Therapie der Multiplen Sklerose mit monoklonalen Antikörpern: aktualisierte Empfehlungen zum Umgang mit Natalizumab im Rahmen eines Expertenmeetings

Zusammenfassung

Die Behandlung der Multiplen Sklerose (MS) wird zunehmend durch innovative Antikörpertherapien erweitert. Neben dem 2006 zugelassenen Natalizumab für den Einsatz bei der hochaktiven, schubförmigen MS werden bereits jetzt im Rahmen von Studien bzw. im Off-label-Ansatz zahlreiche weitere monoklonale Antikörper bei MS-Patienten verwendet, die häufig eine über die übliche immunmodulatorische Therapie hinausreichende Wirksamkeit zeigen. Neben neuen therapeutischen Chancen stellen sich allerdings zunehmend die Risiken dieser Therapien heraus. Als prototypisches Beispiel dient Natalizumab, bei dem die höhere klinische Effektivität mit zwar seltenen, allerdings teilweise schwerwiegenden Nebenwirkungen wie anaphylaktischen Reaktionen oder einer progressiven multifokalen Leukenzephalopathie (PML) einhergeht. Die folgende Übersicht stellt daher den aktuellen Stand von Empfehlungen dar, welche als Resultate eines Expertentreffens im März des Jahres 2010 zusammengestellt sind. Ziel des Treffens war die kritische Diskussion und die Entwicklung von praktischen Anleitungen für den Einsatz von monoklonalen Antikörpern im klinischen Einsatz, speziell Natalizumab. Berücksichtigt sind hierbei auch die Empfehlungen der Europäischen Zulassungsbehörde (European Medicines Agency, EMA) vom 21.1.2010, die eine Aktualisierung der Natalizumab-Arztinformation beinhalten und der aktuellen Einschätzung von Nutzen und Risiko Rechnung tragen. Die aktualisierten Hinweise sollen die Rahmenbedingungen für Indikation, die logistischen Voraussetzungen dieser Therapie, die Therapieüberwachung sowie Diagnostik- und Behandlungsalgorithmen bei Komplikationen definieren. Damit soll ein Beitrag zum praktischen Umgang mit Komplikationen in der Behandlungsrealität geleistet werden. Prinzipiell sollen durch den vernetzten Informationsfluss auf der Basis kooperativer Strukturen wie Versorgungsnetzwerken die Erkennung und Behandlung von Komplikationen verbessert und damit der Einsatz innovativer und teils risikoreicherer monoklonaler Antikörpertherapien erleichtert werden.

Abstract

During recent years a series of novel and powerful monoclonal antibody therapies for the treatment of multiple sclerosis (MS) have been introduced and studied. In the vanguard of these therapies, natalizumab was initially licensed for highly active relapsing MS four years ago. Other monoclonal antibodies are either currently being used as off-label treatments or are being actively studied in clinical trials. The association of monoclonal antibody therapy, e. g., natalizumab, with rare but potentially fatal events such as JC virus-mediated progressive multifocal encephalopathy (PML) represents a major challenge. This report compiles the results of an expert meeting held in March 2010. In consideration of the recent recommendations of the European Medicines Agency (EMA), the following meeting report aims to provide updated suggestions for therapy with natalizumab in daily clinical routine. The aim is to provide a framework for the use of these novel and future immunotherapies in routine clinical practice and to improve the handling of potential complications of these treatments in both inpatient and outpatient settings. The proposed algorithms strongly depend on the structured and ongoing interaction between different levels of health-care providers in order to establish robust quality standards for ensuring patient safety and maintaining a favourable risk-benefit ratio.

Schlüsselwörter

Multiple Sklerose - Immuntherapie - monoklonale Antikörper - Natalizumab - PML

Keywords

multiple sclerosis - immunotherapy - monoclonal antibodies - natalizumab - PML

Literatur

• 1 Gold R, Hartung H P, Hohlfeld R et al. Therapie der Multiplen Sklerose mit monoklonalen Antikörpern: Ergebnisse und Empfehlungen einer Arbeitstagung des Ärztlichen Beirats der Deutschen Multiple Sklerose Gesellschaft.  Akt Neurol. 2009;  36 334-344
• 2 Meier U, Pöhlau D, Gold R et al. Versorgungsnetzwerke für innovative Immuntherapien.  Akt Neurol. 2009;  36 331-333
• 3 Warnke C, Menge T, Hartung H P et al. Natalizumab and progressive multifocal leukoencephalopathy: what are the causal factors and can it be avoided?.  Arch Neurol. 2010;  67 923-930
• 4 Weissert R. Progressive multifocal leukoencephalopathy.  J Neuroimmunol. 2010;  (in press)
• 5 Tan C S, Koralnik I J. Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis.  Lancet Neurol. 2010;  9 425-437
• 6 Piccinni C, Sacripanti C, Poluzzi E et al. Stronger association of drug-induced progressive multifocal leukoencephalopathy (PML) with biological immunomodulating agents.  Eur J Clin Pharmacol. 2010;  66 199-206
• 7 Berger J R, Houff S A, Major E O. Monoclonal antibodies and progressive multifocal leukoencephalopathy.  MAbs. 2009;  1 583-589
• 8 Carson K R, Evens A M, Richey E A et al. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project.  Blood. 2009;  113 4834-4840
• 9 Du Pasquier R A, Clark K W, Smith P S et al. JCV-specific cellular immune response correlates with a favorable clinical outcome in HIV-infected individuals with progressive multifocal leukoencephalopathy.  J Neurovirol. 2001;  7 318-322
• 10 Du Pasquier R A, Kuroda M J, Zheng Y et al. A prospective study demonstrates an association between JC virus-specific cytotoxic T lymphocytes and the early control of progressive multifocal leukoencephalopathy.  Brain. 2004;  127 1970-1978
• 11 del Pilar M M, Cravens P D, Winger R et al. Decrease in the numbers of dendritic cells and CD4+ T cells in cerebral perivascular spaces due to natalizumab.  Arch Neurol. 2008;  65 1596-1603
• 12 Marzocchetti A, Lima M, Tompkins T et al. Efficient in vitro expansion of JC virus-specific CD8(+) T-cell responses by JCV peptide-stimulated dendritic cells from patients with progressive multifocal leukoencephalopathy.  Virology. 2009;  383 173-177
• 13 Krumbholz M, Meinl I, Kumpfel T et al. Natalizumab disproportionately increases circulating pre-B and B cells in multiple sclerosis.  Neurology. 2008;  71 1350-1354
• 14 Zohren F, Toutzaris D, Klarner V et al. The monoclonal anti-VLA-4 antibody natalizumab mobilizes CD34+ hematopoietic progenitor cells in humans.  Blood. 2008;  111 3893-3895
• 15 Warnke C, Smolianov V, Dehmel T et al. CD34+ progenitor cells mobilized by natalizumab are not a relevant reservoir for JC virus.  Mult Scler. 2010; 
• 16 Houff S A, Berger J R. The bone marrow, B cells, and JC virus.  J Neurovirol. 2008;  14 341-343
• 17 Lindberg R L, Achtnichts L, Hoffmann F et al. Natalizumab alters transcriptional expression profiles of blood cell subpopulations of multiple sclerosis patients.  J Neuroimmunol. 2008;  194 153-164
• 18 Chen Y, Bord E, Tompkins T et al. Asymptomatic reactivation of JC virus in patients treated with natalizumab.  N Engl J Med. 2009;  361 1067-1074
• 19 Jilek S, Jaquiery E, Hirsch H H et al. Immune responses to JC virus in patients with multiple sclerosis treated with natalizumab: a cross-sectional and longitudinal study.  Lancet Neurol. 2010;  9 264-272
• 20 Brooks B R, Walker D L. Progressive multifocal leukoencephalopathy.  Neurol Clin. 1984;  2 299-313
• 21 Berger J R, Pall L, Lanska D et al. Progressive multifocal leukoencephalopathy in patients with HIV infection.  J Neurovirol. 1998;  4 59-68
• 22 Boster A, Hreha S, Berger J R et al. Progressive multifocal leukoencephalopathy and relapsing-remitting multiple sclerosis: a comparative study.  Arch Neurol. 2009;  66 593-599
• 23 Bernal-Cano F, Joseph J T, Koralnik I J. Spinal cord lesions of progressive multifocal leukoencephalopathy in an acquired immunodeficiency syndrome patient.  J Neurovirol. 2007;  13 474-476
• 24 Takeda S, Yamazaki K, Miyakawa T et al. Progressive multifocal leukoencephalopathy showing extensive spinal cord involvement in a patient with lymphocytopenia.  Neuropathology. 2009;  29 485-493
• 25 Kleiter I, Schroder M, Lurding R et al. Early changes on electroencephalography in natalizumab-associated progressive multifocal leucoencephalopathy.  Mult Scler. 2010;  16 749-753
• 26 http://www.ema.europa.eu/humandocs/PDFs/EPAR/tysabri/Tysabri_A20-0029_Annex_IV.pdf Internet 2010
• 27 Clifford D B, De L A, Simpson D M et al. Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases.  Lancet Neurol. 2010;  9 438-446
• 28 Lindå H, Heijne A von, Major E O et al. Progressive multifocal leukoencephalopathy after natalizumab monotherapy.  N Engl J Med. 2009;  361 1081-1087
• 29 http://tysabri.de/index.php?inhalt=informationen.materialien Internet 2010
• 30 Sailer M, Fazekas F, Gass A et al. [Cerebral and spinal MRI examination in patients with clinically isolated syndrome and definite multiple sclerosis].  Rofo. 2008;  180 994-1001
• 31 Langer-Gould A, Atlas S W, Green A J et al. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab.  N Engl J Med. 2005;  353 375-381
• 32 Wenning W, Haghikia A, Laubenberger J et al. Treatment of progressive multifocal leukoencephalopathy associated with natalizumab.  N Engl J Med. 2009;  361 1075-1080
• 33 Kleinschmidt-DeMasters B K, Tyler K L. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis.  N Engl J Med. 2005;  353 369-374
• 34 Rudick R A, Sandrock A. Natalizumab: alpha 4-integrin antagonist selective adhesion molecule inhibitors for MS.  Expert Rev Neurother. 2004;  4 571-580
• 35 Tubridy N, Behan P O, Capildeo R et al. The effect of anti-alpha4 integrin antibody on brain lesion activity in MS. The UK Antegren Study Group.  Neurology. 1999;  53 466-472
• 36 Stuve O, Marra C M, Bar-Or A et al. Altered CD4+ / CD8+ T-cell ratios in cerebrospinal fluid of natalizumab-treated patients with multiple sclerosis.  Arch Neurol. 2006;  63 1383-1387
• 37 Khatri B O, Man S, Giovannoni G et al. Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function.  Neurology. 2009;  72 402-409
• 38 Hall C D, Dafni U, Simpson D et al. Failure of cytarabine in progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection. AIDS Clinical Trials Group 243 Team.  N Engl J Med. 1998;  338 1345-1351
• 39 De L A, Ammassari A, Pezzotti P et al. Cidofovir in addition to antiretroviral treatment is not effective for AIDS-associated progressive multifocal leukoencephalopathy: a multicohort analysis.  AIDS. 2008;  22 1759-1767
• 40 Kraemer C, Evers S, Nolting T et al. Cidofovir in combination with HAART and survival in AIDS-associated progressive multifocal leukoencephalopathy.  J Neurol. 2008;  255 526-531
• 41 Brickelmaier M, Lugovskoy A, Kartikeyan R et al. Identification and characterization of mefloquine efficacy against JC virus in vitro.  Antimicrob Agents Chemother. 2009;  53 1840-1849
• 42 Altschuler E L, Kast R E. The atypical antipsychotic agents ziprasidone [correction of zisprasidone], risperdone and olanzapine as treatment for and prophylaxis against progressive multifocal leukoencephalopathy.  Med Hypotheses. 2005;  65 585-586
• 43 Lanzafame M, Ferrari S, Lattuada E et al. Mirtazapine in an HIV-1 infected patient with progressive multifocal leukoencephalopathy.  Infez Med. 2009;  17 35-37
• 44 Elphick G F, Querbes W, Jordan J A et al. The human polyomavirus, JCV, uses serotonin receptors to infect cells.  Science. 2004;  306 1380-1383
• 45 Nukuzuma S, Nakamichi K, Nukuzuma C et al. Inhibitory effect of serotonin antagonists on JC virus propagation in a carrier culture of human neuroblastoma cells.  Microbiol Immunol. 2009;  53 496-501
• 46 Chapagain M L, Verma S, Mercier F et al. Polyomavirus JC infects human brain microvascular endothelial cells independent of serotonin receptor 2A.  Virology. 2007;  364 55-63
• 47 Berger J R, Centonze D, Comi G et al. Considerations on discontinuing natalizumab for the treatment of multiple sclerosis.  Ann Neurol. 2010;  68 409-411
• 48 Killestein J, Vennegoor A, Strijbis E M et al. Natalizumab drug holiday in multiple sclerosis: poorly tolerated.  Ann Neurol. 2010;  68 392-395
• 49 West T W, Cree B A. Natalizumab dosage suspension: are we helping or hurting?.  Ann Neurol. 2010;  68 395-399
• 50 Lenhard T, Biller A, Mueller W et al. Immune reconstitution inflammatory syndrome after withdrawal of natalizumab?.  Neurology. 2010;  75 831-833
• 51 Shelburne III S A, Hamill R J, Rodriguez-Barradas M C et al. Immune reconstitution inflammatory syndrome: emergence of a unique syndrome during highly active antiretroviral therapy.  Medicine (Baltimore). 2002;  81 213-227
• 52 Miller R F, Isaacson P G, Hall-Craggs M et al. Cerebral CD8+ lymphocytosis in HIV-1 infected patients with immune restoration induced by HAART.  Acta Neuropathol. 2004;  108 17-23
• 53 Dhasmana D J, Dheda K, Ravn P et al. Immune reconstitution inflammatory syndrome in HIV-infected patients receiving antiretroviral therapy: pathogenesis, clinical manifestations and management.  Drugs. 2008;  68 191-208
• 54 Ruhwald M, Ravn P. Immune reconstitution syndrome in tuberculosis and HIV-co-infected patients: Th1 explosion or cytokine storm?.  AIDS. 2007;  21 882-884
• 55 Autran B, Carcelain G, Li T S et al. Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease.  Science. 1997;  277 112-116
• 56 Tan K, Roda R, Ostrow L et al. PML-IRIS in patients with HIV infection: clinical manifestations and treatment with steroids.  Neurology. 2009;  72 1458-1464
• 57 Schroder A, Lee D H, Hellwig K et al. Successful management of natalizumab-associated progressive multifocal leukoencephalopathy and immune reconstitution syndrome in a patient with multiple sclerosis.  Arch Neurol. 2010;  67 1391-1394
• 58 Tyler K L. Progressive multifocal leukoencephalopathy: can we reduce risk in patients receiving biological immunomodulatory therapies?.  Ann Neurol. 2010;  68 271-274
• 59 Gorelik L, Lerner M, Bixler S et al. Anti-JC virus antibodies: implications for PML risk stratification.  Ann Neurol. 2010;  68 295-303
• 60 Ryschkewitsch C F, Jensen P N, Monaco M C et al. JC virus persistence following progressive multifocal leukoencephalopathy in multiple sclerosis patients treated with natalizumab.  Ann Neurol. 2010;  68 384-391
• 61 Warnke C, Adams O, Hartung H P et al. Comment to Rudick et al: Assessment of JC virus DNA in blood and urine from natalizumab-treated patients.  Ann Neurol. 2010;  (in press) 68 304-310
• 62 Rudick R A, O’Connor P W, Polman C H et al. Assessment of JC virus DNA in blood and urine from natalizumab-treated patients.  Ann Neurol. 2010;  68 304-310
• 63 Schweikert A, Kremer M, Ringel F et al. Primary central nervous system lymphoma in a patient treated with natalizumab.  Ann Neurol. 2009;  66 403-406
• 64 Phan Ba R, Bisig B, Deprez M et al. Primary central nervous system lymphoma in a patient treated with natalizumab.  Ann Neurol. 2010;  (in press)
• 65 Bozic C, Cristiano L M, Hyde R et al. Utilization and Safety of Natalizumab in Patients with Relapsing Multiple Sclerosis. [Abstract]. Gothenburg: ECTRIMS 2010; 2010 P893
• 66 Vennegoor A, Wattjes M P, van Munster E TL et al. Indolent course of progressive multifocal leukoencephalopathy during natalizumab treatment in MS.  Neurology. 2011;  76 574-576

1 Mitglieder der Expertengruppe:

1 Ortwin Adams, Düsseldorf; Orhan Aktas, Düsseldorf; Gabriele Arendt, Düsseldorf; Karl Baum, Henningsdorf; Antonios Bayas, Augsburg; Joseph Berger, Lexington, Kentucky, USA; Andreas Bitsch, Neuruppin; Mathias Buttmann, Würzburg; Andrew Chan, Bochum; Tobias Derfuß, Erlangen / Basel; Ralf Gold, Bochum; Klaus Gottwald, Stuttgart; Judith Haas, Berlin; Lutz Harms, Berlin; Hans-Peter Hartung, Düsseldorf; Holger Honig, Bremerhaven; Boris Kallmann, Bamberg; Zaza Katsarava, Essen; Bernd Kieseier, Düsseldorf; Christoph Klawe, Trier; Ingo Kleiter, Regensburg; Tania Kümpfel, München; Michael Lang, Ulm; Volker Limmroth, Köln; Ralf Linker, Bochum / Erlangen; Martin Marziniak, Münster; Erich Mauch, Dietenbronn; Matthias Mäurer, Bad Mergentheim; Uwe Meier, Grevenbroich; Ernst-Wilhelm Radü, Basel, Schweiz; Thorsten Rosenkranz, Hamburg; Stephan Schmidt, Bonn; Thorsten Schultheiss, Dresden; Kurt-Wolfram Sühs, Homburg; Martin Stangel, Hannover; Florian Stögbauer, Osnabrück; Björn Tackenberg, Marburg; Florian Then Bergh, Leipzig; Hayrettin Tumani, Ulm; Heinz Wiendl, Münster; Brigitte Wildemann, Heidelberg; Ulf Ziemann, Frankfurt.