Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia

Abstract

Purpose: This multicenter, randomized, open-label, phase III trial compared the efficacy and safety of decitabine with treatment choice (TC) in older patients with newly diagnosed acute myeloid leukemia (AML) and poor- or intermediate-risk cytogenetics.

Patients and methods: Patients (N = 485) age ≥ 65 years were randomly assigned 1:1 to receive decitabine 20 mg/m(2) per day as a 1-hour intravenous infusion for five consecutive days every 4 weeks or TC (supportive care or cytarabine 20 mg/m(2) per day as a subcutaneous injection for 10 consecutive days every 4 weeks). The primary end point was overall survival (OS); the secondary end point was the complete remission (CR) rate plus the CR rate without platelet recovery (CRp). Adverse events (AEs) were recorded.

Results: The primary analysis with 396 deaths (81.6%) showed a nonsignificant increase in median OS with decitabine (7.7 months; 95% CI, 6.2 to 9.2) versus TC (5.0 months; 95% CI, 4.3 to 6.3; P = .108; hazard ratio [HR], 0.85; 95% CI, 0.69 to 1.04). An unplanned analysis with 446 deaths (92%) indicated the same median OS (HR, 0.82; 95% CI, 0.68 to 0.99; nominal P = .037). The CR rate plus CRp was 17.8% with decitabine versus 7.8% with TC (odds ratio, 2.5; 95% CI, 1.4 to 4.8; P = .001). AEs were similar for decitabine and cytarabine, although patients received a median of four cycles of decitabine versus two cycles of TC. The most common drug-related AEs with decitabine were thrombocytopenia (27%) and neutropenia (24%).

Conclusion: In older patients with AML, decitabine improved response rates compared with standard therapies without major differences in safety. An unplanned survival analysis showed a benefit for decitabine, which was not observed at the time of the primary analysis.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

CONSORT diagram showing patient disposition from random assignment to time of ad hoc mature analysis.

Fig 2.

(A) Overall survival (Kaplan-Meier method) in a protocol-specified 2009 clinical cutoff analysis of decitabine and treatment choice (TC) in the intent-to-treat population. (B) Overall survival (Kaplan-Meier method) in an ad hoc mature (2010) analysis of decitabine and TC in the intent-to-treat population.

Fig 3.

Subanalyses of mature overall survival data (2010 clinical cutoff) for decitabine and patient treatment choice with physician advice (TC) in the intent-to-treat population. P values were based on two-sided log-rank test and stratified by age, cytogenetic risk, and Eastern Cooperative Oncology Group (ECOG) performance status (PS). AML, acute myeloid leukemia; Aus., Australia; HR, hazard ratio; Med, median (months).

Fig A1.

Overall survival in Western Europe for the intent-to-treat population. TC, treatment choice.

Fig A2.

Mature overall survival in Western Europe for the intent-to-treat population. TC, treatment choice.