What are the treatment goals for myelodysplastic syndrome (MDS) in an older adult with potential comorbidities in a limited setting facility?

Myelodysplastic Syndrome (MDS) Overview and Treatment Goals in Limited-Resource Settings

What is MDS?

MDS comprises clonal hematopoietic malignancies causing bone marrow dysplasia with peripheral cytopenias (anemia, neutropenia, thrombocytopenia) and increased risk of acute myeloid leukemia (AML) transformation 1. The median age at diagnosis is approximately 70 years, with yearly incidence of 4 per 100,000 people in the United States, rising to 25 per 100,000 in those aged ≥65 years 2. MDS occurs more frequently in older males and those with prior cytotoxic therapy exposure 3, 2.

Risk Stratification Framework

Risk stratification using the International Prognostic Scoring System-Revised (IPSS-R) is essential and determines all treatment decisions 1. This system evaluates:

• Peripheral blood cytopenias severity
• Bone marrow blast percentage
• Cytogenetic abnormalities 1, 3

Lower-risk MDS (IPSS Low and Intermediate-1) patients have median survival of 3-10 years, while higher-risk MDS (IPSS Intermediate-2 and High) patients have median survival <3 years 2, 4.

Treatment Goals by Risk Category

Lower-Risk MDS: Palliation and Quality of Life

In lower-risk MDS, the primary goal is treating cytopenias (especially anemia), improving quality of life, and reducing transfusion burden—NOT necessarily prolonging survival 1. Approximately half of elderly lower-risk patients die from causes unrelated to MDS or AML 1.

Key treatment objectives include:

• Hematologic improvement in blood counts, particularly addressing anemia (the predominant cytopenia) 1
• Minimizing red blood cell (RBC) transfusion requirements 1, 5
• Preventing iron overload from chronic transfusions 1
• Maintaining outpatient management with low-intensity therapies 1

Higher-Risk MDS: Disease Modification and Survival

In higher-risk MDS, treatment goals shift to altering the natural history of disease by delaying AML progression and prolonging overall survival 1, 4. These patients represent 29% of the MDS population with historically dismal outcomes (median survival 0.4-1.1 years without therapy) 4.

Primary treatment objectives are:

• Achieving complete remission (CR) or partial remission (PR) 1
• Prolonging progression-free survival and overall survival 1, 4
• Evaluating for allogeneic stem cell transplantation (allo-SCT)—the only potentially curative option 1

Practical Treatment Approach for Limited-Resource Settings

Lower-Risk MDS Management

For anemia without del(5q) cytogenetic abnormality:

• First-line: Erythropoiesis-stimulating agents (ESAs) such as recombinant EPO (30,000-80,000 units weekly) or darbepoetin (150-300 μg weekly) 1
• ESAs achieve 40-60% erythroid response rates when baseline EPO level is <200-500 U/L and transfusion requirements are low or absent 1
• ESAs are an independent favorable prognostic factor for survival despite not impacting AML progression 1
• Median response duration is 20-24 months; responses occur within 8-12 weeks 1
• Adding G-CSF can improve ESA efficacy 1

When ESAs fail or are unavailable:

• Chronic RBC transfusions become the mainstay supportive treatment 1
• Monitor for iron overload; consider iron chelation therapy if transfusion-dependent 1
• RBC transfusions are associated with chronic anemia and cannot fully correct impaired quality of life 1

Higher-Risk MDS Management

For patients ineligible for allo-SCT (most patients >70 years or with significant comorbidities):

• Hypomethylating agents (HMAs) are the first-line reference treatment 1, 2
• Azacitidine 75 mg/m²/day subcutaneously for 7 consecutive days every 28 days (or "5-2-2" regimens for easier administration) 1
• Administer at least 6 cycles before assessing response, as many patients only respond after several courses 1
• Azacitidine extends survival by up to 74% despite modest complete response rates 4

In limited-resource settings without HMA access:

• Low-dose cytarabine can be considered, though less effective than HMAs 1
• Supportive care alone with RBC transfusions, antibiotics, and symptom management is appropriate for very frail patients 1

For fit patients ≤70 years:

• Evaluate for allo-SCT eligibility at diagnosis—this is the only potentially curative treatment 1
• HLA-identical siblings or matched unrelated donors are preferred 1
• Patients aged <55 years without comorbidities should receive myeloablative conditioning; older patients receive reduced-intensity conditioning 1
• Consider 2-6 cycles of azacitidine before transplant to reduce blast percentage, especially when marrow blasts >10% 1
• Iron chelation should be provided before allo-SCT as iron overload increases infection-related mortality 1

Critical Pitfalls in Limited-Resource Settings

Avoid these common errors:

• Do not withhold ESAs in lower-risk patients based on concerns about AML progression—ESAs improve survival without increasing transformation risk 1
• Do not discontinue azacitidine before 6 cycles in higher-risk patients, as responses are often delayed 1
• Do not assume all elderly patients are ineligible for allo-SCT—particularly fit patients >70 years can sometimes be considered 1
• Do not ignore iron overload in chronically transfused patients, especially those being considered for allo-SCT 1
• Do not use intensive AML-like chemotherapy in higher-risk MDS with unfavorable cytogenetics—these patients show few complete responses and shorter remission duration 1

Response Assessment

Monitor treatment effectiveness using standardized criteria 1:

• Complete blood counts should be evaluated at least monthly to establish durability of responses 1
• Hematologic improvement (HI) is the appropriate endpoint for low-intensity therapies aimed at palliation 1
• Complete remission (CR) or partial remission (PR) are appropriate endpoints for treatments aimed at altering disease natural history 1
• Bone marrow evaluation after hematological recovery or between days 28-35 if recovery is lacking 1

When Treatments Fail

For lower-risk patients failing ESAs:

• Consider clinical trial enrollment if available 1
• Transition to chronic transfusion support 1
• Some patients may warrant escalation to higher-risk MDS treatments based on IPSS-R score or resistance to first-line therapy 1

For higher-risk patients failing HMAs:

• Median survival is <6 months except for those eligible for allo-SCT 1
• Enroll in clinical trials if available 1
• Proceed to allo-SCT if patient becomes eligible 1
• Supportive care alone is appropriate for very frail patients 1