A phase II study of vorinostat (MK‐0683) in patients with polycythaemia vera and essential thrombocythaemia

• Published in: British journal of haematology Vol. 162; no. 4; pp. 498 - 508
• Main Authors: Andersen, Christen L., McMullin, Mary F., Ejerblad, Elisabeth, Zweegman, Sonja, Harrison, Claire, Fernandes, Savio, Bareford, David, Knapper, Steven, Samuelsson, Jan, Löfvenberg, Eva, Linder, Olle, Andreasson, Bjørn, Ahlstrand, Erik, Jensen, Morten K., Bjerrum, Ole W., Vestergaard, Hanne, Larsen, Herdis, Klausen, Tobias W., Mourits‐Andersen, Torben, Hasselbalch, Hans C.
• Format: Journal Article
• Language: English
• Published: Oxford Blackwell 01.08.2013
• Subjects: Adult; Aged; Aged, 80 and over; Biological and medical sciences; Biomarkers; Diseases of red blood cells; essential thrombocythaemia; Fatigue - chemically induced; Female; Gastrointestinal Diseases - chemically induced; Hematologic and hematopoietic diseases; Hematologic Diseases - chemically induced; histone deacetylase inhibition; Histone Deacetylase Inhibitors - adverse effects; Histone Deacetylase Inhibitors - therapeutic use; Humans; Hydroxamic Acids - adverse effects; Hydroxamic Acids - therapeutic use; Janus Kinase 2 - genetics; Male; Medical sciences; Medicin och hälsovetenskap; Middle Aged; Mutation, Missense; Patient Dropouts; phase II study; polycythaemia vera; Polycythemia Vera - drug therapy; Polycythemia Vera - genetics; Polycythemias; Thrombocythemia, Essential - drug therapy; Thrombocythemia, Essential - genetics; Treatment Outcome; Tumors; vorinostat; Antineoplastic agent; Human; Hematology; polycythaemia vera; histone deacetylase inhibition; Polycythemia vera; Malignant hemopathy; Myeloproliferative syndrome; Essential thrombocythemia; Histone deacetylase inhibitor; Cancerology; Treatment; Vorinostat; Phase II trial; phase II study; Cancer; essential thrombocythaemia; vorinostat
• ISSN: 0007-1048; 1365-2141; 1365-2141
• DOI: 10.1111/bjh.12416

Summary Inhibition of histone deacetylases may be an important target in patients with myeloproliferative neoplasms. This investigator‐initiated, non‐randomized, open‐label phase II multi‐centre study included 63 patients (19 essential thrombocythaemia, 44 polycythaemia vera) from 15 centres. The primary objective was to evaluate if vorinostat was followed by a decline in clonal myeloproliferation as defined by European Leukaemia Net. Thirty patients (48%) completed the intervention period (24 weeks of therapy). An intention‐to‐treat response rate of 35% was identified. Pruritus was resolved [19% to 0% (P = 0·06)] and the prevalence of splenomegaly was lowered from 50% to 27% (P = 0·03). Sixty‐five per cent of the patients experienced a decrease in JAK2 V617F allele burden (P = 0·006). Thirty‐three patients (52% of patients) discontinued study drug before end of intervention due to adverse events (28 patients) or lack of response (5 patients). In conclusion, vorinostat showed effectiveness by normalizing elevated leucocyte and platelet counts, resolving pruritus and significantly reducing splenomegaly. However, vorinostat was associated with significant side effects resulting in a high discontinuation rate. A lower dose of vorinostat in combination with conventional and/or novel targeted therapies may be warranted in future studies.