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Akute myeloische Leukämie

Acute myeloid leukemia

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Zusammenfassung

Weiterentwickelte molekulare Techniken haben in den letzten Jahren wesentlich zur Identifizierung und Charakterisierung der molekularen Heterogenität der akuten myeloischen Leukämie (AML) beigetragen. Dabei haben sie wichtige Einblicke in die Pathogenese ermöglicht. Die genetische Diagnostik ist für die Klassifikation, die Prognoseabschätzung und mittlerweile auch für die Wahl der Therapie unverzichtbar. Wesentliche Voraussetzung für einen genotypspezifischen Therapieansatz ist eine rasche, prätherapeutische molekulargenetische Diagnostik, die neben der Bestimmung der rekurrenten AML-assoziierten Genfusionen auch die Mutationsanalyse der Gene NPM1, FLT3 und CEBPA beinhaltet. Ein Teil dieser molekularen Marker kann für das Monitoring der minimalen Resterkrankung verwendet werden und liefert somit zusätzliche klinisch relevante Informationen. Für bestimmte genetisch definierte Subgruppen sind zunehmend molekular zielgerichtete Therapien verfügbar. Sehr solide Daten liegen zur Kombinationstherapie mit All-trans-Retinsäure und Arsentrioxid bei der akuten Promyelozytenleukämie vor; bei Patienten mit Niedrig- und Intermediärrisiko-AML konnte durch die Hinzunahme des Immuntoxins Gemtuzumab-Ozogamicin (GO) sowohl das rezidivfreie als auch das Gesamtüberleben signifikant verbessert werden. Kombinationstherapien mit Tyrosinkinaseinhibitoren werden aktuell bei der AML mit FLT3-Mutation und bei der Core-binding-factor-AML klinisch geprüft. Neue Therapieansätze adressieren Mutationen oder Alterationen in epigenetischen Regulatoren, z. B. mit IDH1/2-Hemmern oder Inhibitoren der Methyltransferase DOT1L. Die vollständige Charakterisierung der genetischen bzw. epigenetischen Mechanismen der AML ist eine wesentliche Voraussetzung für die Entwicklung weiterer zielgenauer Substanzen, mit denen die Therapieergebnisse und somit die Prognose verbessert werden sollen.

Abstract

In recent years, the development of novel molecular techniques has been instrumental in deciphering the genetic heterogeneity of acute myeloid leukemia (AML) as well as in gaining important insights into the pathomechanisms of AML. Genetic diagnostics has become an essential component in the initial work-up for disease classification, prognostication, and genotype-specific therapies. A major prerequisite for such individualized treatment strategies is a rapid pretherapeutic genetic analysis, which includes screening for the recurrent AML-associated gene fusions as well as mutations in the genes NPM1, FLT3, and CEBPA. Some of these molecular markers can be used for monitoring minimal residual disease and therefore provide clinically relevant information. There is an increasing number of promising molecularly targeted therapies in clinical development for distinct genetic AML subgroups. Solid data exist for the combination of all-trans retinoic acid and arsentrioxid in the treatment of acute promyelocytic leukemia; the addition of the immunoconjugate gemtuzumab ozogamicin (GO) to induction therapy has been shown to improve outcome in cytogenetic low- and intermediate-risk AML. Furthermore, there are encouraging data on the combination of intensive chemotherapy with tyrosine kinase inhibitors in patients with AML harboring FLT3 mutations or with core-binding factor AML. Other novel therapeutic approaches address mutations or alterations in epigenetic regulators, such as IDH or DOT1L inhibitors. The comprehensive characterization of the underlying genetic mechanisms is essential for the development of novel target-specific compounds with the aim of improving outcome in AML patients.

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Einhaltung ethischer Richtlinien

Interessenkonflikt. P. Paschka gibt an, dass kein Interessenkonflikt besteht. K. Döhner: Beratungstätigkeit für Novartis und Bristol-Myers Squibb; Unterstützung klinischer Studien durch Novartis und Celgene. H. Döhner: Beratungstätigkeit für Agios, Astellas, Astex Pharmaceuticals, Boehringer Ingelheim, Celgene, Bristol-Myers Squibb, GlaxoSmithKline, Lilly, Mundipharma, Novartis, Lilly, Roche, Seattle Genetics und Tolero.

Alle im vorliegenden Manuskript beschriebenen Untersuchungen am Menschen wurden mit Zustimmung der zuständigen Ethik-Kommission, im Einklang mit nationalem Recht sowie gemäß der Deklaration von Helsinki von 1975 (in der aktuellen, überarbeiteten Fassung) durchgeführt. Von allen beteiligten Patienten liegt eine Einverständniserklärung vor.

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  1. Klinik für Innere Medizin III, Universitätsklinikum Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Deutschland

    K. Döhner, P. Paschka & H. Döhner

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  1. K. Döhner
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Döhner, K., Paschka, P. & Döhner, H. Akute myeloische Leukämie. Internist 56, 354–363 (2015). https://doi.org/10.1007/s00108-014-3596-5

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