Entwicklungen im Verständnis und der Behandlung myeloproliferativer Neoplasien

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Ropeg-Interferon als Standard der High- (und bald) Low-Risk-Polycythaemia-vera Bei der Polycythaemia vera (PV) steht mit Ropeg-Interferon erstmals eine zugelassene Therapieoption mit krankheitsmodifizierendem Effekt im Sinne einer deutlichen Reduktion der Allele-Last zur Verfügung. Ropeg-Interferon ist damit Standard für die PV bei Indikation zur zytoreduktiven Therapie. Auch bei der Low-Risk-PV, die bisher „nur“ mit Aderlässen und niedrigdosierter Acetylsalicylsäure ASS (100 mg) behandelt wurde, zeigt sich eine hohe Rate an Aderlass-Unabhängigkeit und auch ein molekulares Ansprechen. Das Paradigma, dass nur Hochrisiko-PV zytoreduktiv behandelt werden, wird in Zukunft mit hoher Wahrscheinlichkeit fallen.

Neue JAK-Inhibitoren in der Myelofibrose bei Ruxolitinib-Versagen/-Toxizität Fedratinib erzielt in der Behandlung der Myelofibrose eine Reduktion der Splenomegalie und der Symptomlast, auch in einer mit Ruxolitinib vorbehandelten Kohorte. Somit steht erstmals eine therapeutisch wirksame Alternative für Patienten zur Verfügung, die Ruxolitinib-refraktär bzw. -intolerant sind.

Myeloproliferative Neoplasien und sterile Entzündungsprozesse Sterile Entzündungsprozesse wie beispielsweise der Alarmin-Komplex spielen in der Pathogenese und Progression der MPN eine wesentliche Rolle. Hierbei werden inflammatorische Zytokine nicht nur von mutierten Zellen, sondern auch von nicht mutierten Umgebungszellen sezerniert; sie prägen den Krankheitsphänotyp und begünstigen die Entstehung und Expansion mutierter Subklone.

Abstract

Treatment of myeloproliferative neoplasia (MPN) is based on patients’ individual risk-stratification and includes cytoreductive agents for high-risk essential thrombocythemia (ET), polycythemia vera (PV) and Myelofibrosis (MF). Classical cytoreductive drugs largely fail to modify the basic clonal composition of the disease. In contrast, in PV for example treatment with Ropeg-Interferon not only results in higher hematological response rates compared to hydroxyurea but in addition significantly reduces JAK2 allele-burden in high-risk PV patients as well as it depletes concurrent cytogenetic and molecular abnormalities. Treatment with Ropeg-Interferon so far is only approved for high-risk PV. A very recent trial however also demonstrated this disease-modifying effect also in low-risk PV patients in addition to an increased rate of transfusion independence. Thus, Ropeg-Interferon is the current standard for first line treatment of high-risk PV and we assume that the data in low-risk PV will lead also to a broader clinical use of Ropeg-Interferon this particular patient group, as it may decrease transformation to MF or even MPN-blast crisis.

Myelofibrosis management has been extended by novel JAKi. Fedratinib is the first second generation JAK-inhibitor approved for Ruxolitinib-intolerant or refractory patients. Fedratinib reduces both spleen volume as well as symptom burden. Two other second generation JAK-inhibitors are in clinical development for MPN treatment. Pacritinib has demonstrated efficacy in reducing both spleen volume and symptom score in MF including a cohort of Ruxolitinib-pretreated patients and Momelotinib is the only JAK-inhibitor which has been shown to alleviate anemia in addition to its effect on improving spleen volume and symptom. So far, neither Pacritinib nor Momelotinib are currently EMA-approved for MPN treatment.

Finally, it has recently been acknowledged that inflammation is a key driver of MPN pathogenesis. Both, mutated as well as non-clonal inflammatory and other stromal cells produce significant amounts of local cytokines. Also the initiation of the neoplastic process itself seems to depend on inflammatory cytokines. Recent scRNASeq data revealed components of the alarmin complex (S100A8 und S100A9) drive this local sterile inflammation process, which also represents a potential therapeutic target, as the S100A8 and A9 inhibitor Tasquinimod reduced fibrosis in a pre-clinical animal model.

Schlüsselwörter

MPN (myeloproliferative Neoplasie) - Ropeg-Interferon - Fedratinib - Alarmin-Komplex - sterile Entzündung

Key words

MPN (myeloproliferative neoplasia) - Ropeg-Interferon - Fedratinib - alarmin complex - sterile inflammation

Publication History

Article published online:
15 March 2022

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