title: Therapy with the histone deacetylase inhibitor pracinostat for patients with myelofibrosis.
abstract: Approximately half of the patients with myelofibrosis (MF) carry mutant JAK2(V617F) proteins. JAK2(V617F) has been recently shown to translocate to the nucleus and modify specific histones, thus regulating transcription. We report on a phase II study testing the activity and tolerability of the histone deacetylase inhibitor pracinostat given at 60 mg every other day for three weeks per month in 22 patients with intermediate or high risk MF. Eight (36%) patients experienced clinical benefit, with 6 (27%) experiencing reductions in splenomegaly (median 3 cm, range 1-4 cm). According to International Working Group criteria, 2 (9%) patients had clinical improvement (anemia response in both cases). The most frequent side effect associated to pracinostat therapy was fatigue, which occurred in 20 (91%) patients (grade 2 in 3 patients). Grade 3-4 neutropenia, anemia, and thrombocytopenia occurred in 13%, 0%, and 21%, respectively. Twenty-one patients permanently discontinued pracinostat, mainly due to lack of efficacy. In conclusion, pracinostat at the dose tested is reasonably tolerated and has modest activity in patients with MF.
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, TX 77030, USA. aquintas@mdanderson.org
authors.forename: Alfonso
authors.initials: A
authors.lastname: Quintás-Cardama
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: Zeev
authors.initials: Z
authors.lastname: Estrov
authors.forename: Gautam
authors.initials: G
authors.lastname: Borthakur
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
authors.forename: Srdan
authors.initials: S
authors.lastname: Verstovsek
mesh_terms: D000368:Aged; D001562:Benzimidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D009929:Organ Size; D055728:Primary Myelofibrosis / Q000188:drug therapy* / Q000453:epidemiology / Q000473:pathology; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D013163:Splenomegaly / Q000139:chemically induced / Q000453:epidemiology; D016896:Treatment Outcome
chemical_list: D001562:Benzimidazoles; D056572:Histone Deacetylase Inhibitors; C557525:SB939 compound