Abstract
Cutaneous T-cell lymphomas (CTCLs) are a rare group of mature T-cell lymphomas presenting primarily in the skin. The most common subtypes of CTCL are mycosis fungoides and its leukaemic variant Sézary’s syndrome. Patients with early-stage disease frequently have an indolent clinical course; however, those with advanced stages have a shortened survival. For the treating physician, the question of how to choose a particular therapy in the management of CTCL is important. These diseases span the disciplines of dermatology, medical oncology and radiation oncology. Other than an allo-geneic stem cell transplant, there are no curative therapies for this disease. Hence, many treatment modalities need to be offered to the patient over the course of their life. An accepted treatment approach has been to delay traditional chemotherapy, which can cause excessive toxicity without durable benefit. More conservative treatment strategies in the initial management of CTCL have led to the development of newer biological and targeted therapies. These therapies include biological immune enhancers such as interferon a and extracorporeal photopheresis that exert their effect by stimulating an immune response to the tumour cells. Retinoids such as bexarotene have been shown to be effective and well tolerated with predictable adverse effects. The fusion toxin denileukin diftitox targets the interleukin-2 receptor expressed on malignant T cells. Histone deacetylase inhibitors such as vorinostat and romidepsin (depsipeptide) may reverse the epigenetic states associated with cancer. Forodesine is a novel inhibitor of purine nucleoside phosphorylase and leads to apoptosis of malignant T cells. Pralatrexate is a novel targeted antifolate that targets the reduced folate carrier in cancer cells. Lastly, systemic chemotherapy including transplantation is used when rapid disease control is needed or if all other biological therapies have failed. As response rates to most of the biological agents used to treat CTCL are 25–30%, it is also reasonable to consider clinical trials with novel agents if one or two front-line therapies have failed, especially before considering chemotherapy. CTCL is largely an incurable disease with significant morbidity and more active agents are needed.
Similar content being viewed by others
References
Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005 May 15; 105(10): 3768–85
Criscione VD, Weinstock MA. Incidence of cutaneous T-cell lymphoma in the United States, 1973–2002. Arch Dermatol 2007 Jul; 143(7): 854–9
Olsen E, Vonderheid E, Pimpinelli N, et al. Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood 2007 Sep 15; 110(6): 1713–22
Bunn PAJ, Lamberg SI. Report of the Committee on Staging and Classification of Cutaneous T-Cell Lymphomas. Cancer Treat Rep 1979; 63(4): 725–8
Sausville EA, Eddy JL, Makuch RW, et al. Histopathologic staging at initial diagnosis of mycosis fungoides and the Sezary syndrome: definition of three distinctive prognostic groups. Ann Intern Med 1988 Sep 1; 109(5): 372–82
Demierre MF, Kim YH, Zackheim HS. Prognosis, clinical outcomes and quality of life issues in cutaneous T-cell lymphoma. Hematol Oncol Clin North Am 2003 Dec; 17(6): 1485–507
Vonderheid EC, Bernengo MG, Burg G, et al. Update on erythrodermic cutaneous T-cell lymphoma: report of the International Society for Cutaneous Lymphomas. J Am Acad Dermatol 2002 Jan; 46(1): 95–106
Heald P. Probing the immune dysregulation in cutaneous T cell lymphomas. J Invest Dermatol 2005 Dec; 125(6): xvi–ii
National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology—v.2. 2009. Fort Washington (PA): NCCN, 2009
Trautinger F, Knobler R, Willemze R, et al. EORTC consensus recommendations for the treatment of mycosis fungoides/ Sezary syndrome. Eur J Cancer 2006 May; 42(8): 1014–30
Zackheim HS, Kashani-Sabet M, Amin S. Topical corti-costeroids for mycosis fungoides: experience in 79 patients. Arch Dermatol 1998 Aug; 134(8): 949–54
Hoppe RT, Abel EA, Deneau DG, et al. Mycosis fungoides: management with topical nitrogen mustard. J Clin Oncol 1987 Nov;5(11): 1796–803
Vonderheid EC, Tan ET, Kantor AF, et al. Long-term efficacy, curative potential, and carcinogenicity of topical mechlorethamine chemotherapy in cutaneous T cell lymphoma. J Am Acad Dermatol 1989 Mar; 20(3): 416–28
Mahrle G, Thiele B. Retinoids in cutaneous T cell lymphomas. Dermatologica 1987; 175 Suppl. 1: 145–50
Breneman D, Duvic M, Kuzel T, et al. Phase 1 and 2 trial of bexarotene gel for skin-directed treatment of patients with cutaneous T-cell lymphoma. Arch Dermatol 2002 Mar; 138(3): 325–32
Takemori N, Hirai K. Significance of PUVA therapy for adult T-cell leukemia/lymphoma: PUVA therapy can induce apoptosis in leukemic cells. Hum Cell 1995 Sep; 8(3): 121–6
Abel EA, Sendagorta E, Hoppe RT, et al. PUVA treatment of erythrodermic and plaque-type mycosis fungoides: ten-year follow-up study. Arch Dermatol 1987 Jul; 123(7): 897–901
Honigsmann H, Brenner W, Rauschmeier W, et al. Photochemotherapy for cutaneous T cell lymphoma: a follow-up study. J Am Acad Dermatol 1984 Feb; 10 (2 Pt 1): 238–45
Ramsay DL, Lish KM, Yalowitz CB, et al. Ultraviolet-B phototherapy for early-stage cutaneous T-cell lymphoma. Arch Dermatol 1992 Jul; 128(7): 931–3
Clark C, Dawe RS, Evans AT, et al. Narrowband TL-01 phototherapy for patch-stage mycosis fungoides. Arch Dermatol 2000 Jun; 136(6): 748–52
Gathers RC, Scherschun L, Malick F, et al. Narrowband UVB phototherapy for early-stage mycosis fungoides. J Am Acad Dermatol 2002 Aug; 47(2): 191–7
Hofer A, Cerroni L, Kerl H, et al. Narrowband (311-nm) UV-B therapy for small plaque parapsoriasis and early-stage mycosis fungoides. Arch Dermatol 1999 Nov; 135(11): 1377–80
Duvic M, Lemak NA, Redman JR, et al. Combined modality therapy for cutaneous T-cell lymphoma. J Am Acad Dermatol 1996 Jun; 34(6): 1022–9
Jones G, McLean J, Rosenthal D, et al. Combined treatment with oral etretinate and electron beam therapy in patients with cutaneous T-cell lymphoma (mycosis fungoides and Sezary syndrome). J Am Acad Dermatol 1992 Jun; 26(6): 960–7
Micaily B, Campbell O, Moser C, et al. Total skin electron beam and total nodal irradiation of cutaneous T-cell lymphoma. Int J Radiat Oncol Biol Phys 1991 Apr; 20(4): 809–13
Price NM. Topical mechlorethamin: cutaneous changes in patients with mycosis fungoides after its administration. Arch Dermatol 1977 Oct; 113(10): 1387–9
Wilson LD, Licata AL, Braverman IM, et al. Systemic chemotherapy and extracorporeal photochemotherapy for T3 and T4 cutaneous T-cell lymphoma patients who have achieved a complete response to total skin electron beam therapy. Int J Radiat Oncol Biol Phys 1995 Jul 15; 32(4): 987–95
Hoppe RT. Total skin electron beam therapy in the management of mycosis fungoides. Front Radiat Ther Oncol 1991; 25: 80–9; discussion 132-3
Jones GW, Rosenthal D, Wilson LD. Total skin electron radiation for patients with erythrodermic cutaneous T-cell lymphoma (mycosis fungoides and the Sezary syndrome). Cancer 1999 May 1; 85(9): 1985–95
Quiros PA, Jones GW, Kacinski BM, et al. Total skin electron beam therapy followed by adjuvant psoralen/ ultra violet-A light in the management of patients with T1 and T2 cutaneous T-cell lymphoma (mycosis fungoides). Int J Radiat Oncol Biol Phys 1997 Jul 15; 38(5): 1027–35
Wilson LD, Quiros PA, Kolenik SA, et al. Additional courses of total skin electron beam therapy in the treatment of patients with recurrent cutaneous T-cell lymphoma. J Am Acad Dermatol 1996 Jul; 35(1): 69–73
Knobler RM. Photopheresis. Extracorporeal irradiation of 8-MOP containing blood: a new therapeutic modality. Blut 1987 Apr; 54(4): 247–50
Gasparro FP, Chan G, Edelson RL. Phototherapy and photopharmacology. Yale J Biol Med 1985 Nov–Dec; 58(6): 519–34
Edelson RL. Cutaneous T cell lymphoma: the helping hand of dendritic cells. Ann N Y Acad Sci 2001 Sep; 941: 1–11
Berger CL, Hanlon D, Kanada D, et al. The growth of cutaneous T-cell lymphoma is stimulated by immature dendritic cells. Blood 2002 Apr 15; 99(8): 2929–39
Edelson R, Berger C, Gasparro F, et al. Treatment of cutaneous T-cell lymphoma by extracorporeal photo-chemotherapy: preliminary results. N Engl J Med 1987 Feb 5; 316(6): 297–303
Zic JA, Miller JL, Stricklin GP, et al. The North American experience with photopheresis. Ther Apher 1999 Feb; 3(1): 50–62
Zic J, Arzubiaga C, Salhany KE, et al. Extracorporeal photopheresis for the treatment of cutaneous T-cell lymphoma. J Am Acad Dermatol 1992 Nov; 27 (5 Pt 1): 729–36
Arulogun S, Prince HM, Gambell P, et al. Extracorporeal photopheresis for the treatment of Sezary syndrome using a novel treatment protocol. J Am Acad Dermatol 2008 Oct; 59(4): 589–95
Scarisbrick JJ, Taylor P, Holtick U, et al. UK consensus statement on the use of extracorporeal photopheresis for treatment of cutaneous T-cell lymphoma and chronic graftversus-host disease. Br J Dermatol 2008 Apr; 158(4): 659–78
Miller JD, Kirkland EB, Domingo DS, et al. Review of extracorporeal photopheresis in early-stage (IA, IB, and IIA) cutaneous T-cell lymphoma. Photodermatol Photoimmunol Photomed 2007 Oct; 23(5): 163–71
Dippel E, Schrag H, Goerdt S, et al. Extracorporeal photopheresis and interferon-alpha in advanced cutaneous T-cell lymphoma. Lancet 1997 Jul 5; 350(9070): 32–3
Tsirigotis P, Pappa V, Papageorgiou S, et al. Extracorporeal photopheresis in combination with bexarotene in the treatment of mycosis fungoides and Sezary syndrome. Br J Dermatol 2007 Jun; 156(6): 1379–81
Wilson LD, Jones GW, Kim D, et al. Experience with total skin electron beam therapy in combination with extracorporeal photopheresis in the management of patients with erythrodermic (T4) mycosis fungoides. J Am Acad Dermatol 2000 Jul; 43 (1 Pt 1): 54–60
Stadler R. Optimal combination with PUVA: rationale and clinical trial update. Oncology (Williston Park) 2007 Feb; 21 (2 Suppl. 1): 29–32
Bunn Jr PA, Foon KA, Ihde DC, et al. Recombinant leukocyte A interferon: an active agent in advanced cutaneous T-cell lymphomas. Ann Intern Med 1984 Oct; 101(4): 484–7
Olsen EA, Rosen ST, Vollmer RT, et al. Interferon alfa-2a in the treatment of cutaneous T cell lymphoma. J Am Acad Dermatol 1989 Mar; 20(3): 395–407
Olsen EA. Interferon in the treatment of cutaneous T-cell lymphoma. Dermatol Ther 2003; 16(4): 311–21
McGinnis KS, Ubriani R, Newton S, et al. The addition of interferon gamma to oral bexarotene therapy with photopheresis for Sezary syndrome. Arch Dermatol 2005 Sep; 141(9): 1176–8
Dummer R, Dobbeling U, Geertsen R, et al. Interferon resistance of cutaneous T-cell lymphoma-derived clonal T-helper 2 cells allows selective viral replication. Blood 2001 Jan 15; 97(2): 523–7
Urosevic M. Drug evaluation: TG-1042, an adenovirusmediated IFNgamma gene delivery for the intratumoral therapy of primary cutaneous lymphomas. Curr Opin Investig Drugs 2007 Jun; 8(6): 493–8
Dummer R, Hassel JC, Fellenberg F, et al. Adenovirus-mediated intralesional interferon-gamma gene transfer induces tumor regressions in cutaneous lymphomas. Blood 2004 Sep 15; 104(6): 1631–8
Transgene. Study to evaluate the safety and efficacy of adeno-IFN gamma in cutaneous B-cell lymphoma [Clinical Trials.gov identifier NCT00394693]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Jan 11]
Duvic M, Sherman ML, Wood GS, et al. A phase II open-label study of recombinant human interleukin-12 in patients with stage IA, IB, or IIA mycosis fungoides. J Am Acad Dermatol 2006 Nov; 55(5): 807–13
Duvic M, Hymes K, Heald P, et al. Bexarotene is effective and safe for treatment of refractory advanced-stage cutaneous T-cell lymphoma: multinational phase II–III trial results. J Clin Oncol 2001 May 1; 19(9): 2456–71
Olsen E, Duvic M, Frankel A, et al. Pivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma. J Clin Oncol 2001 Jan 15; 19(2): 376–88
Negro-Vilar A, Dziewanowska A, Groves ES, et al. Efficacy and safety of denileukin diftitox (Dd) in a phase III, double-blind, placebo-controlled study of CD25+ patients with cutaneous T-cell lymphoma (CTCL) [abstract no. 8026]. J Clin Oncol ASCO Ann Meet Proc 2007; 25 (Jun 20 Suppl. Pt 1): 18S
Negro-Vilar A, Prince HM, Duvic M, et al. Efficacy and safety of denileukin diftitox (Dd) in cutaneous T-cell lymphoma (CTCL) patients: integrated analysis of three large phase III trials [abstract no. 8551]. J Clin Oncol 2008 May 20; 26 (Suppl.)
Ontak. Prescribing information [online]. Available from URL: http://www.ontak.com/hcp-prescribing-information.asp [Accessed 2010 Jan 11]
Ruddle JB, Harper CA, Honemann D, et al. A denileukin diftitox (Ontak) associated retinopathy? Br J Ophthalmol 2006 Aug; 90(8): 1070–1
Foss F, Demierre MF, DiVenuti G. A phase-1 trial of bexarotene and denileukin diftitox in patients with relapsed or refractory cutaneous T-cell lymphoma. Blood 2005 Jul 15; 106(2): 454–7
Lundin J, Hagberg H, Repp R, et al. Phase 2 study of alemtuzumab (anti-CD52 monoclonal antibody) in patients with advanced mycosis fungoides/Sezary syndrome. Blood 2003 Jun 1; 101(11): 4267–72
Kennedy GA, Seymour JF, Wolf M, et al. Treatment of patients with advanced mycosis fungoides and Sezary syndrome with alemtuzumab. Eur J Haematol 2003 Oct; 71(4): 250–6
Kim YH, Duvic M, Obitz E, et al. Clinical efficacy of zanolimumab (HuMax-CD4): two phase 2 studies in refractory cutaneous T-cell lymphoma. Blood 2007 Jun 1; 109(11): 4655–62
Bolden JE, Peart MJ, Johnstone RW. Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 2006 Sep; 5(9): 769–84
Johnstone RW. Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat Rev Drug Discov 2002 Apr; 1(4): 287–99
Marks PA, Richon VM, Miller T, et al. Histone deacetylase inhibitors. Adv Cancer Res 2004; 91: 137–68
Olsen EA, Kim YH, Kuzel TM, et al. Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol 2007 Jul 20; 25(21): 3109–15
Piekarz RL, Robey R, Sandor V, et al. Inhibitor of histone deacetylation, depsipeptide (FR901228), in the treatment of peripheral and cutaneous T-cell lymphoma: a case report. Blood 2001 Nov 1; 98(9): 2865–8
Bates S, Piekarz R, Wright J, et al. Final clinical results of a phase 2 NCI multicenter study of romidepsin in recurrent cutaneous T-cell lymphoma (molecular analyses included). ASH Annual Meeting Abstracts 2008 Nov 16; 112(11): 1568
Duvic M, Becker JC, Dalle S, et al. Phase II trial of oral panobinostat (lbh589) in patients with refractory cutaneous T-cell lymphoma (CTCL). ASH Annual Meeting Abstracts 2008 Nov 16; 112(11): 1005
O’Connor OA, Pro B, Pinter-Brown L, et al. PROPEL: a multi-center phase 2 open-label study of pralatrexate (PDX) with vitamin B12 and folic acid supplementation in patients with replapsed or refractory peripheral T-cell lymphoma. ASH Annual Meeting Abstracts 2008; 112: 261
Horwitz SM, Duvic M, Kim Y, et al. Pralatrexate (PDX) IS active in cutaneous T-cell lymphoma: preliminary results of a multi-center dose-finding trial. ASH Annual Meeting Abstracts 2008 Nov 16; 112(11): 1569
Duvic M, Forero-Torres A, Foss F, et al. Long-term treatment of CTCL with the oral PNP inhibitor, forodesine [abstract no. 8552]. J Clin Oncol 2009; 27 Suppl.: 15s
BioCryst Pharmaceuticals. Forodesine in the treatment of cutaneous T-cell lymphoma [ClinicalTrials.gov identifier NCT00501735]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Jan 11]
Zinzani PL, Baliva G, Magagnoli M, et al. Gemcitabine treatment in pretreated cutaneous T-cell lymphoma: experience in 44 patients. J Clin Oncol 2000 Jul; 18(13): 2603–6
Duvic M, Talpur R, Wen S, et al. Phase II evaluation of gemcitabine monotherapy for cutaneous T-cell lymphoma. Clin Lymphoma Myeloma 2006 Jul; 7(1): 51–8
Von Hoff DD, Dahlberg S, Hartstock RJ, et al. Activity of fludarabine monophosphate in patients with advanced mycosis fungoides: a Southwest Oncology Group study. J Natl Cancer Inst 1990 Aug 15; 82(16): 1353–5
Kuzel TM, Hurria A, Samuelson E, et al. Phase II trial of 2-chlorodeoxyadenosine for the treatment of cutaneous T-cell lymphoma. Blood 1996 Feb 1; 87(3): 906–11
Saven A, Carrera CJ, Carson DA, et al. 2-Chlorodeoxy-adenosine: an active agent in the treatment of cutaneous T-cell lymphoma. Blood 1992 Aug 1; 80(3): 587–92
O’Brien S, Kurzrock R, Duvic M, et al. 2-Chlorodeoxyadenosine therapy in patients with T-cell lymphoproliferative disorders. Blood 1994 Aug 1; 84(3): 733–8
Kurzrock R, Pilat S, Duvic M. Pentostatin therapy of T-cell lymphomas with cutaneous manifestations. J Clin Oncol 1999 Oct; 17(10): 3117–21
Wollina U, Dummer R, Brockmeyer NH, et al. Multicenter study of pegylated liposomal doxorubicin in patients with cutaneous T-cell lymphoma. Cancer 2003 Sep 1; 98(5): 993–1001
Zinzani PL, Musuraca G, Tani M, et al. Phase II trial of proteasome inhibitor bortezomib in patients with relapsed or refractory cutaneous T-cell lymphoma. J Clin Oncol 2007 Sep 20; 25(27): 4293–7
Akpek G, Koh HK, Bogen S, et al. Chemotherapy with etoposide, vincristine, doxorubicin, bolus cyclophosphamide, and oral prednisone in patients with refractory cutaneous T-cell lymphoma. Cancer 1999 Oct 1; 86(7): 1368–76
Duvic M, Talpur R, Ni X, et al. Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood 2007 Jan 1; 109(1): 31–9
Marchi E, Alinari L, Tani M, et al. Gemcitabine as frontline treatment for cutaneous T-cell lymphoma: phase II study of 32 patients. Cancer 2005 Dec 1; 104(11): 2437–41
Foss FM, Ihde DC, Breneman DL, et al. Phase II study of pentostatin and intermittent high-dose recombinant interferon alfa-2a in advanced mycosis fungoides/Sezary syndrome. J Clin Oncol 1992 Dec; 10(12): 1907–13
Olavarria E, Child F, Woolford A, et al. T-cell depletion and autologous stem cell transplantation in the management of tumour stage mycosis fungoides with peripheral blood involvement. Br J Haematol 2001 Sep; 114(3): 624–31
Herbert KE, Spencer A, Grigg A, et al. Graft-versus-lymphoma effect in refractory cutaneous T-cell lymphoma after reducedintensity HLA-matched sibling allogeneic stem cell transplantation. Bone Marrow Transplant 2004 Sep; 34(6): 521–5
Acknowledgements
No sources of funding were used to assist in the preparation of this article. Dr Foss has acted as a consultant for Gloucester Pharmaceuticals and Eisai Pharmaceuticals. Dr Lansigan has no conflicts of interest that are relevant to the content of this review.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lansigan, F., Foss, F.M. Current and Emerging Treatment Strategies for Cutaneous T-cell Lymphoma. Drugs 70, 273–286 (2010). https://doi.org/10.2165/11532190-000000000-00000
Published:
Issue Date:
DOI: https://doi.org/10.2165/11532190-000000000-00000