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Phase II trial of panobinostat, an oral pan-deacetylase inhibitor in patients with primary myelofibrosis, post-essential thrombocythaemia, and post-polycythaemia vera myelofibrosis.
- Source :
-
British journal of haematology [Br J Haematol] 2013 Aug; Vol. 162 (3), pp. 326-35. Date of Electronic Publication: 2013 May 23. - Publication Year :
- 2013
-
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.<br /> (© 2013 John Wiley & Sons Ltd.)
- Subjects :
- Administration, Oral
Adult
Aged
Aged, 80 and over
Cytokines blood
Drug Administration Schedule
Female
Histone Deacetylase Inhibitors adverse effects
Humans
Hydroxamic Acids adverse effects
Indoles adverse effects
Inflammation Mediators blood
Janus Kinase 2 blood
Male
Middle Aged
Panobinostat
Primary Myelofibrosis blood
Primary Myelofibrosis etiology
Treatment Outcome
Histone Deacetylase Inhibitors therapeutic use
Hydroxamic Acids therapeutic use
Indoles therapeutic use
Polycythemia Vera complications
Primary Myelofibrosis drug therapy
Thrombocythemia, Essential complications
Subjects
Details
- Language :
- English
- ISSN :
- 1365-2141
- Volume :
- 162
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- British journal of haematology
- Publication Type :
- Academic Journal
- Accession number :
- 23701016
- Full Text :
- https://doi.org/10.1111/bjh.12384