Midostaurin plus intensive chemotherapy for younger and older patients with AML and <i>FLT3</i> internal tandem duplications

  • Hartmut Döhner
    1Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany;
  • Daniela Weber
    1Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany;
  • Julia Krzykalla
    2Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany;
  • Walter Fiedler
    3Hubertus Wald University Cancer Center, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany;
  • Gerald Wulf
    4Department of Hematology and Oncology, Georg-August-University Göttingen, Göttingen, Germany;
  • Helmut Salih
    5Department of Hematology and Oncology, Eberhard-Karls University, Tübingen, Germany;
  • Michael Lübbert
    6Department of Medicine I, Medical Center – University of Freiburg, Freiburg, Germany;
  • Michael W. M. Kühn
    7Department of Hematology, Medical Oncology & Pneumology, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany;
  • Thomas Schroeder
    8Department of Hematology, Oncology, and Clinical Immunology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany;
  • Hans Salwender
    9Department of Oncology and Hematology, Asklepios Tumorzentrum Hamburg, AK Altona and AK St. Georg, Hamburg, Germany;
  • Katharina Götze
    10Department of Medicine III, Hematology and Medical Oncology, Technical University of Munich, Munich, Germany;
  • Jörg Westermann
    11Department of Hematology, Oncology and Tumorimmunology, Charité University Medicine Berlin, Campus Virchow Klinikum, Berlin, Germany;
  • Lars Fransecky
    12Department of Internal Medicine II, University Hospital Schleswig Holstein, Campus Kiel, Kiel, Germany;
  • Karin Mayer
    13Department of Hematology, Oncology, University Hospital Bonn, Bonn, Germany;
  • Bernd Hertenstein
    14Department of Hematology and Oncology, Klinikum Bremen-Mitte, Bremen, Germany;
  • Mark Ringhoffer
    15Department of Internal Medicine III, Städtisches Klinikum Karlsruhe, Karlsruhe, Germany;
  • Hans-Joachim Tischler
    16Department of Hematology and Oncology, University Hospital of Minden, Minden, Germany;
  • Sigrid Machherndl-Spandl
    17Department of Hematology and Oncology, Hospital Elisabethinen Linz, Linz, Austria;
  • Anika Schrade
    1Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany;
  • Peter Paschka
    1Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany;
  • Verena I. Gaidzik
    1Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany;
  • Frauke Theis
    1Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany;
  • Felicitas Thol
    18Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany;
  • Michael Heuser
    18Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany;
  • Richard F. Schlenk
    19National Center of Tumor Diseases, German Cancer Research Center, Heidelberg, Germany;
  • Lars Bullinger
    11Department of Hematology, Oncology and Tumorimmunology, Charité University Medicine Berlin, Campus Virchow Klinikum, Berlin, Germany;
  • Maral Saadati
    21Freelance Statistician, Saadati Solutions, Ladenburg, Germany;
  • Axel Benner
    2Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany;
  • Richard Larson
    22Department of Medicine and Comprehensive Cancer Center, University of Chicago, Chicago, IL; and
  • Richard Stone
    23Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
  • Konstanze Döhner
    1Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany;
  • Arnold Ganser
    18Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany;

抄録

<jats:title>Abstract</jats:title> <jats:p>We conducted a single-arm, phase 2 trial (German-Austrian Acute Myeloid Leukemia Study Group [AMLSG] 16-10) to evaluate midostaurin with intensive chemotherapy followed by allogeneic hematopoietic-cell transplantation (HCT) and a 1-year midosta urin maintenance therapy in adult patients with acute myeloid leukemia (AML) and fms-related tyrosine kinase 3 (FLT3) internal tandem duplication (ITD). Patients 18 to 70 years of age with newly diagnosed FLT3-ITD-positive AML were eligible. Primary and key secondary endpoints were event-free survival (EFS) and overall survival (OS). Results were compared with a historical cohort of 415 patients treated on 5 prior AMLSG trials; statistical analysis was performed using a double-robust adjustment with propensity score weighting and covariate adjustment. Results were also compared with patients (18-59 years) treated on the placebo arm of the Cancer and Leukemia Group B (CALGB) 10603/RATIFY trial. The trial accrued 440 patients (18-60 years, n = 312; 61-70 years, n = 128). In multivariate analysis, EFS was significantly in favor of patients treated within the AMLSG 16-10 trial compared with the AMLSG control (hazard ratio [HR], 0.55; P &lt; .001); both in younger (HR, 0.59; P &lt; .001) and older patients (HR, 0.42; P &lt; .001). Multivariate analysis also showed a significant beneficial effect on OS compared with the AMLSG control (HR, 0.57; P &lt; .001) as well as to the CALGB 10603/RATIFY trial (HR, 0.71; P = .005). The treatment effect of midostaurin remained significant in sensitivity analysis including allogeneic HCT as a time-dependent covariate. Addition of midostaurin to chemotherapy was safe in younger and older patients. In comparison with historical controls, the addition of midostaurin to intensive therapy led to a significant improvement in outcome in younger and older patients with AML and FLT3-ITD. This trial is registered at clinicaltrialsregistry.eu as Eudra-CT number 2011-003168-63 and at clinicaltrials.gov as NCT01477606.</jats:p>

収録刊行物

  • Blood Advances

    Blood Advances 6 (18), 5345-5355, 2022-09-21

    American Society of Hematology

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