Background
Phase III RCT of 358 patients with higher-risk MDS assessing azacitidine vs conventional care regimens (CCR) on overall survival. Higher-risk MDS defined as IPSS intermediate-2 or high risk plus FAB-defined RAEB, RAEB-in-transformation, or CMML with ≥10% marrow blasts and WBC <13×10⁹/L. Patients with therapy-related MDS, prior azacitidine, or planned allo-HSCT were excluded.
Interventions and follow up
Arm A: Azacitidine 75 mg/m²/d SC days 1–7 q28d for ≥6 cycles, continued until unacceptable toxicity, relapse, or progression (n=179)
Arm B: Conventional care regimen preselected per patient — best supportive care only (n=105), low-dose cytarabine 20 mg/m²/d SC days 1–14 q28d for ≥4 cycles (n=49), or intensive chemotherapy (cytarabine 100–200 mg/m²/d CIVI ×7d plus 3 days daunorubicin/idarubicin/mitoxantrone) (n=25)
Primary endpoint: Overall survival
mFollow up: 21.1 months
Arm B: Conventional care regimen preselected per patient — best supportive care only (n=105), low-dose cytarabine 20 mg/m²/d SC days 1–14 q28d for ≥4 cycles (n=49), or intensive chemotherapy (cytarabine 100–200 mg/m²/d CIVI ×7d plus 3 days daunorubicin/idarubicin/mitoxantrone) (n=25)
Primary endpoint: Overall survival
mFollow up: 21.1 months
Results
mOS: 24.5 vs 15.0 months (azacitidine vs CCR), HR 0.58, 95% CI 0.43–0.77, P=.0001
2-yr OS: 50.8% vs 26.2%
Median time to AML transformation: 17.8 vs 11.5 months, HR 0.50, 95% CI 0.35–0.70, P<.0001
RBC transfusion independence: 45% vs 11.4% (P<.0001)
CR + PR: 29% (azacitidine) vs 12% (CCR)
2-yr OS: 50.8% vs 26.2%
Median time to AML transformation: 17.8 vs 11.5 months, HR 0.50, 95% CI 0.35–0.70, P<.0001
RBC transfusion independence: 45% vs 11.4% (P<.0001)
CR + PR: 29% (azacitidine) vs 12% (CCR)
Adverse events
Hematologic (Grade ≥3, azacitidine vs CCR): neutropenia 91% vs 76%, thrombocytopenia 85% vs 80%, anemia 57% vs 68%
Infections: febrile neutropenia and infectious events frequent; managed with dose adjustments
Other/mortality: 4 vs 1 fatal adverse events; treatment-related mortality low overall
Infections: febrile neutropenia and infectious events frequent; managed with dose adjustments
Other/mortality: 4 vs 1 fatal adverse events; treatment-related mortality low overall
Conclusions
Azacitidine significantly prolonged median OS (24.5 vs 15.0 months, HR 0.58, P=.0001) and delayed AML transformation compared with conventional care regimens in higher-risk MDS, establishing azacitidine as a standard of care in this population.
Key Limitations
Heterogeneous CCR comparator with physician-preselected subgroups (most received best supportive care alone) limits comparison to intensive chemotherapy; only ~25 patients received intensive chemotherapy, precluding robust subgroup conclusions; open-label design; CMML and RAEB-t are no longer classified as MDS under current WHO criteria; modest CR rate (17%) despite OS benefit; allo-HSCT candidates excluded; no molecular (TP53, ASXL1, etc.) stratification available at the time.
Clinical Context
This trial (AZA-001) established azacitidine as the standard of care for higher-risk MDS and underpinned its EMA approval and prior FDA approval for MDS. It was the first hypomethylating agent to demonstrate an OS advantage in MDS. Azacitidine remains first-line for transplant-ineligible higher-risk MDS; allo-HSCT remains the only curative option and azacitidine often serves as a bridge. Subsequent combination strategies (azacitidine plus venetoclax, magrolimab, or APR-246/eprenetapopam in TP53-mutant disease) have largely failed to improve on azacitidine monotherapy in randomized higher-risk MDS trials, leaving single-agent azacitidine the backbone.