| Myelodysplastic syndrome | |
|---|---|
| Other names | Preleukemia, myelodysplasia[1][2] |
 | |
| Blood smear from a person with myelodysplastic syndrome. A hypogranularneutrophil with apseudo-Pelger-Huet nucleus is shown. There are alsoabnormally shaped red blood cells, in part related to removal of thespleen. | |
| Specialty | Hematology,oncology |
| Symptoms | None,feeling tired,shortness of breath, easybleeding, frequentinfections[3] |
| Risk factors | Previouschemotherapy,radiation therapy, certain chemicals such astobacco smoke,pesticides, andbenzene, exposure tomercury orlead[3] |
| Diagnostic method | Blood test,bone marrow biopsy[3] |
| Treatment | Supportive care, medications,stem cell transplantation[3] |
| Medication | Lenalidomide,antithymocyte globulin,azacitidine[3] |
| Prognosis | Typical survival time 2.5 years[3] |
Amyelodysplastic syndrome (MDS) is one of a group ofcancers in whichblood cells in thebone marrow do not mature, and as a result, do not develop into healthy blood cells.[3] Early on, no symptoms are typically seen.[3] Later, symptoms may includefatigue,shortness of breath,bleeding disorders,anemia, or frequentinfections.[3] Some types may develop intoacute myeloid leukemia.[3]
Risk factors include previouschemotherapy orradiation therapy, exposure to certain chemicals such astobacco smoke,pesticides, andbenzene, and exposure to heavy metals such asmercury orlead.[3] Problems with blood cell formation result in some combination of lowred blood cell,platelet, andwhite blood cell counts.[3] Some types of MDS cause an increase in the production of immature blood cells (calledblasts), in the bone marrow orblood.[3] The different types of MDS are identified based on the specific characteristics of the changes in the blood cells and bone marrow.[3]
Treatments may includesupportive care, drug therapy, andhematopoietic stem cell transplantation.[3] Supportive care may includeblood transfusions,medications to increase the making of red blood cells, andantibiotics.[3] Drug therapy may include the medicationslenalidomide,antithymocyte globulin, andazacitidine.[3] Some people can be cured bychemotherapy followed by a stem-cell transplant from a donor.[3]
About seven per 100,000 people are affected by MDS; about four per 100,000 people newly acquire the condition each year.[4] The typical age of onset is 70 years.[4] The prognosis depends on the type of cells affected, the number of blasts in the bone marrow or blood, and the changes present in thechromosomes of the affected cells.[3] The average survival time following diagnosis is 2.5 years.[4] MDS was first recognized in the early 1900s;[5] it came to be called myelodysplastic syndrome in 1976.[5]
Signs and symptoms are nonspecific and generally related to the blood cytopenias:
Many individuals are asymptomatic, and blood cytopenia or other problems are identified as a part of a routine blood count:[10]
Patients with MDS have an overall risk of almost 30% for developingacute myelogenous leukemia.[11]
Anemia dominates the early course. Most symptomatic patients complain of the gradual onset of fatigue and weakness,dyspnea, andpallor, 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.[12]
Some people have a history of exposure to chemotherapy (especially alkylating agents such asmelphalan,cyclophosphamide,busulfan, andchlorambucil) orradiation (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 andbenzene exposures have been associated with myelodysplasia.Vietnam veterans exposed toAgent Orange are at risk of developing MDS.[13] 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).[14] Children withDown syndrome are susceptible to MDS, and a family history may indicate a hereditary form ofsideroblastic anemia orFanconi anemia.[15]GATA2 deficiency andSAMD9/9L syndromes each account for about 15% of MDS cases in children.[16]
MDS most often develops without an identifiable cause. Risk factors include exposure to an agent known to cause DNA damage, such asradiation, 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 latetoxicity of cancer therapy (therapy-associated MDS, t-MDS). MDS after exposure to radiation oralkylating agents such as busulfan,nitrosourea, orprocarbazine, typically occurs 3–7 years after exposure and frequently demonstrates loss of chromosome 5 or 7. MDS after exposure toDNA 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 asacquired aplastic anemia following immunosuppressive treatment andFanconi anemia, can evolve into MDS.[15]
MDS is thought to arise frommutations in themultipotent bone-marrow stem cell, but the specific defects responsible for these diseases remain poorly understood.Differentiation of blood precursor cells is impaired, and a significant increase in levels ofapoptotic 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-marrowmyeloblasts rises over a particular cutoff (20% forWHO and 30% forFAB), then transformation toacute myelogenous leukemia (AML) is said to have occurred. The progression of MDS to AML is a good example of themultistep theory of carcinogenesis in which a series of mutations occurs in an initially normal cell and transforms it into acancer cell.[17]
Although recognition of leukemic transformation was historically important (seeHistory), a significant proportion of themorbidity andmortality attributable to MDS results not from transformation to AML, but rather from the cytopenias seen in all MDS patients. While anemia is the most commoncytopenia in MDS patients, given the ready availability ofblood 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 toiron overload.[18]
The recognition ofepigenetic changes inDNA structure in MDS has explained the success of two (namely the hypomethylating agents5-azacytidine anddecitabine) of three (the third islenalidomide) commercially available medications approved by theU.S. Food and Drug Administration to treat MDS. ProperDNA 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 approvedDNA methyltransferase inhibitors take advantage of this mechanism by creating a more orderly DNA methylation profile in thehematopoietic stem cellnucleus, thereby restoring normal blood counts and retarding the progression of MDS toacute leukemia.[19]
Some authors have proposed that the loss ofmitochondrial 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 mitochondrialiron deposits in theringed sideroblast as evidence of mitochondrial dysfunction in MDS.[20]
Hematopoietic stem cell aging is thought to be associated with the accrual of multiple genetic andepigenetic aberrations leading to the suggestion that MDS is, in part, related to an inability to adequately cope withDNA damage.[21] An emerging perspective is that the underlying mechanism of MDS could be a defect in one or more pathways that are involved inrepairing damaged DNA.[22] In MDS an increased frequency ofchromosomal breaks indicates defects in DNA repair processes.[23] Also, elevated levels of8-oxoguanine were found in the DNA of a significant proportion of MDS patients, indicating that thebase excision repair pathway that is involved in handling oxidative DNA damages may be defective in these cases.[23]
Since at least 1974, the deletion in the long arm ofchromosome 5 has been known to be associated with dysplastic abnormalities of hematopoietic stem cells.[24][25] By 2005,lenalidomide, achemotherapy drug, was recognized to be effective in MDS patients with the5q- syndrome,[26] and in December 2005, the US FDA approved the drug for this indication. Patients with isolated 5q-, lowIPSS 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]
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 morering sideroblasts.[27]
Mutations in the genes encoding forisocitrate dehydrogenase 1 and 2 (IDH1 andIDH2) occur in 10–20% of patients with myelodysplastic syndrome,[28] and confer a worsened prognosis in low-risk MDS.[29] Because the incidence ofIDH1/2 mutations increases as the disease malignancy increases, these findings together suggest thatIDH1/2 mutations are important drivers of progression of MDS to a more malignant disease state.[29]
GATA2 deficiency is a group of disorders caused by a defect, familial, or sporadicinactivating mutations, in one of the twoGATA2genes. Theseautosomal dominant mutations cause a reduction in the cellular levels of the gene's product, GATA2. The GATA2protein is atranscription factor critical for theembryonic development, maintenance, and functionality ofblood-forming,lymph-forming, and other tissue-formingstem cells. 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.[30][31]
Transient myeloproliferative disease, renamed Transient Abnormal Myelopoiesis (TAM),[32] is the abnormal proliferation of aclone of noncancerousmegakaryoblasts 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 toacute megakaryoblastic leukemia.[33][30][34]
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.[35] 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.[36]
A typical diagnostic investigation includes:
The features generally used to define an MDS are blood cytopenias, ineffective hematopoiesis,dyserythropoiesis, dysgranulopoiesis, dysmegakaropoiesis, and increased myeloblasts.[citation needed]
Dysplasia can affect all three lineages seen in the bone marrow. The best way to diagnose dysplasia is by morphology and special stains(PAS) used on the bone marrow aspirate and peripheral blood smear. Dysplasia in the myeloid series is defined by:
On the bone-marrow biopsy, high-grade dysplasia (RAEB-I and RAEB-II) may showatypical 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 thetrabeculae or surroundingarterioles. 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 (RA and RARS), where normoblasts are seen next to bony trabeculae instead of forming normal interstitially placederythroid islands.[citation needed]
In the late 1990s, a group of pathologists and clinicians working under theWorld 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)[41] systems are both actively in use.[11]
The list of dysplastic syndromes under the 2008 WHO system included the following:
| Myelodysplastic syndrome | Description and WHO 5th ed. counterparts |
|---|---|
| Refractorycytopenia with unilineage dysplasia | Refractory anemia,Refractory neutropenia, andRefractory 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 andSF3B1 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 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.[11]
Patients with MDS occasionally present withleukocytosis orthrombocytosis instead of the usual cytopenia. This may represent overlap syndromes withmyeloproliferative neoplasms.[11]
Most cases of unclassifiable MDS from the 2008 WHO version would be considered Clonal Cytopenias of Undetermined Significance (CCUS) by the WHO 5th ed.[11] CCUS is defined[42] as:
Hypoplastic MDS, MDS with fibrosis, MDS with bi-allelic TP53 inactivation, and CCUS were added to the WHO 5th ed.[11] Another subtype called Myeloid neoplasms with germ line predisposition and organ dysfunction includesCEBPA/DDX41/RUNX1 disorders,GATA2 deficiency andSAMD9/9L syndromes.[16]
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.[43][44] 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.[36] Erythrostimulating agents such asdarbepoetin alfa orerythropoietin 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 thehemoglobin level or a person not requiring a transfusion).[36]
Romiplostim andeltrombopag are thrombopoietin receptor agonists which act onmegakaryocytes (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.[36] However, the two drugs increase the risk of progression to AML, so they are not used in MDS with excess blasts.[36]
For those with high risk MDS (characterized by an IPSS score greater than 3.5), the hypomethylating agentazacitidine showed increased survival compared to standard care (supportive care,cytarabine or chemotherapy) and is considered the standard of care.[36][45] 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.[30] The hypomethylating agentdecitabine has shown a similar survival benefit to azacitidine and has a response rate as high as 43%.[36][46][47][48] Decitabine is available in combination with cedazuridine asDecitabine/cedazuridine (Inqovi) is a fixed-dosedcombination medication for the treatment of adults with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML).[49]
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.[50][36]
Luspatercept is aTGFβ ligand that acts to decreaseSMAD2 andSMAD3 signaling involved inerythropoeisis 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.[51][36][52]
HLA-matchedallogeneicstem 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.[53]
Iron overload may develop in MDS as a result of repeated RBCtransfusions, 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 secondaryhemochromatosis 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]
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< 1000 µg/L.[citation needed] Currently, two ironchelators are available in the US,deferoxamine for intravenous use anddeferasirox 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.[54]
Reversal of some of the consequences of iron overload in MDS by ironchelation 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.[54] Although deferasirox is generally well tolerated (other than episodes of gastrointestinal distress and kidney dysfunction), it is associated with a rare risk ofkidney failure or liver failure. Due to these risks, close monitoring is required.[citation needed]
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 lowerInternational 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.[36]
Stem-cell transplantation offers a possible cure, with survival rates of 50% at 3 years, although older patients do poorly.[55]
Indicators of a good prognosis:Younger age; normal or moderately reduced neutrophil or platelet counts; low blast counts in the bone marrow (< 20%) and no blasts in the blood; no Auer rods; ringed sideroblasts; normal or mixed karyotypes without complex chromosome abnormalities; andin 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 andin vitro bone marrow culture with a leukemic growth pattern
Karyotype prognostic factors:
Cytogenetic abnormalities can be detected by conventional cytogenetics, a FISH panel for MDS, orvirtual 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 inBlood in 1997,[57] then revised to IPSS-R and IPSS-M.[11] 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.[58]
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.[11] In low-risk MDS,IDH1 andIDH2 mutations are associated with worsened survival.[29]
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.[59]
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]
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 Blocket al.[60] 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]
In 1974 and 1975, a group of pathologists from France, the US, and Britain produced the first widely used classification of these diseases. ThisFrench-American-British classification was published in 1976,[61] and revised in 1982. It was used by pathologists and clinicians for almost 20 years. Cases were classified into five categories:
| ICD-O | Name | Description |
|---|---|---|
| M9980/3 | 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 |
| M9982/3 | 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" |
| M9983/3 | Refractory anemia with excess blasts (RAEB) | characterized by 5–19% myeloblasts in the marrow |
| M9984/3 | Refractory anemia with excess blasts in transformation (RAEB-T) | characterized by 5–19% myeloblasts in the marrow (>20% blasts is defined asacute myeloid leukemia) |
| M9945/3 | Chronic myelomonocytic leukemia (CMML), not to be confused withchronic myelogenous leukemia or CML | characterized by less than 20% myeloblasts in the bone marrow and greater than 1*109/Lmonocytes (a type of white blood cell) circulating in the peripheral blood. |
(A table comparing these is available from theCleveland Clinic.[62])
This article incorporates text from this source, which is in thepublic domain.
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