JAK-Inhibitoren für die Behandlung hämatoonkologischer Erkrankungen

Zusammenfassung

Die konstitutive Aktivierung des JAK-STAT-Signalwegs ist charakteristisch für die Pathogenese der myeloproliferativen Neoplasien, speziell der primären Myelofibrose, der Polycythaemia vera und der essentiellen Thrombozythämie. Die Einführung von oral verfügbaren JAK-Inhibitoren in die Klinik brachte einen entscheidenden Fortschritt für die pharmakologische Behandlung der Myelofibrose und der Polycythaemia vera, wenngleich damit noch keine Heilung verbunden ist. Im Vordergrund steht die Verbesserung der Lebensqualität der meist älteren Patienten durch Kontrolle krankheitsbedingter konstitutioneller Symptome, Reduktion einer bestehenden Splenomegalie und Vermeidung insbesondere von thromboembolischen Folgekomplikationen. Darüber hinaus kann die Therapie von Myelofibrose-Patienten mit JAK-Inhibitoren jedoch auch deren Krankheitsverlauf verlangsamen und ihr Gesamtüberleben verlängern. Der bislang einzige in Europa zugelassene JAK-Inhibitor Ruxolitinib hemmt die Isoformen JAK1 und JAK2 und besitzt sowohl antiinflammatorisches als auch antiproliferatives Potenzial. Damit zeigt dieser Inhibitor überdies eine gute Wirkung in der Therapie der Graft-versus-Host-Erkrankung nach allogener hämatopoetischer Stammzelltransplantation. Mit Fedratinib, Pacritinib und Momelatinib befinden sich derzeit 3 weitere vielversprechende JAK-Inhibitoren mit etwas unterschiedlichen Wirkprofilen in der klinischen Phase III-Testung. Diese zeigen auch bei Patienten mit unwirksamer oder unverträglicher Vorbehandlung mit Ruxolitinib Wirksamkeit, sodass eine kontinuierliche Weiterentwicklung der entsprechenden Therapiestrategien abzusehen ist.

Abstract

The constitutive activation of the JAK-STAT signalling pathway is a pathogenetic hallmark of myeloproliferative neoplasms, in particular of primary myelofibrosis, polycythaemia vera and essential thrombocythaemia. The introduction of orally available JAK inhibitors into clinics yielded a major progress for the pharmacological treatment of myelofibrosis and polycythaemia vera, although they have not been able to cure these conditions. The primary goal is to improve the quality of life in the predominantly elderly patients by controlling the constitutional symptoms caused by the disease, to reduce existing splenomegaly and to prevent subsequent thromboembolic complications. Moreover, the therapeutic administration of JAK inhibitors to patients with myelofibrosis may decelerate the course of their disease and prolong their overall survival. So far, Ruxolitinib is the only JAK inhibitor approved in Europe. It targets both isoforms JAK1 and JAK2 and has antiinflammatory as well as antiproliferative potential. Consequently, this inhibitor also proves effective in treating graft-versus-host disease occurring after allogeneic haematopoietic stem cell transplantation. Next in line, Fedratinib, Pacritinib and Momelatinib are three promising JAK inhibitors with slightly different activity profiles, which are currently undergoing clinical phase III testing. They prove effective even in patients with prior ineffective or intolerable exposure to Ruxolitinib. Thus, a continuous improvement of the respective treatment strategies can be expected.

Schlüsselwörter

JAK-Inhibitor - Myeloproliferative Neoplasien - Primäre Myelofibrose - Polycythaemia vera - Graft-versus-Host-Erkrankung

Keywords

JAK inhibitor - primary myelofibrosis - graft-versus-host disease - polycythaemia vera - myeloproliferative neoplasias

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