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Aktuelle Dermatologie 2002; 28(4): 111-117
DOI: 10.1055/s-2002-32050
Übersicht
© Georg Thieme Verlag Stuttgart · New York

Therapie kutaner T-Zell-Lymphome: Standardvorgehen und neue Optionen

Treatment of Cutaneous T-Cell Lymphomas: Standard and New OpinionsE.  Dippel1 , C.  D.  Klemke1 , S.  Goerdt1
  • 1Klinik für Dermatologie, Venerologie and Allergologie, Universitätsklinikum Mannheim, Ruprecht-Karls-Universität Heidelberg, Mannheim
Herrn Prof. Dr. E. G. Jung zum 70. Geburtstag gewidmet.
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Publication Date:
06 June 2002 (online)

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Zusammenfassung

Primäre kutane T-Zell Lymphome (CTCL) sind gekennzeichnet durch einen Tropismus maligner T-Zellen in das Hautorgan und besonders die Epidermis. Die klassischen und häufigsten Formen des CTCL stellen die Mycosis fungoides (MF) und das Sézary-Syndrom (SS). Der Verlauf der Erkrankung ist zu Beginn über viele Jahre indolent, jedoch ist insgesamt eine Progression der Erkrankung mit sukzessivem Befall der Lymphknoten, des Blutes oder der viszeralen Organe zu erwarten. Bei Patienten in den frühen Stadien IA, IB (T1, T2) liegt die 10-Jahres-Überlebensrate zwischen 100 und 67,4 % [1] [2]. Entwickelt sich jedoch eine Transformation des Tumors von einer kleinzelligen in eine großzellige Variante, sinkt die mittlere Lebenserwartung auf 19,4 Monate; sind die Rezirkulationsorgane Lymphknoten (mittlere Lebenserwartung = 4,2 Jahre), Blut oder viszerale Organe (2-Jahres-Überlebensrate = 66 %) befallen, ist die Lebenserwartung deutlich erniedrigt. Häufig führen initial eingeleitete Standardtherapiemaßnahmen zu Remissionen, jedoch kommt es in der Regel zu Rezidiven. Die Therapie bleibt somit palliativ. Im Folgenden wird das Standardvorgehen bei der Behandlung von kutanen T-Zell-Lymphomen dargelegt, das z. B. die Photochemotherapie, Interferone und Retinoide umfasst; darüber hinaus werden neue Therapieoptionen diskutiert.

Abstract

Primary cutaneous T-cell lymphomas (CTCL) are characterized by homing of malignant T-cells into the skin and especially into the epidermis. The classical and most common forms of CTCL are mycosis fungoides (MF) and Sézary syndrome (SS). The course of the disease is usually indolent for several years; progression of the disease, however, occurs slowly in every patient and involves the recirculation compartments, i. e. lymph nodes and peripheral blood, and finally spreads to the visceral organs. Early stage MF patients (stage IA/IB) have a 10-year survival rate of about 100 %/67 % [1]. Patients, however, who undergo transformation to large-cell lymphoma have a poor prognosis (medium time of survival: 19.4 months). Once lymph nodes (medium time of survival: 4.2 years) or blood and visceral organs (2-year survival rate: 66 %) are involved the survival rate also drops consideraly. Although there is an initial response to standard therapy, all patients relapse and therefore treatment for CTCL continues to be palliative. In this review, we present the current therapeutic concepts for treatment of CTCL including photochemotherapy, interferons, and retinoids and discuss novel treatment options.

Literatur

  • 1 Kim Y H, Chow S, Varghese A, Hoppe R T. Clinical characteristics and long-term outcome of patients with generalized patch and/or plaque (T2) mycosis fungoides.  Arch Dermatol. 1999;  135 26-32
    CrossrefPubMedSearch in Google Scholar
  • 2 Kim Y H, Jensen R A, Watanabe G L, Varghese A, Hoppe R T. Clinical stage IA (limited patch and plaque) mycosis fungoides. A long-term outcome analysis.  Arch Dermatol. 1996;  132 1309-1313
    CrossrefPubMedSearch in Google Scholar
  • 3 Dippel E, Assaf C, Hummel M. et al . Clonal T-cell receptor gamma-chain gene rearrangement by PCR-based GeneScan analysis in advanced cutaneous T-cell lymphoma: a critical evaluation.  J Pathol. 1999;  188 146-154
    CrossrefPubMedSearch in Google Scholar
  • 4 Klemke C D, Dippel E, Dembinski A, Poenitz N, Assaf C, Hummel M, Stein H, Orfanos C E, Goerdt S. Clonal T-cell receptor gamma-chain gene rearrangement by PCR-based GeneScan analysis in the skin and the blood of patients with parapsoriasis and early stage mycosis fungoides.  J Pathol. 2002;  in press
    PubMedSearch in Google Scholar
  • 5 Assaf C, Hummel M, Dippel E, Goerdt S, Müller H H, Anagnostopoulos I, Orfanos C E, Stein H. High detection rate of T cell receptor-beta chain rearrangements in T-cell lymphoproliverations by family specific polymerase chain reaction in combination with GeneScan technique and DNA sequencing.  Blood . 2000;  96 640-646
    PubMedSearch in Google Scholar
  • 6 Willemze R, Kerl H, Sterry W. et al . EORTC classification for primary cutaneous lymphomas: a proposal from the cutaneous lymphomas study group of the European organisation for research and treatment of cancer.  Blood. 1997;  90 354-371
    PubMedSearch in Google Scholar
  • 7 Lamberg S I, Green S B, Byar D P. et al . Clinical staging for cutaneous T-cell lymphoma.  Ann Intern Med. 1984;  100 187-192
    PubMedSearch in Google Scholar
  • 8 Dippel E, Goerdt S, Assaf C, Stein H, Orfanos C E. Cutaneous T-cell lymphoma severity index and T-cell gene rearrangement.  Lancet. 1997;  350 1776-1777
    PubMedSearch in Google Scholar
  • 9 Dippel E, Schrag H, Goerdt S, Orfanos C E. Extracorporeal photopheresis and interferon-alpha in advanced cutaneous T-cell lymphoma.  Lancet. 1997;  350 32-33
    CrossrefPubMedSearch in Google Scholar
  • 10 Dummer R, Willers J, Dobbeling U, Burg G. Current pathogenetic aspects of SÅzary syndrome and mycosis fungoides.  Hautarzt. 2001;  52 189-192
    CrossrefPubMedSearch in Google Scholar
  • 11 Rook A H, Heald P. The immunopathogenesis of cutaneous T-cell lymphoma.  Hematol Oncol Clin North Am. 1995;  9 997-1010
    PubMedSearch in Google Scholar
  • 12 Heald P, Edelson R. Immunology of cutaneous T-cell lymphoma.  J Natl Cancer Inst. 1991;  83 400-404
    PubMedSearch in Google Scholar
  • 13 Dummer R, Michie S A, Kell D. et al . Expression of bcl-2 protein and Ki-67 nuclear proliferation antigen in benign and malignant cutaneous T-cell infiltrates.  J Cutan Pathol. 1995;  22 11-17
    PubMedSearch in Google Scholar
  • 14 Sala A, Casella I, Grasso L. et al . Apoptotic response to oncogenic stimuli: cooperative and antagonistic interactions between c-myb and the growth suppressor p53.  Cancer Res. 1996;  56 1991-1996
    PubMedSearch in Google Scholar
  • 15 Brugnoni D, Airo P, Tosoni C. et al . CD3-CD4+ cells with a Th2-like pattern of cytokine production in the peripheral blood of a patient with cutaneous T cell lymphoma.  Leukemia. 1997;  11 1983-1985
    CrossrefPubMedSearch in Google Scholar
  • 16 Buhl L, Sogaard H. Immunohistochemical expression of IL-10 in mycosis fungoides.  Exp Dermatol. 1997;  6 195-198
    PubMedSearch in Google Scholar
  • 17 Dummer R, Heald P W, Nestle F O. et al . SÅzary syndrome T-cell clones display T-helper 2 cytokines and express the accessory factor-1 (interferon-gamma receptor beta-chain).  Blood. 1996;  88 1383-1389
    PubMedSearch in Google Scholar
  • 18 Siegel R S, Pandolfino T, Guitart J, Rosen S, Kuzel T M. Primary cutaneous T-cell lymphoma: review and current concepts.  J Clin Oncol. 2000;  18 2908-2925
    PubMedSearch in Google Scholar
  • 19 Nisce L Z, Safai B, Kim J H. Effectiveness of once-weekly total skin electron irradiation in the treatment of mycosis fungoides.  Cancer. 1981;  47 870-876
    PubMedSearch in Google Scholar
  • 20 Wilson L D, Quiros P A, Kolenik S A. 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;  35 69-73
    CrossrefPubMedSearch in Google Scholar
  • 21 Bisaccia E, Gonzalez J, Palangio M, Schwartz J, Klainer A S. Extracorporeal photochemotherapy alone or with adjuvant therapy in the treatment of cutaneous T-cell lymphoma: a 9-year retrospective study at a single institution.  J Am Acad Dermatol. 2000;  43 263-271
    CrossrefPubMedSearch in Google Scholar
  • 22 Bryson H M, Sorkin E M. Cladribine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in haematological malignancies.  Drugs. 1993;  46 872-894
    PubMedSearch in Google Scholar
  • 23 Brogden R N, Sorkin E M. Pentostatin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in lymphoproliferative disorders.  Drugs. 1993;  46 652-677
    PubMedSearch in Google Scholar
  • 24 Case D C. Combination chemotherapy for mycosis fungoides with cyclophosphamide, vincristine, methotrexate, and prednisolone.  Am J Clin Oncol. 1984;  4 453-461
    PubMedSearch in Google Scholar
  • 25 Detmar M, Kreuser E D, Gollnick H. et al . Primary cutaneous Ki-1/CD30-positive anaplastic large cell lymphoma: complete remission after COP-BLAM regimen with GM-CSF.  Eur J Dermatol. 1992;  35-38
    PubMedSearch in Google Scholar
  • 26 Orfanos C E, Garbe C. Pseudolymphome, Praelymphome und Lymphome der Haut. In: Therapie der Hautkrankheiten. Orfanos CE (ed.)  Springer-Verlag Berlin, Heidelberg,. 1995;  987-1020
    PubMedSearch in Google Scholar
  • 27 Wilson L D, Licata A L, Braverman I M. 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;  32 987-995
    CrossrefPubMedSearch in Google Scholar
  • 28 Winkelmann R K, Diaz-Perez J L, Buechner S A. The treatment of Sézary syndrome.  J Am Acad Dermatol. 1984;  10 1000-1008
    PubMedSearch in Google Scholar
  • 29 Briffa D V, Warin A P, Harrington C I, Bleehen S S. Photochemotherapy in mycosis fungoides.  Lancet. 1980;  2 49-53
    PubMedSearch in Google Scholar
  • 30 Dippel E, Orfanos C E. Indikationen und therapeutischer Nutzen der extrakorporalen Photopherese.  Z Hautkr. 1996;  71 723-725
    PubMedSearch in Google Scholar
  • 31 Kerscher M, Lehmann P, Plewig G. PUVA bath therapy. Indications and practical implementation.  Hautarzt. 1994;  45 526-528
    CrossrefPubMedSearch in Google Scholar
  • 32 Plettenberg H, Stege H, Megahed M. et al . Ultraviolet A1 (340 - 400 nm) phototherapy for cutaneous T-cell lymphoma.  J Am Acad Dermatol. 1999;  41 47-50
    PubMedSearch in Google Scholar
  • 33 Edelson R, Berger C, Gasparro F. et al . Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy. Preliminary results.  N Engl J Med. 1987;  316 297-303
    CrossrefPubMedSearch in Google Scholar
  • 34 Owsianowski M, Garbe C, Ramaker J, Orfanos C E, Gollnick H. Therapeutic experiences with extracorporeal photopheresis. Technical procedure, follow-up and clinical outcome in 31 skin diseases.  Hautarzt. 1996;  47 114-123
    CrossrefPubMedSearch in Google Scholar
  • 35 Asadullah K, Docke W D, Haeussler A, Sterry W, Volk H D. Progression of mycosis fungoides is associated with increasing cutaneous expression of interleukin-10 mRNA.  J Invest Dermatol. 1996;  107 833-837
    CrossrefPubMedSearch in Google Scholar
  • 36 Asadullah K, Friedrich M, Haeubetaler A, Sterry W, Docke W D, Volk H D. Granzyme A mRNA expression in mycosis fungoides progression.  Blood. 1997;  90 3810-3811
    PubMedSearch in Google Scholar
  • 37 Asadullah K, Friedrich M, Docke W D, Jahn S, Volk H D, Sterry W. Enhanced expression of T-cell activation and natural killer cell antigens indicates systemic anti-tumor response in early primary cutaneous T-cell lymphoma.  J Invest Dermatol. 1997;  108 743-747
    CrossrefPubMedSearch in Google Scholar
  • 38 Bunn P AJ, Norris D A. The therapeutic role of interferons and monoclonal antibodies in cutaneous T-cell lymphomas.  J Invest Dermatol. 1990;  95 209S-212S
    CrossrefPubMedSearch in Google Scholar
  • 39 Bunn P A, Foon K A, Ihde D C. et al . Recombinant leukocyte A interferon: an active agent in advanced cutaneous T-cell lymphoma.  Ann Intern Med. 1984;  101 484-487
    PubMedSearch in Google Scholar
  • 40 Stadler R, Ruszczak Z. Interferons. New additions and indications for use.  Dermatol Clin. 1993;  11 187-199
    PubMedSearch in Google Scholar
  • 41 Stadler R. Interferons in dermatology.  Present-day standard.  Dermatol Clin. 1998;  16 377-398
    PubMedSearch in Google Scholar
  • 42 Stadler R. , Mayer da-Silva A, Bratzke B, Garbe C, Orfanos CE. Interferons in Dermatology.  J Am Acad Dermatol. 1989;  20 650-656
    PubMedSearch in Google Scholar
  • 43 Stadler R, Otte H G. Combination therapy of cutaneous T cell lymphoma with interferon alpha- 2a and photochemotherapy.  Recent Results Cancer Res. 1995;  139 391-401
    PubMedSearch in Google Scholar
  • 44 Dippel E, Zouboulis C C, Tebbe B, Orfanos C E. Myopathic syndrome associated with long-term recombinant interferon-alpha treatment in 4 patients with skin disorders.  Arch Dermatol. 1998;  134 880-881
    CrossrefPubMedSearch in Google Scholar
  • 45 Kuzel T M, Gilyon K, Springer E. et al . Interferon alfa-2a combined with phototherapy in the treatment of cutaneous T-cell lymphoma.  J Natl Cancer Inst. 1990;  82 203-207
    PubMedSearch in Google Scholar
  • 46 Otte H G, Herges A, Stadler R. Combination therapy with interferon alfa 2a and PUVA in cutaneous T-cell lymphoma.  Hautarzt. 1992;  43 695-699
    PubMedSearch in Google Scholar
  • 47 Roenigk H H, Kuzel T, Rosen S. Interferons for cutaneous T-cell lymphoma monotherapy or combination with PUVA.  Australas J Dermatol. 1993;  34 13-15
    PubMedSearch in Google Scholar
  • 48 Orfanos C E, Zouboulis C C, Almond-Roesler B, Geilen C C. Current use and future potential role of retinoids in dermatology.  Drugs. 1997;  53 358-388
    PubMedSearch in Google Scholar
  • 49 Thomson K, Hammar S P, Molin L, Volden G. Retinoids plus PUVA (RePUVA) and PUVA in mycosis fungoides, plaque stage.  Acta Derm Venereol. 1989;  69 536-540
    PubMedSearch in Google Scholar
  • 50 Rook A H, Prystowsky M B, Cassin M, Boufal M, Lessin S R. Combined therapy for SÅzary syndrome with extracorporeal photochemotherapy and low-dose interferon alfa therapy. Clinical, molecular, and immunologic observations.  Arch Dermatol. 1991;  127 1535-1540
    CrossrefPubMedSearch in Google Scholar
  • 51 DiRenzo A, Rubegni P, De Aloe G. et al . Extracorporeal photochemotherapy restores Th1/Th2 imbalance in patients with early stage cutaneous T-cell lymphoma.  Immunology. 1997;  92 99-103
    CrossrefPubMedSearch in Google Scholar
  • 52 Stadler R, Otte H G, Luger T, Henz B M, Kuhl P, Zwingers T, Sterry W. Prospective randomized multicenter clinical trial on the use of interferon-2a plus acitretin versus interferon-2a plus PUVA in patients with cutaneous T-cell lymphoma stages I and II.  Blood. 1998;  92 3578-3581
    PubMedSearch in Google Scholar
  • 53 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;  19 2456-2471
    PubMedSearch in Google Scholar
  • 54 Duvic M, Cather J, Maize J, Frankel A E. DAB389IL2 diphtheria fusion toxin produces clinical responses in tumor stage cutaneous T-cell lymphoma.  Am J Hematol. 1998;  58 87-90
    CrossrefPubMedSearch in Google Scholar
  • 55 Lundin J, Osterborg A, Brittinger G. 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 3257-3263
    PubMedSearch in Google Scholar
  • 56 Bigler R D, Crilley P, Micaily B. et al . Autologous bone marrow transplantation for advanced stage mycosis fungoides.  Bone Marrow Transplant. 1991;  7 133-137
    PubMedSearch in Google Scholar
  • 57 Olavarria E, Child F J, Woolford A. et al . T-cell depletion and autologous stem cell transplantation in the management of tumor stage mycosis fungoides with peripheral blood involvement.  Br J Haematol. 2001;  114 624-631
    CrossrefPubMedSearch in Google Scholar

PD Dr. E.  Dippel

Klinik für Dermatologie, Venerologie und Allergologie · Universitätsklinikum Mannheim

Theodor-Kutzer-Ufer 1-3 · 68135 Mannheim

Email: edgar.dippel@haut.ma.uni-heidelberg.de