Abstract
DNA methylation changes are a constant feature of acute myeloid leukemia. Hypomethylating drugs such as azacitidine are active in acute myeloid leukemia (AML) as monotherapy. Azacitidine monotherapy is not curative. The AML-AZA trial tested the hypothesis that DNA methyltransferase inhibitors such as azacitidine can improve chemotherapy outcome in AML. This randomized, controlled trial compared the efficacy of azacitidine applied before each cycle of intensive chemotherapy with chemotherapy alone in older patients with untreated AML. Event-free survival (EFS) was the primary end point. In total, 214 patients with a median age of 70 years were randomized to azacitidine/chemotherapy (arm-A) or chemotherapy (arm-B). More arm-A patients (39/105; 37%) than arm-B (25/109; 23%) showed adverse cytogenetics (P=0.057). Adverse events were more frequent in arm-A (15.44) versus 13.52 in arm-B, (P=0.26), but early death rates did not differ significantly (30-day mortality: 6% versus 5%, P=0.76). Median EFS was 6 months in both arms (P=0.96). Median overall survival was 15 months for patients in arm-A compared with 21 months in arm-B (P=0.35). Azacitidine added to standard chemotherapy increases toxicity in older patients with AML, but provides no additional benefit for unselected patients.
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Acknowledgements
We are grateful to all patients for participation in the clinical trial. We thank all participating Centers and the ZKS in Münster for support. This trial was partially supported by Celgene Inc. (http://www.celgene.com) and Amgen Inc. (http://www.amgen.com). Study medication was provided by Celgene Inc. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Biomarker analysis within the trial was funded by the German Research Foundation (DFG) priority program 1641. AN is supported by the Jose Carreas Leukemia foundation (AN06/01). ZKS Münster is also funded by the German Federal Ministry of Education and Research (BMBF, 01KN1105).
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CMT, PT, KG and UK received payment for lectures from Celgene Inc. CMT received research funding from Celgene Inc. and Amgen Inc. UK and CMT received travel expenses from Celgene Inc. and Amgen Inc. Azacitidine is a product of Celgene Inc. There are no further patents, products in development or marketed products to declare. The remaining authors declare no conflict of interest.
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Müller-Tidow, C., Tschanter, P., Röllig, C. et al. Azacitidine in combination with intensive induction chemotherapy in older patients with acute myeloid leukemia: The AML-AZA trial of the study alliance leukemia. Leukemia 30, 555–561 (2016). https://doi.org/10.1038/leu.2015.306
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DOI: https://doi.org/10.1038/leu.2015.306
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