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 groups, with all patients receiving supportive care as the foundation of management. 1, 2

Risk Stratification Framework

Risk assessment using IPSS or IPSS-R is the critical first step that determines the entire treatment pathway (Category 2A recommendation). 1 The IPSS-R categorization is preferred when available due to more accurate risk stratification. 1

Lower-risk patients include those with:

• IPSS: Low and Intermediate-1 1
• IPSS-R: Very low, low, and intermediate 1
• WPSS: Very low, low, and intermediate 1

Higher-risk patients include those with:

• IPSS: Intermediate-2 and high 1
• IPSS-R: Intermediate, high, and very high 1
• WPSS: High and very high 1

Critical caveat: IPSS-R intermediate patients may be managed as either risk group depending on age, performance status, serum ferritin levels, and serum LDH levels. 1 Additionally, intermediate-risk patients who fail lower-risk therapies should transition to higher-risk treatment strategies. 1

Universal Supportive Care (All Patients)

Every patient with MDS requires supportive care regardless of risk category. 1 This includes:

• RBC transfusions for symptomatic anemia (generally leukocyte-reduced), typically at hemoglobin thresholds of at least 8 g/dL, higher in patients with cardiovascular comorbidities 1, 2
• Platelet transfusions for severe thrombocytopenia or thrombocytopenic bleeding 1
• Clinical monitoring to assess blood count stability over several months to detect disease progression or transformation to AML 1
• Quality-of-life assessment addressing physical, functional, emotional, spiritual, and social domains 1

Treatment of Lower-Risk MDS

The therapeutic goal for lower-risk patients is hematologic improvement rather than altering disease natural history. 1

For Anemia WITHOUT del(5q):

First-line: Erythropoiesis-stimulating agents (ESAs) 1, 2, 3

• Weekly doses of 30,000-80,000 units of recombinant EPO or 150-300 μg darbepoetin 1, 2
• Response rates of 40-60% when baseline serum EPO is <200-500 U/L and transfusion requirement is absent or limited 1
• G-CSF can be added to improve efficacy 1
• Responses occur within 8-12 weeks; median duration of response is 20-24 months 1
• ESAs are an independent favorable prognostic factor for survival 1

For Anemia WITH del(5q):

First-line: Lenalidomide 1, 2, 3

• Initial dose: 10 mg daily for 21 days out of 28 days 1
• Response rate: 60-65% with median RBC transfusion independence of 2-2.5 years 1, 2
• Cytogenetic response achieved in 50-75% (including 30-45% complete cytogenetic response) 1
• Important warning: TP53 mutations (present in ~20% of del(5q) MDS) confer resistance to lenalidomide and higher risk of AML progression 1

For Severe Thrombocytopenia:

• TPO receptor agonists (romiplostim, eltrombopag) are recommended, but only in patients with marrow blasts <5% 2
• Broad-spectrum antibiotics if fever develops 1
• Short-term G-CSF for symptomatic neutropenia 1

Second-line Options After ESA/Lenalidomide Failure:

• Antithymocyte globulin (ATG) ± cyclosporine for selected patients (generally ≤60 years with ≤5% marrow blasts, hypocellular marrows, HLA-DR15 positivity, or PNH clone positivity) 1
• Azacitidine (if approved in this setting) 1
• Lenalidomide ± EPO for non-del(5q) patients 1
• Clinical trials 1

Treatment of Higher-Risk MDS

The therapeutic goal for higher-risk patients is to alter disease natural history and prolong survival. 1

For Transplant Candidates:

Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy and should be considered for all higher-risk patients <70 years without major comorbidities who have a donor. 1, 2, 3

Options include:

• Immediate allo-HCT 1
• Bridging therapy (azacitidine, decitabine, or high-intensity chemotherapy) followed by HCT to reduce marrow blasts to acceptable levels 1

For Non-Transplant Candidates:

First-line: Hypomethylating agents 1, 2, 3

Azacitidine (FDA-approved for all MDS subtypes and IPSS risk groups) 4

• Dose: 75 mg/m² daily for 7 days subcutaneously or intravenously 2, 4
• Repeat cycle every 28 days 4
• Continue treatment as long as patient benefits 4
• Response should be evaluated after at least 6 cycles 1

Decitabine (FDA-approved for all MDS subtypes and IPSS risk groups) 5

• Three-day regimen: 15 mg/m² IV over 3 hours every 8 hours for 3 days, repeat every 6 weeks 5
• Five-day regimen: 20 mg/m² IV over 1 hour daily for 5 days, repeat every 4 weeks 5

After HCT Relapse:

• Consider repeat HCT or donor lymphocyte infusion 1
• Azacitidine or decitabine 1
• Clinical trial 1

Special Populations

Therapy-related MDS: Most patients have poorer prognoses with substantial proportion having poor-risk cytogenetics; these patients are generally managed as higher-risk disease regardless of IPSS score. 1

Patients with monosomy 7: Should be treated in the intermediate-2/high prognostic category even if otherwise lower-risk. 1

Critical Monitoring Requirements

• Complete blood counts and platelet counts should be performed frequently during treatment 4
• Monitor for hematologic response using standardized International Working Group (IWG) response criteria 1
• Assess for renal toxicity, particularly with hypomethylating agents 4
• Monitor for tumor lysis syndrome risk, especially with hypomethylating agents 4
• Evaluate transfusion requirements and serum ferritin for iron overload 1, 2

Common Pitfalls to Avoid

Do not substitute oral azacitidine for azacitidine injection—they have different indications and dosing regimens. 4 The evidence and FDA approval discussed here applies only to injectable formulations.

Do not delay risk stratification. Treatment decisions cannot be made without proper IPSS or IPSS-R scoring, which requires bone marrow evaluation with cytogenetics and blast percentage. 1

Do not use TPO receptor agonists in patients with ≥5% marrow blasts due to theoretical concerns about promoting leukemic progression. 2

Do not give up on hypomethylating agents too early. Responses may take up to 6 cycles of azacitidine to manifest; premature discontinuation is a common error. 1