title: Phase II trial of panobinostat, an oral pan-deacetylase inhibitor in patients with primary myelofibrosis, post-essential thrombocythaemia, and post-polycythaemia vera myelofibrosis.
abstract: Myelofibrosis (MF) is a Philadelphia chromosome-negative stem cell myeloproliferative neoplasm (MPN) associated with cytopenias, splenomegaly, constitutional symptoms, and poor prognosis. MF patients commonly express JAK2 V617F mutation and activation of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling. Agents targeting the JAK/STAT pathway have demonstrated efficacy in patients with MF. This study evaluated panobinostat, a pan-deacetylase inhibitor that depletes JAK2 V617F levels and JAK/STAT signalling in MPN cells, in patients with primary MF, post-essential thrombocythaemia MF, and post-polycythaemia vera MF. Patients received panobinostat 40 mg administered three times per week. Dose reductions were permitted for toxicities. The primary endpoint was response rate at 6 months using International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) consensus criteria. Analyses of peripheral blood cells from treated patients revealed that panobinostat inhibited JAK/STAT signalling, decreased inflammatory cytokine levels, and decreased JAK2 V617F allelic burden. However, panobinostat was poorly tolerated at the dose and schedule evaluated, and only 16 of 35 patients completed ≥2 cycles of treatment. One patient (3%) achieved an IWG-MRT response. Common adverse events were thrombocytopenia (71.4%) and diarrhoea (80.0%). Although molecular correlative analyses suggested that panobinostat inhibits key intracellular targets, limited clinical activity was observed because of poor tolerance.
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. daniel_deangelo@dfci.harvard.edu
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: DeAngelo
authors.forename: Ruben A
authors.initials: RA
authors.lastname: Mesa
authors.forename: Warren
authors.initials: W
authors.lastname: Fiskus
authors.forename: Ayalew
authors.initials: A
authors.lastname: Tefferi
authors.forename: Carole
authors.initials: C
authors.lastname: Paley
authors.forename: Martha
authors.initials: M
authors.lastname: Wadleigh
authors.forename: Ellen K
authors.initials: EK
authors.lastname: Ritchie
authors.forename: David S
authors.initials: DS
authors.lastname: Snyder
authors.forename: Kebede
authors.initials: K
authors.lastname: Begna
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Ganguly
authors.forename: Michael S
authors.initials: MS
authors.lastname: Ondovik
authors.forename: Jessica
authors.initials: J
authors.lastname: Rine
authors.forename: Kapil N
authors.initials: KN
authors.lastname: Bhalla
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016207:Cytokines / Q000097:blood; D004334:Drug Administration Schedule; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000009:adverse effects / Q000627:therapeutic use*; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use*; D018836:Inflammation Mediators / Q000097:blood; D053614:Janus Kinase 2 / Q000097:blood; D008297:Male; D008875:Middle Aged; D000077767:Panobinostat; D011087:Polycythemia Vera / Q000150:complications*; D055728:Primary Myelofibrosis / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D013920:Thrombocythemia, Essential / Q000150:complications*; D016896:Treatment Outcome
chemical_list: D016207:Cytokines; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D018836:Inflammation Mediators; D000077767:Panobinostat; C507924:JAK2 protein, human; D053614:Janus Kinase 2
keywords: histone deacetylase inhibitors; myelofibrosis; myeloproliferative neoplasms; panobinostat