What are the primary goals and treatment options for a patient with Myelodysplastic Syndromes (MDS)?

MDS Therapy: Treatment Goals and Options

Primary Treatment Goals

The primary goals of MDS therapy are fundamentally different based on risk stratification: for lower-risk disease, the goal is hematologic improvement and quality of life enhancement, while for higher-risk disease, the goal is altering the natural history by delaying AML progression and prolonging survival. 1

Lower-Risk MDS Goals

• Achieve hematologic improvement, particularly addressing symptomatic cytopenias 1
• Reduce transfusion burden and maintain acceptable hemoglobin levels 1, 2
• Improve quality of life across physical, functional, emotional, and social domains 1
• Approximately half of elderly lower-risk patients die from causes unrelated to MDS or AML, making symptom management paramount 3

Higher-Risk MDS Goals

• Alter the natural history of disease by delaying AML transformation 1
• Prolong overall survival and progression-free survival 3
• Achieve complete remission or partial remission when possible 3
• Cytogenetic response is an important secondary outcome parameter 1

Risk Stratification Framework

All treatment decisions must begin with IPSS or IPSS-R risk stratification, which divides patients into lower-risk (IPSS low/intermediate-1; IPSS-R very low/low/intermediate) versus higher-risk (IPSS intermediate-2/high; IPSS-R intermediate/high/very high) categories. 1, 3

• The WHO Prognostic Scoring System (WPSS) provides dynamic estimation of prognosis at any time during disease course and incorporates transfusion dependence as a negative prognostic factor 1
• Patient age, performance status, and comorbidities critically influence ability to tolerate intensive treatments 1
• Assess blood count stability over several months to evaluate disease progression and rule out other causes of cytopenias 1

Treatment Options by Risk Category

Lower-Risk MDS Treatment Algorithm

For symptomatic anemia in lower-risk MDS, erythropoiesis-stimulating agents (ESAs) are first-line therapy when baseline serum erythropoietin is <500 mU/mL and transfusion requirements are low. 1, 3, 2

• ESAs (recombinant erythropoietin or darbepoetin) achieve 40-60% erythroid response rates 1, 3, 4
• Darbepoetin dosing of 150-300 mcg subcutaneously per week may yield higher response rates than standard epoetin 1
• Adding G-CSF to ESAs increases response rates to approximately 60%, with synergistic activity demonstrated in phase II studies showing 38% hematologic response (21% complete response) 1, 2
• Predictive features for ESA response include serum erythropoietin <500 mU/mL, low marrow blast percentage, and transfusion requirement <2 units per month 1

For younger patients (<65 years) with lower-risk MDS, hypoplastic marrow, or trisomy 8, immunosuppressive therapy with antithymocyte globulin (ATG) plus cyclosporine A achieves approximately 30% response rates. 3, 2

• Response to immunosuppressive therapy typically occurs within 3-6 months of treatment initiation 2
• This approach is particularly effective in patients with transfusion history <2 years, normal karyotype or trisomy 8, no excess blasts, and thrombocytopenia in addition to anemia 3

Lenalidomide is the drug of choice for lower-risk MDS with del(5q), achieving complete erythroid response and cytogenetic remission in approximately 67% of patients. 5

Higher-Risk MDS Treatment Algorithm

Hypomethylating agents (HMAs), specifically azacitidine or decitabine, are the first-line reference treatment for higher-risk MDS, with azacitidine extending survival by up to 74% despite modest complete response rates. 3, 6

• Azacitidine 75 mg/m² subcutaneously for 7 consecutive days every 28 days is the standard regimen 3
• At least 6 cycles are required before assessing response, as most patients only respond after several courses 3
• Decitabine is FDA-approved for all MDS subtypes including intermediate-1, intermediate-2, and high-risk IPSS groups 7
• Decitabine dosing options include: 15 mg/m² IV over 3 hours every 8 hours for 3 days (repeated every 6 weeks) or 20 mg/m² IV over 1 hour daily for 5 days (repeated every 4 weeks) 7
• A minimum of 4 cycles is required, though complete or partial response may take longer 7

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) should be evaluated at diagnosis for all higher-risk patients, as it represents the only potentially curative treatment. 3, 6, 4

• HLA-identical siblings or matched unrelated donors are preferred 3
• Allo-HSCT should be considered for eligible patients despite being associated with treatment-related mortality 6, 4
• Elevated pretransplantation serum ferritin is associated with lower overall and disease-free survival, increased treatment-related mortality, and higher risk of veno-occlusive disease 1, 2

Universal Supportive Care Measures

All MDS patients require supportive care regardless of risk category, including red blood cell transfusions for symptomatic anemia (generally leukocyte-reduced) and platelet transfusions for severe thrombocytopenia or bleeding. 1

Iron Overload Management

Iron chelation therapy should be initiated when patients become transfusion-dependent with serum ferritin >1,000 ng/mL, as iron overload significantly worsens survival and increases infection-related mortality. 1, 3, 2

• Target serum ferritin <1,000 mcg/L with chelation therapy 3
• Iron overload causes a 30% increase in hazard for every 500 ng/mL increase in serum ferritin above 1,000 ng/mL threshold 1
• The effect of iron overload is most noticeable in patients with refractory anemia (RA and RARS) who have median survival >100 months and are prone to long-term toxicity 1
• Iron overload contributes to cardiac disease (leading cause of death in transfusion-dependent patients), liver disease, and endocrine dysfunction 1, 2

Additional Supportive Measures

• Transfusion therapy decisions should be based on clinical evaluation of anemia-related symptoms and comorbidities, with the goal of preserving quality of life 1
• Psychosocial support and quality-of-life assessment across physical, functional, emotional, spiritual, and social domains 1
• Clinical monitoring and observation for disease progression 1

Critical Treatment Considerations

Dose Modifications for Decitabine

• If hematologic recovery requires >6 but <8 weeks, delay dosing up to 2 weeks and reduce dose temporarily to 11 mg/m² every 8 hours 7
• Delay subsequent treatment for serum creatinine ≥2 mg/dL, SGPT or total bilirubin ≥2 times upper limit of normal, or active/uncontrolled infection until toxicities resolve 7

Response Assessment

• Use standardized International Working Group (IWG) response criteria to evaluate treatment outcomes 1
• Monitor complete blood counts, hematologic improvement, complete remission, and partial remission 3
• Quality of life assessment using instruments such as WHO Performance Score or FACT Questionnaire provides valuable insights 1

Common Pitfalls

• Failing to stratify patients by IPSS/IPSS-R before selecting therapy leads to inappropriate treatment selection 1
• Discontinuing HMAs before 6 cycles results in missed responses, as most patients require several courses to respond 3
• Neglecting iron chelation in transfusion-dependent patients accelerates organ damage and worsens survival 1, 2
• Not evaluating allo-HSCT eligibility at diagnosis in higher-risk patients misses the only curative opportunity 3, 6

Clinical Trial Consideration

• Clinical trial enrollment should be considered for all patients when available, as novel agents are urgently needed given the limited efficacy of current therapies 3, 8
• HMA-based combination therapies have largely failed to show benefits superior to single-agent HMA treatment in clinical trials 8