Cutaneous T-cell lymphoma is a term that encompasses a spectrum of non-Hodgkin’s T-cell lymphomas with primary manifestations in the skin. It describes a heterogeneous group of neoplasms that are characterised by an accumulation of malignant T cells of the CD4 phenotype that have the propensity to home and accumulate in the skin, lymph nodes, and peripheral blood. The two most common variants of cutaneous T-cell lymphoma include mycosis fungoides and the leukemic variant, the Sézary syndrome. While numerous treatments are available for cutaneous T-cell lymphoma and have shown to have success in those with patch and plaque lesions, for those patients with tumour stage or lymph node involvement there is a significant decline in response. The relatively new therapeutic option with the use of histone deacetylase inhibitors is being advanced in the hope of decreasing morbidity and mortality associated with the disease. Histone deacetylase inhibitors have been shown to induce changes in gene expression, affecting cell cycle regulation, differentiation, and apoptosis. The aim of this paper is to discuss CTCL in the context of advances in CTCL treatment, specifically with HDAC inhibitors. 1. Cutaneous T-Cell Lymphoma Cutaneous T-cell lymphomas (CTCLs) are a heterogenous group of extranodal non-Hodgkin’s T-cell lymphomas derived from T lymphocytes that infiltrate the skin [1, 2]. CTCL is characterised by an accumulation of malignant T cells of the CD4 phenotype that target and persist in the skin, yet have the propensity to home and accumulate in the lymph nodes and peripheral blood as the disease progresses [2–6]. The term CTCL was coined in 1974 by Edelson [4, 7] to describe the major classifications of CTCL, including mycosis fungoides (MF) and the leukemic variant the Sézary syndrome (SS). Although a rare condition, in its advanced or transformed stages it is a debilitating and devastating disease, differing dramatically in its clinical and histopathologic presentations and subsequent therapeutic considerations [8]. While a number of therapies are available for the treatment of this disease, generally patients develop progressive disease after becoming treatment intolerant or refractory to multiple therapies. The annual incidence of CTCL is approximately 0.5 per 100,000, having a higher prevalence among men than women (male-to-female ratio of 1.6？:？1–2.0？:？1) and typically seen in adults with a median age of 55–60 years at diagnosis [9, 10]. The exact number of cases is difficult to determine due to the lack of a definitive diagnoses at early stages. This is
References
[1]
R. Willemze, E. S. Jaffe, G. Burg et al., “WHO-EORTC classification for cutaneous lymphomas,” Blood, vol. 105, no. 10, pp. 3768–3785, 2005.
[2]
P. Ponte, V. Serr？o, and M. Apetato, “Efficacy of narrowband UVB vs. PUVA in patients with early-stage mycosis fungoides,” Journal of the European Academy of Dermatology and Venereology, vol. 24, no. 6, pp. 716–721, 2010.
[3]
T. Krejsgaard, K. Kopp, E. Ralfkiaer et al., “A novel xenograft model of cutaneous T-cell lymphoma,” Experimental Dermatology, vol. 19, no. 12, pp. 1096–1102, 2010.
[4]
R. L. Edelson, “Cutaneous T cell lymphoma: mycosis fungoides, Sezary syndrome, and other variants,” Journal of the American Academy of Dermatology, vol. 2, no. 2, pp. 89–106, 1980.
[5]
D. V. Kazakov, G. Burg, and W. Kempf, “Clinicopathological spectrum of mycosis fungoides,” Journal of the European Academy of Dermatology and Venereology, vol. 18, no. 4, pp. 397–415, 2004.
[6]
M. Girardi, P. W. Heald, and L. D. Wilson, “The pathogenesis of mycosis fungoides,” New England Journal of Medicine, vol. 350, no. 19, pp. 1978–1988, 2004.
[7]
R. L. Edelson, “Outsmarting cutaneous T-cell lymphoma cells by decoding the language they speak: focusing past and present insights on future prospects,” Clinical Lymphoma, Myeloma and Leukemia, vol. 10, no. 2, pp. S59–S62, 2010.
[8]
F. Glass, K. L. Keller, J. L. Messina, et al., “The diagnosis and treatment of cutaneous T-cell lymphoma are challenging due the many clnical and histopathologic presentations of the disease,” Cancer Control, vol. 5, no. 1, 1998.
[9]
R. Willemze, “Cutaneous T-cell lymphoma: epidemiology, etiology, and classification,” Leukemia and Lymphoma, vol. 44, supplement 3, pp. S49–S54, 2003.
[10]
P. T. Bradford, S. S. Devesa, W. F. Anderson, and J. R. Toro, “Cutaneous lymphoma incidence patterns in the United States: a population-based study of 3884 cases,” Blood, vol. 113, no. 21, pp. 5064–5073, 2009.
[11]
M. Girardi and R. L. Edelson, “Cutaneous T-cell lymphoma: pathogenesis and treatment,” Oncology, vol. 14, no. 7, pp. 1061–1070, 2000.
[12]
E. Diamandidou, P. R. Cohen, and R. Kurzrock, “Mycosis fungoides and Sezary syndrome,” Blood, vol. 88, no. 7, pp. 2385–2409, 1996.
[13]
A. Markova and M. A. Weinstock, “Trends in cutaneous lymphoma epidemiology,” Clinical Lymphoma, Myeloma and Leukemia, vol. 10, no. 2, pp. S63–S66, 2010.
[14]
B. D. Smith and L. D. Wilson, “Management of mycosis fungoides: Part 1. Diagnosis, staging, and prognosis,” Oncology, vol. 17, no. 9, pp. 1281–1288, 2003.
[15]
R. S. Siegel, T. Pandolfino, J. Guitart, S. Rosen, and T. M. Kuzel, “Primary cutaneous T-cell lymphoma: review and current concepts,” Journal of Clinical Oncology, vol. 18, no. 15, pp. 2908–2925, 2000.
[16]
M. Girardi, P. W. Heald, and L. D. Wilson, “The pathogenesis of mycosis fungoides,” New England Journal of Medicine, vol. 350, no. 19, pp. 1978–1988, 2004.
[17]
P. A. Bunn and S. I. Lamberg, “Report of the committee on staging and classification of cutaneous T-cell lymphomas,” Cancer Treatment Reports, vol. 63, no. 4, pp. 725–728, 1979.
[18]
F. Trautinger, R. Knobler, R. Willemze et al., “EORTC consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome,” European Journal of Cancer, vol. 42, no. 8, pp. 1014–1030, 2006.
[19]
R. Dummer and M. Dreyling, “Primary cutaneous lymphoma: ESMO clinical recommendations for diagnosis, treatment and follow-up,” Annals of Oncology, vol. 19, supplement 2, pp. ii72–ii76, 2008.
[20]
S. M. Horwitz, E. A. Olsen, M. Duvic, P. Porcu, and Y. H. Kim, “Review of the treatment of mycosis fungoides and Sézary syndrome: a stage-based approach,” Journal of the National Comprehensive Cancer Network, vol. 6, no. 4, pp. 436–442, 2008.
[21]
M. Girardi and R. L. Edelson, “Cutaneous T-cell lymphoma: pathogenesis and treatment,” Oncology, vol. 14, no. 7, pp. 1061–1070, 2000.
[22]
J. Alibert, Description des Maladies de la Peau: Observees a L'HospitaL St. Louis, Barrois L'Aine et Fils, Paris, France, 1806.
[23]
K. Ferenczi, R. C. Fuhlbrigge, J. L. Pinkus, G. S. Pinkus, and T. S. Kupper, “Increased CCR4 expression in cutaneous T cell lymphoma,” Journal of Investigative Dermatology, vol. 119, no. 6, pp. 1405–1410, 2002.
[24]
J. J. Campbell, G. Haraldsen, J. Pan et al., “The chemokine receptor CCR4 in vascular recognition by cutaneous but not intestinal memory T cells,” Nature, vol. 400, no. 6746, pp. 776–780, 1999.
[25]
C. Vestergaard, K. Bang, B. Gesser, H. Yoneyama, K. Matsushima, and C. G. Larsen, “A Th2 chemokine, TARC, produced by keratinocytes may recruit CLA+CCR4+ lymphocytes into lesional atopic dermatitis skin,” Journal of Investigative Dermatology, vol. 115, no. 4, pp. 640–646, 2000.
[26]
B. Poligone, “Romidepsin: evidence for its potential use to manage previously treated cutaneous T cell lymphoma,” Core Evidence, vol. 6, pp. 1–12, 2011.
[27]
V. Kumar, N. Fausto, and A. Abbas, Robbins and Cotran Pathologic Basis of Disease, Elsevier Saunders, 9th edition, 2010.
[28]
T. M. Kuzel, H. H. Roenigk, and S. T. Rosen, “Mycosis fungoides and the Sezary syndrome: a review of pathogenesis, diagnosis, and therapy,” Journal of Clinical Oncology, vol. 9, no. 7, pp. 1298–1313, 1991.
[29]
R. Van Doorn, C. W. Van Haselen, P. C. Van Voorst Vader et al., “Mycosis fungoides: disease evolution and prognosis of 309 Dutch patients,” Archives of Dermatology, vol. 136, no. 4, pp. 504–510, 2000.
[30]
S. J. Whittaker, J. R. Marsden, M. Spittle, and R. Russell Jones, “Joint British Association of Dermatologists and U.K. Cutaneous Lymphoma Group guidelines for the management of primary cutaneous T-cell lymphomas,” British Journal of Dermatology, vol. 149, no. 6, pp. 1095–1107, 2003.
[31]
F. J. Kaye, P. A. J. Bunn, S. M. Stinberg, et al., “A randomized trial comparing combination electro beam radiation and chemotherapy with topical therapy in the initial treatment of mycosis fungoides,” The New England Journal of Medicine, vol. 321, no. 26, pp. 1748–1790, 1989.
[32]
H. S. Zackheim, M. Kashani-Sabet, and S. Amin, “Topical corticosteroids for mycosis fungoides: experience in 79 patients,” Archives of Dermatology, vol. 134, no. 8, pp. 949–954, 1998.
[33]
H. S. Zackheim, M. Kashani-Sabet, and S. Amin, “Topical corticosteroids for mycosis fungoides: experience in 79 patients,” Archives of Dermatology, vol. 134, no. 8, pp. 949–954, 1998.
[34]
D. Breneman, M. Duvic, T. Kuzel, R. Yocum, J. Truglia, and V. J. Stevens, “Phase 1 and 2 trial of bexarotene gel for skin-directed treatment of patients with cutaneous T-cell lymphoma,” Archives of Dermatology, vol. 138, no. 3, pp. 325–332, 2002.
[35]
C. J. Karzmark, “Total skin electron therapy: technique and dosimetry,” American Association of Physicists in Medicine Report 23, 1987.
[36]
J. E. Bolden, M. J. Peart, and R. W. Johnstone, “Anticancer activities of histone deacetylase inhibitors,” Nature Reviews Drug Discovery, vol. 5, no. 9, pp. 769–784, 2006.
[37]
P. A. Marks, R. A. Rifkind, V. M. Richon, R. Breslow, T. Miller, and W. K. Kelly, “Histone deacetylases and cancer: causes and therapies,” Nature Reviews Cancer, vol. 1, no. 3, pp. 194–202, 2001.
[38]
M. Dokmanovic, C. Clarke, and P. A. Marks, “Histone deacetylase inhibitors: overview and perspectives,” Molecular Cancer Research, vol. 5, no. 10, pp. 981–989, 2007.
[39]
P. A. Marks, “Histone deacetylase inhibitors: a chemical genetics approach to understanding cellular functions,” Biochimica et Biophysica Acta, vol. 1799, no. 10–12, pp. 717–725, 2010.
[40]
S. Minucci and P. G. Pelicci, “Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer,” Nature Reviews Cancer, vol. 6, no. 1, pp. 38–51, 2006.
[41]
A. Tumber, L. S. Collins, K. D. Petersen et al., “The histone deacetylase inhibitor PXD101 synergises with 5-fluorouracil to inhibit colon cancer cell growth in vitro and in vivo,” Cancer Chemotherapy and Pharmacology, vol. 60, no. 2, pp. 275–283, 2007.
[42]
J. Tan, S. Cang, Y. Ma, R. L. Petrillo, and D. Liu, “Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents,” Journal of Hematology and Oncology, vol. 3, article 5, 2010.
[43]
H. Akazawa and I. Komuro, “Roles of cardiac transcription factors in cardiac hypertrophy,” Circulation Research, vol. 92, no. 10, pp. 1079–1088, 2003.
[44]
T. Kouzarides, “Chromatin modifications and their function,” Cell, vol. 128, no. 4, pp. 693–705, 2007.
[45]
S. Thiagalingam, K. H. Cheng, H. J. Lee, N. Mineva, A. Thiagalingam, and J. F. Ponte, “Histone deacetylases: unique players in shaping the epigenetic histone code,” Annals of the New York Academy of Sciences, vol. 983, pp. 84–100, 2003.
[46]
C. L. Peterson and M. A. Laniel, “Histones and histone modifications,” Current Biology, vol. 14, no. 14, pp. R546–551, 2004.
[47]
P. A. Marks, V. M. Richon, and R. A. Rifkind, “Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells,” Journal of the National Cancer Institute, vol. 92, no. 15, pp. 1210–1216, 2000.
[48]
S. Cang, Y. Ma, and D. Liu, “New clinical developments in histone deacetylase inhibitors for epigenetic therapy of cancer,” Journal of Hematology and Oncology, vol. 2, article 22, 2009.
[49]
S. Y. Roth, J. M. Denu, and C. D. Allis, “Histone acetyltransferases,” Annual Review of Biochemistry, vol. 70, pp. 81–120, 2001.
[50]
B. C. Smith and J. M. Denu, “Chemical mechanisms of histone lysine and arginine modifications,” Biochimica et Biophysica Acta, vol. 1789, no. 1, pp. 45–57, 2009.
[51]
M. H. Kuo, “Roles of histone acetyltransferases and deacetylases in gene regulation,” BioEssays, vol. 20, no. 8, pp. 615–626, 1998.
[52]
J. C. Kim, E. S. Shin, C. W. Kim et al., “In vitro evaluation of histone deacetylase inhibitors as combination agents for colorectal cancer,” Anticancer Research, vol. 29, no. 8, pp. 3027–3034, 2009.
[53]
S. G. Gray and T. J. Ekstr？m, “The human histone deacetylase family,” Experimental Cell Research, vol. 262, no. 2, pp. 75–83, 2001.
[54]
P. A. Marks, V. M. Richon, and R. A. Rifkind, “Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells,” Journal of the National Cancer Institute, vol. 92, no. 15, pp. 1210–1216, 2000.
[55]
A. J. M. De Ruijter, A. H. Van Gennip, H. N. Caron, S. Kemp, and A. B. P. Van Kuilenburg, “Histone deacetylases (HDACs): characterization of the classical HDAC family,” Biochemical Journal, vol. 370, no. 3, pp. 737–749, 2003.
[56]
X. J. Yang and E. Seto, “Collaborative spirit of histone deacetylases in regulating chromatin structure and gene expression,” Current Opinion in Genetics and Development, vol. 13, no. 2, pp. 143–153, 2003.
[57]
T. A. Miller, D. J. Witter, and S. Belvedere, “Histone deacetylase inhibitors,” Journal of Medicinal Chemistry, vol. 46, no. 24, pp. 5097–5116, 2003.
[58]
S. Cang, Y. Ma, and D. Liu, “New clinical developments in histone deacetylase inhibitors for epigenetic therapy of cancer,” Journal of Hematology and Oncology, vol. 2, article 22, 2009.
[59]
D. Siegel, M. Hussein, C. Belani et al., “Vorinostat in solid and hematologic malignancies,” Journal of Hematology and Oncology, vol. 2, article 31, 2009.
[60]
L. Ellis, P. W. Atadja, and R. W. Johnstone, “Epigenetics in cancer: targeting chromatin modifications,” Molecular Cancer Therapeutics, vol. 8, no. 6, pp. 1409–1420, 2009.
[61]
H. M. Prince, M. J. Bishton, and R. W. Johnstone, “Panobinostat (LBH589): a potent pan-deacetylase inhibitor with promising activity against hematologic and solid tumors,” Future Oncology, vol. 5, no. 5, pp. 601–612, 2009.
[62]
B. S. Mann, J. R. Johnson, M. H. Cohen, R. Justice, and R. Pazdur, “FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma,” Oncologist, vol. 12, no. 10, pp. 1247–1252, 2007.
[63]
E. A. Olsen, Y. H. Kim, T. M. Kuzel et al., “Phase IIB multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma,” Journal of Clinical Oncology, vol. 25, no. 21, pp. 3109–3115, 2007.
[64]
M. Crump, B. Coiffier, E. D. Jacobsen et al., “Phase II trial of oral vorinostat (suberoylanilide hydroxamic acid) in relapsed diffuse large-B-cell lymphoma,” Annals of Oncology, vol. 19, no. 5, pp. 964–969, 2008.
[65]
W. K. Kelly, O. A. O'Connor, L. M. Krug et al., “Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer,” Journal of Clinical Oncology, vol. 23, no. 17, pp. 3923–3931, 2005.
[66]
A. Sabharwal and D. Kerr, “Chemotherapy for colorectal cancer in the metastatic and adjuvant setting: past, present and future,” Expert Review of Anticancer Therapy, vol. 7, no. 4, pp. 477–487, 2007.
[67]
K. B. Hymes, “The role of histone deacetylase inhibitors in the treatment of patients with cutaneous T-Cell lymphoma,” Clinical Lymphoma, Myeloma and Leukemia, vol. 10, no. 2, pp. 98–109, 2010.
[68]
C. Mercurio, S. Minucci, and P. G. Pelicci, “Histone deacetylases and epigenetic therapies of hematological malignancies,” Pharmacological Research, vol. 62, no. 1, pp. 18–34, 2010.
[69]
R. L. Piekarz, R. Frye, M. Turner et al., “Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma,” Journal of Clinical Oncology, vol. 27, no. 32, pp. 5410–5417, 2009.
[70]
M. Dickinson, R. W. Johnstone, and H. M. Prince, “Histone deacetylase inhibitors: potential targets responsible for their anti-cancer effect,” Investigational New Drugs, vol. 28, no. 1, pp. S3–S20, 2010.
[71]
V. Sandor, S. Bakke, R. W. Robey et al., “Phase I trial of the histone deacetylase inhibitor, depsipeptide (FR901228, NSC 630176), in patients with refractory neoplasms,” Clinical Cancer Research, vol. 8, no. 3, pp. 718–728, 2002.
[72]
A. Saito, T. Yamashita, Y. Mariko et al., “A synthetic inhibitor of histone deacetylase, MS-27-275, with marked in vivo antitumor activity against human tumors,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 8, pp. 4592–4597, 1999.
[73]
A. Jona, N. Khaskhely, D. Buglio, et al., “The histone deacetylase inhibitor entinostat (SNDX-275) induces apoptosis in Hodgkin lymphoma cells and synergizes with Bcl-2 family inhibitors,” Experimental Hematology, vol. 39, no. 10, pp. 1007.e1–1017.e1, 2011.
[74]
K. R. Suchin, M. Cassin, S. L. Gottleib et al., “Increased interleukin 5 production in eosinophilic Sézary syndrome: regulation by interferon alfa and interleukin 12,” Journal of the American Academy of Dermatology, vol. 44, no. 1, pp. 28–32, 2001.
[75]
B. R. Vowels, M. Cassin, E. C. Vonderheid, and A. H. Rook, “Aberrant cytokine production by Sezary syndrome patients: cytokine secretion pattern resembles murine Th2 cells,” Journal of Investigative Dermatology, vol. 99, no. 1, pp. 90–94, 1992.
[76]
B. R. Vowels, S. R. Lessin, M. Cassin et al., “Th2 cytokine mRNA expression in skin in cutaneous T-cell lymphoma,” Journal of Investigative Dermatology, vol. 103, no. 5, pp. 669–673, 1994.
[77]
K. Asadullah, W. D. D？cke, A. Haeuler, W. Sterry, and H. D. Volk, “Progression of mycosis fungoides is associated with increasing cutaneous expression of interleukin-10 mRNA,” Journal of Investigative Dermatology, vol. 107, no. 6, pp. 833–837, 1996.
[78]
P. Gimsing, “Belinostat: a new broad acting antineoplastic histone deacetylase inhibitor,” Expert Opinion on Investigational Drugs, vol. 18, no. 4, pp. 501–508, 2009.
[79]
X. Qian, G. Ara, E. Mills, W. J. LaRochelle, H. S. Lichenstein, and M. Jeffers, “Activity of the histone deacetylase inhibitor belinostat (PXD101) in preclinical models of prostate cancer,” International Journal of Cancer, vol. 122, no. 6, pp. 1400–1410, 2008.
[80]
P. Gimsing, M. Hansen, L. M. Knudsen et al., “A phase I clinical trial of the histone deacetylase inhibitor belinostat in patients with advanced hematological neoplasia,” European Journal of Haematology, vol. 81, no. 3, pp. 170–176, 2008.
[81]
N. L. Steele, J. A. Plumb, L. Vidal et al., “A phase 1 pharmacokinetic and pharmacodynamic study of the histone deacetylase inhibitor belinostat in patients with advanced solid tumors,” Clinical Cancer Research, vol. 14, no. 3, pp. 804–810, 2008.
[82]
S. S. Ramalingam, C. P. Belani, C. Ruel et al., “Phase II study of belinostat (PXD101), a histone deacetylase inhibitor, for second line therapy of advanced malignant pleural mesothelioma,” Journal of Thoracic Oncology, vol. 4, no. 1, pp. 97–101, 2009.
[83]
W. Shao, J. D. Growney, Y. Feng, et al., “Potent anticancer activity of the pan-deacetylase inhibitor panobinostat (LBH589) as a single agent in in vitro and in vivo tumor models,” Proceedings of the 99th American Association of Cancer Research Annual Meeting, April 2008.
[84]
P. Atadja, “Development of the pan-DAC inhibitor panobinostat (LBH589): successes and challenges,” Cancer Letters, vol. 280, no. 2, pp. 233–241, 2009.
[85]
M. Duvic, J. C. Becker, and S. Dalle, “Phase II trial of oral panobinostat (LBH589) in patients with refractory cutaneous T-cell lymphoma (CTCL),” in Proceedings of the ASH Annual Meeting Abstracts, vol. 112, p. 1005, 2008.
[86]
C. Zhang, V. Richon, X. Ni, R. Talpur, and M. Duvic, “Selective induction of apoptosis by histone deacetylase inhibitor SAHA in cutaneous T-cell lymphoma cells: relevance to mechanism of therapeutic action,” Journal of Investigative Dermatology, vol. 125, no. 5, pp. 1045–1052, 2005.
