Authors: Nikolaus Jahn, Ekaterina Jahn, Maral Saadati, Lars Bullinger, Richard A. Larson, Tiziana Ottone, Sergio Amadori, Thomas W. Prior, Joseph M. Brandwein, Frederick R. Appelbaum, Bruno C. Medeiros, Martin S. Tallman, Gerhard Ehninger, Michael Heuser, Arnold Ganser, Celine Pallaud, Insa Gathmann, Julia Krzykalla, Axel Benner, Clara D. Bloomfield, Christian Thiede, Richard M. Stone, Hartmut Döhner, Konstanze Döhner
Published: 2022-08-03
DOI: 10.1038/s41375-022-01650-w
Source: Full article
AbstractThe aim of this study was to characterize the mutational landscape of patients withFLT3-mutated acute myeloid leukemia (AML) treated within the randomized CALGB 10603/RATIFY trial evaluating intensive chemotherapy plus the multi-kinase inhibitor midostaurin versus placebo. We performed sequencing of 262 genes in 475 patients: mutations occurring concurrently with theFLT3-mutation were most frequent inNPM1(61%),DNMT3A(39%),WT1(21%),TET2(12%),NRAS(11%),RUNX1(11%),PTPN11(10%), andASXL1(8%) genes. To assess effects of clinical and genetic features and their possible interactions, we fitted random survival forests and interpreted the resulting variable importance. Highest prognostic impact was found forWT1andNPM1mutations, followed by white blood cell count,FLT3mutation type (internal tandem duplications vs. tyrosine kinase domain mutations), treatment (midostaurin vs. placebo),ASXL1mutation, and ECOG performance status. When evaluating two-fold variable combinations the most striking effects were found forWT1:NPM1(withNPM1mutation abrogating the negative effect ofWT1mutation), and forWT1:treatment (with midostaurin exerting a beneficial effect inWT1-mutated AML). This targeted gene sequencing study provides important, novel insights into the genomic background ofFLT3-mutated AML including the prognostic impact of co-mutations, specific gene–gene interactions, and possible treatment effects of midostaurin.