Myelodysplastic syndromes: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†☆

Abstract

•This ESMO Clinical Practice Guideline provides key recommendations for managing myelodysplastic syndromes.•It covers diagnosis, classification, staging and risk assessment of myelodysplastic syndromes.•Treatment recommendations for lower- and higher-risk myelodysplastic syndromes are also provided.•All recommendations were compiled by a multidisciplinary group of experts.•Recommendations are based on available scientific data and the authors' expert opinions. Myelodysplastic syndromes (MDS) are clonal haematopoietic stem cell (HSC) disorders predominating in the elderly, characterised by ineffective haematopoiesis leading to blood cytopaenias and progression to acute myeloid leukaemia (AML) in one-fourth to one-third of cases.1Adès L. Itzykson R. Fenaux P. Myelodysplastic syndromes.Lancet. 2014; 383: 2239-2252Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar Their pathophysiology is characterised by a multi-step process involving cytogenetic changes and/or gene mutations,2Bejar R. Stevenson K. Abdel-Wahab O. et al.Clinical effect of point mutations in myelodysplastic syndromes.N Engl J Med. 2011; 364: 2496-2506Crossref PubMed Scopus (1056) Google Scholar abnormalities of the bone marrow microenvironment3Yang L. Qian Y. Eksioglu E. et al.The inflammatory microenvironment in MDS.Cell Mol Life Sci. 2015; 72: 1959-1966Crossref PubMed Google Scholar and widespread gene hypermethylation at advanced stages.4Shen J. Wang S. Zhang Y.J. et al.Genome-wide aberrant DNA methylation of microRNA host genes in hepatocellular carcinoma.Epigenetics. 2012; 7: 1230-1237Crossref PubMed Scopus (48) Google Scholar,5Jiang Y. Dunbar A. Gondek L.P. et al.Aberrant DNA methylation is a dominant mechanism in MDS progression to AML.Blood. 2009; 113: 1315-1325Crossref PubMed Scopus (282) Google Scholar Median age at diagnosis of MDS is ∼70 years and <10% are younger than 50 years.6Neukirchen J. Schoonen W.M. Strupp C. et al.Incidence and prevalence of myelodysplastic syndromes: data from the Dusseldorf MDS-registry.Leuk Res. 2011; 35: 1591-1596Crossref PubMed Scopus (116) Google Scholar The incidence of MDS is about 4 cases/100 000 inhabitants/year (reaching 40-50/100 000 in patients aged ≥70 years).6Neukirchen J. Schoonen W.M. Strupp C. et al.Incidence and prevalence of myelodysplastic syndromes: data from the Dusseldorf MDS-registry.Leuk Res. 2011; 35: 1591-1596Crossref PubMed Scopus (116) Google Scholar There are no known ethnic differences in the incidence of MDS, but in Asian populations, MDS tends to occur at an earlier age, more often with a hypocellular marrow and less often with isolated 5q deletion (‘5q-syndrome’). Trisomy 8 also seems to occur more frequently in Asian populations compared with Western populations.7Miyazaki Y. Tuechler H. Sanz G. et al.Differing clinical features between Japanese and Caucasian patients with myelodysplastic syndromes: analysis from the International Working Group for Prognosis of MDS.Leuk Res. 2018; 73: 51-57Crossref PubMed Scopus (0) Google Scholar The aetiology of MDS is only known in 15% of cases. An inherited predisposition to MDS is seen in one-third of paediatric MDS patients, including Down syndrome, Fanconi anaemia and neurofibromatosis. It is less frequent in adults, but an inherited predisposition should be assessed in MDS occurring in young adults or families with other cases of MDS, AML or aplastic anaemia. Point mutations of several genes including DDX 41, GATA2, RUNX 1, ANKRD 26, ETV6 and telomerase complex genes (TERC, TERT) have been found in such familial cases.8Drazer M.W. Kadri S. Sukhanova M. et al.Prognostic tumor sequencing panels frequently identify germ line variants associated with hereditary hematopoietic malignancies.Blood Adv. 2018; 2: 146-150Crossref PubMed Scopus (35) Google Scholar Environmental factors include previous exposure to chemotherapy (ChT), especially alkylating agents and purine analogues,9Leone G. Fianchi L. Voso M.T. Therapy-related myeloid neoplasms.Curr Opin Oncol. 2011; 23: 672-680Crossref PubMed Scopus (0) Google Scholar radiotherapy (RT) or ionising radiation10Cardis E. Vrijheid M. Blettner M. et al.Risk of cancer after low doses of ionising radiation: retrospective cohort study in 15 countries.BMJ. 2005; 331: 77Crossref PubMed Scopus (439) Google Scholar,11Iwanaga M. Hsu W.L. Soda M. et al.Risk of myelodysplastic syndromes in people exposed to ionizing radiation: a retrospective cohort study of Nagasaki atomic bomb survivors.J Clin Oncol. 2011; 29: 428-434Crossref PubMed Scopus (72) Google Scholar and tobacco smoking.12Nisse C. Haguenoer J.M. Grandbastien B. et al.Occupational and environmental risk factors of the myelodysplastic syndromes in the North of France.Br J Haematol. 2001; 112: 927-935Crossref PubMed Scopus (0) Google Scholar Recognised occupational factors include benzene and its derivatives,13Aksoy M. Ozeris S. Sabuncu H. et al.Exposure to benzene in Turkey between 1983 and 1985: a haematological study on 231 workers.Br J Ind Med. 1987; 44: 785-787PubMed Google Scholar and more cases of MDS are reported among agricultural and industrial workers.12Nisse C. Haguenoer J.M. Grandbastien B. et al.Occupational and environmental risk factors of the myelodysplastic syndromes in the North of France.Br J Haematol. 2001; 112: 927-935Crossref PubMed Scopus (0) Google Scholar,14Rigolin G.M. Cuneo A. Roberti M.G. et al.Exposure to myelotoxic agents and myelodysplasia: case-control study and correlation with clinicobiological findings.Br J Haematol. 1998; 103: 189-197Crossref PubMed Scopus (73) Google Scholar Cases of ‘secondary MDS’, particularly those occurring after ChT (therapy-related MDS), generally have poor prognostic factors, including complex cytogenetic findings involving chromosomes 5 and/or 7 and/or 17p.15Kuendgen A. Nomdedeu M. Tuechler H. et al.Therapy-related myelodysplastic syndromes deserve specific diagnostic sub-classification and risk-stratification – an approach to classification of patients with t-MDS.Leukemia. 2020; https://doi.org/10.1038/s41375-020-0917-7Crossref PubMed Scopus (4) Google Scholar Diagnosis of MDS is based on blood and bone marrow examination, showing blood cytopaenias, generally hypercellular (but sometimes hypocellular) marrow with dysplasia, with or without an excess of blasts.16Arber D.A. Orazi A. Hasserjian R. et al.The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.Blood. 2016; 127: 2391-2405Crossref PubMed Google Scholar Well-established diagnostic tools for MDS with widespread availability are peripheral and differential blood counts, cytomorphology of peripheral blood and bone marrow smears and cytogenetics of bone marrow cells [I, A]. At diagnosis, histology of bone marrow trephine biopsies is strongly recommended, especially to exclude other causes of cytopaenia and because of its potential prognostic information [I, A]. In difficult cases, such as cytopaenias with unspecific morphological changes and no cytogenetic changes, molecular analysis by next generation sequencing techniques to demonstrate clonality [I, A] and, in experienced hands, flow cytometry of blood and marrow cells can be useful for diagnosis [II, B]. Differential diagnoses of MDS include a history of medication or ingestion of alcohol or other drugs and exclusion of other diseases, including autoimmune disorders, renal failure, malignancies, chronic infections, aplastic anaemia and paroxysmal nocturnal haemoglobinuria (PNH).17Valent P. Horny H.P. Bennett J.M. et al.Definitions and standards in the diagnosis and treatment of the myelodysplastic syndromes: consensus statements and report from a working conference.Leuk Res. 2007; 31: 727-736Crossref PubMed Scopus (385) Google Scholar MDS should be classified according to the World Health Organization (WHO) criteria16Arber D.A. Orazi A. Hasserjian R. et al.The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.Blood. 2016; 127: 2391-2405Crossref PubMed Google Scholar with prognosis established by the international prognostic scoring system (IPSS)18Greenberg P. Cox C. LeBeau M.M. et al.International scoring system for evaluating prognosis in myelodysplastic syndromes.Blood. 1997; 89: 2079-2088Crossref PubMed Google Scholar or rather, its revised version (IPSS-R).19Greenberg P.L. Tuechler H. Schanz J. et al.Revised international prognostic scoring system for myelodysplastic syndromes.Blood. 2012; 120: 2454-2465Crossref PubMed Scopus (1541) Google Scholar Prognosis is based on the marrow blast percentage, number and extent of cytopaenias, and cytogenetic abnormalities, which are grouped in the IPSS-R.18Greenberg P. Cox C. LeBeau M.M. et al.International scoring system for evaluating prognosis in myelodysplastic syndromes.Blood. 1997; 89: 2079-2088Crossref PubMed Google Scholar,19Greenberg P.L. Tuechler H. Schanz J. et al.Revised international prognostic scoring system for myelodysplastic syndromes.Blood. 2012; 120: 2454-2465Crossref PubMed Scopus (1541) Google Scholar Treatment varies from symptomatic therapy for cytopaenias, especially transfusions, to allogeneic stem cell transplantation (allo-SCT). Almost all patients with MDS have blood cytopaenias, mostly anaemia (usually macrocytic) with or without other cytopaenias. Laboratory values supporting or excluding the diagnosis of MDS are ferritin, transferrin and transferrin saturation, reticulocyte counts, vitamin B12 and folate concentrations, haptoglobin, and creatinine levels. They can exclude the differential diagnoses of iron deficiency anaemia, haemolytic anaemia, vitamin B12 or folate deficiency and renal anaemia. If MDS is diagnosed, ferritin and lactate dehydrogenase (LDH) also have some prognostic value, and the erythropoietin (EPO) level can support a decision for or against treatment with erythropoiesis-stimulating agents (ESAs). Diagnostic work-up for PNH may be considered in cases with a clinical suspicion as small PNH clones can accompany MDS. The hallmarks of cytomorphology in MDS are dysplastic features in ≥10% of marrow and/or peripheral blood cells of erythroid, granulocytic or megakaryocytic lineage. Marrow histology of trephine biopsies is of additional value. In early MDS with only mild morphological abnormalities, certain cases with persistent, unexplained cytopaenias are called idiopathic cytopaenias of uncertain significance (ICUS). In patients with marrow dysplastic features but no or very mild peripheral blood cytopaenias and normal karyotype, idiopathic dysplasia of unknown significance (IDUS)20Valent P. Horny H.P. Minimal diagnostic criteria for myelodysplastic syndromes and separation from ICUS and IDUS: update and open questions.Eur J Clin Invest. 2009; 39: 548-553Crossref PubMed Scopus (58) Google Scholar can be diagnosed if no other cause of dysplasia is apparent (see Table 1). Patients with clonal somatic mutations and cytopaenias without dysplastic features and normal karyotype [clonal cytopaenias of uncertain significance (CCUS)] constitute a third group of patients with a higher risk of progression to MDS.21Valent P. ICUS, IDUS, CHIP and CCUS: diagnostic criteria, separation from MDS and clinical implications.Pathobiology. 2019; 86: 30-38Crossref PubMed Scopus (13) Google Scholar,22Bejar R. CHIP, ICUS, CCUS and other four-letter words.Leukemia. 2017; 31: 1869-1871Crossref PubMed Scopus (39) Google ScholarTable 1Definition of ICUS, IDUS, CHIP and CCUS21Valent P. ICUS, IDUS, CHIP and CCUS: diagnostic criteria, separation from MDS and clinical implications.Pathobiology. 2019; 86: 30-38Crossref PubMed Scopus (13) Google Scholar,22Bejar R. CHIP, ICUS, CCUS and other four-letter words.Leukemia. 2017; 31: 1869-1871Crossref PubMed Scopus (39) Google ScholarCharacteristicsICUS•Mild cytopaenia for at least 4 months (haemoglobin <11.0 g/dl, neutropaenia <1500/μl and/or thrombocytopaenia <100 000/μl)•No or only mild (<10%) marrow dysplasia•Marrow blasts <5%•No clonal cytogenetic or molecular markers•Exclusion of other diseasesIDUS•No significant cytopaenia (i.e. haemoglobin ≥11 g/dl, neutrophils ≥1500/μl and platelets ≥100 000/μl)•Marked dysplasia in >10% of neutrophilic and/or erythroid and/or megakaryocytes lineages•Marrow blasts <5%•No clonal cytogenetic or molecular markersCHIP•No significant cytopaenia•No or only mild (<10%) dysplasia•Marrow blasts <5%•Presence of one or more MDS-related mutation(s)•Clonality defined by mutation of myeloid disorder associated genes (including particularly DNMT3A, ASXL1, TET2, JAK2 and TP53 genes), with a VAF of between 2% and 30%CCUS•Cytopaenia for at least 4 months (haemoglobin <11.0 g/dl and/or neutropaenia <1500/μl and/or thrombocytopaenia <100 000/μl)•No or only mild (<10%) marrow dysplasia•Marrow blasts <5%•Presence of one or more MDS-related mutation(s)•Clonality defined by mutation of myeloid disorder associated genes (including particularly DNMT3A, ASXL1, TET2, JAK2 and TP53 genes), with a VAF of between 2% and 30%CCUS, clonal cytopaenias of uncertain significance; CHIP, clonal haematopoiesis of indeterminate potential; ICUS, idiopathic cytopaenias of uncertain significance; IDUS, idiopathic dysplasia of unknown significance; MDS, myelodysplastic syndromes; VAF, variant allele frequency. Open table in a new tab CCUS, clonal cytopaenias of uncertain significance; CHIP, clonal haematopoiesis of indeterminate potential; ICUS, idiopathic cytopaenias of uncertain significance; IDUS, idiopathic dysplasia of unknown significance; MDS, myelodysplastic syndromes; VAF, variant allele frequency. When evaluating MDS blood films and marrow slides, certain cytological abnormalities should be considered (see Table 2). For an MDS diagnosis, the recommended number of cells to be reviewed per slide is 200 for the blood film and up to 500 for bone marrow.23Valent P. Orazi A. Steensma D.P. et al.Proposed minimal diagnostic criteria for myelodysplastic syndromes (MDS) and potential pre-MDS conditions.Oncotarget. 2017; 8: 73483-73500Crossref PubMed Scopus (63) Google Scholar The marrow blast count is crucial given its important prognostic value. ‘Blasts’ should include agranular blasts, myeloblasts and promonocytes but not promyelocytes. Staining for iron with Prussian blue (Perls stain) should always be carried out in lower-risk MDS in order to evaluate the presence of ring sideroblasts.Table 2Signs of dysplasia in myelodysplastic syndromesPeripheral blood • GranulocytesPseudo Pelger-Huet cells, abnormal chromatin clumping, hypo-/degranulation, left shift • PlateletsGiant platelets, anisometry of platelets • Red cellsAnisocytosis, poikilocytosis, dimorphic erythrocytes, polychromasia, hypochromasia, megalocytes, basophilic stippling, presence of nucleated erythroid precursors, tear drop cells, ovalocytes, fragmentocytesBone marrow • Cellularity of the marrowTypically hypercellularity, rarely hypocellularity • ErythropoiesisMegaloblastoid changes, multinuclearity, nuclear budding, non-round nuclei, karyorrhexis, nuclear bridges, atypical mitoses, sideroblastosis, ring sideroblasts, periodic acid-Schiff-positive red cell precursors • MegakaryopoiesisMicromegakaryocytes, mononuclear megakaryocytes, dumbbell-shaped nuclei, hypersegmentation, multinuclearity with multiple isolated nuclei • GranulocytopoiesisLeft shift, increased medullary blast count, Auer rods or Auer bodies, hypo-/degranulation, pseudo-Pelger cells, nuclear anomalies (e.g. hypersegmentation, abnormal chromatin clumping), deficiency of myeloperoxidase, increase and morphological abnormality of monocytes Open table in a new tab In the European Union (EU), contrary to the United States, MDS are mainly followed-up by bone marrow aspirate rather than biopsy. Bone marrow trephine biopsy, however, is useful at diagnosis to assess cellularity and fibrosis. In case of hypocellular aspirates or dry puncture, it allows a diagnosis of hypoplastic MDS or fibrotic MDS. It may also exclude other differential diagnoses and may provide additional information on dysplastic features (mainly of megakaryocytes) and prognostic information, especially by showing fibrosis. It is therefore strongly recommended in addition to bone marrow aspiration at diagnosis.24Schemenau J. Baldus S. Anlauf M. et al.Cellularity, characteristics of hematopoietic parameters and prognosis in myelodysplastic syndromes.Eur J Haematol. 2015; 95: 181-189Crossref PubMed Scopus (15) Google Scholar,25Buesche G. Teoman H. Wilczak W. et al.Marrow fibrosis predicts early fatal marrow failure in patients with myelodysplastic syndromes.Leukemia. 2008; 22: 313-322Crossref PubMed Scopus (75) Google Scholar In MDS, clonal chromosome abnormalities are observed in 30% to >80% of patients.26Haase D. Germing U. Schanz J. et al.New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients.Blood. 2007; 110: 4385-4395Crossref PubMed Scopus (606) Google Scholar In the remaining 20%-70% of patients with a normal karyotype, sub-microscopic alterations such as point mutations, microdeletions or amplifications, epigenetic changes or copy number neutral loss such as uniparental disomy (UPD) provide the genetic basis for the disease.2Bejar R. Stevenson K. Abdel-Wahab O. et al.Clinical effect of point mutations in myelodysplastic syndromes.N Engl J Med. 2011; 364: 2496-2506Crossref PubMed Scopus (1056) Google Scholar,27Boultwood J. Wainscoat J.S. Gene silencing by DNA methylation in haematological malignancies.Br J Haematol. 2007; 138: 3-11Crossref PubMed Scopus (0) Google Scholar Currently, standard karyotype still has the highest prognostic value of all IPSS-R parameters.19Greenberg P.L. Tuechler H. Schanz J. et al.Revised international prognostic scoring system for myelodysplastic syndromes.Blood. 2012; 120: 2454-2465Crossref PubMed Scopus (1541) Google Scholar Chromosome banding analysis is carried out on dividing metaphase cells. Whenever possible, 20-25 metaphases should be analysed so as not to miss smaller cell clones that are frequent, especially in low-risk MDS. Complex abnormalities are defined as three or more independent abnormalities in at least two metaphases.28Shaffer L.G. McGowan-Jordan J. Schmid M. ISCN (2013): An International System for Human Cytogenetic Nomenclature. S. Karger, Basel2013Google Scholar Cytogenetic analysis should follow minimal standards fixed by the ‘Workpackage Cytogenetics’ of the European LeukemiaNet (see Figure 1).29Haferlach C. Rieder H. Lillington D.M. et al.Proposals for standardized protocols for cytogenetic analyses of acute leukemias, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloproliferative disorders, and myelodysplastic syndromes.Genes Chromosomes Cancer. 2007; 46: 494-499Crossref PubMed Scopus (0) Google Scholar In an international database of 2124 patients with MDS, 52% had one or more clonal cytogenetic abnormalities. Abnormal karyotypes were clearly associated with the severity of MDS, increasing with marrow blast count and the intensity of dysplasias.26Haase D. Germing U. Schanz J. et al.New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients.Blood. 2007; 110: 4385-4395Crossref PubMed Scopus (606) Google Scholar Several independent studies have proven the dismal outcome related to complex abnormalities.26Haase D. Germing U. Schanz J. et al.New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients.Blood. 2007; 110: 4385-4395Crossref PubMed Scopus (606) Google Scholar,30Sole F. Luno E. Sanzo C. et al.Identification of novel cytogenetic markers with prognostic significance in a series of 968 patients with primary myelodysplastic syndromes.Haematologica. 2005; 90: 1168-1178PubMed Google Scholar,31Schanz J. Steidl C. Fonatsch C. et al.Coalesced multicentric analysis of 2,351 patients with myelodysplastic syndromes indicates an underestimation of poor-risk cytogenetics of myelodysplastic syndromes in the international prognostic scoring system.J Clin Oncol. 2011; 29: 1963-1970Crossref PubMed Scopus (127) Google Scholar Complex abnormalities can be further subdivided by the presence or absence of TP53 mutations, the number of cytogenetic changes and severe anaemia.32Haase D. Stevenson K.E. Neuberg D. et al.TP53 mutation status divides myelodysplastic syndromes with complex karyotypes into distinct prognostic subgroups.Leukemia. 2019; 33: 1747-1758Crossref PubMed Scopus (48) Google Scholar Assessing karyotype during follow-up is also useful as cytogenetic progression is associated with poorer prognosis, while cytogenetic response after a given treatment may be associated with a better outcome.31Schanz J. Steidl C. Fonatsch C. et al.Coalesced multicentric analysis of 2,351 patients with myelodysplastic syndromes indicates an underestimation of poor-risk cytogenetics of myelodysplastic syndromes in the international prognostic scoring system.J Clin Oncol. 2011; 29: 1963-1970Crossref PubMed Scopus (127) Google Scholar,33Neukirchen J. Lauseker M. Hildebrandt B. et al.Cytogenetic clonal evolution in myelodysplastic syndromes is associated with inferior prognosis.Cancer. 2017; 123: 4608-4616Crossref PubMed Scopus (8) Google Scholar,34Bernasconi P. Boni M. Cavigliano P.M. et al.Clinical relevance of cytogenetics in myelodysplastic syndromes.Ann N Y Acad Sci. 2006; 1089: 395-410Crossref PubMed Scopus (0) Google Scholar Acquired molecular mutations are seen in 80%-90% of MDS patients,35Papaemmanuil E. Gerstung M. Malcovati L. et al.Clinical and biological implications of driver mutations in myelodysplastic syndromes.Blood. 2013; 122: 3616-3627Crossref PubMed Scopus (981) Google Scholar,36Haferlach T. Nagata Y. Grossmann V. et al.Landscape of genetic lesions in 944 patients with myelodysplastic syndromes.Leukemia. 2014; 28: 241-247Crossref PubMed Scopus (780) Google Scholar affecting epigenetic regulation and chromatin-remodelling (TET2, DNMT3A, ASXL1, IDH1/2, EZH2), pre-mRNA splicing factors (SF3B1, SRSF2, U2AF1), transcription (TP53, RUNX1) and signal transduction (NRAS, CBL), and can demonstrate clonal disease (Table 3). The most frequent mutations (each present in >10% of patients) affect TET2, SF3B1, ASXL1, SRSF2, DNMT3A and RUNX1, but approximately one or more of around 30 genes are mutated in >1% of patients. Forty percent of patients have more than one mutation. Most mutations, except SF3B1, carry a poor prognosis, and prognosis is worse with a larger number of mutations.35Papaemmanuil E. Gerstung M. Malcovati L. et al.Clinical and biological implications of driver mutations in myelodysplastic syndromes.Blood. 2013; 122: 3616-3627Crossref PubMed Scopus (981) Google Scholar Molecular profiling can also be a valuable diagnostic tool if MDS is uncertain in ICUS or IDUS,37Kwok B. Hall J.M. Witte J.S. et al.MDS-associated somatic mutations and clonal hematopoiesis are common in idiopathic cytopenias of undetermined significance.Blood. 2015; 126: 2355-2361Crossref PubMed Scopus (181) Google Scholar but mutations have limited impact on the clinical management in most cases. Exceptions are SF3B1 mutation in lower-risk MDS (associated with a favourable prognosis and likely to respond to luspatercept) and TP53 mutation in lower-risk MDS with del(5q), associated with an increased risk of leukaemic transformation, lower cytogenetic response rate and shorter response duration to lenalidomide (LEN).38Jadersten M. Saft L. Smith A. et al.TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression.J Clin Oncol. 2011; 29: 1971-1979Crossref PubMed Scopus (327) Google ScholarTable 3Most frequent somatic mutations observed in MDSaOther mutations are seen in <5% of cases.,35Papaemmanuil E. Gerstung M. Malcovati L. et al.Clinical and biological implications of driver mutations in myelodysplastic syndromes.Blood. 2013; 122: 3616-3627Crossref PubMed Scopus (981) Google Scholar,36Haferlach T. Nagata Y. Grossmann V. et al.Landscape of genetic lesions in 944 patients with myelodysplastic syndromes.Leukemia. 2014; 28: 241-247Crossref PubMed Scopus (780) Google ScholarGene functionGeneMutation frequency (%)Epigenetic regulators and chromatin-remodelling factorsTET2ASXL1DNMT3AIDH1/215-2510-20105-10Pre-mRNA splicing factorsSF3B1SRSF2U2AF115-3010-155-10Transcription factorsRUNX1TP5310-155-10Signalling moleculesNRAS/KRAS10Cohesin complexSTAG25-7MDS, myelodysplastic syndromes.a Other mutations are seen in <5% of cases. Open table in a new tab MDS, myelodysplastic syndromes. Somatic mutations seen in myeloid neoplasias have been observed in elderly healthy persons (10%-13% of those aged 70-80 years).39Genovese G. Kähler A.K. Handsaker R.E. et al.Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence.N Engl J Med. 2014; 371: 2477-2487Crossref PubMed Scopus (1391) Google Scholar, 40Jaiswal S. Fontanillas P. Flannick J. et al.Age-related clonal hematopoiesis associated with adverse outcomes.N Engl J Med. 2014; 371: 2488-2498Crossref PubMed Scopus (1699) Google Scholar, 41Xie M. Lu C. Wang J. et al.Age-related mutations associated with clonal hematopoietic expansion and malignancies.Nat Med. 2014; 20: 1472-1478Crossref PubMed Scopus (882) Google Scholar The most frequently affected gene is DNMT3A, followed by TET2, ASXL1, and less often, JAK2, PPM1D, SF3B1, SRSF2 and TP53. Most patients have only one mutation, and generally with variant allele frequency (VAF) of ≤10%. Since individuals examined had no obvious haematological disease, the term ‘clonal haematopoiesis of indeterminate potential’ (CHIP) was established.42Steensma D.P. Bejar R. Jaiswal S. et al.Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes.Blood. 2015; 126: 9-16Crossref PubMed Scopus (737) Google Scholar CHIP is associated with a 13-fold increased risk of developing a haematological neoplasia and a 1.4-fold risk of death also related to an increased incidence of atherosclerotic cardiovascular disease.43Jaiswal S. Natarajan P. Ebert B.L. Clonal hematopoiesis and atherosclerosis.N Engl J Med. 2017; 377: 1401-1402PubMed Google Scholar Patients with CHIP and unexplained cytopaenia but no morphological evidence for myelodysplasia have been classified as CCUS. Over 30% of patients with unexplained cytopaenias appear to have CCUS, with an increased risk of developing myeloid neoplasia depending on the type of mutation.37Kwok B. Hall J.M. Witte J.S. et al.MDS-associated somatic mutations and clonal hematopoiesis are common in idiopathic cytopenias of undetermined significance.Blood. 2015; 126: 2355-2361Crossref PubMed Scopus (181) Google Scholar,44Malcovati L. Galli A. Travaglino E. et al.Clinical significance of somatic mutation in unexplained blood cytopenia.Blood. 2017; 129: 3371-3378Crossref PubMed Scopus (162) Google Scholar Flow cytometry abnormalities of myeloid precursors may support a diagnosis of MDS, but this method should be used by experts according to published guidelines, and should not be used for the evaluation of the percentage of bone marrow blasts.45Alhan C. Westers T.M. Cremers E.M. et al.The myelodysplastic syndromes flow cytometric score: a three-parameter prognostic flow cytometric scoring system.Leukemia. 2016; 30: 658-665Crossref PubMed Scopus (30) Google Scholar,46Duetz C. Westers T.M. van de Loosdrecht A.A. Clinical implication of multi-parameter flow cytometry in myelodysplastic syndromes.Pathobiology. 2019; 86: 14-23Crossref PubMed Scopus (4) Google Scholar The current WHO classification of MDS16Arber D.A. Orazi A. Hasserjian R. et al.The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.Blood. 2016; 127: 2391-2405Crossref PubMed Google Scholar divides MDS with <5% blasts into those with single lineage or multilineage dysplasia (Table 4). In MDS with single lineage dysplasia, patients with ring sideroblasts (MDS-RS) have a low AML progression rate and generally have a prolonged overall survival (OS) if SF3B1 mutation is present and is isolated or at least not associated with poor prognosis mutations such as RUNX1 mutation. The entity of del(5q) MDS is not defined by morphological criteria but by the presence of del(5q), making cytogenetic analysis mandatory. This classification has recognised entities with germline predisposition (Table 5).8Drazer M.W. Kadri S. Sukhanova M. et al.Prognostic tumor sequencing panels frequently identify germ line variants associated with hereditary hematopoietic malignancies.Blood Adv. 2018; 2: 146-150Crossref PubMed Scopus (35) Google Scholar Finally, chronic myelomonocytic leukaemia has been moved to myelodysplastic/myeloproliferative neoplasms.16Arber D.A. Orazi A. Hasserjian R. et al.The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.Blood. 2016; 127: 2391-2405Crossref PubMed Google ScholarTable 4The WHO 2016 classification of MDS16Arber D.A. Orazi A. Hasserjian R. et al.The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.Blood. 2016; 127: 2391-2405Crossref PubMed Google ScholarReprinted with permission.16Arber D.A. Orazi A. Hasserjian R. et al.The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.Blood. 2016; 127: 2391-2405Crossref PubMed Google ScholarNameDysplastic lineagesCytopaeniasaCytopaenias defined as haemoglobin <10 g/dl, platelet count <100 × 109/l and absolute neutrophil count <1.8 × 109/l; rarely, MDS may present with mild anaemia or thrombocytopaenia above these levels. PB monocytes must be <1 × 1