The ASH Agenda for Hematology Research: a roadmap for advancing scientific discovery and cures for hematologic diseases

TO THE EDITOR:

There has never been a more fertile time in research in hematologic diseases. Advances in cancer genomics, stem cell biology, experimental modeling of diseases, and the potential for genome editing and immunotherapy have transformed our understanding of the biologic basis of malignant and nonmalignant hematologic disorders and have opened a new vista of potential therapeutic approaches to improve cure rates and outcomes for our patients. With these advances come multiple challenges. The funding environment for new and established investigators remains difficult and research often involves big science that requires coordinated teams of investigators using sophisticated experimental approaches. Although the ultimate goal of research is to improve quality of life, clinical advances commonly arise from research that addresses fundamental mechanistic questions: without transformative science discoveries, there is little to translate. As a society of hematologists, the American Society of Hematology (ASH) felt that it had an important role in prioritizing key areas of research to facilitate research, stimulate collaboration, advocate for research funding, and educate our membership.

To this end, the Society published the ASH Agenda for Hematology Research,¹  which is updated periodically by the Committee for Scientific Affairs which guides the Society’s scientific activities. Here, I provide an overview of the Agenda and highlight ways that it has been used to advance our research goals.

The Agenda was developed in consultation with the 18 scientific committees of ASH that provide extensive expertise in malignant and nonmalignant disease. Rather than focusing on individual disease areas, we felt that this version of the Agenda would be most relevant and impactful by focusing on cross-cutting themes that impact multiple disease and research types. These themes should be continually revised, updated, and/or replaced in light of scientific and technical advances, including specific priorities for advancing research outcomes.

The first of 6 themes is “Precision Medicine,” which acknowledges great strides in understanding hematologic diseases from genomic sequencing approaches and the potential for genomics and other biomarker-based approaches to improve clinical care. This theme also addresses tailoring of therapy, will help inform drug discovery, and will acknowledge the challenges in transitioning genomics to the clinic.

Current research priorities are to improve understanding of interactions between genetic and epigenomic aberrations and the epigenome and to elucidate their role in disease predisposition and response to therapy; to integrate genomic profiling into drug discovery efforts; to develop infrastructure for genomic data hosting, sharing, and interpretation; and to implement structural changes in the health care community that support the use of genomic information in clinical trials and drug development.

The second theme is “Gene Therapy and Genome Editing.” We acknowledge the transformative potential of these techniques to jumpstart new experimental approaches and precisely modify human genomes for therapeutic potential. We also recognize that critical questions must be addressed to effectively translate these techniques into clinical use. Two specific priorities are to establish strategies that optimize efficacy and safety while reducing the toxicity of genome editing techniques and to apply genome editing technologies that can correct hematopoietic stem cells derived from patients with congenital hematologic disorders.

The third theme focuses on “Epigenomics” and recognizes that disease biology cannot be understood solely from analysis of structural genetic and DNA sequence alterations. Epigenetic modifications are central to gene regulation, are key mechanisms by which disease-associated genetic mutations are pathogenic (eg, DNMT3A, IDH1/2, and TET2 mutations in myeloid malignancies), and are increasingly attractive targets for therapeutic intervention. However, many questions remain unanswered on the functional consequences of complex epigenomic mechanisms in the contexts of physiology and pathology. Current priorities under this theme are to pursue epigenetic targeting as a therapeutic approach for hematologic disorders; to facilitate research on the epigenomic regulation of hemoglobin biosynthesis to help develop novel approaches for treating sickle cell disease, thalassemia, and other hemoglobin disorders; and to develop principles that can be applied broadly to diverse hematologic problems.

Advances in immunotherapy, including checkpoint blockade therapy, engineered T cells, and antibody-based therapy, have shown great promise, even spectacular success, in previously highly refractory tumors, particularly in a subset of lymphoid malignancies. The fourth theme of “Immunologic Treatments of Hematologic Malignancies” focuses on moving beyond the implementation of immunotherapy as a salvage therapy at relapse to using it as a curative approach early in treatment at initial poor treatment response or, ultimately, in first-line treatment regimens. The many remaining challenges include gaining an improved understanding of the basic biology of the immune system, understanding and reverting immune cell anergy, exploiting mutation landscapes and loads in immunotherapy, integrating with “-omic” data to identify new targets, and designing improved weapons against a more diverse range of targets and tumor types. Currently, there are 2 specific priorities. The first is to optimize the use of chimeric antigen receptor (CAR) T-cell and checkpoint blockade strategies to cure hematologic malignancies and eradicate minimal residual disease, improve efficacy, and reduce toxicity for CAR T-cell and checkpoint blockade strategies. The second is to improve effectiveness of existing curative therapies, specifically allogeneic hematopoietic stem cell transplantation.

Hematologists have led research that defines the nature and role of stem cells in development and as a tool for therapy. Recent advances in manipulating stem cells holds further promise for applying stem cell therapy as a curative approach to a range of hematologic conditions as well as creating designer cells that may redefine approaches for the diagnosis and treatment of hematologic diseases. The priorities of the fifth theme, “Stem Cell Biology and Regenerative Medicine,” are to elucidate principles of hematopoietic stem cell biology and use mechanistic insights and novel technologies to develop improved hematopoietic stem cell-based therapies; to engineer artificial and functional hematopoietic stem cell niches that allow expansion of repopulating hematopoietic stem cells; and to develop designer hematopoietic cell products and facilitate large-scale production for therapeutic and diagnostic use.

The sixth theme is specifically focused on biological and translational research areas in “Venous Thromboembolic Disease.” The Society realized that despite improved understanding of genetic risk factors, reduction in recurrence of venous thromboembolism (VTE), and occurrence in high-risk situations, such disorders continue to result in unacceptable morbidity and mortality. To further improve the state of care for VTE, future research must aim to understand pathophysiologic mechanisms that lead to VTE in different patient populations and must address unanswered questions about disease risk profiles and the role of newer antithrombotics for prevention and treatment in different clinical situations. Thus, research priorities are to identify, evaluate, and incorporate biomarkers into risk assessment scoring algorithms; to systematically evaluate the effectiveness of existing antithrombotic agents in preventing VTE in high-risk populations; and to identify new therapeutic targets to enable the development of effective antithrombotics that do not cause bleeding. Given ASH’s vested interest in enhancing the quality of care in this disease area, the Society has committed to developing and releasing 10 evidence-based practice guidelines addressing the prevention, diagnosis, and treatment of VTE.² 

The ASH Agenda for Hematology Research is having an impact. Recognizing that dedicated effort is needed to accomplish these ambitious priorities, the Committee for Scientific Affairs established the Task Force in Precision Medicine and Immunotherapy.³  With support from ASH, the Task Force has led efforts to enhance understanding of the implications of germ line and somatic mutations in hematologic disorders. In addition, by working with ClinGen,⁴  the Task Force has led systematic efforts to curate the validity and actionability of mutations in genes responsible for inherited myeloid and platelet disorders. The Task Force is also working with the National Cancer Institute’s Genome Data Commons to help aggregate hematologic malignancy genomic data to facilitate research.

Recently, and through ASH’s efforts, a pilot project was submitted to the Genome Data Commons that serves as a proof of principle for other hematologists to submit additional data sets to this resource. Many important hematologic conditions have not been adequately represented in genome sequencing efforts such as The Cancer Genome Atlas. Thus, the Society is establishing a pipeline and resources so that the ASH community can propose key disease entities that should undergo comprehensive sequencing with accompanying clinical annotation, and this information will be made available as a public resource. The Society recognizes that small meetings to discuss cutting-edge science and opportunities and challenges in clinical implementation are key to translating basic scientific discoveries. To that end, it has convened workshops on genome editing and immunotherapy. ASH collaborated with the American Society of Clinical Oncology to develop guidelines for managing adverse events related to checkpoint inhibitor therapy.⁵  The Agenda has also stimulated a series of educational review articles on precision medicine,⁶  genome editing,⁷  and immunotherapy.⁸  It has been vital in communicating our research priorities to key federal funding agencies such as the National Cancer Institute and the National Heart, Lung, and Blood Institute and has led these agencies to cooperate in establishing the ASH Hematology Profiling Consortium. The Agenda is a key tool for promoting education and advocacy efforts with the federal government.

The Agenda serves as a reference for the Society to use in developing the program for the Annual Meeting and it can help identify areas that merit attention in special lectures, spotlight sessions, and new Friday Scientific Workshops such as those on Tumor-Immune Interactions, Inherited Hematologic Malignancies, and Hematology and Aging.⁹  The Agenda has stimulated the development of new scientific committees, such as the ad hoc Scientific Committee on Epigenetics and Genomics, which has presented popular and thought-provoking sessions at the Annual Meeting since its inception.

The ASH Agenda for Hematology Research is a living document. For it to remain relevant and useful, it must nimbly reflect and incorporate advances across the basic to translational research spectrum. Along with the Scientific Committees, the Committee for Scientific Affairs regularly updates the Agenda to incorporate such advances and refine priorities, most recently in December 2017,¹⁰  when substantial changes in research priorities for precision medicine, VTE, epigenetic mechanisms, stem cells, and precision medicine were made.

Finally, the Agenda is your document. We encourage you to read the Agenda and discuss it with your colleagues and elected representatives. We greatly welcome your feedback to help improve the Agenda and maximize the Society’s impact in tackling fundamental research questions and translating discoveries to improve clinical outcomes.