Dtsch Med Wochenschr 2006; 131(43): 2414-2419
DOI: 10.1055/s-2006-955025
Übersicht | Review article
Hämatologie, Onkologie
© Georg Thieme Verlag KG Stuttgart · New York

Infektiöse Komplikationen als Folge der Behandlung mit Nukleosidanaloga und monoklonalen Antikörpern

Infectious complications related to nucleoside analogs and monoclonal antibodiesG. Maschmeyer1 , A. Haas1
  • 1Medizinische Klinik, Abt. Hämatologie und Onkologie, Klinikum Ernst von Bergmann, Potsdam
Further Information

Publication History

eingereicht: 15.5.2006

akzeptiert: 24.8.2006

Publication Date:
20 October 2006 (online)

Zusammenfassung

Monoklonale Antikörper gegen CD 20 (Rituximab), CD 52 (Alemtuzumab), CD 25 (Basiliximab), und Tumornekrosefaktor-alfa (Infliximab, Etanercept, Adalimumab) werden bei einem breiten Spektrum von Erkrankungen eingesetzt. Sie haben zu einer deutlichen Verbesserung der Therapiemöglichkeiten etwa bei malignen lymphatischen Neoplasien, bei der Transplantatabstoßung, bei rheumatoider Arthritis und bei chronisch-entzündlichen Darmerkrankungen geführt. Ihr Einsatz ist jedoch mit einer profunden und teils lang anhaltenden Immunsuppression verbunden, die je nach individueller Risikokonstellation zu schweren Infektionen führen kann. Septische bakterielle Infektionen, invasive Mykosen, Zytomegalievirusinfektionen (CMV) sowie Tuberkulosen können insbesondere unter Alemtuzumab und TNF-Antikörpertherapie auftreten. Nukleosidanaloga wie Fludarabin und Cladribin sind wegen ihrer lang anhaltenden T-Zell-Suppression mit einem erhöhten Risiko opportunistischer Infektionen, insbesondere durch CMV oder Pneumocystis jiroveci, assoziiert. Bei intensiv immunsuppressiv vorbehandelten Patienten steigt dieses Risiko deutlich an. Dies gilt ganz besonders für Patienten mit malignen Lymphomen, die mit einer Kombination (bzw. Sequenz) von Nukleosidanaloga und Alemtuzumab behandelt werden. Die prophylaktische Gabe antiviraler Substanzen gegen Herpesviren sowie von Cotrimoxazol ist bei Patienten unter Therapie mit Alemtuzumab oder Nukleosidanalgoa obligat.

Summary

Recombinant monoclonal antibodies targeted against cell surface antigens such as CD 20 (rituximab), CD 52 (alemtuzumab), CD 25 (basiliximab) or against tumor necrosis factor (TNF)-alpha (infliximab, etanercept, adalimumab) are in clinical use for a broad range of diseases, resulting in a significant improvement of treatment options for lymphoid malignancies, transplant rejection, rheumatoid arthritis and chronic inflammmatory bowel disease. However, their administration induces a profound and long lasting immunosuppression which may be associated with serious infections in selected patients. Invasive bacterial and fungal infections as well as systemic viral infections, preferably due to cytomegalovirus (CMV), and mycobacterial infections may emerge particularly in patients treated with alemtuzumab and TNF antibodies. Nucleoside analogs such as fludarabine or cladribine induce a severe T cell suppression putting patients at risk for opportunistic infections caused by CMV, Pneumocystis jiroveci and others. In patients heavily pretreated with immunosuppressive agents, this risk of infectious complications increases significantly. This is particularly important in patients with malignant lymphomas treated with a combination (or sequence) of nucleoside analogs and alemtuzumab. Prophylactic administration of antivirals against Herpes viruses as well as cotrimoxazole is mandatory in patients treated with alemtuzumab or nucleoside analogs.

Literatur

  • 1 Anaissie E J, Kontoyiannis D P, O’Brien S, Kantarjian H, Robertson L, Lerner S, Keating M J. Infections in patients with chronic lymphocytic leukemia treated with fludarabine.  Ann Intern Med. 1998;  129 559-566
  • 2 Byrd J C, Peterson B, Piro L, Saven A, Vardiman J W, Larson R A, Schiffer C. A phase II study of cladribine treatment for fludarabine refractory B cell chronic lymphocytic leukemia: results from CALGB Study 9211.  Leukemia. 2003;  17 323-327
  • 3 Cheson B D. Infectious and immunosuppressive complications of purine analog therapy.  J Clin Oncol. 1995;  13 2431-2448
  • 4 Coiffier B, Lepage E, Brière J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, van den Neste E, Salles G, Gaulard P, Reyes F, Gisselbrecht C. 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
  • 5 Couriel D, Saliba R, Hicks K, Ippoliti C, de Lima M, Hosing C, Khouri I, Andersson B, Gajewski J, Donato M, Anderlini P, Kontoyiannis D P, Cohen A, Martin T, Giralt S, Champlin R. Tumor necrosis factor-alpha blockade for the treatment of acute GVHD.  Blood. 2004;  104 649-654
  • 6 Dinarello C A. Differences between anti-tumor necrosis factor-alpha monoclonal antibodies and soluble TNF receptors in host defense impairment.  J Rheumatol Suppl. 2005;  74 40-47
  • 7 Edwards J C, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close D R, Stevens R M, Shaw T. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis.  N Engl J Med. 2004;  350 2572-2581
  • 8 Emery P, Fleischmann R, Filipowicz-Sosnowska A, Schechtman J, Szczepanski L, Kavanaugh A, Racewicz A J, van Vollenhoven R F, Li N F, Agarwal S, Hessey E W, Shaw T M. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: Results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial.  Arthritis Rheum. 2006;  54 1390-1400
  • 9 Eichhorst B F, Busch R, Hopfinger G, Pasold R, Hensel M, Steinbrecher C, Siehl S, Jäger U, Bergmann M, Stilgenbauer S, Schweighofer C, Wendtner C M, Döhner H, Brittinger G, Emmerich B, Hallek M. German CLL Study Group . Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia.  Blood. 2006;  107 885-891
  • 10 Fortun J, Martin-Davila P, Barcena R, Lumbreras C, Navasa M, Cisneros J, Pahissa A, Rufi G, Munoz P, Montejo M, Asensio A, Pena F, de la Torre J. Influence of different immunosuppressive regimens on infection in liver transplantation.  45th Interscience Conference on Antimicrobial Agents and Chemotherapy 2005, American Society for Microbiology. 2005;  Abstract #K-1809
  • 11 Ghielmini M, Schmitz S F, Cogliatti S B, Pichert G, Hummerjohann J, Waltzer U, Fey M F, Betticher D C, Martinelli G, Peccatori F, Hess U, Zucca E, Stupp R, Kovacsovics T, Helg C, Lohri A, Bargetzi M, Vorobiof D, Cerny T. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule.  Blood. 2004;  103 4416-4423
  • 12 Goldberg S L, Pecora A L, Alter R S, Kroll M S, Rowley S D, Waintraub S E, Imrit K, Preti R A. Unusual viral infections (progressive multifocal leukoencephalopathy and cytomegalovirus disease) after high-dose chemotherapy with autologous blood stem cell rescue and peritransplantation rituximab.  Blood. 2002;  99 1486-1488
  • 13 Gruttadauria S, Vasta F, Mandala L, Cintorino D, Piazza T, Spada M, Verzaro R, Gridelli B. Basiliximab in a triple-drug regimen with tacrolimus and steroids in liver transplantation.  Transplant Proc. 2005;  37 2611-2613
  • 14 Hiddemann W, Kneba M, Dreyling M, Schmitz N, Lengfelder E, Schmits R, Reiser M, Metzner B, Harder H, Hegewisch-Becker S, Fischer T, Kropff M, Reis H E, Freund M, Wörmann B, Fuchs R, Planker M, Schimke J, Eimermacher H, Trümper L, Aldaoud A, Parwaresch R, Unterhalt M. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group.  Blood. 2005;  106 3725-3732
  • 15 Kahan B D, Rajagopalan P R, Hall M. United States Simulect Renal Study Group . Reduction of the occurrence of acute cellular rejection among renal allograft recipients treated with basiliximab, a chimeric anti-interleukin-2-receptor monoclonal antibody.  Transplantation. 1999;  67 276-284
  • 16 Keane J, Gershon S, Wise R P, Mirabile-Levens E, Kasznica J, Schwieterman W D, Siegel J N, Braun M M. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent.  N Engl J Med. 2001;  345 1098-1104
  • 17 Keating M J, Flinn I, Jain V, Binet J L, Hillmen P, Byrd J, Albitar M, Brettman L, Santabarbara P, Wacker B, Rai K R. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study.  Blood. 2002;  99 3554-3561
  • 18 Keating M J, O’Brien S, Albitar M, Lerner S, Plunkett W, Giles F, Andreeff M, Cortes J, Faderl S, Thomas D, Koller C, Wierda W, Detry M A, Lynn A, Kantarjian H. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia.  J Clin Oncol. 2005;  23 4079-4088
  • 19 Leandro M J, Cambridge G, Ehrenstein M R, Edwards J C. Reconstitution of peripheral blood B cells after depletion with rituximab in patients with rheumatoid arthritis.  Arthritis Rheum. 2006;  54 613-620
  • 20 Listing J, Strangfeld A, Kary S, Rau R, von Hinueber U, Stoyanova-Scholz M, Gromnica-Ihle E, Antoni C, Herzer P, Kekow J, Schneider M, Zink A. Infections in patients with rheumatoid arthritis treated with biologic agents.  Arthritis Rheum. 2005;  52 3403-3412
  • 21 Lundin J, Kimby E, Björkholm M, Broliden P A, Celsing F, Hjalmar V, Mollgard L, Rebello P, Hale G, Waldmann H, Mellstedt H, Österborg A. 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
  • 22 Malek S K, Obmann M A, Gotoff R A, Foltzer M A, Hartle J E, Potdar S. Campath-1H induction and the incidence of infectious complications in adult renal transplantation.  Transplantation. 2006;  81 17-20
  • 23 Marty F M, Lee S J, Fahey M M, Alyea E P, Soiffer R J, Antin J H, Baden L R. Infliximab use in patients with severe graft-versus-host disease and other emerging risk factors of non-Candida invasive fungal infections in allogeneic hematopoietic stem cell transplant recipients: a cohort study.  Blood. 2003;  102 2768-2776
  • 24 Montillo M, Tedeschi A, O’Brien S, Di Raimondo F, Lerner S, Ferrajoli A, Morra E, Keating M J. Phase II study of cladribine and cyclophosphamide in patients with chronic lymphocytic leukemia and prolymphocytic leukemia.  Cancer. 2003;  97 114-120
  • 25 Paterson D L, Ndirangu M, Kwak E J, Husain S, Kusne S, Marcos A, Shapiro R, Eghtesad B, Patel K, Abu-Elmagd K, Bond G, McCurry K, Fung J. Opportunistic infections in solid-organ transplant recipients pre-treated with alemtuzumab.  44th Interscience Conference on Antimicrobial Agents and Chemotherapy 2004, American Society for Microbiology. Abstract #K-1427
  • 26 Pfreundschuh M, Trümper L, Österborg A, Pettengell R, Trneny M, Imrie K, Ma D, Gill D, Walewski J, Zinzani P L, Stahel R, Kvaloy S, Shpilberg O, Jaeger U, Hansen M, Lehtinen T, Lopez-Guillermo A, Corrado C, Scheliga A, Milpied N, Mendila M, Rashford M, Kuhnt E, Loeffler M. for the MabThera International Trial (MInT) Group . CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group.  Lancet Oncol. 2006;  7 379-391
  • 27 Ponticelli C, Yussim A, Cambi V, Legendre C, Rizzo G, Salvadori M, Kahn D, Kashi H, Salmela K, Fricke L, Heemann U, Garcia-Martinez J, Lechler R, Prestele H, Girault D. Simulect Phase IV Study Group . A randomized, double-blind trial of basiliximab immunoprophylaxis plus triple therapy in kidney transplant recipients.  Transplantation. 2001;  72 1261-1267
  • 28 Rai K R, Peterson B L, Appelbaum F R, Kolitz J, Elias L, Shepherd L, Hines J, Threatte G A, Larson R A, Cheson B D, Schiffer C A. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia.  N Engl J Med. 2000;  343 1750-1757
  • 29 Rutgeerts P, Sandborn W J, Feagan B G, Reinisch W, Olson A, Johanns J, Travers S, Rachmilewitz D, Hanauer S B, Lichtenstein G R, de Villiers W J, Present D, Sands B E, Colombel J F. Infliximab for induction and maintenance therapy for ulcerative colitis.  N Engl J Med. 2005;  353 2462-2476
  • 30 Schiff M H, Burmester G R, Kent J M, Pangan A L, Kupper H, Fitzpatrick S B, Donovan C. Safety analyses of adalimumab (Humira) in global clinical trials and US postmarketing surveillance of patients with rheumatoid arthritis.  Ann Rheum Dis. 2006;  65 889-894
  • 31 Schulz H, Klein S K, Rehwald U, Reiser M, Hinke A, Knauf W U, Aulitzky W E, Hensel M, Herold M, Huhn D, Hallek M, Diehl V, Engert A. German CLL Study Group . Phase 2 study of a combined immunochemotherapy using rituximab and fludarabine in patients with chronic lymphocytic leukemia.  Blood. 2002;  100 3115-3120
  • 32 Silveira F P, Marcos A, Kwak E J, Husain S, Shapiro R, Thai N, McCurry K R, Abu-Elmagd K, Paterson D L. Bloodstream infections in organ transplant recipients receiving alemtuzumab: No evidence of occurrence of organisms typically associated with profound T cell depletion.  J Infect. 2006;  [Epub ahead of print]
  • 33 Takada K, Danning C L, Kuroiwa T, Schlimgen R, Tassiulas I O, Davis J C, Yarboro C H, Fleisher T A, Boumpas D T, Illei G G. Lymphocyte depletion with fludarabine in patients with psoriatic arthritis: clinical and immunological effects.  Ann Rheum Dis. 2003;  62 1112-1115
  • 34 Tam C S, Wolf M M, Januszewicz E H, Grigg A P, Prince H M, Westerman D, Seymour J F. A new model for predicting infectious complications during fludarabine-based combination chemotherapy among patients with indolent lymphoid malignancies.  Cancer. 2004;  101 2042-2049
  • 35 Tam C S, Seymour J F, Brown M, Campbell P, Scarlett J, Underhill C, Ritchie D, Bond R, Grigg A P. Early and late infectious consequences of adding rituximab to fludarabine and cyclophosphamide in patients with indolent lymphoid malignancies.  Haematologica. 2005;  90 700-702
  • 36 Thursky K A, Worth L J, Seymour J F, Miles Prince H, Slavin M A. Spectrum of infection, risk and recommendations for prophylaxis and screening among patients with lymphoproliferative disorders treated with alemtuzumab.  Br J Haematol. 2006;  132 3-12
  • 37 Tsiodras S, Samonis G, Keating M J, Kontoyiannis D P. Infection and immunity in chronic lymphocytic leukemia.  Mayo Clin Proc. 2000;  75 1039-1054
  • 38 Wallis R S, Broder M S, Wong J Y, Hanson M E, Beenhouwer D O. Granulomatous infectious diseases associated with tumor necrosis factor antagonists.  Clin Infect Dis. 2004;  38 1261-1265
  • 39 Wallis R S, Broder M, Wong J, Beenhouwer D. Granulomatous infections due to tumor necrosis factor blockade: correction.  Clin Infect Dis. 2004;  39 1254-1255
  • 40 Wendtner C M, Ritgen M, Schweighofer C D, Fingerle-Rowson G, Campe H, Jäger G, Eichhorst B, Busch R, Diem H, Engert A, Stilgenbauer S, Döhner H, Kneba M, Emmerich B, Hallek M. German CLL Study Group (GCLLSG) . 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
  • 41 Westhoff T H, Jochimsen F, Schmittel A, Stoffler-Meilicke M, Schafer J H, Zidek W, Gerlich W H, Thiel E. Fatal hepatitis B virus reactivation by an escape mutant following rituximab therapy.  Blood. 2003;  102 1930

Prof. Dr. G. Maschmeyer

Klinikum Ernst von Bergmann, Medizinische Klinik, Abt. Hämatologie und Onkologie

Charlottenstraße 72

14467 Potsdam

Phone: 0331/2416001

Fax: 0331/2416000

Email: gmaschmeyer@klinikumevb.de

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