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Molecular landscape and prognostic impact of FLT3-ITD insertion site in acute myeloid leukemia: RATIFY study results

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Item Type:Article
Title:Molecular landscape and prognostic impact of FLT3-ITD insertion site in acute myeloid leukemia: RATIFY study results
Creators Name:Rücker, F.G. and Du, L. and Luck, T.J. and Benner, A. and Krzykalla, J. and Gathmann, I. and Voso, M.T. and Amadori, S. and Prior, T.W. and Brandwein, J.M. and Appelbaum, F.R. and Medeiros, B.C. and Tallman, M.S. and Savoie, L. and Sierra, J. and Pallaud, C. and Sanz, M.A. and Jansen, J.H. and Niederwieser, D. and Fischer, T. and Ehninger, G. and Heuser, M. and Ganser, A. and Bullinger, L. and Larson, R.A. and Bloomfield, C.D. and Stone, R.M. and Döhner, H. and Thiede, C. and Döhner, K.
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.
Keywords:Antineoplastic Combined Chemotherapy Protocols, Tumor Biomarkers, Combined Modality Therapy, Follow-Up Studies, Hematopoietic Stem Cell Transplantation, Acute Myeloid Leukemia, Insertional Mutagenesis, Prognosis, Retrospective Studies, Survival Rate, Tandem Repeat Sequences, Homologous TransplantationHomologous, fms-Like Tyrosine Kinase 3 / Genetics
Publisher:Nature Publishing Group
Page Range:90-99
Date:January 2022
Official Publication:https://doi.org/10.1038/s41375-021-01323-0
PubMed:View item in PubMed

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