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

Autor: Rücker FG; Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany., Du L; Novartis Pharmaceuticals, Cambridge, MA, USA., Luck TJ; Department of Hematology, Oncology and Tumor Immunology, Charité University, Berlin, Germany., Benner A; Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany., Krzykalla J; Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany., Gathmann I; Novartis Pharmaceuticals, Basel, Switzerland., Voso MT; Department of Biomedicine and Prevention, Università di Roma 'Tor Vergata', Rome, Italy., Amadori S; Department of Biomedicine and Prevention, Università di Roma 'Tor Vergata', Rome, Italy., Prior TW; The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA., Brandwein JM; Department of Medicine, University of Alberta, Edmonton, AB, Canada., Appelbaum FR; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Medeiros BC; Division of Hematology, Stanford Comprehensive Cancer Center, Stanford University, Stanford, CA, USA., Tallman MS; Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA., Savoie L; University of Calgary, Calgary, AB, Canada., Sierra J; Hematology Department, Hospital de la Santa Creu i Sant Pau and Jose Carreras Leukemia Research Institute, Autonomus University of Barcelona, Barcelona, Spain., Pallaud C; Novartis Pharmaceuticals, Basel, Switzerland., Sanz MA; Hospital Universitario la Fe, Hematology Department, Department of Medicine, University of Valencia, Valencia, Spain., Jansen JH; Radboud Institute Molecular Studies, Radboud University Medical Center, Nijmegen, The Netherlands., Niederwieser D; Hematology and Oncology, University of Leipzig, Leipzig, Germany., Fischer T; Department of Hematology and Oncology, Center of Internal Medicine, Otto-von-Guericke University Magdeburg, Magdeburg, Germany., Ehninger G; Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus der TU Dresden, Dresden, Germany., Heuser M; Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany., Ganser A; Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany., Bullinger L; Department of Hematology, Oncology and Tumor Immunology, Charité University, Berlin, Germany., Larson RA; Department of Medicine and Comprehensive Cancer Center, University of Chicago, Chicago, IL, USA., Bloomfield CD; The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA., Stone RM; Department of Medical Oncology, Dana-Farber/Partners CancerCare, Boston, MA, USA., Döhner H; Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany., Thiede C; Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus der TU Dresden, Dresden, Germany., Döhner K; Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany. konstanze.doehner@uniklinik-ulm.de.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2022 Jan; Vol. 36 (1), pp. 90-99. Date of Electronic Publication: 2021 Jul 28.
DOI: 10.1038/s41375-021-01323-0
Abstrakt: 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.
(© 2021. The Author(s).)
Databáze: MEDLINE
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