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Ann Hematol. 2016 Dec;95(12):1931-1942. Epub 2016 Oct 3.

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.

Author information

1
Department of Internal Medicine III, University Hospital of Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany. richard.schlenk@uniklinik-ulm.de.
2
National Center for Tumor Diseases (NCT), German Cancer Research Center, Heidelberg, Germany. richard.schlenk@uniklinik-ulm.de.
3
Department of Hematology and Oncology, University Hospital of Freiburg, Freiburg, Germany.
4
Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany.
5
Department of Internal Medicine III, University Hospital of Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany.
6
Department of Oncology and Hematology, Klinikum Braunschweig, Braunschweig, Germany.
7
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
8
Department of Medicine III, Johannes Gutenberg-University Mainz, Mainz, Germany.
9
Department of Internal Medicine III, University of Regensburg, Regensburg, Germany.
10
Department of Internal Medicine II, University Hospital, Frankfurt, Germany.
11
Department of Hematology and Oncology, Eberhard-Karls University, Tübingen, Germany.
12
Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
13
Department of Internal Medicine II, University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany.
14
Department of Internal Medicine III, University Hospital of Bonn, Bonn, Germany.
15
Department of Internal Medicine III, Technical University of Munich, Munich, Germany.
16
Department of Internal Medicine V, University Hospital Innsbruck, Innsbruck, Austria.
17
Department of Hematology, Oncology and Stem Cell Transplantation, Klinikum Essen Süd, Essen, Germany.
18
Department of Oncology and Hematology, Klinikum Oldenburg, Oldenburg, Germany.
19
Department of Internal Medicine II, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
20
Department of Internal Medicine III, Städtisches Klinikum Karlsruhe, Karlsruhe, Germany.
21
Department of Hematology and Oncology, University Hospital of Göttingen, Göttingen, Germany.
22
Department of Internal Medicine I, University Hospital of Saarland, Homburg, Germany.
23
Department of Internal Medicine I, Klinikum Bremen Mitte, Bremen, Germany.
24
Department of Hematology/Oncology, Asklepios Klinik Altona, Hamburg, Germany.
25
Institute of Human Genetics, Hannover Medical School, Hannover, Germany.

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).

KEYWORDS:

Acute myeloid leukemia; All-trans retinoic acid; Nucleophosmin-1

PMID:
27696203
PMCID:
PMC5093206
DOI:
10.1007/s00277-016-2810-z
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Compliance with ethical standards Conflicts of interest Authors indicated no potential conflict of interest. Authors’ contribution Conception and Design: Richard F. Schlenk, Michael Lübbert, Hartmut Döhner Provision of study materials or patients: Richard F. Schlenk, Michael Lübbert, Jürgen Krauter, Thomas Kindler, Hans Martin, Helmut R. Salih, Andrea Kündgen, Heinz-A. Horst, Peter Brossart, Katharina Götze, David Nachbaur, Mohammed Wattad, Claus-Henning Köhne, Walter Fiedler, Martin Bentz, Gerald Wulf, Gerhard Held, Bernd Hertenstein, Hans Salwender, Verena I Gaidzik, Brigitte Schlegelberger, Konstanze Döhner, Arnold Ganser, Hartmut Döhner. Collection and assembly of data: Richard F. Schlenk, Alexander Lamparter, Daniela Weber. Data analysis and interpretation: Richard F. Schlenk, Alexander Lamparter, Axel Benner, Hartmut Döhner. Manuscript writing: Richard F. Schlenk, Hartmut Döhner. Final approval of manuscript: Richard F. Schlenk, Michael Lübbert, Axel Benner, Alexander Lamparter, Jürgen Krauter, Thomas Kindler, Hans Martin, Helmut R. Salih, Andrea Kündgen, Heinz-A. Horst, Peter Brossart, Katharina Götze, David Nachbaur, Mohammed Wattad, Claus-Henning Köhne, Walter Fiedler, Martin Bentz, Gerald Wulf, Gerhard Held, Bernd Hertenstein, Hans Salwender, Verena I Gaidzik, Brigitte Schlegelberger, Daniela Weber, Konstanze Döhner, Arnold Ganser, Hartmut Döhner.

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