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

Abstract

SummaryInhibition of histone deacetylases may be an important target in patients with myeloproliferative neoplasms. This investigator-initiated, nonrandomized, 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 = 0Á06)] and the prevalence of splenomegaly was lowered from 50% to 27% (P = 0Á03). Sixty-five per cent of the patients experienced a decrease in JAK2 V617F allele burden (P = 0Á006). 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.

Perspectives on chronic inflammation in essential thrombocythemia, polycythemia vera, and myelofibrosis: is chronic inflammation a trigger and driver of clonal evolution and development of accelerated atherosclerosis and second cancer?

“…Ultimately, the abnormal immune homeostasis may imply a defective tumor immune surveillance, which may contribute to the increased frequency of second cancer as well. 52,53 The impressive efficacy of JAK1-2 inhibitor and HDACinhibitor treatment in reducing huge splenomegaly, alleviating hypermetabolic symptoms, and partly also reducing leukocyte and platelet counts [94][95][96] may primarily reflect the very potent antiinflammatory effects of both agents. In this context, the rapid resolution of large splenomegaly may be consequent to elimination of reactive immune cells in the spleen more than a direct antitumor effect, being supported by no or minor reduction in JAK2V617-allele burden despite a pronounced reduction in inflammatory cytokines, including TNF-␣ and IL-6.…”

Emerging treatments for classical myeloproliferative neoplasms

“…Valproic acid, in clinical use as an anticonvulsant, has weak HDACi activity but clinical efficacy in cancer; there is one report of its success in the treatment of MF. 89 Vorinostat (suberanilohydroxamic acid, Zolinza) showed effectiveness in reducing splenomegaly, pruritus, and thrombocytosis/ leukocytosis, but had significant adverse effects in ET/PV 90 ; a study is ongoing in MF. Panobinostat has been shown to promote JAK2V617F degradation synergistically with TG101209.…”

How I treat polycythemia vera

“…Another HDAC inhibitor, vorinostat, showed efficacy in normalizing blood cell counts and reducing pruritus and splenomegaly in newly diagnosed and previously treated PV patients who were in need of cytoreduction or were intolerant to other therapies, but it caused notable side effects, leading to a high discontinuation rate. 98 On the basis of the favorable results of a phase 2 study in 34 patients who were refractory or intolerant to hydroxyurea, 99 a phase 3 trial randomizing PV patients to the JAK1 and JAK2 inhibitor ruxolitinib (n 5 110) vs best available therapy (n 5 112) was designed: the RESPONSE trial. Final results have been presented recently, showing that a statistically significant greater proportion of patients receiving ruxolitinib obtained Hct control, reduction of phlebotomies, reduction of enlarged spleen, and improvement of total symptom score compared with best available therapy; of note, the rate of thrombotic events was lower in patients randomized to ruxolitinib (A.M.V., unpublished data).…”