What is myelodysplastic syndrome (MDS) in older adults with pre-existing medical conditions such as cardiovascular disease or chronic kidney disease?

What is Myelodysplastic Syndrome?

Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders that predominantly affect elderly patients, characterized by ineffective bone marrow production leading to persistent blood cytopenias (low blood counts) and a risk of transformation to acute myeloid leukemia in approximately one-fourth to one-third of cases. 1

Core Pathophysiology

MDS represents a malignant process where the bone marrow stem cells become abnormal and produce defective blood cells through a multistep process involving:

• Cytogenetic abnormalities and gene mutations that drive the clonal disorder 1
• Ineffective hematopoiesis where the bone marrow appears hypercellular (sometimes hypocellular) but fails to produce adequate functional blood cells, resulting in peripheral cytopenias despite active marrow 1
• Widespread gene hypermethylation occurring at advanced disease stages 1
• Bone marrow microenvironment abnormalities contributing to disease progression 1

Clinical Presentation

The typical MDS patient presents with:

• Advanced age: Median age at diagnosis is approximately 70 years, with less than 10% of patients younger than 50 years 1
• Persistent cytopenias: Anemia (>60% of cases), thrombocytopenia (>70%), and/or leukopenia (>40%) that remain relatively stable over several months 1, 2
• Morphologic dysplasia: Including megaloblastoid erythropoiesis, nucleocytoplasmic asynchrony in early myeloid and erythroid precursors, and dysmorphic megakaryocytes 1, 3
• Variable blast percentage: Ranging from <5% in lower-risk subtypes to 5-19% in refractory anemia with excess blasts 3

Epidemiology and Risk Factors

Incidence: Approximately 4 cases per 100,000 inhabitants per year in the general population, increasing dramatically to 40-50 per 100,000 in patients aged ≥70 years 1, 4

Known etiologic factors (identified in only 15% of cases) include:

• Prior chemotherapy exposure: Particularly alkylating agents and purine analogues, leading to therapy-related MDS with poor prognostic features including complex cytogenetics involving chromosomes 5,7, and/or 17p 1
• Radiation exposure: Either therapeutic radiotherapy or ionizing radiation 1
• Occupational exposures: Benzene and its derivatives, with excess cases among agricultural and industrial workers 1
• Tobacco smoking 1
• Inherited predisposition: More common in pediatric cases (one-third) but should be assessed in young adults or families with multiple cases of MDS, AML, or aplastic anemia, with mutations in genes including DDX41, GATA2, RUNX1, ANKRD26, ETV6, and telomerase complex genes 1

Diagnostic Approach

Essential diagnostic tools include:

• Peripheral blood examination: Complete blood count with differential, reticulocyte count, and careful peripheral smear examination showing cytopenias and dysplastic features 1
• Bone marrow evaluation: Aspiration with iron stain and biopsy showing dysplasia in ≥10% of cells in one or more myeloid lineages 1, 3
• Cytogenetic analysis: Mandatory for identifying characteristic abnormalities and risk stratification 1, 3
• Bone marrow histology: Strongly recommended at initial diagnosis, especially to exclude other causes of cytopenia and for prognostic information 1

Critical exclusions before confirming MDS:

• Nutritional deficiencies: Check RBC folate, serum B12, serum ferritin, iron, and total iron-binding capacity 1, 3
• Medication effects: Review for chemotherapy, immunosuppressants, and alcohol use 3
• Other hematologic disorders: Flow cytometry in difficult cases and molecular testing by next-generation sequencing to demonstrate clonality 1

Prognosis and Risk Stratification

Survival varies dramatically by risk category:

• Lower-risk MDS (refractory anemia, refractory anemia with ring sideroblasts): Median survival of 3-10 years with 5-15% risk of AML transformation 1, 4
• Higher-risk MDS (refractory anemia with excess blasts): Median survival of less than 3 years with 40-50% risk of AML transformation 1, 4

The Revised International Prognostic Scoring System (IPSS-R) should be calculated using marrow blast percentage, number and severity of cytopenias, and cytogenetic abnormalities to guide treatment decisions 1, 3

Special Considerations in Older Adults with Comorbidities

Management complexity increases in elderly patients due to:

• Advanced age at presentation (median 65-70 years) with attendant cardiovascular disease, chronic kidney disease, and other comorbidities 1
• Reduced tolerance to intensive therapies including allogeneic stem cell transplantation 1
• Lower response rates to standard AML therapy if disease progresses compared to de novo AML 1
• Treatment selection must balance disease risk against functional status and comorbidity burden, with supportive care and less intensive therapies often appropriate for lower-risk disease in frail elderly patients 1, 4