Oral Azacitidine in Lower-Risk Myelodysplastic Syndromes

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In a phase III trial reported in the Journal of Clinical Oncology, Guillermo Garcia-Manero, MD, and colleagues found that oral azacitidine significantly improved red blood cell (RBC) transfusion independence vs placebo in patients with lower-risk myelodysplastic syndromes. An increase in early deaths—primarily due to infection associated with pretreatment neutropenia—was observed in the oral azacitidine group.

Azacitidine in tablet form was recently approved for the treatment of adult patients with acute myeloid leukemia in first remission following induction chemotherapy who are not able to complete curative therapy.

Guillermo Garcia-Manero, MD

Guillermo Garcia-Manero, MD

Study Details

The double-blind trial included 216 patients from sites in 20 countries with International Prognostic Scoring System (IPPS) lower-risk myelodysplastic syndromes and RBC transfusion–dependent anemia and thrombocytopenia. Patients were randomly assigned between April 2013 and February 2018 to receive oral azacitidine at 300 mg (n = 107) or placebo (n = 109) for 21 days in 28-day cycles.

The primary endpoint was RBC transfusion independence (lasting ≥ 56 consecutive days) assessed after all patients had completed 12 months of treatment or discontinued the study drug. Post hoc assessment showed that 28.3% of patients had high- or very high–risk myelodysplastic syndromes on IPSS-Revised assessment.

RBC Transfusion Independence

RBC transfusion independence was achieved by 30.8% of patients in the azacitidine group vs 11.1% of the placebo group (odds ratio [OR] = 3.6, 95% confidence interval [CI] = 1.7–7.4, P = .0002), with median durations of 11.1 vs 5.0 months (P = .42). RBC transfusion reductions of ≥ 4 RBC units/56 days were observed in 42.1% vs 30.6% of patients (OR = 1.7, 95% CI = 0.9–2.9, P = .12) and were sustained for a median of 10.0 months vs 2.3 months; reductions were sustained for ≥ 16 weeks in 27.1% vs 5.6% of patients. An increase of ≥ 1.5 g/dL in hemoglobin from baseline was achieved in 23.4% vs 4.6%.

Among patients with platelet transfusion dependence at baseline, 5 (16.7%) of 30 vs 5 (14.3%) of 35 had platelet transfusion independence that was sustained for a median of 12.1 months vs 4.4 months. Overall, platelet hematologic improvement occurred in 24.3% vs 6.5% of patients (OR = 4.6, 95% CI = 1.9–11.2, P = .0003).

An underpowered interim overall survival analysis showed no difference between the oral azacitidine and placebo groups (median = 17.3 vs 16.2 months, P = .96). At time of data cutoff (January 2019), death had occurred in 69 patients vs 71 patients. An excess of deaths during the first 56 days of treatment was observed in the oral azacitidine group (16 vs 6).

Post hoc analyses showed that the 16 patients in the oral azacitidine group with early death were severely neutropenic and thrombocytopenic at baseline, with a median absolute neutrophil count (ANC) of 0.57 × 109/L and a platelet count of 15.5 × 109/L; for the 6 patients with early death in the placebo group, median ANC was 2.31 × 109/L and platelet count was 22.0 × 109/L at baseline. The most common reason for early death in the oral azacitidine group was infection (primarily bacterial).


  • RBC transfusion independence was achieved in 30.8% of the azacitidine group vs 11.1% of the placebo group.
  • Early excess death was observed in the oral azacitidine group in association with baseline severe neutropenia.

Adverse Events

Low-grade gastrointestinal adverse events were the most common adverse events reported in both groups. Grade 3 to 4 adverse events occurred in 89.7% of the oral azacitidine group vs 73.4% in the placebo group.

Grade 3 to 4 neutropenia (46.7% vs 11.9%), thrombocytopenia (29.0% vs 15.6%), and febrile neutropenia (28.0% vs 10.1%) were more common in the oral azacitidine group, with the incidence of these events generally being higher in earlier treatment cycles. Grade 3 to 4 infection occurred in 43.0% vs 27.5% of patients. Treatment was permanently discontinued due to adverse events in 29.9% vs 28.4% of patients, with the most common causes in the oral azacitidine group being nausea (3.7%), febrile neutropenia (2.8%), and sepsis (2.8%).

The investigators concluded, “Oral azacitidine significantly improved RBC transfusion independence rate and induced durable bilineage improvements in patients with lower-risk myelodysplastic syndromes and high-risk disease features. More early deaths occurred in the oral azacitidine arm, most related to infections in patients with significant pretreatment neutropenia. Further evaluation of oral azacitidine in myelodysplastic syndromes is needed.”

Dr. Garcia-Manero, of the Department of Leukemia, The University of Texas MD Anderson Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Celgene Corporation, a Bristol Myers Squibb company. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.