Therapieansätze bei Patienten mit Hochrisiko-MDS*

Zusammenfassung

Patienten mit einem prognostisch ungünstigen myelodysplastischen Syndrom (MDS) leiden unter den Folgen ihrer Knochenmarksinsuffizienz (Anämie, Thrombozytopenie, Granulozytopenie) und entwickeln relativ häufig eine akute myeloische Leukämie. Bei einer kleinen Minderheit dieser Patienten kann versucht werden, durch allogene Transplantation hämatopoetischer Stammzellen eine Heilung zu erreichen. Einige Patienten mit fortgeschrittenem MDS können auch von einer intensiven antileukämischen Chemotherapie profitieren, falls ihr Allgemeinzustand die Durchführung einer solchen Behandlung erlaubt und keine ungünstigen Chromosomenanomalien vorliegen, die einen Therapieerfolg unwahrscheinlich machen. Für viele Patienten kommt jedoch weder eine allogene Transplantation noch eine intensive Chemotherapie in Frage. Statt dessen kann eine epigenetische Therapie versucht werden. Mit der demethylierenden Substanz 5-Azacytidin konnte in zwei großen Studien bei Patienten mit fortgeschrittenem MDS eine signifikante Verlängerung des Überlebens ereicht werden. 5-Azacytidin (Vidaza^®) ist seit 2009 in der EU zur Behandlung von MDS-Patienten mit ungünstiger Risikokonstellation zugelassen. Für die Schwestersubstanz Decitabin sind hämatologische Besserungen, aber noch keine signifikante Lebensverlängerung dokumentiert. Eine andere Art der epigenetischen Therapie, nämlich der Einsatz von Histondeacetylase-Inhibitoren (HDACi), kann bei Niedrigrisiko-MDS hämatologische Besserungen erreichen, scheint jedoch für die Behandlung von Patienten mit Hochrisiko-MDS nicht ausreichend wirksam zu sein. Patienten, deren Knochenmarkszellen bei der zytogenetischen Untersuchung eine 5q-Anomalie aufweisen, sollten möglichst einen Therapieversuch mit Lenalidomid unternehmen, welches allerdings in Deutschland für die MDS-Behandlung bisher nur im Rahmen klinischer Studien zur Verfügung steht.

Summary

Patients with a higher-risk myelodysplastic syndrome (MDS) suffer from the consequences of their bone marrow failure (anemia, thrombocytopenie, neutropenia) and frequently develop disease progression to acute myeloid leukemia. In a small minority, cure can be attempted by allogeneic hematopoietic stem cell transplantation (alloSCT). Patients may also benefit from intensive induction chemotherapy, provided that they are in good general condition and their bone marrow cells do not show an unfavourable karyotype on cytogenetic analysis. Many patients are ineligible for alloSCT or intensive chemotherapy. For these patients, epigenetic therapy is an alternative. Two large clinical trials showed a significant survival benefit for patients with higher-risk MDS treated with the demethylating agent 5-Azacytidine (Vidaza^®) which has been licensed in the EU in 2009 for the treatment of such patients. A closely related substance, Decitabine, also achieves hematologic improvement and remissions, but failed to provide a significant survival benefit in a phase III trial. Inhibitors of histone deacetylases (HDAC inhibitors) can also be used for epigenetic treatment. They can produce marked clinical benefit in a proportion of patients with lower-risk MDS, but their effect is apparently not strong enough for successful treatment of higher-risk MDS. Patients whose bone marrow cells show a 5q-anomaly should be considered candidates for a trial of lenalidomide which, however, is not yet licensed for MDS treatment in Europe.

Schlüsselwörter

MDS - myeloblastisches Syndrom - epigenetische Therapie - 5-Azacytidin - Decitabin

Keywords

MDS - myelodysplastic syndrome - epigenetic therapy - 5-Azacytidine - Decitabine

^* Dieser Beitrag erscheint parallel in: Klinische Onkologie 2011/2012, Düsseldorf University Press GmbH

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