Myelodysplastic Syndrome

What is Myelodysplastic Syndrome (MDS)?

Myelodysplastic Syndrome (MDS) refers to a group of neoplasms in which the blood-forming cells in the bone marrow are abnormal and cannot differentiate into the mature cells seen in peripheral blood. As a consequence, there is a reduction (cytopenias) in the different types of cells (red blood cells, white blood cells, and platelets), although the most common finding in the disease is a decrease in red blood cells (anemia). In addition to cytopenias, there is a variable risk, according to the type of MDS, of transformation into acute myeloid leukemia (AML). The presence of dysplasia in one or more cell lineages is crucial in the diagnosis of MDS. Cytogenetic tests and more recently next-generation sequencing tests that identify gene mutations, combined with the presence of dysplasia, assist in the diagnosis.

The presence and severity of cytopenias, presence and quantity of immature cells (blasts), cytogenetic and molecular alterations define risk scores for death and/or transformation to AML. These risks are essential in establishing the treatment strategy.

MDS occurs more frequently in people over 50 years old, especially those over 65 years old. Men are more likely to be affected than women.

Subtypes of Myelodysplastic Syndrome

The World Health Organization (WHO) divides myelodysplastic syndrome into seven categories:

• Refractory Cytopenia with Unilineage Dysplasia (RCUD) – patients have a low number of one type of blood cell, but normal numbers of the other types. Approximately 5% to 10% of all myelodysplastic syndromes are RCUD. This type of myelodysplastic syndrome rarely progresses to acute myeloid leukemia (AML).
• Refractory Anemia with Ring Sideroblasts (RARS) – similar to refractory anemia, except that 15% or more of the red blood cells in the blood or bone marrow contain iron deposits in a ring around the nucleus. It rarely transforms into leukemia.
• Refractory Cytopenia with Multilineage Dysplasia (RCMD) – the count of at least two types of blood cells (red blood cells, white blood cells, or platelets) is decreased. Ring sideroblasts may or may not be present. The number of blasts in the bone marrow is less than 5%. It accounts for about 40% of patients with myelodysplastic syndrome. It can transform into leukemia in about 10% of patients.
• Refractory Anemia with Excess Blasts-1 (RAEB-1) – one or more types of cells are low in the blood and appear abnormal in the bone marrow. The number of blasts in the bone marrow is higher but still less than 10%. The risk of RAEB-1 transforming into acute myeloid leukemia is about 25%.
• Refractory Anemia with Excess Blasts-2 (RAEB-2) – this type is similar to RAEB-1, except that the bone marrow contains 10% to 20% blasts. The risk of RAEB-2 transforming into acute myeloid leukemia can reach 50%.
• Myelodysplastic Syndrome Unclassifiable (MDS-U) – this type of myelodysplastic syndrome is uncommon. To be considered MDS-U, the findings in the blood and bone marrow do not fit into any other type of myelodysplastic syndrome.
• Myelodysplastic Syndrome Associated with Isolated Deletion of Chromosome 5q – in this type, the chromosomes in the bone marrow show that a part of chromosome 5 is missing. In the blood, the red blood cell count is low, but the white blood cell count is normal. Often, the platelet count is increased. For unknown reasons, patients with this type of myelodysplastic syndrome have a very good prognosis and rarely develop leukemia.

Symptoms and signs of myelodysplastic syndrome

The symptoms depend on which type of cell is altered and can evolve very slowly. In general, they include:

• Fatigue, weakness, and other symptoms related to anemia;
• Fever due to infections (if the number of white blood cells decreases);
• Abnormal bleeding;
• Development of bruises (if there is a decrease in the number of platelets);
• Bone pain;
• Loss of appetite.

As these symptoms can also be caused by another disease other than MDS, it is important to seek medical attention for the correct diagnosis of the origin of the symptoms.

Diagnosis of myelodysplastic syndrome

Some people present signs or symptoms suggestive of myelodysplastic syndrome (MDS), and tests are then requested for verification. In some cases, even without symptoms, the suspicion of the syndrome may arise after routine blood tests.

In both situations, the doctor should request complementary tests to analyze the blood cells and bone marrow to confirm the diagnosis. Understand the procedures that can be performed.

• Complete blood count – measures the levels of red blood cells, white blood cells, and platelets in the blood. Patients with MDS usually have low red blood cell counts (anemia). They may also have decreased white blood cells and blood platelets.

Patients with some types of MDS may have myeloblasts (“blasts”) in the blood, which are very early forms of blood cells, normally found only in the bone marrow. Blood abnormalities may suggest MDS, but the doctor cannot make an exact diagnosis without examining a sample of bone marrow cells.

• Other blood tests – tests may be requested to check for other possible causes of the abnormality in the blood count. For example, low levels of iron, vitamin B12, or folic acid can also cause anemia. If any of these are abnormal, the diagnosis of MDS is much less likely.
• Bone marrow tests – Samples are usually collected from the back part of the pelvic bone (hip). These tests are used first for diagnosis and classification and may be repeated later to see if MDS is responding to treatment or transforming into acute leukemia.

Additionally, during the procedure, the skin over the hip and the surface of the bone are numbed, a thin hollow needle is inserted into the bone, and a syringe is used to draw a small amount of liquid bone marrow.

Bone marrow biopsy is also performed by taking a small piece of bone and marrow with a slightly larger needle. The size, shape, and other characteristics of the cells will be examined. For a diagnosis of MDS, the patient must have less than 20% blasts in the bone marrow and blood. A patient with more than 20% blasts is considered to have acute myeloid leukemia (AML).

• Flow cytometry and immunohistochemistry – cell samples are treated with antibodies. These tests can be useful for distinguishing different types of MDS or leukemia from other diseases.

Cytogenetic evaluation is extremely important in the diagnosis of myelodysplastic syndrome, as it examines the chromosomes within the cells. Each cell should have 46 chromosomes (23 pairs), and abnormal chromosomes are common in MDS. Certain chromosomal changes in the cells can help predict the likely course of the syndrome. For example, the deletion of a part of chromosome 5, or del(5q), usually predicts a better outcome (as long as there are no other changes). Changes in 3 or more chromosomes or deletion of chromosome 7 tend to have a slightly worse outlook. Chromosomal tests include:

• Karyotyping with bands – cells are examined under a microscope to check for chromosome abnormalities. The result usually takes 2 to 3 weeks because the cells must grow on laboratory plates before their chromosomes can be visualized;
• Fluorescence in situ hybridization (FISH) – examines the cell’s DNA more closely, using fluorescent dyes that bind only to specific genes or chromosomal changes. FISH does not require cells in active division, so it can usually provide results in a few days;
• Molecular assessment – Polymerase Chain Reaction (PCR) – a highly sensitive DNA test that can detect some very small chromosomal changes that are too small to be seen under a microscope, even if there are few abnormal cells in a sample.
• NGS – Next-generation sequencing – a molecular technique that identifies various mutations that may be related to myeloid neoplasms such as MDS and AML.

Treatment for Myelodysplastic Syndrome

The treatment of MDS varies according to the risk of the disease. It can range from supportive therapies that help treat symptoms or complications to hematopoietic stem cell transplantation (bone marrow transplant), including the use of chemotherapy drugs such as hypomethylating agents. Transplantation is the only potentially curative procedure, but due to its risks, it is indicated only for specific cases with a high risk of death from the disease or transformation to AML.

Supportive therapies help treat the symptoms or complications of myelodysplastic syndromes (MDS). They can be used alone or with other treatments for MDS. For example, for many patients with MDS, one of the main goals of treatment is to prevent problems caused by low blood cell counts.

Alternative treatments:

• Treatment for low red blood cell counts (anemia) – low red blood cell counts (anemia) can cause fatigue and other symptoms. Patients with MDS and anemia may benefit from receiving injections of the growth factor erythropoietin, which helps the bone marrow produce new red blood cells. Another option may be red blood cell transfusions;
• Treatment of iron buildup from blood transfusions – blood transfusions can cause excess iron to accumulate in the body. Over time, the iron can build up in the liver, heart, and other organs, affecting their function. Medications called chelating agents, which bind to iron so that the body can get rid of it, may be used in patients who develop iron overload from red blood cell transfusions (unless they have altered renal function);
• Treatment for low platelet counts – patients with MDS with low platelet counts may have bleeding problems or bruise easily. Options for treating low platelets may include platelet transfusions or treatment with growth factor;
• Treatment for low white blood cell counts – Patients with low white blood cell counts are more likely to get infections. Their doctors should be informed immediately about any possible signs of infection, such as fever, signs of pneumonia (cough, shortness of breath), or urinary tract infection (burning when urinating).
• Hypomethylating agents (azacitidine or decitabine) – are drugs that act on the DNA methylation process. They are important in intermediate and high-risk cases because they increase the patient’s lifespan and reduce the need for transfusions.
• Luspatercept – a drug that acts on the Smad 2/3 cell signaling pathway, producing differentiation and maturation of the erythroid lineage. It is mainly used in the subtype Refractory Anemia with Ring Sideroblasts and/or with the SF3B1 mutation, increasing hemoglobin levels and reducing the need for transfusions.
• Hematopoietic stem cell transplantation – a high-risk procedure that is performed by donating stem cells from a healthy, HLA-compatible donor to the patient. It is used in patients with intermediate or high-risk MDS and with clinical conditions good enough to tolerate this procedure.

Prevention

At the moment, there are no widely recommended tests for screening for myelodysplastic syndromes (MDS), as their cause is typically unknown. It is not possible to prevent the syndrome, only to maintain health and keep up with exams so that, if necessary, the diagnosis occurs early.