Why is azacitidine (a hypomethylating agent) not typically indicated for patients with low-risk Myelodysplastic Syndromes (MDS)?

Why Azacitidine is Not Indicated in Low-Risk MDS

Azacitidine is not indicated in low-risk MDS because it is specifically recommended only for higher-risk disease (IPSS-R intermediate, high, or very high risk), where it has demonstrated survival benefit in randomized trials, whereas no such survival data exist for routine use in lower-risk patients. 1

Evidence-Based Risk Stratification

The indication for azacitidine is explicitly tied to disease risk category:

• Higher-risk MDS (IPSS intermediate-2 or high risk, or IPSS-R intermediate/high/very high risk) is where azacitidine has proven survival benefit in phase III randomized trials 1
• In the pivotal AZA-001 trial, azacitidine demonstrated 50.8% survival at 2 years versus 26.2% with conventional care (P<0.0001) specifically in IPSS intermediate-2 or high-risk patients 1
• Lower-risk MDS (IPSS low or intermediate-1 risk) has fundamentally different natural history with longer survival and lower AML transformation risk, making the risk-benefit calculation entirely different 1

Clinical Rationale for Risk-Based Treatment

The treatment paradigm differs fundamentally by risk category:

• Higher-risk MDS carries major risk of AML progression and short survival, requiring disease-modifying therapy 1
• Lower-risk MDS has median survival of 5.3-8.8 years (IPSS-R low/very low), where treatment goals focus on managing cytopenias rather than altering disease course 1
• The primary treatment approach for lower-risk disease emphasizes supportive care, erythropoiesis-stimulating agents for anemia, and lenalidomide for del(5q) patients 1

Lack of Survival Data in Low-Risk Disease

The evidence base does not support routine azacitidine use in low-risk MDS:

• All major randomized trials demonstrating survival benefit enrolled exclusively higher-risk patients (IPSS intermediate-2 or high) 1
• While retrospective data suggest azacitidine may produce responses in lower-risk MDS (45.9% overall response rate in one Italian series), these studies lack the randomized survival data required for standard indication 2
• A 2022 randomized trial of attenuated-dose hypomethylating agents in lower-risk MDS showed responses but was designed for a selected high-risk cohort within the lower-risk category, not routine low-risk patients 3

Specific Clinical Scenarios Where Lower-Risk Patients Might Receive Azacitidine

Azacitidine may be considered in lower-risk MDS only under specific circumstances:

• Thrombocytopenia or neutropenia unresponsive to other therapies 4
• Anemia refractory to erythropoiesis-stimulating agents and other standard treatments 4
• IPSS-R intermediate-risk patients who have additional adverse features (age, comorbidities, severe cytopenias, adverse mutations) that shift them toward higher-risk treatment algorithms 1

Treatment Algorithm Considerations

The decision framework is clear:

• IPSS-R very low/low risk: Supportive care, ESAs for anemia, lenalidomide for del(5q) 1
• IPSS-R intermediate risk: Individualized based on additional factors (age, comorbidities, cytopenia severity, mutations, response to first-line treatment) 1
• IPSS-R high/very high risk: Azacitidine 75 mg/m² for 7 days every 28 days (minimum 6 cycles) or allogeneic transplant 1, 5

Common Pitfalls to Avoid

• Do not use azacitidine in low-risk MDS simply because a patient has transfusion-dependent anemia—first optimize ESA therapy and consider lenalidomide if del(5q) is present 1
• Do not extrapolate higher-risk MDS survival data to justify azacitidine use in truly low-risk patients without additional high-risk features 1
• Recognize that IPSS-R intermediate-risk represents a gray zone requiring assessment of additional prognostic factors before committing to disease-modifying therapy versus symptom management 1