Abstract
Various myeloid neoplasms, including the myelodysplastic syndromes (MDS), bear a certain risk of progression to secondary acute myeloid leukemia (sAML). The evolution from low-risk to high-risk MDS and finally to sAML suggests that leukemogenesis is a multistep process. However, even before an overt neoplasm, such as an MDS, develops, “prediagnostic” clonal conditions may be identified. With the advent of large-scale genomic screens, such conditions may be detected quite frequently and early in apparently healthy individuals. Recent data suggest that these conditions increase with age and are indeed associated with an increased risk of the occurrence of MDS or another myeloid neoplasm. In other patients, unexplained cytopenia may be detected and may precede MDS. More recently, diagnostic criteria for potential pre-MDS conditions, including idiopathic cytopenia of uncertain significance and clonal hematopoiesis with indeterminate potential, have been proposed. The current article provides an overview of pre-MDS states and related criteria through which these conditions can be discriminated from each other and from MDS. In addition, the clinical implications and management of pre-MDS states are discussed.
References
1.
Nimer SD: Myelodysplastic syndromes. Blood 2008; 111: 4841–4851.
2.
Bejar R, Levine R, Ebert BL: Unraveling the molecular pathophysiology of myelodysplastic syndromes. J Clin Oncol 2011; 29: 504–515.
3.
Giagounidis A, Haase D: Morphology, cytogenetics and classification of MDS. Best Pract Res Clin Haematol 2013; 26: 337–353.
4.
Malcovati L, Cazzola M: Refractory anemia with ring sideroblasts. Best Pract Res Clin Haematol 2013; 26: 377–385.
5.
Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C: Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982; 51: 189–199.
6.
Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C, Cox C: The chronic myeloid leukaemias: guidelines for distinguishing chronic granulocytic, atypical chronic myeloid, and chronic myelomonocytic leukaemia – proposals by the French-American-British Cooperative Leukaemia Group. Br J Haematol 1994; 87: 746–754.
7.
Brunning RD, Bennett JM, Flandrin G, Matutes E, Head D, Vardiman JW, Harris NL: Myelodysplastic syndromes; in Jaffe ES, Harris NL, Stein H, Vardiman JW (eds): World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, IARC Press, 2001, vol 1, pp 62–73.
8.
Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, Harris NL, Le Beau MM, Hellström-Lindberg E, Tefferi A, Bloomfield CD: The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 2009; 114: 937–951.
9.
Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, Cazzola M, Vardiman JW: The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127: 2391–2405.
10.
Stauder R, Nösslinger T, Pfeilstöcker M, Sperr WR, Wimazal F, Krieger O, Valent P: Impact of age and comorbidity in myelodysplastic syndromes. J Natl Compr Canc Netw 2008; 6: 927–934.
11.
Malcovati L, Papaemmanuil E, Bowen DT, Boultwood J, Della Porta MG, Pascutto C, Travaglino E, Groves MJ, Godfrey AL, Ambaglio I, Gallì A, Da Vià MC, Conte S, Tauro S, Keenan N, Hyslop A, Hinton J, Mudie LJ, Wainscoat JS, Futreal PA, Stratton MR, Campbell PJ, Hellström-Lindberg E, Cazzola M: Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms. Blood 2011; 118: 6239–6246.
12.
Schanz J, Steidl C, Fonatsch C, Pfeilstöcker M, Nösslinger T, Tuechler H, Valent P, Hildebrandt B, Giagounidis A, Aul C, Lübbert M, Stauder R, Krieger O, Garcia-Manero G, Kantarjian H, Germing U, Haase D, Estey E: 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: 1963–1970.
13.
Cargo C, Bowen D: Individual risk assessment in MDS in the era of genomic medicine. Semin Hematol 2017; 54: 133–140.
14.
Steensma DP: The evolving role of genomic testing in assessing prognosis of patients with myelodysplastic syndromes. Best Pract Res Clin Haematol 2017; 30: 295–300.
15.
Busque L, Patel JP, Figueroa ME, Vasanthakumar A, Provost S, Hamilou Z, Mollica L, Li J, Viale A, Heguy A, Hassimi M, Socci N, Bhatt PK, Gonen M, Mason CE, Melnick A, Godley LA, Brennan CW, Abdel-Wahab O, Levine RL: Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat Genet 2012; 44: 1179–1181.
16.
Genovese G, Kähler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF, Chambert K, Mick E, Neale BM, Fromer M, Purcell SM, Svantesson O, Landén, Höglund M, Lehmann S, Gabriel SB, Moran JL, Lander ES, Sullivan PF, Sklar P, Grönberg H, Hultman CM, McCarroll SA: Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med 2014; 371: 2477–2487.
17.
Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, Lindsley RC, Mermel CH, Burtt N, Chavez A, Higgins JM, Moltchanov V, Kuo FC, Kluk MJ, Henderson B, Kinnunen L, Koistinen HA, Ladenvall C, Getz G, Correa A, Banahan BF, Gabriel S, Kathiresan S, Stringham HM, McCarthy MI, Boehnke M, Tuomilehto J, Haiman C, Groop L, Atzmon G, Wilson JG, Neuberg D, Altshuler D, Ebert BL: Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 2014; 371: 2488–2498.
18.
Xie M, Lu C, Wang J, McLellan MD, Johnson KJ, Wendl MC, McMichael JF, Schmidt HK, Yellapantula V, Miller CA, Ozenberger BA, Welch JS, Link DC, Walter MJ, Mardis ER, Dipersio JF, Chen F, Wilson RK, Ley TJ, Ding L: Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med 2014; 20: 1472–1478.
19.
Young AL, Challen GA, Birmann BM, Druley TE: Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults. Nat Commun 2016; 7: 12484.
20.
Steensma DP, Bejar R, Jaiswal S, Lindsley RC, Sekeres MA, Hasserjian RP, Ebert BL: Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood 2015; 126: 9–16.
21.
Wimazal F, Fonatsch C, Thalhammer R, Schwarzinger I, Müllauer L, Sperr WR, Bennett JM, Valent P: Idiopathic cytopenia of undetermined significance (ICUS) versus low risk MDS: the diagnostic interface. Leuk Res 2007; 31: 1461–1468.
22.
Valent P, Horny HP, Bennett JM, Fonatsch C, Germing U, Greenberg P, Haferlach T, Haase D, Kolb HJ, Krieger O, Loken M, van de Loosdrecht A, Ogata K, Orfao A, Pfeilstöcker M, Rüter B, Sperr WR, Stauder R, Wells DA: Definitions and standards in the diagnosis and treatment of the myelodysplastic syndromes: consensus statements and report from a working conference. Leuk Res 2007; 31: 727–736.
23.
Valent P, Horny HP: Minimal diagnostic criteria for myelodysplastic syndromes and separation from ICUS and IDUS: update and open questions. Eur J Clin Invest 2009; 39: 548–553.
24.
Schroeder T, Ruf L, Bernhardt A, Hildebrandt B, Aivado M, Aul C, Gattermann N, Haas R, Germing U: Distinguishing myelodysplastic syndromes (MDS) from idiopathic cytopenia of undetermined significance (ICUS): HUMARA unravels clonality in a subgroup of patients. Ann Oncol 2010; 21: 2267–2271.
25.
Valent P, Bain BJ, Bennett JM, Wimazal F, Sperr WR, Mufti G, Horny HP: Idiopathic cytopenia of undetermined significance (ICUS) and idiopathic dysplasia of uncertain significance (IDUS), and their distinction from low risk MDS. Leuk Res 2012; 36: 1–5.
26.
Malcovati L, Cazzola M: The shadowlands of MDS: idiopathic cytopenias of undetermined significance (ICUS) and clonal hematopoiesis of indeterminate potential (CHIP). Hematology Am Soc Hematol Educ Program 2015; 2015: 299–307.
27.
Valent P, Orazi A, Steensma DP, Ebert BL, Haase D, Malcovati L, van de Loosdrecht AA, Haferlach T, Westers TM, Wells DA, Giagounidis A, Loken M, Orfao A, Lübbert M, Ganser A, Hofmann WK, Ogata K, Schanz J, Béné MC, Hoermann G, Sperr WR, Sotlar K, Bettelheim P, Stauder R, Pfeilstöcker M, Horny HP, Germing U, Greenberg P, Bennett JM: Proposed minimal diagnostic criteria for myelodysplastic syndromes (MDS) and potential pre-MDS conditions. Oncotarget 2017; 8: 73483–73500.
28.
Horny HP, Sotlar K, Valent P: Diagnostic value of histology and immunohistochemistry in myelodysplastic syndromes. Leuk Res 2007; 31: 1609–1616.
29.
Orazi A, Czader MB: Myelodysplastic syndromes. Am J Clin Pathol 2009; 132: 290–305.
30.
Valent P, Orazi A, Büsche G, Schmitt-Gräff A, George TI, Sotlar K, Streubel B, Beham-Schmid C, Cerny-Reiterer S, Krieger O, van de Loosdrecht A, Kern W, Ogata K, Wimazal F, Várkonyi J, Sperr WR, Werner M, Kreipe H, Horny HP: Standards and impact of hematopathology in myelodysplastic syndromes (MDS). Oncotarget 2010; 1: 483–496.
31.
Malcovati L, Della Porta MG, Lunghi M, Pascutto C, Vanelli L, Travaglino E, Maffioli M, Bernasconi P, Lazzarino M, Invernizzi R, Caz-zola M: Flow cytometry evaluation of erythroid and myeloid dysplasia in patients with myelodysplastic syndrome. Leukemia 2005; 19: 776–783.
32.
Westers TM, Ireland R, Kern W, Alhan C, Balleisen JS, Bettelheim P, Burbury K, Cullen M, Cutler JA, Della Porta MG, Dräger AM, Feuillard J, Font P, Germing U, Haase D, Johansson U, Kordasti S, Loken MR, Malcovati L, te Marvelde JG, Matarraz S, Milne T, Moshaver B, Mufti GJ, Ogata K, Orfao A, Porwit A, Psarra K, Richards SJ, Subirá D, Tindell V, Vallespi T, Valent P, van der Velden VH, de Witte TM, Wells DA, Zettl F, Béné MC, van de Loosdrecht AA: Standardization of flow cytometry in myelodysplastic syndromes: a report from an international consortium and the European LeukemiaNet Working Group. Leukemia 2012; 26: 1730–1741.
33.
Cremers EM, Westers TM, Alhan C, Cali C, Wondergem MJ, Poddighe PJ, Ossenkoppele GJ, van de Loosdrecht AA: Multiparameter flow cytometry is instrumental to distinguish myelodysplastic syndromes from non-neoplastic cytopenias. Eur J Cancer 2016; 54: 49–56.
34.
Valent P, Jäger E, Mitterbauer-Hohendanner G, Müllauer L, Schwarzinger I, Sperr WR, Thalhammer R, Wimazal F: Idiopathic bone marrow dysplasia of unknown significance (IDUS): definition, pathogenesis, follow up, and prognosis. Am J Cancer Res 2011; 1: 531–541.
35.
Valent P, Akin C, Arock M, Bock C, George TI, Galli SJ, Gotlib J, Haferlach T, Hoermann G, Hermine O, Jäger U, Kenner L, Kreipe H, Majeti R, Metcalfe DD, Orfao A, Reiter A, Sperr WR, Staber PB, Sotlar K, Schiffer C, Superti-Furga G, Horny HP: Proposed terminology and classification of pre-malignant neoplastic conditions: a consensus proposal. EBioMedicine 2017; 26: 17–24.
36.
Steensma DP: Dysplasia has a differential diagnosis: distinguishing genuine myelodysplastic syndromes (MDS) from mimics, imitators, copycats and impostors. Curr Hematol Malig Rep 2012; 7: 310–320.
37.
Valent P: Low blood counts: immune mediated, idiopathic, or myelodysplasia. Hematology Am Soc Hematol Educ Program 2012; 2012: 485–491.
38.
Petrova-Drus K, Hasserjian R, Pozdnyakova O, Dal Cin P, Mathew S, Margolskee E, Orazi A, Geyer JT: Clinicopathologic evaluation of cytopenic patients with isolated trisomy 8: a detailed comparison between idiopathic cytopenia of unknown significance and low-grade myelodysplastic syndrome. Leuk Lymphoma 2016; 7: 1–9.
39.
Neukirchen J, Lauseker M, Hildebrandt B, Nolting AC, Kaivers J, Kobbe G, Gattermann N, Haas R, Germing U: Cytogenetic clonal evolution in myelodysplastic syndromes is associated with inferior prognosis. Cancer 2017; 123: 4608–4616.
40.
Hahn WC, Weinberg RA: Modelling the molecular circuitry of cancer. Nat Rev Cancer 2002; 2: 331–241.
41.
Valent P, Bonnet D, De Maria R, Lapidot T, Copland M, Melo JV, Chomienne C, Ishikawa F, Schuringa JJ, Stassi G, Huntly B, Herrmann H, Soulier J, Roesch A, Schuurhuis GJ, Wöhrer S, Arock M, Zuber J, Cerny-Reiterer S, Johnsen HE, Andreeff M, Eaves C: Cancer stem cell definitions and terminology: the devil is in the details. Nat Rev Cancer 2012; 12: 767–775.
42.
Gillis NK, Ball M, Zhang Q, Ma Z, Zhao Y, Yoder SJ, Balasis ME, Mesa TE, Sallman DA, Lancet JE, Komrokji RS, List AF, McLeod HL, Alsina M, Baz R, Shain KH, Rollison DE, Padron E: Clonal haemopoiesis and therapy-related myeloid malignancies in elderly patients: a proof-of-concept, case-control study. Lancet Oncol 2017; 18: 112–121.
43.
Takahashi K, Wang F, Kantarjian H, Doss D, Khanna K, Thompson E, Zhao L, Patel K, Neelapu S, Gumbs C, Bueso-Ramos C, DiNardo CD, Colla S, Ravandi F, Zhang J, Huang X, Wu X, Samaniego F, Garcia-Manero G, Futreal PA: Preleukaemic clonal haemopoiesis and risk of therapy-related myeloid neoplasms: a case-control study. Lancet Oncol 2017; 18: 100–111.
44.
Gibson CJ, Lindsley RC, Tchekmedyian V, Mar BG, Shi J, Jaiswal S, Bosworth A, Francisco L, He J, Bansal A, Morgan EA, Lacasce AS, Freedman AS, Fisher DC, Jacobsen E, Armand P, Alyea EP, Koreth J, Ho V, Soiffer RJ, Antin JH, Ritz J, Nikiforow S, Forman SJ, Michor F, Neuberg D, Bhatia R, Bhatia S, Ebert BL: Clonal hematopoiesis associated with adverse outcomes after autologous stem-cell transplantation for lymphoma. J Clin Oncol 2017; 35: 1598–1605.
45.
Jaiswal S, Natarajan P, Silver AJ, Gibson CJ, Bick AG, Shvartz E, McConkey M, Gupta N, Gabriel S, Ardissino D, Baber U, Mehran R, Fuster V, Danesh J, Frossard P, Saleheen D, Melander O, Sukhova GK, Neuberg D, Libby P, Kathiresan S, Ebert BL: Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med 2017; 377: 111–121.
46.
Fuster JJ, MacLauchlan S, Zuriaga MA, Polackal MN, Ostriker AC, Chakraborty R, Wu CL, Sano S, Muralidharan S, Rius C, Vuong J, Jacob S, Muralidhar V, Robertson AA, Cooper MA, Andrés V, Hirschi KK, Martin KA, Walsh K: Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science 2017; 355: 842–847.
47.
Shlush LI: Age related clonal hematopoiesis (ARCH). Blood 2018; 131: 496–504.
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2018
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