Zusammenfassung
Primäre Lymphome des zentralen Nervensystems (PZNSL) sind seltene, hoch aggressive diffus großzellige B‑Zell-Non-Hodgkin-Lymphome, die sich ausschließlich in Gehirn, Meningen, Rückenmark und Augen manifestieren. Obwohl sich die Prognose des PZNSL in den letzten Jahrzehnten durch die Implementierung der Hochdosis-Methotrexat-basierten Chemotherapie deutlich verbessert hat, kommt es bei einem Drittel der Patienten zu einem therapierefraktären Verlauf und die Hälfte der Patienten entwickelt nach initialer Remission ein Rezidiv. Neue Therapiestrategien werden dringend benötigt. Die vielversprechendsten Fortschritte wurden auf dem Gebiet der molekular zielgerichteten Therapien erzielt, die in tumortreibende Signalwege des PZNSL eingreifen. Hierzu zählen Inhibitoren der Bruton-Tyrosinkinase sowie Inhibitoren des PI3K/mTOR-Signalwegs. Zudem zeigen die Thalidomidanaloga Lenalidomid und Pomalidomid, die zur Klasse der Immunmodulatoren gehören, Wirksamkeit in der Behandlung des PZNSL. Da eine Immunevasion eine relevante pathogenetische Rolle bei PZNSL spielt, werden auch Immuntherapien in der Therapie des PZNSL intensiv untersucht. Sowohl für Immun-Checkpoint-Inhibitoren als auch für die zelluläre Immuntherapie mit chimären Antigenrezeptor(CAR)-T-Zellen liegen erste klinische Daten im Hinblick auf Verträglichkeit und Wirksamkeit vor. Vor der breiten klinischen Anwendung dieser neuen Therapiestrategien für das PZNSL ist eine Bestätigung der Wirksamkeit in größeren Studien notwendig. Trotz hoher Ansprechraten lässt sich insbesondere mit zielgerichteten Substanzen und Immuntherapien häufig keine dauerhafte Tumorkontrolle erzielen, sodass diese derzeit vor allem im Rahmen von Kombinationsprotokollen untersucht werden.
Abstract
Primary central nervous system lymphomas (PCNSL) are rare highly aggressive diffuse large B cell non-Hodgkin lymphomas confined to the brain, meninges, the spinal cord and the eyes. Although the implementation of high-dose methotrexate-based chemotherapy has significantly improved the prognosis of PCNSL during the last decades, about one third of patients show refractory disease and about half of the patients eventually relapse after having achieved complete response. This highlights the need for novel treatment strategies. The most promising progress has been made in the field of molecular targeted therapy that interferes with the oncogenic signaling pathways of PCNSL. These include inhibitors of Bruton tyrosine kinase and inhibitors of the PI3K/mTOR signaling pathway. In addition, the thalidomide analogues lenalidomide and pomalidomide, which belong to the class of immunomodulators, show efficacy in the treatment of PCNSL. As immune evasion appears to play a relevant pathogenetic role in PCNSL, immunotherapies in the treatment of PCNSL are the subject of intensive research. Promising initial clinical data are available for both immune checkpoint inhibitors and cellular immunotherapy with chimeric antigen receptor (CAR) T cells. Before the widespread clinical application of these novel therapies, the efficacy needs to be confirmed in larger prospective studies. Despite high response rates, targeted therapies and immunotherapy often fail to achieve lasting tumor control. Therefore, novel approaches are currently being investigated in combination protocols.
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Förderung
Information: DFG (SFB TRR 133/B02) Prof. Dr. Louisa von Baumgarten
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S. Seidel, L. Kaulen und L. von Baumgarten geben an, dass kein Interessenkonflikt besteht.
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Seidel, S., Kaulen, L. & von Baumgarten, L. Neue Therapiestrategien beim primären Lymphom des Zentralnervensystems. Nervenarzt 95, 117–124 (2024). https://doi.org/10.1007/s00115-023-01561-w
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DOI: https://doi.org/10.1007/s00115-023-01561-w
Schlüsselwörter
- B‑Zell-Non-Hodgkin-Lymphome
- Molekular zielgerichtete Behandlung
- B‑Zell-Rezeptor-Signalweg
- Immuntherapie
- Chimäre Antigenrezeptor-T-Zellen