Vorinostat in Combination Therapy of Sézary Syndrome with Extracorporeal Photopheresis

摘要

Vorinostat, the first in its class of orally administered histone deacetylase inhibitors, was recently FDA-approved for therapy of skin manifestations of cutaneous T cell lymphoma. Vorinostat monotherapy demonstrated activity in patients with CTCL in clinical trials with an overall response rate of 30%. The combination of vorinostat with other agents or treatment modalities has not been formally evaluated. We hypothesized that the use of vorinostat in combination with extracorporeal photopheresis might be of benefit, theoretically through further induction of cell cycle arrest and apoptosis of malignant T lymphocytes. We present a case report of a patient with refractory Sézary syndrome who responded well to this combination without significant or unexpected side effects. Dr. Larisa Geskin, MD, FAAD is an Assistant Professor of Dermatology at the Department of Dermatology, University of Pittsburgh School of Medicine. Dr. Geskin serves as the Director of the Dermatological Branch of University of Pittsburgh Cancer Institute Multidisciplinary Melanoma Center, the Cutaneous Oncology and Photopheresis Center at the University of Pittsburgh Medical Center. She also is Director of the Dermatology Residency Program at the University of Pittsburgh Medical School.Dr. Larisa Geskin’s broad research interests include exploring etiology of CTCL and abnormalities found in malignant cells of patients with CTCL. Her main focus is to investigate and define immunologic abnormalities found in patients with CTCL and to develop novel immunologic therapies for CTCL. She conducts numerous clinical trials investigating new treatments for CTCL, including a dendritic cell vaccine trial for patients with Sezary syndrome. Introduction Sézary syndrome (SS) is an erythrodermic and leukemic variant of cutaneous T-cell lymphoma. The disease may have an aggressive character and poor outcome (the 5-year overall survival historically was between 10-20%) [1]. Timely and effective palliative therapy remains a cornerstone in the management of these patients.Vorinostat, a novel histone deacetylase inhibitor (HDACi), has been shown to have up to a 30% response rate in heavily pretreated and recalcitrant patients with CTCL; it has an acceptable side effect profile and was not associated with opportunistic infections in clinical trials, thus making it a good candidate for long-term therapy for patients with impaired immunity. The mechanism of action of HDACi is broad, including the increased acetylation of lysine residues that form the octomeric histone core of chromatin decreasing the ability of the histones to bind to DNA. This decreased binding allows chromatin expansion, permitting transcription, which regulates cell proliferation and cell death. Other potential targets, which may be important in induction of clinical responses in patients, are acetylation of non-histone proteins affecting other intracellular processes including chaperone-mediated protein transport, mitosis, oncogene and tumor suppressor gene expression, thus regulating cell proliferation and cell death [2, 3]. CTCL has been shown to be the neoplasm most responsive to HDACi to date [4].Extracorporeal photopheresis (ECP) is one of the first line therapies for SS [5]. An intercalation of 8-methoxypsoralen into the DNA upon exposure to UVA light during ECP creates a pro-apoptotic environment modifying immune responses [6]. We hypothesized that a combination of ECP and HDACi may improve clinical outcome, theoretically through increasing the level of apoptosis of atypical T lymphocytes. We present a case report of use of vorinostat in combination with ECP resulting in improved clinical outcome. Modest response rate of vorinostat as a monotherapy and its potential for synergy with other agents warrants further investigation. Case Report A 38-year-old white female with a 3-year history of lymphadenopathy, rash, and markedly atypical lymphocytosis in peripheral blood was diagnosed with SS, stage IVA (T4N