International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts

Abstract

This multicenter, randomized, open-label, phase 3 trial evaluated azacitidine efficacy and safety vs conventional care regimens (CCRs) in 488 patients age ≥65 years with newly diagnosed acute myeloid leukemia (AML) with >30% bone marrow blasts. Before randomization, a CCR (standard induction chemotherapy, low-dose ara-c, or supportive care only) was preselected for each patient. Patients then were assigned 1:1 to azacitidine (n = 241) or CCR (n = 247). Patients assigned to CCR received their preselected treatment. Median overall survival (OS) was increased with azacitidine vs CCR: 10.4 months (95% confidence interval [CI], 8.0-12.7 months) vs 6.5 months (95% CI, 5.0-8.6 months), respectively (hazard ratio [HR] was 0.85; 95% CI, 0.69-1.03; stratified log-rank P = .1009). One-year survival rates with azacitidine and CCR were 46.5% and 34.2%, respectively (difference, 12.3%; 95% CI, 3.5%-21.0%). A prespecified analysis censoring patients who received AML treatment after discontinuing study drug showed median OS with azacitidine vs CCR was 12.1 months (95% CI, 9.2-14.2 months) vs 6.9 months (95% CI, 5.1-9.6 months; HR, 0.76; 95% CI, 0.60-0.96; stratified log-rank P = .0190). Univariate analysis showed favorable trends for azacitidine compared with CCR across all subgroups defined by baseline demographic and disease features. Adverse events were consistent with the well-established safety profile of azacitidine. Azacitidine may be an important treatment option for this difficult-to-treat AML population. This trial was registered at www.clinicaltrials.gov as #NCT01074047.

Figure 1

Primary and preplanned sensitivity analyses for OS of AML therapy. (A) Primary analysis: OS for the intention-to-treat population. Median OS was 10.4 months (95% CI, 8.0-12.7 months) for the azacitidine arm and 6.5 months (95% CI, 5.0-8.6 months) for the CCR arm. In the analysis stratified by ECOG PS and cytogenetic risk, the HR was 0.85 (95% CI, 0.69-1.03; log-rank P = .1009). One-year survival was 46.5% for the azacitidine arm and 34.2% for the CCR arm (difference, 12.3%; 95% CI, 3.5%-21.0%). Median follow-up for OS was 24.4 months. There were 193 deaths in the azacitidine arm (80.1%) and 201 deaths in the CCR arm (81.4%). (B) Preplanned sensitivity analysis: OS censored for subsequent AML therapy (67 azacitidine patients and 75 CCR patients were censored at the time they received subsequent AML therapy). Median OS was 12.1 months (95% CI, 9.2-14.2 months) for the azacitidine arm and 6.9 months (95% CI, 5.1-9.6) for the CCR arm. In the analysis stratified by ECOG PS and cytogenetic risk, the HR was 0.76 (95% CI, 0.60-0.96; log-rank P = .0190). CIs for the difference in 1-year survival probabilities were derived by using Greenwood’s variance estimate. (○) Censored patient.

Figure 2

Overall survival in univariate analyses of patient subgroups. Patient subgroups were defined by baseline demographic and disease characteristics. The dotted line represents the overall unstratified HR for azacitidine vs CCR.