Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Acute myeloid leukemia

Azacitidine in combination with intensive induction chemotherapy in older patients with acute myeloid leukemia: The AML-AZA trial of the study alliance leukemia

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Juliusson G, Antunovic P, Derolf A, Lehmann S, Mollgard L, Stockelberg D et al. Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry. Blood 2009; 113: 4179–4187.

    Article  CAS  PubMed  Google Scholar 

  2. Büchner T, Berdel WE, Haferlach C, Haferlach T, Schnittger S, Müller-Tidow C et al. Age-related risk profile and chemotherapy dose response in acute myeloid leukemia: a study by the German Acute Myeloid Leukemia Cooperative Group. J Clin Oncol 2009; 27: 61–69.

    Article  PubMed  Google Scholar 

  3. Krug U, Röllig C, Koschmieder A, Heinecke A, Sauerland MC, Schaich M et al. Complete remission and early death after intensive chemotherapy in patients aged 60 years or older with acute myeloid leukaemia: a web-based application for prediction of outcomes. Lancet 2010; 376: 2000–2008.

    Article  CAS  PubMed  Google Scholar 

  4. Röllig C, Thiede C, Gramatzki M, Aulitzky W, Bodenstein H, Bornhäuser M et al. A novel prognostic model in elderly patients with acute myeloid leukemia: results of 909 patients entered into the prospective AML96 trial. Blood 2010; 116: 971–978.

    Article  PubMed  Google Scholar 

  5. Rowe JM . Important milestones in acute leukemia in 2013. Best Pract Res Clin Haematol 2013; 26: 241–244.

    Article  PubMed  Google Scholar 

  6. Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 2013; 368: 2059–2074.

    Article  Google Scholar 

  7. Patel JP, Gönen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 2012; 366: 1079–1089.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Thol F, Damm F, Lüdeking A, Winschel C, Wagner K, Morgan M et al. Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia. J Clin Oncol 2011; 29: 2889–2896.

    Article  CAS  PubMed  Google Scholar 

  9. Gaidzik VI, Schlenk RF, Paschka P, Stölzle A, Späth D, Kuendgen A et al. Clinical impact of DNMT3A mutations in younger adult patients with acute myeloid leukemia: results of the AML Study Group (AMLSG). Blood 2013; 121: 4769–4777.

    Article  CAS  PubMed  Google Scholar 

  10. Marcucci G, Metzeler KH, Schwind S, Becker H, Maharry K, Mrozek K et al. Age-related prognostic impact of different types of DNMT3A mutations in adults with primary cytogenetically normal acute myeloid leukemia. J Clin Oncol 2012; 30: 742–750.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Schoofs T, Müller-Tidow C . DNA methylation as a pathogenic event and as a therapeutic target in AML. Cancer Treat Rev 2011; 37: S13–S18.

    Article  CAS  PubMed  Google Scholar 

  12. Kantarjian HM, Thomas XG, Dmoszynska A, Wierzbowska A, Mazur G, Mayer J et al. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol 2012; 30: 2670–2677.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Fenaux P, Mufti GJ, Hellström-Lindberg E, Santini V, Gattermann N, Germing U et al. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol 2010; 28: 562–569.

    Article  CAS  PubMed  Google Scholar 

  14. Cros E, Jordheim L, Dumontet C, Galmarini CM . Problems related to resistance to cytarabine in acute myeloid leukemia. Leuk Lymphoma 2004; 45: 1123–1132.

    Article  CAS  PubMed  Google Scholar 

  15. Kong XB, Tong WP, Chou TC . Induction of deoxycytidine kinase by 5-azacitidine in an HL-60 cell line resistant to arabinosylcytosine. Mol Pharmacol 1991; 39: 250–257.

    CAS  PubMed  Google Scholar 

  16. Neil GL, Berger AE, Bhuyan BK, DeSante DC . Combination chemotherapy of L1210 leukemia with 1-beta-D-arabinofuranosylcytosine and 5-azacitidine. Cancer Res 1976; 36: 1114–1120.

    CAS  PubMed  Google Scholar 

  17. Avramis VI, Mecum RA, Nyce J, Steele DA, Holcenberg JS . Pharmacodynamic and DNA methylation studies of high-dose 1-beta-D-arabinofuranosyl cytosine before and after in vivo 5-azacitidine treatment in pediatric patients with refractory acute lymphocytic leukemia. Cancer Chemother Pharmacol 1989; 24: 203–210.

    CAS  PubMed  Google Scholar 

  18. Krug U, Koschmieder A, Schwammbach D, Gerss J, Tidow N, Steffen B et al. Feasibility of azacitidine added to standard chemotherapy in older patients with acute myeloid leukemia—a randomised SAL pilot study. PLoS One 2012; 7: e52695.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Scandura JM, Roboz GJ, Moh M, Morawa E, Brenet F, Bose JR et al. Phase 1 study of epigenetic priming with decitabine prior to standard induction chemotherapy for patients with AML. Blood 2011; 118: 1472–1480.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Döhner H, Estey EH, Amadori S, Appelbaum FR, Büchner T, Burnett AK et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010; 115: 453–474.

    Article  PubMed  Google Scholar 

  21. Niederwieser D, Hoffmann VS, Krahl R, Berdel WE, Sauerland MC, Hiddemann W et al. Factors Influencing Complete Remission (CR) Rate in Patients >= 60 Years with Acute Myeloid Leukemia (AML): Report From the German AML Intergroup Study. ASH Annual Meeting Abstracts 2012; 120: 128.

    Google Scholar 

  22. Brunnberg U, Mohr M, Noppeney R, Dürk HA, Sauerland MC, Müller-Tidow C et al. Induction therapy of AML with ara-C plus daunorubicin versus ara-C plus gemtuzumab ozogamicin: a randomized phase II trial in elderly patients. Ann Oncol 2012; 23: 990–996.

    Article  CAS  PubMed  Google Scholar 

  23. Serve H, Krug U, Wagner R, Sauerland MC, Heinecke A, Brunnberg U et al. Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia: results from a randomized, placebo-controlled trial. J Clin Oncol 2013; 31: 3110–3118.

    Article  CAS  PubMed  Google Scholar 

  24. Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH et al. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol 2003; 21: 4642–4649.

    Article  PubMed  Google Scholar 

  25. Fenaux P, Mufti GJ, Hellström-Lindberg E, Santini V, Finelli C, Giagounidis A et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 2009; 10: 223–232.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

Authors

Consortia

Corresponding author

Correspondence to C Müller-Tidow.

Ethics declarations

Competing interests

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.

Additional information

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2015.306

This article is cited by

Search

Quick links