DOI: 10.1002/hon.2437 ORAL PRESENTATIONS KEY NOTE LECTURES M.A. Shipp* Division of Hematologic Neoplasia, Dana‐Farber Cancer Institute, Boston, 1 USA HENRY KAPLAN MEMORIAL LECTURE: “IMMUNOTHERAPY COMES OF AGE TO Genetic signatures of lymphoid malignances identify key signaling and TREAT LYMPHOMAS” survival pathways and associated therapeutic vulnerabilities. Increas- ing evidence suggests that specific lymphoid malignances utilize R. Levy* genetic bases of immune evasion to limit recognition and avoid attack. ‐ Medicine, Stanford University, Stanford, USA We previously identified near universal copy number alternations (CNA) of 9p24.1/CD274(PD‐L1)/ PDCD1LG2(PD‐L2) and associated Introduction: The advent of Monoclonal Antibodies, first made by the increased expression of the two PD‐1 ligands in classical Hodgkin lym- method of Kohler and Milstein, ushered in a new era of treatment for phoma (cHL) and a related lymphoid malignancy, primary mediastinal cancer. Originally, the targets for antibodies were on the tumor. More large B‐cell lymphoma (MLBCL). In these lymphomas, the extended recently, additional targets on the host immune system “Checkpoints” 9p24.1 amplicon also includes JAK2, of note because JAK/STAT signal- have enter our therapeutic tool kit. ing further induces PD‐1 ligand transcription. These observations Methods: The first target was the idiotype of the B cell tumor surface defined 9p24.1 gain as a genetic alteration that increased the gene immunoglobulin. This required a new antibody custom‐made product dosage of the PD‐1 ligands and their induction via JAK/STAT signaling for each patient. Later, an antibody against the CD20 molecule, origi- in specific lymphoid malignances. In additional studies, PD‐1 and PD‐L2 nally described by Nadler and Scholssman, was substituted because it were also infrequently identified as chromosomal translocation part- was a single product for all patients, even though it is present on all ners in cHL and MLBCL. normal mature B cells as well as lymphoma cells. PD‐1 signaling triggers the dephosphorylation of proximal components Results: Rituximab and a number of new versions of antibodies against of the T‐cell receptor complex and inhibition of T‐cell activation and CD20 are included in the standard of care for patients with B cell lym- proliferation, termed “T‐cell exhaustion.” The genetic bases for phoma. New targets are emerging and new forms of monoclonal anti- enhanced PD‐1 ligand expression in cHL and MLBCL prompted clinical bodies that bind to two different targets or that carry drugs are in evaluation of PD‐1 blockade in these diseases. In patients with widespread testing. A special version of an engineered T cell that carries relapsed/refractory cHL, pilot and registration trials of two different a receptor incorporating the recognition unit of an antibody against PD‐1 blocking antibodies, nivolumab and pembrolizumab, revealed CD19 (CAR‐T cells) is the latest and most exciting of these engineered response rates of ~70% with many long‐term remissions. In patients therapies. But, once again this is a patient‐specific, customized therapy. with relapsed/refractory MLBCL, a pilot study of PD‐1 blockade Antibodies against the host immune system (i.e. PD1) are rapidly revealed a response rate of ~40%; a national/international follow up changing the field of cancer treatment and especially of Hodgkin's trial is ongoing. These data established that lymphoid malignancies Disease, where durable response rates in excess of 80% have been with genetic bases of increased PD‐1 ligand expression are very sensi- observed, even in relapsed/refractory patients. tive to PD‐1 blockade, prompting the development of clinical trials at Conclusions: Immunotherapy is now one of the mainstays of treat- earlier stages of treatment. ment for lymphoma. The field is moving rapidly and we can anticipate More recently, we have identified two additional large cell lymphoma even newer versions of immune system therapies and combinations subtypes with frequent 9p24.1 alterations ‐ primary central nervous with existing targeted and cytotoxic therapies in the future. system lymphoma (PCNSL) and primary testicular lymphoma (PTL). In Keywords: immune system. patients with relapsed/refractory PCNSL and PTL, pilot studies of PD‐l blockade with nivolumab revealed a high response rate and 2 long‐term remissions and a national/international phase II trial is GIANNI BONADONNA MEMORIAL ongoing. LECTURE: “GENETIC SIGNATURES AND Important questions include the precise mechanisms of response and TARGETABLE PATHWAYS IN LYMPHOID resistance to PD‐1 blockade in specific lymphoid malignancies and MALIGNANCIES” the optimal way to utilize this promising treatment strategy at earlier Hematological Oncology. 2017;35(S2):23–148.wileyonlinelibrary.com/journal/hon © 2017 The Authors. Hematological Oncology 23 published by John Wiley & Sons, Ltd. 24 ABSTRACT timepoints in treatment. The data also prompt speculation regarding PLENARY SESSION additional targetable genetic bases of immune evasion in other lym- phoid malignancies. 4 INTERIM REPORT FROM A PHASE 2 3 MULTICENTER STUDY OF TAZEMETOSTAT, JOHN ULTMANN MEMORIAL LECTURE: AN EZH2 INHIBITOR, IN PATIENTS WITH ‐ “GENOMES IN TRANSIT: WHAT RELAPSED OR REFRACTORY B CELL ‐ MULTI‐OMICS CAN TELL US ON NON HODGKIN LYMPHOMAS LYMPHOMAS” F. Morschhauser1* | G. Salles2 | P. McKay3 | H. Tilly4 | A. Schmitt5 | J. Gerecitano6 | P. Johnson7 | S. Le Gouill8 | R. Siebert* M.J. Dickinson9 | C. Fruchart10 | T. Lamy11 | A. Chaidos12 | 13 14 15 16 Institute of Human Genetics, University of Ulm & University Hospital of W. Jurczak | S. Opat | J. Radford | P.L. Zinzani | 17 18 19 20 Ulm, Ulm, Germany S. Assouline | G. Cartron | A. Clawson | N. Picazio | S. Ribich21 | S.J. Blakemore22 | J. Larus23 | H. Miao24 | Since the first detection of recurrent chromosomal aberrations in P.T. Ho25 | V. Ribrag26 malignant lymphomas back in the 1970s a wealth of data has been 1 accumulated showing that lymphoma cells differ from their normal Department of Hematology, Centre Hospitalier Universitaire, Lille, 2 ‐ ‐ counterparts on the various levels of cellular information. Despite France; Hematology, Lyon Sud Hospital Center, Pierre Bénite, France; 3 being limited by the resolution, throughput und costs of the analyses Haematology, North Glasgow University Hospitals, Glasgow, UK; 4 the pioneering cytogenetic, molecular cytogenetic as well as targeted Hematology, Centre de lutte Contre le Cancer Henri Becquerel, Rouen, 5 6 molecular and RNA expression analyses unraveled important informa- France; Hematology, Institut Bergonié, Bordeaux, France; Department tion on lymphoma biology and clinical behavior. The data obtained by of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA; 7 these technologies have been fundamental for the present classifica- Medical Oncology, Southampton General Hospital, Southampton, UK; 8 tion of lymphomas. Service d'Hématologie Clinique, Universite De Nantes, Nantes, France; 9 The recent years have seen dramatic technological developments Department of Haematology, Peter MacCallum Cancer Centre, 10 allowing the comprehensive profiling of malignant lymphomas on Melbourne, Australia; Hematologie, Centre François Baclesse, Caen, 11 various OMICs levels. Considering cellular information encoded in France; Service d'Hématologie Clinique, CHU de Rennes, Rennes, 12 nucleic acids high throughput sequencing technologies now enable France; Haematology, Hammersmith Hospital, London, UK; 13 14 the in‐depth investigation of the whole genome as well as the var- Haematology, UJCM, Krakow, Poland; Clinical Haematology, Monash 15 ious layers of the epigenome and transcriptome with a base‐pair University, Clayton, Australia; Molecular & Clinical Cancer Sciences (L5), 16 resolution. Nevertheless, the integrated analysis of these multiple The University of Manchester, Manchester, UK; Hematology, University 17 layers of nucleic acid information is still at its beginning. In this con- of Bologna, Bologna, Italy; Oncology, McGill University, Montreal, 18 text it is important to recognize, that information encoded in nucleic Canada; Department of Hematology, CHU Montpellier, Montpellier, 19 20 acids is in many aspects “fluent”: genomic information transits from France; Biostatistics, Epizyme, Morrisville, USA; Clinical Operations, 21 DNA via epigenomic regulation and expression patterns of RNA to Epizyme, Cambridge, USA; Biological Sciences, Epizyme, Cambridge, 22 23 its ultimate function. Moreover, during tumor evolution the informa- USA; Translational Medicine, Epizyme, Cambridge, USA; Clinical Data 24 tion at all these levels transits from the germline state via driving Sciences, Epizyme, Cambridge, USA; Oncology Clinical Development, 25 changes to complex aberration patterns. Additionally, the informa- Epizyme, Cambridge, USA; Oncology Clinical Development, Epizyme, 26 tion transits from mother to daughter cells which in turn receive Cambridge, USA; Haematology, Gustave Roussy, Villejuif, France further information from environmental factors. Thus, “a” lymphoma Background: New treatments with novel mechanisms of action are is indeed an ecosystem with multiple interacting levels of informa- needed for patients with relapsed/refractory (R/R) DLBCL and FL. tional dysregulation which unlikely is comprehensively described Because tumor cells may depend on the histone methyltransferase by targeted re‐sequencing on DNA level or transcriptional profiling EZH2 to perpetuate a less‐differentiated state, and activating