Treatment with oral azacitidine (CC-486), a hypomethylating agent, significantly improved the rate of red blood cell transfusion independence (RBC-TI) and induced durable bilineage improvements compared with placebo in patients with low-risk myelodysplastic syndrome (LR-MDS) and RBC transfusion dependence, according to the results of a study published in the Journal of Clinical Oncology.

The randomized, placebo-controlled phase 3 trial ( Identifier: NCT01566695) was conducted at 101 sites in 20 countries and enrolled 216 patients with RBC transfusion-dependent anemia and thrombocytopenia due to LR-MDS as defined by the International Prognostic Scoring System. The participants were randomly assigned 1:1 to receive oral azacitidine 300 mg (107 patients) or placebo (109 patients) once daily for 21 days per 28-day treatment cycle. The median age of the patients was 74 years (range, 30-89), and their median platelet count and absolute neutrophil count were 25 x 109/L, and 1.3 x 109/L, respectively.

Among patients who were RBC transfusion-dependent, 31% of the patients in the azacitidine arm and 11% in the placebo arm achieved RBC-TI for more than 56 consecutive days (odds ratio [OR], 3.6; 95% CI, 1.7-7.4; P =.0002). The median RBC-TI durations in the azacitidine and placebo arms were 11.1 and 5.0 months, respectively (P =.42). In the azacitidine and placebo arms, reductions of 4 or more RBC units were attained by 42.1% and 30.6% of patients, respectively, with median durations of 10.0 and 2.3 months.

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There was a significant hematologic improvement in the erythroid response among patients in the azacitidine arm (43%) compared with the placebo arm (31.5%; OR, 1.6; 95% CI, 0.9-2.9; P =.12). A larger proportion of patients (23.4%) in the azacitidine arm had an increase of 1.5 g/dL or more in hemoglobin concentration from baseline compared with the placebo arm (4.6%; OR, 6.3; 95% CI, 2.3-17.1; P <.0001).

The rate of platelet transfusion independence was 16.7% in the azacitidine arm and 14.3% in the placebo arm, which was not significantly different. However, the platelet hematologic improvement rate was higher with azacitidine (24.3%) than with placebo (6.5%; OR, 4.6; 95% CI, 1.9-11.2; P =.0003).

In the interim survival analysis, no significant difference was found in the overall survival between the azacitidine arm (17.3 months) and the placebo arm (16.2 months; (hazard ratio, 0.99; 95% CI, 0.70-1.40; P =.96). However, a higher rate of early death was reported during the first 56 days in the azacitidine arm, which was attributed to infection among patients who had pretreatment neutropenia.

A majority of the patients (90% in the azacitidine arm and 73% in the placebo arm) experienced grade 3 to 4 treatment-emergent adverse events (TEAEs). The most common TEAEs were hematologic and GI events, which occurred in both arms. Grade 3 to 4 neutropenia, thrombocytopenia, and febrile neutropenia occurred more frequently in the azacitidine arm than in the placebo arm.

“These results demonstrate that CC-486 can provide clinically meaningful reductions in RBC transfusion burden and ameliorate thrombocytopenia in patients with LR-MDS with symptomatic disease and refractory cytopenias,” the authors stated.

“Further evaluation of CC-486 in patients with MDS is needed, including rational identification of patients most likely to benefit from the drug,” they concluded.

Disclosure: This research was supported by Celgene Corporation, a Bristol-Myers Squibb company. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Garcia-Manero G, Santini V, Almeida A, et al. Phase III, randomized, placebo-controlled trial of CC-486 (oral azacitidine) in patients with lower-risk myelodysplastic syndromes. J Clin Oncol. 2021;39(13):1426-1436. doi:10.1200/JCO.20.02619