title: Azacitidine with or without Entinostat for the treatment of therapy-related myeloid neoplasm: further results of the E1905 North American Leukemia Intergroup study.
abstract: Therapy-related myeloid neoplasms (tMN) are serious late effects of the treatment of cancer with poor response to conventional treatment. Azacitidine (AZA) has been used to treat patients with tMN but current data are retrospective. We present here 47 tMN patients prospectively enrolled as a specific cohort in the E1905 study. TheE1905 study was a randomized phase 2 study (NCT00313586) testing 10 d of AZA (50 mg/m(2) /d) +/- the histone deacetylase inhibitor entinostat (4 mg/m(2) /d PO day-3 and day-10). A total of 47 patients [29 therapy-related myelosyspastic syndrome (t-MDS) and 18 therapy-related acute myeloid leukaemia (t-AML)] were recruited to the study. 24 patients were treated with AZA monotherapy and 23 with AZA+entinostat. The median number of administered cycles was 4, significantly higher in patients treated with AZA (6 cycles vs. 3 cycles, P = 0·008). Haematological normalization rates were 46% in monotherapy and 17% in the combination arm. Median overall survivals were 13 and 6 months, respectively. The novel 50 * 10 schedule of azacitidine appears effective, with response rates, when given as single agent, comparable to those for patients with de novo MDS/AML treated on the same protocol. However, the combination of AZA and entinostat was associated with increased toxicity and could not be recommended for treatment of tMN.
authors.affiliation: Section of Hematology, Yale Cancer Center, New Haven, CT, USA.
authors.forename: Thomas
authors.identifier: http://orcid.org/0000-0002-6872-625X
authors.initials: T
authors.lastname: Prebet
authors.affiliation: ECOG-ACRIN Biostatistics Center, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Zhuoxin
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Rhett P
authors.initials: RP
authors.lastname: Ketterling
authors.affiliation: Section of Hematology, Yale Cancer Center, New Haven, CT, USA.
authors.forename: Amer
authors.initials: A
authors.lastname: Zeidan
authors.affiliation: Hematology Division, Stanford University Cancer Center, Stanford, CA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Greenberg
authors.affiliation: Johns Hopkins University, Baltimore, MD, USA.
authors.forename: James
authors.initials: J
authors.lastname: Herman
authors.affiliation: University of Wisconsin, Madison, WI, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Juckett
authors.affiliation: Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Mitchell R
authors.initials: MR
authors.lastname: Smith
authors.affiliation: Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Malick
authors.affiliation: North Division, Montefiore Medical Center, Bronx, NY, USA.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Paietta
authors.affiliation: Indiana University Cancer Center, Indianapolis, IN, USA.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Czader
authors.affiliation: University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Figueroa
authors.affiliation: The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: Janice
authors.initials: J
authors.lastname: Gabrilove
authors.affiliation: University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
authors.forename: Harry P
authors.initials: HP
authors.lastname: Erba
authors.affiliation: Leukemia Service, Memorial Sloane-Kettering Cancer Center, New York, NY, USA.
authors.forename: Martin S
authors.initials: MS
authors.lastname: Tallman
authors.affiliation: Division of Hematology, Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Litzow
authors.affiliation: Section of Hematology, Yale Cancer Center, New Haven, CT, USA.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Gore
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001374:Azacitidine / Q000008:administration & dosage* / Q000009:adverse effects; D001549:Benzamides / Q000008:administration & dosage / Q000009:adverse effects; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy*; D016609:Neoplasms, Second Primary / Q000188:drug therapy*; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D001549:Benzamides; D011725:Pyridines; C118739:entinostat; D001374:Azacitidine
keywords: acute myeloid leukaemia; azacitidine; histone deacetylase inhibitor; myelodysplasia; therapy related