The EHA Research Roadmap: Malignant Myeloid Diseases

In 2016, the European Hematology Association (EHA) published EHA Roadmap for Research1 aiming to highlight achievements in diagnostics and treatment of blood disorders, better inform policy makers other stakeholders about urgent clinical scientific needs priorities field hematology. Each section was coordinated by 1–2 editors who were leading international experts field. 5 years that have followed, advances hematology been plentiful. As such, is pleased present an updated Research Roadmap, now including 11 sections, each which will be separately. The identifies most research science, therefore supporting a more informed, focused, ideally funded future research. sections include Normal Hematopoiesis; Malignant Lymphoid Diseases; Myeloid Anemias Related Platelet Disorders; Blood Coagulation Hemostatic Transfusion Medicine; Infections Hematology; Hematopoietic Stem Cell Transplantation; CAR-T Other Cell-based Immune Therapies; Gene Therapy. malignant myeloid diseases discussed this are clonal disorders hematopoietic stem cells (HSCs) progenitor with various underlying molecular basis, different phenotypes largely differing prognosis. Although younger patients may affected, these mainly occur older individuals, median ages ranging from 55 60 chronic leukemia (CML) approximately 75 myelodysplastic syndromes (MDS). Thus, represent increasing burden healthcare systems aging population. recent years, major made understanding basis particular advent next-generation sequencing technologies. researchers involved pivotal studies deciphering single disease genes, such as JAK2 or CALR mutations myeloproliferative neoplasms (MPNs) entire landscapes. Recent provided evidence some gene associated commonly acquired HSCs during aging, phenomenon termed “clonal hematopoiesis indeterminate potential“ (CHIP) “age-related hematopoiesis“ (ARCH). CHIP has diseases, but also increased risk cardiovascular decreased overall survival. paved way precision medicine approaches disorders. This exemplified successful development FLT3-, IDH1/IDH2-, BCL-2 inhibitors acute (AML), tyrosine kinase CML, JAK2-inhibitors MPN. long-standing tradition well-organized trial groups conducting well-designed phase 3 studies, thereby making contributions development. Under umbrella LeukemiaNet (ELN) (EHA), researchers—in collaboration experts—have wealth recommendations guideline papers highly valuable community, patients, care givers, regulatory authorities. Nevertheless, challenges remain improving outcomes quality life diseases. One challenge relates enormous (epi)-genomic complexity multiple epigenetic lesions being at diagnosis, subsequent evolution over course mechanisms resistance. overcoming primary and/or secondary resistance conventional well targeted agents task Roadmap. Another hurdle design. general rare subgroups, conduct become challenging. joint intercontinental effort—in close important patient advocacy groups, biotech pharmaceutical industry—will necessary expedite new therapies our patients. MDSs myelodysplastic/MPNs Introduction HSC characterized peripheral cytopenia, dysplasia one cell lines, propensity evolve into AML. Myelodysplasia not restricted MDS found neoplasms, so-called MDS/MPN, myelomonocytic less frequent atypical neutrophilic leukemia, juvenile MDS/MPN ring sideroblasts, thrombocytosis. crude incidence rate 4 per 100,000 people year, increases up 50 persons year age 60, indicating >30,000 cases expected Europe common hematologic malignancies Western countries. Furthermore, data suggest significantly underestimated, because many underdiagnosed anemia cytopenia elderly. caused somatic HSC, conferring proliferative advantage while inducing ineffective differentiation maturation resulting cytopenia.2–6 genes frequently mutated apparently normal subjects all-cause mortality (ARCH CHIP). show marked heterogeneity, conditions indolent near-normal expectancy entities very poor A risk-adapted strategy mandatory At present, only potentially curative effect allogeneic transplantation (HSCT). Azacitidine can prolong survival high-risk MDS, erythropoiesis-stimulating lenalidomide improve low-risk deletion 5q, respectively.7,8 More recently, luspatercept proven effective reducing transfusion sideroblasts.9 Chronic red remains mainstay therapy MDS. past few genetic means massive parallel DNA sequencing, number seminal performed Europe.2–6 Approximately, 90% carry oncogenic two-thirds them individuals karyotype. Driver identified RNA splicing, methylation, chromatin modification, transcription regulation, repair, signal transduction. Only consistently 10% those regulation (TET2, ASXL1, DNMT3A) splicing factors (SF3B1, SRSF2, U2AF1), long tail >50 frequently.3,4 Mutations SF3B1 specific sideroblasts low progression favorable outcome.5 hematologists developing treatments erythropoietin, azacitidine, lenalidomide, luspatercept.7–9 Recommendations individual HSCT, developed years.10–12 Seminal pediatric hematology, example, elucidating predisposition neoplasms.13 Proposed appear propagated self-renewing mutant HSCs. However, cellular regulate development, propagation, unknown. Studies needed to: characterize resistance, germline predisposition, inflammation, microenvironmental immunological abnormalities, immune escape following transplantation; identify premalignant develop recognize interaction clones multimorbidities complex persons; therapeutic targets efficient elimination MDS-propagating establish suitable frameworks biology-driven trials. While shed light on paving strategies, enabling emergence, selection, leukemic incompletely understood. Single-cell combining analysis genome transcriptome preclinical models warranted impact recurrent abnormalities expression, detect deviation their counterpart, mesenchymal niche disrupted signaling contributing occurrence mutations, expansion.14 Systematic comprehensive mutational profiling within frame population-based registries trials required define implications mutation profiles unbiased homogeneously treated populations. aimed characterizing identifying intraclonal extraclonal variables overt malignancy pave early diagnosis pre-emptive interventions. Emerging pointing toward strong age-related conditions. Population-based analyze relationships between its drivers, gender, age, comorbidities needed. Outcome improvements modest. Identifying further represents priority. Promising strategies combination containing azacitidine (including inhibitors), drugs inhibit erythropoiesis Novel targeting spliceosome, regulators (particularly IDH1 IDH2), TP53 currently under investigation should developed. Establishing frames needed, inclusion encouraged. Reducing toxicity HSCT elderly population critical allow benefit procedure. procedures integrating pretransplant posttransplant Anticipated current lack expansion limiting ability efficiently eradicate lines described above potential decipher intervention. identification no mild expressivity intervention preventing progression. characterization genomic transcriptomic appropriate selected, enrolled ad hoc investigating agents, biomarkers monitoring response identified. eventually lead strategies. Acute (AML) form adults estimated 3.7 17,000 newly diagnosed Europe. rises (median 70 y) implicating rise years.15 disorder arising defects program uncontrolled proliferation bone marrow failure. Genomic techniques unraveled AML guided refinement stratification personalized patients.16,17 prognosis cure rates 40%–50% decreasing <10%–15% Until options mostly limited cytotoxic chemotherapy. Increased donor availability coupled reduced intensity conditioning regimens led becoming increasingly strategy.18 there explosion approved since 2017, majority pathways.19 These novel tested relapsed/refractory disease, whom choice outcome poor. Recently, venetoclax (Ven/Aza) shown patients.20 same time, longstanding performing experienced groups. all comers 3+7 backbone already standard decades. Reduced regimens, graft-versus-host prophylaxis interventions contributed Now druggable available, conducted.19 Given segregation, if delivery practice informing drug transplant accelerated. Already combined effort resulted approval CD33: Gemtuzumab Ozogamycin.21 achievement chemotherapy-free regimen promyelocytic (APL) >95% low- intermediate-risk APL.22 internationally embraced ELN management plays role having transformed practice.18 concept assessment measurable residual (MRD) improved recommendation MRD harmonization standardization flow cytometric monitoring, guidelines informed decision authorities FDA EMA.23 New insights biology mutated, translocated, overexpressed like NPM1, PML-RARA, CEBPA, MECOM (EVI1), germ-like predisposing investigators.17 Collaboration basic, translational, generate continuous progress next years. heterogeneity AML, large cohorts need analyzed capture how aberrations affect outcome.16 Within HARMONY Alliance, pan-European public–private partnership through Innovative Medicines Initiative (IMI), “Big Data Better Outcome” platform built aim put together least 10,000 (https://www.harmony-alliance.eu/). Gene–gene interactions patterns co-occurrence mutual exclusivity correlation provide significant information disease. multiclonal diversity evolution.24 Further increase sensitivity, use instead marrow, automatic analysis, work Working Party.23 Apart established value additionally explored detection; here, panels serial analysis.25 addition, convert positivity negativity done addressing question apart prognostic predictive order accepted surrogate survival.26 Certain defined AMLs (eg, TP53mut, monosomal karyotype, ASXL1mut, RUNX1mut) prognosis.16 strategies/drugs investigated subtypes. Also FLT3mut IDHmut) separate either adding 7+3 combinations triplets based good results Ven/Aza.20,27 Because small questions accomplished collaborations relapse after still cause failure antileukemic treatment, reduce posttransplantation urgently examined prospective randomized maintenance explored. CC-486, oral hypomethylating agent, applied CR/CRi transplantation.28 Maintenance studied immunotherapy, molecules remission. promising immunotherapy armed antibodies, bispecific vaccines, checkpoint inhibitors, cells) intensively we stem/progenitor classical chemotherapy area where programs excel. cells, architecture target them. Finally, curing extending without cure. Quality issues neglected recently relevant part agenda trial. proposed aims ultimately result Big mining instrumental detecting gene–gene interactions, treatment. heterogenous suggests likely Rather, outcome. Accelerated Special attention must paid given unfavorable distinct dismal directions fatal neoplastic CML typically linked Philadelphia Chromosome, shortened chromosome 22 reciprocal translocation chromosomes 9 fusion BCR ABL1 genes. constitutes 15% leukemias occurs 1.2/100,000. went along almost until 20 ago. Through excellent BCR-ABL1 inhibitor (TKI) face prognosis.29–31 Currently, 10%–20% achieve condition treatment-free remission (TFR). interferon alpha (IFN) TKI could induction against clone improvement rate. essential rigorous standardized surveillance methods regularly assess status. Adverse events prevented selection according patients’ profiles. Patients’ partner organizations education, Prevalence TKIs steadily increasing, worldwide. main optimize maximum affordable allocation resources. cooperative study 30–40 ago continuously optimization management. IFN series studies. immunomodulatory agent activity sustained cytogenetic remissions minority patients.29 Meta-analyses conflicting revealed response. place had gradually evolving, displaced first-line 2002, then moving third fourth line option licensing second-generation 2006. From 2001, investigators participated 6 TKIs. National multinational networks clinicians produced fundamental knowledge practice.31–34 Cooperative baseline time dependent contributed. involving >5000 score predicting CML-specific established.32 response, deep velocity expert 2006, 2009, 2013, 2020 key reference worldwide.31 basic translational research, prevent overcome it.34 Molecular developed, optimized, Europe, allowing accurate quantification dynamic range orders magnitude. Such contribution permitted attempt discontinue response.33,35 persistence positive focus origin evolution, negative hematopoiesis. substantially There reasonable proportion objective integrate national network advancements related health care. group Investigators (EICML), created promote performance Standardization diagnostic allows comparison across We (1) tolerability treatment; (2) response; (3) durable stopping TKI. Enhanced inhibition possible TFR response.36 Clinical utilizing rates. Despite blast crisis pathophysiology, level, observation molecularly demand governing behavior might biological crisis. Current efforts continue uncover pathways independent Inhibition BCL2 MEK, both showed promise awaiting testing Translational contribute prediction surveillance. faithfully reflect human phase, simplifying area. Biostatisticians cooperate support coordination Agenda: Increasing TFR; Overcoming multi-TKI failure; Improving accelerated CML; Developing animal recapitulate features Preventing second- third-generation in-depth facilitate regarding prognostication, decisions. Overall, lowering burden, complications and, prospectively, prolonging cost technologies balanced application lessened caregivers; translate society resources capabilities. strengthen integration. achieved comparability recognition interstudy differences Recommendations, meetings, training courses, exchange spread excellence raise standards activities mass added leadership. considerable, rational advanced design higher rates, longer permanently discontinued indicator Myeloproliferative MPNs polycythemia vera (PV), thrombocyt