Investigational histone deacetylase inhibitors (HDACi) in myeloproliferative neoplasms

ABSTRACT

Introduction: The Philadelphia chromosome negative myeloproliferative neoplasms (MPN) mainly comprise polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF, primary or post-PV/ET). Therapy in PV and ET focuses on minimizing thrombosis and bleeding risk, while in MF, prolongation of survival is an important goal. Different cytoreductive agents are employed in high risk PV and ET, while the JAK inhibtior ruxolitinib is the cornerstone of therapy in MF. Histone deacetylase inhibitors (HDACi) are pleiotropic agents with diverse epigenetic and non-epigenetic actions, selectively in transformed cells. A number of HDACi have been or are being investigated in MPN.

Areas covered: The mechanisms of action of HDACI in neoplastic cells are summarized, and the preclinical rationale and data supporting their development in MPN specifically examined, particularly their synergism with JAK inhibitors. Major findings of clinical trials of HDACi, both alone and in combination with ruxolitinib, in MPN are then discussed, with particular attention to their toxicities and disease-modifying effects.

Expert opinion: HDACi are clearly active in MPN, and there is good preclinical rationale for this. Their combination with ruxolitinib in MF is promising, but the long-term tolerability of these agents is an important concern. Further development in PV or ET appears unlikely.

KEYWORDS:

• Histone deacetylase inhibitors
• myeloproliferative neoplasms
• epigenetic
• myelofibrosis
• ruxolitinib
• JAK inhibitors
• rational combinations
• polycythemia vera
• essential thrombocythemia

Article highlights

• HDACi are active, both preclinically and clinically, in MPN.

• HDAC6 inhibitors down-regulate JAK2 and JAK2 V617F by disrupting the chaperone function of HSP90 and synergize with JAK2 inhibitors.

• HDACi have significant chronic toxicities, e.g., diarrhea, fatigue, thrombocytopenia.

• Long-term therapy is required for disease-modifying effects of HDACi in MF to emerge.

• Ongoing trials are investigating combinations of HDACi with ruxolitinib in myelofibrosis.

This box summarizes key points contained in the article.

Declaration of interest

P. Bose has participated on an advisory board for Incyte Corporation. S. Verstovsek has received research support from Incyte Corporation, Roche, Astrazeneca, Lilly Oncology, Geron, Ns Pharma, Bristol Myers Squibb, Celgene, Gilead, Seattle Genetics, Promedior, CTI BioPharma Corp., Galena BioPharma, Pfizer and Genetech. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper has been supported in part by the MD Anderson Cancer Center Support Grant from the National Cancer Institute (P30CA016672).