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.

Andrea Kündgen, Hartmut Döhner, Arnold Ganser, Konstanze Döhner, Daniela Weber, Brigitte Schlegelberger, Verena I Gaidzik, Gerhard Held, Claus-Henning Köhne, Mohammed Wattad, David Nachbaur, Katharina Götze, Peter Brossart, Heinz-A Horst, Martin Bentz, Helmut R Salih, Hans Martin, Wolfgang Herr, Jürgen Krauter, Alexander Lamparter, Michael Lübbert, Richard F Schlenk, Hans Salwender, Axel Benner, Gerald Wulf, Walter Fiedler, Bernd Hertenstein

Journal: Annals of hematology 2017;95(12):1931-1942

PMID: 27696203

Free Full Text on PubMed Central View on PubMed

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/m, days 6-8; 15 mg/m, 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).

Address: Department of Internal Medicine III, University Hospital of Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany. [email protected].; National Center for Tumor Diseases (NCT), German Cancer Research Center, Heidelberg, Germany. [email protected].; Department of Hematology and Oncology, University Hospital of Freiburg, Freiburg, Germany.; Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany.; Department of Internal Medicine III, University Hospital of Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany.; Department of Oncology and Hematology, Klinikum Braunschweig, Braunschweig, Germany.; Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.; Department of Medicine III, Johannes Gutenberg-University Mainz, Mainz, Germany.; Department of Internal Medicine III, University of Regensburg, Regensburg, Germany.; Department of Internal Medicine II, University Hospital, Frankfurt, Germany.; Department of Hematology and Oncology, Eberhard-Karls University, Tübingen, Germany.; Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.; Department of Internal Medicine II, University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany.; Department of Internal Medicine III, University Hospital of Bonn, Bonn, Germany.; Department of Internal Medicine III, Technical University of Munich, Munich, Germany.; Department of Internal Medicine V, University Hospital Innsbruck, Innsbruck, Austria.; Department of Hematology, Oncology and Stem Cell Transplantation, Klinikum Essen Süd, Essen, Germany.; Department of Oncology and Hematology, Klinikum Oldenburg, Oldenburg, Germany.; Department of Internal Medicine II, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Department of Internal Medicine III, Städtisches Klinikum Karlsruhe, Karlsruhe, Germany.; Department of Hematology and Oncology, University Hospital of Göttingen, Göttingen, Germany.; Department of Internal Medicine I, University Hospital of Saarland, Homburg, Germany.; Department of Internal Medicine I, Klinikum Bremen Mitte, Bremen, Germany.; Department of Hematology/Oncology, Asklepios Klinik Altona, Hamburg, Germany.; Institute of Human Genetics, Hannover Medical School, Hannover, Germany.

DOI: 10.1007/s00277-016-2810-z

Link outs

Free resources

Full Text Sources:

Medical:

Other Literature Sources:

Miscellaneous:

https://assays.cancer.gov/non-CPTAC-3340

Subscription / membership required

Full Text Sources:

https://dx.doi.org/10.1007/s00277-016-2810-z

MeSH Terms: Adolescent, Adult, Antineoplastic Combined Chemotherapy Protocols, Female, Follow-Up Studies, Humans, Induction Chemotherapy, Leukemia, Myeloid, Acute, Male, Middle Aged, Nucleophosmin, Survival Rate, Treatment Outcome, Tretinoin, Young Adult