The EHA Research Roadmap: Updates for malignant myeloid disorders

The European Hematology Association (EHA) previously published the EHA Research Roadmap in 2016, highlighting achievements in diagnostics and treatment of blood disorders, as well as informing European policymakers of the urgent clinical and scientific needs and research priorities in the field of hematology. There have been numerous developments and advances in hematology since 2016, which justifies an updated Research Roadmap. Döhner and colleagues, including the chair of the MDS Hub Theo de Witte, co-chair of the AML Hub Charles Craddock, MPN, AML, and MDS Hub steering committee members Alessandro Vannucchi, Claire Harrison, Gert Ossenkoppele, Jorge Sierra, Pierre Fenaux, and Eva Hellstrom-Lindberg, and AML Hub scientific advisory board members Lars Bullinger, Agnieszka Wierzbowska, and Hervé Dombret, have recently published a section on malignant myeloid diseases in the updated EHA Research Roadmap, which outlines the most urgent priorities in this area.¹ The Research Roadmap includes myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and myeloproliferative neoplasms (MPN), and covers research contributions from Europe, proposed direction for future research and its potential impact for each. We are pleased to provide a summary here.

Myelodysplastic syndromes

MDS are clonal disorders of hematopoietic stem cells (HSCs), characterized by their propensity to evolve into AML. The incidence rate of MDS is 4 per 100,000 people per year, but increases greatly over the age of 60 years, with >30,000 new cases expected each year in Europe. Recent studies have provided evidence of healthy individuals acquiring somatic mutations of the most frequently mutated genes in MDS with ageing, a state defined as clonal hematopoiesis of indeterminate potential (CHIP), increasing the risk of hematologic malignancies, cardiovascular disease, and all-cause mortality. Current treatment options for MDS range from allogeneic HSC transplantation (HSCT), azacitidine, erythropoiesis-stimulating agents, lenalidomide, red cell transfusion, and luspatercept.

European research contribution

Several pivotal studies have been performed in Europe, including major advances in understanding the genetic mechanisms of MDS. European researchers have also contributed to developing effective treatments including erythropoietin, azacitidine, lenalidomide, and luspatercept, as well as elucidating the genetic predisposition to MDS and other myeloid neoplasms in pediatric hematology.

Proposed research

• Characterizing cellular and molecular mechanisms involved in disease development, progression, and therapy resistance.
  • Single-cell, genome, and transcriptome studies, as well as pre-clinical studies identifying the impact of molecular abnormalities.
  • Population-based registries with comprehensive mutational profiling of germline and somatic mutations.
  • Clinical trials defining clinical implications of mutation profiles in unbiased and homogenously treated patient populations.
• Identifying precursors associated with increased risk of developing MDS and MDS/MPN, including characterizing CHIP.
  • Population-based studies analyzing the interactions of hematopoietic clones with complex chronic conditions with multimorbidities in the elderly.
• Identifying therapeutic targets for efficient elimination of the MDS-propagating cells and improved survival and quality of life in patients with MDS.
  • Currently novel drugs targeting molecular abnormalities, including spliceosome, epigenetic regulators, and TP53, are under investigation and need to be developed further.
  • Studies exploring strategies to reduce allogeneic HSCT-related toxicity in elderly patients and development of more effective transplantation procedures integrating biology-driven pre- and post-transplant.

Research impact

The proposed research has the potential to decipher the cellular and molecular mechanisms of MDS, enhancing the identification of effective targeted interventions. Identifying the precursors to MDS and MDS/MPN will also help develop effective strategies focused on early diagnosis and interventions aimed at preventing clonal expansion and progression.

Acute myeloid leukemia

There are nearly 17,000 newly diagnosed patients with AML each year in Europe, making AML the most common form of acute leukemia in adults. The incidence of AML increases with age, implying a further increase in future years. Although an understanding of the molecular complexity of AML has led to the refinement of risk stratification and personalized therapeutic strategies, the prognosis and cure rates in both young and older patients remain poor. Lately, allogeneic HSCT has become a potentially curative treatment strategy for AML, owing to donor availability coupled with reduced intensity conditioning regimens.

European research contribution

Collaboration between European trial groups has become important for the accelerated delivery of new drugs and transplant therapies. One such alliance is the combined effort of European trial groups leading to the approval of gemtuzumab ozogamicin, an antibody-drug conjugate targeting CD33. The diagnosis and management of AML has transformed internationally, based on the European Leukemia Network (ELN) recommendations, including minimal residual disease (MRD) assessment, which play an important role in harmonization and standardization of MRD monitoring techniques. European researchers have also elucidated the biology of AML with mutated, translocated, or overexpressed genes, and germline mutations predisposing to AML.

Proposed research

• Single-cell genomic studies to better understand the multiclonal diversity of AML at diagnosis and during evolution and help overcome the resistance to conventional, as well as molecular-targeted agents.
• Studies refining MRD techniques, including next-generation sequencing, establishing ways to convert MRD positivity to negativity, as well as exploring the role of MRD in predicting survival.
• Studies investigating therapeutic strategies in AML subtypes associated with poor prognosis, developing strategies to reduce the risk of relapse rate post-transplantation and studies exploring maintenance treatments.

Research impact

Future research will help to decipher the molecular heterogeneity of AML and identify gene-to-gene interactions, instrumental in refining MRD assessment and developing personalized treatment strategies. Transplant outcomes will improve with accelerated delivery of prospective transplant trials. Particular attention should be paid to the management of older patients with AML, owing to their distinct biology and poor outcomes.

Myeloproliferative neoplasms

MPN are chronic, incurable disorders of HSCs, including polycythemia vera, essential thrombocythemia, prefibrotic and overt primary myelofibrosis, and post-polycythemia vera/post-essential thrombocythemia myelofibrosis, usually occurring in middle-advanced age patients, but recently diagnosed more frequently in younger people. Patients with MPN suffer from major thrombotic events and hemorrhages and have an impaired quality of life.

European research contribution

The World Health Organization (WHO) diagnostic criteria was revolutionized by the breakthrough discoveries of JAK2^V617F, JAK2 exon 12, and CALR mutations by European hemopathologists and the identification of genetic haplotypes predisposing to MPN. European researchers, in collaboration with American colleagues, developed various new disease classification criteria and risk scores such as the Mutation-Enhanced International Prognostic Scoring System for Transplant Age Patients (MIPSS-70) for primary myelofibrosis. The International Prognostic Scoring System (IPSS) and the Dynamic International Prognostic Scoring System (DIPSS) were also developed in Europe, along with some crucial studies leading to approval of the JAK1 and JAK2 inhibitors ruxolitinib and fedratinib.

Proposed research

• Further deciphering of the genetic and epigenetic complexity, including the relationship between phenotype-driver mutations and additional somatic mutations, and the genetic basis for familial clustering of MPN.
• Exploration of new therapeutic approaches, including monoclonal antibodies and antigen-activated immune cells.
• Development of criteria for categorizing patients based on their responses; early interventions and preventive measures in asymptomatic carriers of MPN-driven mutations needs further exploration.

Research impact

Further research from population-derived studies is likely to advance the development of personalized medicine approaches, ranging from diagnostic categories to alternative therapies based on individual risk ratio.

Conclusion

The EHA Research Roadmap for malignant myeloid diseases outlines the main research and policy priorities. Overall, a better understanding of CHIP and the genetic and epigenetic complexity of myeloid diseases, development of new therapeutic targets, and refinement of MRD techniques are the direction of future research, anticipated to further improve the outcomes in patients with MDS, AML, and MPN.