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Genomic landscape of patients with FLT3-mutated acute myeloid leukemia (AML) treated within the CALGB 10603/RATIFY trial

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Item Type:Article
Title:Genomic landscape of patients with FLT3-mutated acute myeloid leukemia (AML) treated within the CALGB 10603/RATIFY trial
Creators Name:Jahn, N. and Jahn, E. and Saadati, M. and Bullinger, L. and Larson, R.A. and Ottone, T. and Amadori, S. and Prior, T.W. and Brandwein, J.M. and Appelbaum, F.R. and Medeiros, B.C. and Tallman, M.S. and Ehninger, G. and Heuser, M. and Ganser, A. and Pallaud, C. and Gathmann, I. and Krzykalla, J. and Benner, A. and Bloomfield, C.D. and Thiede, C. and Stone, R.M. and Döhner, H. and Döhner, K.
Abstract:The 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.
Keywords:Acute Myeloid Leukaemia, Cancer Genetics
Source:Leukemia
ISSN:0887-6924
Publisher:Nature Publishing Group
Volume:36
Number:9
Page Range:2218-2227
Date:September 2022
Official Publication:https://doi.org/10.1038/s41375-022-01650-w
PubMed:View item in PubMed

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