What is the initial treatment approach for patients with Myelodysplastic Syndromes (MDS)?

Initial Treatment Approach for Myelodysplastic Syndromes (MDS)

The initial treatment of MDS is determined by risk stratification using IPSS or IPSS-R scoring systems, which divides patients into lower-risk and higher-risk categories with fundamentally different treatment goals: hematologic improvement for lower-risk disease versus disease modification and survival prolongation for higher-risk disease. 1

Risk Stratification Framework

Risk assessment must be performed first using validated prognostic scoring systems 1, 2:

• Lower-risk MDS: IPSS low/intermediate-1, IPSS-R very low/low/intermediate, WPSS very low/low/intermediate 1
• Higher-risk MDS: IPSS intermediate-2/high, IPSS-R intermediate/high/very high, WPSS high/very high 1

Critical caveat: IPSS-R intermediate patients can be managed as either risk group depending on additional factors including age, performance status, serum ferritin, and serum LDH levels 1. If lower-risk treatment fails, immediately escalate to higher-risk management strategies 1.

Lower-Risk MDS Treatment Algorithm

For Symptomatic Anemia WITHOUT del(5q)

First-line: Erythropoiesis-stimulating agents (ESAs) 1, 2

• Use when serum EPO <500 U/L and transfusion requirement is absent or <2 units/month 1
• Dosing: EPO 30,000-80,000 units weekly OR darbepoetin 150-300 μg weekly 1
• Add G-CSF to improve response rates 1
• Response occurs within 8-12 weeks; median duration 20-24 months 1
• Expected response rate: 40-60% 1

Second-line options after ESA failure 1:

• Lenalidomide ± ESA: 25-30% RBC transfusion independence rate 1
• Immunosuppressive therapy (ATG ± cyclosporine): Use in patients ≤60 years with ≤5% marrow blasts, hypocellular marrow, HLA-DR15 positivity, or PNH clone positivity 1
• Azacitidine or decitabine: 30-40% achieve RBC transfusion independence 1

For Symptomatic Anemia WITH del(5q)

First-line: Lenalidomide 1, 2

• Dosing: 10 mg daily for 21 days out of 28-day cycles 1
• Response rate: 60-65% with median transfusion independence of 2-2.5 years 1
• Cytogenetic response in 50-75% (including 30-45% complete cytogenetic response) 1
• Critical warning: TP53 mutations (present in ~20% of del(5q) MDS) confer resistance to lenalidomide and higher AML progression risk 1. These patients require intensified surveillance and may need higher-risk treatment approaches 1.
• Monitor closely for grade 3-4 neutropenia and thrombocytopenia in first weeks; dose reduce and add G-CSF as needed 1

For Symptomatic Thrombocytopenia

• Broad-spectrum antibiotics if fever develops 1
• Short-term G-CSF 1
• ATG if favorable features present 1
• Thrombopoietin receptor agonists (romiplostim, eltrombopag) only if marrow blasts <5% 2

Higher-Risk MDS Treatment Algorithm

For Transplant-Eligible Patients

Allogeneic hematopoietic cell transplantation (allo-HCT) is the only curative option and should be considered for all higher-risk patients <70 years without major comorbidities who have a donor. 1, 2

Treatment pathway 1:

• If donor available: Proceed directly to allo-HCT OR use azacitidine/decitabine as bridge to transplant 1
• Bridging therapy options: Azacitidine, decitabine, or high-intensity chemotherapy to reduce marrow blasts before transplant 1

For Non-Transplant Candidates

First-line: Hypomethylating agents 2, 3

Azacitidine (preferred by NCCN) 1, 3:

• Dosing: 75 mg/m² daily for 7 days, repeat every 28 days 3
• Route: Subcutaneous or intravenous 3
• Continue for minimum 6 cycles to assess response 1

Decitabine (alternative) 1, 4:

• Three-day regimen: 15 mg/m² IV over 3 hours every 8 hours for 3 days, repeat every 6 weeks 4
• Five-day regimen: 20 mg/m² IV over 1 hour daily for 5 days, repeat every 4 weeks 4
• Indicated for all FAB subtypes and intermediate-1, intermediate-2, and high-risk IPSS groups 4

If no response after 6 cycles of hypomethylating agents: Consider clinical trial or supportive care 1

Universal Supportive Care Measures

All patients require appropriate supportive care regardless of risk category 1:

• RBC transfusions: For symptomatic anemia, generally at hemoglobin ≥8 g/dL (higher thresholds for patients with comorbidities) 1
• Iron chelation therapy: Indicated for transplant candidates with iron overload, non-transplant candidates with major iron overload, or patients receiving 20-60 RBC units or serum ferritin >1000-2500 U/L 2
• Antimicrobial prophylaxis: For neutropenic patients 1
• Platelet transfusions: For symptomatic thrombocytopenia 1

Critical Clinical Pitfalls

Do not substitute oral azacitidine for injectable azacitidine - they have different indications and dosing regimens 3.

Monitor complete blood counts frequently during treatment with lenalidomide (especially first weeks), hypomethylating agents, and ESAs 1, 4, 3.

Patients with monosomy 7 are an exception to standard lower-risk management and should be treated as intermediate-2/high-risk regardless of other factors 1.

Response assessment must use standardized IWG criteria to properly evaluate treatment efficacy 1.