A phase II study of Givinostat in combination with hydroxycarbamide in patients with polycythaemia vera unresponsive to hydroxycarbamide monotherapy

Givinostat, a histone‐deacetylase inhibitor (HDACi), inhibits proliferation of cells bearing the JAK2 V617F mutation and has shown significant activity with good tolerability in patients with chronic myeloproliferative neoplasms (MPN). In this multicentre, open‐label, phase II study, 44 patients with polycythaemia vera (PV), unresponsive to the maximum tolerated doses (MTD) of hydroxycarbamide (HC), were treated with Givinostat (50 or 100 mg/d) in combination with MTD of HC. The European LeukaemiaNet response criteria were used to assess the primary endpoint after 12 weeks of treatment. Complete or partial response was observed in 55% and 50% of patients receiving 50 or 100 mg of Givinostat, respectively. Control of pruritus was observed in 64% and 67% of patients in the 50 and 100 mg groups, respectively. The combination of Givinostat and HC was well tolerated: eight patients (18%) discontinued, four in each treatment arm; grade 3 adverse events were reported in one patient (4·5%) in each treatment arm. The combined use of Givinostat and HC was safe and clinically effective in HC‐unresponsive PV patients.

[1]  M. Introna,et al.  Givinostat and hydroxyurea synergize in vitro to induce apoptosis of cells from JAK2(V617F) myeloproliferative neoplasm patients. , 2013, Experimental hematology.

[2]  M. Cazzola,et al.  Long-Term Efficacy and Safety Results From a Phase II Study of Ruxolitinib in Patients with Polycythemia Vera , 2012 .

[3]  E. Ejerblad,et al.  A Phase II Study of Vorinostat (MK-0683) in Patients with Polycythemia Vera and Essential Thrombocythemia , 2012 .

[4]  Flor A. Cianchetti,et al.  Development of Coagulation Factor Probes for the Identification of Procoagulant Circulating Tumor Cells , 2012, Front. Oncol..

[5]  R. Mantovani,et al.  The HDAC inhibitor Givinostat modulates the hematopoietic transcription factors NFE2 and C-MYB in JAK2(V617F) myeloproliferative neoplasm cells. , 2012, Experimental hematology.

[6]  A. Tefferi JAK inhibitors for myeloproliferative neoplasms: clarifying facts from myths. , 2012, Blood.

[7]  Jason Gotlib,et al.  A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. , 2012, The New England journal of medicine.

[8]  Francisco Cervantes,et al.  JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. , 2012, The New England journal of medicine.

[9]  N. Ebel,et al.  Improved Efficacy Upon Combined JAK1/2 and Pan-Deacetylase Inhibition Using Ruxolitinib (INC424) and Panobinostat (LBH589) in Preclinical Mouse Models of JAK2V617F-Driven Disease , 2011 .

[10]  V. Najfeld,et al.  Prolonged Low Dose Therapy with a Pan-Deacetylase Inhibtor, Panobinostat (LBH589), in Patients with Myelofibrosis , 2011 .

[11]  Z. Estrov,et al.  Therapy with the Histone Deacetylase Inhibitor Sb939 for Patients with Myelofibrosis , 2011 .

[12]  Catriona Jamieson,et al.  Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  M. Griesshammer,et al.  Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  J. Tripodi,et al.  Sequential treatment of CD34+ cells from patients with primary myelofibrosis with chromatin-modifying agents eliminate JAK2V617F-positive NOD/SCID marrow repopulating cells. , 2010, Blood.

[15]  A. Gajra,et al.  Efficacy of vorinostat in a murine model of polycythemia vera. , 2010, Blood.

[16]  Yi Zhang,et al.  Janus kinase 2: an epigenetic 'writer' that activates leukemogenic genes. , 2010, Journal of molecular cell biology.

[17]  A. Tefferi,et al.  Polycythemia vera‐associated pruritus and its management , 2010, European journal of clinical investigation.

[18]  T. Barbui,et al.  A pilot study of the Histone‐Deacetylase inhibitor Givinostat in patients with JAK2V617F positive chronic myeloproliferative neoplasms , 2010, British journal of haematology.

[19]  M. Griesshammer,et al.  A unified definition of clinical resistance and intolerance to hydroxycarbamide in polycythaemia vera and primary myelofibrosis: results of a European LeukemiaNet (ELN) consensus process , 2010, British journal of haematology.

[20]  P. Atadja,et al.  Cotreatment with panobinostat and JAK2 inhibitor TG101209 attenuates JAK2V617F levels and signaling and exerts synergistic cytotoxic effects against human myeloproliferative neoplastic cells. , 2009, Blood.

[21]  Andrew J. Bannister,et al.  JAK2 phosphorylates histone H3Y41 and excludes HP1α from chromatin , 2009, Nature.

[22]  T. Barbui,et al.  Epigenetic therapy in myeloproliferative neoplasms: evidence and perspectives , 2009, Journal of cellular and molecular medicine.

[23]  M. Griesshammer,et al.  Response criteria for essential thrombocythemia and polycythemia vera: result of a European LeukemiaNet consensus conference. , 2009, Blood.

[24]  T. Barbui,et al.  The histone deacetylase inhibitor ITF2357 selectively targets cells bearing mutated JAK2V617F , 2008, Leukemia.

[25]  M. Lübbert,et al.  Selective anti-leukaemic activity of low-dose histone deacetylase inhibitor ITF2357 on AML1/ETO-positive cells , 2008, Oncogene.

[26]  R. Stauber,et al.  Histone deacetylase inhibitors and hydroxyurea modulate the cell cycle and cooperatively induce apoptosis , 2008, Oncogene.

[27]  L. Cuppini,et al.  The histone deacetylase inhibitor ITF2357 has anti-leukemic activity in vitro and in vivo and inhibits IL-6 and VEGF production by stromal cells , 2007, Leukemia.

[28]  T. Barbui,et al.  How I treat patients with polycythemia vera. , 2007, Blood.

[29]  C. Dinarello,et al.  Histone deacetylase inhibitors prevent exocytosis of interleukin-1beta-containing secretory lysosomes: role of microtubules. , 2006, Blood.

[30]  P F Thall,et al.  New designs for the selection of treatments to be tested in randomized clinical trials. , 1994, Statistics in medicine.

[31]  A. Tefferi,et al.  Classification and diagnosis of myeloproliferative neoplasms: The 2008 World Health Organization criteria and point-of-care diagnostic algorithms , 2008, Leukemia.