AUTHOR=Stasik Sebastian , Kramer Michael , Zukunft Sven , Röllig Christoph , Baldus Claudia D. , Platzbecker Uwe , Serve Hubert , Müller-Tidow Carsten , Schäfer-Eckart Kerstin , Kaufmann Martin , Krause Stefan , Sauer Tim , Hänel Mathias , Neubauer Andreas , Ehninger Gerhard , Bornhäuser Martin , Schetelig Johannes , Middeke Jan M. , Thiede Christian 

TITLE=Point Mutations in the FLT3-ITD Region Are Rare but Recurrent Alterations in Adult AML and Associated With Concomitant KMT2A-PTD

JOURNAL=Frontiers in Oncology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.862991

DOI=10.3389/fonc.2022.862991

ISSN=2234-943X

ABSTRACT=<p><italic>FLT3</italic>-ITD mutations are common druggable alterations in patients with acute myeloid leukemia (AML) and associated with poor prognosis. Beside typical ITD mutations, point mutations and deletions in the juxtamembrane domain (JMD) have been observed. However, due to the low frequency of these alterations, there is only limited information on molecular and clinical associations. To evaluate the prognostic impact of non-ITD mutations in the <italic>FLT3</italic> JMD region, we analyzed a large cohort of 1,539 adult AML patients treated in different protocols of the Study Alliance Leukemia, using next-generation sequencing. Non-ITD point mutations and deletions within the <italic>FLT3</italic> JMD were identified with a prevalence of ~1.23% (n = 19). Both <italic>FLT3</italic>-ITD and non-ITD mutations were associated with a higher rate of <italic>NPM1</italic> (42%–61%; <italic>p</italic> &lt; 0.001) and <italic>DNMT3A</italic> mutations (37%–43%; <italic>p</italic> &lt; 0.001), as well as an increased percentage of peripheral blood (54%–65%) and bone marrow blast cells (74%; <italic>p</italic> &lt; 0.001), compared to <italic>FLT3</italic>-wild-type patients. Most significantly, AML patients with <italic>FLT3</italic> non-ITD mutations had a higher rate of concomitant <italic>KMT2A</italic>-PTD mutations (37.5%; <italic>p</italic> &lt; 0.001) as compared to <italic>FLT3</italic>-ITD (7%) or <italic>FLT3</italic>-wild-type cases (4.5%). In a multivariable analysis, <italic>FLT3</italic> non-ITD mutations were not an independent prognostic factor. However, patients with dual <italic>FLT3</italic> non-ITD and <italic>KMT2A</italic>-PTD mutations showed a trend for inferior outcome, which points at a functional interaction in this subset of AML.</p>