The EHA Research Roadmap: Anemias
Authors: Achille Iolascon, Stefano Rivella, Nicholas P. Anagnou, Clara Camaschella, Dorine Swinkels, Martina U. Muckenthaler, Graça Porto, Wilma Barcellini, Immacolata Andolfo, Antonio M. Risitano, Antonis Kattamis, Maria Domenica Cappellini, Ali T. Taher, Lucia De Franceschi, David Rees, Roberta Russo, Hannah Tamary, Reinhard Stauder, Domenico Girelli
Journal: HemaSphere (2021)

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 one to two section editors who were leading international experts in the field. In the five 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 eleven 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. Anemia is still the most common disease among the world population, and it affects 1.6 billion people worldwide.2 In various ages of life, it seems to be particularly prevalent: childhood, females of childbearing age, and old age. In most cases, these are anemias due to acquired causes, while cumulatively the hereditary causes make up about 7% of the total. Among these, thalassemias and other hemoglobinopathies have acquired considerable importance in Europe in consideration of the globalization and the arrival of immigrants from regions with a significant incidence. For these reasons, one of the problems of public health in many European countries is represented by these pathologies which require transfusion interventions and management of chronic and acute pathologies. One of both today's and future goals of these pathology treatments is represented by precision diagnostics, considering that it is no longer enough to identify the causative gene only, but the identification of the cohort of genes that significantly modify the phenotype is mandatory mainly for the outcome definition (Figure 1).Figure 1.: Graphical representations of the aims of the Research Roadmap for Anemias in Europe during the period 2020–2025.A particular emphasis is given to the search for new effective therapies in hereditary diseases. Among them were new stem cell transplantation techniques and new approaches such as gene therapy and genome editing, which allow to solve the problem of transplant rejection and the scarcity of donors. The consequences of morbidity associated with chronic anemia extend to loss of productivity from impaired work capacity, cognitive impairment, increased susceptibility to infection, and in the elderly, a huge contribution to comorbidities, which exerts a very substantial economic burden on healthcare systems.3 Nevertheless, anemia frequently goes unrecognized and untreated, causing high direct and indirect costs at both the individual and national levels. Healthcare services in these countries have to deal with increasingly culturally diverse populations. It is noteworthy that, due to the immigrant movements in Europe, there is a new epidemiology of acquired and inherited anemias.4 It is important for planning for health intervention to know exactly the distribution of the different form of anemia in each country. To carry out this, it appears mandatory to have European guidelines for diagnosis and establish a common and more sustainable therapeutic approach. Moreover, clinical trials on new drugs and therapeutic procedures could ameliorate the quality of patients affected with the diseases, mainly in the inherited form, and enhance the quality of their life and life expectancy. Coordinated efforts should be made to develop strategies for prevention of acquired and inherited anemias in individuals at risk in Europe. Detailed epidemiological studies in all countries, especially western countries, are a prerequisite for the implementation of effective prevention programs. For a correct diagnosis is mandatory to have a shared diagnostic flowchart for each of the main form of anemias. Thus, the development of new tools to reliably diagnose anemias is urgently needed and fits well with the needs of personalized medicine. 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. In the last 15 years, hematology research has made a big leap forward. The emergence of sophisticated genetic and molecular tools (ie, next-generation sequencing [NGS] technique) allowed spectacular progresses in our understanding of the structure and function of the blood cells in health and disease. Our general aim will be to solve several hematologic problems using these new approaches.5,6 Research on rare genetic iron-related diseases that are informative biological models may contribute to further understanding of iron metabolism. Their precise diagnosis might lead to avoid unnecessary and costly diagnostic tests and possibly harmful treatments. New technologies for anemia and related disorders Where we are now Anemia, defined as a decreased amount of hemoglobin, can result from blood loss but also from decreased synthesis of hemoglobin, decreased erythrocyte (RBC) production, or increased RBC destruction. The clinical cost and socio-economic impact of these disorders is tremendous. Anemia of inflammation (AI), chronic kidney disease (CKD), myelodysplastic syndromes (MDS), hemolytic anemias, and some forms of BM failure represent a growing and pressing medical and socioeconomic issue in Europe. Children affected by hemoglobinopathies require long-life transfusion for survival but, eventually, a considerable morbidity develops leading to a decreased lifespan. Clinical management includes administration of anti-inflammatory molecules in AI, erythropoiesis-stimulating agent and iron in CKD, blood transfusion, administration of hematopoietic growth factors, low-intensity chemotherapy, and BM transplantation in MDS. Hemoglobinopathies represent the most frequent disorder worldwide, with at least 300,000 children born with these disorders every year. Clinical management has been focusing on supportive therapy such as blood transfusion, iron chelation and management of pain. Recently, a novel drug, Reblozyl (luspatercept-aamt) that modulates TGFβ-like pathways and improves RBC synthesis as well transfusion regimen, and has been approved for the treatment of β-thalassemia and MDS. BM transplantation has also been utilized as a definitive, although not without risk, curative option. Additional anemias are due to dietary limitation, such as folate, vitamin B12, and ID, while others are due to infections or exposure to toxic agents. Plans for the future Advances have been made in our understanding of molecules and pathways that could be targeted to improve anemia. B-cell-CLL/lymphoma-11A (BCL11A) modulates the production of fetal hemoglobin (HbF), is an important modifier of clinical severity in β-globinopathies.7 Furthermore, small molecule inhibitors inducing HbF, such as epigenetic enzymatic inhibitors, or directly inducing HbF or targeting transcription factors, are currently being evaluated for their therapeutic efficacy.8 Molecules that control dietary iron absorption in the gut and hepcidin production in the liver, such as ferroportin (FPN), transferrin, erythroferrone (ERFE) and type-two transmembrane-serine-protease (TMPRSS6) have also been investigated for their contribution to iron overload and anemia in β-thalassemia.9 Gene therapy either via gene addition of β-globin10 or γ-globin gene11 and gene editing approaches have been introduced as realistic alternatives to treat β-globinopathies. Drugs that limit iron absorption and improve anemia are showing very promising results in preclinical studies.12 Additional drugs that target oxidative stress (like peroxiredoxin-2 agonists) and erythroid cell metabolism (like Glycine Transporter Type I Inhibitor or Pyruvate kinase agonists) are being investigated. Preclinical studies indicate that combinatorial therapies could further improve anemia.13 Gene therapy and gene editing trials for the cure of β-thalassemia and SCD show very promising results.7 These approaches are now waiting for the development of nontoxic myeloablative regimens. Genetic variability will likely influence the efficacy of these new therapeutics or therapies. For this reason, we recommend: The use of next-generation (-omics technologies) to assess the role of genetic makeup of the patients, modifiers, and environment, leading to personalized treatment for each individual affected by hereditary anemias.14 To invest in these new lines of investigations and technologies to validate their potential, and transform them into effective and safe ways of treatment (Figure 1). Efforts to develop new scientific discoveries and therapeutics can have a major impact, at multiple levels on the growing and aging population in Europe. Moreover, many additional incurable disorders could benefit from the development of gene therapy and gene editing technologies designed for β-thalassemia, SCD, and many other diseases that require management of RBC production. Iron deficiency anemia Where we are Iron deficiency anemia (IDA) is the most common form of anemia worldwide. IDA (and ID without anemia, which is even more common) poses a major burden to the society: they may cause cognitive defects in children, increased morbidity and mortality in pregnancy, reduced physical performance in workers, and are common comorbidities in the elderly. Etiology, populations at risk, and algorithms for diagnosing absolute ID/IDA are overall well established. More recently, also whole blood donors are identified as being at risk to develop ID, especially at fast donation rates.15 Major challenges are diagnosing ID in nonerythropoietic tissues (eg, heart, kidney, and lungs) and in the context of inflammation. It is well known that microorganisms compete with the human host for iron. An emerging issue in the field is the role of microbiota. Studies in mouse models suggest that gut microbiota might modulate iron absorption, counteracting the positive effect of duodenal HIF-2 alpha thus contributing to systemic iron homeostasis.16 Iron and iron proteins have a profound effect on erythropoiesis, and erythroid expressed ferroportin, exporting iron, protects red cells from oxidative stress and contributes to the levels of serum iron in ID.17 BM transferrin receptor 2 (TFR2) in complex with the erythroid receptor (EPOR) senses ID and modulates erythroid differentiation accordingly. Both genetic and acquired ID increase megakaryocyte commitment in mice,18 providing a plausible explanation of thrombocytosis that can be observed in severe ID. In the therapeutic field, novel schedules of oral iron administration at alternate day suggest optimal efficacy with less side effects, at least in ID19; indications to intravenous iron both in absolute and functional ID are increasing.20 Plans for the future It is urgent to clarify how ID affects tissues other than erythropoiesis in animal models. In particular, it is important to investigate how kidneys reabsorb iron and whether this participates to systemic homeostasis and to explore the contribution to iron balance of local hepcidin produced by different tissues. The value of soluble transferrin receptor, serum hepcidin levels, and reticulocyte hemoglobin content should be better explored in the diagnosis of complex cases of ID; the standardization of these parameters would further facilitate clinical use. There is a need for identification and validation of functional markers of ID beyond hemoglobin. Future research should address: The physiological role of gut microbiome and its crosstalk with the intestinal machinery of iron absorption. It is relevant to define whether and how gut microbiota modulate iron absorption, the role of microbiota in ID, its potential interference with pharmacological iron absorption and its role—if any—in the side effects caused by oral iron supplementation. There is room for optimizing and personalizing ID treatment modalities: clear schedules should be established for oral iron treatment in IDA, criteria for oral versus intravenous iron should be defined under different conditions and according to disease severity; guidelines to replace total iron needs with single/double infusion(s) of intravenous iron should be drawn; iron supplementation strategies based on individual genetic susceptibility to ID should be considered; long-term complications of intravenous therapy not addressed in clinical trials should be explored; novel therapies for functional ID that counteract hepcidin function or promote EPO production and iron mobilization await clinical introduction. Iron overload disorders Where we are now Disorders of systemic iron overload are a heterogeneous group of diseases classified into several subtypes based on the underlying genetic or acquired cause. These include (1) primary genetic defects in proteins controlling iron homeostasis; (2) erythroid maturation defects resulting in secondary iron overload; and (3) very rare genetic conditions that include disorders of iron transport, such as hypotransferrinemia, aceruloplasminemia, and DMT1 deficiency. Most frequently, misregulation of the hepcidin-ferroportin regulatory axis is responsible for iron overload. In most subtypes of hemochromatosis, reduced hepcidin activity explains increased iron uptake mediated by the iron exporter ferroportin, while mutations in ferroportin hallmark ferroportin disease. In iron loading hematological diseases, including thalassemias, congenital hemolytic diseases, sideroblastic anemias, congenital dyserythropoietic anemias, myelodysplastic syndromes, and aplastic anemia, inefficient erythropoiesis explains some degree of iron overload, which is severely aggravated by regular blood transfusions to treat anemia. In the past 20 years, novel genes with critical roles in the generation of iron overload disorders were discovered and the subsequent development of experimental disease models had a tremendous impact on our understanding of the mechanisms that maintain cellular and systemic iron metabolism. Not only they explained the pathogenesis of hemochromatosis and other primary disorders of the hepcidin-ferroportin axis they also generated new insights into mechanisms underlying iron accumulation in iron loading anemias. This knowledge enabled the development of novel treatment options for iron overload diseases. Additionally, it laid the basis for research on the impact of iron in common acquired diseases, such as chronic liver disease, diabetes, neurodegeneration, atherosclerosis, or cardiovascular disease, where moderate elevations of tissue iron levels may exacerbate the underlying pathologies. A major advance was the identification of erythroferrone (ERFE), a long-sought erythroid regulator of hepcidin synthesis and iron homeostasis,21 and the recognition of its mechanism of action.22 An ERFE immunoassay was developed for human studies of normal and disordered erythropoiesis and its effect on iron homeostasis.23 Mechanisms of iron-induced oxidative stress sensing in the liver were clarified with the demonstration that BMP6 production in sinusoidal endothelial cells24 is under the control of the transcription factor NRF2 in conditions of hepatic iron loading.25 Novel iron overload disease models revealed the importance of tissue-specific iron homeostasis and the impact of iron accumulation in different organs such as retina,26 lungs,27 heart,28 or the cardiovascular system.29 The role of TFR2 on the mutual control of iron homeostasis and erythropoiesis was revealed, opening a new door to potential novel therapeutic targets in iron-loading anemias.30 This was also the era when novel targeted drugs such as hepcidin replacement therapy or hepcidin agonists were tested as novel approaches for treating iron overload under a variety of conditions, including iron-loading anemias.31 In addition, ferroportin inhibitors were first developed for therapeutic purposes.32 The role of the iron status of the mother on child's health was assessed in a preclinical study showing that maternal hepcidin, through regulation of maternal plasma iron concentrations, determines the amount of iron taken up by the placenta and protects the fetus from iron excess even when the mother is iron overloaded.33 Plans for the future We need basic research into mechanisms that maintain iron homeostasis under iron overload conditions and an increased demand for erythropoiesis. We further need to understand how iron accumulation in the BM affects early steps of hematopoiesis and the damage that occurs in diseases such as thalassemia, myelodysplasia, or leukemia. It is of interest to learn how specific organs handle iron or heme released during hemolysis, and the role of ferritin secretion on tissue iron redistribution. We need to investigate the role of the iron status of the mother on child's health. Research is required to identify the role of proteins involved in iron regulation on different cell types, for example, of the immune system or in the brain. Definitely estimate the hemochromatosis prevalence in Europe, describe its natural history and clarify the genetic and environmental determinants of its penetrance. European registries promoted by EuroBloodNet are a critical requirement to fill this gap and for future implementation of preventive strategies. Epidemiological and prospective cohort studies are required to substantiate knowledge on how perturbations of iron homeostasis are linked to disease progression and development of comorbid complications in acquired disorders, such as cancer, cardiovascular, liver, kidney, bone, or neurological diseases. This research may justify the implementation of clinical trials with the novel targeted therapies to reduce systemic iron levels. Research needs to support the initiative by the WHO to define adequate world-wide Hb values and its close link to iron availability. Hemolytic anemias, including membrane and enzyme defects Where we are now Hemolytic anemias (HAs) are a heterogeneous group of hereditary and acquired disorders. The former includes defects of the red cell membrane and metabolism, and the latter warm autoimmune hemolytic anemia (wAIHA) and cold agglutinin disease (CAD). In the past 5 years, substantial improvement has been made with regard to dehydrated hereditary stomatocytosis (DHS) or hereditary xerocytosis (HX), familial pseudohyperkalemia (FP), pyruvate kinase deficiency (PKD), CAD, and wAIHA. Regarding DHS, during the last 5 years, the second causative locus, KCNN4 gene encodes for the Gardos channel, was identified.34–37 Senicapoc, a Gardos channel antagonist, previously proposed for use in sickle cell anemia, showed efficacy in preventing RBC K+ loss and dehydration in both PIEZO1 and KCNN4 mutated cells.38–40 Moreover, two large retrospective cohort studies have been recently described comprising overall 249 patients with several forms of membrane defects due to altered transport function.41,42 These studies highlighted that PIEZO1 was the most frequent mutated gene under these conditions and that the major complication is the severe hepatic iron overload. A recent study demonstrated the role of PIEZO1 in the liver by regulation of hepcidin expression through increased phosphorylation of ERK1/2 and inhibition of the BMP-SMADs pathway. This was the first demonstration of a direct link between PIEZO1 and iron metabolism, which defines the channel as a new hepatic iron metabolism regulator and as a possible therapeutic target of iron overload in DHS and other iron-loading anemias.43 Furthermore, two recent studies have elucidated the role of PIEZO1 during erythroid differentiation. PIEZO1 activation delays erythroid differentiation of normal and DHS1-derived human progenitor cells.44 Patients carrying PIEZO1 mutations showed reduced reticulocyte count respect to patients with KCNN4 mutations, despite the similar Hb levels. Indeed, it has been demonstrated that PIEZO1 gain-of-function (GoF) mutations delay reticulocyte maturation in DHS.45,46 PIEZO1 GoF mutations are also associated to resistance of Plasmodium infection in mice and human. As matter of fact, a novel human GoF PIEZO1 allele, E756del, is present in a third of the African population (Figure 2).47Figure 2.: Schematic representation of pathogenic mechanism of DHS and new discovery on Plasmodium infection. (A) Recent study demonstrated that RBCs of DHS patients with PIEZO1 gain-of-function (GOF) mutations show a low rate of infection by Plasmodium falciparum. (B) RBCs of DHS patients show dehydration that is caused by the increased potassium efflux and increased calcium influx of PIEZO1 GoF mutations or KCNN4/Gardos GoF mutations. Senicapoc, a Gardos antagonist, is able to restore the hydration status in both PIEZO1 and KCNN4 mutants. (C) RBCs of DHS patients with GoF mutations in PIEZO1 show delayed terminal differentiation and reticulocytes maturation. (D) At the hepatic level, PIEZO1 GoF mutations in DHS result in increased intracellular Ca2+ concentrations. The hyperactivation of the mechanoreceptor leads to amplification of the phosphorylation of ERK1/2, which acts in turn by inhibiting the BMP/SMADs pathway. The lack of phosphorylation of SMAD1/5/8 inactivates HAMP transcription.Regarding FP, it was demonstrated that the ABCB6 missense mutations cause elevated potassium ion efflux in RBCs.48 Of note, FP individuals are present in the blood donor population.48,49 Moreover, a genetic mutation in ATP11C, one of the major flippase of RBCs, was identified in a male affected by congenital hemolytic anemia inherited as an X-linked recessive trait.50 The widespread of NGS has revolutionized the field of diagnostic and research of new causative genes in these anemias. Indeed, the NGS targeted panels were routinely introduced in the diagnostic practice facilitating not only the diagnosis, but also the prognostic evaluation of these patients.51–53 Regarding PKD, recommendations for the diagnosis, including pros and cons of enzymatic and molecular testing, have been published.54,55 Moreover, a large retrospective/prospective global registry of 254 patients has been activated, enabling a more precise definition of clinical and molecular features of the disease. In particular, treatments, complications, and their monitoring and management have been described.56,57 The most important therapeutic improvement regards mitapivat, a small molecule, an oral activator of red cell PK, which was administered in 52 nontransfused patients with PKD, obtaining a maximal hemoglobin increase >1 g/dL in half of the patients (median 3.5 g/dL), with an acceptable safety profile.58 Regarding CAD, a large retrospective multicenter study including 232 patients has better defined the clinical characteristics and response to the few available treatments (rituximab alone or in combination with bendamustine or fludarabine).59,60 Consistently, a pivotal study with the complement inhibitor sutimlimab (a humanized anti-C1s monoclonal antibody) has shown a mean hemoglobin increase of 2.6 g/dL, with 20/24 (83.3%) patients displaying hemoglobin increase ≥1 g/dL, along with a meaningful improvement of quality of life.61 Finally, several experts' opinions and an International Consensus meeting have provided recommendations for the diagnosis and treatment of wAIHA and CAD (Figure 3).62,63Figure 3.: Standard and target therapies for warm autoimmune hemolytic anemia (wAIHA) and cold agglutinin disease (CAD). The figure shows the several immunologic mechanisms involved in pathogenesis, including macrophages, T and B lymphocytes, cytokines, activation of the complement cascade, antibody-dependent cellular cytotoxicity (ADCC) in the spleen and/or complement-dependent cytotoxicity (CDC) in the liver, and possible inadequate bone marrow compensation. Standard therapies include steroids and immunosuppressors that act not specifically on the various mechanisms, and splenectomy. Target therapies are directed against specific immunological mechanisms either inhibiting the immune attack or stimulating bone marrow compensation. APC = antigen presenting cell; BAFF = B-cell activating factor; BM = bone marrow; BTK = Bruton tyrosine kinase; CAD = cold agglutinin disease; EPO = erythropoietin; FcRn = neonatal Fc receptor; MMF = mycophenolate mofetil; PI3K = phosphoinositide 3-kinase; Syk = spleen tyrosine kinase.Plans for the future In the next years, regarding the RBCs membrane defects it will be important: to further understand the pathogenic mechanism of anemia in DHS also by the use of the mouse model with PIEZO1 GoF mutations; the mechanism of hepatic iron overload in DHS needs further deeply dissection. to identify new causative genes for the cases still lacking a genetic base that are about 10%–15%. to find new therapeutic treatments. The study of pathogenic mechanism will be useful for the identification and development of therapeutic treatments also in the field of gene therapy. Senicapoc seems to be a good promising drug to treat dehydration in DHS. A future clinical trial on the use of this drug in DHS could confirm its efficacy also in vivo. Regarding FP, could be useful to further dissect the role of ABCB6 and its correlation to blood transfusion. In the next years, ongoing long-term follow-up of mitapivat-treated PKD patients will determine whether the rise in hemoglobin will also be associated with a decreased incidence of complications. Ongoing studies in transfusion-dependent patients will confirm its efficacy in more severe settings (ClinicalTrials.gov NCT03559699). Following preclinical studies using a lentiviral vector in myeloablated PK-deficient mice, a clinical trial on gene therapy is close to start in humans (ClinicalTrials.gov NCT04105166). This promising new therapeutic approach will dramatically change the prognosis of severe PKD, unresponsive to splenectomy and mitapivat, also considering the uncertain results with BM transplant.64 Regarding wAIHA and CAD, several target therapies are under development, including inhibitors of complement (at different levels of the cascade), tyrosine kinases, proteasome, and neonatal Fc-receptor (Figure 3) (ClinicalTrials.gov NCT03538041, NCT03226678, NCT03075878, NCT04256148, NCT04119050, NCT02612558, NCT03764618, NCT04083014, NCT02389231). In the next years, this expanded therapeutic armamentarium will help in defining the best choice, sequence and combination of drugs aimed at "cure" the disease.65 Congenital BM failure, aplastic anemias, PNH Where we are now BM failures (BMFs) are a heterogeneous group of diseases characterized by a quantitative deficiency in one or more blood cell lineages. Inherited BMFs are rare and include different entities such as Fanconi's anemia (FA, which is due to impaired DNA repair and cytokine hypersensitivity),66 Dyskeratosis Congenita (DKC), Diamond Blackfan Anemia (DBA), and Shwachman-Diamond Syndrome (SDS) (all associated with impaired ribosomal or telomere function). Acquired forms of BMF are more frequent; the most typical form is idiopathic aplastic anemia (IAA), characterized by a severe pancytopenia due to an immune-mediated attack of hematopoiesis. PNH is a less common form, where the underlying BM disorder is associated with the expansion of an abnormal, nonmalignant, blood cell population which is deficient in the expression of glycosyl-phosphatidyl-inositol (GPI)-linked proteins due to a somatic PIG-A mutation. Since lacking GPI-linked proteins include the complement regulators CD55 and CD59, the clinical phenotype of PNH is characterized by complement-mediated, intravascular, hemolytic anemia, variously embedded with thromboembolisms and cytopenia. The improved understanding of all BMFs has led to better patient management in Europe; the Severe Aplastic Anemia Working Party (SAAWP) of the EBMT historically has contributed greatly to improved clinical outcome in this field, pioneering the therapeutic use of antithymocyte globulin (ATG) in IAA, as well as the use of HSCT in patients with FA and other inherited forms. The database of the SAAWP of the EBMT contains data on >16,000 patients with different subtypes of BMFs, thereby providing a unique opportunity for investigating many different critical aspects of these diseases. The SAAWP of the EBMT continues to run a multinational database to collect data from all European BMFs, aiming to perform robust retrospective studies. At the same time, the SAAWP is now fully equipped for academic prospective trials: the RACE study, the largest clinical trial performed in IAA, has just been completed. Plans for the future Patients suffering from BMFs continue to represent a challenge for the medical community, for their poor prognosis when the underlying disease is not controlled. Additional efforts are needed to offer the most appropriate treatment to all European patients, and to improve current standards of care. The SAAWP of the EBMT is dedicated to this goal through different research lines. Improvements in HSCT for inherited and acquired forms of BMF. HSCT remains a key treatment option for all BMF patients, with the actual indication depending on the phase/severity of the disease and on the availability of alternative treatments. The SAAWP is actively working to improve the outcome of HSCT in all th