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TABLE OF CONTENTS

WELCOME TO IRELAND ...... 5 ABOUT THE HISTIOCYTE SOCIETY ...... 6 2016 ANNUAL MEETING MOBILE APP ...... 6 ANNUAL MEETING PROGRAM ...... 6 HISTIOCYTOSIS ASSOCIATION AND HISTIOCYTE SOCIETY ...... 7 ACKNOWLEDGEMENTS AND RECOGNITIONS ...... 8 AT-A-GLANCE MEETING AGENDA ...... 10 GUEST SPEAKER HIGHLIGHTS ...... 12 MEETING AGENDA ...... 14 GUEST SPEAKER PRESENTATION ABSTRACTS ...... 27 SCIENTIFIC SESSION I ABSTRACTS ...... 32 SCIENTIFIC SESSION II: PRESIDENTIAL SYMPOSIUM ABSTRACTS ...... 35 SCIENTIFIC SESSION III ABSTRACTS ...... 38 POSTER PRESENTATION SESSION ABSTRACTS ...... 41 SCIENTIFIC SESSION IV ABSTRACTS ...... 76 NESBIT PRIZE IN CLINICAL SCIENCE ...... 78 NEZELOF PRIZE IN BASIC SCIENCE ...... 78 HISTIOCYTE SOCIETY GOVERNING BY-LAWS ...... 79 HISTIOCYTE SOCIETY CONSTITUTION ...... 81 PRESENTING AUTHOR INDEX ...... 82

MEETING SPONSORS

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WELCOME TO DUBLIN

Dear Colleagues,

I am thrilled to welcome you to Dublin, Ireland for the 32nd Annual Meeting of the Histiocyte Society, October 17-19, 2016.

Our meeting venue, the Killashee Hotel, located in the picturesque countryside of Naas, Co. Kildare, exudes Irish charm and sophistication. It is the perfect blend of historic architecture and modern day amenities with plenty of space to accommodate our growing group.

The Board and the Program Committee have prepared a very exciting program that we hope will continue to represent the scientific advances made during the last year while facilitating interactions and development of new collaborations. In addition to our scientific sessions, we have prepared two symposia: one to discuss advances in target therapies for LCH and ECD and another to look at the future of therapies for HLH. We have assembled a great group of speakers that I am sure will make the meeting memorable.

Following the success of last year, we will once again be integrating the use of our Annual Meeting Mobile App into the program. As technology advances and we seek to offer attendees the best possible experience, this mobile app will expand the opportunities for interaction, collaboration and information sharing right at your fingertips. The app is available for all Apple and Android devices by searching “Histiocyte Society” in your app store or visiting www.histiocytesociety.org/app. This year’s app also features a fully functional website version for those using a laptop.

Another highlight of the meeting each year is the Annual Banquet. This year’s banquet will be held at the Guinness Storehouse, located in the heart of the St. James's Gate Brewery in Dublin. Attendees are invited to explore the Storehouse through a self-guided tour, ending with the opportunity to learn how to “pull the perfect pint,” complete with the shamrock design in the head.

As you know, a great deal of time, energy and resources go into planning the meeting each year. We are grateful to our annual key sponsor, the Histiocytosis Association, without whose generous support, this meeting would not be possible. We are also thankful to our other sponsors, the Artemis Association, Histiocytosis UK and Failte Ireland.

I hope you take time to enjoy the beauty and charm of Dublin, Naas and the Irish countryside during your stay. There is much to see and experience!

As the President of the Histiocyte Society, I look forward to seeing you all over the course of this exciting meeting.

Carlos Rodriguez-Galindo President Histiocyte Society

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ABOUT THE HISTIOCYTE SOCIETY

The Histiocyte Society is a professional medical association comprised of more than 200 physicians and scientists from around the world. Members of the organization are considered to be the leaders in understanding and treating histiocytic disorders. The Society is committed to advancing knowledge about histiocytic disorders and improving outcomes for patients through the planning, development, sponsorship and oversight of clinical research.

Building Knowledge

The Histiocyte Society hosts an annual scientific meeting in different locations around the world. Attendance is open to members of the Society as well as other professionals working in the field of histiocytic disorders and related studies. Meetings feature presentations of individual and collective research efforts as well as keynote lectures from guest speakers; special-interest groups convene to discuss and develop new and innovative treatment regimes. This interactive forum allows the best and brightest minds in the histiocytosis community to share the most progressive information and to shape the future of research. Beyond the prolific exchanges that occur during the meeting, presenters work collectively to extend their reach by publishing subsequent articles and manuscripts in scientific journals worldwide.

Advancing Treatment

Through extensive research and collaboration, the Histiocyte Society has made numerous, significant strides in the fight against histiocytic disorders. The Society has established scientific standards for histiocytic disorders that are accepted worldwide; they include: 1) A common language of uniform disease classification, 2) Standardized diagnostic criteria, and 3) Guidelines for patient evaluation and follow-up. The Society remains dedicated to facilitating essential and innovative clinical research – developing critical knowledge and increasingly effective treatments in the pursuit of a cure.

2016 ANNUAL MEETING MOBILE APP

The 2016 Histiocyte Society Annual Meeting has a FREE custom mobile app ready for downloading! The app is available on the App Store, Google Play and in HTML5 for Blackberries, Windows phones, older devices and laptops. All of the information in the program book is also in the app, plus much more! Create your own custom agenda, read all of the abstracts, provide feedback about sessions, see what your colleagues are saying, access maps of Dublin, post pictures, and get the latest news and information right at your fingertips! Find it in your app store or go to www.histiocytesociety.org/app on your mobile device. *Standard data and text messaging rates may apply depending on your service provider.

ANNUAL MEETING PROGRAM

Copyright 2016 by the Histiocyte Society All programs presented at the 2016 Annual Meeting constitute copyrighted presentations owned by the Histiocyte Society. The copyright of the 2016 Histiocyte Society Annual Meeting Program is owned by the Histiocyte Society. The Histiocyte Society reserves the rights to all recordings and reproductions of presentations at this Annual Meeting and all Histiocyte Society educational and scientific meetings. Photography Consent Registration for, attendance at, and participation in the 2016 Histiocyte Society Annual Meeting and other activities constitutes an agreement by the participant to allow the Histiocyte Society to use and distribute (both now and in the future) the registrant’s or attendee’s image and/or voice in photographs, video, electronic reproductions and audio of such events and activities.

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HISTIOCYTOSIS ASSOCIATION AND HISTIOCYTE SOCIETY

Separate Organizations, One Goal

The Road to Partnership

Three-month old Bethany Toughill was diagnosed in 1983. Bethany’s dad, Jeff, and her mother, Sally, experienced the same fear that today’s parents feel when learning that their child has this disease. Alone and frustrated, Sally and Jeff were led to find other families affected by histiocytosis so that they could emotionally support each other. In 1986 they founded the Histiocytosis Association, a community comprised of patients, parents, family members and friends.

At about the same time that the Association was founded, a group of physicians formed the Histiocyte Society – an international group of clinicians and scientists committed to improving the lives of patients with histiocytic disorders by conducting clinical and laboratory research into the causes and treatment of this disease. Recognizing that these two groups had the same goal, Histiocytosis Association President Jeffrey Toughill offered the Association’s business resources to help manage the Histiocyte Society. Thus began the partnership that still exists today.

A True Partnership

The Histiocytosis Association and the Histiocyte Society remain separate organizations working toward a common goal, with the Histiocytosis Association serving as the Society’s administrative center (Secretariat) and primary source of funding. The Histiocytosis Association serves the administrative needs of the Histiocyte Society by:

 Organizing and managing the Society’s annual scientific and Executive Board meetings,  Managing the overall organizational, administrative and financial operations,  Aiding in the development of organizational guidelines and operating procedures,  Building, developing and maintaining the organization and annual meeting websites,  Facilitating communication between Society members and the Executive Board, and  Building and managing the Society’s membership database.

The Histiocytosis Association Mission

The Histiocytosis Association is dedicated to raising awareness about histiocytic disorders, providing educational and emotional support for patients and families and funding research leading to better treatments and a cure.

The Histiocytosis Association Research Program

At the very heart of the Histiocytosis Association is the steadfast commitment to finding a cure for histiocytic disorders. The Histiocytosis Association is committed and focused on a threefold research plan and philosophy:

 Funding basic science research being conducted worldwide identified through a competitive, peer-review process modeled after that of the National Institutes of Health. The Histiocytosis Association requests research proposals on a yearly basis – usually around May. Once research proposals are received the Histiocyte Society Scientific Committee serves as the first-step review. Scores from this review are then submitted to the Histiocytosis Association’s Scientific Advisory Committee (SAC) for a second review. The SAC then makes a recommendation to the Histiocytosis Association’s Board of Trustees concerning grants to be funded.  Funding clinical studies that result in identifying the best possible treatments for histiocytic disorders.  Facilitating research by administratively managing the Histiocyte Society.

Since 1992, 166 individual awards have been made to date, representing more than $6 million to support critical research around the world. Grant amounts now average $50,000 per project but have been awarded in amounts up to $100,000 in the past. The Histiocytosis Association of Canada (HAC) has provided $265,000 of that funding.

Two Organizations, One Goal

The Histiocytosis Association and the Histiocyte Society have been committed partners for nearly 30 years. Though separate organizations, they share a common goal that binds their continued partnership - to find better treatments and, ultimately, a cure leading to a world free of histiocytic disorders.

To learn more about the Histiocytosis Association visit www.histio.org.

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ACKNOWLEDGEMENTS AND RECOGNITIONS

HISTIOCYTE SOCIETY EXECUTIVE BOARD RARE HISTIOCYTIC DISORDERS STEERING COMMITTEE President ...... Carlos Rodriguez-Galindo Oussama Abla, Chairperson ...... 2013-2016 2013-2016 Jorge Braier ...... 2013-2016 President Elect ...... Milen Minkov Eli Diamond ...... 2015-2019 2014-2016 Eric Jacobsen ...... 2015-2019 Treasurer ...... Itziar Astigarraga Ron Jaffe ...... 2015-2019 2014-2016 Zdenka Krenova ...... 2015-2019 Secretary ...... Michael Jordan Jennifer Picarsic ...... 2015-2019 2014-2016

Member-at-Large ...... AnnaCarin Horne 2014-2017 HISTIOCYTE SOCIETY PAST PRESIDENTS Member-at-Large ...... Kim Nichols Jim Whitlock ...... 2010-2013 2014-2017 Alexandra Filipovich ...... 2007-2010 Jan-Inge Henter...... 2004-2007 HISTIOCYTE SOCIETY EDUCATION COMMITTEE R. Maarten Egeler ...... 2001-2004 Kimo Stine, Chairperson ...... 2014-2016 Kenneth McClain ...... 1998-2001 Oussama Abla ...... 2014-2016 Göran Elinder ...... 1996-1998 Anne-Sophie Carret ...... 2015-2017 Helmut Gadner ...... 1992-1996 Barb Degar ...... 2015-2017 Stephan Ladisch...... 1989-1992 Eli Diamond ...... 2015-2017 Blaise Favara ...... 1987-1989 David Dix ...... 2013-2015 Christian Nezelof ...... 1985-1987 Kai Lehmberg ...... 2015-2017

HISTIOCYTE SOCIETY SCIENTIFIC COMMITTEE Yenan Bryceson, Chairperson ...... 2013-2015 Stephan Ehl ...... 2014-2016 Julien Haroche...... 2015-2017 Caroline Hutter ...... 2015-2017 Rebecca Marsh ...... 2015-2017 Barrett Rollins ...... 2014-2016 Johannes Visser ...... 2015-2017 Kejian Zhang ...... 2015-2017

HISTIOCYTE SOCIETY STUDY GROUP CHAIRPERSONS Adult Histiocytosis ...... Michael Girschikofsky Epidemiology/Late Effects ...... Riccardo Haupt /Vasanta Nanduri LCH-IV ...... Milen Minkov/Carlos Rodriguez-Galindo Rare Histiocytic Disorders ...... Oussama Abla

HLH STEERING COMMITTEE Gritta Janka, Chairperson ...... 2013-2016 Maurizio Aricó ...... 2013-2016 Itziar Astigarraga ...... 2013-2016 Stephan Ehl ...... 2014-2018 Lisa Filipovich ...... 2014-2018 Jan-Inge Henter ...... 2014-2018 AnnaCarin Horne ...... 2015-2019 Eiichi Ishii ...... 2014-2017 Michael Jordan ...... 2013-2017 Kim Nichols...... 2015-2019 Elena Sieni ...... 2015-2019 Zhao Wang ...... 2015-2019

LCH STEERING COMMITTEE Cor van den Bos, Chairperson ...... 2015-2019 Carl Allen ...... 2013-2016 Karin Beutel ...... 2013-2017 Jean Donadieu ...... 2013-2017 Michael Girschikofsky ...... 2015-2019 Rima Jubran ...... 2013-2017 Milen Minkov...... 2014-2018 Vasanta Nanduri ...... 2013-2016 Carlos Rodriguez-Galindo ...... 2014-2018 Kimo Stine ...... 2014-2018 Johannes Visser ...... 2015-2019 Sheila Weitzman...... 2013-2016

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ACKNOWLEDGEMENTS AND RECOGNITIONS

NESBIT PRIZE IN CLINICAL SCIENCE AWARDEES HISTIOCYTE SOCIETY GOLDEN PIN RECIPIENTS Alexandra Löfstedt ...... 2015 R. Maarten Egeler ...... 2015 Vasanta Nanduri ...... 2014 Sheila Weitzman ...... 2014 Carl Allen ...... 2013 Shinsaku Imashuku...... 2010 Stephen Simko...... 2012 Helmut Gadner ...... 2008 Thomas Lehrnbecher ...... 2011 Jon Pritchard ...... 2006 Rebecca Marsh ...... 2010 Giulio D’Angio ...... 2002 Rebecca Marsh ...... 2009 Sally Kivilis ...... 2001 Jorge Braier ...... 2008 Elizabeth Kontoyannis ...... 2000 Kenneth McClain...... 2007 Paul Kontoyannis ...... 2000 Loretta Lau ...... 2006 Jeffrey M. Toughill...... 1998 AnnaCarin Horne ...... 2005

Marie Ouachée-Chardin ...... 2004 HISTIOCYTE SOCIETY HONORED MEMBERS Manuel Steiner ...... 2003 Jorge Braier ...... 2002 Helmut Gadner ...... 2008 Wolfgang Holter ...... 2001 Shinsaku Imashuku...... 2007 Kazuhiro Kogawa ...... 2000 Gritta Janka ...... 2007 Valerie Broadbent ...... 2000 NEZELOF PRIZE IN BASIC SCIENCE AWARDEES Blaise Favara ...... 1998 Benjamin Durham ...... 2015 Mark Nesbit ...... 1998 Samuel Chiang Cern Cher ...... 2014 Christian Nezelof ...... 1998 Gayane Badalian-Very/Kim Nichols...... 2013 Edward Behrens ...... 2012 Edward Behrens ...... 2011 Michelle Hermiston ...... 2010 Michael Jordan...... 2009 Matthew Collin ...... 2008 Kejian Zhang ...... 2007 Alessandra Santoro ...... 2006 Udo zur Stadt ...... 2005 Cristiana Costa/Kimberly Risma ...... 2004 Michael B. Jordan ...... 2003 Susan Lee/Joyce Villanueva ...... 2002 Maurizio Aricó ...... 2001 Pieter Leenen...... 2000

TRAVEL SCHOLARSHIP RECIPIENTS

Congratulations to the Histiocyte Society’s 2016 Travel Scholarship recipients:

Vinay Keshavamurthy for the abstract titled, “ACRAL SCLEROSING HISTIOCYTIC NODULES: A NEW ENTITY IN CUTANEOUS HISTIOCYTOSIS?” This abstract will be presented during the Poster Presentation Session on Tuesday, October 18, 2016.

Gitesh Sawatkar for the abstract titled, “IMATINIB FOR THE TREATMENT OF XANTHOMA DISSEMINATUM” This abstract will be presented during the Poster Presentation Session on Tuesday, October 18, 2016.

Ramya Uppuluri for the abstract titled, “HAPLOIDENTICAL STEM CELL TRANSPLANTATION WITH POST TRANSPLANT CYCLOPHOSPHAMIDE IN HAEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS: THE JOURNEY TO SUCCESSFUL ENGRAFTMENT AND CURE” This abstract will be presented during the Poster Presentation Session on Tuesday, October 18, 2016.

Each year the Histiocyte Society awards at least one scholarship based on the applicant’s demonstration of need for financial assistance in order to attend the Annual Meeting. Scholarships are awarded in the amount of $1,000 US and are based on the availability of funds.

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AT-A-GLANCE PRE-MEETING AGENDA

SATURDAY • OCTOBER 15, 2016 0800 – 1330 Executive Board Meeting* ...... Innovation Centre: Brainstorming Room and Syndicate 3 1330 – 1400 Coffee Break...... Innovation Centre 1400 – 1600 HLH Steering Committee Meeting* ...... Innovation Centre 1600 – 1700 Rare Histiocytic Disorders Steering Committee Meeting* ...... Innovation Centre: Syndicate 5 1700 – 1800 LCH Steering Committee Meeting* ...... Innovation Centre: Syndicate 4

SUNDAY • OCTOBER 16, 2016 0800 – 0900 LCH-IV Discussion Session* ...... Rathaskar Suite 0900 – 1030 LCH Disease Discussion Session* ...... Rathaskar Suite 1030 – 1100 Coffee Break...... Rathaskar Reception 1030 – 1130 LCH Adult Disease Discussion Session* ...... Rathaskar Suite 1130 – 1230 Rare Histiocytic Disorders Committee Session* ...... Rathaskar Suite 1130 – 1230 Histiocytosis Collaborative Summit* ...... Belling Suite 1230 – 1330 Lunch ...... Thomson Suite 1230 – 1330 Histiocytosis Association MSAC Committee Meeting* ...... Board Room 1 1330 – 1800 HLH Disease and MAS Discussion Session* ...... Rathaskar Suite 1830 – 2030 HLH “Next Study” Meeting* ...... Board Room 2 * Indicates closed session + Indicates that advance registration was required

After a long day, sit back and relax at “The Snug” Open Saturday, Sunday, Monday and Wednesday nights

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AT-A-GLANCE MEETING AGENDA

MONDAY • OCTOBER 17, 2016 0800 – 1700 Meeting Registration and Check-In ...... Rathaskar Reception 0800 – 0930 Poster Presentation Setup ...... Ainsworth Suite 0800 – 0930 Education Committee Meeting*...... Board Room 1 0800 – 0930 Scientific Committee Meeting* ...... Belling Suite 0930 – 0945 Opening Ceremonies ...... Rathaskar Suite 0945 – 1030 Guest Speaker Presentation: Claire Booth ...... Rathaskar Suite 1030 – 1100 Coffee Break...... Rathaskar Reception 1100 – 1300 HLH Symposium: Targeted Therapies for HLH ...... Rathaskar Suite 1300 – 1400 Lunch ...... Thomson Suite 1300 – 1400 HLH/MAS Meet the Expert Lunch Session+ ...... Board Room 1 1300 – 1400 Rare Meet the Expert Lunch Session+ ...... Belling Suite 1300 – 1400 Family Group and Research Collaboration Lunch* ...... Board Room 2 1400 – 1530 Scientific Session I: Oral Presentations ...... Rathaskar Suite 1530 – 1600 Coffee Break...... Rathaskar Reception 1600 – 1730 Scientific Session II: Presidential Symposium ...... Rathaskar Suite 1730 – 1830 General Assembly Business Meeting* ...... Rathaskar Suite 1830 – 2030 Welcome Reception ...... The Original House, Killashee Hotel

TUESDAY • OCTOBER 18, 2016 0800 – 1300 Meeting Registration and Check-In ...... Rathaskar Reception 0800 – 0900 Clinical Studies and Registries Update ...... Rathaskar Suite 0900 – 0945 Guest Speaker Presentation: Kingston Mills ...... Rathaskar Suite 0945 – 1015 Coffee Break...... Rathaskar Reception 1015 – 1200 LCH/ECD Symposium ...... Rathaskar Suite 1200 – 1300 Lunch ...... Thomson Suite 1200 – 1300 LCH Meet the Expert Lunch Session+ ...... Board Room 1 1200 – 1300 Asian and Middle Eastern Working Group* ...... Belling Suite 1300 – 1430 Scientific Session III: Oral Presentations ...... Rathaskar Suite 1430 – 1445 Presidential Transition ...... Rathaskar Suite 1445 – 1645 Poster Presentation Session ...... Ainsworth Suite 1600 – 1800 HLH Registry Training ...... Fountain Suite 1815 Group Transportation to Histiocyte Society Annual Banquet ...... Killashee Hotel Lobby 1915 – 0100 Histiocyte Society Annual Banquet ...... Guinness Storehouse

WEDNESDAY • OCTOBER 19, 2016 0800 – 1200 Meeting Registration and Check-In ...... Rathaskar Reception 0800 – 0845 Executive Board Meeting* ...... Innovation Centre 0800 – 0845 Education Committee Meeting*...... Board Room 1 0800 – 0845 Scientific Committee Meeting* ...... Belling Suite 0900 – 1000 Jon Pritchard Lecture on the Nikolas Symposium: Barrett Rollins ...... Rathaskar Suite 1000 – 1030 Coffee Break...... Rathaskar Reception 1030 – 1200 Scientific Session IV: Oral Presentations ...... Rathaskar Suite 1200 – 1215 Closing Ceremonies: Awarding of Scientific Prizes ...... Rathaskar Suite

Complimentary Shuttle Service to and from The Osprey Hotel and Killashee Hotel will be available daily.

Pick Up at The Osprey Going to Killashee Hotel: Pick Up at Killashee Returning to The Osprey: Saturday, October 15 through Wednesday, October 19 Saturday, October 15 through Tuesday, October 18 at 0745 and 0830 daily at 1730 daily

Wednesday, October 19 at 1300

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GUEST SPEAKER HIGHLIGHTS

Ed Behrens is the Joseph Lee Hollander Chair in Pediatric Rheumatology and Chief of the Division of Rheumatology at The Children’s Hospital of Philadelphia. He has a particular interest in cytokine storm syndromes including Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome. His research focuses on understanding the immunologic mechanisms that lead to cytokine storm in sick patients, and the control mechanisms that prevent cytokine dysregulation in healthy individuals. Most recently, using mouse models of HLH, his laboratory has uncovered a novel role for the cytokine IL-33 in driving the fatal cytokine response of HLH. This paves the way for blockade of this cytokine and its receptor as a possible therapeutic avenue for HLH and other cytokine storm syndromes.

Claire Booth is a Clinical Lecturer at UCL Institute of Child Health and Honorary Consultant in Paediatric Immunology and Gene Therapy at Great Ormond Street Hospital, London. She graduated from Guy’s, King’s and St. Thomas’ School of Medicine in 2001 and then trained in Paediatrics, subspecialising in Paediatric Immunology and Immunodeficiency. She undertook a PhD in Prof. Bobby Gaspar’s lab developing haematopoietic stem cell gene therapy to treat XLP. She now works as a clinical academic involved in an expanding number of gene therapy clinical trials at Great Ormond Street Hospital which treats patients with immune deficiencies and haematological disorders. Her pre-clinical research focuses on the development of gene therapy strategies to treat XLP-1 and XIAP deficiency using a conventional lentiviral mediated corrective strategy alongside exploration of novel gene editing techniques to facilitate targeted gene addition in both haematopoietic stem cells and T cells. Claire is a member of the HLH Registry Steering Committee, Board Member of the British Society of Gene and Cell Therapy and sits on the International Committee of the American Society of

Gene and Cell Therapy.

Geneviève de Saint Basile studied Medicine in Paris, received an MD from University Paris Descartes and a PhD in Immunology from the University Paris Diderot. She is currently Research Director at INSERM and the head of an INSERM research group at Imagine Institute in Paris. Her main research interests are on the mechanismes involved in the development and the homeostasis of the immune system through the studies of inherited deficiencies. For the last 15 years, her research group has molecularly characterized most of the inherited forms of HLH including Perforin deficiency, Munc13-4 deficiency and Munc18-2 deficiency as causes of FHL and Rab27a deficiency as a cause of Griscelli syndrome. These studies first demonstrated the critical role of the granule dependent cytotoxicity of lymphocytes in the control of immune homeostasis in humans. These studies also allowed to accurately dissect the molecular machinery that regulates cytotoxic granule secretion. Dr. Geneviève de Saint Basile and her research group have generated and explored murine models of HLH and evidenced the contribution of NK cells as well as the role of polygenic mutations in HLH development. Using these experimental murine models she showed the efficacy of anti-INFy in HLH treatment. Geneviève de Saint Basile is also Attached Physician (AP-HP) for the molecular diagnosis of primary immune disorders, at the “Centre d’étude des deficits immunitaires” (CEDI) at Necker-Enfants Malades Hospital in Paris. Geneviève de Saint Basile has been the recipient of the INSERM research prize (2011), Etancelin (Académie des Sciences) prize (2007) and Lucien Tartois (Fondation pour la recherche Médicale) prize (2005) and is a member of the European Molecular Biology Organization since 2009. She is the co-author of 191 publications in peer-reviewed journals.

Jean Donadieu is the founder and coordinator of the french histiocytosis study group and is currently a full time MD in the pediatric hemato oncology department of Trousseau Hospital Paris and managed daily the french Histiocytosis registry (www.histiocytose.org). After a training in pediatric immunology and hematology, he undertook a PhD in public health and epidemiology. He is also coordinating the french neutropenia network. He was the former coordinator of the Euro histio net project and have taken several responsibilities in the Histiocyte Society in the last 20 years and was the president the immuno hematology pediatric society during the last 2 terms. He is currently member of the steering committee of the HS.

Benjamin H. Durham is a hematopathologist and molecular genetic pathologist who currently serves as a genomic pathology research fellow in molecular oncology in the Department of Pathology at Memorial Sloan Kettering Cancer Center. Dr. Durham studies the molecular hematopathology and functional genomics of poorly characterized hematopoietic malignancies such as the histiocytoses and hairy cell leukemia in the laboratories of Omar Abdel-Wahab, M.D., a hematologist and cancer biologist, and Christopher Y. Park, M.D., Ph.D, a hematopathologist and stem cell biologist, in the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center. Dr. Durham’s most recent work under the mentorship of Omar Abdel-Wahab has focused on the genomic landscape and functional genomics of the systemic histiocytic neoplasms that led to the first description of kinase fusions in the histiocytic neoplasms, the discovery of the first activating MAP2K1 and ARAF mutations in the non- Langerhans cell histiocytic neoplasms, and the first published use of MEK inhibition and sorafenib in patients with refractory, life-threatening, systemic histiocytoses, which led to dramatic clinical responses. This work was co-first authored by Eli L. Diamond, Benjamin H. Durham, and Julien Haroche and published in Cancer Discovery late in 2015. Dr. Durham also performs the functional genomic correlative studies for a phase II investigator-initiated clinical trial of single agent cobimetinib in systemic histiocytosis patients being conducted by Eli L. Diamond, M.D. at Memorial Sloan Kettering Cancer Center. Dr. Durham is also actively investigating the cell of origin of the non-Langerhans cell histiocytoses and the development of murine models of histiocytic neoplasms. Dr. Durham received his Bachelor of Science degree in biochemistry and molecular biology from the University of Alabama at Birmingham, Birmingham, AL. He received his M.D. from the University of Alabama School of Medicine. He completed his anatomic and clinical pathology residency at St. Louis University School of Medicine, St. Louis, MO. He then completed his hematopathology fellowship at the University of California, Davis, School of Medicine, Sacramento, CA, and his molecular genetic pathology fellowship at Columbia University College of Physicians and Surgeons, New York, NY.Benjamin Durham has been the recipient of several honors during the course of this work on the histiocytoses that include a 2015-2016 Senior Investigator Research Training Award for Fellows from the American Society of Hematology; a 2015 Stowell-Orbison Award Certificate of Merit from the United States and Canadian Academy of Pathology; the 2015 Pathologist-in-Training Award from the Society for Hematopathology; the 2015 Nezelof Prize in Basic Science from the Histiocyte Society; his selection, along with Eli Diamond, to present their and their co-authors’ work as the keynote address at the 2015 International Erdheim-Chester Disease Medical Symposium; the 2016 Benjamin Castleman Award from the United States and Canadian Academy of Pathology; and his selection as one of the Dr. Jon Pritchard Fellows of the 2016 Nikolas Symposium.

Biographical information provided by guest speakers.

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GUEST SPEAKER HIGHLIGHTS

Julien Haroche is a professor in internal medicine, at Pitié-Salpêtrière hospital, Paris, France. Since 2003, his main research field is Erdheim-Chester disease (ECD) upon which he has acquired a word-renowned experience. To date, he has seen more than 150 patients followed at his institution. His other research fields are the other histiocytoses, such as Langerhans cell histiocytosis, mixed histiocytoses (LCH & ECD) and Rosai-Dorfman disease. He is also interested in vasculitis, lupus and antiphospholipid syndrome. During the past decade, he has described most relevant clinical and radiological aspects and increased the awareness of the disease, and showed that interferon α was a first line efficient therapy. Recently BRAFV600E mutations was shown in 50 to 75 % of ECD cases lending support to the sustained and reproducible efficacy of BRAF inhibitors in severe cases of BRAFV600E mutated ECD. His team was the first to use BRAF inhibitors in BRAF mutated histiocytoses. He is also involved in the description of other recurrent somatic mutations of the MAP kinase and AKT pathways, including mutations of NRAS, and PIK3CA. Following the characterization of recurrent mutations of the MAK kinase pathway in ECD, the disease is now considered as an inflammatory myeloid neoplasia.

Michael Jordan Michael Jordan’s interest in histiocytic disorders starting during his training in Pediatric Hematology/ Oncology in the mid-90’s when he was amazed by the varied and mysterious nature of both LCH and HLH. When the first gene underlying familial HLH was discovered in 1999, he began to study the development of HLH. These studies led to the groundbreaking publication in 2004 first demonstrating that perforin-deficient mice develop HLH after viral challenge. They defined the critical role of T cells and interferon gamma in this disease process, shaping subsequent scientific and clinical thinking. He has continued to focus on understanding and treating HLH, publishing a series of papers better defining its development and treatment in our experimental model. These studies have served, in part, as the basis for ongoing clinical trials (HIT-HLH) and new drug development for patients with HLH (Novimmune, NI-0501). His clinical focus has remained on patients with histiocytic disorders and his efforts have contributed to improvements in salvage therapy for HLH (alemtuzumab) and marrow transplantation for these patients. He has been active within the Histiocyte society for over a decade, serving in several capacities.

Kingston Mills is Professor of Experimental Immunology, School of Biochemistry and Immunology, Trinity College Dublin (TCD). He is Head of the Immunology, Inflammation and Infection research theme at TCD. He trained at as a Postdoctoral Fellow at University College London and the NIMR, Mill Hill, London, before joining the Scientific Staff of NIBSC, Herts, UK. He was appointed to a Personal Chair at Trinity College Dublin in 2001 and was Head of the School of Biochemistry and Immunology from 2008-2011. He is a co-founder of University spin-out companies Opsona Therapeutics and TriMod Therapeutics. He heads an active research team focusing on T cells in infection and autoimmunity.

Kim Nichols is a pediatric oncologist whose research focuses on understanding the molecular and cellular mechanisms that predispose to hemophagocytic lymphohistiocytosis (HLH), particularly when it occurs in the context of Epstein Barr Virus (EBV) infection. Dr. Nichols was among the first to identify the gene defective in X-linked lymphoproliferative disease (XLP), a rare primary immunodeficiency associated with increased risk for EBV-induced HLH, B cell lymphomas and progressive hyopgammaglobulinemia. For the last 18 years, Dr. Nichols and her research group have worked to dissect how the XLP gene product SAP regulates immune cell development and function and coordinates host immunity to EBV. Through these efforts, she and her collaborators have identified key roles for SAP during regulation of Th2-type cytokine production, natural killer (NK) and invariant NKT (iNKT) cell cytotoxicity, iNKT cell development and T cell restimulation-induced cell death. Dr. Nichols has also explored the use of B-cell directed therapies such as rituximab, as well as other targeted approaches in the treatment of children and adults with HLH. Most recently, Dr. Nichols’s research group has examined the therapeutic efficacy of janus kinase inhibition using murine HLH models. She is now working to develop a multi-institution clinical trial for HLH that incorporates the use of this medication. Dr. Nichols is a past member of the Scientific and Education Committees and a current member of the HLH Steering Committee of the Histiocyte Society (HS), where she also participates in several of the HLH working groups and serves as a Member-at-Large on the HS Executive Board.

Barrett J. Rollins serves as the Chief Scientific Officer of Dana-Farber Cancer Institute in Boston, MA, and is a professor of Medicine at Harvard Medical School. Since joining Dana-Farber in 1989, Dr. Rollins has worked in the area of white blood cell trafficking and the interactions between inflammation and cancer. More recently his work has focused on the genetics of LCH. Dr. Rollins graduated from Amherst College and received his M.D. and Ph.D. from Case Western Reserve University. After completing his internship and residency in internal medicine at Beth Israel Hospital, Boston, he was in clinical fellowship in medical oncology and postdoctoral research fellowship at Dana-Farber. Dr. Rollin’s is a member of the Histiocyte Society and the Histiocytosis Association Medical Scientific Advisory Committee.

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MEETING AGENDA: SATURDAY, OCTOBER 15, 2016

Attendance at the Steering Committee Meetings is limited to members of that Steering Committee. A detailed agenda will be provided by the Steering Committee Chairperson. 0800 – 1330 Executive Board Meeting* ...... Innovation Centre: Brainstorming Room and Syndicate 3

1330 – 1400 Coffee Break ...... Innovation Centre

1400 – 1600 HLH Steering Committee Meeting* ...... Innovation Centre

1600 – 1700 Rare Histiocytic Disorders Steering Committee Meeting* ...... Syndicate 5

1700 – 1900 LCH-IV Steering Committee Meeting* ...... Syndicate 4

MEETING AGENDA: SUNDAY, OCTOBER 16, 2016

Attendance at pre-meeting sessions is limited to members of the Histiocyte Society who have registered in advance to participate. A detailed agenda will be provided to those registered for this day at the meeting.

0800 – 0900 LCH-IV Discussion Session* ...... Rathaskar Suite Session Moderator: Milen Minkov, Carlos Rodriguez-Galindo

0900 – 1030 LCH Disease Discussion Session* ...... Rathaskar Suite Session Moderator: Cor van den Bos

1030 – 1100 Coffee Break ...... Rathaskar Reception

1030 – 1130 LCH Adult Disease Discussion Session*...... Rathaskar Suite Session Moderator: Michael Girschikofsy

1130 – 1230 Rare Histiocytic Disorders Discussion Session* ...... Rathaskar Suite Session Moderator: Oussama Abla

1130 – 1230 Histiocytosis Collaborative Summit* ...... Belling Suite

1230 – 1330 Lunch…...... Thomson Suite

1330 – 1800 Histiocytosis Association MSAC Committee Meeting* ...... Board Room 1

1330 – 1800 HLH Disease and MAS Discussion Session* ...... Rathaskar Suite Session Moderator: AnnaCarin Horne, Gritta Janka

1830 – 2030 HLH “Next Study” Meeting* ...... Board Room 2

Silver Sponsor A Special Thank You To

www.histioUK.org

* Indicates Closed Session + Indicates that advance registration was required

14 HISTIOCYTE SOCIETY ANNUAL MEETING 2016

MEETING AGENDA: MONDAY, OCTOBER 17, 2016

0800 – 1700 Meeting Registration and Check-In...... Rathaskar Reception

0800 – 0930 Poster Presentation Setup ...... Ainsworth Suite

0800 – 0930 Education Committee Meeting* ...... Board Room 1 Scientific Committee Meeting* ...... Belling Suite

0930 – 0945 Opening Ceremonies ...... Rathaskar Suite Carlos Rodriguez-Galindo, Histiocyte Society President

0945 – 1030 Guest Speaker Presentation ...... Rathaskar Suite Session Moderator: Stephan Ehl

TOWARDS GENE THERAPY FOR HLH Claire Booth UCL Great Ormond Street Hospital Institute of Child Health, London, United Kingdom

1030 – 1100 Coffee Break ...... Rathaskar Reception

1100 – 1300 HLH Symposium: Targeted Therapies for HLH ...... Rathaskar Suite Session Moderator: Gritta Janka

IL-1 FAMILY MEMBERS IN HLH Ed Behrens Children’s Hospital of Philadelphia, Philadelphia, PA USA

THERAPEUTIC EFFECT OF JAK1/2 BLOCKADE ON THE MANIFESTATIONS OF HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS IN MICE Geneviève de Saint Basile INSERM UMR1163, Imagine Institute, Paris Descartes University-Sorbonne, Paris, France

TARGETING INTERFERON GAMMA (IFN- , THE DRIVER CYTOKINE IN HLH Michael Jordan Cincinnati Children's Hospital, Cincinnati, OH USA

JANUS KINASE INHIBITION IN THE TREATMENT OF HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS Kim Nichols St. Jude Children’s Research Hospital, Memphis, TN USA

1300 – 1400 Lunch ...... Thomson Suite

1300 – 1400 HLH/MAS Meet the Expert Lunch Session+...... Board Room 1 Lunch will be provided to Attendees in the meeting room.

AnnaCarin Horne Karolinska Institutet, Stockholm, Sweden

Kim Nichols St. Jude Children’s Research Hospital, Memphis, TN USA

1300 – 1400 Rare Meet the Expert Lunch Session+ ...... Belling Suite Lunch will be provided to Attendees in the meeting room.

Julien Haroche University Paris, Pitié-Salpêtrière Hospital, Paris, France

1300 – 1400 Family Group and Research Collaboration Lunch* ...... Board Room 2 Lunch will be provided to Attendees in the meeting room.

1400 – 1530 Scientific Session I: Oral Presentations ...... Rathaskar Suite Session Moderators: Scott Baker, Kai Lehmberg

HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS IN LANGERHANS CELL HISTIOCYTOSIS: A MULTICENTER RETROSPECTIVE DESCRIPTIONAL STUDY Deepak Chellapandian, Rui Zhang, Michael Jeng, Cor van den Bos, Vicente Santa-María López, Kai Lehmberg, Elena Sieni, Yini Wang, Taizo Nakano, James Williams, Nicholas Fustino, Itziar Astigarraga, Ira Dunkel, Qi An, Cheng Cheng, Sheila Weitzman, Lillian Sung, Kim E. Nichols

* Indicates closed session + Indicates that advance registration was required WWW.HISTIOCYTESOCIETY.ORG 15

MEETING AGENDA: MONDAY, OCTOBER 17, 2016

HETEROGENEITY OF MOLECULAR DIAGNOSES AND OUTCOMES IN A DIVERSE COHORT OF PATIENTS WITH HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS Ivan K. Chinn, Baruch R. Goldberg, Lisa R. Forbes, Sarah K. Nicholas, Emily M. Mace, Harshal A. Abhyankar, Maria I. Diaz, Luis A. Pedroza, M. Cecilia Poli, Sean A. McGhee, Zeynep C. Akdemir, Shalini N. Jhangiani, Donna M. Muzny, Tram N. Cao, Richard A. Gibbs, James R. Lupski, Jordan S. Orange, Kenneth L. McClain, Carl E. Allen

INNOVATIVE USE OF PK AND PD TO GUIDE DOSE SELECTION FOR A MONOCLONAL ANTIBODY AIMED AT NEUTRALIZING THE HIGH IFN-GAMMA ACTIVITY PRESENT IN PATIENTS WITH MACROPHAGE ACTIVATION SYNDROME (MAS) Cristina de Min, Kathy De Graaf, Maria Ballabio, Robert Nelson, Zoë Johnson, Walter Ferlin, Geneviève Lapeyre, Fabrizio De Benedetti, Philippe Jacqmin

PLASMA PROTEIN PROFILES DISTINGUISH HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS FROM SEPSIS AND SIRS Howard Lin, Baruch R. Goldberg, Brooks P. Scull, Harshal A. Abhyankar, Kenneth McClain, Jordana Goldman, Trung Nguyen, Michael Jordan, Hector Wong, Tsz-Kwong Man, Carl Allen

POLYGENIC MUTATIONS IN THE CYTOTOXICITY PATHWAY INCREASE SUSCEPTIBILITY TO DEVELOP HLH IMMUNOPATHOLOGY IN MICE Fernando E. Sepulveda, Alexandrine Garrigue, Sophia Maschalidi, Meriem Garfa-Traore, Gaël Ménasche, Alain Fischer, Geneviève de Saint Basile

HAPLOIDENTICAL HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR ADULT PATIENTS WITH EPSTEIN-BARR VIRUS-ASSOCIATED HAEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS Zhao Wang, Zhi-Hui Li, Yi-Ni Wang, Jing-Shi Wang, Li Fu, Na Wei, Lin Wu

1530 – 1600 Coffee Break ...... Rathaskar Reception

1600 – 1730 Scientific Session II: Presidential Symposium ...... Rathaskar Suite Session Moderator: Carlos Rodriguez-Galindo

PRESENTATIONS NOMINATED FOR THE NESBIT PRIZE IN CLINICAL SCIENCE (see page 78 for more information)

A COMBINATION OF ATG AND ETOPOSIDE FOR THE TREATMENT OF HLH: RESULTS OF THE HIT-HLH TRIAL Michael Jordan, Michael Henry, Carl Allen, Ken McClain, Jay Greenberg, Stephan Ladisch, Michelle Hermiston, Michael Jeng, Barbara Degar, Julie Kanter, Ahmed Naqvi, Michael Joyce, Kim Nichols, David Teachey, Rebecca Marsh, Michael Grimley, Stella Davies

DEVELOPMENT AND INITIAL VALIDATION OF THE "MH SCORE", A DIAGNOSTIC TOOL THAT DIFFERENTIATES PRIMARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS FROM MACROPHAGE ACTIVATION SYNDROME Francesca Minoia, AnnaCarin Horne, Francesca Bovis, Sergio Davi, Laura Pagani, Graciela Espada, Yi-Jin Gao, Antonella Insalaco, Kai Lehmberg, Helga Sanner, Susan Shenoi, Sheila Weizman, Nicolino Ruperto, Alberto Martini, Randy Q. Cron, Angelo Ravelli

ELEVATED CSF OSTEOPONTIN AND PERIPHERAL BLOOD CELLS WITH BRAF MUTATIONS IN PATIENTS WITH LANGERHANS CELL HISTIOCYTOSIS-ASSOCIATED NEURODEGENERATION Daniel Zinn, Jennifer Picarsic, Rikhia Chakraborty, Howard Lin, Harshal Abhyankar, Brooks Scull, Albert Shih, Karen Lim, Stephen Simko, Olive Eckstein, Tricia L. Peters, Walter Olea, Thomas Burke, Nabil Ahmed, D. Williams Parsons, M. John Hicks, Huy D. Tran, Jeremy Jones, Robert Dauser, Michael Jeng, Robert Baiocchi, Deborah Schiff, Stanton Goldman, Kenneth Heym, Ashish Kumar, Carlos Rodriguez-Galindo, Nicholas Whipple, Patrick Campbell, Geoffrey Murdoch, Simon Heales, Marian Malone, Randy Woltjer, Joseph Quinn, Paul Orchard, Michael Kruer, Ronald Jaffe, Sergio Lira, Miriam Merad, Tsz-Kwong Man, Kenneth L McClain, Carl E. Allen

PRESENTATIONS NOMINATED FOR THE NEZELOF PRIZE IN BASIC SCIENCE (see page 78 for more information)

CD8 T-CELL MEMORY RESULTS IN AN ENHANCED HLH DISEASE THAT IS RESISTANT TO IFN-GAMMA BLOCKADE Edward M. Behrens, Matthew Taylor

BRAF MUTATIONS IN BONE MARROW AND BLOOD OF PATIENTS WITH ERDHEIM CHESTER DISEASE Jean-François Emile, Fleur Cohen-Aubart, Claude Baillou, Damien Roos-Weil, Matthias Papo, Zofia Hélias-Rodzewicz, Makoto Miyara, Omar Ibrahim Abdel-Wahab, Olivier A Bernard, Zahir Amoura, François M Lemoine, Julien Haroche

BLOOD SPECIFIC ACTIVATION OF HIF-1α/HIF-1β CAUSES HLH IMMUNOPATHOLOGY IN C57BL/6 MICE Gang Huang, Rui Huang, Yoshihiro Hayashi, Xiaomei Yan, Michael B. Jordan, Alexandra H. Filipovich

1730 – 1830 General Assembly Business Meeting* ...... Rathaskar Suite

1830 – 2030 Welcome Reception ...... The Original House, Killashee Hotel

* Indicates closed session + Indicates that advance registration was required

16 HISTIOCYTE SOCIETY ANNUAL MEETING 2016

MEETING AGENDA: TUESDAY, OCTOBER 18, 2016

0800 – 1300 Meeting Registration and Check-In ...... Rathaskar Reception

0800 – 0900 Clinical Studies and Registries Update ...... Rathaskar Suite Session Moderator: Carlos Rodriguez-Galindo 0800 – 0815 HLH Registry Update 0815 – 0830 HLH 2004 Update 0830 – 0845 LCH-IV Update 0845 – 0900 Rare Registry Update

0900 – 0945 Guest Speaker Presentation ...... Rathaskar Suite Session Moderator: Jan-Inge Henter

MACROPHAGE AND DENDRITIC CELL MODULATION OF IMMUNE RESPONSES IN DIFFERENT DISEASE SETTINGS Kingston Mills Immune regulation Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland

0945 – 1015 Coffee Break ...... Rathaskar Reception

1015 – 1200 LCH/ECD Symposium...... Rathaskar Suite Session Moderator: Carl Allen

BRAF AND MEK INHIBITORS: HOW TO PREPARE THE NEXT GENERATION THERAPY IN LANGERHANS CELL HISTIOCYTOSIS! Jean Donadieu Service d’Hémato-Oncologie Pédiatrique, Hôpital Trousseau, Paris, France

HISTIOCYTIC NEOPLASMS AND THE RISE OF THE AGE OF PRECISION MEDICINE Benjamin Durham Memorial Sloan Kettering Cancer Center, New York, NY, United States

OUTCOMES OF 63 PATIENTS RECEIVING TARGETED THERAPIES FOR ERDHEIM-CHESTER DISEASE, INCLUDING OLLOW-UP AFTER INTERRUPTION (THE LOVE STUDY) Julien Haroche University Paris, Pitié-Salpêtrière Hospital, Paris, France

1200 – 1300 Lunch ...... Thomson Suite

1200 – 1300 LCH Meet the Expert Lunch Session+ ...... Board Room 1 Lunch will be provided to Attendees in the meeting room.

Jorge Braier Hospital de Niños R. Gutierrez and Hospital Nacional de Pediatría J. Garrahan, Buenos Aires, Argentina

1200 – 1300 Asian and Middle Eastern Working Group* ...... Belling Suite Lunch will be provided to Attendees in the meeting room.

1300 – 1430 Scientific Session III: Oral Presentations ...... Rathaskar Suite Session Moderator: Anne-Sophie Carret, Jim Whitlock

IDENTIFICATION OF NOVEL BRAF ALTERATIONS IN LCH USING AN INTEGRATED GENOMIC PIPELINE Thomas Burke, Rikhia Chakraborty, Oliver Hampton, Daniel Zinn, Brooks Scull, Harshal Abhyankar, Vijetha Kumar, Nipun Kakkar, Kenneth McClain, David Wheeler, Angshumoy Roy, D. Williams Parsons, Carl Allen

CHARACTERIZING INFILTRATING T LYMPHOCYTES IN LANGERHANS CELL HISTIOCYTOSIS (LCH) LESIONS Rikhia Chakraborty, Harshal Abhyankar, Walter Olea, Brooks Scull, Kenneth L. McClain, Carl E. Allen

VEMURAFENIB IN CHILDREN WITH REFRACTORY LCH: 21 PATIENTS TREATED IN FRANCE, UK, ITALY AND LEBANON Jean Donadieu, Johannes Visser, Elena Sieni, Nabil Kabbara, Mathilde Jehanne, Anne Pagnier, Nathalie Aladjidi, Anne Deville, Geneviéve Plat, Anne Lutun, Laurence Blanc, James Nicholson, Alain Lefevre-Utile, Ahmed Idbaih, Olga Slater, Jean François Emile, Sebastien Héritier

AN INHERITED GENETIC VARIANT IN SMAD6 INCREASES SUSCEPTIBILITY TO LANGERHANS CELL HISTIOCYTOSIS Erin Peckham-Gregory, Rikhia Chakraborty, Michael Scheurer, Harshal Abhyankar, Olive Eckstein, Brooks Scull, Daniel Zinn, Amanda Grimes, John Belmont, Albert Shih, Kenneth McClain, Philip Lupo, Carl Allen

* Indicates closed session + Indicates that advance registration was required WWW.HISTIOCYTESOCIETY.ORG 17

MEETING AGENDA: TUESDAY, OCTOBER 18, 2016

INFLAMMATORY PLASMA PROTEINS CLASSIFIERS PREDICT DISEASE SEVERITY AND RESPONSE TO THERAPY IN PATIENTS WITH LCH Brooks Scull, Daniel Zinn, Howard Lin, Albert Shih, Miguel Cantu, Harshal Abhyankar, Rikhia Chakraborty, Karen Lim, Stephen Simko, Tricia Peters, Sergio Lira, Kenneth McClain, Miriam Merad, Tsz-Man, Carl Allen

A HIGHLY SENSITIVE, CLINICALLY-VALIDATED ASSAY TO QUANTITATE BRAF p.V600E MUTATIONS IN BLOOD AND BONE MARROW SAMPLES OF LANGERHANS CELL HISTIOCYTOSIS PATIENTS Lizmery Suarez Ferguson, Renee Webb, Stephen Sarabia, Karla Alvarez, Carl Allen, Kenneth McClain, Jyotinder Punia, Angshumoy Roy, Dolores López-Terrada, Kevin Fisher

1430 – 1445 Presidential Transition ...... Rathaskar Suite Carlos Rodriguez-Galindo will pass the Presidency to Milen Minkov

1445 – 1645 Poster Presentation Session ...... Ainsworth Suite

BASIC HLH POSTER PRESENTATIONS

Poster Location #1 ACTIVATION OF CYTOTOXIC CD4 T CELLS DISTINGUISHES FAMILIAL FROM VIRUS-INDUCED SECONDARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS Sandra Ammann, Kai Lehmberg, Udo zur Stadt, Gritta Janka, Anne Rensing-Ehl, Christian Klemann, Sebastian Bode, Ilka Fuchs and Stephan Ehl for the HLH study of the GPOH#

Poster Location #2 EXCLUSIVE IFN-GAMMA BLOCKADE SIGNIFICANTLY CORRELATES WITH IMPROVED CHIMERISM IN MICE: I MPLICATIONS FOR AN OPTIMIZED THERAPEUTIC APPROACH TO PRIMARY HLH PATIENTS Walter Ferlin, Vanessa Buatois, Laurence Chatel, Maria Ballabio, Cristina de Min

CLINICAL HLH POSTER PRESENTATIONS

Poster Location #3 A REVIEW OF ADULT PATIENTS WITH HAEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS TREATED AT A SPECIALIST REFERRAL CENTRE Robin Dowse, Vasanta Nanduri, Hadil Aabuarquob, Donal McLornan

Poster Location #4 LONG-TERM FOLLOW-UP AFTER BONE MARROW TRANSPLANTATION IN A CHILD WITH FAMILIAL HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (FHL) AND HOMOZYGOUS SYNTAXIN-11 MUTATION Roula Farah, Yenan Bryceson, Alain E Sayad, Eva Rudd, Jan-Inge Henter, Franco Locatelli

Poster Location #5 HIGH LEVELS OF sCD25 AND sCD163 IN PATIENTS DIAGNOSED WITH SEPSIS. COULD THEY BE USEFUL FOR SEPSIS DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS WITH HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH)? Susana Garcia-Obregon, Iratxe Seijas, Javier Pilar-Orive, Carmen Ruano, Ainize Peña, Olatz Zenarruzabeitia, Joana Vitalle, Francisco Borrego, Idoia Ortega-Martinez, Dolores Boyano, Juana Gil, Itziar Astigarraga

Poster Location #6 FACTORS ASSOCIATED WITH ETOPOSIDE USAGE IN CHILDREN WITH MACROPHAGE ACTIVATION SYNDROME COMPLICATING SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS AnnaCarin Horne, Francesca Minoia, Francesca Bovis, Sergio Davi, Itziar Astiggarara, Priyankar Pal, Jordi Anton, Kimo Stine, Sandra Enciso, Ozgur Kasapcopur, Michael Jeng, Rosa Merino, Despoina Maritsi, Randy C. Cron, Angelo Ravelli

Poster Location #7 SURVIVAL AFTER HEMATOPOIETIC STEM CELL TRANSPLANTATION IN HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS COMPARED TO SEVERE COMBINED IMMUNE DEFICIENCY AND SEVERE APLASTIC ANEMIA AnnaCarin Horne, Emma Lindstrӧm, Kim Ramme, Ida Hed Myrberg, Rebecca Marsh, Andre Willasch, Peter Bader, Andrew Gennery and on behalf of the EBMT inborn errors and EBMT paediatric diseases working parties

Poster Location #8 THE ROLE OF G-CSF IN ADULT HLH Zhili Jin, Yini Wang, Lin Wu, Zhao Wang

Poster Location #9 CLINICAL FEATURES AND PROGNOSIS OF HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS WITH EPSTEIN-BARR VIRUS INFECTION Wenyuan Lai, Jingshi Wang, Yini Wang, Zhao Wang

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MEETING AGENDA: TUESDAY, OCTOBER 18, 2016

Poster Location #10 CHARACTERISTICS OF PATIENTS WITH PARTIAL OCULO-CUTANEOUS ALBINISM AND IMMUNODEFICIENCY ASSOCIATED HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AT THE CHILDREN'S HOSPITAL 1 HO CHI MINH CITY My T. Lam, Hong M.T. Nguyen, Lien B. Le, Hung T. Nguyen, Tuasn M. Nguyen, Tâm M.T. Nguyen, Anh H.M. Nguyen, Anh K.N. Tran, Anh L.P. Nguyen, Trang.TT. Pham, Khanh X.T. Luong, Hanh P. Ma, Van T.T. Luong, Cuc TT. Cao, Dao H.T Ngo, Le M.T. Duong, Linh X.D. Bui, Tung T. Tran, Vu A. Hoang

Poster Location #11 ADMINISTRATION OF PARENTERAL EXOGENOUS NOXA IN MUNCHHAUSEN SYNDROME BY PROXY CAN ELICIT THE FULL PICTURE OF HLH Kai Lehmberg, Jan Sperhake, Holger Rohde, Sandra Ammann, Stephan Ehl, Ingo Müller, Gritta Janka

Poster Location #12 AN UNUSUAL PRESENTATION OF HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS IN A PREMATURE INFANT Oya Levendoglu-Tugal, Priyadarshani Giri, Praveen Ballabh, Samir Pandya, Fouzia Shakil, Larisa Debelenko

Poster Location #13 HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS IN AN INFANT WITH KABUKI SYNDROME Oya Levendoglu-Tugal, Alan Pinto, Humayun Islam

Poster Location #14 CLINICAL ANALYSIS OF 6 CASES WITH SUBCUTANEOUS PANNICULITIS-LIKE T-CELL LYMPHOMA ASSOCIATED HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS Wu Lin, Wu Lin, Zhang Jia, Wang Yi-Ni, Wang Jing-Shi, Wang Zhao

Poster Location #15 INCIDENCE OF HLH CNS RELAPSE AFTER TREATMENT WITH REDUCED INTENSITY CONDITIONING HEMATOPOEITIC STEM CELL TRANSPLANT Rebecca Marsh, Dana Lounder, Bibi Shahin Shamsian, Pooja Khandelwal, Sharat Chandra, Michael Jordan, Ashish Kumar, Michael Grimley, Jack Bleesing, Stella Davies

Poster Location #16 A MULTIDISCIPLINARY APPROACH TO A MULTIDISCIPLINARY PROBLEM, THE DEVELOPMENT OF THE HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS TASKFORCE Andrew Martin, Teresa Jones, Marilynn Punaro, Julie Fuller, Katie Stewart, Leandra Woolnough, Lorien Nassi, Tracey Wright, Maite De La Morena, Archana Dhar, Cindy Darnell, Josh Koch, Samuel Davila, David Zwick, Hung Luu, Paul Sue, Michael Sebert, Chris Wysocki

Poster Location #17 YTIC LYMPHOHISTIOCYTOSIS (HLH) IN ADULT RECIPIENTS OF VENTRICULAR ASSIST DEVICES (VADS) FOR CARDIOMYOPATHY (CM) AND FAVORABLE OUTCOMES IN SUBSEQUENT ORTHOTOPIC HEART TRANSPLANTATION (OHT) Beth Ann Martin, Paul Cheng, Richard Ha-Tien, Dipanjan Banerjee

Poster Location #18 INFECTION AND HEMOPHAGOCYTIC SYNDROME: SINGLE CENTER EXPERIENCE Nihal Ozdemir, Begüm Koc, Fatih Varol, Meltem Kivilcim, Deniz Aygün, Yildiz Camccioǧlu, Tiraje Celkan, Hilmi Apak

Poster Location #19 BEAD EMBOLIZATION OF SPLEEN AS TREATMENT FOR HEMATOPHAGOCYTIC LYMPHOHISTIOCYTOSIS ASSOCIATED WITH NON-HODGKINS LYMPHOMA Leslie Padrnos, Tania Jain, Katalin Kelemen, John Camoriano

Poster Location #20 CENTRAL NERVOUS SYSTEM INVOLVEMENT IN HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS Ruijun Pei, Yini Wang, Zhao Wang

Poster Location #21 THE ROLE OF INTERLEUKIN-I RECEPTOR ANTAGONIST, ANAKINRA IN CRITICALLY ILL ADULT PATIENTS WITH HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND MACROPHAGE ACTIVATION SYNDROME, A REVIEW OF SIX CASES Akshjot Puri, Henry J Kyle, Suresh Uppalapu, Robert Raschke

Poster Location #22 TREATMENT OF HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS WITH ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION USING THE CONDITIONING REGIMEN WITH BUSULFAN AND FLUDARABINE: A SINGLE- CENTER STUDY OF 38 CASES Yuan Sun, Juan Xiao, Shifen Fan, Zhouyang Liu, Fei Xu, Lei Zhang, Fan Jiang, Xiaomei Liu

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MEETING AGENDA: TUESDAY, OCTOBER 18, 2016

Poster Location #23 BEYOND FATTY LIVER OF PREGNANCY: A CASE OF HLH IN A 20 YEAR OLD FEMALE Minakshi Taparia

Poster Location #24 HAPLOIDENTICAL STEM CELL TRANSPLANTATION WITH POST TRANSPLANT CYCLOPHOSPHAMIDE IN HAEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS : THE JOURNEY TO SUCCESSFUL ENGRAFTMENT AND CURE Ramya Uppuluri, Sreejith Ramachandrakurup, Divya Subburaj, Lakshman Vaidhyanathan, Revathi Raj

Poster Location #25 HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS WITH CHILDREN AND ADULT: THE REGISTRATION DATA FROM BEIJING HLH WORKGROUP, CHINA Yini Wang, Zhao Wang, Rui Zhang, Caifeng Li, Xiaodong Shi, Qian Wang, Leping Zhang, Yuan Jia, Lihong Li, Xinan Cen, Weihong Zhao, Liangding Hu, Yuan Sun, Jijun Wang, Jianliang Shen, Yingjian Si, Wuhan Hui, Liping Ye

Poster Location #26 PEG-ASPARGASE AND DEP REGIMEN COMBINATION THERAPY FOR REFRACTORY EPSTEIN-BARR VIRUS- ASSOCIATED HEMOPHAGOCYTIC SYNDROME Zhao Wang, Jingshi Wang, Yini Wang , Lin Wu, Jia Zhang, Wenyuan Lai

Poster Location #27 SYMPTOMS, IMAGING FINDINGS AND OUTCOMES OF 179 CHILDREN WITH HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS WHO HAVE CENTRAL NERVOUS SYSTEM (CNS) INVOLVEMENT Yun-ze Zhao, Tian-you Wang, Li Zhang, Hong-yun Lian, Hong-hao Ma, Dong Wang, Xiao-xi Zhao, Rui Zhang

Poster Location #28 ATYPICAL ISOLATED CNS PRESENTATION OF FAMILIAL HLH Nicholas Whipple, Namrata Shah, Brent Orr, Scott Hwang, Ashok Srinivasan, Patrick Campbell

Poster Location #29 CLINICAL PRESENTATION AND OUTCOME OF PEDIATRIC PATIENTS WITH HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS IN CHINA: A RETROSPECTIVE MULTICENTER STUDY Xiao-Jun Xu, Hong-Sheng Wang, Xiu-Li Ju, Shao-Yan Hu, Yan Xiao, Hong-Man Xue, Hong-Yu Shi, Yi-Jin Gao, Guo-Cun Jia, Xue-Rong Li, Wei-Hong Zhao, Ning-Ling Wang, and Yong-Min Tang on behalf of the Histiocytosis Study Group of the Chinese Pediatric Society

Poster Location #30 LARGE STRUCTURAL AND EPIGENETIC DEFECTS IN HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH) ASSOCIATE GENES THAT ARE RESPONSIBLE FOR THE DEVELOPMENT OF CLINICAL HLH Kejian Zhang, Lisa Dyer, Xia Li, James Denton, Brittany Jones, Emily Liston, Danielle Hilton, Abhinav Mathur and C. Alexander Valencia

Poster Location #31 TOUCHING ON HLH INDICATING VALUE OF SERUM FERRITIN Xiaoxi Zhao, Rui Zhang

Poster Location #32 TREATING THE ADULT IDIOPATHIC ENTITY OF HLH WITH ETOPOSIDE, A CASE SERIES AND REVIEW OF LITERATURE Timo Zondag, Jan Alexander Michael van Laar

BASIC LCH POSTER PRESENTATIONS

Poster Location #33 ADSORPTIVE DEPLETION OF BLOOD MONOCYTES REDUCES THE LEVELS OF CIRCULATING INTERLEUKIN-17A IN LANGERHANS CELL HISTIOCYTOSIS Magdalini Lourda, Selma Olsson-Ǻkefeldt, Désirée Gavhed, Ulla Axdorph Nygell, Gӧsta Berlin, Evaldas Laurencikas, Tatiana von Bahr Greenwood, Mattias Svensson, Jan-Inge Henter

Poster Location #34 ECOLOGY OF MERKEL CELL POLYOMAVIRUS IN HEALTHY SKIN SHOWS A CLOSE AGREEMENT WITH INTERLEUKIN-1 LOOP MODEL IN LANGERHANS CELL HISTIOCYTOSIS Ichiro Murakami, Junko Nakashima, Yumiko Hashida, Masanori Daibata, Michiko Matsushita, Takeshi Iwasaki, Satoshi Kuwamoto, Masako Kato, Keiko Nagata, Kazuhiko Hayashi, Takashi Oka, Tadashi Yoshino, Toshihiko Imamura, Akira Morimoto, Shinsaku Imashuku, Jean Gogusev, Francis Jaubert

Poster Location #35 CD207+/CD1A+ CIRCULATING CELLS ARE PRESENT IN PATIENTS WITH ACTIVE LANGERHANS CELL HISTIOCYTOSIS Diego Rosso, Licina Tessone, Ivana Estecho, Graciela Elena, Arnaldo Armesto, Eugenio Carrera Silva, Andrea Errasti

20 HISTIOCYTE SOCIETY ANNUAL MEETING 2016

MEETING AGENDA: TUESDAY, OCTOBER 18, 2016

Poster Location #36 PHARMACOKINETICS STUDY OF VEMURAFENIB IN A PEDIATRIC POPULATION: PRELIMINARY RESULTS Jean Donadieu, Nicolas Fabresse, Islam Amine Larabi, Emuri Abe, Sébastien Héritier, Jean-Claude Alvarez

CLINICAL LCH POSTER PRESENTATIONS

Poster Location #37 RELEVANCE OF BRAFV600E ALLELE DETECTION IN CIRCULATING CFDNA AS A BIOMARKER IN PEDIATRIC LCH Jean Donadieu, Sébastien Héritier, Valery Taly, Sonia Garrigou, Nathalie Terrones, Corinne Normand, Philippe Nizard, Zofia Hélias-Rodzewicz, Jean-François Emile

Poster Location #38 VEMURAFENIB HAD OBTAINED THE ORPHAN DRUG DESIGNATION STATUS IN EUROPE FOR LANGERHANS CELL HISTIOCYTOSIS IN APRIL 2016 Jean Donadieu, Marine Berro, Sébastien Héritier

Poster Location #39 CHALLENGES IN TREATING LANGERHANS CELL HISTIOCYTOSIS AMONG CHILDREN IN DEVELOPING COUNTRIES: CHILDREN'S HOSPITAL LAHORE PAKISTAN EXPERIENCE Alia Ahmad, Fauzia Shafi Khan

Poster Location #40 A COLLABORATIVE STUDY IN CHILDREN AND ADULTS DIAGNOSED WITH LANGERHANS CELL HISTIOCYTOSIS. OUR EXPERIENCE IN 42 CASES Itziar Astigarraga, Susana Garcia-Obregon, Leticia Ceberio, Rosa Adan, Aizpea Echebarria, Miguel Garcia-Ariza, Ricardo Lopez-Almaraz, Ainhoa Gondra

Poster Location #41 PULMONARY LANGERHANS CELL HISTIOCYTOSIS IN CHILDREN: LIFE-THREATENING PNEUMOTHORACES AND THE CHALLENGES OF PROLONGED VENTILATION - REPORT OF 2 CASES Mhairi Barclay, Alice Martin, Jayesh Bhatt, Patrick Davies, Claudiu Faraon, Richard Grundy, Tom Hilliard, Steve Lowis, Vasanta Nanduri, Johannes Visser

Poster Location #42 LONGITUDINAL STUDY OF IL-1β AND PGE2 SALIVARY CONCENTRATIONS IN PEDIATRIC PATIENTS WITH LANGERHANS CELL HISTIOCYTOSIS Carolina Benchuya, Ariel Gualtieri, Bentina Orman, Verónica Paván, Jorge Braier, Virginia Fernández de Preliasco

Poster Location #43 THE LEVELS OF IL-1β AND PGE2 IN SALIVA OF CHILDREN WITH LANGERHANS CELL HISTIOCYTOSIS Carolina Benchuya, Ariel Gualtieri, Betina Orman, Verónica Paván, Jorge Braier, Virginia Fernández de Preliasco

Poster Location #44 TOXICITY PROFILE OF CLOFARABINE IN PATIENTS WITH REFRACTORY OR RECURRENT HISTIOCYTIC DISORDERS Racheal Bingham, Olive Eckstein, Kenneth McClain

Poster Location #45 CLINICAL RELEVANCE OF THE DIFFERENT MAPK-PATHWAY MUTATIONS IN LANGERHANS CELL HISTIOCYTOSIS; A LITERATURE REVIEW UNDERLINING THE NEED FOR PROSPECTIVE CO-OPERATIVE STUDIES Sofie H. Breuking, Lieke Feijen, Cor van den Bos

Poster Location #46 PERMANENT CONSEQUENCES OF LANGERHANS CELL HISTIOCYTOSIS. EXPERIENCE OF AN OBSERVATIONAL TRIAL Gleb Bronin, Roman Miroshkin, Evgeniy Bezunov, Elizaveta Mironova, Elena Fisun, Bulat Kurmanov, Elena Promyslova, Vladimir Kasatkin, Alexander Karelin

Poster Location #47 PERSISTENT OR RECURRENT LANGERHANS CELL HISTIOCYTOSIS TREATED WITH SORAFENIB ALONE:CASE REPORTS AND LITERATURE REVIEW Jing Cao, Xiaodong Shi, Rong Liu, Danqing Luo, Duanfang Shao

Poster Location #48 ISOLATED PULMONARY LANGERHANS CELL HISTIOCYTOSIS IN CHILDREN Veronica Celis, Jaume Mora, Moira Garraus, Maria Correa, Yolanda Jordan, Rosalía Carrasco, Lucas Krauer, Jordi Costa

Poster Location #49 REFRACTORY LCH MONITORING BY URINARY AND BLOOD BRAF TESTING Anthony Chuang, Lilibeth Torno

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Poster Location #50 CRANIOFACIAL AND INTRACRANIAL MANIFESTATIONS OF LANGERHANS CELL HISTIOCYTOSIS IN CHILDREN: ANALYSIS OF 232 CASES Yunze Zhao, Rui Zhang, Li Zhang, Honghao Ma, Dong Wang, Tianyou Wang, Hongyun Lian

Poster Location #51 ASSESSMENT OF SOLITARY SKELETAL LESIONS OF LCH:IS BONE SURVEY MANDATORY? Rina Dvir, Ronit Elhasid

Poster Location #52 EFFICACY OF CLOFARABINE IN PATIENTS WITH REFRACTORY/RECURRENT LANGERHANS CELL HISTIOCYTOSIS Olive S. Eckstein, Rachael Bingham, Erin Peckham, Austin Brown, Kenneth L. McClain, Carl E. Allen

Poster Location #53 LANGERHANS CELL HISTIOCYTOSIS PATIENTS WITH EXTENSIVE PULMONARY CYSTS AND MULTIPLE PNEUMOTHORACES CAN BE CURED WITH PLEURODESES, VIGOROUS SUPPORTIVE CARE, AND CHEMOTHERAPY Olive S. Eckstein, George Mallory, R. Paul Guillerman, Timothy Vecce, Matthew Musick, Carl E. Allen, Jed Nuchtern, Kenneth L. McClain

Poster Location #54 RESPONSE TO BRAF V600E INHIBITOR USED AS MONOTHERAPY OF MULTISYSTEM LANGHERHANS-CELL HISTIOCYTOSIS IN CHILDREN:REPORT OF TWO CASES Dmitry Evseev, Irina Kalinina, Tatyana Salimova, Maria Sharashkina, Alexey Samarin, Elena Raykina, Uliana Petrova, Anna Mitrofanova, Galina Novichkova, Michael Maschan, Alexey Maschan

Poster Location #55 BRAF p.V600E MUTATION DETECTION IN PEDIATRIC LANGERHANS CELL HISTIOCYTOSIS TISSUE SAMPLES USING REAL-TIME PCR AND MUTATION-SPECIFIC IMMUNOHISTOCHEMISTRY: A COMPARISON STUDY Kevin Fisher, Leomar Ballester, Miguel Cantu, Karen Lim, Stephen Sarabia, Renee Webb, Lizmery Suarez Ferguson, Carl Allen, Kenneth McClain, Carrie Mohila, Jyotinder Punia, Angshumoy Roy, Dolores López-Terrada, John Hicks

Poster Location #56 OUTCOME FOR CHILDREN WITH MULTI-SYSTEM LANGERHANS CELL HISTIOCYTOSIS AFTER USING A LCH II- BASED PROTOCOL IN SHANGHAI, CHINA Yi-Jin Gao, Fang-Fang Wu, Ci Pan, Jing Chen, Jing-Yan Tang

Poster Location #57 DABRAFENIB FOR TREATMENT OF HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH) IN 2 PATIENTS WITH LANGERHANS CELL HISTIOCYTOSIS (LCH) WITH BRAF-V660E MUTATION Michael Grimley, Ashish Kumar

Poster Location #58 PRESENTATION OF LANGERHANS CELL HISTIOCYTOSIS IN 9-MONTH OLD MONOZYGOTIC TWINS WITH A REVIEW OF THE LITERATURE Jay Halbert, Harshita Goradia, Amos Burke

Poster Location #59 A PHASE II TRIAL OF LENALIDOMIDE IN ADULTS WITH HISTIOCYTE DISORDERS Eric Jacobsen, Alyssa Nicotra, Victoria Patterson, Robert Redd, Barbara Virchick

Poster Location #60 ACRAL SCLEROSING HISTIOCYTIC NODULES: A NEW ENTITY IN CUTANEOUS HISTIOCYTOSIS? Vinay Keshavamurthy, Gitesh U. Sawatkar, Uma N. Saikia, Sunil Dogra

Poster Location #61 PITUITARY STALK THICKENING AND DIABETES INSIPIDUS PROCEEDING TO LANGERHANS CELL HISTIOCYTOSIS Hande Kizilocak, Nihal Ӧzdemir, Tiraje Celkan

Poster Location #62 CLINICAL PROFILE AND BRAF STATUS OF ADULT LANGERHANS CELL HISTIOCYTOSIS IN JAPAN: TEN-YEAR SINGLE INSTITUTION EXPERIENCE Masayuki Kobayashi, Miho Ogawa, Reina Takeda, Kiyosumi Ochi, Tomomi Takei, Toyotaka Kawamata, Kazuaki Yokoyama, Nobuhiro Ohno, Satoshi Takahashi, Kaoru Uchimaru, Arinobu Tojo

Poster Location #63 THE METRONOMIC CHEMOTHERAPY AND ITS POTENTIAL ROLE IN TREATMENT OF HISTIOCYTIC DISORDERS REVISITED IN THE ERA OF CANCER IMMUNOLOGY REVIVAL Zdenka Krenova, Jaroslav Sterba

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Poster Location #64 MULTIPLY RECURRENT LCH OF THE SKIN SUCCESSFULLY TREATED WITH INDOMETHACIN Matthew Kutny, Raymond Watts

Poster Location #65 RITUXIMAB TREATMENT FOR PATIENTS WITH NEURODEGENERATIVE LANGERHANS CELL HISTIOCYTOSIS DEMONSTRATING INTELLECTUAL AND PROPRIOCEPTIVE DEFICITS Kenneth McClain, Olive Eckstein, Jay Greenberg, Ashish Kumar, Carolyn Fein Levy, Thomas Smith, Brandon Tran, Carl Allen

Poster Location #66 THE ASSOCIATION BETWEEN ORGAN INVOLVEMENTS AND SURVIVAL IN CHILDREN WITH LANGERAHANS CELL HISTIOCYTOSIS; THE RESULTS OF JLSG-96/02 STUDY Akira Morimoto, Yoko Shioda, Toshihiko Imamura, Yukiko Tsunematsu, Shinsaku Imashuku

Poster Location #67 CO-OCCURRENCE OF LANGERHANS CELL HISTIOCYTOSIS AND INTERMEDIATE TYPE OSTEOPETROSIS IN A MALE CHILD Maria Moschovi, Archontis Zampogiannis, Ioannis Nikas, Evangelia Charmandari, Helen Fryssira

Poster Location #68 NATIONAL WEB-BASED MEETINGS HELP TO IDENTIFY HISTIOCYTOSIS PATIENTS WITH REFRACTORY DISEASE OR SEQUELAE WHO NEED INDIVIDUALISED OR NOVEL TREATMENT STRATEGIES Vasanta Nanduri, Maria Michelagnoli, Varun Sudunagunta, Bhumita Vadgama, Venetia Bigley, Simon Bomken, Matthew Collin, Rachael Holmes, Johannes Visser

Poster Location #69 LANGERHANS CELL HISTIOCYTOSIS FOLLOWING BURKITT LYMPHOMA Nihal Ozdemir, Hande Kizilocak, Aylin Canpolat, Tiraje Celkan

Poster Location #70 CLINICAL COURSE OF CHILDREN WITH SINGLE SYSTEM BONE LANGERHANS CELL HISTIOCYTOSIS (LCH) Vassilios Papadakis, Loizos Petrikkos, Kondilia Antoniadi, Vasiliki-Sotiria Tzotzola, Vassilios Dendrinos, Efthymia Rigatou, Kalliopi Stefanaki, Sophia Polychronopoulou

Poster Location #71 PROGRESSIVE ISOLATED PITUITARY STACK THICKENING IN PATIENTS WITH DIABETES INSIPIDUS: MANAGEMENT DILEMMAS Vassilios Papadakis, Elpis Vlachopapadopoulou, Ioannis-Anargyros Vasilakis, Paraskevi Kazakou, Vassilios Petrou, Evangelia Charmandari, Sophia Polychronopoulou

Poster Location #72 CLINICAL PRESENTATION, MANAGEMENT AND OUTCOME OF LANGERHANS CELL HISTIOCYTOSIS (LCH) IN CHILDREN Loizos Petrikkos, Vassilios Papadakis, Vasiliki-Sotiria Tzotzola, Kondilia Antoniadi, Vassilios Dendrinos, Efthymia Rigatou, Kalliopi Stefanaki, Sophia Polychronopoulou

Poster Location #73 REVISITING THE NEUROPATHOLOGY OF CENTRAL NERVOUS SYSTEM LANGERHANS CELL HISTIOCYTOSIS Jennifer Picarsic, Geoffrey Murdoch, Rikhia Chakraborty, Fernando Castro-Silva, Ashok Panigrahy, Ronald Jaffe, Kenneth McClain, Carl Allen

Poster Location #74 CLADRYBINE TREATMENT IN PATIENTS WITH PULMONARY LANGERHANS CELL HISTIOCYTOSIS Elzbieta Radzikowska, Elżbieta Wiatr, Katarzyna Błasińska-Przerwa, Renata Langfort, Kazimierz Roszkowski-Śliż

Poster Location #75 CLINICAL USE OF BRAF MUTATIONS PROFILE IN LCH PATIENTS FOR DIAGNOSIS AND MONITORING OF TREATMENT RESPONSE Vicente Santa-Maria, Veronica Celis, Carmen de Torres C, Jaume Mora

Poster Location #76 FREQUENCIES OF GENETIC ALTERATIONS IN KOREAN CHILDREN WITH LANGERHANS CELL HISTIOCYTOSIS Jong Jin Seo, Kyung-Nam Koh, Sung-Min Chun, Sung Han Kang, Hyeri Kim, Jong Jae Kim, Ho Joon Im

Poster Location #77 REPORT OF 2 RARE CASES OF LANGERHANS CELL HISTIOCYTOSIS(LCH) WITH SEVERE PALPEBRAL INVOLVEMENT Bibi Shahin Shamsian, Mohammad Taghi Arzanian, Mohammad Naderi Sorki, Ahmad Mohammadi Ashianeh, Leili Mhajerzadeh, Maryam Kazemi Aghdam

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Poster Location #78 REACTIVATION AND LONG-TERM OUTCOME OF PEDIATRIC-ONSET LANGERHANS CELL HISTIOCYTOSIS; 50 YEARS' EXPERIENCE AT A SINGLE CENTER Yoko Shioda, Yukiko Tsunematsu, Chikako Kiyotani, Tomoo Osumi, Daisuke Tomizawa, Motohiro Kato, Keita Terashima, Osamu Miyazaki, Michiko Tatsuno, Takako Yoshioka, Atsuko Nakazawa, Kimikazu Matsumoto

Poster Location #79 CHEST CT IMAGING FEATURES IN PEDIATRIC PULMONARY LANGERHANS CELL HISTIOCYTOSIS: ALVEOLAR CONDENSATION AS A POSSIBLE MANIFESTATION OF THE DISEASE Valeria Della Valle, Chiara Sileo, Jessica Kabla, Mohamed Aziz Barkaoui, Ralph Epaud, Hubert Ducou Le Pointe, Jean Donadieu

Poster Location #80 PULMONARY LANGERHANS CELL HISTIOCYTOSIS IN CHILDREN: CT IMAGING FEATURES IN A COHORT OF 48 PATIENTS WITH LUNG INVOLVEMENT AND PROPOSAL OF SCORING Valeria Della Valle, Chiara Sileo, Jessica Kabla, Mohamed Aziz Barkaoui, Ralph Epaud, Hubert Ducou Le Pointe, Jean Donadieu

Poster Location #81 BRAF V600E MUTATION IN PEDIATRIC LANGERHANS CELL HISTIOCYTOSIS AND ITS CLINICAL SIGNIFICANCE Dong Wang, Rui Zhang, Hong-yun Lian, Hong-hao Ma, Chao Gao, Tian-you Wang, Li Zhang* *Corresponding author

Poster Location #82 LANGERHANS CELL HISTIOCYTOSIS: A 30-YEAR BRAZILIAN EXPERIENCE Anna Beatriz Willemes Batalha, José Cordoba, Raquel Toscano, Isis Magalhães

Poster Location #83 NEURODEGENERATIVE LANGERHANS CELL HISTIOCYTOSIS: ARE PEDIATRIC THERAPIES EFFECTIVE IN THE ADULT POPULATION? Debra Wong, Brenda Ernst, Donald Northfelt, Tom Fitch, Robert Arceci, John Camoriano

Poster Location #84 AUTOPSY RESULTS IN MULTISYSTEM LANGERHANS CELL HISTIOCYTOSIS (LCH) Guido Felizzia, Laura Galluzzo, Jorge Braier

RARE HISTIOCYTIC DISORDERS POSTER PRESENTATIONS

Poster Location #85 JUVENILE XANTHOGRANULOMA AND JUVENILE MYELOMONOCITIC LEUKEMIA ASSOCIATION IN THREE PEDIATRIC PATIENTS Guido Felizzia, Agustín González Correas, Andrea Candás, Laura Galluzzo, Julio Goldberg, María Marta Bujan, Jorge Braier, Gabriela Sciucatti, Raquel Staciuk

Poster Location #86 SYSTEMIC JUVENILE XANTHOGRANULOMA WITH A LARGE INTRACRANIAL MASS: RESPONSE TO CLOFARABINE AND CYTARABINE Ron Anderson, Marie-Anne Brundler, Mehmet Albayram, Tony Truong

Poster Location #87 ERDHEIM CHESTER DISEASE - UNUSUAL PRESENTATION OF A RARE HISTIOCYTIC DISORDER IN A 3 YEAR OLD BOY Muhammad Shamvil Ashraf, Muhammad Rafie Raza, Muhammad Rahil Khan

Poster Location #88 ROSAI-DORFMAN DISEASE- OUR EXPERIENCES FROM A SINGLE CENTRE Ferdousi Begum, Afiqul Islam, ATM Atiqur Rahman

Poster Location #89 CHRONIC MYELOMONOCYTIC LEUKEMIA CLONALLY RELATED TO CONCURRENT ERDHEIM CHESTER DISEASE Tejaswini Dhawale, Emily Glynn, David Wu, Daniel E. Sabath, Yi Zhou, Christina Lockwood, Paul Hendrie

Poster Location #90 NEXT-GENERATION DNA SEQUENCING-BASED MUTATION PROFILING IDENTIFIES KRAS MUTATIONS IN ERDHEIM- CHESTER DISEASE Tejaswini Dhawale, David Wu, Colin Pritchard, Gordon A Starkebaum, Paul Hendrie

Poster Location #91 MENINGEAL LANGERHANS CELLS SARCOMA CASE REPORT Blanca Diez, Bernadette Calabrese, Sebastian Cerrato, Alejandro Muggeri, Oscar Alvarez, Naomi Arakaki

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Poster Location #92 THE NEUROLOGIC MANIFESTATIONS OF ERDHEIM CHESTER-DISEASE Juvianee Estrada-Veras, Louisa C. Boyd, Rahul H. Dave, Kevin O'Brien, William Gahl

Poster Location #93 ANAKINRA AS EFFICACIOUS THERAPY FOR INTRACRANIAL ERDHEIM-CHESTER DISEASE IN A CHILD Mark Fluchel, Eli L. Diamond, Omar Abdel-Wahab, Lynn Brody, Maria Arcila, Christian Bowers

Poster Location #94 MENINGEAL ROSAI-DORFMAN DISEASE WITH A STRUCTURAL BREAKPOINT OF PROTEIN TYROSINE PHOSPHATASE RECEPTOR TYPE D TUMOR SUPPRESSOR GENE Chelsea Gawryletz, Bernard R. Bendok, Alyx Porter, Aditya Raghunathan, Sameer Keole, Thomas Colby, John Camoriano

Poster Location #95 HISTIOCYTIC SARCOMA OF THE CENTRAL NERVOUS SYSTEM. CASE REPORT Olga Gryniewicz-Kwiatkowska, Olga Rutynowska, Wiesława Grajkowska, Katarzyna Nowak, Bożenna Dembowska-Bagińska

Poster Location #96 A CASE OF CONCURRENT OCCURRENCE OF ERDHEIM-CHESTER DISEASE AND LEUKEMIA IN A CHILD Joon Pyo Hong, Won Ki Ahn, Joo Yeon Lim, Jo Eun Jung, Seung Min Hahn, Jung Woo Han, Chuhl Joo Lyu

Poster Location #97 ERDHEIM-CHESTER DISEASE IN A TODDLER GIRL Sonia Silva, Leonor Barroso, Joana Serra-Caetano, Maria José Julião, Manuel João Brito

Poster Location #98 IMATINIB FOR THE TREATMENT OF XANTHOMA DISSEMINATUM Gitesh U. Sawatkar, Vinay Keshavamurthy, Pankaj Malhotra, Uma Nahar Saikia, Sunil Dogra

Poster Location #99 DISSEMINATED JUVENILE XANTHOGRANULOMA (DXJ) IN ADOLESCENT; CASE REPORT Fernando Werneck, Fernando Sellos, Patrícia Moura, Vanessa Campos, Ludmilla Parente

1600 – 1800 HLH Registry Training* ...... Fountain Suite

1815 Group Transportation to Histiocyte Society Annual Banquet ...... Killashee Hotel Lobby Group will meet in hotel lobby for bus transportation to the Annual Banquet

1915 – 0100 Histiocyte Society Annual Banquet ...... Guinness Storehouse Buses will return to Killashee Hotel at 2230, 2315, 2400 and 0100 St. James's Gate Dublin, Ireland Phone: +353 1 408 4800 Website: www.guinness-storehouse.com

Silver Sponsor A Special Thank You To

www.histioartemis.gr

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MEETING AGENDA: WEDNESDAY, OCTOBER 19, 2016

0800 – 1200 Meeting Registration and Check-In ...... Rathaskar Reception

0800 – 0845 Executive Board Meeting* ...... Innovation Centre Education Committee Meeting* ...... Board Room 1 Scientific Committee Meeting* ...... Belling Suite

0900 – 1000 Jon Pritchard Lecture on the Nikolas Symposium ...... Rathaskar Suite Session Moderator: Matthew Collin

BEYOND BRAF: MECHANISMS OF RESISTANCE AND THERAPEUTICS DEVELOPMENT IN LCH A SUMMARY OF THE PROCEEDINGS OF THE 26TH NIKOLAS SYMPOSIUM Barrett Rollins Dana-Farber Cancer Institute/Brigham & Women’s Hospital/Harvard Medical School, Boston, MA USA

1000 – 1030 Coffee Break ...... Rathaskar Reception

1030 – 1200 Scientific Session IV: Oral Presentations ...... Rathaskar Suite Session Moderators: Itziar Astigarraga, Kim Nichols

THE HEMATOPOIETIC ORIGIN OF ADULT HISTIOCYTOSIS Matthew Collin, Paul Milne, Venetia Bigley, Antoine Neel, Muzlifah Haniffa, Ben Durham, Eli Diamond, Omar Abdel-Wahab

DABRAFENIB AND TRAMETINIB AS POTENTIAL THERAPY IN BRAF V600E POSITIVE ERDHEIM CHESTER DISEASE (ECD): PRELIMINARY RESULTS Juvianee Estrada-Veras, Kevin O'Brien, Emily Huang, William Gahl

PROSPECTIVE GENOMIC PROFILING OF HISTIOCYTOSES IDENTIFIES NOVEL MUTATIONS AND THERAPY OPTIONS Lynn Lee, Anjelika Gasilina, Jayeeta Roychoudhury, Jason Clark, Francis McCormack, Joseph Pressey, Siraj Ali, Mark Bailey, Phil Stephens, Jeffrey Ross, Vincent Miller, Nicolas Nassar, Ashish Kumar

TCR αβ-DEPLETED HEMATOPOIETIC STEM CELL TRANSPLANTATION IN PATIENTS WITH PRIMARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS Michael Maschan, Elena Gutovskaya, Dmitriy Balashov, Elena Raikina, Viktoria Zaharova, Vladimir Zhogov, Varvara Brilliantova, Larisa Shelikhova, Galina Novichkova, Alexei Maschan

A MULTIDISCIPLINARY APPROACH TO EARLY DETECT NEURODEGENERATIVE LANGERHANS CELL HISTIOCYTOSIS (ND-LCH) AND MONITOR RESPONSE TO INTRAVENOUS IMMUNOGLOBULIN (IVIG) TREATMENT Elena Sieni, Francesca Afrifa, Carmen Barba, Katiuscia Romano, Marzia Mortilla, Claudio De Filippi, Susanna Rizzi, Claudio Favre, Renzo Guerrini

CENTRAL NERVOUS SYSTEM PERFUSION PATTERNS IN CHILDHOOD LANGERHANS CELL HISTIOCYTOSIS Kristen Yeom, Christine Kim, Michael Iv, Michael Jeng

1200 – 1215 Closing Ceremonies...... Rathaskar Suite Milen Minkov, Histiocyte Society President Awarding of Nesbit Prize for Excellence in Clinical Science Awarding of Nezelof Prize for Excellence in Basic Science

* Indicates Closed Session 26 HISTIOCYTE SOCIETY ANNUAL MEETING 2016

MONDAY, OCTOBER 17, 2016 • 0945 GUEST SPEAKER PRESENTATIONS RATHASKAR SUITE

TOWARDS GENE THERAPY FOR HLH

Claire Booth, M.D., Ph.D.

UCL Great Ormond Street Hospital Institute of Child Health, London, United Kingdom

Over recent years autologous haematopoietic stem cell gene therapy has proven an efficacious treatment for a number of primary immune deficiencies and this approach is now being investigated for a wider range of diseases, including certain forms of familial HLH (FHL). Patients with FHL have limited therapeutic options and given the predominant restriction of causative genes to the haematopoietic system, they have become attractive targets for ex vivo haematopoietic cell therapy. Pre-clinical studies in murine models of perforin deficiency and X-linked lymphoproliferative disease (XLP1) have shown correction of the disease phenotype as a result of autologous haematopoietic stem cell (HSC) gene transfer using lentiviral vectors. These encouraging murine studies have led to further work by our group to develop clinically applicable strategies including correction of defective T cells as an alternative approach. I will present here our results to date using both gene modified haematopoietic stem cells and T cells alongside future perspectives for progression to clinical trial.

MONDAY, OCTOBER 17, 2016 • 1100 GUEST SPEAKER PRESENTATIONS RATHASKAR SUITE

HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH) SYMPOSIUM

IL-1 FAMILY MEMBERS IN HLH

Edward Behrens, M.D.

Children’s Hospital of Philadelphia, Philadelphia, PA USA

Just as the diversity of genetic lesions leading to hemophagocytic syndrome has grown dramatically over the past few years, so has the cytokines implicated in driving pathogenesis. The Il-1 family members, IL-1, IL-18, and IL-33 have each been connected to HLH pathogenesis in varying contexts. IL-1 family members play a central role in communicating “danger” to the immune system; that is, these cytokine act as an alarm to alter immune cells to tissue damage often caused by pathogenic infection. Since each of these cytokines and/or their receptors can be targeted therapeutically, understanding the exact role of each cytokine in HLH, and the potential consequences of neutralizing these pathways is of great interest. In this session, we will review the basic biology of the IL-1 family cytokines followed by the evidence from both human and murine data for their involvement in HLH. We will discuss the therapeutic options for targeting these cytokines and consider future directions for both basic and clinical research in this area.

THERAPEUTIC EFFECT OF JAK1/2 BLOCKADE ON THE MANIFESTATIONS OF HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS IN MICE

Geneviève de Saint Basile, M.D., Ph.D.

INSERM UMR1163, Imagine Institute, Paris Descartes University-Sorbonne, Paris, France

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome, characterized by severe hyperinflammation and immunopathological manifestations in several tissues. These features result from organ infiltration by over-activated CD8 T-cells and macrophages, which produce high levels of pro-inflammatory cytokines such as IFN-g, TNF-a, IL-6 and IL-18. Recently, several JAK1/2 inhibitors, as ruxolitinib, have been developed as anti-inflammatory and immunosuppressive agents and showed beneficial effects in several inflammatory conditions. In order to determine whether pharmacological inhibition of the JAK1/2, not only prevents, but has clinical therapeutic efficacy on HLH immunopathology, two complementary cytotoxicity-deficient murine models of HLH, the Prf1-/- and the Rab27a-/- mice, were treated with clinically relevant dose of ruxolitinib at the time they express the full blown syndrome. We show that in vivo, the JAK inhibitor ruxolitinib suppresses the activation of STAT1 and induces recovery from HLH manifestations in both murine models. We indeed observed a considerable improvement of Prf1-/- mice survival rate, and in both murine models, a correction of blood cytopenia and a rapid decrease in the serum levels of IL-6 and TNF-a. During ruxolitinib therapy, liver tissue damage restored concomitantly with a decrease in the number of infiltrating inflammatory macrophages and an increase in the number of alternatively activated macrophages. Involvement of the central nervous system in Rab27a-/- mice is significantly reduced by ruxolitinib therapy. Our findings demonstrate that the JAK1/2 inhibitor ruxolitinib, in clinically relevant doses, suppresses the deleterious consequences of macrophage over-activation characterizing HLH in two murine models, and can be readily translated into the clinic for primary and potentially secondary forms of HLH.

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MONDAY, OCTOBER 17, 2016 • 1100 GUEST SPEAKER PRESENTATIONS RATHASKAR SUITE

TARGETING INTERFERON GAMMA (IFN- , THE DRIVER CYTOKINE IN HLH

Michael B. Jordan, M.D.

Cincinnati Children's Hospital, Cincinnati, OH USA

Interferon gamma (IFN-g) is a cytokine produced principally by T cells and NK cells during responses to many infections, including most viral infections. Human deficiency of IFN-g or its receptor demonstrates that this cytokine plays a critical role for control of a limited spectrum of pathogens, most prominently mycobacteria. Animal models have demonstrated a key role for IFN-g as a driver of HLH disease pathology. Experimental evidence indicates that HLH is fundamentally a disorder in which T cell activation is not properly controlled and that overproduction of this cytokine is the most toxic consequence of this poor regulation. Accordingly, blockade of IFN-g in these models has clear and dramatic therapeutic benefit. Based on this preclinical evidence, a fully human anti-IFN-g monoclonal antibody (NI-0501) has been developed for the treatment of HLH. While a clinical trial in patients with new onset or relapsed/refractory HLH is ongoing, interim analysis suggests significant anti- HLH disease activity and a favorable safety profile of this agent. Interim results of this trial and consideration of how this agent may be integrated into the future treatment of HLH will be discussed.

JANUS KINASE INHIBITION IN THE TREATMENT OF HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS

Kim E. Nichols, M.D.

St. Jude Children’s Research Hospital, Memphis, TN USA

The hemophagocytic lymphohistiocytoses (HLH) comprise a genetically heterogeneous group of disorders characterized by the development of abnormal and severely damaging immune responses. Patients with HLH experience recurring episodes of inflammation associated with the hyper- activation of CD8+ T cells and macrophages, which overproduce numerous cytokines including interferon (IFN)y interleukins (IL)-10, -12 and -18, and to a lesser extent IL-6 and Tumor Necrosis Factor-a. Current treatments include immunosuppressive medications (corticosteroids, anti- thymocyte globulin) with or without chemotherapeutic agents (etoposide). Despite the use of these drugs, up to 50% of HLH patients die from unbridled inflammation. To develop more effective treatments for HLH, our laboratory has focused on blocking the effects of cytokines, which drive inflammation and mediate much of the morbidity and mortality in HLH. We recently demonstrated that targeting the Janus Kinases (JAK1 and JAK2) with the JAK inhibitor ruxolitinib (INCB18424) significantly ameliorates the clinical and laboratory manifestations of HLH using different mouse models (R. Das et al., Blood, 2015). Despite its beneficial effects, ruxolitinib treatment did not completely abrogate disease. We therefore sought to better understand its mechanisms of action and further improve upon these results. In this presentation, we will review recent data in which ruxolitinib is compared to IFNy neutralization and/or combined with dexamethasone as a treatment for inflammation in murine HLH models.

TUESDAY, OCTOBER 18, 2016 • 0900 GUEST SPEAKER PRESENTATIONS RATHASKAR SUITE

MACROPHAGE AND DENDRITIC CELL MODULATION OF IMMUNE RESPONSES IN DIFFERENT DISEASE SETTINGS

Kingston H.G. Mills, Ph.D.

Immune regulation Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland

Tissue macrophages and dendritic cells (DCs) are key cells of the innate immune system that help to control infection and cancer, but can also have pathogenic roles in autoimmune and other immune-mediated diseases. Tissue macrophages, such as infiltrating or resident alveolar macrophages in the lung or microglia in the brain, function to control local infections through phagocytosis and intracellular killing of bacteria and small parasites. The primary function of DCs is to prime naïve T cells. Immature DCs in the tissues are highly phagocytic and take up foreign antigens from microbes and, following activation, the mature DCs migrated to the lymph nodes where they present antigens on surface major histocompatibility complex (MHC) molecules to T cell receptor on naive T cells. The mature DCs also expresses co-stimulatory molecules, CD80 and CD86, which interact with CD28 on T cells providing the second signal for T cells activation. Furthermore, appropriately activated DCs and macrophages produced distinct polarizing cytokines that promote differentiation of naïve T cells into functionally distinct effector T cell subtypes. The key signals for DC maturation and macrophage activation are mediated through pathogen recognition receptors (PRRs), such as Toll-like receptors, following binding of pathogen- associated molecular patterns (PAMPs) from microbes and danger-associated molecular patters (DAMPs) from dead cells. As well as mediating innate and promoting adaptive immune responses macrophages and DCs can also regulate immune responses. Classically activated or M1 macrophages, that produce inflammatory cytokines and nitric oxide, promote inflammation and help to protect against infection, but are pathogenic in autoimmune diseases. On the other hand, alternatively activated or M2 macrophages produce anti-inflammatory mediators that suppress protective immune response to infection and cancer but also control pathogenic T cell responses in autoimmune diseases. Collectively, the emerging data from the field of immunology has provided convincing evidence that mononuclear phagocytes, including DCs and macrophages, not only phagocytose microbes and dead cells but play key roles in directing adaptive immunity. Consequently, these cells are now the targets for drug and vaccine development against a range of human diseases.

28 HISTIOCYTE SOCIETY ANNUAL MEETING 2016

TUESDAY, OCTOBER 18, 2016 • 1015 GUEST SPEAKER PRESENTATIONS RATHASKAR SUITE

LANGERHANS CELL HISTIOCYTOSIS (LCH)/ERDHEIM-CHESTER DISEASE (ECD) SYMPOSIUM

BRAF AND MEK INHIBITORS: HOW TO PREPARE THE NEXT GENERATION THERAPY IN LANGERHANS CELL HISTIOCYTOSIS!

Jean Donadieu, M.D., Ph.D.

Hôpital Trousseau, Paris, France

Since the discovery of recurrent mutations in the MAPK pathway,(1) Langerhans cell histiocytosis (LCH) has been considered an inflammatory myeloid clonal disease. The natural course of LCH is extremely heterogeneous, ranging from a self-healing lesion to a multi-organ disease with life- threatening consequences and lesions that may cause permanent sequelae(2). Even in the worst case - risk organ refractory to standard therapy - survival is now quite good thanks to very aggressive second line therapy(3). However, late sequellae remains an important unsolved issue. It has been now established that BRAFV600E mutation are quite common in LCH, more over in the refractory patients, which should received intensive chemotherapy(4). BRAF inhibitors is a class of drugs, which used has been largely developed for metastatic melanoma and is now patented(5). Preliminary trials in Histiocytosis has show that Vemurafenib is active in Erdheim chester, a sister disease of LCH(6). The used in Langerhans cell histiocytosis arise some difficulties as most of the known experience of anti BRAF therapy are in adult, while the epidemiology of LCH learns that most of the critical indications are in very young children - frequently below age of 1 - and in addition several organ dysfunctions, i.e. pancytopenia, liver dysfunction, low albumin interact with Pharmacokinetic parameters. So far, only a single case report of children with refractory LCH has been issued (7). A larger experience of Vemurafenib of 22 children will be presented while a trial of Dabrafenib is ongoing. Vemurafenib has also received this year the orphan drug status from the EMA. Beyond anti BRAF inhibitors, several other targeted therapies(8) - anti MEK for example - may constitute opportunity to treat patients, in a quicker and safer way as our classical chemotherapy.

Reference List: 1. G. Badalian-Very et al., Blood 116, 1919 (2010). 2. C. Rigaud et al., Br. J Haematol. (2016). 3. J. Donadieu et al., Blood 126, 1415 (2015). 4. S. Heritier et al., J Clin Oncol. (2016). 5. S. Jang, M. B. Atkins, Clin. Pharmacol. Ther. 95, 24 (2014). 6. J. Haroche et al., Blood 121, 1495 (2013). 7. S. Heritier et al., JAMA Oncol. 1, 836 (2015). 8. E. L. Diamond et al., Cancer Discov. 6, 154 (2016).

HISTIOCYTIC NEOPLASMS AND THE RISE OF THE AGE OF PRECISION MEDICINE

Benjamin H. Durham1, Omar Abdel-Wahab2,3, Eli L. Diamond4

1. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY USA 2. Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY USA 3. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY USA 4. Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY USA

Since the discovery of BRAF V600E mutations in Langerhans cell histiocytosis (LCH) and Erdheim-Chester Disease (ECD), diverse kinase alterations have been uncovered in BRAF V600E-wild type histiocytic neoplasms. These recent molecular advances have led to a significant progression in our understanding of the pathogenesis and treatment of these disorders. Activating kinase alterations discovered in BRAF V600E-wild type LCH and non-Langerhans cell histiocytoses (non-LCH) result in constitutive activation of the mitogen-activated protein kinase (MAPK) pathway. These kinase alterations include recurrent activating mutations in ARAF, MAP2K1, NRAS, KRAS, and PIK3CA kinases in LCH and non-LCH; BRAF, ALK, and NTRK1 fusions, as well as the ETV3-NCOA2 fusion in non- LCH; and mutations in MAP2K2, MAP3K1, and HRAS kinases in ECD, LCH, and histiocytic sarcoma, respectively. These discoveries have refined the understanding of the histiocytoses as clonal, myeloid neoplasms driven by constitutive MAPK signaling and identified molecular therapeutic targets with promising clinical responses to RAF and MEK inhibition leading to the wider use of RAF inhibitors for the treatment of BRAF V600E- mutant histiocytoses and the current implementation of MEK inhibitor clinical trials dedicated to patients with histiocytic disorders. Genomic studies over the last 6 years have identified targetable kinase alterations in BRAF V600E-wild type histiocytoses and highlight the importance of comprehensive molecular analyses in the routine evaluation of histiocytic neoplasms. Determining the relevance of these kinase alterations in less systematically studied histiocytic neoplasms such as Rosai-Dorfman disease (RDD) and histiocytic sarcoma will be important. Also, systematically evaluating the therapeutic relevance of activating kinase alterations other than BRAF V600E in the histiocytoses in clinical trial settings will be critical future directions for the management of patients with histiocytic neoplasms. In this presentation we will review updated analyses from our ongoing efforts at cataloging mutations in non-LCH through whole exome sequencing efforts. In addition, we will present current results from our phase II clinical trials of the MEK inhibitor cobimetinib in BRAFV600-wildtype histiocytosis patients, as well as extended followup from the phase I clinical trial of vemurafenib for BRAF V600E-mutant histiocytic neoplasms.

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TUESDAY, OCTOBER 18, 2016 • 1015 GUEST SPEAKER PRESENTATIONS RATHASKAR SUITE

OUTCOMES OF 63 PATIENTS RECEIVING TARGETED THERAPIES FOR ERDHEIM-CHESTER DISEASE, INCLUDING FOLLOW-UP AFTER INTERRUPTION (THE LOVE STUDY)

Julien Haroche, MD, PhD1, Fleur Cohen-Aubart, MD, PhD1, Jean-François Emile, MD, PhD2, Fabrice Carrat, MD, PhD3, Frédéric Charlotte, MD4, Neïla Benameur, PharmD5, Jean Donadieu, MD, PhD6, Ahmed Idbaih, MD, PhD7, Mathilde de Menthon, MD, PhD8, Philippe Maksud, MD, PhD9, Stéphane Barete, MD, PhD10, Zahir Amoura, MD, MSc1

1Department of Internal Medicine and French reference Center for Rare Auto-immune and Systemic Diseases, Institut E3M, University Paris 06, AP-HP, Pitié-Salpêtrière Hospital, Paris, France; 2Research Unit (EA) EA4340 and Pathology Laboratory, Versailles University and AP-HP, Ambroise Paré Hospital, Boulogne, France; 3Pierre Louis Institute of Epidemiology and Public Health, University Paris 06, AP-HP, Saint-Antoine Hospital, Paris, France; 4Department of Pathology, University Paris 06, AP-HP, Pitié-Salpêtrière Hospital, Paris, France, Paris, France; 5Department of Pharmacy, University Paris 06, AP-HP, Pitié-Salpêtrière Hospital, Paris, France; 6Department of Pediatrics, University Paris 06, AP-HP, Trousseau Hospital, Paris, France, Paris, France; 7Department of Neurology, University Paris 06, AP-HP, Pitié-Salpêtrière Hospital, Paris, France; 8Department of Internal Medicine, University Paris Sud, AP-HP, Kremlin Bicêtre Hospital, Le Kremlin-Bicêtre, France; 9Department of Nuclear Medicine, University Paris 06, AP-HP, Pitié-Salpêtrière Hospital, Paris, France; 10Department of Dermatology, University Paris 06, AP-HP, Pitié-Salpêtrière Hospital, Paris, France

Fifty-seven to 75 percent of patients with Erdheim-Chester disease (ECD) harbor a BRAFV600E mutation. Targeted therapy with BRAF inhibitors (VEMURAFENIB, DABRAFENIB) are effective to treat mutated patients. COBIMETINIB, a MEK inhibitor, has been used for wild-type (WT) BRAF patients. Long-term outcomes after targeted treatments have not been reported, particularly after their interruption. We initiated in 2014 the LOVE study, a multi-center study of the Long-term Outcome after VEMURAFENIB / BRAF inhibitors interruption in ECD, Clinical Trial, NCT02089724. All ECD patients treated with VEMURAFENIB, DABRAFENIB and/or COBIMETINIB were enrolled. The primary endpoint was the percentage of partial (PMR) or complete (CMR) metabolic remission at 6 months (3 months for COBIMETINIB). Relapses after interruption were noted, as well as treatment efficacy after resumption.

Fifty-one patients were treated with BRAF inhibitors (49 patients with BRAFV600E mutations and 2 WT BRAF). At 6 months, PMR was obtained for 31 patients and CMR for 6 patients. Three patients were stable and 11 received less than 6 months of therapy at the time of analysis. Additionally, the 2 WT BRAF patients worsened under VEMURAFENIB. The most frequent side effects were: pilar keratosis (n=16), arthralgia (n=7), severe cutaneous allergy or DRESS (n=4), spinocellular carcinoma (n=4), basocellular carcinoma (n=2), melanoma (n=1). Fifteen patients were treated with COBIMETINIB, as sole therapy in 6 patients, and in combotherapy with BRAF inhibitor in 9. Among the 6 patients treated with COBIMETINIB alone, PMR was obtained in 4 and CMR in 1. One was treated for less than 3 months. The most frequent side effects with COBIMETINIB were acneic rash (n=8), rhabdomyolysis (n=4) and nausea (n=4).

Twenty patients stopped BRAF inhibitors after a median time of treatment of 20 months (range 1-31), 7 for severe side-effects, 1 for progression, 1 for progression and side-effect, and 11 because they were in PMR or CMR after 9-31 months of BRAF inhibitor. Relapses occurred in 15 cases (75%), with a median time to relapse of 6 months (range 1-12). Treatment with BRAF inhibitor was resumed in 9 patients leading to improvement in all. Four patients died during follow-up: 2 had experienced severe side effects and treatment was not resumed, 1 died from intracranial hemorrhage without evident link with the disease, and 1 died from gastric carcinoma after VEMURAFENIB was resumed.

BRAF inhibitors and COBIMETINIB are efficacious for treating ECD despite several side effects. After BRAF inhibitor interruption, relapses occur in 75% of cases.

30 HISTIOCYTE SOCIETY ANNUAL MEETING 2016

WEDNESDAY, OCTOBER 19, 2016 • 0900 GUEST SPEAKER PRESENTATIONS RATHASKAR SUITE

JON PRITCHARD LECTURE ON THE NIKOLAS SYMPOSIUM

BEYOND BRAF: MECHANISMS OF RESISTANCE AND THERAPEUTICS DEVELOPMENT IN LCH A SUMMARY OF THE PROCEEDINGS OF THE 26TH NIKOLAS SYMPOSIUM

Barrett J. Rollins, MD, PhD

Department of Medical Oncology, Dana-Farber Cancer Institute Department of Medicine, Brigham & Women’s Hospital Harvard Medical School, Boston, MA

Six years have passed since the first demonstration of activating BRAF mutations in LCH. While this discovery contributed to a better understanding of LCH pathogenesis, that understanding is far from complete and the therapeutic implications of neoplastic ERK pathway activation are not yet incorporated into the care of LCH patients. This year’s Nikolas Symposium focused on both of these shortcomings. In therapeutics, presentations on the efficacy of RAF and MEK targeting in Erdheim-Chester disease illustrated important concepts which will likely be relevant in the treatment of LCH. The experience of treating GIST and melanoma with targeted therapies also provided insight into possible future challenges that might be faced in targeted treatment of LCH, in particular genotype-specific clinical behaviors and the emergence of resistance. Several presentations described approaches to single-cell analysis which could be be critically important tools for evaluating resistance to targeted therapies in LCH should such resistance appear. Some of the difficulties inherent in treating LCH populations were highlighted in a presentation on drug development for pediatric indications. The Symposium’s second area of focus was more closely related to the fundamental nature of LCH. Evidence continues to accumulate in support of LCH as a neoplasm of myeloid progenitors. The presence of clonal mutations in defined myeloid subsets has led to new hypotheses about the mechanisms underlying the astonishing clinical heterogeneity of LCH. Support for some of these hypotheses has already come from animal models. An attempt will be made to use the new information discussed at the Symposium to provide a synoptic view of our understanding of LCH.

NOTES

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MONDAY, OCTOBER 17, 2016 • 1400 SCIENTIFIC SESSION I RATHASKAR SUITE

HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS IN LANGERHANS HETEROGENEITY OF MOLECULAR DIAGNOSES AND CELL HISTIOCYTOSIS: A MULTICENTER RETROSPECTIVE OUTCOMES IN A DIVERSE COHORT OF PATIENTS WITH DESCRIPTIONAL STUDY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS

Deepak Chellapandian1*, Rui Zhang2, Michael Jeng3, Ivan K. Chinn1,2, Baruch R. Goldberg1,2, Lisa R. Forbes1,2, Cor van den Bos4, Vicente Santa-María López5, Kai Lehmberg6, Sarah K. Nicholas1,2, Emily M. Mace1,2, Harshal A. Abhyankar3, Elena Sieni7, Yini Wang8, Taizo Nakano9, James Williams10, Maria I. Diaz3, Luis A. Pedroza4, M. Cecilia Poli1,5, Sean A. McGhee6, Nicholas Fustino11, Itziar Astigarraga12, Ira Dunkel13, Qi An114, Zeynep C. Akdemir7,8, Shalini N. Jhangiani7,8, Donna M. Muzny7,8, Cheng Cheng14, Sheila Weitzman1, Lillian Sung1, Kim E. Nichols15,16 Tram N. Cao1,2, Richard A. Gibbs7,8,9, James R. Lupski17,8,9, Jordan S. Orange1,2, Kenneth L. McClain1,3, Carl E. Allen1,3 1Division of Hematology/Oncology and Bone Marrow Transplantation, Hospital for Sick Children, Toronto, ON, Canada 1Baylor College of Medicine, Department of Pediatrics, Houston, 2Hematology and Oncology Center, Beijing Children's Hospital, Texas, USA Beijing, China 2Texas Children's Hospital, Division of Pediatric Immunology/Allergy/ 3Lucile Packard Children's Hospital Stanford University, Palo Alto, CA, Rheumatology, Houston, Texas, USA USA 3Texas Children's Hospital Cancer Center, Division of Pediatric 4Emma Children's Hospital/Academic Medical Center, Amsterdam, Hematology/Oncology, Houston, Texas, USA The Netherlands 4Universidad San Francisco de Quito, Colegio de Ciencias de la 5Hospital Sant Joan de Dèu, Barcelona, Spain Salud-Hospital de los Valles, Quito, Ecuador 6University Medical Centre Hamburg Eppendorf, Hamburg, Germany 5Universidad de Chile, Department of Pediatrics (North), Santiago, 7Meyer Children's University Hospital, Florence, Italy Chile 8Beijing Friendship Hospital, Beijing, China 6Stanford University School of Medicine, Department of Pediatrics, 9Children's Hospital Colorado, University of Colorado School of Division of Immunology and Allergy, Palo Alto, California, USA Medicine, Denver, CO, USA 7Baylor-Hopkins Center for Mendelian Genomics, Houston, Texas, 10Phoenix Children's Hospital, Phoenix, AZ, USA USA 11Blank Children's Hospital, Des Moines, IA, USA 8Baylor College of Medicine, Human Genome Sequencing Center, 12Hospital Universitario Cruces, BioCruces Health Research Institute, Houston, Texas, USA Bizkaia, Spain 9Baylor College of Medicine Department of Molecular and Human 13Memorial Sloan Kettering Cancer Center, New York City, NY, USA Genetics, Houston, Texas, USA 14Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA Purpose: The spectrum of genetic defects that can lead to 15Children's Hospital of Philadelphia, Philadelphia, PA, USA hemophagocytic lymphohistiocytosis (HLH) and subsequent outcomes 16Department of Oncology, Division of Cancer Predisposition, remain undefined, especially within an ethnically diverse population. St. Jude Children's Research Hospital, Memphis, TN, USA Methods: Families who met HLH-2004 criteria for HLH were prospectively enrolled for genetic studies, including targeted Purpose: The co-existence of Langerhans cell histiocytosis (LCH) with sequencing of familial HLH (fHLH) genes and whole exome hemophagocytic lymphohistiocytosis (HLH) is underreported and often sequencing (WES). Clinical features, therapies, and outcomes were associated with poor outcome. We sought to describe the incidence, captured retrospectively. Results: Overall, 114 subjects were risk factors for development, and outcome of HLH in patients with enrolled, including 51% females. Subjects were ethnically diverse: multisystem-LCH (MS-LCH). Methods: We conducted a retrospective 33% white, 18% black, 35% Hispanic, 4% Asian, and 11% other. study involving 14 centers and collected data on 384 MS-LCH patients Median age at time of HLH diagnosis was 6.5 years (SD = 6.1 years). diagnosed between 2000 and 2015. Results: Of 384 MS-LCH patients, Targeted sequencing of fHLH genes identified only 12 individuals 44 (11%) were identified with HLH. Twenty-nine patients were (11%) with biallelic mutations in PRF1 (9 cases), STX11 (1 case), categorized as having “true-HLH”•, which was defined as disease UNC13D (1 case), and RAB27A (1 case). WES of 50 probands led to fulfilling 5 of 8 HLH-2004 diagnostic criteria. Fifteen had an “HLH-like”• further discovery of biallelic RAB27A (1 case) and UNC13D (1 case) disorder, which was defined as fulfilling <5 of 8 HLH diagnostic criteria mutations. In over 30% of the remaining 48 probands tested, WES but whose disease status was suggestive of HLH, and treated with identified likely disease-causing variants in known primary HLH- and/or LCH-directed therapy. Twenty (45%) patients developed immunodeficiency disease-causing genes (e.g., WAS, STAT2), HLH (true or HLH-like) concurrent (±7 days) with LCH diagnosis, while particularly within intrinsic inflammatory pathways (e.g., NLRC4, 24 (55%) developed HLH >7 days before or after LCH diagnosis. The NLRP12). Among subjects who lacked biallelic mutations in fHLH 3-year cumulative incidence of HLH (true or HLH-like) in MS-LCH was genes, 55 received HLH-94 or HLH-2004 therapy, leading to long-term 16.8%. The 5-year overall survival of LCH patients without HLH was remission in 37 (67%). Of the rest, 8 required no immunomodulation 98 ±9%, while survival for those with an HLH-like disorder or true-HLH because symptoms resolved spontaneously; the remaining individuals was 75 ±12% and 70 ±14%, respectively (P<0.0001). Age <2 years, received other therapies, such as anakinra, resulting in long-term female gender, risk organ involvement (RO+) and lack of bone remission in 6 cases. Twenty-two individuals who lacked genetic involvement at LCH diagnosis were each independently associated evidence for fHLH underwent hematopoietic stem cell transplantation with increased risk for HLH. Among 20 patients with available data, the (HSCT), resulting in survival of 41%. Two subjects who received median soluble interleukin-2 receptor level (sIL-2R) was 16,220 U/mL HSCT and died were discovered to have variants in inflammatory (normal <2,400), ferritin was 505 ng/mL (normal <500), and sIL-2R/ pathway genes. All individuals who did not require immunomodulation ferritin ratio was 42. Conclusion: The development of HLH in patients survived; none who were tested by WES had variants in likely with MS-LCH was not uncommon and associated with a poor candidate genes. Conclusions: Broad genomic testing allows for the prognosis. Young females with RO+ MS-LCH who lack bone lesions at identification of a greater spectrum of molecular causes of HLH, LCH diagnosis were at increased risk of developing HLH. Ferritin potentially impacting therapy and outcomes. levels are lower in comparison to patients who develop HLH in other contexts.

32 HISTIOCYTE SOCIETY ANNUAL MEETING 2016

MONDAY, OCTOBER 17, 2016 • 1400 SCIENTIFIC SESSION I RATHASKAR SUITE

INNOVATIVE USE OF PK AND PD TO GUIDE DOSE SELECTION Purpose: Hemophagocytic lymphohistiocytosis (HLH) is a life- FOR A MONOCLONAL ANTIBODY AIMED AT NEUTRALIZING THE threatening condition characterized by excessive immune activation, HIGH IFN-GAMMA ACTIVITY PRESENT IN PATIENTS WITH where prompt recognition and initiation of treatment is essential for the MACROPHAGE ACTIVATION SYNDROME (MAS) survival. HLH has many overlapping clinical features with sepsis and systemic inflammatory response syndrome (SIRS). This study was Cristina de Min1, Kathy De Graaf1, Maria Ballabio1, Robert Nelson1, designed to determine if plasma biomarkers could differentiate HLH Zoë Johnson1, Walter Ferlin1, Geneviève Lapeyre1, from other inflammatory conditions. Methods: We analyzed Fabrizio De Benedetti2, Philippe Jacqmin3 inflammatory protein profiles in the plasma of children with active HLH using the Luminex platform. We compared concentrations of 135 1NovImmune S.A., Geneva, Switzerland analytes in a discovery set, which consisted of 32 patients with HLH to 2Division of Rheumatology, Ospedale Pediatrico Bambino Gesù 23 pediatric patients with severe sepsis or SIRS. The significant IRCCS, Roma, Italy analytes were validated in an independent cohort, which consisted of 3MnS, Dinant, Belgium 31 HLH patients and 24 patients with severe sepsis or SIRS. Comparisons were made based on the disease status and a classifier Purpose. Data from a MAS animal model and the high IFNγ and IFNγ- was built using various machine learning algorithms to see if the related chemokines (CXCL9, CXCL10) levels in MAS/sJIA patients plasma protein profile could predict whether a patient had HLH or prompted investigating the therapeutic role of IFNγ neutralization in Sepsis/SIRS. Results: Fourteen analytes were found to be significantly MAS. NI-0501, an anti-IFNγ antibody, showed promising efficacy and different between HLH patients and patients with either sepsis or SIRS favourable safety in primary HLH (pHLH). NI-0501 PK/PD data from in the discovery set and validated in the validated set (FDR = 0.1). A the ongoing clinical trial in pHLH was used to define the NI-0501 support vector machine classifier was created using six analytes (IL-6, dosing strategy for investigating the role of IFNγ neutralization in MAS/ MMP-10, EGF, sIL-6R, CXCL11, and TRAIL) that was able to achieve sJIA. Methods. In active HLH measurable circulating IFNγ levels do a sensitivity of 0.903 and a specificity of 0.833 to differentiate HLH not account for the total IFNγ present in the body. Following NI-0501 from sepsis/SIRS in an independent validation cohort. Conclusion: administration in pHLH patients, “total IFNγ”• (free and NI-0501-bound) Patients with HLH are at high risk of death without prompt initiation of is used as a surrogate for IFNγ production, revealing high IFNγ immune suppression, where such an intervention may be production despite the relatively low circulating “free IFNγ” at baseline. contraindicated in other conditions. This unbiased evaluation of Extrapolations allowed estimation of IFNγ production in MAS/sJIA plasma proteins demonstrated that HLH in fact has a distinct patients, based on IFNγ-related chemokines levels at baseline. inflammatory profile compared to severe sepsis and SIRS. An “HLH Results. Total IFNγ measurement in pHLH revealed that the IFNγ classifier”• could be a clinically useful tool to assist with efficient and concentration to be neutralized was several hundred fold higher accurate diagnosis of critically ill children with hyperinflammatory compared to what indicated by baseline free IFNγ (median IFNγ at syndromes. baseline <50 pg/ml; at peak 17,858 pg/ml). Total IFNγ at 48 hours post -NI-0501 administration tightly correlates with IFNγ-related POLYGENIC MUTATIONS IN THE CYTOTOXICITY PATHWAY chemokines levels (CXCL9: r=0.6264, p=0.0008; CXCL10: r=0.6931, INCREASE SUSCEPTIBILITY TO DEVELOP HLH p=0.0001), suggesting CXCL9 and CXCL10 concentrations as an IMMUNOPATHOLOGY IN MICE excellent marker of biologically active IFNγ. The total IFNγ produced in MAS/sJIA patients was indirectly estimated from the total IFNγ Fernando E. Sepulveda1,2, Alexandrine Garrigue1,2, concentration in pHLH patients with comparable CXCL9 and CXCL10 Sophia Maschalidi1,2, Meriem Garfa-Traore3, Gaël Ménasche1,2, levels following NI-0501 administration. This information, coupled with Alain Fischer1,2,4,5, Geneviève de Saint Basile1,2,6 modelling and simulation techniques, allowed determining the NI-0501 dose expected to neutralize rapidly the total amount of IFNγ in the 1INSERM Unité Mixte de Recherche 1163, Laboratory of Normal and majority of MAS/sJIA patients and identifying an appropriate frequency Pathological Homeostasis of the Immune System, Paris, France of NI-0501 administration to avoid unnecessary accumulation. 2Paris Descartes University-Sorbonne Paris Cité, Imagine Institute, Conclusion. This methodology allowed precise determination of the Paris, France dosing strategy for future trials, significantly reducing the risk of 3Cell Imaging Platform, INSERM US24 Centre National de la exposing patients to non-therapeutic NI-0501 doses. Recherche Scientifique Unité Mixte de Service 3633, Structure Fédérative de Recherche Necker, Paris Descartes Sorbonne Paris PLASMA PROTEIN PROFILES DISTINGUISH HEMOPHAGOCYTIC Cité University, Paris, France LYMPHOHISTIOCYTOSIS FROM SEPSIS AND SIRS 4Immunology and Pediatric Hematology Department, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, Howard Lin1, Baruch R. Goldberg3, Brooks P. Scull1, France Harshal A. Abhyankar1, Kenneth McClain1,2, Jordana Goldman3, 5Collège de France, Paris, France Trung Nguyen3, Michael Jordan3, Hector Wong4, Tsz-Kwong Man1,2, 6Centre d'Etudes des Déficits Immunitaires, Assistance Carl Allen1,2 Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France

1 Division of Pediatric Hematology-Oncology, Department of Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening Pediatrics, Baylor College of Medicine, Houston, TX USA hyperinflammatory disease. Inherited forms of HLH are caused by 2Texas Children's Cancer Center, Texas Children's Hospital, Houston, biallelic mutations in several effectors of granule-dependent TX USA lymphocyte-mediated cytotoxicity. A small proportion of patients with a 3Division of Allergy, Immunology, and Rheumatology, Department of so-called “secondary”• form of HLH, which develops in the aftermath of Pediatrics, Texas Children's Hospital, Houston, TX USA infection, autoimmunity, or cancer, carry a monoallelic mutation in one 4Division of Critical Care Medicine, Department of Pediatrics, Texas or more HLH-associated genes. Although this observation suggests Children's Hospital, Houston, TX USA that HLH may have a polygenic mode of inheritance, the latter is very 5Divisions of Immunobiology and Bone Marrow Transplantation and difficult to prove in humans. In order to determine whether the Immune Deficiency, Cincinnati Children's Hospital Medical Center, accumulation of partial genetic defects in lymphocyte-mediated Cincinnati, OH, USA cytotoxicity can contribute to the development of HLH, we generated 6Division of Critical Care Medicine, Cincinnati Children's Hospital mice that were doubly or triply heterozygous for mutations in HLH- Medical Center, Cincinnati, OH USA associated genes, those coding for perforin, Rab27a, and syntaxin-11. We found that the accumulation of monoallelic mutations did indeed

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increase the risk of developing HLH immunopathology after lymphocytic choriomeningitis virus infection. In mechanistic terms, the NOTES accumulation of heterozygous mutations in the two degranulation genes Rab27a and syntaxin-11, impaired the dynamics and secretion of cytotoxic granules at the immune synapse of T lymphocytes. In addition, the accumulation of heterozygous mutations within the three genes impaired natural killer lymphocyte cytotoxicity in vivo. The genetic defects can be ranked in terms of the severity of the resulting HLH manifestations. Our results form the basis of a polygenic model of the occurrence of secondary HLH.

HAPLOIDENTICAL HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR ADULT PATIENTS WITH EPSTEIN- BARR VIRUS-ASSOCIATED HAEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS

Zhao Wang, Zhi-Hui Li, Yi-Ni Wang, Jing-Shi Wang, Li Fu, Na Wei, Lin Wu

Department of Hematology, Beijing Friendship Hospital, Beijing, China

EBV-HLH is the most frequent subtype of secondary HLH with infectious triggers. Its prognosis is usually poor and haplo-HSCT may be an attractive option for the patients lacking sibling donors in China. We retrospectively analyzed 30 cases presented at our institution from May 2013 to December 2015. Twenty patients achieved remission at HSCT after receiving HLH-04 or DEP salvage therapy. The patients underwent HSCT from their related haploidentical donors following myeloablative conditioning, graft source is peripheral blood. 26 patients achieved donor hematopoietic stem cell engraftment. Of those, 23 patients achieved complete chimerism and 3 patients demonstrated mixed chimerism; reactivated EBV infection was found in 25patients; acute GVDH occurred in 18 patients with grade I-II aGVDH in 11 patients and grade III-IV aGVDH in 7 patients; chronic GVDH occurred in 6 patients. Four patients without engraftment died from conditioning regimen related toxicity. Seven patients with engraftment died . Of those, 1 patient died of HSCT-associated TMA, 1 patient died of grade IV aGVDH, and 5 patients died of relapsed

HLH or organ failure as results from unsuccessful treatment of the progressively elevated EBV-DNA load. The 3-year overall survival rate was 63.3% with a median survival time of 14 months (range: 6-40 months). Patients who carry with EBVDNA≤105 copies/ml before transplantation ,overall survival rate was significantly higher than that of EBVDNA>105 copies/ml(90% :50%, p=0.049); who achieved CR+PR OS was significantly higher than that of NR(88% : 20%, p=0.009)ï¼›who range from diagnosis to transplantion≤6 months OS was significantly higher than that of >6 months(77% : 25%, p=0.028).Our results indicate haplo-HSCT is an effective treatment approach for adult patients with EBV-HLH. It is important to reduce TRM by actively treating the reactivated EBV infection after HSCT.

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PRESENTATIONS NOMINATED FOR THE NESBIT PRIZE IN DEVELOPMENT AND INITIAL VALIDATION OF THE "MH SCORE", CLINICAL SCIENCE A DIAGNOSTIC TOOL THAT DIFFERENTIATES PRIMARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS FROM A COMBINATION OF ATG AND ETOPOSIDE FOR THE MACROPHAGE ACTIVATION SYNDROME TREATMENT OF HLH: RESULTS OF THE HIT-HLH TRIAL Francesca Minoia1, AnnaCarin Horne2, Francesca Bovis1, Michael Jordan1,2, Michael Henry3, Carl Allen4, Ken McClain4, Sergio Davi1, Laura Pagani1, Graciela Espada3, Yi-Jin Gao4, Jay Greenberg5, Stephan Ladisch5, Michelle Hermiston6, Antonella Insalaco5, Kai Lehmberg6, Helga Sanner7, Susan Shenoi8, Michael Jeng7, Barbara Degar8, Julie Kanter9, Ahmed Naqvi10, Sheila Weizman9, Nicolino Ruperto1, Alberto Martini1, Michael Joyce11, Kim Nichols12, David Teachey13, Rebecca Marsh2, Randy Q. Cron10, Angelo Ravelli1 Michael Grimley2, Stella Davies2 1Istituto G. Gaslini, Genoa, Italy 1Divisions of Immunobiology and 2Karolinska University Hospital Solna, Stockholm, Sweden 2Bone Marrow Transplantation and Immune Deficiency, Cincinnati 3Hospital de Niños Ricardo Gutierrez, Buenos Aires, Argentina Children's Hospital Medical Center, Cincinnati, OH USA 4Children's Hospital of Fudan, Shanghai, China 3Phoenix Children's Hospital, Phoenix, AZ USA 5Ospedale Pediatrico Bambino Gesù, Rome, Italy 4Division of Pediatric Hematology-Oncology, Department of 6University Medical Center, Hamburg, Germany Pediatrics, Baylor College of Medicine, and Texas Children's Cancer 7Rikshospitalet, Oslo, Norway Center, Texas Children's Hospital, Houston, TX USA 8Seattle Childre's Hospital, Seattle, WA USA 5Department of Hematology/Oncology, Children's National Medical 9Hospital for Sick Kids, Toronto, ON Canada Center, Washington, DC USA 10University of Alabama, Birmingham, AL USA 6Department of Pediatrics, University of California San Francisco, San Francisco, CA USA Purpose. It is common view that macrophage activation syndrome 7Lucile Salter Packard Children's Hospital, Stanford University School (MAS) bears close similarities with primary hemophagocytic of Medicine, Palo Alto, CA USA lymphohistiocytosis (pHLH). Their clinical resemblance may make it 8Harvard Medical School, Harvard University, Pediatric Oncology, difficult to differentiate the two conditions. However, early Dana-Farber/Boston Children's Cancer and Blood Disorders Center, discrimination is important because pHLH is often more severe than Boston, MA USA MAS and the therapeutic approaches are different. We develop and 9Department of Pediatric Hematology-Oncology, Medical University of validate a diagnostic score that discriminates pHLH from sJIA- South Carolina, Charleston, SC USA associated MAS. Methods. 362 patients with sJIA-associated MAS 10Division of Hematology/Oncology, The Hospital for Sick Children, and 258 patients with pHLH were collected in a multinational project Toronto, ON, Canada. involving pediatric rheumatologists and hematologists. 80% of the 11Nemours Children's Health System, Jacksonville, FL USA study population was used to develop the score and the remaining 12St. Jude Children's Research Hospital, Memphis, TN USA 20% as a validation sample. The features with the strongest 13Division of Hematology, The Children's Hospital of Philadelphia, association with pHLH in univariate analyses were scrutinized in Philadelphia, PA USA multivariate procedures and assigned a score, based on their statistical weight. The MH score was made up with the individual Purpose: The standard of care treatment for hemophagocytic scores of the selected variables. The best cut-off in the MH score was lymphohistiocytosis (HLH) remains the etoposide/ dexamethasone- calculated by means of ROC curve analysis. Results. The following 6 based regimen first developed by the Histiocyte Society in the HLH-94 variables were most closely associated with a diagnosis of pHLH: age trial. An alternative regimen, principally utilizing anti-thymocyte at disease onset ≤ 1.6 years, neutrophil count ≤ 1400/µl, fibrinogen ≤ globulin (rabbit ATG) and methylprednisone has been reported to give 131 mg/dl, splenomegaly, platelet count ≤ 78000/µl, hemoglobin ≤ 8.3 relatively prompt and complete responses. However, published data g/dl. The MH score ranged from 0 to 123. Its median value was 97 in suggest that the durability of responses with this regimen is not a good pHLH patients and 12 in MAS patients. A cut-off value > 59 revealed as with etoposide-based regimens. Thus, published data suggest that the best performance in discriminating pHLH from MAS (SE=91%, these approaches may be complementary. Methods: We develop a SP=93%, AUC=0.92, kappa=0.85). The diagnostic power of the MH clinical trial testing a ‘hybrid' treatment regimen for HLH (HIT-HLH) score was confirmed in the validation sample. Conclusion. The MH incorporating ATG, dexamethasone, and etoposide. This regimen score is a powerful tool that facilitates timely discrimination of pHLH begins with ATG, and incorporates etoposide at a lower dose intensity from MAS. Its application in clinical care may aid practitioners to than that used in the HLH-94 study. We tested this regimen starting in identify patients who are more likely to have pHLH and may deserve 2011 in Cincinnati, followed by expansion of the trial to other sites in diagnostic confirmation with appropriate genetic and functional testing. the US and Canada over the following year, and continued the trial until the end of 2015. A parallel trial, based on this regimen and trial protocol, was initiated in Europe. We prospectively gathered detailed response and adverse effects data. Results: Thirty-one (31) patients NOTES were in enrolled in the HIT-HLH trial. Twenty five survived until the end of treatment at 8 weeks, for an overall survival rate of 81% (+/- 14%). Most fatal outcomes occurred with days of study entry, mirroring mortality patterns observed on the HS trials. Three patients were taken off study because they were unable to tolerate the treatment regimen. Detailed response and adverse event data will be presented at the meeting. Conclusion: A hybrid ATG/ etoposide based regimen may provide effective therapy for HLH, but has significant adverse effects. No signal for inferiority to standard of care treatment (HLH-94) was apparent in this pilot study.

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ELEVATED CSF OSTEOPONTIN AND PERIPHERAL BLOOD of pathogenesis are unknown, and no standard approaches to CELLS WITH BRAF MUTATIONS IN PATIENTS WITH surveillance or therapy exist. Methods: CSF biomarkers including LANGERHANS CELL HISTIOCYTOSIS-ASSOCIATED inflammatory proteins and extracellular BRAF-V600E were evaluated NEURODEGENERATION in 40 patients with LCH brain lesions and/or LCH-ND. Peripheral blood and brain biopsy specimens were tested for the presence of Daniel Zinn1, Jennifer Picarsic2, Rikhia Chakraborty1, Howard Lin1, cells harboring BRAF-V600E. Results: Osteopontin was significantly Harshal Abhyankar1, Brooks Scull1, Albert Shih1 Karen Lim1,3, elevated and S100B was decreased in CSF from patients with LCH Stephen Simko1, Olive Eckstein1, Tricia L. Peters1,4, Walter Olea1, compared to patients with brain tumors and other neurodegenerative Thomas Burke1, Nabil Ahmed1, D. Williams Parsons1,5, conditions. While extracellular BRAF-V600E was detected in CSF of M. John Hicks1,4, Huy D. Tran6, Jeremy Jones6, Robert Dauser7, only 2/25 patients with LCH CNS lesions or LCH-ND, peripheral blood Michael Jeng8, Robert Baiocchi9, Deborah Schiff10, cells with BRAF-V600E were detected in 12/37 patients with LCH-ND. Stanton Goldman11, Kenneth Heym12, Ashish Kumar13, Brain biopsies of patients with LCH-ND demonstrate diffuse infiltration Carlos Rodriguez-Galindo14, Nicholas Whipple14, Patrick Campbell14, by BRAF-V600+ cells with microglial phenotype and elevated Geoffrey Murdoch15, Simon Heales16, Marian Malone17, osteopontin expression, surrounded by CD3+ T cells. Three of four Randy Woltjer18, Joseph Quinn18, Paul Orchard19, Michael Kruer20, patients with LCH-ND treated with BRAF inhibitors experienced Ronald Jaffe21, Sergio Lira22, Miriam Merad22,23, Tsz-Kwong Man1, significant clinical and radiologic improvement. Conclusions: Theories Kenneth L McClain1, Carl E. Allen1 of LCH-ND pathogenesis include autoimmune or inflammatory mechanisms. These results support a model of LCH lesions and LCH- 1Texas Children's Cancer Center; Department of Pediatrics Baylor ND arising from a common hematopoietic precursor: Where ERK- College of Medicine, Houston, TX USA activated myeloid precursors differentiate into CD207+ DCs in LCH 2University of Pittsburgh School of Medicine, Pathology Department, lesions in other organs, they may migrate to the brain and differentiate and Children's Hospital of Pittsburgh of UPMC - Pittsburgh, PA USA into hyperactivated inflammatory microglia in LCH-ND. This revised 3Program of Translational Biology and Molecular Medicine, Baylor model of pathogenesis further supports change in current practice to College of Medicine, Houston, TX USA evaluate LCH mutations in serial blood samples prospectively along 4Department of Pathology, Baylor College of Medicine, Houston, with long-term clinical surveillance to identify patients at risk for LCH- TX USA ND who may benefit from early initiation of therapy directed against 5Department of Human Genetics, Baylor College of Medicine, the clonal reservoir of myeloid precursors with activated ERK. Houston, TX USA 6Department of Radiology, Baylor College of Medicine, Houston, PRESENTATIONS NOMINATED FOR THE NEZELOF PRIZE IN TX USA BASIC SCIENCE 7Department of Neurosurgery, Baylor College of Medicine, Houston, TX USA CD8 T-CELL MEMORY RESULTS IN AN ENHANCED HLH 8Department of Pediatrics, Stanford University School of Medicine, DISEASE THAT IS RESISTANT TO IFN-GAMMA BLOCKADE Palo Alto, CA USA 9Department of Internal Medicine, The Ohio State University, Edward M. Behrens, Matthew Taylor Columbus, OH USA 10Department of Pediatrics, University of California-San Diego, La The Children's Hospital of Philadelphia, Philadelphia, PA, USA Jolla, CA USA 11Medical City Dallas Hospital, Dallas TX USA Purpose: The role of immunologic memory in the development of the 12Department of Pediatrics, Cook Children's Medical Center, Fort Hemophagocytic Lymphohistiocytosis (HLH) immune response is Worth, TX USA unknown. We used a well-defined animal model of HLH to examine 13Department of Pediatrics, Cincinnati Children's Medical Center, the effects of immunologic memory on disease outcome and Cincinnati, OH USA immunologic parameters. Methods: Perforin deficient mice were 14St. Jude Children's Research Hospital, Memphis, TN USA infected with 2 x 10^5 PFU of Lymphocytic Choriomeningitis Virus 15University of Pittsburgh School of Medicine, Pathology Department, (LCMV) to induce HLH. Mice were immunized using dendritic cells UPMC Division of Neuropathology Pittsburgh, PA USA pulsed with LCMV epitopes (GP33 and NP396 - CD8 T-cells; GP61 - 16Chemical Pathology, Great Ormond Street Hospital for Children, CD4 T-cells) 30 days prior to HLH induction. Flow cytometry was London, UK used to characterize cellular immune responses. ELISA was used to 17Laboratory Medicine, Great Ormond Street Hospital for Children, measure serum cytokines. Interferon gamma (IFNg) and Interleukin 33 London, UK receptor (ST2) neutralizing antibodies were dosed per standard 18Layton Aging and Alzheimer's Disease Center, Oregon Health protocols to test the effects of these therapies on immunologic Sciences University, Portland, OR USA memory. Results: Immunization with CD8 T-cell, but not CD4 T-cell 19Department of Pediatrics, University of Minnesota, Minneapolis, epitopes resulted in an enhanced HLH disease including decreased MN USA survival, increased hepatitis, increased serum cytokines, and 20Department of Child and Health Genetics, Barrow Neurological worsened cytopenias. IFNg blockade improved the survival of Institute, Phoenix Children's Hospital, University of Arizona College of immunized mice, but did not rescue back to the survival rate of naïve Medicine Phoenix, Phoenix, AZ USA mice. Upon withdrawal of IFNg blockade, immunized mice developed 21Department of Pathology, Magee-Women's Hospital of UPMC, a rapid, fatal relapse of disease while naïve mice did not. ST2 University of Pittsburgh School of Medicine, Pittsburgh, PA USA blockade was equally effective in treating immunized and naïve mice, 22Immunology Institute, Icahn School of Medicine, New York, NY USA and withdrawal did not result in relapse in immunized mice. 23Department of Oncological Sciences, Tisch Cancer Institute, Icahn Conclusion: Prior CD8 T-cell, but not CD4 T-cell immunologic memory School of Medicine, New York, NY USA results in an enhanced HLH disease with worsened survival. Immunologic memory results in decreased response to IFNg blockade Purpose: Langerhans cell histiocytosis (LCH) is characterized by therapy and a dramatic rebound response upon withdrawal. In inflammatory lesions with pathologic CD207+ dendritic cells. Brain contrast, response to ST2 blockade is unaltered by immunologic involvement may include mass lesions or a progressive memory. These results have implications for real world scenarios of neurodegenerative syndrome (LCH-ND). Differentiating isolated cytokine blockade where HLH patients may not be naïve to their pituitary lesions from other conditions is difficult due to risks of biopsy. immunologic triggers. LCH-ND may arise years after LCH is presumed cured, mechanisms

36 HISTIOCYTE SOCIETY ANNUAL MEETING 2016

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BRAF MUTATIONS IN BONE MARROW AND BLOOD OF pathogenesis. Methods: We generated inducible transgenic mice in PATIENTS WITH ERDHEIM CHESTER DISEASE which stable HIF-1α /HIF-1β proteins can be induced in all hematopoietic cell lineages with Vav1-Cre/Rosa26-LSL-rtTA drivers Jean-François Emile1,2, Fleur Cohen-Aubart3,4, Claude Baillou5, after doxycycline administration. In order to dissect the contribution of Damien Roos-Weil6, Matthias Papo3, Zofia Hélias-Rodzewicz1,2, individual immune cell subpopulation to the HLH pathogenesis, Makoto Miyara3,4, Omar Ibrahim Abdel-Wahab7, Olivier A Bernard6, lineage specific Cre transgenic alleles, IFN-γ receptor or Rag1 Zahir Amoura3,4, François M Lemoine5, Julien Haroche3,4 knockout alleles were employed. Results: Within two weeks, high level expression of HIF-1α/HIF-1β proteins in all hematopoietic cells in 1EA4340, Versailles University, Paris-Saclay university, Boulogne, C57BL/6 mice caused lethal HLH-like phenotypes: severe anemia, France thrombocytopenia, multi-organ failure, splenomegaly, and 2Pathology Department, Ambroise Paré hospital, APHP, Boulogne, hemophagocytosis. Type-1 polarized macrophages were significantly France increased, while the frequencies of T and B cells did not change. 3Department of Internal Medicine and French reference Center for Interestingly, absolute number of both total NK cells and mature Rare Auto-immune and Systemic Diseases, Institut E3M, AP-HP, cytotoxic NK cells were significantly reduced in peripheral blood, Pitié-Salpêtrière Hospital, Paris, France spleen, and bone marrow. IFN-γ signaling is critical for Type-1 4Université Pierre et Marie Curie (UPMC), Paris, France macrophage polarization. We found that knockout of IFN-γ receptor 5UPMC , UMR-S INSERM U1135, CNRS ERL 8255, Centre completely blocked the development of HLH. Myeloid cells (LysM- d'Immunologie et Maladies Infectieuses (CIMI-Paris), Paris, France Cre), mature T cells (dLck-Cre), or both lineages (LysM-Cre/dLck-Cre) 6U1170 INSERM, equipe labelisée LNCC, Villejuif, France specific induction of HIF-1α/HIF-1β did not cause HLH, suggesting the 7Memoriam Sloan Kettering Cancer Ctr, New York, NY, USA importance of NK cells' dysregulation in HLH development. In Rag1 knockout background which has defects in T/B cell immunity, HLH Purpose: Somatic oncogenic mutations of BRAFV600E are present in development was also blocked. Thus, T/B cells are also indispensable more than 70% of Erdheim-Chester disease (ECD), Langerhans cell for the development of HLH in our model. Conclusion: HIF-1α/HIF-1β histiocytosis (LCH) or mixed histiocytosis (MH) samples. Thus ECD, overexpression results in HLH characterized by activated LCH and MH are gathered in the revised classification of the Histiocyte macrophages and defective NK cells. This new model may help us to Society. We analyzed bone marrow (BM) and blood cells of adult understand underlying mechanisms of HLH and identify novel patients with ECD or MH. Methods: BM cells from adult patients with therapeutic targets. ECD (n = 17) or MH (n = 4) were collected and sorted by FACS. Clonogenic progenitors from sorted BM CD34+ cells were assayed in methylcellulose cultures. BM CD34+ cells were seeded in liquid NOTES culture under conditions allowing their differentiation into myeloid (mDC) or plasmacytoid (pDC) dendritic cells. BRAFV600E mutations were detected by real time or picodroplet digital PCR. Results: The 5 patients without BRAF mutations in histiocytosis had no mutations in BM or blood samples. Five of the 15 patients with BRAFV600E mutated ECD had mutations in CD34+ BM cells. The BRAF mutant/ wild type ratio (M/wt) was lower than 1%, and lower in CD38- than in CD38+ cells. BRAFV600E mutations were also detected in colonies derived from CD34+ cells (BFU-M in 3 /15, BFU-G in 1 /12), and pDC (2 /14) derived from CD34+ BM cells. BRAFV600E was detected in CD14+ blood monocytes in 6/8 and 3/5 patients with ECD or mixed H respectively. Mutations were always present in CD16low or neg, but in once in CD16high faction. The mean M/wt ratio was 0.20%, range [0.01 to 2.9]. BRAFV600E was also present in CD3+ (4/13) or B (2/11) lymphocytes. Conclusions: ECD and MH are neoplasia characterized by tissue infiltration by mature histiocytes with frequent BRAFV600E mutation. We show here that, in several cases, CD34+ multipotent BM progenitor and CD14+ blood monocytes also carry BRAFV600E mutation, and therefore belong to the tumor clone.

BLOOD SPECIFIC ACTIVATION OF HIF-1α/HIF-1β CAUSES HLH IMMUNOPATHOLOGY IN C57BL/6 MICE

Gang Huang1, Rui Huang1, Yoshihiro Hayashi1, Xiaomei Yan1, Michael B. Jordan2,3, Alexandra H. Filipovich3

Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA 1Program in Cancer Pathology, Division of Pathology and Experimental Hematology and Cancer Biology 2Divisions of Immunobiology 3Bone Marrow Transplantation and Immune Deficiency

Purpose: Hemophagocytic lymphohistiocytosis (HLH) is a life- threatening syndrome characterized by an overwhelming activation of diverse immune cells. Chemotherapy based regimen as a first-line therapy for HLH has substantial risk of mortality. Thus, to explore a novel, less toxic therapy is urgently needed. Accumulating evidence suggests that HIFs play important roles in the regulation of immune system. However, little is known about HIFs' function in HLH

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IDENTIFICATION OF NOVEL BRAF ALTERATIONS IN LCH USING composed of cells without any BRAF mutation is characteristic of AN INTEGRATED GENOMIC PIPELINE LCH, it is likely some of the pathologic manifestations are driven by interactions with normal immune cells reacting to the pathologic Thomas Burke1,2, Rikhia Chakraborty1,2, Oliver Hampton3, DCs. Methods: Our initial experiments indicated existence of clonal Daniel Zinn1,2, Brooks Scull1, Harshal Abhyankar1, Vijetha Kumar2,4, populations among LCH lesion-infiltrating CD3+ T cells. Clonality Nipun Kakkar3, Kenneth McClain1,2, David Wheeler3, was investigated by exploring T cell receptor beta (TCRB) Angshumoy Roy2,4, D. Williams Parsons1,2,3, Carl Allen1,2 rearrangement in patients and showed that the complementarity- determining region 3 (CDR3) of the TCRBV07 gene demonstrated 1Department of Pediatrics, Texas Children's Cancer Center, marked monoclonal expansion, suggesting a potential involvement Houston, TX USA of the CD3+ T cells in the pathogenesis of LCH. Results: Our 2Department of Pediatrics, Baylor College of Medicine, current goal is to analyze the LCH lesional microenvironment and Houston, TX USA determine the precise cellular function(s) of the infiltrating CD3+ T 3Department of Molecular and Human Genetics, Baylor College of cells in the pathogenesis. We investigated the microenvironment in Medicine, Houston, TX USA LCH (n=25) and it revealed that intratumoral T-cells in LCH have 4Department of Pathology, Baylor College of Medicine, high expression of T cell immunoglobulin mucin (TIM-3), Houston, TX USA lymphocyte activated gene 3 (LAG3) and programmed cell death protein 1 (PD-1) compared to healthy controls. Our results indicate Purpose: Langerhans Cell Histiocytosis (LCH) is characterized by that effector T cell exhaustion might be an important mechanism of universal ERK activation in CD207+ cells. Mutually exclusive BRAF- immune suppression in LCH patients. Conclusion: We are V600E and MAP2K1 somatic mutations account for approximately currently pursuing ex vivo inhibitor studies to target TIM-3, LAG3, 75% of cases. The goal of this study was to investigate alternative and PD-1 pathways in to determine if anti-tumor immunity plays a genomic alterations that may result in ERK activation in LCH. role in tumor progression and relapse in LCH and also to Methods: Whole exome sequencing (WES) and whole transcriptome determine if ERK-activation in myeloid DCs and subsequent T cell (RNA-seq) sequencing were performed on LCH patient samples with activation in the LCH model may be relevant in other models of negative BRAF-V600E testing status in order to identify additional tumor immunity. genetic drivers. Illumina RNA-seq libraries were prepared using poly- A+ total RNA from fresh-frozen tumor biopsies, and WES libraries VEMURAFENIB IN CHILDREN WITH REFRACTORY LCH: 21 were prepared from CD207+ cells sorted from LCH lesions. Both RNA PATIENTS TREATED IN FRANCE, UK, ITALY AND LEBANON -seq and WES libraries were paired-end sequenced (2 x 100bp) at 4- plex on a HiSeq 2500. Fusions were detected using the deFuse and Jean Donadieu1, Johannes Visser2, Elena Sieni3, Nabil Kabbara4, SOAPfuse algorithms, while SNVs and Indels were detected using Mathilde Jehanne5, Anne Pagnier6, Nathalie Aladjidi7, Anne Deville8, Atlas-SNP and Atlas-Indel & Pindel algorithms, respectively. Targeted Geneviéve Plat9, Anne Lutun10, Laurence Blanc11, James Nicholson12, validation was performed by RT-PCR and Sanger sequencing followed Alain Lefevre-Utile13, Ahmed Idbaih14, Olga Slater 15, by intracellular phosphoprotein analysis for ERK with or without Jean François Emile16, Sebastien Héritier1, 16 inhibitors of MAPK pathway members. Results: RNA-seq analysis of one LCH lesion revealed a MAPK-activating, in-frame FAM73A-BRAF 1Centre de référence des Histiocytoses, Registre des histiocytoses, fusion lacking the BRAF autoinhibitory region regulatory domain but Hémato Oncologie Pédiatrique, Hôpital Trousseau, APHP, Paris, retaining the kinase domain. Additionally, WES analysis of CD207+ France cells in three LCH cases identified in-frame BRAF deletions in the 3-C 2Department of Paediatric Oncology and Haematology, Leicester loop that result in constitutive BRAF activation. ERK activation induced Children's Hospital, Leicester, UK by the BRAF fusion and deletions was unresponsive to vemurafenib, 3Dipartimento di Oncoematologia Pediatrica Azienda but decreased by MEK inhibitor (U0126) in both in vitro models and Ospedaliero-Universitaria A.Meyer Firenze Italy primary cell culture. Conclusion: FAM73A-BRAF gene fusion and 4Division Pediatric Hematology Oncology Rafic Hariri University BRAF deletions represent novel mechanisms of ERK activation in Hospital Beirut, Lebanon LCH. These results suggest the utility of a staged approach starting 5Centre Hospitalier Universitaire Félix Guyon Saint Denis, with qPCR for BRAF-V600E, followed by targeted sequencing of La Réunion France MAPK pathway genes, and finally RNA-seq to comprehensively 6Centre Hospitalier Universitaire Grenoble, France evaluate specific somatic mutations in LCH patients that have 7Centre Hospitalier Universitaire Bordeaux, France implications for risk stratification and selection of targeted therapies. 8Centre Hospitalier Universitaire Nice, France 9Centre Hospitalier Universitaire Toulouse France CHARACTERIZING INFILTRATING T LYMPHOCYTES IN 10Centre Hospitalier Universitaire Amiens, France LANGERHANS CELL HISTIOCYTOSIS (LCH) LESIONS 11Centre Hospitalier Universitaire Poitiers, France 12Department of paediatric Oncology and Haematology, Cambridge Rikhia Chakraborty, Harshal Abhyankar, Walter Olea, Brooks Scull, University Hospitals, UK Kenneth L. McClain, Carl E. Allen 13Unité d'Immuno Hématologie pédiatrique, Hopital Necker Enfants Malades APHP Paris, France Texas Children's Cancer Center, Texas Children's Hospital, Houston, 14AP-HP, Service de Neurologie 2, Hôpital Universitaire La Pitié TX USA; Section of Hematology-Oncology, Department of Pediatrics, Salpétriére, Paris, France and Program in Translational Biology and Molecular Medicine, Baylor 15 Department of pediatric Hemato Oncology, Great Ormond Street College of Medicine, Houston, TX USA Hospital London, UK 16Université de Versailles-Saint-Quentin-en-Yvelines, France Purpose: Langerhans Cell Histiocytosis (LCH) is a disease characterized by granulomatous lesions, and universal MAPK Purpose: To present a survey of 21 children with LCH bearing pathway activation. LCH lesions are associated with a local BRAFV600E mutation treated with Vemurafenib (Cutoff date: May cytokine storm and exhibit a heterogeneous collection of 24th 2016). Methods: Two groups of patients were considered. Group inflammatory infiltrates (eosinophils, neutrophils and lymphocytes). 1: Multisystem disease, Risk Organ + (n=14) or RO - (n=2) refractory The mechanisms behind tumor formation, both presence of to at least one induction of vinblastine and steroid and for 9 patients pathologic CD207+ DCs, as well as recruitment of inflammatory refractory to 2 CdA (n=5) or 2 CdA Arac (n=4). Group 2: Symptomatic infiltrate, remain to be defined. Since inflammatory infiltrate neurodegenerative (ND) CNS LCH (n=5) which had all previously

38 HISTIOCYTE SOCIETY ANNUAL MEETING 2016

TUESDAY, OCTOBER 18, 2016 • 1300 SCIENTIFIC SESSION III RATHASKAR SUITE received vinblastine + steroid (> 24 months) and retinoic acid and one INFLAMMATORY PLASMA PROTEINS CLASSIFIERS PREDICT intravenous immunoglobulin. After informed consent, Vemurafenib DISEASE SEVERITY AND RESPONSE TO THERAPY IN PATIENTS was provided off label at a dose of 20 mg/kg/day orally for at least 8 WITH LCH weeks. Results: Group 1 included of 16 patients with a median age 0.9 years at diagnosis and Vemurafenib was initiated at median age of 1.9 Brooks Scull1, Daniel Zinn1,2, Howard Lin1, Albert Shih1, Miguel Cantu3, years. Median follow-up was 6 months. The indication was disease Harshal Abhyankar1, Rikhia Chakraborty1,2, Karen Lim1, progression in RO+ in 14 and in bone and soft tissue both after 2 CdA. Stephen Simko1,2, Tricia Peters1,2,4, Sergio Lira7, Kenneth McClain1,2, At week 6, evaluation could be done in 13 while 3 are ongoing. 12 Miriam Merad5,6,7, Tsz-Man1,2, Carl Allen1,2 evaluable patients have a complete response and one a partial response. No grade 3 or 4 side effect was observed. Group 2 (CNS 1Department of Pediatric Hematology-Oncology, Department of ND LCH) was composed of 5 patients, with a median age of 12 years Pediatrics, Baylor College of Medicine, Houston, TX USA at therapy start with a median follow-up of 14 months. One patient 2Texas Children's Cancer Center, Texas Children's Hospital, experienced weakness at therapy onset and a one skin rash resulting Houston, TX USA in withdrawal of therapy. In the three others, 3-month therapy resulted 3University of Texas Medical School at Houston, Houston, TX USA in a limited subjective improvement, but ataxia rating scale score 4Depatment of Pathology and Immunology, “¨Mount Siani School of remains stable. Conclusion: Vemurafenib appears be a very active in Medicine, New York, NY USA systemic RO+ refractory LCH with BRAFV600E mutation, but has a 5Department of Oncological Sciences, Mount Siani School of limited impact on CNS ND LCH. The indications, dosage, optimal Medicine, New York, NY USA duration of therapy and long term outcomes warrant further 6Tisch Cancer Institute, Mount Siani School of Medicine, New York, investigation. NY USA 7Immunology Institute, Mount Siani School of Medicine, New York, AN INHERITED GENETIC VARIANT IN SMAD6 INCREASES NY USA SUSCEPTIBILITY TO LANGERHANS CELL HISTIOCYTOSIS Purpose: Langerhans cell histiocytosis (LCH) is a myeloproliferative Erin Peckham-Gregory1,2, Rikhia Chakraborty1,2, Michael Scheurer1,2, disorder with clinical manifestations ranging from single lesions to Harshal Abhyankar1,2, Olive Eckstein1,2, Brooks Scull1,2, Daniel Zinn1,2, lethal multi-organ disease. No histologic features of LCH lesions Amanda Grimes1,2, John Belmont3, Albert Shih1, Kenneth McClain1,2, correlate with clinical outcomes. We hypothesize that function of Philip Lupo1,2, Carl Allen1,2,4 differentiated CD207+, including interactions with recruited activated lymphocytes, results in plasma protein profiles that reflect disease 1Texas Children's Cancer Center, Texas Children's Hospital, burden and tissue-specific DC-lymphocyte interactions. Plasma Houston, TX USA; proteins may therefore inform mechanisms of pathogenesis, reflect 2Department of Pediatrics, Section of Hematology-Oncology, Baylor disease burden and predict risk of relapse. Methods: We evaluated College of Medicine, Houston, TX USA; inflammatory proteins in pre-therapy plasma of patients with active 3Department of Molecular and Human Genetics, Baylor College of LCH using the Luminex platform. We compared plasma Medicine, Houston, TX USA; concentrations of 121 analytes in 181 patients with LCH to 90 controls 4Program in Translational Biology and Molecular Medicine, Baylor with discovery and validation sets. Comparisons were made based on College of Medicine, Houston, TX USA disease status, age, clinical risk categories, and time to relapse. Classifiers were designed to determine the ability of the plasma Purpose: Langerhans cell histiocytosis (LCH) is a myeloproliferative proteome to predict extent of disease and risk of relapse. Results: neoplasia characterized by inflammatory lesions including pathologic Thirty-one analytes were significantly different between all LCH and CD207 + dendritic cells (DC). Recent data support a model of controls, including proteins mediating chemotaxis and differentiation of pathogenesis in which activating somatic mutations in MAPK pathway lymphocytes and/or dendritic cells: osteopontin, SDF1A, 6CKine, genes arise in myeloid DC precursors. However, little is known about CCL19, CCL20, sIL4R, IL20, and IL23. Eighteen were different in germline susceptibility to this condition. Therefore, we conducted a pediatric low risk compared to high risk patients, with the most genome-wide association study (GWAS) to characterize the role of significant differences in inflammatory proteins including sTNFRI, inherited genetic variants on LCH risk. Methods: For the discovery sTNFRII, TNFα, sIL2Rα, and IL-8. Classifier analysis was able to cohort, LCH case-parent trios (n=118) were recruited from Texas predict risk organ involvement with a specificity of > 96% in both Children's Hospital (TCH). Genotyping was performed on the Illumina discovery and validation sets (p <0.0001). A 4-protein classifier was Omni5 Quad BeadChip. We evaluated the role of common variants able to predict relapse from pre-therapy plasma samples: Relapse (minor allele frequency >5%) on LCH risk using PREMIM-EMIM. We among those identified as high-relapse-risk 65% compared to 35% in applied a genome-wide statistical significance cutoff of P<1.0e-6 to the low-relapse-risk group. (p<0.0001) Conclusions: Distinct plasma inform validation locus selection. For the validation analysis, we used protein profiles exist in LCH, suggesting pathologic myeloid cells drive a case-control approach. TCH LCH cases (n=134) were recruited and the inflammatory pathology of disease. Protein classifiers from pre- control genotype datasets were obtained from dbGaP. Samples were therapy plasma are able to predict extent of disease and risk of genotyped using TaqMan primers specific to our locus of interest for relapse. validation. Results: After exclusion criteria were applied, 1,672,105 autosomal single nucleotide polymorphisms (SNPs) were assessed. An intronic variant in SMAD6on chromosome 15 was associated with germline LCH susceptibility (P=7.99e-7). The association between the SMAD6 locus and LCH risk remained statistically significant in the validation set (P=1.50e-6). Conclusion: In this genome-wide assessment of the role of inherited genetic variation on LCH, we identified SNPs associated with increased risk of LCH. SMAD6, while classically associated with TGF-Beta signaling, has also been reported to impact ERK activation, a critical feature of LCH pathogenesis. These findings support the role of inherited genetic variation on the risk of developing LCH.

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TUESDAY, OCTOBER 18, 2016 • 1300 SCIENTIFIC SESSION III RATHASKAR SUITE

A HIGHLY SENSITIVE, CLINICALLY-VALIDATED ASSAY TO QUANTITATE BRAF p.V600E MUTATIONS IN BLOOD AND BONE NOTES MARROW SAMPLES OF LANGERHANS CELL HISTIOCYTOSIS PATIENTS

Lizmery Suarez Ferguson1, Renee Webb1, Stephen Sarabia2, Karla Alvarez1, Carl Allen3, Kenneth McClain3, Jyotinder Punia1,2, Angshumoy Roy1,2, Dolores López-Terrada1,2, Kevin Fisher1,2

1Department of Pathology, Texas Children's Hospital, Houston, TX, USA 2Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA 3Department of Pediatrics, Hematology and Oncology, Texas Children's Hospital and Baylor College of Medicine, Houston, TX, USA

Purpose: BRAF c.1799A>T, p.V600E mutations have been reported in approximately 60% of Langerhans cell histiocytosis (LCH) lesions, and in tumor cells circulating in the peripheral blood (PB) and bone marrow (BM) of such patients. We designed and implemented a clinical test to quantitate BRAF p.V600E mutations in PB and BM samples to assist diagnosis, therapy, risk stratification, and disease monitoring in LCH patients at our pediatric academic tertiary care hospital. Methods: BRAF exon 15 reference and mutant (c.1799A>T) sequences were amplified using wild-type and allele-specific reverse primers, respectively, each in separate real-time PCR reactions. BRAF targets were multiplexed with primers targeting the CYP17 promoter (inhibition control), and BRAF and CYP17 amplicons were detected using FAM- and VIC-labeled TaqMan probes, respectively. Four BRAF p.V600E calibrators ranging from 0.01%-10.0% were used to generate standard curves, and cycle threshold differences between the reference and mutant curves were calculated to determine the variant allele fraction (VAF). The lower limit of quantitation (LLOQ) was 0.01% (one p.V600E-positive cell in 10,000 cells). Results: 127 samples (110 PB, 17 BM) from 89 patients (50 females, 39 males; median age 4 years, range 4 weeks-50 years) from 14 institutions were tested. Multiple samples were tested from 22 patients (range 2-6). Valid results were obtained from 93.7% (119/127) of samples tested; results from 8 PB samples were inconclusive due to insufficient DNA and/or PCR inhibition. BRAF mutations were detected in 42.8% (51/119) of samples. Mutant VAFs ranged from 0.01%-34.08%, and 48 samples (94.1%) harbored VAFs <1.0%. The assay detected significant VAF changes in serial PB samples and BRAF mutations in two morphologically normal BM biopsies. Conclusions: Quantitative BRAF p.V600E mutation testing is useful for the diagnosis, clinical management, and monitoring of LCH. An LLOQ of 0.01% is required to detect the low mutation fractions in PB and BM samples.

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TUESDAY, OCTOBER 18, 2016 • 1445 POSTER PRESENTATIONS - BASIC HLH AINSWORTH SUITE

Poster Location #1 exclusive IFNγ blockade on improving HSCT chimerism was studied in IFNγR1-/- mice transplanted with immunocompetent IFNγR1+/+donor ACTIVATION OF CYTOTOXIC CD4 T CELLS DISTINGUISHES bone marrow (BM) cells. To mimic transplant conditions performed in FAMILIAL FROM VIRUS-INDUCED SECONDARY hosts with high circulating levels of IFNγ, mice were infected with HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS BCG, Mycobacterium bovis bacillus Calmette-Guérin, prior to HSCT, as described previously by Rottman et al. (PLOS Medicine, 2008). Sandra Ammann1,2, Kai Lehmberg3, Udo zur Stadt4, Gritta Janka3, IFNγ-induced CXCL9 levels were also monitored in context of this Anne Rensing-Ehl1, Christian Klemann1, Sebastian Bode1,5, model. Results: Improved HSCT chimerism of donor IFNγR1+/+ BM Ilka Fuchs1 and Stephan Ehl1,5 for the HLH study of the GPOH# cells in BCG-infected IFNγR1-/- mice was demonstrated by the exclusive blockade of IFNγ. Decreased CXCL9 levels correlated to 1Center for Chronic Immunodeficiency (CCI), Medical Center - improved HSCT chimerism, thus confirming the abrogation of IFNγ- University of Freiburg, Faculty of Medicine, University of Freiburg, signalling. In the ongoing Phase 2/3 study, 10 patients underwent Germany HSCT. All but one had sustained NI-0501 serum concentrations at the 2Faculty of Biology, University Freiburg, Germany time of transplant, and all but one had levels of CXCL9 below the 3Pediatric Hematology and Oncology, University Medical Center lower limit of quantification, indicating IFNγ neutralization. Hamburg Eppendorf, Germany Conclusions: The improved HSCT chimerism afforded by the exclusive 4Center for Diagnostic, University Medical Center Hamburg blockade of IFNγ in the present animal model further supports the Eppendorf, Germany hypothesis that high levels of IFNγ at the time of transplant are 5Center for Pediatrics and Adolescent Medicine, University Medical detrimental for a successful engraftment. NI-0501 therefore offers an Center, Freiburg, Germany additional potential benefit if considered for the management of primary HLH patients to bridge to HSCT. Background: Hemophagocytic lymphohistiocytosis (HLH) is a life- threatening inflammatory syndrome characterized by hyperactivation of lymphocytes and histiocytes. To explore differences in pathogenesis of HLH-subtypes, we compared T-cell activation patterns between NOTES patients with familial HLH without proof of a viral trigger (1°HLH), 2° HLH without apparent infectious trigger (2°HLH) and 2°HLH induced by a viral infection (2°V-HLH). Methods: T cells were analyzed by flow cytometry using surface expression markers: CD45RA, CCR7, CD127, PD-1, CD57 and HLA-DR, as well as Vbeta T cell repertoire analysis. Additionally, perforin expression was analyzed after intracellular staining. Results: Polyclonal CD8 T-cells were highly activated in 1°HLH and 2°V-HLH, but much less in 2°HLH as assessed by HLA-DR and marker combinations of CD45RA, CCR7, CD127, PD-1 and CD57. HLA-DR expression of CD8 T cells correlated with sCD25 serum levels in 1°, but not in 2°HLH. A high proportion of polyclonal CD4 T-cells expressing HLA-DR, CD57, and high perforin expression in CD27+/-CD28+ CD4 T-cells was a signature of 1°HLH that was rarely observed in 2°V-HLH. Conclusion: The similar pattern and extent of CD8 T-cell activation between 1°HLH without apparent infection and virus-triggered 2°HLH raises the possibility that 1°HLH may be triggered by viral infections, although apparently difficult to detect. However, the dramatic activation of cytotoxic CD4 T-cells indicates cellular responses that are characteristic for 1°HLH. Moreover, the data illustrate that the full clinical picture of hemophagocytic syndrome can develop in the absence of relevant T cell activation.

Poster Location #2

EXCLUSIVE IFN-GAMMA BLOCKADE SIGNIFICANTLY CORRELATES WITH IMPROVED CHIMERISM IN MICE: IMPLICATIONS FOR AN OPTIMIZED THERAPEUTIC APPROACH TO PRIMARY HLH PATIENTS

Walter Ferlin, Vanessa Buatois, Laurence Chatel, Maria Ballabio, Cristina de Min

Novimmune SA, Geneva, Switzerland

Purpose: High production of IFNγ plays a critical role in the pathophysiology of primary HLH (pHLH), a rare immune regulatory disorder lethal if untreated. Clinical research is actively ongoing to identify effective pharmacological regimens able to control HLH as a bridge to curative HSCT. The innovative targeted approach of IFNγ neutralization by NI-0501, an anti-IFNγ monoclonal antibody, is presently investigated in a Phase 2/3 study. Preclinical studies in IFNγ -Receptor-1 deficient (IFNγR1-/-) mice have demonstrated that high levels of IFNγ impair hematopoietic stem cell (HSC) differentiation resulting in HSC transplantation (HSCT) rejection. Methods: Benefit of

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TUESDAY, OCTOBER 18, 2016 • 1445 POSTER PRESENTATIONS - CLINICAL HLH AINSWORTH SUITE

Poster Location #3 on the child and his family and was sent to Sweden for genetic studies. Direct sequencing of the coding region of the Syntaxin-11 A REVIEW OF ADULT PATIENTS WITH HAEMOPHAGOCYTIC (STX11) gene was performed. Primers containing the -21M13 and LYMPHOHISTIOCYTOSIS TREATED AT A SPECIALIST M13 complement were used. He was found to be a homozygous REFERRAL CENTRE carrier of a novel mutation in the Syntaxin-11 gene. He had a deletion of the nucleotide C at position 110, leading to a frame shift and a Robin Dowse1, Vasanta Nanduri2, Hadil Aabuarquob1, premature stop codon at base pair position 158, corresponding to Donal McLornan1 codon 62. Both parents were heterozygous carriers. NK cell function studies were performed and showed that this STX11 mutation 1King's College Hospital, London, UK contributes to the disease by affecting NK cell degranulation 2Watford General Hospital, Watford, UK pathways. He reactivated his disease twice since diagnosis and entered remission again. He underwent bone marrow transplantation Purpose: King's College Hospital is a tertiary referral centre for adults in Italy from his HLA compatible sister. Preparative regimen consisted with haematological malignancies from South East England and for of busulfan, thiotepa and fludarabine. Graft-versus-host disease myelodysplastic syndromes and aplastic anaemia for the whole of UK. prophylaxis included cyclosporine-A and short-term methotrexate. On It is also the national referral centre for patients with liver disease. The day + 20 after the allograft, he had sustained donor engraftment and possibility of a diagnosis of haemophagocytic lymphohistiocytosis no signs of GVHD. The NK function after the allograft is normal. He is (HLH) is often raised as the combination of cytopenias with alive and disease-free ten years after bone marrow transplantation. hyperferritinaemia is not an uncommon manifestation with this case Like in other types of FHL, bone marrow transplantation seems to be mix. Methods: We reviewed the presenting features, diagnostic the only curative treatment option in patients carrying this mutation. pathways and treatment algorithm for our patients with HLH in order to standardise our approach to this challenging diagnosis. Results: Over Poster Location #5 a 5 year period, 18 histologically confirmed cases of HLH were found with an age range of 25-76 years (M:F 1.5:1). Patients with fulminant HIGH LEVELS OF sCD25 AND sCD163 IN PATIENTS DIAGNOSED liver failure were often the source of cases as they had some of the WITH SEPSIS. COULD THEY BE USEFUL FOR SEPSIS clinical and laboratory features, although they did not fulfil all DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS WITH diagnostic criteria. We also reviewed cases of hyperferritinaemia to HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH)? determine possible missed cases of HLH but most with ferritin greater than 500ng/ml were attributable to transfusion related iron overload Susana Garcia-Obregon1, Iratxe Seijas2, Javier Pilar-Orive3, and occasionally liver disease. Patients were treated with varying Carmen Ruano4, Ainize Peña1, Olatz Zenarruzabeitia5, Joana Vitalle5, combinations of steroids, etoposide, IVIG and Cyclosporin with no Francisco Borrego5,6, Idoia Ortega-Martinez7, Dolores Boyano7, specific protocol. Conclusions: Outcome in these cases of adult HLH Juana Gil8, Itziar Astigarraga1,9,10 remained poor with a high mortality. Diagnosis was predominantly based on bone marrow morphology rather than using all diagnostic 1Pediatric Oncology Group, BioCruces Health Research Institute, criteria. Treatment strategies were not uniform, due mainly to co- Barakaldo, Spain morbidities and late presentation. It is essential to promote recognition 2Intensive Care Unit, Hospital Universitario Cruces, Barakaldo, Spain of these patients with early referral to specialist services, look at 3Pediatric Intensive Care Unit, Hospital Universitario Cruces, achieving an earlier diagnosis by using cytokine profiles and to Barakaldo, Spain standardise treatment. A national registry of adult HLH is needed to 4Anesthesiology and Reanimation Service. Hospital Universitario better determine presenting features, diagnostic criteria and treatment Cruces, Barakaldo, Spain strategies for this rare disorder. 5Immunopathology Group, BioCruces Health Research Institute, Barakaldo, Spain Poster Location #4 6Ikerbasque, Basque Foundation for Science, Bilbao, Spain. 7Department of Cell Biology and Histology, Faculty of Medicine. LONG-TERM FOLLOW-UP AFTER BONE MARROW University of the Basque Country, UPV/EHU, Leioa, Spain. TRANSPLANTATION IN A CHILD WITH FAMILIAL 8Immunology Service. Hospital Universitario Gregorio Marañon. HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (FHL) AND Madrid, Spain HOMOZYGOUS SYNTAXIN-11 MUTATION 9Paediatric Service, Hospital Universitario Cruces, Barakaldo, Spain 10Department of Paediatric, Faculty of Medicine, University of the Roula Farah1, Yenan Bryceson2, Alain E Sayad1, Eva Rudd2, Basque Country, UPV/EHU, Gipuzkoa, Spain Jan-Inge Henter2 and Franco Locatelli3 Purpose: HLH and septic patients share many clinical features. HLH 1Department of Pediatrics, St Georges Hospital, Balamand University, diagnostic criteria include sCD25>2,400U/ml. sCD163 is a marker for Beirut, Lebanon HLH diagnosis and follow-up. Our aim is to evaluate sCD25 and 2Childhood Cancer Research Unit, Department of Woman and Child sCD163 utility as sepsis markers and to compare their sCD25 levels to Health, Clinical Genetics Unit, Department of Molecular Medicine, those in HLH patients. Methods: Serum concentration for sCD25 and Center for Infectious Medicine, Department of Medicine, Karolinska sCD163 was determined by ELISA assays in 63 patients with sepsis Institutet, Stockholm, Sweden and 60 healthy controls. sCD25 serum concentration was reported in 3Ospedale Gesu Bambino, Roma, Italy 23 HLH cases of HLH-2004 protocol in Spain. Statistical analysis was performed by SPSS program. Results: Sixty-three septic patients FHL is a rare, autosomal recessive disorder with severe and often fatal were included (42males/21females) from 2010 to 2015. Median age: manifestations. It is characterized by a sepsis-like illness with 61.9 years-old (Range: 19-84). Basque Center for Transfusion cytokinemia, proliferating and organ-infiltrating phagocytes and provided 60 healthy donors´ samples (37males/23 females). Median cytopenias. We report a 7 months old Lebanese boy diagnosed with age: 51 years-old (Range: 31-65). Data from 23HLH patients FHL when he presented with fever, hepatosplenomegaly and anemia (13males/10females) were reported. Median age: 1.23 years-old followed by pancytopenia. Triglycerides and ferritin were elevated and (Range:0-49). sCD163 serum median concentration: donors 634.87ng/ fibrinogen was low. Bone marrow aspiration confirmed the presence of ml versus septic patients 1651.95ng/ml. sCD25 median concentration: hemophagocytosis. He was treated according to the HLH-94 protocol donors 844.42pg/ml versus sepsis cases 4072.68pg/ml. sCD25 and with etoposide, oral dexamethasone but no cyclosporine. He showed sCD163 revealed significantly increased levels in sepsis. No excellent response and remission of his disease. DNA was extracted differences were found between septic patients who died and

42 HISTIOCYTE SOCIETY ANNUAL MEETING 2016

TUESDAY, OCTOBER 18, 2016 • 1445 POSTER PRESENTATIONS - CLINICAL HLH AINSWORTH SUITE survivors. sCD25 median concentration in 11 HLH patients was higher Poster Location #7 than in septic patients: 14,550pg/ml (Range:1493-63,130pg/ml). sCD25 results were expressed in U/ml in 12 HLH patients SURVIVAL AFTER HEMATOPOIETIC STEM CELL (median:2765U/ml; Range:147-8000U/ml) and sCD25>2,400U/ml in 7. TRANSPLANTATION IN HEMOPHAGOCYTIC Results expressed in U/ml or pg/ml cannot be compared due to the LYMPHOHISTIOCYTOSIS COMPARED TO SEVERE COMBINED lack of measurement standardization and conversion formula. IMMUNE DEFICIENCY AND SEVERE APLASTIC ANEMIA Conclusion: Our results show that sCD163 and sCD25 could be promising markers in sepsis. Both are elevated significantly in septic AnnaCarin Horne8, Emma Lindstrӧm1, Kim Ramme2, patients compared to donors and sCD25 is increased in HLH when Ida Hed Myrberg3, Rebecca Marsh4, Andre Willasch5, Peter Bader6, compared with septic patients. sCD25 measurement units and cutoff Andrew Gennery7 and on behalf of the EBMT inborn errors and EBMT levels as HLH diagnostic criteria should be considered carefully. Lack paediatric diseases working parties of formula to convert the concentration values among ELISA tests could misinterpret study results. More specific diagnostic criteria are 1) Karolinska Institutet, Stockholm, Sweden; 2) Department of needed for differential diagnosis between sepsis and HLH. Pediatric Hematology, Immunology and Stem Cell Transplantation, Astrid Lindgren's Childrens Hospital, Karolinska University Hospital, Poster Location #6 Stockholm, Sweden; 3) Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, FACTORS ASSOCIATED WITH ETOPOSIDE USAGE IN CHILDREN Sweden; 4) Cincinnati Children's Hospital, Cincinnati, OH USA; 5) WITH MACROPHAGE ACTIVATION SYNDROME COMPLICATING Department of Pediatric Hematology, Oncology and Hemostaseology, SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS Goethe University, Hospital for Children and Adolescents III, Frankfurt, Germany; 6) Goethe University, Frankfurt, Germany; 7) Institute of AnnaCarin Horne1, Francesca Minoia2, Francesca Bovis2, Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Sergio Davi2, Itziar Astiggarara4, Priyankar Pal3, Jordi Anton4, Kingdom; 8) Childhood Cancer Research Unit, Department of Kimo Stine5, Sandra Enciso6, Ozgur Kasapcopur7, Michael Jeng8, Women's and Children's Health, Karolinska Institutet, Karolinska Rosa Merino9, Despoina Maritsi10, Randy C. Cron11, Angelo Ravelli2 University Hospital, Stockholm, Sweden

1Institutet, Stockholm, Sweden, Purpose: Curing children with primary HLH requires allogeneic 2 Giannina Gaslini, Genoa, Italy hematopoietic stem cell transplantation (HSCT). Published data of 3Institute of Child Health, Kolkata, India survival post-HSCT in children with HLH compared with other 4Sant Joan de Deu, Barcelona, Spain diseases is missing. Methods: Retrospective analysis was performed 5Children's Hospital, Little Rock, AR USA on existing data in the European Society for Blood and Marrow 6Hospital Infantil de Mexico City, Mexico City, Mexico Transplantation (EBMT) database. We identified 458 children with 7University of Istanbul, Istanbul, Turkey HLH, 145 with SAA and 1,017 with SCID (eligibility: age 0-18 years, 8Stanford, Palo Alto, CA USA allogeneic HSCT conditioned 2004-2014). Outcome: event free 9Hospital Universitario La Paz, Madrid Spain survival (EFS), with event defined as death, relapse of disease, or re- 10Medical School, Athens, Greece transplantation. Predictors explored in multivariate analysis were sex, 11University of Alabama at Birmingham,, Birmingham, AL USA age, conditioning, type of donor, stem cell source, diagnosis, geographic area, CMV, HLA match, and interaction between diagnosis Purpose: Although macrophage activation syndrome (MAS) has been and donor type. Results: Probability of 5-year EFS post-HSCT was reported in association with almost all rheumatic diseases, it is by far estimated to 57.7% (95% CI=52.7-63.1) in HLH, 65.2% (95% CI=55.7- most common in systemic juvenile idiopathic arthritis (sJIA). Reported 76.3) in SAA (p=0.009) and 60.6% (95% CI=57.1-64.3) in SCID mortality rates in MAS reach 10-20%. Standardized treatment (p=0.120). Among deceased patients, 21% with HLH died from guidelines for MAS are currently lacking, but management commonly disease relapse, compared to 8% with SAA and 6% with SCID includes high-dose corticosteroids combined with another (p=<0.0001). In multivariate analysis, diagnosis and donor type were immunosuppressive agent. Etoposide is a well established therapy in risk factors. The hazard ratio (HR) of an event using Matched Related primary hemophagocytic lymphohistiocytosis. A recent systematic Donor (MRD) was more than three times in children with HLH than in literature review on treatments of MAS in sJIA identified a few patients the SAA group (HR 3.30, 95% CI=1.59-6.85, p=0.001). A similar trend who were given etoposide. We, therefore, aimed to investigate was seen for SCID patients (HR 1.43, p= 0.066). Conclusion: Post- etoposide usage among pediatric patients with MAS complicating sJIA HSCT survival in children with HLH was lower than for children with and to identify predictors of etoposide administration. Methods: SAA and SCID. More than twice as many patients with HLH died from Retrospective collected data from 362 patients included in the relapse of disease, where patients with an MRD had the worst multinational study of the 2016 classification criteria for MAS in sJIA outcome. This raises the question of whether transplantation with were examined to identify patients treated with etoposide and record related donors who are heterozygote carriers of HLH might affect potential predictors of etoposide administration. Variables significantly outcome, or whether the related donors may have been affected by associated with etoposide usage in univariate analysis were entered in unknown biallelic mutations. The high incidence of disease relapse a multivariate regression model. Continuous variables were and death in patients with HLH needs further investigation. dichotomized according to the cut-off value obtained through ROC curve analysis. Results: Forty of the 362 patients (11 %) were treated Poster Location #8 with etoposide. Factors significantly associated with etoposide administration in multivariate analysis included multiorgan failure (OR THE ROLE OF G-CSF IN ADULT HLH 7.9, 95% CI 2.2-28.5), platelet count ≤ 132 x 109/liter (OR 5.8, 95% CI 1.8-18.2), aspartate aminotransferase > 389 units/liter (OR 3.7, 95% Zhili Jin, Yini Wang, Lin Wu, Zhao Wang CI 1.3-10.3), and fibrinogen ≤ 1.53 gm/liter (OR 2.9, 95% CI 1.1-7.5). The AUC of the model was 0.86. In univariate analysis, there was no Beijing Friendship Hospital, Capital Medical University. Beijing. China significant difference in mortality rate between patients given or not given etoposide. Conclusions: Patients treated with etoposide were Purpose: Hemophagocytic lymphohistiocytosis (HLH) is a life- sicker than patients who did not receive this medication. However, threatening hypercytokinemia. Reduction in two or more lineages in mortality rate did not differ between the two treatment groups, the periphery blood accounts for 97.2% and granulocytopenia as the suggesting that etoposide may be part of aggressive therapeutic main symptom can increase the risk of infection. Granulocyte colony- interventions.

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stimulating factor(G-CSF) is mainly used for the treatment of Poster Location #10 granulocytopenia. We keen to explore the role of G-CSF in the adult HLH. Methods: We collected for 203 adult HLH patients who first visit CHARACTERISTICS OF PATIENTS WITH PARTIAL OCULO- and meet the HLH-2004 diagnostic criteria. 104 cases used the G- CUTANEOUS ALBINISM AND IMMUNODEFICIENCY ASSOCIATED CSF when the neutrophil cell lower than 1.0x109/L and stop to use HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AT THE when the neutrophil cell higher than 2.0x109/L; 99 cases did not use CHILDREN'S HOSPITAL 1 HO CHI MINH CITY the G-CSF and compared the time to neutrophil recovery of two groups.Clinical information collected included the patient's(used the G- My T. Lam1, Hong M.T. Nguyen1, Lien B. Le2, Hung T. Nguyen2, CSF) hemogram(WBC,HGB,PLT),•liver enzyme indexes (ALT, AST, T- Tuasn M. Nguyen2, Tâm M.T. Nguyen2, Anh H.M. Nguyen2, BIL, D-BIL),•levels of serum ferritin,•temperature and so on (before and Anh K.N. Tran2, Anh L.P. Nguyen2, Trang.TT. Pham2, after the use of G-CSF). Results: The time to neutrophil recovery of Khanh X.T. Luong2, Hanh P. Ma2, Van T.T. Luong2, group that used of G-CSF is shorter than the other one and with Cuc TT. Cao2, Dao H.T Ngo3, Le M.T. Duong3, Linh X.D. Bui3, significant differences between two groups. Comparison of indexes Tung T. Tran4, Vu A. Hoang5 “before” and “after” application of G-CSF: temperature(Z=0.000); Neutrophil absolute value(Z=0.000);PLT (Z=0.000); ALT(Z=0.007); 1Department of Pediatrics, The University of Medicine and Pharmacy AST(Z=0.000); T-BIL(Z=0.034)These index are significantly different at Ho Chi Minh City, Vietnam and tend to improve. Hemoglobin (P=0.730); triglyceride levels 2Department of Clinical Hematology . The Children's Hospital N1 Ho (P=0.443); levels of serum ferritin(Z=0.056); fibrinogen level Chi Minh City, Vietnam (Z=0.181). There were no significant differences of these index 3Department of Laboratory Hematology . The Children's Hospital N1 between two groups. During the application of G-CSF, 8 cases Ho Chi Minh City, Vietnam (7.69%) patients occurred bone pain or muscle pain, other patients did 4Department of Laboratory Hematology. The Children's Hospital N1 not appear naive cells increase, shock, interstitial pneumonia, and Ho Chi Minh City, Vietnam other serious adverse reactions. Conclusion: G-CSF can increase the 5Department of Genetic Laboratory . The University of Medicine and granulocyte to reduce the risk of infection; no side effects were Pharmacy Ho Chi Minh City, Vietnam observed of the G-CSF treatment.G-CSF is a safe and effective supportive therapy for HLH. Background:Partial Oculocutaneous Albinism and Immunodeficiency (OCA-ID) is an rare autosomal recessive syndrome including Chediak- Poster Location #9 Higashi syndrome (CHS), Griscelli syndrome type 2 (GS2), Hermanski -Pudlak syndrome (HPS), and MAPBP- interacting protein deficiency CLINICAL FEATURES AND PROGNOSIS OF HEMOPHAGOCYTIC syndrome (MAPBPIP- deficiency). Mutation of causal genes of OCA- LYMPHOHISTIOCYTOSIS WITH EPSTEIN-BARR VIRUS ID involve functions of cell types containing lysosomes such as INFECTION melanocytes , immune cells. Clinical characteristics of OCA-ID syndrome are hypopigmentation of skin, hair, recurent infections, and Wenyuan Lai, Jingshi Wang, Yini Wang, Zhao Wang the “accelerated phase”• which is a life- threatening condition of hemophagocytotic lymphohistiocytosis (HLH).Propose: Describe Department of Hematology Beijing Friendship Hospital Capital characteristics of patients with OCA-ID associated HLH and Epstein- Medical University, Beijing, China Barr virus infection (EBV) who were admitted at the Children’s Hospital N1 HCMC from May, 2013 to May,2016. Method: case report. Results: Objective: To analyze the clinical manifestations and prognosis in There were two patients with OCA-ID associated HLH-EBV including adult patients with Hemophagocytic lymphohistiocytosis(HLH) also one 5-year-old boy with CHS and one 5-year-old girl with GS2. Both accompany with Epstein-Barr virus(EBV) infection. Methods: A had fulfilled creteria of HLH associated EBV. Both had partial retrospective study was carried out among 145 adult(>=14 years) HLH hypopigmentation on their faces, silvery hair since birth and history patients with EBV infection (EBV-DNA>=5.0E+2 copies/mL) in Beijing with recurrent infections. Diagnosis of CHS was based on giant Friendship Hospital from March 2009 to December 2015. We divided azurophilic granules inside neutrophilis of blood smear, and bone 111 cases of EBV-HLH into two groups according to the EBV-DNA marrow smear, and regular melanosomes under light microscopes. copies (group 1: EBV-DNA >=5.0E+05 copies/mL, group 2: EBV-DNA Diagnosis of GS2 was based on the mutation in the RAB27A gene in <5.0E+05 copies/mL, 5.0E+05 copies/mL was the cut-off value). the location c 224 C>A (p.T75K) on exon 4 and c377delC Results: In this study, the patients' age ranged from 14 to 78 with a ( p.P126fsx3). Duration of follow-up of patient with CHS and GS2 were median of 26 .There were 101 male cases (69.66%) and 44 female 156 weeks and 15 weeks, respectively.Patient with CHS has partial cases (30.34%). Of the 145 cases, 30 cases were lymphoma- response to HLH-2004 treatment protocol , and patient with GS2 has associated HLH, 3 cases were familial HLH and 111 cases were EBV- temporary response to combination of broad- spectrum antibiotics and associated HLH. The coincidence rate to HLH-2004 criteria were: G-CSF. Conclusion: Clinical diagnosis of OCA-ID should be made on fever (90.3%), cytopenias (93.1%), high level of serum ferritin (92.6%), infants with partial hypopigmentation of skin and hair associated with splenomegaly (89%), hemophagocytosis in bone marrow, spleen or recurrent infections.For pediatricians in remote areas, light lymph nodes (85.8%), hypofibrinogenemia (61.2%), microscopic examination of hair and peripheral blood smear are hypertriglyceridemia (40.1%), increased level of soluble interleukin-2 simple and rapid ways for screening OCA-ID. Early diagnosis of OCA- receptor (89.7%), decreased or absent activity of NK cells (43.8%). ID will help control recurrent infections and occurance of Patients' EBV-DNA ranged from 5.0E+03 to 7.79E+09 copies/mL hemophagocytic lymphohistiocytosis. ( median was 8.8E+05 copies/mL). The 1 year overall survival (OS) of 145 patients was 28%, and the median OS was 58 days. In 111 cases of EBV-HLH, ten patients died early, 22 cases (24.2%) achieved complete response and 20 cases (22%) achieved partial response to HLH-1994 or HLH-2004 regimen. 39 refractory or relapsed cases received DEP regimen, CR was 17.95%, PR was 66.67%. The mortality of group 1 was 79.69%, group 2' was 61.7% (P=0.038). Conclusion: FHLH and LAHLH also can accompany with EBV infection, and HLH patients with EBV infection have a high mortality. DEP regimen can prolong refractory or relapsed EBV-HLH patients' survival. High EBV-DNA copies may lead to poor prognosis.

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Poster Location #11 negative. On DOL#38 she underwent bowel resection. Pathology rendered necrotizing enterocolitis (NEC). A bone marrow aspirate ADMINISTRATION OF PARENTERAL EXOGENOUS NOXA IN showed increased numbers of CD163+ histiocytes. Serum ferritin: MUNCHHAUSEN SYNDROME BY PROXY CAN ELICIT THE FULL 7876-ng/ml (9-120 ug/ml), sIL2R (CD25): 15730 pg/ml (<1033-pg/ml). PICTURE OF HLH Perforin and Granzyme B of NK cells were decreased. The flow cytometry for CD11/CD18 was normal. Serum albumin: 1.5-2.3-g/dl, Kai Lehmberg1, Jan Sperhake1, Holger Rohde1, Sandra Ammann2, sodium:123-125 meq/L, AST: 100, ALT: 300 U/L and direct Stephan Ehl2, Ingo Müller1, Gritta Janka1 bilirubinemia: 6-12-mg/dl. She required daily blood products and fresh frozen plasma infusions. On DOL# 72 a second exploratory 1UKE Hamburg, Germany laparotomy was done due to bowel perforation. CV lines were 2CCI Freiburg, Germany removed at three different time points due to persistently positive blood cultures with Enterobacter cloacea. She developed respiratory A 3.5 year old boy presented with coxitis, followed by severe systemic distress on DO:#98 and was placed on oscillator until her death on inflammation. He developed extensive serositis and required DOL#108. The autopsy revealed diffuse CD163+histiocytes in marrow, ventilation and circulatory support. Subsequently, the full picture of liver, spleen, lungs and lymph nodes. Conclusion: This is an unusual haemophagocytic lymphohistiocytosis (HLH) developed: fever, presentation of HLH in a premature newborn. She met four of the eight substantial splenomegaly, bicytopenia (platelets and hemoglobin criteria of HLH. Delayed umbilical cord separation has been described requiring transfusion), hyperferritinaemia (13,600 µg/L), in neutrophil dysfunctions, including the Chediak Higashi syndrome, hypertriglyceridaemia, consumptive hypofibrinogenaemia (0.4g/L), where patients develop HLH in accelerated phase. Recurrent sepsis elevated sCD25 (15,400 U/mL), and bone marrow despite vigorous antibiotic treatment and attached umbilical cord may haemophagocytosis. After exclusion of masked lymphoma and represent an underlying neutrophil pathology, resulting in HLH. hereditary cytotoxicity defects by flow cytometry, an underlying autoinflammatory condition was suspected and treatment with steroids Poster Location #13 and anakinra initiated. The patient improved and continued on subcutaneous anakinra on an outpatient basis, however he was HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS IN AN INFANT readmitted due to abscesses at the injection sites and became WITH KABUKI SYNDROME critically ill again. During the extensive screening for underlying immunodeficiencies, several investigations rendered abnormal results, Oya Levendoglu-Tugal1, Alan Pinto2, Humayun Islam3 e.g. complete absence of B cells in peripheral blood, T cell proliferation, the alternative complement and NOD2 signaling 1Pediatric Hematology/Oncology and Stem Cell Transplantation, New pathways. While stem cell transplantation was already being York Medical College, Boston Children's Health Physicians, considered, the cumulative evidence of 11 different bacterial and Valhalla, NY USA, fungal pathogens (including phytopathogenic species) in blood and 2 Pediatric Intensive Care New York Medical College, Boston swabs finally pointed towards Munchhausen syndrome by proxy Children's Health Physicians, Valhalla, NY USA, (MbP). Samples taken from infusion bags and lines, and from saline 3Anatomic Pathology New York Medical College, Valhalla, NY USA bottles found in the maternal hospital bedside table displayed a similar variety of microbes. It was assumed intravenous systems and Purpose: To recognize HLH in an infant with Kabuki Syndrome. subcutaneous needles were contaminated with faeces, soil, and other Methods: This is an unusual association of HLH with Kabuki material. Separation from the patient's mother lead to complete syndrome. Results: A two month old male infant with Kabuki resolution of symptoms and gradual restoration of his immune system. syndrome is admitted with RSV pneumonitis. He received oxygen via It took in total more than four months to establish the diagnosis. The nasal cannula and started on steroids and albuterol. Due to the mother has admitted to the allegations and was found guilty in court. In progressively worsening respiratory status he was placed on SIMV. He summary, MbP can mimic an immunodeficiency and the repeated had fevers. Respiratory secretions grew serratia marcescens, and intravenous administration of infectious agents can trigger a full blown urine culture grew klebsiella pneumonia. A chest x-ray showed HLH and lead to alterations of immunological investigations. pneumonia. He was put on ampicillin and cefotaxime. Cultures were sterile in 48 hours, yet he continued to have fevers. He was on breast Poster Location #12 milk via nasogastric tube. He developed generalized edema and hepatomegaly. Laboratory studies were abnormal for pancytopenia, AN UNUSUAL PRESENTATION OF HEMOPHAGOCYTIC hypertriglyceridemia, hypoalbuminemia, elevated transaminases and LYMPHOHISTIOCYTOSIS IN A PREMATURE INFANT hypofibrinogenemia. Hemophagocytic lymphohistiocytosis was suspected. Serum ferritin was 5328-ng/ml, sIL2 was 4710-pg/ml (0- Oya Levendoglu-Tugal1, Priyadarshani Giri2, Praveen Ballabh2, 1033). Immune profile revealed increased percentage of CD8 cell. He Samir Pandya3, Fouzia Shakil4, Larisa Debelenko4 received daily packed red cells, platelet and fresh frozen plasma infusions. A bone marrow aspirate showed hemophagocytic New York Medical College, Valhalla, NY USA histiocytes. A diagnosis of HLH was rendered. He received etoposide 1Pediatric Hematology/Oncology and Stem Cell Transplantation, and dexamethasone. A spinal tap was acellular. A week later he 2Neonatal Medicine developed seizures. A head MRI showed right occipital subacute 3Pediatric Surgery ischemia likely related to HLH. Intrathecal methotrexate was 4Anatomic Pathology administered. Patient's clinical status improved; fever was defervesced. He was extubated. Laboratory abnormalities improved Purpose: To recognize an unusual presentation of HLH in a newborn. over the ensuing days. Upon parental request the patient was Methods: This is a case presentation of HLH in a preterm infant with transferred for further care to another institution. Conclusion: Kabuki necrotizing enterocolitis (NEC) and delayed umbilical cord separation. syndrome is characterized by multiple organ involvement. The patients Results: A 34 week ex-premature neonate was readmitted for fever have reduced serum immunoglobulin levels and show increased and diarrhea. She was previously treated on day of life (DOL)# 7, for susceptibility to infections and autoimmune diseases. Immunologic fever and was discharged home upon sterile cultures. On DOL# 26, profile resembles common variable immunodeficiency. she was readmitted with fever, respiratory distress, distended Hemophagocytic lymphohistiocytosis is one of the known abdomen and attached cord. She had bloody stools and pancytopenia. complications of congenital immune deficiencies. This is the first report An abdominal x-ray and ultrasound showed gaseous distension, of Kabuki syndrome associated with HLH. We recommend close follow ascites, distended bowel loops, and debris. Sepsis work up was up and complete immunologic work up of Kabuki syndrome patients.

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Poster Location #14 29%, and 34%). Donor chimerism for patients with continued CNS disease remained high at 88-100%. Overall survival for patients with CLINICAL ANALYSIS OF 6 CASES WITH SUBCUTANEOUS CNS relapse or continued CNS disease was 50%, compared to 75% PANNICULITIS-LIKE T-CELL LYMPHOMA ASSOCIATED for patients without CNS disease (p=0.079). Conclusions: Incidence of HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS CNS relapse and/or continued CNS disease after RIC HSCT with alemtuzumab, fludarabine, and melphalan is approximately 8%. Our Wu Lin, Wu Lin, Zhang Jia, Wang Yi-Ni, Wang Jing-Shi, Wang Zhao data suggest that risk factors include active CNS disease at the time of transplant, and low level donor chimerism. Response to therapy Beijing Friendship Hospital affliated to Capital Medical University, appears excellent. Surveillance CSF evaluation following RIC HSCT Beijing, China should be performed in patients with risk factors, and CNS directed treatment initiated if appropriate. Objective: To investigate the clinical features and treatment of subcutaneous panniculitis-like T-cell lymphoma with secondary Poster Location #16 hemophagocytic lymphohistiocytosis. Methods: 6 patients were compared, and the clinical manifestations and related laboratory tests, A MULTIDISCIPLINARY APPROACH TO A MULTIDISCIPLINARY the time of disease diagnosis, treatment and prognosis were analyzed. PROBLEM, THE DEVELOPMENT OF THE HEMOPHAGOCYTIC Results: 6 patients were diagnosed as hemophagocytic syndrome. All LYMPHOHISTIOCYTOSIS TASKFORCE of the patients got fever, splenomegaly, elevated ferritin, hemophagocytosis and liver function abnormal. It spent 5 to 18 Andrew Martin1, Teresa Jones2, Marilynn Punaro3, Julie Fuller3, months from the diagnosis of hemophagocytic syndrome to final Katie Stewart1, Leandra Woolnough1, Lorien Nassi3, Tracey Wright3, diagnosis of lymphoma. 1 patients gave up treatment and died, and Maite De La Morena1, Archana Dhar1, Cindy Darnell1, Josh Koch1, the other patients received chemotherapy based on CHOP regimen. 1 Samuel Davila1, David Zwick1, Hung Luu1, Paul Sue1, Michael Sebert1, patients received autologous hematopoietic stem cell transplantation, Chris Wysocki1 and 2 patients received allogeneic hematopoietic stem cell transplantation. 1 patients died of GVHD, and the remaining patients 1UT Southwestern, Dallas TX USA were stable during the follow-up period. Conclusion:Subcutaneous 2Children's Medical Center Dallas, Dallas TX USA panniculitis-like T-cell lymphoma associated hemophagocytic 3Texas Scottish Rite Hospital, Dallas, TX USA comprehensive syndrome is rare. To determine the primary disease, it has to control the symptoms of hemophagocytic syndrome actively. Purpose: Hemophagocytic lymphohistiocytosis (HLH) and The progression is rapidly, and high dose chemotherapy combined macrophage activating syndrome (MAS) are complex diseases with with autologous hematopoietic stem cell transplantation and allogeneic similar presentations and high mortality rates if untreated. Early hematopoietic stem cell transplantation should be considered. diagnosis and therapy initiation are essential to reduce the morbidity and mortality associated with HLH and MAS. Treatment often entails Poster Location #15 consultation by multiple subspecialists, and can result in divergent treatment recommendations, leaving the patient and primary provider INCIDENCE OF HLH CNS RELAPSE AFTER TREATMENT WITH without straightforward guidance for clinical care. Our hypothesis is REDUCED INTENSITY CONDITIONING HEMATOPOEITIC STEM that early identification and improved collaborative treatment will CELL TRANSPLANT decrease the associated morbidity and mortality for patients with HLH and MAS. Methods: Effectively managing patients with HLH and Rebecca Marsh3, Dana Lounder1, Bibi Shahin Shamsian2, MAS requires the expertise of an interdisciplinary team; therefore a Pooja Khandelwal3, Sharat Chandra3, Michael Jordan3, task force was created to aid providers in the diagnosis and treatment Ashish Kumar3, Michael Grimley3, Jack Bleesing3, Stella Davies3 of this disease. This team includes members of subspecialties including, hematology, oncology, rheumatology, infectious disease, 1Cincinnati Children's Hospital Medical Center, Cancer and Blood pediatric intensive care (ICU), immunology, and pathology. This Disease Institute, Cincinnati OH USA taskforce is developing tools to aide in the early identification of HLH 2Mofid Children hospital, Shahid Beheshti Medical University, patients. Results: This task force has created a collaborative model of Tehran, Iran patient care which has benefitted patients and providers. We focused 3Cincinnati Children's Hospital Medical Center, Division on Bone efforts on three main areas thus far: 1) An email listserve to facilitate Marrow Transplant and Immune Deficiency, Cincinnati OH USA discussion of potential cases among the various task force members. 2) Using HLH diagnostic criteria, an alert was created to identify at-risk Purpose: Hemophagocytic Lymphohistiocytosis (HLH) is an immune patients and ensure diagnostic tests are sent efficiently. 3) Order sets regulatory disorder which is characterized by fever, organomegaly, were created to facilitate diagnosis and monitoring of treatment and pancytopenia. CNS involvement is common at diagnosis. responses. This model is currently being piloted in the pediatric ICU. However, there are no data regarding the risk of CNS relapse after Conclusion: HLH and MAS are potentially lethal diagnoses which are reduced intensity conditioning (RIC) hematopoietic stem cell transplant often confusing. Delays in diagnosis are clearly shown to impact (HSCT). We sought to determine the incidence of CNS relapse after survival. We have designed a system to facilitate early diagnosis and RIC HSCT, predisposing risk factors, and outcomes. Methods: We collaborative care of these complicated patients. We offer our performed a retrospective chart review of 94 consecutive patients with experience as a model for other institutions seeking to adopt a similar HLH who received RIC HSCT with alemtuzumab, fludarabine, and multidisciplinary approach to management. melphalan. CNS relapse within 1 year after transplant was determined by review of clinical symptoms, cerebral spinal fluid (CSF) findings, and radiologic findings. Response to therapy and outcomes were also obtained on review on charts. Results: Of the 94 patients, 3 (3.2%) patients had true CNS relapse, 1 (1%) patient had possible CNS relapse, 3 (3.2%) had continued CNS disease, and 1 (1%) patient had progressive CNS disease. All patients responded with CNS directed therapy with intrathecal hydrocortisone and methotrexate and/or intravenous dexamethasone. Donor chimerism at the time of CNS relapse for the 3 patients with definitive CNS relapse was low (1%,

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Poster Location #17 acquired forms. No genetic study was performed in our cases however all of them were adolescents or young adults with no previous history YTIC LYMPHOHISTIOCYTOSIS (HLH) IN ADULT RECIPIENTS OF of a similar event or family story. Three of four patients were safely VENTRICULAR ASSIST DEVICES (VADS) FOR treated with steroids and IVIG without etoposide which has a risk of CARDIOMYOPATHY (CM) AND FAVORABLE OUTCOMES IN causing secondary cancer. EBV-associated HLH may mimic T-cell SUBSEQUENT ORTHOTOPIC HEART TRANSPLANTATION (OHT) lymphoma and we treated with cytotoxic chemotherapy, etoposide in this case. Beth Ann Martin, Paul Cheng, Richard Ha-Tien, Dipanjan Banerjee Poster Location #19 Stanford University, Stanford, CA USA BEAD EMBOLIZATION OF SPLEEN AS TREATMENT FOR Purpose: to describe the association of HLH and VAD insertion, and HEMATOPHAGOCYTIC LYMPHOHISTIOCYTOSIS ASSOCIATED the outcomes of subsequent OHT from January, 2014 to May, 2016. WITH NON-HODGKINS LYMPHOMA Method: IRB approved retrospective chart review. Results: 123 VAD were inserted. Four adults, three with idiopathic non-ischemic CM, one Leslie Padrnos, Tania Jain, Katalin Kelemen, John Camoriano with probable anthracycline induced CM, were found to have HLH following VAD insertion. Age range: 25-71. All patients met at least 5 Mayo Clinic Arizona, Phoenix, AZ USA criteria as per HLH-2004. All had extensive marrow hemophagocytosis. Median soluble IL-2 R at diagnosis was 2,771 U/ Purpose: To describe the use of an interventional radiology procedure ml (range: 2,286-14,600). Median ferritin was 2,570 mcg/L (range to destroy splenic tissue as a successful adjunct to chemotherapy and 643-12,351) None had identifiable malignancy, connective tissue steroids in a life-threatening case of secondary hemophagocytic disorder, family history of HLH, nor identifiable predisposing mutation lymphohistiocytosis (sHLH) associated with aggressive B-cell, Non- in three tested. Viral testing negative except for EBV in one, HHV-6 in Hodgkins Lymphoma (NHL). Methods: A single case report of one. Three patients developed signs of HLH following VAD insertion. community admission to our acute care hospital and a literature Duration of signs of HLH, preceded therapy by 7, 8, 28 days. One review. Results: A previously healthy 59 yo male had brief mild patient with a history of lymphoma, in remission, had signs of HLH 2 thrombocytopenia in Oct 2015. He had night sweats, fatigue, weeks prior to VAD insertion. HLH was diagnosed 3 months later. thrombocytopenia and fever in early 2016 that responded transiently to One patient is currently on Day 10 of HLH-94 therapy. Therapy was steroids. A bone marrow biopsy was normal. He was hospitalized HLH-94 (dexamethasone, etoposide) in three patients with with respiratory failure in May 2016 with massive pulmonary approximately 50% dose reduction in total dexamethasone dose and hemorrhage. He was transferred to our hospital having failed to dexamethasone alone for 6 weeks in one patient. No patient required respond to intravenous immunoglobulins and high dose steroids. a second course of therapy. Three patients subsequently underwent Admission labs showed pancytopenia with platelets of 8,000. Ferritin successful OHT without relapse of HLH. Durations of their VAD was 927 mcg/L and rose to 1.416 mcg/L. Fibrinogen was 141 mg/dl. implants were 4,14, and 31 months. Survivorships from OHT are 2, 9, CT scan showed spleen of 20 cm. Bone marrow showed HLH with and 24 months. The progression free survivorships, free of HLH, from small aggregates of large monoclonal B cells. On day two of the the time of initial therapy for HLH in the three OHT patients are 15, 27, hospitalization abdominal distension led to repeat CT scan showing and 37 months. The incidence of HLH is 2.4% for patients who did not splenic rupture with hemoperitoneum. Immediate angiographic bead have symptoms of HLH prior to VAD. Conclusion: VAD insertion can embolization was performed. Etoposide, dexamethasone and be associated with HLH. HLH does not preclude OHT. rituximab were subsequently given. Rapid improvement clinically and biochemically followed with extubation and discharge from ICU. Poster Location #18 Medline search of HLH cases were cross-referenced with splenectomy and spleen embolization. Although there were many cases of INFECTION AND HEMOPHAGOCYTIC SYNDROME: SINGLE splenectomy reported with variable results we found no report of CENTER EXPERIENCE splenic embolization utilized in sHLH. Conclusion:This is the first case we are aware of where bead embolization was successfully used to Nihal Ozdemir, Begüm Koc, Fatih Varol, Meltem Kivilcim, treat sHLH associated with NHL. Deniz Aygün, Yildiz Camccioǧlu, Tiraje Celkan, Hilmi Apak Poster Location #20 Istanbul University, Cerrahpașa Faculty of Medicine, Pediatric Hematology and Oncology Department, Istanbul, Turkey CENTRAL NERVOUS SYSTEM INVOLVEMENT IN HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a life- threatening clinical syndrome caused by uncontrolled Ruijun Pei ,Yini Wang , Zhao Wang hypercytokinemia and hyperinflammation. Infection is a leading cause of acquired HLH. Method: We evaluated the clinical manifestations, Beijing Friendship Hospital, Capital Medical University, Beijing, China clinical course and outcomes of infection related HLH cases, treated between June 2014 and July 2015 in our clinic. Results: There were Abstract: Central Nervous System(CNS) involvement is a severe four cases of acquired HLH due to EBV, Mycoplasma, Leptospira, and complication of Hemophagocytic lymphohistiocytosis (HLH), which can Brucella infections. Patients had no underlying systemic disease. lead to rapid disease development and higher morality. But this has Three cases were female, one was male. Patients were between 11.5- not been given enough attention in adult HLH. Methods: A 16 years. All cases presented with fever, cytopenia, splenomegaly and retrospective analysis of 97 patients with HLH and combined with CNS elevated liver enzymes. Bone marrow aspiration showed involvement during June 2003 and December 2015 was conducted. hemophagocytosis in all. Two cases were treated with combination Clinical features, cerebrospinal fluid features, image changes and therapy including steroids, cyclosporine and IVIG according to HLH- therapeutic outcomes were analyzed. CNS involvement was defined 2004 protocol, however etoposide was not used. One EBV case was as the presence of neurological symptoms and signs or elevated treated according to HLH-2004 protocol including etoposide. One values of cerebrospinal fluid cells and/or proteins or EBV-DNA or the Mycoplasma case was treated with steroids and IVIG only. All patients abnormal changes of brain parenchyma or the meningeal. Results: recovered however one developed multiorgan failure syndrome. Among the 97 patients, 91(93.8%) had various CNS symptoms, Conclusion: Infections are common triggers of genetic HLH, so whereas 28 patients(28.9%) developed CNS symptoms in the identification of an infection does not discriminate between genetic and pathogenesis of HLH. The most common ones were consciousness

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disorder(45.4%), epileptic attack(18.6%), ataxia(13.4%) and meningitis Poster Location #22 (13.4%). Among the 97 patients, 44 performed cerebrospinal fluid routine examination and skull ECT, including 6 patients who had only TREATMENT OF HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS abnormal cerebrospinal fluid but no CNS clinical manifestations. Four WITH ALLOGENEIC HEMATOPOIETIC STEM CELL patients only presented with neurological symptoms, the remaining 34 TRANSPLANTATION USING THE CONDITIONING REGIMEN WITH cases had two or more abnormality. The image changes were not BUSULFAN AND FLUDARABINE: A SINGLE-CENTER STUDY OF specific, and the most frequently involved areas were brain white 38 CASES matter (50.7%). The features of cerebrospinal fluid were mild to moderate pleocytosis, different degrees of elevated protein content. All Yuan Sun, Juan Xiao, Shifen Fan, Zhouyang Liu, Fei Xu, Lei Zhang, patients were treated according to the HLH-94 or 04 protocols, while Fan Jiang, Xiaomei Liu the mortality was 75.9%. Conclusions: CNS involvement in HLH were not rare, which can result in poor prognosis. Abnormal examination of Beijing Jingdu Children's Hospital, Beijing, China cerebrospinal fluid and skull ECT may present to the patients who had no CNS clinical manifestations, therefore, clinical manifestations can Purpose: We report outcomes after Allogeneic hematopoietic stem not be used individually as exclusion criteria of HLH with CNS cell transplantation for hemophagocytic lymphohistiocytosis(HLH) involvement. To make an early diagnosis of HLH with CNS using the conditioning regimen with busulfan and fludarabine. Patients involvement, it is necessary to make early and repeated examination and Methods: 38 consecutive cases from February 2009 to April 2016 of cerebrospinal fluid and/or skull ECT. in our center were analyzed. The median age of patients was 5 (1-13) years old. Patients with haploidentical transplantation received Poster Location #21 unmanipulated combined marrow and peripheral blood stem cells for transplant and patients with unrelated donor transplantation received THE ROLE OF INTERLEUKIN-I RECEPTOR ANTAGONIST, peripheral blood stem cells after conditioning with etoposide , busulfan ANAKINRA IN CRITICALLY ILL ADULT PATIENTS WITH and fludarabine plus antithymocyte globulin (ATG). Results: Durable HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND hematopoietic reconstitution was seen in 92.1% of recipients. MACROPHAGE ACTIVATION SYNDROME, A REVIEW OF SIX Engraftment failure occurred in 3 cases including 2 cases of primary CASES engraftment failure and 1 case of secondary engraftment failure because of severe EBV infection. The cumulative incidences (CIs) of Akshjot Puri, Henry J Kyle, Suresh Uppalapu, Robert Raschke mixed chimerism was only 4 cases.And there were 3 cases occured relapse. With the median follow-up of 32 (12-134) months, 1-year and Banner University Medical Center, Phoenix, AZ USA 3-year overall survival (OS) rates for all patients were both 73.6% . The event of death of 13 cases occurred within 1 year after Hemophagocytic lymphohistiocytosis (HLH) is a disease of immune transplantation. 1-year OS of transplants for patients in complete dysregulation increasingly-recognized as a cause of life-threatening remission(CR), no remission(NR) were 93.7% and 63.6% respectively multi-system organ failure in the adult ICU. Macrophage activation (p = 0.023). 1-year OS of transplants in haploidentical transplantation syndrome (MAS) is a closely related disease in which diagnostic and unrelated donor transplantation were 61.9% and 94.1% criteria for HLH are satisfied in patients with underlying respectively(p = 0.031). 1-year OS of transplants in primary HLH and rheumatological disease. Standard immunotherapy for HLH is EBV ralated HLH were 80.0% and 70.6% respectively(p = 0.557). etoposide-based, however etoposide has not proven clinically Conclusions: Under current protocol, The good outcome with children beneficial in adult ICU patients with HLH, who may experience severe HLH was acquired with the conditioning of etoposide , busulfan and side-effects. Anakinra has been used successfully in children with fludarabine plus ATG. The cases in CR and as unrelated donor MAS, but only a few isolated case reports describe its use in adults. transplantation gained the better clinical curative effect. Key Words: Methods: Prospective case series of HLH patients presenting to our Hemophagocytic lymphohistiocytosis; transplant; conditioning ICU over the past 8 years. Mortality for patients in three treatment regimen; Overall survival groups were observed: etoposide-based therapy, anakinra, and other (typically corticosteroids combined with other modalities such as Poster Location #23 plasma-exchange). Results: Twenty-eight patients satisfied >5 HLH- 2004 diagnostic criteria after admission to our ICU. Eight received BEYOND FATTY LIVER OF PREGNANCY: A CASE OF HLH IN A etoposide-based therapy and none survived. Five patients had MAS 20 YEAR OLD FEMALE and received anakinra of whom four survived (80%). One patient who had HLH, but not MAS received anakinra and did not survive. Minakshi Taparia Fourteen patients received other forms of therapy of whom only one survived and one lost to follow up. The two patients who died after University Of Alberta Hospital, Edmonton, AB, Canada receiving anakinra both died from disseminated fungal infections. Conclusions: Our study is only hypothesis-generating, but suggests Beyond fatty liver of pregnancy: A case of Hemophagocytic that alternatives to etoposide-based therapy for HLH are needed for Lymphohistiocytosis (HLH) in a 20 year old female. HLH is a relatively adult ICU patients. Anakinra is promising but much further research uncommon but potentially life threatening condition brought by is needed to determine whether it might benefit the high mortality of excessive immune activation. A 20 year old female previously well, these patients. At the present time, it seems most promising in who presented for labor induction as had fever and elevated live4r patients with MAS, but it's potential utility in other patients with HLH is enzymes, she had C-section in April 2014, following that, her course unexplored. We hypothesize that broad-spectrum anti-fungal agents was complicated with perforated duodenal ulcer. Following the surgery started prophylactically before initiating anakinra might be beneficial. she was in ICU, with worsening liver failure and later multiorgan failure, thought to be secondary to sepsis, with no recovery. She had a liver biopsy in June 2014 which showed steatohepatitis. Her platelet counts started dropping early in the course and had anemia. There was no improvement in her course and hematology was consulted a few times initially and again in September. A possibility of HLH was considered. Work up showed elevated ferritin of 59,000, low fibrinogen, fevers, mild splenomegaly, cytopenias, increased triglyceride; BMB showed hemophagocytosis, although was initially reported as not convincing. Given her worsening clinical condition, no

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TUESDAY, OCTOBER 18, 2016 • 1445 POSTER PRESENTATIONS - CLINICAL HLH AINSWORTH SUITE identified other conditions and she met all the criteria for HLH, team Poster Location #25 had a discussion with the family and started treatment with HLH 2004 protocol, with significant improvement over course of few months and HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS WITH CHILDREN was discharged with continuation of the protocol while we were AND ADULT: THE REGISTRATION DATA FROM BEIJING HLH awaiting perforin gene mutation studies. The soluble CD25 was sent WORKGROUP, CHINA before the treatment. Patient was continued for total of 26 weeks before the genetic work up came back and as it came back negative Yini Wang1, Zhao Wang1, Rui Zhang2, Caifeng Li2, Xiaodong Shi3, and there was no HLA identical donor identified, we decided to stop Qian Wang4, Leping Zhang4, Yuan Jia5, Lihong Li6, Xinan Cen6, the treatment and monitor. She is now about 16 months post treatment Weihong Zhao7, Liangding Hu8, Yuan Sun9, Jijun Wang10, and doing very well. This case illustrates how HLH is underdiagnosed Jianliang Shen11, Yingjian Si12, Wuhan Hui13, Liping Ye14 and a high index of suspicion is critical. 1Beijing Friendship Hospital, Capital Medical University, Beijing, China Poster Location #24 2Beijing Children's Hospital, Capital Medical University, Beijing, China 3Capital Institute of Pediatrics HAPLOIDENTICAL STEM CELL TRANSPLANTATION WITH POST 4Peking Union Medical College Hospital, Beijing, China TRANSPLANT CYCLOPHOSPHAMIDE IN HAEMOPHAGOCYTIC 5Peking University People's Hospital, Beijing, China LYMPHOHISTIOCYTOSIS : THE JOURNEY TO SUCCESSFUL 6Beijing Chao-yang Hospital, Capital Medical University, Beijing, ENGRAFTMENT AND CURE China 7Peking University First Hospital, Beijing, China Ramya Uppuluri, Sreejith Ramachandrakurup, Divya Subburaj, 8Affiliated Hospital Academy of Military Medical Science, Beijing, Lakshman Vaidhyanathan, Revathi Raj China 9Beijing Jingdu Children Hospital, Beijing, China Department of Pediatric Hematology, Oncology and BMT and 10Peking University Third Hospital, Beijing, China Department of Stem Cell Apheresis, Apollo Speciality Hospital, 11Navy General Hospital, Beijing, China Chennai, India 12BAYI Children's Hospital, Beijing, China 13Xuanwu Hospital, Capital Medical University, Beijing, China Background: We present two children with Haemophagocytic 14The 309th Hospital of Chinese People's Liberation Army, Beijing, lymphohistiocytosis (HLH) where a haploidentical stem cell China transplantation with post transplant cyclophosphamide (PTCy) resulted in successful engraftment and cure. Patient 1: A 3 year old girl child There is now recognition that hemophagocytic lymphohistiocytosis with Griscelli syndrome had presented with accelerated HLH including (HLH) occurs not only in children, but also in adult. However, there are CNS involvement and was started on HLH 2004 protocol. In view of few comparative studies of child HLH and adult HLH. Here we persistent disease and as a bridge to transplant, she was given presented the 12-year registration data from Beijing HLH Group in antithymocyte globulin (ATG). On day 3 of ATG, she developed status order to make further understanding of this disease. There were epilepticus requiring mechanical ventilation for 48 hours. She was then altogether 1108 patients from 18 clinical centers registered in the past taken up for haploidentical sibling transplantation. Patient 2: A 7 year decade, including 532 children (<18 years) and 576 adults (>18 years) old girl child with primary HLH type 4 and gluten enteropathy received with a median age of 18 years. The main cause of HLH was infection a father donated haplograft. Both children received reduced intensity (45.9%) in both children (60.3%) and adults (32.6%), while the conditioning with Fludarabine, Treosulphan and single dose TBI 2Gy, malignancy associated HLH were much more in adults (26.4%) than in followed by T replete PBSC infusion and cyclophosphamide 50mg/kg/ children (8.8%). Moreover, thirteen adult patients were diagnosed with day on Day+3 and Day+4. Tacrolimus and Mycophenolate mofetil primary HLH after gene sequencing. EBV infection was most frequent were used as GVHD prophylaxis.The graft contained CD34 cells in Chinese patients, involved in any type of HLH. Fever, elevated 5x106 /kg and CD3 less than 2x108 /kg. Results: Both children lactate dehydrogenase (LDH), concentrated ferritin and soluble engrafted by Day+21 and have maintained complete chimerism with Interleukin-2 Receptor were most common in HLH patients. The grade 2-3 skin graft versus host disease (GVHD) in the first child and incidences of abnormalities in clinical symptoms and laboratory grade III gut GVHD in the second child which was responsive to markers had no significant differences between children and adults steroids. Reactivation of cytomegaloviral infection that responded to except in hepatomegaly (86.5% vs 28.1%). However, there were Valganciclovir was the main infectious complication. The children are some differences on clinical symptoms and laboratory markers now 6 months post HSCT with no active GVHD or infections and between each type of HLH. Cytopenia was not severe in rheumatism complete chimerism. Conclusion: Haploidentical transplant with PTCy associated HLH patient, but rather serious in malignancy associated is an attractive and feasible option for HLH and results in a durable HLH. Albumin was significantly lower in malignancy associated HLH graft, when there are no matched sibling donors available. The high patient than in other types, while the liver function might be severe in cost of an unrelated HSCT and the fact that the graft is not available at infection associated HLH. The NK cell activity was lowest and sIL-2R short notice for these sick children makes this option less attractive. was highest in primary HLH. The total response to HLH-94 and HLH- Cure at half the cost is possible which is a reality in resource poor 04 in adult patients was 61.4%, which was much lower than in children settings. (78.3%). The malignancy associated HLH patients showed especially poor response to the treatment (41.4%). Multiple regression analysis showed that the response to initial therapy and the underlying disease of HLH were the important prognostic factors.

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Poster Location #26 children with FHL had the highest ratio of neurological symptoms (47.4%, 9/19), followed by other HLH (28.6%, 18/63) and EBV-HLH PEG-ASPARGASE AND DEP REGIMEN COMBINATION THERAPY (18.6%, 18/97). 81 patients (50.0%, excluding 17 patients without FOR REFRACTORY EPSTEIN-BARR VIRUS-ASSOCIATED imaging data) had cranial imaging abnormalities, such as white-matter HEMOPHAGOCYTIC SYNDROME signal changes, cerebral volume loss, edema, intracerebral calcification and enlargement of ventricles. The largest proportion of Zhao Wang, Jingshi Wang, Yini Wang, Lin Wu, Jia Zhang, changes was in FHL group (72.2%), and next EBV-HLH (50.0%), and Wenyuan Lai then other HLH (42.6%). Abnormalities in either CNS symptom or radiological findings were regarded as CNS involvement. 104 children Department of Hematology, Beijing Friendship Hospital, Capital (64.2%) had CNS involvement. As for the prognosis, with median Medical University, Beijing, China follow-up time of 2.6-year (17 lost follow-up), overall survival (OS) rate was 72.8% (118/162). The probable 3-year OS of children without Purpose: This study investigated the efficacy and safety profile of CNS symptoms was 77.3% (92/119), higher than 60.5% (26/43) with modified DEP regimen in combination with PEG-aspargase (PEG-Asp) CNS symptoms (P=0.045). Similarly, it was also higher in children as a salvage therapy for refractory Epstein-Barr virus-associated without CNS involvement (46/53, 86.8%) than with CNS involvement hemophagocytic lymphohistiocytosis (EBV-HLH). Methods: A total of (67/96, 69.8%) (P=0.027). Conclusion. CNS symptom is more 28 patients (22 males and six females; age range 7-50 years old, common in FHL compared with EBV-HLH and other HLH, which is a median age = 24 years, 23 patients (82.1%) ±18 years old). poor prognostic factor. HLH patients with CNS impairment have worse diagnosed with EBV-HLH received combined treatment of PEG- outcomes compared with ones without CNS involvement. aspargase and DEP regimen (L-DEP). Treatment efficacy and adverse events was evaluated at two, four, six, and eight weeks after L-DEP Poster Location #28 regimen treatment. Results: Leukocyte numbers were significantly elevated four weeks after L-DEP regimen compared to their ATYPICAL ISOLATED CNS PRESENTATION OF FAMILIAL HLH pretreatment levels (P < 0.05). Additionally, platelet levels at two and four weeks after L-DEP regimen were significantly higher than the Nicholas Whipple1, Namrata Shah2, Brent Orr1, Scott Hwang1, pretreatment levels (P < 0.05) while fibrinogen, ferritin, and soluble Ashok Srinivasan1, Patrick Campbell1 interleukin-2 receptor (sCD25) levels were significantly reduced compared to the pretreatment levels (P < 0.05). Medians EBV-DNA 1St. Jude Children's Research Hospital, Memphis, TN, USA before and two weeks after L-DEP regimen were 9.6x105 (1.5x104- 2Le Bonheur Children's Hospital, Memphis, TN, USA 1x109) copies/ml and 2.2x105 (3.8x102-1.2x107) copies/ml, respectively, with the post-treatment levels significantly lower than Purpose: We report an atypical isolated central nervous system (CNS) pretreatment levels (P = 0.048). Of the 28 patients that received L- presentation of familial hemophagocytic lymphohistiocytosis (HLH) for DEP regimen, nine patients achieved complete remission (CR), 15 which clinical diagnostic criteria were not met despite severe patients achieved partial remission (PR), with the overall remission neurologic symptoms and perforin deficiency. This represents a rare rate of 85.7% (CR+PR). the 28 cases comprised 14 cases of survival but important presentation of HLH. Methods: An 8 year-old African- and 14 cases of death, representing a 50% mortality rate. American male presented with persistent headaches, increased Furthermore, 15 patients with ±1x102 fold decline of EBV-DNA copies sleepiness, significant weight loss, and multifocal neurologic deficits had significantly longer survival than 13 patients with <1x102 fold including cranial nerve palsies, weak eye/jaw closure, and unsteady decline of EBV-DNA copies (P = 0.018). The major adverse drug gait. MRI of the brain revealed findings suggestive of acute reactions of L-DEP regimen were elevated amylase, abnormal liver disseminated encephalomyelitis (ADEM) versus CNS infection or function, and coagulation disorders. Conclusion: This study suggests cerebral vasculitis. He developed fever and rapidly progressive that L-DEP regimen may be a safe and effective salvage therapy for neurologic deterioration, and, after a negative infectious workup, refractory EBV-HLH and extends the opportunity for allogeneic treatment with systemic steroids was initiated for presumed ADEM. hematopoietic stem cell transplantation of the patients. Because of worsening mental status and progression of MRI findings, a brain biopsy was obtained and revealed extensive Poster Location #27 meningoencephalitis and inflammation of small vessel walls. Treatment with systemic steroids and cyclophosphamide was initiated SYMPTOMS, IMAGING FINDINGS AND OUTCOMES OF 179 for small vessel CNS vasculitis. Lack of mental status improvement CHILDREN WITH HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS despite immunosuppression prompted review of pathology and workup WHO HAVE CENTRAL NERVOUS SYSTEM (CNS) INVOLVEMENT for HLH. Results: The patient did not meet clinical criteria for HLH with only three of eight diagnostic criteria. Flow cytometry, however, Yun-ze Zhao, Tian-you Wang, Li Zhang, Hong-yun Lian, revealed absent perforin expression. Gene mutation analysis revealed Hong-hao Ma, Dong Wang, Xiao-xi Zhao, Rui Zhang compound heterozygous PRF1 gene mutations, including a novel missense mutation, consistent with familial HLH. One year after initial Beijing Key Laboratory of Pediatric Hematology Oncology, presentation, matched-sibling hematopoietic stem cell transplantation Hematology Oncology Center, Beijing Children's Hospital, Capital (HSCT) was performed. Following transplant and with significant Medical University, Beijing, China rehabilitation therapy, speech and behavioral deficiencies have slowly improved. He remains clinically well with 100% donor chimerism. Purpose. Central nervous system (CNS) involvement is found in many Conclusion: CNS HLH is a rare disorder that requires a high index of hemophagocytic lymphohistiocytosis (HLH) patients. In this study, we suspicion and multidisciplinary approach to diagnose. It is often analyzed neurological symptoms, imaging findings and outcomes in difficult to differentiate onset of CNS involvement in primary HLH from HLH children. Methods. Related data of 179 pediatric patients with that of other CNS inflammatory diseases. Early investigation for HLH admitted to Hematology Oncology Center of Beijing Children's familial HLH and early HSCT may prevent the development of Hospital from January 2010 to December 2015 was analyzed fulminant HLH and result in improved outcomes. retrospectively. Diagnosis and treatment was based on HLH-2004 protocol. According to etiology, we divided these cases into three groups: primary (familial) HLH (FHL) and secondary HLH (Epstein- Barr virus-associated HLH (EBV-HLH) and other HLH). Results. 25.1% (45/179) of total patients had neurological symptoms like seizures, irritability, somnolence and unconsciousness. Among them,

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Poster Location #29 Poster Location #30

CLINICAL PRESENTATION AND OUTCOME OF PEDIATRIC LARGE STRUCTURAL AND EPIGENETIC DEFECTS IN PATIENTS WITH HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS IN HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH) ASSOCIATE CHINA: A RETROSPECTIVE MULTICENTER STUDY GENES THAT ARE RESPONSIBLE FOR THE DEVELOPMENT OF CLINICAL HLH Xiao-Jun Xu1, Hong-Sheng Wang2, Xiu-Li Ju3, Shao-Yan Hu4, Yan Xiao5, Hong-Man Xue6, Hong-Yu Shi7, Yi-Jin Gao8, Guo-Cun Jia9, Kejian Zhang, Lisa Dyer, Xia Li, James Denton, Brittany Jones, Xue-Rong Li10, Wei-Hong Zhao11, Ning-Ling Wang12, and Emily Liston, Danielle Hilton, Abhinav Mathur, Yong-Min Tang1 on behalf of the Histiocytosis Study Group of the C. Alexander Valencia Chinese Pediatric Society Division of Human Genetics, Cincinnati Children's Hospital Medical 1Department of Hematology/Oncology, Children's Hospital of Zhejiang Center, Cincinnati, OH, USA University School of Medicine, Hangzhou, China Department of Pediatrics, University of Cincinnati College of Medicine, 2Department of Hematology/Oncology, Children's Hospital of Fudan Cincinnati, OH, USA University, Shanghai, China 3Department of Pediatrics, Qilu Hospital of Shandong University, Purpose: Hemophagocytic lymphohistiocytosis (HLH) is a Jinan, China heterogeneous disorder. Defects in at least 17 genes (AP3B1, 4Department of Hematology/Oncology, Children's Hospital of BLOC1S6, CD27, ITK, LYST, MAGT1, PRF1, RAB27A, SH2D1A, Soochow University, Soochow, China SLC7A7, STX11, STXBP2, UNC13D (MUNC13-4), XIAP (BIRC4)) 5Department of Pediatrics, Wuhan Union Hospital, Wuhan, China have been associates with familial HLH and clinically similar 6Department of Pediatrics, Second Affiliated Hospital of Sun Yat-Sen conditions. Methods: We designed an exon-centric microarray (ECM) University, Guangzhou, China to detect small copy-number variants (CNV) in HLH associate genes 7Department of Hematology, Children's Hospital of Shanxi, Taiyuan, as a supplemental test if Sanger and Next Generation sequencing China (NGS) based assays cannot fully explain the patients' clinical 8Department of Hematology/Oncology, Shanghai Children's Medical symptomology. In addition X-inactivation analysis, protein analyses Center, Shanghai, China (Perforin, SAP and XIAP by flow cytometry), NK function and CD107a 9Department of Pediatrics, Children's Hospital of Zhengzhou, degranulation analysis are also carried out to confirm the significance Zhengzhou, China of these findings. Results: We found larger deletions in XIAP, 10Department of Pediatrics, the Affiliated Hospital of Qingdao SH2D1A, STXBP2, MAGT1 and RAB27a genes in multiple affected University, Qingdao, China individuals. We also found duplication in LYST, MAGT1 and SLC7A7. 11Department of Pediatrics, Peking University First Hospital, Beijing, While deletions are typically associated with abolished protein China expression, clinical interpretation for duplication is proved to be challenging. For example, due to the high homology sequence in the Purpose: Hemophagocytic lymphohistiocytosis (HLH) is a region, MAGT1 duplications are common and it also found in our heterogenous disease with major diagnostic and therapeutic control populations and it is unlike to cause diseases. In addition, we difficulties. A large-scale, nationwide study of pediatric HLH is still found the inversion in MUNC13-4 that are need special GAP-PCR lacking in China. Methods: The Histiocytosis Study Group of the testing. Interestingly, we also find one female with a de novel mutation Chinese Pediatric Society conducted this retrospective study in 2014. in XIAP along with skewed X-inactivation. Conclusion: To achieve a A total of 323 patients diagnosed with HLH between January 2011 and definitive diagnosis in patients with HLH, a comprehensive approach is December 2013 from 12 hospitals were registered. Results: The desired which includes NGS or Sanger based sequencing for small median age at diagnosis was 2.2 years (range, 0-14.6 years), with 55 base substitutions, deletions and duplication; ECM for larger structural patients (17.0%) younger than 12 months. PRF1 (31.1%), UNC13D variations and special studies for epigenetic defects. In addition, (40.0%) and STXBP2 (37.8%) were the predominant genes involved in functional study of cytotoxic T and NK cells as well as other this cohort, with 26 patients presented monoallelic mutations in one immunological work up are also critical to establish a definitive gene and 13 in two or more genes simultaneously. Epstein-Barr virus diagnosis in patients with HLH and associate disorders. (EBV) infection was documented in 74.4% (201/270) of the patients who underwent EBV detection. Of 252 evaluable patients, 64.7% Poster Location #31 (163/252) achieved non-active disease at 8th week and patients treated with protocol containing etoposide presented higher remission TOUCHING ON HLH INDICATING VALUE OF SERUM FERRITIN rate (75.6% vs. 46.8%, P<0.001). In multivariate analysis, a younger age at diagnosis (<12 months), platelet count less than 80x109/L, Xiaoxi Zhao, Rui Zhang bilirubin concentration higher than 85.0mmol/L, and central nervous system involvement were the independent prognostic factors Hematology Oncology Center, Beijing Children's Hospital, Capital indicating persistent disease. Conclusions: The Chinese pediatric HLH Medical University, Beijing, China patient presented some different features when compared with those in western countries, including older age, vulnerability to EBV infection Purpose: Hemophagocytic lymphohistiocytosis (HLH) is an acute and high incidence of hypomorphic mutations of HLH related genes. A immune disorder with multiple triggers. Predicting of HLH occurrence multicenter prospective study is warranted to standardize the at early phase is critical for the treatment. Among diagnostic diagnosis and treatment of pediatric HLH in China based on the parameters, cut-off value of serum ferritin level, 500ng/mL, has been features of Chinese patients. controversial. Goal of this research is to value serum ferritin level at admission in HLH prediction. Methods: Patients hospitalized in Beijing Children's Hospital between Sep 2009 and Nov 2012 were included, if their ferritin tests were ordered at admission. Patients with systemic juvenile idiopathic arthritis (SJIA) were excluded because macrophage activation syndrome (MAS), which often happens in SJIA, has characteristics overlap those of HLH. Laboratory features were collected within 24 hr of ferritin level. Statistical analysis was operated by SPSS version 13.0, statistical significance was defined as two- sided P -value < 0.05. Results: 98 patients were studied (39 female,

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59 male), 39 of which were diagnosed or developed HLH. The age range was 0.1 to 14 years, with a median of 4. 47 patients had NOTES splenomegaly, 39 had cytopenia affecting 2 or 3 lineages. The median value of serum ferritin levels was 9164ng/mL(193.2 ng/mL-311,700 ng/ mL). Judging from ROC curve, admission ferritin level alone couldn't predict HLH occurrence(P=0.119). Ferritin levels were then divided into 2 groups by 9164ng/mL, χ2 test of ferritin level showed significance in patients fulfilled current diagnostic parameters separately, except patients with hemoglobin<90g/L. Among these, P- values decreased in patients with triglycerides>3mmol/L (P=0.037) or fibrinogen<1.5g/L (P=0.004), from testing on these parameters alone (P=0.057, 0.01). Conclusion: Although helped to distinguish HLH in patients with high triglycerides, serum ferritin level is more of an inflammatory marker than an early indicator of HLH in this research, which is probably due to physiological iron deficiency during this age range. However, results implied that elevating the threshold of serum ferritin level in HLH diagnose is expected.

Poster Location #32

TREATING THE ADULT IDIOPATHIC ENTITY OF HLH WITH ETOPOSIDE, A CASE SERIES AND REVIEW OF LITERATURE

Timo Zondag1, Jan Alexander Michael van Laar2

1Department of Internal Medicine, section of Clinical Immunology, Erasmus University MC, University Medical Center, Rotterdam, The Netherlands; 2Department of Internal Medicine, section of Clinical Immunology and Department of Immunology, Erasmus University MC, University Medical Center, Rotterdam, The Netherlands

Purpose: Hemophagocytic Lymphohistiocytosis (HLH) is a potential fatal inflammatory clinical condition characterized by a dysregulation of immunological response leading to a “cytokine storm”• yielding sepsis- mimicking symptoms. In children its incidence is estimated 1.2 per 1,000,000 children, its mortality being 46%. In literatures largest adult cohort a mortality of 41% is reported. Incidence in adults remains unknown. The treatment protocol as proposed by the histiocyte society includes etoposide. Although this protocol is designed for paediatric patients it is often used for the treatment of adults suffering secondary HLH (sHLH). Little evidence is available on the use of etoposide in these adult HLH patients. Being the largest in literature, this case series describes adults suffering the idiopathic entity of sHLH treated with etoposide containing schedules. Methods: In this observational single centre case series, the medical record of all adult idiopathic HLH patients in the Erasmus Medical Centre between 2001 to 2015 treated with an etoposide-containing schedule are studied. Results: Of 49 adult HLH patients' records, 7 adult idiopathic HLH patients treated with etoposide could be identified. The overall HLH related mortality found is 3 out of 7 (43%). We report an average of 217 days from onset of complains until initiation of etoposide. Relapse was common in our group with 4 out of 7 experiencing a relapse following remission. Conclusion: Since all patients were severely ill, spontaneous remission was not observed and patients did not respond to symptomatic treatment alone, they represent a potential fatal cohort within all other HLH patients we have seen. We thus demonstrate the efficiency of etoposide by showing a similar mortality of our cohort to the overall mortality reported in literature. Despite our cohort being the largest in literature, combined effort of more centres treating adult patients with HLH is needed to support our observation.

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Poster Location #33 Kochi, Japan 2Department of Pathology, National Cerebral and Cardiovascular ADSORPTIVE DEPLETION OF BLOOD MONOCYTES REDUCES Center, Suita, Japan THE LEVELS OF CIRCULATING INTERLEUKIN-17A IN 3Department of Microbiology and Infection, Kochi Medical School, LANGERHANS CELL HISTIOCYTOSIS Kochi University, Kochi, Japan 4Department of Pathobiological Science and Technology, School of Magdalini Lourda1,2 , Selma Olsson-Ǻkefeldt1, Désirée Gavhed1, Health Science, Faculty of Medicine, Yonago, Japan Ulla Axdorph Nygell3, Gӧsta Berlin4, Evaldas Laurencikas5, 5Department of Anatomic Pathology, Graduate School of Medical Tatiana von Bahr Greenwood1, Mattias Svensson2, Jan-Inge Henter1 Sciences, Kyushu University, Fukuoka, Japan 6Division of Molecular Pathology, Faculty of Medicine, Tottori 1Childhood Cancer Research Unit, Department of Women's and University, Yonago, Japan Children's Health, Karolinska Institutet, Karolinska University Hospital, 7Department of Pathology, Okayama University Graduate School of Stockholm, Sweden Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 2Center for Infectious Medicine, Department of Medicine, Karolinska Okayama, Japan Institutet, Karolinska University Hospital, Stockholm, Sweden 8Department of Pediatrics, Kyoto Prefectural University of Medicine, 3Center for Apheresis and Stem Cell Processing, Clinical Immunology/ Graduate School of Medical Science, Kyoto, Japan Transfusion Medicine, Karolinska University Hospital and Department 9Department of Pediatrics, Jichi Medical University School of of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden Medicine, Shimotsuke, Japan 4Department of Clinical Immunology and Transfusion Medicine and 10Division of Laboratory Medicine, Uji-Tokushukai Medical Center, Department of Clinical and Experimental Medicine, Linkӧping Uji, Japan University, Linkӧping, Sweden 11Inserm U507 and U1016, Institut Cochin, Paris, France 5Division of Radiology, Department of Clinical Sciences, Karolinska 12AP-HP Hôpital Necker-Enfants Malades, University Paris Descartes Institutet, Danderyd Hospital, Stockholm, Sweden. (Paris 5), Paris, France

Purpose: Increased cytokine levels in blood and extracranial lesions of Purpose: Langerhans cell histiocytosis (LCH) is a proliferative disorder patients with Langerhans cell histiocytosis (LCH) have been linked to composed of abnormal Langerhans cell-like cells (so-called LCH cells) local and systemic inflammation as well as to more severe disease. In intermingled with inflammatory cells. Whether LCH is reactive or addition, prolonged disease activity is considered as a risk factor for neoplastic proliferation remains a controversial matter. We recently neurodegenerative (ND)-LCH, characterized by low-grade described Merkel cell polyomavirus (MCPyV) as a possible causative inflammation and degenerative changes. Prompted by the need for agent of LCH and proposed the interleukin-1 loop model considering effective treatment for a child with hypercytokinemia and severe, the LCH as a reactive disorder with an underlying oncogenic potential. rapidly progressive ND-LCH, unresponsive to standard treatments, we Previous studies reported presence of the MCPyV-DNA in peripheral searched for new therapeutic alternatives. Methods: Monocytes have blood cells of patients with LCH-risk organ (RO) (+) but not in those been identified as a major source of circulating interleukin (IL)-17A in with LCH-RO (-); this difference reached relevant statistical LCH. We decided to remove such cells using granulocyte-and- significance. In patients with LCH-RO (-), MCPyV-DNA sequences monocyte-apheresis (GMA) in parallel to conventional LCH-treatment. were detected in LCH tissues, and significant differences were We also treated the patient with natalizumab, an effective approach in observed between LCH tissues and control tissues. Although MCPyV other neuroinflammatory conditions. The patient was evaluated by may cause subclinical infection in nearly all individuals, little is known clinical, neurological and neuropsychological examinations, Magnetic about geographical variations in the ecology of MCPyV infection of Resonance Imaging and by measuring cytokine levels in cerebrospinal skin. Methods: This study included 284 Japanese participants. Sun- fluid (CSF) and plasma. Results: No improvement was observed in our unexposed arm and sun-exposed forehead skin swab samples were patient after one-year of natalizumab treatment, therefore natalizumab obtained and analyzed for MCPyV infection, using quantitative was discontinued. Interestingly, GMA (given frequently for >6 years) polymerase chain reaction. Results: This study provides for the first removed cytokine-producing cells from blood and significantly time data on age-specific prevalence and levels of MCPyV infection in impacted on the reduction of IL-17A levels in plasma and CSF. normal skin. Steep increases in prevalence and viral load were Neurofilament protein light chain (NF-L) levels in CSF were also observed in individuals aged > 40 years. MCPyV infections with a high decreased over time, and although the patient's neuromuscular viral load were predominantly observed in subjects of the forehead problems did not improve her condition later stabilized. Conclusion: skin aged > 60 years, among whom a high MCPyV load tended to Since the natural development of the ND-LCH is not well known, we persist. Conclusions: This large study suggests that MCPyV infection cannot be certain if, and if so to what extent GMA contributed to the is widespread and shows a close agreement with the data given by stabilization of our patient. Nevertheless, our study suggests that IL- our previous studies concerning the relationship between LCH and 17A may be used as an additional biomarker for monitoring ND-LCH MCPyV. Although MCPyV causes subclinical infection in nearly and that GMA may be considered as experimental treatment in everyone, patients in pre-LCH status with an underlying oncogenic patients with systemic LCH, aiming at reducing hypercytokinemia and potential may overreact to MCPyV producing an intense cytokine disease activity. storm and develop LCH.

Poster Location #34 Poster Location #35

ECOLOGY OF MERKEL CELL POLYOMAVIRUS IN HEALTHY CD207+/CD1A+ CIRCULATING CELLS ARE PRESENT IN SKIN SHOWS A CLOSE AGREEMENT WITH INTERLEUKIN-1 PATIENTS WITH ACTIVE LANGERHANS CELL HISTIOCYTOSIS LOOP MODEL IN LANGERHANS CELL HISTIOCYTOSIS Diego Rosso1,2, Licina Tessone2, Ivana Estecho2, Graciela Elena1, Ichiro Murakami1, Junko Nakashima2, Yumiko Hashida3, Arnaldo Armesto2, Eugenio Carrera Silva2, Andrea Errasti2 Masanori Daibata3, Michiko Matsushita4, Takeshi Iwasaki5,6, Satoshi Kuwamoto6, Masako Kato6, Keiko Nagata6, 1Hospital de Niños Dr P Elizalde, Buenos Aires, Argentina Kazuhiko Hayashi6, Takashi Oka7, Tadashi Yoshino7, 2Pharmacology Institute, School of Medicine. Universidad de Buenos Toshihiko Imamura8, Akira Morimoto9, Shinsaku Imashuku10, Aires, Argentina Jean Gogusev11, Francis Jaubert12 Background/Purpose: Langerhans Cells Histiocytosis (LCH) is a 1Department of Pathology, Kochi Medical School, Kochi University, disorder characterized by an abnormal accumulation of CD207+CD1a+

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myeloid cells in almost any tissue. It was recently identified that Conclusion: Therapeutic VMF concentrations observed in children monocytes as well as CD1c+ dendritic cells can achieve high levels of Langerhans cell histiocytosis are lower than those noted in adults langerin (CD207), CD1a and Birbeck granules when exposed to TGF- melanoma treatment. b and TSLP. However the precursors of these pathogenic LC cells were not yet clearly defined in vivo. Here, we want to evaluate the hypothesis that circulating precursor cells expressing CD207 and/or NOTES CD1a should be present in active multisystem and/or multifocal LCH patients. Methods: Pediatric patients with confirmed diagnosis of LCH were stratified as unisystem, multisystem, unifocal, mutifocal with active disease (AD) or non-active disease (NAD). The expression of CD1a and CD207 was analyzed in the myeloid compartment of peripheral blood mononuclear cells of LCH children and compared with same compartment of cells from healthy adults and umbilical cord blood by FACS analysis. Results: The myeloid compartment showed a significant increase (p< 0.01) of CD11b fraction including CD11bhigh plus CD11b+ (36.39 ± 3.68, N=11) in AD patients compared to NAD patients (18.87 ± 1.73, N=12) and healthy adults (24.87 ± 1.30, N=12). We have also identified the presence of high percentage of circulating CD11bhighCD11c+CD207+ cells (39.01 ± 9.36, N=12) in AD patients compared with NAD ones (3.06 ± 0.51, N=11), healthy adults (0.65 ± 0.37, N=9) and umbilical cord blood (2.10 ± 0.55, N=5). Moreover, circulating CD11chighCD207+CD1a+ cells (18.99 ± 7.38, N=12) are present in active multisystem patients compared with NAD patients (2.13 ± 0.40, N=12), healthy adults (0.74 ± 0.29, N=8) and umbilical cord blood (2.76 ± 1.11, N=4). Conclusions: CD11b fraction is increased in active disease and interestingly monocytes expressing CD207 as well as DCs expressing CD207/CD1a suggest a potential precursor role in AD patients with multifocal lesions or multisystem involvement.

Poster Location #36

PHARMACOKINETICS STUDY OF VEMURAFENIB IN A

PEDIATRIC POPULATION: PRELIMINARY RESULTS

Jean Donadieu3, Nicolas Fabresse1,2, Islam Amine Larabi1, Emuri Abe1, Sébastien Héritier3, Jean-Claude Alvarez1,2

1Laboratory of Pharmacology-Toxicology, AP-HP, Hôpital Raymond Poincaré, Garches, France 2Université Versailles Saint Quentin en Yvelines, UFR Sciences de la Santé, Montigny-le-Bretonneux, France 3Department of Pediatrics, AP-HP, Centre de Référence des Histiocytoses, Hôpital Trousseau, Paris, France

Purpose: Vemurafenib (VMF) appeared as a potential useful drug in refractory LCH. However, dosage regimen is generally empirically decided, based on the similarity of the body weight related adult reference dose used in melanoma, since no pharmacokinetics data exist for VMF in pediatric populations. Methods: We evaluate the main pharmacokinetics parameters using an LC-MS/MS method in this population. A total of 11 patients were studied and preliminary analysis of 7 children aged from 1 to 8-years-old were enrolled in this prospective study. Results .:. Patients received 14 to 43 mg.kg-1/Day of oral VMF in two administrations. Pills are crushed and dissolved in water. Plasmatic concentrations were evaluated at the D1 and D14 after starting the treatment (T0H, T2H, T3H, T4H, T5H, T6H, T8H, T10H and T12H). AUC at D1 was 61 ±41 µg.ml-1.h-1 (mean ±SD) with a Cmax (T5H) of 6.5 ±5.4 µg.ml-1 and Cmin 4.3 ±2.6 µg.ml-1. AUC at D14 was 164.8 ±90 µg.ml-1.h-1 with a Cmax of 13.0 ±8.8 µg.ml-1 and Cmin 11.3 ±8.5 µg.ml-1. Tmax observed at D1 was equivalent to adult (4.5H Vs. 5H). AUC increase 2.6 fold from D1 to D14 Vs. 15 to 17 fold among adults. AUC, Cmax and Cmin SD underline an important inter-individual variability. Looking intra-patient variability at D14 (mean D14-SD: 2.2 µg.ml-1), kinetics presents few variation according to steady state achievement. Although Cmin observed differs from adult studies (54 and 57 µg.ml-1) with a 4 to 5 fold factor, good clinical response was observed among patients, except for one of them with the lower concentration (3 ng/mL).

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Poster Location #37 European Commission may then grant the medicine orphan status.To be designed as a orphan drug, two major conditions should be RELEVANCE OF BRAFV600E ALLELE DETECTION IN ascertained: 1 epidemiological data should be validated that the CIRCULATING CFDNA AS A BIOMARKER IN PEDIATRIC LCH condition is rare i.e. prevalence should be below 5/10000 in population. 2 Preliminary biological and/or clinical should support the Jean Donadieu1, Sébastien Héritier1, Valery Taly2, Sonia Garrigou2, plausibility of the efficacy of the drug in the condition. Results: In Nathalie Terrones3, Corinne Normand2, Philippe Nizard2, order to foster the commitment of Pharma company in the field of such Zofia Hélias-Rodzewicz3, Jean-François Emile3 a rare disease as Langerhans cell Histiocytosis, the non profit association GROUPE d'ETUDE des HISTIOCYTOSES, Paris, France, 1French Reference Center for Langerhans Cell Histiocytosis, had taken the initiative to apply for an Orphan designation status for Trousseau Hospital, Paris, France VEMURAFENIB for Langerhans cell Histiocytosis. The file was 2INSERM UMR-S1147, CNRS SNC 5014, Université Paris Sorbonne completed in December 2015 with the help of the OrphanDev, an Cité, Paris, France academic platform. The COMP give a positive opinion mid april 2016 3Pathology Department, Ambroise Paré Hospital, Assistance and EC adopted the orphan status. Conclusion: Vemurafenib is now Publique-Hôpitaux de Paris, Boulogne-Billancourt, France the first drug with an orphan drug status in Langerhans cell histiocytosis. With regards to the promising effect of Vemurafenib in Purpose: BRAFV600E mutation was reported in half of the patients refractory LCH, this status will help 1) to develop clinical trials 2) to with Langerhans cell histiocytosis (LCH). Detection of oncogenic apply for EU grants like H2020 3) to foster the commitment of Pharma mutations in circulating cell-free DNA (cfDNA) has been largely company in the field of LCH 4) orphan status in EU can easily be reported in patient with cancer and plasma cfDNA BRAFV600E extended to USA, according to FDA regulation. detection was reported in adults with Erdheim-Chester disease. The present study investigated the BRAFV600E allele detection in Poster Location #39 circulating cfDNA in a pediatric LCH cohort. Methods: BRAFV600E positives LCH cases were investigated at diagnosis and during follow CHALLENGES IN TREATING LANGERHANS CELL up (week 7, month 6, and if applicable at recurrence and additionally HISTIOCYTOSIS AMONG CHILDREN IN DEVELOPING at day 15 after onset of vemurafenib therapy). BRAFV600E allele was COUNTRIES: CHILDREN'S HOSPITAL LAHORE PAKISTAN detected using droplet digital PCR assay with a Raindrop system EXPERIENCE (Raindance Technologies). Quantitative BRAFV600E load was expressed as the percentage of mutant alleles relative to the total Alia Ahmad, Fauzia Shafi Khan number of BRAF alleles detected. Results: Mean BRAF allele detection was 71445 alleles (range, 551-751 093) per samples. At The Children’s Hospital 7 & ICH Lahore, Pakistan diagnosis (n=30), circulating cfDNA BRAFV600E positive detection was found in 9/9 (100%) of risk organ positive multisystem (RO+MS) Purpose: Langerhans Cell Histiocytosis is a relatively rare disease LCH cases, 2/4 (50%) of RO-MS LCH cases and 0/14 (0%) single accounting for < 2% of new cases each year enrolled in The Children’s system (SS) LCH cases (12 bone SS LCH and 2 skin SS LCH) Hospital Lahore. The purpose of this study was to analyze the (P<0.001, Fisher's Exact test). BRAFV600E load was higher in RO+ spectrum of challenges faced in resource limited settings lacking cases (mean, 2.78% range 0.07-6.66%) than in RO- cases (mean, salvage therapy. Methods: Retrospective review of 42 patients 0.08% range 0.06-0.11) (P=0.099, Mann-Whitney test). Follow up is enrolled between January 2011 – December 2015 was done. Data already complete for 9 patients. For 4 cases negative at diagnosis regarding their age, sex, clinical classification, course of therapy, and without reactivation, no further detection of cfDNA BRAFV600E allele outcome analyzed. The therapy mainly comprised of prednisolone and was observed. For positive cases at diagnosis, persistent cfDNA vinblastine/ARA-C pulses and Japanese protocol. Results: Total 42 BRAFV600E allele detection concerned 3/3 patients with persistent patients with age ranging from< 1 to 10 years (19% <2 yrs) were active disease after vinblastine/steroid therapy, but was not detected included. M: F Ratio was 2:1. 30/42 (72%) patients presented with in cases for whom remission was obtained after 2 courses of multisystem-LCH (MS-LCH) with100% mortality in MS-LCH group (p- cladribine/cytarabine therapy (n=1) and after 15 days of vemurafenib value=0.045) and 18/42 (43%) had Risk Organ involvement with 72% therapy (n=1). Conclusion: BRAFV600E quantification in circulating mortality.29/42(70%) of patients had bone lesions while 12/42(29%) cfDNA may be a pertinent biomarker to monitor disease, especially for with central nervous system (CNS) involvement. Total 19/42 (45%) RO+MS LCH children. have completed treatment, 7/42 (17%) are on treatment, 9/42 (21%) abandoned treatment and 7/42 (17%) expired due to progressive Poster Location #38 disease and worsening infection. 16 patients (38%) had reactivations of disease requiring therapy for more than one year (p-value=0.058). VEMURAFENIB HAD OBTAINED THE ORPHAN DRUG 24%of cases received two cycles of initiation therapy before DESIGNATION STATUS IN EUROPE FOR LANGERHANS CELL continuation therapy started (p-value=0.024). The treatment initiated HISTIOCYTOSIS IN APRIL 2016 >6 months after the onset of symptoms in 30/42 (72%) of cases with 100% expiries in this group and 89% of abandonment. The children Jean Donadieu1, Marine Berro2, Sébastien Héritier1 presenting at younger age had risk of having MS-LCH 75% as compared to 36% in age >2years. Conclusion: Treatment 1Centre de référence des Histiocytoses, Registre des histiocytoses, abandonment, delayed diagnosis and poor social support are major Hémato Oncologie Pédiatrique, Hôpital Trousseau, APHP, challenges in treating LCH in developing countries. Early diagnosis Paris, France and timely treatment with effective infection control measures and 2OrphanDev Aix-Marseille Université, Marseille, France strong social support are of utmost importance to improve long term overall survival. Purpose: To inform the "Histiocyte Society" that the VEMURAFENIB had recently obtained the orphan drug designation status for Langerhans cell histiocytosis. Methods: Orphan designation allows a pharmaceutical company to benefit from incentives from the European Medicines Agency to develop a medicine for a rare disease, such as reduced fees and market exclusivity. Applications for orphan designation are evaluated by the Committee for orphan medical products (COMP). If the COMP issues a positive opinion, the

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Poster Location #40 with cystic lung LCH are at risk of recurrent, life-threatening tension pneumothoraces. Those with limited respiratory reserve may also A COLLABORATIVE STUDY IN CHILDREN AND ADULTS require prolonged ventilation, increasing the risk of air leaks. Two DIAGNOSED WITH LANGERHANS CELL HISTIOCYTOSIS. OUR cases are described. Results: Patient 1: A previously well 2 year old EXPERIENCE IN 42 CASES boy presented with cough and sudden deterioration in breathing due to a pneumothorax, which required a chest drain. CT scan revealed Itziar Astigarraga1,2,3, Susana Garcia-Obregon2, Leticia Ceberio4, bilateral diffuse cystic lung disease and T2 vertebra plana. While lung Rosa Adan1,2, Aizpea Echebarria1,2, Miguel Garcia-Ariza1,2, biopsy results were awaited, he was re-admitted following an out of Ricardo Lopez-Almaraz1,2, Ainhoa Gondra3,5 hospital cardiac arrest, secondary to bilateral pneumothoraces. The biopsy confirmed LCH. High dose steroids and vinblastine were 1Paediatric Service, Hospital Universitario Cruces, Barakaldo, Spain initiated (cytarabine later added). He required prolonged ventilation, 2Pediatric Oncology Group, BioCruces Health Research Institute, multiple (23) intercostal drains, bilateral pleurodesis, high frequency Barakaldo, Spain oscillation, airway pressure release ventilation and inotropic support 3Department of Paediatric, Faculty of Medicine and Dentistry, due to recurrent pneumothoraces and pneumonia. Having stabilised, University of the Basque Country, UPV/EHU, Leioa, Spain he was discharged home with oxygen and an emergency action plan. 4 Internal Medicine Department, Hospital Universitario Cruces, Patient 2: A skin biopsy on an 11 month old boy with a rash, otorrhoea Barakaldo, Spain and multi-cystic lung disease revealed LCH. Soon after the initiation of 5 Pediatric Department, Hospital Universitario Basurto, Bilbao, Spain prednisolone and vinblastine, he had a series of pneumothoraces with intrathoracic tensioning events. Brief periods of ventilation led to Purpose: Langerhans Cell Histiocytosis (LCH) can develop at any age. prolonged ventilation and the inability to wean from support. He had Clinical presentation, severity and therapeutic approach vary in multiple bilateral chest drains with ineffective talc pleurodesis. Rash children and adults, but few studies have analyzed the differences. and otorrhoea resolved but repeated CT thorax showed worsening Aim: to compare data between adults and pediatric patients. Methods: widespread large bullae. Cytarabine was added. After 8 weeks of Analysis of epidemiological and clinical data of LCH cases collected therapy and 4 weeks of continued ventilation, tensioning events led to from 1995 to 2015 in 3 hospitals from the Basque Country (Spain) was widespread subcutaneous emphysema, and intensive care was performed by SPSS. Results: Forty-two patients were included withdrawn. Conclusion: Children with severe cystic pLCH need to have (23males/19females). Range of age: 0-84 years-old. Pediatric cases almost immediate access to acute medical care. In addition to LCH (<18 years-old): 18 cases (9females/9males). Median age: 6.6 years- directed therapy, patients may require numerous intercostal drains, old. Initial organ involvement: 17-bones (8 unifocal), 1-skin, 1-lung, 1- pleurodesis and individualised ventilation strategies. gastrointestinal. Multisystem disease found in 8 but no in risk organs involvement. Chemotherapy was administered in 10. Evolution: No Poster Location #42 deaths, relapses in 4. Nowadays, 18 are in complete remission. Adult cases: 24 cases, 10 females and 14 males. Median age at diagnosis: LONGITUDINAL STUDY OF IL-1β AND PGE2 SALIVARY 35.3 years-old. Clinical features: 10-bones (7-unifocal), 11-lung, 6- CONCENTRATIONS IN PEDIATRIC PATIENTS WITH lymph nodes, 4-skin, 2-spleen, 2 CNS, 1-genital, 1-liver, 1- LANGERHANS CELL HISTIOCYTOSIS hematopoietic-system. Multisystem disease was found in 9. Adult patients received different therapies including radiotherapy in five. Carolina Benchuya1, Ariel Gualtieri2, Bentina Orman3, Relapse in 3 patients. Missing data in adult follow-up but 7 deaths and Verónica Paván1, Jorge Braier4, Virginia Fernández de Preliasco1. 5 malignancies associated (2-Hodking, 2-lung, 1-leukemia). Children were included in national/international studies and chemotherapy was 1Department of Comprehensive Children's Dentistry, School of more used. Conclusion: LCH was more frequent in children and in the Dentistry, University of Buenos Aires, Argentina first 40 years of life (median of 20, 75% cases <38 years-old). Bone 2Department of Biophysics, School of Dentistry, University of Buenos lesions were the most common presentation in both groups. Aires, Argentina Multisystem involvement was detected in 44% children and 37% 3Pharmacology Unit, School of Dentistry, University of Buenos Aires, adults. Pulmonary, lymph nodes and risk organ involvement were Argentina more frequent in adults. Prognosis was better in children and 4Hematology/Oncology Department, Children's Hospital Garrahan, associated malignancies and deaths were observed only in adults. Buenos Aires, Argentina LCH clinical presentation and evolution show some differences in pediatric and adult patients. We recommend collaboration among Purpose: The aim of this study was to determine the fluctuation in the physicians for LCH management at any age and the development of concentrations of IL-1β and PGE2 in the saliva of children with international studies for this rare disease. Langerhans Cell Histiocytosis (LCH), at different moments of the course of the disease. Methods: Concentrations of IL-1β and PGE2 in Poster Location #41 saliva of 10 children with diagnosis of LCH were analysed by Elisa, and samples were obtained at different moments of the course of the PULMONARY LANGERHANS CELL HISTIOCYTOSIS IN disease. Follow-up was performed in patients with bone and/or CHILDREN: LIFE-THREATENING PNEUMOTHORACES AND THE mucous involvement and also in patients without oral lesions. Results: CHALLENGES OF PROLONGED VENTILATION - REPORT OF 2 3 of 10 patients had bone lesion, 2 had mucosa and bone CASES involvement, 2 had only mucosa involvement and 3 had no oral lesions. In all of them the variations in the level of the pro-inflammatory Mhairi Barclay1, Alice Martin2, Jayesh Bhatt1, Patrick Davies1, molecules were observed during active disease. Both IL-1β and PGE2 Claudiu Faraon2, Richard Grundy1, Tom Hilliard2, Steve Lowis2, levels were elevated during active disease or reactivation and Vasanta Nanduri3, Johannes Visser4 decreased during periods of no evidence of active disease. IL-1β and PGE2 concentrations both showed similar pattern, drastically 1Nottingham Children's Hospital, Nottingham, United Kingdom decreasing with systemic and topical medication treatment, dental 2Bristol Children's Hospital, Bristol, United Kingdom extraction or lesion infiltration with corticosteroids. Conclusions: IL-1β 3Watford General Hospital, Hertfordshire, United Kingdom and PGE2 concentrations in saliva of patients (with or without oral 4Leicester Children's Hospital, Leicester, United Kingdom involvement) increase during disease activity and decrease during periods of no active disease. Purpose and Methods: Although the lung is no longer considered a ‘risk organ' in childhood Langerhans cell histiocytosis (LCH), patients

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Poster Location #43 patients did require hospital admission for fever management at some point during clofarabine therapy. Additional adverse events included THE LEVELS OF IL-1β AND PGE2 IN SALIVA OF CHILDREN WITH grade 3 anemia, grade 2 dehydration, grade 3 cytopenias, or grade 3 LANGERHANS CELL HISTIOCYTOSIS infection. No patients died while receiving clofarabine. Conclusion: Patients with histiocytic disorders were safely and effectively treated Carolina Benchuya1, Ariel Gualtieri2, Betina Orman3, with clofarabine therapy, most often in outpatient clinics. Toxicity as Verónica Paván1, Jorge Braier4, Virginia Fernández de Preliasco1 well as efficacy of clofarabine compared to other salvage strategies should be evaluated in prospective trials for patients with refractory 1Department of Comprehensive Children's Dentistry, School of histiocytic disorders. Dentistry, University of Buenos Aires, Argentina 2Department of Biophysics, School of Dentistry, University of Buenos Poster Location #45 Aires, Argentina 3Pharmacology Unit, School of Dentistry, University of Buenos Aires, CLINICAL RELEVANCE OF THE DIFFERENT MAPK-PATHWAY Argentina MUTATIONS IN LANGERHANS CELL HISTIOCYTOSIS; A 4Hematology/Oncology Department, Children's Hospital Garrahan, LITERATURE REVIEW UNDERLINING THE NEED FOR Buenos Aires, Argentina PROSPECTIVE CO-OPERATIVE STUDIES

Background/Purpose: Salivary fluid is considered an auxiliary tool in Sofie H. Breuking, Lieke Feijen, Cor van den Bos the diagnosis of diseases of the oral cavity. The aim of this study was to determine and compare the salivary levels of IL-1β and PGE2 in Department of Pediatric Oncology, Emma Children's Hospital/ children with Langerhans cell histiocytosis (LCH), with or without oral Academic Medical Center, Amsterdam, The Netherlands lesions, with unisystem or multisystem involvement, during active disease or no evidence of active disease, and a control group of Purpose: Somatic mutations in genes of the MAPK-pathway are healthy children. Methods: Saliva of 42 children with LCH were studied known to play a central role in the pathophysiology of Langerhans cell and compared to a control group of 28 healthy children. Salivary histiocytosis (LCH). To date, equivocal data regarding the prognostic concentrations of IL-1β and PGE2 were analysed by Elisa. Results: impact of the mutations have been published. In order to evaluate the Significantly sustained high levels of PGE2 and IL-1β in saliva were clinical relevance a systematic review of published data was found in patients with active disease or during remission in relation to performed. Methods: A PubMed search was done in November 2015. healthy individuals (p< 0.05). Significantly high values of IL-1β and Articles describing MAPK-pathway mutations in the context of LCH PGE2 may also appear in LCH patients with or without oral (bone or were included. Differences in clinical presentation were tested using mucosa) involvement in relation to healthy individuals (p< 0.05). Both the Chi-square test. Clinical outcome was evaluated with Kaplan-Meier IL-1β and PGE2 showed similar pattern. Conclusions: The elevated analysis for those patients with available time to event, as well as by levels of IL-1β and PGE2 in saliva of LCH patients without oral Cox regression analysis. Methods of mutation status analysis were involvement may suggest that the disease is systemic, and elevated compared, and other possible biases were evaluated using a levels of these pro-inflammatory molecules in LCH patients without predetermined set of criteria. Results: Nineteen studies describing 707 clinical evidence of disease may suggest that the disease still patients were included. In patients presenting with multi-system LCH subclinical. the BRAF-V600E mutations were more prevalent (77/129=60%) than BRAF-wild type (52/129=40%) compared to those with single-system Poster Location #44 LCH (190/384= 50% BRAF-V600E). This was not statistically significant. For 107 individual patients follow-up data were available. TOXICITY PROFILE OF CLOFARABINE IN PATIENTS WITH No significant differences were found for ‘reactivation’ and survival REFRACTORY OR RECURRENT HISTIOCYTIC DISORDERS rates between those with BRAF-V600E, MAP2K1, other and no known mutations. Mutation status was analyzed by immunohistochemistry Racheal Bingham, Olive Eckstein, Kenneth McClain and / or molecular techniques. None of the studies described the sensitivity of the methods used. Conclusion: With the available data no Texas Children's Cancer Center; Department of Pediatrics, Section of influence of the different MAPK-pathway mutations on either clinical Hematology-Oncology, Baylor College of Medicine, Houston, TX USA presentation or outcome could be detected. Numerous biases were identified. It is concluded that the available data do not allow for a Purpose: Langerhans Cell Histiocytosis (LCH) is myeloid neoplastic clear genotype-phenotype analysis in LCH. Only the use of a well- disorder that can be fatal in high-risk patients, and is associated with defined mutation analysis strategy in a complete cohort of patients significant morbidity in all patients. Treatment failure is associated with using comparable treatment strategies will allow for such an analysis. increased risks of morbidity and mortality. Nucleoside analogs have This will only be possible within the framework of co-operative studies been demonstrated to have efficacy as salvage therapy for patients such as LCH-IV. with recurrent or refractory LCH, though high rates of treatment-related mortality have been reported with very high dose cytarabine/cladribine. Poster Location #46 Clofarabine has been reported to be effective in patients with LCH as well as other histiocytic disorders. The purpose of this study was to PERMANENT CONSEQUENCES OF LANGERHANS CELL report the toxicity profile of patients with histiocytic disorders treated HISTIOCYTOSIS. EXPERIENCE OF AN OBSERVATIONAL TRIAL with clofarabine. Methods: The charts of twenty-six pediatric patients treated at Texas Children's Hospital with clofarabine for histiocytic Gleb Bronin, Roman Miroshkin, Evgeniy Bezunov, Elizaveta Mironova, disorders from 2011 to 2016 were retrospectively reviewed for adverse Elena Fisun, Bulat Kurmanov, Elena Promyslova, Vladimir Kasatkin, events. All patients received clofarabine (25mg/m2/d x 5 days every Alexander Karelin 28 days) for a minimum of 6 months. Results: Clofarabine was frequently given in an outpatient clinic setting 17/26 (65%) patients, Federal Center for Pediatric Hematology n/a D. Rogachev, with the majority of adverse side effects managed outpatient, with Moscow, Russia another 3/26 (11%) who required admission for non-medical reasons. Some 7/26 (27%) patients required admission to manage grade 3 Purpose: The main purpose of our study was evaluation of severity nausea/vomiting. Granulocyte-colony stimulating factor was given to and clinical course of permanent consequences (PC) of Langerhans 12/26 (46%) patients due to history of Grade 3 neutropenia. Only 6/26 cell histiocytosis (LCH) in pediatric age. Methods: 59 children with (23%) patients required dose reduction. A majority (18/26, 70%) of LCH were admitted in our rehabilitation center since January 2015. 25

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of them had onset of the disease more than 5 years ago and were respiratory distress which later developed into bilateral pneumothorax. included in our trial. Male/female ratio was 17/8. Age ranged from 5 to Chest-X-ray and CT scan showed interstitial pulmonary involvement 17 years (median 9), time from diagnosis was 5-14 years (median and a bullous process with bilateral pneumothoraxes. Lung biopsy 8.5). We performed clinical examination with main focus of axiology, confirmed PLCH with Cd1a positivity and negative BRAF mutations. neurological status and features of LCH and its PC. Some patients Extent of disease evaluation did not reveal any other affected organ. underwent visualization and functional tests if needed. Different The patient received chemotherapy with prednisone, vinblastine and 6 biochemistry and endocrinology assays were done. We used number -mercaptopurine. During the first 10 weeks of treatment the patient of Neuropsychology tests of CANTAB eclipse (CambridgeCognition, had recurrent episodes of pneumothorax managed conservatively with UK) for the assessment of cognitive functions. Intelligence rate was chest tube drainage. From week 11th onwards the frequency of estimated by Raven's colored progressive matrices. Behavior pneumothorax declined significantly allowing for bilateral mechanical problems of patients were assessed by Achenbach System. pleurodesis. At week 12th the patient was asymptomatic with Correlation between severity of PC and primary clinical course and decreased number and size of bullae. Lung parenchyma remained treatment was performed. Results: 13 patients had multi-system LCH normal and the pneumothoraxes resolved completely. Repeated (MS-LCH) and 12 had single system LCH (SS-LCH) at onset. 24 infections required aggressive antibiotic treatment. Conclusion: the children received chemotherapy for primary disease. 8 patients improvement of lung parenchyma affection by LCH required several survived reactivation in bones. In 3 cases neurodegeneration (ND) weeks and the recurrent spontaneous pneumothoraxes can be was revealed. 6 children suffered from diabetes insipidus. The most managed conservatively. Despite severe pulmonary involvement, common PC among LCH survivors were psychological deficits (50% of conservative surgical treatment and moderate chemotherapy can cases), the most severe was the cases of ND and panhypopituitarism achieve successful outcomes. which demanded therapeutic intervention. Conclusion: PC in the late period after the discontinuation of primary treatment can be severe Poster Location #49 and affect quality of life. Special examination and well-timed diagnostic of PC in this period are very important for the proper choice of REFRACTORY LCH MONITORING BY URINARY AND BLOOD eventual therapeutic option. BRAF TESTING

Poster Location #47 Anthony Chuang, Lilibeth Torno

PERSISTENT OR RECURRENT LANGERHANS CELL Children's Hospital of Orange County, Orange, CA USA HISTIOCYTOSIS TREATED WITH SORAFENIB ALONE:CASE REPORTS AND LITERATURE REVIEW Purpose: Langerhans cell histiocytosis (LCH) is a rare disorder characterized by clonal proliferation of pathologic histiocytic cells that Jing Cao, Xiaodong Shi, Rong Liu, Danqing Luo, Duanfang Shao occur in single or multiple organs. Therapeutic options for refractory disease include cladribine and cytarabine, with potential new refractory The Affiliated Children's Hospital, Capital Institute of Pediatrics, treatments including dabrafenib. In this case report, we describe the Beijing, China monitoring of a v-raf murine sarcoma viral oncogene homolog B (BRAF) positive LCH patient through the BRAF V600E cell free tumor Objective: Through the report about two cases of patients with DNA Mutation Testing by Trovagene. Methods: We report the case of persistent or recurrent LCH orally treated with Sorafenib alone that can a three year old child with refractory LCH and review pertinent achieve clinical remission, and reviewing related literatures about literature. Results: Three year old female who initially presented with detection of BRAFV600E gene mutation and targeted treatment with multisystem (non-Risk Organ) LCH refractory to medical management Sorafenib in LCH patients, to summiarize the clinical characteristics that included induction chemotherapy per LCH-3 protocol and and to improve the clinician's recognition of oncogenic BRAF-V600E cladribine. Lymph node was BRAF positive. At our hospital, she was mutation detections and targeted therapy. Results: After orally treated initiated on clofarabine. During course of treatment she developed with Sorafenib alone, the clincal manifestions of two patients with persistent fever, leukocytosis, and thrombocytosis, without oncogenic BRAF-V600E mutation receive clinical remission and hepatosplenomegaly. Infectious, leukemic, and Hemophagocytic without any serious adverse drug reactions. Conclusions: Treating with Lymphohistiocytosis workup was negative. Eventually, Sorafenib in patients with oncogenic BRAF-V600E mutations in lymphadenopathy re-occurred and biopsy confirmed LCH. She was peripheral blood is a safe and potent approach. Since the number of then started on dabrafenib in May 2014 with resolution of above sample in this paper is not large, it is necessary for us to take a further symptoms. Patient was monitored using the BRAF V600E Mutation study to verify its efficacy. Long term follow-up is needed for Testing kit by Trovagene. Through the course of treatment, her urine obeservation of adverse reactions and determining the optimal BRAF was positive. A routine MRI performed in March 2016 showed duration of therapy and its stopping standards. new diffuse retroperitoneal and mesenteric lymphadenopathy. Dabrafenib was temporarily discontinued due to concern for disease Poster Location #48 progression. Follow up testing off dabrafenib 3 weeks later revealed blood BRAF to be undetected. Urine BRAF also came back negative. ISOLATED PULMONARY LANGERHANS CELL HISTIOCYTOSIS Patient resumed dabrafenib and in May 2016 follow-up MRI done IN CHILDREN showed interval decrease in the size and number of lymphadenopathy. Patient continues to be closely monitored. It is unclear what triggered Veronica Celis, Jaume Mora, Moira Garraus, Maria Correa, the progression of lymphadenopathy. Conclusion: Monitoring patients Yolanda Jordan, Rosalía Carrasco, Lucas Krauer, Jordi Costa with BRAF mutation positive LCH using BRAF V600E Mutation kit affords a new manner of screening patient's clinical status. Hospital Sant Joan de Dèu, Barcelona, Spain

Purpose: Isolated pulmonary Langerhans Cell Histiocytosis (PLCH) is rare in children and results from the accumulation of abnormally activated histiocytic cells in the interstitial of the lung parenchyma. Here we present the clinical presentation, response to conservative treatment, and outcome of a PLCH case in a very young child. Methods: Isolated PLCH description and literature revision. Results: a 19-months-old male presented with acute history of fever, cough and

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Poster Location #50 patients had subsequent reactivations. Forty six patients performed a skeletal survey at presentation of which two displayed previously CRANIOFACIAL AND INTRACRANIAL MANIFESTATIONS OF unknown lesions (one with multisystem disease and one with a solitary LANGERHANS CELL HISTIOCYTOSIS IN CHILDREN: ANALYSIS low risk lesion), and two were unequivocal with a suspected lesion not OF 232 CASES confirmed by further imaging. A negative skeletal survey did not predict subsequent reactivations. Conclusions: In our retrospective Yunze Zhao, Rui Zhang, Li Zhang, Honghao Ma, Dong Wang, study we evaluated fifty patients with LCH, of which thirty seven had Tianyou Wang, Hongyun Lian solitary bone lesions (including special site or CNS risk lesions).Only one bone survey revealed an asymptomatic lesion in this group of Beijing Key Laboratory of Pediatric Hematology Oncology, patients. Multifocal disease was diagnosed by clinical features or CT/ Hematology Oncology Center, Beijing Children's Hospital, Capital MRI. We propose to consider omitting skeletal surveys in patients with Medical University, Beijing, China a solitary LCH lesion, and reduce unnecessary radiation exposure. Further studies are recommended. Purpose: The objective of this study was to retrospectively analyze the craniofacial and intracranial clinical manifestations and magnetic Poster Location #52 resonance imaging (MRI) of patients with Langerhans cell histiocytosis (LCH). Methods: The retrospective analysis was performed in LCH EFFICACY OF CLOFARABINE IN PATIENTS WITH REFRACTORY/ patients admitted to a single institute between January 2007 and July RECURRENT LANGERHANS CELL HISTIOCYTOSIS 2013. They were stratified and treated according to Histiocyte Society LCH-III protocol. Results: 232 patients who had MRI data of brain Olive S. Eckstein, Rachael Bingham, Erin Peckham, Austin Brown, (709) and pituitary body (1106) were selected from a total of 305 LCH Kenneth L McClain, Carl E. Allen patients, with a median time of 30 months (range from 6 months to 100 months). We noted osseous lesions in craniofacial or skull bones Texas Children's Cancer Center; Department of Pediatrics, Section of in 68.9% of patients, while parietal bones and temporal bones were Hematology-Oncology, Baylor College of Medicine, Houston, TX USA affected in 52.5% and 40.6%, respectively. In the hypothalamic- pituitary region, enlargement of the pituitary stalk occurred in 11.2%; Purpose: Patients with refractory or recurrent Langerhans Cells lack of physiologic hyperintense signal of the posterior pituitary on T1- Histiocytosis (LCH) are at increased risk of mortality and long-term weighted images occurred in 16.8%. After treatment, two patients with morbidity. While effective, salvage therapies with very high dose diabetes insipidus were cured and stopped minirin; three showed cytarabine/cladribine are also associated with very high treatment hyperintense signals. Prehypophysial abnormalities were observed in related mortality. Clofarabine is a nucleoside analog with activity 3.4%. The pineal gland had a cystic appearance in 17.2%, while against LCH reported in case studies, even when given at moderate accentuated Virchow-Robin spaces occurred in 7.7%. White-matter doses. Methods: Medical records were retrospectively reviewed for and gray-matter changes in the cerebellar dentate nucleus, basal pediatric LCH patients who had failed at least one prior systemic ganglia, globuspallidus and pons were identified in a few patients. therapy and were then treated with clofarabine salvage therapy Clinical ND-LCH with overt symptoms was not found. Conclusion: Our (n=21). Patients received a minimum of 6 months of clofarabine study indicates that skull lesions, including involvement of maxill of (typical dose=25 mg/m2/day x 5 days every 28 days) and were acial bones, bital bones and hypothalamic-pituitary axis, are common reassessed for response at the end of therapy and monitored for in LCH patients. Diabetes insipidus occurred in 16.8% of patients. relapse or progression post-treatment. Results: All patients started Among them, some with an irreversible permanent consequence; two treatment under the age of 18 years old (median=1.5 years; range: 0.3 were cured; three were better. Radiologic ND-LCH is frequently found -16.3). Patients received a median of 3 prior treatments (range:1-5). by MRI, but clinical ND-LCH with overt symptoms is rare. It is Overall survival was 100%. Following 6-months of clofarabine, 33% of necessary to detect CNS involvement in LCH patients by long-term patients had complete response, 52% partial, 10% progressed on follow-up with MRI. therapy, and 5% had stable disease. Relapse occurred in 5 (28%) patients after completion of treatment (median time to relapse=22 Poster Location #51 months; range: 1-42). Patients with CNS-risk lesions (n=16) compared to those without (n=4) trended toward higher risk of relapse; patients ASSESSMENT OF SOLITARY SKELETAL LESIONS OF LCH:IS with high risk disease (n=5) relative to standard risk (n=10) also BONE SURVEY MANDATORY? trended toward higher risk of relapse. One of the patients who experienced disease recurrence received an additional 12 cycles of Rina Dvir, Ronit Elhasid clofarabine and is doing well with no active disease. In general, this regimen was delivered in outpatient clinic and was well-tolerated with Tel-Aviv Sourasky Medical Center the most significant toxicities related to prolonged cytopenias. Sackler Medical Schoool, Tel-Aviv University, Tel-Aviv, Israel Conclusion: Clofarabine may be an effective and relatively safe salvage therapy for LCH patients. Future prospective trials would be Introduction: Solitary skeletal lesions of Langerhans Cell Histiocytosis helpful to directly compare efficacy and toxicity relative to more ( LCH) are the most common manifestation of LCH and generally cytotoxic nucleoside analog strategies or targeted inhibitors. harbor an excellent long term prognosis. The basic clinical workup of patients with LCH includes a full physical examination, basic blood tests, an abdominal ultrasound and a skeletal survey for detection of occult skeletal lesions Other imaging studies i.e. bone scans or PET scans, are optional, while MRI/CT is mandatory for skull or CNS lesions. Aims: To assess the yield of a skeletal survey in patients with a solitary LCH lesions, and the predictive value of the skeletal survey for clinical management and subsequent reactivations. Patients and methods: 50 consecutive patients with biopsy proven LCH who presented at our hospital from 2008-2016 were retrospectively reviewed including primary clinical presentation, bone surveys, imaging , therapy and reactivations. Results: Thirty seven patients (74% ) patients had a solitary skeletal lesion at presentation, twelve patients had multifocal disease, and three multisystem disease. Eight

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Poster Location #53 Purpose: to describe two cases of treatment of multisystem LCH in children with BRAF V600E inhibitors monotherapy. Case 1: Patient V. LANGERHANS CELL HISTIOCYTOSIS PATIENTS WITH presented with skin rash at 2 months. At 1 year patient was admitted, EXTENSIVE PULMONARY CYSTS AND MULTIPLE multisystem LCH diagnosis confirmed by bone lesion biopsy. LCH-IV PNEUMOTHORACES CAN BE CURED WITH PLEURODESES, treatment was administered, but after IC-1 serious respiratory VIGOROUS SUPPORTIVE CARE, AND CHEMOTHERAPY compromise due to K.pneumoniae and P.jiroveci pneumonia precluded continuation of chemotherapy. Without specific therapy, Olive S. Eckstein1, George Mallory2, R. Paul Guillerman3, LCH progressed with pancytopenia, hepatomegaly (+12 cm), Timothy Vecce4, Matthew Musick5, Carl E. Allen1, Jed Nuchtern6, splenomegaly (+10 cm). BRAF V600E mutation was detected in bone Kenneth L. McClain1 lesion by PCR. Vemurafenib was administered (initially 240 mg/day (1 tab/day with later dose escalation to 360 mg/day (1.5 tab/day) per 11 1Texas Children's Cancer Center, Division of Pediatric Hematology/ kg). After 2 months of therapy hepatosplenomegaly reduced, Oncology, Baylor College of Medicine, Houston, TX USA hematopoiesis is now restored. The only side effect was QT 2Division of Pediatric Pulmonology, Baylor College of Medicine, prolongation to 0.44 sec. Case 2: Patient D. presented with skin rash Houston, TX USA at 2 months, followed by fever, hepatosplenomegaly, pancytopenia at 3Division of Pediatric Radiology, Baylor College of Medicine, Houston, 6mo. At 7 months patient was admitted to our center, where the TX USA diagnosis was confirmed by skin biopsy. During IC-1 therapy 4Division of Pediatric Pulmonology, University of North Carolina, vinblastine-induced paralytic ileus developed, necessitating dose Chapel Hill, NC USA reduction. Then IC-2 and 2 courses of Ara-C/2-CdA followed with 5Division of Pediatric Critical Care Medicine, Baylor College of continuation therapy. At the age of 1.2 years relapse was confirmed Medicine, Houston, TX USA and Ara-C/2-CdA course was administered. Chemotherapy was 6Division of Pediatric Surgery, Baylor College of Medicine, Houston, complicated by severe respiratory compromise with CMV pneumonia, TX USA enterocolitis, acute kidney injury requiring renal replacement therapy. LCH progressed with pancytopenia and hepatosplenomegaly. After Purpose: To review the clinical course and outcomes of critically ill controlling life-threatening complications vemurafenib was children with Langerhans cell histiocytosis (LCH) who had extensive administered (initially 480 mg/day with later dose escalation to 720 pulmonary cysts and multiple pneumothoraces. There is little mg/day per 10 kg), as BRAF V600E was confirmed in bone marrow guidance in existing literature regarding potential for cure or aspirate. After 2 months of intake hemopoiesis is restored, management strategies. For all of these patients, treatment hepatomegaly reduced. As in case 1, the only side effect was QT discussions included lung transplant and withdrawal of care. Methods: prolongation to 0.47 sec. Conclusion: vemurafenib monotherapy Clinical charts, chest radiographs and CT scans were reviewed for induced objective responses in children with BRAF V600E positive these children diagnosed with LCH from the ages of 1 day to 16 years LCH. This therapy can be offered to patients unresponsive to/ with extra-pulmonary sites including skin(3), pituitary(2), liver and intolerant of standard chemotherapeutic regimens. lymph nodes (1). Results: The one day-old required laser pleurodesis to halt multiple pneumothoraces and did respond to vinblastine/ Poster Location #55 prednisone, but ultimately died of viral pneumonia. A 2 year-old girl required surgical pleurodesis and responded suboptimally to BRAF p.V600E MUTATION DETECTION IN PEDIATRIC vinblastine, prednisone, and methotrexate. She received one course of LANGERHANS CELL HISTIOCYTOSIS TISSUE SAMPLES USING cytarabine/cladribine then 6 courses of cladribine, resulting in REAL-TIME PCR AND MUTATION-SPECIFIC complete response of LCH and ultimately cyst resolution with IMMUNOHISTOCHEMISTRY: A COMPARISON STUDY reconstitution of a large percentage of functional lung parenchyma, now 11 years post treatment. An 11 month-old girl had less than 20% Kevin Fisher1,2, Leomar Ballester2, Miguel Cantu3, Karen Lim3, functional lung tissue, requiring up to 8 simultaneous chest tubes to Stephen Sarabia2, Renee Webb1, Lizmery Suarez Ferguson1, drain recalcitrant pneumothoraces. After treatment with cytarabine for Carl Allen3, Kenneth McClain3, Carrie Mohila1,2, Jyotinder Punia1,2, 12 months, she regained a significant volume of functional lung tissue Angshumoy Roy1,2, Dolores López-Terrada1,2, John Hicks1,2 and clinically normal 6 months off treatment. The 16 year-old boy presented with pneumothoraces, had surgical pleurodeses and was 1Department of Pathology, Texas Children's Hospital, Houston, TX, treated with cytarabine for a year with resolution of LCH and USA disappearance of most of the lung cysts, but relapsed 4 months later. 2Department of Pathology & Immunology, Baylor College of Medicine, He was successfully retreated with clofarabine and is now 3 years off Houston, TX, USA therapy. Conclusion: This series documents that patients with 3Department of Pediatrics, Hematology and Oncology, Texas extensive pulmonary cystic disease complicated by multiple Children's Hospital and Baylor College of Medicine, Houston, TX, USA pneumothoraces can be cured with chemotherapy along with aggressive surgical management with chest tubes and pleurodesis, Purpose: Approximately 60% of Langerhans cell histiocytosis (LCH) with potential for generation of new lung tissue and/or re-expansion of lesions harbor BRAF c.1799A>T p.V600E mutations. However, the compressed lung parenchyma. utility of BRAF V600E mutation-specific immunohistochemistry (IHC) to assess mutation status is unknown. We evaluated the BRAF V600E Poster Location #54 antibody in formalin-fixed, paraffin-embedded (FFPE) pediatric LCH samples using allele-specific real-time PCR (AS-qPCR) as the RESPONSE TO BRAF V600E INHIBITOR USED AS comparative gold-standard. Methods: Twenty-eight pediatric LCH MONOTHERAPY OF MULTISYSTEM LANGHERHANS-CELL FFPE samples (15 males, 13 females; age range 9 months-19 years) HISTIOCYTOSIS IN CHILDREN:REPORT OF TWO CASES with clinical BRAF p.V600E AS-qPCR results (with an established lower limit of detection of 0.05%) were included in the study. IHC was Dmitry Evseev, Irina Kalinina, Tatyana Salimova, Maria Sharashkina, performed on the Leica Bond automated stainer using a BRAF V600E Alexey Samarin, Elena Raykina, Uliana Petrova, Anna Mitrofanova, monoclonal antibody (clone VE1, Spring Bioscience) at a 1:45 dilution, Galina Novichkova, Michael Maschan and Alexey Maschan antigen retrieval with ER2 solution for 40 minutes, and diaminobenzidine (DAB) as a chromogen. Slides were evaluated and Federal Clinical Center of Pediatric Hematology, Oncology and scored for staining intensity (0-3+) and percent (0-100%) tumor Immunology, Moscow, Russia staining. BRAF IHC positivity was determined by both lenient (±1+,>1%, package insert recommendation) and stringent

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(±2+,±10%) scoring criteria. Results: Twenty-six LCH samples (14 Poster Location #57 molecular-positive, 12 molecular-negative) had sufficient tissue for comparative IHC analysis. Using lenient scoring criteria, the sensitivity DABRAFENIB FOR TREATMENT OF HEMOPHAGOCYTIC and specificity of IHC compared to AS-qPCR were 100.0% and 18.2%, LYMPHOHISTIOCYTOSIS (HLH) IN 2 PATIENTS WITH respectively. The poor specificity of lenient IHC analysis was due to LANGERHANS CELL HISTIOCYTOSIS (LCH) WITH BRAF-V660E weak (1+) staining in almost all lesional histiocytes. The specificity MUTATION (100.0%) improved when stringent criteria were implemented at the expensive of sensitivity (80.0%); 3 AS-qPCR-positive cases were Michael Grimley, Ashish Kumar negative by stringent IHC criteria. Conclusions: Unequivocal (2+,±10%) IHC staining is indicative of an underlying BRAF mutation. Bone Marrow Transplant and Immune Deficiency Negative IHC results require additional studies and stringent scoring Cincinnati Children's Hospital Medical Center criteria are essential to avoid false-positive results. Molecular analysis Cincinnati, OH USA remains the gold standard for BRAF p.V600E mutation testing in pediatric LCH. The suboptimal sensitivity and high background Purpose: HLH secondary to LCH is an infrequently reported staining of BRAF V600E IHC preclude its singular use as a surrogate complication of systemic LCH that is often difficult to treat. Methods: 2 for molecular testing. patients with multisystem LCH who failed to respond to standard and salvage LCH treatments were referred to our institution for treatment Poster Location #56 of HLH after developing fevers and pancytopenia. Bone marrow biopsies done prior to transfer were notable for marked histiocytic OUTCOME FOR CHILDREN WITH MULTI-SYSTEM LANGERHANS hyperplasia with hemophagocytosis present that were concerning for CELL HISTIOCYTOSIS AFTER USING A LCH II-BASED the development of HLH. Results: Both patients underwent evaluation PROTOCOL IN SHANGHAI, CHINA and were found to have evidence of both multisystem LCH (bone lesions, skin rash, pancytopenia and liver involvement in one patient Yi-Jin Gao, Fang-Fang Wu, Ci Pan, Jing Chen, Jing-Yan Tang and skin lesions, bone lesions and pancytopenia in the other patient) and HLH (fevers, pancytopenia, elevated soluble IL-2Receptor). Shanghai Children's Medical Center, School of Medicine, Shanghai Repeat bone marrow biopsies on both patients after transfer continued Jiao Tong University, Shanghai, China to have marked histiocytic hyperplasia with hemophagocytosis present. The marrow histiocytes were positive for BRAF-V660E by Purpose: This retrospective cohort study analysed the clinical immunohistiochemical staining. Genetic testing on a liver and bone characteristics and outcomes of children with multi-system marrow biopsy sample in one patient and bone marrow and skin Langerhans cell histiocytosis (MS-LCH) using a LCH II modified biopsy sample in the second patient subsequently confirmed the protocol. Methods: From January 2007 to December 2013, 135 presence of BRAF-V660E mutation. Both patients were started on evaluable newly diagnosed patients with histiopathology-confirmed MS Dabrafenib after the immunohistiochemical stain results for BRAF- -LCH in Shanghai Children's Medical Center (SCMC) were enrolled. V660E were reported. Both patients had an excellent response to All patients were treated on the SCMC-MS-LCH protocol, which Dabrafenib with resolution of the HLH within the first month of therapy consisted of 6 weeks of daily prednisone and weekly vincristine and and improvement in their LCH. Both patients remain on Dabrafenib etoposide (initial treatment) followed by 54 weeks of daily 6- monotherapy for treatment of LCH at this time. Conclusion: HLH mercaptopurine with vincristine/prednisone pulse (continuation secondary to LCH with BRAF-V660E mutation can be treated treatment). Results: Of the 135 patients (89 boys and 46 girls), the successfully with Dabrafenib. Our decision to initiate therapy with median age was 3 years (range, 3 months ~14 years). Sixty-nine Dabrafenib was based on results of the immunohistiochemical stain patients (50%) had risk organ involvement with a majority of liver result. The availability of a rapid diagnostic test for the BRAF-V660E disease (83%, 57/69). Rapid response at week 6 was achieved in 72% mutation is clinically useful and can be used in the evaluation and patients with risk organ involvement and 85% patients without risk treatment of LCH patients. organ involvement, respectively (P=0.007). The 3-year event free survival (EFS) and 3-year overall survival (OS) for all cases were Poster Location #58 (62±5)% and (82±4)%, respectively. In univariate analysis, age at presentation (≤2 years), risk organ involvement, and poor response at PRESENTATION OF LANGERHANS CELL HISTIOCYTOSIS IN 9- week 6 were associated with lower survival rates. In multivariate MONTH OLD MONOZYGOTIC TWINS WITH A REVIEW OF THE analysis, age at presentation (≤2 years) was not an independent LITERATURE prognostic risk factor (OR=1.013, P=0.207). There were 36 patients (27%, 36/135) who experienced disease progression or relapse. The Jay Halbert, Harshita Goradia, Amos Burke time to disease progression or relapse ranged from 1 to 25 months from the initial diagnosis (median, 11 months). Significant lower OS Cambridge University Hospitals, Cambridge, United Kingdom (18±3%) was observed in 20 patients with risk organ involvement at progression/relapse. Conclusions: Risk organ involvement and poor Purpose: We present a case of Langerhans cell histiocytosis (LCH) in response at week 6 are the strongest prognostic factors for patients monozygotic twins that contributes to the growing evidence for a with LCH. Second initial treatment for patients with poor response at genetic basis for LCH. Methods: Key features in the presentation of week 6 and effective salvage therapy need to be taken into account in the twins were identified through a retrospective review of the medical our future studies. notes. A search on PubMed was undertaken to identify reported cases of LCH in twins. Results: Monozygotic twin girls presented at 9 months of age with bloody diarrhoea, vomiting, failure to thrive, otorrhoea, mild hepatomegaly and a pigmented non-blanching maculopapular rash on their scalp, abdomen and back. They had anaemia and hypoalbuminaemia secondary to malabsorption. A diagnosis of multisystem LCH in non-risk organs (skin, gastrointestinal and ear) was confirmed by skin and gastrointestinal biopsies which were positive for CD1a, S100, Langerin and the V600E mutation in the BRAF oncogene. First-line therapy was commenced with prednisolone and vinblastine. Both twins had a partial response to this but then had

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progressive disease after re-induction with prednisolone and Poster Location #60 vinblastine with worsening gastrointestinal symptoms (confirmed with reassessment endoscopy), rash and otorrhoea. Treatment was ACRAL SCLEROSING HISTIOCYTIC NODULES: A NEW ENTITY IN intensified with second-line vincristine, prednisolone and cytarabine CUTANEOUS HISTIOCYTOSIS? which is ongoing. During the first four months of therapy the twins have had waxing and waning symptoms. There have been 18 cases of Vinay Keshavamurthy 1, Gitesh U. Sawatkar1, Uma N. Saikia2, monozygotic twins reported on Pubmed over the last 60 years. The Sunil Dogra1 majority of these twin pairs presented simultaneously as infants with similar clinical symptoms and patterns of dissemination. Dissemination 1Department of Dermatology, Venereology and Leprology, of LCH in monozygotic twins to bone marrow, liver and spleen resulted Postgraduate Institute of Medical Education and Research, in death whilst involvement of non-risk organs only had an improved Chandigarh, India prognosis. Conclusion: There is a very high concordance rate for LCH 2Department of Histopathology, Postgraduate Institute of Medical in monozygotic twins and thus early screening is advisable in any Education and Research, Chandigarh, India asymptomatic monozygotic twin. Further studies are needed to understand the genetic basis of LCH. Purpose: The histiocytoses are a heterogeneous group of diseases characterized by accumulation of reactive or neoplastic histiocytes in Poster Location #59 various tissues. Here, we report a case of a recently described and less known non-Langerhans histiocytosis. Methods and result: A A PHASE II TRIAL OF LENALIDOMIDE IN ADULTS WITH middle-aged female presented with gradually progressive, HISTIOCYTE DISORDERS asymptomatic nodules over hands and feet since past two years. On examination, four well defined, skin coloured to erythematous, nodules Eric Jacobsen1, Alyssa Nicotra1, Victoria Patterson1, Robert Redd2, of size 2-3 cm were noted on the palmar surface of the left hand, Barbara Virchick1 involving the proximal and the middle phalanges of the ring and the little finger. The nodules were firm in consistency and were mobile in 1 Department of Medical Oncology, Dana-Farber Cancer Institute, both horizontal and vertical planes. Multiple small nodules of similar Boston, MA, USA morphology were noted over bilateral feet. Skin biopsy showed 2 Department of Biostatistics and Computational Biology, Dana-Farber thinning of the epidermis with effacement of the rete-ridges. Multiple Cancer Institute, Boston, MA, USA sclerotic, non-necrotising, nodular granulomas, palisaded by spindle shaped macrophages and occasional giant cells were seen in the Purpose: Evaluate the efficacy and safety of lenalidomide in adult dermis and sub-cutis. There was no lipid or haemosiderin pigment or patients with Langerhans cell histiocytosis (LCH), histiocytic sarcoma any cholesterol clefts. The vessels were normal and showed no (HS) and Erdheim-Chester disease (ECD). METHODS: Patients 18 or evidence of vasculitis. On immunohistochemistry, these macrophages older with LCH, ECD or HS in need of systemic therapy are eligible. stained strongly for CD 68 but S-100 was negative. There was no Initial lenalidomide dose is 10 mg daily on days 1-21 of a 28 day cycle. evidence of fungal or mycobacterial infection on tissue staining If no grade 3 or greater toxicity occurs during cycle 1 the dose is (Periodic acid-Schiff and modified Ziehl-Neelsen stain), cultures and escalated to 25 mg. The primary endpoint is overall response rate polymerase chain reaction (for fungal and mycobacterial sequence) of (ORR) per Histiocyte Society criteria using MRI and PET/CT . both punch and excision biopsy specimens. Conclusion: Our patient Secondary endpoints are progression free survival, overall survival, shared many histopathological features with spindle shaped and toxicity. Genomic profiling will be performed on most recent biopsy xanthogranuloma, but with prominent sclerosis. Clinically, our case specimen when possible. Results: 8 patients have received at least was multifocal and showed exclusive acral distribution, unlike spindle one dose of study drug. 5 patients have LCH (2 previously untreated, shaped xanthogranuloma, which are solitary, and occurs 1 patient with 1,2 and 3 prior treatments respectively), 2 ECD (0 and 7 predominantly over head and neck and trunk. Because of the distinct prior treatments), and 1 HS (3 prior treatments). All patients are BRAF differences, we suggest this entity as ‘Acral sclerosing histiocytic V600E wild-type. Amongst LCH patients, 3 had multifocal bone nodules' in the non-Langerhans cell histiocytosis group. disease, 1 bone and pituitary, and 1 multifocal pulmonary disease. Patients have completed a median of 3 cycles of treatment (range 0- Poster Location #61 7). The patient with HS progressed and died of disease after cycle 1. One patient with ECD had worsening symptoms after 3 cycles and PITUITARY STALK THICKENING AND DIABETES INSIPIDUS was removed from protocol. Another patient with ECD has stable PROCEEDING TO LANGERHANS CELL HISTIOCYTOSIS disease by imaging but improvement in symptoms and remains on treatment. Amongst the 5 LCH patients, three have no active disease Hande Kizilocak, Nihal Ӧzdemir, Tiraje Celkan (NAD), one has regressive disease, and one has not been radiographically restaged but has had resolution of bone pain. The Istanbul University, Cerrahpașa Faculty of Medicine, Pediatric only grade 3 or higher AEs occurred in a patient with HS who Hematology and Oncology, Istanbul, Turkey experienced grade 3 thrombosis in the setting of progressive disease and eventual death. Conclusion: Lenalidomide is active and well- Langerhans cell histiocytosis (LCH) is a clonal neoplastic proliferation tolerated in adult LCH patients. Enrollment continues. of CD1a-positive Langerhans cells. LCH is one of the most common etiologies of central diabetes insipidus (CDI) associated with thickened pituitary stalk. Purpose: Pituitary stalk thickening in children has also been reported in association with other CNS malignancies and tuberculosis. Here we report a patient with pituitary stalk thickening and diabetes insipidus who was diagnosed with LCH after three months. Results: A 6-year-old boy was referred for the evaluation of polyuria and polydypsia. After a water deprivation test, central DI was diagnosed. In his MRI a mild thickening of the pituitary stalk was reported. No palpable lymph node or organomegaly were detected on physical examination. His bone scan showed no abnormality. Minirin treatment was started for DI. After three months, at his follow-up visit, the physical examination revealed multiple enlarged cervical lymph

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TUESDAY, OCTOBER 18, 2016 • 1445 POSTER PRESENTATIONS - CLINICAL LCH AINSWORTH SUITE nodes. The pathology result of the lymph nodes biopsy was indicative Poster Location #63 of LCH. He underwent chemotherapy with vinblastine and prednisolone according to LCH-III protocol. At the end of the induction THE METRONOMIC CHEMOTHERAPY AND ITS POTENTIAL ROLE therapy patient was in complete remission. However at the first month IN TREATMENT OF HISTIOCYTIC DISORDERS REVISITED IN THE of the continuation chemotherapy, he presented with a mass at the ERA OF CANCER IMMUNOLOGY REVIVAL sublingual gland. This lesion was considered as a new lesion and the patient underwent a second induction chemotherapy. He has no Zdenka Krenova, Jaroslav Sterba evidence of disease after termination of chemotherapy.Conclusion: Thickening of the pituitary stalk might represent a local manifestation Pediatric Oncology Clinic, Brno, Czech Republic of LCH responsible for the DI. It has been shown that DI may precede manifestations of LCH by as long as 15 years. In conclusion, MRI Immune editing properties of cancer cells and immunomodulatory investigation of the pituitary stalk in children with unexplained central significance of non-neoplastic tumor microenvironment have gained a DI, and follow-up in patients with thickening of the pituitary stalk, is huge attention in the recent years. In the present study we explored necessary to avoid missing other manifestations of a systemic the expression of the key checkpoint molecules. Tissue blocks (FFPE) disease. from 25 pediatric cases of Langerhans cell histiocytosis (CLH) were collected from archives o University Hospital Brno. We analyzed Poster Location #62 expression of PD-L1 on tumour cells and we evaluated the presence of CD 3, CD 4 and CD 8 lymphocytes, regulatory T lymphocytes CLINICAL PROFILE AND BRAF STATUS OF ADULT (FOXP3) and NK cells (CD 56). Over 80 % of our tested tissue blocks LANGERHANS CELL HISTIOCYTOSIS IN JAPAN: TEN-YEAR stained positive for PD-L1 on Langerhans cell (tumor LC) in moderate SINGLE INSTITUTION EXPERIENCE to strong rank. No correlation between disease stage/severity and expression of PD-L1 on tumor cells was observed. The population of Masayuki Kobayashi1, Miho Ogawa2, Reina Takeda2, Kiyosumi Ochi2, CD4-positive CD25(high) FoxP3(high) cells was reported to comprise Tomomi Takei2, Toyotaka Kawamata2, Kazuaki Yokoyama2, Nobuhiro 20% of T cells and appeared to be in contact with LCH cells in the Ohno2, Satoshi Takahashi2, Kaoru Uchimaru2, Arinobu Tojo1 lesions. In our study we can confirmed similar results. Our results of the high level of expression of PD-L1 expression in histiocytoses, 1Division of Molecular Therapy, The Institute of Medical Science, The along with the frequent BRAF and other ERK pathway gene mutations University of Tokyo (IMSUT), Tokyo, Japan provide additional support for testing combination therapeutic 2Department of Hematology/Oncology, IMSUT Hospital, Tokyo, Japan approaches, for patients with multisystem and/or refractory forms of histiocytoses. Besides PD-1, PD-L1 blockers, components of Purpose: During the last decade, there has been a significant progress metronomic therapies should be considered here as well, while anti- in the clinical and basic research in Langerhans Cell Histiocytosis angiogenesis is still an important mechanism of action of metronomic (LCH), the latter of which includes an identification of BRAF-V600E as chemotherapy, other mechanisms, including activation of anti-tumor a major driver mutation. However, the clinical profile and treatment immunity and a decrease in acquired therapeutic resistance, have also outcome in adult LCH is still poorly documented. We report here a been identified. We believe metronomic principles should be single-institution analysis of the clinical features of adult LCH. considered in treatment of histiocytoses, in principle already in use Methods: We performed retrospective analysis of 28 patients referred during maintenance therapy in LCH, however proper dosing and to our hospital since 2005. BRAF-V600E was examined by allele- scheduling of drugs in use for LCH requires much more attention and specific quantitative PCR (AS-qPCR) using cell-free DNA (cfDNA) and identification of potential biomarkers that can be used to evaluate also by immuno-histochemical staining of biopsy specimens. Results: such therapeutic approaches. Patient's median age at diagnosis was 43 (range 24-66) and 50% was female. Twelve patients (43%) had a single organ disease (single- Poster Location #64 system; SS) and others had multi-organ disease (multi-system; MS). Bone (50%) and skin (25%) were main lesions in SS-LCH patients, MULTIPLY RECURRENT LCH OF THE SKIN SUCCESSFULLY which were younger (median 39) than MS-LCH patients (median 45). TREATED WITH INDOMETHACIN High-risk organ such as lung, liver, spleen and bone marrow was involved in 8 MS-LCH patients. AS-qPCR analysis of BRAF-V600E Matthew Kutny1, Raymond Watts2 was performed in 21 patients, resulting in positive data in only 5 MS- LCH patients. Twenty-two patients received Japan LCH Study Group 1Department of Pediatrics, Division of Hematology/Oncology, (JLSG) Special C regimen consisting of vinblastine, prednisolone and University of Alabama at Birmingham, Birmingham, AL, USA; methotrexate with daily 6-mercaptopurine, and 3 refractory patients 2Department of Pediatrics, Louisiana State University Health Sciences were followed by 2-CdA as a salvage therapy. During their clinical Center, New Orleans, LA, USA courses, two MS-LCH patients died of LCH progression and a cerebrovascular event, respectively. BRAF-V600E load in cfDNA Purpose: Indomethacin is a nonsteroidal anti-inflammatory that inhibits correlated with the disease progression. Conclusion: Since adult LCH prostaglandin production by cyclo-oxygenase. Langerhans Cell is quite rare, the diagnosis is generally delayed but the prognosis is Histiocytosis (LCH) cells have been shown to produce prostaglandins rather favorable. BRAF-V600E in cfDNA may be under-estimated and stain strongly for cyclo-oxygenase. Prior case reports/series have since significant parts of patients had already received chemotherapy demonstrated activity of indomethacin in LCH involving the bone, and at the blood sampling. Recent findings of MAPK and PI3K pathway here we report its successful treatment of chronic LCH of the skin. mutation in LCH will facilitate the understanding of its pathogenesis Methods: Single case report. Results: This Caucasian male had and future molecular therapy. isolated eosinophilic granuloma of his left orbital rim treated with curettage at age 16 months. At age 6 years he developed a rash on the foreskin of his penis that spread to involve his groin. Skin biopsy showed LCH and diagnostic evaluation was negative for bone/organ involvement. During the subsequent 10 years he received multiple therapies for chronic skin only LCH with recurrence each time he stopped or weaned therapy. His therapies included 24 months of prednisone and vinblastine, cladribine 5mg/m2 daily 5 days/cycle, and both low dose (100mg/m2) and intermediate dose (1000mg/m2) methotrexate. For 6 years his disease was managed with vinblastine

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and mercaptopurine. Eleven months ago he discontinued vinblastine Poster Location #66 but after 2 months of mercaptopurine monotherapy his rash recurred. At the age of 16 years, the decision was made to attempt to transition THE ASSOCIATION BETWEEN ORGAN INVOLVEMENTS AND him to a non-chemotherapeutic regimen and he started indomethacin SURVIVAL IN CHILDREN WITH LANGERAHANS CELL 75mg daily. His rash quickly resolved within a week. After 6 months of HISTIOCYTOSIS; THE RESULTS OF JLSG-96/02 STUDY remission, he stopped mercaptopurine and for over 3 months he has remained disease free on indomethacin monotherapy. Conclusion: Akira Morimoto, Yoko Shioda, Toshihiko Imamura, This unique case demonstrates that even a very chronic and relapsing Yukiko Tsunematsu, Shinsaku Imashuku case of LCH (treated with a decade of chemotherapy) can have an excellent response to indomethacin allowing termination of all Japan LCH Study Group, Kyoto, Japan chemotherapeutic agents. To our knowledge this is the first report of a case of multiply recurrent LCH of the skin demonstrating the efficacy Purpose: Risk organs for pediatric Langerhans cell histiocytosis (LCH) of indomethacin treatment. had been defined as involvement of the liver, spleen, lung, and/or hematopoietic system. Pulmonary involvement was no more an Poster Location #65 independent prognostic factor in the analysis of international study. We analyzed an association between organ involvements at diagnosis RITUXIMAB TREATMENT FOR PATIENTS WITH and survival in children with multisystem (MS)-LCH registered with NEURODEGENERATIVE LANGERHANS CELL HISTIOCYTOSIS JLSG-96/02 studies. Methods: We conducted a retrospective analysis DEMONSTRATING INTELLECTUAL AND PROPRIOCEPTIVE of 206 children with MS-LCH treated with JLSG-96 (59 patients) and DEFICITS JLSG-02 (147 patients). The Kaplan-Myer method with logrank test was used for analysis of the impact of each organ involvement on Kenneth McClain1, Olive Eckstein1, Jay Greenberg2, Ashish Kumar3, survival. Cox proportion hazard model with forward selection method Carolyn Fein Levy4, Thomas Smith5, Brandon Tran6, Carl Allen1 was used for multivariate analysis as covariates including involved organs with p value less than 0.2 by single variable analysis. Results: 1Texas Children's Cancer Center, Houston, TX USA Involved organs at diagnosis were bone (77%), followed by skin 2Childrens National Medical Center, Washington DC USA (68%), lymph node (39%), hematopoietic system (39%), liver (32%), 3Cincinnati Children's Hospital, Cincinnati OH USA spleen (21%), lungs (18%) and thymus (16%). Overall survival (OS) at 4The Steven and Alexandra Cohen Children's Medical Center of New 5 years in all cases was 95.1% (95%CI, 92.2-98.1). OS between York, NY USA patients with and without bone lesions were 96.2% vs. 91.5%, 5The Children's Hospital, Denver, CO USA p=0.176, skin 93.6% vs. 98.5%, p=0.132, lymph node 92.5% vs. 6Texas Children's Hospital Department of Radiology, Houston, TX 96.8%, p= 0.160, hematopoietic system 88.9% vs. 99.2%, p<0.001, USA liver 86.2% vs. 99.3%, p<0.001, spleen 79.1% vs. 99.4%, p<0.001, lungs 94.7% vs. 95.2%, p=0.896, thymus 97.0% vs. 94.8%, p=0.612. Purpose: To determine the role of Rituximab for treating For the multivariate analysis, spleen was the only significant factor neurodegenerative Langerhans cell histiocytosis (ND-LCH). Methods: (hazard ratio 38.2, 95% CI, 4.8-301.6; p<0.001). Conclusions: Lung Chart review of 7 ND-LCH patients treated with Rituximab after having lesions were confirmed not to be related to survival in our cohort. progressive disease on other therapies. The patients were diagnosed Patients with bone lesions tended to have better survival. By the single with LCH at ages 1.8 to 21 years and included 4 males and 3 females. variable analysis, liver, spleen and hematopoietic system lesions were Central Nervous System (CNS) Risk bone lesions occurred in 3/7 and associated with poor outcome, while by the multivariate analysis, only pituitary involvement with diabetes insipidus (DI) in 5/7. The onset of spleen lesion was related to low survival rate. Liver, spleen and ND-LCH ranged from 1 to 10 years after first diagnosis of LCH and 3- hematopoietic system lesions should be defined as risk organs. 11 years after diagnosis of DI. All patients had been previously treated with a variety of drugs including vinblastine/prednisone, cytarabine, Poster Location #67 clofarabine, alemtuzemab, intravenous immunoglobulin, and oral methotrexate. Six patients received Rituximab 375mg/m2 weekly for 4 CO-OCCURRENCE OF LANGERHANS CELL HISTIOCYTOSIS weeks with repeats every 3 months and some continuing monthly AND INTERMEDIATE TYPE OSTEOPETROSIS IN A MALE CHILD infusions. One patient received 555mg/m2 twice a month then 277mg/ m2 every two months. Time between onset of LCH-ND and treatment Maria Moschovi1, Archontis Zampogiannis1, Ioannis Nikas2, Evangelia with Rituximab ranged from 1-15 years with a median of 7.5 years. Charmandari3, Helen Fryssira4 Responses were assessed for behavior/learning/intellectual change and ataxia/tremors/proprioception. Results: Three patients 1Hematology/Oncology Unit, 1st Department of Pediatrics, National demonstrated remarkable improvement in intellectual/behavior and Kapodistrian University of Athens, Pediatric Oncology Unit findings after 6 months of Rituximab treatments and sustained this “Marianna V Vardinoyannis-Elpid”, “Agia Sophi” Children's Hospital, with monthly infusions. Four patients had no change in these areas. Athens, Greece Assessment of ataxia/tremors/proprioception revealed 2 patients had 2Imaging Department, “AGIA SOPHI”• Children's Hospital, improvement in proprioceptive deficits, 3 patients had improvement of Athens, Greece ataxia and tremors and 1 decreased dysphagia. One patient had no 3Division of Endocrinology, Metabolism and Diabetes, First response. Conclusion: Rituximab treatment results in improved Department of Pediatrics, National and Kapodistrian University of intellectual/behavior/proprioceptive deficits of some patients with ND- Athens Medical School, “AGIA SOPHI”• Children's Hospital, LCH. Patients with ataxia and choking who have not responded to Athens, Greece other therapies may benefit from Rituximab infusions. Monthly 4Department of Medical Genetics, National and Kapodistrian infusions may provide the optimal response. The mechanism of University of Athens, “AGIA SOPHI”• Children's Hospital, response is unknown but may be from decreased LCH-ND-associated Athens, Greece inflammation. A possible role for autoantibodies in ND-LCH remains speculative. Introduction: The skeletal system is the most frequently affected organ by Langerhans Cell Histiocytosis (LCH). The vertebral column is one of the most common sites of osseous involvement. Bone lesions are typically osteolytic and have a variable and often unpredictable behavior. The Erdheim-Chester disease (ECD), a non-Langerhans Histiocytosis, is characterized by osteosclerosis, but there are no

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TUESDAY, OCTOBER 18, 2016 • 1445 POSTER PRESENTATIONS - CLINICAL LCH AINSWORTH SUITE reports of osteosclerosis in LCH unless there is a coexistence of LCH Poster Location #69 with ECD. In this case report, we describe the co-occurrence of intermediate type osteopetrosis and an osseous lytic lesion in a child LANGERHANS CELL HISTIOCYTOSIS FOLLOWING BURKITT with LCH. Case Description: An 11-year-old boy presented with left LYMPHOMA shoulder pain without a history of an injury. Radiological evaluation with plain radiography and CT revealed a lytic lesion with a fracture in Nihal Ozdemir1, Hande Kizilocak1, Aylin Canpolat2, Tiraje Celkan1 the T4 vertebral body and a soft tissue mass. A biopsy was performed and the immunohistochemichal analysis revealed CD1a and S100- 1Istanbul University, Cerrahpasa Medical Faculty, Istanbul, Turkey positive Langerhans cells Histiocytosis. The BRAF (V600E) gene 2Medeniyet University, Goztepe Research and Training Hospital, mutation was detected. The patient had a known history of Istanbul, Turkey osteopetrosis, confirmed by DEXA Scan. The presence of osteopetrosis also in two other siblings, in combination with the Introduction: Proliferation of Langerhans cells may rarely occur in absence of the disease in both parents, indicates that the association with other lymphoproliferative disorders. Langerhans cell osteopetrosis was inherited with an autosomal recessive pattern. histiocytosis (LCH) may precede or follow lymphoid malignancies. Discussion: This case report is the first report of the co-occurrence of Here we present a child who developed LCH following Burkitt LCH with osteopetrosis-intermediate type, inherited with the autosomal leukemia treatment. Case: A 2-year-old male patient who presented recessive pattern. Osteopetrosis in LCH may denote a common with a mandibular mass was diagnosed as Burkitt /lymphoma. Sixteen pathway, between LCH and ECD. months after the end of maintenance treatment, he presented with a left submandibular lymphadenopathy at primary lesion site. Positron Poster Location #68 emission tomography (PET) showed submandibular lymphadenopathy (SUD-max 5.6) with a focal lytic lesion at the mandibula and nodal NATIONAL WEB-BASED MEETINGS HELP TO IDENTIFY biopsy revealed LCH. He received LCH-III protocol including HISTIOCYTOSIS PATIENTS WITH REFRACTORY DISEASE OR prednisolone and vinblastine chemotherapy. However, there was no SEQUELAE WHO NEED INDIVIDUALISED OR NOVEL response to initial induction. After the 2. induction, he was in complete TREATMENT STRATEGIES remission. One year after the end of maintenance, he presented with left ankle pain after trauma. A tru-cut biopsy showed LCH recurrence. Vasanta Nanduri1, Maria Michelagnoli2, Varun Sudunagunta3, The lesion was totally resected after low-dose radiotherapy He has Bhumita Vadgama4, Venetia Bigley5, Simon Bomken5, Matthew been followed up with no evidence of disease for eight months now. Collin5, Rachael Holmes6, Johannes Visser6 Conclusion: Studies have demonstrated a clonal relationship between histiocytic and/or dendritic cell and lymphoid neoplasms occuring in 1Watford General Hospital, Watford, UK the same patient. A subset of cases of histiocytic/dendritic cell 2University College London Hospital, London, UK proliferations that occur with other lymphoproliferative neoplasms may 3Imperial College Medical School, London, UK represent evolution of a common neoplastic clone. There are few 4University Hospital Southampton, Southampton, UK reports of LCH in patients with leukemia or lymphoma. Care and 5Newcastle University, Newcastle, UK treatment of these cases are challanging with a high risk of secondary 6Leicester Children's Hospital, Leicester, UK neoplasms. Further studies may bring light into the possible clonality in these subjects. Purpose: Describe the experience of using a national web-based forum to support local decision-making in challenging histiocytic Poster Location #70 disorders. Methods: The UK Histiocytosis Special Interest Group introduced regular advisory group meetings using a web-based CLINICAL COURSE OF CHILDREN WITH SINGLE SYSTEM BONE application with the ability to share imaging and clinical information. LANGERHANS CELL HISTIOCYTOSIS (LCH) Clinicians who approach the group for advice are invited to the meeting to present their case. This allows for an interactive discussion Vassilios Papadakis1, Loizos Petrikkos1, Kondilia Antoniadi1, with multidisciplinary group members (paediatric and adult Vasiliki-Sotiria Tzotzola1, Vassilios Dendrinos1, Efthymia Rigatou1, haematologists/ oncologists, pathologist and radiologist). Consensus Kalliopi Stefanaki2 and Sophia Polychronopoulou1 advice is provided and written outcome produced for the referring clinician. Results: Over a period of 2.5 years, 25 meetings were held 1Department of Pediatric Hematology-Oncology, “Aghia Sophia”• for cases from 16 institutions. There were 35 case discussions on a Children's Hospital, Athens, Greece total of 29 patients: 23 Langerhans cell histiocytosis (LCH), 3 juvenile 2Department of Pathology, “Aghia Sophia”• Children's Hospital, xanthogranuloma and 3 others (1 presumed LCH, 1 disseminated Athens, Greece atypical tuberculosis and 1 diagnosis unknown). The median age was 7 years (5 months to 46 years), with an equal number of children and Purpose: To describe the experience on single system (SS) bone adults, but only 1 teenager. Of the LCH patients, there were 9 bone, 1 involvement in a cohort of children with LCH treated in single center. skin, 3 central nervous system (CNS), 6 multisystem risk organ Methods: Within a cohort of 37 LCH-patients (median age 5.56 years, negative and 4 multisystem risk organ positive. 20%(7) of range 0.01-15.89 years, males/females ratio 1.47) diagnosed from discussions dealt with refractory/progressive disease, 17%(6) with 1983-2016 and treated according the series of LCH protocols, we reactivation and 23%(8) with sequelae. The other 40% (14) of analyzed the data of patients with SS bone lesions (BLs). Twenty- discussions covered a range of treatment/diagnostic questions. Three three out of 37 (62%) patients (median age 6.81 years - range 1.24- LCH patients were identified to meet criteria for salvage chemotherapy 15.89, males/females ratio 1.56), presented with SS-bone with cytarabine and cladribine. Three patients were identified as involvement: 20 unifocal and 3 multifocal (one with 3-BLs and two with appropriate candidates for rescue treatment with BRAF inhibitors (one 4-BLs). The 20 patients with unifocal-bone LCH were biopsied and on the dabrafenib trial and two on vemurafenib, off label). Advice on curettaged (five with intra-lesional steroid injection); 15/20 patients the monitoring for, and treatment of, a range of sequelae were offered, were followed up (5 with CNS-risk-lesion in retrospect) while 5/20 the commonest being CNS sequelae. Conclusion: This patients received VBL/PDN treatment for 6-12 months due to special multidisciplinary forum provides an opportunity for clinicians to learn site (femoral head 2, vertebrae 2, mandible 1). The 3 patients with from the experience from a range of institutions and helps develop bone-multifocal LCH (all with CNS-risk-lesion) received 12-months individualised treatment plans in challenging clinical scenarios. VBL/PDN treatment (1 patient <2 years/old). Diabetes insipidus was present only in 1/23 (4.34%) patient with multifocal bone disease. Results: Seventeen of 20 unifocal-bone LCH patients remained in

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remission (5 following treatment). Three out of 20 (15%) patients Poster Location #72 eventually relapsed, 2 as unifocal-bone disease and 1 with multisystem disease. One patient with unifocal-bone relapse is in CR2 CLINICAL PRESENTATION, MANAGEMENT AND OUTCOME OF (without additional systemic therapy); another patient with unifocal- LANGERHANS CELL HISTIOCYTOSIS (LCH) IN CHILDREN bone relapse received VBL/PDN treatment for 6-months, had second unifocal-bone relapse and is presently in CR3 following 12-months of Loizos Petrikkos1, Vassilios Papadakis1, Vasiliki-Sotiria Tzotzola1, Ara-C treatment; the 3rd patient with multisystem relapse remains in Kondilia Antoniadi1, Vassilios Dendrinos1, Efthymia Rigatou1, CR2 following VP16/PDN/AraC/VCR treatment. All 3 single-system Kalliopi Stefanaki2 and Sophia Polychronopoulou1 multifocal-bone patients are alive; 2 in CR1 and 1 in CR2, following 2- CdA treatment for CNS-relapse (pituitary-stack thickening). Overall, 19 1Department of Pediatric Hematology-Oncology, “Aghia Sophia”• of 23 patients remain in CR1 with total-cohort OS 100%. Conclusion: Children's Hospital, Athens, Greece Patients with SS-bone-LCH have benign course and excellent survival, 2Department of Pathology, “Aghia Sophia”• Children's Hospital, provided appropriate therapeutic maneuvers are applied, especially Athens, Greece following relapse. Purpose: To present the clinical characteristics, management and Poster Location #71 outcome of a cohort of children with LCH treated in one center. Methods: Thirty-seven patients (22 males, 59%) with histologically PROGRESSIVE ISOLATED PITUITARY STACK THICKENING IN proven LCH, diagnosed during 1983-2016, with a median age of 5.56 PATIENTS WITH DIABETES INSIPIDUS: MANAGEMENT years (range 0.01-15.89 years), and treated according to LCH DILEMMAS protocols are presented. Single-system unifocal: Twenty (20/37) single -bone lesion patients were biopsied and curettage; fifteen (15/20) Vassilios Papadakis1, Elpis Vlachopapadopoulou2, patients only followed up (5/15 with CNS-risk-lesion, in retrospect); five Ioannis-Anargyros Vasilakis3, Paraskevi Kazakou3, Vassilios Petrou2, (5/20) patients received VBL/PDN treatment for 6-12 months due to Evangelia Charmandari3, Sophia Polychronopoulou1 special site (femoral-head 2, vertebrae 2, mandible 1). One (1/37) patient with pituitary only biopsy-proven LCH, received Ara-C/iv-IgG 1Department of Pediatric Hematology-Oncology, “Aghia Sophia”• for 12 months for possible neurodegeneration. Single-system Children's Hospital, Athens, Greece multifocal: Three (3/37) patients had single-system bone multifocal 2Department of Endocrinology- Growth and Development, “P & A CNS-risk+ disease and all received 12-months VBL/PDN treatment Kyriakou”• Children's Hospital, Athens, Greece (one patient <2 years-old). Multi-system LCH: was diagnosed in 13/37 3Division of Endocrinology, Metabolism and Diabetes, First (35%) with a median age of 1.31 years (range, 0.01-10.47, nine Department of Pediatrics, National and Kapodistrian University of patients <2 years-old) while 8/13 had risk-organ (RO) involvement Athens Medical School, “Aghia Sophia”• Children's Hospital, (lung 2, liver 1, lung/BM 1, lung/liver 1, liver/spleen 1, liver/spleen/BM Athens, Greece 1, liver/spleen/BM/lung 1). Diabetes insipidus was present in 5/37 (13.5%), 3/5 with CNS-risk lesions, 1/5 as the only manifestation. Purpose: Patients with isolated hypothalamic/pituitary mass are Results: Seventeen (17/20) patients with single-bone lesion remain in biopsied in our Center, in the absence of other cranial, bonny, remission while 3/20 patients relapsed either with bone-only disease hypochondrial or skin lesions and if CSF/serum markers for germ cell (2/3) or with Multi-System disease (1/3) (all alive, in CR2=2, CR3=1). tumor, infections and other diagnoses are unrevealing. Biopsy is not Three single-system multifocal-bone patients are in CR1=2 and always feasible to guide management. We describe two such patients CR2=1. Five RO(-) multisystem patients remain in CR1=4 or CR3=1. and the use of oral prednisolone (PDN) (LCH-mode of administration) Eight RO(+) patients remain in CR1=5, 1 deceased, 1 in CR4 and one for treatment. Patients: Case 1: A prepubertal 5.9 year-old girl on induction treatment. No secondary malignancies were observed. Of presented with polyuria, polydipsia and decreased growth velocity. note 11 patients were <2 years-old; 9/11 are in CR1, 1 deceased with Endocrinologic evaluation revealed diabetes insipidus, central progressive disease, 1 on treatment. Twenty-eight (28/37) patients hypothyroidism, growth hormone insufficiency and ACTH deficiency. remain in CR1 (EFS: 76%) with total-cohort OS 97.3%. Conclusion: Serial MRI scans showed spherical widening of the mid-pituitary stalk, Careful staging and appropriate LCH treatment stratification remains increasing from 4.5 to 6.9 mm 10 months later. She received PDN 40 the cornerstone for the best outcome. mg/m2/daily for 2 months and then 5-day pulses q2 weeksx7 and q3 weeks for a total of 12 months treatment. Within 3 and 12 months, the Poster Location #73 pituitary stalk measured 4.6 and >3 mm and remains >3 mm 9 months off treatment. Patient is 14 months off treatment on follow up. Case 2: REVISITING THE NEUROPATHOLOGY OF CENTRAL NERVOUS A prepubertal 9.3 year-old girl presented with diabetes insipidus and SYSTEM LANGERHANS CELL HISTIOCYTOSIS 5.6x4.5mm upper pituitary stalk widening. Following 6 weeks 40 mg/ m2/daily PDN treatment MRI images remained unchanged, but the Jennifer Picarsic1, Geoffrey Murdoch1, Rikhia Chakraborty2, pituitary stalk decreased to 4.2x3.5mm following additional 6, 3-day Fernando Castro-Silva3, Ashok Panigrahy4, Ronald Jaffe1, weekly PDN pulses. The patient continues on 5-day q3 weekly PDN Kenneth McClain2, and Carl Allen2 pulses. Results: Iatrogenic Cushing was evident in both patients. Surgical intervention was never performed. There was appropriate 1University of Pittsburgh School of Medicine, Pathology Department, response with diminishing pituitary stalk measurements in both Pittsburgh, PA USA patients. No evidence of neurodegeneration is seen, thus far. 2Baylor College of Medicine, Texas Children's Cancer Center, Conclusion: Biopsy driven, pathology confirmed diagnosis and Houston, TX USA treatment is advisable. Alternatively, in patients that surgery is not 3Cook Children's Medical Center, Fort Worth, TX USA feasible and following extensive, repeated staging, careful PDN LCH- 4University of Pittsburgh School of Medicine, Radiology Department, type treatment can be advised. Prompt response was observed in our Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA USA patients, that is highly suggestive but not confirmatory for LCH diagnosis and careful follow-up is warranted. Purpose: The histologic pattern of Langerhans cell histiocytosis (LCH) within the brain parenchyma is still not well understood. A better understanding of the central nervous system (CNS)-LCH histologic pattern may provide insight to the pathogenesis of neurodegenerative (ND) CNS-LCH lesions. Methods: Three illustrative examples of CNS parenchymal involvement are described with clinicoradiographic

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TUESDAY, OCTOBER 18, 2016 • 1445 POSTER PRESENTATIONS - CLINICAL LCH AINSWORTH SUITE correlation. Results: In two cases with active CNS-LCH, a distinct Poster Location #75 perivascular pattern of LCH cells is noted. There was an inflammatory and hypervascular response in the surrounding brain parenchyma. CLINICAL USE OF BRAF MUTATIONS PROFILE IN LCH Case 1, a basal ganglia biopsy, showed Langerin positive perivascular PATIENTS FOR DIAGNOSIS AND MONITORING OF TREATMENT cells and a surrounding destructive macrophage rich response. The RESPONSE patient had diabetes insipidus (DI) for three years. A MRI showed a small hypodense T1-weighted, intermediate T2W right basal ganglia Vicente Santa-Maria, Veronica Celis, Carmen de Torres C, lesion with extensive surrounding edema. Case 2 showed extensive Jaume Mora cerebellar involvement of LCH with a perivascular predilection and a robust hypervascular, fibrotic inflammatory injury response with Hospital Sant Joan de Déu, Barcelona, Spain demyelination. The lesion was BRAF-V600E positive. The patient had multisystem LCH with DI. A MRI showed heterogeneously enhancing Purpose: Langerhans cell histiocytosis (LCH) is a heterogeneous masses in cerebellum. Case 3 was a CD1a negative, CD68 positive disease with common activation of the MAP-kinase signaling pathway. xanthomatous histiocytic and demyelinating process in the cerebellum BRAF mutations are the most frequent alterations and their detection with dilated perivascular/Virchow-Robbin spaces filled with foamy in peripheral blood (PB) and bone marrow (BM) could be both macrophages and white matter macrophages positive for the BRAF diagnostic and marker of treatment response. The aim of this study is VE1 antibody. MRI was significant for T2 hyperintense foci throughout to describe the institutional experience with the clinical use of BRAF the posterior fossa and brain stem with progressive cerebellar and mutations. Methods: BRAFV600E was analyzed by Competitive Allele- brain stem atrophy, with clinicoradiographic correlation suggestive of Specific TaqMan® PCR on tissue biopsies from 17 newly diagnosed ND CNS-LCH. Conclusion LCH, a myeloid inflammatory neoplasia, LCH patients (January 2014-February 2016). BRAF exon 15 was appears to gain entry into the brain similar to primary CNS analyzed by Sanger sequencing in V600E negative cases. In patients lymphomas, with an angiocentric proliferation expanding the Virchow- with positive biopsies, BRAFV600E was then used as a marker in Robin perivascular cuffs, with subsequent invasion into neural circulating free DNA (PB) and in DNA isolated from BM mononuclear parenchyma or subarachnoid spaces. A unique pattern in active CNS- cells. Results: 14 single system (SS) and 3 multi-system (MS) LCH LCH appears to be the surrounding hypervascular-fibrotic patients were diagnosed. BRAFV600E was detected in 9/14 evaluable inflammatory response. In ND-CNS-LCH, a CD1a-negative, BRAF biopsies and no differences in outcome were found. In two patients mutant precursor cell could be a reservoir cell driving a smoldering management was performed according to mutation profile. A 3 months inflammatory/ demyelinating response. old female with SS-LCH but detectable BRAFV600E in PB and BM was treated as MS-LCH (as per LCH-IV protocol) and progressed on Poster Location #74 treatment. A 3 months old male with BRAFV600E MS-LCH had a MS with organ risk disease reactivation while on maintenance treatment. CLADRYBINE TREATMENT IN PATIENTS WITH PULMONARY Both patients were rescued with 2-cda plus cytarabine. Follow-up and LANGERHANS CELL HISTIOCYTOSIS response were assessed with standard tests and PB and BM BRAFV600E. A correlation between molecular and clinico-radiological Elzbieta Radzikowska, Elżbieta Wiatr, Katarzyna Błasińska-Przerwa, response was found. Both patients currently remain with no evidence Renata Langfort, Kazimierz Roszkowski-Śliż. of disease being monitored for minimal residual disease (MRD) in PB and BM. Conclusion: BRAF mutations were found in most of our LCH National Tuberculosis and Lung Diseases Research Institute, patients without differences in outcome. Determining BRAF mutations Warsaw, Poland in PB and BM proved extremely useful to monitor treatment response. The implementation of MRD monitoring and treatment adaptation in Purpose: Pulmonary Langerhans cell histiocytosis (PLCH) is a rare LCH should be formally evaluated in large cooperative studies. disorder caused by proliferation of CD1a-positive myeloid derived dendritic cells forming granulomas within lung parenchyma. Strong Poster Location #76 association with tobacco smoking in adult cases was shown. Despite that smoking cessation can induce regression of the disease but FREQUENCIES OF GENETIC ALTERATIONS IN KOREAN variable effects on outcome have been observed. Cladribine (2-CdA) CHILDREN WITH LANGERHANS CELL HISTIOCYTOSIS has been proved in treatment of multi-system Langerhans cell histiocytosis and isolated PLCH, however the number of cases is still Jong Jin Seo1, Kyung-Nam Koh1, Sung-Min Chun2, Sung Han Kang1, small. Material: During the period of 4 years, 11 patients (6 females/5 Hyeri Kim1, Jong Jae Kim2, Ho Joon Im1 males; aged 37-55 years,) with LCH with lung involvement (9 multi system and 2 single system) treated with 2-CdA were included in to Center Children's Hospital, University of Ulsan College of Medicine, the study. Patients received 2 to 6 courses of 2-CdA (mean 5.3) in a Seoul, Korea dose of 0.15 mg/kg per day/ iv. for 5 consecutive days at monthly 1Division of Pediatric Hematology/Oncology, Department of Pediatrics intervals. Results: Treatment resulted in improvement or stabilisation 2Department of Pathology, Asan Medical, Seoul, Korea of pulmonary function parameters in 4(36%) and 7(64%) patients respectively. Two patients with bone lesions, one with abdominal Purpose: This study aimed to evaluate the frequency and prognostic changes and one woman with infiltration in vertebra and in periaortic correlation of the genetic alterations in Korean children with space experienced partial regression.Treatment related toxicities Langerhans cell histiocytosis (LCH). Methods: Genomic DNA was were: upper respiratory tract infections grade 2 in 7(64%) patients, and extracted from formaldehyde-fixed and paraffin-embedded samples grade 3 in 2(18%), leukopenia grade 3 in 1(9%), grade 2 in 3(27% ) from the patients who were pathologically confirmed with LCH and patients, lymphopenia grade 2 in 7(64%), and grade 3 in 2(18%) treated at Asan Medical Center. Profiling of somatic mutations for 41 patients, thrombocytopenia grade 2 in 1(9%), grade 4 in one(9%) critical genes related to tumor development was performed using patient, anaemia grade 4 and 2 in one(9%) patient. There was no case OncoMap version 4.4-Core under the MassARRAY technology of LCH progression. During the time of follow-up period (one year after platform (Sequenom, San Diego, CA). Results: A total of 37 LCH finishing the treatment) one patient suddenly died and other one cases were evaluated. A median age at diagnosis was 5.2 years developed chronic melogenic leukaemia. Conclusion: Cladribine as a (range, 0.1-55.8 years). Thirty-one patients had single system disease single agent is effective therapy in adult patients with progressive (18 with unifocal bone disease, 11 multifocal bone disease, 2 with skin PLCH but was mainly resulted in stabilization of pulmonary function. disease), and 6 had multisystem disease (4 without risk organ Myelosuppression, and pulmonary infections were the most important involvement, and 2 with risk organ involvement. OncoMap assay adverse events. revealed that 19 (51.3%) harbored BRAF mutation, and 12 (32.4%) MAP2K1 mutation. One patient had both BRAF and MAP2K1 WWW.HISTIOCYTESOCIETY.ORG 67

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mutations. Other recurrent mutations included MAP3K1 (n = 7), Poster Location #78 CHEK2 (n = 7), MLH1 (n = 6), MET (n = 5), RICTOR (n = 5), ALK (n = 4), ATM (n = 4), BRD4 (n = 4), KDR (n = 4), TET2 (n = 4), and TSC1 REACTIVATION AND LONG-TERM OUTCOME OF PEDIATRIC- (n = 4) mutations. BRAF mutation was significantly more frequent in ONSET LANGERHANS CELL HISTIOCYTOSIS; 50 YEARS' patients with unifocal bone disease (13 of 18 patients, 72.2%, P = EXPERIENCE AT A SINGLE CENTER 0.013) than in others. Other mutations were not significantly associated with organ involvement. The 3-year relapse-free survival Yoko Shioda1, Yukiko Tsunematsu1, Chikako Kiyotani1, (RFS) was 84.6%. RFS was not different according to genetic Tomoo Osumi1, Daisuke Tomizawa1, Motohiro Kato1, mutation. Conclusions: Our study showed that BRAF and MAP2K1 Keita Terashima1, Osamu Miyazaki2, Michiko Tatsuno3, mutations can be frequently demonstrated in pediatric LCH, while Takako Yoshioka3, Atsuko Nakazawa3, Kimikazu Matsumoto1 other critical genes related to tumor development were also detected, but less frequently. The result suggests that genetic mutations do not National Center for Child Health and Development Tokyo, Japan predict the severity of the disease. 1Children's Cancer Center 2Department of Radiology Poster Location #77 3Department of Pathology

REPORT OF 2 RARE CASES OF LANGERHANS CELL Background: The survival rate of Langerhans cell histiocytosis (LCH) HISTIOCYTOSIS(LCH) WITH SEVERE PALPEBRAL has reached to more than 90%. However, approximately 40% of LCH INVOLVEMENT cases with multiple lesions suffer reactivation, which may occur several times in some cases. Although, reactivation in risk organs is Bibi Shahin Shamsian1, Mohammad Taghi Arzanian1, rarely observed and mortality is minimal, it might significantly increase Mohammad Naderi Sorki1, Ahmad Mohammadi Ashianeh1, the risk of permanent consequences. Recently, association of BRAF Leili Mhajerzadeh2, Maryam Kazemi Aghdam3 mutation with increased risk of reactivation is reported. To clarify the long-term prognosis of reactivated cases, we investigated their clinical 1Pediatric Congenital Hematologic Disorders Research Center, Mofid features and outcome. Patients and Methods: A retrospective review Children's Hospital, Shahid Beheshti University of Medical Sciences, was conducted on 134 LCH cases who was diagnosed pathologically Tehran, Iran and received medical care at the National Center for Child Health and 2Pediatric Surgery Research Center, Mofid Children’s Hospital, Development (formerly, National Children's Hospital) between 1966 Shahid Beheshti University of Meical Sciences, Tehran, Iran and 2016. The median observation period of all patients was 6.8 years 3Pathology Research Center, Mofid Children's Hospital, Shahid (range, 0.1-36.4 years). Results: Reactivation occurred in 48 of 121 Beheshti University of Medical Sciences, Tehran, Iran evaluable patients (40.0%): five or more times in 20 cases. Most reactivation episodes (77.1%) occurred within the first 2 years after Introduction: Langerhans cell histiocytosis (LCH) can affect different diagnosis. The 5-year probability of reactivation were as follows: organs. However, LCH with palpebral involvement is a rare 62.7%±12.5% in multi-system disease, 41.2%±23.3% in single- presentation. Here we present 2 cases of multisystemic LCH with system multifocal bone, 8.8%±11.8% in unifocal bone (p<0.01). BRAF palpebral involvement. Case 1: A 6 month old boy was admitted in V600E and V600D mutation was analyzed in 32 patients, and was our hospital in 1998. He had history of macula-papular rash at age of detected in 12 out of 18 patients with multi-system disease. However, 4 month, then palpebral lesions in both eyes with mucopurlent 5-year probability of reactivation was not statistically significant among discharges. Physical exam showed maculopapular skin rash, these cases. Serious permanent consequences such as diabetes palpebral ulserative lesions and left eye cloudiness. Bone survey was insipidus, anterior pituitary hormone deficiency, and normal but CT revealed destructive lesion in left mastoied bone. neurodegenerative cerebellar lesions were observed in 21 (17.4%), 10 Biopsy of skin lesion and immunohistochemistry (IHC-CD1a) was (8.3%), and 7 (5.8%) cases, respectively. Discussion and compatible with LCH. Treatment including Vinblastin, Prednisone (3 Conclusions: Since LCH is a rare disease with various clinical month), then oral maintenance therapy with 6MP and Metotraxate presentations and possible permanent consequences, the analysis of (MTX) were done for 1 year. Surgery was done for palpebral repair long-term observations is valuable. It is necessary to determine and left eye lensectomy duo to cataract . Now he is 18 years old and optimal therapeutic strategies and risk factors of reactivation he is good. Case 2: An 18 months old boy, from Iraq was reffered to prospectively to improve curability and to prevent reactivation and our hospital in 2016 duo to fever, papulo- vesicular skin rash, both permanent consequences. upper and lower palpebral lesions since 8 month ago. Physical exam showed generalized papular rash also in palmar of hand and foot, Poster Location #79 nail involvement, lymphadenopathy, massive hepatomegaly, splenelomegaly and icterus. Lab tests; Increasing level of liver CHEST CT IMAGING FEATURES IN PEDIATRIC PULMONARY function tests. Bone survey: multiple lytic lesions. CT of neck, chest, LANGERHANS CELL HISTIOCYTOSIS: ALVEOLAR abdomen: Bilateral lymphadenopathy, lymphadenopathy of right CONDENSATION AS A POSSIBLE MANIFESTATION OF THE paratracheal, Hepatomegaly with multiple hypodense lesions, DISEASE retroperitoneal lymphadenopathy. Histopathology and IHC report of Skin and Nail biopsy: LCH. Treatment: Vinblastin , prednisone, also Valeria Della Valle1, Chiara Sileo1, Jessica Kabla2, Vp16. After 3 month inspite of marked improvement, still he had Mohamed Aziz Barkaoui2, Ralph Epaud3, Hubert Ducou Le Pointe1, persistant massive hepatomegaly and icterus. So treatment of 2- Jean Donadieu2 chlorodeoxyadenosine (2CDA) was started. Conclusion: In palpebral involvement should be considered the differential diagnosis of 1Radiology Department, Hôpital Trousseau, APHP, Paris, France ophthalmic disease of LCH in children. 2Centre de référence des Histiocytoses, Registre des histiocytoses, Hémato Oncologie Pédiatrique, Hôpital Trousseau, APHP, Paris, France 3Service de Pédiatrie Générale Hôpital Inter communal de Créteil, Créteil, France

Purpose: The aim of this study was to described a peculiar But reccurent aspect observed on chest computed tomography (CT) in pediatric pulmonary Langerhans cell histiocytosis (PLCH). Methods:

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Among 1763 pediatric patients with LCH diagnosis enrolled in the Poster Location #81 French National database for langerhans cell histiocytosis, until April 2016, 167 patients have been diagnosed with PLCH. 146 chest CT BRAF V600E MUTATION IN PEDIATRIC LANGERHANS CELL scans, collected at various time of disease course, of 48 patients could HISTIOCYTOSIS AND ITS CLINICAL SIGNIFICANCE be retrospectively and independently reviewed by a panel of 4 observers composed by 3 pediatric radiologists and 1 pediatric hemato Dong Wang, Rui Zhang, Hong-yun Lian, Hong-hao Ma, Chao Gao, -oncologist. Results: In addition to well known radiological aspect of Tian-you Wang, * Li Zhang PLCH, such as cyst and nodules, we found alveolar condensation in *Corresponding author 12 patients (25%), 5 (17%) of them were presented at diagnosis and 7 on subsequent scans. 5/12 (45%) of these patients presented a pre- Hematology Oncology Center, Beijing Children's Hospital, Capital existing, concomitant or subsequent nodular or cystic lesion. None of Medical University, Beijing, China them showed signs of infection at BAL examination or any improvement after a treatment with a standard antibiotic therapy while Purpose: The objective of this study was to investigate the BRAF they did show regression under the LCH regimen of chemotherapy. All V600E mutation in pediatric patients with langerhans cell histiocytosis patients with such lesions exhibited a disseminated LCH profile with (LCH) and its clinical significance. Methods: A retrospective analysis involvement of risks organs and the diagnosis confirmation was was performed in LCH patients registered between January and established on skin or lung, while in most of the cases, December in 2014 at a single institute. We detected BRAF V600E thrombocytopenia contradicts a lung biopsy. Conclusion: In addition to mutation in pathological specimens and serum of patients by next the well known aspects of PLCH (nodules and cysts), alveolar generation sequencing (NGS). Statistical software SPSS18.0 was condensation was found in 25% of our patients. It was considered as used for data analysis and processing. Results: BRAF V600E mutation LCH related since it was not associated with infections and because of was found in 68% pathological specimens and 59% serum, with 42 its favorable outcome under standard LCH chemotherapy and thus cases (52%) double positive, 15 cases (19%) double negative, 23 could be considered as a possible manifestation of PLCH in children cases (29%) single positive. The correlation was analyzed between with RO+ involvement. groups with or without BRAF V600E mutation in patients' age, gender, clinical group, involved organs, initial therapy response (after 5 weeks) Poster Location #80 or relapse. The results did not show significant relevance, with P values 0.737,0.06,0.718,0.727,0.739,0.879 between seropositive and PULMONARY LANGERHANS CELL HISTIOCYTOSIS IN seronegative groups, P values 0.303,0.88,0.519,0.728,0.088, 0.065 CHILDREN: CT IMAGING FEATURES IN A COHORT OF 48 between pathological positive and negative groups, and P values PATIENTS WITH LUNG INVOLVEMENT AND PROPOSAL OF 0.329,0.718,0.526,0.487,0.367,0.176 between double positive and SCORING negative groups. Conclusions: There was high positive rate of BRAF V600E mutation in Chinese pediatric patients with LCH, which Valeria Della Valle1, Chiara Sileo1, Jessica Kabla2, supports that LCH is a clonal disease. The research did not find Mohamed Aziz Barkaoui2, Ralph Epaud3, Hubert Ducou Le Pointe1, relevance of BRAF V600E mutation in clinical manifestation, treatment Jean Donadieu2 response and prognosis of LCH children. Negative results may due to the small sample size of this study. Sample size remains to be 1Radiology Department, Hôpital Trousseau, APHP, Paris, France expanded in further research. 2Centre de référence des Histiocytoses, Registre des histiocytoses, Hémato Oncologie Pédiatrique, Hôpital Trousseau, APHP, Poster Location #82 Paris, France 3Service de Pédiatrie Générale Hôpital Inter communal de Créteil, LANGERHANS CELL HISTIOCYTOSIS: A 30-YEAR BRAZILIAN Créteil, France EXPERIENCE

Purpose: To describe the chest Computed tomography (CT) scan Anna Beatriz Willemes Batalha, José Cordoba , Raquel Toscano, findings of pulmonary Langerhans cell histiocytosis (PLCH) in Isis Magalhães childhood. Methods: We have reviewed 146 chest CT scan of 48 patients. The CT scans were collected at various time of disease Hospital da Crianca de Brasília, Brasilia, Brazil course and were independently reviewed by a panel of 4 observers. For each CT scan a semiquantitative analysis was performed for Purpose: To describe the varied presentations of children with nodular opacities and cystic abnormalities. Results: Among the 48 Langerhans Cell Histiocytosis (LCH), the clinical course and treatment patients, CT scan was performed at diagnosis in 29 . Of 29 patient outcome. Methods: Retrospective analysis of data on 45 newly evaluated at diagnosis, 18 patients (62%) presented with nodules, 13 diagnosed children, aged 1 -18 years with histopathologically- patients (45%) presented with cysts and 6 patients (21%) presented a confirmed LCH, followed at Brasília's Public Health System , Brazil, combination of both nodular and cystic lesions. On the initial CT scan, over a period of 30 years. All patients were treated on the LCH median nodules total score was 1 (range 0-12) and median cysts total protocols (LCH I -II- III - IV protocol). Results: There were 45 children score was 0 (range 0-20). If we consider the "worst" CT scan observed with LCH between 1986 and 2016. The age ranged from 12 mo to 18 at any time of the follow up in the 48 patients, almost the same years (median: 6 years). Third one children were male. Multisystem proportion of patients with nodules (30 patients, 62 %) was found but disease was documented in 19 (42.2%) children and there were 2 we observed an increase proportion of patients with cysts (30 (4.4%) cases of pulmonary LCH. There were 2 (4.4%) deaths occurred patients, 62 %) and median nodules total score was 1 (range 1-12) in patients with multisystem disease. Diabetes insipidus was the most and median cysts total score was 2 (range 0.-24). The distribution of common sequela. There were 9 patients (20%) who experienced the scores was very asymmetric for a total number of patients with relapse. Conclusions: The clinical manifestations of Langerhans cell nodule score and cyst score >5 (the severe form) of 14 patients (29%) histiocytosis vary widely, with a high relapse rate and low mortality and 19 patients (40%) respectively. The distribution of nodules and rate. cysts was symmetric in the upper, medium and lower fields with an involvement of costo-phrenic angles in 68% of the cases. Conclusion: A semiquantitative score for nodular and cystic lesions on chest CT scans is a useful tool in pediatric PLCH, otherwise extremely difficult to objectively assess. Lung bases were frequently involved in children contrary to adult PLCH.

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Poster Location #83 and 31 months of follow-up. Two patients died of progressive disease after 1 month of follow-up. Laboratory parameters of macrophage NEURODEGENERATIVE LANGERHANS CELL HISTIOCYTOSIS: activation syndrome were not found in the charts. Four autopsies were ARE PEDIATRIC THERAPIES EFFECTIVE IN THE ADULT performed: complete (2), restricted to abdominal cavity (1) and partial POPULATION? (1). Several organs were affected by the presence of LCH: lymph nodes (3/4), spleen (2/4), lungs (2/3), liver (1/4), and bone marrow Debra Wong1, Brenda Ernst1, Donald Northfelt1, Tom Fitch 1,2, (1/2). The microscopic features of LCH cells were typical: no Robert Arceci3, John Camoriano1 pleomorphism was seen and mitotic rate was virtually absent. All cases had profuse macrophage activation, mostly evident in lymph 1Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, nodes, spleen, and liver. One patient had sclerosing cholangitis and AZ USA fibrosing pancreatitis, with no LCH cells. Alveolar diffuse damage was 2Division of Palliative Medicine, Mayo Clinic, Phoenix, AZ USA present in 3/3 examined lungs. Reticulin fibrosis, hemophagocytosis 3Children's Center for Cancer and Blood Disorders, Phoenix and emperipolesis, were present in 2/2 bone marrow samples. Children's Hospital, Phoenix, AZ USA (Posthumous inclusion to Conclusions: Autopsy is a very important tool; it can show the real acknowledge significant contributions to this case) affectation of different organs by LCH, as well as some consequences not directly related to the presence of the cells, like sclerosing Purpose: Neurodegeneration in Langerhans cell histiocytosis (LCH) of cholangits. Fibrosing pancreatitis was a completely unexpected the central nervous system is an uncommon but ominous occurrence. association. Optimal therapy remains unclear and there is a paucity of data on the efficacy of pediatric therapies in adults with neurodegenerative LCH. Methods: A 62-year-old male Veteran with primary biliary cirrhosis, diabetes insipidus, and hypogonadism presented with erythematous NOTES plaques on his scalp, biopsy-proven as LCH. Staging revealed bony lucencies and cystic lung disease. Methotrexate and topical corticosteroids were initiated. Disease remained stable approaching 2y, but then he developed diplopia, ataxia, dysarthria, and emotional

lability. Brain MRI revealed diffuse enhancement in the pons, with extension into the midbrain, cerebellar peduncles, and dentate nuclei, consistent with neurodegenerative LCH. The patient was started on subcutaneous cladribine 0.5mg/kg daily for 5 days on 28-day cycles with intravenous immunoglobulin (IVIG). Results: Interval brain MRI showed improvement, and his symptoms lessened over ensuing months. After 7 cycles of cladribine, the patient was continued on monthly IVIG with ongoing neuropsychiatric improvement. There is no standard of care for neurodegenerative LCH. Cladribine, low-dose cytarabine, and clofarabine have demonstrated activity in pediatric patients with CNS involvement. Similarly, IVIG has been shown to slow progression of ataxia in children. Patients such as ours, with multisystem LCH and endocrinopathies suggestive of pituitary involvement, should have brain imaging to detect abnormalities prior to symptom onset. However, it is unclear whether initiating treatment at the appearance of abnormal MRI findings, in the absence of symptoms, limits neuropsychiatric complications. Conclusion: Our patient's response warrants further research into the efficacy of this regimen and other pediatric therapies in adult populations with

neurodegenerative LCH.

Poster Location #84

AUTOPSY RESULTS IN MULTISYSTEM LANGERHANS CELL HISTIOCYTOSIS (LCH)

Guido Felizzia, Laura Galluzzo, Jorge Braier

Hospital Nacional de Pediatria Dr JP Garrahan, Buenos Aires, Argentina

Purpose: To analyze post-mortem findings in patients with risk multisystem Langerhans Cell Histiocytosis (LCH). Methods: We collected 4 autopsies of patients with risk multisystem LCH from our institution. We reviewed the available tissue, routine stains and immunostains, which were repeated when necessary. LCH diagnosis was based on morphology and positivity for CD1a. Clinical charts were also examined. Results: Median age at diagnosis was 12 months. Diagnosis was established by skin biopsy in all the cases. Three cases had bone involvement. Hematologic (bicytopenia or tricytopenia) and hepatic involvement with hypoalbuminemia was evident in all the cases. Only one patient had lung involvement. All patients were treated according to Histiocyte Society protocols. Two patients partially responded to treatment but then died of progressive disease after 11

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Poster Location #85 months of follow-up, further reduction was noted on MRI scan. Conclusion: This patient with multisystem JXG showed good response JUVENILE XANTHOGRANULOMA AND JUVENILE of skin, liver and spleen to vinblastine and dexamethasone. His MYELOMONOCITIC LEUKEMIA ASSOCIATION IN THREE intracranial lesion showed an encouraging response (25-30% PEDIATRIC PATIENTS reduction) to clofarabine and cytarabine which has continued post treatment. Guido Felizzia², Agustín González Correas1, Andrea Candás2, Laura Galluzzo3, Julio Goldberg³, María Marta Bujan4, Jorge Braier2, Poster Location #87 Gabriela Sciucatti2, Raquel Staciuk1 ERDHEIM CHESTER DISEASE - UNUSUAL PRESENTATION OF A Hospital Garrahan, Buenos Aires, Argentina RARE HISTIOCYTIC DISORDER IN A 3 YEAR OLD BOY 1Bone Marrow Transplantation Department 2Hematology / Oncology Department Muhammad Shamvil Ashraf, Muhammad Rafie Raza, 3Pathology Department Muhammad Rahil Khan 4Dermatology Department Indus Children Cancer Hospital, Kirachi, Pakistan Juvenile Xanthogranuloma (JXG) and Juvenile Myelomonocitic leukemia (JMML) association has been previously reported. We Purpose; To report an unusual presentation of Erdheim Chester describe this association in 3 pediatric patients. Two of them also had Disease(ECD) in a very young boy treated with interferone. Case clinical diagnosis of Neurofibromatosis type 1 (NF1). Age at diagnosis Report: A three year old boy presented with proptosis ,skull swellings, was 11, 19 and 23 months and the follow-up was 1 month, 6 years polyuria and polydipsia for one and half years. Baseline labs were and 3 months respectively. Two patients underwent allogeneic normal. Clinical and radiological findings were favouring Langerhan hematopoietic stem cell transplantation (HSCT) and both presented cell histiocytosis with skeletal survey showing multiple osteolytic failure of engraftment with JMML relapse at 11 and 33 months post- lesions in skull and workup for polyuria was consistent with diabetes transplant. Both patients had chronic graft-versus-host-disease insipidus. MRI Brain showed abnormal signal intensity lesions (GVHD) with severe cutaneous involvement. One of them underwent a bilaterally in calvarium, orbit and clivus , multiple soft tissue sub- second HSCT and he is still in remission. The patient who do not calvarial lesions and large periorbital masses bilaterally. Biopsy underwent a HSCT is receiving treatment with hypomethylating agents revealed fibrocollagenous tissue displacing sheets of foamy histiocytes until availability of a stem cell donor. In our institution, six patients with exhibiting foamy multivacuolated cytoplasm. Immuniohistochemistry JMML underwent HSCT. The two patients with JXG presented severe results showed CD 1a, S100, CD 30 negative and CD 163, CD 68 chronic cutaneous GVHD with relapse of JMML. Patients with diffuse positive in histiocytes. Based on classical clinical picture initially presence of JXG lesions must be carefully studied for JMML and a he received LCH III Protocol with Desmopressin spray. After initial correct long term follow up must be done for this disease. More cases response to treatment his symptoms worsened. Histopathology and will be required to determine a relationship between the presence of literature were reviewed and diagnosis of Erdheim Chester Disease JXG in patients with JMML who received a HSCT and chronic ( ECD ), was made. Further work up with Echo, hormonal levels( LH, cutaneous GVHD with failure of engraftment and relapse of JMML. FSH) and CT Chest were normal. X-ray of leg did not show any sclerotic changes. BRAF mutation tests was also reported positive Poster Location #86 from a lab in France. He received alpha Interferon along with vinblastine, steroids and 6 mercatupurine. Initially Interferon was given SYSTEMIC JUVENILE XANTHOGRANULOMA WITH A LARGE 3million units/m2day 3 times a week for 1 year and as it was tolerated INTRACRANIAL MASS: RESPONSE TO CLOFARABINE AND well so increased to 9 million units/m2 three times a week for another CYTARABINE 1 year. He is alive, 2.5 year from diagnosis and on no treatment since last 4 month. The proptosis and skull lesions have improved. MRI also Ron Anderson, Marie-Anne Brundler, Mehmet Albayram, Tony Truong showed marked Improvement with some residual disease. He has stable disease, no major side effect of interferon and better routine Alberta Children's Hospital; University of Calgary, Calgary, AB Canada activities. To our knowledge this is the youngest patient with ECD.

Purpose: We describe a patient with systemic juvenile Poster Location #88 xanthogranuloma (JXG) with a large intracranial mass which showed reduction in size with clofarabine and cytarabine therapy. Method: A ROSAI-DORFMAN DISEASE- OUR EXPERIENCES FROM A case report. Results: This patient was known prenatally to have SINGLE CENTRE macrocephaly and at 2 days of age MRI scanning showed a large extraaxial intracranial frontal mass. Soft tissue lesions were noted in Ferdousi Begum1, Afiqul Islam2, ATM Atiqur Rahman3 the skin of the left eyebrow, over the right scapula and on the left thigh. The thigh mass was excised and pathology showed 1Pediatric Oncology Department, National Institute of Cancer mononuclear rounded cells with Touton-type cells distributed Research and Hospital, Dhaka, Bangladesh throughout. Staining was positive for CD68 and occasionally S100. 2Pediatric Hematology and Oncology Department, Bangabandhu The final diagnosis was JXG. While waiting for diagnostic Sheikh Mujib Medical University, Dhaka, Bangladesh confirmation, the eyebrow and back lesion spontaneously regressed 3Pediatric Hematology And Oncology Department, Bangabandhu but were still present. At 2 months of age however sunsetting of his Sheikh Mujib Medical University, Dhaka, Bangladesh eyes was noted as well as hepatosplenomegaly. Neurosurgical intervention was judged too risky given the lesions' proximity to the Background: Rosai-Dorfman disease (RDD) is a rare, sporadic superior saggital sinus. Initial chemotherapy was given as per LCH-III histiocytic disorder characterized by painless but protracted with 12 weeks of vinblastine and dexamethasone. The lymphadenopathy. Its etiology remains unknown. It is believed that hepatosplenomegaly regressed, with resolution of all skin lesions, but 70% to 80% of patients have spontaneous improvement of symptoms there was no response of the intracranial mass. Four cycles of without treatment, although they may have alternating episodes of clofarabine followed with a small reduction in size of the intracranial worsening and relieving of symptoms for a long period of time. Some mass. Four further cycles of clofarabine plus cytarabine were given. patients with severe or persistent disease or cases where organ MRI scanning showed 25-30% reduction in the mass size since function is threatened (such as breathing obstruction or kidney failure) starting clofarabine. No further treatment was given and after 10 may require treatment with surgery, steroids, and/or chemotherapy.

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Ideal treatment, however, has not been established, and there is no histiocytic infiltrate in this patient suggests that myeloid neoplasms and ongoing clinical trial. Methods: The Prospective observational study ECD may arise from a shared myeloid progenitor cell. done from june 2013 to December 2016 at pediatric oncology department of Banga Bandhu Sheikh Medical University, Dhaka, Poster Location #90 Bangladesh. We have only three cases, included consecutively. RDD was diagnosed by characteristic histopathological findings, NEXT-GENERATION DNA SEQUENCING-BASED MUTATION Emperipolesis with S-100 immunohistochemical staining. Trial was PROFILING IDENTIFIES KRAS MUTATIONS IN ERDHEIM- given by observation, surgery and or chemotherapy. Results: We CHESTER DISEASE have total 3 cases with age group of 3 to 9 years. All were male and all the patients presented with cervical lymphadenopathy. Two patients Tejaswini Dhawale1, David Wu2, Colin Pritchard2, had bilateral cervical lymphadenopathy. In addition, one of the those Gordon A Starkebaum3 and Paul Hendrie1 two patients had mediastinal lymphadenopathy and other had enlarged adenoid with sleep apnoea and suffering from conductive 1Division of Hematology/Oncology, University of Washington, Seattle, deafness. Among three, one child is being followed up after surgical WA, USA excision of node. Another two child were treated with steroid and 2Department of Laboratory Medicine, University of Washington, vincristine, LCH like treatment. But responses were poor. So, Seattle, WA, USA cyclophosfamide given two course, then maintenance continued with 3Division of Rheumatology, University of Washington, Seattle, low dose steroid and 3 weeky vincristine.One child of 9 years now WA, USA cured and second one is on maintenance therapy. Conclusion: The disease not always runs a benign course and treatment nedded Purpose: Next-generation DNA sequencing can aid the diagnosis and from steroids, to cytotoxic chemotherapy with variable outcomes. treatment of histiocyte disorders. We evaluated two patients using our There should be a uniform guideline for treatment. institutional platform for sequencing of 262 cancer-related genes. In each patient, we identified an activating mutation in KRAS, neither of Poster Location #89 which has been reported in ECD. Method: Patient #1: A 54-year old female presented with fatigue, fevers, weight loss, lower extremity CHRONIC MYELOMONOCYTIC LEUKEMIA CLONALLY RELATED edema and pancytopenia. CT imaging revealed bilateral paraspinal TO CONCURRENT ERDHEIM CHESTER DISEASE masses and a left pararenal mass. A bone scan demonstrated diffuse abnormal uptake in the appendicular skeleton. Patient #2: A 49-year Tejaswini Dhawale1, Emily Glynn2, David Wu2, Daniel E. Sabath2, old gentleman presented with a prolonged history of fibroxanthomas Yi Zhou2, Christina Lockwood2, and Paul Hendrie1 involving his skin, larynx, femur and tibia. The patient did not have erosive arthritis. A bone scan revealed increased radiotracer uptake in 1Division of Hematology/Oncology, University of Washington, Seattle, bilateral distal upper and lower extremities. A diagnosis of WA, USA disseminated juvenile xanthogranuloma (JXG) versus progressive 2Department of Laboratory Medicine, University of Washington, nodular histiocytosis (PNH) was considered. He received treatment Seattle, WA, USA with intermittent surgical excision and corticosteroid injections in addition to systemic methotrexate and adalimumab. Result: Patient #1: Purpose: Chronic myelomonocytic leukemia (CMML) is an aggressive A renal-mass biopsy revealed a diffuse atypical histiocytic infiltrate. hematopoietic stem cell neoplasm characterized by peripheral blood Immunohistochemical stains were positive for CD163, CD68, IgG4, monocytosis, bone marrow dysplasia, cytopenias and S100 and negative for CD1a. The diagnosis of ECD was made. hepatosplenomegaly. We describe a patient with CMML and Erdheim- Molecular analysis of bone marrow detected a mutation in KRAS Chester Disease (ECD), a rare non-Langerhans cell histiocytosis. (NM_004985.3:c.38 G>A, p.G13D) and no mutation in BRAF, NRAS Molecular evaluation of the patient's leukemia and histiocyte-infiltrated or PIK3CA. Patient #2: A skin biopsy revealed large histiocytic cells tissue suggests an association between these disorders. Method: with intervening fibrosis, multinucleated Touton giant cells and foamy Mutation profiling was performed on the patient's blood and macrophages. Molecular analysis detected mutations in KRAS pericardium using our institutional platform for sequencing of 262 (NM_004985.3:c.34 G>C, p.G12R) and no mutation in BRAF, NRAS cancer-related genes. Results: A 67-year-old gentleman presented or PIK3CA. The patient was clinically reclassified as having ECD and with fatigue, lower extremity edema, pleural effusions, a pericardial belonging to the Langerhans group of histiocytoses. Conclusion: We effusion, and retroperitoneal fibrosis encasing the kidneys. A describe two activating KRAS mutations undescribed in ECD and retroperitoneal biopsy revealed fibroblastic spindle cells without IgG4- illustrate the utility of molecular testing in the diagnostic evaluation of positive plasma cells. Peripheral blood counts revealed neutrophilia histiocytoses. Our results further support the pathogenic role of RAS (ANC 14.8k/ul) and monocytosis (11k/ul) without circulating blasts. pathway aberrations in ECD. Bone marrow examination demonstrated a hypercellular marrow (80%) with increased granulocytic and monocytic cells and Poster Location #91 morphological abnormalities in the granulocytes consistent with CMML. He initially improved with prednisone, but developed MENINGEAL LANGERHANS CELLS SARCOMA CASE REPORT worsening pleural and pericardial effusions resulting in hypercarbic respiratory failure and intubation. A bone scan revealed abnormal Blanca Diez, Bernadette Calabrese, Sebastian Cerrato, uptake in bilateral proximal and distal long bones and PET/CT showed Alejandro Muggeri, Oscar Alvarez , Naomi Arakaki diffuse abnormal FDG uptake in the pericardium, pleura, retroperitoneum, mesentery and bone. On biopsy, the pericardial Fleni ( FundaciόPara La Lucha De Enfermedades Neurolόgicas De La tissue contained clusters of foamy histiocytes positive for CD68, Infancia), Buenes Aires, Argentina CD163, and Factor XIIIa and negative for S-100 on immunohistochemistry. Molecular profiling of the peripheral blood and Introduction: Neoplastic proliferations of Langerhans cells are pericardial tissue showed identical mutations in BRAF (V600E), classified by the WHO into Langerhans cells histiocytosis (LCH) and SRSF2 (P95H) and a frameshift deletion in TET2. Within 48 hours of Langerhans cells sarcoma (LCS). LCS is a rare malignant tumor and starting BRAF-targeted therapy with vemurafenib the patient was no primary meningeal involvement has been described. Materials and extubated and experienced significant reduction in his leukocytosis. Methods: A 36-year-old male patient came to the emergency service Unfortunately, he expired shortly thereafter from sudden cardiac suffering from pain in the right side of his face, his physical arrest. Conclusion: Myeloproliferative neoplasms can co-occur with examination was normal. A meningeal right frontal extra-axial lesion ECD. The discovery of identical mutations in leukemic blood and the with calvaria infiltration by contiguity was identified on MRI. Result:

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Exeresis of the lesion wax perfomed. The histopathological findings nervous system. Notably, the neuropathology in ECD closely mimics showed a population of atypical cells with pelomorfic nuclei, isolated multiple sclerosis, potentially leading to underdiagnoses. cells with characteristic nuclear grooving, scattered eosinophils and lymphocites. Positive inmunoreaction for CD1a, CD68 and S100 and Poster Location #93 BRAF V600E mutation lead to the meningeal Langerhans Cell Sarcoma LCS diagnosis. He was treated with 6 cycles of cladribine ANAKINRA AS EFFICACIOUS THERAPY FOR INTRACRANIAL and citarabine and evaluated with PET/CT that did not show evidence ERDHEIM-CHESTER DISEASE IN A CHILD of disease. Conclusions: The histological presentation LCS is similar to (LCH) however malignant transformation of LCH to LCS is unusual, Mark Fluchel1, Eli L. Diamond2, Omar Abdel-Wahab3,4, Lynn Brody5, attributing its origin to the myeloid lineage .The cells are distinguished Maria Arcila6, Christian Bowers7 by their invasive behavior , dysplasia and increased mitotic activity as well as identification of immunohistochemical markers CD 1a ( + ) , 1Department of Pediatrics, Hematology-Oncology, University of Utah, S100 ( + ) , CD21 (- ) CD35 (-) and CD68 (- ). Another tool is electron Primary Children's Hospital, Salt Lake City, UT USA microscopy that provides evidence of cytoplasmic Birbeck granules 2Department of Neurology, Memorial Sloan Kettering Cancer Center, that although some sarcomas do not have, positivity is conclusive. New York, NY USA SCL reports with meningeal involvement unusual. The primary risk 3Leukemia Service, Department of Medicine, Memorial Sloan factor for SCL is immunodeficiency. The treatment is a combination of Kettering Cancer Center, New York, NY USA tumor excision followed by chemotherapy. Recently reported studies 4Human Oncology and Pathogenesis Program, Memorial Sloan showed that BRAF v600E gene mutation helps to determine response Kettering Cancer Center, New York, NY USA and prognosis and eventually positive patients can be treated with 5Department of Radiology, Memorial Sloan Kettering Cancer Center, BRAF inhibitors. New York, NY USA 6Department of Pathology, Memorial Sloan Kettering Cancer Center, Poster Location #92 New York, NY USA 7Department of Neurosurgery, University of Utah, Salt Lake City, THE NEUROLOGIC MANIFESTATIONS OF ERDHEIM CHESTER- UT USA DISEASE Purpose: Erdheim Chester Disease (ECD) is a rare histiocytic Juvianee Estrada-Veras1, Louisa C. Boyd1, Rahul H. Dave2, disorder, often diagnosed in middle-aged adults, which affects a Kevin O'Brien1, William Gahl1 variety of tissues. Due to its rarity and variable presentation, no standard therapy exists. Steroids, chemotherapy, immunotherapy with 1Section of Human Biochemical Genetics, Medical Genetics Branch, interferon and, more recently, cytokine inhibition, have been utilized National Human Genome Research Institute, NIH, Bethesda, with variable success. Central Nervous System (CNS) ECD has MD, USA proven particularly challenging. Methods: We present a case of CNS 2Viral Immunology and Intravital Imaging Section, Neuroimmunology and bone ECD, in a young child, which demonstrated a marked Branch, National Institute of Neurological Disorders and Stroke, NIH, response to Anakinra. Results: A 7 year-old boy presented with Bethesda, MD, USA lethargy, dizziness, hearing loss, anisocoria and left facial palsy. MRI revealed hydrocephalus and an extensive, multi-centric, enhancing Purpose: To characterize the neurologic manifestations of Erdheim- tumor in the inter-hemispheric, cavernous sinus and suprasellar Chester Disease (ECD), an ultra-rare non-Langerhans cell regions. Biopsy was initially interpreted as Juvenile Xanthogranuloma. histiocytosis. Clinical presentation ranges from asymptomatic to multi- After tumor debulking and brainstem decompression, followed by systemic involvement of CD68+, CD163+, CD1a-, CD207-, S100+/-, seven months of observation, the tumor progressed and the patient and anti-factor XIIIa+ foamy macrophages accumulating in bone, experienced a seizure. The lesions were unresponsive to 6 weeks of kidneys, retroperitoneum, orbits, pituitary stalk, and the nervous vinblastine and prednisone, 6 monthly cycles of cladribine and two system. The neurologic manifestations are incompletely described as cycles of clofarabine, while his seizures persisted. Considering his case reports and small series. Methods: Prospective, observational refractory disease, a diagnosis of ECD was considered. A skeletal study of 60 patients with biopsy-confirmed ECD (NIH protocol 11-HG- survey demonstrated bilateral sclerosis in the extremities. Biopsy of a 0207). Evaluation included neurologic assessment, MRI (brain, orbit, tibial bone lesion demonstrated a BRAF-V600E mutation by VE1 pituitary), neurophysiologic testing (electromyogram & nerve antibody staining, confirming ECD. Within three months of starting conduction studies), and other studies as clinically indicated in addition Anakinra monotherapy, the CNS lesions demonstrated decreased to a comprehensive medical evaluation. Results: 87% of patients enhancement followed by slow, but continual improvement in dural exhibited neurologic symptoms or signs, and 96% had radiographic thickening and lesional enhancement over two years. While the most disease. 15% of the patients present with neurologic symptoms. recent MRI evaluation shows residual areas of signal abnormality and Manifestations included cranial neuropathies and brainstem dural enhancement, there has been dramatic improvement since involvement (55%), mild cognitive impairment (48%), cerebellar ataxia initiating Anakinra monotherapy. The patient has been seizure-free for (40%), peripheral neuropathy (43%), visual impairment (25%) and over one year. Osseous surveys showed resolution of the sclerotic seizures (8%). MRI revealed central nervous system parenchymal bone lesions over two years. Conclusion: We report a rare case of lesions (70%), dural involvement (8%), generalized atrophy (33%), ECD with CNS involvement in a child, initially misdiagnosed as JXG, infundibulum thickening (23%), and empty sella syndrome (6%). and for whom Anakinra has provided a robust response. Parenchymal brain lesions had ill-defined borders, minimal displacement, and no edema. Enhancement was observed in brain parenchyma (18%; heterogenous), meninges (8%) and optic nerves (2%). Compressive masses were seen in soft tissue structures around the brain, including extra-ocular muscles (contributing to proptosis and gaze palsies), peripheral nerves, optic nerves, and scalp. Biopsy of CNS lesions revealed histiocyte accumulations in multiple patients. Conclusions: This study has broadened the spectrum of neurologic disease in ECD and demonstrates the import of careful neurologic assessment in these patients. Neurologic dysfunction is a common cause of increased mortality in ECD and occurs throughout the

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Poster Location #94 vision, who was admitted to our centre with a tumour 38x42x40mm in size, located in anterior cranial fossa, found on CT scans performed at MENINGEAL ROSAI-DORFMAN DISEASE WITH A STRUCTURAL a local hospital. A bifrontal craniotomy with macroscopic tumour BREAKPOINT OF PROTEIN TYROSINE PHOSPHATASE resection was performed. Histiocytic sarcoma, juvenile RECEPTOR TYPE D TUMOR SUPPRESSOR GENE xanthogranuloma phenotype (confirmed by Prof R. Jaffe) was diagnosed. Disease staging was performed - routine laboratory tests, Chelsea Gawryletz1, Bernard R. Bendok2, Alyx Porter3, bone marrow biopsy and imaging studies (spinal MRI, bone scan, Aditya Raghunathan4, Sameer Keole5, Thomas Colby6, chest CT, abdominal ultrasound) showed no pathology. MRI of the John Camoriano1 brain after surgery, revealed no lesions in the frontal lobes, no residual tumour but a thickened and hyperintensive dura mater adjacent to the 1Department of Hematology, Mayo Clinic Phoenix, AZ USA operated area. Considering malignant character of the disease and 2Department of Neurosurgery, Mayo Clinic Phoenix, AZ USA microscopic tumour residual in the central nervous system (CNS), 3Department of Neuro-Oncology, Mayo Clinic Phoenix, AZ USA adjuvant chemotherapy with EPOCH protocol alternating with ICE 4Department of Neuro-Pathology, Mayo Clinic, Rochester, MN USA chemotherapy was implemented. Intrathecal MTX and HC was also 5Department of Radiation Oncology, Mayo Clinic Phoenix, AZ USA administered. After four cycles of chemotherapy, patient underwent 6Department of Pathology, Mayo Clinic Phoenix, AZ USA radiotherapy. He continued chemotherapy (ICE/EPOCH), receiving a total of 11 cycles. At present the patient is in complete remission 18 Purpose: To report a case of a structural breakpoint of protein tyrosine months from diagnosis. No neurological deficits are observed. Since phosphatase, receptor type D tumor suppressor gene in Rosai- there is no established protocol for histiocytic sarcoma ( especially Dorfman disease. Methods: Genomic DNA extracted from the patient's with primary in the CNS) we have combined a chemotherapy based blood and formalin fixed paraffin-embedded (FFPE) tumor sample. regimen (EPOCH) for lymphoma with ICE protocol and radiotherapy, Isolated DNA prepared using custom SureSelect XT Target which are a part of some protocols for CNS malignancies. Clinical Enrichment System (Agilent technologies). Libraries clustered on flow trials are warranted to establish optimal treatment for this disease. cell and sequenced using Illumina HiSeq 2500 instrument with 100bp paired-end reads. Sequence data analyzed using bioinformatics tools Poster Location #96 (Ashion pipeline version 2.0). Reference genome NCBI GRCh37. Results: A previously healthy 38 year old pre-menopausal right- A CASE OF CONCURRENT OCCURRENCE OF ERDHEIM- handed woman from Kuwait presented with a 6-month history of CHESTER DISEASE AND LEUKEMIA IN A CHILD bifrontal headaches and two episodes of transient vertigo associated with left-sided numbness and tingling. MRI brain demonstrated Joon Pyo Hong1, Won Ki Ahn1, Joo Yeon Lim1, Jo Eun Jung1, bilateral pachymeningeal enhancement with parenchymal T2 and Seung Min Hahn2, Jung Woo Han2, Chuhl Joo Lyu2 FLAIR hyperintense nonenhancing mass measuring 16.8 x 26 x 20.5mm in the right frontal lobe anteriorly. Lumbar puncture showed 1Department of Pediatrics, Yonsei University College of Medicine, elevated protein and negative infectious tests. Biopsy of the right Seoul, Korea frontal dura demonstrated lymphoid infiltrate with scattered large 2Division of Pediatric Hematology and Oncology, Department of histiocytes, CD-68 and S-100 positive by immunohistochemistry Pediatrics, Yonsei University College of Medicine, Seoul, Korea staining, with emperipolesis, or engulfment of inflammatory mononuclear cells by histiocytes. Patient was initiated on high-dose Erdheim-Chester disease (ECD) is a rare non-Langerhan's cell steroids with resolution of headache. She was transitioned to histiocytosis disorder characterized by replacement of normal tissue Azathioprine, tolerating it well for over 10 months without progression by lipid-laden histiocytes affecting various organs, showing wide range of disease. Molecular profiling was performed and identified a of manifestations. Its usual onset is in the middle age, however, a few structural breakpoint of Protein tyrosine Phosphatase, receptor type, D pediatric cases have been reported. Here we present a child with (PTPRD) tumor suppressor gene. Loss of PTPRD causes constitutive leukemia who was diagnosed as ECD. A 2-year and 11-month old activation of STAT3 and activation of aurora kinase A. We are male patient who was diagnosed with high risk acute lymphoblastic considering therapeutic options including anti-STAT3 or IGF-R leukemia (ALL) at the age of 17 months, received unrelated peripheral monoclonal antibody to attempt to achieve prolonged remission of blood stem cell transplantation in July, 2015, at the age of 2 years old. disease. We are also considering proton beam therapy. Conclusions: His transplantation underwent successfully, however bone marrow This is the first reported case of a structural breakpoint of protein study just before and after transplantation showed aggregations of tyrosine phosphatase, receptor type D tumor suppressor gene in epithelioid histiocytes and foamy macrophages suggesting histiocytic Rosai-Dorfman disease. disorder. There were no other symptoms or signs of histiocytic disorder, hence we decided to follow-up bone marrow study. Six Poster Location #95 months after the transplantation, the patient was admitted to hospital with fever, lower eyelid swelling and palpable left calf nodules. HISTIOCYTIC SARCOMA OF THE CENTRAL NERVOUS SYSTEM. Paranasal sinuses computed tomography showed suspicious lesion CASE REPORT suggesting orbital cellulitis and a 1.8cm sized exophytic mass lesion at inferior orbital wall. Bone marrow study was done to exclude leukemic Olga Gryniewicz-Kwiatkowska, Olga Rutynowska, or malignant involvement and the result again suggested ECD without Wiesława Grajkowska, Katarzyna Nowak, leukemia with complete chimerism status. Excisional biopsy at left calf Bożenna Dembowska-Bagińska nodule showed ‘aggravation of non-Langerhan's cell type epitheloid histiocytes with CD163+, CD68+, and BRAF mutation (+)'; clinically Children's Memorial Health Institute, Warsaw, Poland suggestive of ECD. The patient started to be treated with vinblastine and corticosteroid. This case is a very unusual report of an ECD Histiocytic sarcoma is a rare non-Langerhans histiocyte disorder, with occurred in a pediatric patient who was being treated with ALL. no specific treatment regimen established so far. It's prognosis is poor. Recurrent RAS and PIK3CA mutations have found in ECD patients, There are some reports on high-risk leukaemia protocol used in and some malignancies including acute leukemia might have close histiocytic sarcoma, but only few such cases were published. Due to relationship with ECD. However, the exact pathogenesis of concurrent the rarity of this disease, each case should be confirmed in an occurrence of ALL and ECD is remained to be discovered. experienced pathological centre. We present a case of a 16-year old male, with 10-day history of acute headache and 2 days of double

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Poster Location #97 the skin lesions reflected clinical improvement. No significant adverse effects were encountered. Conclusion: Imatinib, a selective protein ERDHEIM-CHESTER DISEASE IN A TODDLER GIRL tyrosine kinase inhibitor having anti-proliferative and immunomodulatory effects on various cells, demonstrated an Sonia Silva1, Leonor Barroso2, Joana Serra-Caetano3, encouraging response in our case and can be considered a useful Maria José Julião4, Manuel João Brito1 treatment option for XD.

1Servico de Oncologia Pediátrica do Hospital Pediátrico do Centro Poster Location #99 Hospitalar e Universitário de Coimbra, Coimbra, Portugal 2Servico de Cirurgia Maxilo-facial do Centro Hospitalar e Universitário DISSEMINATED JUVENILE XANTHOGRANULOMA (DXJ) IN de Coimbra, Coimbra, Portugal ADOLESCENT; CASE REPORT 3Unidade de Endocrinologia, Diabetes e Crescimento do Hospital Pediátrico do Centro Hospitalar e Universitário de Coimbra, Coimbra, Fernando Werneck, Fernando Sellos, Patrícia Moura, Portugal Vanessa Campos, Ludmilla Parente 4Servico de Anatomia Patológica do Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal Hospital Estadual da Crianҫa, Rio de Janeiro, Brazil

Erdheim-Chester disease (ECD) is a rare systemic non-Langerhans Purpose: DXJ is a rare non- Langerhans cell histiocytosis (LCH) , with histiocytosis that affects multiple organ systems. It occurs more often a male predominance and age mean at presentation in infancy. We in adults and paediatric ECD is extremely rare. The diagnosis can be describe a female adolescent with extensive disease at diagnosis. established based on clinical presentation and imaging but it must be Methods: Case report .Results: Female, 13 yrs old, non white, referred confirmed by biopsy. The authors present a case of a 3-year-old girl to investigate pancitopenia , adynamia and skin infiltration. On with a 6 months progressive history mild left ptosis and proptosis of examination she had plaques on entire face, arms, legs. No signs of the left eye, who had developed diabetes insipidus one month before. neurofibromatosis There were pancitopenia and severe The MRI showed an extensive osteolytic parameningeal lesion with hypoalbuminemia. Bone marrow biopsy showed histiocytic infiltration. left predominance and involvement of the superior maxillary, orbital Histiocytes had foamy cytoplasm and there were some cells “Touton floor and sphenoid and intracranial extension with invasion of the left type”•. Skin biopsy showed also histiocytic infiltration. cavernous sinus. There was also an increasing the pituitary volume Immunohistochemistry positive for S-ptn, CD68 and FXIII and negative and pituitary stalk thickening and another distinct lesion in the right for CD1a..Ultrasonography showed a homogeneous enlarged liver. jaw. The positron emission tomography showed no other lesions and Antibody tests for autoimmune diseases (ATAD) were negative. A the cardiac evaluation was normal. The first biopsy performed at the diagnosis of DJX with liver and bone marrow involvement was left superior maxillary was normal and the histopathological study of established. LCH Protocol was started. Her blood count increased as right jaw showed an abundant infiltration of typically foamy histiocytes well as serum albumin and skin lesions became smaller or vanished. positive for CD68 and CD163 and negative for CD1a, S100 and She developed hyperglicemia due to prednisone and needed insulin. Langerin. The survey of 600 BRAFV600E was positive in 20% of the After the fourth vinblastine dose, she complained about parenthesis cells so it was decided to start treatment with dabrafenib. Currently and the drug was stopped. Neuropathic pain was ruled out. she has been in treatment for 1 month with no relevant side effects Polyarthritis (knees, elbows, ankles, toes) followed. Ibuprofen was and good radiological evolution. This is perhaps the first Portuguese started with disappearance of symptoms. ATAD were repeated toddler with ECD and the first paediatric case of ECD treated with the (negative).She stayed 3 weeks out of chemotherapy ;meanwhile her BRAF inhibitor dabrafenib in our country. serum albumin dropped down and skin lesions enlarged. There was no response after restarting treatment and she was then put on Poster Location #98 salvage therapy with 2CDa + HD ara-c ( 2 courses) . Nowadays she is doing good, almost all skin lesions disappeared, her blood count is IMATINIB FOR THE TREATMENT OF XANTHOMA DISSEMINATUM near normal and serum albumin is around 3.0 mg/dl .She is on maintenance with methotrexate and mercaptopurine. Conclusion: DJX Gitesh U. Sawatkar1, Vinay Keshavamurthy1, at this age, with such extensive involvement at diagnosis is quiet Pankaj Malhotra2, Uma Nahar Saikia3, Sunil Dogra1 difficult to find in literature . Her response to the salvage therapy was also remarkable. 1Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India 2 Department of Internal Medicine, Postgraduate Institute of Medical NOTES Education and Research (PGIMER), Chandigarh, India 3 Department of Histopathology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

Background: Xanthoma disseminatum (XD) is a rare form non- Langerhans cell histiocytoses. Multiple treatment options have been tried but none has been found to be curative. Observation: A young- male presented with multiple yellowish, smooth surfaced papules over face, axilla and groins, with involvement of oral cavity since past 3 years. In addition, he complained of increased frequency of thirst and urination suggestive of diabetes insipidus (DI). The presence of histopathological features including chronic inflammatory infiltrate and multinucleated giant cells in conjunction with classical clinical findings confirmed the clinical possibility of XD. Imatinib was started at a dose of 100mg once daily and was gradually increased to a maximum of 400mg daily for 2 years. The mucosal lesions of XD completely cleared and cutaneous lesions showed marked improvement. Symptoms of DI also showed improvement. Repeat histopathology of

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THE HEMATOPOIETIC ORIGIN OF ADULT HISTIOCYTOSIS response in at least one diameter. Overall partial response at six months was seen in 40% of the cases (N=2). Overall minor response Matthew Collin1, Paul Milne1, Venetia Bigley1, Antoine Neel 2, (<30% reduction in size) was seen in the reminder of the cases. All Muzlifah Haniffa1, Ben Durham3, Eli Diamond3, Omar Abdel-Wahab3 patients reported improvements in their quality of life, activity level, and energy. The most common adverse event was pyrexia followed by 1Newcastle University, Newcastle upon Tyne, UK skin exanthema. Skin was not reported. Four cases required doses 2Hôtel-Dieu University Hopital, Nantes, France modifications. Conclusions. BRAF inhibition in combination with MEK 3Memorial Sloan Kettering Cancer Centre, New York, NY USA inhibition in patients with BRAF V600E ECD is a safe and promising therapy. Skin cancers are less likely to occur. This trial is still open and Purpose: to understand the origin and differential development of enrolling patients. Patients will complete 12 cycles of therapy and then Langerhans Cell Histiocytosis (LCH) and Erdheim Chester Disease followed for 12 months to assess for duration of response and disease (ECD) in adults. Methods: 49 patients with LCH, ECD or LCH/ECD progression. cross-over and 5 patients with hairy cell leukaemia (HCL). Tracking of BRAFV600E mutated bone marrow progenitor fractions, peripheral PROSPECTIVE GENOMIC PROFILING OF HISTIOCYTOSES blood cells and lesional cells by allele-specific PCR. In vitro IDENTIFIES NOVEL MUTATIONS AND THERAPY OPTIONS differentiation of dendritic cells (DCs) and monocytes into histiocyte- like cells using defined growth factors and conditioned media. Lynn Lee1, Anjelika Gasilina1, Jayeeta Roychoudhury1, Jason Clark1, Comparative analysis of gene expression in in vitro derived and Francis McCormack2, Joseph Pressey1, Siraj Ali3, Mark Bailey3, primary histiocytosis lesions. Results: BRAFV600E localised to the Phil Stephens3, Jeffrey Ross3, Vincent Miller3, Nicolas Nassar1, hematopoietic stem cell (HSC) in multi-system LCH, ECD and HCL Ashish Kumar1 and was enriched in myeloid progenitors in multi-system LCH and ECD. In peripheral blood, the pattern of BRAF mutant alleles was 1Cincinnati Children's Hospital Medical Center, Cincinnati, OH USA indistinguishable between LCH and ECD, involving predominantly 2University of Cincinnati College of Medicine, Cincinnati, OH USA monocytes and myeloid DCs. In HCL, mutant alleles were only 3Foundation Medicine, Cambridge, MA USA detectable in HCL cells and B/NK lymphocytes. Detection of BRAFV600E alleles in the blood was more likely in MS-LCH than SS- Purpose: Many patients with histiocytoses have treatment-refractory LCH (p = 0.004) but no correlation with disease stage was observed in disease or suffer recurrences. Several gene mutations have recently ECD. LCH-like cells differentiated from CD1c+ DCs in response to GM been identified in these disorders, creating options for targeted -CSF, TGFbeta or BMP7 and co-culture with primary keratinocytes. In therapies. We sought to determine the utility of prospective contrast, CD68+ macrophages were formed by co-culture of sequencing of select genes to characterize mutations and identify monocytes with fibroblasts. Gene expression studies during specific treatments for patients with histiocytic disorders. Methods: differentiation in vitro confirmed that CD1c+ DCs and monocytes Biopsy samples from patients with histiocytoses were analyzed using remained distinct and did not trans-differentiate despite the expression clinical tests. We performed captured-sequencing of coding regions of of similar surface markers. Conclusions: the results suggest that: MS- 405 genes and select introns of 31 genes involved in rearrangements, LCH, ECD and HCL are all diseases of the HSC; that histiocytosis is and RNA sequencing of 265 genes. Novel mutations were cloned and distinct from HCL but that it is not possible to dissociate the studied further to determine the impact on gene function and response phenotypes of LCH and ECD by the distribution of BRAFV600E alleles to inhibitors. Results: We analyzed results from 49 patients. Nine in peripheral blood. In vitro experiments and lesional transcriptional patients (18%) with either Langerhans cell histiocytosis, Erdheim profiling suggest that LCH arises from DCs and ECD arises from Chester disease or histiocytosis not-otherwise-specified carried the monocytes. However, the reason for this dichotomy remains unclear. known BRAF-V600E mutation. Eight patients (16%) with either LCH or juvenile xanthogranuloma carried various mutations in MAP2K1. Three DABRAFENIB AND TRAMETINIB AS POTENTIAL THERAPY IN LCH patients carried a novel 5 or 6 amino-acid in-frame deletion in BRAF V600E POSITIVE ERDHEIM CHESTER DISEASE (ECD): BRAF (N486_P490del or N486_T491>K). In 4 patients with PRELIMINARY RESULTS histioctyosis-NOS, we found fusions involving the ALK gene. Experimental studies showed that all MAP2K1 mutations and the Juvianee Estrada-Veras1, Kevin O'Brien2, Emily Huang2, novel BRAF in-del induced constitutive activation of downstream William Gahl1,2 extracellular signal-regulated kinase (ERK). Additionally, all MAP2K1 mutants were sensitive to inhibitors of mitogen-activated protein 1Medical Genetics Branch, Section on Human Biochemical Genetics, kinase kinase (MEK, the product of MAP2K1). A patient with multi- NHGRI, NIH, Bethesda, MD USA system LCH including CNS disease was found to carry the novel 2Office of the Clinical Director, NHGRI, NIH, Bethesda, MD USA BRAF in-del. She refused systemic chemotherapy. With the likelihood that the BRAF in-del is resistant to available BRAF inhibitors, we Background: Erdheim-Chester Disease (ECD) is a rare, fatal, multi- treated her with a MEK inhibitor. Within days her lymphadenopathy organ non-Langerhans cell histiocytosis with variable clinical resolved and a few weeks later her CNS symptoms dramatically presentation and progression. The diagnosis is established by clinical, improved. She remains in remission 4 months after initiation of radiologic, and histologic findings; ECD tumors have foamy treatment. Conclusion: Targeted sequencing identified known and macrophages that are CD68+, CD163+, CD1a-, and S-100-. There is novel mutations in histiocytoses and also helped in selecting no approved therapy for ECD and mutations in BRAF and RAS alternative viable therapies. provide potential targets for therapy. Methods: Five patients with confirmed BRAF V600E ECD that met inclusion and exclusion criteria were enrolled on NHGRI protocol 15-HG-0006 “A Phase II Therapeutic Trial of the Use of Dabrafenib and Trametinib in Patients with BRAF V600E Mutation Positive Lesions in Erdheim Chester Disease”• NCT02281760. Patients were started on 150 mg of dabrafenib every 12 hours and 2 mg of trametinib every 24. Safety and efficacy have been monitored for 6 cycles. Results: Patients had at least one lesion that met RECIST 1.1 criteria for target lesion, and up to five lesions were selected for follow up. Lesions were followed at one, two, four, and six months. Eighty percent of the patients (N=4) achieved partial

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TCR αβ-DEPLETED HEMATOPOIETIC STEM CELL monthly 0.5 g/kg IVIG according to previous studies. To monitor the TRANSPLANTATION IN PATIENTS WITH PRIMARY response to treatment, a multidisciplinary follow-up was performed in HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS all patients. Results: Seven patients (3 males), median age 13 years, were enrolled. ND-LCH was diagnosed at a median age of 5.8 years Michael Maschan, Elena Gutovskaya, Dmitriy Balashov, (2.7-21 years), at a median of 3 years after LCH diagnosis. At Elena Raikina, Viktoria Zaharova, Vladimir Zhogov, baseline, before treatment (T0), neurological examination was Varvara Brilliantova, Larisa Shelikhova, Galina Novichkova, abnormal in 5/7 patients (2 severely impaired and 3 pauci- Alexei Maschan symptomatic). SEPs and BAEPs were abnormal respectively in 7/7 and 3/7 patients. MRI scores were: 4(n=3), 3(n=1), 2(n=2), 2(n=1). Dmitriy Rogachev Federal Center For Pediatric Hematology, Oncology Patients received monthly IVIG treatment for a median duration of 19 and Immunology, Moscow, Russia months (11 months-4 years), and were annually followed-up for a median length of 4.4 years (2.9-5.9 years). During the follow-up the Introduction: Allogeneic hematopoietic stem cell transplantation two patients with severe neurological signs at T0 showed clinical (HSCT) is the only curative option for patients with primary worsening and treatment was stopped. Neurological evaluation hemophagocytic lymphohistiocytosis but is associated with significant improved in one of the 5 remaining patients and was stable in 4/5. risks. TCR αβ/CD19-depletion was developed to reduce the risk of BAEPs were stable in all patients. SEPs improved in 2/5 patients graft-versus-host disease and improve outcomes of transplantation. respectively 25 and 10 months after IVIG start and were stable in the We implemented treosulfan-based conditioning regimen and TCR αβ/ remaining 3/5. Conclusions: Our preliminary results showed that 5/7 CD19-depleted HSCT in HLH. Patients and methods: Eleven patients patients who were asymptomatic/pauci-symptomatic at baseline either with HLH were included in this study. Six patients had MUNC13D improved or remained stable after IVIG treatment, while the two mutation, one - STX11 mutation. Median age at HSCT was 2.4 y, 6 patients who were severely impaired worsened. We thereby suggest female/5 male, donors were MUDs (n-9) or haplos (n-2). Preparative our multidisciplinary protocol for selecting patients with early-stage ND regimen included treosulfan 42 g/kg, fludarabin 150mg/m2, -LCH as potentially candidates for IVIG treatment and for monitoring serotherapy (90% - thymoglobulin) +/- thiotepa 300 mg/m2(n-3). Six the response to treatment. patients recieved rituximab at d -1. Mobilized PBSC were depleted of TCR-αβ/CD19 lymphocytes. Final graft contained 11x106 CD34+/kg CENTRAL NERVOUS SYSTEM PERFUSION PATTERNS IN and 40x103 TCRαβ/kg. Post-transplant immune suppression included CHILDHOOD LANGERHANS CELL HISTIOCYTOSIS tacrolimus till day 45-100 +/- short methotrexate (day+1,+3,+6). Results: All patients had primary engrafment (median d+12). One Kristen Yeom1, Christine Kim1, Michael Iv1, Michael Jeng2 patient died due to P.aeruginosa sepsis on day +14. Secondary rejection developed in 2 patients (1 MUD/1 haplo). Both were salvaged Stanford University School of Medicine, Palo Alto, CA USA with a second transplantation. Three patients had acute GVHD grade 1Department of Radiology 2 (skin stage 1-2 and gut stage 1). One had chronic gut GVHD and 2Department of Pediatrics received budesonide. GVHD more than grade 2 was not registred. Three patients had prolonged mixed chimerism in T-cells without Purpose: Patients diagnosed with Langerhans cell histiocytosis (LCH) disease manifestation. After termination of immunosuppression two can develop clinical problems affecting the central nervous system patients showed a trend to increase donor CD3+ chimerism from 2% (CNS) with poor understanding of the underlying physiologic to 60-80%. Chimerism analysis in sorted naive T-cells showed mechanisms. A retrospective study was performed to evaluate predominant donor chimerism (78 and 97%). One patient has stable cerebral hemodynamic properties by analyzing CNS perfusion high-level mixed chimerism (90% autologous CD3+) without disease patterns in children with LCH. Methods: A retrospective quantitative manifestation. Overall and disease-free survivals were 90.9% (follow analysis of cerebral blood flow (CBF) was performed in children with up 3-39 months). Conclusion: The treosulfan-based regimen and biopsy proven LCH. Patients with abnormal CNS anatomy were TCRαβ/CD19-depleted grafts is effective with low toxicity, abscence of excluded. Demographic and clinical information were collected. Brain severe GVHD and provides promising survival rates in HLH. MRI (3.0T magnet) performed during clinical care prior or after therapy were analyzed by Region of Interest Methodology (Chiaravalloti, et al) A MULTIDISCIPLINARY APPROACH TO EARLY DETECT was used to determine arterial spin labeling CBF (ml/100g/min) in the NEURODEGENERATIVE LANGERHANS CELL HISTIOCYTOSIS following regions (bilaterally): angular gyrus (Brodmann area 39), (ND-LCH) AND MONITOR RESPONSE TO INTRAVENOUS anterior prefrontal cortex (Brodmann area 10), orbitofrontal cortex IMMUNOGLOBULIN (IVIG) TREATMENT (Brodmann area 11), dorsal anterior cingulate cortex (Brodmann area 32), hippocampus. Quantile (median) regressions were run for each Elena Sieni1, Francesca Afrifa1, Carmen Barba2, Katiuscia Romano2, ROI location. CBF patterns were compared to age-matched healthy Marzia Mortilla3, Claudio De Filippi3, Susanna Rizzi2 , Claudio Favre1, and post-treatment acute lymphoblastic leukemia cohorts. Results: Renzo Guerrini2 Significantly abnormal CBF (p<0.05) was seen in children with LCH compared to age-matched controls in the angular gyrus [-9.8 1Pediatric Hematology Oncology Department, Children's Hospital p=0.018)], anterior prefrontal cortex [-8.6 p=0.027], and dorsal anterior Meyer-University of Florence, Florence, Italy cingulate cortex [-8.1 p=0.030) at diagnosis compared to age matched 2Neuroscience Department, Children's Hospital Meyer-University of controls, No significant perfusion differences in the hippocampus or Florence, Florence, Italy orbitofrontal cortex in the LCH group or any CNS region in the ALL 3Pediatric Radiology Department, Children's Hospital Meyer-University cohort. Discussion: Children with LCH showed significantly of Florence, Florence, Italy decreased CBF in the angular gyrus, anterior prefrontal cortex, and dorsal anterior cingulate cortex. In comparison, patients with ALL after Purpose: To validate a multidisciplinary diagnostic work-up for therapy did not have any consistent statistically significant differences selecting patients with ND-LCH for IVIG administration and monitoring in CBF, suggesting that this is not treatment-related. These results treatment response. Methods: The diagnostic protocol included suggest that decreased CBF may be part of the physiology of patients structural 3T MRI (score 1, mild, to 4, severe), complete neurological with LCH, and may play a role in the development of the CNS examination, brainstem auditory evoked potentials (BAEPs) and complications of LCH. Further studies are warranted. somatosensory evoked potentials (SEPs). Patients with typical MRI findings of ND-LCH and at least one among neurological and neurophysiological signs of neurodegeneration were treated with

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NESBIT PRIZE IN CLINICAL SCIENCE NEZELOF PRIZE IN BASIC SCIENCE

The Histiocytosis Association, in conjunction with the Histiocyte Society, In order to stimulate the activities of scientists and clinicians from is offering an annual prize for the best clinical article at their Annual around the world studying the histiocytic disorders, the Histiocyte Meeting. It will be given in honor of Dr. Mark Nesbit, renowned pediatric Society is sponsoring an annual prize for the best scientific article at the oncologist, teacher, and supporter of the many families dealing with Annual Meeting. The Award will be given in honor of Dr. Christian histiocytic disorders. The prize will be awarded to a physician or Nezelof, renowned pathologist, investigator, teacher, founding member scientist who is carrying out clinical research to the therapy, biology or and first President of the Society, to a physician or scientist who is pathogenesis of one of the histiocytic disorders. The goal of the Award carrying out basic research on the therapy, biology or pathogenesis of is to stimulate and promote the activities of clinical scientists from all one of the histiocytic disorders. around the world to study specific aspects of these puzzling diseases. Dr. Christian Nezelof studied medicine in Paris, France during and after Dr. Mark Nesbit completed his medical training at George Washington the Second World War. In 1948 he specialized in Pediatrics at the Medical School in 1959. The remainder of his medical training was at Hospital des Enfants Malades. In the early fifties, as a young the University of Minnesota where he specialized in pediatric pediatrician, he published the first clinical report on cystic fibrosis in hematology and oncology. In 1967 he joined the faculty at the University France. In 1956 he worked in the Department of Pathology at the Sick of Minnesota, achieving the rank of Professor of Pediatrics in 1973. Dr. Children Hospital in London under the direction of Professor Bodian, a Nesbit assumed the position of Director of the Division of Pediatric famous British pathologist who first described cystic fibrosis in children. Hematology and Oncology at the University of Minnesota where he built On returning to France he completed training in Pediatric Pathology. one of the most productive and nationally recognized programs during During the period of 1960-1968 Dr. Nezelof served as a full-time his 14 year tenure. Professor Nesbit has been a leader in the pathologist at Necker-Enfants Malades, where he became Chairman of development of clinical research for the treatment of leukemia and has a the Department of Pathology in 1968. In parallel, from 1970, for 15 special interest in histiocytosis, bone tumors and the late complications years he was Head of INSERM Research Unit and created the Groups of cancer survivors. In addition, Dr. Nesbit has helped countless young of Pediatric Pathology located at the Necker-Enfants Malades Hospital. investigators with their careers in the field of pediatric hematology and oncology. The many contributions by Dr. Nezelof include:  Dr. Nezelof contributed significantly to the development of Of the contributions made by Professor Nesbit towards better Pediatric Pathology as a subspecialty by creating a network of understanding of the histiocytic disorders, we highlight the following various specialties and also trained many clinicians and foreign three: pathologists. He has served as a consultant for the world of  Histiocytic disorders have been a continual interest from the onset histiocytosis, always giving a friendly and illuminating answer to of Professor Nesbit's career. His first publication was entitled: anyone's questions. "Histiocytosis X".  In 1960, Dr. Nezelof played a key role in describing a clinical  Dr. Nesbit played an important role in the organization of the condition of immunodeficiency in childhood, in which the existence Histiocyte Society. Besides his active input in the Epidemiology of a "split" in the human lymphoid system toward T and B-cells Study Group of the Histiocyte Society, he served on the Education was recognized. An immune-deficient child was described as Committee. His interest and initiative for increasing the activity and afflicted by a thymic hypoplasia, but with normal level of visibility of the Histiocyte Society has been an important part of the immunoglobulins ("Lympho-cytophtisie avec normogamma- Society's evolution. globlinemie"). In the pediatric literature this condition became  Dr. Nesbit was a member and participant as a Board of Trustees known as Nezelof's syndrome. member of the Histiocytosis Association. His activities in the  In the field of histiocytosis, his seminal contribution was that Association made him a national source of information on the Letterer-Siwe, Hand-Schuller-Christian and eosinophilic diagnosis and treatment of histiocytosis. In 1990, Professor Nesbit granuloma are linked to the same cell, having a common received the Outstanding Investigator Award from the Histiocytosis ultrastructural marker designated as the Langerhans body Association. (Birbeck granule). In his paper "Histiocytosis X: Histogenetic arguments for Langerhans cell origin", he noted the dendritic In conclusion, Dr. Nesbit has made substantial contributions to research lineage of this disease. Not long afterwards the term Langerhans in the field of histiocytosis. His dedication to the organization of cell histiocytosis was introduced. interested investigators has resulted in a strong research agenda to better understand the etiology, diagnosis, treatment and long-term Histiocytic disorders continue to be one of his major fields of interest. In outcome of children with Langerhans cell histiocytosis. His compassion 1982 Dr. Nezelof described the successful growth in nude mice of a for patients and their families has always been evident, by his tumor after injection of cells from the pleural effusion of a child with willingness to consult with both physicians and family members. malignant histiocytosis. After this manuscript entitled: "Tumor cell line characterization of a malignant histiocytosis transplanted into nude The Histiocytosis Association and the Histiocyte Society thought it mice" his team has described successful establishment in vitro of the entirely compatible with the support and the work of Dr. Nesbit within the Malignant Histiocytosis DEL cell line. world of the histiocytoses to offer this prize in his name. The candidates for the Nesbit Award need not be physicians, but the focus of the work The Society thought it entirely consistent with Dr. Nezelof's great should be on some aspect of the histiocytic disorders, be it in clinical interest in new developments of basic pathophysiology, bridged with his medicine, allied pursuits such as nursing, psychology, social work, key-role in supporting others that this prize be given in his honor. The occupational therapy, etc. awardee need not be a physician, but the focus of the work should be on some aspect of the pathophysiology of the histiocytic disorders. Judgment will be based on a written abstract describing work done by the candidate him/herself. It is understood that the winning abstract may Judgment will be based on a written abstract describing work done by have co-authors, but that the first author must be the major contributor the candidate him/herself. It is understood that the winning abstract may who is awarded the Nesbit Award. The Program Committee will provide have co-authors, but that the first author must be the leader of the time during the Annual Meeting for presentation of the winning paper. project and the one who is awarded the Nezelof Award. The Program The decision by a special committee of the Histiocyte Society will be Committee will provide time during the Annual Meeting for presentation based on originality, completeness, scientific accuracy, and contribution of the winning paper. The decision by a special committee of the to science. The prize will consist of $500 US and a certificate. Histiocyte Society will be based on originality, completeness, scientific accuracy, and contribution to science. The prize will consist of $500 US and a certificate.

78 HISTIOCYTE SOCIETY ANNUAL MEETING 2016

HISTIOCYTE SOCIETY GOVERNING BY-LAWS

The Society shall be governed and guided by the principles set annual meeting or by the date fixed by the Board for the payment forth in these By-Laws. thereof. C. Membership may be canceled for failure to pay dues as set forth ARTICLE I: MEMBERSHIP in Article I. Section 1 – Definitions and eligibility The membership of the Society shall consist of: ARTICLE III: OFFICERS OF THE SOCIETY A. Ordinary Members The officers of the Society shall be the president, the immediate past- Ordinary Members are all health care professionals who are president, the president-elect, the secretary, and the treasurer. The active in patient care, education or research in the histiocytic offices of secretary and treasurer may be held by the same person. All disorders. Ordinary Members pay dues, may participate in all officers must be Ordinary Members of the Society and serve without activities of the Society, may hold office, are eligible to vote, financial compensation. Terms begin and end at the end of the receive all communications and publications of the Society, and General Assembly of the Society as the final item of business. have such special rights and privileges that may be decreed by A. President — Elected for a three-year term, and may be re- the Board with the majority-vote consent and approval of the elected for one more term, but the second term may not be Ordinary Members. consecutive. B. Honored Members 1. Presides over annual meetings, is chairperson of the Honored members are distinguished individuals, who in the view Board, appoints all members of committees not otherwise of the Board have made extraordinary contributions to the defined herein, organizes the agendas for Board and Society. Honored Members enjoy all rights and privileges of annual meetings, co-signs contracts and financial Ordinary Members, but do not pay dues, may not hold office, and instruments on behalf of the Society, and serves as an ex- will not receive a copy of the Society’s official journal. officio member of all standing and ad hoc committees of the C. Emeritus Members Society. Emeritus members are Ordinary Members who have retired from 2. Represents the Society in dealing with other organizations active involvement in the field. Emeritus Members enjoy all rights and media. and privileges of Ordinary Members, but do not pay dues, may 3. Becomes a member of the Board as the immediate past- not hold office, and will not receive a copy of the Society’s official president for the year immediately following his/her term of journal. office. Section 2 – Appointment of members and termination of 4. When a member of the Board acts for the then president membership under the conditions of Article IV.1.B. A. A completed application for membership is to be submitted to the B. President-Elect — Elected for a three-year term as president. Secretariat of the Society for consideration by the Board prior to Succeeds to that office at the end of the term of the then- the General Assembly at the Annual Histiocyte Society Meeting. incumbent. Applications should include a relevant curriculum vitae and/or supporting signature from an Ordinary Member. Applications 1. Becomes a member of the Board as the president-elect for approved by the Board must be ratified by the membership the two years prior to assuming the presidency. during the General Assembly of the Histiocyte Society Annual 2. When a member of the Board as the past-president acts for Meeting. the then president under the conditions of Article IV.1.B. B. The Executive Board of the Society shall be the sole judge of 3. Serves as chairperson of the nominating committee. moral, ethical and professional qualifications required for election C. Secretary — Elected for a two-year term with two additional to or termination of membership. terms permitted by re-election. Is responsible for communication C. Applicants will be notified of action taken following the General with members and minutes of all meetings, and is ex-officio Assembly in which their application has been considered. member of all committees. With the president, co-signs D. Honored Members must be proposed to the Board by an contracts and financial instruments on behalf of the Society. Ordinary Member and accepted by the Board before ratification Oversees election of Scientific and Education Committee by the membership during the General Assembly of the chairpersons following the annual General Assembly. Histiocyte Society Annual Meeting. D. Treasurer — Elected for a two-year term with two additional E. Emeritus Members must be proposed to the Board by an terms permitted by re-election. Is responsible for all receipts and Ordinary Member or by themselves and accepted by the Board disbursements of money subject to direction from the Board. before ratification by the membership during the General Such records as are necessary for auditing purposes must be Assembly of the Histiocyte Society Annual Meeting. kept. Recommendations concerning financial matters and the financial status of the Society are reviewed with the Board F. Membership shall be canceled on request of the member or on annually or more often as needed. the grounds of: 1) nonpayment of dues for two successive years, 2) failure of the member to attend an Annual Meeting at least once in three years, or 3) unethical or unprofessional ARTICLE IV: THE EXECUTIVE BOARD behavior by the member. Cancellation of membership must be approved by the Board. Section 1 The Executive Board (herein referred to as the “Board”) is the

governing body responsible for operating the Society. It is composed ARTICLE II: DUES of the immediate Past-President according to Article III.1.A.3., the Section 1 President-Elect according to Article III.1.B.1., the other officers, and two Ordinary members-at-large elected by the membership for a three A. The annual dues for Ordinary Members shall be set by the Board year term. All members serve without financial compensation. and ratified by the General Assembly by a simple majority vote. A. The Board is required to meet no less than once each year, and B. The annual dues shall be due and payable at the time of the it may enroll participation by others, without vote, as needed.

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HISTIOCYTE SOCIETY GOVERNING BY-LAWS

B. If for any reason, as determined by the Board, the president is programs in which the Society is officially involved. The unable to carry out his/her duties, then the President-Elect or the committee may recruit, at its discretion, assistance from others Past-President sitting on the Board at that time assumes the who may or may not be members of the Society. duties and responsibilities of the president. C. Scientific Committee — Vacancies as they occur will be filled C. Candidates for Board member-at-large shall be Ordinary by election held at the General Assembly from a slate prepared Members who have not served on the Board in any capacity for by the Nominating Committee. Officers of the Society and at least two years prior to becoming at-large candidates. members of the Nominating Committee are eligible to serve on D. A Board member-at-large may serve a second non-consecutive this committee. Two-year terms will be staggered. A member term permitted by re-election. may serve no more than six (6) consecutive years if re-elected. The committee will select its own chairperson from its membership within ten (10) days of the close of the annual ARTICLE V: FINANCES meeting. The chairperson will lead the committee and liaison with the president. Section 1 – Financing of the Society will come through membership fees and from other sources approved by the Board. The committee will: Section 2 – Financial records will be audited by an external agency no 1. Review proposals for research and related activities less than every third year. according to guidelines developed by the Board and make recommendations to the Board. Section 3 – An annual budget and accounting of the previous year’s finances are to be presented by the Treasurer to the membership at 2. Present the Board with annual reports and plans each annual meeting. concerning the Society’s research activities. Section 4 – Disbursements from the treasury in excess of $1,000 US D. Education, Constitution and By-Laws Committee — shall require prior approval of the Board. Vacancies as they occur will be filled by election held at the General Assembly from a slate prepared by the Nominating Committee. Two-year terms will be staggered. A member may ARTICLE VI: COMMITTEES serve no more than six (6) consecutive years. The committee will Section 1 select its own chairperson from its membership within ten (10) days of the close of the Annual Meeting. The chairperson will Standing Committees include the Nominating Committee, the Program lead the committee and liaison with the president. Committee, the Scientific Committee, and the Education Committee. The president may, at his/her discretion, appoint other committees on The committee will: an ad hoc basis. The President is responsible for all appointments to 1. Suggest one or more topics to the Program Committee for committees, with review by and approval of the Board, except as an educational session to be conducted at the time of the described below. General Assembly or such other times as are convenient A. Nominating Committee — This committee, composed of the and appropriate. The topics should be such as to attract not most immediate Past-President, the President, and the president only physicians but also nurses, or psychologists or one of -elect (who will act as chairperson), shall be responsible for the other groups described in Article II. 4 of the providing the Board with a slate of officers and candidates for at- Constitution. large membership on the Board and members of the Scientific 2. Review abstracts and select those to be presented at the and Education Committees, the nominees having established a annual meeting. willingness to serve if elected. 3. a) Monitor the Constitution and By-Laws for needed 1. The committee will propose at least one more candidate amendments as circumstances dictate, and than the number of vacancies to be filled by election. b) Be available to the Board for drafting of changes the 2. This slate must be presented to the Board no later than one Board deems advisable. month prior to the upcoming relevant General Assembly. 4. Present the Board with an annual assessment of the 3. The committee will be responsible for presentation of the Constitution and By-Laws. slate, as approved by the Board, and for carrying out the

election at the relevant General Assembly. ARTICLE VII: OPERATIONAL BASIS 4. Elections for Secretary and/or Treasurer and the Board Members-at-Large shall be conducted at the meeting Section 1 – Business year marking the beginning of the then-incumbents’ last year in The Society’s official year will be January 1st through December 31st office. of each year. 5. Elections for president shall be conducted at the meeting Section 2 – Authority of procedure marking the beginning of the last two (2) years in office of the then-incumbent President. The president-elect “Robert’s Rules of Order, Revised” will guide all procedure, but where thereupon becomes a member of the Board according to in conflict, these By-Laws shall prevail. Article III.B.1. Section 3 – Quorum B. Program Committee — The President, Secretary, Chairperson Ten percent (10%) of the ordinary members shall constitute a quorum of the Education Committee, Chairperson of the Scientific of the transaction of business at all General Assemblies of the Society. Committee, representative of Secretariat, and local ARTICLE VIII: GENERAL MEETINGS representative(s) chosen by the Board among the members of the Society, if available, will act as a Program Committee for the Section 1 upcoming annual meeting. The President shall act as The Society shall meet at least once annually in a combined business chairperson. The committee shall be responsible for planning the and scientific session (The Annual Meeting). The business meeting meeting and for presenting plans to the Board for approval. It will shall be termed the General Assembly. Special meetings may be organize and execute the approved program. The committee will called by the Board. Times and places thereof will be determined by also be responsible for planning, organizing and executing other the Board in consultation with the Scientific and Education

80 HISTIOCYTE SOCIETY ANNUAL MEETING 2016

HISTIOCYTE SOCIETY GOVERNING BY-LAWS

Committees, and notice thereof shall be mailed to all members at least Proposed changes may originate with any Ordinary member of the four (4) months prior to annual meetings and at least two (2) months Society. They should be submitted to the Secretary at least four (4) prior to specially called meetings. months prior to the General Assembly. A. Scientific meetings Section 3 Scientific meetings will be open to all persons who are eligible for Changes properly proposed to the Board will be presented at the next membership as defined in Article I and to others who share the General Assembly with the recommendation of the Board. objectives of the Society. B. Business meetings Business meetings (the General Assembly) are open only to members of the Society, consultants and guests invited by an officer of the Society. Section 2 The agenda for the annual meeting shall be made available to the members no less than three (3) months prior to the meeting and will include: 1. Secretary’s report 2. Treasurer’s report 3. President’s report 4. Ratification of new members 5. Nominations and elections 6. Committee reports 7. Old business 8. New business 9. Other items

ARTICLE IX: AMENDMENTS AND REVISIONS Section 1 Amendments and revisions may be made by an affirmative vote of two -thirds (2/3) of a quorum at a General Assembly of the Society, provided proposed changes have been submitted to and approved by the Board and circulated among the members at least three (3) months prior to the General Assembly. Section 2

HISTIOCYTE SOCIETY CONSTITUTION

Article I: Name The name of the society shall be the “Histiocyte Society”. This is a non-profit organization duly registered in the United States of America.

Article II: Aims 1. To improve the state of knowledge of the histiocytic disorders and the welfare of patients with these disorders and their families. 2. To promote, facilitate and carry out research in histiocytic disorders. 3. To facilitate and provide a forum for health professionals for effective communication concerning these aims. 4. To promote education and to educate physicians, nurses, other health professionals, scientists, legislators, and other lay persons in matters related to the histiocytic disorders. 5. To advise lay organizations in educational and other matters concerning histiocytic disorders. 6. To collaborate with other organizations with common aims.

Article III: Amendments and Revisions 1. Changes may be made by an affirmative vote of two-thirds (2/3) of a quorum at a general meeting of the Society, provided proposed changes have been submitted to and approved by the Board and circulated among the members at least one (1) month prior to the general meeting. 2. Proposed changes may originate with any ordinary member of the Society. They should be submitted to the Secretary at least two (2) months prior to the general meeting. 3. Changes properly proposed to the Board will be presented at the next general meeting with the recommendation of the Board.

Article IV: Dissolution 1. Dissolution shall be proposed, processed, and voted on as for amendments and revisions, Article III. 2. In a case of dissolution of the Society, any funds remaining after payment of all outstanding debts will be donated to one or more organizations, with aims and objectives consonant with those of the Society, to be selected by the Board.

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PRESENTING AUTHOR INDEX

DATE AUTHOR ABSTRACT TITLE SESSION PAGE TIME CHALLENGES IN TREATING LANGERHANS CELL HISTIOCYTOSIS Oct 18 Ahmad, Alia AMONG CHILDREN IN DEVELOPING COUNTRIES: CHILDREN'S Poster 55 HOSPITAL LAHORE PAKISTAN EXPERIENCE 1430 ACTIVATION OF CYTOTOXIC CD4 T CELLS DISTINGUISHES FAMILIAL Oct 18 Ammann, Sandra FROM VIRUS-INDUCED SECONDARY HEMOPHAGOCYTIC Poster 41 LYMPHOHISTIOCYTOSIS 1430 SYSTEMIC JUVENILE XANTHOGRANULOMA WITH A LARGE Oct 18 Anderson, Ron INTRACRANIAL MASS: RESPONSE TO CLOFARABINE AND Poster 71 CYTARABINE 1430

Ashraf, Muhammad ERDHEIM CHESTER DISEASE - UNUSUAL PRESENTATION OF A RARE Oct 18 Poster 71 Shamvil HISTIOCYTIC DISORDER IN A 3 YEAR OLD BOY. 1430 A COLLABORATIVE STUDY IN CHILDREN AND ADULTS DIAGNOSED Oct 18 Astigarraga, Itziar WITH LANGERHANS CELL HISTIOCYTOSIS. OUR EXPERIENCE IN 42 Poster 56 CASES 1430 PULMONARY LANGERHANS CELL HISTIOCYTOSIS IN CHILDREN: LIFE- Oct 18 Barclay, Mhairi THREATENING PNEUMOTHORACES AND THE CHALLENGES OF Poster 56 PROLONGED VENTILATION - REPORT OF 2 CASES 1430

ROSAI-DORFMAN DISEASE- OUR EXPERIENCES FROM A SINGLE Oct 18 Begum, Ferdousi Poster 71 CENTRE 1430 Presidential CD8 T-CELL MEMORY RESULTS IN AN ENHANCED HLH DISEASE THAT Oct 17 Behrens, Edward Symposium 36 IS RESISTANT TO IFN-GAMMA BLOCKADE 1600 SS II LONGITUDINAL STUDY OF IL-1β AND PGE2 SALIVARY Oct 18 Benchuya, Carolina CONCENTRATIONS IN PEDIATRIC PATIENTS WITH LANGERHANS CELL Poster 56 HISTIOCYTOSIS 1430

THE LEVELS OF IL-1β AND PGE2 IN SALIVA OF CHILDREN WITH Oct 18 Benchuya, Carolina Poster 57 LANGERHANS CELL HISTIOCYTOSIS. 1430

TOXICITY PROFILE OF CLOFARABINE IN PATIENTS WITH Oct 18 Bingham, Racheal Poster 57 REFRACTORY OR RECURRENT HISTIOCYTIC DISORDERS 1430 CLINICAL RELEVANCE OF THE DIFFERENT MAPK-PATHWAY MUTATIONS IN LANGERHANS CELL HISTIOCYTOSIS; A LITERATURE Oct 18 Breuking, Sofie Poster 57 REVIEW UNDERLINING THE NEED FOR PROSPECTIVE CO-OPERATIVE 1430 STUDIES

PERMANENT CONSEQUENCES OF LANGERHANS CELL Oct 18 Bronin, Gleb Poster 57 HISTIOCYTOSIS. EXPERIENCE OF AN OBSERVATIONAL TRIAL 1430

IDENTIFICATION OF NOVEL BRAF ALTERATIONS IN LCH USING AN Oct 18 Burke, Thomas SS III 38 INTEGRATED GENOMIC PIPELINE 1330 PERSISTENT OR RECURRENT LANGERHANS CELL HISTIOCYTOSIS Oct 18 Cao, Jing TREATED WITH SORAFENIB ALONE:CASE REPORTS AND LITERATURE Poster 58 REVIEW 1430

ISOLATED PULMONARY LANGERHANS CELL HISTIOCYTOSIS IN Oct 18 Celis, Veronica Poster 58 CHILDREN 1430

CHARACTERIZING INFILTRATING T LYMPHOCYTES IN LANGERHANS Oct 18 Chakraborty, Rikhia SS III 38 CELL HISTIOCYTOSIS (LCH) LESIONS 1330

HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS IN LANGERHANS CELL Oct 17 Chellapandian, Deepak HISTIOCYTOSIS: A MULTICENTER RETROSPECTIVE DESCRIPTIONAL SS I 32 STUDY 1400

82 HISTIOCYTE SOCIETY ANNUAL MEETING 2016

PRESENTING AUTHOR INDEX

DATE AUTHOR ABSTRACT TITLE SESSION PAGE TIME HETEROGENEITY OF MOLECULAR DIAGNOSES AND OUTCOMES IN A Oct 17 Chinn, Ivan DIVERSE COHORT OF PATIENTS WITH HEMOPHAGOCYTIC SS I 32 LYMPHOHISTIOCYTOSIS 1400 REFRACTORY LCH MONITORING BY URINARY AND BLOOD BRAF Oct 18 Chuang, Anthony Poster 58 TESTING 1430 Oct 19 Collin, Matthew THE HEMATOPOIETIC ORIGIN OF ADULT HISTIOCYTOSIS SS IV 76 1030 INNOVATIVE USE OF PK AND PD TO GUIDE DOSE SELECTION FOR A MONOCLONAL ANTIBODY AIMED AT NEUTRALIZING THE HIGH IFN- Oct 17 de Min, Christina SS I 33 GAMMA ACTIVITY PRESENT IN PATIENTS WITH MACROPHAGE 1400 ACTIVATION SYNDROME (MAS)

CHRONIC MYELOMONOCYTIC LEUKEMIA CLONALLY RELATED TO Oct 18 Dhawale, Tejaswini Poster 72 CONCURRENT ERDHEIM CHESTER DISEASE 1430

NEXT-GENERATION DNA SEQUENCING-BASED MUTATION PROFILING Oct 18 Dhawale, Tejaswini Poster 72 IDENTIFIES KRAS MUTATIONS IN ERDHEIM-CHESTER DISEASE 1430 Oct 18 Diez, Blanca MENINGEAL LANGERHANS CELLS SARCOMA CASE REPORT Poster 72 1430

PHARMACOKINETICS STUDY OF VEMURAFENIB IN A PEDIATRIC Oct 18 Donadieu, Jean Poster 54 POPULATION: PRELIMINARY RESULTS 1430

RELEVANCE OF BRAFV600E ALLELE DETECTION IN CIRCULATING Oct 18 Donadieu, Jean Poster 55 CFDNA AS A BIOMARKER IN PEDIATRIC LCH 1430 VEMURAFENIB HAD OBTAINED THE ORPHAN DRUG DESIGNATION Oct 18 Donadieu, Jean STATUS IN EUROPE FOR LANGERHANS CELL HISTIOCYTOSIS IN Poster 55 APRIL 2016 1430

VEMURAFENIB IN CHILDREN WITH REFRACTORY LCH: 21 PATIENTS Oct 18 Donadieu, Jean SS III 38 TREATED IN FRANCE, UK, ITALY AND LEBANON. 1330 A REVIEW OF ADULT PATIENTS WITH HAEMOPHAGOCYTIC Oct 18 Dowse, Robin LYMPHOHISTIOCYTOSIS TREATED AT A SPECIALIST REFERRAL Poster 42 CENTRE 1430 ASSESSMENT OF SOLITARY SKELETAL LESIONS OF LCH:IS BONE Oct 18 Dvir, Rina Poster 59 SURVEY MANDATORY? 1430

EFFICACY OF CLOFARABINE IN PATIENTS WITH REFRACTORY/ Oct 18 Eckstein, Olive Poster 59 RECURRENT LANGERHANS CELL HISTIOCYTOSIS 1430 LANGERHANS CELL HISTIOCYTOSIS PATIENTS WITH EXTENSIVE PULMONARY CYSTS AND MULTIPLE PNEUMOTHORACES CAN BE Oct 18 Eckstein, Olive Poster 60 CURED WITH PLEURODESES, VIGOROUS SUPPORTIVE CARE, AND 1430 CHEMOTHERAPY Presidential BRAF MUTATIONS IN BONE MARROW AND BLOOD OF PATIENTS WITH Oct 17 Emile, Jean-Francois Symposium 37 ERDHEIM CHESTER DISEASE SS II 1600 DABRAFENIB AND TRAMETINIB AS POTENTIAL THERAPY IN BRAF Estrada-Veras, Oct 19 V600E POSITIVE ERDHEIM CHESTER DISEASE (ECD): PRELIMINARY SS IV 76 Juvianee RESULTS. 1030

Estrada-Veras, Oct 18 THE NEUROLOGIC MANIFESTATIONS OF ERDHEIM CHESTER-DISEASE Poster 73 Juvianee 1430 RESPONSE TO BRAF V600E INHIBITOR USED AS MONOTHERAPY OF Oct 18 Evseev, Dmitry MULTISYSTEM LANGHERHANS-CELL HISTIOCYTOSIS IN Poster 60 CHILDREN:REPORT OF TWO CASES 1430

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DATE AUTHOR ABSTRACT TITLE SESSION PAGE TIME

LONG-TERM FOLLOW-UP AFTER BONE MARROW TRANSPLANTATION IN A CHILD WITH FAMILIAL HEMOPHAGOCYTIC Oct 18 Farah, Roula Poster 42 LYMPHOHISTIOCYTOSIS (FHL) AND HOMOZYGOUS SYNTAXIN-11 1430 MUTATION.

AUTOPSY RESULTS IN MULTISYSTEM LANGERHANS CELL Oct 18 Felizzia, Guido Poster 70 HISTIOCYTOSIS (LCH) 1430

JUVENILE XANTHOGRANULOMA AND JUVENILE MYELOMONOCITIC Oct 18 Felizzia, Guido Poster 71 LEUKEMIA ASSOCIATION IN THREE PEDIATRIC PATIENTS 1430 EXCLUSIVE IFN-GAMMA BLOCKADE SIGNIFICANTLY CORRELATES Oct 18 Ferlin, Walter WITH IMPROVED CHIMERISM IN MICE: IMPLICATIONS FOR AN Poster 41 OPTIMIZED THERAPEUTIC APPROACH TO PRIMARY HLH PATIENTS 1430 BRAF p.V600E MUTATION DETECTION IN PEDIATRIC LANGERHANS CELL HISTIOCYTOSIS TISSUE SAMPLES USING REAL-TIME PCR AND Oct 18 Fisher, Kevin Poster 60 MUTATION-SPECIFIC IMMUNOHISTOCHEMISTRY: A COMPARISON 1430 STUDY ANAKINRA AS EFFICACIOUS THERAPY FOR INTRACRANIAL ERDHEIM- Oct 18 Fluchel, Mark Poster 73 CHESTER DISEASE IN A CHILD 1430 OUTCOME FOR CHILDREN WITH MULTI-SYSTEM LANGERHANS CELL Oct 18 Gao, Yi-Jin HISTIOCYTOSIS AFTER USING A LCH II-BASED PROTOCOL IN Poster 61 SHANGHAI, CHINA 1430 HIGH LEVELS OF sCD25 AND sCD163 IN PATIENTS DIAGNOSED WITH Garcia-Obregon, SEPSIS. COULD THEY BE USEFUL FOR SEPSIS DIAGNOSIS AND Oct 18 Poster 42 Susana DIFFERENTIAL DIAGNOSIS WITH HEMOPHAGOCYTIC 1430 LYMPHOHISTIOCYTOSIS (HLH)? MENINGEAL ROSAI-DORFMAN DISEASE WITH A STRUCTURAL Oct 18 Gawryletz, Chelsea BREAKPOINT OF PROTEIN TYROSINE PHOSPHATASE RECEPTOR Poster 74 TYPE D TUMOR SUPPRESSOR GENE 1430 DABRAFENIB FOR TREATMENT OF HEMOPHAGOCYTIC Oct 18 Grimley, Michael LYMPHOHISTIOCYTOSIS (HLH) IN 2 PATIENTS WITH LANGERHANS Poster 61 CELL HISTIOCYTOSIS (LCH) WITH BRAF-V660E MUTATION 1430

Gryniewicz- HISTIOCYTIC SARCOMA OF THE CENTRAL NERVOUS SYSTEM. CASE Oct 18 Poster 74 Kwiatkowska, Olga REPORT. 1430

PRESENTATION OF LANGERHANS CELL HISTIOCYTOSIS IN 9-MONTH Oct 18 Halbert, Jay Poster 61 OLD MONOZYGOTIC TWINS WITH A REVIEW OF THE LITERATURE. 1430

A CASE OF CONCURRENT OCCURRENCE OF ERDHEIM-CHESTER Oct 18 Hong, Joon Pyo Poster 74 DISEASE AND LEUKEMIA IN A CHILD 1430 FACTORS ASSOCIATED WITH ETOPOSIDE USAGE IN CHILDREN WITH Oct 18 Horne, AnnaCarin MACROPHAGE ACTIVATION SYNDROME COMPLICATING SYSTEMIC Poster 43 JUVENILE IDIOPATHIC ARTHRITIS 1430 SURVIVAL AFTER HEMATOPOIETIC STEM CELL TRANSPLANTATION IN Oct 18 Horne, AnnaCarin HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS COMPARED TO SEVERE Poster 43 COMBINED IMMUNE DEFICIENCY AND SEVERE APLASTIC ANEMIA 1430 Presidential BLOOD SPECIFIC ACTIVATION OF HIF-1α/HIF-1β CAUSES HLH Oct 17 Huang, Gang Symposium 37 IMMUNOPATHOLOGY IN C57BL/6 MICE 1600 SS II

A PHASE II TRIAL OF LENALIDOMIDE IN ADULTS WITH HISTIOCYTE Oct 18 Jacobsen, Eric Poster 62 DISORDERS 1430 Oct 18 Jin, Zhili THE ROLE OF G-CSF IN ADULT HLH Poster 43 1430

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PRESENTING AUTHOR INDEX

DATE AUTHOR ABSTRACT TITLE SESSION PAGE TIME Presidential A COMBINATION OF ATG AND ETOPOSIDE FOR THE TREATMENT OF Oct 17 Jordan, Michael Symposium 35 HLH: RESULTS OF THE HIT-HLH TRIAL 1600 SS II

ACRAL SCLEROSING HISTIOCYTIC NODULES: A NEW ENTITY IN Oct 18 Keshavamurthy, Vinay Poster 62 CUTANEOUS HISTIOCYTOSIS? 1430

PITUITARY STALK THICKENING AND DIABETES INSIPIDUS Oct 18 Kizilocak, Hande Poster 62 PROCEEDING TO LANGERHANS CELL HISTIOCYTOSIS 1430 CLINICAL PROFILE AND BRAF STATUS OF ADULT LANGERHANS CELL Oct 18 Kobayashi, Masayuki HISTIOCYTOSIS IN JAPAN: TEN-YEAR SINGLE INSTITUTION Poster 63 EXPERIENCE 1430 THE METRONOMIC CHEMOTHERAPY AND ITS POTENTIAL ROLE IN Oct 18 Krenova, Zdenka TREATMENT OF HISTIOCYTIC DISORDERS REVISITED IN THE ERA OF Poster 63 CANCER IMMUNOLOGY REVIVAL 1430

MULTIPLY RECURRENT LCH OF THE SKIN SUCCESSFULLY TREATED Oct 18 Kutny, Matthew Poster 63 WITH INDOMETHACIN 1430

CLINICAL FEATURES AND PROGNOSIS OF HEMOPHAGOCYTIC Oct 18 Lai, Wenyuan Poster 44 LYMPHOHISTIOCYTOSIS WITH EPSTEIN-BARR VIRUS INFECTION 1430 CHARACTERISTICS OF PATIENTS WITH PARTIAL OCULO-CUTANEOUS ALBINISM AND IMMUNODEFICIENCY ASSOCIATED HEMOPHAGOCYTIC Oct 18 Lam, My T. Poster 44 LYMPHOHISTIOCYTOSIS AT THE CHILDREN'S HOSPITAL 1 HO CHI 1430 MINH CITY

PROSPECTIVE GENOMIC PROFILING OF HISTIOCYTOSES IDENTIFIES Oct 19 Lee, Lynn SS IV 76 NOVEL MUTATIONS AND THERAPY OPTIONS 1030 ADMINISTRATION OF PARENTERAL EXOGENOUS NOXA IN Oct 18 Lehmberg, Kai MUNCHHAUSEN SYNDROME BY PROXY CAN ELICIT THE FULL Poster 45 PICTURE OF HLH 1430

AN UNUSUAL PRESENTATION OF HEMOPHAGOCYTIC Oct 18 Levendoglu-Tugal, Oya Poster 45 LYMPHOHISTIOCYTOSIS IN A PREMATURE INFANT 1430

HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS IN AN INFANT WITH Oct 18 Levendoglu-Tugal, Oya Poster 45 KABUKI SYNDROME 1430

PLASMA PROTEIN PROFILES DISTINGUISH HEMOPHAGOCYTIC Oct 17 Lin, Howard SS I 33 LYMPHOHISTIOCYTOSIS FROM SEPSIS AND SIRS 1400 CLINICAL ANALYSIS OF 6 CASES WITH SUBCUTANEOUS Oct 18 Lin, Wu PANNICULITIS-LIKE T-CELL LYMPHOMA ASSOCIATED Poster 46 HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS 1430 ADSORPTIVE DEPLETION OF BLOOD MONOCYTES REDUCES THE Oct 18 Lourda, Magdalini LEVELS OF CIRCULATING INTERLEUKIN-17A IN LANGERHANS CELL Poster 53 HISTIOCYTOSIS 1430 INCIDENCE OF HLH CNS RELAPSE AFTER TREATMENT WITH Oct 18 Marsh, Rebecca REDUCED INTENSITY CONDITIONING HEMATOPOEITIC STEM CELL Poster 46 TRANSPLANT 1430 A MULTIDISCIPLINARY APPROACH TO A MULTIDISCIPLINARY Oct 18 Martin, Andrew PROBLEM, THE DEVELOPMENT OF THE HEMOPHAGOCYTIC Poster 46 LYMPHOHISTIOCYTOSIS TASKFORCE. 1430 YTIC LYMPHOHISTIOCYTOSIS (HLH) IN ADULT RECIPIENTS OF VENTRICULAR ASSIST DEVICES (VADS) FOR CARDIOMYOPATHY (CM) Oct 18 Martin, Beth Ann Poster 47 AND FAVORABLE OUTCOMES IN SUBSEQUENT ORTHOTOPIC HEART 1430 TRANSPLANTATION (OHT)

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DATE AUTHOR ABSTRACT TITLE SESSION PAGE TIME

TCR αβ-DEPLETED HEMATOPOIETIC STEM CELL TRANSPLANTATION Oct 19 Maschan, Michael IN PATIENTS WITH PRIMARY HEMOPHAGOCYTIC SS IV 77 LYMPHOHISTIOCYTOSIS 1030

RITUXIMAB TREATMENT FOR PATIENTS WITH NEURODEGENERATIVE Oct 18 McClain, Kenneth LANGERHANS CELL HISTIOCYTOSIS DEMONSTRATING INTELLECTUAL Poster 64 AND PROPRIOCEPTIVE DEFICITS 1430

DEVELOPMENT AND INITIAL VALIDATION OF THE "MH SCORE", A Presidential DIAGNOSTIC TOOL THAT DIFFERENTIATES PRIMARY Oct 17 Minoia, Francesca Symposium 35 HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS FROM MACROPHAGE 1600 ACTIVATION SYNDROME SS II THE ASSOCIATION BETWEEN ORGAN INVOLVEMENTS AND SURVIVAL Oct 18 Morimoto, Akira IN CHILDREN WITH LANGERAHANS CELL HISTIOCYTOSIS; THE Poster 64 RESULTS OF JLSG-96/02 STUDY 1430

CO-OCCURRENCE OF LANGERHANS CELL HISTIOCYTOSIS AND Oct 18 Moschovi, Maria Poster 64 INTERMEDIATE TYPE OSTEOPETROSIS IN A MALE CHILD 1430 ECOLOGY OF MERKEL CELL POLYOMAVIRUS IN HEALTHY SKIN Oct 18 Murakami, Ichiro SHOWS A CLOSE AGREEMENT WITH INTERLEUKIN-1 LOOP MODEL IN Poster 53 LANGERHANS CELL HISTIOCYTOSIS 1430 NATIONAL WEB-BASED MEETINGS HELP TO IDENTIFY HISTIOCYTOSIS Oct 18 Nanduri, Vasanta PATIENTS WITH REFRACTORY DISEASE OR SEQUELAE WHO NEED Poster 65 INDIVIDUALISED OR NOVEL TREATMENT STRATEGIES 1430

INFECTION AND HEMOPHAGOCYTIC SYNDROME: SINGLE CENTER Oct 18 Ozdemir, Nihal Poster 47 EXPERIENCE 1430

LANGERHANS CELL HISTIOCYTOSIS FOLLOWING BURKITT Oct 18 Ozdemir, Nihal Poster 65 LYMPHOMA 1430 BEAD EMBOLIZATION OF SPLEEN AS TREATMENT FOR Oct 18 Padrnos, Leslie HEMATOPHAGOCYTIC LYMPHOHISTIOCYTOSIS ASSOCIATED WITH Poster 47 NON-HODGKINS LYMPHOMA 1430

CLINICAL COURSE OF CHILDREN WITH SINGLE SYSTEM BONE Oct 18 Papadakis, Vassilios Poster 65 LANGERHANS CELL HISTIOCYTOSIS (LCH) 1430

PROGRESSIVE ISOLATED PITUITARY STACK THICKENING IN Oct 18 Papadakis, Vassilios Poster 66 PATIENTS WITH DIABETES INSIPIDUS: MANAGEMENT DILEMMAS 1430

Peckham-Gregory, AN INHERITED GENETIC VARIANT IN SMAD6 INCREASES Oct 18 SS III 39 Erin SUSCEPTIBILITY TO LANGERHANS CELL HISTIOCYTOSIS 1300

CENTRAL NERVOUS SYSTEM INVOLVEMENT IN HEMOPHAGOCYTIC Oct 18 Pei, Ruijun Poster 47 LYMPHOHISTIOCYTOSIS 1430

CLINICAL PRESENTATION, MANAGEMENT AND OUTCOME OF Oct 18 Petrikkos, Loizos Poster 66 LANGERHANS CELL HISTIOCYTOSIS (LCH) IN CHILDREN 1430

REVISITING THE NEUROPATHOLOGY OF CENTRAL NERVOUS SYSTEM Oct 18 Picarsic, Jennifer Poster 66 LANGERHANS CELL HISTIOCYTOSIS 1430 THE ROLE OF INTERLEUKIN-I RECEPTOR ANTAGONIST, ANAKINRA IN CRITICALLY ILL ADULT PATIENTS WITH HEMOPHAGOCYTIC Oct 18 Puri, Akshjot Poster 48 LYMPHOHISTIOCYTOSIS AND MACROPHAGE ACTIVATION 1430 SYNDROME, A REVIEW OF SIX CASES

CLADRYBINE TREATMENT IN PATIENTS WITH PULMONARY Oct 18 Radzikowska, Elzbieta Poster 67 LANGERHANS CELL HISTIOCYTOSIS 1430

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DATE AUTHOR ABSTRACT TITLE SESSION PAGE TIME

CD207+/CD1A+ CIRCULATING CELLS ARE PRESENT IN PATIENTS WITH Oct 18 Rosso, Diego Poster 53 ACTIVE LANGERHANS CELL HISTIOCYTOSIS 1430

Santa-Maria Lopez, CLINICAL USE OF BRAF MUTATIONS PROFILE IN LCH PATIENTS FOR Oct 18 Poster 67 Vicente DIAGNOSIS AND MONITORING OF TREATMENT RESPONSE 1430 Oct 18 Sawatkar, Gitesh IMATINIB FOR THE TREATMENT OF XANTHOMA DISSEMINATUM Poster 75 1430

INFLAMMATORY PLASMA PROTEINS CLASSIFIERS PREDICT DISEASE Oct 18 Scull, Brooks SS III 39 SEVERITY AND RESPONSE TO THERAPY IN PATIENTS WITH LCH 1330

FREQUENCIES OF GENETIC ALTERATIONS IN KOREAN CHILDREN Oct 18 Seo, Jong Jin Poster 67 WITH LANGERHANS CELL HISTIOCYTOSIS 1430

POLYGENIC MUTATIONS IN THE CYTOTOXICITY PATHWAY INCREASE Oct 17 Sepulveda, Fernando SS I 33 SUSCEPTIBILITY TO DEVELOP HLH IMMUNOPATHOLOGY IN MICE 1400

REPORT OF 2 RARE CASES OF LANGERHANS CELL HISTIOCYTOSIS Oct 18 Shamsian, Bibi Shahin Poster 68 (LCH) WITH SEVERE PALPEBRAL INVOLVEMENT 1430 REACTIVATION AND LONG-TERM OUTCOME OF PEDIATRIC-ONSET Oct 18 Shioda, Yoko LANGERHANS CELL HISTIOCYTOSIS; 50 YEARS' EXPERIENCE AT A Poster 68 SINGLE CENTER 1430 A MULTIDISCIPLINARY APPROACH TO EARLY DETECT NEURODEGENERATIVE LANGERHANS CELL HISTIOCYTOSIS (ND-LCH) Oct 19 Sieni, Elena SS IV 77 AND MONITOR RESPONSE TO INTRAVENOUS IMMUNOGLOBULIN 1030 (IVIG) TREATMENT Oct 18 Silva, Sonia ERDHEIM-CHESTER DISEASE IN A TODDLER GIRL Poster 75 1430

A HIGHLY SENSITIVE, CLINICALLY-VALIDATED ASSAY TO QUANTITATE Suarez Ferguson, Oct 18 BRAF p.V600E MUTATIONS IN BLOOD AND BONE MARROW SAMPLES SS III 40 Lizmery OF LANGERHANS CELL HISTIOCYTOSIS PATIENTS 1330

TREATMENT OF HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS WITH ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION USING Oct 18 Sun, Yuan Poster 48 THE CONDITIONING REGIMEN WITH BUSULFAN AND FLUDARABINE: A 1430 SINGLE-CENTER STUDY OF 38 CASES

BEYOND FATTY LIVER OF PREGNANCY: A CASE OF HLH IN A 20 YEAR Oct 18 Taparia, Minakshi Poster 48 OLD FEMALE 1430 HAPLOIDENTICAL STEM CELL TRANSPLANTATION WITH POST TRANSPLANT CYCLOPHOSPHAMIDE IN HAEMOPHAGOCYTIC Oct 18 Uppuluri, Ramya Poster 49 LYMPHOHISTIOCYTOSIS : THE JOURNEY TO SUCCESSFUL 1430 ENGRAFTMENT AND CURE CHEST CT IMAGING FEATURES IN PEDIATRIC PULMONARY Oct 18 Valle, Valeria Della LANGERHANS CELL HISTIOCYTOSIS: ALVEOLAR CONDENSATION AS Poster 68 A POSSIBLE MANIFESTATION OF THE DISEASE 1430 PULMONARY LANGERHANS CELL HISTIOCYTOSIS IN CHILDREN: CT Oct 18 Valle, Valeria Della IMAGING FEATURES IN A COHORT OF 48 PATIENTS WITH LUNG Poster 69 INVOLVEMENT AND PROPOSAL OF SCORING. 1430

BRAF V600E MUTATION IN PEDIATRIC LANGERHANS CELL Oct 18 Wang, Dong Poster 69 HISTIOCYTOSIS AND ITS CLINICAL SIGNIFICANCE 1430

HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS WITH CHILDREN AND Oct 18 Wang, Yini ADULT: THE REGISTRATION DATA FROM BEIJING HLH WORKGROUP, Poster 49 CHINA 1430

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DATE AUTHOR ABSTRACT TITLE SESSION PAGE TIME HAPLOIDENTICAL HEMATOPOIETIC STEM CELL TRANSPLANTATION Oct 17 Wang, Zhao FOR ADULT PATIENTS WITH EPSTEIN-BARR VIRUS-ASSOCIATED SS I 34 HAEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS 1400 PEG-ASPARGASE AND DEP REGIMEN COMBINATION THERAPY FOR Oct 18 Wang, Zhao REFRACTORY EPSTEIN-BARR VIRUS-ASSOCIATED Poster 50 HEMOPHAGOCYTIC SYNDROME 1430

DISSEMINATED JUVENILE XANTHOGRANULOMA (DXJ) IN Oct 18 Werneck, Fernando Poster 75 ADOLESCENT; CASE REPORT 1430 Oct 18 Whipple, Nicholas ATYPICAL ISOLATED CNS PRESENTATION OF FAMILIAL HLH Poster 50 1430

Willemes Batalha, LANGERHANS CELL HISTIOCYTOSIS: A 30-YEAR BRAZILIAN Oct 18 Poster 69 Anna Beatriz EXPERIENCE 1430

NEURODEGENERATIVE LANGERHANS CELL HISTIOCYTOSIS: ARE Oct 18 Wong, Debra Poster 70 PEDIATRIC THERAPIES EFFECTIVE IN THE ADULT POPULATION? 1430 CLINICAL PRESENTATION AND OUTCOME OF PEDIATRIC PATIENTS Oct 18 Xu, Xiao-Jun WITH HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS IN CHINA: A Poster 51 RETROSPECTIVE MULTICENTER STUDY 1430

CENTRAL NERVOUS SYSTEM PERFUSION PATTERNS IN CHILDHOOD Oct 19 Yeom, Kristen SS IV 77 LANGERHANS CELL HISTIOCYTOSIS 1030 LARGE STRUCTURAL AND EPIGENETIC DEFECTS IN HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH) ASSOCIATE Oct 18 Zhang, Kejian Poster 51 GENES THAT ARE RESPONSIBLE FOR THE DEVELOPMENT OF 1430 CLINICAL HLH Oct 18 Zhao, Xiaoxi TOUCHING ON HLH INDICATING VALUE OF SERUM FERRITIN Poster 51 1430 CRANIOFACIAL AND INTRACRANIAL MANIFESTATIONS OF Oct 18 Zhao, Yunze LANGERHANS CELL HISTIOCYTOSIS IN CHILDREN: ANALYSIS OF 232 Poster 59 CASES 1430 SYMPTOMS, IMAGING FINDINGS AND OUTCOMES OF 179 CHILDREN Oct 18 Zhao, Yunze WITH HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS WHO HAVE Poster 50 CENTRAL NERVOUS SYSTEM (CNS) INVOLVEMENT 1430

ELEVATED CSF OSTEOPONTIN AND PERIPHERAL BLOOD CELLS WITH Oct 18 Zinn, Daniel BRAF MUTATIONS IN PATIENTS WITH LANGERHANS CELL Poster 36 HISTIOCYTOSIS-ASSOCIATED NEURODEGENERATION 1430

TREATING THE ADULT IDIOPATHIC ENTITY OF HLH WITH ETOPOSIDE, Oct 18 Zondag, Timo Poster 52 A CASE SERIES AND REVIEW OF LITERATURE 1430

88 HISTIOCYTE SOCIETY ANNUAL MEETING 2016

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October 2-4, 2017 Singapore

Registration Opens in April www.histiocytesociety.org/2017mtg

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