Myelodysplastic Syndrome
Disease Details
Family Health Simplified
- Description
- Myelodysplastic syndrome is a group of disorders caused by poorly formed or dysfunctional blood cells due to bone marrow's inability to produce healthy cells.
- Type
- Myelodysplastic syndrome (MDS) is a type of cancer that affects the bone marrow and blood. Most cases of MDS are not inherited and occur sporadically. However, in rare instances, MDS can be associated with inherited genetic mutations, though the specific mode of genetic transmission can vary depending on the mutation. Generally, these inherited forms do not follow a simple Mendelian inheritance pattern and can involve various genetic and environmental factors.
- Signs And Symptoms
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Signs and symptoms are nonspecific and generally related to the blood cytopenias:
Anemia (low RBC count or reduced hemoglobin) – chronic tiredness, shortness of breath, chilled sensation, sometimes chest pain
Neutropenia (low neutrophil count) – increased susceptibility to infection
Thrombocytopenia (low platelet count) – increased susceptibility to bleeding and ecchymosis (bruising), as well as subcutaneous hemorrhaging resulting in purpura or petechiaeMany individuals are asymptomatic, and blood cytopenia or other problems are identified as a part of a routine blood count:
Neutropenia, anemia, and thrombocytopenia
Splenomegaly or rarely hepatomegaly
Abnormal granules in cells, abnormal nuclear shape and size
Chromosome abnormality, including chromosomal translocations and abnormal chromosome numberAlthough some risk exists for developing acute myelogenous leukemia, about 50% of deaths occur as a result of bleeding or infection. However, leukemia that occurs as a result of myelodysplasia is notoriously resistant to treatment. Anemia dominates the early course. Most symptomatic patients complain of the gradual onset of fatigue and weakness, dyspnea, and pallor, but at least half the patients are asymptomatic and their MDS is discovered only incidentally on routine blood counts. Previous chemotherapy or radiation exposure is an important factor in the person's medical history. Fever, weight loss and splenomegaly should point to a myelodysplastic/myeloproliferative neoplasm (MDS/MPN) rather than pure myelodysplastic process. - Prognosis
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The outlook in MDS is variable, with about 30% of patients progressing to refractory AML. The median survival time varies from years to months, depending on type. Stem-cell transplantation offers possible cure, with survival rates of 50% at 3 years, although older patients do poorly.Indicators of a good prognosis:
Younger age; normal or moderately reduced neutrophil or platelet counts; low blast counts in the bone marrow (< 20%) and no blasts in the blood; no Auer rods; ringed sideroblasts; normal or mixed karyotypes without complex chromosome abnormalities; and in vitro marrow culture with a nonleukemic growth pattern
Indicators of a poor prognosis:
Advanced age; severe neutropenia or thrombocytopenia; high blast count in the bone marrow (20–29%) or blasts in the blood;
Auer rods; absence of ringed sideroblasts; abnormal localization or immature granulocyte precursors in bone marrow section;
completely or mostly abnormal karyotypes, or complex marrow chromosome abnormalities and in vitro bone marrow culture with a leukemic growth pattern
Karyotype prognostic factors:
Good: normal, -Y, del(5q), del(20q)
Intermediate or variable: +8, other single or double anomalies
Poor: complex (>3 chromosomal aberrations); chromosome 7 anomaliesThe IPSS is the most commonly used tool in MDS to predict long-term outcome.Cytogenetic abnormalities can be detected by conventional cytogenetics, a FISH panel for MDS, or virtual karyotype.
The best prognosis is seen with RA and RARS, where some nontransplant patients live more than a decade (typical is on the order of three to five years, although long-term remission is possible if a bone-marrow transplant is successful). The worst outlook is with RAEB-T, where the mean life expectancy is less than one year. About one-quarter of patients develop overt leukemia. The others die of complications of low blood count or unrelated diseases. The International Prognostic Scoring System is another tool for determining the prognosis of MDS, published in Blood in 1997. This system takes into account the percentage of blasts in the marrow, cytogenetics, and number of cytopenias. - Onset
- Myelodysplastic syndrome (MDS) typically has an insidious onset, often developing slowly over months or years. It is more common in older adults, usually diagnosed in people aged 65 and older. Early symptoms may include fatigue, shortness of breath, easy bruising or bleeding, and frequent infections due to ineffective production of blood cells.
- Prevalence
- The prevalence of myelodysplastic syndromes (MDS) varies, but it is estimated to be between 4 to 5 cases per 100,000 people annually in the general population. The condition is more common in older adults, with significantly higher rates in those over the age of 60.
- Epidemiology
- The exact number of people with MDS is not known because it can go undiagnosed and no tracking of the syndrome is mandated. Some estimates are on the order of 10,000 to 20,000 new cases each year in the United States alone. The number of new cases each year is probably increasing as the average age of the population increases, and some authors propose that the number of new cases in those over 70 may be as high as 15 per 100,000 per year.The typical age at diagnosis of MDS is between 60 and 75 years; a few people are younger than 50, and diagnoses are rare in children. Males are slightly more commonly affected than females.
- Intractability
- Myelodysplastic syndrome (MDS) can be challenging to treat and is often considered intractable, especially in its advanced stages. Treatment options such as chemotherapy, blood transfusions, and bone marrow transplants may help manage symptoms and improve quality of life, but they often do not lead to a complete cure. The intractability of MDS varies based on the specific subtype, the patient's overall health, and how early the condition is diagnosed.
- Disease Severity
- Myelodysplastic syndrome (MDS) severity varies significantly among patients and is classified based on the risk of progression to acute myeloid leukemia (AML), cytopenias, and overall prognosis. The revised International Prognostic Scoring System (IPSS-R) categorizes MDS into very low, low, intermediate, high, and very high risk, considering factors such as bone marrow blast percentage, cytogenetics, and blood counts.
- Healthcare Professionals
- Disease Ontology ID - DOID:0050908
- Pathophysiology
- MDS most often develops without an identifiable cause. Risk factors include exposure to an agent known to cause DNA damage, such as radiation, benzene, and certain chemotherapies; other risk factors have been inconsistently reported. Proving a connection between a suspected exposure and the development of MDS can be difficult, but the presence of genetic abnormalities may provide some supportive information. Secondary MDS can occur as a late toxicity of cancer therapy (therapy associated MDS, t-MDS). MDS after exposure to radiation or alkylating agents such as busulfan, nitrosourea, or procarbazine, typically occurs 3–7 years after exposure and frequently demonstrates loss of chromosome 5 or 7. MDS after exposure to DNA topoisomerase II inhibitors occurs after a shorter latency of only 1–3 years and can have a 11q23 translocation. Other pre-existing bone-marrow disorders such as acquired aplastic anemia following immunosuppressive treatment and Fanconi anemia can evolve into MDS.MDS is thought to arise from mutations in the multipotent bone-marrow stem cell, but the specific defects responsible for these diseases remain poorly understood. Differentiation of blood precursor cells is impaired, and a significant increase in levels of apoptotic cell death occurs in bone-marrow cells. Clonal expansion of the abnormal cells results in the production of cells that have lost the ability to differentiate. If the overall percentage of bone-marrow myeloblasts rises over a particular cutoff (20% for WHO and 30% for FAB), then transformation to acute myelogenous leukemia (AML) is said to have occurred. The progression of MDS to AML is a good example of the multistep theory of carcinogenesis in which a series of mutations occurs in an initially normal cell and transforms it into a cancer cell.Although recognition of leukemic transformation was historically important (see History), a significant proportion of the morbidity and mortality attributable to MDS results not from transformation to AML, but rather from the cytopenias seen in all MDS patients. While anemia is the most common cytopenia in MDS patients, given the ready availability of blood transfusion, MDS patients rarely experience injury from severe anemia. The two most serious complications in MDS patients resulting from their cytopenias are bleeding (due to lack of platelets) or infection (due to lack of white blood cells). Long-term transfusion of packed red blood cells leads to iron overload.
- Carrier Status
- Myelodysplastic syndrome (MDS) is not typically associated with a "carrier status" because it is primarily an acquired condition rather than a hereditary one. MDS involves the ineffective production of blood cells in the bone marrow and is more common in older adults. It can be linked to prior chemotherapy or radiation therapy, environmental factors, or occur without any known risk factors. Genetic predispositions are not usually a primary concern in MDS.
- Mechanism
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Myelodysplastic syndrome (MDS) is a group of hematopoietic stem cell disorders characterized by ineffective hematopoiesis, leading to blood cytopenias and a risk of progressing to acute myeloid leukemia (AML).
**Mechanism:**
The primary mechanism involves the clonal expansion of abnormal hematopoietic stem cells in the bone marrow. This results in defective differentiation and maturation of blood cells, causing cytopenias (low blood cell counts).
**Molecular Mechanisms:**
1. **Genetic Mutations:** MDS is often associated with mutations in genes involved in epigenetic regulation (e.g., DNMT3A, TET2, ASXL1), splicing machinery (e.g., SF3B1, SRSF2), and signal transduction pathways (e.g., NRAS, JAK2).
2. **Chromosomal Abnormalities:** Common chromosomal abnormalities include deletions, translocations, and aneuploidies, such as del(5q), -7/del(7q), and trisomy 8. These abnormalities can disrupt normal cell function and promote clonal proliferation.
3. **Epigenetic Alterations:** Aberrant DNA methylation and histone modifications contribute to altered gene expression and disrupted cell maturation.
4. **Spliceosome Mutations:** Mutations in splicing factor genes can lead to defective RNA splicing, producing abnormal or ineffective proteins.
5. **Inflammatory Cytokines:** Increased levels of inflammatory cytokines in the bone marrow microenvironment can exacerbate ineffective hematopoiesis and promote apoptosis of progenitor cells.
These molecular alterations collectively disrupt normal hematopoiesis, leading to the clinical manifestations of myelodysplastic syndrome. - Treatment
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For myelodysplastic syndrome (MDS), the treatment options vary based on the specific type of MDS, the patient's overall health, and the severity of symptoms. Common treatments include:
1. **Supportive Care:**
- Blood transfusions to manage anemia.
- Platelet transfusions for thrombocytopenia.
- Growth factors like erythropoiesis-stimulating agents (ESAs) to boost red blood cell production.
- Antibiotics to prevent or treat infections.
2. **Medications:**
- Hypomethylating agents (e.g., azacitidine, decitabine) to help normalize bone marrow function.
- Immunosuppressive therapy for certain types.
- Lenalidomide, especially for those with a specific chromosomal abnormality (deletion 5q).
3. **Chemotherapy:**
- Used in cases that may progress to acute myeloid leukemia (AML) or in higher-risk MDS.
4. **Stem Cell Transplant:**
- The only potential cure for MDS. Suitable mainly for younger, healthier patients due to the risks involved.
Clinical trials may also be an option for some patients, offering access to new and experimental treatments. Treatment plans should be tailored to individual patient needs and coordinated by a healthcare professional specializing in MDS. - Compassionate Use Treatment
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Compassionate use treatment and off-label or experimental treatments for myelodysplastic syndromes (MDS) can include several options:
1. **Luspatercept**: Approved for anemia in very low- to intermediate-risk MDS with ring sideroblasts, it is sometimes used off-label for other MDS subtypes.
2. **Venetoclax**: A BCL-2 inhibitor, typically used for chronic lymphocytic leukemia, is being investigated for MDS in clinical trials.
3. **Immune Checkpoint Inhibitors**: Drugs like pembrolizumab and nivolumab are being explored for their efficacy in MDS through clinical trials.
4. **Hypomethylating Agents (HMAs)**: While azacitidine and decitabine are standard treatments, their use in combination with other agents, such as chemotherapy or novel drugs, can be considered experimental or compassionate.
5. **Stem Cell Transplantation**: For eligible patients, hematopoietic stem cell transplantation (HSCT) is considered, often as a compassionate use treatment.
6. **Experimental Drugs**: Several new drugs and treatment combinations are under investigation in clinical trials, and patients may access these through compassionate use programs.
These options should be discussed with a healthcare provider to evaluate their suitability and potential benefits for individual cases. - Lifestyle Recommendations
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For individuals with myelodysplastic syndrome (MDS), lifestyle recommendations can help manage the condition and improve overall well-being. Here are some general suggestions:
1. **Nutrition**: Maintaining a balanced diet rich in fruits, vegetables, whole grains, lean proteins, and healthy fats is crucial. Foods high in antioxidants and vitamins can support immune function.
2. **Exercise**: Regular physical activity can help improve energy levels, muscle strength, and overall quality of life. Low-impact exercises such as walking, swimming, or yoga are often recommended, but it's important to tailor activity to individual capabilities and consult with a healthcare provider.
3. **Avoid Infections**: Due to a weakened immune system, individuals with MDS should take precautions to avoid infections. This includes frequent hand washing, avoiding large crowds during flu season, and staying up-to-date with vaccinations (after consulting with a healthcare provider).
4. **Avoiding Toxins**: Limiting exposure to environmental toxins and chemicals that may worsen the bone marrow's functioning is advisable. This includes avoiding smoking and limiting alcohol consumption.
5. **Stress Management**: Chronic stress can negatively impact health. Techniques such as meditation, deep-breathing exercises, or engaging in hobbies can help manage stress levels.
6. **Regular Medical Check-ups**: Continuous monitoring by a healthcare provider is essential for managing MDS. Regular blood tests and follow-up appointments help track the disease's progression and effectiveness of treatments.
7. **Stay Hydrated**: Adequate fluid intake is important for overall health and can help alleviate some side effects of treatments.
Consulting with healthcare professionals for personalized advice and recommendations is essential when managing myelodysplastic syndrome. - Medication
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Myelodysplastic syndrome (MDS) is typically treated with various medications depending on the specific subtype and severity. Common medications include:
1. **Hypomethylating Agents**:
- Azacitidine
- Decitabine
2. **Immunomodulatory Drugs**:
- Lenalidomide (especially for patients with a deletion 5q cytogenetic abnormality)
3. **Immunosuppressive Therapy**:
- Antithymocyte globulin (ATG)
- Cyclosporine
4. **Growth Factors**:
- Erythropoiesis-stimulating agents (e.g., erythropoietin, darbepoetin alfa)
- Granulocyte colony-stimulating factors (G-CSFs) like filgrastim
5. **Chemotherapy**:
- Limited use in higher-risk MDS, often similar agents used in acute myeloid leukemia (AML)
6. **Targeted Therapy**:
- Luspatercept (for anemia in lower-risk MDS with ring sideroblasts)
The choice of medication can vary based on individual patient factors, including genetic mutations, blood counts, and overall health. - Repurposable Drugs
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There are several drugs originally developed for other conditions that have shown potential for repurposing in the treatment of myelodysplastic syndromes (MDS). These include:
1. **Lenalidomide**: Initially used for multiple myeloma, lenalidomide is effective, particularly in patients with deletion 5q chromosomal abnormality.
2. **Azacitidine and Decitabine**: Originally developed for acute myeloid leukemia, these hypomethylating agents are now standard treatments for MDS.
3. **Vorinostat**: Primarily used for cutaneous T-cell lymphoma, this histone deacetylase inhibitor is being studied in combination therapies for MDS.
Research continues to explore other potential repurposable drugs for MDS. - Metabolites
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In myelodysplastic syndrome (MDS), several metabolic disturbances can be observed. Key metabolites that may be altered include:
1. **Amino Acids**: Variations in amino acid levels like glutamine, glycine, and serine may be detected.
2. **Lipid Metabolism**: Lipid profiles, including abnormal cholesterol and fatty acid levels, can show changes.
3. **Energy Metabolites**: Alterations in glucose metabolism and energy-related metabolites such as ATP, ADP, and lactate can occur.
4. **Oxidative Stress Markers**: Increased oxidative stress markers like malondialdehyde (MDA) and decreased levels of antioxidants such as glutathione.
Detailed metabolic profiling can provide insights into the metabolic imbalances associated with MDS. - Nutraceuticals
- In the context of myelodysplastic syndrome (MDS), nutraceuticals refer to food-derived products that provide health benefits, potentially beyond basic nutrition. Examples could include vitamins, minerals, antioxidants, and herbal supplements. These can sometimes be used to support overall health and manage symptoms, but they are not a cure for MDS. It is crucial to consult with a healthcare provider before starting any nutraceuticals, as they can interact with conventional treatments and might affect the progression of the disease.
- Peptides
- Myelodysplastic syndrome (MDS) is a group of disorders caused by poorly formed or dysfunctional blood cells. Peptides and nanoparticles (nan) are being explored in research for their potential roles in diagnostics and treatments. Peptides may be used as biomarkers for early detection or as therapeutic agents targeting specific pathways involved in MDS. Nanoparticles are being investigated for targeted drug delivery systems to improve the efficacy and reduce the toxicity of treatments.