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

Initial Treatment Approach for Myelodysplastic Syndrome (MDS)

The initial treatment approach for myelodysplastic syndrome should be based on risk stratification using the Revised International Prognostic Scoring System (IPSS-R), with lower-risk patients receiving erythropoiesis-stimulating agents or lenalidomide (for del(5q)), and higher-risk patients receiving hypomethylating agents such as azacitidine or consideration for allogeneic stem cell transplantation. 1, 2

Risk Stratification

Risk stratification is the essential first step in determining treatment approach:

• Use IPSS-R to categorize patients into risk groups:

  • Very low, low, intermediate (lower-risk MDS)
  • High, very high (higher-risk MDS)

• IPSS-R considers:

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

• Additional factors to consider:

  • Age
  • Performance status
  • Comorbidities
  • Molecular mutations (especially TP53 and SF3B1) 2

Treatment for Lower-Risk MDS

For Symptomatic Anemia:

1. First-line therapy based on serum erythropoietin (EPO) level:

   • If serum EPO <500 U/L: Erythropoiesis-stimulating agents (ESAs) ± G-CSF
     • Response rate: 40-60%
     • Responses typically occur within 8-12 weeks 2
   • If serum EPO ≥500 U/L: Consider alternative options

2. For patients with del(5q):

   • Lenalidomide 10 mg/day for 3 weeks every 4 weeks
     • Response rate: 60-65% achieve transfusion independence
     • Median duration of response: 2-2.5 years 2
   • Monitor for neutropenia and thrombocytopenia, which occur in ~60% of patients 1

3. For patients with ring sideroblasts (MDS-RS) or SF3B1 mutation:

   • Luspatercept, especially after ESA failure 1, 2

4. Second-line options after ESA failure:

   • For patients without del(5q):
     • Antithymocyte globulin (ATG) ± cyclosporine (especially in younger patients)
     • Hypomethylating agents (azacitidine or decitabine)
     • Lenalidomide ± ESAs 2

For Thrombocytopenia/Neutropenia:

• Generally managed with supportive care
• Consider thrombopoietin receptor agonists for severe thrombocytopenia if bone marrow blasts <5% 1
• Short-term G-CSF for severe neutropenia with infection 2

Treatment for Higher-Risk MDS

1. For eligible patients ≤70 years:

   • Allogeneic hematopoietic stem cell transplantation (allo-HSCT) - the only potentially curative option
   • Consider hypomethylating agents (HMAs) as a bridge to transplant 1, 2, 3

2. For patients >70 years or not eligible for transplantation:

   • Azacitidine 75 mg/m²/day subcutaneously for 7 days every 28 days, for at least 6 cycles
     • FDA-approved for various MDS subtypes including refractory anemia, RAEB, RAEB-T, and CMMoL 4
     • Continue treatment as long as patient benefits 4
   • Alternative: Decitabine or oral decitabine/cedazuridine 5

3. For very frail patients:

   • Supportive care only 1

Supportive Care (for all patients)

• RBC transfusions for symptomatic anemia
• Platelet transfusions for severe thrombocytopenia or bleeding
• Infection management with broad-spectrum antibiotics when appropriate
• Iron chelation therapy for heavily transfused patients at risk of iron overload 2

Monitoring and Follow-up

• Regular complete blood counts to assess disease stability
• Monitor for treatment-related toxicities
• For azacitidine: Monitor hematologic response and renal function; delay or reduce dosage as appropriate 4
• Repeat bone marrow examinations as clinically indicated 2

Special Considerations

• TP53 mutations in lower-risk MDS with del(5q) confer resistance to lenalidomide and higher risk of AML progression 1
• IPSS-R intermediate-risk patients may be treated as either lower or higher risk based on additional factors 1
• Response to treatment may take time - at least 6 cycles of azacitidine are recommended before assessing efficacy 1

The treatment algorithm should be reassessed regularly as new molecular insights and therapeutic options continue to emerge in this rapidly evolving field.