Background
Phase 3, multicenter, randomized, open-label trial (AZA-AML-001). N=488 patients aged ≥65 years with newly diagnosed AML with >30% bone marrow blasts who were ineligible for intensive chemotherapy. Before randomization, a conventional care regimen (CCR) was preselected by the treating investigator for each patient (standard induction chemotherapy [IC], low-dose cytarabine [LDAC], or best supportive care [BSC]). Patients then assigned 1:1 to azacitidine vs their preselected CCR. Published Blood 2015.
Interventions and follow up
Arm A: Azacitidine 75 mg/m² SC days 1–7 of a 28-day cycle until disease progression or unacceptable toxicity (N=241)
Arm B: Conventional care regimen (preselected: IC 18%, LDAC 41%, BSC 41%) (N=247)
Primary endpoint: Overall survival
mFollow up: Not specified (event-driven analysis)
Arm B: Conventional care regimen (preselected: IC 18%, LDAC 41%, BSC 41%) (N=247)
Primary endpoint: Overall survival
mFollow up: Not specified (event-driven analysis)
Results
OS (primary analysis): 10.4 vs 6.5 months, HR 0.85 (95% CI 0.69–1.03), P=.1009 — primary endpoint NOT met
1-year OS: 46.5% vs 34.2% (difference +12.3%, 95% CI 3.5–21.0%)
OS (sensitivity analysis, censoring post-study AML therapy): 12.1 vs 6.9 months, HR 0.76 (0.60–0.96), P=.019
OS favored azacitidine across all prespecified subgroups: in univariate analysis (directionally consistent but individually underpowered)
1-year OS: 46.5% vs 34.2% (difference +12.3%, 95% CI 3.5–21.0%)
OS (sensitivity analysis, censoring post-study AML therapy): 12.1 vs 6.9 months, HR 0.76 (0.60–0.96), P=.019
OS favored azacitidine across all prespecified subgroups: in univariate analysis (directionally consistent but individually underpowered)
Adverse events
Overall: AEs consistent with the known azacitidine safety profile; rates comparable to the CCR arm with no new safety signals.
Hematologic: Most common grade ≥3 events were thrombocytopenia and neutropenia.
Infectious: Febrile neutropenia among the most common grade ≥3 toxicities.
Hematologic: Most common grade ≥3 events were thrombocytopenia and neutropenia.
Infectious: Febrile neutropenia among the most common grade ≥3 toxicities.
Conclusions
Azacitidine did not significantly improve overall survival vs conventional care regimens in elderly unfit AML (HR 0.85, P=.1009), failing to meet the primary endpoint. A sensitivity analysis censoring post-study AML treatment showed a statistically significant OS benefit (HR 0.76, P=.019), suggesting confounding from post-discontinuation therapy crossover in the primary analysis.
Key Limitations
Primary endpoint not met — the positive sensitivity analysis is exploratory and may reflect informative censoring. CCR arm was heterogeneous (IC, LDAC, BSC preselected), making interpretation of azacitidine vs any single comparator difficult. The trial was designed before venetoclax was available, making results largely of historical interest. Crossover in CCR arm after study discontinuation diluted OS benefit in primary analysis. The >30% blast threshold is no longer used in modern AML classification (now WHO/ICC 2022 uses ≥20%).
Clinical Context
AZA-AML-001 established azacitidine as an active but not proven superior option vs conventional care in elderly unfit AML. The trial was largely superseded by VIALE-A (venetoclax + azacitidine), which showed robust OS benefit (HR 0.66, P<.001) in the same population — making ven+AZA the current standard of care. ESMO-MCBS: not applicable (negative primary endpoint).