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

Richard F Schlenk, Michael Lübbert, Axel Benner, Alexander Lamparter, Jürgen Krauter, Wolfgang Herr, 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, German-Austrian Acute Myeloid Leukemia Study Group, Richard F Schlenk, Michael Lübbert, Axel Benner, Alexander Lamparter, Jürgen Krauter, Wolfgang Herr, 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, German-Austrian Acute Myeloid Leukemia Study Group

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.

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.

Figures

Fig. 1
Fig. 1
Flow chart on study conduct. Flow chart showing enrollment, program completion and/or drop-out according to the randomization result. Abbreviations: IC informed consent, RD refractory disease, HCT hematopoietic cell transplantation
Fig. 2
Fig. 2
Survival analyses according to randomization according to intention-to-treat and per-protocol analysis
Fig. 3
Fig. 3
Survival after relapse according to European LeukemiaNet (ELN) classification analyzed on an intention-to-treat basis. a ELN favorable-risk group; b all other ELN risk groups

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