Journal Article

DKFZ-2021-01743

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Molecular landscape and prognostic impact of FLT3-ITD insertion site in acute myeloid leukemia: RATIFY study results.

Rücker, F. G. ; Du, L. ; Luck, T. J. ; Benner, A.DKFZ* ; Krzykalla, J.DKFZ* ; Gathmann, I. ; Voso, M. T. ; Amadori, S. ; Prior, T. W. ; Brandwein, J. M. ; Appelbaum, F. R. ; Medeiros, B. C. ; Tallman, M. S. ; Savoie, L. ; Sierra, J. ; Pallaud, C. ; Sanz, M. A. ; Jansen, J. H. ; Niederwieser, D. ; Fischer, T. ; Ehninger, G. ; Heuser, M. ; Ganser, A. ; Bullinger, L. ; Larson, R. A. ; Bloomfield, C. D. ; Stone, R. M. ; Döhner, H. ; Thiede, C. ; Döhner, K.

2022
Springer Nature London

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Please use a persistent id in citations: doi:10.1038/s41375-021-01323-0

Abstract: In acute myeloid leukemia (AML) internal tandem duplications of the FLT3 gene (FLT3-ITD) are associated with poor prognosis. Retrospectively, we investigated the prognostic and predictive impact of FLT3-ITD insertion site (IS) in 452 patients randomized within the RATIFY trial, which evaluated midostaurin additionally to intensive chemotherapy. Next-generation sequencing identified 908 ITDs, with 643 IS in the juxtamembrane domain (JMD) and 265 IS in the tyrosine kinase domain-1 (TKD1). According to IS, patients were categorized as JMDsole (n = 251, 55%), JMD and TKD1 (JMD/TKD1; n = 117, 26%), and TKD1sole (n = 84, 19%). While clinical variables did not differ among the 3 groups, NPM1 mutation was correlated with JMDsole (P = 0.028). Overall survival (OS) differed significantly, with estimated 4-year OS probabilities of 0.44, 0.50, and 0.30 for JMDsole, JMD/TKD1, and TKD1sole, respectively (P = 0.032). Multivariate (cause-specific) Cox models for OS and cumulative incidence of relapse using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable identified TKD1sole as unfavorable and HCT as favorable factors. In addition, Midostaurin exerted a significant benefit only for JMDsole. Our results confirm the distinct molecular heterogeneity of FLT3-ITD and the negative prognostic impact of TKD1 IS in AML that was not overcome by midostaurin.

Note: 2022 Jan;36(1):90-99

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Contributing Institute(s):

1. C060 Biostatistik (C060)

Research Program(s):

1. 313 - Krebsrisikofaktoren und Prävention (POF4-313) (POF4-313)

Appears in the scientific report 2021

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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