CCR Drug Updates Romidepsin for Cutaneous T-cell Lymphoma H. Miles Prince 1,2 and Michael Dickinson 1,2 Abstract Cutaneous T-cell lymphomas (CTCL) are relatively rare lymphomas with an annual incidence of approximately 0.2 to 0.8/100,000 and comprise a variety of clinical entities; mycosis fungoides or its leukemic variant Sezary syndrome account for the majority of cases. Advanced-stage disease is typically treated with bexarotene (a retinoid), interferon, or conventional chemotherapeutic agents, but relapses are inevitable. Histone deacetylase inhibitors, which modify the epigenome, are an attractive addition to the armamentarium. On the basis of 2 large phase II studies, the U.S. Food and Drug Administration approved intravenous romidepsin for patients with relapsed and/or refractory CTCL. Romidepsin provides a subset of patients with an opportunity for prolonged clinical responses with a tolerable side effect profile. Clin Cancer Res; 18(13); 3509–15. Ó2012 AACR. The Histone Deacetylase Inhibitors The histone deacetylase (HDAC) inhibitors target not only the epigenome via histone modification, but also numerous nucleic and cytoplasmic nonhistone proteins. They are powerful and selective inducers of cancer cell apoptosis and modifiers of the tumor microenvironment, as reviewed recently by Dickinson and colleagues (1) and depicted in Fig. 1. HDACs are one target for HDAC inhibitors and can be grouped according to their structure and homo- logy to yeast enzymes and share a common mechanism of action in binding a zinc ion critical to HDAC function. The simplest method of grouping HDAC inhibitors is based on specificity. Class I–specific HDAC inhibitors include benzamide derivatives (entinostat, mocetinostat) and cyclic tetrapeptides. Romidepsin, isolated from Chro- mobacterium violaceum (previously called depsipeptide, FK228, FR901228) is one such bicyclic peptide (1). The pan-HDAC inhibitors include the hydroxamic acid deriva- tives [trichostatin A, vorinostat (suberoylanilide hydroxa- mic acid), and panobinostat (LBH589)]. They were thought to inhibit all of the zinc-dependent HDACs; however, recent data suggest a relatively reduced effect of the hydoxamates on class IIa enzymes (HDACs 4, 5, 7, and 9; ref. 2). A key difference between the pan-HDAC inhibitors and the class I–specific HDAC inhibitors is thought to be the inhibition of cytoplasmic HDAC6. It is important to note here that, currently, very little suggests that this potential mechanistic difference between the pan-HDAC inhibitors and the iso- type-selective HDAC inhibitors, such as romidepsin, affects the response rates [in cutaneous T-cell lymphoma (CTCL), at least]. Response rates to the pan-HDAC inhibitor vorino- stat in CTCL are similar to those of romidepsin; however, there may be a difference in toxicity profiles. Preliminary Studies of Romidepsin Romidepsin induces apoptosis in many human tumor cell lines and in various xenograft models (3–5). The most comprehensive preclinical studies of romidepsin in a CTCL model have been done by Piekarz and colleagues (6). These investigators used the human T-cell lymphoma cell line HUT78 to test for sensitivity and molecular response. Administration of romidepsin resulted in his- tone acetylation, induction of p21 expression, expression of the interleukin-2 receptor, apoptosis without cell-cycle arrest, and induction of the multidrug resistance pump P- glycoprotein (PGP/ABCB1). PGP was overexpressed in romidepsin-resistant cells, raising the possibility that romidepsin directly induces a mechanism for its own resistance (6). Romidepsin Metabolism and Pharmacokinetics Romidepsin is extensively metabolized in vivo, primarily by cytochromes P450 (CYP) 3A4 and to a lesser extent by CYP3A5. In rats, 66% of the dose is excreted into the bile, thought to be via PGP/ABCB1. Romidepsin is also likely to be a substrate of the organic anion transporter OATP1B3, an influx transporter encoded by SLCO1B3, as other cyclic peptides have been found to interact with the same transporter. Romidepsin is currently only available as an i.v. formu- lation. In humans, following a 4-hour infusion, its half-life is approximately 3.5 hours, more than 90% protein bound, metabolized predominantly by CYP3A4, and 66% excreted in bile. The disposition of romidepsin has been shown to Authors' Affiliations: 1 Department of Haematology, Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne; 2 Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia Corresponding Author: H. Miles Prince, Division Cancer Medicine, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett Street, Melbourne, Victoria, Australia. Phone: 61 3 9656 1700; Fax: 61 3 9656 1408; E-mail: Miles.Prince@petermac.org doi: 10.1158/1078-0432.CCR-11-3144 Ó2012 American Association for Cancer Research. Clinical Cancer Research www.aacrjournals.org 3509 Downloaded from http://aacrjournals.org/clincancerres/article-pdf/18/13/3509/2921265/3509.pdf by guest on 22 November 2022