Akute Myeloische Leukämie – Individualisierte Therapieansätze für eine genetisch heterogene Erkrankung

Die akute myeloische Leukämie (AML) ist eine genetisch sehr heterogene Erkrankung und ohne Integration von genetischen Aberrationen in den klinischen Alltag sind eine korrekte Klassifikation, die Prognoseabschätzung und vor allem die Auswahl der optimalen und passenden Therapiestrategie für den einzelnen Patienten heutzutage nicht mehr möglich.

Essentiell für individualisierte Therapieansätze ist die prätherapeutisch durchgeführte genetische Diagnostik, die mindestens die Bestimmung der Fusionsgene PML-RARA, RUNX1-RUNX1T1 und CBFβ-MYH11 sowie die Mutationen in den Genen NPM1, FLT3, und CEBPA umfassen sollte. Wichtige neue Behandlungskonzepte auf dem Weg zu einer Genotyp-adaptierten Therapiestrategie sind die Kombinationstherapie von all-trans-Retinsäure und Arsentrioxid bei der akuten Promyelozytenleukämie, die Kombination von intensiver Chemotherapie mit Tyrosinkinase-Inhibitoren, wie KIT-Inhibitoren bei der Core-binding-Factor-AML und FLT3-Inhibitor bei der akuten myeloischen Leukämie mit aktivierenden FLT3-Mutationen sowie Gemtuzumab-Ozogamicin bei Patienten ohne zytogenetische Hochrisiko-Veränderungen. Durch den Einsatz der Next-generation-Sequenziertechnologien konnte aktuell ein großer Schritt in Richtung einer ausschließlich auf dem genetischen Hintergrund basierten Krankheitsklassifikation erreicht werden; vom Einsatz dieser Technologie im Rahmen klinischer Studien werden in naher Zukunft wichtige Erkenntnisse zur individuellen Therapiesteuerung erwartet.

Acute myeloid leukemia (AML) is a genetically very heterogeneous disease and without the integration of genetic markers into routine patient care a correct classification of the disease, prognostication and most importantly selection of the best available therapy for an individual patient are to date no longer possible.

Prerequisites of an individualized therapeutic approach are the pre-therapeutically performed genetic diagnostics including at least the fusion-genes PML-RARA, RUNX1-RUNX1T1 and CBFβ-MYH11 as well as mutations of NPM1, FLT3, und CEBPA. Currently genotype-adapted therapeutic approaches include the combination of all-trans retinoic acid and arsenic trioxide for acute promyelocytic leukemia, the combination of tyrosine-kinase inhibitors and intensive chemotherapy, such as KIT-inhibitors in core-binding factor AML and FLT3 inhibitors in AML with activating FLT3 mutations as well as gemtuzumab ozogamicin in AML without high-risk cytogenetic abnormalities.

Results from next-generation sequencing currently impacted significantly disease classification enabling a purely genetic based categorization; it's application within clinical studies will soon foster new insights into an individualized clinical decision making.

Key words

Acute myeloid leukemia - molecular screening - purely genetically defined disease classification - genotype-adapted treatment strategy - next-generation sequencing technology

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