What is myelodysplastic syndrome (MDS)?

Myelodysplastic Syndrome (MDS)

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic stem cell disorders characterized by peripheral blood cytopenias, dysplastic changes in bone marrow cells, ineffective hematopoiesis, and an increased risk of transformation to acute myeloid leukemia (AML). 1, 2

Epidemiology and Risk Factors

• Incidence: Approximately 4-5 per 100,000 people in the general population
• Age: Primarily affects older adults with median age of 70 years
• Gender: More common in men than women (5.4 vs 2.9 per 100,000)
• Risk increases significantly with age: 22-45 per 100,000 in those over 70 years 1, 3

Risk Factors:

• Advanced age
• Prior exposure to:
  • Chemotherapy (therapy-related MDS)
  • Radiation therapy
  • Environmental toxins (e.g., benzene)
• Unknown etiology in approximately 80% of cases 1, 3

Pathophysiology

MDS develops through a multistep genetic process affecting various cellular functions:

• Transcription factors: RUNX1, NRAS, KRAS, JAK2, MPL, FLT3
• Histone modifications: ASXL1, EZH2
• Splicing factors: SF3B1, SRSF2, U2AF1, ZRSR2
• DNA methylation: TET2, DNMT3A, IDH1/2
• Cohesin factors: STAG2, SMC1A, SMC3 1

Clinical Presentation

MDS typically presents with symptoms related to cytopenias:

• Fatigue, weakness, and exercise intolerance (anemia)
• Recurrent or severe infections (neutropenia)
• Easy bruising or bleeding (thrombocytopenia) 2, 3

Diagnostic Evaluation

Required Tests:

• Complete blood count with differential and reticulocyte count
• Peripheral blood smear examination
• Bone marrow aspiration and biopsy with:
  • Iron staining (to identify ring sideroblasts)
  • Cytogenetics
• Serum erythropoietin level (prior to RBC transfusion)
• Iron studies (ferritin, iron, total iron-binding capacity)
• Vitamin B12 and folate levels 1, 2

Additional Considerations:

• Molecular genetic testing for mutations
• Flow cytometry to evaluate for PNH clone or LGL disease
• HLA typing if platelet support is indicated
• Evaluation for copper deficiency 1, 2

Classification

WHO Classification (2016):

• MDS with single lineage dysplasia (MDS-SLD)
• MDS with multilineage dysplasia (MDS-MLD)
• MDS with ring sideroblasts (MDS-RS)
• MDS with excess blasts (MDS-EB-1: 5-9% blasts; MDS-EB-2: 10-19% blasts)
• MDS with isolated del(5q)
• MDS, unclassifiable (MDS-U) 1

Risk Stratification

The Revised International Prognostic Scoring System (IPSS-R) is the most widely used tool for risk stratification, considering:

• Cytogenetic abnormalities
• Bone marrow blast percentage
• Hemoglobin level
• Platelet count
• Absolute neutrophil count 2

Risk categories determine prognosis and guide treatment:

• Lower-risk MDS: Median survival 3-10 years
• Higher-risk MDS: Median survival less than 3 years
• Overall 5-year survival rate: Approximately 37% 2, 3

Treatment Approaches

Treatment is risk-stratified based on IPSS-R classification:

Lower-Risk MDS:

1. Erythropoiesis-stimulating agents (ESAs) ± G-CSF

   • First choice for patients with serum erythropoietin <500 U/L
   • Response rate: 40-60%
   • Response typically occurs within 8-12 weeks

2. Lenalidomide

   • Specifically for MDS with deletion 5q
   • Dosage: 10 mg/day for 3 weeks every 4 weeks
   • Response rate: 60-65% for transfusion independence
   • Median response duration: 2-2.5 years

3. Luspatercept

   • For patients with ring sideroblasts (MDS-RS) or SF3B1 mutation
   • Particularly after failure of ESAs

4. Hypomethylating agents (HMAs)

   • For patients who have failed ESA treatment
   • Options include azacitidine or decitabine
   • Transfusion independence rate: 30-40% 2, 4

Higher-Risk MDS:

1. Hypomethylating agents

   • First-line therapy for those not eligible for transplantation
   • Decitabine is FDA-approved for all MDS subtypes 4

2. Allogeneic stem cell transplantation

   • Only potentially curative option
   • Considered for eligible patients ≤70 years with available donor 2

Supportive Care:

• Red blood cell transfusions for symptomatic anemia (hemoglobin threshold ≥8 g/dL)
• Platelet transfusions for severe thrombocytopenia or bleeding
• Broad-spectrum antibiotics for fever
• Iron chelation therapy for patients with iron overload after 20-30 RBC transfusions 2

Monitoring and Follow-up

• Regular complete blood counts to assess disease stability
• Monitoring for treatment-related toxicities
• Repeat bone marrow examinations as clinically indicated
• Assessment for disease progression or transformation to AML 2

Prognosis

• Secondary (therapy-related) MDS generally has poorer prognosis
• Risk of transformation to AML varies by subtype:
  • Low-risk (RA/RARS): 5-15%
  • High-risk (RAEB/RAEB-T): 40-50% 1, 2

Clinical Pearls

• MDS is now considered the most common form of leukemia in adults
• Diagnosis requires persistent cytopenias (≥4 months) and exclusion of other causes
• Only allogeneic stem cell transplantation offers potential cure
• Newer agents like luspatercept have expanded treatment options for specific MDS subtypes
• Regular monitoring is essential due to risk of disease progression 3, 5