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ASH Agenda for Hematology Research

ASH COVID-19 Research Agenda for Hematology

The ASH COVID-19 Research Agenda for Hematology was created in response to the COVID-19 pandemic because it is clear that COVID-19 induces significant hematologic complications. Several of these complications have revealed fundamental gaps in our understanding of hematopoiesis and coagulation/thrombosis. As hematologists and blood science researchers have been called upon to assist in COVID-19 diagnosis, clinical management, and research, ASH convened experts to identify key questions in the pathophysiology and clinical implications of COVID-19 related to hematology science.

This original document outlined hematology-related basic science and clinical research questions that emerged in the first few months of the pandemic. Since the ASH COVID-19 Research Agenda is a living document, we continue to update our perspective and priorities as our understanding of the natural history and treatment of COVID-19 improves. The questions outlined below identify significant questions about the biology, pathophysiology, and underlying clinical implications of COVID-19 as they relate to hematology science and clinical care. These questions are meant to inspire research that leads to enhanced understanding of the disease process, decreased hematologic complications in COVID-19, and improved care of patients with hematologic disease.

Minority populations within the US are disproportionally affected by COVID-19 infection and disease-driven sequelae. This is a critical need to delineate relationships between socioeconomic status, race/ethnicity, comorbid conditions including hematologic disorders, and outcomes of COVID-19 disease. Research questions include:

What are the risk factors for severe COVID-19, poor response to vaccination and breakthrough infections among hematology patients and is there variation by race/ethnicity and other demographic factors? This includes COVID-19 risk factors for specific diseases such as sickle cell disease.
How does access to testing, care, and medication impact COVID-19 disease diagnosis, incidence, and severity? Are there specific populations with a high incidence of hematologic disorders where this is particularly evident?
Do patients with hematologic disorders have sufficient access to the COVID-19 vaccine and to the clinical expertise/information needed to make informed decisions about vaccination?

Thrombosis, both clinically-apparent and subclinical, has emerged as a hallmark of severe COVID-19 disease, and is a major component of morbidity and mortality for patients with COVID-19 infection. However, the underlying pathophysiology of COVID-19 associated thrombosis, including inflammation, endothelial damage, platelet hyperactivity, NETosis, and other prothrombotic processes remain unclear. Multiple clinical trials are ongoing to resolve the role of pre-emptive or sequelae-based anticoagulation for patients with COVID-19. Information on the following questions is critical to delineating the relationship between COVID-19 and thrombosis/coagulation and designing interventions to reduce disease severity.

What is the incidence of COVID-19 associated coagulopathy? What are diagnostic and prognostic tools for COVID-19 associated coagulopathy, including clinical and subclinical thrombosis?
What are underlying hemostatic and thromboinflammatory processes leading to dysregulated coagulation and thrombosis in COVID-19?
How do underlying risk factors, such as vascular dysfunction or endothelialitis, contribute to higher rates of thrombosis, organ failure, and death, particularly in vulnerable patient populations?
What are the optimal antithrombotic strategies to prevent or reduce thrombotic sequelae in different stages of COVID-19?
What are the underlying mechanisms responsible for autoimmune-induced (e.g., vaccine or autoantibody) thrombosis?

An effective immune response is required to recover from SARS-CoV-2 infection as well as to respond to vaccination. However, a hyperactivated or misdirected immune response has been implicated in severe COVID-19 and in adverse vaccine reactions. Changes in the numbers, functions, location, and production of inflammatory molecules of blood, bone marrow, and tissue immune cells may contribute to severe COVID-19 and its complications (e.g., post-acute Covid [“Long COVID”] and pediatric multisystem inflammatory syndrome).

What genetic or acquired factors underlie detrimental acute or late hyperinflammatory responses to SARS-CoV-2 infection? How do hematologic disorders such as sickle cell disease, clonal hematopoiesis, or immune disorders affect susceptibility to and severity of COVID-19 infection and complications?
Which blood or immune cells or cytokines promote severe COVID-19 versus desirable control of the viral infection? How can these processes be attenuated prior to counterproductive inflammatory tissue damage while stimulating effective immunity?
How does immune system impairment in benign and malignant hematologic disorders impact the inflammatory response to SARS-CoV-2 infection and/or alter the capacity to mount a productive immune response to vaccination?
What are the roles of T and B cells in initial control of SARS-CoV2 infection, detrimental hyperinflammatory responses, and vaccine responses, particularly in patients unable to produce protective antibodies? Can immune-directed anti-viral interventions (e.g., antibodies or targeted cellular therapies) improve control of SARS-CoV-2 infection in high-risk patients without triggering hyperinflammation or evolution of immune-evading viral variants?

The interplay between hematopoiesis/immune function and viral infections including COVID-19 are complex and incompletely understood. Moreover, it is clear that specific hematopoietic parameters, including lymphopenia, neutrophilia, and hematologic disorders are risk factors for developing severe COVID-19. It is paramount to investigate the interplay between the hematopoietic compartment and SARS-CoV-2 infection, and to determine how hematopoietic responses and hematopoietic disorders impact COVID-19 pathophysiology and disease severity. Research questions include:

What is the relationship between hematopoietic function and the response to SARS-CoV-2 infection? How do hematopoietic disorders affect COVID-19 pathophysiology and disease severity?
How does COVID-19 infection impact hematopoietic function, including in stem/progenitor cells, megakaryocytes, and immune effector cells? Is there evidence of long-term impairment in hematopoiesis, particularly in patients with “long COVID” syndrome?
What is the incidence and severity of COVID-19 infection in immune compromised patients, including patients undergoing/surviving stem cell transplantation or receiving immunomodulatory therapy? To what extent is this severity dictated by underlying hematopoietic dysfunction and/or therapy?
How does hematopoietic dysfunction affect the extent and durability of the immune response to COVID-19 vaccination? Are additional vaccine doses ('boosters') beneficial in this population?

Hematologic malignancies are associated with perturbations of both innate and adaptive immunity. The impact of lymphomas, myeloma, acute and chronic leukemias, and of their treatments on specific COVID-19 manifestations and eventual outcomes are poorly understood. Conversely, the impact of COVID-19 , for instance inflammation, on the pathogenesis and prognosis hematologic malignancies has not been well-defined. Research questions include:

How do different hematologic malignancies and malignancy treatments affect the immune response to COVID-19 and to vaccines? Do current or prior chemotherapy and/or immunotherapy affect antibody testing or other biomarkers of response to COVID-19, or alter the development of protective antibodies in response to COVID-19 vaccination or acute infection? What is the balance of risks and benefits associated with maintenance therapies, such as rituximab or immunomodulatory treatments, with respect to COVID-19 disease and short/long-term vaccination response?
What clinical studies should be done to assess the efficacy of vaccine boosters in different blood cancer patient subsets?
Do immunomodulatory treatments (e.g., tyrosine kinase inhibitors, JAK inhibitors, and/or BTK inhibitors) increase risk of SARS-CoV-2 infection and/or COVID-19 severity? Conversely, do these agents lessen the impact of cytokine and thromboinflammatory signaling?

Extrapolating from experience with prior viral outbreaks, studies evaluating efficacy of convalescent plasma, or concentrated COVID-19 H-Ig, are being widely undertaken across US and international blood centers. There is a critical need to understand the value of this approach and how to use, test, and optimize this therapy. Research questions include:

How do we identify appropriate donors? When is the best time to collect plasma from previously infected donors (optimal antibody titer, how long is the titer maintained, should we use donors who have been subsequently vaccinated)?
Can convalescent plasma be used to generate passive immunization within the unaffected population, including patients who cannot mount a productive immune response to COVID-19 vaccines?
Which patients will benefit the most from antibody therapy? Should convalescent plasma be given for maximal benefit and if so, when?
How predictive are antibody titers, either to the virus or to vaccination, of infectious risk, including in patients with hematologic disorders?