Benefits of Vorinostat in Treating Advanced Cutaneous T-cell Lymphoma

Abstract

Vorinostat (suberoylanilide hydroxamic acid) is the first US Food and Drug Administration (FDA)-approved histone deacetylase (HDAC) inhibitor for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphomas (CTCLs) who have progressive, persistent, or recurrent disease on or following two systemic therapies. In two phase II trials, vorinostat was safe and effective at an oral dose of 400mg/day, with an overall response rate of 24–30% in refractory advanced patients with CTCL including large cell transformation and Sézary syndrome. Most patients with CTCL also experience significant itching relief with vorinostat therapy. The most frequent side effects of vorinostat include gastrointestinal symptoms, fatigue, and thrombocytopenia. These side effects are dose-related and reversible upon cessation of therapy. Translational studies have shown that vorinostat hasin vitroandin vivoantitumor activities against CTCL, including selective induction of tumor T-cells, inhibition of angiogenesis, suppression of STATs, and upregulation of proapoptotic proteins. Constitutive activation of STATs may predict vorinostat resistance in CTCL, and inhibitors of JAK/STAT combined with vorinostat may help to overcome resistance and improve the clinical response of vorinostat. Further identification of predictive biomarkers of vorinostat will help to select patients most likely to benefit from treatment and to develop better combination therapies for patients with CTCL.