Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study

Abstract

Background: Drug treatments for patients with high-risk myelodysplastic syndromes provide no survival advantage. In this trial, we aimed to assess the effect of azacitidine on overall survival compared with the three commonest conventional care regimens.

Methods: In a phase III, international, multicentre, controlled, parallel-group, open-label trial, patients with higher-risk myelodysplastic syndromes were randomly assigned one-to-one to receive azacitidine (75 mg/m(2) per day for 7 days every 28 days) or conventional care (best supportive care, low-dose cytarabine, or intensive chemotherapy as selected by investigators before randomisation). Patients were stratified by French-American-British and international prognostic scoring system classifications; randomisation was done with a block size of four. The primary endpoint was overall survival. Efficacy analyses were by intention to treat for all patients assigned to receive treatment. This study is registered with ClinicalTrials.gov, number NCT00071799.

Findings: Between Feb 13, 2004, and Aug 7, 2006, 358 patients were randomly assigned to receive azacitidine (n=179) or conventional care regimens (n=179). Four patients in the azacitidine and 14 in the conventional care groups received no study drugs but were included in the intention-to-treat efficacy analysis. After a median follow-up of 21.1 months (IQR 15.1-26.9), median overall survival was 24.5 months (9.9-not reached) for the azacitidine group versus 15.0 months (5.6-24.1) for the conventional care group (hazard ratio 0.58; 95% CI 0.43-0.77; stratified log-rank p=0.0001). At last follow-up, 82 patients in the azacitidine group had died compared with 113 in the conventional care group. At 2 years, on the basis of Kaplan-Meier estimates, 50.8% (95% CI 42.1-58.8) of patients in the azacitidine group were alive compared with 26.2% (18.7-34.3) in the conventional care group (p<0.0001). Peripheral cytopenias were the most common grade 3-4 adverse events for all treatments.

Interpretation: Treatment with azacitidine increases overall survival in patients with higher-risk myelodysplastic syndromes relative to conventional care.

Figure 1. Investigator preselection

Before randomisation, investigators preselected the most appropriate of the three conventional care regimens for all patients on the basis of age, general condition, comorbidities, and patient preference. Patients randomised to conventional care were to receive the investigator preselected treatment option.

Figure 2

Trial profile

Figure 3

Overall survival

Figure 4. Hazard ratio and 95% CI for overall survival in the intention-to-treat analysis

Hazard ratios and CIs determined with stratified Cox proportional hazards model adjusted for treatment, subgroup, Eastern Cooperative Oncology Group performance status (ECOG PS), lactate dehydrogenase, haemoglobin, number of previous red-blood-cell transfusions, and presence or absence of the cytogenetic –7/del(7q) abnormality. No subgroup-by-treatment interactions were significant (p>0·20). The horizontal axis uses a logarithmic scale. The dotted line is the hazard ratio in the primary intention to treat (ITT) analysis; the hazard ratio and CI are from the stratified Cox regression model with treatment as the only term. FAB=French–American–British. RAEB=refractory anaemia with excess blasts. RAEB-T=RAEB in transformation. IPSS=international prognostic scoring system. BM=bone marrow.