View source for Myelodysplastic syndrome

{{Short description|Diverse collection of blood-related cancers}}
{{Use dmy dates|date=December 2024}}
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{{Infobox medical condition (new)
| name            = Myelodysplastic syndrome
| synonyms        = Preleukemia, myelodysplasia<ref>{{cite web|title=Myelodysplasia|url=https://seer.cancer.gov/seertools/hemelymph/53319917e4b0626b1927628f/|website=SEER|access-date=27 October 2016|url-status=live|archive-url=https://web.archive.org/web/20161027130438/https://seer.cancer.gov/seertools/hemelymph/53319917e4b0626b1927628f/|archive-date=27 October 2016}}</ref><ref name=NORD2019>{{cite web |title=Myelodysplastic Syndromes |url=https://rarediseases.org/rare-diseases/myelodysplastic-syndromes/ |website=NORD (National Organization for Rare Disorders) |access-date=23 May 2019}}</ref>
| image           = Hypogranular neutrophil with a pseudo-Pelger-Huet nucleus in MDS.jpg
| caption         = [[Blood smear]] from a person with myelodysplastic syndrome. A hypogranular [[neutrophil]] with a [[Pelger–Huet anomaly|pseudo-Pelger-Huet nucleus]] is shown. There are also [[poikilocytosis|abnormally shaped red blood cells]], in part related to removal of the [[spleen]].
| field           = [[Hematology]], [[oncology]]
| symptoms        = None, [[fatigue (medical)|feeling tired]], [[shortness of breath]], easy [[bleeding]], frequent [[infections]]<ref name=NCI2015/>
| complications   =
| onset           = 
| duration        =
| causes          =
| risks           = Previous [[chemotherapy]], [[radiation therapy]], certain chemicals such as [[tobacco smoke]], [[pesticides]], and [[benzene]], exposure to [[Mercury (element)|mercury]] or [[lead]]<ref name=NCI2015/>
| diagnosis       = Blood test, [[bone marrow biopsy]]<ref name=NCI2015/>
| differential    =
| prevention      =
| treatment       = [[Supportive care]], medications, [[stem cell transplantation]]<ref name=NCI2015/>
| medication      = [[Lenalidomide]], [[antithymocyte globulin]], [[azacitidine]]<ref name=NCI2015/>
| prognosis       = Typical survival time 2.5 years<ref name=NCI2015/>
| frequency       =
| deaths          =
}}
<!-- Definition and symptoms -->

A '''myelodysplastic syndrome''' ('''MDS''') is one of a group of [[cancer]]s in which [[blood cell]]s in the [[bone marrow]] do not mature, and as a result, do not develop into healthy blood cells.<ref name=NCI2015/> Early on, no symptoms are typically seen.<ref name=NCI2015/> Later, symptoms may include [[fatigue]], [[shortness of breath]], [[bleeding disorders]], [[anemia]], or frequent [[infections]].<ref name=NCI2015/> Some types may develop into [[acute myeloid leukemia]].<ref name=NCI2015>{{cite web |title=Myelodysplastic Syndromes Treatment (PDQ®) – Patient Version |url=https://www.cancer.gov/types/myeloproliferative/patient/myelodysplastic-treatment-pdq#section/all |publisher=NCI|access-date=27 October 2016 |archive-url=https://web.archive.org/web/20161005015558/https://www.cancer.gov/types/myeloproliferative/patient/myelodysplastic-treatment-pdq |date=12 August 2015|archive-date =5 October 2016}}</ref>

<!-- Cause, mechanism, and diagnosis -->
Risk factors include previous [[chemotherapy]] or [[radiation therapy]], exposure to certain chemicals such as [[tobacco smoke]], [[pesticides]], and [[benzene]], and exposure to heavy metals such as [[Mercury (element)|mercury]] or [[lead]].<ref name=NCI2015/> Problems with blood cell formation result in some combination of low [[anemia|red blood cell]], [[thrombocytopenia|platelet]], and [[white blood cell]] counts.<ref name=NCI2015/> Some types of MDS cause an increase in the production of immature blood cells (called [[blast cell|blasts]]), in the bone marrow or [[peripheral blood|blood]].<ref name=NCI2015/> The different types of MDS are identified based on the specific characteristics of the changes in the blood cells and bone marrow.<ref name=NCI2015/>

<!-- Prevention and treatment -->
Treatments may include [[supportive care]], drug therapy, and [[hematopoietic stem cell transplantation]].<ref name=NCI2015/> Supportive care may include [[blood transfusions]], [[erythropoiesis-stimulating agents|medications to increase the making of red blood cells]], and [[antibiotic]]s.<ref name=NCI2015/> Drug therapy may include the medications [[lenalidomide]], [[antithymocyte globulin]], and [[azacitidine]].<ref name=NCI2015/> Some people can be cured by [[chemotherapy]] followed by a stem-cell transplant from a donor.<ref name=NCI2015/>

<!-- Epidemiology and history -->
About seven per 100,000 people are affected by MDS; about four per 100,000 people newly acquire the condition each year.<ref name=Gem2013/> The typical age of onset is 70 years.<ref name=Gem2013>{{cite journal | vauthors = Germing U, Kobbe G, Haas R, Gattermann N | title = Myelodysplastic syndromes: diagnosis, prognosis, and treatment | journal = Deutsches Ärzteblatt International | volume = 110 | issue = 46 | pages = 783–90 | date = November 2013 | pmid = 24300826 | pmc = 3855821 | doi = 10.3238/arztebl.2013.0783 }}</ref> The prognosis depends on the type of cells affected, the number of blasts in the bone marrow or blood, and the changes present in the [[chromosome]]s of the affected cells.<ref name=NCI2015/> The average survival time following diagnosis is 2.5 years.<ref name=Gem2013/> MDS was first recognized in the early 1900s;<ref name=Hol2010/> it came to be called myelodysplastic syndrome in 1976.<ref name=Hol2010>{{cite book|last1=Hong|first1=Waun Ki|last2=Holland|first2=James F. |title=Holland-Frei Cancer Medicine |date=2010|publisher=PMPH-USA|isbn=978-1-60795-014-1|page=1544|edition=8th|url=https://books.google.com/books?id=R0FbhLsWHBEC&pg=PA1544 |url-status=live|archive-url=https://web.archive.org/web/20161027123519/https://books.google.ca/books?id=R0FbhLsWHBEC&pg=PA1544 |archive-date=2016-10-27}}</ref>
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==Signs and symptoms==
[[File:Tumor Myelodysplastic Spleen.JPG|thumb|Enlarged spleen due to myelodysplastic syndrome; CT scan coronal section, spleen in red, left kidney in green]]
Signs and symptoms are nonspecific and generally related to the blood cytopenias:
* [[Anemia]] (low [[red blood cell|RBC]] count or reduced [[hemoglobin]]) – chronic tiredness, shortness of breath, chilled sensation, sometimes chest pain<ref>{{cite web |url= https://www.lecturio.com/concepts/anemia-overview/| title= Anemia: Overview
|website=The Lecturio Medical Concept Library |access-date= 15 August 2021}}</ref>
* [[Neutropenia]] (low neutrophil count) – increased susceptibility to [[infection]]<ref>{{cite web |url= https://www.lecturio.com/concepts/neutropenia/| title= Neutropenia|website=The Lecturio Medical Concept Library |access-date= 15 August 2021}}</ref>
* [[Thrombocytopenia]] (low platelet count) – increased susceptibility to [[bleeding]] and [[ecchymosis]] (bruising), as well as subcutaneous [[hemorrhage|hemorrhaging]] resulting in [[purpura]] or [[petechia]]e<ref>{{cite book |title=Myelodysplastic Syndrome |publisher=The Leukemia & Lymphoma Society |location=White Plains, NY |date=2001 |oclc=64551506 |page=24 }}</ref><ref>{{cite web |url= https://www.lecturio.com/concepts/thrombocytopenia/| title= Thrombocytopenia|website=The Lecturio Medical Concept Library |access-date= 15 August 2021}}</ref>

Many individuals are asymptomatic, and blood cytopenia or other problems are identified as a part of a routine blood count:<ref>{{cite web |url= https://www.lecturio.com/concepts/myelodysplastic-syndromes/| title= Myelodysplastic Syndromes
|website=The Lecturio Medical Concept Library |access-date= 11 August 2021}}</ref>
* Neutropenia, anemia, and thrombocytopenia
* [[Splenomegaly]] or rarely [[hepatomegaly]]
* Abnormal granules in cells, abnormal nuclear shape and size
* [[Chromosome abnormality]], including [[chromosomal translocation]]s and abnormal chromosome number

Patients with MDS have an overall risk of almost 30% for developing [[acute myelogenous leukemia]].<ref name=Hasserjian23 />

Anemia dominates the early course. Most symptomatic patients complain of the gradual onset of fatigue and weakness, [[dyspnea]], and [[pallor]], but at least half the patients are asymptomatic and their MDS is discovered only incidentally on routine blood counts. Fever, weight loss and splenomegaly should point to a myelodysplastic/myeloproliferative neoplasm (MDS/MPN) rather than pure myelodysplastic process.<ref>{{cite journal|last1=Patnaik|first1=Mrinal M.|last2=Lasho|first2=Terra|date=2020-12-04|title=Evidence-Based Minireview: Myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes: a focused review|journal=Hematology|volume=2020|issue=1|pages=460–4|doi=10.1182/hematology.2020000163|pmid=33275673|pmc=7727594}}</ref>

==Cause==
Some people have a history of exposure to chemotherapy (especially alkylating agents such as [[melphalan]], [[cyclophosphamide]], [[busulfan]], and [[chlorambucil]]) or [[radiation]] (therapeutic or accidental), or both (e.g., at the time of stem cell transplantation for another disease). Workers in some industries with heavy exposure to hydrocarbons, such as the petroleum industry, have a slightly higher risk of contracting the disease than the general population. [[Xylene]] and [[benzene]] exposures have been associated with myelodysplasia. [[Vietnam veteran]]s exposed to [[Agent Orange]] are at risk of developing MDS.<ref>{{cite journal |vauthors=Sperling AS, Leventhal M, Gibson CJ, Ebert BL, Steensma DP |title=Myelodysplastic syndromes (MDS) occurring in Agent Orange exposed individuals carry a mutational spectrum similar to that of ''de novo'' MDS |journal=Leuk Lymphoma |volume=61 |issue=3 |pages=728–731 |date=March 2020 |pmid=31714164 |pmc=7268906 |doi=10.1080/10428194.2019.1689394 }}</ref> A link may exist between the development of MDS "in atomic-bomb survivors 40 to 60 years after radiation exposure" (in this case, referring to people who were in close proximity to the dropping of the atomic bombs in Hiroshima and Nagasaki during World War II).<ref>{{cite journal | vauthors = Iwanaga M, Hsu WL, Soda M, Takasaki Y, Tawara M, Joh T, Amenomori T, Yamamura M, Yoshida Y, Koba T, Miyazaki Y, Matsuo T, Preston DL, Suyama A, Kodama K, Tomonaga M | title = Risk of myelodysplastic syndromes in people exposed to ionizing radiation: a retrospective cohort study of Nagasaki atomic bomb survivors | journal = Journal of Clinical Oncology | volume = 29 | issue = 4 | pages = 428–34 | date = February 2011 | pmid = 21149671 | doi = 10.1200/JCO.2010.31.3080 }}</ref> Children with [[Down syndrome]] are susceptible to MDS, and a family history may indicate a hereditary form of [[sideroblastic anemia]] or [[Fanconi anemia]].<ref name="Dokal 1236–1240">{{cite journal|last1=Dokal|first1=Inderjeet|last2=Vulliamy|first2=Tom|date=August 2010|title=Inherited bone marrow failure syndromes|journal=Haematologica|volume=95|issue=8|pages=1236–40|doi=10.3324/haematol.2010.025619|pmc=2913069|pmid=20675743}}</ref> [[GATA2 deficiency]] and [[SAMD9]]/9L syndromes each account for about 15% of MDS cases in children.<ref name =Hall24>{{cite journal |vauthors=Hall T, Gurbuxani S, Crispino JD |title=Malignant progression of preleukemic disorders |journal=Blood |volume=143 |issue=22 |pages=2245–55 |date=May 2024 |pmid=38498034 |doi=10.1182/blood.2023020817 |pmc=11181356 }}</ref>

==Pathophysiology==
MDS most often develops without an identifiable cause. Risk factors include exposure to an agent known to cause DNA damage, such as [[radiation]], benzene, and certain chemotherapies; other risk factors have been inconsistently reported. Proving a connection between a suspected exposure and the development of MDS can be difficult, but the presence of genetic abnormalities may provide some supportive information. Secondary MDS can occur as a late [[toxicity]] of cancer therapy (therapy-associated MDS, t-MDS). MDS after exposure to radiation or [[alkylating agents]] such as busulfan, [[nitrosourea]], or [[procarbazine]], typically occurs 3–7 years after exposure and frequently demonstrates loss of chromosome 5 or 7. MDS after exposure to [[Topoisomerase inhibitor|DNA topoisomerase II inhibitors]] occurs after a shorter latency of only 1–3 years and can have an 11q23 translocation. Other pre-existing bone-marrow disorders, such as [[acquired aplastic anemia]] following immunosuppressive treatment and [[Fanconi anemia]], can evolve into MDS.<ref name="Dokal 1236–1240"/>

MDS is thought to arise from [[mutation]]s in the [[hematopoietic stem cell|multipotent bone-marrow stem cell]], but the specific defects responsible for these diseases remain poorly understood. [[Cellular differentiation|Differentiation]] of blood precursor cells is impaired, and a significant increase in levels of [[apoptosis|apoptotic]] cell death occurs in bone-marrow cells. Clonal expansion of the abnormal cells results in the production of cells that have lost the ability to differentiate. If the overall percentage of bone-marrow [[myeloblast]]s rises over a particular cutoff (20% for [[#World Health Organization|WHO]] and 30% for [[#French-American-British (FAB) classification|FAB]]), then transformation to [[acute myelogenous leukemia]] (AML) is said to have occurred. The progression of MDS to AML is a good example of the [[Knudson hypothesis|multistep theory of carcinogenesis]] in which a series of mutations occurs in an initially normal cell and transforms it into a [[cancer]] cell.<ref>{{cite journal|last=Bejar|first=Rafael|date=December 2018|title=What biologic factors predict for transformation to AML?|journal=Best Practice & Research. Clinical Haematology|volume=31|issue=4|pages=341–5|doi=10.1016/j.beha.2018.10.002|pmid=30466744|s2cid=53712886}}</ref>

Although recognition of leukemic transformation was historically important (see [[Myelodysplastic#History|History]]), a significant proportion of the [[morbidity]] and [[death|mortality]] attributable to MDS results not from transformation to AML, but rather from the cytopenias seen in all MDS patients. While anemia is the most common [[cytopenia]] in MDS patients, given the ready availability of [[blood transfusion]], MDS patients rarely experience injury from severe anemia.  The two most serious complications in MDS patients resulting from their cytopenias are bleeding (due to lack of platelets) or infection (due to lack of white blood cells).  Long-term transfusion of packed red blood cells leads to [[iron overload#Secondary hemochromatosis|iron overload]].<ref>{{Citation|last1=Rasel|first1=Mohammad|title=Transfusion Iron Overload|date=2022|url=https://www.ncbi.nlm.nih.gov/books/NBK562146/|work=StatPearls|place=Treasure Island (FL)|publisher=StatPearls Publishing|pmid=32965817|access-date=2022-02-03|last2=Mahboobi|first2=Sohail K.}}</ref>

===Genetics===
The recognition of [[epigenetic]] changes in [[DNA]] structure in MDS has explained the success of two (namely the hypomethylating agents [[5-azacytidine]] and [[decitabine]]) of three (the third is [[lenalidomide]]) commercially available medications approved by the [[Food and Drug Administration (United States)|U.S. Food and Drug Administration]] to treat MDS. Proper [[DNA methylation]] is critical in the regulation of proliferation genes, and the loss of DNA methylation control can lead to uncontrolled cell growth and cytopenias.  The recently approved [[DNA methyltransferase inhibitor]]s take advantage of this mechanism by creating a more orderly DNA methylation profile in the [[hematopoietic stem cell]] [[Cell nucleus|nucleus]], thereby restoring normal blood counts and retarding the progression of MDS to [[acute leukemia]].<ref>{{cite journal|pmid=25605373|year=2015|last1=Wolach|first1=O|title=How I treat mixed-phenotype acute leukemia|journal=Blood|volume=125|issue=16|pages=2477–85|last2=Stone|first2=R. M.|doi=10.1182/blood-2014-10-551465|doi-access=free}}</ref>

Some authors have proposed that the loss of [[mitochondrial]] function over time leads to the accumulation of DNA mutations in hematopoietic stem cells, and this accounts for the increased incidence of MDS in older patients.  Researchers point to the accumulation of mitochondrial [[iron]] deposits in the [[ringed sideroblast]] as evidence of mitochondrial dysfunction in MDS.<ref name="pmid12406866">{{cite journal | vauthors = Cazzola M, Invernizzi R, Bergamaschi G, Levi S, Corsi B, Travaglino E, Rolandi V, Biasiotto G, Drysdale J, Arosio P | title = Mitochondrial ferritin expression in erythroid cells from patients with sideroblastic anemia | journal = Blood | volume = 101 | issue = 5 | pages = 1996–2000 | date = March 2003 | pmid = 12406866 | doi = 10.1182/blood-2002-07-2006 | s2cid = 5729203 | doi-access = free }}</ref>

===DNA damage===
[[Hematopoietic stem cell]] aging is thought to be associated with the accrual of multiple genetic and [[epigenetics|epigenetic]] aberrations leading to the suggestion that MDS is, in part, related to an inability to adequately cope with [[DNA damage (naturally occurring)|DNA damage]].<ref>{{cite journal |vauthors=Zhou T, Chen P, Gu J, Bishop AJ, Scott LM, Hasty P, Rebel VI |title=Potential relationship between inadequate response to DNA damage and development of myelodysplastic syndrome |journal=Int J Mol Sci |volume=16 |issue=1 |pages=966–89 |date=January 2015 |pmid=25569081 |pmc=4307285 |doi=10.3390/ijms16010966 |doi-access=free }}</ref>  An emerging perspective is that the underlying mechanism of MDS could be a defect in one or more pathways that are involved in [[DNA repair|repairing damaged DNA]].<ref>{{cite journal |vauthors=Zhou T, Hasty P, Walter CA, Bishop AJ, Scott LM, Rebel VI |title=Myelodysplastic syndrome: an inability to appropriately respond to damaged DNA? |journal=Exp Hematol |volume=41 |issue=8 |pages=665–74 |date=August 2013 |pmid=23643835 |pmc=3729593 |doi=10.1016/j.exphem.2013.04.008 }}</ref>  In MDS an increased frequency of [[chromosome abnormality|chromosomal breaks]] indicates defects in DNA repair processes.<ref name = Jankowska2008>{{cite journal |vauthors=Jankowska AM, Gondek LP, Szpurka H, Nearman ZP, Tiu RV, Maciejewski JP |title=Base excision repair dysfunction in a subgroup of patients with myelodysplastic syndrome |journal=Leukemia |volume=22 |issue=3 |pages=551–8 |date=March 2008 |pmid=18059482 |doi=10.1038/sj.leu.2405055 }}</ref>  Also, elevated levels of [[8-oxoguanine]] were found in the DNA of a significant proportion of MDS patients, indicating that the [[base excision repair]] pathway that is involved in handling oxidative DNA damages may be defective in these cases.<ref name = Jankowska2008/>

===5q- syndrome===
Since at least 1974, the deletion in the long arm of [[chromosome 5]] has been known to be associated with dysplastic abnormalities of hematopoietic stem cells.<ref name="pmid3552346">{{cite journal | vauthors = Bunn HF | title = 5q- and disordered haematopoiesis | journal = Clinics in Haematology | volume = 15 | issue = 4 | pages = 1023–35 | date = November 1986 | pmid = 3552346 }}</ref><ref name="pmid4421285">{{cite journal | vauthors = Van den Berghe H, Cassiman JJ, David G, Fryns JP, Michaux JL, Sokal G | title = Distinct haematological disorder with deletion of long arm of no. 5 chromosome | journal = Nature | volume = 251 | issue = 5474 | pages = 437–38 | date = October 1974 | pmid = 4421285 | doi = 10.1038/251437a0 | s2cid = 4286311 | bibcode = 1974Natur.251..437V }}</ref>  By 2005, [[lenalidomide]], a [[chemotherapy]] drug, was recognized to be effective in MDS patients with the [[5q- syndrome]],<ref name="pmid15703420">{{cite journal | vauthors = List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, Fuchs D, Rimsza L, Heaton R, Knight R, Zeldis JB | title = Efficacy of lenalidomide in myelodysplastic syndromes | journal = The New England Journal of Medicine | volume = 352 | issue = 6 | pages = 549–57 | date = February 2005 | pmid = 15703420 | doi = 10.1056/NEJMoa041668 | doi-access = free }}</ref> and in December 2005, the US FDA approved the drug for this indication. Patients with isolated 5q-, low [[International Prognostic Scoring System|IPSS]] risk, and transfusion dependence respond best to lenalidomide. Typically, the prognosis for these patients is favorable, with a 63-month median survival. Lenalidomide has dual action, by lowering the malignant clone number in patients with 5q-, and by inducing better differentiation of healthy erythroid cells, as seen in patients without 5q deletion.{{citation needed|date=July 2020}}

===Splicing factor mutations===

Mutations in splicing factors have been found in 40–80% of people with MDS, with a higher incidence of mutations detected in people who have more [[ring sideroblasts]].<ref name=Rozovski2012>{{cite journal |vauthors=Rozovski U, Keating M, Estrov Z |title=The significance of spliceosome mutations in chronic lymphocytic leukemia |journal=Leuk Lymphoma |volume=54 |issue=7 |pages=1364–6 |date=July 2013 |pmid=23270583 |pmc=4176818 |doi=10.3109/10428194.2012.742528 }}</ref>

=== ''IDH1'' and ''IDH2'' mutations ===
Mutations in the genes encoding for [[isocitrate dehydrogenase]] 1 and 2 (''IDH1'' and ''IDH2'') occur in 10–20% of patients with myelodysplastic syndrome,<ref>{{cite journal | vauthors = Molenaar RJ, Radivoyevitch T, Maciejewski JP, van Noorden CJ, Bleeker FE | title = The driver and passenger effects of isocitrate dehydrogenase 1 and 2 mutations in oncogenesis and survival prolongation | journal = Biochimica et Biophysica Acta (BBA) - Reviews on Cancer | volume = 1846 | issue = 2 | pages = 326–41 | date = December 2014 | pmid = 24880135 | doi = 10.1016/j.bbcan.2014.05.004 }}</ref> and confer a worsened prognosis in low-risk MDS.<ref name=":0">{{cite journal | vauthors = Molenaar RJ, Thota S, Nagata Y, Patel B, Clemente M, Przychodzen B, Hirsh C, Viny AD, Hosano N, Bleeker FE, Meggendorfer M, Alpermann T, Shiraishi Y, Chiba K, Tanaka H, van Noorden CJ, Radivoyevitch T, Carraway HE, Makishima H, Miyano S, Sekeres MA, Ogawa S, Haferlach T, Maciejewski JP | title = Clinical and biological implications of ancestral and non-ancestral IDH1 and IDH2 mutations in myeloid neoplasms | journal = Leukemia | volume = 29 | issue = 11 | pages = 2134–42 | date = November 2015 | pmid = 25836588 | pmc = 5821256 | doi = 10.1038/leu.2015.91 }}</ref> Because the incidence of ''IDH1/2'' mutations increases as the disease malignancy increases, these findings together suggest that ''IDH1/2'' mutations are important drivers of progression of MDS to a more malignant disease state.<ref name=":0" />

=== GATA2 deficiency ===
GATA2 deficiency is a group of disorders caused by a defect, familial, or sporadic [[Gain-of-function mutation|inactivating mutation]]s, in one of the two ''[[GATA2]]'' [[gene]]s. These [[autosomal dominant]] mutations cause a reduction in the cellular levels of the gene's product, GATA2. The GATA2 [[protein]] is a [[transcription factor]] critical for the [[Embryogenesis|embryonic development]], maintenance, and functionality of [[blood|blood-forming]], [[Lymphatic system|lymph-forming]], and other tissue-forming [[stem cell]]s. In consequence of these mutations, cellular levels of GATA2 are low, and individuals develop over time hematological, immunological, lymphatic, or other presentations. Prominent among these presentations is MDS that often progresses to acute myelocytic leukemia, or less commonly, [[chronic myelomonocytic leukemia]].<ref name="pmid28179280">{{cite journal | vauthors = Crispino JD, Horwitz MS | title = GATA factor mutations in hematologic disease | journal = Blood | volume = 129 | issue = 15 | pages = 2103–10 | date = April 2017 | pmid = 28179280 | pmc = 5391620 | doi = 10.1182/blood-2016-09-687889 }}</ref><ref name="pmid28643018">{{cite journal | vauthors = Hirabayashi S, Wlodarski MW, Kozyra E, Niemeyer CM | title = Heterogeneity of GATA2-related myeloid neoplasms | journal = International Journal of Hematology | volume = 106 | issue = 2 | pages = 175–82 | date = August 2017 | pmid = 28643018 | doi = 10.1007/s12185-017-2285-2 | doi-access = free }}</ref>

=== Transient myeloproliferative disease ===
[[Transient myeloproliferative disease]], renamed Transient Abnormal Myelopoiesis (TAM),<ref>{{cite book |vauthors=Takasaki K, Chou ST |title=Transcription factors in blood cell development |chapter=GATA1 in Normal and Pathologic Megakaryopoiesis and Platelet Development |series=Adv Exp Med Biol |volume=1459 |pages=261–287 |date=2024 |pmid=39017848 |doi=10.1007/978-3-031-62731-6_12 |isbn=978-3-031-62730-9 }}</ref> is the abnormal proliferation of a [[Clone (cell biology)|clone]] of noncancerous [[megakaryoblast]]s in the liver and bone marrow. The disease is restricted to individuals with Down syndrome or genetic changes similar to those in Down syndrome, develops during pregnancy or shortly after birth, and resolves within 3 months, or in about 10% of cases, progresses to [[acute megakaryoblastic leukemia]].<ref name="pmid27510823">{{cite journal | vauthors = Bhatnagar N, Nizery L, Tunstall O, Vyas P, Roberts I | title = Transient Abnormal Myelopoiesis and AML in Down Syndrome: an Update | journal = Current Hematologic Malignancy Reports | volume = 11 | issue = 5 | pages = 333–41 | date = October 2016 | pmid = 27510823 | pmc = 5031718 | doi = 10.1007/s11899-016-0338-x }}</ref><ref name="pmid28179280"/><ref name="pmid22867885">{{cite journal | vauthors = Seewald L, Taub JW, Maloney KW, McCabe ER | title = Acute leukemias in children with Down syndrome | journal = Molecular Genetics and Metabolism | volume = 107 | issue = 1–2 | pages = 25–30 | date = September 2012 | pmid = 22867885 | doi = 10.1016/j.ymgme.2012.07.011 }}</ref>

== Diagnosis ==
The elimination of other causes of cytopenias, along with a dysplastic bone marrow, is required to diagnose a myelodysplastic syndrome, so differentiating MDS from other causes of anemia, thrombocytopenia, and leukopenia is important.<ref>{{cite journal |vauthors=Mecham B, Drissi W, Brummell G, Dadi N, Martin DE |title=Severe B12 Deficiency Causing a Maturation Defect Mimicking Myelodysplastic Syndrome With Excess Blasts |journal=Cureus |volume=16 |issue=5 |article-number=e60837 |date=May 2024 |pmid=38910768 |pmc=11191413 |doi=10.7759/cureus.60837 |doi-access=free}}</ref> MDS is diagnosed with any type of cytopenia (anemia, thrombocytopenia, or neutropenia) being present for at least 6 months, the presence of at least 10% dysplasia or blasts (immature cells) in 1 cell lineage, and MDS associated genetic changes, molecular markers or chromosomal abnormalities.<ref name="Sekeres 2022" />

A typical diagnostic investigation includes:
* [[Full blood count]] and examination of [[blood film]]: The blood film morphology can provide clues about [[hemolytic anemia]], clumping of the platelets leading to spurious [[thrombocytopenia]], or [[leukemia]].
* Blood tests to eliminate other common causes of cytopenias such as [[Lupus erythematosus|lupus]], [[hepatitis]], [[vitamin B12|B<sub>12</sub>]], [[folate]], or other [[vitamin]] deficiencies, [[kidney failure]] or [[heart failure]], [[HIV]], [[hemolytic anemia]], [[monoclonal gammopathy]]: Age-appropriate [[cancer screening]] should be considered for all anemic patients.
* [[Bone marrow examination]] by a [[hematopathologist]]: This is required to establish the diagnosis since all hematopathologists consider dysplastic marrow the key feature of myelodysplasia.<ref>{{cite web|title=Rudhiram Hematology Clinic - Google Search|url=https://www.google.com/search?q=Rudhiram+Hematology+Clinic&ludocid=5150959102409787010&lpsid=CIHM0ogKEICAgIDmpez2cA&lsig=AB86z5XrzWBckbIx8_P21jwulFPG|access-date=2022-02-03|website=www.google.com}}</ref>
* [[Cytogenetics]] or chromosomal studies: This is ideally performed on the [[bone marrow aspirate]]. Conventional cytogenetics requires a fresh specimen since live cells are induced to enter [[metaphase]] to allow chromosomes to be seen.
* Interphase [[fluorescence in situ hybridization]] testing, usually ordered together with conventional cyto[[genetic testing]], offers rapid detection of several chromosome abnormalities associated with MDS, including del 5q, −7, +8, and del 20q.
* [[Virtual karyotype|Virtual karyotyping]] can be done for MDS,<ref>{{cite journal |vauthors=Gondek LP, Tiu R, O'Keefe CL, Sekeres MA, Theil KS, Maciejewski JP |title=Chromosomal lesions and uniparental disomy detected by SNP arrays in MDS, MDS/MPD, and MDS-derived AML |journal=Blood |volume=111 |issue=3 |pages=1534–42 |date=February 2008 |pmid=17954704 |pmc=2214746 |doi=10.1182/blood-2007-05-092304 }}</ref> which uses computational tools to construct the [[karyogram]] from disrupted DNA. Virtual karyotyping does not require cell culture and has a dramatically higher resolution than conventional cytogenetics, but cannot detect [[balanced translocation]]s.
* [[Flow cytometry]] is helpful to identify blasts, abnormal myeloid maturation, and establish the presence of any [[lymphoproliferative]] disorder in the marrow.
* Testing for [[copper deficiency]] should not be overlooked, as it can morphologically resemble MDS in bone-marrow biopsies.<ref>{{cite journal | vauthors = Huff JD, Keung YK, Thakuri M, Beaty MW, Hurd DD, Owen J, Molnár I | title = Copper deficiency causes reversible myelodysplasia | journal = American Journal of Hematology | volume = 82 | issue = 7 | pages = 625–30 | date = July 2007 | pmid = 17236184 | doi = 10.1002/ajh.20864 | s2cid = 44398996 | doi-access = free }}</ref> Risk factors for copper deficiency include bariatric surgery, zinc supplementation, and celiac disease.<ref>{{cite journal |vauthors=Luo T, Zurko J, Astle J, Shah NN |title=Mimicking Myelodysplastic Syndrome: Importance of Differential Diagnosis |journal=Case Rep Hematol |volume=2021 |issue= |article-number=9661765 |date=2021 |pmid=34881068 |pmc=8648467 |doi=10.1155/2021/9661765 |doi-access=free}}</ref>

The features generally used to define an MDS are blood cytopenias, ineffective hematopoiesis, [[dyserythropoiesis]], dysgranulopoiesis, dysmegakaropoiesis, and increased myeloblasts.{{Citation needed|date=October 2024}}

Dysplasia can affect all three lineages seen in the bone marrow. The best way to diagnose dysplasia is by morphology and special stains
([[Periodic acid–Schiff–diastase|PAS]]) used on the bone marrow aspirate and peripheral blood smear. Dysplasia in the myeloid series is defined by:
* Granulocytic series{{Citation needed|date=October 2024}}:
*# Hypersegmented [[neutrophil]]s (also seen in vit B<sub>12</sub>/folate deficiency)
*# Hyposegmented neutrophils ([[Pelger–Huet anomaly#Acquired or pseudo-Pelger–Huët anomaly|pseudo Pelger-Huet]])
*# Hypogranular neutrophils or [[pseudo Chediak-Higashi]] (large [[azurophilic granule]]s)
*# [[Auer rod]]s – automatically [[RAEB II]] (if blast count <&nbsp;5% in the peripheral blood and <&nbsp;10% in the bone marrow aspirate); also note Auer rods may be seen in mature neutrophils in [[Acute myeloid leukemia|AML]] with translocation t(8;21)
*# Dimorphic granules (basophilic and eosinophilic granules) within [[eosinophil]]s
* Erythroid series{{Citation needed|date=October 2024}}:
*# [[Binucleated cells|Binucleated]] erythroid precursors and [[karyorrhexis]]
*# Erythroid nuclear budding
*# Erythroid nuclear strings or internuclear bridging (also seen in [[congenital dyserythropoietic anemia]]s)
*# Loss of [[e-cadherin]] in [[normoblast]]s is a sign of aberrancy.
*# PAS (globular in [[vacuole]]s or diffuse cytoplasmic staining) within erythroid precursors in the bone marrow aspirate (has no bearing on paraffin-fixed bone-marrow biopsy). Note: one can see PAS vacuolar positivity in L1 and L2 blasts (FAB classification; the L1 and L2 nomenclature is not used in the WHO classification)
*# [[Ringed sideroblast]]s (10 or more iron granules encircling one-third or more of the nucleus) seen on [[Perls' Prussian blue]] iron stain (>15% ringed sideroblasts when counted among red cell precursors for [[refractory anemia with ring sideroblasts]])
* Megakaryocytic series (can be the most subjective){{Citation needed|date=October 2024}}:
*# Hyposegmented nuclear features in platelet-producing megakaryocytes (lack of lobation)
*# Hypersegmented ([[osteoclast]]ic appearing) [[megakaryocyte]]s
*# Ballooning of the platelets (seen with [[interference contrast microscopy]])

On the bone-marrow biopsy, high-grade dysplasia (RAEB-I and RAEB-II) may show [[atypical localization of immature precursors]], which are islands of immature precursors cells (myeloblasts and promyelocytes) localized to the center of the intertrabecular space rather than adjacent to the [[trabecula]]e or surrounding [[arteriole]]s. This morphology can be difficult to differentiate from treated leukemia and recovering immature normal marrow elements. Also, topographic alteration of the nucleated erythroid cells can be seen in early myelodysplasia ([[refractory anemia|RA]] and RARS), where normoblasts are seen next to bony trabeculae instead of forming normal interstitially placed [[erythroid island]]s.{{citation needed|date=July 2020}}

=== Classification ===

====World Health Organization and International Consensus Classification====
In the late 1990s, a group of pathologists and clinicians working under the [[World Health Organization]] (WHO) modified this classification, introducing several new disease categories and eliminating others. In 2008, 2016, and 2022, the WHO developed new classification schemes that incorporated genetic findings (5q-) alongside morphology of the cells in the peripheral blood and bone marrow. As of 2024, the WHO 5th edition and International Consensus Classification (ICC)<ref>{{cite journal |vauthors=Arber DA, Orazi A, Hasserjian RP, Borowitz MJ, Calvo KR, Kvasnicka HM, Wang SA, Bagg A, Barbui T, Branford S, Bueso-Ramos CE, Cortes JE, Dal Cin P, DiNardo CD, Dombret H, Duncavage EJ, Ebert BL, Estey EH, Facchetti F, Foucar K, Gangat N, Gianelli U, Godley LA, Gökbuget N, Gotlib J, Hellström-Lindberg E, Hobbs GS, Hoffman R, Jabbour EJ, Kiladjian JJ, Larson RA, Le Beau MM, Loh ML, Löwenberg B, Macintyre E, Malcovati L, Mullighan CG, Niemeyer C, Odenike OM, Ogawa S, Orfao A, Papaemmanuil E, Passamonti F, Porkka K, Pui CH, Radich JP, Reiter A, Rozman M, Rudelius M, Savona MR, Schiffer CA, Schmitt-Graeff A, Shimamura A, Sierra J, Stock WA, Stone RM, Tallman MS, Thiele J, Tien HF, Tzankov A, Vannucchi AM, Vyas P, Wei AH, Weinberg OK, Wierzbowska A, Cazzola M, Döhner H, Tefferi A |title=International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data |journal=Blood |volume=140 |issue=11 |pages=1200–28 |date=September 2022 |pmid=35767897 |pmc=9479031 |doi=10.1182/blood.2022015850 }}</ref> systems are both actively in use.<ref name =Hasserjian23>{{cite journal |vauthors=Hasserjian RP, Germing U, Malcovati L |title=Diagnosis and classification of myelodysplastic syndromes |journal=Blood |volume=142 |issue=26 |pages=2247–57 |date=December 2023 |pmid=37774372 |doi=10.1182/blood.2023020078 }}</ref>

The list of dysplastic syndromes under the 2008 WHO system included the following:
{| class="wikitable"
|-
! Myelodysplastic syndrome
! Description and WHO 5th ed. counterparts
|-
| Refractory [[cytopenia]] with unilineage dysplasia
| Refractory anemia, [[Refractory neutropenia]], and [[Refractory thrombocytopenia]].  Revised to MDS with LB (low blasts)
|-
| [[Refractory anemia with ringed sideroblasts]] (RARS)
| Revised to MDS with LB and RS or MDS with LB and [[SF3B1]] mutation
Includes the subset Thrombocytosis (MDS/MPN-T) [[myelodysplastic/myeloproliferative disorder]]
|-
|[[Refractory cytopenia with multilineage dysplasia]] (RCMD)
| Includes the subset Refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS). Revised to MDS with LB.
|-
| [[Refractory anemia with excess blasts]] I and II
| RAEB was divided into RAEB-I (5–9% blasts) and RAEB-II (10–19%) blasts, which has a poorer prognosis than RAEB-I.
Revised to MDS with IB1 and MDS with IB2.
(Increased Blasts)
|-
| [[5q- syndrome]]
| Typically seen in older women with normal or high platelet counts and isolated deletions of the long arm of chromosome 5 in bone marrow cells.
|-
|Myelodysplasia unclassifiable
| Seen in those cases of megakaryocyte dysplasia with fibrosis and others. 
|-
|[[Refractory cytopenia of childhood]] (dysplasia in childhood)
| –
|}

==== MDS with single lineage dysplasia ====
MDS may present with isolated neutropenia or thrombocytopenia without anemia and with dysplastic changes confined to a single lineage. This is called MDS-Low Blasts in the WHO 5th ed.<ref name=Hasserjian23 />

==== MDS with increased blood counts ====
Patients with MDS occasionally present with [[leukocytosis]] or [[thrombocytosis]] instead of the usual cytopenia.  This may represent overlap syndromes with [[myeloproliferative]] neoplasms.<ref name=Hasserjian23 />

==== MDS unclassifiable ====
Most cases of unclassifiable MDS from the 2008 WHO version would be considered Clonal Cytopenias of Undetermined Significance (CCUS) by the WHO 5th ed.<ref name=Hasserjian23 /> CCUS is defined<ref>{{cite journal |vauthors=DeZern AE, Malcovati L, Ebert BL |title=CHIP, CCUS, and Other Acronyms: Definition, Implications, and Impact on Practice |journal=Am Soc Clin Oncol Educ Book |volume=39 |issue= 39|pages=400–410 |date=January 2019 |pmid=31099654 |doi=10.1200/EDBK_239083 }}</ref> as:
* One or more somatic mutations otherwise found in patients with myeloid neoplasms detected in bone marrow or peripheral blood cells with an allele burden of ≥ 2%
* Persistent cytopenia (≥ 4 months) in one or more peripheral blood cell lineages
* Diagnostic criteria of myeloid neoplasm not fulfilled
* All other causes of cytopenia and molecular aberration excluded

====New categories in WHO 5th ed.====
Hypoplastic MDS, MDS with fibrosis, MDS with bi-allelic TP53 inactivation, and CCUS were added to the WHO 5th ed.<ref name=Hasserjian23 /> Another subtype called Myeloid neoplasms with germ line predisposition and organ dysfunction includes [[CEBPA]]/[[DDX41]]/[[RUNX1]] disorders, [[GATA2]] deficiency and [[SAMD9]]/9L syndromes.<ref name=Hall24 />

==Management==
The goals of therapy are to control symptoms, improve quality of life, improve overall survival, and decrease progression to AML.

The IPSS scoring system can help guide therapy for patients with MDS.<ref>{{cite journal | vauthors = Cutler CS, Lee SJ, Greenberg P, Deeg HJ, Pérez WS, Anasetti C, Bolwell BJ, Cairo MS, Gale RP, Klein JP, Lazarus HM, Liesveld JL, McCarthy PL, Milone GA, Rizzo JD, Schultz KR, Trigg ME, Keating A, Weisdorf DJ, Antin JH, Horowitz MM | title = A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome | journal = Blood | volume = 104 | issue = 2 | pages = 579–85 | date = July 2004 | pmid = 15039286 | doi = 10.1182/blood-2004-01-0338 | s2cid = 17907118 | doi-access = free }}</ref><ref name =Bernard22>{{cite journal |vauthors=Bernard E, Tuechler H, Greenberg PL, Hasserjian RP, Arango Ossa JE, Nannya Y, Devlin SM, Creignou M, Pinel P, Monnier L, Gundem G, Medina-Martinez JS, Domenico D, Jädersten M, Germing U, Sanz G, van de Loosdrecht AA, Kosmider O, Follo MY, Thol F, Zamora L, Pinheiro RF, Pellagatti A, Elias HK, Haase D, Ganster C, Ades L, Tobiasson M, Palomo L, Della Porta MG, Takaori-Kondo A, Ishikawa T, Chiba S, Kasahara S, Miyazaki Y, Viale A, Huberman K, Fenaux P, Belickova M, Savona MR, Klimek VM, Santos FP, Boultwood J, Kotsianidis I, Santini V, Solé F, Platzbecker U, Heuser M, Valent P, Ohyashiki K, Finelli C, Voso MT, Shih LY, Fontenay M, Jansen JH, Cervera J, Gattermann N, Ebert BL, Bejar R, Malcovati L, Cazzola M, Ogawa S, Hellström-Lindberg E, Papaemmanuil E |title=Molecular International Prognostic Scoring System for Myelodysplastic Syndromes |journal=NEJM Evid |volume=1 |issue=7 |article-number=EVIDoa2200008 |date=July 2022 |pmid=38319256 |doi=10.1056/EVIDoa2200008 }}</ref> In those with low risk MDS (designated by an IPSS score less than 3.5), no disease specific treatment has been found to be helpful and treatment is focused on supportive care by maintaining blood counts.<ref name="Sekeres 2022" /> Erythrostimulating agents such as [[darbepoetin alfa]] or [[erythropoietin]] may be used to raise the red blood cell count. The mean duration of response to erythrostimulating agents is 8-23 months, and the response rate is about 39% (with a response defined as a 1 mg/dL rise in the [[hemoglobin]] level or a person not requiring a transfusion).<ref name="Sekeres 2022" />

[[Romiplostim]] and [[eltrombopag]] are thrombopoietin receptor agonists which act on [[megakaryocytes]] (platelet precursor cells) to increase platelet production. They are used to increase platelet counts and have been shown to reduce the need for platelet transfusions.<ref name="Sekeres 2022" /> However, the two drugs increase the risk of progression to AML, so they are not used in MDS with excess blasts.<ref name="Sekeres 2022" />

For those with high risk MDS (characterized by an IPSS score greater than 3.5), the hypomethylating agent [[azacitidine]] showed increased survival compared to standard care (supportive care, [[cytarabine]] or chemotherapy) and is considered the standard of care.<ref name="Sekeres 2022" /><ref name="Fenaux 2009">{{cite journal |last1=Fenaux |first1=Pierre |last2=Mufti |first2=Ghulam J |last3=Hellstrom-Lindberg |first3=Eva |last4=Santini |first4=Valeria |last5=Finelli |first5=Carlo |last6=Giagounidis |first6=Aristoteles |last7=Schoch |first7=Robert |last8=Gattermann |first8=Norbert |last9=Sanz |first9=Guillermo |last10=List |first10=Alan |last11=Gore |first11=Steven D |last12=Seymour |first12=John F |last13=Bennett |first13=John M |last14=Byrd |first14=John |last15=Backstrom |first15=Jay |last16=Zimmerman |first16=Linda |last17=McKenzie |first17=David |last18=Beach |first18=Cl |last19=Silverman |first19=Lewis R |title=Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study |journal=The Lancet Oncology |date=March 2009 |volume=10 |issue=3 |pages=223–232 |doi=10.1016/S1470-2045(09)70003-8|pmid=19230772 |pmc=4086808 }}</ref> Azacitidine had increased survival (24 months vs 15 months) and higher rates of partial or complete therapeutic response (29% vs 12%) as compared to conventional care.<ref name="pmid28179280" /> The hypomethylating agent [[decitabine]] has shown a similar survival benefit to azacitidine and has a response rate as high as 43%.<ref name="Sekeres 2022" /><ref name="pmid17133405">{{cite journal | vauthors = Kantarjian HM, O'Brien S, Shan J, Aribi A, Garcia-Manero G, Jabbour E, Ravandi F, Cortes J, Davisson J, Issa JP | title = Update of the decitabine experience in higher risk myelodysplastic syndrome and analysis of prognostic factors associated with outcome | journal = Cancer | volume = 109 | issue = 2 | pages = 265–73 | date = January 2007 | pmid = 17133405 | doi = 10.1002/cncr.22376 | s2cid = 41205800 | doi-access = free }}</ref><ref name="pmid16532500">{{cite journal | vauthors = Kantarjian H, Issa JP, Rosenfeld CS, Bennett JM, Albitar M, DiPersio J, Klimek V, Slack J, de Castro C, Ravandi F, Helmer R, Shen L, Nimer SD, Leavitt R, Raza A, Saba H | title = Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study | journal = Cancer | volume = 106 | issue = 8 | pages = 1794–803 | date = April 2006 | pmid = 16532500 | doi = 10.1002/cncr.21792 | s2cid = 9556660 | doi-access = free }}</ref><ref name="pmid16882708">{{cite journal | vauthors = Kantarjian H, Oki Y, Garcia-Manero G, Huang X, O'Brien S, Cortes J, Faderl S, Bueso-Ramos C, Ravandi F, Estrov Z, Ferrajoli A, Wierda W, Shan J, Davis J, Giles F, Saba HI, Issa JP | title = Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia | journal = Blood | volume = 109 | issue = 1 | pages = 52–57 | date = January 2007 | pmid = 16882708 | doi = 10.1182/blood-2006-05-021162 | doi-access = free }}</ref> Decitabine is available in combination with cedazuridine as [[Decitabine/cedazuridine]] (Inqovi) is a fixed-dosed [[combination medication]] for the treatment of adults with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML).<ref name="Inqovi FDA PR">{{cite press release | title=FDA Approves New Therapy for Myelodysplastic Syndromes (MDS) That Can Be Taken at Home | website=U.S. [[Food and Drug Administration]] (FDA) | date=7 July 2020 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-new-therapy-myelodysplastic-syndromes-mds-can-be-taken-home | archive-url=https://web.archive.org/web/20200707205829/https://www.fda.gov/news-events/press-announcements/fda-approves-new-therapy-myelodysplastic-syndromes-mds-can-be-taken-home | archive-date=7 July 2020 | access-date=7 July 2020}} {{PD-notice}}</ref>

[[Lenalidomide]] is effective in reducing red blood cell transfusion requirement in patients with the chromosome 5q deletion subtype ([[5q- syndrome]]) of MDS, and the median duration of response is greater than 2 years.<ref name="pmid17021321">{{cite journal | vauthors = List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E, Powell B, Greenberg P, Thomas D, Stone R, Reeder C, Wride K, Patin J, Schmidt M, Zeldis J, Knight R | title = Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion | journal = The New England Journal of Medicine | volume = 355 | issue = 14 | pages = 1456–65 | date = October 2006 | pmid = 17021321 | doi = 10.1056/NEJMoa061292 | doi-access = free }}</ref><ref name="Sekeres 2022" />

[[Luspatercept]] is a [[TGFβ]] ligand that acts to decrease [[SMAD2]] and [[SMAD3]] signaling involved in [[erythropoeisis]] and may be used in MDS with anemia that is not responsive to erythrocyte-stimulating agents or mild MDS with ring sideroblasts. Luspatercept was shown to decrease the need for transfusions, and this effect lasted for a median of 30.6 weeks.<ref name="Fenaux 2020">{{cite journal |last1=Fenaux |first1=Pierre |last2=Platzbecker |first2=Uwe |last3=Mufti |first3=Ghulam J.|title=Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes |journal=New England Journal of Medicine |date=9 January 2020 |volume=382 |issue=2 |pages=140–151 |doi=10.1056/NEJMoa1908892|pmid=31914241 |hdl=2158/1193441 |hdl-access=free }}</ref><ref name="Sekeres 2022" /><ref>{{cite journal |vauthors=Hellström-Lindberg ES, Kröger N |title=Clinical decision-making and treatment of myelodysplastic syndromes |journal=Blood |volume=142 |issue=26 |pages=2268–81 |date=December 2023 |pmid=37874917 |doi=10.1182/blood.2023020079 }}</ref>

[[Human leukocyte antigen|HLA]]-matched [[allogeneic]] [[stem cell transplantation]], particularly in younger (i.e., less than 40 years of age) and more severely affected patients, offers the potential for curative therapy. The success of bone marrow transplantation has been found to correlate with severity of MDS as determined by the IPSS score, with patients having a more favorable IPSS score tend to have a more favorable outcome with transplantation.<ref>{{cite journal | vauthors = Oosterveld M, Wittebol SH, Lemmens WA, Kiemeney BA, Catik A, Muus P, Schattenberg AV, de Witte TJ | title = The impact of intensive antileukaemic treatment strategies on prognosis of myelodysplastic syndrome patients aged less than 61 years according to International Prognostic Scoring System risk groups | journal = British Journal of Haematology | volume = 123 | issue = 1 | pages = 81–89 | date = October 2003 | pmid = 14510946 | doi = 10.1046/j.1365-2141.2003.04544.x | s2cid = 24037285 | doi-access = free }}</ref>

===Iron levels===
Iron overload may develop in MDS as a result of repeated RBC [[transfusions]], which are a major part of the supportive care for anemic MDS patients. Although the specific therapies patients receive may obviate the need for RBC transfusion, many MDS patients may not respond to these treatments, and thus may develop secondary [[hemochromatosis]] due to iron overload from repeated transfusions.
Patients with chronic iron overload can have iron deposits in their liver, heart, and endocrine glands.{{Citation needed|date=October 2024}}

For patients requiring many transfusions, [[serum ferritin]] levels, the number of transfusions received, and associated organ dysfunction (heart, liver, and pancreas) should be monitored to determine iron levels. The goal is to maintain ferritin levels to {{nowrap|< 1000 µg/L}}.{{Citation needed|date=October 2024}} Currently, two iron [[Chelation|chelators]] are available in the US, [[deferoxamine]] for intravenous use and [[deferasirox]] for oral use. A third chelating agent is available, [[deferiprone]], but it has limited utility in MDS patients because of a major side effect of neutropenia.<ref name="Parisi 2021">{{cite journal |last1=Parisi |first1=Sarah |last2=Finelli |first2=Carlo |title=Prognostic Factors and Clinical Considerations for Iron Chelation Therapy in Myelodysplastic Syndrome Patients |journal=Journal of Blood Medicine |date=December 2021 |volume=12 |pages=1019–30 |doi=10.2147/JBM.S287876|doi-access=free |pmid=34887690 |pmc=8651046 }}</ref>

Reversal of some of the consequences of iron overload in MDS by iron [[chelation therapy]] has been shown. Iron overload not only leads to organ damage but also induces genomic instability and modifies the hematopoietic niche, favoring progression to acute leukemia. Chelation therapy should be considered to decrease iron overload in selected MDS patients.<ref name="Parisi 2021" /> Although deferasirox is generally well tolerated (other than episodes of gastrointestinal distress and kidney dysfunction), it is associated with a rare risk of [[kidney failure]] or liver failure. Due to these risks, close monitoring is required.{{citation needed|date=July 2020}}

==Prognosis==
The outlook in MDS is variable, with about 30% of patients progressing to refractory AML. Low-risk MDS (which is associated with favorable genetic variants, decreased myeloblastic cells [less than 5% blasts], less severe anemia, thrombocytopenia, or neutropenia or lower [[International Prognostic Scoring System]] scores) is associated with a life expectancy of 3–10 years. Whereas high-risk MDS is associated with a life expectancy of less than 3 years.<ref name="Sekeres 2022">{{cite journal |last1=Sekeres |first1=Mikkael A. |last2=Taylor |first2=Justin |title=Diagnosis and Treatment of Myelodysplastic Syndromes: A Review |journal=JAMA |date=6 September 2022 |volume=328 |issue=9 |pages=872–880 |doi=10.1001/jama.2022.14578|pmid=36066514 }}</ref>

Stem-cell transplantation offers a possible cure, with survival rates of 50% at 3 years, although older patients do poorly.<ref name="Harrison's">{{cite book|author1=Kasper, Dennis L |author2=Braunwald, Eugene |author3=Fauci, Anthony |title=Harrison's Principles of Internal Medicine |url=https://archive.org/details/harrisonsprincip00kasp |url-access=limited |edition=16th |publisher=McGraw-Hill|location=New York|year=2005|page=[https://archive.org/details/harrisonsprincip00kasp/page/n653 625] |isbn=978-0-07-139140-5|display-authors=etal}}</ref>

'''Indicators of a good prognosis''':
Younger age; normal or moderately reduced neutrophil or platelet counts; low blast counts in the bone marrow (<&nbsp;20%) and no blasts in the blood; no Auer rods; ringed sideroblasts; normal or mixed karyotypes without complex chromosome abnormalities; and ''in vitro'' marrow culture with a nonleukemic growth pattern

'''Indicators of a poor prognosis''':
Advanced age; severe neutropenia or thrombocytopenia; high blast count in the bone marrow (20–29%) or blasts in the blood;
Auer rods; absence of ringed sideroblasts; abnormal localization or immature granulocyte precursors in bone marrow section;
completely or mostly abnormal karyotypes, or complex marrow chromosome abnormalities and ''in vitro'' bone marrow culture with a leukemic growth pattern

'''Karyotype''' prognostic factors:
* Good: normal, -Y, del(5q), del(20q)
* Intermediate or variable: +8, other single or double anomalies
* Poor: complex (>3 chromosomal aberrations); chromosome 7 anomalies<ref name="pmid10691865">{{cite journal | vauthors = Solé F, Espinet B, Sanz GF, Cervera J, Calasanz MJ, Luño E, Prieto F, Granada I, Hernández JM, Cigudosa JC, Diez JL, Bureo E, Marqués ML, Arranz E, Ríos R, Martínez Climent JA, Vallespí T, Florensa L, Woessner S | title = Incidence, characterization and prognostic significance of chromosomal abnormalities in 640 patients with primary myelodysplastic syndromes. Grupo Cooperativo Español de Citogenética Hematológica | journal = British Journal of Haematology | volume = 108 | issue = 2 | pages = 346–56 | date = February 2000 | pmid = 10691865 | doi = 10.1046/j.1365-2141.2000.01868.x | s2cid = 10149222 }}</ref>

Cytogenetic abnormalities can be detected by conventional cytogenetics, a FISH panel for MDS, or [[virtual karyotype]].

The best prognosis is seen with RA and RARS, where some nontransplant patients live more than a decade (typical is on the order of three to five years, although long-term remission is possible if a bone-marrow transplant is successful). The worst outlook is with RAEB-T, where the mean life expectancy is less than one year. About one-quarter of patients develop overt leukemia. The others die of complications of low blood count or unrelated diseases. The International Prognostic Scoring System is the most commonly used tool for determining the prognosis of MDS, first published in ''Blood'' in 1997,<ref name="International scoring system for ev">{{cite journal | vauthors = Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J | title = International scoring system for evaluating prognosis in myelodysplastic syndromes | journal = Blood | volume = 89 | issue = 6 | pages = 2079–88 | date = March 1997 | pmid = 9058730 | doi = 10.1182/blood.V89.6.2079 | doi-access = free }}</ref> then revised to IPSS-R and IPSS-M.<ref name=Hasserjian23 />  This system takes into account the percentage of blasts in the marrow, cytogenetics, and number of cytopenias, as well as molecular features in the case of IPSS-M. Other prognostic tools include the 2007 WHO Prognostic Scoring System (WPSS), the MDA-LR (MD Anderson Lower-Risk MDS Prognostic Scoring System), EuroMDS, and the Cleveland Clinic Foundation/Munich Leukemia Laboratory scoring systems.<ref>{{cite journal |vauthors=DeZern AE, Greenberg PL |title=The trajectory of prognostication and risk stratification for patients with myelodysplastic syndromes |journal=Blood |volume=142 |issue=26 |pages=2258–67 |date=December 2023 |pmid=37562001 |doi=10.1182/blood.2023020081 }}</ref>

=== Genetic markers ===
The IPSS-M incorporates 31 somatic genes in its risk stratification model. IPSS-M determined that multihit TP53 mutations, FLT3 mutations, and partial tandem duplication mutations of KMT2A (MLL) were strong predictors of adverse outcomes. Some SF3B1 mutations were associated with favorable outcomes, whereas certain genetic subsets of SF3B1 mutations were not.<ref name=Hasserjian23 />  In low-risk MDS, ''IDH1'' and ''IDH2'' mutations are associated with worsened survival.<ref name=":0" />

==Epidemiology==
The exact number of people with MDS is not known because it can go undiagnosed, and no tracking of the syndrome is mandated. Some estimates are on the order of 10,000 to 20,000 new cases each year in the United States alone. The number of new cases each year is probably increasing as the average age of the population increases, and some authors propose that the number of new cases in those over 70 may be as high as 15 per 100,000 per year.<ref name="pmid11503953">{{cite journal | vauthors = Aul C, Giagounidis A, Germing U | title = Epidemiological features of myelodysplastic syndromes: results from regional cancer surveys and hospital-based statistics | journal = International Journal of Hematology | volume = 73 | issue = 4 | pages = 405–10 | date = June 2001 | pmid = 11503953 | doi = 10.1007/BF02994001 | s2cid = 24340387 }}</ref>

The typical age at diagnosis of MDS is between 60 and 75 years; a few people are younger than 50, and diagnoses are rare in children. Males are slightly more commonly affected than females.{{citation needed|date=November 2021}}

==History==
Since the early 20th century, some people with acute myelogenous leukemia have been recognized to have a preceding period of anemia and abnormal blood cell production. These conditions were grouped with other diseases under the term "refractory anemia".  The first description of "preleukemia" as a specific entity was published in 1953 by Block ''et al.''<ref>{{cite journal | vauthors = Block M, Jacobson LO, Bethard WF | title = Preleukemic acute human leukemia | journal = Journal of the American Medical Association | volume = 152 | issue = 11 | pages = 1018–28 | date = July 1953 | pmid = 13052490 | doi = 10.1001/jama.1953.03690110032010 }}</ref>  The early identification, characterization and classification of this disorder were problematical, and the syndrome went by many names until the 1976 FAB classification was published and popularized the term MDS.{{citation needed|date=July 2020}}

=== French-American-British (FAB) classification ===
In 1974 and 1975, a group of pathologists from France, the US, and Britain produced the first widely used classification of these diseases. This [[French-American-British classification]] was published in 1976,<ref name="pmid188440">{{cite journal | vauthors = Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C | title = Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group | journal = British Journal of Haematology | volume = 33 | issue = 4 | pages = 451–58 | date = August 1976 | pmid = 188440 | doi = 10.1111/j.1365-2141.1976.tb03563.x | s2cid = 9985915 }}</ref> and revised in 1982. It was used by pathologists and clinicians for almost 20 years. Cases were classified into five categories:

{| class="wikitable"
|-
! [[ICD-O]]
! Name
! Description
|-
| {{ICDO|9980|3}}
| [[Refractory anemia]] (RA)
| characterized by less than 5% primitive blood cells ([[myeloblasts]]) in the bone marrow and pathological abnormalities primarily seen in red cell precursors
|-
| {{ICDO|9982|3}}
| [[Refractory anemia with ring sideroblasts]] (RARS)
| also characterized by less than 5% myeloblasts in the bone marrow, but distinguished by the presence of 15% or greater of red cell precursors in the marrow, being abnormal iron-stuffed cells called "ringed sideroblasts"
|-
| {{ICDO|9983|3}}
| [[Refractory anemia with excess blasts]] (RAEB)
| characterized by 5–19% myeloblasts in the marrow
|-
| {{ICDO|9984|3}}
| [[Refractory anemia with excess blasts in transformation]] (RAEB-T)
| characterized by 5–19% myeloblasts in the marrow (>20% blasts is defined as [[acute myeloid leukemia]])
|-
| {{ICDO|9945|3}}
| [[Chronic myelomonocytic leukemia]] (CMML), not to be confused with [[chronic myelogenous leukemia]] or CML
| characterized by less than 20% myeloblasts in the bone marrow and greater than 1*10<sup>9</sup>/L [[monocytes]] (a type of white blood cell) circulating in the peripheral blood.
|}

(A table comparing these is available from the [[Cleveland Clinic]].<ref name="urlTable 1: French-American-British (FAB) Classification of MDS">{{cite web |url=http://www.clevelandclinicmeded.com/diseasemanagement/hematology/myelo/table1.htm |title=Table 1: French-American-British (FAB) Classification of MDS |url-status=live |archive-url=https://web.archive.org/web/20060117162808/http://www.clevelandclinicmeded.com/diseasemanagement/hematology/myelo/table1.htm |archive-date=2006-01-17 }}</ref>)

== People with MDS ==
* [[Michael Brecker]], musician<ref>{{cite web |date=14 January 2007 |title=Saxophonist Brecker dies from MDS |url=https://variety.com/2007/music/markets-festivals/saxophonist-brecker-dies-from-mds-1117957370/ |access-date=23 September 2018 |website=Variety}}</ref>
* [[Laurentino Cortizo]], the [[President of Panama]]<ref>{{cite news |date=2023-12-06 |title=Panama says President Cortizo still in remission from rare blood disorder |work=Reuters |url=https://www.reuters.com/world/americas/panama-says-president-cortizo-still-remission-rare-blood-disorder-2023-12-06/ |access-date=2023-12-06}}</ref>
* [[Roald Dahl]], writer<ref>{{cite web |url=http://www.findmypast.com/BirthsMarriagesDeaths.jsp |title=Deaths England and Wales 1984–2006 |publisher=Findmypast.com |access-date=28 January 2011 |archive-date=28 February 2009 |archive-url=https://web.archive.org/web/20090228000620/http://www.findmypast.com/BirthsMarriagesDeaths.jsp }}</ref>
* [[Nora Ephron]], journalist, writer, and filmmaker
* [[Pat Hingle]], actor<ref>{{cite web |last=Staff |first=JournalNow |title=Veteran actor Pat Hingle dies at 84 in NC home |url=https://www.journalnow.com/news/local/veteran-actor-pat-hingle-dies-at-in-nc-home/article_439f8c0e-92f1-51df-9b0f-2706a36dca84.html |website=Winston-Salem Journal|date=4 January 2009 }}</ref>
* [[Paul Motian]], musician<ref>{{cite news |last1=McClellan |first1=Dennis |date=November 24, 2011 |title=Paul Motian dies at 80; jazz drummer and composer |work=[[Los Angeles Times]] |url=https://www.latimes.com/local/obituaries/la-me-paul-motian-20111124-story.html |access-date=22 February 2020 |archive-url=https://web.archive.org/web/20160414022230/https://www.latimes.com/local/obituaries/la-me-paul-motian-20111124-story.html |archive-date=April 14, 2016}}</ref>
* [[Amrish Puri]], actor<ref>{{cite web |url=http://www.tribuneindia.com/2005/20050113/main4.htm |title=The Tribune, Chandigarh, India – Main News |publisher=Tribuneindia.com |access-date=21 June 2019 |archive-url=https://web.archive.org/web/20081211063823/http://www.tribuneindia.com/2005/20050113/main4.htm |archive-date=11 December 2008 |url-status=live }}</ref>
* [[Carl Sagan]], astrophysicist<ref>{{cite web |date=9 November 2012 |title=Remembering Carl Sagan |url=http://www.universetoday.com/98390/remembering-carl-sagan-2/ |url-status=live |archive-url=https://web.archive.org/web/20170312044306/http://www.universetoday.com/98390/remembering-carl-sagan-2/ |archive-date=12 March 2017 |access-date=10 March 2017 |website=Universe Today}}</ref>
* [[Susan Sontag]], author<ref>{{cite news |date=4 December 2005 |title=Illness as More Than Metaphor |website=The New York Times Magazine |url=https://www.nytimes.com/2005/12/04/magazine/illness-as-more-than-metaphor.html |access-date=18 December 2017}}</ref>
* [[Norm Macdonald]], comedian<ref>{{Cite news |last=Edgers |first=Geoff |date=2022-05-29 |title=Norm Macdonald had one last secret |url=https://www.washingtonpost.com/arts-entertainment/2022/05/29/norm-macdonald-nothing-special-netflix/ |access-date=2025-05-19 |newspaper=The Washington Post |language=en-US}}</ref>

== References ==
{{reflist}}

== External links ==
{{Commons category|Myelodysplastic syndrome}}
* {{Cite journal |vauthors=Fenaux P, Haase D, Sanz GF, Santini V, Buske C |title=Myelodysplastic syndromes: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up |journal=Ann Oncol |volume=25 |issue=Suppl 3|pages=III57–III69 |date=September 2014 |pmid=25185242 |doi=10.1093/annonc/mdu180 |hdl=2158/1078046 |hdl-access=free }}

{{Medical resources
| eMedicine_mult  = {{eMedicine2|ped|1527}}
| DiseasesDB      = 8604
| ICD10           = {{ICD10|D|46||d|37}}
| ICD9            = {{ICD9|238.7}}
| ICDO            = 9980/0-{{ICDO|9989|3}}
| OMIM            =
| MedlinePlus     =
| eMedicineSubj   = med
| eMedicineTopic  = 2695
| MeshID          = D009190
| Orphanet        = 52688
| SNOMED CT       = 109995007
}}
{{Myeloid malignancy|us=y}}
{{Portal bar | Medicine}}
{{Authority control}}

{{DEFAULTSORT:Myelodysplastic Syndrome}}
[[Category:Myeloid neoplasia]]
[[Category:Syndromes affecting blood]]
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