Elsevier

The Lancet Oncology

Volume 10, Issue 3, March 2009, Pages 223-232
The Lancet Oncology

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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

https://doi.org/10.1016/S1470-2045(09)70003-8Get rights and content

Summary

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/m2 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.

Funding

Celgene Corporation.

Introduction

Myelodysplastic syndromes are malignant diseases of bone-marrow stem-cells, characterised by ineffective haemopoiesis leading to peripheral-blood cytopenias and, in many patients, progression to acute myeloid leukaemia.1, 2 Myelodysplastic syndromes are categorised morphologically with the French–American–British (FAB) and, more recently, WHO3, 4 classifications. Individual prognosis is determined using the international prognostic scoring system.5

Patients with myelodysplastic syndromes who had intermediate-2 or high-risk scores on the international prognosis scoring system (known as higher-risk myelodysplastic syndromes) have a median survival of 1·2 years or 0·4 years, respectively,5 and a high-risk for progression to acute myeloid leukaemia.5 Although increasing survival and suppression of leukaemic transformation are the primary goals of treatment,6 no treatment strategies other than allogeneic stem-cell transplantation offer meaningful potential to change the natural history of the disease.7, 8, 9, 10, 11, 12, 13, 14, 15 Results of a Cancer and Leukemia Group B (CALGB) trial comparing treatment with azacitidine, a DNA methyltransferase inhibitor, with best supportive care suggested improved overall survival with azacitidine, but the study was inconclusive because of its crossover design and absence of an active comparator.16

This large, prospective, randomised, phase III, clinical trial was done to assess the effect of treatment on overall survival with azacitidine. The control arm included the three most commonly used treatments in higher-risk myelodysplastic syndromes (best supportive care, low-dose cytarabine, or intensive chemotherapy).6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17

Section snippets

Patients

Patients were eligible for enrolment if they were aged 18 years or older, with higher-risk myelodysplastic syndromes (an international prognosis scoring system rating of intermediate-2 or high risk) and FAB-defined refractory anaemia with excess blasts, refractory anaemia with excess blasts in transformation, or chronic myelomonocytic leukaemia3 with at least 10% bone-marrow blasts and a white-blood-cell count lower than 13×109 cells per L. Patients needed an Eastern Cooperative Oncology Group

Results

Between Feb 13, 2004, and Aug 7, 2006, 358 patients (intention-to-treat population) at 79 sites from 15 countries were randomly assigned to receive either azacitidine (n=179) or conventional care regimens (n=179). Of those assigned to conventional care, 105 were to receive best supportive care, 49 low dose cytarabine, and 25 intensive chemotherapy (figure 2). Median age was 69 years (range 38–88 years) with 258 (72%) of 358 patients age 65 years or older. Baseline characteristics were well

Discussion

Treatment with azacitidine prolongs overall survival and lowers the risk of progression to acute myeloid leukaemia in patients with higher-risk myelodysplastic syndrome compared with treatment with conventional care regimens.

The previous CALGB trial16 included a heterogeneous population of patients, best-supportive care as the only comparator, and a crossover design, and 53% of patients who received best-supportive care subsequently received azacitidine. Our study aimed to include only patients

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