title: Phase II study of the histone deacetylase inhibitor belinostat (PXD101) for the treatment of myelodysplastic syndrome (MDS).
abstract: The inhibition of histone deacetylase (HDAC) can induce differentiation, growth arrest, and apoptosis in cancer cells. This phase II multicenter study was undertaken to estimate the efficacy of belinostat, a potent inhibitor of both class I and class II HDAC enzymes, for the treatment of myelodysplastic syndrome (MDS). Adults with MDS and ≤2 prior therapies were treated with belinostat 1,000 mg/m(2) IV on days 1-5 of a 21-day cycle. The primary endpoint was a proportion of confirmed responses during the first 12 weeks of treatment. Responding patients could receive additional cycles until disease progression or unacceptable toxicity. Twenty-one patients were enrolled, and all were evaluable. Patients were a median 13.4 months from diagnosis, and 14 patients (67%) had less than 5% bone marrow blasts. Seventeen patients (81%) were transfusion dependent. Prior therapy included azacytidine (n = 7) and chemotherapy (n = 8). The patients were treated with a median of four cycles (range, 1-8) of belinostat. There was one confirmed response-hematologic improvement in neutrophils-for an overall response rate of 5% (95% CI, 0.2-23). Median overall survival was 17.9 months. Grades 3-4 toxicities considered at least to be possibly related to belinostat were: neutropenia (n = 10), thrombocytopenia (n = 9), anemia (n = 5), fatigue (n = 2), febrile neutropenia (n = 1), headache (n = 1), and QTc prolongation (n = 1). Because the study met the stopping rule in the first stage of enrollment, it was closed to further accrual.
authors.affiliation: Washington University School of Medicine, St Louis, MO 63110, USA. acashen@dom.wustl.edu
authors.forename: Amanda
authors.initials: A
authors.lastname: Cashen
authors.forename: Mark
authors.initials: M
authors.lastname: Juckett
authors.forename: Alcee
authors.initials: A
authors.lastname: Jumonville
authors.forename: Mark
authors.initials: M
authors.lastname: Litzow
authors.forename: P J
authors.initials: PJ
authors.lastname: Flynn
authors.forename: John
authors.initials: J
authors.lastname: Eckardt
authors.forename: Betsy
authors.initials: B
authors.lastname: LaPlant
authors.forename: Kristina
authors.initials: K
authors.lastname: Laumann
authors.forename: Charles
authors.initials: C
authors.lastname: Erlichman
authors.forename: John
authors.initials: J
authors.lastname: DiPersio
mesh_terms: D000368:Aged; D018450:Disease Progression; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000503:physiopathology; D013449:Sulfonamides; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D013449:Sulfonamides; D006655:Histone Deacetylases; C487081:belinostat