title: 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.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Thomas Prebet, James Herman, Lisa Malick, and Steven D. Gore, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Zhuoxin Sun, Dana-Farber Cancer Institute, Boston, MA; Maria E. Figueroa and Ari Melnick, Weill Cornell Medical College; Janice Gabrilove, Mount Sinai School of Medicine; Martin S. Tallman, Leukemia Service, Memorial Sloane-Kettering Cancer Center, New York; Elisabeth Paietta, North Division, Montefiore Medical Center, Bronx, NY; Rhett Ketterling and Mark Litzow, Mayo Clinic, Rochester, MN; Peter L. Greenberg, Stanford University Cancer Center, Stanford, CA; Mark Juckett, University of Wisconsin, Madison, WI; Mitchell R. Smith, Fox Chase Cancer Center, Philadelphia, PA; Magdalena Czader, Indiana University Cancer Center, Indianapolis, IN; and Harry P. Erba, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI.
authors.forename: Thomas
authors.initials: T
authors.lastname: Prebet
authors.forename: Zhuoxin
authors.initials: Z
authors.lastname: Sun
authors.forename: Maria E
authors.initials: ME
authors.lastname: Figueroa
authors.forename: Rhett
authors.initials: R
authors.lastname: Ketterling
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.forename: Peter L
authors.initials: PL
authors.lastname: Greenberg
authors.forename: James
authors.initials: J
authors.lastname: Herman
authors.forename: Mark
authors.initials: M
authors.lastname: Juckett
authors.forename: Mitchell R
authors.initials: MR
authors.lastname: Smith
authors.forename: Lisa
authors.initials: L
authors.lastname: Malick
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Paietta
authors.forename: Magdalena
authors.initials: M
authors.lastname: Czader
authors.forename: Mark
authors.initials: M
authors.lastname: Litzow
authors.forename: Janice
authors.initials: J
authors.lastname: Gabrilove
authors.forename: Harry P
authors.initials: HP
authors.lastname: Erba
authors.forename: Steven D
authors.initials: SD
authors.lastname: Gore
authors.forename: Martin S
authors.initials: MS
authors.lastname: Tallman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001374:Azacitidine / Q000008:administration & dosage*; D001549:Benzamides / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D015477:Leukemia, Myelomonocytic, Chronic / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000473:pathology; D011725:Pyridines / Q000008:administration & dosage; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D001549:Benzamides; D011725:Pyridines; C118739:entinostat; D001374:Azacitidine