Do histone deacytelase inhibitors and azacitidine combination hold potential as an effective treatment for high/very-high risk myelodysplastic syndromes?

ABSTRACT

Introduction

Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disorder, predominantly seen in elderly patients with variable clinical outcome and high tendency for leukemic transformation. Allogeneic hematopoietic stem cell transplantation (alloHCT) is the only potential curative option but limited to a selected group of patients, for the rest, disease control is the goal and enrollment in clinical trial is always encouraged. Mechanistically, azacitidine (AZA) and histone deacetylase inhibitors (HDACi) is a promising combination for patient with high-risk MDS to improve clinical outcome, but the combination has yet to demonstrate its efficacy in randomized clinical trials.

Areas covered

In this review the authors discuss the salient features, pharmacokinetics, safety, and efficacy data of AZA and HDACi combination in patients with MDS. Future strategies on how to possibly improve clinical outcome of patients with MDS using AZA and HDACi combination are discussed.

Expert opinion

Pre-clinical and clinical data demonstrated synergistic activity of AZA and HDACi in patients with MDS. So far, the efficacy of this combination is undermined by toxicity; mainly gastrointestinal. Careful patient selection and alternative dosing schedule is needed in future clinical trials to evaluate clinical outcome.

KEYWORDS:

• Azacitdine
• pracinostat
• high risk MDS
• HDAC inhibitors
• hypomethylating agents

Article highlights

• High-risk MDS is an incurable disease with high propensity for transformation to AML.

• Hypomethylating agents and lenalidomide are the only FDA-approved chemotherapy agents for the treatment of patients with MDS and none are curative.

• Less intensive, better-tolerated treatment combinations are needed for MDS patients who are ineligible for alloHCT.

• Most recent HDACi (Pracinostat) has better bioavailability, longer half-life and more distribution in cancer cells than previous HDACi.

• Non-hematological toxicities resulting in early treatment discontinuation has hindered progress of AZA plus HDACi as a novel combination in patients with MDS.

• Better patient selection using predictive biomarkers, alternative dosing schedule of HDACi is warranted in future studies to explore benefit of HDACi plus AZA combination in patients with MDS.

This box summarizes key points contained in the article.

Disclosure

T Badar has received developmental funds from Mayo Clinic Cancer Center; grant no. P30 CA015083. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

I have received Mayo Clinic Cancer Center Support Grant for investigator initiated studies (grant no. P30 CA015083), which I have to mention in every publication.  I have not received any funding for this publication.