Prolonged Administration of Azacitidine Improves Response in Myelodysplasia, Less So in Combination With Entinostat


Key Points

  • Prolonged administration of lower-dose azacitidine produced a high rate of hematologic normalization.
  • The hematologic normalization rate was lower with the combination of azacitidine and entinostat, with pharmacodynamic antagonism being observed.

In the phase II US Leukemia Intergroup Trial E1905 reported in the Journal of Clinical Oncology, Prebet et al found that prolonged administration of lower-dose azacitidine produced a high response rate in patients with myelodysplastic syndrome or acute myeloid leukemia (AML) with myelodysplastic syndrome–related changes. The response rate was lower in patients receiving azacitidine in combination with the HDAC inhibitor entinostat, and there was evidence of antagonism between the two agents.

Study Details

In this open-label study, 149 patients with myelodysplastic syndrome (n = 97) or AML with myelodysplastic syndrome–related changes (n = 52) were randomly assigned to receive subcutaneous azacitidine at 50 mg/m2/d for 10 days with (n = 75) or without (n = 74) oral entinostat at 4 mg/m2/d on days 3 and 10 every 28 days. The 10-day schedule of azacitidine was developed to optimize DNA methylation via prolonged administration of lower daily doses designed to cause less cell-cycle inhibition. After six cycles, patients with clinical response continued on treatment for a total of 24 cycles or until disease progression.

The primary objective was to determine whether either treatment significantly increased the rate of hematologic normalization, defined as complete remission, partial remission, or major trilineage hematologic improvement, compared with results achieved in the Cancer and Leukemia Group B (CALGB) 9221 trial. CALGB 9221 showed a 16% hematologic normalization rate with azacitidine in myelodysplastic syndrome, and the specific aim of the current trial was to show an approximate doubling of the hematologic normalization rate to 30%.

The combination and azacitidine groups were generally balanced for age (median, 72 years in both), sex (52% and 50% male), disease classification (International Prognostic Scoring System [IPSS] low/intermediate-1 myelodysplastic syndrome in 19% and 18%, IPSS intermediate-2/high myelodysplastic syndrome in 43% and 45%, chronic myelomonocytic leukemia in 4% and 3%, AML with myelodysplastic syndrome-related changes in 35% in both), and IPSS cytogenetic risk group (favorable in 31% and 27%, intermediate in 19% and 11%, high risk in 33% and 41%).

Hematologic Normalization Rates

Hematologic normalization occurred in 27% (95% confidence interval [CI] = 17%–39%) of the azacitidine/entinostat group (including complete remission in 8%, partial remission in 7%, and trilineage improvement in 12%) and 32% (95% CI = 22%–44%) of the azacitidine group (including complete remission in 12%, partial remission in 8%, and trilineage improvement in 12%). Although rates and lower bounds of the 95% confidence interval in both groups exceeded the 16% rate observed in CALBG 9221, only the azacitidine-alone group reached the target rate of 30%.

Rates of overall hematologic response were 44% and 46%. Median time to first response was 4 months, median time to best response was 6 months, and median duration of response was 12 months in both groups. Median overall survival was 13 vs 18 months, including 14.7 vs 21.2 months among patients with myelodysplastic syndrome or chronic myelomonocytic leukemia and 5.3 vs 7.1 months in those with AML.

DNA methylation studies showed a global loss of DNA methylation after treatment with the study regimens; however, demethylation was of significantly reduced magnitude in the combination group compared with the azacitidine-alone group, suggesting pharmacodynamic antagonism between the two agents.


Grade 3 or 4 adverse events occurred in 91% of the combination group and 87% of the azacitidine group (P = .23), including anemia in 50% vs 53%, thrombocytopenia in 76% vs 72%, and neutropenia in 73% vs 73%. Grade 3 or 4 nonhematologic toxicities occurred in 57% and 43%, with the most common being infection (including neutropenic fever) in 47% vs 38%, fatigue/asthenia in 19% vs 12%, hyponatremia in 12% vs 1%, hypoalbuminemia in 8% vs 1%, confusion/dizziness in 7% vs 2%, and nausea/vomiting in 5% vs 3%. There was no difference between groups in proportions of patients discontinuing treatment due to adverse events. Nine patients died during the study, due to infection in two combination group patients and four azacitidine patients, multiorgan failure in one patient in each group, and sudden death in one combination group patient.

The investigators concluded, “Addition of entinostat to [azacitidine] did not increase clinical response as defined by the protocol and was associated with pharmacodynamic antagonism. However, the prolonged administration of [azacitidine] by itself seems to increase [hematologic normalization] rate compared with standard dosing and warrants additional investigation.”

Steven Gore, MD, of Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, is the corresponding author for the Journal of Clinical Oncology article.

The study was supported by grants from the Leukemia and Lymphoma Society of America and the Fulbright Franco-American Commission/Foundation Monahan. For full disclosures of the study authors, visit

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