Myelodysplastic Syndrome

What is Myelodysplastic Syndrome?

Myelodysplastic syndrome (MDS) refers to a variety of blood cancers, often described as a type of abnormality in the stem cells that produce blood cells, leading to faulty and unproductive blood cell creation in the bone marrow. In some cases, patients with MDS may progress to develop a more aggressive blood cancer known as acute myeloid leukemia (AML). Typically, MDS is found more commonly in older people over the age of 65.

The symptoms of this syndrome involve a decrease in red blood cells (the cells that carry oxygen in the body), platelets (the cells that help stop bleeding), and white blood cells (the cells that fight infections). However, the progression of MDS can vary from patient to patient. Not all patients need immediate treatment, as there’s no evidence that treating patients who don’t show symptoms, or who are deemed ‘low risk,’ would increase their lifespan. Hence, treatment is usually given to patients who show symptoms, including those who need frequent blood transfusions.

The outlook and overall survival rate for MDS patients depend on various factors, including the severity of the decrease in blood cells, the percentage of immature white blood cells (also known as blasts) in the blood and bone marrow, and the presence of specific chromosome abnormalities (referred to as the karyotype).

What Causes Myelodysplastic Syndrome?

Myelodysplastic Syndromes (MDS) is a condition caused by the abnormal functioning of a type of stem cells in your bone marrow, called myeloid stem cells. This can occur by itself, or it could be a result of damage to the bone marrow. Certain situations, like exposure to chemotherapy, radiation or environmental toxins like benzene, have been linked to MDS. It’s also known to run in families, but that is quite rare.

For MDS that arises on its own, we’re not entirely sure what causes it. It’s thought to be a result of a process that causes abnormal growth, leading to one or more mutations in the genes of cells. Thanks to advances in gene sequencing technology, we’ve recently been able to identify gene mutations, or changes, in about 80% to 90% of people with MDS. Some of the most common gene mutations include SF3B1, TET2, SRSF2, ASXL1, DNMT3A, RUNX1, U2AF1, TP53, and EZH2. For example, one mutation, RUNX1, disrupts the normal development of blood cells (hematopoiesis).

Over 100 different genes are known to have mutations in MDS. The changes in these genes affect various aspects of cell function – from how they splice their genes, to how their DNA is packed, to how they control their activity levels. Changes in these genes are linked to different features of MDS, including how severe the disease is, the percentage of immature blood cells, genetic factors, and how long people with MDS are expected to live. Although these gene mutations are not used to predict the progression of MDS, they can affect how long some patients survive. For example, one gene, TP53 (also known as a tumor suppressor gene), when mutated, is associated with a poorer prognosis compared to other mutations.

MDS can start on its own (de novo) or can be a result of previous treatment with chemotherapy drugs (treatment-related MDS or t-MDS). Treatment-related MDS is generally considered worse than de novo MDS and usually shows up 5 to 7 years after having chemotherapy. Chemotherapy drugs called alkylating agents, such as cyclophosphamide, have been linked with treatment-related MDS. This condition is typically associated with the loss of chromosomes 5 or 7 and complex genetic changes. This type of MDS can also often progress to acute myeloid leukemia (AML), a type of cancer of the blood and bone marrow. In one study of 112 patients with treatment-related MDS, 55% developed AML, compared to only about 30% of people with de novo MDS. The average survival time for patients with treatment-related MDS is around 30 weeks.

Risk Factors and Frequency for Myelodysplastic Syndrome

Myelodysplastic Syndromes (MDS) are diseases with variable occurrence rates in the United States, as indicated by medical data ranging from 2007 to 2011, which estimated about 4.9 incidents per 100,000 people and around 20,541 new cases every year. It’s crucial to note that the probability of developing MDS increases as we age, with the majority of cases reported in individuals older than 65 years. However, it’s most common in people over 80 years, with a rate of 58 per 100,000. MDS is often found more frequently in males and Caucasians.

• Myelodysplastic Syndromes (MDS) have varying rates across the U.S., with estimates around 4.9 cases per 100,000 people and about 20,541 new cases annually.
• The occurrence of MDS often increases as people age, mostly appearing in people over 65.
• MDS is most commonly seen in individuals over 80 years old, with a rate of 58 per 100,000.
• Males and Caucasians are generally more likely to be diagnosed with MDS.

Signs and Symptoms of Myelodysplastic Syndrome

Patients with MDS, or Myelodysplastic Syndromes, might not show any symptoms for years. When doctors do routine tests, they might find that the patient has fewer blood cells than is typical. Some people with MDS start to show signs of bone marrow failure, like tiredness, bleeding, or infections. These symptoms usually worsen slowly over time.

Many people with MDS feel tired, have a hard time breathing, experience chest pain, or feel dizzy. These symptoms are due to anemia, which is the most common effect of MDS. Other effects, like bleeding from low platelet count or infections from low white blood cell count, are less common.

During a physical exam, individuals with MDS might look pale, or they might have petechiae, which are small, red or purple spots on the body caused by minor bleeding. They could also have larger than normal organs, although this is rare in MDS cases.

• Symptoms might not appear for years
• Tiredness, shortness of breath, chest pain, or dizziness due to anemia
• Bleeding or tiny red or purple spots on the skin due to low platelet count
• Infections due to low white blood cell count
• Pale skin
• Perhaps larger than normal organs

Testing for Myelodysplastic Syndrome

If your doctor believes you might have MDS, a type of blood and bone marrow disorder, they will run some specific tests. The test checks for certain abnormalities in your blood cells, usually for six months or longer, to make sure these abnormalities aren’t caused by something else. The most common symptom of MDS is anemia, which means you have fewer healthy red blood cells than normal, and your red blood cells could be of normal size or larger than usual.

Your doctor might perform other lab tests if they think other conditions may be causing your anemia. These tests could include measurements of iron, ferritin, B12 and folate levels, tests to check for hemolysis (breakdown of red blood cells), and tests to rule out multiple myeloma, a type of cancer that makes too many strange proteins. In unusual circumstances, deficiencies of zinc and copper – nutritional elements – can cause anemia that seems a lot like MDS.

MDS often leads to an increase in the size of your red blood cells, but this symptom generally doesn’t get better by taking more B12 or folate vitamins. In addition, you might experience neutropenia, a condition where you have fewer than normal white blood cells, and/or thrombocytopenia, where you lack sufficient platelets in your blood. These symptoms can occur with anemia or happen later on in the disease. Your initial evaluation would consist of a complete blood count, a look at a drop of your blood under a microscope, and any other relevant laboratory tests. A further diagnostic test should include a bone marrow biopsy and aspiration, flow cytometry immunophenotyping (this checks your body’s immune response), and a study of your genes to look for mutations that might indicate MDS.

Your doctor will look at your blood tests in detail, where they might notice a decrease in one or more types of blood cells, changes in the appearance of white blood cells or platelets, and signs of immature myeloid progenitors (a type of immature white blood cell that should not typically be present in blood). In order to confirm the MDS diagnosis, the doctor will have to perform the bone marrow biopsy to look for changes in one or more types of blood cells.

To diagnose MDS, a doctor will perform an examination of the blood and bone marrow using a special dye called Giemsa and evaluating the iron in the blood cells. The doctor will check the number of young blood cells in the peripheral blood and bone marrow and count the unusual cells known as myeloblasts. If the myeloblast count is too high, the doctor might consider diagnosing someone with Acute Myeloid Leukemia, a type of blood cancer, instead of MDS.

Your doctor will also use a test called FISH to look for abnormalities in your chromosomes. While half of MDS patients show no chromosome abnormalities, the other half do, and the nature of these abnormalities can influence treatment choices and predict how the disorder will progress. For example, patients with a deletion in chromosome 5 (del(5q)) generally do better and respond well to a specific MDS medication called lenalidomide. Some chromosome changes are linked to prior chemotherapy with certain drugs.

Lastly, genetic testing will reveal any abnormal mutations present in the cells. About 80% to 90% of MDS patients have one or more mutations, and these can often inform us about the underlying cause of MDS, thereby enabling doctors to make better treatment choices.

Treatment Options for Myelodysplastic Syndrome

Myelodysplastic syndromes (MDS) are a group of disorders caused by poorly formed blood cells or ones that don’t work properly. Frequently, treatment is often based on the specific symptoms and potential health risks of each patient. Some individuals with MDS don’t need to be treated right away if they aren’t experiencing any symptoms. Often, these patients can be adequately managed with supportive care, like receiving blood or platelet transfusions from time to time.

MDS tends to progress slowly, but it can turn into a more severe disease called acute myeloid leukemia (AML) in some cases. Doctors will use tools called the IPSS or R-IPSS scoring systems to help choose the best treatment option, which could include supportive care, mild treatment with certain medications, or more intense treatment like a type of transplant called an allogeneic stem cell transplant. This kind of transplant is the only treatment that can potentially cure MDS, but it’s a tough choice, especially for older patients, due to the potential risks and the possibility of serious complications related to the transplant. That being said, high-risk patients who are in good enough health to undergo a transplant have a survival rate of nearly 50% after 3 years. Decisions about treatment should be personalized, considering the potential benefits and drawbacks for each patient.

MDS doesn’t usually respond to traditional chemotherapy, but medications like hypomethylating agents and lenalidomide have shown some promise. Milder forms of MDS may be managed with transfusions or medications that help stimulate blood cell production, but more severe forms may need a stem cell transplant or systemic treatment with stronger medications.

For patients with less severe MDS and only a few blood or platelet transfusions needed, hematopoietic growth factors can be used. These are substances in our bodies that give signals to stem cells to form more blood cells. If a test shows that levels of a substance called erythropoietin (EPO) are below normal, medications like EPO agents can be given to help the body produce more red blood cells. But if EPO levels are high, patients might need other treatments.

Lenalidomide, a kind of medication derived from thalidomide, can be used for patients with symptoms from their anemia and a specific genetic abnormality (known as deletion 5q). It is taken orally, with patients typically seeing improvement after about three months of treatment. This medication also often helps them avoid the need for more blood transfusions.

Azacitidine and decitabine are medications that can help immature cells (blasts) in the bone marrow transform into mature cells. It usually takes a few months of treatment before their effects can be observed. However, patients’ disease often progress with time, and their blood counts may drop (known as cytopenias).

The use of these medications is supported by data from clinical trials. For example, azacitidine has been shown to improve blood counts and overall survival, particularly for those with high-risk MDS. Another medication, decitabine, gives response in about 30% to 50% of patients and is thought to be slightly more potent than azacitidine.

What else can Myelodysplastic Syndrome be?

When doctors come across symptoms that resemble certain diseases, they have to consider all possible causes before making a diagnosis. These could include:

• Nutritional deficiencies like vitamin B12 or folate
• Infections, such as parvovirus or HIV
• Medication use, for example, methotrexate
• Excessive alcohol consumption

They also have to consider other diseases that start in the bone marrow. This could include conditions where the marrow produces too many blood cells or a mix of two conditions called myelodysplastic and myeloproliferative disorders, such as CMML.

What to expect with Myelodysplastic Syndrome

The future health condition of patients with MDS (myelodysplastic syndromes), a group of disorders caused by poorly formed blood cells, can vary a lot. It often depends on the genetic makeup of the patient’s cells and the severity of abnormalities in their blood cells. For example, patients with a specific genetic abnormality called 5q- typically have a better expected health outcome compared to MDS patients with a condition called monosomy 7.

Doctors often use the International Prognostic Scoring System (IPSS) or the revised IPSS (R-IPSS) to predict the health outcome of MDS patients and guide the treatment. These systems consider factors like the patient’s age, other health issues, percentage of immature cells (blasts) in the bone marrow, abnormalities in the chromosomes of cells (karyotype), and the number of blood cell types with abnormal counts (cytopenias).

For instance, certain chromosome patterns such as normal karyotype -Y, deletion 5q, and deletion 20q usually indicate a better prognosis. In contrast, complex cytogenetics (more than three abnormalities) or chromosome 7 abnormalities often point to a worse prognosis. Other chromosome patterns are categorized as intermediate risk.

Based on these factors, a risk score of low, intermediate-1, intermediate-2, or high risk is generated to guide the treatment plan.

A newer version of the scoring system, known as the Revised International Prognostic Scoring System (R-IPSS), has been developed. Besides taking into account the patient’s genetics and the percentage of blast cells, it also considers the patient’s white blood cell count, hemoglobin levels, and platelet count. This revised system has been shown to predict patient outcomes more accurately. For example, patients classified as very high risk using R-IPSS typically survive for about 0.8 years, whereas very low-risk patients can survive for about 8.8 years on average.

Patients classified as high-risk or having an unfavorable prognosis likely need treatment and may consider a procedure called an allogeneic stem cell transplant to maintain their remission, that is, the period during which their disease is under control. However, even patients with a favorable risk score may suffer significant health issues and death from MDS. Also, about a third of patients with MDS may develop a more severe form of the disease, acute myeloid leukemia (AML), which often has a very poor prognosis.

Patients with only a deletion of 5q might live longer than other MDS patients. One study found that such patients survived for about five years, with untreated patients surviving at a 40% rate and treated patients at a 54% rate.