Powered by EHA Perspective OPEN ACCESS The EHA Research Roadmap: Malignant Myeloid Diseases Hartmut Döhner1, Luca Malcovati2, Gert J. Ossenkoppele3, Andreas Hochhaus4, Alessandro Maria Vannucchi5, Lars Bullinger6,7, Francisco Cervantes8, Charles Craddock9, Theo de Witte10, Konstanze Döhner1, Hervé Dombret11, Pierre Fenaux12, Jan Geissler13, Ulrich Germing14, Francois Guilhot15, Claire Harrison16, Eva Hellström-Lindberg17, Francesco Passamonti18, Jorge Sierra20, Radek Skoda21, Agnieszka Wierzbowska22 Correspondence: Hartmut Döhner (Hartmut.Doehner@uniklinik-ulm.de). 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 11 sections, each of which will be published separately. The updated EHA Research Roadmap identifies the most urgent priorities in hematology research and clini- cal 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. T he malignant myeloid diseases discussed in this section as JAK2 or CALR mutations in myeloproliferative neoplasms are clonal disorders of hematopoietic stem cells (HSCs) (MPNs) or entire molecular disease landscapes. Recent studies and progenitor cells with various underlying molecular have provided evidence that some of these gene mutations asso- basis, different clinical phenotypes and largely differing ciated with malignant myeloid disease are commonly acquired prognosis. Although younger patients may be affected, these dis- in HSCs during aging, a phenomenon that was termed “clonal orders mainly occur in older individuals, with median ages of hematopoiesis of indeterminate potential“ (CHIP) or “age-re- patients ranging from 55 to 60 years in chronic myeloid leuke- lated clonal hematopoiesis“ (ARCH). CHIP has been associated mia (CML) to approximately 75 years in myelodysplastic syn- with malignant myeloid diseases, but also with an increased risk dromes (MDS). Thus, malignant myeloid disorders represent an of cardiovascular diseases and decreased overall survival. increasing burden for healthcare systems in an aging population. The better understanding of the molecular basis has paved the In recent years, major advances have been made in the under- way for precision medicine approaches in malignant myeloid standing of the molecular basis of malignant myeloid disorders, disorders. This is exemplified by the successful development in particular with the advent of the next-generation sequencing of FLT3-, IDH1/IDH2-, or BCL-2 inhibitors in acute myeloid technologies. European researchers have been leading and were leukemia (AML), of next-generation tyrosine kinase inhibitors involved in pivotal studies deciphering single disease genes, such in CML, or of JAK2-inhibitors in MPN. European research in 1 Department of Internal Medicine III, Ulm University Hospital, Germany 15 University of Poitiers, France 2 Department of Molecular Medicine, University of Pavia & Department of 16 Department of Haematology, Guys and St Thomas’Hospital, London, United Hematology Oncology, IRCCS S. Matteo Hospital Foundation, Pavia, Italy Kingdom 3 Amsterdam UMC, Department of Hematology, VU University Medical Center, 17 Center for Hematology and Regenerative Medicine, Karolinska Institutet, Amsterdam, The Netherlands Karolinska University Hospital, Stockholm, Sweden 4 Universitätsklinikum Jena, Klinik für Innere Medizin II, Hämatologie/Onkologie, 18 University of Insubria, Varese, Italy Jena, Germany 19 Department of Clinical and Biological Sciences, University of Turin, San Luigi 5 Center Research and Innovation of Myeloproliferative neoplasms, CRIMM, University Hospital, Italy University of Florence, Azienda Ospedaliera-universitaria Careggi, Italy 20 Hospital de la Santa Creu i de Sant Pau and Jose Carreras Leukemia Research 6 Department of Hematology, Oncology, and Tumor Immunology, Campus Virchow Institute, Barcelona, Spain Klinikum, Charité-Universitätsmedizin Berlin, Germany 7 Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 21 Department of Biomedicine, Experimental Hematology, University Hospital Basel Germany and University of Basel, Switzerland 8 Hospital Clínic Barcelona, Spain 22 Multi-specialized Center of Oncology and Traumatology, Lodz, Poland 9 Centre For Clinical Haematology, Queen Elizabeth Hospital, Birmingham, United Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc. Kingdom on behalf of the European Hematology Association. This is an open-access 10 Radboud University Medical Centre, Nijmegen, The Netherlands article distributed under the terms of the Creative Commons Attribution-Non 11 Institut de Recherche Saint-Louis (IRSL), Université de Paris, Hôpital Saint- Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible Louis, Paris, France to download and share the work provided it is properly cited. The work cannot 12 Département (DMU) d’hématologie et immunologie, Assistance Publique be changed in any way or used commercially without permission from the Hôpitaux de Paris, Hôpital St Louis, Université de Paris, France journal. 13 Leukemia Patient Advocates Foundation, Bern, Switzerland HemaSphere (2021) 5:9(e635). 14 Klinik für Hämatologie, Onkologie und Klinische Immunologie, Universitätsklinikum http://dx.doi.org/10.1097/HS9.0000000000000635. Düsseldorf, Heinrich-Heine Universität Düsseldorf, Germany Received: 17 May 2021 / Accepted: 3 August 2021 1 Döhner et al Research Roadmap: Malignant Myeloid Diseases hematology has a long-standing tradition of well-organized clin- associated with deletion 5q, respectively.7,8 More recently, lus- ical trial groups conducting well-designed pivotal phase 3 stud- patercept has been proven effective in reducing transfusion bur- ies, thereby making major contributions to this development. den in MDS with ring sideroblasts.9 Chronic red cell transfusion Under the umbrella of the European LeukemiaNet (ELN) remains the mainstay of therapy for many patients with MDS. and the European Hematology Association (EHA), European researchers—in collaboration with other international experts—have published a wealth of recommendations and European research contributions guideline papers that have been highly valuable for the scien- In the past few years, major advances in the understanding of tific community, patients, care givers, and also for regulatory the genetic basis of MDS have been made by means of massive authorities. parallel DNA sequencing, and a number of seminal studies have Nevertheless, major challenges remain in improving out- been performed in Europe.2–6 comes and quality of life for patients with malignant myeloid Approximately, 90% of MDS patients carry one or more diseases. One challenge relates to the enormous (epi)-genomic oncogenic mutations with two-thirds of them are found in indi- complexity of most of these disorders, with multiple epigenetic viduals with a normal karyotype. Driver mutations have been lesions being present at diagnosis, and subsequent clonal evolu- identified in genes involved in RNA splicing, DNA methylation, tion over the disease course with various mechanisms of resis- chromatin modification, transcription regulation, DNA repair, tance. Thus, overcoming primary and/or secondary resistance and signal transduction. Only a few genes are consistently to conventional as well as targeted agents will be a major task mutated in 10% or more MDS patients, including those involved in this Research Roadmap. Another hurdle relates to challenges in epigenetic regulation (TET2, ASXL1, and DNMT3A) and in future clinical trial design. Malignant myeloid disorders in splicing factors (SF3B1, SRSF2, and U2AF1), while a long tail general are rare diseases, and with the development of precision of >50 genes are mutated less frequently.3,4 Mutations in SF3B1 medicine in molecular subgroups, the conduct of pivotal phase have been found to be highly specific for MDS with ring sidero- 3 studies has become challenging. Thus, a joint European and blasts and are associated with a very low risk of disease progres- intercontinental effort—in close collaboration with important sion and a favorable outcome.5 stakeholders such as patient advocacy groups, biotech and phar- European hematologists have provided pivotal contribu- maceutical industry—will be necessary to expedite the develop- tions to developing effective treatments for MDS, including ment of new therapies for our patients. erythropoietin, azacitidine, lenalidomide, and luspatercept.7–9 Recommendations for treatment of the individual patient with MDS, including allogeneic HSCT, have also been developed in MDSs and myelodysplastic/MPNs recent years.10–12 Seminal contributions have also been made in pediatric hema- Introduction tology, for example, in elucidating the genetic predisposition to The MDSs are clonal disorders of HSC which are charac- juvenile myelomonocytic leukemia, as well as to MDS or other terized by peripheral blood cytopenia, dysplasia in one or myeloid neoplasms.13 more myeloid cell lines, and a propensity to evolve into AML. Myelodysplasia is not restricted to MDS but may be found also in other myeloid neoplasms, in particular in the so-called MDS/ Proposed research for the Roadmap MPN, which mainly include chronic myelomonocytic leukemia Myeloid malignancies appear to be propagated by rare and less frequent diseases, including atypical CML, chronic neu- self-renewing mutant HSCs. However, the cellular and molec- trophilic leukemia, juvenile myelomonocytic leukemia, MDS/ ular mechanisms that regulate development, propagation, and MPN with ring sideroblasts, and thrombocytosis. therapy resistance of these myelodysplastic stem cells remain The crude incidence rate of MDS is 4 per 100,000 people per unknown. Studies are needed to: year, but increases up to 50 per 100,000 persons per year over the age of 60, indicating that >30,000 new cases are expected 1. characterize cellular and molecular mechanisms involved in Europe each year and making MDS one of the most common in disease development, progression and therapy resistance, hematologic malignancies in Western countries. Furthermore, including germline predisposition, chronic inflammation, recent data suggest that this incidence may be significantly microenvironmental and immunological abnormalities, as underestimated, because many MDS patients may remain well as immune escape following stem cell transplantation; underdiagnosed as anemia or cytopenia of the elderly. 2. identify premalignant conditions associated with increased risk to develop MDS and MDS/MPN and recognize the MDSs are caused by somatic mutations that occur in HSC, interaction of hematopoietic clones with multimorbidities conferring a proliferative advantage to HSC while inducing and complex chronic conditions in older persons; ineffective differentiation and maturation of hematopoietic 3. identify therapeutic targets for efficient elimination of the progenitor cells resulting in peripheral blood cytopenia.2–6 MDS-propagating cells and establish suitable frameworks Recent studies provided evidence that somatic mutations in for biology-driven clinical trials. some of the genes frequently mutated in MDS are commonly acquired in HSC during aging, and that apparently normal sub- While recent advances have shed light on the genetic complex- jects with these mutations have increased risk of hematologic ity of MDS paving the way for precision medicine strategies, the malignancies and increased cardiovascular and all-cause mor- factors enabling the emergence, selection, and subsequent leuke- tality (ARCH or CHIP). mic evolution of these clones remain incompletely understood. MDS and MDS/MPN show marked clinical heterogeneity, Single-cell studies combining analysis of the genome and tran- ranging from conditions with an indolent clinical course and scriptome as well as preclinical models are warranted to iden- a near-normal life expectancy to entities with very poor prog- tify the impact of recurrent molecular abnormalities on gene nosis. A risk-adapted treatment strategy is therefore mandatory expression, to detect the deviation of mutant cells from their for these disorders. At present, the only treatment with a poten- normal counterpart, and to identify mesenchymal niche abnor- tially curative effect is allogeneic HSC transplantation (HSCT). malities and disrupted signaling contributing to the occurrence Azacitidine can prolong survival in patients with high-risk of somatic mutations, their selection, and subsequent clonal MDS, while erythropoiesis-stimulating agents and lenalidomide expansion.14 Systematic studies of comprehensive mutational improve anemia in patients with low-risk MDS and the MDS profiling of germline and somatic mutations within the frame 2 (2021) 5:9 www.hemaspherejournal.com of population-based registries and clinical trials are required to elderly. Until recently, therapeutic options were mostly limited define the clinical implications of mutation profiles in unbiased to cytotoxic chemotherapy. Increased donor availability coupled and homogeneously treated patient populations. with the advent of reduced intensity conditioning regimens has Studies aimed at characterizing CHIP and identifying intra- led to allogeneic HSCT becoming an increasingly important clonal and extraclonal variables associated with progression potentially curative treatment strategy.18 into overt malignancy are required and will pave the way to However, there has been an explosion of newly approved early diagnosis and pre-emptive interventions. Emerging data drugs since 2017, with the majority of them targeting specific are pointing toward a strong interaction of myelodysplastic gene mutations and/or pivotal cell survival pathways.19 These clones with age-related chronic inflammation, as well as with novel agents have been tested mainly in older patients with multimorbidities and complex chronic conditions. Population- comorbidities and/or relapsed/refractory disease, in whom the based studies that analyze the relationships between clonal treatment of choice is limited and the clinical outcome is very hematopoiesis and its genetic drivers, gender, age, and comor- poor. Recently, the combination of venetoclax and azacitidine bidities are needed. (Ven/Aza) has been shown to improve survival in elderly AML Outcome improvements in MDS patients remain modest. patients.20 At the same time, increased donor availability cou- Identifying therapeutic agents that may further improve survival pled with the advent of reduced intensity conditioning regimens and quality of life of patients with MDS represents a priority. has led to allogeneic HSCT becoming an increasingly important Promising strategies include combination treatment containing potentially curative treatment strategy.18 azacitidine in high-risk MDS (including BCL-2 inhibitors), and drugs that inhibit ineffective erythropoiesis and improve ane- mia in those with low-risk MDS. Novel drugs targeting molec- European research contributions ular abnormalities, including spliceosome, epigenetic regulators Europe has a longstanding tradition in performing well-de- (particularly IDH1 and IDH2), and TP53 mutations, are cur- signed phase 3 studies by experienced and well-organized rently under investigation and should be further developed. AML trial groups. Until recently, these studies were mainly per- Establishing suitable frames for biology-driven clinical trials is formed in all comers investigating new drugs in combination needed, and patient inclusion in clinical trials should be encour- with the 3+7 backbone already standard of care for decades. aged. Reducing the toxicity of allogeneic HSCT in MDS and Reduced intensity conditioning regimens, graft-versus-host MDS/MPN elderly population will be critical to allow more disease prophylaxis and posttransplant interventions in allo- patients to benefit from the procedure. More effective transplan- geneic HSCT all have contributed to the better outcome of tation procedures integrating biology-driven pretransplant and AML. Now since druggable genetic biomarkers are identified posttransplant should be developed. and new targeted drugs have become available, more targeted trials will be conducted.19 Given this segregation, collaboration Anticipated impact of research between European trial groups are required if the delivery of practice informing trials of new drug and transplant therapies is The current lack of understanding the molecular mechanisms to be accelerated. Already a combined effort of European trial that regulate MDS stem cell expansion and their escape from groups has resulted in the approval of a drug targeting CD33: therapeutic and immunological targeting is limiting our abil- Gemtuzumab Ozogamycin.21 Another major achievement is the ity to efficiently eradicate these disorders. The research lines successful development of a chemotherapy-free regimen in acute described above have the potential to decipher these mecha- promyelocytic leukemia (APL) with cure rates >95% in low- nisms and identify suitable targets for effective intervention. and intermediate-risk APL.22 The identification of premalignant conditions with no or mild The internationally embraced ELN recommendations on the clinical expressivity will allow to develop effective strategies of diagnosis and management of AML now plays a pivotal role early diagnosis and intervention aimed at preventing clonal in the management of AML internationally having transformed expansion and progression. clinical practice.18 The European concept of the assessment of The characterization of genomic and transcriptomic pro- measurable residual disease (MRD) has significantly improved files of each individual patient with MDS or MDS/MPN will the management of AML. The ELN recommendation on MRD allow the most appropriate treatment to be selected, patients to plays an important role in harmonization and standardization be enrolled in ad hoc clinical trials investigating new targeted of flow cytometric and molecular techniques for MRD monitor- therapeutic agents, and molecular biomarkers for monitoring ing, resulted in the development of new clinical guidelines and response to treatment to be identified. This will eventually lead informed decision making by regulatory authorities including to precision medicine strategies. the FDA and EMA.23 New insights in the biology of AML with mutated, trans- located, or overexpressed genes, like NPM1, PML-RARA, Acute myeloid leukemia CEBPA, MECOM (EVI1), and germ-like mutations, predis- posing to the development of AML have been identified by Introduction European investigators.17 Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults with an estimated incidence of Proposed research for the Roadmap 3.7 per 100,000 individuals, resulting in 17,000 newly diag- nosed patients each year in Europe. The incidence rises with Collaboration between basic, translational, and clinical age (median age is 70 y) implicating a further rise in future hematologists will be required to generate continuous major years.15 This is a clonal disorder arising from hematopoietic progress in the next years. progenitor cells characterized by defects in their maturation Given the molecular heterogeneity underlying AML, large program resulting in uncontrolled proliferation and subsequent cohorts need to be analyzed to better capture how genetic aber- bone marrow failure. Genomic techniques have unraveled the rations can affect treatment outcome.16 Within the HARMONY molecular complexity of AML that guided refinement of risk Alliance, a large pan-European public–private partnership stratification and personalized therapeutic strategies for AML funded through the Innovative Medicines Initiative (IMI), a patients.16,17 The prognosis is poor with cure rates of 40%–50% large “Big Data for Better Outcome” platform for AML has in the younger population decreasing to <10%–15% in the been built with the aim to put together at least 10,000 cases 3 Döhner et al Research Roadmap: Malignant Myeloid Diseases of AML (https://www.harmony-alliance.eu/). Gene–gene inter- outcome. Accelerated delivery of prospective transplant trials will actions analysis will detect new patterns of co-occurrence and also provide insights into strategies to improve transplant outcome. mutual exclusivity and correlation with clinical outcome will Special attention must also be paid to the better management of provide significant information on treatment and course of the older patients, given the more unfavorable and distinct biology and disease. Genomic analysis of single cells will lead to a better the still dismal outcome of the disease in these patients. understanding of the multiclonal diversity of AML at diagnosis The proposed research directions are expected to provide and during evolution.24 major contributions to improving outcome in patients with this Further standardization and development of MRD techniques fatal disease. to increase sensitivity, making use of peripheral blood instead of bone marrow, automatic analysis, is work in progress in the ELN MRD Working Party.23 Apart from the already established value Chronic myeloid leukemia of diagnosis next-generation sequencing should additionally be explored for MRD detection; here, gene panels will also allow to Introduction further elucidating clonal evolution and resistance in serial analy- Chronic myeloid leukemia (CML) is a neoplastic disease of sis.25 In addition, studies to convert MRD positivity to negativity HSCs. CML is typically linked to the Philadelphia Chromosome, pretransplant have to be done as well as studies addressing the a shortened chromosome 22 as the result of a reciprocal translo- question that MRD apart from prognostic value also has predic- cation of chromosomes 9 and 22 leading to fusion of BCR and tive value in order to be accepted as surrogate for survival.26 ABL1 genes. CML constitutes about 15% of all leukemias and Certain genetic and molecular defined AMLs (eg, TP53mut, occurs with an incidence of about 1.2/100,000. CML went along monosomal karyotype, ASXL1mut, and RUNX1mut) are associ- with an almost fatal outcome until 20 years ago. Through the ated with a poor prognosis.16 New therapeutic strategies/drugs excellent results of BCR-ABL1 tyrosine kinase inhibitor (TKI) should be investigated in these AML subtypes. Also AMLs with treatment, most CML patients face an excellent prognosis.29–31 druggable mutations (eg, FLT3mut and IDHmut) should be investi- Currently, about 10%–20% of patients will achieve a condition gated in separate trials either by adding new drugs to a 7+3 back- of treatment-free remission (TFR). The use of interferon alpha bone or in combinations or triplets based on the good results (IFN) in parallel with or after TKI therapy could be associated with the combination Ven/Aza.20,27 Because these are only small with the induction of an immune response against the leukemic subgroups, these research questions only can be accomplished clone with further improvement of the remission rate. The essen- by collaborations between all the major trial groups in Europe. tial part of the management of CML patients is a rigorous use of Because relapse after transplantation is still an important cause standardized surveillance methods to regularly assess the resid- of failure after the most effective antileukemic treatment, strat- ual disease status. Adverse events should be prevented by indi- egies to reduce the risk of relapse rate posttransplantation are vidual selection of therapy according to patients’ risk profiles. urgently needed and are currently being examined through pro- Patients’ advocacy groups have become partner organizations in spective randomized trials led by European groups. education, clinical practice and research. Prevalence of patients The role of maintenance treatment should be explored. with CML treated with TKIs is steadily increasing, which is a Recently, CC-486, an oral hypomethylating agent, applied as challenge for healthcare systems worldwide. The main task is maintenance has been shown to improve overall survival in to optimize treatment for patients’ maximum benefit with an elderly patients in CR/CRi not suitable for transplantation.28 affordable allocation of the resources. Maintenance treatment should be studied by appropriate deliv- ery of immunotherapy, hypomethylating agents, and targeted small molecules in remission. European research contributions The promising impact of immunotherapy (eg, armed antibod- ies, bispecific antibodies, vaccines, immune checkpoint inhibi- European cooperative CML study groups have been estab- tors, and CAR-T cells) should be intensively explored. lished 30–40 years ago and have continuously contributed to At the same time, we need a better understanding of mecha- the optimization of management. The impact of IFN has been nisms of leukemic stem/progenitor resistance to classical chemo- investigated in a series of large studies. IFN as an immunomod- therapy and targeted agents, an area where European scientific ulatory agent has activity in CML and has resulted in sustained programs excel. A better understanding and characterization of cytogenetic remissions in an important minority of patients.29 leukemic stem/progenitor cells, the impact of the clonal archi- Meta-analyses between conflicting studies revealed new prog- tecture of leukemia, and the clonal evolution during the disease nostic factors for IFN response. The place of allogeneic HSCT in course should pave the way to target them. disease management had been gradually evolving, having been Finally, we are now improving not only curing patients but displaced as the first-line treatment by 2002, and then moving also extending survival without cure. Quality of life issues have to a third or fourth line option after the licensing of the sec- ond-generation TKIs in 2006. From 2001, European investi- been neglected in AML, and have more recently become more gators have participated in the clinical development of 6 TKIs. and more relevant and should become part of our research National and multinational (ELN) networks of European CML agenda and each clinical trial. investigators and clinicians have produced fundamental knowl- edge for clinical practice.31–34 Cooperative studies have contrib- Anticipated impact of the research uted to the understanding of the biology of TKI response. In addition, the impact of combination therapies and baseline and The proposed research aims at further deciphering the com- time dependent prognostic factors contributed. As a result of a plex molecular heterogeneity of myeloid diseases, which ulti- study of the ELN involving >5000 patients, a new score predict- mately will result in further refinement of this disease. Big data ing the CML-specific survival on TKI therapy was established.32 mining will be instrumental for detecting gene–gene interac- The predictive value of early molecular response, deep molecu- tions, performing automatic analysis of MRD and developing lar response, and the velocity of response has been identified in personalized treatment. Europe. ELN expert recommendations for CML management The heterogenous clonal architecture of the disease suggests published in 2006, 2009, 2013, and 2020 and have become a that most likely no single drug is expected to cure AML. Rather, key reference for CML treatment worldwide.31 the combination of classical standard chemotherapy with novel In basic and translational research, European investigators agents or combinations of novel agents are expected to improve the significantly contributed to the understanding of the mechanisms 4 (2021) 5:9 www.hemaspherejournal.com of TKI resistance and how to prevent and overcome it.34 prolonging survival. The cost of novel technologies and treat- Molecular monitoring of CML has been developed, optimized, ments might be balanced by their more specific application as and standardized in Europe, allowing accurate quantification of well as a favorable impact on the patients’ quality of life and the residual disease in a dynamic range of 6 orders of magnitude. lessened burden for caregivers; this will translate into a more Such contribution permitted the successful attempt to discon- general favorable impact for the society in general by reducing tinue treatment after deep molecular response.33,35 Currently, use of resources and improving individual work capabilities. biology of persistence of BCR-ABL1 positive stem cells has been Standardization of diagnostics and therapeutic procedures will a major focus of research. Other research directions include the further strengthen integration. The thereby achieved compara- origin of CML, the clonal molecular evolution, and the charac- bility of outcome will facilitate recognition of interstudy differ- terization of the BCR-ABL1 negative hematopoiesis. ences and rare subtypes. Recommendations, network meetings, training courses, and exchange of researchers will spread excel- lence and raise standards of research and patient care across Proposed research for the Roadmap Europe. The CML network and its activities provide the critical mass for added value and European leadership. The impact on TKIs have substantially improved the survival of CML the future management of CML patients is expected to be con- patients. There is reasonable expectancy to cure the disease in siderable, since a rational advanced treatment design will likely a significant proportion of patients. The main objective is to lead to higher remission rates, longer survival and a higher pro- integrate the leading European national trial groups in CML portion of patients in which treatment can be permanently dis- to form a cooperative network for advancements in CML continued as an indicator of cure. related research and health care. Within the group of European Investigators on CML (EICML), a clinical trials platform was created to promote the performance of clinical trials with new Myeloproliferative neoplasms drugs and/or treatment strategies. Standardization of diagnostic and therapeutic procedures allows outcome comparison across Introduction Europe. We aim to improve (1) tolerability of the treatment; (2) The MPNs are disorders of HSC, and include polycythemia the rate of deep molecular response; and (3) the rate of patients vera (PV), essential thrombocythemia (ET), prefibrotic and in durable remission after stopping TKI. Enhanced inhibition of overt primary (PMF), and post-PV/post-ET myelofibrosis. These BCR-ABL1 with more specific inhibitors or drug combinations are chronic disorders usually affecting middle-advanced age are possible strategies to improve TFR by increasing the rates of patients; however, younger patients are now more frequently deep molecular response.36 Clinical approaches utilizing immune diagnosed thanks to greater awareness and broad availability of surveillance to eradicate residual leukemic cells are potential assays for MPN-associated driver mutations (JAK2V617F, JAK2 future research directions to improve TFR rates. Despite major exon12, MPL, and CALR mutation). The estimated annual improvement in the standard of care for CML, the complexity incidence rate of MPN in RARECAREnet registry (http://www. of CML blast crisis pathophysiology, together with the failure rarecarenet.eu) is 2.17 cases ×105/year; prevalence remains dif- of TKIs to eradicate CML at the stem cell level, as well as the ficult to determine, but it is likely raising owing to improved observation of molecularly defined BCR-ABL1 negative clones management. MPN remain incurable diseases. While many demand further research. A better understanding of the events patients with ET and PV display survival similar to control pop- governing leukemic stem cell behavior might lead to the bio- ulation, median survival in PMF is 6 years, although it may be logical cure of CML and effective treatment of blast crisis. improving following the introduction of ruxolitinib as standard Current efforts continue to uncover new pathways involved in of care. MPN patients suffer from major thrombotic events and BCR-ABL1 independent TKI resistance. Inhibition of BCL2 and hemorrhages. Quality of life is often impaired, most frequently MEK, for example, both showed promise in preclinical models in MF, due to a hyperinflammatory condition, responsible for awaiting and testing in clinical trials. Translational studies will disabling constitutional symptoms, and due to clonal cell prolif- contribute to early outcome prediction and treatment surveil- eration that causes cytosis, hepatosplenomegaly and extramed- lance. Establishing preclinical models that more faithfully reflect ullary hematopoiesis. A rapidly fatal, therapy-refractory, acute human CML and its progression to blast phase, along with sim- leukemia may develop in up to 15%–20% of all MPN. plifying clinical trials will also be critical for progress in this area. Biostatisticians and patient advocacy groups cooperate with the study groups with a European clinical trials platform European research contributions which will support the coordination of the studies. The contribution of European scientists to basic, trans- Research Agenda: lational and clinical research is long standing and valuable. European researchers made the breakthrough discoveries of the • Increasing the rate of TFR; JAK2V617F, JAK2 exon 12, and CALR mutations, which radi- • Overcoming TKI resistance in patients with multi-TKI cally modified the understanding of MPN pathophysiology and failure; revolutionized the WHO diagnostic criteria, to which European • Improving outcomes for patients with accelerated and blast hemopathologists gave substantial contributions. Genetic hap- phase CML; lotypes predisposing to MPN were primarily discovered in • Developing better animal models that more faithfully reca- Europe. The prognostic impact of driver and subclonal muta- pitulate features of human CML; tions in MF was described by European researchers, in collabo- • Preventing cardiovascular toxicity associated with second- ration with American colleagues, and promoted the development and third-generation TKIs. of new disease classification criteria and risk scores such as the MIPSS-70 score for PMF,37 the MySEC-PM score for secondary Anticipated impact of research MF,38 the MTSS score for MF patients undergoing HSCT,39 and an integrated genomic score for all MPN.40 The IPSS and DIPSS A more in-depth molecular and cellular characterization of score for MF were also products of research mostly done in CML patients might facilitate personalized medicine regard- Europe. European researchers were deeply involved in pivotal ing diagnosis, prognostication, and therapeutic decisions. studies leading to the approval of the JAK1 and JAK2 inhibitors Overall, this will have a major impact in lowering the disease ruxolitinib and fedratinib,41–43 and more recently of ropeg-in- burden, reducing the rate of complications and, prospectively, terferon in PV44; several other ongoing clinical trials exploring 5 Döhner et al Research Roadmap: Malignant Myeloid Diseases novel targeted therapies are leaded in Europe. Notably, fun- damental studies conducted in Europe, that established new Summary box: Main research & policy priorities paradigms of clinical management, were investigator-initiated 1. Deeper understanding of the role of CHIP for the devel- trials, such as: the ECLAP study, on low-dose aspirin in PV; the opment of overt myeloid malignancies and other age-re- CytoPV trial, that established the optimal hematocrit target lated chronic conditions. in PV; the PT-1 and the ANAHYDRET study, that compared 2. Further deciphering of the genetic and epigenetic com- hydroxyurea versus anagrelide for high-risk ET patients; a pro- plexity of malignant myeloid disorders. spective comparison of hydroxyurea plus aspirin with aspirin 3. Identification of new therapeutic targets and development alone in younger patients with low-risk ET45; the low-PV trial of new precision medicine strategies. with ropeg-interferon in low-risk PV. European researchers 4. Overcoming primary and/or secondary resistance to con- active in the MPN field refer to several national and supra-na- ventional as well as molecular-targeted agents. tional (the ELN) networks that have produced popular guide- 5. Harmonization and standardization of existing and lines, expert opinions, drug intolerance/resistance and treatment emerging techniques for the assessment of MRD. response criteria, and endpoints for novel drug studies.46 An European initiative (E-MPN network) connecting major centers involved in translational and clinical research has been launched concepts and approaches for personalized medicine approach, recently with the aim to generate large bio-registries/biobanks. ranging from refined diagnostic categories to alternative thera- Strong, productive partnerships between European researchers pies based on prediction of the individual benefit/risk ratio. This and excellence research and clinical centers outside Europe, par- will not only impact favorably on the diseased individual, but ticularly in the United States, are well established. may strengthen the relationships between European academy and the industry by fostering pharmaceutical research, and positively impact on patients’ families and the society in general by optimiz- Proposed research for the Roadmap ing use of resources and improving individual work capabilities. Fundamental questions on the molecular architecture of MPN remain unanswered: in about 20% of patients with ET and PMF the disease-initiating mutation remains unknown (“triple negative” Disclosures patients); the relationships between the phenotype-driver muta- HD received honoraria from AbbVie, Agios, Amgen, Astellas, tions and additional somatic mutations need to be defined in more Astex Pharmaceuticals, AstraZeneca, Berlin-Chemie, BMS, Celgene, detail (impact of the order of events); the genetic basis for familial GEMoaB, Gilead, Helsinn, Janssen, Jazz, Novartis, Oxford Biomedica, clustering of MPN and, above all, the genetic events that under- Roche, Syndax. Research grants from AbbVie, Agios, Amgen, Astellas, lie transformation of chronic MPN to aggressive acute leukemia Bristol Myers Squibb, Celgene, Jazz Pharmaceuticals, Novartis, Pfizer. need to be fully understood. Use of novel, high-throughput, sin- AH received research grants from Novartis, BMS, Pfizer, Incyte. AMV gle-cell platforms, coupled with massive sequencing of noncoding provided lectures for Novartis, BMS, AbbVie, AOP and an advisory regions, DNA methylation profiling, proteomic studies, targeted board member for Novartis, Incyte, BMS, AOP, AbbVie, GSK. PF gene manipulation, and PDX, humanized animal models, will received research grants from BMS, Jazz, Abbvie, Janssen, Novartis. contribute to advancing our knowledge of MPN pathophysiology. UG is Speakers horonaria from Celgene, Advice: Celgene, Institutional Results from these basic/translational studies are predicted to have research support from Celgene, Novartis. LB is consulting for Abbvie, rapid and valuable impact on diagnosis, risk stratification, and Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Gilead, Hexal, Janssen, novel therapeutic developments. We need criteria for categorizing Jazz Pharmaceuticals, Menarini, Novartis, Pfizer, and received research patients, especially MF, according to their response to novel thera- grants from Bayer, Jazz Pharmaceuticals, royalties of payments from pies, to identify those who have the greatest chance to benefit from Abbvie, Amgen, Astellas, Bristol-Myers Squibb, Celgene, Daiichi one drug, or drug combination, or conversely have poor or short- Sankyo, Janssen, Jazz Pharmaceuticals, Novartis, Pfizer, Sanofi, Seattle term responses, and/or suffer from toxicities, thereby allowing early Genetics. KD is consulting for Abbvie, Lectures honoraria from BMS/ shift to alternatives. Since the JAK inhibitors are not curative, bet- Celgene, Novartis, JAZZ, Daiichi Sankyo, an advisory board member for ter understanding of clonal cells’ abnormalities, cell-autonomous Novartis, JAZZ, BMS/Celgene. HD received personal fees from Amgen, and microenvironment-directed signals, and host unique genomic Celgen, Pfizer, Incyte, Novartis, Jazz Pharma, Cellectis, Immunogen, signature, might all facilitate discovery of novel targets. Strategies Daiichi Sankyo, Sunesis, Astellas, Janseen, Servier, Shire-Baxalta, AbbVie, to develop early interventions and possibly preventive measures Otsuka, Menarini, research grants from Amgen, Novartis, Pfizer, Jazz in asymptomatic carriers of MPN-driven mutations (CHIP) need Pharma, Incyte, Servier. AW is in Advisory board for Abbvie, Novartis, to be explored. Entirely new therapeutic approaches, including Janssen, Pfizer, grants from Jazz Pharmaceuticals, royalties of payments monoclonal antibodies and antigen-activated immune cells, are from Abbvie, Novartis, Janssen, Celgene/BMS. CC is consulting for also worthwhile of being explored. Treatment of post-MPN acute AbbVie, BMS, Novartis, Pfizer, Roche, and received grants from BMS. leukemia represents an urgent unmet need. Preclinical and clinical FC received speaker fees from Celgene and Pfizer. JG is consulting for studies might be fostered by reinforcing the existing networks of Alnylam, Bayer, Biehringer-Ingelheim, Biomarin, Daiichi Sankyo, Gilead, European researchers to share annotated patients’ samples, take Janssen, Novartis, Pfizer, Roche, Servier, Sanofi, Sobi, UCB, and received advantage of new technologies and expertise, and facilitate patient grants from Novartis, Incyte, Bristol Myers Squibb, Pfizer, Takeda. CH is referral for phase 1/2 clinical trials. consulting for CTI, Sierra, Kartos, BMS, Novartis, Keros, Galecto, and received grants from Novartis, BMS, Constellation, royalties of payments from Novartis, BMS, AOP, Roche, Jannsen. FP is an Advisory board mem- Anticipated impact of research ber for Novartis, Celgene BMS, Janssen, and received the research grant The great advances in understanding and managing MPN that from BMS. RK is an Advisory board member for Novartis and Celgen/ happened in the last decade had profound impact on the patients’ BMS. All the other authors have no conflicts of interest to disclose. journey, opened new avenues in cell and molecular biology and promoted the development of an entirely new class of agents as are the JAK inhibitors, that are finding unanticipated roles in dis- References eases far from MPN, such as the graft-versus-host disease, auto- 1. Engert A, Balduini C, Brand A, et al. The European Hematology immune disorders and possibly COVID-19.47,48 The next steps Association Roadmap for European Hematology Research: a consen- are to use insights from population-derived studies to develop sus document. 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