What is the role of erythropoietin (Epo) in managing anemia in patients with myelodysplastic syndrome?

Erythropoietin in Myelodysplastic Syndrome

Erythropoiesis-stimulating agents (ESAs) such as erythropoietin are effective first-line therapy for symptomatic anemia in lower-risk MDS patients, achieving erythroid response rates of 40-60%, with the best outcomes in patients who have serum erythropoietin levels <500 mU/mL, require <2 units of RBC transfusions per month, and have low marrow blast percentages. 1

Patient Selection for ESA Therapy

Ideal Candidates

• Lower-risk MDS patients (IPSS low or intermediate-1; IPSS-R very low, low, or intermediate) with symptomatic anemia 1
• **Serum erythropoietin <500 mU/mL** - this is the critical threshold, as patients with levels >500 mU/mL have very low response rates and should not receive ESAs 1
• Low transfusion burden (<2 units RBC per month) - these patients have significantly higher response rates 1
• Low marrow blast percentage - associated with better response 1
• Patients with <15% ringed sideroblasts may respond to ESA monotherapy 1

Poor Candidates

• Serum erythropoietin >500 mU/mL 1
• High transfusion dependence (≥2 units per month) 1
• Higher-risk MDS (IPSS intermediate-2 or high) 1

Dosing Regimens

Erythropoietin Monotherapy

• 40,000-60,000 units subcutaneously 1-3 times per week 1
• Start at higher doses for more prompt response 1
• Darbepoetin alfa: 150-300 mcg subcutaneously per week 1
• Assess response after 6-8 weeks of treatment 1

Combination Therapy with G-CSF

• Add G-CSF if no response to ESA alone - this combination shows synergistic activity and increases response rates to approximately 38-39% 1
• G-CSF dosing: 1-2 mcg/kg subcutaneously daily or 1-3 times per week - use doses sufficient to normalize or double the neutrophil count 1
• Particularly effective in patients with ≥15% ringed sideroblasts where ESA monotherapy response rates are very low 1

Expected Outcomes

Response Rates

• ESA monotherapy: 40-60% combined major and minor responses in lower-risk patients 1
• ESA + G-CSF combination: 38-39% hematologic response rate 1
• Median duration of response: 23-24 months with maintenance therapy 1

Survival Benefits

• Treatment with EPO + G-CSF associated with improved survival (HR 0.61; 95% CI 0.44-0.83; P=0.002) compared to untreated controls 1
• Survival benefit most significant in IPSS low-risk patients requiring <2 units RBC transfusions per month 1
• No negative impact on AML progression - studies show ESA therapy does not increase risk of leukemic transformation 1

Treatment Algorithm

1. Verify iron repletion before starting ESA therapy - iron deficiency must be corrected first 1
2. Measure baseline serum erythropoietin level 1
3. If serum EPO <500 mU/mL and low transfusion burden:
   • Start ESA monotherapy (epoetin 40,000-60,000 units 1-3x/week or darbepoetin 150-300 mcg/week) 1
4. Assess response at 6-8 weeks 1
5. If no response to ESA alone:
   • Add G-CSF 1-2 mcg/kg subcutaneously 1
   • Reassess after another 6-8 weeks 1
6. If response achieved:
   • Continue maintenance therapy at same dose 1
   • Attempt dose reduction to tolerance while maintaining response 1
7. If no response after ESA + G-CSF:
   • Discontinue therapy 1
   • Consider alternative treatments (lenalidomide for del(5q), azacitidine, clinical trials) 1

Safety Considerations

Target Hemoglobin

• Goal hemoglobin ≤12 g/dL - do not target levels >12 g/dL due to increased mortality, thromboembolism, and possible tumor promotion observed in other patient populations 1

Monitoring

• Weekly CBC during initial treatment to assess response 1
• Monitor for thromboembolic events - increased risk when targeting higher hemoglobin levels 1
• Verify iron stores remain adequate during treatment 1

Common Pitfalls

• Using ESAs in patients with serum EPO >500 mU/mL - these patients have negligible response rates and therapy is not cost-effective 1
• Inadequate dosing - MDS requires much higher doses than renal anemia (40,000-60,000 units vs standard renal dosing) 1
• Not checking iron status - iron deficiency will prevent ESA response 1
• Continuing therapy beyond 8 weeks without response - if no response by 6-8 weeks, treatment should be discontinued 1
• Targeting hemoglobin >12 g/dL - associated with increased adverse events 1
• Not adding G-CSF in patients with ringed sideroblasts - this subgroup has very low response to ESA alone but improved response with combination therapy 1