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. Early on, no symptoms are typically seen. Later symptoms may include fatigue, shortness of breath, bleeding disorders, anemia, 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 of MDS cause an increase in the production of immature blood cells (called blasts), in the bone marrow or blood. The different types of MDS are identified based on the specific characteristics of the changes in the blood cells and bone marrow.
Treatments may include supportive care, drug therapy, and hematopoietic 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. Some people can be cured by chemotherapy followed by a stem-cell transplant from a donor.
Myelodysplastic syndrome (MDS) occurs primarily in older adults. The median age at diagnosis is around 73 years, and the incidence increases with age. Approximately 86% of cases are diagnosed in individuals aged 60 or more, while about 6% of cases are in those aged 50 or more. Although rare in children, the annual incidence is estimated at one to four cases per million each year, with the median age being 6.8 years in pediatric cases.
In the United States, an estimated 10,000-15,000 new cases of MDS are diagnosed annually. It is estimated that between 60,000 to 170,000 individuals currently live with MDS in the US. The overall annual incidence rate is approximately 4.0 to 4.9 per 100,000 people for the general population, increasing to more than 60 per 100,000 among individuals over 85 years of age.However, these figures are believed to underestimate the true incidence due to underdiagnosed or underreported patients.
MDS is more common in males than females, with a male-to-female incidence ratio around 4.5:2 per 100,000 individuals.The disease also appears more frequently in white populations compared to other racial and ethnic groups.
Most deaths among MDS patients come from the disease getting worse and turning into leukemia. It can transform into acute myeloid leukemia (AML) when accumulating genetic mutations cause immature blood cells to stop maturing, so instead they proliferate uncontrollably in the bone marrow.A study was done on 137 patients with MDS, who had died. Most deaths (27.4%) were from MDS progressing rapidly, turning into AML (21.7%), pneumonia (16%), and sepsis (8.5%) in high-risk groups.
Signs and symptoms
Many individuals with MDS have no noticeable symptoms when diagnosed. The condition is often first identified after blood tests show low blood cell counts.
Anemia, caused by a lack of red blood cells, is the most common symptom in MDS. Because red blood cells carry oxygen throughout the body, low red blood cell counts can lead to symptoms like fatigue, weakness, shortness of breath, dizziness, and pale skin. Some people experience chest pain because of decreased oxygen in the body.
Neutropenia, a reduction in neutrophils (a type of white blood that fights bacterial infections), increases the risk of infection. People with neutropenia often experience infections and fevers. Sometimes, infections can be the symptom that leads to a diagnosis.
A low platelet count, called thrombocytopenia, can harm normal blood clotting, so many bruise easily and bleed for longer times. Small red or purple spots on the skin, known as petechiae, occur because of bleeding under the skin.
Many individuals are asymptomatic, and blood cytopenia or other problems are identified as a part of a routine blood count: Neutropenia, anemia, and thrombocytopenia Splenomegaly or rarely hepatomegaly Abnormal granules in cells, abnormal nuclear shape, and size Chromosome abnormality, including chromosomal translocations, and abnormal chromosome number
Patients with MDS have an overall risk of almost 30% for developing AML.
Anemia dominates the early course. Most symptomatic patients complain of the gradual onset of fatigue and weakness, dyspnea, and pallor. 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.
Cause Myelodysplastic syndrome begins with a change in a single stem cell in the bone marrow; these mutated cells start accumulating, leaving little room for healthy cells. Bone marrow is designed to make new cells that develop over time; MDS is the result of a disruption to this process. MDS is not usually inherited from parents or grandparents; it is a mutation that occurs over a person’s lifetime. Although it may be genetically inherited, it is extremely rare. GATA2 deficiency and SAMD9/9L syndromes each account for about 15% of MDS cases in children. Causes for MDS are not known, but cancer treatments such as chemotherapy (especially alkylating agents such as melphalan, cyclophosphamide, busulfan, and chlorambucil) and radiotherapy can affect a person’s bone marrow, which can eventually cause MDS. Blood conditions such as clonal hematopoiesis of indeterminate significance, idiopathic cytopenia of unknown significance, or clonal cytopenia of unknown significance can increase the risk of developing MDS.
Long-term chemical exposure can increase the risk of developing MDS; some of these chemicals include benzene (tobacco smoke/manufacturing), pesticides, chemical fertilizers, or radiation. Workers in some industries with heavy exposure to hydrocarbons, such as the petroleum industry, have a slightly higher risk of contracting the disease. Xylene and benzene exposures have been associated with myelodysplasia. People 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".
Pathophysiology MDS most often develops without an identifiable cause. Risk factors include exposure to an agent known to cause DNA damage, such as radiation, benzene, and certain chemotherapies; other risk factors have been inconsistently reported. Proving a connection between a suspected exposure and the development of MDS can be difficult, but the presence of genetic abnormalities may provide some supportive information. Secondary MDS can occur as a late toxicity of cancer therapy (therapy-associated MDS, t-MDS). MDS after exposure to radiation or alkylating agents such as busulfan, nitrosourea, or procarbazine typically occurs 3–7 years after exposure and frequently demonstrates loss of chromosome 5 or 7. MDS after exposure to 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.
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 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.
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.
Genetics The recognition of epigenetic changes in DNA structure in MDS has explained the success of two (namely the hypomethylating agents 5-azacytidine and decitabine) of three (the third is lenalidomide) commercially available medications approved by the 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.
DNA damage 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. 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. In MDS an increased frequency of chromosomal breaks indicates defects in DNA repair processes. 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.
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, 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.
Splicing factor mutations
Mutations in splicing factors have been found in 40–80% of people with MDS, with a higher incidence of mutations detected in people who have more ring sideroblasts.
IDH1 and IDH2 mutations