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000181024 1001_ $$aJahn, Nikolaus$$b0
000181024 245__ $$aGenomic landscape of patients with FLT3-mutated acute myeloid leukemia (AML) treated within the CALGB 10603/RATIFY trial.
000181024 260__ $$aLondon$$bSpringer Nature$$c2022
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000181024 500__ $$a2022 Sep;36(9):2218-2227
000181024 520__ $$aThe aim of this study was to characterize the mutational landscape of patients with FLT3-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 the FLT3-mutation were most frequent in NPM1 (61%), DNMT3A (39%), WT1 (21%), TET2 (12%), NRAS (11%), RUNX1 (11%), PTPN11 (10%), and ASXL1 (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 for WT1 and NPM1 mutations, followed by white blood cell count, FLT3 mutation type (internal tandem duplications vs. tyrosine kinase domain mutations), treatment (midostaurin vs. placebo), ASXL1 mutation, and ECOG performance status. When evaluating two-fold variable combinations the most striking effects were found for WT1:NPM1 (with NPM1 mutation abrogating the negative effect of WT1 mutation), and for WT1:treatment (with midostaurin exerting a beneficial effect in WT1-mutated AML). This targeted gene sequencing study provides important, novel insights into the genomic background of FLT3-mutated AML including the prognostic impact of co-mutations, specific gene-gene interactions, and possible treatment effects of midostaurin.
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000181024 7001_ $$aJahn, Ekaterina$$b1
000181024 7001_ $$aSaadati, Maral$$b2
000181024 7001_ $$aBullinger, Lars$$b3
000181024 7001_ $$00000-0001-9168-3203$$aLarson, Richard A$$b4
000181024 7001_ $$aOttone, Tiziana$$b5
000181024 7001_ $$aAmadori, Sergio$$b6
000181024 7001_ $$aPrior, Thomas W$$b7
000181024 7001_ $$aBrandwein, Joseph M$$b8
000181024 7001_ $$aAppelbaum, Frederick R$$b9
000181024 7001_ $$00000-0001-6972-8137$$aMedeiros, Bruno C$$b10
000181024 7001_ $$aTallman, Martin S$$b11
000181024 7001_ $$aEhninger, Gerhard$$b12
000181024 7001_ $$00000-0001-5318-9044$$aHeuser, Michael$$b13
000181024 7001_ $$aGanser, Arnold$$b14
000181024 7001_ $$aPallaud, Celine$$b15
000181024 7001_ $$aGathmann, Insa$$b16
000181024 7001_ $$0P:(DE-He78)5a7a75d1b29b770f98f1bb2062fc3df9$$aKrzykalla, Julia$$b17$$udkfz
000181024 7001_ $$0P:(DE-He78)e15dfa1260625c69d6690a197392a994$$aBenner, Axel$$b18$$udkfz
000181024 7001_ $$00000-0001-5465-7591$$aBloomfield, Clara D$$b19
000181024 7001_ $$00000-0003-1241-2048$$aThiede, Christian$$b20
000181024 7001_ $$00000-0002-7526-2633$$aStone, Richard M$$b21
000181024 7001_ $$aDöhner, Hartmut$$b22
000181024 7001_ $$00000-0002-2261-9862$$aDöhner, Konstanze$$b23
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