Michael Lübbert1,2, Olga Grishina1, Claudia Schmoor1, Richard F Schlenk3,4, Edgar Jost5, Martina Crysandt5, Michael Heuser6, Felicitas Thol6, Helmut R Salih7, Marcus M Schittenhelm8, Ulrich Germing9, Andrea Kuendgen9,10, Katharina S Götze11,12, Hans-Walter Lindemann13, Carsten Müller-Tidow4,14,15, Gerhard Heil16, Sebastian Scholl17, Gesine Bug18,19, Carsten Schwaenen20,21, Aristoteles Giagounidis22, Andreas Neubauer23, Jürgen Krauter24, Wolfram Brugger25, Maike De Wit26, Ralph Wäsch1, Heiko Becker1,2, Annette M May1, Justus Duyster1,2, Konstanze Döhner3, Arnold Ganser6, Björn Hackanson1,27, Hartmut Döhner3. 1. Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany. 2. German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Freiburg, Germany. 3. University Hospital of Ulm, Ulm, Germany. 4. Heidelberg University Hospital, Heidelberg, Germany. 5. University Hospital Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany. 6. Hannover Medical School, Hannover, Germany. 7. German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Tübingen, Germany. 8. Eberhard-Karls-University, Tübingen, Germany. 9. Faculty of Medicine, Heinrich-Heine University, Düsseldorf, Germany. 10. German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Düsseldorf, Germany. 11. Technical University of Munich, Munich, Germany. 12. German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Munich, Germany. 13. Catholic Hospital, Hagen, Germany. 14. University Hospital of Münster, Münster, Germany. 15. German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. 16. Klinikum Lüdenscheid, Lüdenscheid, Germany. 17. Universitätsklinikum Jena, Jena, Germany. 18. University Hospital Frankfurt, Goethe University, Frankfurt, Germany. 19. German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Frankfurt, Germany. 20. Hospital Esslingen, Esslingen, Germany. 21. Offenburg Hospital, Offenburg, Germany. 22. Marien-Hospital Düsseldorf, Düsseldorf, Germany. 23. University Clinic Gießen/Marburg, Marburg, Germany. 24. Städtisches Klinikum Braunschweig, Braunschweig, Germany. 25. Hospital Villingen-Schwenningen, Villingen-Schwenningen, Germany. 26. Vivantes Klinikum Neukoelln, Berlin, Germany. 27. Universitätsklinikum Augsburg, Augsburg, Germany.
Abstract
PURPOSE: DNA-hypomethylating agents are studied in combination with other epigenetic drugs, such as histone deacetylase inhibitors or differentiation inducers (eg, retinoids), in myeloid neoplasias. A randomized, phase II trial with a 2 × 2 factorial design was conducted to investigate the effects of the histone deacetylase inhibitor valproate and all-trans retinoic acid (ATRA) in treatment-naive elderly patients with acute myeloid leukemia (AML). PATIENTS AND METHODS: Two hundred patients (median age, 76 years; range, 61-92 years) ineligible forinduction chemotherapy received decitabine (20 mg/m2 intravenously, days 1 to 5) alone (n = 47) or in combination with valproate (n = 57), ATRA (n = 46), or valproate + ATRA (n = 50). The primary endpoint was objective response, defined as complete and partial remission, tested at a one-sided significance level of α = .10. Key secondary endpoints were overall survival, event-free survival, and progression-free survival and safety. RESULTS: The addition of ATRA resulted in a higher remission rate (21.9% with ATRA v 13.5% without ATRA; odds ratio, 1.80; 95% CI, 0.86 to 3.79; one-sided P = .06). For valproate, no effect was observed (17.8% with valproate v 17.2% without valproate; odds ratio, 1.06; 95% CI, 0.51 to 2.21; one-sided P = .44). Median overall survival was 8.2 months with ATRA v 5.1 months without ATRA (hazard ratio, 0.65; 95% CI, 0.48 to 0.89; two-sided P = .006). Improved survival was observed across risk groups, including patients with adverse cytogenetics, and was associated with longer response duration. With valproate, no survival difference was observed. Toxicities were predominantly hematologic, without relevant differences between the 4 arms. CONCLUSION: The addition of ATRA to decitabine resulted in a higher remission rate and a clinically meaningful survival extension in these patients with difficult-to-treat disease, without added toxicity.
RCT Entities:
PURPOSE: DNA-hypomethylating agents are studied in combination with other epigenetic drugs, such as histone deacetylase inhibitors or differentiation inducers (eg, retinoids), in myeloid neoplasias. A randomized, phase II trial with a 2 × 2 factorial design was conducted to investigate the effects of the histone deacetylase inhibitor valproate and all-trans retinoic acid (ATRA) in treatment-naive elderly patients with acute myeloid leukemia (AML). PATIENTS AND METHODS: Two hundred patients (median age, 76 years; range, 61-92 years) ineligible for induction chemotherapy received decitabine (20 mg/m2 intravenously, days 1 to 5) alone (n = 47) or in combination with valproate (n = 57), ATRA (n = 46), or valproate + ATRA (n = 50). The primary endpoint was objective response, defined as complete and partial remission, tested at a one-sided significance level of α = .10. Key secondary endpoints were overall survival, event-free survival, and progression-free survival and safety. RESULTS: The addition of ATRA resulted in a higher remission rate (21.9% with ATRA v 13.5% without ATRA; odds ratio, 1.80; 95% CI, 0.86 to 3.79; one-sided P = .06). For valproate, no effect was observed (17.8% with valproate v 17.2% without valproate; odds ratio, 1.06; 95% CI, 0.51 to 2.21; one-sided P = .44). Median overall survival was 8.2 months with ATRA v 5.1 months without ATRA (hazard ratio, 0.65; 95% CI, 0.48 to 0.89; two-sided P = .006). Improved survival was observed across risk groups, including patients with adverse cytogenetics, and was associated with longer response duration. With valproate, no survival difference was observed. Toxicities were predominantly hematologic, without relevant differences between the 4 arms. CONCLUSION: The addition of ATRA to decitabine resulted in a higher remission rate and a clinically meaningful survival extension in these patients with difficult-to-treat disease, without added toxicity.
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