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@ARTICLE{Rcker:170080,
      author       = {F. G. Rücker and L. Du and T. J. Luck and A. Benner$^*$
                      and J. Krzykalla$^*$ and I. Gathmann and M. T. Voso and S.
                      Amadori and T. W. Prior and J. M. Brandwein and F. R.
                      Appelbaum and B. C. Medeiros and M. S. Tallman and L. Savoie
                      and J. Sierra and C. Pallaud and M. A. Sanz and J. H. Jansen
                      and D. Niederwieser and T. Fischer and G. Ehninger and M.
                      Heuser and A. Ganser and L. Bullinger and R. A. Larson and
                      C. D. Bloomfield and R. M. Stone and H. Döhner and C.
                      Thiede and K. Döhner},
      title        = {{M}olecular landscape and prognostic impact of {FLT}3-{ITD}
                      insertion site in acute myeloid leukemia: {RATIFY} study
                      results.},
      journal      = {Leukemia},
      volume       = {36},
      number       = {1},
      issn         = {1476-5551},
      address      = {London},
      publisher    = {Springer Nature},
      reportid     = {DKFZ-2021-01743},
      pages        = {90-99},
      year         = {2022},
      note         = {2022 Jan;36(1):90-99},
      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.},
      cin          = {C060},
      ddc          = {610},
      cid          = {I:(DE-He78)C060-20160331},
      pnm          = {313 - Krebsrisikofaktoren und Prävention (POF4-313)},
      pid          = {G:(DE-HGF)POF4-313},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:34316017},
      doi          = {10.1038/s41375-021-01323-0},
      url          = {https://inrepo02.dkfz.de/record/170080},
}