INFORMATION ON DIAGNOSIS AND TREATMENT
The myelodysplastic syndromes
(MDS, myelodysplasia) are a group of blood disorders associated with low blood counts. Normally, blood cells are produced by the bone marrow (the spongy area in the middle of bones), however in MDS, the bone marrow does not function effectively to produce one or more types of blood cells, including red blood cells, white blood cells, and platelets.
Each type of blood cell performs a number of functions, including the following:
- Red blood cells carry oxygen throughout the body
- White blood cells help to protect the body from infection
- Platelets helps blood to clot normally
Normally, an organ in the abdomen (the spleen) works to balance the number of these cells in the body by removing aging cells and storing platelets. In people with MDS, the bone marrow is unable to produce enough cells to keep up with the number of cells removed by the spleen. This leads to a reduced number of cells in the body, increasing the risk of bleeding, infection, and problems related to anemia. Anemia occurs when there is a reduced number of red blood cells, which can cause fatigue, shortness of breath, or heart failure.
MDS may occur on its own (called de novo MDS) or many years after being exposed to chemotherapy or radiation (called treatment-related MDS). Treatment-related MDS is less common and is usually more difficult to treat. Most people (approximately 75 percent) are older than 60 years when they are diagnosed with MDS, although it rarely develops during childhood.
SIGNS AND SYMPTOMS — Some people with MDS have no symptoms, and are diagnosed after laboratory testing is done for another reason. Most people with MDS seek care due to symptoms of anemia, including fatigue, weakness, becoming tired quickly during activities, chest pain, dizziness, difficulty thinking clearly, or shortness of breath.
Less commonly, a person with MDS is diagnosed as a result of an infection, easy bruising, or bleeding. Symptoms such as fever and weight loss are uncommon early in the disease.
DIAGNOSIS — MDS is primarily diagnosed based upon laboratory testing, which includes the following:
- A complete blood count indicates the number of red and white blood cells, and platelets
- A blood smear involves examining a small sample of blood under a microscope to examine the number, size, shape, and type of blood cells
- Cytogenetic analysis examines the blood or bone marrow cells for signs of genetic abnormalities in the chromosomes. Researchers have discovered that the genetic makeup of the cells can vary, which can affect how a particular patient responds to treatment.
- Bone marrow aspiration and biopsy is performed to remove a sample of bone marrow from inside of a bone (usually the hip bone) and examine it with a microscope to look for abnormal cells.
TYPES OF MYELODYSPLASTIC SYNDROME — Patients with MDS have been classified into subgroups, based in large part upon the blood counts, the number of abnormal cells in the bone marrow, and the cytogenetic studies. This classification system is called the World Health Organization classification and criteria for the myelodysplastic syndromes. A person's subgroup may change over time, as the disease progresses. Approximately 10 to 15 percent of people with MDS eventually develop acute myelogenous leukemia (AML).
Perhaps the most useful clinical classification system for MDS is the International Prognostic Scoring System (IPSS). This model was devised to consider variables such as age, type of blood abnormality present, as well as studies of the genetic makeup of the abnormal cells. Based on these criteria, four risk groups were defined: low, intermediate-1, intermediate-2, and high-risk groups.
Treatment recommendations are based upon the patient's IPSS risk group; a person with low risk type MDS may live for many years before needing treatment while a person with intermediate or high-risk type MDS usually needs more immediate treatment.
TREATMENT — Other than bone marrow transplantation, there is currently no cure for MDS, although a number of treatment options are available to control symptoms, prevent complications of MDS, and improve quality of life.
Practice guidelines of the National Comprehensive Cancer Network (NCCN) suggest that treatment should be based upon the patient's age, performance status (a measure of how well a patient can perform normal daily tasks), and their risk group.
High versus low intensity — Treatment is considered to be "high" or "low" intensity, as follows:
- High intensity treatment may require hospitalization and includes intensive combination chemotherapy and blood or bone marrow transplantation.
- Low intensity treatment includes those that do not require a person to remain in the hospital, and include use of hematopoietic growth factors, low intensity chemotherapy, immunosuppressive treatments, or a thalidomide derivative.
Treatment recommendations — MDS treatment guidelines from the National Comprehensive Cancer Network include the following:
- Patients less than 61 years of age who have minimal symptoms and who are in the IPSS intermediate-2 or high risk categories (expected survival 0.3 to 1.8 years) are generally treated with high intensity therapies.
- Patients in the low or intermediate-1 category (expected survival 5 to 12 years) are generally treated with low intensity therapy.
- Patients >60 years of age with good performance status and expected survival between 0.4 and 5 years are generally treated with low intensity therapy, although selected patients may be candidates for high intensity therapies.
- For patients with a limited life expectancy, supportive care and/or low intensity therapies are recommended.
- For most patients, the best approach is to participate in a clinical trial. Clinical trials are helpful in determining the best treatment or combination of treatments.
LOW INTENSITY TREATMENTS
Supportive treatments — Supportive care includes treatment for the signs or symptoms of MDS, including a low white blood cell, platelet, or red blood cell count. Due to the advanced age of most patients with MDS and the chronic nature of the disease, supportive care is an important part of treatment for all patients. These treatments are not intended to cure the disease, although they can improve a person's quality of life and may prolong survival.
Blood transfusions — If a person's red blood cell or platelet count becomes dangerously low, it is possible to give donated blood. A person may donate whole blood or single components, such as red blood cells or platelets. All donated blood and blood products are tested for infectious diseases. Thus, the risk of developing an infection as a result of transfused blood products is now very low.
Red blood cells — Transfusions of red blood cells may be needed to treat signs or symptoms of anemia, including feeling tired or short of breath. If frequent or multiple transfusions of red blood cells are needed, iron overload may occur. A treatment called iron chelation may be recommended to remove this excessive iron from the body. Excessive levels of iron can cause organ damage. Iron chelation treatments can be taken by mouth or as an injection under the skin or into a vein.
Platelets — Transfusions of platelets may be needed to prevent or treat bleeding problems caused by too few platelets.
Hematopoietic growth factors — The hematopoietic growth factors are proteins that promote the growth and development of blood cells. The use of growth factors may reduce a person's need for blood transfusions. However, many people with MDS do not respond normally to hematopoietic growth factors because of the bone marrow's defective production of blood cells.
- Recombinant human granulocyte colony-stimulating factor (G-CSF, Neupogen®) or recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulate white blood cell (granulocyte) production, and may raise the patient's white blood cell count. Use of G-CSF alone is not recommended.
- Recombinant human erythropoietin (EPO, Procrit®, Epogen®) promotes the growth of red cells, and decreases the need for red cell transfusions in 20 percent of MDS patients.
Combination therapy, using G-CSF along with EPO, may be more effective than using EPO alone, especially in people with low to intermediate risk MDS who have low levels of EPO and in whom blood transfusions are infrequently needed.
Immunosuppressive drugs — In some patients with MDS, the immune system causes the bone marrow to slow production of blood cells. This may be especially true in people with a reduced number of cells in the bone marrow (called marrow hypoplasia).
Some of these patients, particularly those who are younger, with early stage disease and a reduced cell content of the bone marrow, respond to immunosuppressive therapies, which counter this immune attack on the bone marrow, with a resulting increased effective blood cell production. Use of an immunosuppressive therapy may allow between 50 to 60 percent of people who have the HLA DR2 tissue type to discontinue red blood cell transfusions.
Examples of immunosuppressive therapies include antithymocyte globulin (ATG) and cyclosporine. ATG is usually given into a vein once per day for four days while cyclosporine is usually taken by mouth twice per day for as long as it is effective.
Most everyone who is treated with ATG develops serum sickness, which causes hives, swelling, and fever. This reaction can be minimized by giving a steroid treatment along with the ATG.
Thalidomide derivatives — Thalidomide is a drug that may work to stimulate the immune system, causing some types of cancer to regress. A thalidomide-like drug (eg, Revlimid®, lenalidomide) has been successful in treating anemia with another type of blood cancer (multiple myeloma).
Lenalidomide is particularly effective for people with anemia and low or intermediate risk MDS with abnormalities of chromosome 5 (called the 5q minus syndrome). Such patients may no longer require red blood cell transfusions after treatment with this agent.
Chemotherapy
Low intensity chemotherapy — Chemotherapy medications in MDS aim to change bone marrow cells to develop more normally, allowing for improved production of red cells, white cells, and platelets. Low doses of a single chemotherapy drug may be recommended for people with intermediate or high IPSS scores who cannot tolerate high intensity chemotherapy or stem cell transplantation.
- Azacitidine — The chemotherapy drug, azacitidine (Vidaza®), is of great benefit, as shown in one trial that showed a longer survival and better quality of life in patients who took azacitidine compared to those who used only supportive treatments.
- Decitabine — Decitabine (Dacogen®) is similar to azacitidine. Serious side effects can occur with decitabine, including fever, infection, and low blood counts. The use of low doses of decitabine is being investigated.
HIGH INTENSITY TREATMENTS
High intensity chemotherapy — Patients with intermediate or high risk type MDS may be treated with a chemotherapy regimen similar to that used for treatment of acute myeloid leukemia. In this group, chemotherapy is used to destroy abnormal cells or prevent them from growing. However, this treatment is only recommended if the person is relatively young (eg, <60 years), with a good performance status and normal cytogenetics. High intensity chemotherapy may also be recommended for a person who is eligible for Bone marrow (stem cell) transplantation but who has no eligible donor.
High intensity chemotherapy is not generally recommended for people who are older than 60 or who have abnormal cytogenetics or a poor performance status. In this group, the expected benefit (prolonged survival) may not be worth the anticipated discomfort, hospitalization, or risk of dying from the toxicity of chemotherapy.
In some patients, supportive care can provide benefits that are equal to chemotherapy, with a lower risk of complications or toxicity. Some people do better with an approach that treats MDS- related problems, such as infection or anemia, as they occur rather than trying to cure the disease. Transfusions and antibiotics can be given as needed in place of more aggressive forms of therapy.
Stem cell transplantation — Stem cell transplantation (also called bone marrow transplantation) is the only treatment for MDS that has the potential to induce long-term remission. However, transplantation involves the use of high intensity chemotherapy, sometimes with whole body radiation, to eliminate all dividing cells in the bone marrow. However, the risks of treatment may be greater than the benefits in some situations.
In the past, patients over age 50 were not considered for stem cell transplantation, mostly due to the risk of transplant-related complications. Improvements have allowed the upper age limit for such transplantation to expand to people age 60 or more. However, approximately 75 percent of patients with MDS are older than 60 at diagnosis, so conventional transplantation can only be offered to a minority of individuals.
For treatment of MDS, the optimal source of stem cells is a brother or sister with a similar genetic makeup (ie, a matched related donor). In general, parents, children, and relatives are not suitable donors, since they do not share the same parents and therefore do not have the same genetic material. In recent years, a donor's blood has largely replaced bone marrow the source of stem cells.
Transplantation is recommended for people with intermediate-1, intermediate-2, and high risk MDS who are under the age of 60 and who have a tissue-matched sibling donor, but not for people with low risk disease. Although there is a significant chance of cure after stem cell transplantation in low risk patients (approximately 60 percent), transplant-related deaths and the relapse rate at five years are also high (as high as 40 percent).
Matched unrelated donors — The use of tissue-matched unrelated donors for patients with MDS has been limited. One study found that age was an important factor in the success of unrelated stem cell transplants; younger patients had better survival than older patients.
Reduced intensity regimens — Use of a reduced intensity treatment before transplantation may allow some patients with MDS, who would not otherwise be eligible, to undergo transplantation with a lower incidence of transplant-related complications. Reduced intensity regimens use less intensive chemotherapy with low dose or no radiation before transplantation with a sibling's matched stem cells. However, long-term data with reduced intensity regimens show an increased risk of relapse compared to normal intensity regimens.
PROGNOSIS — For people who are diagnosed with MDS, the average length of survival depends upon IPSS risk category, presence of underlying medical problems, and age. It is important to remember that these numbers represent averages, and do not necessarily predict what will happen in your situation. There is considerable variation from patient to patient, especially in the low-risk group.
CLINICAL TRIALS — Many patients will be asked about enrolling in a clinical (research) trial. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask your doctor for more information, or read about clinical trials at:
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable.
