Neue Therapiestrategien für BCR/ABL-negative myeloproliferative Neoplasien

Zusammenfassung

Mit der Identifizierung der JAK2V617F-Mutation bei der essentiellen Thrombozythämie (ET), der Polyzythämia vera (PV) und der Myelofibrose (MF) im Jahr 2005, wurden erstmals neue und wichtige Einblicke in die Pathogenese myeloproliferativer Neoplasien (MPN) gewonnen werden. Basierend auf diesen Erkenntnissen wurden eine Reihe neuer Substanzen entwickelt oder bereits etablierte Substanzen weiter modifiziert, die derzeit in klinischen Studien bei Patienten mit MPN evaluiert werden. Die meisten Daten liegen derzeit zu den JAK-Inhibitoren, sog. „ATP mimetics” zur Therapie der MF vor. Hier wurden aktuell erste, sehr viel versprechende Ergebnisse aus zwei Phase-III-Studien publiziert, die zeigen konnten, dass die Therapie mit dem JAK1 /2-Inhibitor Ruxolitinib zu einer signifikanten Milzgrößenreduktion und einer deutlichen Verbesserung der Lebensqualität von MF-Patienten führt. Neben den JAK-Inhibitoren werden derzeit auch immunmodulatorische Substanzen, die IMiDs, zur Therapie der MPN eingesetzt. Hier hat sich Pomalidomid als sehr aktive Substanz in Phase-II-Studien erwiesen. Darüber hinaus kommen weitere Kinase-Inhibitoren sowie Histon-Deacetylase-(HDAC-) Inhibitoren und Inhibitoren des mTOR-Signalweges im Rahmen klinischer Studien zum Einsatz. Aufgrund ihrer unterschiedlichen, teils synergistischen Wirkmechanismen sind auch erste Kombinationstherapien in Planung, durch die man sich eine weitere Verbesserung des Ansprechens erhofft.

In der Übersichtsarbeit sollen die aktuellen Ergebnisse zum Einsatz dieser Substanzen vorgestellt und diskutiert sowie weitere neue Therapieansätze vorgestellt werden.

Abstract

Since the discovery of the JAK2V617F mutation in essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF) in 2005, the field of myeloproliferative neoplasms (MPN) experiences a significant gain of knowledge. Based on the novel insights in the molecular pathomechanisms of MPN many innovative drugs have been developed that are currently under investigation in clinical trials. Most data are available on the JAK inhibitors, the so called “ATP mimetics” for the treatment of MF. Recent data from two large phase-III studies showed that the JAK1 /2 inhibitor Ruxolitinib is very effective in the reduction of spleen size and the improvement of quality of life in MF patients. Beside JAK inhibitors, immunomodulatory drugs (IMiD) are currently under investigation. Here, pomalidomide showed significant activity in several phase-II studies in MF patients. In addition, other kinase inhibitors as well as histone deacetylase (HDAC) inhibitors and inhibitors of the mTOR signalling pathway are currently evaluated in clinical trials. Based on their potential synergistic action combination therapy of these substances represents another option for MPN therapy.

In this review the most recently published studies using innovative treatment strategies in MPN patients are reported, and some future aspects for MPN treatment are adressed.

Schlüsselwörter

myeloproliferative Neoplasien - essentielle Thrombozythämie - Polycythaemia vera - Myelofibrose - JAK2V617F-Mutation

Keywords

myeloproliferative neoplasms - essential thrombocythemia - polycythemia vera - myelofibrosis - JAK2V617F mutation

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