA similarities were frequently detected, including a high frequency (25%) of the Western-European A*29:02-B*44:03-C*16:01-DRB1*07:01-DQA1*02:01-DQB1*02:02 haplotype.

Conclusions. CD4+ T-cells of SS/MF express restricted antigen receptors (highly expanded and correlated TRA and TRB CDR3-P, CDR3-AIP in the same SS patient, and shared CDR3 regions enriched in AgM between distinct SS/MF patients) and HLA similarities. These findings allude to increased stimulation by common antigens, potentially inducing malignant T-cell proliferation.

Acknowledgements. PI18/00021, FEHH.

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SESSION M - MOLECULAR CHARACTERIZATION OF RARE CUTANEOUS LYMPHOMAS I

M-01 MOLECULAR STUDY OF SUBCUTANEOUS PANNICULITIS-LIKE T-CELL LYMPHOMA, LUPUS PANNICULITIS AND OVERLAP CASES

Machan, S.1; Rodríguez Moreno, M.2; Manso Aonso, R.2; Rodríguez-Peralto, J.L.3; Cerroni, L.4; García, C.5; González Núñez, M.Á.6; García Toro, E.7; Estrach, T.8; Ferrer, B.9; Torres, Á.10; Lobo, C.11; Sigues, N.11; Alfonso Martin, J.L.12; Borrego, L.13; Montenegro, T.13; Monteagudo, C.14; Limeres Gonzalez, M.Á.15; Córdoba, R.16; Piris, M.Á.17; Requena, L.1; Rodríguez-Pinilla, S.M.18 1Dermatology, Fundación Jiménez Díaz, Madrid, Spain; 2Pathology, Fundación Jiménez Díaz; CIBERONC., Madrid, Spain; 3Pathology, Hospital Universitario 12 de Octubre, Madrid, Spain; 4Research Unit of Dermatopathology. Dermatology, Medical University of Graz, Graz, Austria; 5Dermatology, Hospital Universitario de Canarias, Tenerife, Spain; 6Dermatology, Hospital Ciudad de Coria; Hospital San Pedro de Alcántara, Cáceres, Spain; 7Dermatology, Hospital Universitario de Burgos, Burgos, Spain; 8Dermatology, Hospital Clínic de Barcelona, Barcelona, Spain; 9Pathology, Hospital Vall d’Hebron, Barcelona, Spain; 10Dermatology, Hospital Universitario Río Hortega, Valladolid, Spain; 11Dermatology, Hospital Universitario Donostia, San Sebastián, Spain; 12Pathology, Hospital Materno-Infantil, Las Palmas de Gran Canaria, Spain; 13Pathology, Hospital del Henares, Madrid, Spain; 14Pathology, Hospital de la Malva-Rosa, Valencia, Spain; 15Pathology, Hospital Universitario de Gran Canaria Doctor Negrín, Las Palmas de Gran Canaria, Spain; 16Hematology, Fundación Jiménez Díaz, Madrid, Spain; 17Pathology, Fundación Jiménez Díaz, CIBERONC, Madrid, Spain; 18Pathology, Fundación Jiménez Díaz. CIBERONC, Madrid, Spain.

Introduction & Objectives: Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare cytotoxic T-cell lymphoma, with aggressive behavior and peculiar clinicopathological features. Up to 20% of patients can associate an autoimmune disease, mainly systemic lupus erythematosus. Differential diagnosis with lupus panniculitis (LPan) may be challenging, and overlapping cases have been described. In this study we investigate whether Gene Expression Profiling using a customized Nanostring platform may identify markers that can be used to improve our understanding of the disease and to make a more precise differential diagnosis.

Materials & Methods: We have analyzed 26 cases with diagnosis of SPTCL, LPan and overlapping cases using a customized NanoString platform that includes 208 genes related to T-cell differentiation, stromal signatures, oncogenes and tumor suppressor genes. The different expression of these genes is being validated by immunohistochemistry in an independent group of patients.

Results: By means of the unsupervised analysis of the gene expression of the samples, 2 clusters of samples were found recognizing neoplastic samples versus LPan. A comparative analysis identified 11 up-regulated genes and 7 down-regulated genes. The Gene Set Enrichment Analysis (GSEA) recognized gene sets defining cytotoxic T-cells, mast cells and others, defining both group of cases (LPan versus SPTCL). Specific diagnostic markers are suggested by the analysis.

Conclusions: This study adds to the scarce knowledge about molecular characterization of SPTCL.

M-02 GERMLINE TIM-3 MUTATIONS CHARACTERIZE SUB-CUTANEOUS PANNICULITIS-LIKE T2 CELL LYMPHOMAS WITH HEMOPHAGOCYTIC LYMPHOHISTIOCYTIC SYNDROME

Mccormack, C.1; Khuong-Quang, D.A.2

1Surgical Oncology, Peter Macallum Cancer Center, Melbourne, Australia; 2Paediatric Oncology, Royal Children's Hospital, Melbourne, Australia.

Introduction: Sub-cutaneous panniculitis T-cell lymphomas (SPTCL), a rare non-Hodgkin lymphoma, can be associated with hemophagocytic lymphohistiocytosis (HLH), a life-threatening activation of the immune system which adversely impacts survival. T-cell immunoglobulin mucin 3 (TIM-3) is a modulator of immune responses expressed on subgroups of T- and innate immune cells. In this work we describe the first germline variants associated with SPTCL, which are in the TIM-3 gene.

Methods: We sequenced 27 SPTCL cases to identify gene variants. We performed TIM-3 functional analysis on immune cells from patients and HEK293 cells engineered to overexpress wild-type or mutant TIM-3.

Results: We identified homozygous, germline, loss-of-function, missense variants in highly conserved residues of TIM-3, namely p.Y82C and p.I97M in about 60% (16/27) of SPTCL cases. These samples were drawn from cases series across 3 continents. Patients with bi-allelic TIM-3 mutations were younger at diagnosis, and several had life-threatening HLH and severe disease course. TIM-3 mutations show specific geographic distribution. Y82C TIM-3 mutations occur on a founder chromosome in patients with East-Asian and Polynesian ancestry, while I97M TIM-3 is observed in Caucasians. Both variants induce protein misfolding and cytoplasmic retention of TIM-3. Loss of TIM-3 membrane expression in TIM-3 mutants abrogates the PD-1/PDL-1 checkpoint and prevents the termination of a Th1-immune response. In HEK293 cells, mutant TIM-3 was not expressed on the cell surface. Defective TIM-3 expression leads to persistent immune activation with increased production of inflammatory cytokines including TNF-alpha and IL-1beta by innate immune cells.

Conclusion: Our findings highlight HLH/SPTCL as a new genetic entity where loss of the TIM-3 immune checkpoint is associated with T-cell infiltration of adipose tissue and inflammasome activation. This is the first causative germline defect identified in SPTCL. While our findings indicate that TIM-3-mutant HLH/SPTCL benefit from immunomodulation, therapeutic repression of the TIM-3 checkpoint could have serious adverse consequences.

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M-03 COMPARATIVE GENOMIC ANALYSIS OF CD30+ LYMPHOPROLIFERATIVE DISORDERS

Abdulla, F.1; Parekh, V.2; Song, J.2; Querfeld, C.3; Zain, J.4; Rosen, S.4; Honda, K.5

1Department of Surgery, Section of Dermatology, City of Hope, Duarte, United States; 2Department of Pathology, City of Hope, Duarte, United States; 3Department of Pathology; Department of Surgery, City of Hope, Duarte, United States; 4Department of Hematology, City of Hope, Duarte, United States; 5Department of Dermatology, University Hospitals Cleveland, Cleveland, United States.

Introduction & Objectives: Cutaneous CD30+ lymphoproliferative disorders (CD30+ LYPD), which encompass both lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large cell lymphoma (pcALCL), have vastly different clinical courses and prognoses despite histologic overlap. However, rapidly progressing or aggressive disease occurs. The purpose of our study is to use whole exome sequencing to gain a better understanding of the genomics of these diseases in which no consistent cytogenetic abnormalities or oncogenes have been identified.

Materials & Methods: Array‐comparative genomic hybridization and next‐generation sequencing analysis was performed on FFPE from lesional skin biopsies of LyP and pALCL (5 cases each) and was correlated with clinicopathologic features and TCR rearrangement status. Gene sequencing profiles of LyP and pALCL were compared to each other and against matched normal skin specimens.

Results: Histopathologic features and immunophenotyping identified the number of large CD30+ T cells and the level of background inflammation including eosinophils, neutrophils and histiocytes. GATK-MuTect2 (v4.0.11.0) was used to identify novel somatic mutations. The number of genomic abnormalities was higher in pALCL compared to LyP, but also shared common mutations.

Conclusions: The data from our pilot study confirm that both entities are within the same disease spectrum; however, additional genomic aberrations may be helpful to use as biomarker in delineating locally/regionally aggressive from indolent behavior. Analysis is ongoing.

M-04 SYSTEMIC AND CUTANEOUS ANAPLASTIC T-CELL LYMPHOMAS DIFFER IN THEIR EXPRESSION PROFILE

Wu Yang, A.Y.S.1; Manso Alonso, R.1; Prieto-Torres, L.2; Pajares, R.1; Cereceda, L.1; Piris, M.A.1; Rodriguez Pinilla, S.M.1

1Pathology, Fundación Jiménez Díaz, Madrid, Spain; 2Dermatology, Fundación Jiménez Díaz, Madrid, Spain.

Introduction: Anaplastic Large Cells Lymphomas (ALCLs) are relatively common T-cell lymphomas, which are divided in systemic and primary cutaneous. The systemic ALCLs are divided into ALK-positive or negative, with very different outcomes; while the primary cutaneous ALCLs (PC-ALCLs) are mainly ALK-negative and have a good prognosis.

Material and methods: 31 systemic ALCL (15 ALK+ and 16 ALK-) and 14 primary cutaneous ALCL- (ALK-) were analyzed for a panel of 17 different antibodies in a Tissue Micro Array (TMA). Markers selected for the study included surrogate markers of activation of the WNT signaling, T-cell development- T-cell transcription factors or T-cell regulation pathways. Statistical analysis (c2 contingency tests) was carried out with SPSS20.0. FISH studies for DUSP22 and TP63 locus were performed; results are still being evaluated.

Results: Systemic ALCL cases showed differences depending on the existence of ALK translocation. Thus ALK-positive cases showed increased expression of NFACT1, p-STAT3 and ki67; while ALK-negative cases a higher expression of TOX1 and LEF1.

Comparison between systemic and cutaneous ALCLs showed that primary cutaneous ALCL cases displayed higher level of expression of MYC, TOX1, p-STAT1, Ki67, P53, LEF1 and PD1. On the contrary, CyclinD3 was most frequently expressed in the systemic ALCL cases. When we subtracted ALK-positive cases, we still found that primary cutaneous ALCLs showed increased expression of MYC, p-STAT1, PD1, LEF1 and KI67. Moreover, the expression of p-STAT3 and t-BET was also increased in ALK-negative primary cutaneous ALCLs.

Data regarding cytogenetic subgroups of ALK-negative ALCL are still being analyzed.

Conclusion: The immmunohistochemical expression profile of ALCL is heterogeneous, thus reflecting the diverse cytogenetic background and clinical behavior. ALK negative ALCL showed also differences when comparing systemic vs. primary cutaneous types, reflecting their different prognostic and therapeutic regimens.

M-05 CLONAL RELATIONSHIP BETWEEN BLASTIC PLASMACYTOID DENDRITIC CELL NEOPLASM AND MYELOID NEOPLASMS

Colomo, L.1; Fernandez, C.1; Papaleo, N.1; Vazquez, I.1; Gallardo, F.2; Calvo, X.1; Bellosillo, B.1; Pujol, R.2; Arenillas, L.1

1Pathology, Hospital del Mar, Barcelona, Spain; 2Dermatology, Hospital del Mar, Barcelona, Spain.

Introduction & Objectives: Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) is an aggressive tumor derived from the precursors of plasmacytoid dendritic cells. Rare cases of BPDCN associate with another myeloid neoplasm (MN), mainly myelodysplastic syndromes (MDS), acute myeloid leukemia, and chronic myelomonocytic leukemia (CMML). To evaluate the relationship between both diseases, we studied a series cases with concurrent BPDCN and MN.

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Materials & Methods: We included 5 patients with concurrent BPDCN and MN (2 with refractory cytopenia with multilineage dysplasia -RCMD-, 2 CMML and 1 MDS with isolated del5q). The tumors were characterized by their morphology, immunophenotype by flow cytometry and/or immunohistochemistry, cytogenetics and targeted sequencing of the whole codifying sequence of 21 genes recurrently mutated in MN.

Results: The patients were 3 males and 2 females with a median age of 74 years (range 61-82 years). BPDCN and MDS were synchronic in 2 cases (both RCMD), whereas BPDCN followed the MN in 3 cases (2 CMML, 1 MDS 5q-). All cases had involvement of the skin by BPDCN except the case of MDS 5q- (bone marrow involved only). In this case, del5q was identified in the tumor cells of BPDCN. In one case, trisomy 8 was identified in the tumor cells of BPDCN and CMML. All cases hadTET2 mutations. Mutations in the splicing factors ZRSR2 or U2AF1 were observed in 2 CMML and 1 RCMD. The majority of mutations seen in the MDS/CMML phase were also observed when BPDCN appeared, with the exception of TP53, IKZF1 and NRAS mutations, only detected in BPDCN.

Conclusions: The findings of this series demonstrate a deferred clonal relationship between BPDCN and MN.

SESSION N - MOLECULAR CHARACTERIZATION OF RARE CUTANEOUS LYMPHOMAS II

N-01 CELLULAR ORIGINS AND GENETIC LANDSCAPE OF CUTANEOUS GAMMA DELTA T CELL LYMPHOMAS

Daniels, J.1; Doukas, P.1; Martinez Escala, M.1; Ringbloom, K.1; Shih, D.J.2; Yang, J.1; Tegtmeyer, K.1; Park, J.1; Thomas, J.J.1; Selli, M.E.1; Altunbulakli, C.1; Gowthaman, R.3; Mo, S.H.1; Jothishankar, B.4; Pease, D.R.1; Pro, B.5; Abdulla, F.R.6; Shea, C.4; Sahni, N.2; Gru, A.A.7; Pierce, B.G.3; Louissaint Jr., A.8; Guitart, J.1; Choi, J.1

1Department of Dermatology, Northwestern University, Chicago, United States; 2Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, United States; 3Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, United States; 4Department of Dermatology, University of Chicago, Chicago, United States; 5Medicine (Hematology/Oncology), Northwestern University, Chicago, United States; 6Division of Dermatology, City of Hope, Duarte, United States; 7Department of Pathology, University of Virginia, Charlottesville, United States; 8Department of Pathology, Massachussets General Hospital, Boston, United States.

Introduction & Objectives: Primary cutaneous T cell lymphomas (PCGDTLs) represent a heterogeneous group of uncommon but aggressive cancers. Median survival for patients with PCGDTL is 31 months; 5-year survival is 19.9%. There are no effective therapies for this disease with the lone exception of allogeneicγδ hematopoietic stem cell transplantation. The clinical and histological presentations of PCGDTL are highly variable. Some cases of PCGDTL predominantly involve the epidermis/dermis, while others are centered in subcutaneous adipose tissue (i.e. panniculitic disease). Lesions can present as thin patches or thick nodules with or without ulcerations or cytotoxic markers. The molecular basis of this clinicopathological heterogeneity is unknown. Other than a single prior study evaluating JAK/STAT mutations in PCGDTL, the genetic underpinnings remain obscure. Given the aggressive, fatal nature of PCGDTL, there is a critical unmet need to elucidate the pathogenesis of this disease and to identify novel therapeutic targets.

Materials & Methods: We assembled a large cohort of over 40 clinically annotated PCGDTL cases. From these cases, we identified 28 samples with sufficient material for molecular analyses including DNA sequencing, RNA sequencing, and T cell receptor sequencing.

Results: First, we found that lymphomas arising from different skin compartments have distinct cells of origin. The cells of origin reflect the distribution of T cells in normal skin. Lymphomas from different compartments have distinctive transcriptional profiles, which may help explain clinical phenotypes including cytokine driven syndromes. Genetic analysis reveals similar mutational profiles across PCGDTLs, includingγδ recurrent mutations in MAPK, MYC, JAK/STAT, and chromatin modification pathways. Importantly, targetable mutations in the MAPK and JAK/STAT pathways were uncovered.

Conclusions: This study elucidates for the first time the cellular origins and genomic landscape of this uncommon but aggressive disease. These findings have clinical implications, including paving the way for new, rationally designed therapies for this fatal disease.

N-02 GENOMIC AND TRANSCRIPTOMIC CHARACTERIZATION OF PRIMARY CUTANEOUS GAMMA/DELTA T-CELL LYMPHOMAS REVEALS DISTINCT GENETIC ALTERATIONS AND ENRICHMENT FOR VARIOUS SIGNALING PATHWAYS

Pulitzer, M.1; Bowman, A.S.1; Zehir, A.1; Horwitz, S.2; Ho, C.1; Myskowski, P.L.3; Geller, S.4

1Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States; 2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States; 3-, Memorial Sloan Kettering Cancer Center, New York, United States; 4Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

Introduction & Objectives: Cutaneous gamma/delta T-cell lymphoma (GDTCL) is a rare, aggressive T-cell lymphoma. This study aims to characterize the genomic and transcriptomic features of GDTCL.

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Materials & Methods: 20 patients were identified. DNA mutation and copy number alteration (CNA) assessments were performed in 17 cases by a next generation sequencing (NGS)-based assay (MSK-IMPACT Heme), with germline variant filtering using matched nail controls. Clonal T-cell receptor gamma (TRG) rearrangement was assessed in 13 cases by a NGS-based assay (Lymphotrack). Total RNA sequencing was performed in 7 cases. Using data from cutaneous T-cell lymphoma (CTCL), normal skin, hepatosplenic T-cell lymphoma (HSTL), and peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) RNA-sequenced samples pulled from GEO repositories GSE113113 and GSE55716, Salmon was used to quantify gene expression of samples and DESeq2 was used for differential expression (DE) analysis.

Results: Tumors were from13 male and 7 female (17 Caucasian, 3 Black) patients aged 20-77 (median 58) at presentation, 11 of whom died of disease. Mutations in ATM, TNFAIP3, FAT1, EGFR, JAK3, KMT2C were found in =/>2 cases. Common CNA included loss of ARID1A, CDKN2A/CDKN2B, TNFAIP3, ATM. Clonal TRG rearrangement showed gene usage bias for TRGV3, followed by TRGV2. Reactome pathway analysis of observed transcriptional alterations using WebGestalt and ConsensusPathDB (CPDB) showed enrichment for pathways related to PI3K/AKT signaling.

Comparison # Differentially expressed genes GDTCL vs CTCL 15001 GDTCL vs HSTL 13004 GDTCL vs PTCL-NOS 11504 GDTCL vs normal skin 6950

DE of GDTCL samples against CTCL, HSTL, and PTCL-NOS revealed a subset of 1724 genes with DE in all comparisons. Pathway analysis of these genes revealed enrichment for Interferon Signaling, De-ubiquitination, and ESR-mediated signaling.

Conclusions: DNA and RNA-based assays revealed common mutations, CNAs, gene usage bias in TRG rearrangements, and enrichment in certain signaling pathways in GDTCL, requiring further elucidation for therapeutic targeting.

N-03 WHOLE-GENOME ANALYSIS UNCOVERS RECURRENT IKZF1 INACTIVATION AND ABERRANT CELL ADHESION IN BLASTIC PLASMACYTOID DENDRITIC CELL NEOPLASM

Bastidas Torres, A.1; Cats, D.2; Mei, H.2; Fanoni, D.3; Gliozzo, J.4; Corti, L.4; Paulli, M.5; Vermeer, M.1; Willemze, R.1; Berti, E.4; Tensen, C.1

1Dermatology, Leiden University Medical Center, Leiden, Netherlands; 2Sequencing analysis support core, Leiden University Medical Center, Leiden, Netherlands; 3Pathophysiology and Transplantation, University of Milan, Milan, Italy; 4Dermatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; 5Molecular Medicine, University of Pavia, Pavia, Italy.

Introduction and Objectives: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressive hematological malignancy with a poorly understood pathobiology and no effective therapeutic options. Despite a few recurrent point mutations and indels have been identified in BPDCN, none are disease-specific, and more importantly, none explain its genesis or clinical behavior. This study aimed at characterizing the landscape of structural genomic alterations in BPDCN by employing Whole Genome Sequencing (WGS) and RNA-sequencing (RNA-seq).

Materials and Methods: BPDCN tumors were subjected to WGS (10 patients) and RNA-seq (4 patients) on the Illumina HiSeq X-Ten and HiSeq-4000 platforms, respectively. Raw data were processed using in-house customized pipelines. Differential expression (DE) analysis was performed by comparing the transcriptomes of BPDCN tumors with publicly available transcriptomes of normal plasmacytoid dendritic cells. Select genomic alterations were validated by sanger sequencing and digital droplet PCR (ddPCR).

Results: We have characterized for the first time the landscape of genomic rearrangements and copy number alterations of BPDCN using high resolution next-generation sequencing. Notably, IKZF1, a critical gene for the development of plasmacytoid dendritic cell precursors, was found to be recurrently inactivated by structural alterations. Transcriptome analysis revealed a loss-of-IKZF1 expression pattern and up-regulation of cellular processes responsible for cell-cell and cell-ECM interactions, which is a hallmark of IKZF1 deficiency in immune cells.

Conclusion: Our findings suggest that IKZF1 inactivation plays a central role in the pathobiology of the disease, and consequently, therapeutic approaches directed at reestablishing the function of this gene might be beneficial for patients.

38 ORAL PRESENTATIONS

SESSION O - CUTANEOUS B-CELL LYMPHOMAS

O-01 PRIMARY CUTANEOUS FOLLICULAR LYMPHOMA IS GENETICALLY DISTINCT FROM SECONDARY CUTANEOUS FOLLICULAR LYMPHOMA

Zhou, X.1; Yang, J.1; Ringbloom, K.G.1; Martinez-Escala, M.E.1; Wenzel, A.2; Moy, A.P.3; Morgan, E.A.4; Harkins, S.5; Paxton, C.N.6; Hong, B.7; Andersen, E.F.7; Guitart, J.1; Weinstock, D.M.8; Cerroni, L.9; Choi, J.10; Louissaint, Jr, A.11

1Dermatology, Northwestern University Feinberg School of Medicine, Chicago, United States; 2Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, United States; 3Pathology, Medical Oncology, Northwestern University Feinberg School of Medicine, Boston, United States; 4Pathology, Brigham and Women's Hospital, Boston, United States; 5Pathology, Massachusetts General Hospital, Boston, United States; 6Pathology, ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, United States; 7Pathology, University of Utah School of Medicine, Salt Lake City, United States; 8Medical Oncology, Dana-Farber Cancer Institute, Broad Institute of Harvard and MIT, Boston, United States; 9Dermatology, Medical University of Graz, Graz, Austria; 10Dermatology, Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, United States; 11Pathology, Medical Oncology, Massachusetts General Hospital, Dana-Farber Cancer Institute, Boston, United States.

Introduction & Objectives: Cutaneous follicle center lymphomas comprise primary cutaneous follicle center lymphomas (PCFCLs) that originate and stay in the skin, PCFCLs that subsequently spread to other sites (~10% of all PCFCLs), and typical nodal follicular lymphomas (TNFLs) that occasionally spread to the skin secondarily. The purpose of this study is to identify clinicopathologic and genetic features that differentiate PCFCLs that remain skin-limited from those that subsequently spread systemically and from TNFLs that secondarily spread to the skin.

Materials & Methods: We collected clinicopathologic data from 41 cases of cutaneous follicular lymphomas from 3 academic institutions, including 27 skin-limited PCFCL, 4 PCFCLs that subsequently spread systemically, and 10 secondary cutaneous follicular lymphomas (SCFL). Whole exome sequencing was performed on 19 PCFCLs and 6 SCFLs and copy number analysis on 5 PCFCLs.

Results: Skin-limited PCFCL have very little genetic overlap with SCFL, which resemble TNFL. PCFCLs that later spread systemically resemble SCFL and TNFL more than skin-limited PCFCL. Histologically, skin-limited PCFCLs are associated with reduced CD21+ follicular dendritic cell meshworks and increased proliferation indices. Genetically, they possessed frequent damaging mutations or deletions in TNFRSF14 and lacked BCL2 translocations or recurrent epigenome mutations in CREBBP, KMT2D, ARID1A, EP300 and EZH2 seen in TNFL. In contrast, SCFL and PCFCL that spread systemically closely mirror TNFL with frequent CREBBP, KMT2D and EZH2 mutations and BCL2 translocation in nearly every sample. Among follicular lymphoma subtypes, skin-limited PCFCL most closely resembled pediatric type follicular lymphoma (PTFL), which is similarly anatomically localized and has less aggressive course. Conclusions: A unique combination of clinicopathologic and genetic features differentiates follicle center lymphomas that stay localized to the skin from those that spread systemically or those that started nodally and spread to the skin. These may enhance diagnosis and treatment strategies for these cohorts.

O-02 CHALLENGES IN THE DIAGNOSIS OF PRIMARY CUTANEOUS LARGE B-CELL-LYMPHOMAS

Sarah, M.1; Audrey, G.2; Philippe, R.3; Marie, P.2; Eric, F.4; Anne, P.L.2; Marie, B.B.2; Fabrice, J.5; Béatrice, V.2; Jean-Philippe, M.2

1INSERM U1053, Université Bordeaux, Bordeaux, France; 2INSERM U1053, CHU et Université Bordeaux, Bordeaux, France; 3INSERM U918, Centre Henri Becquerel, Rouen, France; 4Biostatistics and Methodology, CHU et Université Bordeaux, Bordeaux, France; 5INSERM U918, Centre Henri Becquerel, Bordeaux, France.

Introduction and objectives: The 2017 WHO and 2018 updated WHO/EORTC criteria distinguishes primary cutaneous follicle center lymphoma (PCFCL) from primary cutaneous diffuse large B-cell lymphoma-leg type (PCDLBCL-LT) which is crucial for therapy and prognosis. These criteria primarily based on morphology, architecture and phenotype may have limitations to differentiate PCFCL, large cell and PCDLBCL-LT.

Materials & Methods: We evaluated the 2017 WHO classification criteria to categorize 64 primary cutaneous large B-cell lymphomas (PCLBCL), containing ≥80% of large cells and a proliferative rate of ≥40%. We also employed a new cost-effective RT-MLPA technique allowing MYD88 status determination and genomic profiling of large B-cell lymphoma as germinal center (GC) or non-GC in parallel with the modified Hans algorithm.

Results: Morphology and phenotype identified 32 PCLBCL-LT and 25 PCFCL-LC. Seven cases (11%) remained borderline. Phenotype analysis was more reproducible than morphological criteria between observers. Relevant markers for the differential diagnosis were CD10, MUM1 and FOXP1. Dual expression of MYC and BCL2 also favored PCDLBCL-LT diagnosis. BCL6 determination was neither reproducible nor discriminant. The use of the modified Hans algorithm classified 26 cases as germinal center (GC) and a 38 as non-GC. The use of RT-MPLA profiling on 21 PCFCL, LC cases confirmed their categorization as GC and of 23 PCDLBCL-LT as non-GC. The MYD88 mutation was specifically present in the PCDLBCL-LT group. Overall survival was poorer for patients with PCLBCL-LT than with PCFCL-LC (p = 0.0002). In parallel, non-GC cases had poorer overall survival than GC cases (p = 0.0007).

39 ORAL PRESENTATIONS

Conclusions: For borderline cases, the WHO/EORTC update admits to classify cases with confluent sheets of centroblast as PCLBCL-LT or to classify rare cases as PCLBCL,NOS. Our data strongly support the use of the modified Hans algorithm and/or of genomic profiling to differentiate PCFCL, large cell and PCDLBCL-LT according to their GC or non-GC profile.

O-03 MUTATIONS OF THE B-CELL RECEPTOR PATHWAY CONFER CHEMORESISTANCE IN PRIMARY CUTANEOUS DIFFUSE LARGE B-CELL LYMPHOMA LEG-TYPE

Océane, D.1; Marie, B.B.1; Anne, P.L.1; Elodie, B.2; Pierre-Julien, V.2; Thomas, B.3; Nicolas, F.3; Eric, F.4; Béatrice, V.1; Fabrice, J.2; Jean-Philippe, M.1; Audrey, G.1

1INSERM U1053, CHU et Université Bordeaux, Bordeaux, France; 2INSERM U1245, Centre Henri Becquerel, Rouen, France; 3Tumor Biology, CHU Bordeaux, Bordeaux, France; 4Biostatistics and Methodology, CHU et Université Bordeaux, Bordeaux, France.

Introduction: Primary cutaneous diffuse large B-cell lymphoma leg-type (PCLBCL-LT) is the most aggressive cutaneous B-cell lymphoma requiring a combination of poly-chemotherapy with Rituximab as first line therapy. About 50% of patients will experience progression or relapse without so far any predictive biologic marker. We previously characterized the specific mutational profile of PLCBCL-LT of activated B-cells leading to constitutive activation of the NF- B and B-cell receptor (BCR) signaling pathways, as reported for central nervous system or testicular lymphoma. Here, we tried to determine if the genomic profile may predict therapeutic response and help to design personalized second line therapy. κ

Material and Methods: Using lymphopanel next generation sequencing, we analyzed 14 PCLBCL-LT cases with complete response and 18 with relapsing/refractory disease. Among the latter, 14 tumor pairs at diagnosis and relapse/progression were analyzed to assess genetic changes.

Results: PCLBCL-LT patients harboring one mutation that targets one of the following BCR signaling genes (CD79A/B or CARD11) displayed a reduced progression-free survival and specific survival (median 18 months, P=0.002 and 51 months, P=0.03 respectively, whereas median duration in the wild type group was not reached) and were associated with therapeutic resistance (P=0.0006). Longitudinal analyses showed that both MYD88 and CD79B were the earliest and among the most conserved mutated genes.

Conclusion: Evaluating the genomic profile of cutaneous large B-cell lymphoma has not only a descriptive/diagnostic interest but also may help to predict therapeutic resistance in patients with BCR mutations who may benefit from adjuvant or second-line selected therapy.

O-04 LIMITED DIAGNOSTIC VALUE OF HANS AND LYMPH2CX IN DIFFERENTIATING BETWEEN PRIMARY CUTANEOUS FOLLICLE CENTER LYMPHOMA AND PRIMARY CUTANEOUS DIFFUSE LARGE B-CELL LYMPHOMA, LEG TYPE

Schrader, A.M.1; De Groen, R.A.2; Jansen, P.M.1; Vermeer, M.H.3; Quint, K.D.3; Van Den Berg, A.4; Diepstra, A.4; Van Wezel, T.1; Willemze, R.3; Vermaat, J.S.2

1Pathology, Leiden University Medical Center, Leiden, Netherlands; 2Hematology, Leiden University Medical Center, Leiden, Netherlands; 3Dermatology, Leiden University Medical Center, Leiden, Netherlands; 4Pathology, University Medical Center Groningen, Groningen, Netherlands.

Introduction & Objectives: Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) and primary cutaneous follicle center lymphoma (PCFCL) are both primary cutaneous large B-cell lymphomas, but with different clinical characteristics and behavior. Following cell-of-origin (COO) classification in systemic DLBCL, gene-expression profiling (GEP) with micro-array analysis of a limited number of cases showed similarities of PCDLBCL-LT with the activated B-cell-like (ABC) subtype and PCFCL with the germinal center B-cell-like (GCB) subtype. We now evaluated the diagnostic utility of COO classification in patients with PCDLBCL-LT and PCFCL.

Material & Methods: COO was classified on formalin-fixed and paraffin-embedded tissue of 40 PCDLBCL-LT and 12 PCFCL patients using the immunohistochemistry-based Hans algorithm and the NanoString gene-expression-based Lymph2Cx algorithm. COO was correlated with patient characteristics and disease outcome, as well as with previously determined next-generation sequencing and fluorescence in situ hybridization data.

Results: All 12 PCFCL patients were classified as GCB by both the Hans and Lymph2Cx algorithms. In PCDLBCL-LT, 28 cases (70%) were classified as non-GCB and 12 cases (30%) as GCB with Hans, while the Lymph2Cx algorithm classified only 7 cases (18%) as ABC and 17 cases (43%) as GCB. The remaining 16 patients (40%) were unclassifiable/intermediate. The more heterogeneous COO classification in PCDLBCL-LT, as observed in this study, correlates with the detection of GCB genetic events, such as rearrangements of MYC, mutations in CREBBP, GNA13 and HIST1H1E, and aberrant somatic hypermutation, in addition to the frequent mutations in ABC-associated genes, such as MYD88, CD79B and PIM1. Patient characteristics and disease outcome did not differ between the COO subgroups in PCDLBCL- LT.

Conclusions: Our data confirms the GCB-phenotype of PCFCL, but surprisingly shows that many PCDLBCL-LT cases do not have an ABC- phenotype. Therefore, COO classification with both the Hans and Lymph2Cx algorithms have limited value in differentiation between PCFCL and PCDLBCL-LT patients.

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O-05 PRIMARY CUTANEOUS MARGINAL ZONE B-CELL LYMPHOMA IN CHILDREN AND YOUNG ADULTS

Jo-Velasco, M.1; Matteo, E.2; Machan, S.3; Vivanco Allende, B.4; De Dios Velazquez, A.5; Garcia Solano, M.6; Sánchez Frías, M.E.7; Requena Caballero, L.3; Rodriguez-Pinilla, S.M.1; Piris Pinilla, M.A.1

1Anatomia patológica, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain; 2Anatomia patológica, Hospital de Niños Dr. Ricardo Gutiérrez, Buenos Aires, Argentina; 3Dermatología, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain; 4Anatomia patológica, Hospital Universitario Central de Asturias, Oviedo, Spain; 5Dermatologia, Hospital Universitario Central de Asturias, Oviedo, Spain; 6Anatomia patológica, HCU Arrixaca, Murcia, Spain; 7Anatomia patológica, Hospital Universitario de Córdoba, Cordoba, Spain.

Introduction: Primary cutaneous marginal zone B-cell lymphoma is rare in children and adolescents (PCPMZL) with only 23 previously reported cases in patients below 20 years-old. We present 5 cases of PCPMZL and review the previously published cases.

Materials & Methods: We collected 5 cases of PCMZL in pediatric and young adult patients at our institution from 2016 to 2019. Ten biopsies were available for histopathological and molecular analysis. In all cases, routine light microscopy, immunohistochemical studies, and molecular biologic studies (IgH rearrangements) were performed. Clinical data of all cases was reviewed.

Results: Patients (3 females and 2 males ) age ranged from 9 to 21 years, with median age at diagnosis of 12 years. Two patients had clinical history of chronic diarrhea; one suffered from atopic dermatitis, one of hereditary increase of lipoprotein A and the other one a previous history of lymphoblastic B-cell leukemia. Four patients presented with multiple lesions involving different anatomic sites: trunk, limbs and arms. Whereas in one patient, 3 small papules on the left elbow were seen. Two patients, suffered recurrence of the disease two years after diagnosis. Histopathologically, the characteristic appearance of PCMZL was found in 8 of 10 specimens, with nodular infiltrates composed of small lymphocytes in the interfollicular compartment, surrounding reactive germinal centers, with presence of clusters of monotypic plasma cells situated mainly at the interface with the normal dermis or epidermis. Expression of MNDA, PD1, CD123, CD30 and SIgG is still being evaluated. IgH and TCR PCR studies were performed.

Conclusions: PCMZL in pediatric or young patients are rare. They differed from cases published in adults in their initial multicentric location and frequent rate of recurrence. Biological features that could be related to this peculiar biological behavior are still being investigated.

O-06 FIRST - LINE RADIOTHERAPY DOES NOT IMPROVE THE RISK OF DISEASE PROGRESSION IN PRIMARY CUTANEOUS DIFFUSE LARGE B CELL LYMPHOMA, LEG TYPE

Dimitriou, F.1; Zehnder, M.2; Amarov, B.3; Saulite, I.4; Dummer, R.1; Cozzio, A.4; Anzengruber, F.1; Mühleisen, B.1; Navarini, A.2; Guenova, E.1

1Dermatology, University Hospital of Zurich, Zurich, Switzerland; 2Dermatology, University Hospital of Basel, Basel, Switzerland; 3Institute of Statistics and Econometrics, Sofia University "St. Kliment Ohridski", Sofia, Bulgaria;4 Dermatology, Kantonsspital St Gallen, St. Gallen, Switzerland.

Background: Primary cutaneous diffuse large B cell lymphoma, leg type (PCDLBCL, LT) is an aggressive lymphoma variant. Anthracycline – based chemotherapy with rituximab is recommended as first – line treatment. Radiotherapy (RT) has been considered as a therapeutic option for local disease control.

Results: Twenty (N = 20) patients diagnosed with PCDLBC, LT were treated either with RT - alone as first – line treatment (N = 8) or with investigator`s choice (N = 12). One patient had a systemic disease involvement. Investigator`s choice included chemotherapy alone (N = 2) or combined with RT (N = 7) and was chosen regardless of extent of involved skin and lesion type, although the median age of this cohort was significantly lower compared to RT – alone (69 versus 83 years). Three patients were treated with wide local excision.

Complete response (CR) was achieved in eight patients from the first group and nine from the second group, with one treatment failure. Six patients treated with RT – alone relapsed, either locally (N = 3) or distant (N = 1) or systemic (N = 2), with median time to relapse (TTR) 12.5 months. In the second group, two patients had local relapse, two distant and one systemic. Median TTR was 5.2 months. RT showed high rates of local disease control in both groups. Comparison of both groups did not reveal differences in the survival distribution. Still, chemotherapy was eventually used for most patients who experienced disease relapse and were previously treated with RT – alone.

Conclusion: This analysis could not reveal any difference in the survival distribution between the two groups. RT seems a viable treatment option for local disease control and can be greatly combined with systemic treatment. The strength of this analysis needs to be evaluated in a larger patient cohort.

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SESSION P - QUALITY OF LIFE

P-01 THE EVALUATION OF THE QOL AND DAILY FUNCTIONING OF POLISH PATIENTS WITH CUTANEOUS T-CELL LYMPHOMA COGNOSCO LLC COMMISSIONED BY THE FIRM TAKEDA PHARMA LLC

Giza, A.1; Sokołowska-Wojdyło, M.2; Ciepłuch, H.3

1Department of Hematology, Collegium Medicum of the Jagiellonian Univeristy, Krakow, Poland; 2Department of Dermatology, Venerology and Allergology, Medical University of Gdansk, Gdansk, Poland; 3Copernicus, Regional Oncology Centre, Gdansk, Poland.

Introduction and Objectives: Cutaneous T cell lymphomas (CTCLs) is a chronic, incurable disease with involvement of a visible organ, and thereby having a profound impact on patients’ well-being. The goal of our study is the evaluation of QoL of the Polish CTCLs pts and of the influence of the disease on their daily functioning.

Materials and methods: Part I explorative: an interview with pts and physicians about various aspects of the disease and the design of questionnaire. Part II quantitative: 67 pts with treated CTCL, after 1 line treatment and 20 physicians taking care of them completed this and SKINDEX-29 questionnaire.

Results: Of the studied population: 63% were men, the mean age was 60 years, 64% pts lived with family and had support from them and 22% were alone. The mean time of the disease duration is 7 years. The mean time from the occurrence of symptoms to diagnosis is 2,8 years and in 29% pts longer. Statistically, until pts receive the proper diagnosis, they visit 3 physicians, 25% patients even 5. 74% pts manifest an anxiety associated with the diagnosis. 35% pts declare financial problems. 64% pts feel that they spend too much time on visits, travel too long, 59% have to take a day off work. The daily functioning is impaired by CTCL in opinion of 87% pts and 95% physicians, physical activity respectively, of 52% pts and 62% physicians, and insomnia of 54% and 16 %. The impairment of the emotional functioning is declared by 79% pts and by an even larger (95%) number of physicians. More physicians (71%) than pts (57%) point at the need psychological/psychiatric support for CTCL pts.

Conclusions: Our analysis has demonstrated of the profound impact of CTCL on each aspect of QoL (the physical, the emotional and the professional)

P-02 SKIN-SPECIFIC QUALITY OF LIFE IN CUTANEOUS T-CELL LYMPHOMA COMPARED WITH OTHER DERMATOLOGIC DISEASES

Bhat, T.1; Herbosa, C.1; Rosenberg, A.1; Mehta-Shah, N.2; Semenov, Y.3; Musiek, A.1

1Division of Dermatology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States; 2Division of Hematology & Oncology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States; 3Department of Dermatology, Massachusetts General Hospital, Boston, MA, United States.

Introduction/Objectives: Cutaneous T-cell lymphoma (CTCL) profoundly impacts patients’ health-related quality of life (HRQoL) relative to the general population. However, few studies have assessed the HRQoL impact of CTCL compared to other dermatologic diseases.

Materials/Methods: Patients age >=18 with mycosis fungoides or Sezary syndrome were recruited in an academic dermatology clinic from 5/2017-9/2019. HRQoL was assessed using the Skindex-29 questionnaire, and scores were compared to published data for various dermatologic diseases. Data were analyzed using t-tests (Welch correction) for categorical variables and simple linear regression for continuous variables.

Results: 130 CTCL patients completed >75% of the Skindex (median age 66 [range 24-91]; 45% female; 81% white; 19% advanced-stage [IIB-IV]). Advanced-stage patients had worse QoL than early-stage patients in all domains. The Emotions subscore improved with age

(F1,129=7.54; p=0.0069). The Symptoms subscore was worse in patients with all-stage CTCL than vitiligo and non-melanoma skin cancer (NMSC), and the Emotions and Functioning subscores were also worse in all-stage CTCL than NMSC. Patients with advanced-stage CTCL had worse QoL than patients with acne and psoriasis (all domains); pemphigus (Symptoms, Emotions); cutaneous lupus erythematosus (Symptoms, Functioning); eczema and epidermolysis bullosa (Emotions, Functioning); and dermatomyositis (Functioning) (all p<0.01 to minimize experiment-wise error rate).

Conclusions: Compared to other dermatologic diseases, CTCL, especially in advanced stages, is associated with poorer HRQoL. The improvement in Emotions subscore with age mirrors findings in psoriasis and CLE and suggests that the psychosocial impact of cutaneous disease may be greater in younger patients. The Emotions subscore must therefore be interpreted cautiously as a comparator measure, as age may be a confounding factor when comparing HRQoL in skin diseases with different age distributions. The marked findings in the CTCL population underscore the importance of including HRQoL as an essential outcome measure when evaluating clinical progress and designing clinical trials in this patient population.

42 ORAL PRESENTATIONS

P-03 QUALITATIVE ASSESSMENT OF THE QUALITY OF LIFE IN PATIENTS WITH CUTANEOUS T-CELL LYMPHOMA (CTCL)

Bhat, T.1; Herbosa, C.1; Rosenberg, A.1; Jeffe, D.2; Mehta-Shah, N.3; Semenov, Y.4; Musiek, A.1

1Division of Dermatology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States; 2Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, United States; 3Division of Hematology & Oncology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States; 4Department of Dermatology, Massachusetts General Hospital, Boston, MA, United States.

Introduction/Objectives: Cutaneous T-cell lymphoma (CTCL) negatively impacts health-related quality of life (HRQoL), but existing HRQoL instruments may not comprehensively reflect patients’ experience. To our knowledge, this is the first qualitative study specifically aimed at identifying relevant concerns to incorporate into HRQoL questionnaires designed for the CTCL patient population.

Materials/Methods: Semi-structured, one-on-one interviews were conducted with a purposive sample of CTCL patients between May and June 2019. Once data saturation was achieved, data were analyzed by an inductive thematic approach using Dedoose Version 8.0.35.

Results: Single interviews were completed by 18 patients (median age 62 [range 26-80]; 56% female; 72% white; 39% advanced stage [IIB-IV]), lasting a median of 43 minutes. Emerging themes included the pervasive nature of CTCL on patients’ physical, psychological, and social functioning, and the impact of treatment on patients’ lives. The most common complaints included itch, pain, fatigue, skin fissures and sores, and skin flaking. A majority of patients (11/18) reported that their symptoms interfered with sleep, which impacted daily functioning. Additionally, many patients were bothered by the burden of treatment (15/18), trouble coping with daily demands (13/18), uncertainty (12/18), depression (11/18), suicidality (4/18), and hopelessness (9/18). Nearly all patients (17/18) reported a sense of “otherness” (not feeling “normal” or “like themselves”). Most patients (16/18) specifically mentioned concerns about their physical appearance, which differentiates CTCL from other non-cutaneous malignancies.

Conclusions: Our findings identified several CTCL-specific concerns that may not be adequately addressed by generic orgeneral dermatologic HRQoL surveys. While there is no existing instrument that addresses all of these concerns, our results do confirm the utility of many questions included in a recently published CTCL-specific HRQoL questionnaire. Identifying the unique concerns of patients with CTCL, including difficulties with sleep and self-image, is crucial in developing a comprehensive HRQoL instrument that adequately captures their experience.

P-04 THE IMPACT OF GENDER, AGE, RACE/ETHNICITY, AND STAGE ON QUALITY OF LIFE IN A SPECTRUM OF CUTANEOUS LYMPHOMAS

Martinez, X.1; Stiller, T.2; Palmer, J.2; Loscalzo, M.3; Barrios, E.3; Abdulla, F.1; Zain, J.4; Rosen, S.4; Querfeld, C.1

1Surgery, Division of Dermatology, City of Hope, Duarte, United States; 2Division of Biostatistics, City of Hope, Duarte, United States; 3Patient & Family Resource Center, City of Hope, Duarte, United States; 4Hematology/Hematopoietic Cell Transplantation, City of Hope, Duarte, United States.

Introduction: Cutaneous lymphomas (CLs) are a group of rare, potentially disfiguring and disabling cancers that can have a significant impact on quality of life (QoL). While previous studies have examined QoL in patients with mycosis fungoides (MF) and Sezary syndrome (SS), QoL in patients with other types of CL has not been evaluated.

Objective: To determine what factors impact QoL in all CL patients.

Materials and Methods: The Cutaneous Lymphoma Distress Questionnaire (CL-DQ) was used to assess QoL in all CL patients that were seen in a multidisciplinary CL clinic setting. The CL-DQ scores were analyzed and compared to patient demographics, i.e. gender, age, and race/ethnicity, and clinical data, i.e. type of CL, clinical stage for patients with MF/SS, type of treatment, and involvement of social work.

Results: The study population consisted of 151 patients presenting with distinct types of cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma (CBCL). QoL was found to be most negatively affected in females, younger patients, Blacks, and patients with advanced MF and SS. Common among all types of CL was frustration related to skin disease (44%), worry that skin rashes could progress/spread (43%), endorsement of itching/pruritus (32%), and feeling embarrassed/ashamed about appearance of skin disease (28%).

Conclusions: QoL is most significantly impaired in patients with advanced MF/SS, and correlates with other characteristics suchas gender, age, and race/ethnicity. However, other distinct types of CL also affect QoL and are associated with psychological distress. Our findings highlight the need for QoL assessment in all CL patients. Social work intervention, education, and counseling may improve symptoms.

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P-05 PSYCHIATRIC COMORBIDITY IN PATIENTS WITH CUTANEOUS T-CELL LYMPHOMA (CTCL)

Bhat, T.1; Herbosa, C.1; Rosenberg, A.1; Mehta-Shah, N.2; Musiek, A.1; Semenov, Y.3

1Division of Dermatology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States; 2Division of Hematology & Oncology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States; 3Department of Dermatology, Washington University School of Medicine in St. Louis, Boston, MA, United States.

Introduction/Objectives: Cutaneous T-cell lymphoma (CTCL) is associated with poor health-related quality of life (HRQoL), and CTCL patients often report symptoms of depression and anxiety. However, the prevalence of psychiatric comorbidity in the CTCL population remains unknown.

Methods/Materials: Patients with mycosis fungoides (MF) or Sezary syndrome (SS) (n=132) and general dermatology controls (n=132) were recruited at an academic dermatology clinic between 5/2017-10/2019. HRQoL was assessed using Health Utilities Index (HUI3), RAND SF-36, and Skindex questionnaires. Psychiatric and medical comorbidities and use of psychotropic medication were assessed from electronic medical records. Medication use for pruritus, pain, insomnia, and other indications was excluded. HRQoL scores of MF/ SS patients were compared to controls using multivariate regression models adjusted for demographics and medical comorbidities.

Results: The prevalence of documented depression or anxiety disorders was similar between CTCL patients and controls (38/132[28.8%] vs. 40/132[30.3%])(p>0.05). However, CTCL patients were more likely to be taking medication intended to treat depression or anxiety symptoms without a documented diagnosis (18/132[13.6%] vs. 6/132[4.6%])(p<0.05). CTCL patients scored significantly worse than controls on all relevant QoL instruments, including the HUI3 Emotions score (-0.06), HUI3 composite score (-0.12), SF Role Emotional score (-17.9), SF Emotional Well-Being score (-5.9), and Skindex Emotions score (+19.1)(all p<0.05).

Conclusions: The prevalence of documented depression or anxiety in CTCL patients is similar to the normative dermatologic population but significantly higher than the general population. However, CTCL patients exhibit significantly worse HRQoL than dermatologic controls, with significant decrements on all HRQoL subscales used to assess depressive symptoms; they are also more likely tobe taking psychotropic medications intended to treat symptoms of depression or anxiety. This suggests a greater burden of undiagnosed psychiatric comorbidity among patients with CTCL. A multidisciplinary approach that incorporates routine HRQoL assessment is essential to adequately capture symptoms of depression and anxiety in this patient population.

SESSION R - PRECLINICAL DEVELOPMENT OF PERSONALIZED THERAPIES I

R-01 PRE-CLINICAL PRECISION THERAPEUTIC TARGETING NF-KB IN PATIENTS WITH SEZARY SYNDROME

Gallardo, F.1; Garcia-Colmenero, L.1; Andrades, E.1; Gonzalez, J.2; Iglesias, A.2; Blanco, G.3; Conde, D.4; Rodriguez, E.5; Pujol, R.M.1; Bigas, A.2; Espinosa, L.2

1Dermatology, Hospital del Mar, Barcelona, Spain; 2Cancer Stem Cell Research Group, IMIM, Barcelona, Spain; 3Pathology and Cytogenetics, Hospital del Mar, Barcelona, Spain; 4Pharmacy, Hospital del Mar, Barcelona, Spain; 5Nephrology, Hospital del Mar, Barcelona, Spain.

Introduction & Objectives: Integrated genomic datasets identified key elements and pathways that could be used to stratify Sézary Syndrome (SS) patients that would potentially benefit from future targeted therapies. In particular, work from others and our group has pointed out several elements of the NF-kB pathway, such as TAK1, as candidate drivers of SS and CTCL pathogenesis.

Methods: Patient-derived SS samples (n=5) were obtained from fresh peripheral blood mononuclear cells recovered by Ficoll gradient separation. A selected panel of 32 compounds that are known inhibitors of signaling different pathways involved in SS pathogenesis including NF-kBi, MAPKi, HDAC, mTORi or JAK/STATi was used for in vitro drug sensitivity testing. Cells were cultured in the presence of different concentrations of the drugs at 72 hours. Non-drug exposed primary SS cells were used as controls. IC50 was determined to select best drug-response for individual human samples. SS cell viability was evaluated using CellTiter-Glo_3D Cell Viability Assay (Promega) and flow cytometry analysis. We validated results obtained with the NF-kB inhibitor Bortezomib using SS cells xenotransplanted to NSG mice.

Results: Our pre-clinical data showed different drug-sensitivities on primary malignant SS cells. In vitro testing recorded responses to NF-kBi (5), MAPKi (2), mTORi (1), HDACi (1) and JAK/STATi (1), particularly. In addition, further preliminary in vivo data using SS xenogratfs in NSG mice reproduced responses to the NF-kB inhibitor Bortezomib that was observed in the in vitro testing.

Conclusions: These findings may have direct implications for future therapy design in CTCL through selective targeting of patient- specific genomic or molecular profile, since CTCL are heterogeneous malignanies and the different therapies do not fit all patients.

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R-02 SYNERGISTIC THERAPEUTIC DRUG SCREENING USING JAK INHIBITION FOR CTCL

Yumeen, S.1; Mirza, F.N.1; Lewis, J.M.1; King, A.L.O.1; Kim, S.R.1; Carlson, K.1; Foss, F.2; Girardi, M.1

1Dermatology, Yale School of Medicine, New Haven, United States; 2Internal Medicine, Yale School of Medicine, New Haven, United States.

Introduction and Objectives: High-throughput screening has emerged as a method for identification of novel therapeutic compounds; cutaneous T cell lymphoma (CTCL) is driven by single nucleotide and copy number variants in pathways of T cell activation, cell cycle regulation, and DNA structural regulation - dysregulation of JAK/STAT signalling has also been described. Ruxolitinib is a small molecule inhibitor of Jak1/2, and has been reported to inhibit in vitro proliferation of three CTCL cell lines; we sought to examine its effects on CTCL cells in vitro and evaluate synergy with known and putative therapies for CTCL.

Materials and Methods: Malignant CTCL cells were antibody magnetic-bead isolated from patients’ peripheral blood and exposed to high-throughput single and combination drug screening. Cytotoxic effects were evaluated as cell viability via ATP quantitation at 72h. Synergy was evaluated by the Chou-Talalay method. Changes in gene expression were evaluated by qRT-PCR at 24h.

Results: CTCL patient-derived cells showed differential responses to ruxolitinib. Of fourteen patient samples tested, seven appeared resistant with a mean IC50 of 0.14µM, while seven were sensitive with a mean IC50 of 119 µM. Ruxolitinib-sensitive samples showed synergy when combined with either a Bcl-2 (venetoclax), proteasome (bortezomib), Bet (mivebresib) or HDAC inhibitor (vorinostat) with combination index (CI) <1. Ruxolitinib-resistant samples also showed strong kill potentiation with these same inhibitors. BCL2 gene expression was repressed in sensitive samples treated with ruxolitinib alone or in combination with venetoclax, suggesting a mechanism for cooperative activity.

Conclusions: Jak monotherapeutic targeting has differential response on the viability of CTCL cells. However, when used in combination with a BCL-2 inhibitor, proteasome, BET or HDAC inhibitor, Jak inhibition demonstrates consistent synergistic efficacy, regardless of monotherapy sensitivity. Thus, JAK inhibition, in combination with other agents, may represent a novel therapeutic strategy in treatment of CTCL.

R-03 ROMIDEPSIN COMBINATION THERAPIES INVOLVING REGULATION OF THE JAK/STAT PATHWAY INHIBIT TUMOR PROLIFERATION IN CUTANEOUS T-CELL LYMPHOMA

Palomero, T.1; Cortes, J.1; Patrone, C.2; Quinn, S.A.1; Cooke, A.1; Gu, Y.2; Mackey, A.1; Sanchez Martin, M.1; Ferrando, A.1; Geskin, L.2

1Institute for Cancer Genetics, Columbia University, New York, United States; 2Department of Dermatology, Columbia University Medical Center, New York, United States.

Introduction & Objectives: Romidepsin, a histone deacetylase inhibitor, is an FDA approved treatment for CTCL that has shown remarkable results as a single therapy. However, treatment with romidepsin is only efficient in a subset of the patients and the duration of response is frequently short-lived, underscoring the need for the development of novel combination therapies to improve response to romidepsin.

Materials & Methods: Here, we have analysed the efficacy of romidepsin in combination with mechloretamine, and alkylating agent, and ruxolitinib, an inhibitor of JAK1/2 kinases using analysis of CTCL cell lines, patient samples and preclinical models of Sezary syndrome.

Results: Our data demonstrates the existence of a synergistic effect of the combination of romidepsin and mechloretamine in CTCL cell lines and primary samples. Moreover, the combination of romidepsin and mechloretamine significantly decreased tumor load in an in vivo model of Sezary Syndrome, inducing complete responses in 9/10 animals. Gene expression profiling demonstrated specific effects of the romidepsin-mechloretamine drug combination on signalling pathways involved in T-cell proliferation and survival, most remarkably a down-regulation of the JAK/STAT pathway. We propose that the activity of the JAK/STAT pathway is important for the response to romidepsin, and thus, the combination of romidepsin and JAK inhibitors could be effective for the treatment of CTCL. Indeed, the combination of romidepsin and the JAK inhibitors momelotinib or ruxolitinib decreased cell viability in cell lines and primary samples compared to each drugs as single agents and romidepsin-ruxolitinib combination demonstrate increased efficacy in a mouse model of CTCL.

Conclusions: Overall, we demonstrated that romidepsin combination therapies targeting the JAK/STAT signalling pathway have stronger anti-tumor effect than single agents in in vitro and preclinical models of CTCL, warranting further studies to test the efficacy of these combinations in a clinical setting.

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R-04 PHOSPHOLIPASE C GAMMA 1 (PLCG1) MUTATIONS IN SÉZARY CELLS DRIVE NFKB, AP-1 AND NFAT SIGNALLING AND MEDIATE RESISTANCE TO THE CALCINEURIN INHIBITOR TACROLIMUS

Flanagan, C.E.; Patel, V.M.; Jones, C.L.; Whittaker, S.J.; Mitchell, T.J.

St. John’s Institute of Dermatology, King’s College London, london, United Kingdom.

Introduction & Objectives: Somatic mutations in PLCG1 frequently occur in Mycosis Fungoides and Sézary Syndrome (SS). The aims of this in vitro study were to determine the effect of PLCG1 mutations on i) PLC1 downstream signalling pathways and ii) the activity of the calcineurin inhibitor Tacrolimus.

Materials & Methods: Reporter constructs for 9 PLCG1 mutations (p.R48W, p.S312L, p.D342N, p.S345F, p.S520F, p.R1158H, p.E1163K, p.D1165H and the in-frame indel p.VYEEDM1161V) identified in SS, were generated by site directed mutagenesis of wild-type PLCG1. PLC 1 expression was confirmed by western blotting. NFAT, AP-1 and NF-kB transcriptional activity was determined by luciferase reporter assays in HEK293 cells and the J.gamma1 (PLC 1 null) T-cell lymphoma line. Cell staining for caspase activation and flow cytometry were usedγ to determine cellular apoptosis in response to Tacrolimus treatment (30 μM;20 hrs). γ Results: Our data demonstrates in basal conditions, the majority of the mutations confer PLC 1 gain-of-function activity through significant (p≤0.03) downstream activation of NF B, AP-1 and NFAT transcriptional activity in HEK293 cells. Furthermore, in contrast to wild-type PLC 1, activating mutations do not require p.Y783 phosphorylation to stimulate downstreamγ NF B, NFAT, and AP-1 activity. Results for R48W and S345F, the two commonestκ PLCG1 mutations reported in CTCL, were confirmed in J.gamma1 cells. Interestingly, the gain of functionγ activity associated with R48W was significantly higher in the T-cell derived cell line thanκ in HEK293 cells. J.gamma cells transduced R48W and S345F, followed by treatment with the calcineurin inhibitor Tacrolimus were shown to be significantly (p<0.01) less apoptotic than cells transduced with wild-type PLC 1.

Conclusions: These data show that PLCG1 mutations commonlyγ reported in CTCL lead to constitutive activation of PLC 1 and enhance cell survival in response to Tacrolimus treatment. This study provides compelling evidence to support the development of therapeutic strategies targeting mutant PLC 1. γ

γ R-05 SCREENING FOR NOVEL COMBINATION TREATMENTS FOR CUTANEOUS T CELL LYMPHOMA FOR EXPEDITED DEVELOPMENT

Mirza, F.N.; Yumeen, S.; Lewis, J.M.; King, A.L.O.; Kim, S.R.; Carlson, K.R.; Foss, F.M.; Girardi, M.

Department of Dermatology, Yale School of Medicine, New Haven, United States.

Introduction & Objectives: Cutaneous T cell lymphoma (CTCL) is incurable and often fatal in advanced stages, with an overall response rate (~30-50%) to current FDA-approved therapies that warrants a search for new and more effective treatments. Following a high- throughput screen of 1000+ agents (Selleckchem Kinase Inhibitors, MicroSource Gen-Plus, Enzo Phosphatase Inhibitors) on patient- derived CTCL cells, several promising agents were also further evaluated for their synergistic/potentiating effects in combination.

Materials & Methods: Malignant cells were isolated from the peripheral blood from 7 CTCL patients using antibody-magnetic bead sorting for CD3+CD4+ and CD7- and/or CD26- based on the known aberrant phenotype of the patient. Cells were exposed to seven agents with prior FDA-approval for alternative indications or available over the counter as natural compounds – sanguinarine, BIIB021, pyrvinium, ciclopirox, salinomycin, gentian violet, and NVP-BGT226 – individually and in combination. Cell viability was assessed using an ATP luminescence assay at 72h, and synergy or potentiation was evaluated by the Chou-Talalay method.

Results: Single agent titrations identified the the following agents with the highest average potencies against CTCL cells: pyrvinium, salinomycin, gentian violet, sanguinarine, ciclopirox. In combination, the average Chou-Talalay synergy indices revealed synergy for the following combinations: salinomycin + gentian violet; salinomycin + pyrvinium; ciclopirox + sanguinarine; and sanguinarine + gentian violet. While several patient samples demonstrated resistance to NVP-BGT226 and BIIB021 as single agents, combinations revealed strong potentiation for salinomycin and NVP-BGT226 and sanguinarine and BIIB021. Furthermore, both NVP-BGT226 and BIIB021 demonstrated at least moderate potentiation for nearly all drug combinations.

Conclusions: Taken together, these results suggest that salinomycin and pyrvinium, alone and in combination, may represent novel therapies for the treatment of CTCL, while NVP-BGT226 and BIIB021 may represent important potentiators in other drug combination strategies. The compounds validated in this screen may allow for expedited development for use in CTCL.

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R-06 THE SYNERGISTIC PRO-APOPTOTIC EFFECT OF HDAC AND PARP-1 INHIBITION IN CUTANEOUS T-CELL LYMPHOMA IS MEDIATED VIA BLIMP-1

Kruglov, O.1; Wu, X.2; Hwang, S.2; Akilov, O.1

1Dermatology, University of Pittsburgh, Pittsburgh, United States; 2Dermatology, University of California Davis, Davis, United States.

Introduction and Objectives: The therapy of advanced mycosis fungoides (MF) still presents a therapeutic challenge, and search for new therapeutic targets is ongoing. Poly(ADP-ribose) polymerase 1 (PARP-1) was shown to be upregulated in patients with advanced MF and could be druggable by a new class of chemotherapeutic agents, PARP1 inhibitors, which are already in clinical trials for other malignancies. However, the role of PARP1 inhibitors in MF has never been established.

Materials and Methods: We used MBL2 murine model of cutaneous lymphoma to investigate the clinical benefit of PARP1 inhibitor, talazoparib alone and in combination with other anti-lymphoma medications. Mechanism of action was investigated with RNA sequencing assay and confirmed by flow cytometry and Western blotting.

Results: The cytotoxic effect of talazoparib on MBL2 cells was due to G2/M cell cycle arrest via the upregulation of MDM4 and CDKN1A. The in vivo experiments confirmed the clinical effect of talazoparib on cutaneous lymphoma tumors. When talazoparib was combined with HDAC inhibitor, romidepsin, the cytotoxic effect was synergized via downregulation of DNA-repair genes, FANCA, FANCD2, and TOPBP1 and stimulation of apoptosis via Blimp-1/Bax axis. Romidepsin increased the expression of IRF8 and Bcl-6, leading to upregulation of Blimp1 and Bax; while talazoparib upregulated Blimp-1 and Bax via upregulation IRF4 leading to cleavage of caspases 6 and 7.

Conclusions: Thus, a combination of talazoparib with romidepsin demonstrated the synergistic anti-lymphoma effect and warranted further investigation in a clinical trial.

SESSION S - PRECLINICAL DEVELOPMENT OF PERSONALIZED THERAPIES II

S-01 A SMALL MOLECULE CCR2 ANTAGONIST DEPLETES TUMOR MACROPHAGES AND SYNERGIZES WITH ANTI-PD1 IN A MURINE MODEL OF CUTANEOUS T CELL LYMPHOMA

Wu, X.1; Singh, R.2; Hsu, D.1; Zhou, Y.1; Yu, S.1; Han, D.1; Shi, Z.1; Huynh, M.1; Campbell, J.3; Hwang, S.1

1Dermatology, University of California Davis, Sacramento, United States; 2Research, ChemoCentryx, Inc., Mountain View, United States; 3Dermatology, ChemoCentryx, Inc., Mountain View, United States.

Introduction/objectives: Tumor-associated macrophages (TAMs) recruited from blood monocytes are key in establishing an immunosuppressive tumor microenvironment (TME) for supporting tumor growth. We hypothesize that blocking monocyte trafficking through inhibition of specific chemokine receptors into skin can influence tumor development.

Materials/ methods: Herein, we examine the effects of oral administration of a small molecule drug, CCR2i, which blocks CCR2-mediated chemotaxis of monocytes, in a mouse syngeneic T cell lymphoma in skin.

Results: Following CCR2i administration, depletion of macrophages was achieved as early as two days after tumor initiation in the ear TME, while neutrophils were not blocked. Quantitative RT-PCR detected increases in the levels of immune stimulatory inflammatory cytokines, e.g. IFN- , IL-12, and CXCL10, in CCR2i- vs. vehicle-treated mice. Within two weeks the tumors from control groups attained the maximum size, while CCR2i-treated mice exhibited much smaller tumor sizes and weights. Immunohistochemistry revealed CCR2i- treated tumors possessedγ significantly more CD8+ T cells, which were demonstrated to be indispensable for CCR2i-induced tumor inhibition. Finally, combining anti-PD1 with CCR2i significantly increased anti-tumor activity, not only decreasing the tumor size, but also increasing the efficacy of tumor eradication, which were shown to be related with activation of IFN- -producing CD8-T cells.

Conclusions: The CCR2 antagonist CCR2i, particularly in combination with an immune checkpoint inhibitor,γ reduces tumor growth and is a potential future treatment of cutaneous T cell lymphomas.

S-02 INVESTIGATING THE ROLE FOR POT1 GENE DYSFUNCTION IN PRIMARY CUTANEOUS T-CELL LYMPHOMA

Bakr, F.; Holdich, A.; Jones, C.; Whittaker, S.; Mitchell, T.

St John's Institute of Dermatology, Kings College London, London, United Kingdom.

Introduction & Objectives: Somatic single nucleotide variants (SSNVs) in the POT1 (protection of telomeres 1) gene are frequently

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occurring in CTCL. This study investigates the hypothesis that POT1 mutations lead to telomere length (TL) dysregulation and inappropriate activation of DNA damage repair responses (DDRR), which contribute to genomic instability in CTCL.

Materials & Methods: Tetracycline inducible stably transfected Flp-In cell lines were generated with the integration of a single copy of either wild-type (WT) or mutant POT1. Sanger sequencing, Q-PCR and immunoprecipitation (IP) were used to confirm integration and expression of the POT1 gene and protein. TL was measured in both WT and mutant cell lines using Q-PCR. The effects of POT1 mutation on the DDRR was determined by FLOW cytometry and immunofluorescence using a panel of antibodies to DNA damage markers.

Results: Sequencing confirmed the successful generation of six stably transfected POT1 (WT and five mutant) Flp-In cell lines. Q-PCR revealed tetracycline induction of POT1 mRNA as well as a 2-fold increase in mRNA expression in 2 mutants. Immunoprecipitation confirmed the presence of POT1 at the protein level. TL Q-PCR revealed up to a 3-fold increase in telomere length in 3 out of 5 mutants compared to WT. Mutant cells also displayed significantly increased expression of DNA damage markers including yH2AX, p53, 53BP1 and RPA.

Conclusions: This study demonstrates telomere length dysregulation as well as providing evidence for exaggerated DNA damage responses in the context of POT1 mutation, that may contribute to genomic instability, a key feature of CTCL. Crucially, increased expression of the ATR DNA damage pathway marker (RPA) provide a POT1-specific mechanism. Future work will focus on determining whether increased telomere length is related to telomerase activity and if the effects of mutated POT1 protein on its ability to bind telomeric DNA are compromised.

S-04 INTEGRIN ΑVΒ3 INHIBITION IMPROVES REXINOIDS ANTITUMORAL ACTIONS ON CUTANEOUS T CELL LYMPHOMA (CTCL) Cayrol, M.F.1; Revuelta, M.V.2; Debernardi, M.M.1; Phillip, J.M.2; Zamponi, N.2; Diaz Flaque, M.C.1; Magro, C.3; Ruan, J.3; Cremaschi, G.1; Cerchietti, L.2

1Laboratorio de Neuroinmunomodulación y Oncología Molecular, Instituto de Investigaciones Biomedicas UCA CONICET, Buenos Aires, Argentina; 2Department of Medicine, Hematology and Oncology Division, Weill Cornell Medicine, New York, United States; 3Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, United States.

Introduction & Objectives: Bexarotene (Bex) is an oral RXR agonist that is effective for the treatment of early and advanced-stage CTCL. However, Bex is associated with hypothyroidism in about 95% of patients, which are prophylactically managed with the administration of high doses of thyroid hormone (TH) levothyroxine. Paradoxically, we have previously found that physiological levels of TH increase the proliferation of CTCL cells by activating both the nuclear TRA and membrane integrin V 3 receptors. Here, we determined the influence of TH replacement therapy on the anti-lymphoma activity of Bex, an unknown topic with clinical implications. α β Materials & Methods: We performed in vitro and in vivo experiments with HuT78 and MJ human CTCL cells and EL4 murine cells, using RNA sequencing, RT-qPCR techniques and functional assays to determine cell viability, apoptosis and motility.

Results: We found that in standard culture conditions bexarotene regulates gene and pathways related to “cell proliferation and differentiation” (REL, CCND1) and “immune system” (TBX21, IFNG, MX1) and “motility and extracellular matrix interaction” (CCR7, CCR4). Bex also induce biological changes in CTCL cells that lead to a decreased cell proliferation and chemotaxis, as well an increased cell apoptosis and interferon response. Although lack of TH supplementation during bexarotene treatment significantly increased apoptosis and decreased cell proliferation of CTCL cells in vitro and in vivo, it also decreased the antitumor immune response. Since levothyroxine activates both the ubiquitous TRA nuclear receptor and the integrin V 3 membrane receptor that is overexpressed in CTCL cells, we investigated their role in bexarotene treatment. We demonstrated that genetic and pharmacologic inhibition of the integrin V 3 receptor resulted in improved bexarotene-induced effects on apoptosis,α β cell proliferation and chemotaxis while maintaining the antitumor immunity. α β

S-05 HDAC INHIBITOR RESMINOSTAT COUNTERACTS DISEASE-RELATED GENE EXPRESSION AND CYTOKINE SECRETION IN CTCL CELLS

Streubel, G.1; Bretz, A.C.1; Wulff, T.1; Parnitzke, U.1; Hannah, K.1; Kronthaler, K.1; Borgmann, M.2; Hamm, S.1

1Translational Pharmacology, 4SC AG, Planegg-Martinsried, Germany; 2Development, 4SC AG, Planegg-Martinsried, Germany.

Introduction & Objectives: Cutaneous T cell lymphoma (CTCL) is characterized by malignant skin-homing T cells with an increasing bias towards the Th2 cell type during disease progression. A key challenge in the treatment of CTCL is to maintain and to stabilize initial therapeutic responses. Addressing this clinical need, the HDAC inhibitor resminostat is currently under clinical evaluation for disease control after systemic therapy (NCT02953301). Here, the mode-of-action of resminostat was explored.

Material & Methods: Several CTCL cell lines representing mycosis fungoides and Sézary syndrome were used in cell biological and molecular assays. Moreover, genome-wide expression analysis was performed.

Results: Resminostat mediated anti-proliferative and pro-apoptotic effects on both MF and SzS cells. In addition to cytotoxic effects, HDAC inhibitors have been reported to change the chromatin landscape and to modulate gene transcription. Indicating an interference with epigenetic processes, resminostat induced hyperacetylation on specific histone residues linked with transcriptional regulation.

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Global gene expression analysis upon resminostat treatment uncovered extensive gene expression changes and an enrichment of oncogenic driver signaling pathways among the down-regulated genes. Moreover, resminostat modulated the mRNA level of genes associated with the pathogenesis of CTCL. The expression of skin-homing receptors, which mediate the infiltration of malignant T cells into the skin, was reduced by resminostat. Furthermore, resminostat up-regulated a gene expression signature representative of Th1 cell type and down-regulated genes of the Th2 cell type, thus favoring the beneficial Th1 T cell phenotype. In agreement with this observation, resminostat decreased the mRNA level and protein secretion of the Th2 cytokine and itch-mediator IL-31, suggesting that resminostat might improve pruritus in CTCL.

Conclusion: Taken together, resminostat has the potential to reduce the malignant T cell population in CTCL. In conclusion, our preclinical data support the hypothesis that resminostat treatment will improve or stabilize CTCL and its symptoms.

S-06 SINGLE CELL RNA SEQUENCING ANALYSIS TO DEFINE THERAPEUTIC TARGETS IN CUTANEOUS T-CELL LYMPHOMA

Querfeld, C.1; Wu, X.2; Gunes, E.G.3; Jonsson, V.4; Rosen, S.T.4

1Div of Dermatology and Hematologic Malignancies & Stem Cell Transplantation Institute, City of Hope, Duarte, United States; 2Molecular Medicine, City of Hope, Duarte, United States; 3Beckman Research Institute, City of Hope, Duarte, United States; 4Hematologic Malignancies & Stem Cell Transplantation Institute, City of Hope, Duarte, United States.

Introduction and background: T cell exhaustion is a hallmark of CTCL and alterations in mRNA profiles relate to immune checkpoint expression, with potential clinical relevance (Querfeld et al. 2018). There is no marker that can distinguish malignant CD4+ T cells from benign CD4+ T cells in the infiltrate and intratumoral heterogeneity poses a major challenge to treatments and long term remissions. The microenvironment in CTCL harbors multiple immune cells that may contribute to the development of resistance to drug treatments; however, the genomic and molecular determinants of response to therapeutic agents remain incompletely understood. The aim of our study was to distinguish malignant from non-malignant T cells based on TCR / repertoires and to understand the transcriptional landscapes of malignant and non-malignant cells in the TME while on anti-PD-L1 therapy. α β Methods and results: We performed paired single-cell RNA and T cell receptor (TCR) sequencing on ~ 3000-4000 cells (for each treatment naïve and anti-PDL1 treated) from skin lesions of 6 MF patients at baseline and during treatment. Through this combined analysis, we revealed differences in the diversity, clonal expansion and T cell phenotype that differentiated expanded malignant T cell populations from non-malignant tumor infiltrating lymphocytes. Notably, of the single cells with productive TCRs in the treatment- naïve skin lesion, 70% consisted of a single highly expanded T cell clonotype containing TCR variable regions TRAV12-2/TRBV9 exhibited gene enrichment related to high proliferation, and high T cell activation. Non-malignant T cell phenotyping revealed an enriched CD8+ memory population in the untreated sample, as well as upregulation of T cell exhaustion markers LAG3 and PD1.

Conclusions: Single cell analysis revealed differences in the diversity, clonal expansion and T cell phenotype that differentiated expanded malignant T cell populations from non-malignant tumor infiltrating lymphocytes and other immune cells.

SESSION T - NOVEL THERAPEUTICS

T-01 CUSATUZUMAB FOR TREATMENT OF CD70-POSITIVE RELAPSED/REFRACTORY CUTANEOUS T-CELL LYMPHOMA IN A PHASE 1/2 CLINICAL TRIAL

Bagot, M.1; Maerevoet, M.2; Zinzani, P.L.3; Offner, F.4; Morschhauser, F.5; Michot, J.M.6; Ribrag, V.7; Battistella, M.8; Moins-Teisserenc, H.9; Alleri, A.C.10; Dalle, S.11; Beylot-Barry, M.12; Zwanenpoel, K.13; De Winne, K.14; Marie-Cardine, A.15; Cayuela, J.M.16; Tabanelli, V.10; Motta, G.10; Melle, F.10; Hultberg, A.17; Gandini, D.18; Moshir, M.17; Delahaye, T.17; Zabrocki, P.17; Silence, K.17; Van Rompaey, L.17; Bensussan, A.9; De Haard, H.17; Pauwels, P.14; Leupin, N.19; Pileri, S.10

1Department of Dermatology. Research Unit INSERM U976, Saint Louis Hospital, Paris, France; 2Hematology, Jules Bordet, Brussels, Belgium; 33Institute of Hematology "Seràgnoli", University of Bologna, Bologna, Italy; 4Hematology, University hospital Gent, Gent, Belgium; 5GRITA Groupe de Recherche sur les formes Injectables et les Technologies Associées, University Lille, lille, France; 6Hematology and Innovative Drugs, Gustave Roussy, Villejuif Cedex, France; 7Hematology, Gustave Roussy, Villjuif Cedex, France; 8Pathology, Saint Louis Hospital, Paris, France; 9Immunology, Saint Louis Hospital, Paris, France; 10Pathology, European Institute of Oncology (IEO), IRCCS, Milan, Italy; 11Dermatology, Centre Hospitalier Lyon Sud, Pierre Bénite, France; 12Dermatology, Hôpital Saint-André, Centre Hospitalier, Bordeaux, France; 13Pathology, University Hospital Antwerp, Antwerp, Belgium; 14Pathology, University Hospital Antwerp, Antwerp, Belgium; 15Hematology, Saint Louis Hospital, Paris, France; 16Clinical Hematology, Saint Louis Hospital, Paris, France; 17R&D, Argenx, Zwijnaarde, Belgium; 18Clinical Operations, Argenx, Zwijnaarde, Belgium; 19Clinical, Argenx, Zwijnaarde, Belgium.

Introduction & Objectives: Cusatuzumab (ARGX-110) targeting CD70 was investigated in relapsed/refractory (R/R) Cutaneous T-cell lymphoma (CTCL) patients in a Phase 1/2 trial.

Materials & Methods: As part of the trial (NCT01813539), 27 patients with CD70+ R/R CTCL of different subtypes and stages were included for determination of the optimal dose, exploratory efficacy and safety evaluation, and to characterize pharmacokinetics (PK) and biomarkers of drug activity. Cusatuzumab was administered intravenously at 1 (N=11) or 5 mg/kg (N=16) every three weeks. Adverse events were graded according to NCI-CTCAE v. 4.03.

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Results: Cusatuzumab was safe and well tolerated at both doses in CTCL patients with a median age of 67 years (range: 25-84 years). A total of 106 treatment-emergent adverse events (TEAE) were reported in 26 patients, most common was pyrexia and asthenia (5 patients each). Forty events in 16 patients were considered drug-related by the investigator of which infusion-related reactions (IRRs) were the most common (22 events in 8 patients). Eighteen SAEs were reported in 11 patients, one was considered drug related. Best response was one complete response (CR) and five partial responses (PR) in 26/27 patients evaluable for response (overall response rate (ORR) of 23%). Mean duration on the study was 4 months with two patients still on the study at cut-off: 1 patient in CR (subcutaneous panniculitis-like T-cell lymphoma, 24 months) and 1 patient in PR (Sézary Syndrome, 6.5 months). The recommended phase 2 dose (RP2D) was 5 mg/kg, chosen based on safety, PK (mean half-life of 8-12 days) and immunogenicity data. IHC staining for drug- and disease-specific markers showed results supporting clinical benefit.

Conclusions: Clinical anti-tumor activity in patients with R/R CTCL was observed after treatment with cusatuzumab at both 1 and 5 mg/ kg, indicating a safe and promising treatment option for advanced CTCL.

T-02 A PHASE 1B STUDY EVALUATING THE SAFETY AND EFFICACY OF TOPICAL ADMINISTRATION OF WP1220, A STAT3 INHIBITOR, FOR MYCOSIS FUNGOIDES (MF)

Sokołowska-Wojdyło, M.1; Błażewicz, I.2; Olszewska, B.1; Zak, E.3; Silberman, S.4; Priebe, W.5

1Department of Dermatology, Venereology and Allergology, Medical University of Gdańsk (GUMed), Gdansk, Poland; 2Department of Dermatology, Venereology and Allergology, Medical University in Gdansk, Gdansk, Poland; 3Clinical Research, Dermin Spz.oo, Warsaw, Poland; 4Clinical Research, Moleculin Biotech, Houston, Texas, United States; 5Experimental Therapeutics, MD Anderson Cancer Center, Houston, TX, United States.

Introduction & Objectives: MF, the most common variant of cutaneous T-cell lymphoma (CTCL) is a disease with symptomatic, disfiguring skin lesions. STAT3, an oncogenic transcription factor, has been identified as a critical regulator of MF, activation leading to tumor proliferation and suppression of immune responses. WP1220, a synthetic compound potently inhibits p-STAT3 and the growth of CTCL cell lines. This Phase 1b study was designed to demonstrate safety and efficacy of WP1220 after topical treatment of MF

Materials and Methods: Topical treatment of 2-6 baseline index lesions in adults with Stage I, II or III CTCL was with a 10% w/w strength ointment. Eligible subjects with progressive MF applied ointment 2X daily. Primary endpoint was change from baseline CAILS (Composite Assessment of Index Lesion Severity) scores for 84 days. Secondary objectives included photographic validation by independent dermatologists. Biopsies were evaluated for STAT3 pathway activation. Adverse events (AE) were monitored.

Results: Of 5 subjects enrolled, 9 lesions were assessed by the CAILS score. The only AE was mild contact dermatitis in one subject. CAILS scores on index lesions were significantly decreased in four of the subjects, with a median reduction of 56% (range 25%-94%). Improvement was noted by 7 days of treatment and maintained 1 month after discontinuation. Independent dermatologic review based on photographic documentation will be provided, as well as evaluations of the biopsy samples for the status of p-STAT3 in lesions.

Conclusions: WP1220, an inhibitor of p-STAT3, shows safety and significant efficacy in MF after 3 months of topical treatment in progressive MF. This is the first demonstration that inhibition of the STAT3 activation pathway with topical therapy has efficacy in CTCL. Updated, more comprehensive data from this study and assessment of STAT3 phosphorylation in treated lesions will be reported. A larger Phase 2 study is now being planned.

T-03 HIGH DOSE RATE BRACHYTHERAPY FOR THE TREATMENT OF PRIMARY CUTANEOUS LYMPHOMA AT COMPLEX SITES AND COMPLEX CURVES SKIN SURFACES

Sim, V.R.1; Defrancesco, I.1; Child, F.2; Wain, M.2; Whittaker, S.2; Freeman, K.3; Jones, E.3; Aldridge, S.4; Morris, S.1

1Clinical Oncology, Guy's Cancer Centre, London, United Kingdom; 2Dermatology, St John's Institute of Dermatology, Guy's Hospital, London, United Kingdom; 3Radiotherapy, Guy's Cancer Centre, Guy's Hospital, London, United Kingdom; 4Radiotherapy, Guy's Cancer Centre, London, United Kingdom.

Introduction & Objectives: Radiotherapy is an important treatment for cutaneous lymphomas with high response rates. Some sites of skin involvement are difficult to treat with standard orthovoltage or electron beam radiotherapy. We present a service evaluation of our experience using HDR brachytherapy.

Methods: Patients referred for radiotherapy to primary cutaneous lymphomas at difficult complex curves sites were selected for treatment with HDR brachytherapy. Two methods were used; Friesburg flap or 3D printed mould therapy. The patients were CT planned using Oncentra planning system and treated with I-192 on the Flexitron afterloader system. Patient’s response and toxicity outcomes were collected with photographs of the areas treated pre and post treatment.

Results: 19 patients (18 Mycosis Fungoides, 1 PCMZL treated) were treated using HDR brachytherapy from February 2014 – September 2019. 4 patients were planned using 3D printed mould technique and 15 patients were planned with a Friesburg flap applicator. The sites treated are hand =5, forearm =5 lower limb =3, foot =3, nose =2, and eyebrow =1. Small fields were treated with 8Gy/2# or 12GY/3#, larger fields and re irradiation were treated with 24GY/12# or 20Gy/10#.

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All patients had complete response to HDR Brachytherapy locally. Toxicities recorded were G2 radiation dermatitis = 1, cellulitis =1, G2 localised pain =2. 5 patient had a small local recurrence within the treated field that responded to superficial radiotherapy.

Conclusion: HDR brachytherapy is a useful technique for treating complex surfaces involved with cutaneous lymphoma, with a very high response rate and minimal toxicity.

T-04 INTRALESIONAL ONCOLYTIC VIROTHERAPY RESULTS IN TUMOR REGRESSION ASSOCIATED WITH THE INFLUX OF CYTOTOXIC T CELLS IN CUTANEOUS B-CELL LYMPHOMA

Ramelyte, E.1; Tastanova, A.1; Balazs, Z.2; Menzel, U.3; Turko, P.1; Beisel, C.3; Krauthammer, M.2; Levesque, M.P.1; Dummer, R.1

1Dermatology Department, University Hospital Zurich, Zurich, Switzerland; 2Quantitative Biomedicine, University Hospital Zurich, Zurich, Switzerland; 3Genomics facility Basel, Department of Biosystems Science and Engineering, Basel, Switzerland.

Introduction and Objectives. Cutaneous B cell lymphomas (CBCL) are a group of B-cell derived lymphoproliferative diseases with cutaneous tropism. We initiated an investigator initiated trial to investigate the impact of oncolytic virus on the immune compartment and clinical anti-tumor efficacy in CBCL.

Materials & Methods. Patients with CBCL limited to skin received intralesional oncolytic herpes virus Talimogene laherparepvec. First injection of 4ml x 106 PFU/ml was followed by an injection of 4ml x 108 PFU/ml 3 weeks later and every two weeks up to 9 injections. Biopsies were taken at baseline, after 2 and 5 injections. Samples were stained for H&E, CD79a and CD8. Clinical response was defined as reduction of erythema and infiltration. Histological response was defined as reduction of CD79a+ cells compared to baseline biopsy. In 3 patients sequential fine needle aspirations were collected for single cell RNA sequencing.

Results. To date, seven CBCL patients were treated in this study. The median age was 62y (range 46-79). 4 patients had cMZL, 2 had cDLBCL and 1 had cFL. All patients developed clinical and histological response in the injected lesions. 5 patients developed complete or near complete clinical response, 2 patients showed partial response. In histology, all patients showed reduction of CD79a+ and increase in CD8+ cells in after 5 injections compared to baseline, 2 patients developed histological complete response. All patients developed adverse events, 97% of those were grade 1-2. Single cell RNA sequencing of lesions demonstrated substantial alterations in the composition of the immune compartment and the activation status of malignant and reactive cell populations.

Conclusions. Oncolytic virotherapy with intralesional T-VEC shows efficacy in CBCL lesions. It causes clinical response and reduction of CD79a+ B-cell infiltration. The adverse events were mostly mild and self-limited, suggesting good safety profile.

SESSION U - STEM CELL TRANSPLANT

U-01 A PHASE II PROSPECTIVE STUDY USING NON-MYELOABLATIVE ALLOGENEIC TRANSPLANTATION IN PATIENTS WITH ADVANCED STAGE MYCOSIS FUNGOIDES AND SEZARY SYNDROME

Weng, W.K.1; Arai, S.1; Khodadoust, M.2; Hoppe, R.T.3; Kim, Y.H.4

1BMT/Medicine, Stanford University, Stanford, United States; 2Oncology/Medicine, Stanford University, Stanford, United States; 3Radiation Oncology, Stanford University, Stanford, United States; 4Dermatology, Stanford University, Stanford, United States.

Introduction: We report a phase II study of allogeneic transplant using a novel non-myeloablative conditioning in stage IIB-IV MF/SS patients.

Method: Patients received TSEBT (20-36 Gy) as part of conditioning, immediately followed by total-lymphoid-irradiation (TLI, 8-12 Gy) and anti-thymocyte-globulin (ATG), and received allograft infusion as outpatients. This unique TSEBT-TLI-ATG conditioning may have reduced the disease burden in skin, lymph node and blood, respectively. The primary efficacy end point is day+180 PFS with a target rate of 75%.

Result: The study has completed the enrollment and transplanted 35 patients as planned (13 MF, 22 SS; median age 62 years (range 20- 74); median prior systemic therapies of 5 (range 2-13); 7 stage IIB, 28 stage IV). All had active disease at the time of conditioning (skin: 100%, blood: 34%, lymph node: 63%, visceral: 14%). Patients tolerated the transplant well with 1- and 2-year NRM of 3% and 14%, respectively. The day+180 grade II-IV acute GVHD incidence was 16% and the 2-year moderate/severe chronic GVHD incidence was 32%. The 3-month post- transplant global ORR is 80% (20 CR, 8 PR). The day+180 PFS was estimated to be 73% (95% CI, 55-85%). The 2-, 3- and 5-year OS were 68%, 62% and 56%, respectively. Using HTS of the T-cell receptor for MRD monitoring, we observed that 43% of the patients achieved molecular remission, which was associated with significantly lower incidence of disease progression/relapse (13% vs 94%, p<0.0001). Our study also included a much older population than other reported series with 8 patients 60-64 y/o and 12 patients > 65 y/o at the time of transplant. However, the 5-year OS is not different between patients who were > 65 y/o and < 65 y/o (50% vs 60%, p=0.791).

Conclusion: We have developed an effective and potentially curative non-myeloablative allogeneic transplant for advanced stage MF/ SS patients.

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U-02 ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION AS A CURATIVE TREATMENT STRATEGY FOR PATIENTS WITH ADVANCED MYCOSIS FUNGOIDES AND SÉZARY SYNDROME: 2019 UPDATE OF THE MILAN EXPERIENCE

Onida, F.1; Valli, V.1; Saporiti, G.2; Alberti-Violetti, S.2; Grifoni, F.1; Goldaniga, M.1; Casarin, F.1; Schiavone, C.3; Fanoni, D.2; Baldini, L.1; Grillo Ruggieri, F.3; Berti, E.2

1Hematology - BMT Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico - University of Milan, Milano, Italy; 2Dermatology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico - University of Milan, Milano, Italy; 3Radiotherapy Unit, Ospedali Galliera, Genova, Italy.

Introduction & Objectives: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents the only potential curative strategy in selected patients with advanced stage MF and SS. Here we update the previously reported results of our RIC allo-HSCT program in CTCL.

Patients & Methods: Since 09/2000, 45 patients (median age 54 years) with stage IIB/IV refractory MF (n=32) or SS (n=13) and a median time from diagnosis of 46 months underwent allo-HSCT. Donors were HLA-identical sibling in 18, unrelated in 23, and haploidentical related in 4 patients. Median number of previous treatment lines was 6. Bridge to transplant strategy included TSEB in 13 patients and Brentuximab in 1 with pulmonary CD30+ disease infiltration. Conditioning regimens included FC/TBI200 or pentostatin/TBI200 in case of HLA-identical sibling donor, fludarabine/melphalan in MUD and Thiotepa/CTX/Flu/TBI in case of haploidentical donor.

Results: A clinical CR was achieved in 28 patients (62%). As of October 2019, with a median follow-up of 80 months, 23 patients were alive with confirmed CR in 22 (95%). Out of the 17 patients who did not achieve CR, 13 died from progressive disease, 3 were treated with TSEB +/- donor lymphocyte infusion achieving a new durable CR status, while 1 is alive with disease 74 months after transplant. Transplant-related death occurred in 7 patients. Acute grade II-IV GvHD occurred in 15 patients (33%). Chronic GvHD occurred in 20 of the 41 evaluable patients (49%), being severe in 3 (7%). Outcomes at 5-years were: OS 51% (33%-66%), DFS 40% (20%-50%), NRM 15% (4%-27%) and relapse incidence 48% (32%-65%). Of note, all the four patients who underwent haploidentical transplantation were alive and disease-free at the time of last f-up.

Conclusions: We confirm the efficacy of RIC allo-HSCT as a powerful therapeutic strategy in inducing and maintaining remission in selected chemo/radio-sensitive patients, with results particularly encouraging in SS.

U-03 NON-MYELOABLATIVE ALLOGENEIC STEM CELL TRANSPLANTATION USING TSEB TLI AND ATG FOR MYCOSIS FUNGOIDES(MF) AND SEZARY SYNDROME(SS). MEDIUM TERM RESULTS FROM A LARGE SINGLE CENTRE COHORT

Morris, S.1; Palanicawandar, R.2; Grandi, V.3; Defrancesco, I.1; Child, F.3; Mary, W.3; Whittaker, S.3; Mangar, S.4; Kanfer, E.2

1Clinical Oncology, Guys Hospital, London, United Kingdom; 2Hematology, Hammersmith Hospital, London, United Kingdom; 3Dermatology, Guys Hospital, London, United Kingdom; 4Clinical Oncology, Hammersmith Hospital, London, United Kingdom.

Introduction: Advanced Stage MF and SS has a poor prognosis. In 2012 we introduced a protocol involving TSEB, TLI and ATG conditioning. We report out medium term outcomes.

Methods: Patients were selected with stage IIB to IVB MF and SS who had failed at least one prior systemic therapy. Patients were referred for transplant once a global partial or complete response was attained. The conditioning protocol involved TSEB (12Gy/8,24Gy/16or 30Gy/20) followed by TLI 8Gy/10and ATG 0.5mg/kg per day on Day-11 to Day -7, cyclosporine was started on day -3 and on day 0 oral MMF was started. Outcomes on response, toxicity and survival were collected.

Results: 30 patients were transplanted between August 2012 and May 2019. Median follow-up 3.08 years (range 0.5 - 6.7 years). 27 patients had MF and 3 patients had SS. Stage prior to transplant was IIB=6, IIIA=2, IVA2=16, IVB=6. Median number of prior systemic treatments was 4. The 1-year OS was 72.4%, 2-year OS 64.3% and 3-year OS 58.29%. The median progression free survival was 1.29 years and 3-year PFS 37.3%. 14 patients have relapsed with a median time to relapse of 3.77 months (0.87 to 55.4 months). 9 patients received Donor lymphocyte infusions (7 for relapse and 2 for low chimerism). 2 patients went into CR following DLI. At last follow up 14 patients are alive in CR; 5 patients are alive with disease and 11 patients have died. 19 patients developed acute GVHD most commonly mild involving the skin. 5 patients (16%) had grade 2 or higher acute GVHD. The 1- year non relapse mortality was 10%.

Conclusion: The TSEB TLI ATG allogeneic stem cell transplant conditioning protocol is associated with durable remissions, high medium- term overall survival rates and low rates of NRM.

U-04 OUTCOMES FOR ALLOGENEIC STEM CELL TRANSPLANTATION IN REFRACTORY CUTANEOUS LYMPHOMAS

Foss, F.1; Isufi, I.1; Seropian, S.1; Roberts, K.2; Wilson, L.D.2; Gowda, L.2; Girardi, M.3

1Hematology, Yale University School of Medicine, New Haven, CT, United States; 2Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, United States; 3Dermatology, Yale University School of Medicine, New Haven, CT, United States.

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Introduction: There is limited data regarding outcomes after allogeneic stem cell transplantation for cutaneous lymphomas.

Methods: We report results on 24 patients (pts) who underwent allogeneic stem cell transplantation with a reduced intensity conditioning regimen consisting of infusional pentostatin and 6 Gy of fractionated total body irradiation (n=21) or reduced intensity haploidentical conditioning with post-transplant cyclophosphamide (n=3). All pts had skin involvement and 8 pts received a minimum of 12 Gy of total skin electron beam irradiation within four weeks of allogeneic conditioning (6 received TSEBT at various times prior to conditioning) The median age was 53 (range 20-73), 6 pts were African American and 2 were Hispanic. Diagnosis was Sezary syndrome (SS) in 6, tumor stage Mycosis Fungoides (MF) in 11, primary cutaneous gamma delta T cell lymphoma (PCGCT) in 6, and panniculitis like T cell lymphoma in 1. Donors included 10/10 HLA matched unrelated in 9, 5/10 haploidentical in 3, and matched related in 12. Thirteen were in a clinical complete remission at the time of transplant.

Results: The 100-day TRM was 8%. At a median follow up of 5 years, 18 pts (75%) are alive and 14 are in complete remission. One of 6 pts with SS relapsed and responded to donor lymphocyte infusion and one pt with SS died from GVHD at day 481. Three of 11 pts with tumor stage MF died, 2 with progressive disease and one from acute GVHD. Of the 6 pts with PCGDT, two died from progressive disease, three relapsed and all 3 responded to salvage chemotherapy or DLI. Overall, 8 pts had recurrent disease of which 5 are alive.

Conclusions: Our results demonstrate that allogeneic stem cell transplantation is a potentially curative modality in pts with CTCL, including patients with SS, PCGDT, and tumor stage MF.

SESSION V - THERAPEUTICS I

V-01 THERAPY OF BRENTUXIMAB VEDOTIN IN CUTANEOUS T-CELL LYMPHOMAS. MULTI INSTITUTIONAL ANALYSIS

Andrade Campos, M.1; Muniesa, C.2; Sanchez, B.1; Perez-Ferriols, A.3; Servitje, O.4; Stracht, T.5; Bielsa, I.6; Lopez, I.7; Salar, A.1; Gallardo, F.8

1Hematology, Hospital del Mar, Barcelona, Spain; 2Dermatology, Hospital de Viladecans, Viladecans, Spain; 3Dermatology, Hospital General de Valencia, Valencia, Spain; 4Dermatology, Hospital de Bellvitge, Barcelona, Spain; 5Dermatology, Hospital Clínic de Barcelona, Barcelona, Spain; 6Dermatology, Hospital Germans Trias I Pujol, Badalona, Spain; 7Dermatology, Hospital d'Vall d'Hebron, Barcelona, Spain; 8Dermatology, Hospital del Mar, Barcelona, Spain.

Introduction and objectives: Here we summarize the experience in the use of Brentuximab Vedotin (BV) in the therapy of cutaneous T-cell lymphoma in different institutions in Spain.

Material and Methods: This is a multi-institutional study including all 18+ years patients with diagnosis of cutaneous T-Cell lymphoma, treated with BV. We recorded demographic and clinical information. Time to response was calculated since the first dose to partial response (PR). Best response was recorded according with TNM and mSWAT scores.

Results: 20 cases were included from 6 institutions. Fifteen males mean age: 54.5 (31-76) years. Five were cutaneous angioimmunoblastic T-cell lymphoma, Mycosis Fungoide: 14 (7 transformed) and 1 sèzary syndrome. All relapsed, previous lines were 4 (1-9). Eight received alkylants agents (Gemcytabine or CHOP), two autologous and one allo stem cell transplant. The median expression of CD30 was 20% (10%-80%). TNM classification was: IB: 2 cases, IIB: 7, III: 3, IVA: 5, IVB: 2, missing data 1 case. Median mSWAT was 64,92 (20-92). Median time since diagnosis to BV was 36 months (6-300). Median number of cycles was 6 (1-16) cycles. Response was evaluated in 18 cases, 94.4% (17) responded, 7 achieved a complete response. (3 cATCL, 3 MF and 1 SS) and 10 a partial response (1 cATCL and 9 MF). The median number of cycles to the best response was 2 (1-4) cycles. The mean duration of the response was 14 months, during the follow-up, 7 cases has progressed. Safety: 8 (40%) patients developed neuropathy. One grade 2 infusion reaction, two skin rash was registered, nauseas and alopecia in 1 case and myopathy grade 1 in one case.

Conclusion: In our cohort BV was used in heavily treated patients, almost 40% of them achieve a complete response. Side effects were manageable and no deaths were related with the therapy.

V-02 BRENTUXIMAB VEDOTIN TREATMENT PRODUCES SUPERIOR SKIN RESPONSES AND FEWER STAGE PROGRESSIONS THAN ORAL BEXAROTENE, CHEMOTHERAPY, AND SKIN-DIRECTED THERAPY IN LARGE CELL TRANSFORMED MYCOSIS FUNGOIDES

O'donnell, M.; Zaya, R.; Porcu, P.; Nikbakht, N.

Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, United States.

Background:​ Mycosis fungoides with large cell transformation (MF-LCT) is associated with an aggressive course yet previous studies have not addressed treatment outcomes in MF-LCT.

Objective​: To determine the prevalence and overall survival of MF-LCT in a cohort of patients with MF and assess factors affecting

53 ORAL PRESENTATIONS

survival, including treatment modality.

Methods​: In this retrospective single-center study, we enrolled patients with a histological diagnosis of MF-LCT from 2012-2019. Patients were divided into four groups based on the treatment received: brentuximab, oral bexarotene, chemotherapy, and skin-directed therapy (SDT). Treatment outcomes for each group were assessed by mean changes in mSWAT for patients with early disease (stages IA to IIA) or mean changes in stage for patients with advanced disease (stages IIB to IVB), calculated by assigning positive or negative points for interval changes: from early disease to IIB +1 point, IIB to IIIA/IIIB +1 point, IIIA/IIIB to IVA +1 point, and IVA to IVB +1 point.

Results​: Of 171 patients with MF, 23 (13.5%) had histological diagnosis of MF-LCT. The overall survival rate for MF-LCT was 74% and was not significantly associated with gender, age, initial stage at the time of MF-LCT diagnosis, plasma lactate dehydrogenase levels, or histological features of epidermotropism, folliculotropism, syringotropism, and CD30 positivity. Brentuximab showed the greatest mean decrease in mSWAT (-14.1) in early disease and on average no stage progression in advanced MF-LCT compared to oral bexarotene (mSWAT: -8.67; stage: +0.5), chemotherapy (stage: +0.167), and SDT (mSWAT: +1.5; stage: +0.43).

Conclusion​: Our data revealed prevalence and survival rates comparable to prior studies. However, we did not identify any disease characteristics significantly associated with overall survival in our MF-LCT cohort. For the first time, we report superior treatment outcomes for brentuximab compared to oral bexarotene, chemotherapy, and SDT in MF-LCT patients in both early and advanced disease.

V-03 REAL-LIFE EXPERIENCE ON THE USE OF BRENTUXIMAB VEDOTIN ON NINE MYCOSIS FUNGOIDES PATIENTS: TIME TO RE- DISCUSS TREATMENT PROTOCOLS?

Cury-Martins, J.1; Miyashiro, D.1; Neder Ramires Abdo, A.2; Pereira, J.2; Sanches, J.A.3

1Dermatology, University of Sao Paulo, Sao Paulo, Brazil; 2Hematology, University of Sao Paulo, Sao Paulo, Brazil; 3Dermatology, University of Sao Paulo, Madrid, Brazil.

Introduction & objectives: Brentuximab vedotin (BV) is an anti-CD30 antibody–drug conjugate approved for CD30+ CTCL. The recommended regimen is 1.8mg/kg, intravenous, once every 3 weeks, for up to 16 cycles. The aim of this study is to report a single center experience of BV use for mycosis fungoides(MF) in real-life setting, with particularities not included on a clinical trial.

Methods: retrospective analysis of MF patients treated with BV.

Results: Nine patients were included, 55% were male, 2 had folliculotropic MF and all presented large-cell transformation. Median CD30+ on skin biopsies was 30% (<10-100), with 6 patients presenting at least 1 prior biopsy negative for CD30. At BV start, median age was 40 years (29-70), median number of prior treatments was 5 (2-8). Patients were treated for a median of 14 cycles; 8/9 presented neuropathy. Main deviations of the recommended protocol were: INTERVAL – one patient was treated every 30d with good response and one was treated every 6 weeks after tumoral lesions regressed; DOSE: two were treated with 1.2mg/kg since start; COMBINED THERAPIES: PUVA was added in 1 patient, one had PD after cycle7 with association of local radiotherapy, followed by chemotherapy, one used BV in association to methotrexate. Eight patients had partial response after 1st cycle; three progressed while on treatment (on cycles 2 – rapid progression, 7 and 14). Two patients were re-exposed to BV after a complete treatment and one is continuing BV after 16th cycle.

Conclusion: Clinical trials are essential, but they may not always reflect real-life scenario. Most treatments available for MF rarely induces long-term remissions, and cure is not the main objective. Therefore, BV use in lower doses, larger intervals and/or in combination to other therapies (skin-directed or systemic) might help prolonging clinical benefits and time-to-next-treatment, while reducing its main related adverse event, neuropathy.

V-04 BRENTUXIMAB VEDOTIN (BV) AND LENALIDOMIDE (LEN) IN RELAPSED/REFRACTORY (R/R) CUTANEOUS (CTCL) AND PERIPHERAL (PTCL) T-CELL LYMPHOMAS; INTERIM RESULTS OF A PHASE II TRIAL

William, B.; Johnson, A.; Huang, Y.; Reneau, J.; Brammer, J.; Chung, C.

Internal Medicine, The Ohio State University, Columbus, United States.

Introduction & Objectives: Patients with r/r tumor stage CTCL and/or PTCL have a poor prognosis. Both BV and LEN are active in patients with r/r CTCL/PTCL. The objective of this study is to determine the safety and efficacy of BV+Len combination in patients with r/r CTCL/ PTCL

Methods: All patients received BV 1.2 mg/kg IV and Len 20 mg PO daily q3 weeks for a maximum 16 cycles. After 7 patients were treated, we reduced Len to 10 mg given tolerability concerns. Responses are assessed by ISCL/EORTC Global response criteria (for CTCL) and Cheson criteria (for PTCL).

Results: As of July 1, 2019, 17 subjects were treated; 10 (59%) with mycosis fungoides (MF), 2 (12%) with Sezary syndrome (SS), 2 (12%) with CD30+ lymphoproliferative disorder, and 3 (18%) with PTCL. Median age was 60 (49-90) years and 76% were males. Median CD30 staining (immunohistochemistry) was 7.5% (range 1-75%). Median number of prior therapies was 5 (range 1-9). Grade 3 adverse events (AEs) were reported in 11/17 patients; including neutropenia (4), thrombocytopenia (1), bronchitis (1), dyspnea (1), abdominal pain (2), vertigo (1), , DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) syndrome (1), urinary tract infection (1), and tumor flare (2).

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Median number of cycles received was 4 (range 1-17). Best response in 14 evaluable patients were 2 (14%) complete response, 3 (21%) partial response, and 8 (57%) stable disease with overall response rate of 33% (95% confidence interval:12-62%). Median duration of response was 3.2 (range 2.5-13) months. Of note, 7/14 patients (50%) patients with CTCL had >50% reduction in their Skindex-16 scores after a median of 2 cycles (range 1-3).

Conclusions: BV + Len is combination is safe and efficacious in a heavily pre-treated patients with CTCL. Len doses higher than 10 mg daily are associated with excess tumor flare.

V-05 FINAL ALCANZA RESULTS: BRENTUXIMAB VEDOTIN VERSUS PHYSICIAN'S CHOICE IN PREVIOUSLY TREATED CD30-POSITIVE CUTANEOUS T-CELL LYMPHOMA (MYCOSIS FUNGOIDES OR PRIMARY CUTANEOUS ANAPLASTIC LARGE CELL LYMPHOMA)

Scarisbrick, J.1; Horwitz, S.2; Dummer, R.3; Whittaker, S.4; Duvic, M.5; Kim, Y.6; Quaglino, P.7; Zinzani, P.L.8; Bechter, O.9; Eradat, H.10; Pinter- Brown, L.11; Akilov, O.12; Geskin, L.J.13; Sanches, J.14; Ortiz Romero, P.L.15; Weichenthal, M.16; Fisher, D.17; Walewski, J.18; Trotman, J.19; Taylor, K.20; Dalle, S.21; Stadler, R.22; Lisano, J.23; Brown, L.24; Palanca-Wessels, M.C.23; Bunn, V.25; Little, M.26; Prince, H.M.27

1Department of Dermatology, University Hospital Birmingham, Birmingham, United Kingdom; 2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States; 3Department of Dermatology, University Hospital Zürich and University Zürich, Zürich, Switzerland; 4Department of Dermatology, St John’s Institute of Dermatology, Guys and St Thomas NHS Foundation Trust, London, United Kingdom; 5Department of Dermatology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States; 6Department of Dermatology, Stanford University School of Medicine and Stanford Cancer Institute, Stanford, United States; 7Department of Medical Sciences, Dermatologic Clinic, University of Turin, Turin, Italy; 8Department of Haematology, Institute of Haematology, University of Bologna, Bologna, Italy; 9Department of General Medical Oncology, University Hospitals Leuven, KU Leuven, Belgium; 10Division of Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, United States; 11Division of Hematology Oncology, Chao Family Comprehensive Cancer Center, University of California, Irvine, United States; 12Department of Dermatology, University of Pittsburgh, Pittsburgh, United States; 13Department of Dermatology, Columbia University, New York, United States; 14Division of Clinical Dermatology, University of São Paulo Medical School, São Paulo, Brazil; 15Department of Dermatology, University Hospital 12 de Octubre, Institute i+12 Medical School, University Complutense, Madrid, Spain; 16Department of Dermatology, University Hospital of Schleswig-Holstein, Kiel, Germany; 17Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States; 18Lymphoid Malignancies, Maria Sklodowska-Curie Institute and Oncology Centre, Warsaw, Poland; 19Department of Haematology, Concord Repatriation General Hospital, University of Sydney, Concord, Australia; 20Department of Hematology, ICON Cancer Care, South Brisbane, Australia; 21Department of Dermatology, Hospices Civils de Lyon, Claude Bernard Lyon 1 University, Lyon, France; 22Department of Dermatology, University Clinic for Dermatology, Johannes Wesling Medical Centre, Minden, Germany; 23Medical Affairs, Seattle Genetics, Inc., Bothell, United States; 24Biostatistics, Seattle Genetics, Inc., Bothell, United States; 25Oncology Statistics, Millennium Pharmaceuticals, Inc., Cambridge, United States; 26Oncology Clinical Research, Millennium Pharmaceuticals, Inc., Cambridge, United States; 27Division of Cancer Medicine, Peter MacCallum Cancer Centre and Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia.

Introduction and Objectives: The randomised phase 3 ALCANZA study (NCT01578499) demonstrated significantly improved objective response lasting ≥4 months (ORR4) and progression-free survival (PFS) with brentuximab vedotin (BV) versus physician’s choice (PC) in patients with CD30-positive cutaneous T-cell lymphoma (Prince, Lancet, 2017). We report the final ALCANZA results.

Materials and Methods: For detailed methods see Prince, Lancet, 2017.

Results: The intent-to-treat population comprised 128 patients (mycosis fungoides, n=97; primary cutaneous anaplastic large cell lymphoma, n=31). BV significantly improved ORR4 per independent review facility (IRF) (54.7% versus 12.5%; P<0.001) and median PFS per IRF (16.7 versus 3.5 months, P<0.001) compared with PC. Final response data by stage/compartment, and duration of response will be presented. 78% (BV; n=50) versus 75% (PC; n=48) of patients received subsequent antineoplastic therapy; 33/48 patients in the PC arm received BV as subsequent therapy. Median time to next therapy (TTNT) was significantly longer with BV versus PC (14.2 versus 5.6 months; hazard ratio, 0.269; 95% confidence interval [CI]: 0.171–0.424; P<0.001). With median follow-up of 45.9 months, 3-year OS estimates were 64.4% (95% CI: 50.7–75.2) with BV and 61.9% (95% CI: 47.3–73.6) with PC. 44/66 patients treated with BV (safety population) and 4/62 patients treated with PC experienced peripheral neuropathy (PN; standardised MedDRA query). In the BV arm, most PN events were Grade (G) 1 (18/44) or 2 (20/44); 6 patients had G3 PN. At final data cut-off, 86% of BV-treated patients who experienced PN had complete resolution (n=26) or improvement (by ≥1 grade; n=12) of all PN events; ongoing PN was G1/2 in 15/3 patients, similar to the primary analysis.

Conclusions: Final ALCANZA data show significantly improved PFS and TTNT with BV versus PC, suggesting that durable BV responses were clinically meaningful. PN is ongoing in 27% (18/66) of patients treated with BV (predominantly G1).

V-06 BRENTUXIMAB VEDOTIN FOR RELAPSED/REFRACTORY SÉZARY SYNDROME: A SINGLE-CENTER EXPERIENCE

Lewis, D.1; Haun, P.1; Samimi, S.1; Landsburg, D.2; Svoboda, J.2; Barta, S.2; Berg, S.1; Del Guzzo, C.1; Jariwala, N.1; Vittorio, C.1; Villasenor-Park, J.1; Nasta, S.2; Schuster, S.2; Rook, A.1; Kim, E.1

1Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States; 2Department of Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States.

Introduction/Objectives: Brentuximab vedotin (BV) is a CD30-directed antibody-drug conjugate approved for CD30+ cutaneous T-cell lymphoma. However, limited data exist on its efficacy in Sézary syndrome (SS), including in the pivotal phase III ALCANZA trial.

55 ORAL PRESENTATIONS

Treatment options for SS are limited and associated with relatively low response rates.

Materials/Methods: Between 2017-19, nine SS patients at the University of Pennsylvania received BV infusions 1.8 mg/kg q21 days. Only SS patients with B2 blood involvement as defined by the 2011 EORTC/ISCL criteria at the time of BV treatment were included. Outcomes were assessed in the skin and lymph nodes per EORTC/ISCL response criteria and in the blood per PROCLIPI revised blood response criteria.

Results: Nine patients (6 males, 3 females, median age 67) received BV after a median of 6 prior therapies (range 0–12). Skin biopsies showed CD30-positivity (>10%) in 5/9 patients. 2/9 patients (22%) had a global response (one CR with 15-20% skin CD30+, 1 PR with 1% skin CD30+). Time to response was 6 weeks with treatment duration of 9 cycles (PR) and 13 cycles (CR), and response duration of 22 and 105 weeks (ongoing), respectively. In the 5 patients in whom blood response could be assessed, 3 responded (1 CR, 2 PR). 2/3 patients showed a response (1 PR, CR) in lymph nodes (LN) on PET/CT. One patient (skin CD30 95%) received BV as first-line therapy and achieved SD (PR in blood, SD in skin and LN). Grade 1-2 neuropathy occurred in 4/9 patients, lasted a median of 62 weeks (range, 23-91 weeks), and resolved in 1/4 patients. No grade 3-4 adverse events occurred.

Conclusions: This study suggests a therapeutic role for BV in SS even in setting of low CD30 expression, but with a lower global response rate than that observed in the ALCANZA trial (22% vs 56.3%).

SESSION W - THERAPEUTICS & CLINICAL TRIALS II

W-01 RESOLUTION OF SÉZARY SYNDROME AFTER COMBINATION OF MOGAMULIZUMAB WITH PEGYLATED INTERFERON Α2-A IS MEDIATED BY CD56DIM NKP30+ IFN-Γ+ NK CELLS

Patino, P.; Kruglov, O.; Akilov, O.

Dermatology, University of Pittsburgh, Pittsburgh, United States.

Introduction and Objectives: The recent advances in the immunobiologic therapy of cancer made a significant impact on patients' life. Combination strategies demonstrated to be more advantageous in comparison with monotherapy leading to faster disease resolution and prolonged disease-free survival.

Materials and Methods: Targeted single-cell RNA sequencing and flow cytometry were performed on samples from 3 patients before and after the combinational therapy of mogamulizumab with pegylated interferon 2-a.

Results: We report an exceptional outcome of the combination of mogamolizumab αand pegylated interferon- 2a resulting in 3 patients with a partial clinical response as soon as two weeks after initiation of the therapy and complete response after only two months of therapy. Targeted single-cell RNA sequencing with subsequent flow cytometry demonstrated that the activationα of CD56dim NKp30 NK cells by pegylated interferon- 2a was crucial in the induction of antibody-dependent cytotoxicity against CCR4+ Sezary cells.

Conclusions: Our clinical data andα evidence of efficacy justify future immunotherapy combinations that can be evaluated in the clinical trial for patients with Sezary syndrome.

W-02 A NOVEL REGIMEN OF INTERFERON GAMMA, BEXAROTENE, PHOTOPHERESIS AND 12 GY TOTAL SKIN ELECTRON BEAM CAN PRODUCE LONG TERM REMISSION: CLINICAL, IMMUNOLOGICAL AND MOLECULAR ANALYSIS

Jariwala, N.N.1; Zhang, K.K.1; Wysocka, M.1; Benoit, B.1; Maity, A.2; Berg, S.1; Del Guzzo, C.1; Lewis, D.J.1; Kim, E.J.1; Vittorio, C.1; Teague, J.E.1; Clark, R.A.1; Rook, A.H.1

1Dermatology, University of Pennsylvania, Philadelphia, United States; 2Radiation Oncology, University of Pennsylvania, Philadelphia, United States.

Sezary syndrome (SS) is an advanced form of cutaneous T-cell lymphoma which has a poor prognosis with few long term remissions observed. We recently evaluated four previously treatment-refractory patients with a lengthy history of SS who experienced long term remissions when treated in a multimodality fashion with combined interferon gamma, bexarotene, photopheresis and low dose (12Gy) total skin electron beam (TSEB). Methods: The four patients underwent extensive clinical, molecular and immunological assessment to fully characterize their responses. Patients were evaluated clinically monthly to bimonthly, peripheral blood flow cytometry was performed every 4 months to assess phenotypically abnormal T-cells, and peripheral blood lymphocytes were obtained for 12 color flow cytometry to determine expression of hallmarks of immune exhaustion and immune deficiency, production of Type 1 cytokines (Th1) and for performance of high throughtput T-cell receptor sequencing (HTS). Results: Following administration of TSEB and maintenance of the other therapies, remissions have ranged from 18 to 72 months and are still ongoing among three patients without detection of skin lesions, lymphadenopathy or phenotypically abnormal circulating T-cells. Markers of immune exhaustion including PD-1, TIGIT, CTLA4, TOX and Foxp3 were significantly reduced from baseline on circulating CD4 and CD8 T-cells measured more than 6 months following TSEB, along with markedly enhanced production capacity of interferon gamma by lymphocytes following activation stimuli. HTS demonstrated near complete eradication of the circulating clone among 3 of 4 patients with stable levels among one. Conclusions:

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This well tolerated multimodality regimen can induce long term clinical and hematological remissions among patients with SS and is associated with amelioration of parameters of immunological exhaustion and suppression. Clinical trials utilizing this therapeutic approach should be considered.

W-03 CLINICAL ACTIVITY AND SAFETY OF LOW-DOSE TOTAL SKIN ELECTRON BEAM THERAPY COMBINED WITH MOGAMULIZUMAB IN REFRACTORY SÉZARY SYNDROME: SUPPORT FOR A CLINICAL TRIAL IN CTCL

Fong, S.1; Hong, E.1; Khodadoust, M.S.2; Hiniker, S.3; Li, S.1; Wang, E.B.1; Hoppe, R.T.3; Kim, Y.H.2

1Dermatology, Stanford University, Stanford, United States; 2Dermatology, and Medicine, Stanford University, Stanford, United States; 3Radiation Oncology, Stanford University, Stanford, United States.

Introduction & Objectives: Management of patients with refractory mycosis fungoides (MF) and Sézary syndrome (SS) is often challenging as available therapies lack durable response and/or consistent activity across disease compartments. Combining low-dose total skin electron beam therapy (LD-TSEBT) upfront with mogamulizumab could optimize the clinical outcome of these patients. LD-TSEBT is effective in clearing skin disease, and mogamulizumab is an anti-tumor immunotherapy with long-term tolerability suggesting its potential as a maintenance therapy after maximal response. To generate supportive experience for a clinical trial, we examined the combination regimen in previously treated SS patients.

Materials & Methods: Two patients with SS were treated following the planned study design (Figure 1) of an investigator-initiated, phase 2 clinical trial of LD-TSEBT and mogamulizumab (TSE-Moga) in previously treated patients with MF/SS. Both patients received mogamulizumab 1mg/kg weekly x 4 and then bi-weekly; LD-TSEBT (12 Gy) was initiated within 2 days of starting mogamulizumab and given over 2-3 weeks. Safety and clinical response were evaluated. Results: TSE-Moga was well-tolerated without any unanticipated adverse events. Patient 1 (T4N2M0B2) is a 63 yo female with 4 prior systemic therapies; time to global response (TTR) with TSE-Moga was 9 weeks. Patient 2 (T4NxM0B2) is a 75 yo male with 5 prior systemic therapies; TTR was 4 weeks. Both patients lacked global response to their prior therapies but achieved global complete response (CR, blood and skin) with TSE-Moga. After a follow-up of 45 weeks and 14 weeks respectively, global CR continues.

Conclusions: TSE-moga demonstrated excellent tolerability and promising clinical activity with ongoing global complete responses in two patients with refractory SS. This encouraging experience supports our upcoming clinical trial evaluating the efficacy and safety of TSE-Moga in MF/SS. Comprehensive translational studies are planned.

Figure 1. Study Design

Figure 2. Global CR; Patient 1 (A-B), Patient 2 (C-D

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SESSION X - OBSERVATIONS AND PERSPECTIVES

X-01 TREATMENT OF ADVANCED-PHASE MYCOSIS FUNGOIDES: RESULTS FROM THE PROSPECTIVE CUTANEOUS LYMPHOMA INTERNATIONAL STUDY (PROCLIPI STUDY)

Quaglino, P.1; Bagot, M.2; Cozzio, A.3; Evison, F.4; Geskin, L.5; Hodak, E.6; Horwitz, S.7; Papadavid, E.8; Porcu, P.9; Prince, M.10; Ortiz-Romero, P.11; Stadler, R.12; Vermeer, M.13; Willemze, R.13; Kim, Y.14; Scarisbrick, J.15

1Medical Sciences, Dermatologic Clinic, Torino, Italy; 2Dermatology, Dermatologic Clinic, Paris, France; 3Dermatology, St Gallen Hospital, st Gallen, Switzerland; 4Dermatology, Birmingham Hospital, Birmingham, United Kingdom; 5Dermatology, Columbia University, New York, United States; 6Dermatology, Tel Aviv University, Tel Aviv, Israel; 7Oncology, Sloan Memorial Kettering, New York, United States; 8Dermatology, 2nd Athens University, Athens, Greece; 9Hematology, Jefferson Univ Hospital, Jefferson, United States; 10Molecular Oncology & Hematology, Birmingham Hospital, Melbourne, Australia; 11Dermatology, Dermatologic Clinic, Madrid, Spain; 12Dermatology, University Hospital Minden, Minden, Germany; 13Dermatology, Leiden Univ, Leiden, Netherlands; 14Cancer Institute, Stanford Univ, San Francisco, United States; 15Dermatology, Univ Hospital Birmingham, Birmingham, United Kingdom.

On behalf the CLIC Alliance, CLIC Treatment Working Group, EORTC and ISCL and all the PROCLIPI centers YK and JS share equal seniorship

Introduction & objectives: The PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) Study opened in July 2015 collecting international data on MF including treatments. This study reports on the first-line treatments used in advanced-stage MF with the objectives to ascertain whether there are differences in first-line approach according to the TNMB staging; to identify which are the parameters related to different systemic approach; to describe response rates.

Materials & methods: A total of 362 advanced stage MF patients were recruited from 41 centers in 16 different countries.

Results: The percentage of patients with a first systemic treatment was 45% in IIB, 65% in IIIA, 77% in IIIB, 83%in IVA1, 74% in IVA2 and 69% in IVB. Patients not receiving a first line systemic include radiotherapy (32%), phototherapy (30%) , expectant (17%). The overall RR to first line sytemic was 49%, stage IIB patients had a better RR than those diagnosed IIIA/IIIB (68% vs 46%, p=0.006), no difference in the RR in first line systemic for those diagnosed IVA1 compared to IV2/IVB (52% vs 43%, p=0.385). 90 had received a 2nd line systemic and TTNT to the next systemic treatment was a median of 15 days (IQR:0-37days) in IIB, IIIA,IIIB,IVA1,IVA2 and IVB. 23 had progressive disease during a median FU of 18 months. The median number of systemic treatments was 1 (IQR:1-3) in survivors and 2 (IQR:1-4) in those who died from disease. The duration of first line systemic was longer in responders (median 7 months (4-14) vs 2.5 months (0-9), p<0.0001)

Conclusions: first preliminary data on treatment approaches world-wide in real life in a controlled cohort of new MF/SS diagnosis patients recruited in a prospective way.

X-02 WHAT HAPPENS WHEN AN EFFECTIVE ANTI-CTCL DRUG IS DISCONTINUED FROM PRODUCTION?

Rooke, B.1; De Brito, M.2; Jayaprakash, S.2; Azurdia, R.3; Arumainathan, A.4; Cowan, R.5; Farquharson, N.6; Parry, E.6; Ngu, I.7; Weatherhead, S.8; James, E.9; Gallop-Evans, E.10; Dunnill, G.11; Wachsmuth, R.12; Furtado, M.13; Yoo, J.2; Scarisbrick, J.2

1Dermatology, University Hospitals Birmingham, Birmingham, United Kingdom; 2Department of Dermatology, University Hospitals Birmingham, Birmingham, United Kingdom; 3Department of Dermatology, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom; 4Department of Haematology, Liverpool University Hospitals NHS Foundation Trust & The Clatterbridge Cancer Centre, Liverpool, United Kingdom; 5Department of Oncology, Christie Hospital, Manchester, United Kingdom; 6Department of Dermatology, Christie Hospital, Manchester, United Kingdom; 7Department of Dermatology, Glasgow Royal Infirmary, Glasgow, United Kingdom; 8Department of Dermatology, Royal Victoria Infirmary, Newcastle, United Kingdom;9 Department of Oncology, Nottingham University Hospitals, Nottingham, United Kingdom; 10Department of Oncology, Velindre Cancer Centre, Cardiff, United Kingdom; 11Department of Dermatology, Bristol Royal Infirmary, Bristol, United Kingdom;12 Department of Dermatology, Royal Devon and Exeter Hospital, Exeter, United Kingdom; 13Department of Haematology, Royal Cornwall Hospitals Trust, Cornwall, United Kingdom.

Introduction: Interferon alfa-2 (IFNa-2) is recommended for the management of early-stage mycosis fungoides (MF) refractory to skin-directed therapy, advanced-stage MF and Sezary syndrome (SS). The manufacture of two IFNa-2 formulations, Intron-A (interferon-alfa-2b) and Roferon-A (interferon-alfa-2a), were discontinued in 2019 forcing MF/SS patients receiving these formulations to seek alternative treatment.

Methods: Retrospective analysis of the cutaneous lymphoma database at University Hospitals Birmingham evaluates efficacy of IFNa- 2 in MF/SS. A prospective observational cohort study examines outcomes of patients losing access to IFNa-2 treatment at UK centres.

Results: 62 MF/SS patients at University Hospitals Birmingham received IFNa-2 since 2010; 47% had early-stage MF (29/62), 45% advanced-stage MF (28/62), and 8% SS (5/62). 69 treatment episodes were received by 62 patients. Response rate (RR) was 39% (24/62; RR not reported for 7 episodes), with complete response in 10% (6/62). Median time to next treatment (TTNT) was 10 months. 10 centres responded to a UK survey and identified 30 patients receiving ongoing treatment with IFNa-2 formulations at the time of ceased manufacture (Liverpool University Hospitals;n=9; University Hospitals Birmingham;n=8; Christie Hospital, Manchester;n=6; Glasgow

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Royal Infirmary;n=3; Royal Victoria Infirmary, Newcastle;n=3; Nottingham University Hospitals;n=1). These 30 patients require alternative treatment; we will report on their responses/outcomes to next treatments.

Conclusions: Our data confirms that Intron-A and Roferon-A are effective treatments for MF/SS. Pegylated interferon alfa-2a (Pegasys) is a contender for substitution of IFNa-2. 13 IA/IB MF patients treated with pegylated interferon alfa-2a in a phase I/II dose-escalation study showed dose-dependent RRs from 50-83%; advanced-stage MF/SS were not included in this study (Schiller M et al. Dose-escalation study evaluating pegylated interferon alfa-2a in patients with cutaneous T-cell lymphoma. JEADV 2017;31:1841-1847). We present the impact of losing access to IFNa-2 on the management of MF/SS patients in UK, including next treatment type and outcomes of this UK patient cohort.

X-03 IMPROVED SURVIVAL FOR SKIN-PRIMARY PRESENTATION OF ADULT T-CELL LEUKEMIA/LYMPHOMA (ATLL)

Goyal, A.1; O'leary, D.2; Bohjanen, K.1

1Dermatology, University of Minnesota, Minneapolis, United States; 2Hematology/Oncology, University of Minnesota, Minneapolis, United States.

Introduction & Objectives: Adult T-cell leukemia/lymphoma (ATLL) is an uncommon and aggressive systemic leukemia that can present in the liver, spleen, CNS, bone marrow, GI tract, and skin. ATLL is caused by viral integration of the human T-cell leukemia virus-1 (HTLV- 1) into the host genome. ATLL is most commonly found in Japanese and Caribbean populations, with an age of onset of 60 years and 40 years, respectively. The Shimoyama classification divides ATLL into four subtypes, each with their own cutaneous manifestations: smoldering, chronic, lymphomatous, and acute, in order of worsening prognosis.

Materials & Methods: We examined 3140 cases of ATLL from the U.S. in the Surveillance, Epidemiology, and End Results-18 (SEER-18) database from 1975-2016 to assess differences in survival based on initial site of diagnosis (skin, lymph node, bone marrow, or other) as well as differences in race, sex, and age of diagnosis.

Results: Of the 3140 cases, 3126 patients had complete data for further analysis. Shimoyama classification is not recorded in SEER. Data were subject to two-sided t-test and chi-square with p<0.05 being significant. We identified 24 patients whose disease presented primarily in the skin (0.76%), 804 in the lymph node (25.61%), 2245 in the bone marrow (71.50%), and 53 other presentations (1.69%) (Table 1). Of the 24 with skin-primary disease, 7 (29%) had localized disease, 2 (8%) had regional disease, 10 (41%) had distant disease. Patients who presented with skin-primary disease had markedly better 2- and 5-year survival rates than patients with other primary sites of diagnosis. Cox regression model confirmed that skin as site of primary diagnosis was a potent protective factor.

Conclusions: We find that patients with skin-primary ATLL have improved survival as compared to patients with other primary sites.

X-04 TREATMENT AND PROGNOSIS OF RARE PATIENTS WITH A PRIMARY CUTANEOUS CD30-POSITIVE LYMPHOPROLIFERATIVE DISORDER WHO DEVELOP EXTRACUTANEOUS LOCALISATIONS

Melchers, R.1; Willemze, R.1; Vermaat, J.2; Jansen, P.3; Daniëls, L.4; Putter, H.5; Bekkenk, M.6; De Haas, E.7; Horvath, B.8; Van Rossum, M.9; Sanders, C.10; Veraart, J.11; Vermeer, M.1; Quint, K.1

1Dermatology, Leiden University Medical Center, Leiden, Netherlands; 2Hematology, Leiden University Medical Center, Leiden, Netherlands; 3Pathology, Leiden University Medical Center, Leiden, Netherlands; 4Radiotherapy, Leiden University Medical Center, Leiden, Netherlands; 5Biomedical Data Sciences, Leiden University Medical Center, Leiden, Netherlands; 6Dermatology, Academic Medical Centre and Vrije University Medical Centre, Amsterdam, Amsterdam, Netherlands; 7Dermatology, Erasmus Medical Center, Rotterdam, Netherlands; 8Dermatology, University Medical Center of Groningen, Groningen, Netherlands; 9Dermatology, Radboud University Medical Center, Nijmegen, Netherlands; 10Dermatology, University Medical Center Utrecht, Utrecht, Netherlands; 11Dermatology, Maastricht University Medical Center, Maastricht, Netherlands.

Introduction & Objectives: Development of extracutaneous disease in patients with primary cutaneous CD30-positive lymphoproliferative disorders (pcCD30+LPD; lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma) is uncommon and patients‘ outcomes are largely unknown. This multicentre study assessed the efficacy of conventional therapies and prognosis in pcCD30+LPD patients developing extracutaneous disease.

Materials & Methods: Between 1985 and 2017, 48/785 (6.1%) pcCD30+LPD patients, included in the Dutch registry of cutaneous lymphomas, developed histologically proven extracutaneous localisations. After excluding ALK-positive pcCD30+LPD (n=1) and immunodeficiency (n=3), 43 patients were suitable for analyses.

Results: Extracutaneous disease developed after a median of 35 months (range 5-264). Most patients (34/43; 79%) were treated with anthracycline-based chemotherapies. A complete response was observed in 26/43 (60%) patients and 16/26 (62%) patients developed a relapse. Five-year progression free survival (PFS5), five-year disease specific survival (DSS5) and overall survival (OS5) after extracutaneous development were 45%, 53% and 47%, respectively. Thirteen patients with localised lesions and a solitary regional involved lymph node (T1-2;N1;M0) showed superior survival compared with advanced disease patients (85% versus 29% PFS5; log-rank p<0.01, 83% versus 41% DSS5; log-rank p=0.02, 62% versus 41% OS5; log-rank p=0.16).

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Conclusions: Extracutaneous manifestations in pcCD30+ LPDs are rare and can develop after many years. Treatment results and prognosis observed in pcCD30+LPDs with extracutaneous development are similar to systemic ALK-negative anaplastic large cell lymphoma. For T1-2;N1;M0 patients radiotherapy can be considered. Patients with advanced disease showed poor survival rates and studies evaluating new treatment algorithms are required.

X-05 WINKELMANN REGIMEN: ORAL CHLORAMBUCIL FOR MYCOSIS FUNGOIDES AND SEZARY SYNDROME

Doss, G.1; De Francesco, I.1; Grandi, V.2; Child, F.2; Wain, M.2; Whittaker, S.2; Morris, S.1

1Clinical Oncology, Guys & St Thomas NHS trust, London, United Kingdom; 2Dermatology, Guys & St Thomas NHS trust, London, United Kingdom.

Introduction: Patients with advanced Stage Mycosis Fungoides and Sezary Syndrome have a poor prognosis and are resistant to multiple treatments. Treatment can cause significant morbidity. We report our experience of oral Chlorambucil using the Winkelmann regimen

Methods: We retrospectively reviewed cases treated at our institution with the Winkelmann regimen oral Chlorambucil 2mg daily on a 28-day cycle. Cases were identified from the skin tumour unit research database. Outcomes and toxicity results were obtained from the staging and progression information recorded on the database and from the patient’s electronic oncology notes.

Results: 26 patients were identified who received treatment between 2007 and 2018. 17 Male and 9 Female. The stage prior to treatment was IIB=1, 111A=2, IIIB=3, IVA1=6, IVA2 = 12, IVB = 2. (B2 = 15, B1 = 4, B0 =7) The median number of prior treatments was 4 (range 0 to 10). The patients received a median of 5 cycles of Chlorambucil (range 1 to 24). The global response rates after 3 cycles were PR 38%, SD 42% and PD 20%. In patients with B2 blood involvement the response in blood after 3 cycles was ORR =54%, SD 33%, PD=13%. The median PFS was 9.97 months. At last follow up 24 patients have died and 2 patients are alive. The median OS was 13.9 months. The rates of toxicity were low with no cases neutropenic sepsis.

Conclusions: The Winkelmann regimen of oral Chlorambucil is a useful low toxicity palliative treatment option for patients with advanced Mycosis Fungoides and Sezary Syndrome.

X-06 CHARACTERIZATION OF RASH ASSOCIATED WITH MOGAMULIZUMAB

Hirotsu, K.E.; Neal, T.M.; Wang, J.Y.; Rieger, K.E.; Kim, Y.H.; Kwong, B.Y.

Dermatology, Stanford University, PALO ALTO, United States.

Introduction & Objectives: Mogamulizumab, a humanized defucosylated monoclonal antibody targeting CC chemokine receptor 4 recently approved for mycosis fungoides and Sézary syndrome (SS), was associated with reported drug rash in 25% of patients in the pivotal trial. We aimed to characterize the clinical and pathologic features of this rash associated with mogamulizumab (RAM).

Materials & Methods: Utilizing our cutaneous lymphoma database, we searched for patients treated with mogamulizumab who presented with a new rash with skin biopsy consistent with drug eruption. We excluded patients with no biopsy.

Results: Twelve patients with SS were identified, median age of 64 [range 38-78], seven female, five male. The median time from first mogamulizumab dose to rash onset was 88 days [range 56-273]. Morphology was heterogeneous, and distribution was on the head & neck, trunk, and/or extremities, often accentuated on photo-exposed or scalp areas. Nine patients stopped mogamulizumab primarily due to rash. Most patients had near-complete clearing of SS at the time of new rash onset. Histopathology demonstrated granulomatous, lymphohistiocytic lichenoid, folliculotropic/adnexotropic, interface, and psoriasiform reaction patterns. Immunohistochemistry frequently showed CD8 predominance among epidermotropic lymphocytes. All patients had molecular diagnostic evaluation with TCR high-throughput sequencing demonstrating a polyclonal process. For management of RAM, six patients improved with topical steroids (2 to 11 months), seven improved with systemic steroids (2 weeks to 5 months). Three patients required prolonged steroids and improved with the addition of methotrexate. Three patients experienced rash again when later retreated with mogamulizumab.

Conclusion: Differentiating RAM from disease progression is crucial for patient management. The skin eruption in our cohort improved or resolved with steroids +/- a steroid-sparing agent. Given the difficulty of clinically differentiating RAM from disease progression, and the heterogeneous pathology, TCR high-throughput sequencing can aid in diagnosis. Study is ongoing to understand the mechanism of RAM.

X-07 CHARACTERIZATION OF THE HISTOPATHOLOGIC AND MOLECULAR FEATURES OF RASH ASSOCIATED WITH MOGAMULIZUMAB

Wang, J.Y.1; Hirotsu, K.E.2; Neal, T.M.2; Kwong, B.Y.2; Kim, Y.H.2; Rieger, K.E.1

1Pathology and Dermatology, Stanford University School of Medicine, Stanford, United States; 2Dermatology, Stanford University School of Medicine, Stanford, United States.

Introduction & Objectives: Mogamulizumab is a monoclonal antibody against C-C chemokine receptor 4 used in the treatment of cutaneous T-cell lymphomas, including mycosis fungoides/Sezary Syndrome (MF/SS). Adverse cutaneous eruptions have been reported in association with mogamulizumab. However, little is known regarding the histopathologic features of rash associated with mogamulizumab (RAM).

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Materials & Methods: A retrospective review of the multidisciplinary cutaneous lymphoma clinical research database and dermatopathology database was performed to identify patients with skin biopsies of rashes clinically suspicious for MAR. Histopathologic and immunophenotypic features were graded quantitatively and descriptively. Clonality studies of T-cell receptor genes were reviewed, when available. Biopsies were excluded if they demonstrated evidence of TCR clonality.

Results: A total of 42 biopsies from 15 patients met inclusion criteria. Patients received mogamulizumab for treatment of MF/SS (14/15) or adult T-cell leukemia/lymphoma (1/15), and 14/42 biopsies were performed within 1 month of the last treatment cycle. Five primary reaction patterns were observed, including granulomatous, lymphohistiocytic lichenoid, psoriasiform, adnexotropic/folliculotropic, and interface dermatitis. Cases demonstrated mild to moderate epidermal spongiosis with variable acanthosis and parakeratosis. Features suggestive of MF were frequently identified, including epidermotropism, lamellar fibroplasia, and lymphocyte “toy soldiering.” The dermal infiltrate was mild to robust and predominantly lymphocytic. Histiocytes and well-formed granulomas were variably present and eosinophils occasionally increased. On immunohistochemistry, most cases demonstrated predominance of CD8-positive epidermotropic lymphocytes and mixed CD4 and CD8 expression in the dermis. Molecular studies showed polyclonality by PCR or high- throughput sequencing in all but one specimen. In some cases, a previously identified dominant clone characteristic of the underlying disease was detected, but at clinically insignificant levels.

Conclusions: RAM may present as a range of inflammatory reaction patterns and may mimic MF/SS histomorphologically. However, skewing towards CD8 expression among epidermotropic lymphocytes and polyclonality of T-cell receptor genes may favor RAM over disease.

SESSION Y - TOPICAL CHEMOTHERAPY

Y-01 REAL-LIFE EXPERIENCE WITH CHLORMETHINE GEL: MOVING BEYOND CLINICAL TRIAL DATA

Prag Naveh, H.; Amitay-Laish, I.; Zidan, O.; Hodak, E.

1Dermatology, Rabin Medical Center, Petach Tikva, Israel.

Introduction: Data on real-life experience with the novel 0.016% chlormethine gel approved (FDA and EMA) for topical treatment of mycosis fungoides (MF) is strikingly sparse.

Objective: To assess the efficacy and safety of chlormethine gel in early-stage MF patients in a real-life setting.

Methods: Data on early-stage MF patients treated with chlormethine gel during 2016-2019 was retrospectively collected from the records of the MF Clinic of Rabin Medical Center. All patients had at least one follow-up visit after initiation of treatment, and in each patient the best response was assessed.

Results: Overall, 66 early-stage MF patients received chlormethine gel: 51 male (77%), mean age 57 years (range 24-83), 37 had stage IA, 27-stage IB, 2 stage IIA, and 7- folliculotropic MF. Regional application of chlormethine gel was given to 57 patients (86%), and total body application- to 9 (14%), as monotherapy (most of the time)- in 48 patients (73%), in combination with topical corticosteroids- in 13 (20%), and in combination with systemic treatment- in 5 (7%), for and an average duration of 342 days (7-1096). Overall response rate (≥50% clearance from baseline) was 59% (39/66), and only 2 patients achieved complete response (100% clearance). Cutaneous side effects (SE) were seen in 32 patients (48%) that were mild in the vast majority of the patients. Dermatitis, specifically irritation, and localized pruritus were the most frequently observed SEs and were manageable by a reduction in application frequency and/ or application of topical steroids, or temporary treatment interruption. Eight patients had unmasking effect, and 7- hyperpigmentation at application site. Treatment withdrawals for S/Es occurred in 12 patients, and in 6 during the first month.

Conclusion: Our single-center experience showed that topical chlormethine gel improves the skin lesions of early- stage MF, with cutaneous S/Es that are manageable. However, complete response is rarely achieved.

Y-02 MECHLORETHAMINE TREATMENT DURATION AS A FUNCTION OF CLINICIAN-LEVEL PATIENT VOLUME FOR MYCOSIS FUNGOIDES CUTANEOUS T-CELL LYMPHOMA (MF-CTCL)

Querfeld, C.1; Pacheco, T.2; Haverkos, B.3; Binder, G.4; Angello, J.4; Poligone, B.5

1Dermatology and Beckman Research Institute, City of Hope National Medical Center, Duarte, United States; 2Dermatology, University of Denver, Denver, United States; 3Hematology, University of Denver, Denver, United States; 4Research & Development, Helsinn Therapeutics US, Inc., Iselin, United States; 5Dermatology, Rochester Skin Lymphoma Medical Group, Fairport, United States.

Introduction & Objectives: NCCN guidelines recommend skin-directed therapies for early-stage MF-CTCL, including topical mechlorethamine. Mechlorethamine yields high response rates, particularly with treatment >3 months (Lessin, 2013, Kim 2003); early discontinuation is often attributed to dermatitis. We evaluated the association of patient volume with early discontinuation and overall treatment duration for United States clinicians prescribing standardized 0.016% gel formulation mechlorethamine.

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Methods: We evaluated dispensing records 10/2013-4/2019 (>99% a one-month supply) representing the majority of US utilization, and for each prescriber calculated average cumulative quantity of dispenses per patient. We excluded patients initiating treatment ≤100 days of data cutoff. Clinicians were grouped by number of patients treated with mechlorethamine gel. Kruskal-Wallis significance testing was performed on groups and logistic regression on early discontinuation.

Results: We assigned 4922 patients to 2004 clinicians. The monthly discontinuation rate was 33% in treatment months 1-3; thereafter rates averaged 16%. Patients receiving >1 dispense had 5 months median treatment duration (range 2-65). The 52 clinicians with >15 patients (mean 41.3) treated 44% of total patients, with 6.3 median dispenses/patient. 128 clinicians with 5-15 patients had 4.3 median dispenses and the interquartile range was 6.625-3.325. As volume further declined, variability and early discontinuation increased; 1348 clinicians with a single patient had 2 median dispenses, with 33% having only one dispense (p<0.0001). Early discontinuation was significantly associated with lower volume (OR 0.80; CI 0.754-0.842).

Conclusions: Individual clinicians prescribing mechlorethamine gel for MF-CTCL varied considerably in patient volume and treatment duration. Clinicians with higher patient volume consistently sustained longer treatment duration and, importantly, avoided early discontinuation, perhaps attributable to experience managing the condition and dermatitis, and setting patient expectations. The early discontinuation noted may identify lack of patient education on how to adhere to treatment.

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Y-03 THE PROVE STUDY: REAL-WORLD EXPERIENCE WITH CHLORMETHINE GEL AND OTHER THERAPIES IN THE TREATMENT OF MYCOSIS-FUNGOIDES CUTANEOUS T-CELL LYMPHOMA PATIENTS

Kim, E.1; Geskin, L.2; Querfeld, C.3; Girardi, M.4; Guitart, J.5; Musiek, A.6; Mink, D.7; Williams, M.7; Angello, J.8; Bailey, W.8

1Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States; 2Dermatology, Columbia University, New York, United States; 3Dermatology, City of Hope, Duarte, United States; 4Dermatology, Yale School of Medicine, New Haven, United States; 5Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, United States; 6Dermatology, Washington University School of Medicine, St. Louis, United States; 7Biostatistics and Medical Writing, ICON Clinical Research, Dublin, Ireland; 8Research & Development, Helsinn Therapeutics (U.S.) Inc., Iselin, United States.

Introduction & Objectives: Topical chlormethine (mechlorethamine) 0.016% w/w gel (equivalent to 0.02% chlormethine HCl) is a skin- directed therapy approved in the US, EU, and Israel for the treatment of mycosis-fungoides cutaneous T-cell lymphoma (MF-CTCL). The PROVe registry study assessed treatment patterns and efficacy, safety, and health-related quality of life (HR-QoL) outcomes in MF-CTCL patients treated with chlormethine gel and other therapies in a real-world setting in the US.

Materials & Methods: In total, 298 adult patients with any stage MF-CTCL who were initiating or continuing chlormethine gel were enrolled in this prospective, open-label, single-arm, multicenter, observational study (NCT02296164) and followed for 24 months. Clinical response (≥50% reduction from baseline in BSA involvement at 12 months) was evaluated in patients with baseline and post-baseline assessments. HR-QoL was assessed by the Skindex-29 questionnaire score (with higher scores indicating lower HR-QoL or higher impact of disease).

Results: At 12 months, the proportion of stage IA–IB responders was 45.1%, with the peak clinical response occurring at 18 months (66.7%). Over a 24-month period, the weighted mean Skindex-29 scores for emotions, symptoms, and functioning favored the responders group, with significantly lower scores in responders (26.6, 25.3, and 13.3, respectively) than in non-responders (36.2, 34.4, and 21.2; all p<0.001).

Conclusions: PROVe is the largest prospective observational study of real-world use of chlormethine gel in the US. Data indicate a significant association between clinical response and improvement in HR-QoL. Peak clinical response among stage IA–IB MF-CTCL patients was higher (66.7%) but took longer than that observed in the post-hoc by-time analysis of the pivotal study (55.7%). This is probably due to flexibility in dosing with more gradual dose escalation permitted in PROVe. A lower rate of skin-related adverse events was observed in the PROVe study compared to the pivotal study. Chlormethine gel was well tolerated.

Y-04 INCIDENCE AND TYPES OF CONTACT DERMATITIS AFTER CHLORMETHINE GEL TREATMENT IN PATIENTS WITH MYCOSIS FUNGOIDES-TYPE CUTANEOUS T-CELL LYMPHOMA: THE MIDAS STUDY

Gilmore, E.S.1; Alexander-Savino, C.V.1; Chung, C.G.2; Poligone, B.1

1Rochester Skin Lymphoma Medical Group, Fairport, United States; 2Departments of Dermatology and Pathology, The Ohio State University, Columbus, United States.

Introduction & Objectives: Chlormethine (=mechlorethamine) is an efficacious therapy for early stage mycosis fungoides cutaneous T-cell lymphoma (MF-CTCL), with overall response rates of 59–95%. Cutaneous reactions at the site of application, particularly dermatitis, can lead to non-compliance and treatment discontinuation. The Mechlorethamine Induced Contact Dermatitis Avoidance study (MIDAS; NCT03380026) investigates the incidence and types of contact dermatitis (CD) following treatment with chlormethine gel in patients with MF-CTCL.

Materials & Methods: MIDAS is an ongoing non-randomized, open-label, split-face, 2-arm study. Patients ≥18 years with stage IA–IB MF-CTCL confirmed by biopsy were treated with 0.016% chlormethine w/w gel (equivalent to 0.02% chlormethine HCl), applied once- nightly to representative patches or plaques of MF ≥8 cm2, over a 4-month period. Half of the lesions also received 0.1% triamcinolone. Patients with CD were patch tested to characterize the nature of CD. Additionally, T.R.U.E Test® was used to assess contributing contact allergens.

Results: As of September 2019, 26 patients were enrolled. Nine patients (34.6%) developed CD (average time: 2.1 months; range 1–3.5). The majority of cases were allergic CD (n=8, 30.8%) and 1 case was irritant CD (3.8%). Two patients with severe reactions were unable to restart chlormethine therapy. Patch testing for contributing contact allergens revealed that 6 of 7 patients who had reactions to chlormethine also reacted to various components of the T.R.U.E. Test.

Conclusions: Preliminary results indicate development of CD in approximately a third of the patients, with the nature of CD being mostly allergic. Furthermore, data suggest that patients who develop allergic CD in response to chlormethine gel treatment may have an allergic-type phenotype that predisposes to cutaneous reactions to common allergens, unrelated to chlormethine treatment. Understanding the presentation of dermatitis in MF-CTCL patients treated with chlormethine can help dermatologists improve its management, with patch testing being a useful tool.

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SESSION Z1 - CLINICAL OBSERVATIONS I

Z-01 PARADOXICAL RESPONSE OF CUTANEOUS T-CELL LYMPHOMA IN A PATIENT WITH CONCOMITANT ANGIOIMMUNOBLASTIC T-CELL LYMPHOMA

Johnson, A.1; Ren, R.2; William, B.1; Chung, C.1

1Internal Medicine, The Ohio State University, Columbus, United States; 2Pathology, The Ohio State University, Columbus, United States.

A 69-year-old Hispanic woman with a 2-year history of relapsed angioimmunoblastic T-cell lymphoma (AITL) presented for evaluation of violaceous discoloration of the right third toe. She was diagnosed with stage III AITL 2 years prior and achieved remission following 6 cycles of CHOP. She experienced disease relapse 18 months later and was treated with rituximab + ICE with disease progression followed by a clinical trial where she received combination therapy with brentuximab vedotin and lenalidomide that resulted in complete remission. She noted swelling and violaceous discoloration of the right third toe that preceded any treatment for AITL that became more prominent immediately following each infusion with brentuximab vedotin before subsequent return to baseline. She denied associated symptoms including pruritus or tenderness. Skin biopsy demonstrated a diffuse proliferation of small to intermediate-sized pleomorphic CD3-positive T cells. A large number of lesional cells also expressed PD-1. T-cell gene rearrangement studies by PCR confirmed a monoclonal population of T-cells distinct from that observed in her prior lymph node biopsy for AITL. This case highlights two unusual phenomena, the first being a co-occurring primary cutaneous T-cell lymphoma with a T-follicular helper phenotype similar to AITL, but with a distinctly separate clonal population of T-lymphocytes from her systemic disease. Her lack of clinical response despite complete remission of systemic disease further supports two discrete lymphomas. The second unusual finding is paradoxical response of her cutaneous disease to treatment. Despite a similar immunophenotype to her systemic lymphoma, she experienced a “tumor flare” with treatment rather than clinical response. These findings suggest that a deeper understanding of the molecular basis of some T-cell lymphomas may be necessary for more targeted therapy and response to treatment.

Z-02 PROGRESSION OF CUTANEOUS T-CELL LYMPHOMA AFTER DUPILUMAB: CASE REVIEW OF 6 PATIENTS

Espinosa, M.L.1; Nguyen, M.T.1; Agirre, A.S.1; Martinez-Escala, M.E.1; Walker, C.J.1; Pontes, D.1; Silverberg, J.I.2; Choi, J.3; Pro, B.4; Pincus, L.5; Guitart, J.1; Zhou, X.1

1Dermatology, Northwestern University Feinberg School of Medicine, Chicago, United States; 2Dermatology, The George Washington University School of Medicine and Health Sciences, Washington DC, United States; 3Dermatology, Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, United States; 4Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, United States; 5Dermatology, University of California, San Francisco, San Francisco, United States.

Background: Dupilumab is a monoclonal antibody that inhibits IL-4 and IL-13 signaling pathways and is approved for treatment of moderate-to-severe atopic dermatitis (AD). Cutaneous T-cell lymphoma (CTCL) may resemble AD in its clinical presentation, role of Th2 cells, and skin-barrier disruption. We identified six patients who were treated with dupilumab, and shortly after were either diagnosed with CTCL/mycosis fungoides (MF) following initial diagnosis of AD, or experienced rapid progression of previously diagnosed CTCL.

Results: Six patients (33.3% female; median age=66 [range 58-77] years) were identified. Dupilumab was initiated for clinically presumed AD in three patients and off-label use in recalcitrant CTCL (stages IB-IIIA MF) with severe pruritus in three patients. Patients showed worsening of body surface area (n=6), pruritus (n=4), lymphadenopathy (n=3), systemic symptoms (n=3), and development of blood involvement in all three with previously diagnosed CTCL. Some patients had brief initial improvement of pruritus and skin involvement (n=5, mean=11.4 weeks) before worsening. Mean duration of dupilumab treatment was 7.7 months (range 3-25 months). After stopping dupilumab, all three stage IVA patients developed higher Sézary counts (two died of disease progression), and one stage IIIA and one stage IB patient experienced skin improvement with narrowband UVB and topical steroids. The remaining patient, with stage IA disease, continued dupilumab given atopic benefits but weighed discontinuation.

Conclusion: Our experience raises concern about the use of dupilumab in CTCL patients and patients with atypical recalcitrant dermatitis without proper exclusion of CTCL. Based on our observation, dupilumab should be avoided in CTCL patients and in patients with atypical dermatitis prior to properly excluding CTCL.

Z-03 RESPONSE IN A PATIENT WITH REFRACTORY FOLLICULTROPIC MYCOSIS FUNGOIDES TO A TOPICAL HYPERICIN CREAM ACTIVATED WITH FLUORESCENT LIGHT

Poligone, B.1; Alhafnawi, M.1; Alexander-Savino, C.1; Pullion, C.2

1Dermatology, Rochester Skin Lymphoma Medical Group, Fairport, NY, United States; 2Clinical Research Manager, Soligenix, Inc., Princeton, NY, United States.

Introduction & Objectives: Early stage mycosis fungoides (MF) is generally treated with skin-directed therapies. First line systemic therapies are reserved for later stage disease. However, the follicultropic variant of MF, even when early stage, has been an exception to

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this rule. The NCCN guidelines recommends first line systemic therapy for follicultropic MF. In the current study we report response of a patient with follicultropic MF to a novel topical therapy, SGX301.

Methods: The FLASH [Fluorescent Light Activated Synthetic Hypericin] clinical study utilized topical SGX301 (Synthetic Hypericin) for the treatment of MF. It is an ongoing randomized, placebo controlled clinical study in patients with stage IA, IB, and IIA MF. An otherwise well, 46-year-old patient with stage IB MF with folliculotropic disease, who had previously failed ultrapotent topical steroids, topical tazarotene, topical imiquimod, oral bexarotene, and narrowband UVB (NBUVB) phototherapy, met inclusion criteria and received topical SGX301. The patient’s treatment response was determined by the Composite Assessment of Index Lesion Disease Severity (CAILS) score.

Results: The patient received at least 12 weeks of topical SGX301 (hypericin ointment) during the open labeled cross over portion of the study and the 6 weeks open labeled extension. During that time his CAILS scored decreased from a baseline of 47 to 23 at week 16, and 21 at week 24. The patient ultimately had a complete response on maintenance home phototherapy.

Conclusions: A patient with refractory, folliculotropic mycosis fungoides had a partial response to topical SGX301 ointment activated by fluorescent light. Considering the depth of fluorescent light absorption in the skin and the depth of hair follicles in the skin, this response in folliculotropic disease was unexpected. Additional study will be necessary in order to determine the mechanism of this response and whether SGX301 may be an option for patients with folliculotropic MF.

Z-04 PRIMARY CUTANEOUS B-CELL LYMPHOMA – CASE SERIES OF TWO UNIQUE CUTANEOUS PRESENTATIONS TREATED WITH RITUXIMAB

Stoll, J.1; Pulitzer, M.2; Moskowitz, A.3; Myskowski, P.1; Noor, S.1

1Dermatology, Memorial Sloan Kettering Cancer Center, New York/Memorial Sloan Kettering Cancer Center, United States; 2Pathology, Memorial Sloan Kettering Cancer Center, New York/Memorial Sloan Kettering Cancer Center, United States; 3Medicine, Memorial Sloan Kettering Cancer Center, New York/Memorial Sloan Kettering Cancer Center, United States.

Introduction: Primary cutaneous B-cell lymphomas (PCBCL) make up 25% of primary cutaneous lymphomas including primary cutaneous follicle center lymphoma (PCFCL) and primary cutaneous marginal zone lymphoma (PCMZL). Most cases of PCBCL present with solitary or grouped lesions that are typically treated with local treatment modalities (e.g. topical/intralesional steroids, excision, radiation), and less commonly, systemic treatment (rituximab), with possibility of recurrence but overall indolent course. We present two unique presentations of multifocal PCBCL (1 PCMZL and 1 PCFCL) that were ultimately treated with rituximab.

Case 1: A 43-year-old male with no significant past medical history presented with erythematous indurated plaque of 15 month duration involving bilateral ear helix and earlobes that was intermittently painful and pruritic. A skin biopsy showed primary cutaneous marginal zone lymphoma, and systemic workup including imaging was negative for extracutaneous involvement . He was treated with Rituximab 375 mg/m2 weekly for four weeks, with clinical improvement.

Case 2: A 35-year-old female with no past medical history presented with a five-year history of asymptomatic erythematous papulonodules on the face, previously treated as cutaneous lupus (due to elevated ANA titers) with hydroxychloroquine, prednisone, and mycophenolate mofetil. Biopsy was consistent with primary cutaneous follicle center lymphoma, with negative systemic workup. She was similarly treated with rituximab 375 mg/m2 weekly for four weeks, with significant flattening of the papules and reduced erythema.

Conclusion: Multifocal or unusual presentations of PCBCL can complicate management. Although first-line treatment of PCBCL is typically localized/skin-directed treatment, the diffuse multifocal presentation in these patients made rituximab a more feasible choice with clinical improvement and no adverse effects. Duration of response and maintenance regimen remains to be determined. Further studies evaluating impact of PCBCL on quality of life may also help guide treatment decision, and determine which patients would benefit from systemic treatment.

Z-05 TONSIL INVOLVEMENT AS A MARKER OF ADVANCED DISEASE IN MYCOSIS FUNGOIDES

Csányi, I.1; Ócsai, H.1; Varga, E.1; Hideghéty, K.2; Marschalkó, M.3; Krenács, L.4; Borbényi, Z.5; Gurbity Pálfi, T.5; Oláh, J.2; Kemény, L.1; Baltás, E.1

1Department of Dermatology and Allergology, Albert Szent-Györgyi Health Centre - University of Szeged - Faculty of Medicine, Szeged, Hungary; 2Department of Oncotherapy, Albert Szent-Györgyi Health Centre - University of Szeged - Faculty of Medicine, Szeged, Hungary; 3Department of Dermatology, Venereology and Dermatooncology, Semmelweis University - Faculty of Medicine, Budapest, Hungary; 4Laboratory of Tumor Pathology and Molecular Diagnostics, Laboratory of Tumor Pathology and Molecular Diagnostics, Szeged, Hungary; 5Second Department of Internal Medicine and Cardiology Centre, Albert Szent-Györgyi Health Centre - University of Szeged - Faculty of Medicine, Szeged, Hungary.

Oral involvement has been reported in less than 1% in mycosis fungoides (MF), but based on autopsy studies it is more frequent (7-18%) and is associated with poor prognosis.

Case 1: The 75-year-old male patient presented with a 3-month history of disseminated skin tumors. Histology revealed tumor stage of MF with large cell transformation. Flow cytometry showed elevated CD7-, CD26- and CD4+/CD8+ cell population. CT scans described axillar and inguinal lymhadenomegaly. Low dose interferon (IFN) and subsequent radiotherapy to the bulky tumors resulted in complete response (CR). Three months

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later, the patient complained about sore throat. The right tonsil was enlarged due to tumor involvement of the Waldeyer lymphatic ring. Because of the airway obstruction, urgent tracheostomy was performed and palliative radiotherapy was initiated to the tonsil, resulting in CR. Two months later novel tumors occurred on the skin. Radiotherapy lead to CR, but due to a rapid deterioration in general health, we lost our patient. Case 2: The 63-year-old male patient presented with a 10-year history of erythroderma. The first histology revealed lymphomatoid papulosis, the second showed plaque stage of MF. Phototherapy and retinoids were ineffective, the third biopsy described tumor stage of MF with large cell transformation. Flow cytometry, bone marrow biopsy were negative. PET-CT described cutaneous manifestations. IFN therapy had to be stopped due to progressive hear loss. Few months later the patient complained about sore throat. Histology of the tonsils showed extracutaneous manifestations of MF. Chemotherapy followed by brentuximab vedotin and autologous stem cell transplantation was initiated to stop disease progression. Based on the few reported cases in the literature and on our experiences, tonsil involvement can be a marker for advanced disease in MF. Although it is very rare, clinicians must be aware of it, because it can lead to severe complications requiring urgent interventions.

Z-06 EPSTEIN-BARR VIRUS-POSITIVE MUCOCUTANEOUS ULCER IN A PATIENT WITH DYSKERATOSIS CONGENITA

Fornons, R.1; Climent, F.2; González-Barca, E.M.3; Muniesa, C.1; Bauer, A.1; Llobera, C.1; Servitje, O.1

1Dermatology, Hospital Universitari de Bellvitge, L´Hospitalet de Llobregat, Spain; 2Pathology, Hospital Universitari de Bellvitge, L´Hospitalet de Llobregat, Spain; 3Hematology, Institut Catalá d´Oncología - Hospital Duran i Reynals, L´Hospitalet de Llobregat, Spain.

Epstein-Barr virus (EBV)-positive mucocutaneous ulcer (EBVMCU) has been included as a provisional entity in the 2016 WHO Classification of Lymphoproliferative Disorders. EBVMCU was initially described as a solitary, sharply circumscribed ulcer in the oropharyngeal mucosa, skin or gastrointestinal tract in patients with age-related or iatrogenic immunosuppression. Recent reports have shown that its clinicopathologic spectrum is wider than initially described and other immunosuppressive conditions could be associated. We report a case of a 53-year-old man with a history of repeated respiratory infections and bronchiectasis, who was referred to our clinic for an oral ulcer of 3 months duration. Additional skin examination revealed skin and nails changes suggestive of dyskeratosis congenita. He has a twin with the same skin and nail changes and a 3-year-old niece diagnosed with dyskeratosis congenita in another hospital. The biopsy of the oral ulcer showed a polymorphous lymphoid infiltrate with abundant large lymphoid cells, some of them with Reed-Sternberg-like features, which stained positive for CD20, PAX-5, CD30 and EBERs. PET-CT revealed FDG activity only of oral lesions, without other remarkable findings. Serum EBV PCR was negative. HIV testing was negative. Routine blood tests were normal except for a reduced number of B and CD4+ T lymphocytes. Genetic studies revealed a mutation in TERC (48A>T) with relative telomeric length about 50-25%. The oral lesion underwent complete spontaneous remission after the biopsy was performed. In conclusion, this case was consistent with a EBVMCU associated with immunosuppression in the context of dyskeratosis congenita. To the extent of our knowledge, this association has not been previously reported.

Z-07 LONG LASTING COMPLETE RESPONSE TO BRENTUXIMAB VEDOTIN IN A PATIENT WITH PRIMARY CUTANEOUS ANAPLASTIC LARGE CELL LYMPHOMA

Altuna, A.1; Iriondo, J.1; Zeberio, I.1; Lopez, A.2; Arregui, M.A.2; Segues, N.3; Silva, M.J.3; Urraca, J.M.4; Lombardi, C.1; Ondarra, L.1; Mendivil, B.1; Zumalde, A.1; Araiz, M.1

1Hematology, Hospital Donostia, San Sebastián, Spain; 2Dermatology, Hospital Donostia, San Sebastián, Spain; 3Pathology, Hospital Donostia, San Sebastián, Spain; 4Radiation Oncology, Hospital Donostia, San Sebastián, Spain.

Primary cutaneous anaplastic large cell lymphoma (PC-ALCL) is a CD30+ lymphoproliferative disorder of the skin. It encompasses 20% of all cutaneous lymphomas, representing the second most common cutaneous T-cell neoplasm. Unlike systemic ALCL, it usually lacks expression of epithelial membrane antigen (EMA) and anaplastic lymphoma kinase (ALK). Most patients present with solitary or grouped nodules on the upper half of the body that grow over weeks to months and typically ulcerate with time. Although 20-42% of cases show spontaneous regression, up to half of them recur. We present a case of a male patient diagnosed with PC-ALCL in 2009 at the age of 71. He initially presented with a single cutaneous erythematous nodule on the left thigh (stage T1aN0M0), which was surgically removed. Two years later he suffered a relapse on the scar, with the lesion being removed and local radiotherapy given after a diagnose of a high grade soft tissue sarcoma. The patient was then referred to our center and a diagnosis of PC-ALCL was made after reviewing the biopsy material. During the following years he suffered multiple relapses and progressed to other regions of both lower extremities (stage T3aN1M0), requiring systemic treatment; from 2013 to 2017 he received various lines of treatment with Methotrexate, Bexarotene and Gemcitabine combined with local radiotherapy, but the disease showed no response. In July 2017 treatment with Brentuximab Vedotin (BV), a conjugated anti-CD30 monoclonal antibody, was initiated. He received 8 cycles in total and achieved complete response after the first one, which still lasts nowadays (27 months). BV was accepted for treatment of relapsed cutaneous CD30+ lymphomas after at least a systemic treatment based on the ALCANZA trial, which showed superior global responses lasting at least 4 months compared to Methrotrexate/Bexarotene.

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SESSION Z2 - CLINICAL OBSERVATIONS II

Z-08 CLINICAL, HISTOLOGICAL AND MOLECULAR CHARACTERISTICS OF ANAPLASTIC LYMPHOMA KINASE-POSITIVE PRIMARY CUTANEOUS ANAPLASTIC LARGE CELL LYMPHOMA

Melchers, R.1; Willemze, R.1; Van De Loo, M.1; Jansen, P.2; Cleven, A.2; Solleveld, N.2; Bekkenk, M.3; Van Kester, M.4; Diercks, G.5; Vermeer, M.1; Quint, K.1

1Dermatology, Leiden University Medical Center, Leiden, Netherlands; 2Pathology, Leiden University Medical Center, Leiden, Netherlands; 3Dermatology, Academic Medical Center and Vrije University Medical Center Amsterdam, Amsterdam, Netherlands; 4Dermatology, University Medical Center of Groningen, Groningen, Netherlands; 5Pathology, University Medical Center of Groningen, Groningen, Netherlands.

Introduction & Objectives: Anaplastic Lymphoma Kinase (ALK) expression is mostly reserved to systemic anaplastic large cell lymphoma, in contrast to primary cutaneous anaplastic large cell lymphoma (C-ALCL). In literature few case series described a small subgroup of ALK-positive C-ALCL and are conflicting in terms of prognosis.

Materials & Methods: A total of 6/297 (2%) C-ALCL patients included in the Dutch registry for cutaneous lymphomas between 1993 and 2018 showed immunohistochemical ALK expression. Clinical characteristics, histological characteristics and disease course were evaluated. Furthermore, underlying ALK translocations were analyzed with anchored multiplex PCR based targeted next-generation sequencing (Archer® FusionPlex®).

Results: Median age was 39 years (range 16-53). All patients presented with solitary lesions and treatment consisted of radiotherapy (n=4), combined methotrexate and radiotherapy (n=1) and anthracycline-based chemotherapy (n=1) with complete responses in all 6 patients. However, three patients developed a relapse. After a median of 41 months, 5 patients were alive without disease and one patient died of lymphoma. Immunohistochemically, three cases (50%) showed combined nuclear and cytoplasmic ALK expression with underlying NPM1-ALK fusions, while three cases (50%) showed solely cytoplasmic ALK expression with variant ALK fusion partners (TRAF1, ATIC, TPM3).

Conclusions: ALK-positive C-ALCL is extremely uncommon and has a comparable favorable prognosis to ALK-negative C-ALCL, and should be treated likewise. Combined nuclear and cytoplasmic ALK expression corresponds with a NPM1 fusion partner and cytoplasmic ALK expression with variant fusion partners. NPM1, TRAF1, ATIC and TPM3 were identified as ALK fusion partners. Fusion partner identification should be performed in ALK-positive C-ALCL as a potential prognostic marker.

Z-09 LUPUS ERYTHEMATOSUS TUMIDUS MIMICKING PRIMARY CUTANEOUS MARGINAL ZONE B CELL LYMPHOMA

Trager, M.1; Ram-Wolff, C.2; Bouaziz, J.D.2; Battistella, M.3; Vignon-Pennamen, M.D.2; Rivet, J.3; Brice, P.4; Michel, L.5; De Masson, A.2; Bagot, M.2; Dobos, G.2

1Vagelos College of Physicians and Surgeons, Columbia University, New York City, United States; 2Dermatology, Saint-Louis Hopital, Paris, France; 3Pathology, Saint-Louis Hopital, Paris, France; 4Hematology-Oncology, Saint-Louis Hopital, Paris, France; 5INSERM U976, Université de Paris, Paris, France.

We present two clinical cases of a difficult diagnosis of lupus erythematosus tumidus (LET), who were initially diagnosed as having marginal zone lymphoma (MZL).

A 19-year-old female presented with papulonodules on the arms and face developing over four years. An initial biopsy showed pseudolymphoma versus MZL without evidence of lymphocytic clonality or light chain restriction (LCR). Two additional biopsies found possible LET with infiltration of small lymphocytes, histiocytes, and plasmocytes across the entire thickness of the dermis. There were numerous eosinophils and granular C3 deposits along the dermo-epidermal junction. The infiltrate was composed of T and B lymphocytes. The auto-immune panel was negative. Clinicopathologic correlation favored a diagnosis of LET and the patient responded to third line thalidomide.

A 20-year old female presented with red papulonodules on the trunk, thighs, and face. The initial biopsy revealed a dermal lymphoid infiltrate comprised of B and T cells, read as pseudolymphoma versus MZL. Diagnosis of MZL was validated at the tumor board because of the strong B-cellular infiltrate. Treatment with rituximab was ineffective. A thorough workup found a negative autoimmune panel (except ANA 1:80). Repeat biopsy showed perivascular infiltrate across the entire dermis with small lymphocytes and some eosinophils and occasional B lymphocytes. A few TFH cells were observed (PD1+, ICOS+, BCL6+, focal CXCL13+). CD123 staining showed a large population of dendritic plasmocytoid cells clustered over the entire dermis. There was no LCR and clonality was negative. Treatment with prednisolone and chloroquine resulted in improvement.

These cases highlight the difficulty in distinguishing MZL from LET both clinically and histopathologically, and suggest the importance of considering LET in cases of discrete lymphoid infiltrates. Some MZL may lack detectable IgH clonality and LCR. It is important to call into question the diagnosis of MZL if refractory to standard treatments and of atypical evolution.

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Z-10 MYCOSIS FUNGOIDES – GRANULOMATOUS SLACK SKIN IN ASSOCIATION WITH HODGKIN LYMPHOMA

Della Ripa Rodrigues Assis, G.; De Melo Miranda, V.J.; Visentainer, L.; Machado De Moraes, A.; Fantelli Stelini, R.; Nunes Secamilli, E.; Massuda, J.Y.

Dermatology, State University of Campinas, Campinas, Brazil.

Granulomatous Slack Skin is a rare variant of Mycosis Fungoides, a subtype of T-cell cutaneous lymphoma, with few cases described. It is characterized by pendulous slack skin in the axillary and inguinal folds. The present case stands out for its rarity and for demonstrating the association between granulomatous slack skin and Hodgkin Lymphoma. A 59-year old man, diagnosed previously with Hodgkin Lymphoma, presented with pruritic, erythematous-desquamative lesions, atrophic, elastotic areas and poikiloderma, with pendulous skin in the inguinal and hypogastric regions. Histology revealed marked reduction of the collagen and elastic fibers, with moderate interstitial lymphocyte infiltrate in the dermis that extended to the epidermis, with intraepidermal aggregates and Pautrier’s microabscesses. Verhoeff staining showed reduction in number and fragmentation of elastic fibers. In immunohistochemical examination, infiltrate was positive for CD2 and CD5 in most part of the lymphocytes, with CD8 and CD20 positive in 5%. The diagnosis of Mycosis Fungoides – Granulomatous Slack Skin in association with Hodgkin Lymphoma was made. Treatment with topical corticosteroids and 8-methoxypsoralen with solar exposure was initiated, with satisfactory control of the lesions. The disease is characterized by erythematous or violaceous plaques, with atrophy on the surface, flaccid skin areas, predominantly in the axillary and inguinal regions, with a chronic course. It may affect both sex and all ages, with predilection for male adults. Histology shows a lymphohistiocytic infiltrate in the upper dermis, with cerebriform nuclei, loss of the elastic fibers and elastophagocytosis. There may also be epidermotropism and Pautrier’s microabscesses. The course may be indolent, with a slow progression. However, in half of the cases there is an association with lymphoproliferative diseases, being Hodgkin Lymphoma the most common. The treatment includes use of topical and oral corticosteroids, PUVA, radiotherapy, immunosupressors, interferon and surgical treatment.

Z-11 AGGRESSIVE CUTANEOUS T-CELL LYMPHOMAS: A SERIES OF 19 CASES

Molgó, M.1; Reyes-Baraona, F.1; Ogueta, I.1; Acle, R.1; González, S.2

1Dermatology, Pontificia Universidad Catolica de Chile, Santiago, Chile;2 Pathology, Private practice, Santiago, Chile.

Introduction & Objective: Aggressive subtypes of cutaneous T-cell lymphomas (CTCL) are associated with a poor response to therapy and short survival. We report the aggressive subtypes of CTCL evaluated in the Dermatology department of our center.

Patients & Methods: Clinical cases, demographic characteristics, histopathology, treatment and evolution of patients with diagnosis of primary CTCL at our center between 1986 and 2019 were analyzed.

Results: 19 cases of aggressive CTCL were found: 7 Sézary syndrome (SS), 2 transformed mycosis fungoides (T-MF), 4 subcutaneous panniculitis-like T-cell lymphomas (SPL), 1 gamma/delta CTCL ( / ), 4 extranodal NK/T-Cell nasal type (NK/T) lymphomas and 1 CTCL unspecified. About SS patients, 4 were female and 3 male, with an average ageγ ofδ 70 years. All patients were treated with chemotherapy (chlorambucil or CHOP) and 2 received extracorporeal photopheresis. All patients died between 1 and 3 years after diagnosis except 1 who remains in control. The patients with T-MF were a 65-year-old female and a 29-year-old male. They were treated with chemotherapy and bexarotene. The 2 patients died within 1 year. Regarding the SPL patients, 2 were female and 2 male, with an average age of 38 years. All were treated with chemotherapy. 3 patients died 1 year after diagnosis and 1 died 3 years after. The patient with / was a 36-year-old-male that received chemotherapy (CHOPE and SMILE) but died 1 month after diagnosis. About NK/T patients, all were female with an average age of 42 years,γ δwere treated with chemotherapy (mainly CHOP) and died between 3 and 9 months later. The patient with CTCL unspecified was a male of 53 year-old treated with chemotherapy and radiotherapy who died 2 years after diagnosis.

Conclusions: These cases show us the importance of an early clinical suspicion and of the knowledge of the ominous prognosis of these aggressive subtypes.

Z-12 ANETODERMA: SECUNDARY TO SYPHILIS OR MYCOSIS FUNGOIDES?

Lopes Iori, N.; Della Ripa Rodrigues Assis, G.; Cintra, M.L.; Massuda, J.Y.; Fantelli Stelini, R.; Nunes Secamilli, E.

Dermatology, State University of Campinas, Campinas, Brazil.

Mycosis fungoides accounts for more than half of cases of cutaneous cell lymphomas. Its etiology is still cloudy, the main hypothesis being the chronic stimulation of T lymphocytes by a persistent antigen, associated with inhibition of tumor cell apoptosis. The classic form of mycosis fungoides may have different clinical manifestations according to the evolutionary stage of disease, making it, like syphilis, one of the "great imitators." Another common relationship between mycosis fungoides and old Lues, are anethodermal lesions, which are skin lesions due to changes in it’s elastic, fibers turning it flaccid and herniated. The so-called secondary anethoderms are

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the most common, being widely associated with mycosis fungoides and syphilis. This case report is about a 68-year-old woman with horseshoe-shaped erythematous plaque lesion and anetodermic-looking lesions on flanks, lower back and right thigh. Biopsy revealed lymphocyte infiltrate in the subepidermal band, permeating the epidermis at some points, with slight spongiosis associated, outlining intraepidermal lymphocyte aggregate. Lymphocytes presented predominantly small volume and papillary dermis showed fibroplasia. Immunohistochemistry showed positivity for CD2, CD3 and CD5 in lymphocytes; CD7 in part of lymphocytes; Granzyme B and TIA-1 in sparse lymphomononuclear cells and inconclusive CD8, CD30 and CD56. Laboratory tests were positive for syphilis, with no other changes. Three doses of 2.4 million IU of benzathine penicillin were prescribed for late syphilis treatment, with clinical improvement of the lesions. The patient has been receiving UVB-NB phototherapy sessions and maintains outpatient follow-up.

Z-13 CD8+ MYCOSIS FUNGOIDES PALMARIS ET PLANTARIS WITH PERIPHERAL BLOOD INVOLVEMENT

Yumeen, S.1; Mirza, F.N.1; Lewis, J.M.1; Carlson, K.R.1; King, B.1; Cowper, S.2; Bunick, C.G.1; Mcniff, J.2; Girardi, M.1

1Dermatology, Yale School of Medicine, New Haven, United States; 2Dermatology and Pathology, Yale School of Medicine, New Haven, United States.

Cutaneous T cell lymphoma (CTCL) is a primary non-Hodgkin lymphoma of T lymphocytes that presents in the skin and is subclassified by its immunophenotype and clinical behavior. The majority of CTCL variants typically show a T-helper CD4+ phenotype and are characterized on the mycosis fungoides/Sézary syndrome (MF/SS) spectrum. MF palmaris et plantaris represents a subtype of MF limited to the palms and soles. CTCL variants with CD8+ immunophenotype are relatively rare and include primary cutaneous aggressive epidermotropic cytotoxic T cell lymphoma and CD8+ variants of mycosis fungoides, including a reported case of CD8+ MF palmaris et plantaris limited to the skin. Blood involvement with a CD8+ CD4- immunophenotype remains a rare entity. We describe a rare case of CD8+ MF palmaris et plantaris with peripheral blood involvement. The patient presented with a longstanding history of relapsing-remitting palmoplantar skin disease recalcitrant to numerous therapies for dyshidrotic eczema and psoriasis, including immunomodulatory therapies. Skin biopsy histology, immunohistochemistry (IHC), and molecular analyses eventually indicated the presence of an epidermotropic clonal CD8+ (CD4-) T cell population of the palms and soles. High-throughput sequencing of the T cell receptor gene rearrangements of unsorted peripheral blood leukocytes and samples from the palms and soles revealed precise clonal matches in blood to both palm and sole skin sites, with sequence frequencies >10%. Previous reported cases of CTCL have revealed unmasking and progression after anti-TNF therapy, and such may have contributed to the patho-etiology in our patient. This case presents a rare instance of CD8+ MF palmaris et plantaris with peripheral blood involvement, and highlights the importance of high clinical suspicion for CTCL in patients with chronic unremitting inflammatory dermatoses recalcitrant to treatment, especially when systemic immunomodulatory treatments are considered or utilized, as such may exacerbate underlying malignancy.

Z-14 LYMPHOMATOID DRUG ERUPTION AFTER TREATMENT OF HEPATITIS C VIRUS INFECTION WITH SOFOSBUVIR: A NEW DESCRIBED ADVERSE REACTION

Michel, M.; Farouk, M.; Ibrahim, M.

Dermatology, Venereology and Andrology, Ain Shams University, Cairo, Egypt, Cairo, Egypt.

Sofosbuvir (Sovaldi®) is an anti-viral drug used successfully in treatment of hepatitis C virus (HCV) infection that was not reported to cause lymphomatoid drug eruption. Differentiation between lymphomatoid drug reactions and cutaneous T-cell lymphomas can be difficult and may need clinicopathological, immunohistochemical, and clonal correlation. In many cases clinical improvement following withdrawal of the drug is the only definitive way to identify the benign nature of the atypical lymphoid infiltrates. We describe a case of a 53-year-old HCV positive male who presented with itchy scaly erythematous macules and papules over face and trunk one month after his last dose of Sofosbuvir. Two weeks later he developed areas of exfoliations all over his body along with generalized lymphadenopathy. Our clinical differential diagnosis included maculopapular drug eruption and pityriasis rosea. However, histopathological examination of the skin biopsy showed moderate superficial and mid-dermal perivascular and perifollicular lymphocytic infiltrate, infiltrating the overlying epidermis with epidermotropism and many haloed lymphocytes were seen displaying mild atypia, the papillary dermis also showed fibroplasia however no eosinophils could be identified. The immunohistochemical examination of the infiltrate was positive for CD3 and negative for CD7. Pan CT scan with contrast showed generalized benign reactionary lymphadenopathy. The diagnosis of primary cutaneous T-cell lymphoma was suggested. Interestingly, during follow up the patient showed complete resolution of all the lesions within two months. Therefore, we reached a final diagnosis of lymphomatoid drug eruption reporting a new adverse reaction that may occur with anti-viral treatment of HCV infection.

Z-15 MYCOSIS FUNGOIDES, LYMPHOMATOID PAPULOSIS AND HODGKIN’S LYMPHOMA IN THE SAME PATIENT: APROPOS OF A POSSIBLE MONOCLONAL ORIGIN

Molgó, M.1; Espinoza-Benavides, L.1; Rojas, P.2; González, S.3

1Dermatology, Pontificia Universidad Católica de Chile, Santiago, Chile; 2Hematology, Pontificia Universidad Católica de Chile, Santiago, Chile; 3Pathology, Pontificia Universidad Católica de Chile, Santiago, Chile.

A 59-year-old man with Hodgkin’s lymphoma was referred by a hematologist for consultation for cutaneous issues. Physical examination

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revealed generalized scaling and erythematous scaly patches located in the groin, abdomen, and arms. The biopsy was compatible with mycosis fungoides (MF). At hist next medical visit, painful nodules with erythematous halo and a scabby surface were noted, and a subsequent biopsy was compatible with lymphomatoid papulosis (LyP). Mycosis fungoides, the most common primary cutaneous T-cell lymphoma, is usually defined in its classic form as a CD4+ non-Hodgkin lymphoma; LyP corresponds to a CD30+ lymphoproliferative disorder; and Hodgkin’s lymphoma (HL) constitutes a lymphomaid neoplasia characterized by the presence of Reed-Sternberg cells and its variants. Although these entities have been defined independently, evidence suggest the possibility of a common monoclonal origin. To our knowledge, this is the first reported case of MF, LyP, and HL in a single patient.

Z-16 PAGETOID RETICULOSIS: A RARE VARIANT OF MYCOSIS FUNGOIDES

Secamilli, E.N.1; Massuda, J.Y.1; Stelini, R.F.2; Adad, M.A.H.1; Magalhães, R.F.1; Cintra, M.L.2; Souza, E.M.1

1Dermatology, State University of Campinas, Campinas, Brazil; 2Pathology, State University of Campinas, Campinas, Brazil.

Pagetoid reticulosis, also known as Woringer-Kolopp disease, is a variant of mycosis fungoides. It is characterized by persistent psoriasiform or verrucous plaque localized on the limbs and its name derives from its histological features showing intraepidermal pagetoid distribution of the neoplastic lymphocytes. We report a case of a 49-year-old man that presented in 2012 to our dermatologic clinic complaining of itching and burning in a thickened plaque on the back of his left hand continuously growing for 18 months. At dermatologic examination, there was an erythematous and squamous plaque of 10 centimeters localized on the dorsal aspect of the left hand. The complementary exams, including CBC, serologies for HIV and HTLV, and thorax, abdomen and pelvis computed tomography scanning were normal. Skin biopsy was performed, and its histopathological examination showed epidermal hyperplasia and a proeminent intraepidermal lymphocyte infiltration, with cerebriform nuclei. Immunohistochemistry staining was CD3-, CD8+ and CD30+. The diagnosis of pagetoid reticulosis was made, and the patient was treated with localized radiotherapy. He has been followed for seven years and he is free of disease since then. Pagetoid reticulosis was firstly described by Woringer and Kolopp in 1939. Since 1984, about 50 cases have been reported. The diagnosis is made by clinical-histological correlation, when a solitary or localized psoriasiform or verrucous plaques in the acral region presents with the histologic features of epidermal hyperplasia and parakeratosis with epidermotropic and pagetoid atypical lymphocytes. In most of the cases, the lymphocytic infiltrate is CD3+CD8+. The clinical differential diagnoses include psoriasis and verrucous infections like tuberculosis and paracoccidiodomycosis. Histologically, it should be distinguished from primary CD8+ cytotoxic T-cell lymphoma. Treatment should be skin directed, and localized radiotherapy, phototherapy, surgical excision and topical steroids are the main options. The prognosis is excellent since neither extracutaneous dissemination nor disease related deaths have been reported.

SESSION Z3 - CLINICAL OBSERVATIONS III

Z-17 MAINTENANCE THERAPY – A NEGLECTED TOPIC

Stadler, R.

Dermatology, University Clinic for Dermatology, Minden, Germany.

Introduction & Objectives: Patients with advanced stage (IIB-IVB) Mycosis fungoides (MF) or Sézary Syndrome (SS) have a high symptom burden (e.g. pruritus) and a poor prognosis (median overall survival <5 years) [1,2,3]. Most patients with advanced disease are responding to systemic treatment approaches, but responses are generally not durable (median time to next treatment, TTNT: 5.4 months) [4]. Currently approved therapies were primarily developed to treat patients after disease progression. After inducing a clinically relevant remission, the key question how to prolong remission and avoid disease progression remains [2].

Materials & Methods: Maintenance therapy can be defined as a continuous exposure to a skin directed or systemic therapy once remission has been achieved with the aim to maintain response and prevent relapse and progression [1]. Qualifying criteria for the use as maintenance modality might be effectivity, availability, safety, only as little interference with quality of life as possible, and convenience i.e. [1, 2]. Maintenance systemic treatment may also be required in patients with early-stage disease lacking a durable response to skin-directed treatment [5].

Results: However, there is no guiding evidence existing on the indication and selection of maintenance in MF/SS [2]. Also missing are defined clinical endpoints. [1, 6].

Conclusions: In sum, clinical studies are required that address key aspects of effective maintenance. Among different approaches an advanced compound for maintenance indication, resminostat has the potential to improve the disease when disease remission or stabilization has been achieved with prior systemic therapy.

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Z-18 ROBUST GRAFT-VERSUS-LYMPHOMA (GVL) RESPONSE MIMICKING CUTANEOUS RELAPSE OF T-CELL LYMPHOMA

Johnson, A.1; Ren, R.R.2; William, B.1; Chung, C.1

1Internal Medicine, The Ohio State University, Columbus, United States; 2Pathology, The Ohio State University, Columbus, United States.

A 65-year-old woman with a history of peripheral T-cell lymphoma, unspecified, characterized by intermittent dermal and subcutaneous nodules on the trunk and extremities, with no evidence of systemic disease, was previously well-controlled on intermittent oral methotrexate. Initial skin biopsy demonstrated an atypical CD4-positive lymphocytic infiltrate with aberrant loss of CD7 and diffuse PD-1 expression. After three years, she experienced rapid progression of numerous dermal and subcutaneous nodules on the trunk and extremities, with similar histopathologic findings to prior biopsies, with marrow and peripheral blood involvement. She was in complete remission after multiple lines of systemic therapy including a clinical trial (brentuximab vedotin and lenalidomide). She underwent peripheral blood allogeneic stem cell transplant from a fully human leukocyte antigen (HLA)- matched, unrelated, male donor. She engrafted, with no evidence of graft vs host disease, achieved 55/100% peripheral blood (PB) CD3/CD33 donor chimerism, and was discharged home at day +21 post-transplant. At D+48 after transplant, she developed edematous pink papules and nodules on the hands and axillae. Biopsy demonstrated a perivascular to nodular dermal infiltrate composed of pleomorphic lymphocytes with diffuse CD3, CD4, and PD-1 expression, concerning for disease relapse. Fluorescent in situ hybridization (FISH) demonstrated XY pattern in 99% of lymphocytes with XX pattern in squamous cells and fibroblasts, consistent with a donor-driven process. She had no evidence of peripheral blood or visceral disease on imaging and PB immunophenotyping. She was treated with immune suppression withdrawal and 12 Gy total skin electron beam radiation with resolution of skin lesions and is currently without evidence of disease 5 months post- transplant. This case highlights a novel presentation of an immunologic GVL response that has not been previously reported, to the best of our knowledge, where cutaneous infiltrate by donor lymphocytes resembles cutaneous relapse of T-cell lymphoma; with similar histologic and and immunophenotypic features.

Z-19 SUBCUTANEOUS PANNICULITIS-LIKE T-CELL LYMPHOMA IN THE MESENTERY WITH ASSOCIATED HEMOPHAGOCYTIC SYNDROME TREATED BY CHEMOTHERAPY CHOEP, MODIFIED HLH 2014 PROTOCOL AND HDT AND AUTO SCT

Giza, A.1; Jońca, M.2; Raźny, M.2; Zimowska-Curyło, D.3; Wilk, M.3; Goldman- Mazur, S.3; Piątkowska- Jakubas, B.1; Sacha, T.1

1Department of Hematology, Collegium Medicum of the Jagiellonian University, Krakow, Poland; 2Department of Hematology, Rydygier Hospital, Krakow, Poland; 3Department of Hematology, Collegium Medicum of the Jagiellonian University, Krakow, Poland.

Background: Subcutaneous panniculitis-like T-cell lymphoma (SPTL) is a rare, disease involving subcutaneous adipose tissue. SPTL is associated in <20% with hemophagocytic syndrome (HPS); a 5-year overall survival rate is 46% in pts with SPTL and HPS as compared with 91% in pts without HPS.

Case presentation: A 35 -years old Caucasian man previously fit presented with a one-month history of fever, cough, fatigue and weight loss with the suspicion of Still’s disease. At presentation leucopenia 2,66 x 10^9/L, (ref:4,0-10,0), increased lactate dehydrogenase 1340 U/L (ref:<248), ferritin 27219 ng/ml(ref:21,81-274,66), sIl-R2 4899U/ml (ref:<100 U/ml), triglycerides 4,32 mmol/l (ref <1,7) was present. On physical palpation there was found hepatosplenomegaly and right supraclavicular tumor 11x15mm. Trephine biopsy revealed reactive bone marrow. Histopathology of surrounded LN adipose tissue showed SPTL with secondary HLH. The abdomen MRI presented generalized edema of adipose tissue of mesentery and mucosa of colon. The patient was subjected to CHOEP and modified HLH 2014 protocols. Due to hepatotoxicity of chemotherapy etoposide was delayed. Maximum level of ferritin on treatment was 156422ng/ml. The first cycle of CHOEP was complicated by pancytopenia and abdominal pain, the second by pneumonia and left lung abscess. PET CT after third cycle of CHOEP revealed uptake 18 F-FDG in left lung 68X65mm. The patient was not qualified to allo SCT due to the high risk of the procedure. The chemotherapy was continued and after the 5th cycle of CHOEP PET CT showed significant regression of active mass in lung and no active signs of disease. After the 6th cycle of CHOEP and 2 doses of plerixafor we successfully collected HSC 2,96x10^6 CD34+ cells. Finally, the patient was subjected to HDT (BEAM) supported by auto SCT.

Conclusion: There was a good outcome of the disease treated by intensive protocol but longer follow-up is required.

Z-20 AGGRESSIVE EPIDERMOTROPIC CD8+ T CELL LYMPHOMA PRESENTING WITH TARGETOID LESIONS

El-Zawahry, K.; Daruish, M.; Ibrahim, M.A.H.

Dermatology, Venereology and Andrology, Ain shams university, Cairo, Egypt.

A 49 years old male presented with generalized ulcerations and eschars of 2 years duration. There were eschars formation, massive pustulation over the scalp and targetoid lesions over the upper and lower extremities. On Histopathological examination there were atypical lymphocytes invading the epidermis. Blood vessels in the upper dermis showed angioinvasion and angiodestruction. Immunomarkers revealed the infiltrating cells were CD3, CD7 and CD8 Positive while CD4, CD20 and CD56 were negative. Internal organs involvement was excluded by PET- Ct scan. Cytotoxic markers are not available in Egypt. The patient was diagnosed as Primary Cutaneous Aggressive Epidermotropic CD8+ T Cell Lymphoma (PCAETCL); a rare subtype of Primary cutaneous T cell lymphoma. PCAETCL is classified as a provisional entity in the 2016 lymphoid neoplasm classification. It is characterized by suddenly appearing

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annular plaques with ulceration and occasional targetoid lesions. The tumor cells release cytotoxic granules destroying the epidermis when activated. The disease progresses rapidly with poor prognosis and high mortality rate due to extensive epidermal necrosis and not extracutaneous involvement. Our patient received CHOP but died one month after the diagnosis. Hematopoietic stem cell transplantation can lead to durable partial or complete remission. Only one case has been reported with complete remission on aggressive chemotherapy (hyper-CVAD); cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine.

Z-21 CD4/CD8 DOUBLE-NEGATIVE FOLLICULOTROPIC MYCOSIS FUNGOIDES/SEZARY SYNDROME PRESENTING AS SEVERE LEONINE FACIES

Merkel, E.1; Chovatiya, R.1; Guggina, L.1; Pro, B.2; Guitart, J.1; Zhou, X.1

1Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States; 2Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States.

A 64-year-old man presented with severe facial swelling and a generalized pruritic rash. The rash had been previously treated with multiple biologics, including TNF and IL-17A inhibitors, systemic corticosteroids and cyclosporine. Physical examination revealed thick, scaly, indurated nodular plaques over the face and ears that formed deep furrows over the forehead and cheeks. Erythematous scaly plaques were seen throughout the trunk, arms and proximal thighs, covering >50% body surface area.

Laboratory examination revealed significant leukocytosis (52,600/uL) with lymphocytosis (15,300/uL) and eosinophilia (23,100/uL). Lactic dehydrogenase was elevated (1189 U/L) and flow cytometry revealed a large abnormal CD4-, CD8-, CD3+, CD7+, CD26-, alpha-beta+ T cell population (~10,200/uL). T-cell gene rearrangement testing demonstrated monoclonality from peripheral blood and skin samples with identical clonal bands.

Skin biopsies of the face and trunk showed numerous elongated lymphocytes infiltrating the follicular units and an adjacent perivascular lymphohistiocytic infiltrate with scattered eosinophils. Immunohistochemical profile was similar to the peripheral blood and demonstrated atypical CD4-/CD8- T-cells.

The patient was diagnosed with CD4/CD8 double-negative folliculotropic mycosis fungoides and Sezary syndrome. He was started on gemcitabine, followed by C(H)OEP, with worsening tumor burden on the face. Repeat skin biopsy from the face demonstrated large cell transformation. The patient received one round of palliative radiation with improvement of facial swelling, and is currently receiving brentuximab. Leonine facies is a rare presentation of mycosis fungoides, with fewer than 30 cases reported. Among these, typical features include folliculotropism, stage IV disease and blood involvement. CD4/CD8 double-negativity is also a rare finding in MF and the prognostic significance is largely unknown. To our knowledge, this is the first report of CD4/CD8 double-negative folliculotropic mycosis fungoides presenting with leonine facies.

SESSION Z4 - CLINICAL OBSERVATIONS IV

Z-22 AIN-SHAMS CUTANEOUS LYMPHOMA CLINIC – SUGGESTED GUIDELINES FOR THE TREATMENT OF MYCOSIS FUNGOIDES IN COUNTRIES WITH LIMITED RESOURCES

Ibrahim, M.A.H. 1, El-Tayeb, N. 1, Michel, M. 1, Nassar, A. 1, Mohamed, A. 1, Daruish, M. 1, El-Zimaity, M. 2, El-Afifi, A. 2, Abdelbary, H. 2, El-lithy, M. 3, Mostafa, A. 3, El-Sayed, M.H. 1

1Dermatology, Ain Shams University hospitals, Cairo, Egypt; 2Hematology, Ain Shams University hospitals, Cairo, Egypt; 3Oncology, Ain Shams University hospitals, Cairo, Egypt.

Introduction & Objective: Though many treatment options for mycosis fungoides (MF) are emerging, many of the currently used treatment modalities (e.g. bexarotene, extracorporeal photophoresis, histone deacetylase inhibitors, and biologics) are unavailable in Egypt and other African/Arab countries. In addition, there is a lack of consensus for the treatment of hypopigmented MF that is frequently encountered in our population. Our aim is to figure out a practical treatment algorithm based on our institutional experience, treatment availability and consistent with international guidelines.

Methodology: Treatment approach is based on literature research for the international guidelines for the treatment of MF. Special attention is also given to studies conducted on patients with skin phototype (III-IV). This consensus was established among dermatologists, hematologists and oncologists at Ain-Shams cutaneous lymphoma clinic through a series of consecutive discussion. Recommended treatment options are presented as an algorithm according to disease stage. Dose and treatment duration are provided; and maintenance/follow-up protocol is designed. Level of evidence is specified for each treatment option.

Results: for hypopigmented MF, phototherapy is recommended as a first line treatment, while low dose methotrexate is considered a

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second line. For early classical MF, we recommend phototherapy which is a well tolerated treatment option in dark phenotype. Addition of either methotrexate or acitretin -an alternative to the unavailable bexarotene- is recommended as a second line, total skin electron beam (TSEB) or monochemotherapy is considered a third line option. All patients with complete response enter a consolidation phase followed by maintenance phase by phototherapy. For late stage, PUVA plus acitretin or methotrexate is recommended as first line, TSEB or monochemotherapy is considered a second line option. Polychemotherapy is regarded as a final option.

Conclusions: A practical algorithm for the treatment of mycosis fungoides is suggested for patients with dark phenotype living in countries with limited resources.

Z-23 PATIENTS WITH MYCOSIS FUNGOIDES ARE AT INCREASED RISK OF LUNG CANCER: A SYSTEMATIC REVIEW AND POPULATION- BASED ANALYSIS

Goyal, A.

Dermatology, University of Minnesota, Minneapolis, United States.

Introduction & Objectives: Numerous recent studies have implicated mycosis fungoides (MF) as being a significant risk factor in the development of second primary malignancies. Newer studies have recently shined a light on the risk of solid malignancies, including lung, breast, prostate, and colon cancers, and melanoma. Based on this literature, the solid malignancies that pose the greatest risk to MF patients are cancers of the lung, bronchus, and trachea.

Materials & Methods: A systematic review of manuscripts published between 1950-2019 identified 13 populations of patients: 5 insitutionally based cohorts and 8 nationally based registries (4 of which contain data from the SEER database). Of 9 unique populations with calculated standardized incidence ratios (SIR), 6 identified NHL (SIR 5.1-66.9), 5 identified lung/trachea/bronchus (SIR 2.7-114.4), and 5 identified Hodgkin lymphoma (SIR 7.8-105.3) as having a statistically significantly elevated risk. To better characterize the population of MF patients who develop lung cancer, we identified 69 (1.1%) patients out of 6300 with MF from 2000-2016 and examined demographics, causes of death, and survival.

Results: Patients who were diagnosed with lung cancer were older at the time of diagnosis of MF (63.0 years vs. 57.1 years, p<0.0001). Mean time between diagnosis of MF and diagnosis of lung cancer was 5.75 years. There was no significant difference in gender breakdown between the two groups. The majority of lung cancer patients were diagnosed with stage IV disease. Patients with lung cancer were substantially more likely to die (50.7% vs. 24.7% death over the follow-up period, p<0.0001).

Conclusions: Patients with MF are at increased risk of lung cancer is consistent across multiple populations, both institutional cohorts and national databases. At this time there is insufficient evidence of make recommendations regarding screening for lung cancer in this population, and clinical trials will be necessary.

Z-24 EPIDEMIOLOGICAL ANALYSIS AND REVIEW OF HISTOPATHOLOGICAL PARAMETERS OF PATIENTS DIAGNOSED WITH MYCOSIS FUNGOIDES AND ITS VARIANTS IN FOLLOW-UP AT STATE UNIVERSITY OF CAMPINAS

Machado Toribio, J.; Abdala, S.M.; Ferreira Magalhães, R.; Nunes Secamilli, E.; Fantelli Stelini, R.; Massuda, J.Y. , Suzuki, N.N.

Dermatology, State University of Campinas, Campinas, Brazil.

Introduction: Mycosis fungoides and its variants represent both diagnostic and therapeutical challenges. Clinical presentations are broad and the findings of anatomopathological examinations are often nonspecific, which makes it difficult to diagnose and delays adequate therapy, compromising patient's prognosis.

Material and methods: This retrospective study evaluated patient's histological criteria and allowed us to establish diagnosis of Mycosis fungoides and its variants. In addition, epidemiology of patients was detailed. Twenty-two patients with a diagnosis of Mycosis fungoides and its variants were selected for this study. A correlation was established between the epidemiological profile and the histological criteria. The significance level adopted for the statistical tests was 5%.

Results: We observed that the criteria of epidermotropism, characterized by lymphocyte small collections, was statistically significant, present in 40% of the female cases, and absent in male patients. Another statistically significant finding was papillary dermal fibrosis, which was observed in all female patients. In the male patients, the same characteristic was seen in only 50% of the cases. We observed that the correlation between papillary dermal fibrosis and absence of spongiosis was statistically significant.

Conclusions: Therefore, the differentiation between early lesions of Mycosis fungoides and inflammatory skin diseases remains a challenge for pathologists. Histological criteria, when analyzed in isolation, are of limited importance due to low specificity. Therefore, the correlation between clinical and histological findings is fundamental to establish the early diagnosis of Mycosis fungoides.

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Z-25 AN OVERVIEW: OUR EXPERIENCE OF MICROBIOLOGICAL CAUSES OF INPATIENT ADMISSIONS FOR PATIENTS WITH MYCOSIS FUNGOIDES AND SÉZARY’S SYNDROME AT PETER MACCALLUM CANCER CENTRE, MELBOURNE, AUSTRALIA

Buelens, O.1; Prince, H.M.2; Campbell, B.A.3; Mccormack, C.4; Van Der Weyden, C.1; Twigger, R.1; Bupha- Intr, O.5; Slavin, M.6; Thursky, K.7; Teh, B.8; Valentine, J.9

1Clinical Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia; 2Clinical Haematology, Director of Molecular Oncology and Cancer Immunology, Peter MacCallum Cancer Centre, University of Melbourne, Monash University, Epworth Healthcare, Melbourne, Australia; 3Radiation Oncology, Department of Clinical Pathology, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Australia; 4Dermatology/ Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia; 5Department of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne, Australia; 6Deparment of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne, Australia; 7Infectious Diseases, National Centre for Infections in Cancer, National Centre for Antimicrobial Stewardship,, Peter MacCallum Cancer Centre, National Health and Medical Research Council, Royal Melbourne Hospital at the Doherty, Melbourne, Australia; 8Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne, Australia; 9Paediatric Integrated Cancer Service, National Centre for Infections in Cancer, Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia.

Introduction and Objectives: Cutaneous Lymphomas have a profound impact on many facets of patients’ lives and the lives of those caring for them. Infection and chronic skin trauma from scratching continue to be hurdles to overcome for patients living with Cutaneous Lymphomas. The skin is a physiological barrier against infection. On traumatisation through scratching and disease, it is easier for these patients with Cutaneous Lymphomas to develop secondary infections and complications. Infection is not only a challenge for patients and their carers but also their health care providers. It is a complication which can directly impact on patient care, comfort, future treatment plans and long term survival. Infections continue to be a complexity that has many implications for patients living with Cutaneous Lymphomas, carers and health professionals as well as health care facilities. The aim of this study was to identify the most common infectious organisms that lead to hospitalisation in patients with Mycosis Fungoides and Sézary’s Syndrome.

Materials and methods: At Peter MacCallum Cancer Centre in Melbourne, Australia, sepsis continues to be one of the leading causes of inpatient admissions for patients with cutaneous lymphomas. A retrospective audit of Mycosis Fungoides and Sézary’s Syndrome patients admitted for inpatient hospitalisation was completed. Review of patient records and the Peter MacCallum Cancer Centre Infectious Diseases Database was performed to assist in the identification of infections amongst this group of patients.

Results: The Australian National Cutaneous Lymphoma database was utilised to identify eligible patients. Bacterial, viral and fungal infections were identified through a retrospective audit of the data base and review of patient records.

Conclusions: Ongoing collaborative research projects are underway between the multi-disciplinary Cutaneous Lymphoma Service and the Infectious Diseases Service at Peter MacCallum Cancer Centre, with the driving goal to provide optimal care for this unique group of patients.

Z-26 THE USE OF GATA3 IN CHALLENGING CASES OF CD30+ MYCOSIS FUNGOIDES (MF) VERSUS ANAPLASTIC LARGE CELL LYMPHOMA (ALCL)

Parente Almeida, I.1; Cury Martins, J.1; Miyashiro, D.1; Neder Ramires Abdo, A.2; Abrantes Giannotti, M.3; Barros Domingues, R.3; Pereira, J.2; Sanches, J.A.1

1Department of Dermatology, Hospital das Clinicas, University of São Paulo Medical School, São Paulo, Brazil; 2Department of Hematology, Hospital das Clinicas, University of São Paulo Medical School, São Paulo, Brazil; 3Department of Pathology, Hospital das Clinicas, University of São Paulo Medical School, São Paulo, Brazil.

Introduction & objectives: CD30 is a cell surface receptor that is classically expressed in lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma (cALCL). Some cases of mycosis fungoides (MF), transformed MF (tMF), and systemic lymphomas with cutaneous involvement like systemic anaplastic large cell lymphoma (sALCL) can also express CD30. Some of these disorders can be associated and have overlapping features, making the diagnosis a challenge. This study proposed the use of GATA3 as an additional tool for the distinction of four doubtful cases of CD30-positive lymphomas involving the skin.

Methods: Retrospective analysis of clinical charts, histological and immunohistochemical data, including GATA3 staining of four challenging cases, where the differentiation between MF, ALCL, or overlap of both entities could not be well defined with regular markers. GATA3 expression on the dermis was calculated in percentage of the infiltrate and was compared to the biopsies of typical cases of MF, cALCL, tMF and sALCL. Results were also compared to the data available in the literature.

Results: Preliminary data showed high expression of GATA3 in tumoral lesions of 3 patients and no expression in one patient. Involved lymph node was also negative for GATA3 in one patient. Analysis of involved lymph node of one patient and comparison to control cases are still being analyzed.

Conclusion: GATA3 is a marker of Th2 cell differentiation. Literature shows that while early MF presents a Th1 profile, the late-stage exhibits a Th2 profile. Some studies showed that tumor lesions of MF highly expressed GATA3, as opposed to lesions of cALCL. Although, in most of our cases, GATA3 expression aided to the differentiation of CD30-positive MF and ALCL, in some cases the distinction was still inconclusive, making GATA3 a helpful marker, but still with the need of other markers to help on this challenging task.

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Z-27 CD30 EXPRESSION IS DETECTABLE IN MOST RARE CUTANEOUS LYMPHOMA SUBTYPES

Ulrike, W.1; Christina, M.2; Marion, W.3; Roland, S.4; Uwe, H.5; Sarja, S.1; Mehmet, B.6; Bernd, H.7; René, S.8; Jan, N.9; Claus-Detlev, K.10; Werner, K.11; Chalid, A.6

1Department of Dermatology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany; 2Department of Dermatology, University Medical Center Goettingen, Göttingen, Germany; 3Department of Dermatology, University Hospital Würzburg, Würzburg, Germany; 4Department of Dermatology, Ludwigshafen, Ludwigshafen, Germany; 5Department of Dermatology, Vivantes Klinikum Neukölln, Berlin, Germany; 6Department of Dermatology, Helios-Klinikum Krefeld, Krefeld, Germany; 7Department of Pathology, Helios-Klinikum Krefeld, Krefeld, Germany; 8Department of Dermatology, Johannes Wesling Klinikum, UKRUB, University Bochum, Bochum, Germany; 9Department of Dermatology, University Hospital Mannheim, Mannheim, Germany; 10Department of Dermatology, Städtisches Klinikum Karlsruhe, Akademisches Lehrkrankenhaus der Universität Freiburg, Karlsruhe, Germany; 11Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.

Introduction: CD30-targeted treatment has been explored and approved for CD30+ cutaneous T-cell lymphomas (TCL). Treatment for the rarer cutaneous lymphoma (CL) subtypes is a challenge, and clinical trials in this indication are scarce. The present study adds 20% more evaluable cases to our previously presented data and details the CD30 expression in rare CL.

Material/methods: 105 biopsies of 101 patients with rare CL from 10 centers were collected. 47 TCLs: 18 CD4+ small/medium sized lymphoproliferations, 9 subcutaneous panniculitis-like TCL, 6 peripheral TCL-NOS, 6 CD8+ aggressive epidermotropic cytotoxic TCL, 4 / , 4 NK/TCL; and 39 B-cell lymphomas (BCL): 38 diffuse large BCL (DLBCL)–leg-type, 1 EBV+DLBCL; and 14 blastoid plasmacytoid dendritic cell neoplasms. CD30 stains were performed in one center evaluated by six dermatologist/dermatopathologists. γ δ

Results: 100 rare CL cases were appropriate for CD30 evaluation. In more than two third of cases, an expression of CD30 was detectable (71/100; 71%). Most cases showed a low degree of CD30 expression (<1-5% (59/71; 83.1%). Staining intensity was regarded as weak or moderate (61/71; 85.9%). Expression was detected mostly in the cytoplasm with or without combined membrane and/or Golgi-reactivity (64/71; 90.1%).

Conclusion: CD30 expression can be detected in the majority of rare lymphoma cases. However, the expression is limited in most cases to a low percentage of the infiltrate and shows weak to moderate staining intensity, predominantly in the cytoplasm. For NK-TCL and other primary cutaneous TCL cases with low expression of CD30 have previously been treated with good results with targeted therapy; thus, these results might represent the basis for the initiation of a clinical study for rare CL.

Z-28 CD8+ MYCOSIS FUNGOIDES WITH DIVERSE ATYPICAL CLINICAL AND PATHOLOGICAL PRESENTATIONS

Ibrahim, M.1; Nassar, A.1; Abdelbary, H.2

1Dermatology, Ain Shams University hospitals, Cairo, Egypt; 2Hematology, Ain Shams University hospitals, Cairo, Egypt.

Mycosis fungoides (MF) is a great masquerader that can mimic many dermatoses either clinically or histopathologically. Herein, we present a rare case of MF that has multiple atypical presentations and poses a diagnostic dilemma. 25 year-old female patient presented with recurrent abscesses on the groin, axillae and the trunk of 6 years duration. The patient was previously diagnosed as hidradenitis suppurativa. On examination, there were, in addition, comedones and ichthyosis allover her back and abdomen. There were also painful indurated dusky red plaques on the groin and mons pubis; and scaly hyperpigmented patches over the thighs. Multiple biopsies were taken; the first from the ichthyotic skin with comedones and the second biopsy from a nodule in the axilla and both revealed non-epidermotropic superficial dermal perivascular infiltrate of hyperchromatic lymphocytes with deep dermal nodular lymphocytic infiltrate and multiple granulomas. The third biopsy was taken from the indurated plaque over the groin and showed band like dermal infiltrate, made up of hyerchromatic lymphocytes. The fourth biopsy was taken from the patches over the thigh and revealed perifollicular and periappendageal infiltrate, where atypical lymphocytic infiltrate was seen infiltrating the follicular epithelium and the eccrine glands forming folliculotropism and syringotropism. Immunohistochemistry was done and revealed positive staining for CD3, CD8, and negative staining for CD4, CD7 and CD30. Multiple reactive CD20 follicles were detected surrounded by positive CD3 cells. T cell receptor gene rearrangement was monoclonal for all types of lesions. Based on the clinical/ pathological/ immunohistochemical/ molecular findings, we reached the diagnosis of CD8+ MF with atypical clinical presentations (hidradenitis suppurativa and ichthyosis) and atypical pathological presentations (granulomatous, follicular and syringotropic) and with reactive B-cell proliferation. The patient received pegylated interferon alpha and PUVA for 6 months and showed good response.

Z-29 THE THERAPEUTIC POTENTIAL OF CANNABINOIDS FROM CANNABIS SATIVA EXTRACTS FOR MYCOSIS FUNGOIDES / SÉZARY SYNDROME - AN IN VITRO AND EX VIVO STUDY

Amitay-Laish, I.1; Moyal, L.2; Tiroler, A.3; Mazuz, M.3; Stalin, R.N.3; Ajjampura, V.C.3; Gorovitz-Haris, B.4; Lubin, I.4; Drori, A.5; Drori, G.5; Van Cauwenberghe, O.6; Namdar, D.3; Koltai, H.3; Hodak, E.7

1Dermatology, Rabin Medical Center - Beilinson Hospital, and Sackler Faculty of Medicine, Tel Aviv University, Kiryat-Ono, Israel; 2Laboratory for Molecular Dermatology, Felsenstein Medical Research Center, Rabin Medical Center - Beilinson Hospital, Sackler Faculty of Medicine, Tel Aviv University, Petach Tikva, Israel; 3Agricultural Research Organization, Agricultural Research Organization, Volcani Center, Rishon LeZion, Israel; 4Laboratory for Molecular Dermatology, Felsenstein Medical Research Center, Rabin Medical

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Center - Beilinson Hospital, Petach Tikva, Israel; 5MedC Biopharma Corporation, MedC Biopharma Corporation, MedC Biopharma Corporation, Canada; 6AgMedica Bioscience Inc, Chatham, AgMedica Bioscience Inc, Chatham, Ontario, Canada; 7Dermatology, Felsenstein Medical Research Center, Rabin Medical Center - Beilinson Hospital, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Petach Tikva, Israel.

Introduction: Cannabis sativa (C.sativa), produce more than 600 different metabolites, including phytocannabinoids and terpenes. Studies have provided evidence that different cannabinoids exhibit antitumor effects in a wide array of animal cancer models, and cell- lines, including leukemia cell-lines, when used alone or combined. There is no data on the effect of cannabinoids on mycosis fungoides (MF)/Sézary syndrome (SS).

Objectives: To study the effect of different fractions of C.sativa and their combinations on MF/SS, and to identify a mixture with the optimal cytotoxic effect.

Methods: Ethanol extracts of C.sativa were analyzed by high-performance liquid chromatography and gas chromatography-mass spectrometry, and their cytotoxic activity was determined, using Alamar Blue-based assay (Resazurin) and tetrazolium dye-based assay (XTT), on MyLa and HUT-78 cell-lines and on peripheral blood lymphocytes from Sézary patients (SPBL). Apoptotic effect was determined by FACS analysis of Annexin V-staining and PI. RNA sequencing was used to determine gene expression of MyLa and HUT-78 cells following treatments with individual compounds and synergistic combinations.

Results: Active fractions from cannabis that have cytotoxic activity against MyLa and HUT-78 were identified, and the optimal concentration of each fraction for attaining a synergistic-cytotoxic affect was specified. These mixtures were shown to be active, and induced a higher apoptosis of the CD4+CD26- SPBL (malignant sézary enriched cell population) than in the non-CD4+CD26- SPBL. Gene expression profile was determined in MyLa and HUT-78 cells following treatments.

Conclusions: Fractions of C.sativa and their specific combinations induce cytotoxic activity against MF/SS cells. This provides the first indication that C.sativa specific compound may hold promise as a possible new therapy for MF/SS.

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PRIMARY CUTANEOUS LYMPHOMA, CLINICAL & PATHOLOGICAL - MYCOSIS FUNGOIDES

001 UNDERSTANDING THE FUNCTION OF CD30 IN CUTANEOUS T-CELL LYMPHOMA – IMPLICATIONS FOR THERAPY AND PROGNOSIS

Braun, J.D.1; Goerdt, S.1; Krammer, P.H.2; Nicolay, J.P.1

1Department of Dermatology, Venereology and Allergy, University Medical Center Mannheim/Ruprecht Karls University of Heidelberg, Mannheim, Germany; 2Division of Immunogenetics, German Cancer Research Center, Heidelberg, Germany.

Introduction & Objectives: In mycosis fungoides (MF), an increased expression of CD30, a receptor that is normally restricted to a small population of activated B- and T-cells, seems to be associated with advanced disease stage and large-cell transformation. Since the functional role of CD30 in cutaneous T-cell lymphoma (CTCL) still remains unknown, this study aims to determine the expression of CD30 and its ligand (CD30L) in several CTCL cell lines and primary CD4-positive cells from CTCL patients. In addition, we investigate the dynamics of CD30 expression over time and after treatment as well as pathways involved in CD30 signaling and function in CTCL.

Materials & Methods: CD30 and CD30L expression was measured in different CTCL cell lines and in primary CD4-positive T-cells isolated from fresh blood samples of patients with Sezary syndrome by FACS and western blot. The cells were treated with different therapeutic stimuli for 24 hours. CD30 was stimulated via its natural ligand for various periods of time and pathways were analyzed by western blot and/or luciferase assay.

Results: Among all tested CTCL cell lines, CD30 expression was highest in HH cells. The so far analyzed primary CD4-positive cells were negative for CD30 surface expression in FACS whereas intracellular CD30 protein was detectable via western blot. CD30 levels were influenced by cell culture conditions in HH cells and significantly reduced upon therapeutic NF B inhibition in HH, MyLa, SeAx and HUT- 78 cells. Therefore, CD30 stimulation seems to influence MEK/ERK and NF- B pathway in HH cells. κ Conclusions: Our results indicate a dynamic nature of CD30 expression in CTCL,κ which might account for the described effectiveness of the antibody-drug conjugate brentuximab vedotin directed to CD30 also in patients diagnosed as CD30 low-expressing. The therapeutic potential of CD30 stimulation is currently under investigation and will be evaluated in vitro and in vivo.

002 LOW-DOSE GEMCITABINE THERAPY IN CUTANEOUS T-CELL LYMPHOMAS - "REAL-LIFE" DATA OF THE GERMAN CUTANEOUS LYMPHOMA NETWORK

Christoph, B.1; René, S.2; Rudolf, S.2; Thilo, G.3; Sarja, S.4; Ulrike, W.4; Claus-Detlev, K.5; Marion, W.6; Joanna, O.6; Jan P., N.7; Chalid, A.1

1Dermatology, HELIOS Klinikum, Krefeld, Germany; 2Dermatology, Johannes –Wesling-Klinikum Universitätsklinik, Minden, Germany; 3Dermatology, Universitätsklinik Bochum, Bochum, Germany; 4Dermatology, Universitätsklinik Kiel, Kiel, Germany; 5Dermatology, Städtisches Klinikum Karlsruhe, Karlsruhe, Germany; 6Dermatology, Universitätsklinik Würzburg, Würzburg, Germany; 7Dermatology, Universitätsmedizin Mannheim, Mannheim, Germany.

Introduction & Objectives: Gemcitabine is a frequently used agent in advanced stages of Cutaneous T-cell lymphoma (CTCL). Serious adverse effects (AE) such as leukopenia to agranulocytosis and renal insufficiency are largely dose-dependent and limiting leading to premature therapy termination in elderly patients. The question is therefore whether an equally good response of the therapy is achievable with lower dose of gemcitabine.

Material & Methods: Between 2009 - 2019, 65 patients in 7 centres with CTCL stage ≥IIB were treated with a lower than standard dose (1200 mg/m² KO at d1, 8, 15 a total of 6 cycles); evaluation of therapy and AE was done 4-6 weeks after the 6th cycle.

Results: In 51/65 patients (78.5%) at least one other systemic therapy preceded Gemcitabine treatment. As a result, 41 of 63 patients (OR: 65.1%) responded to therapy (CR 11%, PR 52%) after 6 cycles. The progression-free interval was between 0 and 123 months, on median 12 months. In total, few patients showed serious side effects, e.g. one patient with port episode and one patient with acute renal failure under low- dose gemcitabine therapy. Almost 75% of the patients showed no to moderate side effects (CTCAE Grade 0-2).

Conclusions: In conclusion, with 65,1% OR, the low-dose therapy shows a comparable response rate compared to the standard dose (68-75%) with a comparable PFS (12 vs. 11 months) and CR (11% vs. 9-20%). AEs in patients with lower dose gemcitabine were significantly less than compared with the standard regimen. In summary, treating patients with lower dose gemcitabine seems to be more suitable especially for our elder CTCL patients. Limitation of the present study is the retrospective evaluation of a non-standardized but real-life patient-collective.

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003 GRANULOMATOUS MYCOSIS FUNGOIDES WITH ASSOCIATED LOCAL THROMBOTIC VASCULOPATHY

Combalia, A.1; Riera-Monroig, J.1; Frigola, G.2; Garcia-Herrera, A.2; Campo, E.2; Estrach, T.1

1Dermatology, Hospital Clínic de Barcelona, Barcelona, Spain; 2Pathology, Hospital Clínic de Barcelona, Barcelona, Spain.

Case report We present the case of a 58-year-old woman with a clinical history of type 2 diabetes mellitus, dyslipidemia, depressive disorder; an active smoker of 30 cigarettes/day who was diagnosed with psoriasis in 1999 and treated successfully with topical corticosteroids. She was referred to our department because of a one-year-history of painful skin lesions characterized by erythematous plaques on the left calf that suddenly worsened. Physical examination showed multiple infiltrated livedoid plaques in the lower extremities, abdomen and arms, some of them ulcerated with retiform, and some residual achromic lesions were also observed in the forearms and legs. A skin biopsy was performed revealing a dense lymphohistiocytic infiltrate through the dermis and subcutaneous tissue together with epidermotropism. Non-necrotizing granulomas were also observed in the panniculus, and some recanalized thrombosed vessels without necrosis were described. However, no angiocentricity or angiodestruction was observed. Immunohistochemistry demonstrated a T phenotype of the atypical lymphocytes CD2 +, CD3 +, CD4 +, with partial loss of CD5 and almost complete loss of CD7. Accompanying T cells were CD8+ and TIA1 +, and there were also accumulations of CD20 + lymphocytes. Ki67 was < 20%, and clonal TCR-gamma gene rearrangement (TCR) was monoclonal. Blood tests showed microcytic and hypochromic anemia suggesting iron deficiency, and no trombophilic disorders were detected, and associated autoimmune diseases were discarded. Bone marrow biopsy and CT-PET body showed no abnormalities. The diagnosis of Granulomatous mycosis fungoides with thrombotic vasculopathy was made. The case will be further discused.

004 HISTOPATHOLOGICAL CRITERIA FOR THE DIAGNOSIS OF EARLY AND ERYTHRODERMIC MYCOSIS FUNGOIDES

De Freire Cassia, F.1; Pineiro-Maceira, J.M.2

1Dermatology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; 2Dermatology, State University of Rio de Janeiro, Rio de Janeiro, Brazil.

Introduction and objective: Mycosis fungoides (MF) is a T cell cutaneous lymphoma (CTCL) characterized by patch, plaque and tumor stages.A few patients may present erythroderma. The diagnosis of the patch stage is often difficult, clinically and histopathologically, because patients with patch stage mycosis fungoides present erythematous patches or plaques minimally infiltrated resembling inflammatory lesions, that may persist for a long time. The histologic findings of such stage are subtle. The same difficulty is seen in patients with erythroderma. The aim of this study is to identify the most relevant criteria for the histopathologic diagnosis of patch stage and of the erytrodermic form of mycosis fungoides.

Materials and Methods: Sixty-five patients with clinical and histologic diagnosis of patch stage or erythrodermic form of mycosis fungoides were recovered from the files of the Department of Pathology of HUCFF/UFRJ in a 20 year-period. Forty two hematoxilin-eosin- stained skin sections were evaluated and searched for parakeratosis, acanthosis, epidermal atrophy, dyskeratosis, spongiosis, exocytosis, disproportionate epidermotropism, Pautrier’s microabscess, basal layer damage, papillary fibrosis, papillary edema, telangiectasia, perieccrine lymphocytes, follicular epidermotropism, epithelioid granulomas and eosinophils, haloed lymphocytes, single basal lymphocytes and dermal and epidermal lymphocytes with hiperconvoluted nuclei.

Results: Hiperconvoluted nuclei lymphocytes within the epidermis (81,25%) and haloed lymphocytes (75,0%) were the most frequent findings in the patch stage. In the erythrodermic form, disproportionate epidermotropism was seen in 92,3% of the cases. Hiperconvoluted nuclei lymphocytes within the epidermis and dermis appered in equal proportions (88,46%), while the haloed lymphocytes were seen in 84,61%. Pautrier microabscesses were seen in about one fourth of the cases.

Conclusions: Disproportionate epidermotropism, hiperconvoluted nuclei lymphocytes (within the epidermis and dermis), haloed lymphocytes and a dermal infiltrate with eosinophils are the most relevant histopathologic findings patch and erythrodermic mycosis fungoides. Pautrier microabscesses should not be necessary for the diagnosis of MF in such stages.

005 MYCOSIS FUNGOIDES SUCESSFULLY TREATED WITH PUVA AND ACITRETIN

De Freire Cassia, F.; Da Costa Llanos, F.

Dermatology, Institute of Dermatology Prof. Rubem David Azulay, Rio de Janeiro, Brazil.

We present a male patient, 44y, phototype V, with a history of polycystic kidneys. He reported pruritus in the posterior region of both thighs for 5 years, associated with further appearance of erythematous plaques at the same site. The lesions progressed over the years, compromising the gluteal region and posterior thighs. Treatment with topical corticosteroids of high potency was indicated in the first instance, with no response. Cutaneous biopsy showed mycosis fungoides. Immunohistochemistry study showed CD3+, CD4+ and CD5+. CD7 and CD8 were negative. Serology was performed for HTLV 1 and 2, both negative. PUVA treatment, 2 sessions per week, was indicated. After 20 sessions, there was a slight improvement of the lesions. Later he was referred to our center specialized in Cutaneous Lymphomas due to persistence of the clinical picture. It was decided to associate 0.05% Clobetasol cream 2 times a day and maintain PUVA with Methoxalene 40mg twice a week. But pruritus got worse, as the appearance of new lesions in the inner region

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of both thighs. it was decided to suspend Clobetasol, and initiate Acitretin 20mg a day and maintain PUVA at the same doses. One months latter, patient returned to the clinic, and reported complete absence of pruritus and almost complete disappearance of the previously described lesions. Two months latter, there was only residual post-inflammatory hyperpigmentation. Control tests showed no biochemical alterations. So far, the only retinoid approved by the FDA to treat cutaneous lymphoma is Bexarotene, which is not available in our country. In this sense, the use of widely available retinoids such as Acitretin and Isotretinoin are presented as an effective option with a good safety profile, compared to other systemic drugs for cancer use. However, currently evidence indicates that they are most effective when associated with other treatments such as phototerapy.

006 EPIDEMIOLOGICAL, CLINICAL AND PATHOLOGICAL PROFILE OF OUTPATIENTS WITH MYCOSIS FUNGOIDES: HIGH PREVALENCE OF HIPOCROMIC VARIANT IN A MISCIGENATED POPULATION

De Freire Cassia, F.; Brito Pinheiro Ramos Santos, S.; Pereira Quintella, L.

Dermatology, Institute of Dermatology Prof. Rubem David Azulay, Rio de Janeiro, Brazil.

Introduction and objectives: Mycosis fungoides (MF) is the most common type of T cell primary cutaneous lymphoma. Hypochromic MF (HMF) is a rare variant mainly described in younger and high phototype individuals. The miscigenated origin of Brazilian population accounts for a high percentage of mestizos, and darkened skin patients. The objectives of this study are to evaluate the prevalence of HMF in our outpatient unit and to describe clinical, epidemiological and histopathological aspects of this variant.

Methods: Observational, cross-sectional, descriptive study, based on a review of the outpatient medical records of patients with mycosis fungoides between January 2002 and July 2015. The diagnosis of MF was based on clinical-pathological correlation . Histopathological slides from hipopigmented lesions were reviewed.

Results: There were 56 patients with MF, and 23 had hipocromic MF (41%). Most patients with HMF (65.2%) were female; the age of onset ranged from 2 to 56 years, with a median of 26 years. The age at diagnosis ranged from 6 to 57 years (median age of 41 years-old). There was a predominance of phototypes IV –VI (82,6%). Patients were staged IA and IB. The lesions were purely hypochromic in 82.6%, not desquamative in 56.6% and asymptomatic in 60.8%. Pruritus was the most reported symptom (39%). When compared to patients with NHMF, the ages of onset and diagnosis of HMF were significantly lower and the predominance of people with dark skin among MFH patients was also significant. The most frequent histopathological findings were epidermotropism, presence of lymphocytes surrounded by halo and lymphocytes in the basal layer.

Conclusions: HMF was prevalent in our series, with a predilection for younger and darker skinned individuals, presenting clinically by hypopigmented lesions associated or not with pruritus. Histopathological changes were the same as seen in early-stage mycosis fungoides.

007 SUBCUTANEOUS PANNICULITIS-LIKE T CELL LYMPHOMA

Castro, L.1; Fernandes Pinheiro, L.S.1; Nobre, A.2; De Freire Cassia, F.1

1Dermatology, Lagoa Federal Hospital, Rio de Janeiro, Brazil; 2Pathology, Lagoa Federal Hospital, Rio de Janeiro, Brazil.

We present a young adult male patient, with a history of seven months of evolution of fever, weight loss, myalgia and painless, erythematous nodules, affecting the trunk, upper and lower limbs. Hepatosplenomegaly, pancitopenia, increased liver enzymes and ferrritin were detected. Skin biopsy showed slightly atypical subcutaneous mononuclear infiltrate simulating lobular panniculitis. Immunohistochemical examination showed positivity for CD3, CD8 and granzyme in T cells around adipocytes, with rare plasma cells. Bone marrow biopsy showed hematophagocytosis. The final diagnosis was subcutaneous panniculitis like lymphoma with macrophage activation syndrome. Multidrug therapy with CHOEP was initiated, with complete response so far. It is important to be aware of this lymphoma subtype, because of the differential diagnosis with benign panniculitis (such as lupic panniculitis) and other lymphomas, and for its association with macrophage activation syndrome, which is a life threatening condition.

008 HIGH THROUGHPUT SEQUENCING OF THE T-CELL RECEPTOR BETA GENE IN LESIONAL SKIN IN THE DIAGNOSIS OF PRIMARY CUTANEOUS T-CELL LYMPHOMA: ANALYSIS OF 76 PATIENTS

De Masson, A.1; Battistella, M.2; Gruber, A.3; Jouenne, F.3; Sadoux, A.3; Ram-Wolff, C.1; Vignon-Pennamen, M.D.2; Rivet, J.2; Lebbé, C.1; Bagot, M.1; Mourah, S.3

1Dermatology, Saint-Louis Hospital, Paris, France; 2Pathology, Saint-Louis Hospital, Paris, France; 3Pharmacogenomics, Saint-Louis Hospital, Paris, France.

Introduction and objectives. The diagnosis of primary cutaneous T-cell lymphoma (CTCL) may be challenging, especially in early-stage mycosis fungoides (MF). T-cell clonality studies by high throughput sequencing (HTS) of the T-cell receptor beta (TCRB) gene in lesional skin have been used as a new diagnostic tool in the case of suspicious primary CTCL. We reviewed HTS data of 66 patients with a confirmed or suspicious primary CTCL and 10 patients with inflammatory skin diseases as controls.

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Material and methods. The data of 76 patients with histopathological and HTS data in lesional skin were analyzed. The final diagnosis was made after correlation of the clinical and histological data.

Results. A diagnosis of primary CTCL was reached in 54 patients, including 47 patients with MF (36 with early-stage MF) or Sezary syndrome, 4 patients with CD30+ lymphoproliferative diseases, and 3 patients with other primary CTCL. Among these 54 patients, 38 (70%) had a dominant T-cell clone identified by HTS (i.e., productive frequency of the dominant clone>3 times that of the second most frequent clone in the sample). Sixteen patients had no identified dominant T-cell clone, including 13 with early-stage MF. None of the 10 patients with inflammatory skin diseases had a dominant T-cell clone. No definitive diagnosis could be reached in 12 patients with suspicious primary CTCL, among them, one only had a dominant T-cell clone in skin. The median productive frequency of the most abundant clone in the sample was 13% in CTCL (12% in early-stage MF) versus 2% in controls (p=0.002) and patients with undetermined diagnosis (p=0.0003).

Conclusions. HTS of the TCRB is a useful diagnostic tool to differentiate primary CTCL from inflammatory skin diseases. The absence of identification of a dominant T-cell clone by HTS does not rule out the diagnosis of CTCL, especially in early-stage MF.

009 PILOT STUDY OF A NOVEL THERAPEUTIC APPROACH FOR REFRACTORY ADVANCED STAGE FOLLICULOTROPIC MYCOSIS FUNGOIDES

Del Guzzo, C.; Rook, A.

Dermatology, University of Pennsylvania, Philadelphia, PA, United States.

Introduction & Objectives: Folliculotropic mycosis fungoides (FMF) is a variant of cutaneous T-cell lymphoma characterized as having a folliculocentric infiltrate of malignant T-cells along with a worse prognosis in comparison to the epidermotropic variants. Patients with advanced forms of FMF are often poorly responsive to both skin-directed and systemic therapies. We propose a novel therapeutic approach for refractory folliculotropic mycosis fungoides using interferon gamma in combination with topical carmustine and low dose isotretinoin, and in some cases concomitant localized, skin-directed therapies.

Materials & Methods: Inclusion criteria for this retrospective study included patients treated in the Penn Cutaneous Lymphoma Clinic from 2009 to 2018 with Stage IB or greater FMF that proved refractory to two or more therapies, including one systemic therapy, prior to initiation of interferon-gamma in addition to topical carmustine and/or low dose isotretinoin. Six patients met inclusion criteria for the study.

Results: Three patients experienced complete responses with the other three having nearly complete responses (<2% BSA) while being treated with this regimen. Four of the six patients also received skin directed therapy, consisting of local electron beam radiation in three patients and PUVA in one patient, in an effort to completely clear the skin. The regimen was well tolerated without significant adverse events. Conclusions: We demonstrate a novel multimodality therapy for FMF with therapeutic agents that likely target more effectively the deeply penetrating lymphocytes in the follicular unit that characterize the disease.

010 DIAGNOSTIC CHALLENGE: PITYRIASIS LICHENOIDES, MYCOSIS FUNGOIDES OR BOTH?

Gainza Apraiz, I.; Blanch Rius, L.; González Romero, N.; Gómez Muga, S.; Sánchez Díez, A.; Izu Belloso, R.M.

Dermatology, Hospital de Basurto - Osakidetza, Bilbao, Spain.

Introduction: We present a challenging cutaneous lymphoma case in a pediatric patient.

Case presentation: A 9-year-old girl without relevant medical history presented to the dermatology department with a 1-year history of small desquamative erythematous papules in her trunk and upper extremities. Lesions where slightly pruriginous and improved with sun exposure, resolving with residual hypopigmentation. Suspecting pityriasis lichenoides (PL), a skin biopsy was performed, which confirmed the diagnosis. During the following 6 years, several relapses occurred and were treated with oral erythromycin and narrowband UVB, with good disease control. At the age of 15, intensely pruritic erythematous-desquamative plaques were observed on physical examination, besides her usual papular lesions. New plaques did not respond to topical corticosteroids. A cutaneous biopsy of the plaques revealed mycosis fungoides (MF) with monoclonal T-cell receptor (TCR) gene rearrangement.

Discussion: Pityriasis lichenoides is a lymphoproliferative disorder whose malignant potential is still controversial. There are scarce cases published in the literature of children with PL that develop cutaneous T cell lymphomas (CTCL). Furthermore, pityriasis lichenoides like mycosis fungoides has been reported both in adults and children. Therefore, a clinical-pathological correlation is essential in these patients, as well as a long-term follow-up, as they might evolve into a CTCL or may even be an atypical presentation of MF since the beginning.

011 INCREASED RISK OF MALIGNANCY IN MYCOSIS FUNGOIDES: A SINGLE-CENTER PERSPECTIVE

Goyal, A.1; O'leary, D.1; Lazaryan, A.2

1Dermatology, University of Minnesota, Minneapolis, United States; 2Hematology/Oncology, University of Minnesota, Minneapolis, United States.

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Introduction & Objectives: Mycosis fungoides (MF) is a rare, generally indolent non-Hodgkin lymphoma of the skin. In a large, population- based study of the SEER-18 database, we previously found that patients with mycosis fungoides are at increased risk of developing second malignancies.

Materials & Methods: This case-control study examines factors associated with development of second malignancies in 172 MF patients treated at the University of Minnesota from 2005-2017. We identified 172 patients with MF, median age of 59 years (range, 8-89). As a control group, we identified 175 patients with seborrheic dermatitis (SD), median age of 61.4 years (range 14.4-88.3, p > 0.3).

Results: Patients with MF were significantly more likely to develop a second malignancy (24 of 172) than control patients with SD (3 of 175, odds ratio [OR] 9.4, p < 0.001). Median follow-up for MF patients was 5 years (range 0-40) versus 4.1 years (range 0-24) for those with SD (p < 0.001). Patients with tumor stage MF were significantly more likely to develop a second malignancy (9 of 26) than those with patch/plaque stage disease (14 of 110, OR 3.6, p < 0.01). Similarly, patients with advanced stage disease (stage IIB or higher) were significantly more likely to develop malignancy (11 of 37) than those with early stage disease (stage IA-IIA, 13 of 131, OR 3.8, p < 0.004). Means of diagnosis of second malignancy was documented in 19 of 24 cases (79.1%). The majority (78.9%) of second malignancies were found based on patient-reported symptoms or regular health screening studies.

Conclusions: These results demonstrate that patients with MF are at increased risk of developing second malignancies independent of treatment. Patients with advanced stage disease are more likely to develop second malignancies independent of staging scans.

012 PUVA AND INTERFERON Α2B COMBINED THERAPY FOR PATIENTS WITH MYCOSIS FUNGOIDES AT DIFFERENT STAGES IN RUSSIA

Olisova, O.1; Grekova, E.1; Smirnov, K.2; Gorenkova L.G.3

1V.A. Rakhmanov Department of Skin and Venereal Diseases, I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation; 2V.A. Rakhmanov Hospital of Skin and Venereal Diseases, I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation , 3 National Medical Hematology Research Center, Moscow, Russian Federation.

Introduction: Cutaneous T-Cell Lymphomas (CTCLs) include a clinical-pathologically heterogeneous group of non-Hodgkin lymphomas primarily developing and affecting the skin. The aim was to investigate the efficacy and tolerability of combined PUVA and IFN- 2b therapy in patients with different stages of MF, refractory to first line treatment with PUVA. α Material and Methods: We observed 15 patients with MF. The diagnoses were verified with histological, immunohictochemical methods and molecular analysis. In terms of the stage of the disease, patients were distributed as follows: IB – 1 (7%), IIA – 4 (27%), IIB – 4 (27%), IIIA – 2 (12,5%), IIIB – 1 (7%), IVA – 1 (7%), IVB – 2 (12,5%). IFN- 2b was administered at a dose of 3 MU three times weekly. The dose was increased according to patient’s tolerance up to 6 MU three times weekly. The total dose was 109±36 IU. For PUVA therapy, 0,8 mg/kg oral 8-methoxypsoralen was given 1.5 hours before UVA radiation,α four times a week. The course of therapy consisted of 39±7 procedures. Results: After the therapy, 11 (73%) patients with stage IB-IIIA witnessed mSWAT index reduction of 90-100%, which corresponded to complete clinical remission manifested in the disappearance of cutaneous manifestations and subjective perceptions. 3 (20%) of patients with stage IIIB-IVA saw mSWAT index decreasing from 50 to 75% and 1 (7%) patient with stage IVB of MF did not experience an effect of the therapy (Fig.1). The combined therapy resulted well tolerated. Moderate (WHO Grade II) adverse events were seen in 11 out of 15 patients (73.3%). Flu-like symptoms were the most common side effect being observed in 73.3%.

Discussion: This PUVA and IFN- 2b combined therapy protocol showed to be effective in both early and advanced MF disease stage, even if significantly better outcomes were observed for IB-IIB disease stage. α

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013 THE DIAGNOSTIC DILEMMA OF LARGE CD30 POSITIVE CELL TRANSFORMATION IN THE LYMPH NODES

Nassar, A.; Ibrahim, M.; Michel, M.

Department of Dermatology and Venereology, Ain Shams University, Cairo, Egypt.

Differentiation between transformed Mycosis fungoides (MF) and anaplastic T-cell lymphoma is a major diagnostic pitfall where the presence of large CD30+ cells constituting more than 75% of the infiltrate in the lymph nodes may occur in both entities. The clinical features and outcome are the most discriminative features.

We describe a case of a 57 year-old male who gave history of itchy skin lesions that developed 15 years ago with no response to topical treatment. Two years ago, he developed generalized lymphadenopathy and parotid swelling along with the concurrent skin nodules. The lymph node biopsy showed total effacement by sheets of large atypical CD30+ cells constituting more than 75% of the infiltrate. Similarly, skin biopsy showed large atypical cells with minimal epidermotropism that showed positivity for CD3 and CD4, as well as CD30, consistent with the diagnosis of systemic (nodal) anaplastic T-cell lymphoma with secondary skin metastasis. Therefore, the patient received chemotherapy followed by bone marrow transplantation resulting in remission.

Unfortunately, recurrence of the skin lesions occurred 4 months ago. Examination revealed dusky red patches and plaques over the face along with crusted firm nodular lesions on the trunk, the back and the limbs. Histopathological examination showed psorisiform epidermal hyperplasia with moderate perivascular infiltrate in addition to prominent epidermotropism with medium-sized cerebriform cells admixed with large atypical cells. CD30 was found to be positive in 30% of the infiltrate. Accordingly, we suggested the diagnosis of MF with CD30+ large cell transformation.

However, owing to the initial diagnosis of nodal anaplastic lymphoma, we needed to do immunohistochemical staining with anaplastic large cell lymphoma kinase (ALK) on the lymph node biopsy. Surprisingly, ALK turned to be negative which excluded the initial diagnosis and we reached a final diagnosis of MF with CD30+ large cell transformation in the skin and the lymph nodes.

014 REDEFINING THE PATHOGENESIS OF MYCOSIS FUNGOIDES

Iyer, A.1; Hennessey, D.1; O'keefe, S.1; Patterson, J.2; Wang, W.2; Wong, G.2; Gniadecki, R.1

1Medicine, Dermatology, University of Alberta, Edmonton, Canada; 2Medicine, University of Alberta, Edmonton, Canada.

According to the long-standing dogma, mycosis fungoides (MF) arises from a transformed skin resident T-cell, which clonally expands and accumulates mutations, as the disease progresses from the early patch/plaque stage to the tumors. To gain further insight into the pathogenesis of MF we performed whole exome sequencing(WES) from microdissected clusters of malignant MF cells and from the peripheral blood. By comparing the number of TCR clonotypes to the tumor cell fraction in the sample, we found that MF does not comprise a single TCR clonotype but is clonally diverse. To determine the mechanism of clonotypic diversity, we compared TCR sequences in the blood and in the skin and found evidence for circulating neoplastic cells, even in the early stages of the disease. By longitudinal sampling of blood and the skin for TCR sequences we were able to conclude that the circulating neoplastic clones are indeed a source of the clonotypic heterogeneity by seeding to the skin. By a detailed analysis of the landscape of genomic aberrations in the lesional skin in MF we found that the evolution of these clones is not linear but of multiple malignant subclones. In conclusion, we propose that MF develops from a large and diverse pool of circulating (pre)neoplastic T-cells that lead to the genetically heterogeneous lesions. Our model readily explains the clinical observations of frequent disease relapses after treatment and identifies circulating cells as a possible therapeutic target.

015 BRANCHED EVOLUTION AND GENOMIC INTRATUMOR HETEROGENEITY IN THE PATHOGENESIS OF CUTANEOUS T-CELL LYMPHOMA

Iyer, A.1; Hennessey, D.1; O'keefe, S.1; Patterson, J.2; Wang, W.2; Wong, G.2; Gniadecki, R.1

1Medicine, Dermatology, University of Alberta, Edmonton, Canada; 2Medicine, University of Alberta, Edmonton, Canada.

Mycosis fungoides (MF) is a slowly progressive cutaneous T-cell lymphoma (CTCL) for which there is no cure. In the early plaque stage the disease is indolent, but development of tumors heralds an increased risk of metastasis and death. Previous research into the genomic landscape of CTCL revealed a complex pattern of >50 driver mutations implicated in more than a dozen of signaling pathways. However, the genomic mechanisms governing disease progression and treatment resistance remain unknown. Building on our previous discovery of the clonotypic heterogeneity of MF, we hypothesized that this lymphoma does not progress in a linear fashion as currently thought, but comprises heterogeneous mutational subclones. We sequenced exomes of 49 cases of MF and identified 28 previously unreported putative driver genes. MF exhibited extensive intratumoral heterogeneity (ITH) of a median of six subclones showing branched pattern of phylogenetic relationships. Stage progression was correlated with an increase in ITH and redistribution of mutations from the stem to the clades. The pattern of clonal driver mutations was highly variable with no consistent mutations between patients. A similar intratumoral heterogeneity was detected in leukemic CTCL (Sézary syndrome). Based on these findings we propose a model of the pathogenesis of MF comprising neutral, divergent evolution of cancer subclones and discuss how ITH impacts the efficacy of targeted drug therapies and immunotherapies of CTCL.

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016 ALOPECIA AREATA UNIVERSALIS AS AN ATYPICAL PRESENTATION OF CLASSIC MYCOSIS FUNGOIDES

Iznardo, H.1; López-Sánchez, C.1; Mozos, A.2; Puig, L.1; Garcia-Muret, M.P.1

1Dermatology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 2Pathology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.

An 83-year-old hypertense and dyslipemic male presented to the dermatology department with a 1-month history of rapidly evolving hair loss. He was otherwise asymptomatic and there hadn’t been recent changes in his medication. Upon examination he showed generalized alopecia of the scalp with mild erythema and desquamation. Two weeks later he presented with erythematous papules and plaques on the abdomen and the alopecia had further progressed, now involving the whole scalp, face, trunk and extremities. Histological study from scalp and abdominal lesions showed atypical T lymphocytes infiltrating both the epidermis and follicular epithelium. Follicular mucinosis was absent. Immunohistochemical study showed an increased CD4:CD8 ratio with loss of CD7. Mollecular T-cell receptor studies showed 1 clonal V-gamma and 2 V-beta gene rearrangements that were identical for all the specimens. A diagnosis of mycosis fungoides (MF) was made and the patient was started on photochemotherapy with 8-Methoxypsoralene.

Patchy alopecia has been classically associated with folliculotropic MF, and complete hair loss is common in erythrodermic Sézary syndrome (SS) patients. A recent review of 1550 patients with MF and SS analyzed the patterns of hair loss in these entities, being described as a rare phenomenon only present in 2.5% (38/1550) of them. In this study, the majority had alopecic plaques within clinical lesions of MF, whereas very few of them showed hair loss identical to alopecia areata. Furthermore, only 5 patients presented total-body hair loss, all of them in the context of erythrodermic SS.

Our case illustrates an atypical presentation of classic MF, manifesting as an alopecia areata universalis-like hair loss without generalized MF lesions or erythroderma.

017 IMPROVED OVERALL SURVIVAL AFTER MULTIMODALITY TREATMENT IN A SINGLE-INSTITUTION COHORT OF 36 PATIENTS WITH FOLLICULOTROPIC MYCOSIS FUNGOIDES

Laggis, C.1; Lamb, A.1; Secrest, A.1; Ufkes, N.2; Halwani, A.S.3; Tao, R.4; Miles, R.5; Florell, S.1; Bowen, G.1; Wada, D.1

1Dermatology, University of Utah, Salt Lake City, United States; 2Dermatology, Medical University of South Carolina, Charleston, United States; 3Oncology, University of Utah, Salt Lake City, United States; 4Radiation Oncology, University of Utah, Salt Lake City, United States; 5Pathology, University of Utah, Salt Lake City, United States.

Introduction: Folliculotropic mycosis fungoides is a distinct entity with worse prognosis compared to non-folliculotropic mycosis fungoides (MF). Within FMF, there are distinct categories: early/indolent disease (E-FMF) with 5- and 10-year overall survival (OS) of 92- 94% and 72%, respectively; and advanced/aggressive disease (A-FMF) with 5- and 10-year OS of 55-69% and 28%. FMF is less responsive to first-line skin-directed therapies. Acitretin, rarely used for MF, is not cited in a recent review of therapies for FMF. We aim to identify factors associated with improved outcomes and highlight therapies used in our FMF cohort.

Methodology: In this single-institution, retrospective cohort study, we identified 36 patients with FMF diagnosed and treated between January 2008 and January 2019. Categorization between E-FMF and A-FMF was based on clinical presentation and progression.

Results: Of 36 patients, 19 had E-FMF and 17 had A-FMF. Three were lost-to-follow-up, all with E-FMF. The median follow-up for all patients was 3.4 years. Three patients, all with A-FMF, died resulting in an overall survival of >90% in our cohort. Patients with A-FMF has a higher stage (p=0.007) and were initially treated more aggressively, often with systemic retinoids or interferon with radiation therapy. Topical agents and light therapy were often effective in E-FMF. Acitretin was used in 15 patients with a complete response in 5/15, two of whom were treated with monotherapy, and with a partial response in 7/15. Two of the 15 had no response to acitretin and two did not tolerate acitretin. Acitretin was combined with radiation therapy in 9/15 patients, typically for debulking.

Conclusions: Although this is a retrospective study with limited sample size and follow-up, our data suggest that therapy tailored to aggressiveness of clinical presentation improves outcomes in FMF. We are interested in multicenter collaboration to further define the role of acitretin in treatment of FMF.

018 ANALYSIS OF EXPRESSION, AND FUNCTION OF MEIOSIS REGULATORY GENES AND LINE-1 RETROTRANSPOSON REACTIVATION IN CUTANEOUS T-CELL LYMPHOMAS (CTCL)

Gantchev, J.1; Tsang, M.2; Martínez Villarreal, A.1; Litvinov, I.3

1Experimental Medicine, McGill University, Montreal, Canada; 2Pathology, University of Ottawa, Ottawa, Canada; 3Dermatology, McGill University, Montreal, Canada.

Introduction & Objectives: Genomic instability is a hallmark of cancer and an enabling factor for genetic alterations that drive cancer development/progression. The clashing of mitosis and aberrantly expressed meiosis machineries, which may contribute to genomic instability, has been coined cancer “meiomitosis”. LINE-1 retrotransposition, a process active in germ cells, acts outside of the meiotic machinery to create DNA double strand breaks (DNA DSBs). We have previously demonstrated that in CTCL several cancer

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testis/meiosis regulatory genes are expressed. Furthermore, this cancer exhibits extensive and ongoing chromosomal/microsatellite instability.

Materials & Methods: We analyzed immortalized, primary CTCL-patient-derived cells and lesional skin biopsy samples. We performed RT-PCR, western blotting, immunohistochemical and confocal microscopy analyses to study the expression of the cancer testis/ meiosis regulatory genes. We performed LINE-1 functional assay to determine whether LINE-1 ORF1 and 2 proteins are active in CTCL cells. We analyzed the transcriptional expression of our genes of interest genes in Sézary Syndrome patients and healthy controls using publicly-available RNA sequencing (RNA-Seq) data.

Results: We found that proteins involved in meiosis and LINE-1 retrotransposition are expressed (using RT-PCR, Western Blotting, Immunohistochemistry and via in silico analysis of publicly-available RNA-Seq data) in CTCL. Upregulation of these genes was associated with chromosomal instability and DNA DSB formation. Using cell cycle synchronization, we demonstrate G1/S phase- transition-specific expression of meiosis proteins. Using the Alu retrotransposition assay, we demonstrate the functional activity of LINE-1 retrotransposon in CTCL. Histone acetyltransferase inhibition results in downregulation of the ectopic germ cell programs and concomitant decrease in DNA DSBs foci formation.

Conclusions: Taken together, our results indicate that malignant cells in culture undergo “cancer meiomitosis” rather than the classic mitosis division. The ectopic expression of meiosis genes and reactivation of LINE-1 may be contributing to genomic instability and represent novel targets for immunotherapy.

019 MYCOSIS FUNGOIDES WITH LARGE CELL TRANSFORMATION

Lobato Izagirre, A.1; Gainza Apraiz, I.1; González Del Tánago Diago, J.1; Pérez Parrio, S.1; Lázaro Serrano, M.1; Cancho Galán, G.2; Izu Belloso, R.M.1

1Dermatology, Hospital de Basurto - Osakidetza, Bilbao, Spain; 2Pathology, Hospital de Basurto - Osakidetza, Bilbao, Spain.

Introduction: Cutaneous T-cell lymphomas (CTCL) represent 75-80% of cutaneous lymphomas. Mycosis fungoides (MF) is the most frequent CTCL, and represents approximately 50% of all primary cutaneous lymphomas. MF generally has an indolent course, and patients characteristically progress from patch stage to plaque stage and finally to tumor stage disease, over years or decades.

Case presentation: A 88-year-old man presented with several erythematous-violet nodules, between 1-2 cm, on his left thigh and both legs. The initial skin biopsy was compatible with a tumor stage MF. The patient was treated with conventional external radiotherapy with good response. However, one month later, he presented with new tumoral lesions in lower extremities, trunk and an adenopathic conglomerate in his left groin. The biopsy of one of his new nodules and an inguinal lymph node revealed a proliferation of medium- large lymphocytes with atypical nuclei, which stained positively for CD3 and CD4 and negatively for CD8 and CD30. With this data the diagnosis of MF with large cell transformation (LCT) was established.

Discussion: Large cell transformation constitutes a histopathological variant of MF. It is characterized by the presence of large cells (lymphocytes that are at least 4 times greater in size than small lymphocytes) exceeding 25% of the lymphoid population. The incidence of LCT varies from 8% to 55% and it is more frequent in advanced stage disease. LCT is associated with poor prognosis, with a median survival after the diagnosis of transformation between 12 and 36 months.

Conclusion: We present a case of tumoral MF as first manifestation with rapid progression to LCT with a poor prognosis.

020 DIAGNOSTIC AND PROGNOSTIC VALUE OF GENOTYPIC ANALYSIS IN CUTANEOUS LYMPHOPROLIFERATIVE PROCESSES USING THE STANDARDIZED BIOMED-2 POLYMERASE CHAIN REACTION PROTOCOLS

López Aventín, D.1; Gallardo, F.2; Bellosillo, B.3; Ferrer, A.4; Duran, X.5; Pujol, R.M.2

1Medicine (PhD program), Universitat Autònoma de Barcelona, Barcelona, Spain; 2Dermatology, Hospital del Mar, Barcelona, Spain; 3Pathology (Molecular Biology), Hospital del Mar, Barcelona, Spain; 4Pathology, Hospital del Mar, Barcelona, Spain; 5Serveis cientificotècnics, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain.

Introduction & Objectives: The standardized BIOMED-2 polymerase chain reaction (PCR) protocols are widely used for detection of clonal populations of T/B-cells and represent an important diagnostic tool in the diagnosis of cutaneous lymphomas (CL). The purpose of this study was to assess the diagnostic and prognostic value of the genotyping results obtained by these techniques in daily clinical practice.

Materials & Methods: 222 lesional skin biopsies were retrospectively reviewed from 93 patients listed in the Hospital Registry of CL and diagnosed according to the WHO-EORTC classification as: 71 cutaneous T-cell lymphomas (CTCL) and 22 cutaneous B-cell lymphomas (CBCL). 232 biopsy specimens from 168 patients with benign lymphoid infiltrates served as controls. From all patients formalin-fixed, paraffin-embedded tissue was studied and in 123 cases extracutaneous samples (mostly peripheral blood) were also analyzed. T-cell receptor (TCR) and immunoglobulin rearrangements were assessed using BIOMED-2 PCR protocols. Median follow-up was 5 and 4 years in CL and control subjects, respectively.

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Results: The BIOMED-2 PCR protocol is a useful method in order to distinguish CTCL from benign T-cell-rich infiltrates in the skin with high sensitivity (96%) and meaningful specificity (84%). The BIOMED-2 method has also been helpful in differentiating CBCL from benign cutaneous B-cell infiltrates with very high sensitivity (100%) and reasonable specificity (77%). Clonal heterogeneity among sequential or different skin sites biopsies was identified in 5% of CTCL and 17% of CBCL. Detection of the same dominant TCR gene rearrangement in skin and extracutaneous samples is associated with higher disease-specific mortality rates in CTCL (p= 0.006) and mycosis fungoides/ Sézary syndrome patients (p=0.015).

Conclusions: The BIOMED-2 PCR protocol has proved to be a useful diagnostic strategy, with some prognostic implications, for studying patients with cutaneous lymphoproliferative processes.

021 HYPEREOSINOPHILIC SYNDROME WITH T- CELL LYMPHOMA DEVELOPMENT

Meruelo Ruano, M.1; Juliá Manresa, M.1; Lobato Izaguirre, A.1; Mariscal Polo, A.1; Zaldua Arrese, M.1; Cancho Galán, G.2; Izu Belloso, R.M.1

1Dermatology, Hospital de Basurto - Osakidetza, Bilbao, Spain; 2Anatomical Pathology, Hospital de Basurto - Osakidetza, Bilbao, Spain.

Introduction: Hypereosinophilic Syndrome (HES) is defined as a heterogeneous group of diseases characterized by a persistent eosinophilia of unexplained cause accompanied by organic damage. The lymphocytic variant (HES-L) is characterized by presenting a subset of abnormal T cells that causes an increase in eosinophils. It is a known fact that patients with HES-L are predisposed to develop a T-cell lymphoma, without knowing if the latter is a cause or consequence of it.

Materials and methods: Presentation of a clinical case and literature review.

Clinical case: We present a 67-year-old male with no previous significant past medical history who began presenting polyartralgias, weight loss, generalized papular rash, inguinal and axillary adenopathies and important eosinophilia with the presence of migratory pulmonary nodules in CT. The study of allergies, autoimmunity and parasites was negative. Bone marrow biopsy immunohistochemistry showed an increase in atypical lymphocytes. Bronchoscopy and cytogenetics of peripheral blood showed an important predominance of eosinophils. With these results, a probable HES-L was diagnosed. Two months later the skin biopsy revealed a T-lymphoid infiltrate with positive monoclonality. Treatment with prednisone, methotrexate, phototherapy, interferon alpha 2-A, and bexarotene was initiated. The patient did not respond to treatment, presenting within two weeks Sézary cells in blood and dying four days later despite the beginning of chemotherapy with CHOP.

Discussion and Conclusions: A case of HES-L with development of a Sézary Syndrome. It has a special interest due to: (i) the unusual of this entity, highlighting the diagnostic difficulty of this lymphoproliferative disorder; (ii) its complex relationship with a less aggressive entity such as HES and, (iii) the difficulty of its treatment.

The authors declare no conflict of interest.

022 PAPULAR MYCOSIS FUNGOIDES: REPORT OF THREE CASES

Michelena, M.J.1; Córdoba, A.2; Cascante, L.1; Azcona, M.1; Yanguas, I.1

1Dermatology, Hospital de Navarra, Pamplona, Spain; 2Anatomic pathology, Hospital de Navarra, Pamplona, Spain.

Introduction: Papular mycosis fungoides is a rare variant of early mycosis fungoides (MF) characterized with the presence of persistent papular lesions with histopathologic findings of MF, absence of spontaneous regression, and no other evidence of MF or lymphomatoid drug reaction .So far, less than 30 cases have been reported in the literature.

Case report: We report the clinical and histopathological characteristics of three new patients with papular MF.

Discussion: Papular MF is a new variant of early MF characterized by a good prognosis in the long term follow-up. The differential diagnosis for papular MF includes lymphomatoid papulosis (LyP) type B, pityriasis lichenoides chronica and linfhomatoid drug eruption. The hystopathologic distinction between PMF and LyP may be impossible. PMF should be distinguished clinically from LyP. LyP is characterized by a chronic self-healing papulo-nodular eruption whereas papular MF is characterized with the presence of persistent papular lesions. Some authors have questioned whether PMF exists, they suggest that most cases may be regarded as a variant of LyP type B. These cases are presented in order to keep in mind papular MF, which is a rare variant of MF.

023 CLINICOPATHOLOGICAL FEATURES OF MYCOSIS FUNOIDES WITH CD8+ AND CD56+ PHENOTYPE

Papaleo, N.1; Rovira, R.2; Vazquez, I.1; Gallardo, F.2; Pujol, R.2; Colomo, L.1

1Pathology, Hospital del Mar, Barcelona, Spain; 2Dermatology, Hospital del Mar, Barcelona, Spain.

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Introduction & Objectives: Mycosis fungoides (MF) is a primary cutaneous CD4+ T-cell lymphoma, which rarely presents cytotoxic phenotypes. We describe the clinicopathological features of two MF with CD8+/CD56+ immunophenotype.

Materials & Methods: Case #1 A 54 years old male patient explained a 25-year history of plaques localized in the buttocks, treated as eczema. Clinical examination revealed an apparently healthy man with 5-6 erythematous plaques with desquamation in both buttocks; the biggest one was palpable. No lymph nodes were detected. Case #2 A 74 years old male patient presented with a 20 years history of progressive macular lesions in legs and trunk, diagnosed as parapsoriasis. Clinical examination only revealed erythematous macules and plaques that involved less than 10% of the body surface in the arms, abdomen, buttocks and the inner side of the legs. Some of them were hypopigmented. No lymph nodes were palpable.

Results: Skin biopsies were performed, and both had similar features. An intraepidermal infiltrate of atypical small and intermediate lymphocytes was identified. The immunohistochemical study showed a T-cell population with expression of CD3, CD8 and CD56, with loss of CD5 and CD7. Beta chain of the T receptor (beta F1), TIA-1 and granzyme B were positive (negative in case #2). Molecular analysis of the γ, β and δ chains of the T-cell receptor genes detected monoclonality for the TCRγ and β, but not for TCRδ. The former patient was treated with phototherapy and the latter received topical steroids, and both had a partial response.

Conclusions: MF with CD8 and CD56 coexpression raises a differential diagnosis with other primary cutaneous lymphomas with aggressive biological behavior. The clinical features of the disease are very relevant to recognize these entities and therefore avoid aggressive treatments.

024 HEMATOLOGIC DISORDERS IN PATIENTS WITH MYCOSIS FUNGOIDES: RESULTS FROM A TERTIARY REFERRAL CENTER IN NORTHERN GREECE

Pikou, O.1; Georgiou, E.2; Koletsa, T.3; Papathemeli, D.1; Lazaridou, E.1; Patsatsi, A.1

12nd Department of Dermatology and Venereology, Cutaneous Lymphoma Outpatient Clinic, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece; 2Department of Biochemistry, 2nd Department of Dermatology and Venereology, Cutaneous Lymphoma Outpatient Clinic, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece; 3Department of Pathology, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Introduction & Objectives: Mycosis fungoides (MF), an extranodal, non-Hodgkin T-cell lymphoma, is considered a cutaneous lymphoproliferative disorder. The risk of developing a second primary malignancy, especially lymphoid malignancies, in the context of MF is well documented in the literature. Our objective was to investigate the incidence of hematologic diseases, including primary hematologic neoplasms, in patients with MF.

Materials & Methods: Clinical files of all patients with clinical and histopathologically verified MF were retrieved from the database of our cutaneous lymphoma outpatient clinic in a tertiary referral center, between 2012 and 2019. Hematologic disorders classified as adverse events due to MF treatment were not included in the study.

Results: We evaluated ninety eight patients with MF. In 9 (9/98) cases further diagnosis of a hematologic disease was established either previously of subsequently to MF diagnosis. The majority of these disorders involved the diagnosis of a primary hematologic cancer, whereas few cases did not fulfill the criteria of a malignancy. Follow-up data was available for all patients.

Conclusions: In this retrospective study we report the coexistence MF and other hematologic diseases in our database. Our findings reinforce existing evidence regarding an increased risk of developing a second primary malignancy in patients with MF. The limitation of the study is the small size sample and the selected populations. Thus, multicenter studies are needed in order to investigate the incidence of preceding, concomitant or secondary hematologic disorders in patients with MF.

025 BRENTUXIMAB SIDE-EFFECTS IN MYCOSIS FUNGOIDES PATIENTS

Pileri, A.1; Guglielmo, A.1; Bertuzzi, C.2; Sabattini, E.2; Broccoli, A.2; Casadei, B.2; Zinzani, P.L.2; Agostinelli, C.2; Patrizi, A.1

1Dermatology Unit, Department of Experimental, Diagnostic and Specialty Medicine, Bologna University, Bologna, Italy; 2Haematopathology Unit, Department of Experimental, Diagnostic and Specialty Medicine, Bologna University, Bologna, Italy.

Background: Brentuximab Vedotin (BV) has recently been the subject of two clinical trials showing encouraging results in patients affected by cutaneous T-cell lymphoma (CTCL). However, little is known on BV skin side effects (SAE).

Materials and Methods: Mycosis fungoides (MF) cases treated with BV who experienced SAE, were searched. The beginning of new concomitant drugs was ruled out, while treatments that had started months or years before the SAE were continued. The diagnosis of SAE was confirmed by a skin biopsy.

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Results: Three patients in various stage (one in IIB and two IVA1 patienst) were retrieved. Those had experienced an MF clinical regression, while after a median of 3 cycles developed SAE. All patients developed erythroderma (in one patient along with enanthema). In contrast to the CD4+ diagnostic biopsy, in all the cases a focally epidermotropic dermal infiltrate consisting of small to medium-sized lymphocytes was observed. At immunohistochemistry, the infiltrate expressed cytotoxic markers such as CD8, TIA-1, Granzyme B, while CD4 molecule showed a reduced expression. After an enduring and slowly-tapered steroid administration, MF reappeared after a median time of 2 months form steroid suspension.

Conclusions: We report for the first time a detailed description of BV SAE. As erythroderma can be a clinical presentation in CTCL, the recognition of a BV SAE is not a banal finding. A misdiagnosis of MF/SS relapse may lead to starting an inappropriate therapy, which could have harmful consequences.

026 MOLECULAR SIGNATURE PATTERNS RELATED TO THE DEVELOPMENT OF CONTACT DERMATITIS IN PATIENTS WITH MYCOSIS FUNGOIDES-TYPE CUTANEOUS T-CELL LYMPHOMA TREATED WITH CHLORMETHINE GEL

Alexander-Savino, C.V.1; Chung, C.G.2; Gilmore, E.S.1; Poligone, B.1

1Rochester Skin Lymphoma Medical Group, Fairport, United States; 2Departments of Dermatology and Pathology, The Ohio State University, Columbus, United States.

Introduction & Objectives: Mycosis fungoides cutaneous T-cell lymphoma (MF-CTCL) is a rare non-Hodgkin lymphoma often diagnosed in early stage, when skin-directed therapy is recommended. Topical chlormethine (=mechlorethamine) 0.016% w/w gel (equivalent to 0.02% chlormethine HCI) has been shown safe and effective but can result in contact dermatitis (CD). The Mechlorethamine Induced Contact Dermatitis Avoidance Study (MIDAS; NCT03380026) assesses a possible intervention against the development of chlormethine- induced CD by using a newly formulated 0.016% w/w gel, and investigates clonal sequencing of dermatitis.

Materials & Methods: Patients ≥18 years with histologically confirmed stage IA–IB MF-CTCL and no known hypersensitivity to chlormethine were enrolled. MIDAS is an ongoing non-randomized, split-face, 2-arm, open-label study. Patients were treated by applying 0.016% w/w chlormethine gel once-nightly over a designated area ≥8 cm2 with representative patches or plaques of MF, over a period of 4 months. Half the lesions studied also received topical triamcinolone. To evaluate dermatitis etiology, T-cell receptor immunosequencing was performed.

Results: To date (September 2019), 26 patients have been enrolled. Moderate to severe CD was observed in 9 (34.6%) patients treated with chlormethine gel. Preliminary results showed promising responses, including complete responses despite dermatitis and treatment interruptions. Data on T-cell receptor sequencing indicated that the abundance of several T-cell clones differed between control and treated samples. Post-treatment samples mostly showed an expansion of clones present in control samples, with some newly expanded clones detected.

Conclusions: A T-cell repertoire turnover can be detected in CD between control and chlormethine-treated samples. Most differences related to expansion of clones present in both repertoires rather than newly expanded clones. Further data will be presented at the time of the meeting.

027 EXPRESSION OF CCR3 AND CCR4 SUGGESTS A POOR PROGNOSIS IN MYCOSIS FUNGOIDES AND SÉZARY SYNDROME

Suga, H.1; Kawana, Y.1; Kamijo, H.1; Boki, H.1; Miyagaki, T.2; Sugaya, M.3; Sato, S.1

1Dermatology, University of Tokyo, Tokyo, Japan; 2Dermatology, St Marianna University, Kawasaki, Japan; 3Dermatology, International University of Health and Welfare, Chiba, Japan.

Introduction & objectives: Tumor cells in cutaneous T-cell lymphoma (CTCL) express limited numbers of chemokine receptors on their cell surface. The objectives in this study are to analyze the expression patterns of CXCR3, CCR3, CCR4 and CCR10 in skin samples from patients with CTCL and to investigate the relationship between chemokine receptor expression and survival prognosis.

Materials & Methods: Clinical skin samples (n = 121) were collected in our department. Skin samples from cases of mycosis fungoides (MF; n = 76), Sézary syndrome (SS; n = 12), lymphomatoid papulosis (LyP; n = 10), anaplastic large cell lymphoma (ALCL; n = 5) and atopic dermatitis (AD; n = 18) were used. Fresh-frozen skin samples were used for immunohistochemistry.

Results: CXCR3 expression was detected in 86% of MF cases and 94% of AD cases but in no ALCL cases. CCR3 expression was positive in more than 70% of LyP and ALCL cases but in less than 30% of MF, SS and AD cases. The frequency of CCR4-positive cases was nearly equal in MF, SS, LyP and ALCL cases, ranging from 30–42%, significantly lower than that in AD cases (72%, P < 0.05). CCR10 expression was detected in 50% of MF/SS cases, a significantly higher percentage than that of CD30-positive lymphoproliferative disorders and AD cases (13% and 11%, respectively). As for survival prognosis, patients strongly positive for CCR3 expression had a significantly lower survival rate than CCR3-negative patients or patients weakly positive for CCR3 expression. Similarly, MF/SS patients strongly positive for CCR4 expression exhibited a significantly lower survival rate than CCR4-negative or weakly positive patients.

Conclusions: Differential patterns of CXCR3, CCR3, CCR4 and CCR10 expression were useful for the diagnosis of CTCL. Moreover, expression of CCR3 or CCR4 suggested a poor prognosis in CTCL.

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028 DIAGNOSIS IN THE HANDS: A RARE VARIANT OF MYCOSIS FUNGOIDES

Suzuki, N.N.; Rytenband, F.; Ferreira Magalhães, R.; Fantelli Stelini, R.; Nunes Secamilli, E.; Massuda Serrano, J.Y.

State University of Campinas, Campinas, Brazil.

Mycosis fungoides (MF) is the most common cutaneous T-cell lymphoma (CTCL), accounting for approximately half of all primary cutaneous lymphomas. While MF classically presents with cutaneous lesions, such as patches, plaques and tumors in unexposed areas, distinct MF variants may show skin involvement restricted to specific areas, like the palmoplantar region. MF palmaris et plantaris was described by Resnik et al as a rare variant comprising only 0,6% of all MF cases. Several clinical forms have been described for palmoplantar MF: hyperkeratotic plaques, which can be solitary or multiple and sometimes fissured or ulcerated, vesicles, pustules and dysidrotic lesions. These lesions are frequent findings on subacute and chronic dermatitis of the hand or soles, such as primary dermatophyte infection, palmoplantar psoriasis, contact dematitis and dysidrose, all of which make palmoplantar MF diagnosis challenging.

This case report is about a 55-year-old patient with arthritis rheumatoids using infliximab for 14 years who presented lichenified hyperpigmented plaques on the palm and fingers, specially in contact areas. A first skin biopsy revealed frequent T lymphocytes permeating the basal layers with areas of delineating lymphocytes aggregates. Immunohistochemical staining showed positivity to CD2, CD3, CD4, CD5, CD7 and CD8, with less than 50% CD7+ relative to CD3+ cells. As she used to work as a cleaning woman, her lesions were assumed to be due to contact dermatitis and were treated accordingly with topical clobetasol for three months, without success. A second biopsy was obtained and histological findings were identical to those of the previous sample, with T lymphocytes blurring the dermoepidermal interface aligned to the basal layer. The lack of response to contact dermatitis treatment and the set of anatomoclinical findings supported palmar MF hypotheses. Treatment with imiquimod was initiated and infliximabe was suspended. Patient maintains outpatient follow-up.

029 A CASE OF MOGAMULIZUMAB INDUCED LICHENOID REACTION

Trager, M.1; De Clippelé, D.2; Ram-Wolff, C.2; Vignon-Pennamen, M.D.3; Battistella, M.3; De Masson, A.2; Michel, L.4; Bagot, M.2; Dobos, G.2

1Vagelos College of Physicians and Surgeons, Columbia University, New York City, United States; 2Dermatology, Saint-Louis Hospital, Paris, France; 3Pathology, Saint-Louis Hospital, Paris, France; 4INSERM U976, Université de Paris, Paris, France.

Autoimmune reactions as a side effect of checkpoint inhibitors are described and likely to be associated with better outcome. We present a case of oral lichenoid reaction occurring after nine months of treatment with mogamulizumab.

A 60-year-old woman was managed at Hopital Saint-Louis for plaque-stage Mycosis Fungoides (MF) stage TIBN0B0. The initial treatment with psoralen and ultraviolet A was discontinued due to intolerance, and methotrexate was ineffective. The third line treatment with bexarotene effectively reduced the patches and plaques, although neutropenia developed. After dose-reduction extracorporeal photophoresis (ECP) was added for one year. Because of a relapse the treatment was switched to bexarotene and meclorethamine gel. At that time she had a diagnosis of erythrodermic MF with an mSWAT over 40 and B0 blood staging.

An off-label request was made for mogamulizumab treatment, which was started in January 2019. The patient had a good response with improved cutaneous symptoms (mSWAT 6) and histology. After 8 months of treatment the patient developed an isolated striated oral leukoplasia on the right inner side of the upper lip. The histology showed a hyperplasic epiderm with some orthokeratosis, some round bodies and mononuclear infiltration, interpreted as lichenoid reaction.

Previous case reports described an association of autoimmune manifestations and treatment with mogamulizumab. These included autoimmune hepatitis, vitiligo, alopecia areata, autoimmune thyroiditis and autoimmune hemolytic anemia (Bonnet et al. 2019). Interestingly, these patients had long-term remission of CTCL without maintenance treatment suggesting that the autoimmune side- effects could be a sign of treatment efficacy.

Cutaneous lichenoid changes due to mogamulizumab were reported previously. To our knowledge, this is the first report of an oral lichenoid reaction after treatment with mogamulizumab in MF. This patient also had a good response to treatment with improvement in cutaneous symptoms further suggesting that autoimmune side-effects could be linked to treatment response.

030 INTRAOCULAR INVOLVEMENT IN MYCOSIS FUNGOIDES

Urigoitia Ugalde, P.1; Ispizua Mendivil, E.2; Meruelo Ruano, M.1; Gonzalez Romero, N.1; Gainza Apraiz, I.1; Izu Belloso, R.1

1Dermatology Department, Hospital de Basurto - Osakidetza, Bilbao, Spain; 2Ophthalmology Department, Hospital de Basurto - Osakidetza, Bilbao, Spain.

Introduction: mycosis fungoides is the most common type of cutaneous T-cell lymphoma. Initially, it presents in the skin as patches, plaques or tumors and it may involve lymph nodes and visceral organs. Ocular involvement is rare. We report a case of folliculotropic mycosis fungoides that developed intraocular involvement.

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Case report: a 67-year-old female with a 10-year history of folliculotropic mycosis fungoides presented with progressive visual loss of the right eye. Previously, she had been treated with multiple therapies (PUVA, bexarotene, interferon alpha-2b and electron beam therapy) and the work-up had not shown lymph node, blood or bone marrow involvement (T3N0M0B0, IIB). Ophthalmological examination showed anterior uveitis and vitritis. Diagnostic vitrectomy was performed and microscopic examination of the vitreous fluid showed a monomorphic population of atypical medium-sized lymphoid cells with kidney-shaped nuclei. Flow cytometry of the vitreous specimen revealed abnormal immunophenotype of T lymphocytes (CD4+, CD3-, CD7-). These findings were consistent with intraocular infiltration by mycosis fungoides.

Conclusions: ocular involvement in mycosis fungoides is rare and in most cases it involves the eyelid skin and ocular surface. Intraocular involvement is even more rare. Retinal, choroidal, vitreous and optic nerve infiltration have been reported in the context of advanced disease. Even though ocular involvement is rare, it should be taken into consideration in patients with a history of advanced stage mycosis fungoides who present with new ocular symptoms.

PRIMARY CUTANEOUS LYMPHOMA, CLINICAL & PATHOLOGICAL - CD30+ LYMPHOPROLIFERATIVE DISORDERS

032 PITFALLS OF PSEUDOEPITHELIOMATOUS HYPERPLASIA IN CD30+ LYMPHOPROLIFERATIVE DISORDERS

Davis, M.1; Linos, K.2; Lansigan, F.3; Carter, J.1

1Department of Surgery, Division of Dermatology, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, United States; 2Department of Pathology and Laboratory Medicine, Dartmouth Hitchcock Medical Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, United States; 3Hematology/Oncology, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, United States.

Pseudoepitheliomatous hyperplasia is a rare yet well-established phenomenon in the setting of CD 30+ lymphoproliferative disorders1,2,3. It is a benign condition characterized by hyperplasia of the epidermis and adnexal structures; however, it remains a challenge because it can be easily mistaken for squamous cell carcinoma (SCC) both clinically and histologically. As the second most common of all skin cancers, SCC can arise in patients with anaplastic large cell lymphoma, further emphasizing the necessity of careful review of all such cases4. We present three patients showcasing the variability of presentation for this condition.

A 58-year-old man presented with a 1.7 cm erythematous and indurated plaque with serous crust on the left medial canthus thought to be SCC. Biopsy revealed a dense proliferation of mitotically active CD30+ irregular, large cells and areas of infiltrative squamous proliferation with cytologic atypia and suppurative inflammation favored to be pseudoepitheliomatous hyperplasia in the setting of primary cutaneous anaplastic large cell lymphoma. A 30-year-old woman was evaluated for a 5 mm pink scaly papule on the right dorsal hand that was thought to be a dermatofibroma. Biopsy demonstrated numerous CD30+ large lymphocytes in the upper dermis with associated neutrophils and marked epidermal hyperplasia. With clinicopathologic correlation, a diagnosis of pseudoepitheliomatous hyperplasia of lymphomatoid papulosis was made.

A 56-year-old woman presented with a 6 mm ulcerated papule with deep peripheral erythema concerning for infection. Biopsy was consistent with anaplastic large cell lymphoma with adjacent endophytic and exophytic squamous proliferation that did not appear to be infiltrated by the lymphomatous neoplasm. This adjacent proliferation was thought to be a genuine SCC arising adjacent to the CD 30+ proliferation.

The similarities yet key differences in these cases emphasize the pitfalls of pseudoepitheliomatous hyperplasia in the setting of CD30+ lymphoproliferative disorders and stress the importance of clinicopathologic correlation.

033 PRIMARY CUTANEOUS CD30-POSITIVE ANAPLASTIC LARGE CELL LYMPHOMA

De la Torre Gomar, F.J.; Sáenz Aguirre, A.; Roses Gibert, P.; Gimeno Castillo, J.; Aspe Unanue, L.; García Río, I.; Carnero González, L.; Trébol Urra, I.; Martínez De Lagrán Álvarez De Arcaya, Z.; González Pérez, R.

Dermatology, Araba University Hospital, Vitoria, Spain.

Introduction: Cutaneous CD30+ T-cell lymphoproliferative disorders (CD30+ T-LPD) represent a spectrum encompassing lymphomatoid papulosis (LyP), primary cutaneous anaplastic large-cell lymphoma (pcALCL) and borderline lesions.

Clinical case: An 82-year-old male presented to us with 6 nodules of contusiform appearance on the right leg of three months of duration. He was previously diagnosed of LyP in another hospital. Two of them became large tumors with central necrotic ulcer within 4 weeks. The histopathological examination guided the diagnosis to pcALCL CD3 and CD30 positive. T cell receptor (TCR) gene rearrangements

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showed a monoclonal T cell proliferation. PET-CT showed hypercaptation at the level of the posterior third of the right leg. The patient was treated with oral methotrexate 15 mg/week and 20 sessions of radiotherapy. After that, he presented complete resolution of the lesions and disappearance of hypercaptation in PET-CT. Currently the patient is in follow-up and continues asymptomatic.

Discussion: PyL and pcALCL share the expression of CD30 as a common phenotypic marker. Characteristically, PyL presents as small papules with occasional necrosis that appear and involve spontaneously over months-years. pcALCL is usually presented as a larger single ulcerated nodule which does not return spontaneously in most cases. In both cases the histopathological study shows an infiltrate of anaplastic CD30 cells, although in the pcALCL it is usually deeper, affecting the subcutaneous cell tissue. In both cases there may be a clonal rearrangement of TCR. Overlapping features of LyP and pcALCL with themselves and with other cutaneous and systemic lymphomas emphasize the importance of careful clinicopathologic correlation in the diagnosis of CD30+ T-LPD. Complete surgical excision or radiotherapy are the treatment of choice in localiced pcALCL forms. Low dose methotrexate is preferred in forms with multiple lesions. Brentuximab vendotine has proven to be effective in cases that do not respond to other treatments.

034 PRIMARY CUTANEOUS ANAPLASTIC LARGE CELL LYMPHOMA CD30+ TREATED WITH BRENTUXIMAB

González Romero, N.1; Lobato Izagirre, A.1; Meruelo, M.1; Gomez Bringas, C.1; Márquez Navarro, J.A.2; Calderón Gutiérrez, M.J.1; Izu Belloso, R.1

1Dermatology, Hospital Universitario Basurto, Bilbao, Spain; 2Hematology, Hospital Universitario Basurto, Bilbao, Spain.

Introduction. Primary cutaneous anaplastic large cell lymphoma (pcALCL) usually appears as a single or grouped nodular lesion with a tendency to autoinvolution. The prognosis is excellent, although recurrences after treatment are frequent.

Case presentation. A 79-year-old woman diagnosed of pcALCL in 2011, with skin involvement of the scalp and parotid gland infiltration. Initially she received chemotherapy (CHOP) achieving complete remission. Eight months later, she presented generalized progression of skin lesions. Since then, she has received multiple treatments (bexarotene, phototherapy, methotrexate, Interferon-Alfa, and Total Skin Electron Beam Radiation Therapy), being refractory to all of them. In June 2016, treatment with Brentuximab Vedotin (BV) was initiated, reaching complete remission. Nine months later, new lesions appeared and 17 months after treatment, she developed a frank progression of skin lesions, so a new cycle of BV was decided, reaching again complete remission, which was maintained for 13 months. In December 2018, new skin lesions appear and in September 2019 she presents generalization of them, so a new BV cycle was decided. Currently, she is waiting to start a new cycle of treatment.

Discussion. BV is a monoclonal antibody with antitumor activity against cells expressing CD30. A recent international phase III randomized clinical trial (ALCANZA) showed a higher response rate with BV (67%) compared to conventional therapies with methotrexate or bexarotene (20%) in the treatment of MF and pcALCL, as well as a significant improvement in the duration of the response (at least 4 months in 56% of patients). This evidence led to the approval of BV for the treatment of adults with advanced stage CTCL CD30 + by the European Medicines Agency (2017) and by UK National Institute of Clinical Excellence (2019).

Conclusions. We present this case because of its unusual aggressiveness and an extraordinary response to BV, with a long duration of response.

035 THE IMPORTANCE OF DIFFERENTIATING BETWEEN MYCOSIS FUNGOIDES WITH CD30 POSITIVE LARGE CELL TRANSFORMATION AND MYCOSIS FUNGOIDES WITH CO-EXISTENT PRIMARY CUTANEOUS ANAPLASTIC LARGE CELL LYMPHOMA

Mccormack, C.; Gao, C.

Surgical Oncology, Peter Macallum Cancer Centre, Melbourne, Australia.

In patients with mycosis fungoides (MF), it can be difficult to distinguish between co-existent lesions of primary cutaneous anaplastic large cell lymphoma (pcALCL) versus CD30-positive large cell transformation (LCT). This is due to the clinical and histological similarities between the two entities. We conducted a retrospective analysis of our cutaneous lymphoma database to explore the disease behaviour of co-existent MF/pcALCL. We sought to investigate if these patients experienced significantly different clinical outcomes compared to patients with MF/LCT, and those with a solitary diagnosis of pcALCL-alone or MF-alone. We analysed patients with co-existent MF/pcALCL (n = 13), pcALCL-alone (n = 51), MF-alone (n = 95), and MF/LCT (n = 40). With respect to overall survival (OS), there was no difference between those with MF/pcALCL compared to those with pcALCL-alone (p = 0.81) or MF- alone (p = 0.99), with median survival not yet reached in all three groups. However, in our cohort, we found that the OS in patients with co-existent MF/pcALCL was significantly better compared to those with MF/LCT (p = 0.05). This emphasises the need to discriminate between these two distinct pathological entities, as this has important prognostic and therapeutic implications.

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036 PROGNOSIS OF PRIMARY CUTANEOUS ANAPLASTIC LARGE CELL LYMPHOMA (PCALCL) WITH CLINICALLY SUPERFICIAL NODES AT DIAGNOSTIC

Clémentine, D.1; Marie, B.B.2; Saskia, O.3; Martine, B.4; Pascal, J.5; Florent, G.6; Henri, A.7; Stéphane, D.8; Michel, D.1

1Dermatology and Cutaneous Oncology, CHU Clermont-Ferrand, Hôpital Estaing, Clermont-Ferrand, France; 2Dermatology and Cutaneous Oncology, CHU Bordeaux, Bordeaux, France; 3Dermatology and Cutaneous Oncology, Henri Mondor Hospital, Créteil, France; 4Dermatology and Cutaneous Oncology, Hôpital Saint-Louis, Paris, France; 5Dermatology and Cutaneous Oncology, CHU Rouen, Hôpital Charles Nicolle, Rouen, France; 6Dermatology and Cutaneous Oncology, CHU Reims, Reims, France; 7Dermatology and Cutaneous Oncology, CHU Rennes, Rennes, France; 8Dermatology and Cutaneous Oncology, CHU Lyon-Sud, Lyon, France.

In contrast with systemic ALCL, prognosis of pcALCL is excellent. However little is known about the outcome of pcALCL with regional lymph nodes at diagnosis. Only one series reported no impact on the prognosis. Our aim was to evaluate the prognosis of pcALCL presenting, at time of diagnosis or during the six following months, one or more clinically superficial nodes.

From the GFELC data base (1998-2018) we collected patients with a pcALCL stages T1a to T2c and palpable regional node at diagnosis. Overall survival (OS) and Disease Specific Survival (DSS) at 5 years were calculated. Impact on prognosis of T and N stages, first line treatment, localization of lesions and node histology were evaluated.

27 patients were included (T1: 15, T2: 12). In 5, node biopsy was not performed (imaging argued for benignity). Biopsy revealed benign lymphadenopathy (N0) in 4, lymphoma in 17 (all in the cutaneous lesion draining area, N1). Patients were initially treated with polychemotherapy (n=11), local treatment or methotrexate or a combination (n=15). Mean follow up was 53.4 months. Complete remission was obtained in 81.5%. Nine relapsed, 7 in the skin, 2 in superficial node. Eight died (4 from lymphoma). OS and DSS were 73% and 91% respectively. There were no statistical differences between stages T (p=0.904) or N (p=0.36) but a trend for a better OS and DSS was observed when the lesions were on the thighs (p=0.08) and when polychemotherapy was used (p=0.13)

pcALCL with superficial nodes at diagnosis are rare (3% in our database, 0% in a series from the Spanish Group). As reported by the Dutch Lymphoma Group, our study confirms the good prognosis whatever the nodal status. Due to the small size of this series, we could not conclude whether they should be heavily treated or not.

037 LYMPHOMATOID PAPULOSIS: A RETROSPECTIVE REVIEW OF CLINICAL CHARACTERISTICS, SYMPTOMATOLOGY, TREATMENTS, AND ASSOCIATED MALIGNANCIES AT A SINGLE-INSTITUTION

Stoll, J.1; Pulitzer, M.2; Moskowitz, A.3; Horwitz, S.4; Myskowski, P.1; Noor, S.1

1Dermatology, Memorial Sloan Kettering Cancer Center, New York/Memorial Sloan Kettering Cancer Center, United States; 2Pathology, Memorial Sloan Kettering Cancer Center, New York/Memorial Sloan Kettering Cancer Center, United States; 3Medicine, MSKCC, New York/Memorial Sloan Kettering Cancer Center, United States; 4Medicine, Memorial Sloan Kettering Cancer Center, New York/Memorial Sloan Kettering Cancer Center, United States.

Introduction & Objectives: Lymphomatoid papulosis (LyP) is a relapsing and remitting CD30+ lymphoproliferative disorder. Treatment is variable and can include observation, topical/skin-directed therapies, and systemic treatment (including anti-CD30 antibody-drug conjugate brentuximab vedotin). Therapy decision is based on extent of skin disease, symptomatology, and disease impact on quality of life. The purpose of this study is to summarize demographic, clinical, and treatment characteristics of our patient population, and evaluate if these features impacted treatment decision.

Materials & Methods: A retrospective chart review of LyP patients between 2003-2019 identified 108 patients. Data collected includes patients’ demographic and clinical characteristics (number of lesions, symptomatology), treatment(s), associated malignancies, and treatment response.

Results: Our baseline demographics were similar to the literature [mean age of diagnosis of 51, M:F ratio ~1:1, 80% Caucasian]. The majority of patients (85%) had multiple lesions on initial presentation Our study highlights the higher prevalence of symptoms such as pruritus (55%), pain (36%), ulceration (41%), and scarring/dyspigmentation (57%). Associated hematologic malignancies were found in 41% of patients, with Mycosis Fungoides most common (73%). Overall, 53% of associated hematologic malignancies occurred before, 37% after, and 10% concurrent with LyP. Treatment options varied with 16% on observation, 79% treated with topical therapy, 14% treated with phototherapy, and 28% treated with systemic therapy including methotrexate, bexarotene, and brentuximab with four patients receiving more than one systemic agent. Further analyses on demographic and clinical factors that affected treatment decision is pending.

Conclusions: This study highlights both the high prevalence of associated symptoms that may impact quality of life, as well as variability in treatment. Prospective studies are needed to determine how LyP and what features of LyP affect quality of life and treatment decision.

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038 PRIMARY CUTANEOUS CD30+ LYMPHOPROLIFERATIVE DISORDERS IN HIV+: A SINGLE CENTER CASE SERIES

Riera Monroig, J.1; Combalia, A.1; Alsina, M.1; García-Herrera, A.2; Estrach, T.1

1Dermatology, Hospital Clínic de Barcelona, Barcelona, Spain; 2Pathology, Hospital Clínic de Barcelona, Barcelona, Spain.

Although HIV+ patients are at higher risk of peripheral T-cell lymphoma, there is little information regarding primary cutaneous (pc) CD30+ lymphoproliferative disorders (LPD). Therefore, we aimed to determine the main features of these diseases in HIV patients.

The medical records of patients diagnosed with both HIV and pcCD30+LPD from 2003 to 2019 were reviewed.

A 55-year-old woman presented with multiple papules on trunk. Her CD4 count was 790/uL and viral load undetectable. Pathology showed T-cell lymphoid infiltrate with large CD30+, CD8+ lymphocytes. T-cell-receptor rearrangement (TCRR) was negative. A diagnosis of Lymphomatoid Papulosis (LyP) was made and lesions resolved in 1.5 months. Second patient was a 37-year-old male under antiretroviral therapy, with a CD4 count of 210. He developed an ulcerated plaque on left shoulder and isolated nodules with necrotic crust on trunk. Biopsy showed atypical lymphoid infiltrate with occasional larger, CD30+ cells. In situ hybridization for Epstein-Barr virus was positive and TCRR was negative. The final diagnosis was CD30+LPD associated with EBV infection. Methotrexate 10mg/week was administered for two months with complete response. Third patient was a 41-year-old male who developed papules-nodules on trunk. His CD4 count was 294 cells/uL and viral load undetectable. Pathology exam revealed an atypical lymphoid infiltrate with large CD30+ cells, and partial loss of CD5 and CD7. With the final diagnosis of LyP, lesions resolved spontaneously.

There are few cases of pcCD30+LPD in HIV patients, with anaplastic large cell lymphoma (ALCL) being more frequent. The longest series published reported 7 pcALCL out of 21 pc lymphomas. Most of them had an advanced infection. No specific case series on LyP have been described. According to our results, LyP in HIV patients under antiretroviral treatment did not differ in terms of outcome from non-HIV infected individuals. However, multicenter larger studies are needed to confirm this hypothesis.

039 FACIAL PRIMARY CUTANEOUS CD30+ LYMPHOPROLIFERATIVE DISORDER MIMICKING KERATOACANTHOMA: TWO CASE REPORTS

Riera-Monroig, J.1; Pigem, R.1; Combalia, A.1; Alos, L.2; Estrach, T.1; García-Herrera, A.2

1Dermatology, Hospital Clínic de Barcelona, Barcelona, Spain; 2Pathology, Hospital Clínic de Barcelona, Barcelona, Spain.

The differential diagnosis of keratoacanthoma mainly includes squamous carcinoma. However, there are other less frequent entities that may be clinically similar to keratoacanthoma, such as the primary cutaneous CD30+ lymphoproliferative syndromes. Herein, we describe two cases of lymphomatoid papulosis (LyP) that clinically mimicked a keratoacanthoma.

A woman and man of 76 and 66 years old, respectively, with unremarkable medical history, consulted for solitary tumors of rapid growth, located in lower left eyelid and right nasolabial fold. On physical examination, both cases showed tumors 1-2 cm in diameter with scab and central ulceration. The two patients were biopsied with the clinical suspicion of keratoacanthoma. The pathology exam showed ulceration with hyperplasia of the adjacent epithelium and a dense dermal infiltrate consisting of atypical large cells, interspersed with small lymphocytes, neutrophils and eosinophils. Phenotypically the atypical cells were CD2, CD3 and CD5 positive, with loss of CD7 and coexpression of CD4 and CD30. Both cases showed a clonal peak for TCR beta chain and no DUSP22 rearrangements were observed. Both tumors completely involuted within a few weeks after biopsy. The diagnosis after clinical-pathological correlation was of LyP. The lab tests did not show any alterations. In the case of the male, he developed two similar lesions in head and trunk during the follow-up.

In conclusion, LyP can clinically simulate a keratoacanthoma. Pseudoepitheliomatous hyperplasia has been described in chronic leg ulceration and granulomatous diseases. Rarely, it has been reported in primary cutaneous anaplastic CD30+ large cell lymphoma and LyP, with keratinocyte atypia and pseudocarcinomatous changes. The epithelial hyperplasia has been hypothesized to be secondary to aberrant production of EGFR in some CD30+ anaplastic large cell lymphoma. 040 PERIPHERAL T-CELL LYMPHOMA NOT OTHERWISE SPECIFIED INVOLVING THE SKIN IN A YOUNG FEMALE PATIENT

Rytenband, F.; Lopes Iori, N.; Cassoli Cortez, A.; Kosa Lino Duarte, B.; Fantelli Stelini, R.; Massuda, J.Y.; Nunes Secamilli, E.

State University of Campinas, Campinas, Brazil.

Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) is a rare, heterogeneous group of nodal and extranodal mature T-cell lymphomas that do not correspond to any of the defined T-cell entities according to the World Health Organization (WHO) classification. It can either originate in or secondarily involve the skin and there is a paucity of data regarding clinical and histopathologic features and its clinical course due to its rarity. Cutaneous manifestations of PTCL-NOS include papules, patches, plaques, tumors, ulceration, or a combination of these lesions. They show a higher incidence in middle aged to elderly male individuals at diagnosis, B-symptoms and multifocal lesions predict poor survival in patients with PTCL-NOS. We report a case of a 22-year-old woman with multifocal violaceous tumors on the lower back, abdomen and right temporal region with sudden onset in October/2019 which rapidly increased in size becoming ulcerated and was associated with weight loss, night sweats and fever. Past medical history included a relapsing erythema multiforme requiring prednisone courses which remitted ten months earlier. Computed tomography showed hepatosplenomegaly, intestinal lesions and mediastinal lymph node enlargement suggesting systemic involvement. Skin biopsy revealed a non-Hodgkin lymphoma with high proliferative index (about 60%). The immunohistochemistry

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stains showed positivity for CD2, CD3 in the tumor, CD5 in part of the lymphocytes while CD4, CD7, CD30 and CD56 were negative. Bone marrow biopsy showed no abnormalities. The diagnose of peripheral T-cell lymphoma NOS was made and the patient has been treated with 2 lines of chemotherapy with poor outcome, subsequently dying due to febrile neutropenia. The importance of this report lies in the rarity of the case and the difficulty in diagnosing and treating the PTCL-NOS, while reinforcing the importance of the dermatologist in the early diagnose.

PRIMARY CUTANEOUS LYMPHOMA, CLINICAL & PATHOLOGICAL - PRIMARY CUTANEOUS B-CELL LYMPHOMAS, INCLUDING FOLLICLE CENTER LYMPHOMA, MARGINAL ZONE, AND DIFFUSE LARGE B-CELL LYMPHOMA

041 MARGINAL ZONE LYMPHOMA OF THE TOES

Coralie, Z.1; Sarah, I.2; Sara, L.R.3; Mohanad, A.1; Antoine, M.3; Sabine, B.2; Thorsten, B.2; Eve, M.1; Liliane, L.1

1Dermatology, Avicenne University Hospital, Bobigny, France; 2Hematology, Avicenne University Hospital, Bobigny, France; 3Pathology, Avicenne University Hospital, Bobigny, France.

Introduction: Skin involvement in primary cutaneous marginal zone lymphoma (MZL) and secondary MZL favours preferentially trunk/ upper extremities and head/neck respectively. We report a unique case of MZL with isolated cutaneous nodules on the toes of both feet.

Observation : A 72-year-old female was referred to our department for recently painful toes lesions evolving for 9 months. She had a medical history of Sjogren syndrome and hyperlymphocytosis (5 G/L) diagnosed simultaneously 17 years before. Laboratory tests showed a CD20+CD5+,CD23-,FMC7+,CD79b+ B cell proliferation in peripheral blood with B cell clonality. No autoantibodies, nor cytopenia, monoclonal peak, and hypogammoglobulinemia were detected. There was no peripheral lymphadenopathy nor splenomegaly on CT scan. Clinical examination showed symmetrical violaceous and angiomatous nodules involving toes of both feet associated with dystrophic nails. Physical examination was otherwise unremarkable. Skin biopsy revealed a heavy diffuse and nodular dermal infiltrate consisting of small- to medium- sized marginal zone cells admixed with lymphocytes and some lymphoplasmacytoid cells at the margins of the infiltrate. The neoplastic population expressed strongly CD20+ and Bcl-2, and weakly CD5. CD10 was negative. Lymphoplasmocytoid cells showed a monotypic expression of IgM and kappa Ig light chain. No MYD88 L265 P mutation was detected. Final diagnosis was secondary cutaneous involvement from a systemic MZL, based on histologic findings in conjunction with the leukemic phase. No other investigations were performed since it would not have modified the treatment.

Conclusion Isolated nodules of the toes are described in Kaposi sarcoma, sarcoidosis, cutaneous T cell lymphoma. To our knowledge it is the first report of cutaneous involvement strictly localized on toes in MZL.

042 PRIMARY CUTANEOUS FOLLICLE CENTER LYMPHOMA WITH UNUSUAL, LONGTERM POOR OUTCOME

Lastrucci, I.1; Kovalchuk, S.2; Maio, V.3; Simontacchi, G.4; Grandi, V.5; Santucci, M.3; Pimpinelli, N.1

1Department Health Sciences, sections Dermatology, University of Florence, Florence, Italy; 2Dept. Experimental and Clinical Medicine, sections Hematology, University of Florence, Florence, Italy; 3Dept. Health Sciences, sections Pathologic Anatomy, University of Florence, Florence, Italy; 4Dept. Experimental and Clinical Medicine, sections Radiotherapy, University of Florence, Florence, Italy; 5Department Health Sciences, sections Dermatology, St. Thomas and Guy’s Hospital, London, UK, London, United Kingdom.

Primary cutaneous follicle center lymphoma (pcFCL) is an indolent entity, which can undergo poor outcome in rare cases. We report two cases of pcFCL which underwent late extracutaneous spread with CNS involvement after a clinical complete remission (CR) following radiotherapy (RT). The first patient, a 53 year-old male, presented with nodular lesions of the left lower limb, diagnosed as pcFCL (bcl6+, bcl2-/+, MUM-1 -, FOX-P1- large cell infiltrate). The patient was treated by RT and i.v. rituximab, with CR which lasted two years before the development of sudden visual impairment due to the rapid growth of an intracranial mass. The biopsy showed features of diffuse large B-cell lymphoma (DLBCL). Notwithstanding aggressive chemotherapy with R-MATRX (METHOTREXATE, CYTARABINE, THIOTEPA, RITUXIMAB), the patient died after 6 months. The second case concerns a 70 year-old male, who presented with a single plaque of the left leg, diagnosed as pcFCL (bcl6+, bcl2+ faint, MUM-1 -, FOX-P1- large cell infiltrate). The patient was treated by RT and i.v. rituximab, with CR which lasted more than 5 years before the sudden occurrence of intracranial hypertension syndrome due to the rapid growth of an intracranial mass. The biopsy showed features of diffuse large B-cell lymphoma (DLBCL). An aggressive chemotherapy with R-MATRX was started and is ongoing.

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pcFCL is an indolent entity, yet location on the legs, FOX-P1 and bcl-2 expression by infiltrating cells have been associated with a worse prognosis, which is anyway certainly rare. Recently, a further category - DLBCL, NOS - has been proposed. Its germinal center (GC) or non- GC histogenetic profile are associated with a less (FCL-like) or more aggressive (DLBCL-like) clinical behaviour. The interest of the cases reported concerns the typically indolent course and longlasting complete remission, and the late occurrence of a type of extracutaneous spread which is instead typical of DLBCL,leg type.

043 LONG-TERM CD30+ DIFFUSE PRIMARY CUTANEOUS LARGE CELL B-CELL LYMPHOMA

Soria Gili, X.1; Fernández Armenteros, J.M.1; Àngel Baldó, J.1; Canal García, E.1; Pérez Manich, J.1; Casanova Seuma, J.M.1; Vilardell Vilellas, F.2; Martí Laborda, R.M.1

1Dermatology, Hospital Universitari Arnau de Vilanova. Universitat de Lleida. Institut de Recerca Biomèdica de Lleida (IRBLleida), Lleida, Spain; 2Pathology, Hospital Universitari Arnau de Vilanova. Universitat de Lleida. Institut de Recerca Biomèdica de Lleida (IRBLleida), Lleida, Spain.

Introduction: CD30 + primary cutaneous lymphoproliferative disorders include anaplastic large cell lymphoma and lymphomatoid papulosis, both of T-cell origin. There are few described cases of CD30+ diffuse primary cutaneous large cell B-cell lymphomas (DLBCL).

Case report: A 46-year-old woman with a 20-year history of pruritic erythematoviolaceous plaques of 1 to >10cm located on the trunk. Some lesions resolved spontaneously in a few months and left hyperpigmented atrophic skin but new ones appeared at different locations. Development of tumoral lesions in the last 4 months on both healthy skin and previous plaques motivated the patient to search for medical advice. Histopathologic study of a tumor showed a dermal and subcutaneous dense and diffuse infiltrate of large cells. No epidermotropism was present. Immunohistochemical study showed CD30 +, CD20 +, CD79 +, Bcl2 +, Bcl6 +, MUM-1 +, ALK-, LMP-1-, KI67> 50%. A plaque biopsy revealed a less dense infiltrate in the dermis mixed with a small cell component, CD20 +, Bcl2 +, Bcl6 +, few CD30 + and MUM-1 + cells, LMP-1 -, KI67 < 50%. EBV PCR of both plaque and tumor were negative and IgH receptor analysis was clonal in both samples. Blood tests, thoracoabdominal CT scan and bone marrow biopsy were normal. The patient received 3 R-CHOP cycles with complete remission after 8 years of follow-up.

Discussion: DLBCL CD30 + usually appear in elderly as a solitary or small number of plaques or tumors at the same location. Some cases appear following the administration of methotrexate for rheumatoid arthritis and/or express EBV RNA. In contrast to extracutaneous types of DLBCL and leg-type DLBCL, CD30 + primary skin lesions appear to have a better prognosis. We present a DLBCL CD30 + case, given its exceptional nature and its prolonged course.

044 FLOWCYTOMETRY OF THE SKIN CAN BE A USEFUL DIAGNOSTIC TOOL FOR PRIMARY CUTANEOUS B-CELL LYMPHOMA AND CUTANEOUS B-CELL PSEUDOLYMPHOMA

Nakagawa, Y.1; Hamada, T.2; Takahashi, T.3; Morizane, S.1; Iwatsuki, K.3

1Dermatology, Okayama University Hospital, Okayama, Japan; 2Dermatology, Takamatsu Red Cross Hospital, Kagawa, Japan; 3Division of Medical Support, Okayama University Hospital, Okayama, Japan.

Introduction & Objectives: Cutaneous B-cell pseudolymphoma mimicks primary cutaneous B-cell lymphoma clinically and histologically, which is sometimes difficult to distinguish. They are diagnosed by the combination of clinical presentation, histology, immunohistochemistry, light chain restriction, and gene rearrangement. None of the single diagnostic methods is perfect. In our hospital, we perform the flowcytometry (FCM) of the skin infiltrates in cutaneous lymphoma and we investigated how skin FCM is useful as a diagnostic method for primary cutaneous B-cell lymphoma and cutaneous B-cell pseudolymphoma.

Materials & Methods: We reviewed the skin FCM of 19 primary cutaneous B-cell lymphoma patients and 7 cutaneous B-cell pseudolymphoma patients. We compared the result of FCM, especially light chain restriction, with the clinical course, the results of the histology, immunohistochemistry, immunoglobulin H (IGH) gene rearrangement and / in situ hybridization.

Results: None of the cutaneous B-cell pseudplymphoma patients showed light chainκ λ restriction (Specificity:100%). 14 out of 18 (Sensitivity:78%) of the primary cutaneous B-cell lymphoma patients showed light chain restriction. In the primary cutaneous B-cell lymphoma cases which didn’t show light chain restriction, the differentiation of the tumor cells and technical error were possible causes.

Conclusions: FCM of the skin is not a perfect diagnostic tool, but in the combination of the other present methods, it gives additional proof when distinguishing cutaneous B-cell pseudolymphoma from B-cell lymphoma.

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045 TWO PATIENTS WITH CUTANEOUS B-CELL TUMORS SHARING THE SAME MYD88 MUTATION WITH PREVIOUS SYSTEMIC DIFFUSE LARGE B-CELL LYMPHOMAS. DIVERGENT EVOLUTION?

Prieto Torres, L.1; Trascasa, A.2; Olmedilla, G.3; Ara Martín, M.1; Piris Pinilla, M.Á.2; Rodríguez Pinilla, S.M.2

1Dermatology, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain; 2Pathology, Fundación Jiménez Díaz, Madrid, Spain; 3Pathology, Hospital Universitario La Paz, Madrid, Spain.

There are rare published cases of paired hematological tumors in the same patient that may originate from divergent evolution of common precursor cells (CPC) through accumulation of distinct mutations. We present two cases of patients which have had two B-cell neoplasms, one primary cutaneous and one systemic, with the same MYD88 mutation but different IgH gene rearrangement, supporting this possible divergent evolution. The first patient was a 75-year-old man who had a testicular diffuse large-B-cell lymphoma in 2011 which was treated with R-CHOP achieving a complete remission. Seven years after the first tumor, he developed a primary cutaneous marginal zone B-cell lymphoma with the same MYD88 mutation but different IgH rearrangement from the first tumor. The second patient was a woman who had a central nervous system diffuse large B-cell lymphoma in 2005. After that she developed in 2019 a diffuse large B-cell lymphoma, ABC type in the back. Both tumors shared the same MYD88 mutation too, but differ in the IgH rearrangement. MYD88 is an essential adapter protein, which activates the NFkB pathway by interacting with the cytoplasmic portion of Toll-like receptors (TLR) and IL1R and activating downstream signaling components such as IRAK1 and IRAK4. Somatic mutations occurring later in these MYD88 mutated cells may bies the location of the tumor.

046 EPIDERMOTROPIC B-CELL LYMPHOMA. A PECULIAR HISTOPATHOLOGICAL SUBTYPE OFTEN ASSOCIATED WITH EXTRANODAL (SPLENIC) MARGINAL ZONE B-CELL LYMPHOMA

Rovira-López, R.1; Gallardo, F.1; Colomo Saperas, L.2; Pujol Vallverdú, R.M.1

1Dermatology, Hospital del Mar, Barcelona, Spain; 2Pathology, Hospital del Mar, Barcelona, Spain.

Primary and secondary cutaneous B-cell lymphomas can rarely show histologically intensely epidermotropic lymphoid infiltrates that can resemble those observed in mycosis fungoides and/or other CTCL.

An 84-year-old woman presented with a 3-months history of multiple erythematous papules and plaques on her trunk, abdomen, back and nipples. Past medical history was unremarkable and the rest of physical examination showed no additional features. Histopathological examination of an skin biopsy revealed a band-like dermal infiltrate with extension of atypical lymphocytes to the dermoepidermal junction showing epidermotropism. The infiltrate was composed predominantly of small- to-medium-sized lymphocytes showing monocytoid appearance, expressing B-cell markers CD20 and bcl-2, with negative CD10, CD23, bcl-6 and CD30. The accompanying T-lymphocytes consisted of mixed CD4+ and CD8+ forms with no loss of pan-T-cell antigens. B-cell clonality was detected. On work up, the patient showed mild splenomegaly, and peripheral blood, bone marrow and digestive tract involvement by a B-cell infiltrate with a clonal IgH peak. An extranodal marginal B-cell lymphoma with epidermotropic cutaneous involvement was diagnosed. Considering her history and absence of cytopenias or other symptoms, our patient has been followed up without splenectomy or other systemic therapy. Cutaneous lesions resolved without treatment.

Epidermotropic B-cell marginal zone lymphoma is an exceedingly rare nosological histological variant of cutaneous B-cell lymphomas. Previously reported cases seem to show distinctive and common clinical and histologic features. It has been mostly reported in elderly patients, and cutaneous lesions are usually the initial manifestation. Clinically they are characterized by multiple patches and/or with variable pruritus involving the trunk and proximal extremities. Cutaneous lesions are often associated with extranodal splenic and bone marrow involvement. The majority of cases of epidermotropic marginal zone lymphoma have an indolent clinical behavior and may therefore be managed conservatively.

047 PRIMARY CUTANEOUS MARGINAL ZONE B-CELL LYMPHOMA ASSOCIATED TO AMYLOID DEPOSIT

Saenz Aguirre, A.1; De la Torre Gomar, F.J.1; Rosés Gibert, P.1; Gimeno Castillo, J.1; Arrue Michelena, I.1; Martínez-González, M.I.1; Martínez De Lagrán Álvarez De Arcaya, Z.1; Caton Santaren, B.2; González-Pérez, R.1

1Dermatology Department, Hospital Universitario Araba, Vitoria, Spain; 2Pathology Department, Hospital Universitario Araba, Vitoria, Spain.

Introduction: Primary cutaneous marginal zone B-cell lymphoma (PCMZL) associated to amyloid deposit is a low-grade lymphoma, showing a pleomorphic infiltrate with abundant plasma cells and light-chain restriction.

Clinical case: A 80 year-old woman complained about an asymptomatic subcutaneous nodule on her wrist for 2 years, which had grown progressively. An ultrasound examination was performed showing a 5 mm hyperechoic rounded lesion with an hypoechoic center. A surgical excision was performed and the subsequent histological examination revealed a pseudonodular infiltrate composed of small lymphocites and abundant monotypic plasma cells with lambda light-chain restriction. There were extensive non-cellular areas corresponding to amyloid deposit as well. The lymphocitic aggregates showed positivity for CD79a and CD2O. IgH gene showed

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monoclonal rearrangement. Thus, PCMZL associated to amiloid deposit was diagnosed. A CT scan and a bone-marrow biopsy ruled out systemic lymphoproliferative disease. Systemic amyloidosis was ruled out as well. An exhaustive review of the previous history revealed that the patient had been evaluated 6 years before due to some erythematous nodules on the back which histologically had shown a dermal lymphoid infiltrate, composed of T an B lymphocites with a monoclonal IgH gene rearrangement. One year after the surgical removal of the lesion on the wrist, the patient remains asympthomatic, without clinical relapse.

Discussion: PCMZL constitutes aproximately 30% of primary cutaneous B cell lymphomas. Although the association between PCMZL and amyloid deposit is very unusual, some cases have already been reported. Furthermore, it has been proposed that these cases could represent a peculiar variant of PCMZL. In this particular case, we consider that the diagnosed was consistent with a PCMZL with amyloid deposit from the begining of the disease, being amyloid deposit a manifestation of a more advanced stage.

049 PRIMARY CUTANEOUS FOLLICLE CENTER LYMPHOMA (PCFCL) - DOES LOCATION MATTER? A CLINICAL AND HISTOLOGICAL COMPARISON BETWEEN SCALP INVOLVEMENT VERSUS OTHER SITES

Walker, C.J.1; Espinosa, M.L.1; Walton, K.E.2; Martinez-Escala, E.1; Amin, S.M.3; Guitart, J.1

1Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, United States; 2Department of Dermatology, Medical College of Wisconsin, Milwaukee, United States; 3Dermatopathology, Clin-Path Associates, Tempe, United States.

Introduction and Objectives: Primary cutaneous follicle center lymphoma (PCFCL) is a rare cutaneous B-cell lymphoma which commonly presents on the scalp and torso. Limited data is available on location dependent clinical course and histopathological features. Purpose of this study was to evaluate similarities and differences in clinical presentation and histological features of PCFCL manifestation on the scalp versus other body sites and to compare common PCFCL treatment modalities.

Material and Methods: Retrospective single-center chart review of PCFCL patients presented at our institution between 2006 and 2019.

Results: Sixty-nine PCFCL (50M, 19F) patients, median age fifty-six years (31- 88), with male overrepresentation (p<0.01) were identified. Most common sites of presentations were on the head and neck (74%; 51/69), especially the scalp (42/51). We compared scalp (42/69) versus other sites (27/69) of PCFCL manifestation. Androgenetic alopecia was more prevalent in the scalp PCFCL group (p<0.01). Clinical presentation was notably for lower T stages in the scalp group but overall similar clinical outcome. Local recurrence was very common (41%) and occurred more often, sooner and with high same site prevalence in the scalp group versus other sites involvement (46% vs. 33%; 24 vs. 51 months; 82% vs. 63%). Comparison of common treatment modalities for each group and TNM stage was performed. Highest local recurrence was seen after intralesional corticosteroid treatment (64%), lowest after radiotherapy (20%) (p<0.5). Most prevalent histopathological subtype was nodular (62%). Scalp group showed lesser histopathological subtypes variety (29% vs. 41%) and lower BCL-2 co-expression (10% vs. 32%, p<0.05).

Conclusions: PCFCL manifests with male predominance and high scalp involvement with significant concomitant androgenetic alopecia. Comparison between scalp and other sites manifestations showed similar indolent course but differences in recurrence, treatment and histological features. Radiotherapy was associated with less recurrence.

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PRIMARY CUTANEOUS LYMPHOMA, CLINICAL & PATHOLOGICAL - UNCOMMON PRIMARY CUTANEOUS LYMPHOMAS

050 A CASE OF AN EPSTEIN-BARR VIRUS-POSITIVE MUCOCUTANEOUS ULCER IN A PATIENT TREATED WITH ABATACEPT

Aranguren-López, I.1; Arregui-Murua, M.A.1; Silva-Carmona, M.Y.2; Zeberio-Etxetxipia, I.3; López-Pestaña, A.1; Bengoechea-Nerecan, E.3; Zubizarreta-Salvador, J.1

1Dermatology, Hospital Donostia, San Sebastián, Spain; 2Pathology, Hospital Donostia, San Sebastián, Spain; 3Hematology, Hospital Donostia, San Sebastián, Spain.

Epstein-Barr Virus-positive mucocutaneous ulcer (EBVMCU) is an uncommon lymphoproliferative disorder (LPD) firstly described in 2010 and recently included as a distinct entity by the World Health Organization. It is considered the benign end of a spectrum of EBV- associated LPDs, caused by a disbalance in host-virus homeostasis. Lesions occur in oral mucosa, and more uncommonly in skin and gastrointestinal tract; they affect immunosuppressed patients, most of them under immunosuppressive agents. We present a case of EBVMCU in skin related to immunosuppression with abatacept. A 79-year-old woman, with rheumatoid arthritis in treatment with abatacept for 3 years, presented with a 6-month history of an asymptomatic ulcer on her left scapular region. Physical examination showed a 3cm-diameter shallow ulcer, with well-defined elevated borders and a central crust. The rest of the physical examination was normal. Due to clinical suspect of nonmelanoma skin cancer, the lesion was surgically excised. Histopathological analysis showed an extensive epidermal ulceration, as well as a dense nodular infiltrate in dermis, composed of medium to large atypical lymphocytes and scarce Hodgkin-like cells, surrounded by a polymorphous inflammatory background with predominance of CD8+ T-cells. Large atypical lymphocytes were positive for CD30, CD79, CD20, PAX5, OCT2 and MUM1, with variable expression of CD15 and BCL- 6. Immunostaining for CD3, CD5, CD10, CD56 and ALK was negative. Extensive immunohistochemical positivity for EBV was observed. Gene rearrangement was positive for TCR and negative for IgH. PET-CT scan and bone marrow biopsy ruled out systemic disease. All these findings led to the diagnosis of EBVMCU. Abatacept was discontinued. No relapse has been observed during 7-month follow-up. We present a case of a cutaneous EBVMCU with no mucosal involvement that did not recur after withdrawal of abatacept, a fusion protein widely used for rheumatoid arthritis and not previously reported to be involved in the development of EBVMCU.

051 PRIMARY CUTANEOUS GAMMA-DELTA T CELL LYMPHOMA, A POTENTIAL MIMICKER OF LUPUS ERYTHEMATOSUS PANNICULITIS: A CASE REPORT

De la Torre Gomar, F.J.1; Roses Gibert, P.1; Sáenz Aguirre, A.1; Gimeno Castillo, J.1; Arrue Michelena, I.1; Sagasta Lacalle, A.2; Martínez De Lagrán Álvarez De Arcaya, Z.1; Goula Fernández, S.1; Urtaran Ibarzábal, A.1; González Pérez, R.1

1Dermatology Department, Araba University Hospital, Vitoria, Spain; 2Pathological Anatomy Department, Araba University Hospital, Vitoria, Spain.

Introduction: Primary cutaneous gamma-delta T cell lymphoma (PCGD-TCL) is a rare and aggressive entity that accounts for less than 1% of all skin lymphomas.

Clinical case: A 62-year-old female presented with an erythematous nodule on the front thigh for two months. Histopathological examination showed a predominantly septal panniculitis. During the following months the patient developed new lesions located at both thighs, hips and abdomen; which became ulcerated. A new biopsy was performed, showing a predominantly lobar panniculitis with interface dermatitis and mucin deposits, so lupus erythematosus panniculitis (LEP) was suggested. During the next nine months, some new ulcerated and necrotic plaques developed on the left thigh. Overall status worsened, and fever and pancytopenia were detected. Computed tomography revealed splenomegaly, which lead to a bone marrow biopsy, not showing any evidence of malignancy. Examination of a new cutaneous biopsy revealed an atypical T cell lymphoid proliferation, with positivity for CD2, CD3, CD56, granzyme B and gamma TCR with loss of CD4, CD5, CD7 and CD8. These findings are in keeping with PCGD-TCL. The patient was sent to the Hematology Department, who started a pretransplant chemotherapy based on hematopoietic precursors. The patient succumbed to the disease a few days later.

Discussion: PCGD-TCL represents an aggressive and infrequent variant of skin lymphomas. Its clinical manifestations are variable, being the most common form the plaques or nodules that tends to ulcerate, mainly located in limbs. They respond poorly to conventional treatments and have an average survival of 15 months. We present a case of a 63-year-old woman with a first biopsy resembling LEP, which aggressive clinical course and whose further biopsies led to a final diagnosis of PCGD-TCL. This entity needs to be carefully excluded in any worrisome-looking panniculitic lesion and multiple biopsies can be required to obtain the correct diagnosis.

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052 EPSTEIN-BARR VIRUS POSITIVE MUCOCUTANEOUS ULCER ACCOMPANIED WITH B-CHRONIC LYMPHOCYTIC LEUKEMIA

Fujii, K.; Hatanaka, M.; Higashi, Y.; Kanekura, T.

Dermatology, Kagoshima University, Kagoshima, Japan.

A 77-year-old Japanese man with a history of an ulcer at the angle of his mouth since one month was referred to our clinic. He had been diagnosed with chronic lymphocytic leukemia (CLL) five years ago, with no consultation in the past three years and had not received immunosuppressive therapies. Upon physical examination, a one-centimeter indurated erythemic nodule with ulceration at the right angle of the mouth was observed. No mucosal ulcer was observed in the oral cavity, with absence of any swollen nodes in the neck. White blood cell count was determined to be 430,600/μL with 99% abnormal lymphoid cells with B-cell phenotype (CD20-, CD5-, CD22-, CD23-, CD19-, and CD38-positive) and 1% neutrophils. Flow cytometric analysis showed normal lymphocyte (CD3-positive) count to be less than 1% in the peripheral blood. Red blood cell count was decreased to 2.18 × 106/μL and hemoglobin was 7.4 g/dL. A biopsy specimen of the tumor tissue showed dense infiltration of lymphoid, plasmacytoid, and large abnormal lymphoid cells, suggestive of malignant lymphoma. The infiltrating large cells expressed CD20, CD79a, CD30, and EBV-encoded RNA. In addition, many small CD3- positive and CD3 negative cells were present in the peripheral blood. Small cells were positive for CD4 or CD8, and TIA-1-positive cells were also observed. Computed tomography scan showed mediastinal and paraaortic lymphadenopathy and hepatosplenomegaly, which are associated with CLL. Later, liver and bone marrow biopsies were performed, and CLL invasion was proved pathologically. The presence of Epstein–Barr virus-positive mucocutaneous ulcer (EMU) was observed in the cutaneous lesion. CLL was designated as Rai Stage III and treatment with oral prednisolone (10 mg/day) and cyclophosphamide (50 mg/day) was prescribed. The EMU lesion completely disappeared within two weeks after starting the treatment; however, CLL did not show any improvement for more than a year.

053 MONOMORPHIC EPITHELIOTROPIC INTESTINAL ΓΔ T-CELL LYMPHOMA WITH SECONDARY CUTANEOUS INVOLVEMENT. A DIAGNOSTIC CHALLENGE

Gallardo, F.1; Olmos, F.1; Vazquez, I.2; Papaleo, N.2; Colomo, L.2; Pujol, R.M.1

1Dermatology, Hospital del Mar, Barcelona, Spain; 2Pathology, Hospital del Mar, Barcelona, Spain.

Introduction. Monomorphic epitheliotropic intestinal T-cell lymphoma is a rare and aggressive peripheral T-cell lymphoma that often presents in adults with gastrointestinal symptoms. Skin involvement has rarely been reported (< 5%). In very rare instances cutaneous lesions can be the first manifestation of the disease and in the absence of gastrointestinal symptoms, the definite diagnosis could represent a diagnostic challenge.

Case Report: A 45 year-old woman, with past-history of right breast adenocarcinoma was referred for evaluation of a left breast nodule detected in a control mammography. An ultrasound-guided needle biopsy showed a dense dermal/subcutaneous infiltration of atypical lymphocytes, sparing the upper dermis and distributed around isolated adipocytes. Neoplastic cells were CD3+/CD5-/C4-/CD8+/TIA1/ CD30-/EBV-. A PET-TC scan demonstrated an intense hypermetabolic lesion on the left breast and a consolidative lesion in inferior left pulmonary lobule. Peripheral blood clonality/immunophenotype and bone marrow biopsy were normal. Subcutaneous panniculitis-like T-cell lymphoma was suspected. A biopsy of the breast nodule showed similar histopathological and immunohistochemical features. ßF1 was negative, rising up the possibility of a cutaneous T-cell lymphoma. Despite treatments with CHOP and SMILE, a disease progression was detected with jejunum perforation. Jejunum histopathology showed mucosal atypical lymphoid infiltration with a similar immunohistochemistry profile. Multiple plaques developedγδ on the trunk, with a dense lichenoid atypical lymphocytic infiltrate with intense epidermotropism. Taking into account the clinicopathological/immunophenotypical/evolutive features the final diagnosis of epitheliotropic intestinal T-cell lymphoma with secondary cutaneous involvement was established.

Conclusions: This case highlightsγδ the overlapping clinico-pathological and immunophenotypical features of cutaneous cytotoxic lymphomas. In this particular case, different possible diagnoses were considered and the clinical evolution allowed establishing the final diagnosis. Taking into consideration the lung-bowel-skin tropism of T-cells, it is of paramount importance to rule out systemic origin in those cases of T-cell lymphomas presenting initially in the skin. γδ γδ 054 EPSTEIN-BARR VIRUS-ASSOCIATED PLASMABLASTIC LYMPHOMA

Jost, M.1; Oschlies, I.2; Wehkamp, U.1

1Dermatology, UKSH Kiel, Kiel, Germany; 2Institute of Pathology, Hematopathology Section, UKSH Kiel, Kiel, Germany.

We present a 79-year old, human immunodeficiency virus (HIV)-negative patient who came to our department in January 2019. Erythematous nodules had developed since September 2018 on his left leg. The medical history of the patient included a heart-transplantation 20 years ago and a recently diagnosed non-small cell lung cancer. Due to the heart-transplantation, he was on long term immunosuppressants (cyclosporine and everolimus). A biopsy of the skin revealed the diagnosis of an Epstein-Barr virus associated plasmablastic lymphoma (PBL). A PET/CT scan showed two thoracic lymph nodes with metabolic activity; 1.4% atypical lymphocytes were found in the blood with an immuno- phenotype identical to skin. There was no visceral involvement. Because of the reduced general condition of the patient, the tumor board decided for the application of rituximab in combination with local radiotherapy of the leg (30 Gy). This treatment induced complete remission of the skin lesions. Unfortunately, the patient passed away three months after the last treatment; the cause of death was unknown. PBL is a rare form of diffuse large B-cell non-Hodgkin’s lymphoma. It primarily affects HIV-positive patients (70%) but can arise in otherwise immunocompromised patients such as transplant recipients (10%) exemplified in our case, as well as in rare cases of immunocompetent individuals. The most commonly affected site is the oral cavity. Extra-oral PBL is more common in HIV-negative patients.

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The diagnosis can be challenging, because of an undifferentiated cytomorphology and negativity for classical B-cell markers, potentially leading to misdiagnosis, e.g., melanoma or other primary skin tumors. Treatment recommendations include combination chemotherapy, regimens with bortezomib and early consideration of stem cell transplantation. Other and additional options include excision, radiotherapy, antiretroviral/antiviral therapy in case of HIV-infection, and if applicable and possible reduction of immunosuppressive medication. PBL is prone to an early disease dissemination resulting in most cases in fatal outcomes.

055 POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDER MANIFESTING AS A SOLITARY ERYTHEMATOUS INDURATED PLAQUE ON THE LEG

Lopez-Lerma, I.1; Ferrer, B.2; Castellvi, J.2; Garcia-Patos, V.1

1Dermatology, Hospital Universitari Vall d´Hebrón, Barcelona, Spain; 2Pathology, Hospital Universitari Vall d´Hebrón, Barcelona, Spain.

A 60-year-old female with a history of a second renal transplant presented with an asymptomatic skin lesion on the right leg. Clinical, histological and staging findings were consistent with post-transplant lymphoproliferative disorder (Epstein-Barr virus-positive diffuse large B-cell lymphoma) without systemic involvement. Post-transplant lymphoproliferative disorder (PTLD) is an uncommon complication after solid-organ transplants and hematopoietic stem cell transplants. PTLD are a heterogeneous spectrum of predominantly B‐cell disorders, often extra‐nodal, and variable clinical presentations determined by pathologic subtype. Isolated involvement of the skin without systemic involvement in PTLD is rare. WHO pathology classification of a tissue biopsy remains the gold standard for PTLD diagnosis. Primary cutaneous PTLD is generally categorized as either cutaneous T-cell lymphoma or cutaneous B-cell lymphoma, with variable Epstein-Barr virus positivity. Current diagnostic and therapeutic approaches will be discussed. This case underscores the importance of collaboration between dermatology, dermatopathology and hematopathology in order to diagnose these challenging cases.

056 PRIMARY CUTANEOUS CD4+ SMALL‐TO MEDIUM‐SIZED T‐CELL LYMPHOPROLIFERATIVE DISORDER: CLINICAL, HISTOPATHOLOGICAL FEATURES AND FOLLOW-UP IN 9 PATIENTS

Rosell-Diaz, A.M.1; Nieto-Benito, L.M.1; Mateos-Mayo, A.1; Sanchez-Herrero, A.1; Rodriguez-Lomba, E.1; Parra-Blanco, V.2; Campos-Domínguez, M.1; Pulido-Perez, A.1

1Dermatology, Hospital General Universitario Gregorio Marañón, Madrid, Spain; 2Pathology, Hospital General Universitario Gregorio Marañón, Madrid, Spain.

Introduction: Primary cutaneous small/medium CD4T-cell lymphoma (PCSM-TCL) , now known as primary cutaneous CD4+ small‐to medium‐sized T‐cell lymphoproliferative disorder (PCSM-LPD), is a rare and benign T-cell proliferation not fully understood nowadays. Materials and Methods A retrospective study of patients diagnosed with PCSM‐TCL or PCSM-LPD from 2011 to 2019 was conducted at our center.

Results: Nine patients were included in the study: seven women and two men. Most of them were adults (8/9) with a median age of 49 years (5-74); none had personal or familiar history of cancer. Six patients presented with a single lesion frequently localized in head and neck area; two of them had multifocal lesions on the limbs. No patients showed extracutaneous disease at any evaluation. Three patients were treated with local radiation (one with previous excision) and one patient was treated with intralesional steroids. Three patients presented spontaneous remission after biopsy. The treatment was successful in all cases. Follow-up data were available for eight patients (mean follow-up time: 27 months), all of them were alive without evidence of skin recurrence or extracutaneous disease. Histopathologic features were characterized by infiltrates of small- to medium-sized pleomorphic T lymphocytes localized in dermis. One case presented focal epidermotropism. Immunohistochemistry showed positivity for CD4. Partial loss of CD7 was detected in two cases and CD8 positive cells were found in two biopsies. Seven samples were PD1 positive. All were CD30 negative. Ki67 index was variable (10-60%).

Conclusions: Our results, similar to those described in the literature, show the favourable behaviour of this entity. Although it is highly uncertain if they represent a frank malignancy, integration of histologic, immunophenotypic, imaging and clinical data remain essential for an accurate diagnosis.

057 CUTANEOUS LYMPHOPROLIFERATIVE DISORDER OF SMALL AND MEDIUM-SIZED CD4 POSITIVE T CELL- A CASE SERIES OF 3 PATIENTS

Rosés Gibert, P.1; De la Torre Gomar, F.J.1; Saenz Aguirre, A.1; Gimeno Castillo, J.1; Heras González, S.1; Fatsini Blanch, V.1; Martínez-Aracil, A.P.2; Martínez De Lagrán Álvarez De Arcaya, Z.1; González Pérez, R.1

1Dermatology, Hospital Universitario Araba, Vitoria-Gasteiz, Spain; 2Dermatopathology, Hospital Universitario Araba, Vitoria-Gasteiz, Spain.

Clinical case: A 49-year-old woman consulted for an 8mm erythematous papule in the left side of the preauricular region which had been initially treated with topical antibiotic by her primary care physician without any improvement. A biopsy-excision was performed whose dermatopathology report revealed a dermal and follicular epithelial occupation by a polymorphic population consisting of cells of varying sizes, predominantly small cells and occasional eosinophils. Given the clinicopathological findings, we diagnosed the patient with primary cutaneous small and medium CD4 positive T-cell lymphoproliferative disorder. An extension study was conducted which showed no metastatic disease.

100 POSTER PRESENTATIONS

Discussion: In the classification of cutaneous lymphomas of the World Health Organization European Organization for Research and Treatment of Cancer (WHO-EORTC) of 2005 and 2008, primary cutaneous T lymphoma of small and medium cells was included as a provisional entity within cutaneous T-cell lymphomas. In the WHO-EORTC classification of 2018, the use of the term primary cutaneous lymphoproliferative disorder of small and medium CD4 positive T cells is recommended due to its clinical-pathological and evolutionary similarity with pseudolymphomas and its uncertain malignant potential. It is an infrequent entity, generally indolent and limited to the skin, which usually presents as a single lesion on the face, neck or upper trunk region. Patients with localized disease are usually treated locally with surgical excision, topical or intralesional corticosteroids or radiotherapy with an excellent prognosis. Data suggests that multifocal forms could have a more aggressive clinical course. We present the case of a primary cutaneous T lymphoproliferative disorder of small and medium-sized CD4 positive cell presented as a single lesion which had a favorable clinical evolution after surgical excision.

058 COMPLETE REMISSION OF AGGRESSIVE EPIDERMOTROPIC CD8+ T-CELL LYMPHOMA AFTER TOTAL SKIN ELECTRON BEAM THERAPY. AN INDOLENT SUBTYPE, DIAGNOSTIC FAILURE OR TOO EARLY DECLARATION OF RECOVERY?

Szakonyi, J.1; Vízkeleti, J.2; Csomor, J.3; Szepesi, Á.3; Marschalkó, M.1

1Department of Dermatology, Venereology and Dermatooncology, Semmelweis University, Budapest, Hungary; 2Center of Radiotherapy, National Institute of Oncology, Budapest, Hungary; 31st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.

Primary cutaneous agressive epidermotropic CD8+ T-cell lymphoma (PCAETCL) is a rare etitiy with a very unfavorable prognosis. Clinical picture is dominated by rapidly evolving papules, frequently anular plaques and tumors. The histological diagnosis is based on the epidermotropic infiltrate of cytotoxic T-cells with dermal infiltrate consisting of atypical cells of different size. Once diagnosis is established, allogenic stem cell transplantation is the only potentially curative therapeutic option. Interferon and PUVA are contraindicated. We present the case of a 67-year-old man with extended, anular, partially ulcerating plaques. Although PCAECTCL was diagnosed, ASCT was contraindicated because of his age and comorbidities (metabolic syndrome). As systemic involment could not be detected, and the performance status of the patient was good, we decided to give total skin electron beam (TSEB) therapy. The patient received 32 Gy radiation with acceptable side effects. The patient got in complete remission, and no relapse was observed during the 6 months of follow up.

059 TWO CASES OF CYCLOSPORIN-REFRACTORY SUBCUTANEOUS PANNICULITIS-LIKE T-CELL LYMPHOMA

Szakonyi, J.1; Nagy, Z.2; Demeter, J.2; Csomor, J.3; Szepesi, Á.3; Marschalkó, M.1

1Department of Dermatology, Venereology and Dermatooncology, Semmelweis University, Budapest, Hungary; 21st Department of Medicine, Semmelweis University, Budapest, Hungary; 31st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.

Subcutaneous panniculitis-like T-cell lymphoma (SPLTCL) is an uncommon lymphoproloferative disorder, which can mimic lupus panniculitis and is often associated with autoimmune conditions. This strange relationship with autoimmunity is manifested also in the fact that SPLTCL can usually be efficiently treated with immunosuppressants. We present two of our SPTCL cases where immunmodulatory drugs as cyclosporin and methotrexate alone or in combination with corticosteroid failed to control the disease and prevent progression. Our first case is a 61-year-old man who had been suffering from a painful subcutaneous infiltration for a yaer. The diagnosis was established by histopathology (CD8+/granzyme P + cutaneous-subcutaneous T-cell infiltration). Staging examinations ruled out systemic disease and so cyclosporin therapy was launched. Because of progression, methotrexate, and later an elevated dose of cyclosporin with drug monitoring combined with corticosteroid was tried without significant effect. The patient was referred to the hematology department where CHOEP polychemoterapy was started. After the 4th cycle the patient got to complete clinical and metabolic remission. The second patient is a 55-year-old man presenting with a two-year history of erythematosus plaques with a two-year history. First histology supected lupus erythematosus profundus, but the analysis of the second sample showed monoclonal CD8+, CD56+ infiltration with granzyme B1 phenotype. Cyclosporin was ineffective, methylprednisolon was not tolerated. PET-CT scan and bone marrow biopsy showed no systemic involvement. Systemic chemotherapy has not been started at the moment.

101 POSTER PRESENTATIONS

BASIC RESEARCH - ETIOLOGY AND PATHOMECHANISMS - GENOMICS, GENETICS AND EPIGENETICS

060 ABNORMAL DNA METHYLATION GRADIENTS IN MYCOSIS FUNGOIDES AND SÉZARY SYNDROME

Moerman-Herzog, A.1; Rahmatallah, Y.2; Glazko, G.2; Wong, H.K.1

1Dermatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States; 2Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States.

Introduction & objectives: Genetic studies on mycosis fungoides (MF) and Sézary syndrome (SS) have identified abundant mutations affecting genes in T cell signaling and growth pathways important to neoplastic transformation, yet no distinct mutation signature nor specific gene has been validated as a reliable and reproducible biomarker of MF/SS. We have identified highly expressed genes in SS compared to normal donors by microarray studies, including PLS3, FCRL3 and TIGIT. The mechanism of altered gene expression is unknown, and we hypothesize that epigenetic mechanisms play a critical role. We propose to analyze DNA methylation to assess changes in methylation in MF/SS.

Materials & methods: Genome-wide DNA methylation of T cells from SS blood, MF blood and MF tumor were analyzed by Illumina Methyl Epic (850K) beadchips. Findings from MF/SS cases were compared to normal donors and psoriasis disease controls.

Results: In SS blood and MF tumor specimens, SS biomarker genes including PLS3, FCRL3 and TIGIT, were more hypomethylated than in MF blood, psoriasis blood and normal blood. SS showed more hypomethylation than MF tumor.

Conclusions: The DNA methylation changes in MF and SS show a gradient of abnormal DNA methylation where correlation of hypomethylation is related to clinical stage. Assessing the degree of DNA hypomethylation of SS biomarker genes may be a valuable criterion to better understand changes in epigenetics in the development of CTCL.

BASIC RESEARCH - ETIOLOGY AND PATHOMECHANISMS - MOLECULAR PATHWAYS

061 WORSENING OF MYCOSIS FUNGOIDES AFTER IMMUNOTHERAPY WITH IPILIMUMAB AND NIVOLUMAB

Jeroen, P.1; Annemie, R.2; Vasiliki, S.3; An, B.1

1Dermatology, Antwerp University Hospital, Antwerp, Belgium; 2Oncology, GasthuisZusters Antwerpen, Antwerp, Belgium; 3Anatomopathology, Antwerp University Hospital, Antwerp, Belgium.

Case report: In 2015 a 62-year-old male was diagnosed with uveal melanoma for which he received treatment with iodine-125 brachytherapy and an endoresection of the choroidal melanoma. In 2017 he developed a generalized, mildly itchy, erythrosquamous rash. Lesional biopsies showed mycosis fungoides (MF). A few months later, metastases of the uveal melanoma were found in his liver and an immunotherapy with ipilimumab and nivolumab was started. He presented at our clinic for the treatment of MF and reported flare-ups of the MF always one week after immunotherapy. His skin looked very inflammatory and a drug eruption was suspected. A biopsy ruled this differential diagnosis out and confirmed the diagnosis of MF. A treatment with a topical corticosteroid was initiated, with little to no improvement and the man died in 2018 as a result of the metastasized uveal melanoma.

Discussion: CTLA-4 and PD-1 seem to be linked with MF. CTLA-4 is a member of the costimulatory family of molecules for T cells that plays an important role in immunoregulation and its function is to inhibit T-cell activation and proliferation. CTLA-4 expression is increased in MF, with a correlation between higher expression of CTLA-4 and a higher grade of MF. The PD-1 pathway is an immune checkpoint to attenuate T-cell-mediated immune responses and may be exploited by tumors to avoid immune surveillance. PD-1 is frequently expressed at the early, patch and plaque stages of cutaneous T cell lymphoma. Therefore, the aggravation of MF our patient experienced one week after treatment with ipilimumab (anti-CTLA-4 agent) and nivolumab (anti-PD-1 agent) seems to be counterintuitive. In literature we found one case report where a patient achieved complete remission of cutaneous MF during ipilimumab treatment. A phase Ib study described an objective response rate of 15% among patients with MF who received nivolumab.

102 POSTER PRESENTATIONS

BASIC RESEARCH - ETIOLOGY AND PATHOMECHANISMS - IMMUNOLOGY, HOST RESPONSE AND TUMOR MICROENVIRONMENT

062 ANTIBIOTICS INHIBIT TUMOR AND DISEASE ACTIVITY IN CUTANEOUS T CELL LYMPHOMA

Lindahl, L.M.1; Willerslew-Olsen, A.2; Gjerdrum, L.M.R.3; Becker, J.C.4; Blümel, E.2; Herpers, B.5; Johansen, C.6; Buus, T.B.2; Krejsgaard, T.2; Givskov, M.2; Kilian, M.6; Woetmann, A.2; Litman, T.2; Iversen, L.1; Ødum, N.2

1Aarhus University Hospital, Aarhus, Denmark; 2University of Copenhagen, Copenhagen, Denmark; 3Zealand University Hospital, Roskilde, Denmark; 4University Hospital of Essen, Essen, Germany; 5Regional Public Health Laboratory Kennemerland, Haarlem, Netherlands; 6Aarhus University, Aarhus, Denmark.

It has been proposed that CD4 T cell responses to Staphylococcus aureus (SA) can inadvertently enhance neoplastic progression in models of skin cancer and cutaneous T cell lymphoma (CTCL). In this prospective study, we explored the effect of transient antibiotic treatment on tumor cells and disease activity in eight patients with advanced stage CTCL. All patients experienced significant decrease in clinical symptoms in response to aggressive, transient antibiotic treatment. In some patients, clinical improvements lasted for more than 8 months. In six out of eight patients, a malignant T cell clone could be identified in lesional skin, and a significant decrease in the fraction of malignant T cells was observed following antibiotics but an otherwise unchanged treatment regimen. Immunohistochemistry, global mRNA expression, and cell-signaling pathway analysis indicated that transient aggressive antibiotic therapy was associated with decreased expression of IL-2 high-affinity receptors (CD25), STAT3 signaling, and cell proliferation in lesional skin. In conclusion, this study provides novel evidence suggesting that aggressive antibiotic treatment inhibits malignant T cells in lesional skin. Thus, we provide a novel rationale for treatment of SA in advanced CTCL.

063 CHARACTERIZING THE MACROPHAGES INVOLVED IN GRANULOMATOUS SLACK SKIN

Cury-Martins, J.1; Wehkamp, U.2; Assaf, C.3; Abrantes Giannotti, M.4; Miyashiro, D.1; Miotto, I.1; Nacagami Sotto, M.4; Pereira, J.5; Sanches, J.A.1

1Dermatology, University of Sao Paulo, Sao Paulo, Brazil; 2Dermatology and Allergology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany; 3Dermatology and Venerology, HELIOS Klinikum Krefeld - Academic Teaching Hospital of the University of Aachen, Krefeld, Germany; 4Pathology, University of Sao Paulo, Sao Paulo, Brazil; 5Hematology, University of Sao Paulo, Sao Paulo, Brazil.

Introduction & objectives: Granulomatous slack skin (GSS) is the rarest variant of MF, with around 50 cases registered worldwide. Its behavior is extremely indolent but it is associated with an increased risk of other potentially aggressive systemic lymphomas in about 30% of cases. Macrophages in solid tumors, also called tumor associated macrophages (TAMs) are thought to create a tumor promoting environment by multiple mechanisms. One of their major functions seems to be a suppression of the T-cell mediated immune response via PD-L1 expression. The typical characteristics in GSS are granulomatous, histiocytic infiltrates which have not yet been characterized in detail and might potentially contribute to a pro-tumorigenic environment. Therefore, the aim of this study is to better characterize these histiocytes.

Methods: retrospective analysis of skin biopsy samples of 12 GSS cases of one institution in Brazil and two in Germany, with additional staining for CD163, an M2 macrophage marker. CD163 staining will also be evaluated in classical MF cases for comparison.

Results: Twelve patients were included. CD163 was rated as percentage of positivity A)on the total dermal infiltrate (%TDI) and B)on the histiocytoid cells (%HC). Analysis are still ongoing but on the eight GSS cases already evaluated, %TDI was 40% in four cases, 60% in two, 80% in one and >90% in one; %HC was >90% in six cases and of 50% in two.

Conclusion: Preliminary results suggest that GSS associated macrophages are predominantly M2, same profile suggested for TAMs. Since TAMs are usually considered “protumoral macrophages” and are usually related to a worse prognosis, and opposed to that, GSS in considered an indolent disease, the exact role of those GSS related M2 macrophages still need to be better clarified, with one important question to be answered: do TAMs play a role in GSS?

103 POSTER PRESENTATIONS

TRANSLATIONAL AND CLINICAL RESEARCH - BIOMARKERS & PATHOGENESIS

064 DIAGNOSTIC IMPACT OF CIRCULATING MICRORNAS IN CUTANEOUS T-CELL LYMPHOMA

Papadaki, M.1; Saraki, K.1; Piperi, C.2; Damoraki, G.3; Koufargyris, P.3; Papadavid, E.1

1Investigative Dermatology, National and Kapodistrian University of Athens, Attikon hospital, Athens, Greece; 2Biological Chemistry, National and Kapodistrian University of Athens, Medical School, Athens, Greece; 3Department of Internal Medicine, National and Kapodistrian University of Athens, Attikon hospital, Athens, Greece.

Introduction & Objectives: The diagnosis of early stage Mycosis Fungoides (MF) can be very challenging because clinicopathologic findings overlap with various reactive and inflammatory dermatoses. Liquid biopsy may be a promising non-invasive technique for diagnosis. There are important studies on prognostic and diagnostic significance of microRNAs in MF skin lesions; however the use of liquid biopsy has not been properly investigated in the diagnosis of CTCL. Our aim was to investigate whether the peripheral blood microRNAs can act as diagnostic biomarkers to differentiate inflammatory diseases from early MF.

Materials & Methods: Serum samples were analysed for microRNAs expression by specifically-primed qRT-PCR from 10 patients with early stage of MF (7 of them in stage IA and 3 in stage IB) compared to 4 psoriasis and 4 atopic dermatitis patients. We validated our findings in serum samples form 4 patients from the lymphoma clinic with histologically proved dermatitis. We have used a panel of microRNAs (miR-148a, miR-338-3p, miR-26a, miR-146a, miR-451) based on bioinformatic analysis and literature and compared their expression with clinicopathological findings. microRNAs detection was further validated in early and advanced stage CTCL cell lines.

Results: We have shown that miR-148a, miR-338-3p, miR-26a, miR-146a were upregulated in early MF patients and cell lines. miR-451 reported to play a critical role in the progression of other hematologic malignancies, was found overexpressed in MF. According to our early results, miR-146a and miR-26a were the most overexpressed miRNAs in MF patients suggesting that could be promising diagnostic biomarkers and we further validated their expression in CTCL cell lines.

Conclusions: Liquid biopsy method has shown the upregulation of specific microRNAs in early stage MF, presenting a useful non- invasive technique for differential diagnosis between early MF and inflammatory skin diseases.

065 TOX-1 EXPRESSION IN MYCOSIS FUNGOIDES

Pileri, A.1; Bertuzzi, C.2; Roncador, G.3; Sabattini, E.2; Guglielmo, A.1; Patrizi, A.1; Agostinelli, C.2

1Dermatology Unit, Department of Experimental, Diagnostic and Specialty Medicine, Bologna University, Bologna, Italy; 2Haematopathology Unit, Department of Experimental, Diagnostic and Specialty Medicine, Bologna University, Bologna, Italy; 3Centro National de Investigaciones Oncologicas, Centro National de Investigaciones Oncologicas, Madrid, Spain.

Background: Early mycosis fungoides (MF) diagnosis can be difficult and most of the patients experience a delay. Thus, EORTC/CLTF have proposed an algorithm based on clinic-pathologic criteria and the absence of pan-T cell marker (i.e. CD2, CD5 or CD7) as well. However, no positive marker expression at immunohistochemistry (IHC) has been proposed. TOX is involved in T-cell differentiation of immature T-cells in thymus and usually silenced in mature T-cells. Recent studies have shown that TOX is overexpressed in MF cells and may be regarded as a marker of worse prognosis. Contrasting results on TOX stage-related both at gene level and at IHC have been reported. The aim of our preliminary study is to analyse whether TOX-1 expression may be a reliable marker to distinguish early MF form reactive conditions.

Materials and Methods: MF patients in different stage and reactive conditions were selected from our database. TOX expression in all cases was evaluated at high power field. The number of positive cells was scored as follow: 1 (+ < 10% of positive cells) 2 (10-50%), 3 (>50%). T Mann-Whitney U and ANOVA tests were performed to analyse differences between MF and reactive cases.

Results: Ten MF patients and 10 reactive conditions were retrieved. Statistical analysis showed a significant difference at Mann-Whitney U Test (U-value 21, p-value <0.5).

Conclusions: Our preliminary data corroborate what previously reported in the literature on TOX expression in MF. We can hypothesise whether TOX may be helpful in early MF diagnosis. Further investigations on TOX expression in different stages as well as on prognosis are warranted.

104 POSTER PRESENTATIONS

TRANSLATIONAL AND CLINICAL RESEARCH - NEW TARGETS IN THE TREATMENT OF CUTANEOUS LYMPHOMAS

066 THROMBOSPONDIN-1 PROMOTES TUMOR PROGRESSION IN CUTANEOUS T-CELL LYMPHOMA VIA CD47

Kamijo, H.1; Miyagaki, T.2; Takahashi-Shishido, N.3; Nakajima, R.1; Oka, T.1; Suga, H.1; Sugaya, M.3; Sato, S.1

1Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan; 2Department of Dermatology, St. Marianna University School of Medicine, Kanagawa, Japan; 3Department of Dermatology, International University of Health and Welfare, Chiba, Japan.

Introduction & Objectives: CD47, which is highly expressed on various hematopoietic malignancies, enables cancer cells to avoid immunosurveillance by sending “do not eat me” signal to phagocytotic cells through SIRP , suggesting that blocking CD47/SIRP interactions should be potentially an effective method of cancer therapy. Thromobospondin-1 (TSP-1), a multifunctional protein, is another ligand for CD47 and CD47/TSP-1 interactions promote tumor progression in various malignancies.α In this study, we investigatedα roles of TSP-1 and CD47 in cutaneous T-cell lymphoma (CTCL).

Materials & Methods: Skin samples were collected from 47 cases of CTCL as well as 20 healthy controls. Peripheral blood mononuclear cells were obtained from 7 patients with Sézary syndrome and 6 healthy controls. CD47 and TSP-1 expression in lesional skin of CTCL or CTCL cells were examined by immunohistochemistry, quantitative RT-PCR, and flow cytometry. The effects of CD47/TSP-1 interactions on CTCL cell lines (Hut78, HH, and MyLa cells) were investigated using anti-CD47/anti-TSP-1 neutralizing antibody, recombinant TSP-1 protein, or gene knockdown of c-Myc or CD47.

Results: Flow cytometric analysis and immunohistochemistry showed that CTCL tumor cells and CTCL cell lines overexpressed CD47 compared with normal CD4+ T cells. CD47 expression was increased by high c-Myc expression in CTCL tumor cells. TSP-1 mRNA expression levels in CTCL lesional skin were higher than those in normal skin and correlated with increased risk of disease-related death. Moreover, TSP-1 was expressed on CTCL tumor cells by immunohistochemistry. TSP-1 promotes proliferation and survival of CTCL tumor cells, which is inhibited by anti-CD47 neutralizing antibody or CD47 knockdown. Stimulation with TSP-1 also induces cell migration and in vivo growth. These effects were mediated by phosphorylation of ERK1/2 and AKT and expression of survivin.

Conclusions: CD47/TSP-1 interactions are potentially therapeutic targets for CTCL and therapies targeting CD47 can be more effective than therapies targeting SIRP in CTCL.

α 067 INCREASED DELTA-LIKE LIGAND 4 EXPRESSION IN MYCOSIS FUNGOIDES

Miyagaki, T.1; Boki, H.2; Shono, Y.2; Kamijo, H.2; Oka, T.2; Suga, H.2; Sugaya, M.3; Sato, S.2

1Dermatology, St. Marianna University School of Medicine, Kawasaki, Japan; 2Dermatology, the University of Tokyo Graduate School of Medicine, Tokyo, Japan; 3Dermatology, International University of Health and Welfare, Ichikawa, Japan.

Introduction & Objectives: In many malignancies, dysregulation of the Notch pathways composed of four Notch receptors (Notch1-4) and five Notch ligands (Jagged1-2, Delta-like ligand (DLL)-1, 3-4) is associated with their development. In mycosis fungoides (MF), interaction between Notch1 and Jagged1 is known to activate the Notch pathways and promote the proliferation of tumor cells. However, the involvement of other Notch ligands has not been reported. In this study, we investigated the expression and roles of DLL4 in MF.

Materials & Methods: DLL4 messenger RNA expression in early (n = 24) and advanced (n = 28) MF skin, and normal skin (n = 14) were examined by quantitative RT-PCR. DLL4 expression in lesional skin was also examined by immunohistochemistry. Moreover, we assessed the effect of DLL4 on proliferation of CTCL cell lines (MyLa, HH and HUT78 cells).

Results: DLL4 mRNA levels in lesional skin of MF patients were significantly elevated than those of normal controls and correlated with disease-specific mortality. By immunohistochemical staining, we demonstrated prominent expression of DLL4 on vascular endothelial cells and dermal infiltrating cells in MF lesional skin. In addition, exogenous DLL4 administration augmented the proliferation of CTCL cell lines in vitro.

Conclusions: These results suggest that enhanced DLL4 expression can contribute to the progression of MF through proliferating tumor cells directly.

068 TOTAL SKIN ELECTRON BEAM THERAPY AS SKIN CONDITIONING FOR STEM-CELL TRANSPLANTATION IN SÉZARY SYNDROME

Nieto Benito, L.M.1; Rosell Díaz, A.M.1; Mateos Mayo, A.1; Sanchez Herrero, A.1; Balaguer Franch, I.1; Hernandez De La Torre Díaz, E.1; García Piqueras, P.1; Lacasta Plasin, C.1; Bastos Oreiro, M.2; Dorado Herrero, N.2; Parra Blanco, V.3; Menarguez Palanca, J.3; Suarez Fernandez, R.1; Bergon Sendin, M.1; Pulido Perez, A.1

105 POSTER PRESENTATIONS

1Dermatology and Venereology, Hospital General Universitario Gregorio Marañón, Madrid, Spain; 2Hematology, Hospital General Universitario Gregorio Marañón, Madrid, Spain; 3Pathology, Hospital General Universitario Gregorio Marañón, Madrid, Spain.

Introduction & Objective: Sézary syndrome accounts for approximately 5% of cutaneous T-cell lymphomas (CTCLs). Although new treatments for CTLT, they allow patients to remain palliative. Allogeneic hematopoietic stem-cell transplantation (HSCT) with a graft- versus-tumor effect may rescue the patient´s immune system after chemotherapy and remain complete skin response after total skin electron beam therapy (TSEB). We describe our experience in TSEB and allogeneic HSCT in two patients with Sézary Syndrome.

Materials & Methods: Two patients with advance CTLC underwent TSEB radiation (total skin radiation 30 Gy, plus 5Gy administered twice in palms, soles, head, perineum and axilla) in our National Reference Unit of TSEB (Department of Radiation Oncology, Puerta de Hierro Hospital, Madrid) followed by allogeneic HSCT between September 2017 and September 2019. Dose reduced conditioning scheme based on fludarabine and melphalan was used.

Results: Case 1 was a 54-year-old woman who had a story of palmoplantar hiperqueratosis and onycodistrofia for the past year that had progressed to erythrodermia. After detail clinical examination and laboratory findings, Sezary Syndrome diagnosis was made. Extracorporeal photopheresis, bexarotene, interferon-alpha, brentuximab vedotin and gemcitabine were administered with blood response but skin progression. TSEB was initiated with cutaneous remission and followed by allogeneic HSCT with full donor chimerism. Rash (grade 3 CTCAEs) secondary to TSEB was observed. Nor nail/pigmentation changes neither acute/chronic GVHD were experienced. Case 2 was a 58-year-old man who presented in our hospital with erythroderma and generalized lymphadenopathy. Clinical, blood and cutaneous and ganglionar histopathological findings were suggestive of Sézary syndrome. CHOP chemotherapy, brentuximab vedotin and extracorporeal photopheresis were administered without response. TSEB was iniciated prior to allogeneic HSCT.

Conclusions: Combination of TSEB radiation with reduced-intensity allogeneic HSCT is a promising alternative therapeutic option for Sézary syndrome. TSEB allows cutaneous remission and eases total blood remission after HSCT.

TRANSLATIONAL AND CLINICAL RESEARCH - COMBINATION THERAPIES: PROSPECTS AND PROBLEMS

069 RESMINOSTAT INCREASES NK CELL-MEDIATED LYSIS OF MALIGNANT CELLS AND ENHANCES THE FUNCTION OF OPSONIZING ANTIBODIES

Ulrike, P.1; Kerstin, K.1; Tanja, W.1; Anne Catherine, B.1; Gundula, S.1; Matthias, B.2; Svetlana, H.1

1Translational Pharmacology, 4SC AG, Planegg-Martinsried (Munich), Germany; 2Product Development, 4SC AG, Planegg-Martinsried (Munich), Germany.

Introduction & Objectives: Natural killer (NK) cells are potent effectors of the anti-tumoral innate defense. Histone deacetylase inhibitors (HDACi) were shown to increase sensitivity of tumor cells to NK-cell-mediated lysis by up-regulating NKG2D-ligands. The clinical relevance of this effect was questioned since some HDACis were reported to inhibit viability and cytolytic function of NK-cells. Furthermore, HDACi vorinostat was shown to reduce efficacy of mogamulizumab, an anti-CCR4 opsonizing antibody approved for CTCL and ATCLL, by down- regulating CCR4. Resminostat is an oral broad-spectrum HDACi currently in clinical evaluation in CTCL. Here, we show pre-clinical data demonstrating resminostat's benefitial effects on anti-tumoral activitiy of opsonizing antibodies mediated by NK-cells.

Material & Methods: Expression of NKG2D-ligands or CCR4 and CD20 was measured by RT-PCR or flow cytometry. The effect of resminostat on purified NK-cells was examined by measuring cell viability and CD69 as activation marker by flow cytometry. To analyse the activity of NK-cells, lymphoma cells were pretreated with resminostat and incubated with purfied NK-cells or with PBMC with or without opsonizing antibodies (rituximab, mogamulizumab). Cytolytic effect was assessed after 4-6hrs either by PI-staining or by ToxiLight-assay.

Results: Resminostat increased the expression of various NKG2D-ligands on tumor cells and positively affected the tumor cell sensitivity towards NK-cells. Pre-treatment of NK-cells with resminostat did not inhibit NK-cell function, on the contrary it resulted in NK cell activation and an increase of their cytolytic function. Resminostat did not affect expression of CD20 or CCR4 on malignant T cell lymphoma cells. Furthermore, the combination of resminostat with opsonizing antibodies resulted in an enhanced NK-cell cytolytic activity against tumor cells above the effects of single agent treatments.

Conclusion: Resminostat promotes NK-cell-mediated lysis of cancer cells and enhanced the activity of opsonizing antibodies, providing a rationale for combination with opsonizing antibodies as treatment option in hematological cancers.

106 POSTER PRESENTATIONS

TRANSLATIONAL AND CLINICAL RESEARCH - CLINICAL TRIALS

070 NALOXONE LOTION FOR RELIEF OF PRURITUS ASSOCIATED WITH CUTANEOUS T-CELL LYMPHOMA (CTCL): PHASE 3 DEVELOPMENT UPDATE

Phillips, S.1; Fezatte, H.2; Bernstein, J.2

1Department of Clinical Research, Elorac, Inc., Vernon Hills , Illinois, United States; 2Department of Clinical Research, Elorac, Inc., Vernon Hills, Illinois, United States.

Introduction&Objectives: Chronic pruritus experienced by most CTCL patients is only modestly responsive to chemotherapeutic treatments for the disease,is unresponsive to antihistamines,and has been speculated to involve mediation by endogenous opiates.The pruritus not only negatively impacts quality of life(QOL),but also causes substantial morbidity,and materially contributes to mortality.A double-blind,crossover,pilot-study was completed to evaluate the effectiveness of a topically applied lotion containing naloxone,an opioid antagonist,in ameliorating this pruritus.Fourteen CTCL patients with chronic pruritus experienced a 20.9% greater improvement in a visual analog scale for itching after 8days of therapy,and greater improvement with naloxone in both subject and physician global evaluations of pruritus relief.A Phase3 study has been initiated to confirm these findings,with an interim study status presented here.

Materials&Methods: This Phase3 study is a multicenter double-blind,crossover study comparing the efficacy of naloxone 0.5% lotion versus vehicle. CTCL patients with moderate to severe pruritus daily for >1 month applied either naloxone or vehicle lotion TID for a 14- day treatment period, and following a wash-out period, applied the alternative study medication for a second 14-day treatment period. Efficacy parameters include a Numerical Rating Scale(NRS) for Pruritus, NRS for Sleep, and assessments of skin integrity and QOL.

Results: To date,36 patients are enrolled; 16female,20male; ages22-82; 25MF,11SS. While improvements in pruritus have been observed, the study remains blinded.The most common adverse events(7patients) have been application site reactions(ASR),e.g. erythema, pruritus, rash, and burning sensations, and 3 patients have dropped due to possibly or probably-related ASR. Conclusion: A Phase3 study of naloxone lotion is underway to confirm the positive findings of a pilot study.Naloxone lotion continues to be well tolerated and without safety signals that would restrict its use.This Phase3 study will be expanded to include sites in Europe and elsewhere. A protocol amendment is also being submitted to permit open-label use of naloxone lotion for up to 6months following the double-blind phase.

071 PHASE I STUDY OF COBOMARSEN, A MIR-155 INHIBITOR, IN PATIENTS WITH AGGRESSIVE HTLV-1 ASSOCIATED ATLL: DISEASE STABILIZATION AND BIOMARKER ANALYSIS

Foss, F.M. 1, Querfeld, C. 2, Zain, J. 2, Pinter-Brown, L.C. 3, Joyce, R. 4, Moskowitz, A. 5, Janakarim, M. 6, Phillips, A. 7, Ramos, J. 8, Schroeder K.M.S. 9, Lopert, P. 9, Pestano, LA: 9, Cheronis, I. 9, Williams, P.J. 9, McDonald, R. 9, Curatolo, A.M. 9, Marshall, W.S. 9, Rubin, P. 9, Escolar, D.M. 9

1Yale University School of Medicine, New Haven CT, United States 2City of Hope, Duarte, CA, United States 3University of California-Irvine, Irvine, CA, United States 4Beth Israel Deaconess Medical Center, Boston, MA, United States 5Memorial Sloan Kettering Cancer Center, New York, NY, United States 6Montefiore Medical Center, Bronx, NY, United States 7Weill Cornell Medical College, New York, NY, United States 8University of Miami Miller School of Medicine, Miami, FL, United States 9Miragen Therapeutics Inc, Boulder, CO, United States.

The upregulation of miR-155 in ATL tumor cell lines and mononuclear cells from patients with HTLV-1-associated adult T-cell leukemia/ lymphoma (ATLL) is well documented in the literature, suggesting that miR-155-5p expression is involved in the pathogenesis of ATLL. A multi-center Phase Ib trial of Cobomarsen, a synthetic inhibitor of miR-155-5p, has been initiated for patients with cutaneous T cell lymphomas, diffuse large B cell lymphomas, chronic lymphocytic leukemias, and ATLL. We report results for the first 15 patients with aggressive subtypes of ATLL who were treated with cobomarsen at doses of 600, 900 and 1200 mg by IV infusion. Of the 15 patients, 9 were actively relapsing at time of screening and 6 had residual nodal or circulating leukemic disease after chemotherapy or other systemic therapies. In these 6 patients, the duration of cobomarsen treatment ranged from 3.8 to 22.3 months (median 12.6 months), with 3 subjects still on study as of the data cutoff. Median survival on these patients is 23 months, compared with 8 months median survival reported in retrospective series in the literature from external cohorts. All patients are alive to the date of this submission. In these subjects, chronic administration of cobomarsen has been well tolerated up to the 900 mg dose by IV infusion, with a favorable safety profile. Analysis of the circulating ATL tumor cells during study treatment demonstrated sustained decreases in the expression of two activation markers (CD69 and HLA-DR) and one proliferation marker (Ki-67), with significant reductions in the percentage of actively proliferating tumor cells while the subjects remained clinically stable on cobomarsen treatment. This Phase I clinical data demonstrates prolonged clinical stabilization of disease and significant increases in overall survival in these 6 aggressive ATLL patients. Cobomarsen decreases activation and proliferation of ATL cells, suggesting a mechanism underlying the observed prolonged clinical stabilization. Enrollment is ongoing.

107 POSTER PRESENTATIONS

072 MULTICENTRE, DOUBLE BLIND, TRIAL EVALUATING RESMINOSTAT FOR MAINTENANCE TREATMENT OF ADVANCED STAGE MF OR SS PATIENTS AFTER DISEASE CONTROL WITH SYSTEMIC THERAPY – RESMAIN STUDY

Stadler, R.1; Scarisbrick, J.2; Robert, K.3; Quaglino, P.4; Borgmann, M.5; Orlovius, M.6; Reimann, P.6; Danhauser-Riedl, S.6

1Dermatology, Johannes Wesling Klinikum, Minden, Germany; 2Dermatology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom; 3Dermatology, Medical University Vienna, Vienna, Austria; 4Dermatology, University of Torino, Torino, Italy; 5Senior Product Manager, 4SC AG, Martinsried, Germany; 6Clinical Operations, 4SC AG, Martinsried, Germany.

Introduction & Objectives: CTCL is characterized by the presence of a clonal T-cell population in the skin and/or blood, lymph nodes or visceral organs. Remissions in patients with advanced-stage disease, who require systemic treatment are short-lived. Resminostat is an orally available broad-spectrum HDAC-inhibitor, which induces changes in gene expression resulting in growth inhibition, modified cell differentiation and enhanced tumor immunogenicity. Resminostat has a good safety profile, i.e. no significant effects on the cardiovascular system were observed and most AEs were mild to moderate, manageable and reversible.

Materials & Methods: The RESMAIN study is a multicentre, double blind, randomized, placebo-controlled, prospective efficacy trial. Up to 190 patients with advanced stage MF or SS (stage IIB-IV) in disease control after prior systemic therapy or TSEB are randomized 1:1 to resminostat or placebo and stratified according to their remission status and disease stage. Patients progressing on placebo can switch to resminostat. The primary objective is to determine if maintenance treatment with resminostat prolongs progression free survival (PFS) compared to placebo. As a key secondary endpoint, the effect of resminostat on time to symptom worsening (TTSW) of pruritus is assessed. Further secondary endpoints include TTP, TTNT, ORR, OS and HrQoL. An exploratory biomarker analysis is performed.

Results: The study is conducted at 53 sites in Europe and at 5 sites in Japan. As of Sep 2019, 142 patients have been randomized. A blinded status update of the RESMAIN study will be presented.

Conclusion: To our knowledge, this is the first randomized study that investigates the efficacy and safety of an HDAC inhibitor as maintenance therapy in advanced-stage CTCL patients.

TRANSLATIONAL AND CLINICAL RESEARCH - MULTINATIONAL COLLABORATIVE STUDIES

073 POSITRON EMISSION TOMOGRAPHY (PET) SCAN AS A SURROGATE FOR LYMPH NODE BIOPSIES IN MYCOSIS FUNGOIDES AND SEZARY SYNDROME

Guenova, E.1; Battistella, M.2; Bagot, M.2; Ram-Wolff, C.2; Dimitriou, F.3; Vercellino, L.2; Quaglino, P.4; Guggenberger, R.1; Haralambieva, E.1; Deandreis, D.4; Mirhadi, S.5; Yoo, J.5; Hughes, S.5; Scarisbrick, J.5

1University Hospital Zurich, Zurich, Switzerland; 2St Louis Hospital, Paris, France; 3University Hospital Zurich, Zurich, France; 4University of Turino, Turino, Italy; 5University Hospital Birmingham, Birmingham, United Kingdom.

Introduction & Objectives: Partial or complete nodal effacement with lymphomatous cells of 1+ lymph nodes (LN) is classed N3 in mycosis fungoides(MF)/Sezary syndrome(SS) and staged IVA2 which has a very poor outcome with median survival ~1-year. Dermatopathic nodes (classed-N1) or those with clusters of lymphomatous cells (N2) upstage early-MF to IIA but doesn’t alter stage in advanced-MF. As MF/SS treatments are stage related identifying patients with N3 nodes is vital to best manage patients. Guidelines recommend excisional LN biopsies of the largest, enlarged node (>15mm long axis), from computerised tomography (CT) scan preferencing cervical>axillary>inguinal to best identify the most lymphomatous node. However, excision of LNs in MF/SS is associated with considerable morbidity. PET/CT scans could offer a better proxy of the most lymphomatous node and possibly be a surrogate for excisional lymph node biopsy.

Materials & Methods: MF/SS patients who had PET/CT imaging prior to LN biopsy were identified at 4 specialist centres. The standard uptake value (SUV) of the biopsied node and MF/SS skin lesions alongside the size of the biopsied node were recorded. LN histology and PET scans were arranged for central review. Results: 26 patients were identified, 17 male, 9 female age range 28-68 years, mean 47 years. N-class was N1=4,N2=5,N3=17. No correlation could be made between LN size, SUV of LN or SUV LN/SUV skin lesion. One patient with a dermatopathic node had SUV>5. In several patients with N3 the SUV of the node was <5. Furthermore, in N3 patients the SUV of the skin lesions did not match the SUV of the node.

Conclusions: In this pilot study PET scan did not appear as a predictor of N-class in MF/SS. Careful central review of the PET scan in these cases will be vital to determine if any correlation may be possible between PET and N-class.

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PATIENT CARE IN CUTANEOUS LYMPHOMA - PERSONALIZED MEDICINE

074 LOCAL EXPERIENCE OF PHOTOTHERAPY IN MANAGING MYCOSIS FUNGOIDES

Khalid, A.; Dawe, R.S.

Dermatology, Ninewells Hospital and Medical School, Dundee, United Kingdom.

Introduction and objectives: Phototherapy is a well-established treatment for Mycosis fungoides (MF), the commonest form of cutaneous T cell lymphoma. Narrowband UVB phototherapy (UVB) and psoralen-UVA (PUVA) are widely used for early disease. Long wave UVA phototherapy (UVA1) though effective, is not widely available. Multiple courses and varying modalities of phototherapy may be needed for disease control. We present our experience of managing MF with phototherapy within Tayside, Scotland.

Materials and methods: Retrospective analysis of patients receiving whole-body phototherapy over last 20 years using the phototherapy database ‘Photonet’. Of total 11,586 patients treated with 19,870 courses of phototherapy, 98 cases (0.84%) of MF were identified. Staging data was not available. Outcomes were grouped as ‘very good’ for clear or minimal residual activity, ‘moderate’ for lesser degrees of documented improvement and ‘other’ if no change, worsening or failure to attend.

Results: A total of 66 patients received 113 courses of UVB. PUVA was used in 31 for total 48 courses and 1 received UVA1. The maximum treatments received per course was 264 for PUVA and 84 for UVB. ‘Very good’ response was seen in 82 of the 113 UVB courses (73%), moderate improvement in 9 courses (8%) and ‘other’ in 22 courses (19%). Of the PUVA cohort, 29 of 48 courses (60%) showed ‘very good’ response, 9 courses (19%) showed moderate response with ‘other’ in 8 (17%). Moderate improvement was noted in the case managed with UVA1.

Conclusions: Our experience of phototherapy in MF reflects available evidence. A slight increased response to UVB (difference of 13%, 95%confidence interval -3% to 29%, P=0.10) noted in our cohort could be a chance finding, but more likely reflects selection of patients with mild disease. Prolonged courses may represent use of maintenance phototherapy reflecting recurrent relapses of MF.

PATIENT CARE IN CUTANEOUS LYMPHOMA - GUIDELINES

075 ITALIAN EXPERT-BASED RECOMMENDATIONS ON THE USE OF PHOTO(CHEMO)THERAPY IN THE MANAGEMENT OF MYCOSIS FUNGOIDES AND SEZARY SYNDROME: RESULTS OF AN E- DELPHI CONSENSUS

Grandi, V.1; Baldo, A.2; Berti, E.3; Quaglino, P.4; Rupoli, S.5; Alaibac, M.6; Alberti Violetti, S.3; Amerio, P.7; Brazzelli, V.8; Bruni, P.L.9; Burlando, M.10; Calzavara Pinton, P.11; Cozzani, E.10; Fargnoli, M.C.12; Gambini, D.13; Iacovelli, P.14; Longo, C.15; Molinelli, E.16; Monfrecola, G.2; Motolese, A.17; Mozzicafreddo, G.18; Offidani, A.M.16; Pacifico, A.14; Parodi, A.10; Pellegrino, M.19; Piccinno, R.20; Pigatto, P.21; Pileri, A.22; Savoia, P.23; Trovato, E.19; Simonacci, M.24; Venturini, M.25; Pimpinelli, N.26

1St John's Institute of Dermatology, GSTT NHS Foundation Trust, London, United Kingdom; 2Clinica Dermatologica, Azienda Ospedaliera Universitaria Federico II, Napoli, Italy; 3Clinica Dermatologica, Fondazione IRCSS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy; 4Clinica Dermatologica, AOU Città della Salute e della Scienza, Università degli Studi di Torino, Torino, Italy; 5SOD Clinica Ematologica, Ospedali Riuniti di Ancona, Ancona, Italy; 6Clinica Dermatologica, Università degli Studi di Padova, Padova, Italy; 7Clinica Dermatologica, Università degli Studi G. D’Annunzio, Chieti, Italy; 8S. C. Dermatologia, Policlinico San Matteo IRCSS, Pavia, Italy; 9Struttura Complessa di Clinica Dermatologica, Azienda Ospedaliera S. Maria, Terni, Italy; 10U.O Dermatologia, Ospedale Policlinico IRCSS AOU San Martino, Genova, Italy; 11Clinica Dermatologica, Università di Brescia e U.O. Dermatologia, ASST Spedali Civili, Brescia, Italy; 12Presidio Ospedaliero, UOSD di Dermatologia Generale ed Oncologica, L'Acquila, Italy; 13UOC Dermatologia, ASST Papa Giovanni XXIII, Bergamo, Italy; 14Istituto Dermatologico San Gallicano, IFO, Roma, Italy; 15Clinica Dermatologica, Università degli Studi di Modena e Reggio Emilia, Modena, Italy; 16SOD Clinica di Dermatologia, Azienza Ospedaliero Universitaria Ospedali Riuniti di Ancona, Ancona, Italy; 17Clinica Dermatologica, Ospedale di Circolo e Fondazione Macchi ASST Settelaghi, Varese, Italy; 18UO Dermatologia, INRCA-IRCSS, POR, Ancona, Italy; 19Clinica Dermatologica, Ospedale Policlinico Santa Maria alle Scotte, Siena, Italy; 20UOS Fotoradioterapia, IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milano, Italy; 21Dermatologia, IRCCS ISTITUTO ORTOPEDICO GALEAZZI,, Milano, Italy; 22Clinica Dermatologica, Policlinico S. Orsola Malpighi, Bologna, Italy; 23Unità Operativa Dermatologia, Azienda Ospedaliera Universitaria, Ospedale Maggiore della Carità, Novara, Italy; 24Unità Operativa Dermatologia, Ospedale di Macerata, Macerata, Italy; 25Clinica Dermatologica Università di Brescia e U.O. Dermatologia, ASST Spedali Civili, Brescia, Italy; 26Clinica Dermatologica, Universita’ degli Studi di Firenze, Firenze, Italy.

109 POSTER PRESENTATIONS

Introduction & Objectives: NB-UVB and PUVA are a mainstay of the treatment of Mycosis Fungoides and Sezary Syndrome. However, the level of evidence for their use in this context is scarce, mostly due to lack of a unified schedule. Primary aim of this study is to establish the first Italian expert-based consensus on the indications and technical schedules for NB-UVB and PUVA for Mycosis Fungoides and Sezary Syndrome. Secondary aim is to determine the level of consensus of each specific item.

Materials & Methods: E- delphi study, two consecutive phases, 3 iterative rounds each. Item-specific expert consensus was defined as rate of “Totally Agree” results >= to the 80% of the panelists. Cronbach alpha index >/= 0.7.has been used as measure of homogeneity in the responses among questions related to the same topic.

Results: 25 experts from 19 Centers participated to the study. Overall, there was a high homogeneity among repliers overall, as proof of adequate expertise of the panelists and pertinence of the questions (0.78) On specific topics, the highest grade has been observed on technical items (0.8) then on topics related to indications for early stages (0.73) and finally for advanced stages (0.7).

Conclusions: This study generated the first standardized consensus recommendations on the use of phototherapy for the treatment of Mycosis Fungoides and Sezary Syndrome. High rates of agreement have been achieved on questions related to the most canonical indications of phototherapy and on items related on treatment schedules. There is consensus about the use of treatment schedules proposed by USCLC both for the induction and consolidation phases. We discourage the routine use of maintenance phase until better evidences are accumulated.

PATIENT CARE IN CUTANEOUS LYMPHOMA AVAILABLE THERAPIES - NEW TARGETS

076 EXTRACOPOREAL PHOTOPHERESIS FOR THE TREATMENT OF PATIENTS WITH SEZARY´S SYNDROME AND ERYTHRODERMIC MF: REAL-WORLD DATA

Enciso Olivera, L.J.; Rueda, X.; Toquica, A.

Cutaneous Lymphoma Clinic, Instituto Nacional de Cancerología, Bogotá, Colombia.

Introduction and Objectives: Extracorporeal photopheresis is associated with high response rates in patients with Sezary syndrome and erythrodermic Mycosis Fungoides (MF). Our objective is to describe the results of this treatment in our cohort of patients.

Materials and Methods: Electronic health records of adult patients that received at least one ECP cycle were peer-reviewed and clinical and laboratory data recorded. Continuous and categorical variables were analyzed. For survival analysis, the Kaplan-Meier method was used.

Results: Fifteen patients were included and nine (60%) were male. The median age for all patients was 52.9 years with significance difference by sex [P-Value: 0.013]. Nine patients (60%) were diagnosed with SS and 6 with erythrodermic MF. The time from diagnosis to first cycle was 293 days. The mean number of previous systemic therapies was 2 (0-4), including combination chemotherapy in 47%. All patients have progressive disease at the time of the first cycle. The mean number of cycles for patients was 29. The mean reduction in the pruritus scale (VAS) was 4.06 cms and the mean reduction in mSWAT was 98.6 points. The ORR (CR + PR) was 66.67%. A clinical benefit (at least stable disease with a reduction in pruritus) was observed in 13/15 patients. The most frequent complications were venous access dysfunction (2.3% of cycles). One patient develops a pulmonary embolism. Three patients died: one for sepsis in the first cycle, one for bacterial meningitis and others for unknown reasons. The median OS from the first cycle was 2.24 years.

Conclusions: Extracorporeal photopheresis is an active and well-tolerated therapy for patients with SS and erythrodermic MF with a low complication rate. This is the first report of this therapy in our country.

PATIENT CARE IN CUTANEOUS LYMPHOMA - QUALITY OF LIFE/ SUPPORTIVE THERAPIES

077 BURDEN OF DISEASE IN EARLY MF OF CUTANEOUS T-CELL LYMPHOMA (CTCL): CONSISTENT RESULTS FROM CLINICIAN INTERVIEWS AND FOCUS GROUP PARTICIPANTS

Chavda, R.1; Mansukhani, S.2; Dias Barbosa, C.3; Thornton, S.4; Gabriel, S.1; Puelles, J.1; Bagot, M.5

1Galderma SA, La Tour-de-Peilz, Switzerland; 2Evidera, Bethesda, United States; 3Evidera, London, United Kingdom; 4Cutaneous Lymphoma Foundation, Troy, MI, United States; 5Assistance Publique Hopitaux de Paris, Paris, France.

110 POSTER PRESENTATIONS

Introduction & Objectives: Primary cutaneous T-cell lymphoma (CTCL) is a rare disease characterized by patches, plaques and pruritus due to migration of malignant T-cells to the skin. The objective of this study was to qualitatively investigate the disease burden in CTCL patients and understand the impact of the disease from the patients’ and clinicians’ perspective.

Materials & Methods: A focus group with ten CTCL patients was conducted in the US in December 2017. Four clinical experts were interviewed over telephonically. Semi-structured discussion guides were utilized with both patients and clinicians, focusing on eliciting symptoms and impacts of these symptoms on daily lives. The discussions were audio-recorded, verbatim transcribed and analyzed following content analysis approach. All study material was approved by an US ethical board.

Results: Clinicians expressed that the burden of disease varied with the stage of the disease and is increasing with the intensification of pruritus and burning in advanced stage causing sleep disturbance. Stigma regarding visibility of lesions and pruritis impacted patients’ work and social life: “Patients wear their disease”. Patients were 70% males with over 60% > 60 years old, 70% in early stage and 50% having their diagnosis ≤5 years ago. The most common symptoms reported by patients were: pruritus, brown lumps, infections, red/reddish-brown plaque patches, skin pain, fatigue and discomfort. Pruritus was reported as the most bothersome impacting daily lives even in early stage followed by scaly patches and plaques. Pruritus was described as “incredibly horrible”, “most annoying”, and was associated with poor sleep quality, anxiety, stigma, limited clothing options and restricted social engagements.

Conclusions: Pruritus is the most bothersome symptoms especially in patients with early stage CTCL that impacts the QoL as they have difficulty sleeping and feel fatigued. Stigma associated with visibility of lesions negatively impact the work and social life of patients.

078 CUTANEOUS LYMPHOMA PATIENTS’ PERCEPTIONS REGARDING CANNABIS: A SURVEY STUDY

Coolman, T.1; Howard, O.2; Shinohara, M.3

1Osteopathic Medicine, A.T. Still University - Kirksville College of Osteopathic Medicine, Kirksville, MO, United States; 2College of Medicine, Howard University, Washington, D.C., United States; 3Department of Medicine, University of Washington School of Medicine, Seattle, Washington, United States.

Introduction and Objectives: A common and debilitating symptom of cutaneous lymphoma (CL) is pruritus. Cannabis is known to have anti-pruritic properties. Few studies have evaluated the use of and opinions towards cannabis among patients with CL.

Material and Methods: An anonymous electronic survey was provided to patients with CL via the Cutaneous Lymphoma Foundation. The survey asked patients to characterize their diagnosis, symptoms, and use of and opinions on cannabis. A visual analog scale (VAS, reported as 0-100) was used for several items, such as interest in cannabis (e.g. not interested to very interested).

Results: Most respondents had mycosis fungoides (88/119; 74%), stage 1a/b (46/86; 54%). Over half of respondents (60/110) reported ever having used cannabis. Twenty-four respondents (40%) were currently using cannabis, with about half (13/24) starting after their diagnosis. Half of those who used cannabis did so to alleviate anxiety, pain, and stress, while a quarter (6/24) reported using cannabis to treat itch. Patients reported cannabis reducing their itch (median VAS 65/100, minor to major improvement) and improving their symptoms overall (median VAS 67/100). There was strong interest in cannabis as a possible treatment for CL (median VAS 84/100). Most respondents (94/108; 87%) indicated willingness to discuss cannabis with a physician.

Conclusion: Cannabis use is high among patients with CL (40%) when compared to the general public (13%). Patients with CL are curious about cannabis as an adjunct treatment for CL and are eager to engage with their medical care team regarding its use. Those who have used cannabis to treat symptoms reported improvement.

079 APREPITANT IN REFRACTORY PRURITUS OF SYSTEMIC LYMPHOPROLIFERATIVE DISORDERS

Pulido-Perez, A.1; Carretero-Lopez, F.2; Bergon-Sendin, M.1; Nieto-Benito, L.M.1; Rosell-Diaz, A.1; Romero-Jimenez, R.3; Dorado-Herrero, N.4; Bastos-Oreiro, M.4; Suarez-Fernandez, R.1

1Dermatology, Hospital General Universitario Gregorio Marañón, Madrid, Spain; 2Radiology, Hospital General Universitario Gregorio Marañón, Madrid, Spain; 3Pharmacy, Hospital General Universitario Gregorio Marañón, Madrid, Spain; 4Haematology, Hospital General Universitario Gregorio Marañón, Madrid, Spain.

Introduction &Objectives: In recent years aprepitant has shown promising results in the treatment of refractory pruritus of primary cutaneous T-cell lymphomas. However, its effect on paraneoplastic pruritus of systemic lymphoproliferative disorders has been poorly documented.

Materials & Methods: A retrospective study of patients with systemic lymphoproliferative disorders and refractory pruritus who received aprepitant at our center from March 2017 to June 2019 was performed.

Results: There were 6 patients, 4 men and 2 women, with an average age of 64.5 years (32-87). 3 patients had a diagnosis of T-cell lymphoma, 1 follicular lymphoma and 2 Hodgkin lymphomas. 3 patients received chemotherapy for active disease, 2 patients were in study for suspected disease relapse and 1 patient followed up without evidence of recurrence. All patients had been treated with two

111 POSTER PRESENTATIONS

or more systemic drugs and/or phototherapy. 3 patients had skin lesions (2 patients with secondary skin infiltration and 1 patient with chronic graft-versus-host disease). The baseline itching score ranged from 10 to 6 (mean 7.8). In 5 patients it was difficult to rest at night due to pruritus. In 3 cases aprepitant was administered at a standard biweekly dose of 125mg, 80mg, 80mg on three consecutive days, in 2 patients the same weekly pattern and in 1 patient 40mg daily. 4 patients achieved a reduction in the intensity of pruritus of 3 or more points (3 to 5 points) and in 4 cases night rest improved (in 2 patients the hypnotic drugs were discontinued). No side effects or drug interactions were documented.

Conclusions: Although this is a small number of cases, it appears that aprepitant may be a valid option in the symptomatic treatment of refractory pruritus in patients with extracutaneous lymphoproliferative syndromes. The effect appears superior in patients with secondary skin lesions.

080 PAYING THE PRICE OF CTCL: AN ANALYSIS OF RECENT TRENDS IN SKIN-DIRECTED AND SYSTEMIC TREATMENT COSTS FOR CUTANEOUS T-CELL LYMPHOMA

Rosenthal, J.M.; Holton, J.; Samimi, S.; Vittorio, C.; Rook, A.H.; Haun, P.; Villasenor-Park, J.; Kim, E.J.

Dermatology, University of Pennsylvania, Philadelphia, United States.

Introduction & Objectives: Cutaneous T-cell Lymphoma (CTCL) is a rare disease requiring chronic treatment. Several skin directed (SDTs) and systemic therapies (STs) are in use for CTCL in the US, however, the exponentially high costs of medications in the US has reduced access and increased cost burden particularly for patients with rare diseases. We conducted an exploratory analysis of SDT and self- administered ST costs in CTCL. In addition, we compared the prices of CTCL medications with that of atopic dermatitis (AD), a more common inflammatory skin disorder.

Materials & Methods: Costs of current SDTs and self-administered STs for CTCL and AD were analyzed from the perspective of the third- party payer using the average wholesale price (AWP), excluding medications used in both conditions (topical/oral steroids, phototherapy, methotrexate). The costs of a 1-month supply of each medication were calculated, assuming a patient weight of 80kg.

Results: In the US, current total monthly costs for CTCL SDTs ranged from $436 (imiquimod cream 5%) to $34,990 (bexarotene gel 1%), whereas total monthly costs of AD SDTs ranged from $1,072 (tacrolimus ointment 0.1%/0.03%) to $1,266 (crisaborole ointment 2%). Current total monthly costs of CTCL self-administered STs ranged from $675 (interferon alfa-2b) to $65,863 (interferon gamma), whereas total monthly costs of AD STs ranged from $239 (mycophenolate mofetil) to $3,623 (dupilumab). The average monthly cost for CTCL SDTs is $10,453 versus $1,178 for AD SDTs, for CTCL STs $14,978 versus $1,422 for AD STs.

Conclusion: In the U.S., excluding steroids, phototherapy, and methotrexate, prices of SDTs and self-administered STs for CTCL are significantly higher than for AD, likely related to the rarity of CTCL, research development costs, and lack of generic equivalents. The disease-related financial burden among patients with CTCL impacts treatment planning and health-related quality of life.

081 HEALTH CARE USE AMONG MYCOSIS FUNGOIDES AND SÉZARY SYNDROME PATIENTS IN 1998-2016 - A POPULATION-WIDE STUDY

Vakeva, L.1; Hahtola, S.1; Linna, M.2; Keto, J.3

1Helsinki Univercity Central Hospital, Helsinki, Finland; 2Aalto University, Helsinki, Finland; 3Kyowa Kirin International, Helsinki, Finland.

Introduction and Objectives: Previous information about health care use and costs of cutaneous T-cell lymphoma (CTCL) patients is limited, particularly in a European setting.

Materials and Methods: In this population-wide study we set out to investigate trends in health care use in two CTCL subtypes, mycosis fungoides (MF) and Sézary syndrome (SS) by using nation-wide register linkage.

Results: We found a significant decrease in inpatient treatment of MF/SS in the past two decades, while mean numbers of outpatient visits remained stable. Most MF/SS-related outpatient visits occurred in the medical specialty of dermatology. In ten-year follow-up after MF/SS diagnose, the main causes for outpatient visits and inpatient stays were MF/SS itself, other cancers, and other skin conditions. Also cardiovascular disease and infections added to the number of inpatient days.

Conclusions: We present an exceptionally long data series of nearly two decades on all mycosis fungoides and Sézary syndrome (MF/SS) patients in Finland. For this period, we present trends in prevalence by age group, trends in treatment of MF/SS (inpatient vs. outpatient visits; medical specialty), and an exceptional analysis of total secondary health care use and its costs by cause in 10-year follow-up after MF/SS diagnose. As dermatologists have a key role in the treatment of MF/SS patients, they should be aware of the high burden of comorbidities among their patients.

112 POSTER PRESENTATIONS

PATIENT CARE IN CUTANEOUS LYMPHOMA - DIFFICULT TO TREAT/ RARE LYMPHOMAS

082 CASE REPORT: VENETOCLAX FOR TREATMENT OF RELAPSED/REFRACTORY MYCOSIS FUNGOIDES, TUMOR STAGE, WITH FOLLICULOTROPISM AND LARGE CELL TRANSFORMATION

Martinez, X.1; Abdulla, F.1; Querfeld, C.1; Rosen, S.2; Zain, J.2

1Surgery, Division of Dermatology, City of Hope, Duarte, United States; 2Hematology/Hematopoietic Cell Transplantation, City of Hope, Duarte, United States.

Mycosis fungoides (MF) is a chronic and incurable disease. Patients frequently relapse, requiring many lines of therapy for management of disease. Poor prognostic indicators, such as large cell transformation (LCT), further decrease overall survival. Thus, a need for novel therapies exists. Venetoclax is a Bcl-2 inhibitor that has been approved for the treatment of multiple hematologic malignancies. However, there are no prior reports of the use of venetoclax to treat T-cell lymphomas. We present a case of a 73-year-old female with MF, tumor stage, with folliculotropism and LCT, who had previously failed multiple lines of therapy. Recent skin biopsies demonstrated Bcl-2 expression in B and T cells. The patient was treated on protocol with venetoclax and, currently, has demonstrated a partial response with complete resolution of tumors. This is the first report on the effectiveness of venetoclax in patients with MF.

113 INDEX OF AUTHORS

A Anne, Pham-Ledard O-02, O-03 Abdala, Suraya Maria Z-24 Annemie, Rutten 061 Abdelbary, Haitham Z-22, Z-28 Antoine, Martin 041 Abdo, André C-04 Anzengruber, Florian O-06 Abdulla, Farah K-04, L-01, M-03, N-01, Ara Martín, Mariano 045 P-04, 082 Arai, Sally U-01 Abrantes Giannotti, Z-26, 063 Araiz, Maria Z-07 Marcelo Aranguren-López, Iñigo 050 Acheampong, Daniel L-03 Arenillas, Leonor M-05 Acle, Renata D-04, Z-11 Arkin, Coral K-03 Adad, Marcio Antonio Z-16 Haro Armand, Bensussan J-03 Agirre, Amaia S. Z-02 Arregui-Murua, Maria Z-07, 050 Asuncion Agostinelli, Claudio 025, 065 Arrue Michelena, Itziar 047, 051 Ajjampura, Vinayaka C. Z-29 Arumainathan, Arvind X-02 Akilov, Oleg C-01, E-03, R-06, V-05, W-01 Aspe Unanue, Libe 033 Alaibac, Mauro 075 Assaf, Chalid H-01, Z-27, 002, 063 Alani, Ali B-06 Audrey, Gros O-02, O-03 Alberti Violetti, Silvia U-02, 075 Aung, Phyu B-06 Aldridge, Sarah T-03 Azcona, Maialen 022 Alekseeva, Ekaterina I-03 Azurdia, Richard X-02 Alexander-Savino, Carolina Y-04, Z-03, 026 B V. Bagot, Martine B-01, B-02, C-01, C-02, Alfonso Martin, Juan Luis M-01 D-01, I-01, T-01, X-01, Z-09, Alhafnawi, Mohammed Z-03 008, 029, 073, 077 Alleri, Angelica C. T-01 Baik, Sarah J-04 Almeida, J. G-03 Bailey, William Y-03 Alos, Llucia 039 Bakr, Farrah S-02 Alsina, Mercè 038 Balaguer Franch, 068 Inmaculada Altuna, Ane Z-07 Balazs, Zsolt T-04 Altunbulakli, Can L-01, N-01 Baldasseroni, Lyla K-02 Amarov, Boyko O-06 Baldini, Luca U-02 Amerio, Paolo 075 Baldo, Antonello 075 Amin, Sapna M. 049 Baltás, Eszter Z-05 Amitay-Laish, Iris Y-01, Z-29 Bar-Natan, Michal L-02 An, Bervoets 061 Barrios, Estella P-04 Andersen, Erica F. O-01 Barros Domingues, Regina Z-26 Andrade Campos, Marcio V-01 Barta, Stefan V-06 Andrade, Andrea D-05 Bastidas Torres, Armando N-03 Andrades, Evelyn R-01 Bastos Oreiro, Mariana 068, 079 Àngel Baldó, Joan 043 Battistella, Maxime B-01, B-02, C-01, C-02, I-01, Angello, James Y-02, Y-03 T-01, Z-09, 008, 029, 073 Angles, Valeria D-05 Bauer, Andrea Z-06 Anne Catherine, Bretz 069 Bauer, Wolfgang J-01 Anne, Boland J-03 Béatrice, Vergier O-02, O-03

114 INDEX OF AUTHORS

Bechter, Oliver V-05 Brown, Lisa V-05 Becker, Jürgen C. 062 Bruey, Silvina D-05 Beisel, Christian T-04 Bruni, Pier Luigi 075 Bekkenk, Marcel X-04, Z-08 Brunner, Patrick M. J-01 Beksac, Burcu J-04 Buelens, Odette Z-25 Bellosillo, Beatriz M-05, 020 Bunick, Christopher G. Z-13 Beltraminelli, Helmut B-01, B-02 Bunn, Veronica V-05 Bengoechea-Nerecan, 050 Bupha- Intr, Olivia Z-25 Enrique Burlando, Martina 075 Benoit, Bernice W-02 Busschots, Anne-Marie C-01, C-02 Bensussan, Armand I-01, T-01 Buus, Terkild B. L-02, 062 Berg, Sara V-06, W-02 C Bergon Sendin, Marta 068, 079 Calderon Gutierrez, Maria 034 Bernd, Hemmerlein Z-27 Jose Bernstein, Joel 070 Calvo, Xavier M-05 Berti, Emilio C-01, N-03, U-02, 075 Calzavara Pinton, 075 Bertuzzi, Clara 025, 065 Piergiacomo Beylot-Barry, Marie C-01, K-02, T-01 Campbell, Belinda A. Z-25 Bhat, Trisha P-02, P-03, P-05 Campbell, James S-01 Bielsa, Isabel V-01 Campo, Elias 003 Bigas, Anna R-01 Campos-Dominguez, 056 Minia Binder, Gary Y-02 Canal García, Elena 043 Blanch Rius, Laura 010 Cancho Galán, Goikoane 019, 021 Blanco, Gonzalo L-04, R-01 Carlson, Kacie R. R-02, R-05, Z-13 Błażewicz, Izabela T-02 Carnero González, Lucia 033 Blümel, Edda 062 Carretero-Lopez, Fernando 079 Boggon, Titus J. L-01 Carter, Joi 032 Bohjanen, Kimberly D-06, X-03 Casadei, Beatrice 025 Boki, Hikari 027, 067 Casanova Seuma, Josep 043 Borbényi, Zita Z-05 Manel Borgmann, Matthias S-05, 072 Casarin, Francesca U-02 Borrego, Leopoldo M-01 Cascante, Lourdes 022 Borregon, Jennifer H-03 Cassoli Cortez, Anita 040 Bouaziz, Jean-David Z-09 Castellvi, Josep 055 Bowen, Glen 017 Castro, Liza 007 Bowman, Anita S. N-02 Caton Santaren, Blanca 047 Brammer, Jonathan V-04 Cats, Davy N-03 Braun, Jana Dorothea 001 Cayrol, Maria Florencia S-04 Brazzelli, Valeria 075 Cayuela, Jean-Michel T-01 Bretz, Anne Catherine S-05 Cerchietti, Leandro S-04 Brice, Pauline Z-09 Cereceda, Laura H-03, M-04 Brito Pinheiro Ramos 006 Cerroni, Lorenzo C-01, M-01, O-01 Santos, Sarah Chavda, Rajeev 077 Britt M, Hermes G-06 Chebly, Alain K-02 Broccoli, Alessandro 025

115 INDEX OF AUTHORS

Cheng, Anthony L-02 Daniels, Jay L-01, N-01 Cheronis, Ioanna 071 Daniëls, Laurien X-04 Chevret, Edith K-02 Daruish, Maged Z-20, Z-22 Child, Fiona T-03, U-03, X-05 Davis, Michael 032 Choi, Jaehyuk L-01, N-01, O-01, Z-02 Dawe, Robert S. 074 Choi, Sara L-01 De Brito, Marianne X-02 Chovatiya, Raj Z-21 De Clippelé, Donatienne 029 Christina, Mitteldorf Z-27 De Dios Velazquez, Alvaro O-05 Christoph, Blazejak 002 De Francesco, Irene X-05 Christophe, Battail J-03 De Freire Cassia, Flavia 004, 005, 006, 007 Chung, Catherine G. V-04, Y-04, Z-01, Z-18, 026 De Groen, Ruben A.l. O-04 Ciepłuch, Hanna P-01 De Haard, Hans T-01 Cintra, Maria Leticia Z-12, Z-16 De Haas, Ellen X-04 Clark, Rachael A. W-02 De La Torre Gomar, 033, 047, 051, 057 Claus-Detlev, Klemke Z-27, 002 Francisco Javier Clémentine, Descours 036 De Masson, Adèle D-01, I-01, J-03, Z-09, 008, 029 Cleven, Arjen Z-08 De Melo Miranda, Vitor Z-10 Climent Esteller, Fina B-02, Z-06 José Colomo, Luis M-05, 023, 046, 053 De Winne, Koen T-01 Combalia, Andrea 003, 038, 039 Dean, George G-02, L-02 Comfere, Nneka I. B-05 Deandreis, Desiree 073 Conde, David R-01 Debernardi, Maria S-04 Conran, Carly L-01 Mercedes Cooke, Anisha R-03 Defrancesco, Irene T-03, U-03 Coolman, Tyler 078 Degasperi, Andrea G-04 Coralie, Zumelzu 041 Del Guzzo, Christina V-06, W-02, 009 Córdoba, Alicia 022 Delahaye, Tim T-01 Córdoba, Raúl M-01 Della Ripa Rodrigues Z-10, Z-12 Cortes, Jose R-03 Assis, Gabriela Corti, Laura N-03 Demeter, Judit 059 Cowan, Richard C-01, C-02, X-02 Devaney, Alice H-02 Cowper, Shawn Z-13 Di Raimondo, Cosimo K-04 Cozzani, Emanuele 075 Dias Barbosa, Carla 077 Cozzio, Antonio B-01, B-02, O-06, X-01 Diaz Flaque, Maria Celeste S-04 Cremaschi, Graciela S-04 Diepstra, Arjan O-04 Csányi, Ildikó Z-05 Diercks, Gillis Z-08 Csomor, Judit 058, 059 Dimitriou, Florentia O-06, 073 Curatolo, Ann Marie 071 D'incan, Michel 036 Curry, Jonathan B-06 Dorado Herrero, Nieves 068, 079 Cury-Martins, Jade C-04, V-03, Z-26, 063 Doss, Gowardhanan X-05 Doukas, Peter G. L-01, N-01 D Downey, Camila D-04 Da Costa Llanos, Felipe 005 Drori, Avi Z-29 Dalle, Stephane T-01, V-05 Drori, Guy Z-29 Damoraki, Georgia 064 Dummer, Reinhard O-06, T-04, V-05 Danhauser-Riedl, Susanne 072

116 INDEX OF AUTHORS

Dunnill, Giles X-02 Ferrer, Ana 020 Duran, Xavier 020 Ferrer, Berta M-01, 055 Duvic, Madeleine B-01, B-02, B-05, B-06, Ferrer, Jacky K-02 V-05 Fezatte, Heidi 070 E Fisher, David V-05 El-Afifi, Amal Z-22 Flanagan, Charlotte E. R-04 El-Lithy, Mahmoud Z-22 Florell, Scott 017 Elodie, Bohers O-03 Florent, Grange 036 El-Sayed, Mahira Hamdy Z-22 Fong, Sophia W-03 El-Tayeb, Nada Z-22 Fornons, Rosa Z-06 El-Zawahry, Khaled Z-20 Foss, Francine R-02, R-05, U-04, 071 El-Zimaity, Maha Z-22 Freeman, Kirsty T-03 Enciso Olivera, Leonardo J 076 Frigola, Gerard 003 Enz, Paula D-05 Fujii, Kazuyasu 052 Eradat, Herbert V-05 Fulmer, Yi G-02 Eric, Frison O-02, O-03 Furtado, Michelle X-02 Escolar, Diana M. 071 G Espinet, Blanca L-04 Gabor, Dobos D-01, J-03, Z-09, 029 Espinosa, Lluis R-01 Gabriel, Sylvie 077 Espinosa, Maria L. B-04, B-05, Z-02, 049 Gainza Apraiz, Isabel 010, 019, 030 Espinoza-Benavides, Z-15 Gallardo, Fernando L-04, M-05, R-01, V-01, Leonardo 020, 023, 046, 053, Estrach, Teresa C-01, L-04, M-01, 003, 038, Gallop-Evans, Eve X-02 039 Gambini, Daniele 075 Eve, Maubec 041 Gandini, Domenica T-01 Evison, Felicity C-01, C-02, X-01 Gantchev, Jennifer 018 F Gao, Crytal 035 Fabrice, Jardin O-02, O-03 García Piqueras, Paloma 068 Fajnerman Tel-Dan, Shira C-03 García Río, Irene 033 Fanok, Melania G-02 Garcia Solano, Maria O-05 Fanoni, Daniele N-03, U-02 García Toro, Enrique M-01 Fantelli Stelini, Rafael Z-10, Z-12, Z-16, Z-24, 028, 040 García, Candelaria M-01 Fargnoli, Maria Concetta 075 Garcia-Colmenero, Lidia R-01 Farlik, Matthias J-01 Garcia-Herrera, Adriana 003, 038, 039 Farouk, Mohamed Z-14 Garcia-Muret, M. Pilar L-04, 016 Farquharson, Nina X-02 Garcia-Patos, Vicente 055 Fatsini Blanch, Vanesa 057 Geller, Shamir C-03, I-02, N-02 Fernandes Pinheiro, Livia 007 Georgiou, Elisavet F-03, 024 Stefania Geskin, Larisa B-01, B-02, G-01, G-02, Fernández Armenteros, 043 L-02, R-03, V-05, X-01, Josep Manel Y-03 Fernandez, Concepcion M-05 Giefing, Maciej K-01 Ferrando, Adolfo R-03 Gilmore, Elaine S. Y-04, 026 Ferreira Magalhães, Z-16, Z-24, 028 Gimeno Castillo, Javier 033, 047, 051, 057 Renata Ginhoux, Florent I-01

117 INDEX OF AUTHORS

Giordano, María Consuelo D-04 Gundula, Streubel 069 Girardi, Michael D-02, R-02, R-05, U-04, Gunes, E. Gulsen E-01, S-06 Y-03, Z-13 Gurbity Pálfi, Tímea Z-05 Givskov, Michael 062 H Giza, Agnieszka P-01, Z-19 Habib, Zouali J-03 Gjerdrum, Lise M. R. 062 Hahtola, Sonja 081 Glazko, Galina L-03, 060 Halbritter, Florian J-01 Gliozzo, Jessica N-03 Halwani, Ahmad S. 017 Gniadecki, Robert 014, 015 Hamada, Toshihisa 044 Goerdt, Sergij 001 Hamm, Svetlana S-05 Goldaniga, Maria U-02 Han, Dan S-01 Goldberg, Ilan C-03 Hannah, Kallus S-05 Goldman- Mazur, Sarah Z-19 Haralambieva, Eugenia 073 Gomez Bringas, Cristina 034 Harkins, Shannon O-01 Gómez Muga, Susana 010 Hatanaka, Miho 052 Gómez-Llonín, Andrea L-04 Haun, Paul B-01, B-02, V-06, 080 González Del Tánago 019 Haverkos, Bradley Y-02 Diago, Jaime Hennessey, Dylan 014, 015 González Núñez, María M-01 Ángeles Henri, Adamski 036 González Pérez, Ricardo 033, 051, 057 Heras González, Sonia 057 González Romero, Nerea 010, 030, 034 Herbosa, Christina P-02, P-03, P-05 Gonzalez, Jessica R-01 Hernandez De La Torre 068 Díaz, Elisa González, Sergio D-04, Z-11, Z-15 Herpers, Bjorn 062 González-Barca, Eva M. Z-06 Herrera, Alberto G-02, L-02 González-Pérez, Ricardo 047 Hideghéty, Katalin Z-05 Gorovitz, Batia K-03, Z-29 Higashi, Yuko 052 Goula Fernández, Sofia 051 Hiniker, Susan W-03 Gowda, Lohith U-04 Hirotsu, Kelsey E. X-06, X-07 Gowthaman, Ragul N-01 Ho, Caleb I-02, N-02 Goyal, Amrita D-06, X-03, Z-23, 011 Hodak, Emily X-01 Grandi, Vieri G-04, H-02, U-03, X-05, 042, 075 Hodak, Emmilia B-01, B-02, C-01, C-02, K-03, Y-01, Z-29 Grekova, Ekaterina I-03, 012 Holdich, Alexandra S-02 Grifoni, Federica U-02 Holton, Joseph 080 Grillo Ruggieri, Filippo U-02 Honda, Kord M-03 Gru, Alejandro B-01, B-02, C-01, N-01 Hong, Bo O-01 Gruber, Aurélia 008 Hong, Eric C-01, C-02, W-03 Gu, Yuhan R-03 Hoppe, Richard T. U-01, W-03 Guenova-Hotzenecker, B-01, B-02, C-01, O-06, 073 Emmanuella Horvath, Barbara X-04 Guggenberger, Roman 073 Horwitz, Steven B-05, I-02, N-02, V-05, X-01, 037 Guggina, Lauren Z-21 Howard, Olivia 078 Guglielmo, Alba 025, 065 Hsu, Daniel S-01 Guitart, Joan B-01, B-02, B-04, B-05, L-01, N-01, O-01, Y-03, Z-02, Huang, Ying V-04 Z-21, 049

118 INDEX OF AUTHORS

Huen, Auris B-06 Jost, Marion 054 Hughes, Simon 073 Jothishankar, Balaji L-01, N-01 Hultberg, Anna T-01 Jouenne, Fanélie 008 Huynh, Mindy S-01 Jo-Velasco, Margarita O-05 Hwang, Sam E-03, R-06, S-01 Joyce, Robin 071 Hymes, Kenneth G-02, L-02 Juliá Manresa, Marc 021 Junkins-Hopkins, B-01, B-02 I Jacqueline Iacovelli, Paolo 075 Jürgen, Harder G-06 Ibrahim, Mona Abdel- Z-14, Z-20, Z-22, Z-28, 013 Halim K Idrissi, Yamina K-02 Kadin, Marshall E. F-01, G-02, L-02 Iglesias, Arnau R-01 Kamijo, Hiroaki G-05, 027, 066, 067 Iriondo, June Z-07 Kanekura, Takuro 052 Ispizua Mendivil, Estibaliz 030 Kanfer, Edward U-03 Isufi, Iris U-04 Kawana, Yuki 027 Iversen, Lars 062 Kemény, Lajos Z-05 Iwatsuki, Keijii 044 Kempf, Werner B-01, B-02, C-01 Iyer, Aishwarya 014, 015 Kerstin, Kronthaler 069 Iznardo, Helena 016 Keto, Jaana 081 Izu Belloso, Rosa María 010, 019, 021, 030, 034 Khalid, Amina 074 Iżykowska, Katarzyna K-01 Khodadoust, Michael S. J-02, U-01, W-03 Khuong-Quang, Dong- M-02 J Anh James, Eleanor X-02 Kilian, Mogens 062 Jan P., Nicolay H-01, Z-27, 002 Kim, Ellen V-06, W-02, Y-03, 080 Jana, Braun H-01 Kim, Sa Rang R-02, R-05 Janakarim, Murali 071 Kim, Youn H. B-01, B-02, B-05, C-01, Janela, Baptiste I-01 C-02, J-02, U-01, V-05, Jansen, Patty B-03, O-04, X-04, Z-08 W-03, X-01, X-06, X-07 Jariwala, Neha V-06, W-02 King, Amber Loren O. R-02, R-05 Jayaprakash, Sindoora X-02 King, Brett Z-13 Jean-François, Deleuze J-03 Knaneh, Jamal K-03 Jean-Philippe, Merlio O-02, O-03 Knobler, Robert B-01, B-02, C-01 Jeffe, Donna P-03 Koletsa, Triantafyllia F-03, 024 Jeroen, Pyl 061 Koltai, Hinanit Z-29 Joanna, Olk 002 Koralov, Sergei G-01, G-02, L-02 Johansen, Claus 062 Kosa Lino Duarte, Bruno 040 John F, Baines G-06 Koufargyris, Panagiotis 064 Johnson, Amy V-04, Z-01, Z-18 Kouttab, Nick F-01 Johnson, Courtney D-03 Kovalchuk, Sofia 042 Johnson, Lisa E-03 Krammer, Peter H. 001 Jonak, Constanze C-02, J-01 Krauthammer, Michael T-04 Jońca, Marcin Z-19 Krejsgaard, Thorbjørn 062 Jones, Christine L. G-04, H-02, R-04, S-02 Krenács, László Z-05 Jones, Emma T-03 Kronthaler, Kerstin S-05 Jonsson, Vanessa S-06 Kruglov, Oleg E-03, R-06, W-01

119 INDEX OF AUTHORS

Kumar, Erica S. B-05 López-Sánchez, Manuela L-04 Kwok, Pui-Yan L-01 Loscalzo, Matthew P-04 Kwong, Bernice Y. X-06, X-07 Louissaint Jr., Abner L-01, N-01, O-01 L Lubin, Ido Z-29 Lacasta Plasin, Clara 068 M Laggis, Caroline 017 Machado De Moraes, Z-10 Aparecida Laird, Mary G-02 Machado Toribio, Z-24 Lamb, Andrew 017 Jaqueline Landsburg, Daniel V-06 Machan, Salma H-03, M-01, O-05 Lansigan, Frederick 032 Mackey, Adam R-03 Lastrucci, Irene 042 Maerevoet, Marie T-01 Latkowski, Jo-Ann G-02, L-02 Magro, Cynthia S-04 Laurence, Michel J-03 Maio, Vincenza 042 Lazaridou, Elizabeth F-03, 024 Maity, Amit W-02 Lázaro Serrano, Mireya 019 Mangar, Steven U-03 Lazaryan, Aleksandr 011 Mangold, Aaron R. B-05 Lebbé, Céleste 008 Manso Aonso, Rebeca H-03, M-01, M-04 Leupin, Nicolas T-01 Mansukhani, Sonal 077 Levesque, Mitchell Paul T-04 Marie, Beylot-Barry O-02, O-03, 036 Lewis, Daniel V-06, W-02 Marie, Parrens O-02 Lewis, Julia M. R-02, R-05, Z-13 Marie-Cardine, Anne I-01, T-01 Li, Shufeng W-03 Marion, Jost G-06 Liliane, Laroche 041 Marion, Wobser H-01, Z-27, 002 Limeres Gonzalez, Miguel M-01 Mariscal Polo, Amaya 021 Ángel Marquez Navarro, Jose 034 Lindahl, Lise Marie 062 Antonio Linna, Miika 081 Marschalkó, Márta C-01, Z-05, 058, 059 Linos, Konstantinos 032 Marschalko, Martha C-02 Lisano, Julie V-05 Marshall, William S. 071 Litman, Thomas 062 Martí Laborda, Rosa Maria 043 Little, Meredith V-05 Martin, Rubeta C-02 Litvinov, Ivan 018 Martine, Bagot J-03, 036 Liu, Fengjie 031 Martínez De Lagrán 033, 047, 051, 057 Llobera, Clàudia Z-06 Álvarez De Arcaya, Zuriñe Lobato Izagirre, Ane 019, 021, 034 Martinez Escala, Maria N-01 Lobo, Carmen M-01 Martínez Villarreal, Amelia 018 Lombardi, Clara Z-07 Martinez, Xochiquetzal P-04, 082 Longo, Caterina 075 Martínez-Aracil, Álvaro 057 Lopert, Pamela 071 Pérez Lopes Iori, Nathalia Z-12, 040 Martinez-Escala, Maria B-04, B-05, L-01, O-01, Estela Z-02, 049 López Aventín, Daniel L-04, 020 Martínez-González, María 047 Lopez, Arantxa Z-07 Isabel Lopez-Lerma, Ingrid L-04, V-01, 055 Mary, Wain U-03 López-Pestaña, Arantxa 050 Massuda Serrano, Juliana Z-10, Z-12, Z-16, Z-24, 028, López-Sánchez, Cristina 016 Yumi 040

120 INDEX OF AUTHORS

Mateos-Mayo, Ana 056, 068 Montenegro, Társila M-01 Matin, Rubeta C-01 Morgan, Elizabeth A. O-01 Matteo, Elena O-05 Morgan, John F-01 Matthias, Borgmann 069 Morimura, Sohshi G-05 Max, Schlaak H-01 Morizane, Shin 044 Mazuz, Moran Z-29 Morris, Stephan X-05 Mccormack, Christopher M-02, Z-25, 035 Morris, Stephen T-03, U-03 McDonald, Ryan 071 Morschhauser, Franck T-01 Mcniff, Jennifer Z-13 Moshir, Mahan T-01 Medhi, Syed Jafar E-02, L-03 Moskowitz, Alison I-02, Z-04, 037, 071 Mehmet, Baltaci Z-27 Mostafa, Ahmed Z-22 Mehta-Shah, Neha P-02, P-03, P-05 Motolese, Alberto 075 Mei, Hailiang N-03 Motta, Giovanna T-01 Melchers, Rutger X-04, Z-08 Mourah, Samia 008 Melle, Federica T-01 Moy, Andrea P. O-01 Menarguez Palanca, Javier 068 Moyal, Lilach K-03, Z-29 Mendivil, Begoña Z-07 Mozos, Ana 016 Menzel, Ulrike T-04 Mozzicafreddo, Giorgio 075 Merkel, Emily Z-21 Mühleisen, Beda O-06 Merlio, Jean-Philippe K-02 Muniesa, Cristina V-01, Z-06 Meruelo Ruano, Mikel 021, 030, 034 Muro, Manuel L-04 Michel, Laurence Z-09, 029 Musette, Philippe I-01 Michel, Mirna Z-14, Z-22, 013 Musiek, Amy P-02, P-03, P-05, Y-03 Michelena, Miren Josune 022 Myskowski, Patricia L. I-02, N-02, Z-04, 037 Michot, Jean-Marie T-01 N Miles, Rodney 017 Nacagami Sotto, Mirian 063 Mimitou, Eleni L-02 Nagarajan, Priyadharsini B-06 Mink, David Y-03 Nagy, Zsolt 059 Miotto, Isadora 063 Najidh, Safa G-03 Miranda, Roberto B-06 Nakagawa, Yuki 044 Mirhadi, Sara 073 Nakajima, Rina 066 Mirza, Fatima N. D-02, R-02, R-05, Z-13 Namdar, Dvora Z-29 Mitchell, Tracey J. G-04, H-02, R-04, S-02 Nassar, Ahmed Z-22, Z-28, 013 Mitteldorf, Christina B-01, B-02, C-01, C-02 Nasta, Sunita V-06 Miyagaki, Tomomitsu G-05, 027, 066, 067 Navarini, Alexander O-06 Miyashiro, Denis C-04, V-03, Z-26, 063 Navarrete-Viveros, Jesus B-06 Mo, Samuel H. N-01 Neal, Tatiana M. X-06, X-07 Moerman-Herzog, Andrea E-02, L-03, 060 Neder Ramires Abdo, V-03, Z-26 Mohamed, Abdelrahman Z-22 Andre Mohanad, Aljundi 041 Ngu, Ivy X-02 Moins-Teisserenc, Hélène T-01 Nguyen, Morgan T. Z-02 Molgó, Montserrat D-04, Z-11, Z-15 Nicolas, Faur O-03 Molinelli, Elisa 075 Nicolay, Jan P. 001 Monfrecola, Giuseppe 075 Nieto-Benito, Lula Maria 056, 068, 079 Monteagudo, Carlos M-01 Nikbakht, Neda J-04, V-02

121 INDEX OF AUTHORS

Nik-Zainal, Serena G-04 Parekh, Vishwas M-03 Nobre, Aretha 007 Parente Almeida, Isabella Z-26 Noor, Sarah I-02, Z-04, 037 Park, Joonhee L-01, N-01 Nowica, Karina K-01 Park, Katherine E. B-05 Nunes Secamilli, Elisa Z-10, Z-12, Z-16, Z-24, 028, Parnitzke, Ulrike S-05 040 Parodi, Aurora 075 O Parra Blanco, Veronica 056, 068 Océane, Ducharme O-03 Parry, Eileen X-02 Ócsai, Henriette Z-05 Pascal, Joly 036 O'donnell, Megan J-04, V-02 Patel, Varsha M. R-04 Odum, Niels G-02, L-02, 062 Patino, Patricia W-01 Offidani, Anna Maria 075 Patrizi, Annalisa 025, 065 Offner, Fritz T-01 Patrone, Christina R-03 Ogueta, Isabel Z-11 Patsatsi, Aikaterini F-03, 024 Oka, Tomonori G-05, 066, 067 Patterson, Jordan 014, 015 O'keefe, Sandra 014, 015 Paulli, Marco N-03 Oláh, Judit Z-05 Pauwels, Patrick T-01 O'leary, Daniel X-03, 011 Paxton, Christian N. O-01 Olek-Hrab, Karolina K-01 Pearson, David D-06 Olisova, Olga I-03, 012 Pease, David R. L-01, N-01 Olmedilla, Gabriel 045 Pellegrino, Michele 075 Olmos, Ferran 053 Pereira Quintella, Leonardo 006 Olszewska, Berenika T-02 Pereira, Juliana C-04, V-03, Z-26, 063 Ondarra, Laida Z-07 Pérez Manich, Juliette 043 Onida, Francesco U-02 Pérez Parrio, Silvia 019 Orlovius, Martin 072 Perez, Nuria H-03 Ortiz Romero, Pablo L. B-01, B-02, C-01, V-05, X-01 Perez-Ferriols, Amparo V-01 Oschlies, Ilske 054 Pestano, Linda A. 071 Ouyang, Zhengqing L-02 Pham-Ledard, Anne K-02 P Philippe, Ruminy O-02 Pacheco, Theresa Y-02 Phillip, Jude M. S-04 Pacifico, Alessia 075 Phillips, Adrienne 071 Paczkowska, Julia K-01 Phillips, Scott 070 Pajares, Raquel M-04 Piątkowska- Jakubas, Beata Z-19 Palanca-Wessels, Maria V-05 Piccinno, Roberta 075 Corinna Pierce, Brian G. N-01 Palanicawandar, Renuka U-03 Pierre-Julien, Viailly O-03 Palmer, Joycelynne P-04 Pigatto, Paolo 075 Palomar Moreno, Carmen H-03 Pigem, Ramon 039 Irene Pikou, Olga F-03, 024 Palomero, Teresa R-03 Pileri, Alessandro 025, 065, 075 Papadaki, Marianna 064 Pileri, Stefano T-01 Papadavid, Evangelia B-01, B-02, C-01, C-02, X-01, 064 Pimpinelli, Nicola C-01, 042, 075 Papaleo, Natalia M-05, 023, 053 Pincus, Laura B-05, Z-02 Papathemeli, Despoina F-03, 024

122 INDEX OF AUTHORS

Pineiro-Maceira, Juan 004 Rassek, Karolina K-01 Manuel Raźny, Małgorzata Z-19 Pinter-Brown, Lauren V-05, 071 Reimann, Philip 072 Piperi, Christina 064 Ren, Rongqin Ren Z-01, Z-18 Piris Pinilla, Miguel Ángel H-03, M-01, M-04, O-05, René, Stranzenbach H-01, Z-27, 002 045 Reneau, John V-04 Podkowik, Magdalena G-02 Requena Caballero, Luis M-01, O-05 Poglio, Sandrine K-02 Revuelta, Maria Victoria S-04 Poligone, Brian Y-02, Y-04, Z-03, 026 Reyes-Baraona, Francisco D-04, Z-11 Pontes, David Z-02 Ribrag, Vincent T-01 Porcu, Pierluigi J-04, V-02, X-01 Rieger, Kerri E. B-05, X-06, X-07 Porkert, Stefanie J-01 Riera-Monroig, Josep 003, 038, 039 Prag Naveh, Hadas Y-01 Ringbloom, Kimberly G. L-01, N-01, O-01 Priebe, Waldemar T-02 Rivet, Jaqueline Z-09, 008 Prieto Torres, Lucia M-04, 045 Robert, Knobler 072 Prieto, Victor B-06 Roberts, Ken U-04 Prince, Henry Miles C-01, V-05, X-01, Z-25 Robson, Alistair B-01, B-02 Pro, Barbara L-01, N-01, Z-02, Z-21 Rodríguez Moreno, Marta M-01 Prochazkova-Carlotti, K-02 Martina Rodríguez Pinilla, Socorro H-03, M-01, M-04, O-05, 045 María Przybylski, Grzegorz K-01 Rodriguez, Eva R-01 Puelles, Jorge 077 Rodriguez-Lomba, 056 Puig, Lluis 016 Enrique Puiggros, Anna L-04 Rodríguez-Peralto, Jose M-01 Pujol Vallverdú, Ramon M. C-02, L-04, M-05, R-01, Luis 020, 023, 046, 053 Rojas, Patricio Z-15 Pulido-Perez, Ana 056, 068, 079 Roland, Schneiderbauer Z-27 Pulitzer, Melissa B-01, B-02, B-05, I-02, Romero-Jimenez, Rosa 079 N-02, Z-04, 037 Roncador, Giovanna 065 Pullion, Christopher Z-03 Rook, Alain H. V-06, W-02, 009, 080 Putter, Hein X-04 Rook, Bathanie B-02 Q Rooke, Bethanie B-01, X-02 Quaglino, Pietro B-01, B-02, C-01, V-05, Ropio, Joana K-02 X-01, 072, 073, 075 Rosell Díaz, Angel Manuel 056, 068, 079 Querfeld, Christiane B-01, B-02, C-01, C-02, E-01, K-04, M-03, P-04, Rosen, Steve T. E-01, K-04, M-03, P-04, S-06, Y-02, Y-03, 071, 082 S-06, 082 Quinn, S. Aidan R-03 Rosenberg, Abby P-02, P-03, P-05 Quint, Koen D. B-03, O-04, X-04, Z-08 Rosenthal, Jaclyn M. 080 Roses Gibert, Pau 033, 047, 051, 057 R Roshal, Mikhail I-02 Rabionet, Raquel L-04 Rovira-López, Roger 023, 046 Rahmatallah, Yasir L-03, 060 Rozati, Sima D-03 Ramelyte, Egle T-04 Ruan, Jia S-04 Ramos, Juan 071 Rubin, Paul 071 Ram-Wolff, Caroline D-01, Z-09, 008, 029, 073 Rudolf, Stadler H-01, 002 Rao, Deepak L-01 Rueda, Xavier 076

123 INDEX OF AUTHORS

Rupoli, Serena 075 Segues, Nerea Z-07 Rytenband, Fernanda 028, 040 Selli, Mehmet E. N-01 S Semenov, Yevgeniy P-02, P-03, P-05 Sabattini, Elena 025, 065 Sergij, Goerdt H-01 Sabine, Brechignac 041 Seropian, Stuart U-04 Sacha, Tomasz Z-19 Servitige, O. C-02 Sadoux, Aurélie 008 Servitje, Octavio C-01, L-04, V-01, Z-06 Sáenz Aguirre, Amaia 033, 047, 051, 057 Shaw, Lisa J-01 Sagasta Lacalle, Amaia 051 Shea, Christopher N-01 Sahni, Nidhi L-01, N-01 Shi, Zhenrui S-01 Salar, Antonio V-01 Shih, David J.H. L-01, N-01 Samimi, Sara V-06, 080 Shimauchi, Takatoshi F-04 Samuel, Samira H-02 Shinohara, Michi 078 Sanches Jr, Jose Antonio B-01, B-02, C-04, V-03, Shono, Yuki 067 V-05, Z-26, 063 Shopsin, Bo G-02 Sánchez Díez, Ana 010 Sigues, Nerea M-01 Sánchez Frías, Marina O-05 Silberman, Sandra T-02 Esther Silence, Karen T-01 Sanchez Herrero, 068 Silva-Carmona, Mary Z-07, 050 Alejandro Yohana Sanchez Martin, Marta R-03 Silverberg, Jonathan I. Z-02 Sanchez, Blanca V-01 Sim, Van Ren T-03 Sanchez-Herrero, 056 Simonacci, Marco 075 Alejandro Simontacchi, Gabriele 042 Sanders, Cornelus X-04 Singh, Rajinder S-01 Santucci, Marco 042 Slavin, Monica Z-25 Saporiti, Giorgia U-02 Smibert, Peter L-02 Sara, Laurent Roussel 041 Smirnov, Konstantin 012 Sarah, Ivanoff 041 Soares, Paula K-02 Sarah, Menguy O-02 Sokołowska-Wojdyło, P-01, T-02 Saraki, Konstantina 064 Małgorzata Sarja, Stendel Z-27, 002 Solar, Irit C-03 Saskia, Oro 036 Solleveld, Nienke Z-08 Sato, Shinichi G-05, 027, 066, 067 Song, Joo M-03 Saulite, Ieva O-06 Sonigo, Gabrielle I-01 Savoia, Paola 075 Sophie, Ly Ka So J-03 Scarisbrick, Julia B-01, B-02, C-01, C-02, Soria Gili, Xavier 043 V-05, X-01, X-02, 072, 073 Souza, Elemir Macedo Z-16 Scher, Jose G-02 Sprecher, Eli C-03 Schiavone, Concetta U-02 Stadler, Rudolf B-01, B-02, C-01, V-05, Schrader, Anne M.R. O-04 X-01, Z-17, 072 Schroeder, Kristin M. S. 071 Stalin, Rajan N. Z-29 Schuster, Stephen V-06 Stehr, Henning J-02 Secrest, Aaron 017 Stéphane, Dalle 036 Seffens, Angelina G-01, G-02, L-02 Stiller, Tracey P-04 Segal, Leopoldo G-02 Stoll, Joseph Z-04, 037

124 INDEX OF AUTHORS

Stracht, Teresa V-01 Trager, Megan Z-09, 029 Streubel, Gundula S-05 Trascasa, Alvaro 045 Suarez-Fernandez, 068, 079 Trébol Urra, Izaskun 033 Ricardo Trotman, Judith V-05 Subtil, Antonio B-01, B-02 Trovato, Emanuele 075 Suga, Hiraku G-05, 027, 066, 067 Tsang, Mathew 018 Sugaya, Makoto G-05, 027, 066, 067 Turko, Patrick T-04 Sun, Amy L-02 Twigger, Robert Z-25 Suzuki, Natalia Naomi 028 U Sven, Schneider H-01 Ufkes, Nicole 017 Svetlana, Hamm 069 Uger, Robert E-03 Svoboda, Jakub V-06 Ulrike, Parnitzke 069 Szakonyi, József 058, 059 Urigoitia Ugalde, Peru 030 Szepesi, Ágota 058, 059 Urraca, Jose Maria Z-07 T Urtaran Ibarzábal, Amaia 051 Tabanelli, Valentina T-01 Uwe, Hillen Z-27 Takahashi, Takahide 044 V Takahashi-Shishido, G-05, 066 Vakeva, Liisa C-01, 081 Naomi Valentine, Jake Z-25 Tan, Timothy B-04 Valli, Viviana U-02 Tanja, Wulff 069 Van Cauwenberghe, Owen Z-29 Tao, Randa 017 Van De Loo, Merel Z-08 Tastanova, Aizhan T-04 Van Den Berg, Anke O-04 Tatsuno, Kazuki F-04 Van Der Sluijs-Gelling, A.J. G-03 Taylor, Kerry V-05 Van Der Weyden, Carrie Z-25 Teague, Jessica E. W-02 Van Dongen, J.J.M. G-03 Tegla, Cosmin G-02, L-02 Van Hall, Thorbald G-03 Tegtmeyer, Kyle L-01, N-01 Van Kester, Marloes Z-08 Teh, Benjamin Z-25 Van Rompaey, Luc T-01 Tensen, Cornelis P. G-03, N-03 Van Rossum, Michelle X-04 Tetzlaff, Michael B-06 Van Santen, Suzanne B-03 Thilo, Gambichler 002 Van Wezel, Tom O-04 Thomas, Bandres O-03 Varga, Erika Z-05 Thomas, Jane J. L-01, N-01 Vasiliki, Siozopoulou 061 Thonnart, Nicolas I-01 Vazquez, Ivonne M-05, 023, 053 Thornton, Susan 077 Venturini, Marina 075 Thorsten, Braun 041 Veraart, Joep X-04 Thursky, Karin Z-25 Vercellino, Laetitia 073 Tiroler, Amir Z-29 Vermaat, Joost S.P. O-04, X-04 Tokura, Yoshiki F-04 Vermeer, Maarten H. B-03, C-01, G-03, N-03, Tomb, Roland K-02 O-04, X-01, X-04, Z-08 Toquica, Alejandra 076 Vignon-Pennamen, Marie- Z-09, 008, 029 Torres Cabala, Carlos A. B-01, B-02, B-05, B-06 Dominique Torres, Ángeles M-01 Vilardell Vilellas, Felip 043 Torres, Victor G-02 Villasenor-Park, Jennifer V-06, 080

125 INDEX OF AUTHORS

Visentainer, Lorena Z-10 X Vittorio, Carmela V-06, W-02, 080 Xu, Haiying F-01 Vivanco Allende, Blanca O-05 Y Vízkeleti, Jűlia 058 Yang, Jingyi L-01, N-01, O-01 Volonteri, Victoria D-05 Yanguas, Ignacio 022 W Yoo, Jinah C-02, X-02, 073 Wachsmuth, Rachel X-02 Yu, Sebastian S-01 Wada, David 017 Yumeen, Sara D-02, R-02, R-05, Z-13 Wain, Mary T-03, X-05 Z Walewski, Jan V-05 Zabrocki, Piotr T-01 Walker, Christina J. B-04, B-05, Z-02, 049 Zain, Jasmine K-04, M-03, P-04, 071, 082 Walton, Kara E. 049 Zak, Ewa T-02 Wang, Erica B. J-02, W-03 Zaldua Arrese, Miguel 021 Wang, Jennifer Y. X-06, X-07 Zaletaev, Dmitry I-03 Wang, Weiwei 014, 015 Zamponi, Nahuel S-04 Wang, Yang F-01 Zaya, Romsin V-02 Weatherhead, Sophie X-02 Zeberio-Etxetxipia, Z-07, 050 Wehkamp, Ulrike C-01, C-02, G-06, H-01, Izaskun Z-27, 002, 054, 063 Zehir, Ahmet N-02 Weichenthal, Michael V-05 Zehnder, Mara O-06 Weinstock, David M. O-01 Zhang, Chunlei S-03 Weng, Wen-Kai U-01 Zhang, Kevin K. W-02 Wenzel, Alexander O-01 Zhang, Yancong L-01 Werner, Kempf Z-27 Zhou, Xiaolong O-01, Z-21, Z-02 Whittaker, Sean J. C-01, G-04, H-02, R-04, Zhou, Yan S-01 S-02, T-03, U-03, V-05, X-05 Zic, John B-01, B-02 Wilk, Mateusz Z-19 Zidan, Omri Y-01 Willemze, Rein B-03, C-01, N-03, O-04, Zimowska-Curyło, Z-19 X-01, X-04, Z-08 Dagmara Willerslew-Olsen, Andreas 062 Zinzani, Pier Luigi T-01, V-05, 025 William, Basem V-04, Z-01, Z-18 Zoutman, Willem H. G-03 Williams, Michael Y-03 Zubizarreta-Salvador, José 050 Williams, Paul J. 071 Zumalde, Amaia Z-07 Wilson, Lynn D. U-04 Żurawek, Magdalena K-01 Wobser, Marion C-01 Zwanenpoel, Karen T-01 Woetmann, Anders 062 Wong, Gane 014, 015 Wong, Henry K. E-02, L-03, 060 Wong, Mark E-03 Wu Yang, Ana Yi-Shi M-04 Wu, Xiwei K-04, S-06 Wu, Xuesong E-03, R-06, S-01 Wulff, Tanja S-05 Wysocka, Maria W-02

126

Technical Secretariat Grupo Pacifico C/ Maria Cubi, 4. 08006 Barcelona Spain [email protected]