What is the recommended management of anemia in patients with myelodysplastic syndrome?

Management of Anemia in Myelodysplastic Syndrome

The treatment of anemia in MDS is stratified by disease risk (lower vs. higher), del(5q) status, ring sideroblast/SF3B1 mutation status, and serum erythropoietin (EPO) levels, with specific first-line agents recommended for each clinical scenario. 1, 2

Lower-Risk MDS Without del(5q)

Patients WITH Ring Sideroblasts ≥15% (or ≥5% with SF3B1 mutation)

Luspatercept is the preferred first-line treatment (Category 1) for transfusion-dependent patients with ring sideroblasts or SF3B1 mutations. 1, 3

• Luspatercept demonstrated superior RBC transfusion independence versus erythropoiesis-stimulating agents (ESAs) in the COMMANDS trial, particularly in SF3B1-mutated patients (response difference 0.38) 3
• Consider ESAs (epoetin alfa or darbepoetin alfa) if serum EPO ≤200 mU/mL as an alternative first-line option 1
• Imetelstat is recommended as first-line therapy if serum EPO >500 mU/mL (making patient ineligible for ESAs) 1

After luspatercept failure or relapse:

• If serum EPO ≤500 mU/mL: Imetelstat is preferred (Category 1), or ESAs ± G-CSF 1
• If serum EPO >500 mU/mL: Imetelstat (if not previously used) or luspatercept (if not previously used) are preferred 1

Patients WITHOUT Ring Sideroblasts <15% (or <5% with SF3B1 mutation)

ESAs (epoetin alfa or darbepoetin alfa) are recommended first-line for anemia when serum EPO ≤500 mU/mL. 2

• ESAs achieve response rates of 15-40% with median duration of 8-23 months 4
• After ESA failure, consider lenalidomide, hypomethylating agents (HMAs), or immunosuppressive therapy (ATG/cyclosporine) in younger patients 2

Lower-Risk MDS WITH del(5q)

Lenalidomide is the most effective first-line drug (Category 1) for transfusion-dependent anemia in del(5q) MDS, alone or with one other cytogenetic abnormality (excluding chromosome 7 abnormalities). 1, 2

• Consider ESAs if serum EPO ≤500 mU/mL as an alternative 1
• If serum EPO >500 mU/mL, imetelstat (Category 1) is preferred 1
• After lenalidomide failure, switch to imetelstat or ESAs based on EPO levels 1

Higher-Risk MDS

Azacitidine is recommended for patients with higher-risk MDS without major comorbidities who are not immediately eligible for allogeneic stem cell transplantation (allo-SCT). 2

• Allo-SCT should be proposed to all higher-risk MDS patients <70 years old without major comorbidities who have a donor 2
• AML-like chemotherapy is recommended for fit patients (generally <70 years) with favorable cytogenetics and marrow blasts ≥10%, preferably as a bridge to allo-SCT 2

Imetelstat Dosing and Monitoring

Imetelstat is dosed at 7.1 mg/kg intravenously monthly, with potential dose decrements due to frequent transient thrombocytopenia and neutropenia. 1

• Starting platelet count should be ≥75,000/μL and neutrophil count ≥1,500/μL 1
• 91% of patients experienced grade 3-4 treatment-emergent adverse events, with neutropenia (68%) and thrombocytopenia (62%) being most common 1

Supportive Care Considerations

Iron chelation is strongly recommended in transplant candidates and in non-transplant candidates with major iron overload (e.g., significantly reduced cardiac T2).* 2

• Oral deferasirox is preferred over parenteral deferoxamine 2
• Pre-transplant iron overload is associated with increased transplant-related mortality 2

Critical Treatment Sequencing Algorithm

1. Determine disease risk (IPSS/IPSS-R): Lower-risk vs. higher-risk 2
2. For lower-risk MDS, check cytogenetics for del(5q) 1, 2
3. Measure serum EPO level to guide therapy selection 1
4. Assess for ring sideroblasts ≥15% or SF3B1 mutation 1, 3
5. Select first-line therapy based on above parameters 1, 2
6. Reassess response at 3-6 months and adjust therapy accordingly 1

Common Pitfalls

• Do not use ESAs when serum EPO >500 mU/mL—these patients are unlikely to respond 1
• In del(5q) MDS, lenalidomide is superior to ESAs regardless of EPO level 2
• Luspatercept has limited benefit (27% response) in ring sideroblast-negative disease 1
• Thrombopoietin receptor agonists should only be used in patients with marrow blasts <5% due to theoretical leukemia progression risk 2