Two feasibility studies suggest that NGS could be an important tool in the future for assessing the risk of AML progression of individuals with clonal hematopoiesis of indeterminate potential (CHIP) (Desai et al. Nat Med 2018, Abelson et al. Nature 2018). In retrospective studies, both research groups were able to use NGS-based mutational analysis to develop a prediction model that allows AML to be predicted up to ten years before clinical AML diagnosis. There is currently not enough therapeutics for early intervention as well as prospective studies on the feasibility and clinical benefit of AML prediction. Nevertheless, both studies illustrate the potential of molecular diagnostics—also in terms of detecting myeloid neoplasms at an early stage. This not only applies to AML but also to MDS and (unclear) cytopenias (cf. also MLL News 1/2019).

The current WHO classification recognizes three molecular genetic definitions of AML subtypes: AML with NPM1, RUNX1, and biallelic CEBPA mutation. In this case, NGS diagnostics is crucial for diagnosis. The mutation status of certain genes must be known in order to determine the risk stratification in accordance with European LeukemiaNet (ELN) recommendations (Döhner et al. Blood 2017) and the Medical Research Council (MRC) (Grimwade et al. Blood 2016). Both classification systems include mutations in NPM1, FLT3-ITD, CEBPA (biallelic), RUNX1, ASXL1, and TP53. In addition, MRC classification takes KMT2A-PTD and DNMT3A mutations into consideration.

The detection of the mutation has been therapeutically relevant for FLT3, for which the tyrosine-kinase inhibitor Midostaurin is available. An IDH2 inhibitor is currently undergoing European approval procedures. The detection of KIT mutations should be considered when selecting the appropriate consolidation therapy for AML with t(8; 21) and inv(16) or t(16; 16) (NCCN AML Guideline 2.2019). Based on this genetic background, studies on the presence of a KIT mutation under standard high-dose Cytarabine therapy have shown increased incidence of recurrence and, to some extent, decreased overall survival.

In The New England Journal of Medicine 2018, Jongen-Lavrencic et al. reported on just how relevant NGS diagnostics are for determining measurable residual disease (MRD) in patients with AML. At least one mutation was detected in 89% of the patients; 2.9 mutations were detected on average. The study emphasized how using a NGS panel for the characterization of genetics can lay the foundation for identifying MRD at a later stage. After induction therapy, the detection of persistent mutations was closely associated with an increased risk of recurrence. Only mutations in genes that are usually associated with CHIP were not affected by this effect: DNMT3A, TET2, and ASXL1. In the future, this could enable molecular genetic MRD diagnostics for virtually all AML subtypes.