Myelodysplastic syndrome


Myelodysplastic syndromes are a group of cancers in which immature blood cells in the bone marrow do not mature, so do not become healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may include feeling tired, shortness of breath, easy bleeding, or frequent infections. Some types may develop into acute myeloid leukemia.
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. Problems with blood cell formation result in some combination of low red blood cell, platelet, and white blood cell counts. Some types have an increase in immature blood cells, called blasts, in the bone marrow or blood. The types of MDS are based on specific changes in the blood cells and bone marrow.
Treatments may include supportive care, drug therapy, and stem cell transplantation. Supportive care may include blood transfusions, medications to increase the making of red blood cells, and antibiotics. Drug therapy may include the medications lenalidomide, antithymocyte globulin, and azacitidine. Certain people can be cured with chemotherapy followed by a stem-cell transplant from a donor.
About seven per 100,000 people are affected with about four per 100,000 people newly acquiring the condition each year. The typical age of onset is 70 years. The outlook 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. The typical survival time following diagnosis is 2.5 years. The conditions were first recognized in the early 1900s. The current name came into use in 1976.

Signs and symptoms

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:
Although some risk exists for developing acute myelogenous leukemia, about 50% of deaths occur as a result of bleeding or infection. However, leukemia that occurs as a result of myelodysplasia is notoriously resistant to treatment.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. Previous chemotherapy or radiation exposure is an important fact in the person's medical history. Fever and weight loss should point to a myeloproliferative rather than myelodysplastic process.

Cause

Some people have a history of exposure to chemotherapy or radiation, or both. 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 exposure has been associated with myelodysplasia. Vietnam veterans exposed to Agent Orange are at risk of developing MDS. A link may exist between the development of MDS "in atomic-bomb survivors 40 to 60 years after radiation exposure". Children with Down syndrome are susceptible to MDS, and a family history may indicate a hereditary form of sideroblastic anemia or Fanconi anemia.

Pathophysiology

MDS most often develops without an identifiable cause. Risk factors include exposure to an agent known to cause DNA damage, such as radiation, benzene, and certain chemotherapies; other risk factors have been inconsistently reported. Proving a connection between a suspected exposure and the development of MDS can be difficult, but the presence of genetic abnormalities may provide some supportive information. Secondary MDS can occur as a late toxicity of cancer therapy. 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 a 11q23 translocation. Other pre-existing bone marrow disorders such as acquired aplastic anemia following immunosuppressive treatment and Fanconi anemia can evolve into MDS.
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 which have lost the ability to differentiate. If the overall percentage of bone marrow myeloblasts rises over a particular cutoff, then transformation to acute myelogenous leukemia 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.
While recognition of leukemic transformation was historically important, 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 suffer injury from severe anemia. The two most serious complications in MDS patients resulting from their cytopenias are bleeding or infection. Long-term transfusion of packed red blood cells leads to iron overload.

Genetics

The recognition of epigenetic changes in DNA structure in MDS has explained the success of two of three 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.
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.

5q- syndrome

Since at least 1974, the deletion in the long arm of chromosome 5 has been known to be associated with dysplastic abnormalities of hematopoietic stem cells. By 2005, lenalidomide, a chemotherapy drug, was recognized to be effective in MDS patients with the 5q- syndrome, 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, 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.

Splicing factor mutations

Mutations in splicing factors have been found in 40-80% of cases with myelodysplastic syndrome, particularly in those with ringed sideroblasts.

''IDH1'' and ''IDH2'' mutations

Mutations in the genes encoding for isocitrate dehydrogenase 1 and 2 occur in 10-20% of patients with myelodysplastic syndrome, and confer a worsened prognosis in low-risk MDS. 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.

GATA2 deficiency

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.

Transient myeloproliferative disease

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.

Diagnosis

The elimination of other causes of cytopenias, along with a dysplastic bone marrow, is required to diagnose a myelodysplastic syndrome, so differentiating MDS from anemia, thrombocytopenia, and leukopenia is important.
A typical diagnostic investigation includes:
The features generally used to define a MDS are blood cytopenias, ineffective hematopoiesis, dyserythropoiesis, dysgranulopoiesis, dysmegakaropoiesis, and increased myeloblasts.
Dysplasia can affect all three lineages seen in the bone marrow. The best way to diagnose dysplasia is by morphology and special stains used on the bone marrow aspirate and peripheral blood smear. Dysplasia in the myeloid series is defined by:
Other stains can help in special cases in eosinophils is a marker of abnormality seen in chronic eosinophilic leukemia and is a sign of aberrancy.
On the bone marrow biopsy, high-grade dysplasia may show atypical localization of immature precursors, which are islands of immature precursors cells 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, where normoblasts are seen next to bony trabeculae instead of forming normal interstitially placed erythroid islands.

Differential diagnosis

Myelodysplasia is a diagnosis of exclusion and must be made after proper determination of iron stores, vitamin deficiencies, and nutrient deficiencies are ruled out. Also, congenital diseases such as congenital dyserythropoietic anemia have been recognized, Pearson's syndrome, Jordans anomaly - vacuolization in all cell lines may be seen in Chanarin-Dorfman syndrome, aminolevulinic acid enzyme deficiency, and other more esoteric enzyme deficiencies are known to give a pseudomyelodysplastic picture in one of the cell lines; however, all three cell lines are never morphologically dysplastic in these entities with the exception of chloramphenicol, arsenic toxicity, and other poisons.
All of these conditions are characterized by abnormalities in the production of one or more of the cellular components of blood.

Classification

French-American-British (FAB) classification

In 1974 and 1975, a group of pathologists from France, the US, and Britain produced the first widely used classification of these diseases. This French-American-British classification was published in 1976, and revised in 1982. It was used by pathologists and clinicians for almost 20 years. Cases were classified into five categories:
ICD-ONameDescription
Refractory anemia characterized by less than 5% primitive blood cells in the bone marrow and pathological abnormalities primarily seen in red cell precursors
Refractory anemia with ring sideroblasts 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"
Refractory anemia with excess blasts characterized by 5-19% myeloblasts in the marrow
Refractory anemia with excess blasts in transformation characterized by 5%-19% myeloblasts in the marrow
Chronic myelomonocytic leukemia, not to be confused with chronic myelogenous leukemia or CMLcharacterized by less than 20% myeloblasts in the bone marrow and greater than 1*109/L monocytes circulating in the peripheral blood.

The best prognosis is seen with RA and RARS, where some nontransplant patients live more than a decade. The worst outlook is with RAEB-T, where the mean life expectancy is less than 1 year. About one-quarter of patients develop overt leukemia. The others die of complications of low blood count or unrelated disease. The International Prognostic Scoring System is another tool for determining the prognosis of MDS, published in Blood in 1997. This system takes into account the percentage of blasts in the marrow, cytogenetics, and number of cytopenias.

World Health Organization

In the late 1990s, a group of pathologists and clinicians working under the World Health Organization modified this classification, introducing several new disease categories and eliminating others. Most recently, the WHO has evolved a new classification scheme that is based more on genetic findings. However, morphology of the cells in the peripheral blood, bone marrow aspirate, and bone marrow biopsy are still the screening tests used to decide which classification is best and which cytogenetic aberrations may be related.
The list of dysplastic syndromes under the new WHO system includes:
Old systemNew system
Refractory anemia Refractory cytopenia with unilineage dysplasia
Refractory anemia with ringed sideroblasts Refractory anemia with ring sideroblasts

Refractory anemia with ring sideroblasts - thrombocytosis which is in essence a myelodysplastic/myeloproliferative disorder and usually has a JAK2 mutation - New WHO classification 2008
Refractory cytopenia with multilineage dysplasia includes the subset Refractory cytopenia with multilineage dysplasia and ring sideroblasts. RCMD includes patients with pathological changes not restricted to red cells dysplasia.
Refractory anemia with excess blasts Refractory anemias with excess blasts I and II. RAEB was divided into RAEB-I and RAEB-II blasts, which has a poorer prognosis than RAEB-I. Auer rods may be seen in RAEB-II which may be difficult to distinguish from acute myeloid leukemia.
Refractory anemia with excess blasts in transformation This category was eliminated; such patients are now considered to have acute leukemia.
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, was added to the classification.
Chronic myelomonocytic leukemia CMML was removed from the myelodysplastic syndromes and put in a new category of myelodysplastic-myeloproliferative overlap syndromes.
Myelodysplasia unclassifiable
Refractory cytopenia of childhood - New in WHO classification 2008

Note : not all physicians concur with this reclassification, because the underlying pathology of this diseases is not well understood.

Myelodysplastic syndrome unclassified

The WHO has proposed a criterion for diagnosis and classification of MDS that may apply to most cases. However, occasional cases are difficult to classify into defined categories because of one or more unusual features:
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 triage patients for more aggressive treatment as well as help determine the best timing of this therapy. Supportive care with blood products and hematopoietic growth factors is the mainstay of therapy. The regulatory environment for the use of erythropoietins is evolving, according to a recent US Medicare National coverage determination. However, no comment on the use of hematopoeitic growth factors for MDS was made in that document.
Agents have been approved by the U.S. Food and Drug Administration for the treatment of MDS:
  1. 5-azacytidine: 21-month median survival
  2. Decitabine: Complete response rate reported as high as 43%. A phase I study has shown efficacy in AML when decitabine is combined with valproic acid.
  3. Lenalidomide: Effective in reducing red blood cell transfusion requirement in patients with the chromosome 5q deletion subtype of MDS
  4. Decitabine/cedazuridine is a fixed-dosed combination medication for the treatment of adults with myelodysplastic syndromes and chronic myelomonocytic leukemia.
Chemotherapy with the hypomethylating agents 5-azacytidine and decitabine has been shown to decrease blood transfusion requirements and to retard the progression of MDS to AML. Lenalidomide was approved by the FDA in December 2005 only for use in the 5q- syndrome. In the United States, treatment of MDS with lenalidomide costs about $9,200 per month.
The chemotherapy can be supported by other drugs like all-trans retinoic acid. Therefore, Küley-Bagheri et al. conducted a Cochrane review with randomised controlled phase II and III trials in 2018 to evaluate the harms and benefits of all-trans retinoic acid in addition to chemotherapy for adults that suffer from acute myeloid leukaemia. The measured results count for patients that suffer from acute myeloid leukaemia and a high-risk myelodysplastic syndrome as this syndrome can develop into an acute myeloid leukaemia. If the participants suffered from a myelodysplastic syndrome, they were only allowed to participate in the studies if they had more than 20% of blasts. ATRA was given to participants in the intervention group in addition to chemotherapy while people were getting either an induction therapy or a consolidation therapy. Further details can be found in the original review. The review authors conducted an analysis to compare ATRA in addition to chemotherapy to chemotherapy alone: The evidence is very uncertain about the effect of ATRA in addition to chemotherapy on diarrhoea grade III/IV, nausea/vomiting grade III/IV and cardiac toxicity grade III/IV. ATRA in addition to chemotherapy probably results in little to no difference in the mortality which was measured instead of the overall survival within 24 months, the on-study mortality and the infections grade III/IV. Moreover, ATRA in addition to chemotherapy likely does not reduce the mortality, relapse and progress which was measured instead of disease- or relapse-free survival.
HLA-matched allogeneic stem cell transplantation, particularly in younger and more severely affected patients, offers the potential for curative therapy. 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 tending to have a more favorable outcome with transplantation. If patient receive a stem cell transplant, they can develop a graft-versus-host disease. Therefore, Fisher et al. conducted a Cochrane review with randomised controlled trials in 2019 to measure the safety and efficacy of mesenchymal stromal cells for people suffering from a graft-versus-host disease after receiving a haematopoietic stem cell transplantation as treatment for their haematological disease. Fisher et al. included trials that used MSCs either for therapeutic or prophylactic reasons. The exact inclusion and exclusion criteria and information regarding the dose can be found in the original Cochrane review. In the therapeutic trials it was necessary that the study participants already suffered from a GvHD. Fisher et al. conducted one analysis: MSCs compared to control/ placebo for treating immune mediated inflammation post-transplantation and in autoimmunity: Mesenchymal stromal cells may reduce the all-cause mortality if they are used for a therapeutic reason. Moreover, the therapeutic use of MSCs may increase the complete response of acute and chronic GvHD, but the evidence is very uncertain. The evidence suggests that MSCs for prophylactic reason result in little to no difference in the all-cause mortality, in the relapse of malignant diseases and in the incidence of acute GvHD. The evidence suggests that MSCs for prophylactic reason reduce the incidence of chronic GvHD.
Patients that receive a stem cell transplant or a chemotherapy as a treatment might have a higher risk for bleeding. Therefore, Estcourt et al. conducted a Cochrane review with randomised controlled trials in 2012 to assess which use of platelet transfusions is the most effective one to prevent bleeding if people suffer from a haematological disorder and undergo a stem cell transplantation or a chemotherapy. A study participation was only possible if the patients did not have an active bleeding within the last 5 days and did not receive a previous platelet transfusion because of the chemotherapy or stem cell transplantation. The exact inclusion and exclusion criteria and details regarding the dose can be found in the original Cochrane review. Estcourt et al. conducted four analyses to answer their research question. In the first analysis they compared therapeutic/ non-prophylactic platelet transfusions to prophylactic platelet transfusions: The evidence suggests that therapeutic platelet transfusions result in little to no difference in the mortality secondary to bleeding. Furthermore, they may result in a slight reduction in the number of days on which a significant bleeding event occurred. The evidence suggests that therapeutic platelet transfusions result in a large increase in the number of patients with at least one significant bleeding event and they likely result in a large reduction in the number of platelet transfusions. In the second analysis, the review authors conducted a comparison of prophylactic platelet transfusions at threshold of 10.000 to a higher transfusion threshold : Prophylactic platelet transfusions at threshold of 10.000 may result in little to no difference in the mortality due to bleeding. These transfusions probably reduce the number of platelet transfusions per patient slightly. Prophylactic platelet transfusions at threshold of 10.000 probably increase the number of patients with at least one significant bleeding event and they likely result in a large increase in the number of days on which a significant bleeding event occurred. Prophylactic platelet transfusion with one dose schedules were compared to prophylactic platelet transfusions with another dose schedule in the third analysis: Prophylactic platelet transfusions at one dose schedule may result in little to no difference in the mortality secondary to bleeding if low dosage platelet transfusions are compared to standard dose platelet transfusions. Furthermore, the transfusions at one dose schedule probably result in little to no difference in the mortality secondary to bleeding if high dose platelet transfusions and standard dosage platelet transfusions are compared to each other. Prophylactic platelet transfusions with one dose schedule result in little to no difference in the number of participants with a significant bleeding event if low dosage platelet transfusions or high dosage platelet transfusions are compared to standard dose platelet transfusions. The last analysis was conducted to compare prophylactic platelet transfusions to platelet-poor plasma: The evidence is very uncertain about the effect of prophylactic platelet transfusion on mortality secondary to bleeding, the number of participants with a significant bleeding event and the number of platelet transfusions. Moreover, Estcourt et al. renewed the second analysis from their Cochrane review from 2012 in 2015 with randomised controlled trials and aimed to evaluate whether different platelet transfusion thresholds for the management of prophylactic platelet transfusions have an influence on the safety and efficacy for patients that suffer from a haematological disorder and receive a stem cell transplantation or myelosuppressive chemotherapy. Estcourt et al. conducted the following analysis: Prophylactic platelet transfusion at threshold of 10.000 compared to higher transfusion threshold : The evidence suggests that prophylactic platelet transfusions at threshold of 10.000 result in little to no different in the time to the first bleeding episode, the number of participants with WHO Grade 3 or 4 bleeding and clinically significant bleedings per participant. The evidence suggests that prophylactic platelet transfusions at threshold of 10.000 reduce the number of platelet transfusions per participants slightly. Moreover, the evidence suggests that these transfusions increase the number of participants with at least one significant bleeding event. Prophylactic platelet transfusions at threshold of 10.000 may result in a large increase in the mortality due to all causes. Apart from the time to the first bleeding, all endpoints are related to the first 30 days after the study entry.
The treatment of the myelodysplastic syndrome can be supported by alternative treatments. Therefore, Knips et al. conducted a Cochrane review with randomised controlled trials in 2019 to re-evaluate the safety, efficacy and feasibility of physical exercises in addition to the standard treatment for  adult patients with haematological malignancies. The exact inclusion and exclusion criteria and further details can be found in the original Cochrane review. The study participants were in disease stage I to IV. As aerobic physical exercises were only an additional treatment, participants also received chemotherapies or stem cell transplantations/ bone marrow transplantations. Knips et al. compared aerobic physical exercises additional to the standard treatment to standard treatment alone: The evidence is very uncertain about the effect of aerobic physical exercises on anxiety and serious adverse events. Aerobic physical exercises may result in little to no difference in the mortality, in the quality of life and in the physical functioning. These exercises may result in a slight reduction in depression. Furthermore, aerobic physical exercises probably reduce fatigue.

Iron levels

Iron overload can develop in MDS as a result of the RBC transfusions, which are a major part of the supportive care for anemic MDS patients. A particular risk exists of delayed engraftment and a need for repeated red-cell transfusion following HLA-identical allogeneic stem-cell transplantation if the recipient is blood type O and the stem-cell donor, type A. Although the specific therapies patients receive may alleviate the RBC transfusion need in some cases, many MDS patients may not respond to these treatments, thus may develop secondary hemochromatosis due to iron overload from repeated RBC transfusions.
Patients requiring relatively large numbers of RBC transfusions can experience the adverse effect of chronic iron overload on their liver, heart, and endocrine functions. The resulting organ dysfunction from transfusional iron overload might be a contributor to increased illness and death in early-stage MDS.
For patients requiring many RBC transfusions, serum ferritin levels, number of RBC transfusions received, and associated organ dysfunction should be monitored to determine iron levels. Monitoring serum ferritin may also be useful, aiming to decrease ferritin levels to.Currently, two iron chelators are available in the US, deferoxamine for intravenous use and deferasirox for oral use. These options now provide potentially useful drugs for treating this iron overload problem. A third chelating agent is available in Europe, deferiprone, for oral use, but is not available in the US.
Clinical trials in the MDS are ongoing with iron chelating agents to address the question of whether iron chelation alters the natural history of patients with MDS who are transfusion dependent. Reversal of some of the consequences of iron overload in MDS by iron chelation therapy have been shown.Both the MDS Foundation and the National Comprehensive Cancer Network MDS Guidelines Panel have recommended that chelation therapy be considered to decrease iron overload in selected MDS patients. Evidence also suggests a potential value exists to iron chelation in patients who will undergo a stem-cell transplant.Although deferasirox is generally well tolerated, recently a safety warning by the FDA and Novartis was added to deferasirox treatment guidelines. Following postmarketing use of deferasirox, rare cases of acute kidney failure or liver failure occurred, some resulting in death. Due to this, patients should be closely monitored on deferasirox therapy prior to the start of therapy and regularly thereafter.

Prognosis

The outlook in MDS is variable, with about 30% of patients progressing to refractory AML. The median survival time varies from years to months, depending on type. Stem-cell transplantation offers possible cure, with survival rates of 50% at 3 years, although older patients do poorly.
Indicators of a good prognosis:
Younger age; normal or moderately reduced neutrophil or platelet counts; low blast counts in the bone marrow 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 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:
The IPSS is the most commonly used tool in MDS to predict long-term outcome.
Cytogenetic abnormalities can be detected by conventional cytogenetics, a FISH panel for MDS, or virtual karyotype.

Genetic markers

Although not yet formally incorporated in the generally accepted classification systems, molecular profiling of myelodysplastic syndrome genomes has increased the understanding of prognostic molecular factors for this disease. For example, in low-risk MDS, IDH1 and IDH2 mutations are associated with significantly worsened survival.

Epidemiology

The exact number of people with MDS is not known because it can go undiagnosed and no tracking of the syndrome is mandated. Some estimates are on the order of 10,000 to 20,000 new cases each year in the United States alone. The number of new cases each year is probably increasing as the average age of the population increases, and some authors propose that the number of new cases in those over 70 may be as high as 15 per 100,000 per year.
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.

History

Since the early 20th century, some people with acute myelogenous leukemia were begun to be recognized to have a preceding period of anemia and abnormal blood cell production. These conditions were lumped together 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. 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.

Notable cases