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Myelodysplastic syndrome
Myelodysplastic syndrome
Myelodysplastic syndrome
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Myelodysplastic syndrome
Other namesPreleukemia, myelodysplasia[1][2]
Blood smear from a person with myelodysplastic syndrome. A hypogranular neutrophil with a pseudo-Pelger-Huet nucleus is shown. There are also abnormally shaped red blood cells, in part related to removal of the spleen.
SpecialtyHematology, oncology
SymptomsNone, feeling tired, shortness of breath, easy bleeding, frequent infections[3]
Risk factorsPrevious chemotherapy, radiation therapy, certain chemicals such as tobacco smoke, pesticides, and benzene, exposure to mercury or lead[3]
Diagnostic methodBlood test, bone marrow biopsy[3]
TreatmentSupportive care, medications, stem cell transplantation[3]
MedicationLenalidomide, antithymocyte globulin, azacitidine[3]
PrognosisTypical survival time 2.5 years[3]

A myelodysplastic syndrome (MDS) is one of a group of cancers in which blood cells in the bone 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 include fatigue, shortness of breath, bleeding disorders, anemia, or frequent infections.[3] Some types may develop into acute myeloid leukemia.[3]

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 or lead.[3] Problems with blood cell formation result in some combination of low red blood cell, platelet, and white blood cell counts.[3] Some types of MDS cause an increase in the production of immature blood cells (called blasts), in the bone marrow or blood.[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 include supportive care, drug therapy, and hematopoietic stem cell transplantation.[3] Supportive care may include blood transfusions, medications to increase the making of red blood cells, and antibiotics.[3] Drug therapy may include the medications lenalidomide, antithymocyte globulin, and azacitidine.[3] Some people can be cured by chemotherapy 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 the chromosomes 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

[edit]
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:

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 developing acute myelogenous leukemia.[11]

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.[12]

Cause

[edit]

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 veterans exposed to Agent 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 with Down syndrome are susceptible to MDS, and a family history may indicate a hereditary form of sideroblastic anemia or Fanconi anemia.[15] GATA2 deficiency and SAMD9/9L syndromes each account for about 15% of MDS cases in children.[16]

Pathophysiology

[edit]

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 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.[15]

MDS is thought to arise from mutations in the multipotent 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 of 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 myeloblasts rises over a particular cutoff (20% for WHO and 30% for 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 multistep theory of carcinogenesis in which a series of mutations occurs in an initially normal cell and transforms it into a cancer cell.[17]

Although recognition of leukemic transformation was historically important (see History), a significant proportion of the morbidity and 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.[18]

Genetics

[edit]

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 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 inhibitors take advantage of this mechanism by creating a more orderly DNA methylation profile in the hematopoietic stem cell nucleus, thereby restoring normal blood counts and retarding the progression of MDS to acute leukemia.[19]

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.[20]

DNA damage

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Hematopoietic stem cell aging is thought to be associated with the accrual of multiple genetic and epigenetic aberrations leading to the suggestion that MDS is, in part, related to an inability to adequately cope with DNA damage.[21] An emerging perspective is that the underlying mechanism of MDS could be a defect in one or more pathways that are involved in repairing damaged DNA.[22] In MDS an increased frequency of chromosomal breaks indicates defects in DNA repair processes.[23] 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.[23]

5q- syndrome

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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.[24][25] By 2005, lenalidomide, a chemotherapy drug, was recognized to be effective in MDS patients with the 5q- syndrome,[26] and in December 2005, the US FDA approved the drug for this indication. Patients with isolated 5q-, low 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]

Splicing factor mutations

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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.[27]

IDH1 and IDH2 mutations

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Mutations in the genes encoding for isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) occur in 10–20% of patients with myelodysplastic syndrome,[28] and confer a worsened prognosis in low-risk MDS.[29] 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.[29]

GATA2 deficiency

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GATA2 deficiency is a group of disorders caused by a defect, familial, or sporadic inactivating mutations, in one of the two GATA2 genes. 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 embryonic development, maintenance, and functionality of blood-forming, lymph-forming, and other tissue-forming stem 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

[edit]

Transient myeloproliferative disease, renamed Transient Abnormal Myelopoiesis (TAM),[32] is the abnormal proliferation of a clone of noncancerous megakaryoblasts 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.[33][30][34]

Diagnosis

[edit]

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 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 trabeculae or surrounding arterioles. 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 placed erythroid islands.[citation needed]

Classification

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World Health Organization and International Consensus Classification

[edit]

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)[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
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

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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]

MDS with increased blood counts

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Patients with MDS occasionally present with leukocytosis or thrombocytosis instead of the usual cytopenia. This may represent overlap syndromes with myeloproliferative neoplasms.[11]

MDS unclassifiable

[edit]

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:

  • 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.

[edit]

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 includes CEBPA/DDX41/RUNX1 disorders, GATA2 deficiency and SAMD9/9L syndromes.[16]

Management

[edit]

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 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).[36]

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.[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 agent azacitidine 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 agent decitabine 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 as Decitabine/cedazuridine (Inqovi) is a fixed-dosed combination 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 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.[51][36][52]

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.[53]

Iron levels

[edit]

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]

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 iron 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.[54]

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.[54] 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]

Prognosis

[edit]

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.[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; 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[56]

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,[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]

Genetic markers

[edit]

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 and IDH2 mutations are associated with worsened survival.[29]

Epidemiology

[edit]

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]

History

[edit]

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.[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]

French-American-British (FAB) classification

[edit]

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,[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 as acute myeloid leukemia)
M9945/3 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*109/L monocytes (a type of white blood cell) circulating in the peripheral blood.

(A table comparing these is available from the Cleveland Clinic.[62])

People with MDS

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References

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[edit]
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Myelodysplastic syndrome

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from Grokipedia
Myelodysplastic syndromes (MDS) are a group of clonal disorders characterized by ineffective hematopoiesis, resulting in peripheral blood cytopenias and dysplastic changes in one or more myeloid cell lines within the . These myeloid malignancies primarily affect older adults, with an incidence of approximately 4–5 cases per 100,000 people annually in the United States, rising to approximately 25–30 per 100,000 among those aged 65 and older (as of 2023), and a estimated at 60,000–170,000 individuals. MDS encompasses several subtypes as defined by the 2022 (WHO) and International Consensus (ICC) classifications, and about 30% of cases may progress to (AML). Common symptoms of MDS arise from the resulting low blood cell counts and include fatigue, weakness, and shortness of breath due to anemia; easy bruising, prolonged bleeding, or petechiae from thrombocytopenia; and recurrent infections from neutropenia. Many patients are asymptomatic at diagnosis, with cytopenias detected incidentally through routine blood tests, though symptoms often develop as the disease progresses. The of MDS is multifactorial, with the majority of cases idiopathic, though prior exposure to , , or environmental toxins such as increases risk. Genetic in hematopoietic stem cells, including those in genes like TP53, DNMT3A, and ASXL1, drive the clonal expansion and impaired differentiation observed in MDS. typically involves analysis, peripheral blood smear, , and cytogenetic testing to assess , blast percentage, and chromosomal abnormalities for risk stratification using systems like the Revised International Prognostic Scoring System (IPSS-R). Treatment strategies for MDS are tailored to risk level and symptoms, focusing on supportive care such as blood transfusions and growth factors for lower-risk patients, while higher-risk cases may involve hypomethylating agents like azacitidine or decitabine, lenalidomide for specific subtypes, or allogeneic hematopoietic stem cell transplantation as the only potentially curative option. Prognosis varies widely, with median survival ranging from months in high-risk disease to over 5 years in low-risk cases, influenced by factors like cytogenetics, blast count, and cytopenias. Ongoing research emphasizes targeted therapies and clinical trials to improve outcomes for this heterogeneous group of disorders.

Clinical Features

Signs and Symptoms

Myelodysplastic syndrome (MDS) often presents with symptoms arising from peripheral cytopenias, which result from ineffective hematopoiesis in the . Many are asymptomatic in the early stages and are diagnosed incidentally during routine tests, such as complete blood counts performed for unrelated reasons. Anemia, the most common cytopenia in MDS, leads to , weakness, , and due to reduced oxygen-carrying capacity of the . manifests as easy bruising, petechiae (small red or purple spots on the skin caused by minor bleeding), and increased bleeding tendencies, including epistaxis (nosebleeds) or gingival bleeding. Neutropenia predisposes patients to recurrent infections, fever, and a heightened risk of , often presenting as frequent or prolonged episodes of illness such as or urinary tract infections. Less common findings include splenomegaly, which occurs in approximately 5–15% of patients with pure MDS and is enriched for adverse mutations such as ASXL1, RUNX1, and EZH2; it suggests marrow stress or fibrosis with extramedullary hematopoiesis and is more typical of MDS/MPN overlap syndromes or primary myelofibrosis. Less common symptoms include unexplained , which may occur in more advanced cases.

Complications

One of the most significant complications of myelodysplastic syndrome (MDS) is its potential progression to (AML), occurring in approximately 30% of cases overall, with rates reaching up to 40% in higher-risk subtypes characterized by increased blasts or adverse cytogenetic features. This transformation typically arises from the accumulation of genetic mutations in hematopoietic stem cells, leading to a more aggressive clonal expansion. Chronic and in MDS often necessitate repeated transfusions, resulting in that can deposit in vital organs such as the heart, liver, and endocrine glands, causing , , , and . This secondary hemochromatosis exacerbates morbidity and mortality, particularly in transfusion-dependent patients without . Persistent predisposes MDS patients to severe bacterial, fungal, and viral infections, which account for a substantial portion of non-leukemic deaths due to impaired immune function and mucosal barriers. Common sites include the lungs, skin, and , with chronic low-grade amplifying the risk of and multi-organ failure. Thrombocytopenia can lead to bleeding complications ranging from mucocutaneous petechiae to life-threatening hemorrhages in critical areas like the gastrointestinal tract, central nervous system, or retina, affecting up to 10% of patients severely. These events are often exacerbated by concurrent platelet dysfunction, increasing the likelihood of spontaneous or trauma-induced bleeding in vital organs. Less commonly, MDS is associated with autoimmune phenomena, such as , , or , occurring in 10-20% of cases and potentially driven by dysregulated immune responses to clonal hematopoiesis. Additionally, there is an elevated risk of secondary solid tumors, including , , and cancers, linked to shared genetic predispositions or prior exposures, though the absolute incidence remains low compared to hematologic progression.

Etiology and Risk Factors

Causes

Myelodysplastic syndrome (MDS) is idiopathic in the majority of cases, with no identifiable cause despite extensive evaluation. A significant proportion of MDS cases, approximately 10-20%, arise as therapy-related MDS (t-MDS) following prior exposure to or for other malignancies. Alkylating agents, such as , are commonly implicated in t-MDS, typically manifesting 5-7 years after exposure and often associated with complex cytogenetic abnormalities. II inhibitors, including and , also contribute to t-MDS , frequently leading to balanced translocations like 11q23 rearrangements. Environmental and occupational exposures represent another established causal pathway for MDS. , a found in industrial settings, has been directly linked to MDS development through its genotoxic effects on hematopoietic stem cells. Similarly, prolonged contact with pesticides, fertilizers, or such as mercury and lead increases MDS risk, particularly in agricultural or manufacturing workers. Certain inherited genetic predisposition syndromes confer susceptibility to MDS. , characterized by DNA repair defects, heightens the lifetime risk of developing MDS due to genomic instability in progenitors. (trisomy 21) is another well-documented predisposition, where the extra disrupts normal hematopoiesis and predisposes individuals to transient myeloproliferative disorders that can evolve into MDS. Iatrogenic causes, beyond cytotoxic therapies, include prolonged use of immunosuppressive agents such as , which has been associated with MDS emergence through induction of chromosomal aberrations in hematopoietic cells.

Risk Factors

Advanced age is the most significant demographic risk factor for myelodysplastic syndrome (MDS), with approximately 86% of cases occurring in individuals aged 60 years or older. The median age at is typically in the 70s, reflecting the disease's strong association with aging dysfunction. MDS also exhibits a male predominance, with a male-to-female ratio of approximately 1.5:1, potentially influenced by higher rates of exposure to risk factors such as among men. Among modifiable factors, cigarette has been consistently linked to increased MDS risk, with meta-analyses showing an of about 1.45 for ever-smokers compared to non-smokers, attributed to carcinogenic compounds in that damage hematopoietic stem cells. Evidence regarding alcohol consumption is mixed; some studies suggest a dose-dependent increase in risk, while others, including larger cohort analyses, find no significant association or even a potential protective effect from moderate intake. Prior hematologic disorders elevate MDS susceptibility, particularly in cases where evolves into clonal hematopoiesis; up to 15% of acquired patients may progress to MDS within 10 years due to shared pathogenic mechanisms involving immune dysregulation and genetic instability. Familial history plays a role in rare hereditary forms of MDS, often linked to mutations in genes such as , which predispose affected families to MDS or through and impaired hematopoiesis. Chemical exposures, such as to , represent additional environmental risks that may contribute to MDS development.

Pathophysiology

Dysplasia and Ineffective Hematopoiesis

Myelodysplastic syndromes (MDS) are characterized by morphologic in precursors across one or more myeloid lineages, reflecting abnormal cellular maturation and differentiation. In the erythroid lineage, megaloblastoid changes manifest as enlarged, immature-appearing erythroblasts with asynchronous nuclear and cytoplasmic development, contributing to defective production. Dysgranulopoiesis often includes the pseudo-Pelger-Huët anomaly, where neutrophils exhibit hyposegmented, bilobed nuclei and hypogranular , impairing their functionality. Ring sideroblasts, a hallmark of certain MDS subtypes, appear as erythroid precursors with iron-laden mitochondria encircling at least one-third of the nucleus, detectable by staining and indicative of mitochondrial dysfunction in synthesis. These dysplastic features arise from intrinsic defects in hematopoietic progenitors, leading to multilineage involvement in many cases. A central mechanism in MDS pathophysiology is ineffective hematopoiesis, particularly ineffective , where erythroid progenitors undergo accelerated intramedullary , resulting in reduced mature cell output despite initial proliferation. This is mediated by upregulated death receptors such as Fas and TRAIL, as well as pro-inflammatory cytokines like TNF-α, predominantly in low-risk MDS, causing premature cell death within the . is similarly impaired, with dysplastic neutrophils showing reduced maturation and survival, while megakaryopoiesis features micromegakaryocytes—small, hypolobated cells with abnormal nuclear features—that fail to produce adequate platelets. These processes collectively disrupt normal production, exacerbated by clonal expansion of mutated hematopoietic stem cells that outcompete and displace healthy progenitors, further suppressing effective hematopoiesis. Despite these defects, the in MDS is typically hypercellular or normocellular, reflecting compensatory proliferation of abnormal clones that paradoxically leads to peripheral blood cytopenias, including , , and . This discordance between marrow cellularity and peripheral counts underscores the inefficiency of the dysplastic process, where increased progenitor turnover fails to yield functional cells due to ongoing and maturation blocks. Genetic alterations in stem cells drive this clonal dominance, but the phenotypic and functional impairments remain the proximate causes of cytopenias.

Molecular and Genetic Alterations

Myelodysplastic syndrome (MDS) is characterized by a heterogeneous array of molecular and genetic alterations that disrupt normal hematopoiesis and contribute to disease progression. These changes include both cytogenetic abnormalities and somatic mutations in key genes involved in , epigenetic regulation, and other cellular processes. Approximately 50% of MDS cases harbor chromosomal abnormalities at , which often correlate with clinical outcomes. Common chromosomal alterations in MDS include deletions of the long arm of (del(5q)), 7 (-7), and complex karyotypes defined as three or more independent abnormalities. Del(5q) occurs in about 10% of cases, frequently as an isolated anomaly or with limited additional changes, and is associated with a distinct subtype featuring and thrombocytosis. 7 or del(7q) is seen in roughly 10% of patients and is linked to more aggressive disease, often occurring in younger individuals and conferring a higher risk of leukemic transformation. Complex karyotypes, present in 10-15% of MDS cases, are particularly adverse, especially when combined with specific , and are found in up to 91% of high-risk subgroups. Somatic in splicing factor genes are among the most frequent molecular events in MDS, affecting up to 50% of patients and leading to aberrant processing that impairs hematopoietic differentiation. The SF3B1 gene, mutated in 20-30% of cases, is the most common, with over 90% of these occurring in patients with ring sideroblasts—abnormal erythroid precursors containing iron-laden mitochondria. SF3B1 alterations typically define a lower-risk subtype with indolent progression and favorable survival, though co-occurring can modify this . Other splicing factors like SRSF2, U2AF1, and ZRSR2 are mutated in 10-15% of cases combined, often associating with multilineage . Mutations in the TP53 occur in 10-20% of MDS patients and are strongly tied to therapy resistance and dismal outcomes, with median survival often under one year in affected cases. These alterations, particularly biallelic or "multi-hit" variants (e.g., high variant allele frequency >50% or combined with loss of the wild-type allele), are enriched in complex karyotypes and predict rapid progression to . TP53 mutations disrupt and , rendering cells more vulnerable to genomic instability. Epigenetic dysregulation plays a central role in MDS through mutations in genes controlling and modification, affecting up to 50% of cases. TET2 mutations, found in 20-25% of patients, impair by reducing 5-hydroxymethylcytosine levels, leading to hypermethylation of hematopoietic regulators and clonal expansion. ASXL1 alterations, present in 15-20% of cases, disrupt polycomb repressive complex 2 function, promoting aberrant modifications and multilineage involvement with worse survival. DNMT3A mutations, occurring in 10-15% of MDS, cause de novo methyltransferase deficiency, resulting in global hypomethylation that facilitates leukemic evolution, though their prognostic impact varies with co-mutations. These epigenetic changes often arise early, as seen in clonal hematopoiesis, and sensitize cells to hypomethylating agents like . IDH1 and IDH2 mutations, detected in 5-10% of MDS cases, encode isocitrate dehydrogenases that produce the oncometabolite 2-hydroxyglutarate, inhibiting TET enzymes and histone demethylases to induce hypermethylation and block differentiation. IDH2 mutations are more common than IDH1 (roughly 4% vs. 2%), and both are enriched in higher-risk disease with severe , associating with inferior survival and potential responsiveness to targeted IDH inhibitors.

Diagnosis

Clinical and Laboratory Evaluation

The clinical evaluation of suspected myelodysplastic syndrome (MDS) begins with a detailed to identify persistent cytopenias, recurrent infections, or unexplained bleeding, which often prompt initial assessment. A thorough review of prior exposure to , , or other risk factors is essential, as these can contribute to MDS development. Physical examination focuses on signs of anemia such as , , or , as well as evidence of including easy bruising or petechiae. , if present, is uncommon in MDS and may suggest alternative diagnoses. Laboratory evaluation starts with a (CBC), which typically reveals persistent cytopenias, including hemoglobin less than 13 g/dL in men or 12 g/dL in women, below 1.8 × 10^9/L, and platelet count under 150 × 10^9/L. These findings, when unexplained by other causes, raise suspicion for MDS. A peripheral blood smear is then examined to detect dysplastic features, such as hypogranular or hyposegmented neutrophils (pseudo-Pelger-Huët anomaly), macro-ovalocytes, or in red blood cells. These morphologic abnormalities support the need for further investigation while helping differentiate MDS from nutritional deficiencies or reactive processes. Additional initial laboratory tests include a count, which is often inappropriately low relative to the degree of , indicating ineffective . Serum (LDH) levels may be elevated, suggesting increased cell turnover, and measurements of and are performed to exclude deficiencies as alternative causes of cytopenias.

Bone Marrow Examination

Bone marrow examination is a cornerstone of diagnosing myelodysplastic syndrome (MDS), involving both aspiration and to directly assess marrow cellularity, morphology, and other features in the context of persistent cytopenias observed on peripheral evaluation. Bone marrow aspiration typically yields 2-3 mL of liquid marrow, which is air-dried and stained with May-Grünwald-Giemsa or Wright-Giemsa for morphologic analysis; if aspiration results in a "dry tap," touch preparations from the core can substitute. The concomitant bone marrow trephine provides a tissue core for histologic , complementing the aspirate by revealing architectural details and excluding alternative pathologies such as or metastatic disease. Assessment of bone marrow cellularity, expressed as the percentage of hematopoietic cells relative to fat and stroma in the biopsy, is routinely performed and often reveals hypercellularity exceeding 30% of the marrow space in MDS cases, though normocellular or hypocellular marrows can occur, particularly in subtypes like hypocellular MDS. This evaluation helps contextualize the ineffective hematopoiesis underlying the disease, as hypercellularity contrasts with the peripheral cytopenias. Morphologic evaluation focuses on identifying , defined as abnormal maturation and development in hematopoietic cells, requiring at least 10% dysplastic cells in one or more lineages—erythroid, granulocytic, or megakaryocytic—on the aspirate smear for diagnostic significance. Dysplastic features may include megaloblastoid changes in erythroids, hypogranulation or pseudo-Pelger-Huët anomalies in granulocytes, or micromegakaryocytes and hypolobated forms in megakaryocytes, with multilineage involvement common in higher-risk MDS. This assessment, performed by counting at least 200-500 cells per lineage, is essential for confirming the dysplastic nature of the marrow. Iron staining, typically using , is applied to the aspirate to detect ring sideroblasts, which are erythroid precursors with iron-laden mitochondria forming a ring around at least one-third of the nucleus; their presence is quantified as at least 15% of mature erythroid cells, or 5% in cases associated with specific , indicating subtypes like MDS with ring sideroblasts. This finding highlights disordered iron utilization in and supports subtype delineation when combined with other morphologic data. Flow cytometry on bone marrow samples enhances diagnostic precision by detecting aberrant antigen expression on hematopoietic cells, particularly on CD34-positive blasts and maturing myeloid or erythroid progenitors, which may show abnormal patterns such as underexpression of CD13 or , overexpression of CD56, or dyssynchronous maturation (e.g., altered CD11b/ ratios on neutrophils). These immunophenotypic abnormalities, assessed via multiparameter panels including markers like CD45, CD117, , and lineage-specific antigens, occur in over 80% of MDS cases and provide supportive evidence when morphology is equivocal, though they are not entirely specific to MDS. Standardized scoring systems, such as the Ogata or integrated flow cytometry scores, can quantify these aberrancies to aid in risk assessment. Enumeration of blasts in the , counted as a of total nucleated cells on the aspirate smear (at least 500 cells), is critical, with levels below 20% supporting an MDS and distinguishing it from , where blasts reach or exceed 20%. Increased blasts (5-19%) indicate higher-risk disease, while counts under 5% align with lower-risk categories, guiding further management. Cytogenetic analysis of the , including conventional karyotyping (at least 20 metaphases) and (FISH) for common abnormalities if needed, is essential to identify chromosomal changes such as deletion 5q, 7, or complex karyotypes, which inform , subtype, and . Molecular , typically via targeted next-generation sequencing (NGS) panels, detects somatic mutations in recurrently mutated genes including SF3B1, TP53, DNMT3A, ASXL1, and others; these findings are crucial for defining genetically driven MDS subtypes and refining risk assessment per current classifications.

Classification Systems

The classification of myelodysplastic syndromes (MDS) relies on two primary contemporary frameworks: the 5th edition of the (WHO) classification of haematolymphoid tumours (WHO5), published in 2022, and the International Consensus Classification (ICC), also released in 2022. These systems integrate morphologic, cytogenetic, and genetic features to define subtypes, aiming to reflect shared and guide clinical management, while resolving ambiguities from prior iterations like the 2016 WHO revision. In the WHO5, MDS is categorized into entities defined by genetics or morphology, with blasts limited to less than 20% in bone marrow or blood to distinguish from (AML). Genetically defined subtypes include MDS with low blasts and SF3B1 mutation (requiring ≥15% ring sideroblasts or ≥5% if SF3B1-mutated), MDS with low blasts and isolated del(5q), and MDS/ with mutated TP53 (biallelic inactivation, blasts <20%). Morphologic subtypes encompass MDS with low blasts and single lineage dysplasia (SLD, dysplasia ≥10% in one lineage), MDS with low blasts and multilineage dysplasia (MLD, dysplasia ≥10% in ≥2 lineages), and MDS with increased blasts type 1 (IB1, 5-9% bone marrow blasts or 2-4% peripheral blood blasts) or type 2 (IB2, 10-19% bone marrow blasts or 5-19% peripheral blood blasts). Additional categories recognize MDS, hypoplastic (bone marrow cellularity <30-40%, adjusted for age) and MDS with fibrosis (grade 2-3 myelofibrosis). The ICC similarly emphasizes integrated diagnostics but introduces refinements for overlap with AML. Genetically defined types include MDS with mutated SF3B1 (variant allele frequency >10%, blasts <5% in bone marrow and <2% in blood), MDS with del(5q) (isolated or with one other abnormality excluding -7/del(7q), blasts <5%), and MDS with mutated TP53 (multi-hit, variant allele frequency >10%, blasts 0-9% for MDS or 10-19% for MDS/AML). Morphologic categories fall under MDS, not otherwise specified (NOS), with single lineage dysplasia, multilineage dysplasia, or without dysplasia (all blasts <5%), alongside MDS with excess blasts (5-9% bone marrow blasts, 2-5% peripheral blood blasts) and a distinct MDS/AML for cases with 10-19% blasts. Unlike WHO5, ICC does not designate separate hypocellular or fibrotic subtypes as primary entities. Key differences between the systems include WHO5's explicit incorporation of hypocellularity and fibrosis as defining features, reflecting their prognostic relevance, whereas ICC prioritizes genetic drivers and creates an MDS/AML hybrid for intermediate blast counts to better align with AML thresholds. WHO5 also permits SF3B1-mutated MDS with wild-type ring sideroblasts under certain conditions, while ICC mandates the mutation without requiring sideroblasts. Both frameworks eliminate prior ambiguous categories like refractory anemia with ring sideroblasts and unify dysplasia thresholds at ≥10% per lineage, but ICC more aggressively integrates complex karyotypes with TP53 for higher-risk designations.
Feature/SubtypeWHO5 (2022)ICC (2022)
Genetically Defined: SF3B1MDS-LB-SF3B1 (≥15% RS or ≥5% if mutated; <5% blasts)MDS-SF3B1 (>10% VAF; <5% blasts)
Genetically Defined: del(5q)MDS-LB-del(5q) (isolated; <5% blasts)MDS-del(5q) (isolated or +1 abn.; <5% blasts)
Genetically Defined: TP53MDS/AML-TP53 (biallelic; <20% blasts)MDS-TP53 (multi-hit; 0-9% blasts) or MDS/AML-TP53 (10-19% blasts)
Morphologic: SLD/MLDMDS-LB-SLD/MLD (<5% blasts)MDS-NOS-SLD/MLD (<5% blasts)
Excess BlastsMDS-IB1 (5-9% BM) / IB2 (10-19% BM)MDS-EB (5-9% BM); MDS/AML (10-19% blasts)
HypocellularMDS, hypoplastic (<30-40% cellularity)Not a primary subtype
FibrosisMDS with fibrosis (grade 2-3)Not a primary subtype
These classifications enhance precision by prioritizing molecular data alongside traditional morphology, though diagnostic overlap may require both systems for comprehensive evaluation in select cases.

Management

Supportive Care

Supportive care forms the foundation of management for patients with myelodysplastic syndrome (MDS), aiming to alleviate symptoms, prevent complications, and improve quality of life without targeting the underlying clonal disorder. This approach is particularly crucial for lower-risk MDS, where cytopenias such as anemia, thrombocytopenia, and neutropenia predominate, and is applicable across all risk groups to address transfusion needs and infection risks. Key interventions include blood product transfusions, growth factor support, antimicrobial prophylaxis, iron chelation, and nutritional supplementation when deficiencies are identified. Blood transfusions are a primary supportive measure for managing severe and in MDS. Red blood cell (RBC) transfusions are indicated for symptomatic , such as or , with approximately 50% of newly diagnosed patients requiring them; decisions are guided by individual symptoms rather than fixed thresholds to optimize . Platelet transfusions are used prophylactically or therapeutically for bleeding risks associated with low platelet counts, though their short duration often necessitates repeated administration. To mitigate risks, leukoreduced and irradiated products are recommended, as alloimmunization—developing antibodies against donor antigens—occurs in 10-23% of transfusion-dependent MDS patients, complicating future transfusions and increasing hemolytic reaction risks. Frequent RBC transfusions can lead to secondary , potentially causing organ damage like cardiac or hepatic dysfunction. Erythropoiesis-stimulating agents (ESAs), such as or darbepoetin alfa, are first-line therapy for in lower-risk MDS patients with low endogenous levels (<500 U/L). These agents stimulate production, reducing transfusion dependence in about 40% of responsive cases, with benefits including improved levels and overall survival when initiated early. Response is typically assessed after 8-16 weeks of treatment, and combination with low-dose (G-CSF, e.g., ) may enhance efficacy in specific subtypes like MDS with ring sideroblasts. For , G-CSF is employed to boost counts and reduce infection frequency in patients with recurrent severe infections, while prophylaxis is recommended during periods of profound to prevent bacterial complications like . Iron chelation therapy is essential for transfusion-dependent patients to prevent or treat , particularly in lower-risk MDS with expected survival exceeding 1-2 years. Oral is the preferred agent, as demonstrated in the TELESTO trial, where it reduced iron burden and improved event-free survival compared to . is initiated after 20-25 units of RBCs or when serum ferritin exceeds 1,000 ng/mL, with monitoring of non-transferrin-bound iron and renal function to guide dosing. Additionally, supplementation with folic acid and is routinely provided if deficiencies are detected through evaluation, as these nutrients support and may mitigate in MDS.

Pharmacologic Therapies

Pharmacologic therapies for myelodysplastic syndrome (MDS) primarily target the underlying clonal hematopoiesis and are selected based on disease risk and cytogenetic or molecular features. Hypomethylating agents, immunomodulatory drugs, erythroid maturation agents, inhibitors, and targeted molecular therapies represent the main approved classes, offering disease-modifying benefits such as improved survival, transfusion independence, and reduced severity in specific MDS subtypes. Hypomethylating agents, including and , are standard first-line treatments for higher-risk MDS, where they inhibit DNA methyltransferases to promote gene re-expression and induce differentiation of abnormal hematopoietic cells. In the phase 3 AZA-001 , extended median overall survival by approximately 9 months compared to conventional care regimens (24.5 months versus 15.0 months) in patients with intermediate-2 or high-risk MDS per International Prognostic Scoring System criteria. , administered in cycles similar to , has shown comparable hematologic improvement rates and is approved for the same higher-risk population, though its survival benefit is supported by phase 3 data demonstrating delayed progression to . These agents achieve complete response rates of 15-20% and overall response rates up to 50%, with common side effects including , cytopenias, and injection-site reactions. Lenalidomide, an immunomodulatory agent, is approved specifically for transfusion-dependent lower-risk MDS with isolated deletion of the long arm of (del(5q)). By modulating the immune microenvironment and inhibiting the haplodeficient in del(5q) clones, induces sustained transfusion independence in 60-70% of responsive patients, with median duration exceeding 2 years in phase 3 trials like MDS-004. Cytogenetic complete responses occur in about 25% of cases, correlating with durable hematologic improvement, though myelosuppression and rash are frequent adverse events requiring dose adjustments. For lower-risk MDS with ring sideroblasts (MDS-RS), luspatercept, a that promotes late-stage by targeting the TGF-β pathway, reduces transfusion burden by enhancing ineffective red cell production. In the phase 3 MEDALIST trial, luspatercept achieved an 8-week transfusion independence rate of 37.9% versus 13.2% with in erythropoiesis-stimulating agent-refractory or non-responsive patients with MDS-RS, with benefits extending to 24 weeks in over 30% of responders. Administered subcutaneously every 3 weeks, it is associated with , , and , but offers a novel non-cytotoxic mechanism distinct from hypomethylating agents. Imetelstat, a first-in-class inhibitor, was approved in 2024 for adults with low- or intermediate-1-risk MDS who have transfusion-dependent refractory to erythropoiesis-stimulating agents. By binding telomeres and shortening them in malignant stem cells, imetelstat achieved 8-week red blood cell transfusion independence in 39.7% of patients in the phase 3 IMerge trial, compared to 15.0% with , with median duration of 51.2 weeks and evidence of multilineage responses in over 50% of cases. Intravenous dosing every 4 weeks is linked to and , but provides a disease-modifying option for non-del(5q) lower-risk disease. Targeted therapies like olutasidenib, a selective oral inhibitor of mutant 1 (IDH1), address specific molecular alterations in MDS. In phase 2 studies of treatment-naïve or relapsed IDH1-mutated cases, olutasidenib disrupts the oncometabolite 2-hydroxyglutarate, restoring normal and yielding overall response rates of 47-86% when combined with . , , and differentiation syndrome are notable toxicities, but it represents a precision approach for the 5-10% of MDS patients harboring IDH1 mutations.

Hematopoietic Stem Cell Transplantation

Allogeneic (HSCT) is the only curative treatment modality for myelodysplastic syndrome (MDS), offering the potential for long-term disease eradication through replacement of the defective hematopoietic system. It is primarily indicated for fit patients with intermediate- or high-risk disease, as determined by established prognostic systems, where the benefits outweigh the risks of procedure-related morbidity. Long-term survival rates after allogeneic HSCT typically range from 30% to 50%, with durable remissions achieved in a substantial proportion of responders, particularly when performed before disease progression to . For older patients exceeding 60 years of age, who constitute the majority of MDS diagnoses, reduced-intensity conditioning (RIC) regimens are standard to reduce regimen-related toxicity while preserving graft-versus-leukemia effects. These regimens, often incorporating agents like and low-dose , , or treosulfan (approved by the FDA in combination with as a preparative regimen in January 2025), enable transplantation in patients previously deemed ineligible due to comorbidities. Donor selection prioritizes (HLA)-matched siblings for optimal outcomes, but matched unrelated donors from registries or haploidentical family members serve as viable alternatives, with haploidentical approaches facilitated by post-transplant to mitigate rejection and (GVHD). Post-transplant complications remain significant challenges, including acute and chronic GVHD affecting up to 40-50% of recipients, in 20-40% of cases driven by persistent clonal hematopoiesis, and opportunistic infections due to prolonged . Management strategies, such as prophylactic antimicrobials and GVHD-directed therapies, have improved non- mortality to 10-30%. Optimal timing of allogeneic HSCT emphasizes early intervention in higher-risk patients to capitalize on lower tumor burden and better , yielding superior overall survival compared to delayed approaches. The MDS-HOPE score, a validated prognostic tool from the Center for International Blood and Marrow Transplant Research, integrates clinical factors like age, , , and blood parameters to assess post-HSCT risk and inform patient selection and timing decisions. This model stratifies patients into low- to very high-risk groups, with 3-year overall survival ranging from 71% in low-risk to 25% in very high-risk categories, aiding in personalized counseling.

Prognosis

Risk Stratification Models

Risk stratification models for myelodysplastic syndromes (MDS) are essential tools that integrate clinical, cytogenetic, and molecular features to predict progression, overall survival, and the likelihood of transformation to , thereby informing therapeutic strategies. These systems categorize patients into risk groups ranging from very low to very high, with associated median survivals spanning more than 8 years in the lowest-risk categories to less than 1 year in the highest-risk ones, enabling differentiation between supportive care for lower-risk and more aggressive interventions for higher-risk cases. The Revised International Prognostic Scoring System (IPSS-R), developed in 2012, refines the original IPSS by incorporating five key variables: the severity of cytopenias (assessed by , platelet, and ), percentage of bone marrow blasts, and cytogenetic abnormalities. Each parameter is assigned points based on predefined thresholds, yielding a total score that stratifies patients into five risk categories: very low, low, intermediate, high, and very high. This model demonstrated superior prognostic accuracy compared to its predecessor in a large cohort of over 7,000 untreated MDS patients, particularly in identifying intermediate-risk subgroups with distinct outcomes. Building on the IPSS-R, the Molecular International Prognostic Scoring System (IPSS-M), introduced in 2022, enhances by integrating mutational from targeted next-generation sequencing of 31 genes alongside the IPSS-R components of cytopenias, blasts, and . Mutations such as those in TP53 are weighted heavily due to their association with adverse , allowing for reclassification of up to 46% of patients compared to IPSS-R and improving for and leukemic in a derivation cohort of 2,955 patients. The IPSS-M expands to six risk categories—very low, low, moderate-low, moderate-high, high, and very high—offering refined granularity, especially for lower-risk patients, and has been validated in independent datasets for its clinical utility in guiding management decisions. The WHO classification-based Prognostic Scoring System (WPSS), established in , provides a dynamic framework that incorporates the WHO MDS subtype classification, cytogenetic (intermediate or poor), and transfusion dependence as its three core components. Scores are calculated at and can be updated over time to reflect evolution, stratifying patients into very low, low, intermediate, high, and very high groups. Validated in over 2,500 patients, the WPSS outperforms earlier models by accounting for transfusion burden, a key indicator of severity, and remains particularly valuable for monitoring progression in real-world clinical settings. These models collectively facilitate the identification of low-risk MDS patients who may benefit from or supportive measures versus high-risk individuals requiring intensive therapies, though molecular profiling via IPSS-M is increasingly recommended for optimal precision.

Survival and Outcomes

The for patients with myelodysplastic syndrome (MDS) varies widely depending on risk stratification, with overall median ranging from 2.5 to 5 years. In lower-risk disease, median often exceeds 5 years; specifically, for IPSS-M very low and low risk groups, median overall survival is 6–10+ years, often near-normal when adjusted for age, especially in younger patients. while in higher-risk cases, it is typically less than 1.5 years. The 5-year overall is approximately 40%, though this figure fluctuates significantly by subtype; for instance, patients with isolated deletion 5q (del(5q)) have a favorable with 5-year rates of approximately 50-60% with treatment, whereas those with complex karyotypes have poor outcomes with median often less than 1 year. Progression to (AML) represents a critical , occurring in about 30% of patients over 10 years, with the risk escalating in those with excess blasts. Age, , and comorbidities further modulate these outcomes; older age and poor are associated with shortened survival, particularly in lower-risk MDS, while severe comorbidities can reduce median survival by up to 50%, independent of disease-specific factors. In lower-risk MDS, age <60 years represents a strong favorable prognostic factor with markedly improved outcomes, due to lower competing comorbidities, higher tolerance for interventions such as hematopoietic stem cell transplantation if required, and distinct biology often featuring fewer high-risk mutations; survival frequently extends beyond cohort medians toward age-matched population norms, with many patients dying with rather than of the disease. Splenomegaly worsens prognosis, being associated with shorter overall survival, higher risk of AML transformation, poorer treatment response, and reduced engraftment rates post-transplant. Modern therapies, such as hypomethylating agents (HMAs), have improved prognosis in higher-risk MDS by extending survival by approximately 24%, as demonstrated in pivotal trials where median overall survival reached 24.5 months compared to 15 months with conventional care. More recent therapies, such as imetelstat approved in 2024 for transfusion-dependent lower-risk MDS, have further improved anemia management and , potentially extending survival in select patients. Additionally, new prognostic models like MDS-HOPE (2025) refine predictions for transplant outcomes. These advancements highlight the evolving landscape of MDS management, though overall outcomes remain influenced by individual patient characteristics.

Epidemiology

Incidence and Prevalence

Myelodysplastic syndromes (MDS) have an estimated annual age-adjusted incidence of 4 to 5 cases per 100,000 individuals in the United States and similar high-income countries. This translates to approximately 10,000 to 15,000 new diagnoses annually in the US population. The incidence increases dramatically with advancing age, from about 2.5 per 100,000 in the sixth decade of life to 25 to 30 per 100,000 in the eighth decade and older, reflecting the disease's strong association with elderly populations. Prevalence estimates for MDS in the range from 60,000 to 170,000 cases, a figure driven primarily by the expanding aging demographic and improved survival rates among diagnosed patients. Globally, the age-standardized incidence has remained stable at approximately 4 per 100,000, but the absolute number of cases has doubled from 171,000 in 1990 to 341,000 in 2021 due to population aging. These numbers underscore the growing burden of MDS, with projections indicating further increases as global populations age. Diagnosis rates have risen over recent decades, attributable to enhanced awareness, advanced diagnostic technologies such as and cytogenetic analysis, and the demographic shift toward older age groups. Reported rates vary by region, with similar figures to the (~4 per 100,000) in and (~2-4 per 100,000 age-adjusted), while lower reported rates in parts of and (often <2 per 100,000) likely reflect underreporting due to limited access to diagnostics. In low-resource settings, particularly in and certain Asian countries, significant underreporting occurs due to limited access to biopsies, cytogenetic testing, and specialized services, leading to underestimation of the true burden.

Demographic Characteristics

Myelodysplastic syndrome (MDS) primarily affects older individuals, with a age at ranging from 70 to 75 years across large population-based studies. The incidence rises sharply with advancing age, reaching rates as high as 35 per 100,000 in those aged 80 years and older, reflecting the cumulative impact of acquired somatic mutations in hematopoietic stem cells. Diagnoses in younger patients are infrequent; MDS is rare in individuals under 40 years without underlying predispositions, such as genetic syndromes or prior cytotoxic therapy, comprising less than 5% of cases in most registries. MDS exhibits a notable sex disparity, with diagnosed approximately 1.5 to 2 times more frequently than females, based on age-adjusted incidence rates of 4.4 per 100,000 for versus 2.5 per 100,000 for females in U.S. surveillance data. This male predominance may stem in part from X-chromosome effects, as hemizygous are more susceptible to pathogenic in X-linked genes like ZRSR2 and PHF6, which are recurrent in MDS and show higher prevalence in male patients. Ethnic variations in MDS incidence are evident, with higher rates observed among Caucasians compared to Asians and African Americans; for example, SEER data report an age-adjusted rate of 3.3 per 100,000 for non-Hispanic whites, versus lower figures for Asian/Pacific Islanders (around 2.0 per 100,000) and African Americans (approximately 2.5 per 100,000). Geographic patterns also highlight clusters in regions with industrial activity, particularly near petrochemical sites or areas of high chemical exposure, where elevated MDS incidence has been linked to environmental factors like benzene and solvents in multiple epidemiological analyses. The rising prevalence of MDS in elderly populations is closely tied to the age-dependent increase in clonal hematopoiesis of indeterminate potential (CHIP), a premalignant condition detected in over 10% of individuals aged 70 and older, which serves as a precursor state with an annual progression to MDS or other hematologic malignancies in about 0.5–1% of cases.

History

Early Recognition

The earliest descriptions of what is now recognized as myelodysplastic syndrome (MDS) emerged in the early 20th century, often conflated with other hematologic disorders. In 1900, German physician Wilhelm von Leube reported a case of "leukanemia," characterized by severe that preceded the onset of overt , marking one of the first documented instances of a variant with dysplastic features. This observation highlighted ineffective and cytopenias without initial leukemic transformation, though the condition was not yet distinctly categorized. By the mid-20th century, further case reports refined the clinical picture. In 1938, and W. Halsey Barker analyzed 100 cases of refractory anemia, emphasizing persistent cytopenias unresponsive to standard therapies and subtle bone marrow abnormalities, which laid groundwork for identifying non-regenerative anemias as distinct entities. Subsequently, in 1949, J.L. Hamilton-Paterson introduced the term "preleukemic anemia" to describe patients with refractory anemia that often progressed to , underscoring the pre-leukemic nature of these states. During the 1950s and 1960s, accumulating evidence from clinical observations solidified the recognition of these disorders as pre-leukemic conditions featuring multilineage cytopenias and dysplastic marrow changes. Multiple case series documented patients with bone marrow dysplasia—manifesting as abnormal cell morphology and maturation defects—without frank leukemia, distinguishing these from acute processes. This period also saw pivotal insights into etiology, particularly through studies of atomic bomb survivors in Hiroshima and Nagasaki, where mid-1950s analyses, such as a 1955 report by Lange et al. on six Nagasaki survivors developing refractory anemia 4–7 years post-exposure, revealed elevated rates of refractory cytopenias linked to radiation exposure. The term "myelodysplastic syndromes" was proposed in 1976 by the French-American-British (FAB) cooperative group to encompass these preleukemic conditions characterized by dysplastic changes in hematopoietic cells.

Evolution of Classifications

The classification of myelodysplastic syndromes (MDS) was first formalized in 1982 by the French-American-British (FAB) cooperative group, which established a morphology-based system to standardize and facilitate . This inaugural framework categorized MDS into five subtypes: refractory anemia (RA), refractory anemia with ring sideroblasts (RARS), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-t), and (CMML), primarily relying on blast percentages and dysplastic features in blood cells. The (WHO) introduced its initial classification in 2000 (published 2001-2002), refining the FAB system by integrating cytogenetic and clinical data to better reflect disease biology and . A pivotal change was the elimination of the RAEB-t category, reassigning cases with 20% or more blasts in or peripheral blood to (AML) and thus lowering the AML blast threshold from 30% to 20%; this adjustment aimed to distinguish more accurately between MDS progression and de novo AML. Additionally, the WHO recognized 5q- as a distinct subtype, defined by isolated del(5q) cytogenetic abnormality, fewer than 5% blasts, and a favorable in lower-risk patients. Subsequent WHO revisions in 2008 and 2016 built on these foundations, incorporating evolving evidence from , , and clinical outcomes to enhance subclassification precision. The 2008 update integrated elements of the International Prognostic Scoring System (IPSS), such as cytogenetic risk groups, into diagnostic considerations and formally acknowledged hypocellular MDS—characterized by bone marrow cellularity below 30%—as a morphological variant that may overlap with but requires careful differentiation based on and . The 2016 revision further refined blast count thresholds, multilineage criteria, and cytogenetic abnormalities, emphasizing their prognostic implications while maintaining compatibility with prior systems for longitudinal studies. The 2022 editions of the WHO fifth classification and the International Consensus Classification (ICC) represented a by prioritizing alongside morphology, enabling the definition of biologically homogeneous entities. These systems introduced MDS with mutated SF3B1 as a specific subtype, recognizing its association with ring sideroblasts and relatively indolent course, and MDS with mutated TP53, highlighting biallelic mutations (variant allele frequency ≥10%) as indicative of high-risk disease with poor response to therapy. They also created an MDS/AML overlap category for cases with 10-19% blasts, bridging the traditional diagnostic boundary to better capture transitional biology and guide targeted interventions. This progression from morphology-centric FAB criteria to molecularly informed WHO and ICC frameworks has transformed MDS , shifting toward precision-based subclassification that informs and treatment stratification.

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