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 before initiating any disease-directed therapy, as this determines the entire treatment algorithm 1:

• Lower-risk MDS: IPSS low/intermediate-1, IPSS-R very low/low/intermediate, or WPSS very low/low/intermediate 1
• Higher-risk MDS: IPSS intermediate-2/high, IPSS-R intermediate/high/very high, or WPSS high/very high 1
• IPSS-R intermediate patients can be managed as either risk group depending on age, performance status, serum ferritin, and serum LDH levels 1

Additional prognostic factors beyond scoring systems include age, performance status, comorbidities, transfusion requirements, and molecular mutations (particularly TP53) 1

Lower-Risk MDS Treatment Algorithm

For Anemia WITHOUT del(5q)

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

• Use recombinant EPO 30,000-80,000 units weekly OR darbepoetin 150-300 μg weekly 1
• Only use when serum EPO <200-500 U/L (this is the critical predictor of response) 1
• Add G-CSF to improve response rates 1
• Expected response rate: 40-60% with median duration of 20-24 months 1
• Assess response within 8-12 weeks 1

Second-line options after ESA failure 1:

• Immunosuppressive therapy (ATG ± cyclosporine) for patients ≤60 years with ≤5% marrow blasts, hypocellular marrows, HLA-DR15 positivity, or PNH clone positivity 1
• Lenalidomide (without del(5q)): 25-30% RBC transfusion independence 1
• Lenalidomide + ESA combination: higher response rates than lenalidomide alone 1
• Azacitidine or decitabine: 30-40% achieve RBC transfusion independence 1

For Anemia WITH del(5q)

First-line: Lenalidomide 10 mg daily for 21 days out of 28-day cycles 1, 2

• Response rate: 60-65% with median transfusion independence of 2-2.5 years 1, 2
• Cytogenetic response in 50-75% (including 30-45% complete cytogenetic response) 1
• Critical caveat: TP53 mutations (present in ~20% of del(5q) MDS) confer resistance to lenalidomide and higher AML progression risk 1
• Monitor closely for grade 3-4 neutropenia and thrombocytopenia (occurs in ~60% during first weeks) 1
• ESAs have lower response rates and shorter duration in del(5q) MDS compared to non-del(5q) 1

After lenalidomide failure in del(5q): Consider hypomethylating agents or allogeneic transplant, especially if TP53 mutated 1

For Thrombocytopenia

• Thrombopoietin receptor agonists (romiplostim, eltrombopag) only if marrow blasts <5% 2
• ATG ± cyclosporine if favorable features present 1
• Azacitidine if approved in your region 1

For Neutropenia

• G-CSF for short-term use during infections 1
• Broad-spectrum antibiotics if febrile 1
• ATG if favorable features present 1

Higher-Risk MDS Treatment Algorithm

Transplant-Eligible Patients

Allogeneic hematopoietic cell transplantation is the only curative option and should be considered for all patients <70 years without major comorbidities who have a donor 1, 2, 3

• Can proceed directly to transplant OR use bridging therapy with azacitidine or decitabine to reduce marrow blasts first 1
• Bridging therapy can also be used while awaiting donor availability 1

Non-Transplant Candidates

First-line: Hypomethylating agents 1, 2, 4, 5

Azacitidine 75 mg/m² daily for 7 days every 28 days (subcutaneous or IV) 1, 4

• This is the NCCN-recommended first-line therapy 1, 2
• Continue for minimum of 6 cycles before assessing response 1

OR Decitabine 1, 5:

• 15 mg/m² IV over 3 hours every 8 hours for 3 days, repeat every 6 weeks 5
• OR 20 mg/m² IV over 1 hour daily for 5 days, repeat every 4 weeks 5

Alternative for non-transplant candidates: High-intensity chemotherapy followed by transplant if donor becomes available 1

After Relapse Post-Transplant

• Consider second allogeneic transplant or donor lymphocyte infusion 1
• Azacitidine or decitabine 1
• Clinical trial 1

Universal Supportive Care (All Risk Categories)

All patients require supportive care regardless of disease-directed therapy 1:

• RBC transfusions: For symptomatic anemia, generally at hemoglobin ≥8 g/dL (higher thresholds for patients with cardiovascular comorbidities) 1
• Use leukocyte-reduced blood products 1
• Iron chelation therapy: Recommended for transplant candidates with iron overload, non-transplant candidates with major iron overload, or patients with favorable prognosis who have received 20-60 RBC units or serum ferritin >1000-2500 U/L 2
• Platelet transfusions: For severe thrombocytopenia or thrombocytopenic bleeding 1
• Psychosocial support and quality-of-life assessment 1

Critical Decision Points and Pitfalls

Monitor blood counts over several months before initiating therapy to assess disease stability and exclude other causes of cytopenias 1

Do not substitute azacitidine for injection for oral azacitidine - they have different indications and dosing regimens 4

Patients with monosomy 7 should be treated as higher-risk regardless of IPSS category 1

If lower-risk therapy fails, escalate to higher-risk management strategies 1

Therapy-related MDS generally has poorer prognosis and should be managed as higher-risk disease 1

Response assessment must use standardized IWG criteria 1