What is the treatment approach for myelodysplastic syndrome (MDS)?

Treatment Approach for Myelodysplastic Syndrome (MDS)

The treatment of myelodysplastic syndrome should be risk-stratified based on the Revised International Prognostic Scoring System (IPSS-R), with higher-risk MDS patients receiving hypomethylating agents like azacitidine or allogeneic stem cell transplantation, while lower-risk MDS patients receive supportive care with transfusions, growth factors, and targeted therapies based on specific genetic abnormalities. 1

Diagnosis and Risk Stratification

Before initiating treatment, proper diagnosis and risk stratification are essential:

Diagnostic Approach

• Complete blood count with differential and peripheral blood smear examination
• Bone marrow aspiration and biopsy to assess dysplasia, blast percentage, and cellularity
• Cytogenetic analysis to identify chromosomal abnormalities
• Molecular testing for somatic mutations (especially TP53, SF3B1, RUNX1, ASXL1)
• Exclusion of secondary causes of cytopenias 1, 2

Risk Stratification

The IPSS-R is the gold standard for risk stratification, categorizing patients into:

• Very low risk
• Low risk
• Intermediate risk
• High risk
• Very high risk

Risk calculation incorporates:

• Cytogenetic abnormalities
• Bone marrow blast percentage
• Hemoglobin level
• Platelet count
• Absolute neutrophil count 1

Treatment Algorithm

Higher-Risk MDS (IPSS-R High, Very High, and some Intermediate)

1. For fit patients ≤70 years with a donor:

   • Allogeneic stem cell transplantation (allo-SCT) is the only potentially curative option
   • May be preceded by hypomethylating agents to reduce blast percentage 1, 3

2. For patients >70 years or without a donor:

   • Azacitidine 75 mg/m²/day subcutaneously for 7 consecutive days every 28 days (at least six cycles)
   • Alternative "5-2-2" regimen (5 days on, 2 days off, 2 days on) is acceptable
   • Dose reduction for frail patients 1, 4

3. For very frail patients:

   • Supportive care with red blood cell transfusions and antibiotics 1

Lower-Risk MDS (IPSS-R Very Low, Low, and some Intermediate)

1. For patients with symptomatic anemia:

   • Erythropoiesis-stimulating agents (ESAs) for patients with serum erythropoietin <500 mU/mL
   • Lenalidomide for patients with del(5q) abnormality
   • Luspatercept for patients with ring sideroblasts who failed ESA therapy 3, 5

2. For patients with thrombocytopenia:

   • Platelet transfusions for bleeding or severe thrombocytopenia
   • Thrombopoietin receptor agonists may be considered in clinical trials 6

3. For patients with neutropenia:

   • Infection prophylaxis and prompt treatment of infections
   • G-CSF for recurrent infections 3

Special Considerations

MDS with del(5q)

• Lenalidomide is the treatment of choice for lower-risk MDS with isolated del(5q)
• Monitor for TP53 mutations which predict poorer response 1

Therapy-related MDS

• Generally has poorer prognosis
• Consider early allo-SCT evaluation if eligible
• Hypomethylating agents if not transplant eligible 5

MDS after Hypomethylating Agent Failure

• Clinical trial participation is recommended
• Consider allo-SCT if eligible and not previously performed
• Limited effective options outside clinical trials 6, 5

Monitoring and Response Assessment

• Response assessment using International Working Group (IWG 2006) criteria
• Complete remission (CR), partial remission (PR), or hematological improvement (HI)
• For patients on hypomethylating agents, at least 6 cycles should be given before determining lack of response
• Regular monitoring of blood counts, transfusion requirements, and bone marrow examinations as clinically indicated 1

Common Pitfalls to Avoid

• Premature discontinuation of hypomethylating agents: Response may take 4-6 cycles to manifest
• Delaying transplant evaluation in eligible higher-risk patients
• Overreliance on blast percentage alone for risk stratification without considering cytogenetics and molecular features
• Inadequate supportive care including iron chelation for heavily transfused patients
• Failure to reassess risk status over time, as MDS can progress 6, 5

The treatment landscape for MDS continues to evolve with new targeted therapies in development, making regular reassessment of treatment strategies essential for optimal patient outcomes.