Azacitidine for High-risk MDS

Abstract & Commentary

By William B. Ershler, MD

Synopsis: In an international, multi-center trial of azacitidine in patients with either intermediate-2 or high-risk MDS, overall survival was significantly increased when compared to conventional therapy, which at the discretion of the investigator and patient, could have included intense chemotherapy, low-dose cytarabine, or best supportive care.

Source: Fenaux P, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomized, open-label, phase III study. Lancet Oncol. 2009;10:223-232.

Myelodysplastic syndromes (MDS) are heterogeneous in clinical presentation but, as a group, are considered a neoplastic disorder of bone marrow stem cells.1 Coupling the French-American-British (FAB)2 or World Health Organization (WHO) classification system3 with cytogenetic and clinical features, an international prognostic scoring system has been developed,4 and is now commonly used, to assess prognosis and determine treatment strategy. Using this, patients with intermediate-2 or high-risk scores (known as higher risk myelodysplastic syndromes) have a median survival of 1.2 years or 0.4 years, respectively.4 Unfortunately, other than allogeneic bone marrow transplantation, no interventions have consistently resulted in improved survival.5-8

The current phase III, international, multi-center, controlled, parallel-group, open-label trial was undertaken to assess the effect of azacitidine on overall survival compared with three conventional care regimens. For this, 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 randomization on the basis of age, general condition, comorbidities, and patient preferences). Thus, the patient received either the azacitidine or the selected conventional regimen. Patients were stratified by FAB and international prognostic scoring system classifications, and the primary endpoint was overall survival. Efficacy analyses were by intention-to-treat for all patients assigned to receive treatment.

Over approximately 2.5 years, 358 patients were randomly assigned to receive azacitidine (n = 179) or conventional care regimens (n = 179). After a median follow-up of 21.1 months (Intra Quartile Range [IQR] 15.1-26.9), median overall survival was 24.5 months (9.9-not reached) for the azacitidine group vs. 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 two 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.


In a previous trial conducted by the Cancer and Leukemia Group B (CALGB), azacitidine was compared with best supportive care.9 However, that trial included a cross-over design (53% of patients who received best-supportive care subsequently received azacitidine), making any conclusions about an observed survival advantage somewhat tenuous. However, the data from the trial indicated azacitidine treatment was associated with improved quality of life, reduced risk of leukemic transformation and improved survival, compared with supportive care. The current trial focused on those at highest risk, was larger, and offered an active treatment comparator, rather than supportive care alone. Another feature of the trial was the novel approach to the randomization process, which allowed a comparison of the efficacy of azacitidine with that of a control group of patients that were treated much as they would be in a community practice. As such, the observed increased survival and reduced rate of leukemia transformation associated with azacitidine treatment represents a significant step forward in the management of this difficult disease.


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