American Society of Hematology

2017 Special Scientific Symposia

These sessions will take place from Saturday through Monday and will feature transformative research with implications for scientific investigation and clinical practice across the field of hematology.

Special Scientific Symposium on Hot Topics in Hematology: New Pathways Linking Hematopoiesis, Thrombosis, and Cardiovascular Disease

Saturday, December 9, 2017, 9:30 a.m. - 11:00 a.m.
Georgia World Congress Center, Bldg C- Lvl 3- Georgia BR 1-3

Fascinating new relationships between the hematologic and cardiovascular systems have recently been uncovered, with potential therapeutic implications. Speakers in this session will draw on major epidemiologic data sets as well as murine models to provide novel insights into how cardiovascular risks are linked to hematologic abnormalities.

Dr. Benjamin Ebert will present on the surprising link between clonal hematopoiesis in older patients and an increased risk of death from cardiovascular disease, drawing on human epidemiologic studies, analysis of patients undergoing transplantation, and murine models.

Dr. Dale Abel will introduce a link between the sex steroid hormonal milieu and platelet mitochondria in the regulation of thrombosis, based on observations from epidemiologic studies linking expression of a gene regulating mitochondrial dynamics to cardiovascular events. He will further dissect this relationship in murine models and provide a possible explanation for the marked differences in cardiovascular risk between men and women. 

Dr. Alan Tall will connect signaling abnormalities in hematopoietic stem and progenitor cells and increased cardiovascular risk, drawing on both epidemiologic data and murine models. Pathways activating TPO or JAK2 signaling result in leukocytosis, platelet activation (and resultant platelet aggregation), and increased atherosclerosis.

Chair:

Cynthia E. Dunbar, MD
National Heart, Lung, and Blood Institute, National Institutes of Health
Bethesda, MD

Speakers:

Benjamin L. Ebert, MD, PhD
Brigham and Women's Hospital
Boston, MA
Clonal Hematopoiesis Influences Cardiovascular Risk

E. Dale Abel, MD, PhD
University of Iowa
Iowa City, IA
Sex Matters: The Hormonal Milieu Regulates Thrombosis

Alan Tall, MD
Columbia University
New York, NY
Lipids, Hematopoiesis, and Athero-Thrombosis

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Special Scientific Symposium on Targeted Therapy: What Is the Best Target?

Sunday, December 10, 2017, 9:30 a.m. - 11:00 a.m.
Georgia World Congress Center, Bldg A- Lvl 4- A411-A412

Advances in genomic characterization, drug development, and clinical trials have led to the development of novel, effective, molecularly targeted therapies for hematologic malignancies and solid tumors. In recent years, our understanding of how to develop mechanism-based targeted therapies has expanded; and novel approaches targeting malignancy-specific gene regulatory and differentiation features are also showing significant promise. This session will focus on recent advances in the development of targeted therapies aimed at specific molecular drivers, epigenetic alterations, and aberrant differentiation, each of which can be leveraged for novel therapeutic approaches against hematologic malignancies.

Dr. Neil Shah will discuss the development of molecularly targeted therapies against mutant, constitutively activated tyrosine kinases, including BCR-ABL inhibitors for chronic myeloid leukemia (CML) and acute lymphocytic leukemia (ALL) as well as more recent efforts to target FLT3 in acute myeloid leukemia (AML). He will review the current status of drug development, molecular determinants of drug sensitivity and resistance, and novel approaches to prevent and reverse kinase inhibitor resistance.

Dr. Mark Dawson will discuss the challenges and opportunities of targeting the epigenome for therapeutic gain in hematologic malignancies. Given that the dynamic plasticity of the epigenome lends itself well to therapeutic manipulation, the past few years have witnessed an unprecedented investment in the development, characterization, and translation of targeted epigenetic therapies. Several of these epigenetic therapies have now transitioned into the clinical arena, and emerging evidence suggests that these drugs are well tolerated and show single agent efficacy in a range of hematopoietic cancers. The enduring challenge for clinicians and scientists will be to decipher the cellular and molecular mechanisms that govern sensitivity and resistance to these agents. In this session, Dr. Dawson will provide an overview of the new epigenetic therapies currently being evaluated in clinical trials, their molecular and cellular mechanism of action, and the pre-clinical evidence for their therapeutic efficacy. He will also highlight the emerging evidence for how therapeutic resistance may develop and what future combination strategies may increase the clinical value of this class of drugs.

Dr. Kimberly Stegmaier will discuss targeting the differentiation as a therapy approach in AML. Impaired myeloid differentiation, whether due to disordered genetics or epigenetics, is a defining feature in AML. While most patients with AML will be treated with high-dose cytotoxic chemotherapy, patients with the most successfully treated subtype of AML, acute promyelocytic leukemia (APL), are treated with the pro-differentiating agents all-trans retinoic acid (ATRA) and arsenic trioxide. These drugs target the defining lesion in APL, the PML-RARa fusion gene, overcoming PML-RARa-induced transcriptional repression to induce neutrophilic maturation. Other subtypes of AML have been demonstrated to maintain the molecular machinery necessary for differentiation – and newer drugs, including modulators of epigenetic regulators and signal transduction, have more recently been reported to induce AML differentiation. This presentation will focus on the history of differentiation therapy in AML as well as promising recent advances in the field.

Chair:

Ross L. Levine, MD
Memorial Sloan Kettering Cancer Center
New York, NY

Speakers:

Neil P. Shah, MD, PhD
University of California, San Francisco
San Francisco, CA
Targeting Somatic Kinase Mutations

Mark Dawson, MD, PhD
Peter Maccallum Cancer Centre
Melbourne, AUS
Targeting the Epigenome

Kimberly Stegmaier, MD
Dana-Farber Cancer Institute
Boston, MA
Targeting Regulators of Differentiation

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Special Scientific Symposium on Understanding and Modulating the DNA Damage Response

Saturday, December 9, 2017, 2:00 p.m. - 3:30 p.m.
Georgia World Congress Center, Bldg C- Lvl 3- Georgia BR 1-3

Hematologic malignancies, like other cancers, have underlying genomic instability, resulting in important clinical consequences. On the one hand, genomic instability leads to a more aggressive cellular phenotype, resulting in chromosome translocations, tumor suppressor gene inactivation, and amplification of drug-resistant genes. On the other hand, genomic instability is caused by defects in DNA repair, resulting in the heightened sensitivity of cancer cells to conventional chemotherapy and radiation.

Dr. Andre Nussenzweig will discuss the wide array of recurrent, non-random chromosome translocations that are found in some secondary leukemias. These translocations often arise following the use of DNA topoisomerase inhibitors. These topoisomerase cleavage complex-dependent DNA breakage sites are distinct from other known chromosome fragile sites because they are independent of transcription, DNA replication, and cell type. Dr. Nussenzweig will characterize these novel sites of translocation and describe how they are related to the overall three dimensional organization of chromosomes. 

Dr. Alan D'Andrea will review the major DNA repair pathways and DNA damage response (DDR) pathways. Inherited mutations in these pathways underlie numerous leukemia and bone marrow failure syndromes, such as Fanconi anemia, dyskeratosis congenita, and ataxia telangiectasia. New agents that modulate DNA repair, such as poly ADP ribose polymerase (PARP) inhibitors and checkpoint kinase inhibitors, are now entering the clinic.

Dr. Feyruz Rassool will discuss the emerging use of PARP inhibitors in the treatment of cancers that have an underlying defect in homologous recombination DNA repair. Recent studies indicate that PARP inhibitor efficacy can be enhanced through novel drug combinations. Dr. Rassool will describe how a DNA methyltransferase inhibitor in combination with the PARP inhibitor talazoparib can modulate DNA repair and lead to enhanced activity against acute myeloid leukemia (AML). She will discuss results from a phase I clinical trial evaluating this combination for AML, along with its correlative studies.

Chair:

Alan D. D'Andrea, MD
Dana-Farber Cancer Institute
Boston, MA

Speakers:

Andre Nussenzweig, PhD
National Cancer Institute, National Institutes of Health
Bethesda, MD
Genome Organization Drives Chromosome Fragility

Alan D. D'Andrea, MD
Dana-Farber Cancer Institute
Boston, MA
DNA Repair Targets in Bone Marrow Failure and Cancer

Feyruz Rassool, PhD
University of Maryland
Baltimore, MD
Targeting DNA Damage and Repair in Cancer: Bench to Bedside in Acute Myeloid Leukemia

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Special Symposium on the Basic Science of Hemostasis and Thrombosis

Monday, December 11, 2017, 4:30 p.m. - 6:30 p.m.
Georgia World Congress Center, Bldg B- Lvl 3- B304-B305

New therapeutic approaches to treat bleeding and thrombosis due to a variety of pathological conditions are needed. This session will present new biochemical findings into the hemostatic system that have unveiled promising molecular targets to treat these conditions. These strategies include targeting the protein C pathway for hemophilia, selectively inhibiting platelet activation, and blocking the contact pathway to prevent thrombosis.

Dr. James Huntington will explain his approach for targeting the protein C anticoagulant system. Blood coagulation is regulated by a complex network of pro- and anti-coagulant factors that work simultaneously to ensure rapid, stable clot formation at sites of vascular damage, while limiting clot grown to prevent thrombosis. Deficiency in pro-coagulant factors VIII and IX cause hemophilia A and B, respectively, and result in bleeding due to an imbalanced hemostatic system. All current treatments aim to rebalance the system by replacing the missing factors or by adding other pro-coagulant factors. A more recent approach is to redress the imbalance by down-tuning anticoagulant forces. Anti-TFPI antibodies and an anti-antithrombin siRNA are in the clinic as treatments for hemophilia. Dr. Huntington will discuss how his lab designed a serpin that is specific for activated protein C (APC) over other clotting factors and will show preclinical data on efficacy and safety in mouse models.

Dr. Steve Watson will discuss the role of the tyrosine kinase-linked receptors GPVI and CLEC-2 in hemostasis and thrombosis, and whether they represent novel drug targets in thrombotic disease. The two receptors can be targeted by direct inhibition or through their tyrosine kinase-driven signalling pathways. Inhibitors of Src, Syk, and Tec family kinases have recently entered the clinic or are under clinical development. There is particular interest in the Btk inhibitor ibrutinib and in the next generation of inhibitors because of their irreversible action. By analogy to aspirin, this offers the potential of using a low dose of ibrutinib to selectively inhibit platelet activation. Unexpectedly, ibrutinib selectively inhibits platelet activation by CLEC-2 relative to GPVI. The molecular basis of this will be discussed.

Dr. David Gailani will discuss the roles of the plasma proteins prekallikrein, factor XII, and factor XI (the contact factors) in thrombosis, with an emphasis on coagulation induced by artificial surfaces (e.g., extracorporeal circuits and implantable devices). Given the limited contributions of these proteins to hemostasis, it is anticipated that antithrombotics targeting them would be associated with a low risk of bleeding. Recent work suggests that the contact factors express protease activity in their single-chain precursor forms. This activity may serve as a trigger for the contact system when blood is exposed to a surface.

Co-Chairs:

Rodney M. Camire, PhD
Children's Hospital of Philadelphia
Philadelphia, PA

David A. Garcia, MD
University of Washington
Seattle, WA

Michael Holinstat, PhD
University of Michigan
Ann Arbor, MI

Speakers:

James A. Huntington, PhD
University of Cambridge
Cambridge, United Kingdom
Targeting Activated Protein C to Treat Hemophilia

Steve P. Watson, PhD
University of Birmingham
Birmingham, United Kingdom
Targeting ITAM Receptors in Disease With Ibrutinib and Other Tyrosine Kinase Inhibitors

David Gailani, MD
Vanderbilt University
Nashville, TN
Initiation of Surface-Mediated Thrombosis Events

Yunfeng Chen
The Scripps Research Institute
La Jolla, CA
Identification of a VWFA1 Mutation Attenuating Thrombus Growth but Not Platelet Adhesion

Rodney M. Camire, PhD
The Children’s Hospital of Philadelphia
Philadelphia, PA
Best of ASH in Hemostasis and Thrombosis 1

David A. Garcia, MD
University of Washington
Seattle, WA
Best of ASH in Hemostasis and Thrombosis 2

Michael Holinstat, PhD
University of Michigan
Ann Arbor, MI
Best of ASH in Hemostasis and Thrombosis 3

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