title: A phase II study of vorinostat (MK-0683) in patients with polycythaemia vera and essential thrombocythaemia.
abstract: Inhibition of histone deacetylases may be an important target in patients with myeloproliferative neoplasms. This investigator-initiated, non-randomized, open-label phase II multi-centre study included 63 patients (19 essential thrombocythaemia, 44 polycythaemia vera) from 15 centres. The primary objective was to evaluate if vorinostat was followed by a decline in clonal myeloproliferation as defined by European Leukaemia Net. Thirty patients (48%) completed the intervention period (24 weeks of therapy). An intention-to-treat response rate of 35% was identified. Pruritus was resolved [19% to 0% (P = 0·06)] and the prevalence of splenomegaly was lowered from 50% to 27% (P = 0·03). Sixty-five per cent of the patients experienced a decrease in JAK2 V617F allele burden (P = 0·006). Thirty-three patients (52% of patients) discontinued study drug before end of intervention due to adverse events (28 patients) or lack of response (5 patients). In conclusion, vorinostat showed effectiveness by normalizing elevated leucocyte and platelet counts, resolving pruritus and significantly reducing splenomegaly. However, vorinostat was associated with significant side effects resulting in a high discontinuation rate. A lower dose of vorinostat in combination with conventional and/or novel targeted therapies may be warranted in future studies.
authors.affiliation: Department of Haematology, Roskilde Hospital, Roskilde, Denmark. christenla@gmail.com
authors.forename: Christen L
authors.initials: CL
authors.lastname: Andersen
authors.forename: Mary F
authors.initials: MF
authors.lastname: McMullin
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Ejerblad
authors.forename: Sonja
authors.initials: S
authors.lastname: Zweegman
authors.forename: Claire
authors.initials: C
authors.lastname: Harrison
authors.forename: Savio
authors.initials: S
authors.lastname: Fernandes
authors.forename: David
authors.initials: D
authors.lastname: Bareford
authors.forename: Steven
authors.initials: S
authors.lastname: Knapper
authors.forename: Jan
authors.initials: J
authors.lastname: Samuelsson
authors.forename: Eva
authors.initials: E
authors.lastname: Löfvenberg
authors.forename: Olle
authors.initials: O
authors.lastname: Linder
authors.forename: Bjørn
authors.initials: B
authors.lastname: Andreasson
authors.forename: Erik
authors.initials: E
authors.lastname: Ahlstrand
authors.forename: Morten K
authors.initials: MK
authors.lastname: Jensen
authors.forename: Ole W
authors.initials: OW
authors.lastname: Bjerrum
authors.forename: Hanne
authors.initials: H
authors.lastname: Vestergaard
authors.forename: Herdis
authors.initials: H
authors.lastname: Larsen
authors.forename: Tobias W
authors.initials: TW
authors.lastname: Klausen
authors.forename: Torben
authors.initials: T
authors.lastname: Mourits-Andersen
authors.forename: Hans C
authors.initials: HC
authors.lastname: Hasselbalch
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006402:Hematologic Diseases / Q000139:chemically induced; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000009:adverse effects / Q000627:therapeutic use*; D053614:Janus Kinase 2 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010352:Patient Dropouts; D011087:Polycythemia Vera / Q000188:drug therapy* / Q000235:genetics; D013920:Thrombocythemia, Essential / Q000188:drug therapy* / Q000235:genetics; D016896:Treatment Outcome; D000077337:Vorinostat
chemical_list: D015415:Biomarkers; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; C507924:JAK2 protein, human; D053614:Janus Kinase 2
keywords: essential thrombocythaemia; histone deacetylase inhibition; phase II study; polycythaemia vera; vorinostat