title: All-trans retinoic acid as adjunct to intensive treatment in younger adult patients with acute myeloid leukemia: results of the randomized AMLSG 07-04 study.
abstract: The aim of this clinical trial was to evaluate the impact of all-trans retinoic acid (ATRA) in combination with chemotherapy and to assess the NPM1 status as biomarker for ATRA therapy in younger adult patients (18-60 years) with acute myeloid leukemia (AML). Patients were randomized for intensive chemotherapy with or without open-label ATRA (45 mg/m2, days 6-8; 15 mg/m2, days 9-21). Two cycles of induction therapy were followed by risk-adapted consolidation with high-dose cytarabine or allogeneic hematopoietic cell transplantation. Due to the open label character of the study, analysis was performed on an intention-to-treat (ITT) and a per-protocol (PP) basis. One thousand one hundred patients were randomized (556, STANDARD; 544, ATRA) with 38 patients treated vice versa. Median follow-up for survival was 5.2 years. ITT analyses revealed no difference between ATRA and STANDARD for the total cohort and for the subset of NPM1-mutated AML with respect to event-free (EFS; p = 0.93, p = 0.17) and overall survival (OS; p = 0.24 and p = 0.32, respectively). Pre-specified PP analyses revealed better EFS in NPM1-mutated AML (p = 0.05) and better OS in the total cohort (p = 0.03). Explorative subgroup analyses on an ITT basis revealed better OS (p = 0.05) in ATRA for genetic low-risk patients according to ELN recommendations. The clinical trial is registered at clinicaltrialsregister.eu (EudraCT Number: 2004-004321-95).
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany. richard.schlenk@uniklinik-ulm.de.|National Center for Tumor Diseases (NCT), German Cancer Research Center, Heidelberg, Germany. richard.schlenk@uniklinik-ulm.de.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Schlenk
authors.affiliation: Department of Hematology and Oncology, University Hospital of Freiburg, Freiburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Lübbert
authors.affiliation: Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Benner
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Lamparter
authors.affiliation: Department of Oncology and Hematology, Klinikum Braunschweig, Braunschweig, Germany.|Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Krauter
authors.affiliation: Department of Medicine III, Johannes Gutenberg-University Mainz, Mainz, Germany.|Department of Internal Medicine III, University of Regensburg, Regensburg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Herr
authors.affiliation: Department of Internal Medicine II, University Hospital, Frankfurt, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Martin
authors.affiliation: Department of Hematology and Oncology, Eberhard-Karls University, Tübingen, Germany.
authors.forename: Helmut R
authors.initials: HR
authors.lastname: Salih
authors.affiliation: Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Kündgen
authors.affiliation: Department of Internal Medicine II, University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany.
authors.forename: Heinz-A
authors.initials: HA
authors.lastname: Horst
authors.affiliation: Department of Internal Medicine III, University Hospital of Bonn, Bonn, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Brossart
authors.affiliation: Department of Internal Medicine III, Technical University of Munich, Munich, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Götze
authors.affiliation: Department of Internal Medicine V, University Hospital Innsbruck, Innsbruck, Austria.
authors.forename: David
authors.initials: D
authors.lastname: Nachbaur
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, Klinikum Essen Süd, Essen, Germany.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Wattad
authors.affiliation: Department of Oncology and Hematology, Klinikum Oldenburg, Oldenburg, Germany.
authors.forename: Claus-Henning
authors.initials: CH
authors.lastname: Köhne
authors.affiliation: Department of Internal Medicine II, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Fiedler
authors.affiliation: Department of Internal Medicine III, Städtisches Klinikum Karlsruhe, Karlsruhe, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Bentz
authors.affiliation: Department of Hematology and Oncology, University Hospital of Göttingen, Göttingen, Germany.
authors.forename: Gerald
authors.initials: G
authors.lastname: Wulf
authors.affiliation: Department of Internal Medicine I, University Hospital of Saarland, Homburg, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Held
authors.affiliation: Department of Internal Medicine I, Klinikum Bremen Mitte, Bremen, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Hertenstein
authors.affiliation: Department of Hematology/Oncology, Asklepios Klinik Altona, Hamburg, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Salwender
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany.
authors.forename: Verena I
authors.initials: VI
authors.lastname: Gaidzik
authors.affiliation: Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schlegelberger
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Weber
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany.
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
authors.affiliation: Department of Hematology/Oncology, Asklepios Klinik Altona, Hamburg, Germany.
authors.forename: Arnold
authors.initials: A
authors.lastname: Ganser
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D060828:Induction Chemotherapy / Q000379:methods* / Q000401:mortality; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D000090243:Nucleophosmin; D015996:Survival Rate / Q000639:trends; D016896:Treatment Outcome; D014212:Tretinoin / Q000008:administration & dosage*; D055815:Young Adult
chemical_list: C000716967:NPM1 protein, human; D000090243:Nucleophosmin; D014212:Tretinoin
keywords: Acute myeloid leukemia; All-trans retinoic acid; Nucleophosmin-1