Prolonged administration of azacitidine with or without entinostat for myelodysplastic syndrome and acute myeloid leukemia with myelodysplasia-related changes: results of the US Leukemia Intergroup trial E1905. Academic Article Article uri icon

Overview

MeSH

  • Adult
  • Aged
  • Aged, 80 and over
  • Benzamides
  • Drug Administration Schedule
  • Female
  • Humans
  • Male
  • Middle Aged
  • Pyridines
  • Survival Analysis
  • Treatment Outcome

MeSH Major

  • Antimetabolites, Antineoplastic
  • Antineoplastic Combined Chemotherapy Protocols
  • Azacitidine
  • Leukemia, Myeloid, Acute
  • Leukemia, Myelomonocytic, Chronic
  • Myelodysplastic Syndromes

abstract

  • Although azacitidine (AZA) improves survival in patients with high-risk myelodysplastic syndrome, the overall response remains approximately 50%. Entinostat is a histone deacetylase inhibitor that has been combined with AZA with significant clinical activity in a previous phase I dose finding study. Open label phase II randomized trial comparing AZA 50 mg/m(2)/d given for 10 days ± entinostat 4 mg/m(2)/d day 3 and day 10. All subtypes of myelodysplasia, chronic myelomonocytic leukemia, and acute myeloid leukemia with myelodysplasia-related changes were eligible for the study. The primary objective was the rate of hematologic normalization (HN; complete remission + partial remission + trilineage hematological improvement). One hundred forty-nine patients were analyzed, including 97 patients with myelodysplastic syndrome and 52 patients with acute myeloid leukemia. In the AZA group, 32% (95% CI, 22% to 44%) experienced HN and 27% (95% CI, 17% to 39%) in the AZA + entinostat group. Both arms exceeded the HN rate of historical control (Cancer and Leukemia Group B 9221 trial), but only the AZA group fulfilled the primary objective of the study. Rates of overall hematologic response were 46% and 44%, respectively. Median overall survivals were 18 months for the AZA group and 13 months for the AZA + entinostat group. The combination arm led to less demethylation compared with the monotherapy arm, suggesting pharmacodynamic antagonism. Addition of entinostat to AZA did not increase clinical response as defined by the protocol and was associated with pharmacodynamic antagonism. However, the prolonged administration of AZA by itself seems to increase HN rate compared with standard dosing and warrants additional investigation.

publication date

  • April 20, 2014

has subject area

  • Adult
  • Aged
  • Aged, 80 and over
  • Antimetabolites, Antineoplastic
  • Antineoplastic Combined Chemotherapy Protocols
  • Azacitidine
  • Benzamides
  • Drug Administration Schedule
  • Female
  • Humans
  • Leukemia, Myeloid, Acute
  • Leukemia, Myelomonocytic, Chronic
  • Male
  • Middle Aged
  • Myelodysplastic Syndromes
  • Pyridines
  • Survival Analysis
  • Treatment Outcome

Research

keywords

  • Clinical Trial, Phase II
  • Journal Article
  • Multicenter Study
  • Randomized Controlled Trial

Identity

Language

  • eng

PubMed Central ID

  • PMC3986386

Digital Object Identifier (DOI)

  • 10.1200/JCO.2013.50.3102

PubMed ID

  • 24663049

Additional Document Info

start page

  • 1242

end page

  • 1248

volume

  • 32

number

  • 12