Molecular landscape and prognostic impact of FLT3 -ITD insertion site in acute myeloid leukemia : RATIFY study results
Rücker, Frank G. (University Hospital of Ulm (Alemanya))
Du, Ling (Novartis Pharmaceuticals, Cambridge)
Luck, Tamara J. (Charité University, Berlin)
Benner, Axel (German Cancer Research Center, Heidelberg)
Krzykalla, Julia (German Cancer Research Center, Heidelberg)
Gathmann, Insa (Novartis Pharmaceuticals, Basel)
Voso, Maria Teresa (Università di Roma "Tor Vergata", Rome)
Amadori, Sergio (Università di Roma "Tor Vergata", Rome)
Prior, Thomas W. (The Ohio State University Comprehensive Cancer Center, Columbus)
Brandwein, Joseph M. (University of Alberta, Edmonton)
Appelbaum, Frederick (Fred Hutchinson Cancer Research Center, Seattle)
Medeiros, Bruno (Stanford University)
Tallman, Martin S. (Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York)
Savoie, Lynn (University of Calgary, Calgary)
Sierra, Jorge (Institut d'Investigació Biomèdica Sant Pau)
Pallaud, Celine (Novartis Pharmaceuticals, Basel)
Sanz, Miguel A.. (Hospital Universitari i Politècnic La Fe (València))
Jansen, Joop H. (Radboud University Medical Center, Nijmegen)
Niederwieser, Dietger (Hematology and Oncology, University of Leipzig, Leipzig)
Fischer, Thomas (Otto-von-Guericke University Magdeburg, Magdeburg)
Ehninger, Gerhard (Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus der TU Dresden)
Heuser, Michael (Hannover Medical School, Hannover)
Ganser, Arnold (Oncology and Stem Cell Transplantation, Hannover)
Bullinger, Lars (Charité University, Berlin)
Larson, Richard A. (University of Chicago, Chicago)
Bloomfield, Clara D. (The Ohio State University Comprehensive Cancer Center, Columbus)
Stone, Richard M. (Dana-Farber/Partners CancerCare, Boston)
Döhner, Hartmut (University Hospital of Ulm (Alemanya))
Thiede, Christian (Universitätsklinikum Carl Gustav Carus der TU Dresden, Dresden)
Döhner, Konstanze (University Hospital of Ulm (Alemanya))
Universitat Autònoma de Barcelona

Data:	2021
Resum:	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.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Leukemia, Vol. 36 (july 2021) , p. 90-99, ISSN 1476-5551

DOI: 10.1038/s41375-021-01323-0
PMID: 34316017

1.2 MB

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