9Q486_HemaSphereBooklet_V5_53019_FLIPBOOK-compressed

24th EHA Congress Edition

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ront cover page.pdf 1 5/8/19 10:45 AM EDITORIAL BOARD

Editors-in-Chief Andreas Engert, MD University of Cologne, Cologne, Germany

Jan Cools, PhD VIB-KU Leuven Center for Cancer Biology, Leuven, Belgium

Associate Editors

24th EHA Congress Edition Stephen Ansell , Mayo Clinic, Rochester, MN, USA Paolo Corradini , Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy Martin Dreyling , Klinikum der Universität München, Germany Jeroen Eikenboom , Leiden University Medical Centre, Leiden, The Netherlands Stefan Froehling , National Center for Tumor Diseases (NCT) Heidelberg, Germany Paolo Ghia , Università Vita-Salute San Raffaele, Milan, Italy Claire Harrison , Guy’s and St Thomas’ NHS Foundation Trust, London, UK Robert Hills , University of Oxford, UK Elizabeth Macintyre , Hôpital Necker-Enfants Malades et Université Paris, France

Martina Muckenthaler , University of Heidelberg, Germany Juerg Schwaller , University Hospital Basel, Switzerland Evangelos Terpos , University of Athens, Greece

Simon Hallam , St.Bartholomew’s Hospital, Barts Health NHS Trust, London, UK Michael Milsom , German Cancer Research Center (DKFZ), Heidelberg, Germany Melania Tesio , Institute Necker des Enfantes Malades, Paris, France Francesca Vinchi , Heidelberg University Hospital, Germany/NY Blood Center, USA Roger Schutgens , University Medical Center Utrecht, the Netherlands Scientific Editors

Editorial Coordinators Frederique Belliard f.belliard@ehaweb.org

Ciaran Finn hemasphere@wolterskluwer.com

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LETTER FROM THE EDITORS

HemaSphere was launched in 2017 as the official journal of the European Hematology Association (EHA). HemaSphere is not just another online journal in the field of hematology, but aims to support hematology researchers by offering a fast and constructive review process, full open access and low publication fees. The journal publishes basic, translational and clinical research of very high level as well as insightful review articles with recommendations for future research and clinical applications. A series of review articles on CAR-T cell therapy was published in 2019. HemaSphere is also a hematology information resource, with discussions and opinions on recent evolutions published in the HemaTopics section of the journal. PubMed Central ® is reviewing the journal’s application for indexing and a decision is expected soon.

Andreas Engert, MD Prof. Dr. Andreas Engert is a specialist in Internal Medicine, Hematology and Oncology at the University Hospital in Cologne, Germany. He is the chairman of the German Hodgkin Study Group (GHSG). Based on a number of experimental research model, the treatment of Hodgkin lymphoma has substantially improved with nearly 20.000 Hodgkin lymphoma patients treated within GHSG clinical

trials. More recently, targeted drugs such as checkpoint inhibitors opened new perspectives for Hodgkin lymphoma that will lead to further reduction of chemo- and radiotherapy in this disease.

Jan Cools, PhD Jan Cools is Professor at the Center for Cancer Biology of VIB and KU Leuven (Leuven, Belgium). His research focuses on the genetics of acute lymphoblastic leukemia and on the development of mouse models to study the role of oncogenes.

ront cover page.pdf 1 5/8/19 10:45 AM CAR T CELLS: A SNAPSHOT ON THE GROWING OPTIONS TO DESIGN A CAR Holzinger, Astrid; Abken, Hinrich HemaSphere : February 2019 - Volume 3 - Issue 1 - p e172

24th EHA Congress Edition Adoptive cell therapy of malignant diseases with chimeric antigen receptor (CAR) modified T cells rapidly advanced from pre-clinical models to commercial approvals within 2 decades. CARs redirect patient’s T cells towards cancer cells and activate the engineered cells for a cytolytic attack resulting in the destruction of the cognate target cell. CAR T cells have demonstrated their powerful capacities in inducing complete and lasting remissions of leukemia/

lymphoma in an increasing number of trials worldwide. Since the early 90’s, the design of CARs went through various steps of optimization until the very recent developments which include CARs with logic gating in the recognition of antigen patterns on target cells and TRUCKs with a target recognition induced delivery of immune modulating agents. Here we review the generations in CAR design, the

impact of specific modifications, the strategies to improve the safety of CAR T cell therapy, and the challenges to adapt the CAR design for broader applications.

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CONTROVERSIES IN THE TREATMENT OF CLASSICAL HODGKIN LYMPHOMA

Dennis A. Eichenauer; Marc André; Peter Johnson; Alexander Fossa; Oliver Casasnovas; Andreas Engert HemaSphere : October 2018 - Volume 2 - Issue 5 - p e149

Hodgkin lymphoma (HL) is a B-cell-derived malignancy that mostly affects young adults. Pathologically, HL is divided into classical HL (cHL) and the rare entity of nodular lymphocyte-predominant HL. Classical HL is characterized by few malignant cells termed Hodgkin and Reed–Sternberg cells embedded in an inflammatory background. The treatment of cHL has consistently improved over the last decades so that current standard approaches result in long-term remission rates in excess of 80%. However, potentially lethal therapy-related late complications affect an increasing number of survivors. For this reason, issues regarding the optimal treatment of cHL patients are still fiercely debated. Questions under discussion include how treatment can be guided by interim positron emission tomography, the best initial treatment for advanced-stage disease and the use of targeted drugs such as the antibody–drug conjugate brentuximab vedotin and the anti-PD-1 antibodies nivolumab and pembrolizumab. The identification of patients who should undergo allogeneic stem cell transplantation is another unsolved issue. The present article highlights the most relevant clinical trials and addresses controversial open questions in the treatment of cHL.

Despite substantial progress, there are still major controversies in Hodgkin lymphoma including the choice of treatment as well as how to best integrate checkpoint inhibitors, both, in first-line and the relapsed setting.

- Dennis Eichenauer

MEET THE FIRST AUTHOR Dr. Dennis A. Eichenauer is a specialist in internal medicine, hematology and oncology at the University Hospital Cologne, Germany. He is associated with the German Hodgkin Study Group since 2007. His major research focus in the recent years has been the rare entity of nodular lymphocyte-predominant Hodgkin lymphoma. He served as trial secretary in a number of prospective studies conducted by the German Hodgkin Study Group.

FROM BIOLOGY TO THERAPY: THE CLL SUCCESS STORY

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Deyan Y. Yosifov; Christine Wolf; Stephan Stilgenbauer; Daniel Mertens HemaSphere : April 2019 - Volume 3 - Issue 2 - p e175

24th EHA Congress Edition Chemoimmunotherapy has been the standard of care for patients with chronic lymphocytic leukemia (CLL) over the last decade. Advances in monoclonal antibody technology have resulted in the development of newer generations of anti-CD20 antibodies with improved therapeutic effectiveness. In parallel, our knowledge about the distinctive biological characteristics of CLL has progressively deepened and has revealed the importance of B-cell receptor (BCR) signaling and upregulated antiapoptotic proteins for survival and expansion of malignant cell clones. This knowledge provided the basis for development of novel targeted agents that revolutionized treatment of CLL. Ibrutinib and idelalisib inhibit the Bruton tyrosine kinase (BTK) and phosphoinositide 3-kinase (PI3K) delta, respectively, thus interfering with supportive signals coming from the microenvironment via the BCR. These drugs induce egress of CLL cells from secondary lymphoid organs and remarkably improve clinical outcomes, especially for patients with unmutated immunoglobulin heavy-chain genes or with p53 abnormalities that do not benefit from classical treatment schemes. Latest clinical trial results have established ibrutinib with or without anti-CD20 antibodies as the preferred first-line treatment for most CLL patients, which will reduce the use of chemoimmunotherapy in the imminent future. Further advances are achieved with venetoclax, a BH3-mimetic that specifically inhibits the antiapoptotic B-cell lymphoma 2 protein and thus

causes rapid apoptosis of CLL cells, which translates into deep and prolonged clinical responses including high rates of minimal residual disease negativity. This review summarizes recent advances in the development of targeted CLL therapies, including new combination schemes, novel BTK and PI3K inhibitors, spleen tyrosine kinase inhibitors, immunomodulatory drugs, and cellular immunotherapy.

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Achille Iolascon; Lucia De Franceschi; Martina Muckenthaler; Ali Taher; David Rees; Mariane de Montalembert; Stefano Rivella; Androulla Eleftheriou; Maria Domenica Cappellini HemaSphere : June 2019 - Volume 3 - Issue 3 - p e208 The inherited disorders of hemoglobin, which include sickle cell disease and thalassemias, are the most common and widespread distributed monogenic disorders. Due to a selective advantage in malaria regions, these hemoglobin defects are particularly frequent in Africa, Asia, or in the Mediterranean areas, where malaria was endemic until the last century. In recent decades, the globalization of migration has contributed to generate multiethnic European societies. Due to migration from countries or regions with high hemoglobinopathy frequencies such as Africa, Middle East, or Asia, large numbers of patients with these disorders are living in almost every European country today. Furthermore, the numbers are increasing because of increasing refugee flows toward Europe. Additional requirements are the development of European recommendations and guidelines for diagnosis and effective therapeutic approaches. These, together with the advancement of clinical trials using new drugs and therapeutic procedures could ameliorate the quality of life of patients affected with these diseases and increase their life expectancy. Lastly, coordinated efforts should be made to develop diagnostic pathways for thalassemias and hemoglobinopathies, in order to plan interventions, including prenatal diagnosis and cure. For these reasons, the development of new tools to reliably diagnose anemias is urgently needed and fits well with the needs of personalized medicine. In the last 15 years, hematology research has made many big leaps forward. Our general aimwill be to solve several hematologic problems using these new approaches. We expect that the development of such a diagnostic tool will improve timely diagnosis throughout Europe, especially in those countries where it is difficult to gain access to “classical” diagnostic tests. EHA RESEARCH ROADMAP ON HEMOGLOBINOPATHIES AND THALASSEMIA: AN UPDATE MEET THE FIRST AUTHOR Prof. Achille Iolascon is Professor of Medical Genetics at the University Federico II of Naples (Italy) and chairman of the Clinical Unity of medical genetics. His interest in pediatric hematology dates to 1978, when he began to study hemoglobinopathies, thalassemia syndromes and related red cell diseases. He made pivotal studies in red cell membrane

disorders (such as hereditary spherocytosis, elliptocytosis and stomatocytoses) and on congenital diserythropoietic anemias. AUTHOR’S INSIGHTS Hemoglobinopathies are an emerging health problem in European countries due to migratory fluxes. Hematologists must be aware of this and have to know how to manage these situations. New therapeutical approaches could improve the life expectancy of these patients.

24th EHA Congress Edition Previous retroviral and knock-in approaches to model human t(11;19)+ acute mixed-lineage leukemia in mice resulted in myeloproliferation and acute myeloid leukemia not fully recapitulating the human disease. The authors established a doxycycline (DOX)-inducible transgenic mouse model “iMLL-ENL” in which induction in long-term hematopoietic stem cells, lymphoid primed multipotent progenitor cells, multipotent progenitors (MPP4) but not in more committed myeloid granulocyte-macrophage progenitors led to a fully reversible acute leukemia expressing myeloid and B-cell markers. iMLL-ENL leukemic cells generally expressed lower MLL-ENL mRNA than those obtained after retroviral transduction. Disease induction was associated with iMLL-ENL levels exceeding the endogenous Mll1 at mRNA and protein levels. In leukemic cells from t(11;19)+ leukemia patients, MLL-ENL mRNA also exceeded the endogenous MLL1 levels suggesting a critical Vaia Stavropoulou; Marwa Almosailleakh; Hélène Royo; Jean-François Spetz; Sabine Juge; Laurent Brault; Patrick Kopp; Michelina Iacovino; Michael Kyba; Alexandar Tzankov; Michael B. Stadler; Gianni Cazzaniga; Antoine H.F.M. Peters; Juerg Schwaller HemaSphere : August 2018 - Volume 2 - Issue 4 - p e51 A NOVEL INDUCIBLE MOUSE MODEL OF MLL-ENL-DRIVEN MIXED-LINEAGE ACUTE LEUKEMIA

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threshold for transformation. Expression profiling of iMLL-ENL acuteleukemia revealed gene signatures that segregated t(11;19)+ leukemia patients from those without an MLL translocation. Importantly, B220+ iMLL-ENL leukemic cells showed a higher in vivo leukemia initiation potential than coexisting B220− cells. Collectively, characterization of a novel transgenic mouse model indicates that the cell- of-origin and the fusion gene expression levels are both critical determinants for MLL-ENL-driven acute leukemia.

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Klaus Herfarth; Peter Borchmann; Sven Schnaidt; Karin Hohloch; Volker Budach; Marianne Engelhard; Andreas Viardot; Rita Engenhart-Cabillic; Ulrich Keller; Gabriele Reinartz; Hans-Theodor Eich; Mathias Witzens-Harig; Clemens F.Hess; Bernd Dörken; Jan Dürig; Thomas Wiegel; Wolfgang Hiddemann; Eva Hoster; Christiane Pott; Martin Dreyling HemaSphere : December 2018 - Volume 2 - Issue 6 - p e160 The MabThera and Involved field Radiotherapy study investigated efficacy and safety of involved field (IF) radiotherapy in combination with the anti-CD20 antibody Rituximab for early-stage follicular lymphoma(FL) in a prospective, single-armmulticenter phase 2 design. Eighty-five stage I–II FL patients received 8 cycles of Rituximab (375 mg/m2) and IF irradiation (30/40 Gy). The primary endpoint was progression-free survival (PFS) 2 years from treatment start. Secondary endpoints were overall survival (OS), complete response rates, toxicity, quality of life, and minimal residual disease (MRD) response with protocol defined visits up to month 30. For the primary endpoint, PFS at 2 years was 85% for the intention-to-treat set. Long-term data were captured in selected sites and evaluated as post hoc analysis in the per protocol (PP) set: PFS and OS were 78% and 96% at 5 years with a median follow-up of 66 or 78 months, respectively. There were 17/76 recurrences in the PP set, of which 14 were outside the radiation volume only. MRD analyses revealed a clonal marker in 36% of patients at diagnosis. All but 1 marker positive patients experienced a molecular treatment response. There were 13 serious adverse events (4 related to thetherapy) during the first 30 months. IF radiotherapy combined with Rituximab is well tolerated and highly efficient with low RITUXIMAB WITH INVOLVED FIELD IRRADIATION FOR EARLY-STAGE NODAL FOLLICULAR LYMPHOMA RESULTS OF THE MIR STUDY

rates of recurrence in the first years in early-stage FL. The efficacy is comparable with more aggressive therapy approaches without compromising the quality of life and maintains for an extended follow-up of more than 5 years.

24th EHA Congress Edition Phosphatidylinositol 3-kinase-delta (PI3Kδ) signaling is critical for proliferation, survival, homing, and tissue retention of malignant B cells. Idelalisib, a selective oral inhibitor of PI3Kδ, has shown considerable single-agent activity in patients with heavily pretreated chronic lymphocytic leukemia (CLL). This study evaluated the safety and clinical activity of idelalisib in combination with bendamustine (IB) or rituximab (IR) or both (IBR) in patients with relapsed or refractory (R/R) CLL. Idelalisib was given continuously at 100 or 150 mg twice daily in combination with rituximab (375 mg/m2 weekly × 8 doses), bendamustine (70 or 90 mg/m2, days 1 and 2 every 4 weeks × 6 cycles) or BR (rituximab, 375 mg/ m2 every 4 weeks and bendamustine, 70 mg/m2, days 1 and 2 every 4 weeks × 6 cycles). The primary endpoint was safety; secondary endpoints included overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS). Fifty-two patients (median age 64 years) with a median of 3 prior therapies were enrolled. ORR was 84.6% (89.5% IR group, 77.8% IB group, and 86.7% IBR group). The overall median PFS was 25.6 months, and median DOR was 26.6 months. The most common grade ≥3 adverse events (≥10% of patients) were pneumonia (19.2%), diarrhea (13.5%), and febrile neutropenia (17.3%). Idelalisib- based combination therapy Steven E. Coutre; Ian W. Flinn; Sven de Vos; Jacqueline C. Barrientos; Marshall T. Schreeder; Nina D. Wagner-Johnson; Jeff P. Sharman; Thomas E. Boyd; Nathan Fowler; Lyndah Dreiling; Yeonhee Kim; Siddhartha Mitra; Kanti Rai; John P. Leonard; Richard R. Furman HemaSphere : June 2018 - Volume 2 - Issue 3 - p e39 IDELALISIB IN COMBINATION WITH RITUXIMAB OR BENDAMUSTINE OR BOTH IN PATIENTS WITH RELAPSED/ REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA

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with bendamustine and/ or rituximab was highly active, resulting in durable tumor control in patients with heavily pretreated R/R CLL. However, its tolerability profile suggests that these regimens should be used cautiously in this patient population. ClinicalTrials. gov ID: NCT01088048.

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Madlen Jentzsch, Marius Bill, Juliane Grimm, Julia Schulz, Stefanie Beinicke, Janine Häntschel, Karoline Goldmann, Wolfram Pönisch, Georg-Nikolaus Franke, Vladan Vucinic, Michael Cross, Gerhard Behre, Thoralf Lange, Dietger Niederwieser, Sebastian Schwind HemaSphere : February 2019 - Volume 3 - Issue 1 - p e167 PROGNOSTIC IMPACT OF BLOOD MN1 COPY NUMBERS BEFORE ALLOGENEIC STEM CELL TRANSPLANTATION IN PATIENTS WITH ACUTE MYELOID LEUKEMIA

High expression of the leukemia-associated gene meningioma-1 (MN1) is frequently found at diagnosis ofacute myeloid leukemia (AML) and associates with adverse outcomes. The presence of measurable residual disease (MRD) in complete remission (CR) indicates high risk of relapse and worse outcome inAML patients. However, the prognostic impact of MN1 expression levels as MRD marker has not been evaluated. Digital droplet polymerase chain reaction (ddPCR) is a novel technique allowing sensitive and specific absolute gene expression quantification. We retrospectively analyzed 124 AML patients who received allogeneic hematopoietic stem cell transplantation (HSCT) in CR or CR with incomplete peripheral recovery. Absolute MN1 copy numbers in peripheral blood were assessed prior to HSCT (median 7; range 0–29 days) using ddPCR. High pre-HSCT MN1/Abelson murine leukemia viral oncogene homolog 1 gene

(ABL1) copy numbers associated with a higher cumulative incidence of relapse after HSCT and—inrelapsing patients—shorter time to relapse. In multivariable analysis, high pre-HSCT MN1/ABL1 copynumbers remained an independent prognosticator for relapse after HSCT. Patients with the highest pre-HSCT MN1/ABL1 copy numbers also had the highest risk of relapse. MN1 copy number assessment also added prognostic information to nucleophosmin 1 gene (NPM1) mutation- and brain and acute leukemia, cytoplasmic (BAALC) and Wilm’s tumor gene 1 (WT1) expression-based MRD evaluation. Our study demonstrates the feasibility of the novel ddPCR technique for MN1/ABL1 copy number assessment as a marker for MRD. Evaluation of MN1/ABL1 copy numbers allows the identification of patients at high risk of relapse, independently of other diagnostic risk factors and MRD markers.

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24th EHA Congress Edition

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CALL FOR PAPERS ON GENE THERAPY This special issue will focus on various aspects of gene therapy in hematology. Submit your manuscript by December 15, 2019 and have your research highlighted in this special issue. We welcome the submission of all article types. For review articles, please send your proposal to hemasphere@ehaweb.org. All submitted articles will undergo independent external peer review.

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