TY  - JOUR
AU  - Jahn, Ekaterina
AU  - Saadati, Maral
AU  - Fenaux, Pierre
AU  - Gobbi, Marco
AU  - Roboz, Gail J
AU  - Bullinger, Lars
AU  - Lutsik, Pavlo
AU  - Riedel, Anna
AU  - Plass, Christoph
AU  - Jahn, Nikolaus
AU  - Walter, Claudia
AU  - Holzmann, Karlheinz
AU  - Hao, Yong
AU  - Naim, Sue
AU  - Schreck, Nicholas
AU  - Krzykalla, Julia
AU  - Benner, Axel
AU  - Keer, Harold N
AU  - Azab, Mohammad
AU  - Döhner, Konstanze
AU  - Döhner, Hartmut
TI  - Clinical impact of the genomic landscape and leukemogenic trajectories in non-intensively treated elderly acute myeloid leukemia patients.
JO  - Leukemia
VL  - 37
IS  - 11
SN  - 0887-6924
CY  - London
PB  - Springer Nature
M1  - DKFZ-2023-01725
SP  - 2187-2196
PY  - 2023
N1  - 2023 Nov;37(11):2187-2196
AB  - 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), DDX41wildtype/FLT3-ITDneg/TP53wildtype (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.
LB  - PUB:(DE-HGF)16
C6  - pmid:37591941
DO  - DOI:10.1038/s41375-023-01999-6
UR  - https://inrepo02.dkfz.de/record/282341
ER  -