Advances in Hodgkin’s lymphoma pharmacotherapy: a focus on histone deacetylase inhibitors

ABSTRACT

Introduction

Classical Hodgkin lymphomas (cHL) usually have excellent cure rates. Yet, for patients with refractory or relapsed cHL, prognosis deteriorates as the disease becomes resistant to subsequent lines of therapies: autologous stem cell transplantation, brentuximab vedotin, and checkpoint inhibitors. Immune escape and drug resistance are hallmarks of Hodgkin Reed Sternberg cell survival, prompting the need for additional therapeutic strategies. Histone modification-based combination is an effective clinical strategy.

Areas covered

In this review, we discuss the different histone deacetylase (HDAC) inhibitor molecules that have been developed and studied in cancer therapy with a focus on cHL. We review their preclinical and clinical activities both as single agents and in combination studies. Literature search was conducted in PubMed, Google Scholar, and ClinicalTrials.gov databases, using search terms ‘Hodgkin lymphoma,’ ‘histone deacetylase inhibitor’, and variations on such (e.g. ‘HDAC’ and individual drug names) in combination using operators ‘AND,’ ‘OR,’ and ‘NOT’ according to Boolean logic.

Expert opinion

HDAC inhibitors alone will not be sufficient for the treatment of R/RcHL, but given their disease control capacity, synergistic interaction with currently approved drugs, and ability to overcome drug resistance, particularly PD-1 inhibitors, we believe that HDACinhibitors will eventually become incorporated into the treatment armamentarium of cHL.

KEYWORDS:

• Hodgkin lymphoma
• histone deacetylase inhibitors
• drug resistance
• synergism
• tumor microenvironment

Article highlights

• While the majority of classical Hodgkin lymphoma have excellent cure rates with chemotherapy, relapsed/refractory cHL has a poor prognosis. Despite novel agents such as brentuximab vedotin and checkpoint inhibitors, there is an unmet need for additional therapeutic strategies to overcome immune escape and drug resistance.

• The molecular and cellular hallmarks, which enable Hodgkin Reed Sternberg cells to escape immunosurveillance are epigenetically regulated via chemical processes such as histone acetylation.

• HDAC inhibitors play an important role in inducing cell cycle arrest, intrinsic and extrinsic apoptotic cell death, and in decreasing angiogenesis.

• The mechanism of HDAC inhibition in cHL is still incompletely understood, but involves multiple pathways such as NF-KB, Bcl2, and JAK/STAT, leading to downstream effects on PD1, CD30, O×40 L, and altering the tumor microenvironment.

• HDAC inhibitor monotherapy has poor clinical outcomes in R/R cHL. HDAC inhibitors in combination with checkpoint inhibitors have shown promising early synergistic efficacy with tolerable toxicity.

• Larger prospective clinical trials are needed to evaluate HDAC inhibitors in combination with immunotherapy.

Declaration of interest

V Yazbeck reports grants, personal fees from Seagen, grants, personal fees from AstraZeneca, personal fees from ADC Therapeutics, personal fees from Verastem, grants, personal fees from Gilead, personal fees from TG Therapeutics, grants, personal fees from Beigene, grants, personal fees from Genmab, personal fees from MorphoSys, outside of the submitted work.

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.

Reviewer disclosures

A reviewer on this manuscript has disclosed receiving research funding from MERCK. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.