Myelodysplastic Syndromes (MDS): The Basics

Eric T. Shinohara, MD, MSCI
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: January 11, 2009

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What is Myelodysplastic Syndrome (MDS)?

MDS is a diverse group of syndromes which are characterized by the atypical (dysplastic) or ineffective production of blood cells. These syndromes are considered to be malignant stem cell disorders. Stem cells are immature cells in the bone marrow that gradually mature to form the various components of blood. There are three main cell lines which form blood:

  • Red blood cells (also known as erythrocytes), which carry inhaled oxygen from the lungs to other organs and carry carbon dioxide from the organs to the lungs to be exhaled.
  • Platelets (also known as thrombocytes), which form clots.
  • White blood cells (also known as leukocytes), which are comprised of granulocytes, lymphocytes, and monocytes, each of which has a different role in the immune system. Lymphocytes are made up of B and T lymphocytes.

In MDS, the stem cells do not mature properly and create immature cells in the blood, known as blasts MDS can potentially transform into more aggressive malignancies such as acute leukemia

Am I at Risk for Myelodysplastic Syndrome?

The exact incidence of MDS is not known, however, estimates suggest that there are approximately 10,000 cased of MDS in the United States annually. Studies based on a large Cancer Registry in the United States suggested that there were approximately 3.3 people diagnosed with MDS per 100,000 people between 2001 and 2004.

Aging is a major risk factor for developing MDS. Recent studies have suggested that the number of people who will develop MDS is about 0.5 out of 100,000 people for people younger than 50 years of age. However this risk gradually increases; 89 out of 100,000 people who are older than 80 will develop MDS. The average age at which people are diagnosed with MDS is around 65 years of age. It is rare to see MDS diagnosed in people younger than 50 years of age unless the person has been exposed to substances which are mutagenic or have certain types of medical conditions. These conditions include a variety of genetic diseases such as Down’s syndrome and neurofibromatosis type I. Additionally people with defects in their ability to repair DNA damage, such as those individuals with Ataxia telangiectasia or Xeroderma pigmentosum are at increased risk for MDS. Prior treatment with certain types of chemotherapies, which damage the DNA (alkylating agents, topoisomerase inhibitors), also increase the risk of developing MDS. Certain chemical exposures, such as pesticides, solvents (such as benzene) and tobacco smoke can also increase the risk of developing MDS. Men and Caucasians appear to be at a slightly higher risk for developing MDS.

Though rare, MDS can occur in children at an average age of 6. There are two types of MDS which occur in children, juvenile myelomonocytic leukemia and monosomy-7 syndrome, both of which present in a similar fashion. Children with either of these diseases can present with an increased white blood cell count with a decreased red blood cell count and platelet count. The spleen may be enlarged and the skin may be involved as well. There may also be an increase in antibody production (polyclonal gammopathy).

How can I prevent MDS?

There are not any specific preventative interventions which can prevent MDS. Many of the risk factors can not be avoided, such as aging. Generally, if someone has a malignancy requiring chemotherapy or radiation it is difficult to avoid using these agents without compromising the treatment of the malignancy. One can avoid exposure to known mutational substances such as pesticides, solvents, and tobacco smoke.

What Screening Tests are Available?

There is not a specific test for MDS, however, routine blood work can be used as a screen to check the red and white blood cell counts as well as the platelet count. These tests can help with the diagnosis of MDS and prompt further more invasive testing such as a bone marrow biopsy.

What are the Signs of MDS?

People with MDS often have no symptoms which can make the disease difficult to detect. Often times people feel fine and the only signs of an abnormality are seen on laboratory testing. When people do have symptoms it is most commonly related to a low red blood cell count (anemia). 60% of people will be anemic at presentation and 26% will have bruising or other signs of decreased platelets. Less than 5% of people will have a low white blood cell count or platelet count without anemia. Anemia commonly presents as paleness. Other symptoms can include generalized fatigue as well as more fatigue with activity, such as with exercise. People may also develop chest pain and dizziness as the heart has to work harder to get adequate oxygen to the brain and other organs when the red blood cell count is low. People may also develop symptoms related to a decrease in the platelet or white blood cell count such as infections (decreased white blood cell count), and easy bruising or bleeding (low platelet count), though these symptoms are less common. Petechiae are small pinpoint spots of blood under the skin which can signify poor platelet function. Infections are due to both decreased white blood cell counts as well as dysfunction of the white blood cells. Bacterial infections are most common and they may respond slowly to antibiotics. Infections represent the most common cause of death in people with MDS.

Other problems with the immune system can also occur in people with MDS. Studies have suggested that about 15% of people with MDS have autoimmune related symptoms (where the body’s immune system attacks normal tissues). This can include damage to normal blood vessels (vasculitis), heart (pericarditis), skin, eyes (iritis), muscles (myositis), nerves (peripheral neuropathy) and red blood cells (pure red blood cell aplasia). Occasionally autoimmune diseases such as Raynaud's phenomenon and Sjogren’s disease have been associated with MDS, but it does not appear that one causes the other. Generally, the autoimmune syndrome will resolve with immunosuppressants, but treatment with these agents may increase the risk for infection.

People may also occasionally present with enlargement of the liver (hepatomegaly), spleen (splenomegaly), or enlargement of the lymph nodes (lymphadenopathy). These signs can be more common in people with a certain subtype of MDS: chronic myelomonocytic leukemia.

Symptoms, which develop late in the course of MDS, can include fevers and weight loss.

How is MDS Diagnosed?

As people, who have MDS, are often asymptomatic, laboratory tests are often used to help make the diagnosis of MDS:

Complete Blood Count (CBC):

CBC is the test people generally think of when they get their blood drawn. It allows the number of red blood cells, platelets and white blood cells to be counted. The amount of hemoglobin, the substance which carries oxygen in red blood cells, can also be checked on a CBC. A low red blood cell count is known as anemia. Decreased white blood cell counts can be seem on CBC (leucopenia) and specifically, the cells which fight bacterial infection (neutrophils) can be decreased in up to 50% of patients with MDS.

Peripheral Blood Smear:

A small sample of blood can be smeared on a slide and examined both to help count cells as well as examine them for defects.

Anemia is commonly seen in MDS. The body’s normal response to anemia is to form new blood cells (by increasing the production of immature red blood cell knows as reticulocytes) and this response may be poor in people with MDS. Reticulocytes can be counted to see if the body is responding appropriate to the low red blood cell count. Red blood cells may appear normal in MDS on a peripheral smear, but often times they have defects where then can have bizarre shapes, reflecting defective production of the red blood cells. In 8% of patients, the defects in the red blood cell shape appear similar to those seen in alpha thallasemia, another disease, which affects red blood cells. Defects in red blood cell development may also be seen on bone marrow biopsies, which can aid in diagnosis.

Defects in the appearance of the white blood cells can also be seen on a peripheral smear examined by a pathologist. These defects reflect the abnormal function of these white blood cells and people with these defects are at an increased risk of infection. There can also be defects in another type of white blood cell, known as lymphocytes. These cells have a variety of functions related to fighting infections. These defects can result in a decrease in immunoglobulin production and affect the efficacy of the immune system.

Bone Marrow Biopsy:

The person to be biopsied has local anesthetic injected into the buttock region and a small core of bone marrow is taken out using a needle. In MDS the bone marrow usually demonstrates a larger number of cells than normally seen (hypercellular marrow). This increase in cells can be in one cell line or multiple cell lines. For example an increase in the number of megakaryocytes, which will go on to form platelets in the blood, can be seen. These megakaryocytes can also appear abnormal under the microscope. Increased (thrombocytosis) or decreased (thrombocytopenia) platelets can be seen in the blood of people with MDS. Approximately 25% of people with MDS will have low platelets. This can occur because though there is an increase in the number of megakaryocytes many will die prior to becoming platelets. Increased platelets are rarer with only about 8% of people with MDS presenting with an increased platelet count. Occasionally it is possible to see a decrease in the number of cells in the bone marrow (hypocellular marrow).

There are a number of specific terms that pathologists use to describe findings seen on a blood smear or bone marrow biopsy:

  • Auer Rods: are comprised of granules which accumulate in a rod like pattern that can be seen in white blood cell blasts. They are most commonly associated with Acute Myeloid Leukemia (AML) and their presence suggests a leukemic process rather than MDS.
  • Blasts: are defined as immature blood cells
  • Monocytes: are a normal component of the immune system which can ingest (phagocytize) substances which are foreign to the body. They can go on to form macrophages when they exit the blood, which also play an important role in ingesting foreign substances (such as bacteria). Elevated monocyte counts can indicate a number of disease states including MDS.
  • Sideroblasts and Ringed Sideroblasts: When a stain for iron is used on bone marrow biopsy specimens, deposits of iron may be seen in red blood cells and these deposits are known as sideroblasts. If a large amount of iron is seen then they are known as ringed sideroblasts. This usually occurs due to a defect in the formation of hemoglobin which carries the oxygen in blood.

A number of special studies can be done to help with the diagnosis of MDS:

  • Iron Staining: for detecting sideroblasts (described above)
  • Periodic Acid Schiff (PAS) Staining: a stain to detect defects in red blood cell maturation
  • Peroxidase/Sudan Black: can be used to help define if a blast (defined below) is part of the white blood cell line
  • Esterase Stain: Can be used to detect abnormal white blood cells
  • Cytogenetic Studies: Examination of the chromosomes to check for genetic defects
  • Iron, B12 and folate levels: This are essential building blocks for red blood cells and determining if your body has adequate levels of these are important in people who are anemic
  • Serum erythropoietin (EPO) levels: EPO stimulates the bone marrow to produce more red blood cells. Low levels of EPO may be a contributing factor for anemia.

MDS can be broken down into five subtypes depending on various laboratory tests:

  • Refractory Anemia (RA): If less than 5% of the marrow on bone marrow biopsy contains blastic cells and less than or equal to 1% of the peripheral blood contains blastic cells in the setting of a limited number of monocytes, ringed sideroblasts, and Auer rods, then the MDS is classified as RA.
  • Refractory Anemia with Ringed Sideroblasts (RARS): People who have all the findings of RA, but who have greater than 15% ringed sideroblasts (instead of a limited number of sideroblasts as seen in RA).
  • Refractory Cytopenia with Multilineage Dysplasia (RCMD): People, who have less than 5% of their bone marrow involved with blasts, but, who have decreased or dysfunctional of two or more cell lines, (for example platelets and red blood cells) are considered to have RCMD.
  • Refractory Anemia with Excess Blasts (RAEB): People, who have bone marrow, which contains 5-19% blast, are considered to have RAEB. This group is further subdivided into two categories, RAEB-1 and RAEB-2, and this distinction is based on the number of blasts in the blood and bone marrow, with RAEB-2 having more of both. RAEB-2 appears to have a worse prognosis. This condition can progress to acute myeloid leukemia.
  • Refractory Anemia with Excess Blasts in Transformation (RAEB-T): People with this form of MDS have 21-30% blasts in the bone marrow or 5% or greater blasts in the blood. Auer rods in the blood are also suggestive of this condition. Some classification systems consider this condition an evolving acute myeloid leukemia.
  • Chronic Myelomonocytic Leukemia (CMML): People with CMML can have up to 20% blasts in their bone marrow and have less than 5% blasts in the peripheral blood. Their peripheral blood monocyte count is greater than 1000/microL.
  • 5q-syndrome: The 5q refers to the chromosomal abnormality associated with this type of MDS. This type of MDS tends to be more common in women and anemia is very common (80% of people will have anemia), while other blood cell lines tend to be in the normal range. This type of MDS less frequently transforms into acute leukemia (16%).
  • MDS, unclassified (MDS-U): People, who have cytopenias, but have only a few or no blasts, are classified as having MDS-U. No Auer rods should be seen on bone marrow biopsy or in the blood.

What are the Treatments for MDS?

The treatment for MDS is centered around the two main goals of:

  1. limiting the symptoms associated with the various types of decreased blood counts to improve quality of life
  2. decrease the risk of progression of this disease to acute leukemia and improve overall survival. Selecting the appropriate treatment for a patient is very important and a number of studies have demonstrated ways to determine which treatment is appropriate for a given person.

The most widely used classification system uses the International Prognosis Score System (IPSS) as one of its criteria. The IPSS assigns a point value based on various abnormalities. These abnormalities include: the percentage of blasts seen on bone marrow biopsy, type of chromosomal abnormality seen, and the number of blood lines which are decreased. These points are added up to calculate a score specific to each person. This score can be used as a measure of the aggressiveness of the disease. Additionally, the age at diagnosis and how generally healthy the person is at the time of diagnosis are taken into account when selecting a therapy.

Given that most people present with MDS at an older age and that MDS is a chronic disease, supportive care is extremely important to limit symptoms of the MDS and maintain a high quality of life. These treatments include:

Red Blood Cell Transfusions: Often times people with MDS require frequent transfusions of red blood cells to limit symptoms of anemia. This can cause large amounts of iron to build up in the person’s body which can cause damage to various organs such as the liver, pancreas and heart. Iron chelation therapy, such as with Deferoxamine, can be used to bind up the iron such that it can be passed out via the urine in the event that numerous transfusions are required.

Growth Factors: Several types of growth factors can be used to maintain the various cell lines. Granulocyte-macrophage colony stimulating factor (GM-CSF) can be used to help maintain white blood cell counts. However, people with MDS tend to develop a progressively poorer response to growth factors because their bone marrow tends to function poorly. Hence, GM-CSF is usually reserved for use in people with a low white blood cell countwho have an infection or fever that is resistant to antibiotics. Early studies have suggested that Interleukun-11 injections may be helpful in increasing platelet counts and is generally well tolerated. Erythropoietin (EPO) and darbepoetin can be used to help maintain red blood cell counts without transfusion. Some studies have suggested that using GM-CSF with EPO may be more effective than using either agent alone.

Lenalidomide: is a derivative of thalidomide which has less toxicity. It has been found to work very well in people with 5q-syndrome, though it also appears to work in some people with other types of MDS.

Hydroxyurea: is a drug which is thought to interfere with the synthesis of DNA and is used in the treatment of CMML.

Chemotherapy: There are a variety of chemotherapy options available for the treatment of MDS and the intensity of the chemotherapy treatment depends on what the physician feels the patient with MDS can tolerate and their IPSS score.

  • Low Intensity Chemotherapy: Drugs in this group include cytarabine, azacitidine and decitabine. These drugs may decrease the risk of the MDS transforming into leukemia and in some patients may improve survival.
  • High Intensity Chemotherapy: This type of chemotherapy is similar to what is used in the treatment of AML. In addition to using drugs in the low intensity group, other chemotherapeutics like daunorubicin and mitoxantrone can be used.

Stem Cell Transplant: Allogeneic stem cell transplants (where the bone marrow comes from a donor) can be used to treat MDS. This is the only potential cure for people with MDS and is generally used for people in good health who are younger than 60 who have a matched donor. However, stem cell transplants which use a less intense treatment regimen may be safe in older or very young patients. The number of blasts present must also be sufficiently low to be eligible for transplant with different cut offs used at different institutions.

Follow-up Testing

After a diagnosis of MDS, people need to be followed closely using many of the same tests that were used for diagnosis. These tests are important as they can track how well the disease is responding to therapy. This can help guide your physician’s recommendations regarding whether to continue a certain treatment of to modify therapy.

After completing treatment routine follow up is required to ensure that the MDS has not recurred.

References

Doll DC. Et al. www.uptodateonline.com

Greenberg PL. et al. NCCN Practice Guidelines in Oncology; v.1.2009 www.nccn.org

Hamblin T. Hematol Oncol Clin North Am 1992 Jun;6(3):571-86.

Linman JW. Et al Nouv Rev Fr Hematol Blood Cells 1976;17(1-2):11-31.

Ma X. et al. Cancer. 2007 Mar 7;109(8):1536-1542

Noel P. et al. Crit Rev Oncol Hematol 1992;12(3):193-215.

Nowell PC. Et al. Semin Oncol 1992 Feb;19(1):25-33.

Steensma DP. Et al Blood 2004 Feb 15;103(4):1518-20. Epub 2003 Oct 23.

National Cancer Institute Myelodysplastic Syndromes Treatment (PDQ)


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