RSS-Feed abonnieren
DOI: 10.1055/s-2005-922073
© Georg Thieme Verlag Stuttgart · New York
Innovative Antikörper-Therapien bei malignen Lymphomen
Novel antibody-therapies for malignant lymphomasPublikationsverlauf
eingereicht: 18.4.2005
akzeptiert: 5.10.2005
Publikationsdatum:
24. November 2005 (online)
![](https://www.thieme-connect.de/media/dmw/200548/lookinside/thumbnails/10.1055-s-2005-922073-1.jpg)
Zusammenfassung
Non-Hodgkin-Lymphome (NHL) sind eine in ihrer Inzidenz stetig zunehmende Gruppe maligner lymphatischer Neoplasien, an denen insbesondere Ältere erkranken. Aufgrund dieser Altersverteilung ist es unerlässlich, neue und gut verträgliche Behandlungsoptionen - neben „konventionellen“ Therapien, wie der Standardchemo- oder Hochdosischemotherapie mit Stammzelltransplantation - zu prüfen. Als eine dieser neuen, zielgerichteten Therapien haben sich monoklonale Antikörper, wie der anti-CD20-Antikörper Rituximab, etabliert. Andere, wie der anti-CD52-Antikörper Alemtuzumab, stehen für die Behandlung der chronisch lymphatischen Leukämie (CLL) sowie von T-Zell-Lymphomen zur Verfügung und werden in klinischen Studien geprüft. Als Weiterentwicklung zielgerichteter Therapeutika werden kombinierte Radioimmuntherapien für den klinischen Einsatz verwendet. Erste Erfahrungen bei fortgeschrittenen, indolenten Lymphomen sind vielversprechend. Der Einsatz bei aggressiven Lymphomen und in der Primärtherapie wird weiter in Studien geprüft. Dieser Beitrag soll einen Überblick über den klinischen Einsatz und die bisherigen Studienergebnisse innovativer Immuntherapien geben, wobei insbesondere auf die Indikationsgebiete und praktische Anwendung im klinischen Alltag eingegangen wird.
Summary
Non-HodgkinŽs lymphoma (NHL) includes a group of malignant lymphoproliferative disorders, that particularly occur in the elderly and have an continuously increasing incidence. Because of the age distribution new treatment options with low toxicity and minor side effects - apart from „conventional“ therapies like standard or high dose chemotherapy - are needed. Within these novel therapeutic modalities the use of the monoclonal antibody rituximab has been widely established. Other monoclonal antibodies, such as the anti-CD52-antibody alemtuzumab, are available for the treatment of chronic lymphatic leukemia (CLL) and T-cell-lymphomas and are being tested in clinical trials. Furthermore the option of combining targeted therapies, in which antibodies are used with radiotherapy, has led to the development of radio-immunotherapies that are now becoming available for clinical use. Current results in the treatment of advanced indolent lymphomas are promising, and their use in high-grade lymphoma and as first-line therapy is under investigation. This article summarizes the application of these novel immunotherapies and reviews the results of recent clinical trials, with particular emphasis on indications and practical aspects in everyday clinical life.
Literatur
- 1 Avivi I, Robinson S, Goldstone A. Clinical use of rituximab in haematological malignancies. Br J Cancer. 2003; 89 1389-1394
- 2 Berger D, Engelhardt R, Mertelsmann R. Das Rote Buch. Kapitel 2.5 (2. Auflage): Potthoff K, Lindemann A: Monoklonale Antikörper und Signaltransduktionshemmer 2002: 155
- 3 Borghaei H, Schilder R J. Safety and efficacy of radioimmunotherapy with yttrium 90 ibritumomab tiuxetan (Zevalin). Semin Nucl Med. 2004; 34 (Suppl 1) 4-9
- 4 Byrd J C, Stilgenbauer S, Flinn I W. Chronic lymphocytic leukemia. Hematology (Am Soc Hematol Educ Program). 2004; 163-183
- 5 Coiffier B, Lepage E, Briere J. et al . CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002; 346 235-242
- 6 Connors J M. Radioimmunotherapy - Hot new treatment for lymphoma. N Engl J Med. 2005; 352 496-498
- 7 Czuczman M S, Weaver R, Alkuzweny B, Berlfein J, Grillo-Lopez A J. Prolonged clinical and molecular remission in patients with low-grade or follicular non-Hodgkin’s lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow-up. J Clin Oncol. 2004; 22 4711-4716
- 8 Davies A J, Rohatiner A Z, Howell S. et al . Tositumomab and iodine I 131 tositumomab for recurrent indolent and transformed B-cell non-Hodgkin’s lymphoma. J Clin Oncol. 2004; 22 1469-1479
- 9 Davis T A, Kaminski M S, Leonard J P. et al . The radioisotope contributes significantly to the activity of radioimmunotherapy. Clin Cancer Res. 2004; 10 7792-7798
- 10 Emmanouilides C. Radioimmunotherapy for non-Hodgkin’s lymphoma. Sem Oncol. 2003; 30 531-544
- 11 Enblad G, Hagberg H, Erlanson M. et al . A pilot study of alemtuzumab (anti-CD52 monoclonal antibody) therapy for patients with relapsed or chemotherapy-refractory peripheral T-cell lymphomas. Blood. 2004; 103 2920-2924
- 12 Engelhardt M, Berger D, Mertelsmann R. Das Blaue Buch. www.cancer.de. GCP-m@nual 5.1. 2005
- 13 Faderl S, Thomas D A, O’Brien S. et al . Experience with alemtuzumab plus rituximab in patients with relapsed and refractory lymphoid malignancies. Blood. 2003; 101 3413-3415
- 14 Ferrajoli A, O’Brien S M, Cortes J E. et al . Phase II study of alemtuzumab in chronic lymphoproliferative disorders. Cancer. 2003; 98 773-778
- 15 Fischer M, Behr T, Grunwald F, Knapp W H, Trumper L, von Schilling C.. German Society for Hematology and Oncology . Guideline for radioimmunotherapy of rituximab relapsed or refractory CD20(+) follicular B-cell non-Hodgkin’s lymphoma. Nuklearmedizin. 2004; 43 171-176
- 16 Forstpointner R, Dreyling M, Repp R. et al. German Low-Grade Lymphoma Study Group . The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2004; 104 3064-3071
- 17 Ghobrial I, Witzig T. Radioimmunotherapy: a new treatment modality for B-cell non-Hodgkin’s lymphoma. Oncology (Huntingt). 2004; 18 623-630
- 18 Glass B, Kloess M, Engert A. et al . Dose escalated CHOP + etoposide and repetitive autologous stem cell transplantation (MegaCHOEP) with and without rituximab for primary treatment of aggressive NHL (abstr.). J Clin Oncol. 2005; 23 6654
- 19 Golay J, Manganini M, Rambaldi A, Introna M. Effect of alemtuzumab on neoplastic B cells. Haematologica. 2004; 89 1476-1483
- 20 Gopal A K, Rajendran J G, Petersdorf S H. et al . High-dose chemo-radioimmunotherapy with autologous stem cell support for relapsed mantle cell lymphoma. Blood. 2002; 99 3158-3162
- 21 Gordon L I, Molina A, Witzig T. et al . Durable responses after ibritumomab tiuxetan radioimmunotherapy for CD20+ B-cell lymphoma: long-term follow-up of a phase 1/2 study. Blood. 2004; 103 4429-4431
- 22 Hernandez M C, Knox S J. Radiobiology of radioimmunotherapy: targeting CD20 B-cell antigen in non-Hodgkin’s lymphoma. Int J Radiat Oncol Biol Phys. 2004; 59 1274-1287
- 23 Horning S J, Younes A, Jain V. et al . Efficacy and safety of tositumomab and iodine-131 tositumomab (Bexxar) in B-cell lymphoma, progressive after rituximab. J Clin Oncol. 2005; 23 712-719
- 24 Kaminski M S, Tuck M, Estes J. et al . 131I-tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med. 2005; 352 441-449
- 25 Kaminski M S, Zelenetz A D, Press O W. et al . Pivotal study of iodine I 131 tositumomab for chemotherapy-refractory low-grade or transformed low-grade B-cell non-Hodgkin’s lymphomas. J Clin Oncol. 2001; 19 3918-3928
- 26 Keating M J, Cazin B, Coutre S. et al . Campath-1H treatment of T-cell prolymphocytic leukemia in patients for whom at least one prior chemotherapy regimen has failed. J Clin Oncol. 2002; 20 205-213
- 27 Keating M J, Flinn I, Jain V. et al . Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabin: results of a large international study. Blood. 2002; 99 3554-3561
- 28 Lenz G, Dreyling M, Hoster E. et al . Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol. 2005; 23 1984-1992
- 29 Lohri A, Herrmann R. Zevalin Radioimmunotherapie (RIT) als neue Therapieoption beim follikulären B-Zell-Lymphom. Schweiz Med Forum. 2004; 4 1145-1148
- 30 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
- 31 Lundin J, Kimby E, Bjorkholm M. et al . Phase II trial of subcutaneous anti-CD52 monoclonal antibody alemtuzumab (Campath-1H) as first-line treatment for patients with B-cell chronic lymphocytic leukemia (B-CLL). Blood. 2002; 100 768-773
- 32 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
- 33 Moreton P, Hillmen P. Alemtuzmab therapy in B-cell lymphopoliferative disorders. Seminars in Oncology. 2003; 30 493-501
- 34 Morris E, Thomson K, Craddock C. et al . Outcomes after alemtuzumab-containing reduced-intensity allogeneic transplantation regimen for relapsed and refractory non-Hodgkin lymphoma. Blood. 2004; 104 3865-3871
- 35 Müller A MS, Ihorst G, Mertelsmann R, Engelhardt M. Epidemiology of non-Hodgkin’s lymphoma (NHL): trends, geographic distribution, and etiology. Ann Hematol. 2005; 84 1-12
- 36 Osterborg A, Dyer M J, Bunjes D. et al . Phase II multicenter study of human CD52 antibody in previously treated chronic lymphocytic leukemia. European Study Group of CAMPATH-1H Treatment in Chronic Lymphocytic Leukemia. J Clin Oncol. 1997; 15 1567-1574
- 37 Pfreundschuh M, Truemper L, Gill D. et al . First Analysis of the Completed Mabthera International (Mint) Trial in Young Patients with Low-Risk Diffuse Large B-Cell Lymphoma (DLBCL): Addition of Rituximab to a CHOP-Like Regimen Significantly Improves Outcome of All Patients with the Identification of a Very Favorable Subgroup with IPI = O and No Bulky Disease (abstr.). Blood. 2004; 104 157
- 38 Press O W, Eary J F, Gooley T. et al . A phase I/II trial of iodine-131-tositumomab (anti-CD20), etoposide, cyclophosphamide, and autologous stem cell transplantation for relapsed B-cell lymphomas. Blood. 2000; 96 2934-2942
- 39 Press O W, Unger J M, Braziel R M. et al . A phase 2 trial of CHOP chemotherapy followed by tositumomab/iodine I 131 tositumomab for previously untreated follicular non-Hodgkin lymphoma: Southwest Oncology Group Protocol S9911. Blood. 2003; 102 1606-1612
- 40 Rai K R, Freter C E, Mercier R J. et al . Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine. J Clin Oncol. 2002; 20 3891-3897
- 41 Stilgenbauer S, Dohner H. Campath-1H-induced complete remission of chronic lymphocytic leukemia despite p53 gene mutation and resistance to chemotherapy. New Engl J Med. 2002; 347 452-453
- 42 Vose J M, Bierman P J, Enke C. et al . Phase I trial of iodine-131 tositumomab with high-dose chemotherapy and autologous stem-cell transplantation for relapsed non-Hodgkin’s lymphoma. J Clin Oncol. 2005; 23 461-467
- 43 Wendtner C M, Ritgen M, Schweighofer C D. et al . Consolidation with alemtuzumab in patients with chronic lymphocytic leukemia (CLL) in first remission-experience on safety and efficacy within a randomized multicenter phase III trial of the German CLL Study Group (GCLLSG). Leukemia. 2004; 18 1093-1101
- 44 Wilson W H, Dunleavy K, Pittaluga S. et al . Dose-Adjusted EPOCH-Rituximab Is Highly Effective in the GCB and ABC Subtypes of Untreated Diffuse Large B-Cell Lymphoma (abstr.). Blood. 2004; 104 159
- 45 Wiseman G A, Gordon L I, Multani P S. et al . Ibritumomab tiuxetan radioimmunotherapy for patients with relapsed or refractory non-Hodgkin lymphoma and mild thrombocytopenia: a phase II multicenter trial. Blood. 2002; 99 4336-4342
- 46 Wiseman G A, Kornmehl E, Leigh B. et al . Radiation dosimetry results and safety correlations from 90Y-ibritumomab tiuxetan radioimmunotherapy for relapsed or refractory non-Hodgkin’s lymphoma: combined data from 4 clinical trials. J Nucl Med. 2003; 44 465-474
- 47 Witzig T E. Efficacy and safety of 90Y ibritumomab tiuxetan (Zevalin) radioimmunotherapy for non-Hodgkin’s lymphoma. Semin Oncol. 2003; 6 (Suppl 17) 11-16
- 48 Witzig T E, Flinn I W, Gordon L I. et al . Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin’s lymphoma. J Clin Oncol. 2002; 20 3262-3269
- 49 Witzig T E, Gordon L I, Cabanillas F. et al . Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma. J Clin Oncol. 2002; 20 2453-2463
- 50 Witzig T E, White C A, Wiseman G A, Gordon L I, Emmanouilides C, Raubitschek A. Phase I/II trial of IDEC-Y2B8 Radioimmunotherapy for treatment of relapsed or refractory CD20+ B-cell Non-Hodgkin’s lymphoma. J Clin Oncol. 1999; 17 3793-3803
Prof. Dr. Monika Engelhardt
Medizinische Universitätsklinik, Hämatologie/Onkologie
Hugstetterstraße 55
79106 Freiburg
Telefon: 0761/2703401
Fax: 0761/2703318
eMail: engelhardtm@mm11.ukl.uni-freiburg.de