What is Myelodysplastic Syndrome?
Myelodysplastic syndrome is a group of hematological conditions resulting from the ineffective function or production of the myeloid blood cells. Formerly known as pre-leukemia, the bone marrow develops progressive failure and results in cytopenias (low blood count). About 30% of patients with MDS progress to acute myelogenous leukemia, which can occur within a few months or years from the onset of the condition.
MDS originates from a disorder in the stem cell in the bone marrow which reduces the number of blood-forming cells, resulting in impaired blood production or hematopoiesis. There is an increase in myeloblasts which are immature and unable to produce mature red blood cells. The primary manifestation of MDS is anemia due to low red blood cell production.
Classification of Myelodysplastic Syndrome
Myelodysplastic syndrome can be classified as:
- Refractory Anemia. This involves less than 5% of myeloblasts and pathological conditions in the red blood cell precursors.
- Refractory Anemia with ringed sideroblasts (RARS). This involves less than 5% of myeloblasts, but with greater numbers of abnormal iron-stuffed red blood cell precursors known as the ringed sideroblasts.
- Refractory Anemia with Excess blasts (RAEB). This involves up to 20% of myeloblasts in the bone marrow.
- Refractory Anemia with Excess Blasts in Transformation (RAEB-T). This involves 21-30% of myeloblasts in the bone marrow.
- Chronic Myelomonocytic Leukemia (CMML). This involves less than 20% of myeloblasts with greater than 109/uL monocytes in the blood.
Some cases of MDS are difficult to classify, as in cases with neutropenia (decreased circulating neutrophils) and thrombocytopenia (decreased platelet count). The incidence of MDS increases with age. People aged 70 or over are more at risk, but some documented cases were in patients younger than 50 years of age. MDS in children is rare, and males have a higher incidence of developing MDS than females. The incidence of MDS is up to 20,000 cases per year.
History of MDS
MDS was first described as pre-leukemia in 1953. There were many terms that described MDS until 1976 when it was popularly known as myelodysplastic syndrome.
Death occurring from MDS is not directly related to the progression to leukemia, but is influenced by infections and hemorrhage, despite absence of leukemia. MDS which progresses to leukemia is also resistant to treatment.
What are the Symptoms of Myelodysplastic Syndrome?
Symptoms of myelodysplastic syndrome are related to the decreased circulating blood component levels. These include:
- Anemia. Symptoms and signs include shortness of breath, chronic fatigue. chest pains, chillis and paleness
- Thrombocytopenia. Symptoms and signs include increased bleeding episodes, bruising (ecchymosis), purpura (several hematoma) and petechial rash (reddish pinpoint rash on the skin)
- Neutropenia. Symptoms and signs include increased risk of infection and sore throat
- Hepatomegaly or splenomegaly. This is due to rapid hemolysis of the blood component, which is filtered by the spleen and liver.
- Abnormal characteristics of blood cells. These are normally identified by examination
What Causes Myelodysplastic Syndrome?
The exact cause of myelodysplastic syndrome is not known, but several risk factors contribute to its development. Risk factors include:
- Smoking or tobacco use.
- Old age (more than 60 years old).
- Exposure to radiation such as in the presence of an atomic bomb or nuclear reactors.
- Exposure to benzene and chemicals used in the production of rubber and petroleum.
- Previous radiation or chemotherapy and radiomimetic agents such as nitrosourea, busulfan and procarbazine.
- Disorders such as Fanconi anemia, acquired aplastic anemia, congenital neutropenia, familial platelet disorder and Shwachman-Diamond syndrome
The disorder occurs along with the mutation of the bone marrow stem cell which causes impairment in the blood precursor cells. There is also an increased rate in apoptosis (cell death) of bone marrow cells leading to impaired blood cell production.
How to Diagnose Myelodysplastic Syndrome?
The exact diagnosis of MDS is difficult because genetic testing needs to be done to determine gene mutations. However, several general tests are normally done to determine the extent of blood cell impairment. Other causes of low blood component levels should be ruled out to diagnose MDS. These include:
- Medical History and Physical Assessment. The complete medical history of the patient is assessed to check for any risk of development of MDS. Physical examinations are also done to assess any signs and symptoms of the disorder.
- Complete Blood Count. The complete blood count is taken to determine levels of RBCS, hemoglobin, hematocrit, WBCs, and platelets in the blood. Specific levels of WBC type are also taken such as the neutrophils and monocytes.
Types of MDS are identified using the following indicators:
- Refractory Anemia – there are few RBCs, but the WBC and platelets are normal
- Refractory Anemia with ringed sideroblasts – there are few RBCs with excessive iron in them. WBC and platelets are normal.
- Refractory Anemia with excess blasts – there are few RBCs with up to 20% of blasts in the bone marrow with normal amount of blasts in the blood. WBCs and platelets are sometimes low.
- Refractory Anemia with excess blasts in transformation – there are few RBCs, platelets and WBCs in the blood. Up to 30% of bone marrow cells and more than 5% of blood cells are blasts.
- Unclassifiable MDS – there are few blood cells in the blood, the level of blasts is normal and the condition is not characterized as MDS syndrome.
- Bone marrow aspiration – Samples of the bone marrow are collected using a long-thin needle on the pelvis or breastbone of the patient. The samples are subjected to biopsy or cytogenetic analysis.
- Biopsy – The bone marrow cells are examined to determine any cellular aberrations or changes. The common finding is a dysplasia of the bone marrow cells.
Source – cancer.gov
- Cytogenetic Analysis – Sample bone marrow cells are examined under a microscope to check the chromosome and cell characteristics.
- Peripheral blood smear – This involves the checking of the shape, size and iron-loading of the red-blood cells. Certain types of MDS show excessive iron in the red blood cell precursors.
- Tests for other causative factors of anemia – Diagnostic tests for renal failure, vitamin B deficiency, hepatitis, lupus, heart failure, HIV and hemolytic anemia are done to determine if the anemia is caused by other factors or by MDS.
How to Treat Myelodysplastic Syndrome?
Treatments for MDS is focused on alleviating the symptoms, improving survival rate and preventing progression to acute myelogenous leukemia. These include:
Chemotherapy is administered with hypomethylating agents to reduce the DNA methylation that causes abnormal and excessive production of blood cell components. Chemotherapeutic drugs include 5-azacytidie, Lenalidomide and Decitabine. These drugs are expensive averaging $9,000 per month of therapy. Chemotherapy with these agents may lessen requirements for blood transfusions and may increase the life expectancy of clients with MDS.
Stem Cell Transplantation
Bone marrow transplantation is done to replace the non-functional stem cells that produce abnormal blood components. Bone marrow transplantation is done with severe forms of MDS. Stem cells are usually taken from compatible donors.
Transfusions with blood components are essential to normalize the blood component levels in the body. Anemia may require RBC transfusions and thrombocytopenia with platelet transfusions. Blood transfusions should be monitored because frequent transfusions may lead to iron overload.
Iron Chelation Therapy
Patients with high iron levels in the blood may be treated with deferoxamine (IV) or deferasirox (oral) to decrease iron overload.
The prognosis of MDS depends on the type. Refractory anemia and RARS have the best prognosis among possible MDS types. Patients with these types of MDS may live up to one more decade, even without transplantation. The worst prognosis is from RAEB-T which has a life-expectancy of less than 1 year upon diagnosis. Patients with RAEB-T may also progress to having acute myelogenous leukemia.
Prognosis also depends on the following factors:
Good prognosis factors
- Younger patients
- Moderate neutropenia
- Moderate thrombocytopenia
- Low blasts count in the bone marrow (less than 5%)
- No blasts in the blood
Poor prognosis factors
- Old age
- Severe thrombocytopenia and neutropenia
- High levels of blasts in the bone marrow and in the blood
- Abnormal karyotypes or chromosomal abnormalities
Life Expectancy and Survival Rate
The life expectancy of patients with MDS also depends on the type of MDS. The mean life-expectancy is 18 to 24 months in mild cases of MDS or longer when stem cell transplantation is done. Mild cytopenias, low blasts and normal chromosomes have this range of life-expectancy. On the other hand, patients with severe cytopenias, chromosome abnormalities and high blast levels in the bone marrow and blood have a mean survival time of 6 to 12 months. There is a low survival rate of MDS, and patients may only live up to a maximum of 10 years when treatments are instituted.
Complications of MDS may result, such as:
- Iron overload. Patient receiving frequent blood transfusions due to anemia and cytopenias may develop iron overload.
- Severe anemia. This is the most common complication of MDS due to decrease in RBC production rate.
- Infection. This is the most common reason for death among MDS patients. This results from low WBC count which decreases the immune system.
- Hemorrhage. This results from low platelet count in the body which reduces the blood clotting mechanism.
- Leukemia. Severe types of MDS can progress to acute myelogenous leukemia over a period of months or years.
Although there is a big genetic predisposition to MDS, some risk factors can be avoided to help prevent the disease. These include:
- Avoiding too much radiation exposure.
- Wearing personal protective equipment in factories to prevent exposure to chemicals.
- Stopping smoking and tobacco use, and avoiding other forms of carcinogens.
The Role of Genetics
Researchers have indicated that there is a loss of mitochondrial function and accumulation of DNA mutations in the stem cells of the bone marrow. The mutation occurs specifically in the gene U2AF1. The role of genetics has led to the use of DNA methyltransferase inhibitors which improves the DNA methylation profile of the bone marrow stem cells. Loss of DNA methylation results in abnormal and uncontrolled cell growth. Inhibiting its dysfunctional DNA methylation by the DNA methlytransferase inhibitors restores normal blood cell production and prevents progression to leukemia.
Edited and proofreading done by Chris