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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2021-07-28

AUTHORS

Frank G. Rücker, Ling Du, Tamara J. Luck, Axel Benner, Julia Krzykalla, Insa Gathmann, Maria Teresa Voso, Sergio Amadori, Thomas W. Prior, Joseph M. Brandwein, Frederick R. Appelbaum, Bruno C. Medeiros, Martin S. Tallman, Lynn Savoie, Jorge Sierra, Celine Pallaud, Miguel A. Sanz, Joop H. Jansen, Dietger Niederwieser, Thomas Fischer, Gerhard Ehninger, Michael Heuser, Arnold Ganser, Lars Bullinger, Richard A. Larson, Clara D. Bloomfield, Richard M. Stone, Hartmut Döhner, Christian Thiede, Konstanze Döhner

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. More... »

PAGES

90-99

Journal

TITLE

Leukemia

ISSUE

1

VOLUME

36

Author Affiliations

  • Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany
  • Novartis Pharmaceuticals, Cambridge, MA, USA
  • Department of Hematology, Oncology and Tumor Immunology, Charité University, Berlin, Germany
  • Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany
  • Novartis Pharmaceuticals, Basel, Switzerland
  • Department of Biomedicine and Prevention, Università di Roma “Tor Vergata”, Rome, Italy
  • The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
  • Department of Medicine, University of Alberta, Edmonton, AB, Canada
  • Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
  • Division of Hematology, Stanford Comprehensive Cancer Center, Stanford University, Stanford, CA, USA
  • Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA
  • University of Calgary, Calgary, AB, Canada
  • Hematology Department, Hospital de la Santa Creu i Sant Pau and Jose Carreras Leukemia Research Institute, Autonomus University of Barcelona, Barcelona, Spain
  • Hospital Universitario la Fe, Hematology Department, Department of Medicine, University of Valencia, Valencia, Spain
  • Radboud Institute Molecular Studies, Radboud University Medical Center, Nijmegen, The Netherlands
  • Hematology and Oncology, University of Leipzig, Leipzig, Germany
  • Department of Hematology and Oncology, Center of Internal Medicine, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
  • Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus der TU Dresden, Dresden, Germany
  • Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
  • Department of Medicine and Comprehensive Cancer Center, University of Chicago, Chicago, IL, USA
  • Department of Medical Oncology, Dana-Farber/Partners CancerCare, Boston, MA, USA
  • Related Patents

    Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41375-021-01323-0

    DOI

    http://dx.doi.org/10.1038/s41375-021-01323-0

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1139977804

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/34316017


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