A phase 2 study of pracinostat combined with ruxolitinib in patients with myelofibrosis

Abstract

Although ruxolitinib improves symptoms and splenomegaly in patients with advanced myelofibrosis, whether this agent is truly disease-modifying remains unclear. Histone deacetylase inhibitors (HDACi) downregulate JAK2 via interference with chaperone function. Pracinostat, a pan-HDACi, has modest single-agent activity in myelofibrosis. We conducted a single-institution, phase 2, investigator-initiated trial of ruxolitinib plus pracinostat (begun after 12 weeks of ruxolitinib) in 25 patients with myelofibrosis, of whom 20 received both agents. Sixteen (80%) patients had objective responses (all ‘clinical improvement’). The rate of spleen response (by palpation) was 74%, and that of symptom response 80%. Most responses occurred prior to pracinostat initiation. Three patients experienced improvement in bone marrow fibrosis, and one a near-complete molecular response after two years on study treatment. All patients discontinued pracinostat and are currently off-study. Pracinostat interruptions and dose reductions were frequent, often due to worsening anemia. These findings do not support continued development of pracinostat in myelofibrosis.

Keywords:

• Myelofibrosis
• JAK2 inhibitors
• HDAC inhibitors
• rational combinations
• targeted therapies

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article online at https://doi.org/10.1080/10428194.2018.1543876.

Additional information

Funding

This work was supported in part by MEI Pharma, who provided pracinostat and financial support for the study, as well as the MD Anderson Cancer Center Support Grant P30 CA016672 from the National Cancer Institute (National Institutes of Health).