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

Stasik S, Kramer M, Zukunft S, Rollig C, Baldus CD, Platzbecker U, Serve H, Muller-Tidow C, Schafer-Eckart K, Kaufmann M, Krause S, Sauer T, Hanel M, Neubauer A, Ehninger G, Bornhauser M, Schetelig J, Middeke JM, Thiede C (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Frontiers in Oncology Frontiers Media

Book Volume: 12

DOI: 10.3389/fonc.2022.862991

Abstract

FLT3-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 FLT3 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 FLT3 JMD were identified with a prevalence of ~1.23% (n = 19). Both FLT3-ITD and non-ITD mutations were associated with a higher rate of NPM1 (42%-61%; p < 0.001) and DNMT3A mutations (37%-43%; p < 0.001), as well as an increased percentage of peripheral blood (54%-65%) and bone marrow blast cells (74%; p < 0.001), compared to FLT3-wild-type patients. Most significantly, AML patients with FLT3 non-ITD mutations had a higher rate of concomitant KMT2A-PTD mutations (37.5%; p < 0.001) as compared to FLT3-ITD (7%) or FLT3-wild-type cases (4.5%). In a multivariable analysis, FLT3 non-ITD mutations were not an independent prognostic factor. However, patients with dual FLT3 non-ITD and KMT2A-PTD mutations showed a trend for inferior outcome, which points at a functional interaction in this subset of AML.

Authors with CRIS profile

Stefan Krause Department of Medicine 5 – Haematology and Oncology

Involved external institutions

Universitätsklinikum Carl Gustav Carus Dresden DE Germany (DE) Charité - Universitätsmedizin Berlin DE Germany (DE) Universitätsklinikum Leipzig DE Germany (DE) Universitätsklinikum Frankfurt am Main (KGU) DE Germany (DE) Universitätsklinikum Heidelberg DE Germany (DE) Nuremberg Hospital North, North Hospital / Klinikum Nürnberg Nord, Nordklinikum DE Germany (DE) Robert-Bosch-Krankenhaus DE Germany (DE) Klinikum Chemnitz DE Germany (DE) Philipps-Universität Marburg DE Germany (DE)

How to cite

APA:

Stasik, S., Kramer, M., Zukunft, S., Rollig, C., Baldus, C.D., Platzbecker, U.,... Thiede, C. (2022). Point Mutations in the FLT3-ITD Region Are Rare but Recurrent Alterations in Adult AML and Associated With Concomitant KMT2A-PTD. Frontiers in Oncology, 12. https://doi.org/10.3389/fonc.2022.862991

MLA:

Stasik, Sebastian, et al. "Point Mutations in the FLT3-ITD Region Are Rare but Recurrent Alterations in Adult AML and Associated With Concomitant KMT2A-PTD." Frontiers in Oncology 12 (2022).

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