• Daniel J DeAngelo, Ruben A Mesa, Warren Fiskus, Ayalew Tefferi, Carole Paley, Martha Wadleigh, Ellen K Ritchie, David S Snyder, Kebede Begna, Siddhartha Ganguly, Michael S Ondovik, Jessica Rine, and Kapil N Bhalla.
• Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. daniel_deangelo@dfci.harvard.edu
• Br. J. Haematol. 2013 Aug 1;162(3):326-35.

AbstractMyelofibrosis (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.© 2013 John Wiley & Sons Ltd.

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