Phase II trial of panobinostat, an oral pan-deacetylase inhibitor in patients with primary myelofibrosis, post-essential thrombocythaemia, and post-polycythaemia vera myelofibrosis

被引:60
|
作者
DeAngelo, Daniel J. [1 ]
Mesa, Ruben A. [2 ]
Fiskus, Warren [3 ]
Tefferi, Ayalew [4 ]
Paley, Carole [5 ]
Wadleigh, Martha [1 ]
Ritchie, Ellen K. [6 ]
Snyder, David S. [7 ]
Begna, Kebede
Ganguly, Siddhartha [3 ]
Ondovik, Michael S. [5 ]
Rine, Jessica [5 ]
Bhalla, Kapil N. [3 ]
机构
[1] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA
[2] Mayo Clin, Scottsdale, AZ USA
[3] Methodist Hosp Res Inst, Cockrell Ctr Adv Therapeut, Houstony, TX USA
[4] Mayo Clin, Rochester, MN USA
[5] Novartis Pharmaceut, E Hanover, NJ USA
[6] Cornell Univ, Weill Cornell Med Coll, New York, NY 10021 USA
[7] City Hope Natl Med Ctr, Duarte, CA USA
关键词
myelofibrosis; myeloproliferative neoplasms; panobinostat; histone deacetylase inhibitors; MYELOPROLIFERATIVE NEOPLASMS; JAK2; INHIBITOR; EFFICACY; THERAPY; LBH589; EZH2; CELL;
D O I
10.1111/bjh.12384
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 center dot 4%) and diarrhoea (80 center dot 0%). Although molecular correlative analyses suggested that panobinostat inhibits key intracellular targets, limited clinical activity was observed because of poor tolerance.
引用
收藏
页码:326 / 335
页数:10
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