The EHA Research Roadmap: Transfusion Medicine

HemaSphere, vol. 6, pp. e670

Abstract

In 2016, the European Hematology Association (EHA) published the EHA Roadmap for European Hematology Research1 aiming to highlight achievements in the diagnostics and treatment of blood disorders, and to better inform European policy makers and other stakeholders about the urgent clinical and scientific needs and priorities in the field of hematology. Each section was coordinated by 1–2 section editors who were leading international experts in the field. In the 5 years that have followed, advances in the field of hematology have been plentiful. As such, EHA is pleased to present an updated Research Roadmap, now including eleven sections, each of which will be published separately. The updated EHA Research Roadmap identifies the most urgent priorities in hematology research and clinical science, therefore supporting a more informed, focused, and ideally a more funded future for European hematology research. The 11 EHA Research Roadmap sections include Normal Hematopoiesis; Malignant Lymphoid Diseases; Malignant Myeloid Diseases; Anemias and Related Diseases; Platelet Disorders; Blood Coagulation and Hemostatic Disorders; Transfusion Medicine; Infections in Hematology; Hematopoietic Stem Cell Transplantation; CAR-T and Other Cell-based Immune Therapies; and Gene Therapy. We dedicate this paper in honor of Anneke Brand, who was a wonderful colleague and mentor to so many in European transfusion medicine. Transfusion medicine Transfusion medicine is a broad discipline, encompassing not just use of blood components, but many areas of donor recruitment and safeguarding, apheresis, and novel cellular therapies. This roadmap provides a framework for discussion of research priorities in transfusion medicine moving forward. Although one could highlight many future research areas of direct relevance to donor and patient care, important themes remain centered on minimizing risks to patients and donors, and for the development of stratified or personalized transfusion strategies. It is clear that wide-scale genetic typing of donors and patients can now be delivered at low-cost, and the introduction of these technologies heralds a new era for transfusion medicine, which has been grounded in serological tests. Summary of main research and policy priorities Continued need for evidence for safe and effective use of blood components, including how donor/donation characteristics impact on outcomes after transfusion. Strategies for addressing prevention and management of alloimmunization, and the role of genotyping of donors and patients for matching. Defining evidence-informed indications for therapeutic apheresis and use of immunoglobulins, including dose and formulations alongside addressing self-sufficiency at a European level. Initiatives on safety and hemovigilance should specifically include donor vigilance of blood, plasma, and cell donation. Research in new areas of cellular therapies and the place of ex vivo generation and storage of blood cells. Use of blood components Introduction The most commonly transfused blood component remains red blood cells (RBCs), followed by plasma and platelets. After the first Roadmap, the evidence base for transfusion therapy continues to expand with an increasing number of randomized trials, as highlighted by the European Frankfurt consensus conference.2 The randomized trials of red cell transfusion typically compare giving more or fewer transfusions, at higher and lower hemoglobin (Hb) concentration thresholds, termed liberal and restrictive transfusion policies, respectively. In the main, most studies continue to show no harm when applying a more restrictive red cell transfusion policy compared to more liberal policy to maintain a higher Hb concentration posttransfusion. However, subgroups of patients may benefit from more liberal transfusions. A European trial, REALITY,3 is the largest randomized trial comparing a restrictive versus a liberal blood transfusion strategy in myocardial infarction patients with anemia, and results indicated noninferiority. Only one large trial with 300 patients has been conducted in patients with hematological diseases, which again reported no benefits for a liberal red cell policy in adult patients undergoing HSCT.4 Further analyses of all randomized trials may reveal a more precise definition of the benefits of restricted and liberal use for particular patient and age groups. Transfusion is potentially life-saving in major bleeding. The use of whole blood, providing all components of blood, and the role of cold stored platelets, which may have added functionality, continue to be important areas of research interest. Despite historical precedence and biological plausibility, repeated clinical trials have shown lack of effectiveness for convalescent plasma in unselected patients with COVID-19, although further studies may identify a role for convalescent plasma in specific groups of patients, for example in immunocompromised patients, without anti-SARS-COV2 antibodies; these results enable health care resources to be better allocated to other areas of patient need during a pandemic.5 Proposed research Many clinical settings for use of blood continue to be defined by variation in practice beyond that explained by case-mix, reflecting an inadequate evidence base. The degree to which the optimal Hb transfusion threshold and target for transfusion should be modified for subgroups of patients or those with specific risk factors (eg, elderly, coronary disease) still remains unclear. Therefore, there is a need for further trials of red cell transfusions in nonbleeding patients in clinical settings where there are currently no adequately powered randomized controlled trials data, for example patients with cardiovascular disease, brain injury, and hematological malignancies including especially chronic transfusion-dependent anemias such as myelodysplasia.6 Better diagnostic tests and biomarkers identifying transfusion needs remain an area of research need. The Hb concentration is still used to define the need for red cell transfusions, calculate the dose of RBCs required, and monitor the response to transfusion or alternative treatment. However, Hb is a surrogate marker, and research should address better-targeted or physiological measures of oxygen requirements that can identify specific patient needs and personalize transfusion interventions. There remains a lack of evidence to guide prophylactic use of platelet and plasma transfusions, to cover invasive/surgical procedures. Of concern is the finding from trials of platelet transfusions in neonates, and intracerebral bleeding in adult patients on antiplatelet agents, which reported evidence of harm with use of platelets.7,8 The mechanism by which platelets might be responsible for adverse effects in these trials is unclear, but platelets have well recognized roles beyond coagulation and hemostasis. Research to tackle the safety of prophylaxis will require efficiently designed studies to identify predictive risk factors for negative effects of platelet transfusions. These topics may be addressed by analysis of real-world data, such as through registries, and large clinical datasets drawing on information captured by electronic medical record systems.9 Anticipated impact of the research Research will continue to refine the optimal and evidence-informed use of blood components. New methodological approaches to trial design, incorporating routine data, will be an increasing area of active interest in transfusion medicine. Indeed, a common feature of many hospital IT systems is limited ability for researchers to access and analyze comprehensive real-world data through electronic medical record systems, yet such approaches could significantly enhance the delivery of research. Cost-effectiveness is an increasingly important objective for research given the costs (alongside unwanted effects) of unnecessary transfusions. Plasma-derived and recombinant human plasma proteins Introduction Plasma is a source of many proteins for medicinal use. Intravenous immunoglobulins (IVIGs), a pooled normal IgG from the plasma of several thousand healthy donors, are used for the treatment of hypogammaglobulinemia, autoimmune, and inflammatory conditions. The recent mechanistic studies performed by European researchers show that IVIG could exert anti-inflammatory effects by inducing autophagy in inflammatory immune cells and by inducing IL-4 in human basophils through direct interaction with FcεRI bound IgE.10–12 Proposed research A better understanding of the (cost-) effectiveness of IVIG continues to be needed. IVIG infusion by intravenous route requires trained personnel, hospital admission and also leads to loss of working days. To address these issues, alternative IgG formulations for subcutaneous administration (SCIg) have been developed, and may have roles beyond well-established uses in patients with primary immunodeficiencies, for example, to treat autoimmune and inflammatory diseases and at lower dosages.13–15 Recent studies have highlighted possible benefits that early initiation of IgM-enriched immunoglobulin therapy may reduce the risk of mortality and duration of mechanical ventilation in subpopulations of sepsis patients.16,17 There is interest in the application of therapeutic molecules as alternatives to IVIG to overcome its potential limitations of supply and cost. Analogous to IVIG, a pooled normal IgA from plasma of several thousand healthy donors has been explored in experimental models of autoimmune diseases and have yielded promising results, which require further evaluation.18,19 In addition, rozanolixizumab, an antihuman FcRn monoclonal antibody, and efgartigimod, an IgG1 Fc fragment, have been investigated to promote catabolism of autoantibodies.20,21 The phase I randomized, double-blind, placebo-controlled, dose-escalating study showed that rozanolixizumab and efgartigimod reduce the concentrations of circulating IgG. Furthermore, a phase 2 study of efgartigimod in generalized myasthenia gravis and primary immune thrombocytopenia demonstrated promising therapeutic benefits.22,23 Data from these studies warrant further investigation of FcRn antagonists as a novel therapeutic approach to treat autoimmune diseases. Anticipated impact of the research Better evidence from good quality comparative studies would define more appropriate use of IVIg for replacement, and define the role of novel plasma derived and synthetic therapeutic molecules for autoimmune and inflammatory diseases. Apheresis Introduction Apheresis procedures are a resource intensive intervention applied for diverse indications. The American Society for Apheresis (ASFA) provides an evidence-based synthesis of indications for hospital practice, but for many indications, the optimal role of apheresis therapy is not established. Some indications for apheresis appear more common practice in Europe, for example the use of adsorption columns for IgG-removal in case of HLA- or ABO-antibodies in organ transplant recipients or for lipid binding in combination with plasma separation devices. Apheresis procedures are commonly used in donor practice, for example plasmapheresis for the collection of plasma as a source for polyvalent immunoglobulins for intravenous (IVIG) or subcutaneous (SCIg) use. Apheresis collection of platelets is practiced in many blood services, although the nature of the clinical benefit and adverse transfusion reaction profile compared to whole blood-derived platelets has not been demonstrated. European plasma-collection from nonremunerated donors is not sufficient to meet demands, and strategies are required to promote and expand the nonremunerated donor population alongside appropriate surveillance of donor safeguarding. The collection of progenitor hemopoietic cells or immune cells for autologous and allogeneic use is a significant growth area. Of >50,000 hematopoietic stem cell transplants (HSCTs) performed worldwide each year, over 70% are obtained by blood stem cell apheresis. Apheresis procedures support the collection of mononuclear cells (CD3+ T-cells) for donor lymphocyte infusion after HCST. Ex vivo processing of the collected leukocytes for cellular therapies is underpinning novel potent anticancer treatment or antiviral vaccination therapy. Proposed research There remains an ongoing need to contribute to evidence base indications for therapeutic apheresis. The establishment of a global standardized surveillance system for related stem cell donor care comparable to care for unrelated volunteer donors is in development, as a joint effort of the World Marrow Donor Association and EBMT. The safety of new stem cell mobilization drugs (eg, biosimilars and CXCR4 agonists) requires pan-European collaboration.24 The request for CD3+ immune cells for the cellular therapies is increasing, but many aspects of production and processing remain poorly defined for optimal practice. Manufacturing and processing need to be studied alongside trials to evaluate benefits in recipients and require attention to the potential risks for the donor including procedure-related stress. Other developments are the need of cells from volunteer donors to improve processes, and to develop allogeneic chimeric antigen receptor T cells (CAR-T). For plasma and platelet donation from unrelated donors, safety of donors remains paramount. Further study risks include repeated exposure to citrate and protein removal, which may impact on risks for osteoporosis and hypogammaglobulinemia in the long term. There is a need to address European self-sufficiency of plasma collection. Anticipated impact of the research New cellular treatments will be an area of expansion. Although short-term adverse effects of patient as well as donor apheresis are considered minimal, long-term effects of many procedures applied in healthy (volunteer, nonremunerated) donors are less well studied. The proposed research subjects can provide the European community with information about the risk and safety issues for donors, and promote policies for greater protection of nonremunerated donors. Immunological transfusion complications (alloimmunization/TRIM/hemovigilance) Introduction Blood transfusions are biological interventions. A new encounter with a cognitive antigen by transfusion, pregnancy, or transplantation can cause morbidity and mortality. The overall prevalence of alloimmunization across Europe is unknown and varies between patient categories and according to the numerous antigens expressed on blood cells and blood substances. Molecular genotyping of most blood cell antigens is now possible,25,26 and cost-efficient genotyping of donors are real advances happening now in transfusion practice. Taken together, the next 5 years will see a paradigm shift in matching abilities for transfusion practice. For selection of HLA compatible stem cell and organ transplants, Europe has established registries that cooperate, including research networks to characterize the genetic HLA diversity of populations with impact on both, public health and fundamental research (Allele Frequency Net Database).27 Eurotransplant offers over 25 years an acceptable mismatch program for heavily immunized patients, which is regularly updated. Until 2021 over 1700 highly sensitized patients received a compatible renal graft with good graft survival.28,29 A feasible goal is to extend these European initiatives to other settings including compatibility of classic blood components used for transfusion. Recent work has defined the determination of fetal blood groups from maternal blood to avoid unnecessary treatment. Proposed research Broad research goals can be summarized as addressing: (1) epidemiology; (2) prevention; (3) reversal of immunity; and (4) new strategies for mitigation of severe alloimmune reactions. One major research focus will be to define which of the genetic information available for donors and patients needs to be considered for safe transfusion and transplantation. This requires integration of available technological platforms for testing new concepts of logistical assignment of blood products into clinical practice. A European platform has provided a signpost to implement “RBC blood match on a chip” with next-generation sequencing (NGS) approaches targeting HLA, HNA, HPA, and RBC genes.26 This provides the information for improved matching, including epitope rather than antigen matching,29 in the transfusion as well as transplantation of is important to appropriate for blood and stem cell donation and for of HLA, HNA, and typing platforms of donors and of immune blood products (eg, for is to of patients severe clinical versus patients with no or from a comparable will to personalized medicine into acceptable and risk both, in patient and In a joint for and safe of has been as well as of blood to support and other genotyping A large of blood donors for international use is coordinated by the Blood in and for highly immunized patients blood is at several European To be on or in the genetic of of the defined RBC antigens be to the and to match for of between the donor and Despite all patients still immunized (eg, during of genetic and factors for and and in the of and New drugs and approaches are to immune such as and other of reactions. may and New CAR-T cells might the to specifically T cells unwanted alloimmune reactions. important new field is to overcome of allogeneic immune cells used to treat malignancies or autoimmune to overcome the of use to autologous which is a Anticipated impact of the research genetic typing of donors and patients can now be delivered at low-cost, and should enhance the personalized transfusion but needs to be for benefit and in real The benefits include or alloimmunization in patients at risk for the of particular research require and support through systems for and of blood components Introduction technologies have been to further reduce the risks of transfusion and to potential approach for the of risk from transfusion is to human blood components with alternatives or These include recombinant coagulation immunoglobulins and Ex vivo red blood cells and platelets are development, as in the next Proposed research may have important in immunocompromised patients, but the risks and of in hematological patients have not been of potential include and to blood safety may include donor and donation vaccination of patients at risk and of blood the other the need of blood safety measures will the of blood components and limited health In addition, donor selection can to of blood donors with or no research may in evidence-based related to related to of blood should be These that require further research To the platelet is the clinical and safety of for the of cellular blood to costs and evaluate the of are the in the clinical and safety of blood products by comparative to of and to limitations of the strategies and a lack of to all and blood component are not sufficient to blood from the blood Anticipated impact of the research The proposed research will contribute to the quality of established technologies for of platelets and plasma A of to include and will further reduce the and of with blood transfusions. blood cells for therapeutic use Introduction in understanding of and enable to in red blood cells and platelets that could be used for transfusion These are now for at production of these blood cells and the potential for blood but are currently still to at the for transfusion therapy. are the and might be to reduce risks such as alloimmunization for example, blood and also the generation of cells therapeutic molecules or research groups in Europe develop to transfusion These use a of to the and These include hematopoietic stem cells from adult blood or stem cells or derived from and more novel adult cell or and are for the production of and of genetic Proposed research of and products requires a approach to the more to of the and to develop a blood designed to be for safe use in as many patients as In the of development, or has been derived from adult blood stem cells as this cellular source is most and more clinical trials are in the These clinical trials as researchers is a Research and to a Manufacturing of a quality and safety for use in developments of this will or cell (eg, These the potential of more of or that can be stored and for use. clear of these is that can from donors with blood groups or specific cellular that can for The for the field remain production of or that higher of hematopoietic cells and that maintain a during A cell and supply are also for and of stem cells or or cell is to develop and and new to large of or efficiently with loss of A major for the field is to enable to at cell to the of cells on an To most has on growth factors and The new is to and cell and cell at a of required to and for red cells and and efficiently of Anticipated impact of the research the research in production and of and will (1) better care for patients from chronic anemia, with patients with alloimmune or those with blood groups who are to source blood for (2) in cellular therapies delivery as red the to the red cell to that could for the red cells of to (3) blood cells to or enhance beyond the of possible with donor derived for example that or have therapeutic and (4) a on in the production and for support of other cellular for example novel and novel that enhance cells. is in is a for the of a for the of from is by Blood received from from and modified 2 is by Blood received research from is a scientific of and received research support from and of from is for and a and of is for received and from and and research is funded by the other have no of interest to

Authors 8

1. Srini V. Kaveri

   Inserm · Sorbonne Université · Centre de Recherche des Cordeliers

   Affiliation as printed

   Institut National de la Santé et de la Recherche Médicale, Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, France

2. Jagadeesh Bayry

   Inserm · Sorbonne Université · Centre de Recherche des Cordeliers · Indian Institute of Technology Palakkad

   Affiliation as printed

   Indian Institute of Technology Palakkad, Kerala, India

   Institut National de la Santé et de la Recherche Médicale, Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, France

3. Miloš Bohoněk

   Military University Hospital Prague

   Affiliation as printed

   Department of Hematology and Blood transfusion, Military University Hospital Prague, Czech Republic

4. Andreas S. Buser

   Swiss Red Cross · University Hospital of Basel

   Affiliation as printed

   Department of Hematology, University Hospital Basel, Switzerland

   Regional Blood Transfusion Service, Swiss Red Cross, Basel, Switzerland

5. Jean‐Daniel Tissot

   University of Lausanne

   Affiliation as printed

   Faculty of Biology and Medicine, University of Lausanne, Switzerland

6. Ashley Mark Toye

   National Health Service · NHS Blood and Transplant · University of Bristol · Bristol Institute for Transfusion Sciences

   Affiliation as printed

   Bristol Institute of Transfusion Sciences, NHS Blood and Transplant, Filton, United Kingdom

   School of Biochemistry, Biomedical Sciences Building, University Walk Bristol, United Kingdom

7. Emile van den Akker

   Sanquin · Amsterdam University Medical Centers · University of Amsterdam

   Affiliation as printed

   Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, Department of Hematopoiesis, University of Amsterdam, The Netherlands

8. Sacha Sergio Zeerleder

   University of Bern · University Hospital of Bern · Sanquin · Amsterdam University Medical Centers · University of Amsterdam

   Affiliation as printed

   Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Switzerland

   Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, Department of Hematopoiesis, University of Amsterdam, The Netherlands