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@ARTICLE{Cocciardi:297977,
      author       = {S. Cocciardi and M. Saadati$^*$ and N. Weiß and D. Späth
                      and S. Kapp-Schwoerer and I. Schneider and A. Meid and V. I.
                      Gaidzik and S. Skambraks and W. Fiedler and M. W. M. Kühn
                      and U. Germing and K. T. Mayer and M. Lübbert and E.
                      Papaemmanuil and F. Thol and M. Heuser and A. Ganser and L.
                      Bullinger and A. Benner$^*$ and H. Döhner and K. Döhner},
      title        = {{I}mpact of myelodysplasia-related and additional gene
                      mutations in intensively treated patients with
                      {NPM}1-mutated {AML}.},
      journal      = {HemaSphere},
      volume       = {9},
      number       = {1},
      issn         = {2572-9241},
      address      = {Hoboken},
      publisher    = {John Wiley $\&$ Sons Ltd.},
      reportid     = {DKFZ-2025-00152},
      pages        = {e70060},
      year         = {2025},
      abstract     = {This study aimed to evaluate the impact of the
                      myelodysplasia-related gene (MRG) as well as additional gene
                      mutations on outcomes in intensively treated patients with
                      NPM1-mutated (NPM1 mut) AML. Targeted DNA sequencing of 263
                      genes was performed in 568 NPM1 mut AML patients (median
                      age: 59 years) entered into the prospective AMLSG 09-09
                      treatment trial. Most commonly co-mutated genes were DNMT3A
                      $(49.8\%),$ FLT3-TKD $(25.9\%),$ PTPN11 $(24.8\%),$ NRAS
                      $(22.7\%),$ TET2 $(21.7\%),$ IDH2 $(21.3\%),$ IDH1 $(18\%),$
                      and FLT3-ITD $(17.3\%).$ MRG mutations were identified in
                      $18.1\%$ of cases (18-60 years: $9.8\%;$ >60 years:
                      $28.7\%).$ When focusing on the 470 patients with 2022 ELN
                      favorable-risk NPM1 mut AML, multivariable analysis for
                      event-free survival (EFS) identified age (p < 0.001), DNMT3A
                      R882 (p < 0.001), IDH1 (p = 0.007), and MRG mutations (p =
                      0.03) as unfavorable factors, cohesin gene co-mutations (p =
                      0.001) and treatment with gemtuzumab ozogamicin (p = 0.007)
                      as favorable factors. Restricting the analysis to a subset
                      of CR/CRi patients with available data on NPM1 mut
                      measurable residual disease (MRD) status in blood post cycle
                      2 in the model, MRG mutations lost their significant effect,
                      whereas DNMT3A R882, MYC, and cohesin gene mutations
                      retained the adverse and favorable effects. For OS, age (p <
                      0.001), DNMT3A R882 (p = 0.042), IDH1 (p = 0.045), and KRAS
                      (0.003) mutations were unfavorable factors, sole favorable
                      factor was IDH2 co-mutation (p = 0.037). In 2022 ELN
                      favorable-risk NPM1 mut AML, MRG mutations are associated
                      with inferior EFS; however, this effect is no longer present
                      when considering NPM1 mut MRD status post cycle 2; DNMT3A
                      R882 and MYC mutations remained adverse, and cohesin gene
                      mutations favorable prognostic factors independent of the
                      NPM1 mut MRD status.},
      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:39816531},
      pmc          = {pmc:PMC11733593},
      doi          = {10.1002/hem3.70060},
      url          = {https://inrepo02.dkfz.de/record/297977},
}