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Clinical impact of the genomic landscape and leukemogenic trajectories in non-intensively treated elderly acute myeloid leukemia patients

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Item Type:Article
Title:Clinical impact of the genomic landscape and leukemogenic trajectories in non-intensively treated elderly acute myeloid leukemia patients
Creators Name:Jahn, E. and Saadati, M. and Fenaux, P. and Gobbi, M. and Roboz, G.J. and Bullinger, L. and Lutsik, P. and Riedel, A. and Plass, C. and Jahn, N. and Walter, C. and Holzmann, K. and Hao, Y. and Naim, S. and Schreck, N. and Krzykalla, J. and Benner, A. and Keer, H.N. and Azab, M. and Döhner, K. and Döhner, H.
Abstract:To characterize the genomic landscape and leukemogenic pathways of older, newly diagnosed, non-intensively treated patients with AML and to study the clinical implications, comprehensive genetics analyses were performed including targeted DNA sequencing of 263 genes in 604 patients treated in a prospective Phase III clinical trial. Leukemic trajectories were delineated using oncogenetic tree modeling and hierarchical clustering, and prognostic groups were derived from multivariable Cox regression models. Clonal hematopoiesis-related genes (ASXL1, TET2, SRSF2, DNMT3A) were most frequently mutated. The oncogenetic modeling algorithm produced a tree with five branches with ASXL1, DDX41, DNMT3A, TET2, and TP53 emanating from the root suggesting leukemia-initiating events which gave rise to further subbranches with distinct subclones. Unsupervised clustering mirrored the genetic groups identified by the tree model. Multivariable analysis identified FLT3 internal tandem duplications (ITD), SRSF2, and TP53 mutations as poor prognostic factors, while DDX41 mutations exerted an exceptionally favorable effect. Subsequent backwards elimination based on the Akaike information criterion delineated three genetic risk groups: DDX41 mutations (favorable-risk), DDX41(wildtype)/FLT3-ITD(neg)/TP53(wildtype) (intermediate-risk), and FLT3-ITD or TP53 mutations (high-risk). Our data identified distinct trajectories of leukemia development in older AML patients and provide a basis for a clinically meaningful genetic outcome stratification for patients receiving less intensive therapies.
Keywords:Acute Myeloid Leukemia, fms-Like Tyrosine Kinase 3, Genomics, Mutation, Nucleophosmin, Prognosis, Prospective Studies, Transcription Factors
Publisher:Nature Publishing Group
Page Range:2187-2196
Date:November 2023
Additional Information:Erratum in: Leukemia 2023 Oct 3
Official Publication:https://doi.org/10.1038/s41375-023-01999-6
PubMed:View item in PubMed

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