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Hematological Cancer
Benefits of Vorinostat in Treating Advanced Cutaneous T-cell Lymphoma
Chunlei Zhang, MD, PhD
1
and Madeleine Duvic, MD
2
1. Assistant Professor; 2. Professor of Internal Medicine and Dermatology, and Deputy Chairman,
Department of Dermatology, University of Texas MD Anderson Cancer Center
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 has in vitro and in vivo antitumor 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.
Keywords
Cutaneous T-cell lymphoma, histone deacetylases, vorinostat, clinical trial, translational study
Disclosure: The authors have received clinical and basic support from Aton/Merck for conducting clinical trials and translational studies. This article was independently
commissioned and no fee was received for preparation of the manuscript.
Received: November 17, 2008 Accepted: May 12, 2009
Correspondence: Madeleine Duvic, MD, Department of Dermatology – Box 434, UT MD Anderson Cancer Center, 1515 Holcombe Blvd. Houston, TX 77030.
E: mduvic@mail.mdanderson.org
Current Treatment Options for phototherapy or mustargen). More advanced or late stages (T1–4N0
Cutaneous T-cell Lymphoma –3M0–1; IIB–IVB) of MF or SS require both systemic and skin-directed
Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of therapies. Patients who have extensive refractory skin involvement,
extranodal non-Hodgkin’s lymphomas characterized by their surface blood involvement, tumors, or nodal disease require systemic therapy.
markers and biological behavior. Mycosis fungoides (MF) and its Refractory or extensive skin involvement including SS responds to
leukemic variant Sézary syndrome (SS) are the most frequently systemic biologic response modifiers (retinoids, bexarotene, interferon,
encountered CTCLs resulting from a progressive clonal expansion of and denileukin diftitox), skin radiation and photopheresis. Single- or
CD4
+
CD45RO
+
CLA
+
CCR
+
helper/memory T cells. The malignant clones multi-agent chemotherapies are used for patients with large numbers of
may have loss of common T-cell markers (CD7 and/or CD26).
1
transformed tumors or nodal/visceral disease. In general, a combination
Progression of MF/SS is accompanied by clonal dominance,
2
secretion of either sequential or concomitant therapies gives a higher rate of
of Th2 cytokines,
3
impaired immune responses, and cell growth response, but advanced patients often relapse and curative therapy is
advantage.
1,4
The malignant T cells exhibit abnormal apoptotic elusive for most.
1
mechanisms, such as loss of Fas or expression of Bcl-2, that result in
loss of activation-induced cell death, prolonged life span, and The US Food and Drug Administration (FDA) approved the histone
accumulation. These cells typically become resistant to treatment deacetylase inhibitor (HDAC-I) vorinostat (suberoylanilide hydroxamic
over time.
5
acid [SAHA]) in 2006 for the treatment of cutaneous manifestations of
CTCL based on data from two phase II clinical trials.
6,7
Translational
The choice of therapy should be based on the stage of disease. Patients studies have shown that vorinostat has in vitro and in vivo antitumor
with early MF have disease limited to the skin (T1–2N0–1M0; IA–IIA) and activity against CTCL.
6,8
As such, HDAC-Is represent an attractive new
can be put into remission with topical agents (topical steroids, retinoids, strategy for targeted therapy of advanced CTCL. This article provides a
© TOUCH BRIEFINGS 2009 27
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