Myelodysplastic Syndrome (MDS)

Overview

Myelodysplastic syndrome (MDS) is a group of hematologic disorders characterized by ineffective hematopoiesis, leading to peripheral blood cytopenias despite a hypercellular bone marrow. Often referred to as "preleukemia," MDS represents a clonal stem cell disorder where the bone marrow produces abnormal, immature blood cells (dysplastic cells) that cannot function properly.

The condition primarily affects older adults, with a median age at diagnosis of approximately 70 years. MDS encompasses several subtypes, each with distinct characteristics, prognosis, and treatment approaches. The hallmark of MDS is the presence of dysplastic changes in blood cell lineages, including red blood cells, white blood cells, and platelets, resulting in anemia, neutropenia, and thrombocytopenia.

MDS has the potential to progress to acute myeloid leukemia (AML) in approximately 30% of patients, making early diagnosis and appropriate management crucial. The condition can be primary (de novo) or secondary (therapy-related), with secondary MDS typically having a worse prognosis. Treatment strategies range from supportive care to aggressive interventions like allogeneic stem cell transplantation, depending on the patient's age, overall health, and disease characteristics.

Symptoms

MDS symptoms are primarily related to the underlying cytopenias (low blood cell counts) and can develop gradually over months or years. Many patients may be asymptomatic initially, with the condition discovered incidentally through routine blood tests.

Primary Symptoms

Anemia-Related Symptoms

• Fatigue: Persistent tiredness and lack of energy
• Weakness: General physical weakness
• Shortness of breath: Dyspnea on exertion or at rest
• Pale skin: Pallor of skin, gums, and nail beds
• Dizziness: Lightheadedness or feeling faint
• Rapid heartbeat: Tachycardia or palpitations
• Cold intolerance: Feeling cold or having cold hands and feet

Neutropenia-Related Symptoms

• Frequent infections: Recurrent bacterial, viral, or fungal infections
• Fever: Persistent or recurrent fevers
• Chills: Feeling cold with shivering
• Slow healing: Delayed wound healing
• Oral infections: Mouth sores or gum infections
• Respiratory infections: Pneumonia or bronchitis
• Skin infections: Cellulitis or abscesses

Thrombocytopenia-Related Symptoms

• Easy bruising: Bruises from minor trauma
• Petechiae: Small red or purple spots on skin
• Prolonged bleeding: Extended bleeding from cuts
• Nosebleeds: Frequent or prolonged epistaxis
• Gum bleeding: Bleeding during brushing or eating
• Heavy menstrual periods: Menorrhagia in women
• Blood in urine or stool: Hematuria or melena

Constitutional Symptoms

• Weight loss: Unintentional weight loss
• Loss of appetite: Decreased food intake
• Night sweats: Profuse sweating during sleep
• Bone pain: Aching in bones and joints
• Cognitive changes: Difficulty concentrating or memory problems

Advanced Disease Symptoms

• Severe infections: Life-threatening bacterial or fungal infections
• Bleeding complications: Intracranial or gastrointestinal hemorrhage
• Transfusion dependency: Requiring regular blood transfusions
• Iron overload symptoms: From frequent transfusions
• Blast crisis: Progression to acute leukemia

Organ-Specific Manifestations

Cardiac

• Heart palpitations
• Chest pain
• Exercise intolerance
• Congestive heart failure (in severe anemia)

Neurological

• Difficulty speaking
• Confusion or altered mental status
• Headaches
• Stroke (rare, due to bleeding or thrombosis)

Gastrointestinal

• Nausea and vomiting
• Abdominal pain
• Gastrointestinal bleeding
• Poor appetite

Causes

MDS results from acquired mutations in hematopoietic stem cells that lead to abnormal blood cell development. The exact cause is often unknown, but several factors can contribute to its development.

Primary (De Novo) MDS

• Idiopathic: Unknown cause in most cases
• Age-related changes: Accumulation of genetic mutations over time
• Clonal hematopoiesis: Normal aging process gone awry
• Spontaneous mutations: Random genetic alterations

Secondary (Therapy-Related) MDS

Previous Cancer Treatment

• Alkylating agents: Cyclophosphamide, melphalan, busulfan
• Topoisomerase II inhibitors: Etoposide, doxorubicin
• Radiation therapy: Ionizing radiation exposure
• Combined modality therapy: Chemotherapy plus radiation
• Latency period: Typically 2-10 years after treatment

Specific Chemotherapy Agents

• Nitrogen mustards: Mechlorethamine, chlorambucil
• Nitrosoureas: BCNU, CCNU
• Platinum compounds: Cisplatin, carboplatin
• Antimetabolites: In some cases

Environmental and Occupational Exposures

• Benzene: Industrial solvent exposure
• Petroleum products: Gasoline, diesel fuel
• Pesticides: Agricultural chemical exposure
• Heavy metals: Lead, mercury exposure
• Formaldehyde: Industrial chemical exposure
• Radiation: Atomic bomb survivors, nuclear accidents

Genetic Factors

Inherited Syndromes

• Fanconi anemia: DNA repair disorder
• Diamond-Blackfan anemia: Ribosomal protein defects
• Shwachman-Diamond syndrome: Exocrine pancreatic insufficiency
• Severe congenital neutropenia: ELANE mutations
• Dyskeratosis congenita: Telomere maintenance defects

Familial MDS

• GATA2 mutations: MonoMAC syndrome
• RUNX1 mutations: Familial platelet disorder
• CEBPA mutations: Familial acute myeloid leukemia
• DDX41 mutations: Late-onset familial MDS

Molecular Pathogenesis

Common Genetic Mutations

• SF3B1: RNA splicing factor mutations
• TET2: DNA methylation regulation
• ASXL1: Chromatin modification
• DNMT3A: DNA methyltransferase
• TP53: Tumor suppressor gene
• SRSF2: Splicing factor mutations

Cellular Mechanisms

• Apoptosis dysregulation: Increased cell death
• Cell cycle abnormalities: Impaired DNA damage response
• Epigenetic alterations: DNA methylation changes
• RNA splicing defects: Abnormal mRNA processing
• Immune dysfunction: Autoimmune components

Risk Progression Factors

• Cytogenetic abnormalities: Chromosomal changes
• Blast percentage: Higher blast counts
• Multilineage dysplasia: Multiple cell line involvement
• Specific mutations: TP53, EZH2, ETV6, RUNX1
• Complex karyotype: Multiple chromosomal abnormalities

Risk Factors

Several factors can increase the likelihood of developing MDS. Understanding these risk factors helps in early detection and prevention strategies where possible.

Demographic Risk Factors

• Age: Risk increases significantly with age, median age 70
• Gender: Slightly more common in males
• Race: More common in Caucasians
• Geographic location: Higher incidence in developed countries

Previous Cancer Treatment

High-Risk Treatments

• Alkylating agents: Particularly high cumulative doses
• Radiation therapy: Especially to bone marrow-containing areas
• Combined therapy: Chemotherapy plus radiation
• Autologous stem cell transplant: Previous transplantation

Cancer Types with Higher MDS Risk

• Hodgkin lymphoma
• Non-Hodgkin lymphoma
• Breast cancer
• Ovarian cancer
• Testicular cancer
• Multiple myeloma

Occupational and Environmental Exposures

• Chemical industry workers: Benzene and petroleum exposure
• Healthcare workers: Radiation and chemical exposure
• Agricultural workers: Pesticide exposure
• Nuclear industry workers: Radiation exposure
• Rubber industry workers: Chemical solvent exposure
• Military personnel: Agent Orange exposure

Medical Conditions

• Aplastic anemia: Previous bone marrow failure
• Paroxysmal nocturnal hemoglobinuria (PNH): Clonal blood disorder
• Autoimmune diseases: Systemic lupus erythematosus
• Immunodeficiency syndromes: Primary or acquired
• Chronic inflammatory conditions: Long-term inflammation

Genetic Predisposition

Inherited Bone Marrow Failure Syndromes

• Fanconi anemia: DNA repair defects
• Dyskeratosis congenita: Telomere disorders
• Diamond-Blackfan anemia: Ribosomal disorders
• Shwachman-Diamond syndrome: Bone marrow dysfunction
• Severe congenital neutropenia: Neutrophil disorders

Cancer Predisposition Syndromes

• Li-Fraumeni syndrome: TP53 mutations
• Neurofibromatosis type 1: NF1 mutations
• Down syndrome: Chromosomal abnormality
• Familial platelet disorder: RUNX1 mutations

Lifestyle Factors

• Smoking: Tobacco use increases risk
• Alcohol consumption: Heavy drinking
• Diet: Poor nutrition and low antioxidant intake
• Obesity: May increase risk

Medications

• Immunosuppressive drugs: Long-term use
• Chloramphenicol: Antibiotic exposure
• Phenylbutazone: Anti-inflammatory drug
• Anti-epileptic drugs: Some antiseizure medications

Age-Related Factors

• Clonal hematopoiesis: Age-related mutations
• Immune senescence: Declining immune function
• DNA repair deficiency: Reduced repair mechanisms
• Telomere shortening: Cellular aging

Diagnosis

Diagnosing MDS requires a comprehensive evaluation including blood tests, bone marrow examination, and specialized studies. Early and accurate diagnosis is crucial for appropriate treatment planning.

Initial Assessment

• Medical history: Previous treatments, exposures, family history
• Physical examination: Signs of anemia, bleeding, infection
• Performance status: Functional assessment
• Symptom evaluation: Fatigue, bleeding, infections

Laboratory Tests

Complete Blood Count (CBC)

• Anemia: Low hemoglobin and hematocrit
• Neutropenia: Low absolute neutrophil count
• Thrombocytopenia: Low platelet count
• Macrocytosis: Elevated mean corpuscular volume
• Blast cells: May be present in peripheral blood

Peripheral Blood Smear

• Dysplastic changes: Abnormal cell morphology
• Pseudo-Pelger-Huët anomaly: Neutrophil abnormalities
• Giant platelets: Large, abnormal platelets
• Oval macrocytes: Large, oval red blood cells
• Blast cells: Immature cells

Additional Blood Tests

• Vitamin B12 and folate: Rule out nutritional deficiencies
• Iron studies: Ferritin, transferrin saturation
• LDH: Lactate dehydrogenase (cell turnover marker)
• Erythropoietin level: Endogenous hormone level
• Direct antiglobulin test: Rule out hemolysis

Bone Marrow Examination

Bone Marrow Aspiration

• Cellularity: Usually hypercellular
• Blast percentage: <20% blasts (vs. AML >20%)
• Dysplastic changes: Abnormal cell development
• Iron stores: Often increased
• Ring sideroblasts: Pathological iron deposits

Bone Marrow Biopsy

• Architecture: Bone marrow structure
• Fibrosis: Degree of scarring
• Megakaryocyte morphology: Platelet precursor abnormalities
• Immunohistochemistry: Specific cell markers

Specialized Studies

Cytogenetics

• Conventional karyotyping: Chromosomal abnormalities
• FISH analysis: Fluorescence in situ hybridization
• Common abnormalities: del(5q), del(7q), +8, del(20q)
• Complex karyotype: Multiple abnormalities

Molecular Studies

• Next-generation sequencing: Mutation analysis
• Common mutations: SF3B1, TET2, ASXL1, SRSF2
• Prognostic mutations: TP53, EZH2, ETV6, RUNX1
• Clonality studies: X-chromosome inactivation

Flow Cytometry

• Blast immunophenotyping: Cell surface markers
• Aberrant expression: Abnormal marker patterns
• Minimal residual disease: Treatment monitoring
• Paroxysmal nocturnal hemoglobinuria: CD55/CD59 testing

Classification Systems

WHO Classification (2016)

• MDS with single lineage dysplasia
• MDS with multilineage dysplasia
• MDS with ring sideroblasts
• MDS with excess blasts (5-19%)
• MDS with isolated del(5q)
• MDS, unclassifiable

Prognostic Scoring Systems

• IPSS-R: Revised International Prognostic Scoring System
• WPSS: WHO-based Prognostic Scoring System
• Variables: Cytogenetics, blast percentage, cytopenias
• Risk categories: Very low, low, intermediate, high, very high

Differential Diagnosis

• Aplastic anemia
• Acute myeloid leukemia
• Vitamin B12 or folate deficiency
• Autoimmune cytopenias
• Viral infections (EBV, CMV, parvovirus)
• Drug-induced cytopenias
• Primary myelofibrosis
• Hypersplenism

Treatment Options

MDS treatment is individualized based on patient age, performance status, disease characteristics, and prognosis. Treatment approaches range from supportive care to curative stem cell transplantation.

Risk Stratification for Treatment

Lower-Risk MDS

• IPSS-R: Very low, low, intermediate risk
• Goals: Improve quality of life, reduce transfusion burden
• Approach: Supportive care with disease-modifying agents

Higher-Risk MDS

• IPSS-R: High, very high risk
• Goals: Prolong survival, delay AML transformation
• Approach: Aggressive therapy, transplant consideration

Supportive Care

Transfusion Support

• Red blood cell transfusions: For symptomatic anemia
• Platelet transfusions: For bleeding or very low counts
• Leukoreduced products: Reduce alloimmunization
• CMV-negative products: For potential transplant candidates

Iron Chelation

• Indications: Ferritin >1000 ng/mL with ongoing transfusions
• Deferasirox (Jadenu): Oral iron chelator
• Deferoxamine: IV/subcutaneous administration
• Monitoring: Cardiac and hepatic function

Infection Prevention

• Prophylactic antibiotics: For severe neutropenia
• Growth factors: G-CSF for recurrent infections
• Vaccinations: Influenza, pneumococcal
• Avoid crowds: During neutropenic periods

Disease-Modifying Therapy

Hypomethylating Agents

• Azacitidine (Vidaza): 75 mg/m² SC x 7 days every 28 days
• Decitabine (Dacogen): 20 mg/m² IV x 5 days every 28 days
• Mechanism: DNA methyltransferase inhibition
• Response rate: 40-60% overall response
• Duration: Continue until progression or intolerance

Immunomodulatory Drugs

• Lenalidomide (Revlimid): Particularly for del(5q) MDS
• Dosing: 10 mg daily x 21 days every 28 days
• Response rate: 65% in del(5q) patients
• Monitoring: Blood counts, thromboembolism risk

Erythropoiesis-Stimulating Agents

• Epoetin alfa: 40,000-60,000 units weekly
• Darbepoetin alfa: 300-500 mcg every 2-3 weeks
• Predictors of response: Low transfusion burden, low EPO level
• Response rate: 15-20% in unselected patients

Intensive Therapy

Allogeneic Stem Cell Transplantation

• Curative therapy: Only potentially curative treatment
• Age limits: Generally <75 years, fit patients
• Donor sources: Matched sibling, unrelated, haploidentical
• Conditioning: Myeloablative or reduced-intensity
• Outcomes: 40-50% long-term survival

Induction Chemotherapy

• Limited role: Generally not recommended
• Exceptions: Younger patients, high blast count
• Regimens: AML-type protocols (7+3, FLAG-IDA)
• Bridge to transplant: Reduce disease burden

Emerging Therapies

• Venetoclax: BCL-2 inhibitor combinations
• IDH inhibitors: Ivosidenib, enasidenib for mutated patients
• Luspatercept: TGF-β ligand trap for anemia
• Glasdegib: Hedgehog pathway inhibitor
• Checkpoint inhibitors: Immune therapy approaches

Treatment by Subtype

MDS with del(5q)

• First-line: Lenalidomide
• Second-line: Hypomethylating agents
• Supportive care: As needed

MDS with Ring Sideroblasts

• SF3B1 mutated: Luspatercept consideration
• Pyridoxine: Limited efficacy
• Standard therapy: Hypomethylating agents

Monitoring and Follow-up

• CBC monitoring: Weekly to monthly
• Response assessment: Every 3-6 months
• Blast monitoring: Watch for AML transformation
• Iron studies: Monitor transfusion-related iron overload
• Quality of life: Symptom assessment

Prevention

While most cases of MDS cannot be prevented due to unknown causes or age-related factors, certain risk reduction strategies may help decrease the likelihood of developing therapy-related MDS.

Therapy-Related MDS Prevention

• Minimize exposure: Use lowest effective doses of chemotherapy and radiation
• Alternative treatments: Consider less leukemogenic regimens when possible
• Risk-benefit analysis: Weigh cancer cure vs. secondary malignancy risk
• Long-term follow-up: Monitor cancer survivors for secondary malignancies

Occupational Safety

• Chemical exposure limits: Follow OSHA guidelines for benzene and solvents
• Personal protective equipment: Use appropriate respirators and gloves
• Workplace monitoring: Regular air quality assessments
• Medical surveillance: Periodic blood count monitoring for high-risk workers

Environmental Precautions

• Avoid tobacco smoke: Both active smoking and secondhand exposure
• Limit benzene exposure: Gasoline vapors, industrial solvents
• Pesticide safety: Follow label instructions, use protective equipment
• Radon testing: Test homes for radon gas

Lifestyle Modifications

• Smoking cessation: Eliminate tobacco use
• Healthy diet: Antioxidant-rich foods, fruits and vegetables
• Limit alcohol: Moderate alcohol consumption
• Exercise: Regular physical activity
• Weight management: Maintain healthy body weight

Medical Management

• Drug safety: Avoid unnecessary medications that can cause cytopenias
• Regular monitoring: Periodic blood counts if on high-risk medications
• Genetic counseling: For families with inherited bone marrow failure syndromes
• Vaccination: Stay current with recommended immunizations

High-Risk Population Management

Cancer Survivors

• Surveillance: Regular CBC monitoring
• Long-term follow-up: Dedicated survivorship clinics
• Symptom awareness: Education about warning signs
• Risk assessment: Calculate individual risk based on treatment history

Genetic Predisposition

• Family screening: Genetic testing for known syndromes
• Early detection: Regular monitoring for high-risk individuals
• Reproductive counseling: Discuss risks with family planning
• Research participation: Consider enrollment in prevention studies

Healthcare Provider Strategies

• Risk assessment: Evaluate all patients for MDS risk factors
• Monitoring protocols: Establish surveillance schedules
• Early recognition: Investigate unexplained cytopenias
• Referral guidelines: Prompt hematology consultation

Research and Development

• Biomarker studies: Identify early detection markers
• Prevention trials: Test protective interventions
• Risk prediction models: Develop better risk assessment tools
• Mechanistic studies: Understand disease development

When to See a Doctor

Early recognition of MDS symptoms can lead to prompt diagnosis and appropriate treatment. Some symptoms require immediate medical attention, while others warrant scheduled evaluation.

Seek Emergency Care (Call 911) If You Experience:

• Severe bleeding that won't stop
• Signs of severe infection (high fever, confusion, severe illness)
• Severe shortness of breath at rest
• Chest pain with difficulty breathing
• Loss of consciousness or severe dizziness
• Severe weakness preventing normal activities

Schedule Urgent Medical Evaluation For:

• Persistent fatigue lasting more than 2-3 weeks
• Easy bruising or unusual bleeding
• Frequent infections or slow healing
• Unexplained fever lasting more than a few days
• Shortness of breath with normal activities
• Pale skin, lips, or nail beds
• Petechiae (small red spots on skin)

High-Risk Individuals Should See a Doctor For:

• Any new or worsening symptoms
• Changes in energy level or exercise tolerance
• New bleeding or bruising patterns
• Recurrent infections
• Any concerning blood test results

Routine Monitoring Recommended For:

• Cancer survivors who received chemotherapy or radiation
• Individuals with known bone marrow failure syndromes
• Family members of patients with inherited MDS
• Workers with significant benzene or chemical exposure

Warning Signs by Category

Anemia Symptoms

• Progressive fatigue and weakness
• Shortness of breath during normal activities
• Rapid heartbeat or palpitations
• Dizziness or lightheadedness
• Cold hands and feet
• Pale appearance

Bleeding/Platelet Symptoms

• Easy bruising from minor bumps
• Prolonged bleeding from cuts
• Frequent nosebleeds
• Gum bleeding when brushing teeth
• Heavy menstrual periods
• Small red spots on skin (petechiae)

Infection/White Blood Cell Symptoms

• Frequent bacterial or viral infections
• Slow healing of wounds or infections
• Persistent fever without obvious cause
• Oral infections or mouth sores
• Skin infections or abscesses

Special Populations

Cancer Survivors

• Annual CBC monitoring for at least 10 years
• Immediate evaluation of any new cytopenias
• Awareness of increased MDS risk
• Discussion with oncologist about surveillance

Elderly Patients

• May have subtle or atypical symptoms
• Consider MDS in any unexplained cytopenias
• Regular monitoring if taking multiple medications
• Evaluation of cognitive changes

Before Your Appointment

• Document symptom timeline and severity
• List all medications and supplements
• Compile medical history including cancer treatments
• Note family history of blood disorders
• Bring previous blood test results
• Document occupational or environmental exposures

Related Conditions

MDS is related to several other blood disorders and may be associated with various underlying conditions or progress to more serious malignancies.

Hematologic Malignancies

• Acute lymphoblastic leukemia - Different type of acute leukemia
• Chronic lymphocytic leukemia - Lymphoid malignancy
• Multiple myeloma - Plasma cell disorder
• Hodgkin lymphoma - May increase MDS risk after treatment

Bone Marrow Failure Syndromes

• Fanconi anemia - Inherited DNA repair disorder
• Diamond-Blackfan anemia - Ribosomal dysfunction
• Shwachman-Diamond syndrome - Bone marrow failure syndrome
• Dyskeratosis congenita - Telomere disorder

Secondary Complications

• Iron overload from transfusions
• Transfusion-related infections
• Alloimmunization to blood products
• Cardiac complications from anemia
• Bleeding complications
• Opportunistic infections

Associated Conditions

• Autoimmune disorders
• Paroxysmal nocturnal hemoglobinuria
• Solid tumors (in therapy-related MDS)
• Inflammatory conditions
• Metabolic disorders

Frequently Asked Questions

References

1. Arber DA, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016.
2. Greenberg PL, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012.
3. Malcovati L, et al. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood. 2013.
4. Fenaux P, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes. Lancet Oncology. 2009.
5. List A, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. New England Journal of Medicine. 2006.
6. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Myelodysplastic Syndromes. NCCN. 2024.