Vorinostat has recently been listed on the Pharmaceutical Benefits Scheme (PBS) for the treatment of cutaneous T-cell lymphoma (CTCL) in patients with relapsed or chemotherapy-refractory disease. CTCL is a rare type of non-Hodgkin lymphoma that affects the skin. Topical therapies are often prescribed for Stage I disease while systemic agents are required for more advanced disease.

Vorinostat is a histone deacetylase (HDAC) inhibitor. Histones are proteins found in the nuclei that allow DNA to condense into a complex called chromatin. The level of histone acetylation plays a critical role in the regulation of gene transcription. Hypoacetylation often occurs in CTCL which reduces the expression of genes responsible for cell differentiation, cell-cycle control, apoptosis, and tumour suppression. While the antineoplastic effect of vorinostat has not been fully elucidated, it is thought that the accumulation of acetylated proteins promotes apoptotic pathways.

The rareness of CTCL and the need to individualise therapy makes it difficult to conduct randomised controlled trials. Therefore, data to support the efficacy of vorinostat is somewhat limited. A small non-randomised, open-label trial demonstrated an overall response rate of 29.7%, with a mean time to response of 56 days. Common adverse effects include diarrhoea, fatigue, nausea, and anorexia which are usually mild to moderate. More serious adverse effects include thromboembolic events, thrombocytopenia, anaemia, dehydration, gastrointestinal haemorrhage, and ischaemic stroke. Vorinostat has a negligible effect on cytochrome P450 at therapeutic doses and is not a substrate for P-glycoprotein. Therefore, clinically significant drug interactions are not expected to occur via these pathways. However, vorinostat may increase the INR when co-administered with warfarin. Vorinostat should not be administered with other HDAC inhibitors such as valproic acid due to the potential for additive class-specific adverse effects.

References:

  1. Primary Cutaneous Lymphomas. In: Clinical Practice Guidelines for the Diagnosis and Management of Lymphoma. Pg. 313-34.
  2. Olsen EA, Kim YH, Kuzel TM, Pacheco TR, Foss FM, Frankel SR, et al. Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol. 2007; 25(21): 3109-15.
  3. Pharmaceutical Benefits Advisory Committee. Vorinostat: Public Summary Document – March 2017. PBAC; 2017.
  4. Zolinza® (vorinostat) approved product information. Macquarie Park: Merck Sharp & Dohme. Approved December 2009.

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