Andreas Burchert1, Gesine Bug2, Lea V Fritz1, Jürgen Finke3, Matthias Stelljes4, Christoph Röllig5, Ellen Wollmer1, Ralph Wäsch3, Martin Bornhäuser5, Tobias Berg2, Fabian Lang2, Gerhard Ehninger5, Hubert Serve2, Robert Zeiser3, Eva-Maria Wagner6, Nicolaus Kröger7, Christine Wolschke7, Michael Schleuning8, Katharina S Götze9, Christoph Schmid10, Martina Crysandt11, Eva Eßeling4, Dominik Wolf12, Ying Wang1, Alexandra Böhm13, Christian Thiede5, Torsten Haferlach14, Christian Michel1, Wolfgang Bethge15, Thomas Wündisch1, Christian Brandts2, Susanne Harnisch16, Michael Wittenberg16, Heinz-Gert Hoeffkes17, Susanne Rospleszcz18, Alexander Burchardt19, Andreas Neubauer1, Markus Brugger20, Konstantin Strauch20,21, Carmen Schade-Brittinger16, Stephan K Metzelder1. 1. Department of Internal Medicine, Hematology, Oncology and Immunology, Philipps University Marburg and University Hospital Gießen and Marburg, Campus Marburg, Marburg, Germany. 2. Department of Medicine 2, Hematology and Oncology, Goethe University Frankfurt, Frankfurt, Germany. 3. Department of Internal Medicine I, Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, Freiburg, Germany. 4. Department of Medicine A/Hematology and Oncology, University of Muenster, Münster, Germany. 5. Medical Department I, University Hospital Carl Gustav Carus, Technische Universitat Dresden, Germany. 6. Medical Department III, Hematology, Medical Oncology and Pneumology, University Mainz, Germany. 7. Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 8. German Clinic for Diagnostics, Helios Clinic, Wiesbaden, Germany. 9. Department of Medicine III, Technical University of Munich, Munich, Germany. 10. Department of Hematology and Oncology, University Hospital Augsburg, Augsburg, Germany. 11. Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany. 12. Department of Hematology and Oncology, University Hospital Bonn, Bonn, Germany; and Department of Hematology and Oncology, Innsbruck Medical University, Innsbruck, Austria. 13. Department of Hematology/Oncology/Stem Cell Transplantation, Ordensklinikum Linz Elisabethinen, Linz, Austria. 14. Munich Leukemia Laboratory, Munich, Germany. 15. University of Tuebingen Medical Center, Tuebingen, Germany. 16. Coordinating Center for Clinical Trials, Philipps University Marburg, Marburg, Germany. 17. Tumorklinik (Medizinische Onkologie, Palliativmedizin, Hämatologie und Hämostasiologie), Klinikum Fulda, Fulda, Germany. 18. Chair of Genetic Epidemiology, Institut für Medizinische Informationsverarbeitung Biometrie und Epidemiologie, Faculty of Medicine, Ludwigs Maximilian Universität München and Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany. 19. Department of Internal Medicine, Hematology, Oncology and Immunology, University Hospital Gießen and Marburg, Campus Gießen, Gießen, Germany. 20. Institut für Medizinische Informationsverarbeitung Biometrie und Epidemiologie, Faculty of Medicine, Ludwigs Maximilian Universität München and Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany and Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center, Johannes Gutenberg University, Mainz, Germany. 21. Institute of Medical Biometry and Epidemiology, Philipps University Marburg, Marburg, Germany.
Abstract
PURPOSE: Despite undergoing allogeneic hematopoietic stem cell transplantation (HCT), patients with acute myeloid leukemia (AML) with internal tandem duplication mutation in the FMS-like tyrosine kinase 3 gene (FLT3-ITD) have a poor prognosis, frequently relapse, and die as a result of AML. It is currently unknown whether a maintenance therapy using FLT3 inhibitors, such as the multitargeted tyrosine kinase inhibitor sorafenib, improves outcome after HCT. PATIENTS AND METHODS: In a randomized, placebo-controlled, double-blind phase II trial (SORMAIN; German Clinical Trials Register: DRKS00000591), 83 adult patients with FLT3-ITD-positive AML in complete hematologic remission after HCT were randomly assigned to receive for 24 months either the multitargeted and FLT3-kinase inhibitor sorafenib (n = 43) or placebo (n = 40 placebo). Relapse-free survival (RFS) was the primary endpoint of this trial. Relapse was defined as relapse or death, whatever occurred first. RESULTS: With a median follow-up of 41.8 months, the hazard ratio (HR) for relapse or death in the sorafenib group versus placebo group was 0.39 (95% CI, 0.18 to 0.85; log-rank P = .013). The 24-month RFS probability was 53.3% (95% CI, 0.36 to 0.68) with placebo versus 85.0% (95% CI, 0.70 to 0.93) with sorafenib (HR, 0.256; 95% CI, 0.10 to 0.65; log-rank P = .002). Exploratory data show that patients with undetectable minimal residual disease (MRD) before HCT and those with detectable MRD after HCT derive the strongest benefit from sorafenib. CONCLUSION:Sorafenib maintenance therapy reduces the risk of relapse and death after HCT for FLT3-ITD-positive AML.
RCT Entities:
PURPOSE: Despite undergoing allogeneic hematopoietic stem cell transplantation (HCT), patients with acute myeloid leukemia (AML) with internal tandem duplication mutation in the FMS-like tyrosine kinase 3 gene (FLT3-ITD) have a poor prognosis, frequently relapse, and die as a result of AML. It is currently unknown whether a maintenance therapy using FLT3 inhibitors, such as the multitargeted tyrosine kinase inhibitor sorafenib, improves outcome after HCT. PATIENTS AND METHODS: In a randomized, placebo-controlled, double-blind phase II trial (SORMAIN; German Clinical Trials Register: DRKS00000591), 83 adult patients with FLT3-ITD-positive AML in complete hematologic remission after HCT were randomly assigned to receive for 24 months either the multitargeted and FLT3-kinase inhibitor sorafenib (n = 43) or placebo (n = 40 placebo). Relapse-free survival (RFS) was the primary endpoint of this trial. Relapse was defined as relapse or death, whatever occurred first. RESULTS: With a median follow-up of 41.8 months, the hazard ratio (HR) for relapse or death in the sorafenib group versus placebo group was 0.39 (95% CI, 0.18 to 0.85; log-rank P = .013). The 24-month RFS probability was 53.3% (95% CI, 0.36 to 0.68) with placebo versus 85.0% (95% CI, 0.70 to 0.93) with sorafenib (HR, 0.256; 95% CI, 0.10 to 0.65; log-rank P = .002). Exploratory data show that patients with undetectable minimal residual disease (MRD) before HCT and those with detectable MRD after HCT derive the strongest benefit from sorafenib. CONCLUSION:Sorafenib maintenance therapy reduces the risk of relapse and death after HCT for FLT3-ITD-positive AML.
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