Safety and Tolerability of Histone Deacetylase (HDAC) Inhibitors in Oncology
Histone deacetylases (HDACs) are expressed at increased levels in cells of various malignancies, and the use of HDAC inhibitors has improved outcomes in patients with haematological malignancies (T-cell lymphomas and multiple myeloma). However, they are not as effective in solid tumours. Five agents are currently approved under various jurisdictions, namely belinostat, chidamide, panobinostat, romidepsin and vorinostat. These agents are associated with a range of class-related and agent-specific serious and/or severe adverse effects, notably myelosuppression, diarrhoea and various cardiac effects. Among the cardiac effects are ST-T segment abnormalities and QTc interval prolongation of the electrocardiogram, isolated cases of atrial fibrillation and, in rare instances, ventricular tachyarrhythmias. In order to improve the safety profile of this class of drugs as well as their efficacy in indications already approved and to further widen their indications, a large number of newer HDAC inhibitors with varying degrees of HDAC isoform selectivity have been synthesised and are currently under clinical development. Preliminary evidence from early studies suggests that they may be effective in non-haematological cancers as well when used in combination with other therapeutic modalities, but that they too appear to be associated with the above class-related adverse effects. As the database accumulates, the safety, efficacy and risk/benefit of the newer agents and their indications will become clearer.
Compliance with Ethical Standards
This is a review of the data in the public domain and the author declares compliance with all ethical standards.
No sources of funding were used to assist in the preparation of this review.
Conflict of interest
Rashmi Shah has no conflicts of interest that are relevant to the content of this review and has not received any financial support for writing it. He was formerly a Senior Clinical Assessor at the Medicines and Healthcare products Regulatory Agency (MHRA), London, UK, and now provides expert consultancy services to a number of pharmaceutical companies.
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