Cutaneous T-Cell Lymphoma

  • Ellen J. Kim
  • Camille E. Introcaso
  • Stephen K. Richardson
  • Alain H. Rook
  • Cutaneous T-cell lymphomas are a group of extranodal non-Hodgkin’s lymphomas that present initially in the skin.

  • The incidence of this condition is approximately 0.52–0.64/100,000 person-years.

  • Cutaneous T-cell lymphomas usually present as indolent patches and plaques, but may also present with more aggressive tumors or erythroderm. The survival is highly dependent on the stage of the disease.

  • The diagnosis is made with clinical findings and histology. Staging of this disease is critical, and this may include history and physical examination, blood tests, peripheral blood flow cytometry, and Sézary cell preparations, and scans for internal involvement.

  • Cell trafficking of malignant T cells into the skin and the epidermis is critical in the pathophysiology of this disease, and involves chemokines and chemokine receptors.

  • The immunology of this condition suggests that T-helper-2 (Th2) lymphocyte cytokine patterns are associated with the malignant cells, and there is a progressive loss of cellular immunity with advancing disease.

  • There are two major categories of treatments for this condition: skin-directed therapies or systemic therapies. Combination therapies are effective and have immunomodulatory effects.

  • Bone marrow transplantation is an emerging therapy for patients with advanced disease that is refractory to skin and systemic therapy.


Chemokine Receptor Mycosis Fungoides Denileukin Diftitox Cutaneous Anaplastic Large Cell Lymphoma CTCL Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Kaye FJ, et al. A randomized trial comparing combination electron-beam radiation and chemotherapy with topical therapy in the initial treatment of mycosis fungoides. N Engl J Med 1989;321(26):1784–90.PubMedGoogle Scholar
  2. 2.
    Willemze R, et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005;105(10):3768–85.PubMedCrossRefGoogle Scholar
  3. 3.
    Morton LM, et al. Lymphoma incidence patterns by WHO subtype in the United States 1992–2001. Blood 2006;107(1):265–76.PubMedCrossRefGoogle Scholar
  4. 3a.
    3a. Criscione VD, Weinstock MA. Incidence of cutaneous T-cell lymphoma in the United States, 1973–2002. Arch Dermatol. 2007;143(7):854–9.PubMedCrossRefGoogle Scholar
  5. 4.
    Girardi M, Heald PW, Wilson LD. The pathogenesis of mycosis fungoides. N Engl J Med 2004350(19): 1978–88.PubMedCrossRefGoogle Scholar
  6. 5.
    Kim EJ, et al. Immunopathogenesis and therapy of cutaneous T cell lymphoma. J Clin Invest 2005;115(4):798–812.PubMedGoogle Scholar
  7. 6.
    Kazakov DV, Burg G, Kempf W. Clinicopathological spectrum of mycosis fungoides. J Eur Acad Dermatol Venereol 2004;18(4):397–415.PubMedCrossRefGoogle Scholar
  8. 7.
    Axelrod PI, Lorber B, Vonderheid EC. Infections complicating mycosis fungoides and Sezary syndrome. JAMA 1992;267(10):1354–8.PubMedCrossRefGoogle Scholar
  9. 8.
    Liu HL, et al. CD30+ cutaneous lymphoproliferative disorders: the Stanford experience in lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. J Am Acad Dermatol 2003;49(6):1049–58.PubMedCrossRefGoogle Scholar
  10. 9.
    Huang KP, et al. Second lymphomas and other malignant neoplasms in patients with mycosis fun-goides and Sezary syndrome: evidence from population-based and clinical cohorts. Arch Dermatol 2007;143(1):45–50.PubMedCrossRefGoogle Scholar
  11. 10.
    Wood GS, et al. Detection of clonal T-cell receptor gamma gene rearrangements in early mycosis fungoides/Sezary syndrome by polymerase chain reaction and denaturing gradient gel electrophoresis (PCR/DGGE). J Invest Dermatol 1994;103(1):34–41.PubMedCrossRefGoogle Scholar
  12. 11.
    Pimpinelli N, et al. Defining early mycosis fun-goides. J Am Acad Dermatol 2005;53(6):1053–63.PubMedCrossRefGoogle Scholar
  13. 12.
    Ponti R, et al. T-cell receptor gamma gene rearrangement by multiplex polymerase chain reaction/heter-oduplex analysis in patients with cutaneous T-cell lymphoma (mycosis fungoides/Sezary syndrome) and benign inflammatory disease: correlation with clinical, histological and immunophenotypical findings. Br J Dermatol 2005;153(3):565–73.PubMedCrossRefGoogle Scholar
  14. 13.
    Alessi E, et al. The usefulness of clonality for the detection of cases clinically and/or histopathologi-cally not recognized as cutaneous T-cell lymphoma. Br J Dermatol 2005;153(2):368–71.PubMedCrossRefGoogle Scholar
  15. 14.
    Ortonne N, et al. Significance of circulating T-cell clones in Sezary syndrome. Blood 2006;107(10):4030–8.PubMedCrossRefGoogle Scholar
  16. 15.
    Guitart J. Beyond clonal detection: defining the T-cell clone. Arch Dermatol 2005;141(9):1159–60.PubMedCrossRefGoogle Scholar
  17. 16.
    Lamberg SI, Bunn PA Jr. Cutaneous T-cell lympho-mas. Summary of the Mycosis Fungoides Cooperative Group-National Cancer Institute Workshop. Arch Dermatol 1979;115(9):1103–5.PubMedCrossRefGoogle Scholar
  18. 17.
    Vonderheid EC, Bernengo MG. The Sezary syndrome: hematologic criteria. Hematol Oncol Clin North Am 2003;17(6):1367–89, viii.PubMedCrossRefGoogle Scholar
  19. 18.
    Vonderheid EC, Pena L, Nowell P. Sezary cell counts in erythrodermic cutaneous T-cell lymphoma: implications for prognosis and staging. Leuk Lymphoma 2006;47(9):1841–56.PubMedCrossRefGoogle Scholar
  20. 19.
    Beylot-Barry M, et al. Is bone marrow biopsy necessary in patients with mycosis fungoides and Sezary syndrome? A histological and molecular study at diagnosis and during follow-up. Br J Dermatol 2005;152(6):1378–9.PubMedCrossRefGoogle Scholar
  21. 20.
    Kim YH, et al. Long-term outcome of 525 patients with mycosis fungoides and Sezary syndrome: clinical prognostic factors and risk for disease progression. Arch Dermatol 2003;139(7):857–66.PubMedCrossRefGoogle Scholar
  22. 21.
    Kim YH, et al. Clinical stage IA (limited patch and plaque) mycosis fungoides. A long-term outcome analysis. Arch Dermatol 1996;132(11):1309–13.PubMedCrossRefGoogle Scholar
  23. 22.
    Kim YH, et al. Clinical characteristics and long-term outcome of patients with generalized patch and/or plaque (T2) mycosis fungoides. Arch Dermatol 1999;135(1):26–32.PubMedCrossRefGoogle Scholar
  24. 23.
    Morales MM, et al. Survival of mycosis fungoides in patients in the Southeast of England. Dermatology 2005;211(4):325–9.PubMedCrossRefGoogle Scholar
  25. 24.
    Klemke CD, et al. Prognostic factors and prediction of prognosis by the CTCL Severity Index in mycosis fungoides and Sezary syndrome. Br J Dermatol 2005;153(1):118–24.PubMedCrossRefGoogle Scholar
  26. 25.
    Kari L, et al. Classification and prediction of survival in patients with the leukemic phase of cutaneous T cell lymphoma. J Exp Med 2003;197(11):1477–88.PubMedCrossRefGoogle Scholar
  27. 26.
    Nebozhyn M, et al. Quantitative PCR on 5 genes reliably identifies CTCL patients with 5–99% circulating tumor cells with 90% accuracy. Blood 2006;107(8):3189–96.PubMedCrossRefGoogle Scholar
  28. 27.
    Murdoch C, Finn A. Chemokine receptors and their role in inflammation and infectious diseases. Blood 2000;95(10):3032–43.PubMedGoogle Scholar
  29. 28.
    Robert C, Kupper TS. Inflammatory skin diseases, T cells, and immune surveillance. N Engl J Med 1999;341(24):1817–28.PubMedCrossRefGoogle Scholar
  30. 29.
    Ferenczi K, et al. Increased CCR4 expression in cutaneous T cell lymphoma. J Invest Dermatol 2002;119(6):1405–10.PubMedCrossRefGoogle Scholar
  31. 30.
    Poznansky MC, et al. Active movement of T cells away from a chemokine. Nat Med 2000;6(5):543–8.PubMedCrossRefGoogle Scholar
  32. 31.
    Kallinich T, et al. Chemokine receptor expression on neoplastic and reactive T cells in the skin at different stages of mycosis fungoides. J Invest Dermatol 2003;121(5):1045–52.PubMedCrossRefGoogle Scholar
  33. 32.
    Morales J, et al. CTACK, a skin-associated chemokine that preferentially attracts skin-homing memory T cells. Proc Natl Acad Sci U S A 1999;96(25):14470–5.PubMedCrossRefGoogle Scholar
  34. 33.
    Sokolowska-Wojdylo M, et al. Circulating clonal CLA(+) and CD4(+) T cells in Sezary syndrome express the skin-homing chemokine receptors CCR4 and CCR10 as well as the lymph node-homing chemokine receptor CCR7. Br J Dermatol 2005;152(2):258–64.PubMedCrossRefGoogle Scholar
  35. 34.
    Sokolowska-Wojdylo M, et al. Absence of CD26 expression on skin-homing CLA+ CD4+ T lymphocytes in peripheral blood is a highly sensitive marker for early diagnosis and therapeutic moni-toring of patients with Sezary syndrome. Clin Exp Dermatol 2005;30(6):702–6.PubMedCrossRefGoogle Scholar
  36. 35.
    Narducci MG, et al. Skin homing of Sezary cells involves SDF-1—CXCR4 signaling and down-regulation of CD26/dipeptidylpeptidase I V. Blood 2006;107(3):1108–15.PubMedCrossRefGoogle Scholar
  37. 36.
    Bernengo MG, et al. The relevance of the CD4+ CD26- subset in the identification of circulating Sezary cells. Br J Dermatol 2001;144(1):125–35.PubMedCrossRefGoogle Scholar
  38. 37.
    Introcaso CE, et al. Association of change in clinical status and change in the percentage of the CD4+CD26- lymphocyte population in patients with Sezary syndrome. J Am Acad Dermatol 2005;53(3):428–34.PubMedCrossRefGoogle Scholar
  39. 38.
    Kagami S, et al. Elevated Serum CTACK/CCL27 Levels in CTCL. J Invest Dermatol 2006;126(5): 1189–91.PubMedCrossRefGoogle Scholar
  40. 39.
    Homey B, et al. CCL27–CCR10 interactions regulate T cell-mediated skin inflammation. Nat Med 2002;8(2):157–65.PubMedCrossRefGoogle Scholar
  41. 40.
    Notohamiprodjo M, et al. CCR10 is expressed in cutaneous T-cell lymphoma. Int J Cancer 2005;115(4):641–7.PubMedCrossRefGoogle Scholar
  42. 41.
    Kakinuma T, et al. Thymus and activation-regulated chemokine (TARC/CCL17) in mycosis fun-goides: serum TARC levels reflect the disease activity of mycosis fungoides. J Am Acad Dermatol 2003;48(1):23–30.PubMedCrossRefGoogle Scholar
  43. 42.
    Tensen CP, et al. Epidermal interferon-gamma inducible protein-10 (IP-10) and monokine induced by gamma-interferon (Mig) but not IL-8 mRNA expression is associated with epidermotropism in cutaneous T cell lymphomas. J Invest Dermatol 1998;111(2):222–6.PubMedCrossRefGoogle Scholar
  44. 43.
    Yamanaka K, et al. Skin-derived interleukin-7 contributes to the proliferation of lymphocytes in cutaneous T-cell lymphoma. Blood 2006;107(6):2440–5.PubMedCrossRefGoogle Scholar
  45. 44.
    Smoller BR, et al. Histopathology and genetics of cutaneous T-cell lymphoma. Hematol Oncol Clin North Am 2003;17(6):1277–311.PubMedCrossRefGoogle Scholar
  46. 45.
    Sommer VH, et al. In vivo activation of STAT3 in cutaneous T-cell lymphoma. Evidence for an antiapoptotic function of STAT3. Leukemia 2004;18(7):1288–95.PubMedCrossRefGoogle Scholar
  47. 46.
    Dereure O, et al. Infrequent Fas mutations but no Bax or p53 mutations in early mycosis fungoides: a possible mechanism for the accumulation of malignant T lymphocytes in the skin. J Invest Dermatol 2002;118(6):949–56.PubMedCrossRefGoogle Scholar
  48. 47.
    Ni X, et al. Resistance to activation-induced cell death and bystander cytotoxicity via the Fas/Fas ligand pathway are implicated in the pathogenesis of cutaneous T cell lymphomas. J Invest Dermatol 2005;124(4):741–50.PubMedCrossRefGoogle Scholar
  49. 48.
    van Doorn R, et al. Epigenetic profiling of cutaneous T-cell lymphoma: promoter hypermethylation of multiple tumor suppressor genes including BCL7a, PTPRG, and p73. J Clin Oncol 2005;23(17): 3886–96.PubMedCrossRefGoogle Scholar
  50. 49.
    Nagasawa T, et al. Multi-gene epigenetic silencing of tumor suppressor genes in T-cell lymphoma cells; delayed expression of the p16 protein upon reversal of the silencing. Leuk Res 2006;30(3): 303–12.PubMedCrossRefGoogle Scholar
  51. 50.
    Sors A, et al. Down-regulating constitutive activation of the NF-kappaB canonical pathway overcomes the resistance of cutaneous T-cell lymphoma to apopto-sis. Blood 2006;107(6):2354–63.PubMedCrossRefGoogle Scholar
  52. 51.
    Rosato RR, Grant S. Histone deacetylase inhibitors: insights into mechanisms of lethality. Expert Opin Ther Targets 2005;9(4):809–24.PubMedCrossRefGoogle Scholar
  53. 52.
    Talpur R, et al. CD25 expression is correlated with histological grade and response to denileukin diftitox in cutaneous T-cell lymphoma. J Invest Dermatol 2006;126(3):575–83.PubMedCrossRefGoogle Scholar
  54. 53.
    Wasik MA, et al. Increased serum concentration of the soluble interleukin-2 receptor in cutaneous T-cell lymphoma. Clinical and prognostic implications. Arch Dermatol 1996;132(1):42–7.PubMedCrossRefGoogle Scholar
  55. 54.
    Vowels BR, et al. Aberrant cytokine production by Sezary syndrome patients: cytokine secretion pattern resembles murine Th2 cells. J Invest Dermatol 1992;99(1):90–4.PubMedCrossRefGoogle Scholar
  56. 55.
    Vowels BR, et al. Th2 cytokine mRNA expression in skin in cutaneous T-cell lymphoma. J Invest Dermatol 1994;103(5):669–73.PubMedCrossRefGoogle Scholar
  57. 56.
    Asadullah K, et al. Progression of mycosis fungoides is associated with increasing cutaneous expression of interleukin-10 mRNA. J Invest Dermatol 1996;107(6):833–7.PubMedCrossRefGoogle Scholar
  58. 57.
    Hoppe RT, et al. CD8—positive tumor-infiltrating lymphocytes influence the long-term survival of patients with mycosis fungoides. J Am Acad Dermatol 1995;32(3):448–53.PubMedCrossRefGoogle Scholar
  59. 58.
    Zackheim HS, et al. Psoriasiform mycosis fungoides with fatal outcome after treatment with cyclosporine. J Am Acad Dermatol 2002;47(1):155–7.PubMedCrossRefGoogle Scholar
  60. 59.
    Wysocka M, et al. Sezary syndrome patients demonstrate a defect in dendritic cell populations: effects of CD40 ligand and treatment with GM-CSF on dendritic cell numbers and the production of cytokines. Blood 2002;100(9):3287–94.PubMedCrossRefGoogle Scholar
  61. 60.
    Yamanaka K, et al. Expression of interleukin-18 and caspase-1 in cutaneous T-cell lymphoma. Clin Cancer Res 2006;12(2):376–82.PubMedCrossRefGoogle Scholar
  62. 61.
    Berger CL, et al. Cutaneous T cell lymphoma, malignant proliferation of T-regulatory cells. Blood 2005;105(4):1640–7.PubMedCrossRefGoogle Scholar
  63. 62.
    Walsh PT, et al. A role for regulatory T cells in cutaneous T-Cell lymphoma; induction of a CD4 + CD25 + Foxp3+ T-cell phenotype associated with HTLV-1 infection. J Invest Dermatol 2006;126(3):690–2.PubMedCrossRefGoogle Scholar
  64. 63.
    Wong HK, et al. Increased expression of CTLA-4 in malignant T-cells from patients with mycosis fungoides—cutaneous T cell lymphoma. J Invest Dermatol 2006;126(1):212–9.PubMedCrossRefGoogle Scholar
  65. 64.
    Tiemessen MM, et al. Lack of suppressive CD4+CD25+FOXP3+ T cells in advanced stages of primary cutaneous T-cell lymphoma. J Invest Dermatol 2006;126(10):2217–23.PubMedCrossRefGoogle Scholar
  66. 65.
    Yamano Y, et al. Virus-induced dysfunction of CD4+CD25+ T cells in patients with HTLV-I-asso-ciated neuroimmunological disease. J Clin Invest 2005;115(5):1361–8.PubMedGoogle Scholar
  67. 66.
    French LE, et al. Impaired CD40L signaling is a cause of defective IL-12 and TNF-{alpha} production in Sezary syndrome: circumvention by hexam-eric soluble CD40L. Blood 2005;105(1):219–225.PubMedCrossRefGoogle Scholar
  68. 67.
    Yawalkar N, et al. Profound loss of T-cell receptor repertoire complexity in cutaneous T-cell lymphoma. Blood 2003;102(12):4059–66.PubMedCrossRefGoogle Scholar
  69. 68.
    Yamanaka K, et al. Decreased T-cell receptor excision circles in cutaneous T-cell lymphoma. Clin Cancer Res 2005;11(16):5748–55.PubMedCrossRefGoogle Scholar
  70. 69.
    Yoo EK, et al. Complete molecular remission during biologic response modifier therapy for Sezary syndrome is associated with enhanced helper T type 1 cytokine production and natural killer cell activity. J Am Acad Dermatol 2001;45(2):208–16.PubMedCrossRefGoogle Scholar
  71. 70.
    Wysocka M, et al. Enhancement of the host immune responses in cutaneous T-cell lymphoma by CpG oligodeoxynucleotides and IL-15. Blood 2004;104(13):4142–9.PubMedCrossRefGoogle Scholar
  72. 71.
    Goldgeier MH, et al. An unusual and fatal case of disseminated cutaneous herpes simplex. Infection in a patient with cutaneous T cell lymphoma (mycosis fungoides). J Am Acad Dermatol 1981;4(2):176–80.PubMedGoogle Scholar
  73. 72.
    Lee J, et al. Progressive Multifocal Leukoenceph-alopathy (JC Virus) in a patient with advanced Mycosis Fungoides. J Am Acad Dermatol (submitted) 2007;57(5):893–5.CrossRefGoogle Scholar
  74. 73.
    Evans AV, et al. Cutaneous malignant melanoma in association with mycosis fungoides. J Am Acad Dermatol 2004;50(5):701–5.PubMedCrossRefGoogle Scholar
  75. 74.
    Pielop JA, Brownell I, Duvic M. Mycosis fungoides associated with malignant melanoma and dysplastic nevus syndrome. Int J Dermatol 2003;42(2):116–22.PubMedCrossRefGoogle Scholar
  76. 75.
    Molin L, Thomsen K, Volden G. Serum IgE in mycosis fungoides. Br Med J 1978;1(6117):920–1.PubMedCrossRefGoogle Scholar
  77. 76.
    Tancrede-Bohin E, et al. Prognostic value of blood eosinophilia in primary cutaneous T-cell lympho-mas. Arch Dermatol 2004;140(9):1057–61.PubMedCrossRefGoogle Scholar
  78. 77.
    Suchin KR, et al. Increased interleukin 5 production in eosinophilic Sezary syndrome: regulation by interferon alfa and interleukin 12. J Am Acad Dermatol 2001;44(1):28–32.PubMedCrossRefGoogle Scholar
  79. 78.
    Kim YH, et al. Topical nitrogen mustard in the management of mycosis fungoides: update of the Stanford experience. Arch Dermatol 2003;139(2):165–73.PubMedCrossRefGoogle Scholar
  80. 79.
    Zackheim HS. Topical carmustine (BCNU) for patch/plaque mycosis fungoides. Semin Dermatol 1994;13(3):202–6.PubMedGoogle Scholar
  81. 80.
    Zhang C, Duvic M. Retinoids: therapeutic applications and mechanisms of action in cutaneous T-cell lymphoma. Dermatol Ther 2003;16(4):322–30.PubMedCrossRefGoogle Scholar
  82. 81.
    Herrmann JJ, et al. Treatment of mycosis fungoides with photochemotherapy (PUVA): long-term follow-up. J Am Acad Dermatol 1995;33(2 pt 1):234–42.PubMedCrossRefGoogle Scholar
  83. 82.
    Querfeld C, et al. Long-term follow-up of patients with early-stage cutaneous T-cell lymphoma who achieved complete remission with psoralen plus UV-A monotherapy. Arch Dermatol 2005;141(3): 305–11.PubMedCrossRefGoogle Scholar
  84. 83.
    Jones G, Wilson LD, Fox-Goguen L. Total skin electron beam radiotherapy for patients who have mycosis fungoides. Hematol Oncol Clin North Am 2003;17(6):1421–34.PubMedCrossRefGoogle Scholar
  85. 84.
    McGinnis KS, et al. Psoralen plus long-wave UV-A (PUVA) and bexarotene therapy: An effective and synergistic combined adjunct to therapy for patients with advanced cutaneous T-cell lymphoma. Arch Dermatol 2003;139(6):771–5.PubMedCrossRefGoogle Scholar
  86. 85.
    McGinnis KS, et al. Low-dose oral bexarotene in combination with low-dose interferon alfa in the treatment of cutaneous T-cell lymphoma: clinical synergism and possible immunologic mechanisms. J Am Acad Dermatol 2004;50(3):375–9.PubMedCrossRefGoogle Scholar
  87. 86.
    Singh F, Lebwohl MG. Cutaneous T-cell lymphoma treatment using bexarotene and PUVA: a case series. J Am Acad Dermatol 2004;51(4):570–3.PubMedCrossRefGoogle Scholar
  88. 87.
    Rupoli S, et al. Long-term experience with low-dose interferon-alpha and PUVA in the management of early mycosis fungoides. Eur J Haematol 2005;75(2):136–45.PubMedCrossRefGoogle Scholar
  89. 88.
    Rook AH, Kuzel TM, Olsen EA. Cytokine therapy of cutaneous T-cell lymphoma: interferons, interleukin-12, and interleukin-2. Hematol Oncol Clin North Am 2003;17(6):1435–48, ix.PubMedCrossRefGoogle Scholar
  90. 89.
    Kuzel TM, et al. Effectiveness of interferon alfa-2a combined with phototherapy for mycosis fungoides and the Sezary syndrome. J Clin Oncol 1995;13(1):257–63.PubMedGoogle Scholar
  91. 90.
    Chiarion-Sileni V, et al. Phase II trial of interferon-alpha-2a plus psolaren with ultraviolet light A in patients with cutaneous T-cell lymphoma. Cancer 2002;95(3):569–75.PubMedCrossRefGoogle Scholar
  92. 91.
    Knobler RM, et al. Treatment of cutaneous T cell lymphoma with a combination of low-dose inter-feron alfa-2b and retinoids. J Am Acad Dermatol 1991;24(2 pt 1):247–52.PubMedGoogle Scholar
  93. 92.
    Zhang C, et al. Induction of apoptosis by bexarotene in cutaneous T-cell lymphoma cells: relevance to mechanism of therapeutic action. Clin Cancer Res 2002;8(5):1234–40.PubMedGoogle Scholar
  94. 93.
    Budgin JB, et al. Biological effects of bexarotene in cutaneous T-cell lymphoma. Arch Dermatol 2005;141(3):315–21.PubMedCrossRefGoogle Scholar
  95. 94.
    Duvic M, 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;19(9):2456–71.PubMedGoogle Scholar
  96. 94a.
    Lin J, et al. Clinical and in-vitro resistance to bex-arotene in Adult T-cell leukemia: loss of RXR-alpha receptor. Blood 2008 (in press).Google Scholar
  97. 95.
    Fox FE, et al. Retinoids synergize with interleukin-2 to augment IFN-gamma and interleukin-12 production by human peripheral blood mononuclear cells. J Interferon Cytokine Res 1999;19(4):407–15.PubMedCrossRefGoogle Scholar
  98. 96.
    Richardson SK, et al. High clinical response rate with multimodality immunomodulatory therapy for Sezary syndrome. Clin Lymphoma Myeloma 2006;7(3):226–32.PubMedCrossRefGoogle Scholar
  99. 97.
    Suchin KR, et al. Treatment of cutaneous T-cell lym-phoma with combined immunomodulatory therapy: a 14-year experience at a single institution. Arch Dermatol 2002;138(8):1054–60.PubMedCrossRefGoogle Scholar
  100. 98.
    Yoo EK, et al. Apoptosis induction of ultraviolet light A and photochemotherapy in cutaneous T-cell Lymphoma: relevance to mechanism of therapeutic action. J Invest Dermatol 1996;107(2):235–42.PubMedCrossRefGoogle Scholar
  101. 99.
    Heald PW, Edelson RL. Photopheresis for T cell mediated diseases. Adv Dermatol 1988;3:25–40.PubMedGoogle Scholar
  102. 100.
    Girardi M, et al. Transimmunization for cutaneous T cell lymphoma: a Phase I study. Leuk Lymphoma 2006;47(8):1495–503.PubMedCrossRefGoogle Scholar
  103. 101.
    Kim S, Elkon KB, Ma X. Transcriptional suppression of interleukin-12 gene expression following phagcytosis of apoptotic cells. Immunity 2004;21(5):643–53.PubMedCrossRefGoogle Scholar
  104. 102.
    Kaplan EH, et al. Phase II study of recombinant human interferon gamma for treatment of cutaneous T-cell lymphoma. J Natl Cancer Inst 1990;82(3):208–12.PubMedCrossRefGoogle Scholar
  105. 103.
    McGinnis KS, et al. The addition of interferon gamma to oral bexarotene therapy with photo-pheresis for Sezary syndrome. Arch Dermatol 2005;141(9):1176–8.PubMedCrossRefGoogle Scholar
  106. 104.
    Shapiro M, et al. Novel multimodality biologic response modifier therapy, including bexarotene and long-wave ultraviolet A for a patient with refractory stage IVa cutaneous T-cell lymphoma. J Am Acad Dermatol 2002;47(6):956–61.PubMedCrossRefGoogle Scholar
  107. 105.
    Wysocka M, et al. Synthetic imidazoquinolines potently and broadly activate the cellular immune response of patients with cutaneous T-cell lym-phoma: synergy with interferon-gamma enhances production of interleukin-12. Clin Lymphoma Myeloma 2007;7(8):524–34.PubMedCrossRefGoogle Scholar
  108. 106.
    Dummer R, et al. Adenovirus-mediated intral-esional interferon-gamma gene transfer induces tumor regressions in cutaneous lymphomas. Blood 2004;104(6):1631–8.PubMedCrossRefGoogle Scholar
  109. 107.
    vanderSpek JC, et al. Structure/function analysis of the transmembrane domain of DAB389-interleukin-2, an interleukin-2 receptor-targeted fusion toxin. The amphipathic helical region of the transmembrane domain is essential for the efficient delivery of the catalytic domain to the cytosol of target cells. J Biol Chem 1993;268(16): 12077–82.PubMedGoogle Scholar
  110. 108.
    Olsen E, 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;19(2):376–88.PubMedGoogle Scholar
  111. 109.
    Dannull J, et al. Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells. J Clin Invest 2005;115(12): 3623–33.PubMedCrossRefGoogle Scholar
  112. 110.
    Camacho LH, Ribas A, Glaspy JA, et al. Phase 1 clinical trial of anti-CTLA4 human monoclonal antibody CP-675,206 in patients with advanced solid malignancies. J Clin Oncol 2004;22(14 S):2505.Google Scholar
  113. 111.
    Phan GQ, et al. Cancer regression and autoim-munity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA 2003;100(14):8372–7.PubMedCrossRefGoogle Scholar
  114. 112.
    Wu JJ, Huang DB, Tyring SK. Resiquimod: a new immune response modifier with potential as a vaccine adjuvant for Th1 immune responses. Antiviral Res 2004;64(2):79–83.PubMedGoogle Scholar
  115. 113.
    Dockrell DH, Kinghorn GR. Imiquimod and resiq-uimod as novel immunomodulators. J Antimicrob Chemother 2001;48(6):751–5.PubMedCrossRefGoogle Scholar
  116. 114.
    Suchin KR, Junkins-Hopkins JM, Rook AH. Treatment of stage IA cutaneous T-Cell lym-phoma with topical application of the immune response modifier imiquimod. Arch Dermatol 2002;138(9):1137–9.PubMedCrossRefGoogle Scholar
  117. 115.
    Dummer R, et al. Imiquimod induces complete clearance of a PUVA-resistant plaque in mycosis fungoides. Dermatology 2003;207(1):116–8.PubMedCrossRefGoogle Scholar
  118. 116.
    Hurwitz DJ, Pincus L, Kupper TS. Imiquimod: a topically applied link between innate and acquired immunity. Arch Dermatol 2003;139(10): 1347–50.PubMedCrossRefGoogle Scholar
  119. 117.
    Kawai T, et al. Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat Immunol 2004;5(10):1061–8.PubMedCrossRefGoogle Scholar
  120. 118.
    Schon MP, Schon M. Immune modulation and apoptosis induction: two sides of the antitumoral activity of imiquimod. Apoptosis 2004;9(3): 291–8.PubMedCrossRefGoogle Scholar
  121. 119.
    Jones T. Resiquimod 3 M. Curr Opin Invest Drugs 2003;4(2):214–8.Google Scholar
  122. 120.
    Krieg AM. CpG motifs: the active ingredient in bacterial extracts? Nat Med 2003;9(7):831–5.PubMedCrossRefGoogle Scholar
  123. 121.
    Lonsdorf AS, et al. Intratumor CpG-oligodeoxy-nucleotide injection induces protective antitumor T cell immunity. J Immunol 2003;171(8):3941–6.PubMedGoogle Scholar
  124. 122.
    Kim YH, et al. TLR9 agonist immunomodulator treatment of cutaneous T-cell lymphoma (CTCL) with CPG7909 [abstract]. American Society of Hematology Meeting, 2004.Google Scholar
  125. 123.
    Tritel M, et al. Prime-boost vaccination with HIV-1 Gag protein and cytosine phosphate guanosine oligodeoxynucleotide, followed by adenovirus, induces sustained and robust humoral and cellular immune responses. J Immunol 2003;171(5): 2538–47.PubMedGoogle Scholar
  126. 124.
    Bergstrom RT, et al. CD40 monoclonal antibody activation of antigen-presenting cells improves therapeutic efficacy of tumor-specific T cells. Otolaryngol Head Neck Surg 2004;130(1): 94–103.PubMedCrossRefGoogle Scholar
  127. 125.
    Watanabe S, et al. The duration of signaling through CD40 directs biological ability of dendritic cells to induce antitumor immunity. J Immunol 2003;171(11):5828–36.PubMedGoogle Scholar
  128. 126.
    Rook AH, et al. Interleukin-12 therapy of cutaneous T-cell lymphoma induces lesion regression and cyto-toxic T-cell responses. Blood 1999;94(3):902–8.PubMedGoogle Scholar
  129. 127.
    Duvic M, 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;55(5):807–13.PubMedCrossRefGoogle Scholar
  130. 128.
    Zaki MH, et al. Dysregulation of lymphocyte inter-leukin-12 receptor expression in Sezary syndrome. J Invest Dermatol 2001;117(1):119–27.PubMedCrossRefGoogle Scholar
  131. 129.
    Berger CL, et al. Tumor-specific peptides in cutaneous T-cell lymphoma: association with class I major histocompatibility complex and possible derivation from the clonotypic T-cell receptor. Int J Cancer 1998;76(3):304–11.PubMedCrossRefGoogle Scholar
  132. 130.
    Winter D, et al. Definition of TCR epitopes for CTL-mediated attack of cutaneous T cell lym-phoma. J Immunol 2003;171(5):2714–24.PubMedGoogle Scholar
  133. 131.
    Muche JM, Sterry W. Vaccination therapy for cutaneous T-cell lymphoma. Clin Exp Dermatol 2002;27(7):602–7.PubMedCrossRefGoogle Scholar
  134. 132.
    Maier T, et al. Vaccination of patients with cutaneous T-cell lymphoma using intranodal injection of autologous tumor-lysate-pulsed dendritic cells. Blood 2003;102(7):2338–44.PubMedCrossRefGoogle Scholar
  135. 133.
    Rook AH, et al. The potential therapeutic role of interleukin-12 in cutaneous T-cell lymphoma. Ann N Y Acad Sci 1996;795:310–8.PubMedCrossRefGoogle Scholar
  136. 134.
    Berard M, et al. IL-15 promotes the survival of naive and memory phenotype CD8+ T cells. J Immunol 2003;170(10):5018–26.PubMedGoogle Scholar
  137. 135.
    Son YI, et al. Interleukin-18 (IL-18) synergizes with IL-2 to enhance cytotoxicity, interferon-gamma production, and expansion of natural killer cells. Cancer Res 2001;61(3):884–8.PubMedGoogle Scholar
  138. 136.
    Strengell M, et al. IL-21 in synergy with IL-15 or IL-18 enhances IFN-gamma production in human NK and T cells. J Immunol 2003;170(11):5464–9.PubMedGoogle Scholar
  139. 137.
    Miller G, et al. Endogenous granulocyte-macrophage colony-stimulating factor overexpression in vivo results in the long-term recruitment of a distinct dendritic cell population with enhanced immunostimulatory function. J Immunol 2002;169(6):2875–85.PubMedGoogle Scholar
  140. 138.
    Chang DZ, et al. Granulocyte-macrophage colony stimulating factor: an adjuvant for cancer vaccines. Hematology 2004;9(3):207–15.PubMedCrossRefGoogle Scholar
  141. 139.
    Kim YH, et al. Clinical efficacy of zanolimu-mab (HuMax-CD4): two Phase II studies in refractory cutaneous T-cell lymphoma. Blood 2007;109(11):4655–62.PubMedCrossRefGoogle Scholar
  142. 140.
    Lundin J, et al. CAMPATH-1H monoclonal antibody in therapy for previously treated low-grade non-Hodgkin's lymphomas: a phase II multicenter study. European Study Group of CAMPATH-1H Treatment in Low-Grade Non-Hodgkin's Lymphoma. J Clin Oncol 1998;16(10):3257–63.PubMedGoogle Scholar
  143. 141.
    Lundin J, et al. Phase 2 study of alemtuzumab (anti-CD52 monoclonal antibody) in patients with advanced mycosis fungoides/Sezary syndrome. Blood 2003;101(11):4267–72.PubMedCrossRefGoogle Scholar
  144. 142.
    Ishida T, Ueda R. CCR4 as a novel molecular target for immunotherapy of cancer. Cancer Sci 2006;97(11):1139–46.PubMedCrossRefGoogle Scholar
  145. 143.
    Ishida T, et al. The CC chemokine receptor 4 as a novel specific molecular target for immunotherapy in adult T-Cell leukemia/lymphoma. Clin Cancer Res 2004;10(22):7529–39.PubMedCrossRefGoogle Scholar
  146. 144.
    Hino R, Shimauchi T, Tokura Y. Treatment with IFN-gamma increases serum levels of Th1 chem-okines and decreases those of Th2 chemokines in patients with mycosis fungoides. J Dermatol Sci 2005;38(3):189–95.PubMedCrossRefGoogle Scholar
  147. 145.
    Richardson SK, et al. Bexarotene blunts malignant T-cell chemotaxis in Sezary syndrome: reduction of chemokine receptor 4 (CCR4)-positive lymphocytes and decreased chemotaxis to thymus and activation regulated chemokine (TARC). Am J Hematol 2007;82(9):792–7.PubMedCrossRefGoogle Scholar
  148. 146.
    Richardson S, et al. Low-dose bexarotene and low-dose interferon alfa-2b for adult T-cell leukemia/ lymphoma associated with human T-lymphotropic virus 1. Arch Dermatol 2005;141(3):301–4.PubMedCrossRefGoogle Scholar
  149. 147.
    Mitsiades N, et al. Molecular sequelae of histone deacetylase inhibition in human malignant B cells. Blood 2003;101(10):4055–62.PubMedCrossRefGoogle Scholar
  150. 148.
    Kelly WK, et al. Phase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamic acid administered intravenously. Clin Cancer Res 2003;9(10 Pt 1):3578–88.PubMedGoogle Scholar
  151. 149.
    Piekarz RL, et al. Inhibitor of histone deacetyla-tion, depsipeptide (FR901228), in the treatment of peripheral and cutaneous T-cell lymphoma: a case report. Blood 2001;98(9):2865–8.PubMedCrossRefGoogle Scholar
  152. 150.
    Piekarz RL, et al. T-cell lymphoma as a model for the use of histone deacetylase inhibitors in cancer therapy: impact of depsipeptide on molecular markers, therapeutic targets, and mechanisms of resistance. Blood 2004;103(12):4636–43.PubMedCrossRefGoogle Scholar
  153. 151.
    Piekarz R, Bates S. A review of depsipeptide and other histone deacetylase inhibitors in clinical trials. Curr Pharm Des 2004;10(19):2289–98.PubMedCrossRefGoogle Scholar
  154. 152.
    Duvic M, et al. Phase 2 trial of oral vorinos-tat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood 2007;109(1):31–9.PubMedCrossRefGoogle Scholar
  155. 153.
    Shao RH, et al. Arginine butyrate increases the cytotoxicity of DAB(389)IL-2 in leukemia and lymphoma cells by upregulation of IL-2Rbeta gene. Leuk Res 2002;26(12):1077–83.PubMedCrossRefGoogle Scholar
  156. 154.
    Oyama Y, et al. High-dose therapy and bone marrow transplantation in cutaneous T-cell lym-phoma. Hematol Oncol Clin North Am 2003;17(6): 1475–83, xi.PubMedCrossRefGoogle Scholar
  157. 155.
    Storb R, et al. Allogeneic hematopoietic stem cell transplantation: from the nuclear age into the twenty-first century. Transplant Proc 2000;32(7):2548–9.PubMedCrossRefGoogle Scholar
  158. 156.
    Baron F, Sandmaier BM. Current status of hemat-opoietic stem cell transplantation after nonmy-eloablative conditioning. Curr Opin Hematol 2005;12(6):435–43.PubMedCrossRefGoogle Scholar
  159. 157.
    Bigler RD, et al. Autologous bone marrow transplantation for advanced stage mycosis fungoides. Bone Marrow Transplant 1991;7(2):133–7.PubMedGoogle Scholar
  160. 158.
    Olavarria E, et al. T-cell depletion and autolo-gous stem cell transplantation in the management of tumour stage mycosis fungoides with peripheral blood involvement. Br J Haematol 2001;114(3):624–31.PubMedCrossRefGoogle Scholar
  161. 159.
    Burt RK, et al. Allogeneic hematopoietic stem cell transplantation for advanced mycosis fun-goides: evidence of a graft-versus-tumor effect. Bone Marrow Transplant 2000;25(1):111–3.PubMedCrossRefGoogle Scholar
  162. 160.
    Masood N, et al. Induction of complete remission of advanced stage mycosis fungoides by allogeneic hematopoietic stem cell transplantation. J Am Acad Dermatol 2002;47(1):140–5.PubMedCrossRefGoogle Scholar
  163. 161.
    Soligo D, et al. Treatment of advanced mycosis fungoides by allogeneic stem-cell transplantation with a nonmyeloablative regimen. Bone Marrow Transplant 2003;31(8):663–6.PubMedCrossRefGoogle Scholar
  164. 162.
    Guitart J, et al. Long-term remission after allogeneic hematopoietic stem cell transplantation for refractory cutaneous T-cell lymphoma. Arch Dermatol 2002;138(10):1359–65.PubMedCrossRefGoogle Scholar
  165. 163.
    Molina A, et al. Durable clinical, cytogenetic, and molecular remissions after allogeneic hemat-opoietic cell transplantation for refractory Sezary syndrome and mycosis fungoides. J Clin Oncol 2005;23(25):6163–71.PubMedCrossRefGoogle Scholar
  166. 164.
    Fijnheer R, et al. Complete remission of a radio-chemotherapy-resistant cutaneous T-cell lym-phoma with allogeneic non-myeloablative stem cell transplantation. Bone Marrow Transplant 2003;32(3):345–7.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag London Limited 2008

Authors and Affiliations

  • Ellen J. Kim
    • 1
  • Camille E. Introcaso
    • 2
  • Stephen K. Richardson
    • 2
  • Alain H. Rook
    • 2
  1. 1.Division of Dermatology, Department of Medicine, David Geffen School of MedicineUniversity of California at Los AngelesLos AngelesUSA
  2. 2.Department of DermatologyUniversity of Pennsylvania School of MedicinePhiladelphiaUSA

Personalised recommendations