Novel Therapeutic Agents for Cutaneous T-Cell Lymphoma Salvia Jain1, Jasmine Zain1 and Owen O’Connor2*

Jain et al. Journal of Hematology & Oncology 2012, 5:24 http://www.jhoonline.org/content/5/1/24 JOURNAL OF HEMATOLOGY & ONCOLOGY REVIEW Open Access Novel therapeutic agents for cutaneous T-Cell lymphoma Salvia Jain1, Jasmine Zain1 and Owen O’Connor2* Abstract Mycosis fungoides (MF) and Sezary Syndrome (SS) represent the most common subtypes of primary Cutaneous T-cell lymphoma (CTCL). Patients with advanced MF and SS have a poor prognosis leading to an interest in the development of new therapies with targeted mechanisms of action and acceptable safety profiles. In this review we focus on such novel strategies that have changed the treatment paradigm of this rare malignancy. Introduction OS was inferior ranging between 1.4-4.7 years. This retro- Cutaneous T-cell lymphomas (CTCL) are a rare hetero- spective analysis confirmed the previously observed dis- geneous group of non-Hodgkin lymphomas derived mal median OS of patients with SS (7% patients in this from skin-homing mature T-cells. Mycosis fungoides study were diagnosed to have SS), which was noted to be (MF) and Sezary Syndrome (SS) represent the most 3.1 years in this study from the time of diagnosis [4]. common subtypes of primary CTCL, with an incidence Owing to the heterogeneity and rarity of this neoplasm, rate of 4.1/1,000,000 person-years and male predomin- there are few randomized trials to support treatment ance [1]. The prognosis of MF and SS depends on the recommendations and step-wise treatment algorithms in age at presentation, type and extent of skin lesions, over- various stages of CTCL, particularly advanced stage. all stage and presence or absence of peripheral blood in- Hence choice of treatment is often determined by phys- volvement and extra-cutaneous disease. In 2007, a ician or patient preference and is based on several factors, revised staging system of MF and SS by the International including stage of disease, use of previous therapies, avail- Society for Cutaneous Lymphomas (ISCL)/European ability and side-effect profile of the treatment, duration of Organization for Research and Treatment of Cancer response, patient convenience and expense. Treatment (EORTC) was proposed, incorporating stratification of decisions vary considerably across both US and Europe. early stage (TI/T2) into patch alone and both patch and Hence the National Cancer Center Network (NCCN) and plaque disease, as well as detailed histologic and molecu- EORTC have published guidelines for the management of lar classification of lymph node and peripheral blood in- this malignancy that are based on consensus statements volvement leading to a uniform and standardized staging rather than evidence-based data [5,6]. Most experts tend and classification system [2]. Agar et al. have validated to start with a single modality or agent of treatment and this new staging system by analyzing the outcome of add additional therapies at the time of progression based 1502 MF and SS patients treated at their institution [3]. on consensus recommendations or institutional and indi- In this study the median reported follow–up period was vidual experience. Patients with limited stage disease are 5.9 years (range, 0.4–35.5 years). Seventy one percent of effectively treated with skin-directed therapies; these in- the patients had ‘limited-stage’ disease (stages IA, IB and clude topical nitrogen mustard, corticosteroids, bexaro- IIA) with median overall survival (OS) ranging between tene, localized radiotherapy or psoralen plus ultraviolet A 15.8 to 35.5 years whereas 20 percent of the patients had therapy, as listed in the NCCN and EORTC guidelines. ‘advanced–stage’ disease (stages IIB, III and IV) and their Most patients will achieve short-term clinical response but will have recurrent disease for many years but still * Correspondence: [email protected] have a normal life expectancy [5-7]. Recurrent disease 2Center for Lymphoid Malignancies, The New York Presbyterian Hospital - after a durable remission can often be retreated with the Columbia University Medical Center, Columbia University Hospital - College same modality. If skin-directed therapies are ineffective or of Physicians and Surgeons, 6 East 60th St., New York, N.Y 10022, USA Full list of author information is available at the end of the article if the patient develops advanced stage disease then systemic © 2012 Jain et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Jain et al. Journal of Hematology & Oncology 2012, 5:24 Page 2 of 15 http://www.jhoonline.org/content/5/1/24 therapies are introduced, which may include α-interferon, inhibit the activity of HDACs in a wide range of concen- bexarotene, photopheresis, denileukin diftitox, vorinostat, trations from low nM to high mM. To date, there are alemtuzumab, cytotoxic chemotherapy, or combination several HDAC inhibitors in development with focus on therapies. In advanced stage disease, responses are often greater potency and improved tolerability. The bulk of partial and seldom durable and there is no treatment for the clinical experience with these compounds has fo- which improved survival has been demonstrated [3,4,8]. cused on the pan-HDAC inhibitors (i.e., those inhibiting Allogeneic stem cell transplant is reserved for selected class I, II and IV enzymes). By causing accumulation of young patients with advanced-stage disease in order to ex- acetylated histones and non-histone proteins in the cell, ploit a graft versus lymphoma effect for long-term disease HDAC inhibitors lead to several effects, including tran- control. Since most patients require prolonged therapy, the scriptional modification and altered function of proteins key to successful disease management is to enhance im- regulating cell proliferation, cell cycle progression, differ- mune function and minimize immunosuppressive therapies entiation and apoptosis [10,11]. HDAC inhibitors can in order to reduce life threatening infectious complications. block cell proliferation and cause apoptosis in human This has led to development of new therapies with targeted tumor derived cell lines by causing cell cycle arrest in mechanisms of action and acceptable safety profile that G1 or G2/M phase with relative sparing of normal cells may change the paradigm of treating this disease. Further- through dysregulation of proteins that control cell cycle more, clinical trials in MF and SS have suffered from lack progression and coordinate the G1/S and G2/M transi- of standardized criteria to assess response and clinical end tion such as cyclins, cyclin-dependent kinases (Cdk) and points. This has made interpretation of clinical trials in- their associated regulators [12-14]. HDAC inhibitors can volving various agents performed to date cumbersome. also induce upregulation of p21, p27 and p16, which The following consensus guideline was recently proposed bind to and inactivate CDK2 and CDK4, hence leading toassessauniformcompositeresponsebasedontheISCL, to inhibition of cell cycle progression [15,16]. HDAC USCLC and EORTC recommendations to facilitate collab- inhibitors have also been observed to increase the ex- oration among investigators: complete remission was pression of genes that encode for death receptors and defined as (100% clearance of all skin lesions + all lymph their ligands, such as Fas and the Apo 2 L/TRAIL recep- nodes ≤ 1.5 cm in long axis + normal size of visceral organs tors, DR4 and DR5, downregulate c-FLIP, c1AP2 and by imaging + ≤ 5% sezary cells in peripheral blood) while X1AP and induce generation of reactive oxygen species partial remission was defined as [50–99% clearance of skin (ROS) all of which contribute towards apoptosis [17-22]. lesions, + ≥ 50% reduction in SPD (sum of the product of Other non-histone targets of HDAC inhibitors include the longest bidimensional diameters) + ≥ 50% regression of transcriptional co-regulators, DNA binding transcrip- measurable disease in the organs + > 50% decrease in tional factors, chaperone proteins, steroid receptors and blood tumor burden] [9]. DNA repair enzymes [23-25]. HDAC inhibitors have been shown to have antiangiogenic effects by various Novel therapeutic agents in cutaneous T-cell lymphoma mechanisms, including up-regulation of angiogenesis While the lack of insight into the biology of CTCL has inhibitors such as thrombospondin and von-Hippel Lin- hindered the development of true ‘targeted therapies’, dau factor, as well as downregulation of factors that pro- there is now an abundance of new drugs that have mote vasculogenesis, such as VEGF and hypoxia- shown potentially significant activity either alone or in induced protein (HIF-[alpha]) [26,27]. Marquard et al. combination with conventional agents. investigated HDAC expression and histone acetylation by immunohistochemical staining in 73 patients with Histone deacetylase inhibitors (HDAC inhibitors) CTCL [28]. The expression of HDAC1, HDAC2, HDAC6, Histone deacetylase inhibitors have become a critical and acetylated H4 were correlated to histological subtypes component of the CTCL treatment armamentarium in and overall survival. HDAC2 and acetylated H4 were the relapsed/refractory setting. These are epigenetic more common in aggressive forms of CTCLs compared agents that regulate gene transcription by physical with indolent CTCLs whereas

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