What is the initial treatment approach for myelodysplastic syndrome?

Initial Treatment Approach for Myelodysplastic Syndrome

The initial treatment approach for myelodysplastic syndrome (MDS) should be risk-stratified based on the International Prognostic Scoring System (IPSS) or IPSS-Revised (IPSS-R), with lower-risk patients receiving erythropoiesis-stimulating agents (ESAs) as first-line therapy for anemia (except in del(5q) MDS where lenalidomide is preferred), while higher-risk patients should receive hypomethylating agents like azacitidine or be evaluated for allogeneic stem cell transplantation. 1

Risk Stratification

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

• IPSS and IPSS-R are the standard tools for risk stratification, categorizing patients into lower-risk (IPSS low/int-1 or IPSS-R very low/low/intermediate) and higher-risk (IPSS int-2/high or IPSS-R high/very high) groups 1
• Risk assessment should consider: cytopenias, bone marrow blast percentage, cytogenetic abnormalities, and increasingly, molecular mutations 1, 2
• Patient factors including age, performance status, comorbidities, and transfusion requirements also guide treatment decisions 1

Treatment of Lower-Risk MDS

For Anemia (most common cytopenia):

• Without del(5q):

  • First-line: ESAs (especially EPO alpha) at weekly doses of 30,000-80,000 units or darbepoetin 150-300 μg 1
  • Best responses occur in patients with serum EPO <500 U/l and limited transfusion requirements 1
  • Response rates: 40-60% with median duration of 20-24 months 1
  • G-CSF can be added to improve response in selected patients 1

• With del(5q):

  • Lenalidomide is the most effective first-line treatment with 60-65% response rates and median transfusion independence of 2-2.5 years 1
  • Recommended dose: 10 mg/day for 3 weeks every 4 weeks 1
  • Monitor for cytogenetic response and TP53 mutations, which confer resistance and higher AML risk 1

• After ESA failure:

  • For MDS-RS (ring sideroblasts): Luspatercept is recommended 1
  • For younger patients with specific features: ATG with cyclosporine 1
  • Other options include lenalidomide ± ESA or hypomethylating agents (not approved in all regions) 1

For Thrombocytopenia:

• TPO receptor agonists (romiplostim, eltrombopag) may be considered for severe thrombocytopenia, but only in patients with marrow blasts <5% 1
• High-dose androgens can provide transient improvement in about one-third of patients 1

For Neutropenia:

• G-CSF can be used for severe neutropenia or during neutropenic fever 1
• Avoid medications that worsen neutropenia 1

Treatment of Higher-Risk MDS

• First-line therapy:

  • Azacitidine 75 mg/m² daily for 7 days is recommended for patients not immediately eligible for allogeneic stem cell transplantation (allo-SCT) 1, 3
  • Decitabine is an alternative hypomethylating agent approved for all MDS subtypes 4
  • AML-like chemotherapy may be considered for fit patients <70 years with favorable cytogenetics and marrow blasts ≥10%, preferably as a bridge to allo-SCT 1

• Allogeneic stem cell transplantation:

  • Should be proposed to all higher-risk MDS patients <70 years without major comorbidities who have a donor 1
  • Consider reducing marrow blast count before allo-SCT with hypomethylating agents or AML-like chemotherapy when blasts are ≥10% 1
  • Iron chelation is strongly recommended before allo-SCT to reduce transplant-related mortality 1

Supportive Care

• RBC transfusions for symptomatic anemia, generally at hemoglobin thresholds of at least 8 g/dl (higher in patients with comorbidities) 1
• Platelet transfusions for severe thrombocytopenia or bleeding 1
• Iron chelation therapy is recommended for:
  • Transplant candidates with iron overload 1
  • Non-transplant candidates with major iron overload (e.g., reduced cardiac T2* on MRI) 1
  • Patients with relatively favorable prognosis who have received 20-60 RBC concentrates or if serum ferritin rises above 1000-2500 U/l 1

Common Pitfalls and Caveats

• Delaying risk stratification can lead to inappropriate treatment selection 1, 2
• Underutilizing ESAs in appropriate lower-risk patients without attempting to predict response 1
• Failing to monitor for iron overload in transfusion-dependent patients 5, 6
• Not considering allo-SCT early in the disease course for eligible higher-risk patients 1, 7
• Inadequate monitoring for disease progression, which requires treatment adjustment 1, 2

Treatment decisions should be reassessed regularly as MDS is a dynamic disease that can progress over time, requiring adjustment of therapeutic strategies 1, 7.