Neue Therapiestrategien bei kutanen T-Zell-Lymphomen[1]

Zusammenfassung

Kutane T-Zell-Lymphome sind eine Gruppe extranodaler Non-Hodgkin-Lymphome mit großer klinischer und histopathologischer Heterogenität, die sich am Hautorgan manifestieren. Sie zeigen eine große Bandbreite klinischer und histologischer Erscheinungsformen. Aktuelle Ergebnisse aus der Grundlagenforschung bestätigten die Heterogenität und erlaubten tiefere Einblicke in die Tumorbiologie, die Tumorimmunologie und die molekulare Genetik der Lymphome. Dabei ergab sich eine Fülle von neuen Zielstrukturen auf den malignen Lymphomzellen, die es nun ermöglichen, neue Therapiestrategien zu entwickeln. Je genauer die Zuordnung zu den einzelnen Lymphomentitäten und die Erhebung diagnostischer Informationen zu individuellen Patienten mit kutanen T-Zell-Lymphomen gelingt, umso zielgerichteter kann die Therapie erfolgen. Eine kurative Therapie ist jedoch noch nicht in Sicht, daher bleibt die bisherige allgemeine Behandlungsstrategie der kutanen T-Zell-Lymphome mit einer stadiengerechten Ausrichtung weiterhin erhalten.

Abstract

Cutaneous T-cell lymphomas are a group of extranodal non-Hodgkin lymphomas which show a broad heterogenity regarding clinical and histological manifestations in the skin. Current research has confirmed the heterogentity of cutaneous T-cell lymphomas and has given insight into their biology, immunology and molecular genetics. The knowledge of target structures of malignant T-cells has opend new pathways in developing new therapeutic strategies. The accurate classification of specific clinical entities and specific information regarding individual patients is necessary in order to choose a targeted therapy. However, since a curative treatment is currently not available, the commonly used stage-adapted therapy still remains the recommended approach.

1 Dieses Manuskript ist dem 10-jährigen Jubiläum der Berliner Stiftung für Dermatologie gewidmet.

Literatur

• 1 Willemze R, Jaffe E S, Burg G. et al . WHO-EORTC classification for cutaneous lymphomas.  Blood. 2005;  105 3768-3785
• 2 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;  110 1713-1722
• 3 Kim Y H, Willemze R, Pimpinelli N. et al . TNM classification system for primary cutaneous lymphomas other than 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;  110 479-484
• 4 Klemke C D, Goerdt S, Schrama D, Becker J C. New insights into the molecular biology and targeted therapy of cutaneous T-cell lymphomas.  JDDG. 2006;  5 395-406
• 5 Kondapalli L, Soltani K, Lacouture M E. The promise of molecular targeted therapies: protein kinase inhibitors in the treatment of cutaneous malignancies.  J Am Acad Dermatol. 2005;  53 291-302
• 6 van Doorn R, Zoutman W H, Dijkman 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 3886-3896
• 7 Booken N, Gratchev A, Utikal J. et al . Sézary syndrome is a unique cutaneous T-cell lymphoma as identified by an expanded gene signature including diagnostic marker molecules CDO1 and DNM3.  Leukemia. 2008;  22 393-399
• 8 Duvic M, Martin A G, Kim Y. et al . Phase 2 and 3 clinical trial of oral bexarotene (Targretin capsules) for the treatment of refractory or persistent early-stage cutaneous T-cell lymphoma.  Arch Dermatol. 2001;  137 581-593
• 9 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
• 10 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;  19 376-388
• 11 Foss F M, Waldmann T A. Interleukin-2 receptor-directed therapies for cutaneous lymphomas.  Hematol Oncol Clin North Am. 2003;  17 1449-1458
• 12 Foss F, Demierre M F, DiVenuti G. A phase-1 trial of bexarotene and denileukin diftitox in patients with relapsed or refractory cutaneous T-cell lymphoma.  Blood. 2005;  106 454-457
• 13 Hagberg H, Pettersson M, Bjerner T, Enblad G. Treatment of a patient with a nodal peripheral T-cell lymphoma (angioimmunoblastic T-Cell lymphoma) with a human monoclonal antibody against the CD4 antigen (Hu-Max-CD4).  Med Oncol. 2005;  22 191-194
• 14 Piekarz R L, 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;  98 2865-2868
• 15 Sandor V, Bakke S, Robey R W. et al . Phase I trial of the histone deacetylase inhibitor, depsipeptide (FR901228, NSC 630176), in patients with refractory neoplasms.  Clin Cancer Res. 2002;  8 718-728
• 16 Groll M, Berkers C R, Ploegh H D, Ovaa H. Crystal structure of the boronic acid-based proteosome inhibitor Bortezomib in complex with yeast 20S proteosome.  Structure. 2006;  14 451-456
• 17 O'Connor O A. Targeting histones and proteosomes: New strategies for treatment of lymphoma.  J Clin Oncol. 2005;  23 6429-6436
• 18 Zinzani P L, 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;  25 4293-4297
• 19 Lindemann R K, Gabrielli B, Johnstone R W. Histonedeacetylase inhibitors for the treatment of cancer.  Cell Cycle. 2004;  3 779-788
• 20 Johnstone R W. Histone-deacetylase inhibitors: novel drugs for the treatment of cancer.  Nat Rev Drug Discov. 2002;  1 287-299
• 21 Zhang C, Richon V, Ni X. et al . Selective induction of apoptosis by histone deacetylase inhibitor SAHA in cutaneous T-cell lymphoma cells: Relevance to mechanism therapeutic action.  J Invest Dermatol. 2005;  125 1045-1052
• 22 Olsen E, Kim Y H, Kuzel T M. et al . Phase IIB multicenter trial of vorinostat in patients with persistent, progressive or treatment-refractory cutaneous T-cell lymphoma.  J Clin Oncol. 2007;  25 3109-3115
• 23 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;  109 31-39
• 24 Almenara J, Rosato R, Grant S. Synergistic induction of mitochondrial damage and apoptosis in human leukemia cells by flavopiridol and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA).  Leukemia. 2002;  16 1331-1343
• 25 Machion D C, Bicaku E, Daud A I. et al . Sequence-specific potentiation of topoisomerase II inhibitors by the histone deacetylase inhibitor suberoylanilide hydroxamic acid.  J Cell Biochem. 2004;  92 223-237
• 26 Lakshmikanthan V, Kaddour-Djebbar I, Lewis R W, Kumar M V. SAHA-sensitized prostate cancer cells to TNF-alpha-related apoptosis-inducing ligand (TRAIL): Mechanisms leading to synergistic apoptosis.  Int J Cancer. 2006;  119 221-228
• 27 Piekarz R L, Robey R, Sandor V. Inhibitor of histone deacetylation, depsipeptide (FR901228), in the treatment of peripheral and cutaneous T-cell lymphoma: A case report.  Blood. 2001;  98 (9) 2865-2868
• 28 Knox S J, Levy R, Hodgkinson S. et al . Observations on the effect of chimeric anti-CD4 monoclonal antibody in patients with mycosis fungoides.  Blood. 1991;  77 20-30
• 29 Kim Y H, Duvic M, Obitz E. et al . Clinical efficacy of Zanolimumab (HuMax-CD4): two phase 2 studies in refractory cutaneous T-cell lymphoma.  Blood. 2007;  109 4655-4662
• 30 Dearden C E, Matutes E, Cazin B. et al . High remission rate in T-cell prolymphocytic leukemia with CAMPATH-1H.  Blood. 2001;  98 1721-1726
• 31 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;  101 4267-4272
• 32 Dippel E, Gellrich S, Klemke C D. et al . Kutane T-Zell Lymphome.  JDDG. 2003;  1 965-981
• 33 Assaf C, Hummel M, Steinhoff M. et al . Early TCR-beta and TCR-gamma PCR detection of T-cell clonality indicates minimal tumor disease in lymph nodes of cutaneous T-cell lymphoma: Diagnostic and prognostic implications.  Blood. 2005;  105 503-510
• 34 Dippel E, Klemke C D, Goerdt S. Current status of cutaneous T-cell lymphoma: Molecular diagnosis, pathogenesis, therapy and future directions.  Onkologie. 2003;  26 477-483

1 Dieses Manuskript ist dem 10-jährigen Jubiläum der Berliner Stiftung für Dermatologie gewidmet.