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@ARTICLE{Dhner:276086,
      author       = {H. Döhner and D. Weber and J. Krzykalla$^*$ and W. Fiedler
                      and M. W. M. Kühn and T. Schroeder and K. Mayer and M.
                      Lübbert and M. Wattad and K. Götze and L. Fransecky and E.
                      Koller and G. Wulf and J. Schleicher and M. Ringhoffer and
                      R. Greil and B. Hertenstein and J. Krauter and U. M. Martens
                      and D. Nachbaur and M. A. Samra and S. Machherndl-Spandl and
                      N. Basara and C. Leis and A. Schrade and S. Kapp-Schwoerer
                      and S. Cocciardi and L. Bullinger and F. Thol and M. Heuser
                      and P. Paschka and V. I. Gaidzik and M. Saadati and A.
                      Benner$^*$ and R. F. Schlenk$^*$ and K. Döhner and A.
                      Ganser},
      collaboration = {G. A. S. Group},
      othercontributors = {H. Döhner and D. Weber and J. Krzykalla$^*$ and W. Fiedler
                          and M. W. M. Kühn and T. Schroeder and K. Mayer and M.
                          Lübbert and M. Wattad and K. Götze and L. Fransecky and E.
                          Koller and G. Wulf and J. Schleicher and M. Ringhoffer and
                          R. Greil and B. Hertenstein and J. Krauter and U. M. Martens
                          and D. Nachbaur and M. A. Samra and S. Machherndl-Spandl and
                          N. Basara and C. Leis and A. Schrade and S. Kapp-Schwoerer
                          and S. Cocciardi and L. Bullinger and F. Thol and M. Heuser
                          and P. Paschka and V. I. Gaidzik and M. Saadati and A.
                          Benner$^*$ and R. F. Schlenk$^*$ and K. Döhner and A.
                          Ganser},
      title        = {{I}ntensive chemotherapy with or without gemtuzumab
                      ozogamicin in patients with {NPM}1-mutated acute myeloid
                      leukaemia ({AMLSG} 09-09): a randomised, open-label,
                      multicentre, phase 3 trial.},
      journal      = {The lancet / Haematology},
      volume       = {10},
      number       = {7},
      issn         = {2352-3026},
      address      = {London [u.a.]},
      publisher    = {Elsevier},
      reportid     = {DKFZ-2023-00992},
      pages        = {e495-e509},
      year         = {2023},
      note         = {2023 Jul;10(7):e495-e509},
      abstract     = {Acute myeloid leukaemia with mutated NPM1 is associated
                      with high CD33 expression and intermediate-risk
                      cytogenetics. The aim of this study was to evaluate
                      intensive chemotherapy with or without the anti-CD33
                      antibody-drug conjugate gemtuzumab ozogamicin in
                      participants with newly diagnosed, NPM1-mutated acute
                      myeloid leukaemia.This open-label, phase 3 trial was
                      conducted at 56 hospitals in Germany and Austria. Eligible
                      participants were 18 years or older and had newly diagnosed
                      NPM1-mutated acute myeloid leukaemia and an Eastern
                      Cooperative Oncology Group performance status of 0-2.
                      Participants were randomly assigned, using age as a
                      stratification factor (18-60 years vs >60 years), 1:1 to the
                      two treatment groups using allocation concealment; there was
                      no masking of participants and investigators to treatment
                      groups. Participants received two cycles of induction
                      therapy (idarubicin, cytarabine, and etoposide) plus
                      all-trans retinoic acid (ATRA) followed by three
                      consolidation cycles of high-dose cytarabine (or an
                      intermediate dose for those older than 60 years) and ATRA,
                      without or with gemtuzumab ozogamicin (3 mg/m2 administered
                      intravenously on day 1 of induction cycles 1 and 2, and
                      consolidation cycle 1). The primary endpoints were
                      short-term event-free survival and overall survival in the
                      intention-to-treat population (overall survival was added as
                      a co-primary endpoint after amendment four of the protocol
                      on Oct 13, 2013). The secondary endpoints were event-free
                      survival with long-term follow-up, rates of complete
                      remission, complete remission with partial haematological
                      recovery (CRh), and complete remission with incomplete
                      haematological recovery (CRi), cumulative incidences of
                      relapse and death, and number of days in hospital. This
                      trial is registered with ClinicalTrials.gov (NCT00893399)
                      and has been completed.Between May 12, 2010, and Sept 1,
                      2017, 600 participants were enrolled, of which 588 (315
                      women and 273 men) were randomly assigned (296 to the
                      standard group and 292 to the gemtuzumab ozogamicin group).
                      No difference was found in short-term event-free survival
                      (short-term event-free survival at 6-month follow-up, $53\%$
                      $[95\%$ CI 47-59] in the standard group and $58\%$ [53-64]
                      in the gemtuzumab ozogamicin group; hazard ratio [HR] 0·83;
                      $95\%$ CI 0·65-1·04; p=0·10) and overall survival between
                      treatment groups (2-year overall survival, $69\%$ [63-74] in
                      the standard group and $73\%$ [68-78] in the gemtuzumab
                      ozogamicin group; 0·90; 0·70-1·16; p=0·43). There was no
                      difference in complete remission or CRi rates (n=267
                      $[90\%]$ in the standard group vs n=251 $[86\%]$ in the
                      gemtuzumab ozogamicin group; odds ratio [OR] 0·67; $95\%$
                      CI 0·40-1·11; p=0·15) and complete remission or CRh rates
                      (n=214 $[72\%]$ vs n=195 $[67\%];$ OR 0·77; 0·54-1·10;
                      p=0·18), whereas the complete remission rate was lower with
                      gemtuzumab ozogamicin (n=172 $[58\%]$ vs n=136 $[47\%];$ OR
                      0·63; 0·45-0·80; p=0·0068). Cumulative incidence of
                      relapse was significantly reduced by gemtuzumab ozogamicin
                      (2-year cumulative incidence of relapse, $37\%$ $[95\%$ CI
                      31-43] in the standard group and $25\%$ [20-30] in the
                      gemtuzumab ozogamicin group; cause-specific HR 0·65;
                      0·49-0·86; p=0·0028), and there was no difference in the
                      cumulative incidence of death (2-year cumulative incidence
                      of death $6\%$ [4-10] in the standard group and $7\%$ [5-11]
                      in the gemtuzumab ozogamicin group; HR 1·03; 0·59-1·81;
                      p=0·91). There were no differences in the number of days in
                      hospital across all cycles between treatment groups. The
                      most common treatment-related grade 3-4 adverse events were
                      febrile neutropenia (n=135 $[47\%]$ in the gemtuzumab
                      ozogamicin group vs n=122 $[41\%]$ in the standard group),
                      thrombocytopenia (n=261 $[90\%]$ vs n=265 $[90\%]),$
                      pneumonia (n=71 $[25\%]$ vs n=64 $[22\%]),$ sepsis (n=85
                      $[29\%]$ vs n=73 $[25\%]).$ Treatment-related deaths were
                      documented in 25 participants $(4\%;$ n=8 $[3\%]$ in the
                      standard group and n=17 $[6\%]$ in the gemtuzumab ozogamicin
                      group), mostly due to sepsis and infections.The primary
                      endpoints of the trial of event-free survival and overall
                      survival were not met. However, an anti-leukaemic efficacy
                      of gemtuzumab ozogamicin in participants with NPM1-mutated
                      acute myeloid leukaemia is shown by a significantly lower
                      cumulative incidence of relapse rate, suggesting that the
                      addition of gemtuzumab ozogamicin might reduce the need for
                      salvage therapy in these participants. The results from this
                      study provide further evidence that gemtuzumab ozogamicin
                      should be added in the standard of care treatment in adults
                      with NPM1-mutated acute myeloid leukaemia.Pfizer and Amgen.},
      cin          = {C060 / W010},
      ddc          = {610},
      cid          = {I:(DE-He78)C060-20160331 / I:(DE-He78)W010-20160331},
      pnm          = {313 - Krebsrisikofaktoren und Prävention (POF4-313)},
      pid          = {G:(DE-HGF)POF4-313},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37187198},
      doi          = {10.1016/S2352-3026(23)00089-3},
      url          = {https://inrepo02.dkfz.de/record/276086},
}