Advances in Therapy

, 28:1 | Cite as

Azacitidine for the treatment of patients with acute myeloid leukemia with 20%–30% blasts and multilineage dysplasia

Review

Abstract

Azacitidine is approved in the EU for the treatment of adult patients who are not candidates for allogeneic stem cell transplantation, and who have intermediate-2 risk or high-risk myelodysplastic syndromes, according to the International Prognostic Scoring System. The approval includes the treatment of patients with acute myeloid leukemia (AML) with 20%–30% blasts and multilineage dysplasia, according to the World Health Organization (WHO) classification. This review focuses on the outcomes with azacitidine in this latter group of patients, previously classified as refractory anemia with excess of blasts in transformation, as defined by the French-American-British classification criteria. The main clinical evidence is based on the results of two large phase III clinical trials (Cancer and Leukemia Group B 9221, and AZA-001). The AZA-001 trial shows azacitidine significantly prolongs median overall survival in older patients with low marrow blasts (20%–30%) according to WHO-defined AML, and significantly improved several patient morbidity measures, compared with conventional care regimens. In addition, the review examines the results of azacitidine in combination with other treatments currently used in AML.

Keywords

azacitidine acute myeloid leukemia myelodysplastic syndromes 

References

  1. 1.
    Silverman LR. Targeting hypomethylation of DNA to achieve cellular differentiation in myelodysplastic syndromes (MDS) Oncologist. 2001;6(suppl. 5):8–14.PubMedCrossRefGoogle Scholar
  2. 2.
    Leone G, Teofili L, Voso MT, Lübbert M. DNA methylation and demethylating drugs in myelodysplastic syndromes and secondary leukemias. Haematologica. 2002;87:1324–1341.PubMedGoogle Scholar
  3. 3.
    Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89:2079–2088.PubMedGoogle Scholar
  4. 4.
    Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 2002;100:2292–2302.PubMedCrossRefGoogle Scholar
  5. 5.
  6. 6.
    Fenaux P, Mufti G, Hellstrom-Lindberg E, 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.PubMedCrossRefGoogle Scholar
  7. 7.
    National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology. Acute Myeloid Leukemia. V.2.2011. Available at: http://www.nccn.org/professionals/physician_gls. Accessed January 30, 2011.
  8. 8.
    Appelbaum F, Gundacker H, Head D, et al. Age and acute myeloid leukemia. Blood. 2006;107:3481–3485.PubMedCrossRefGoogle Scholar
  9. 9.
    Kantarjian H, O’Brien S, Cortes J, et al. Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: predictive prognostic models for outcome. Cancer. 2006;106:1090–1098.PubMedCrossRefGoogle Scholar
  10. 10.
    Deschler B, de Witte T, Mertelsmann R, et al. Treatment decision-making for older patients with high-risk myelodysplastic syndrome or acute myeloid leukemia: problems and approaches. Haematologica. 2006;91:1513–1522.PubMedGoogle Scholar
  11. 11.
    Gardin C, Turlure P, Fagot T, et al. Postremission treatment of elderly patients with acute myeloid leukemia in first complete remission after intensive induction chemotherapy: results of the multicenter randomized Acute Leukemia French Association (ALFA) 9803 trial. Blood. 2007;109:5129–5135.PubMedCrossRefGoogle Scholar
  12. 12.
    Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the Cancer and Leukemia Group B. J Clin Oncol. 2002;20:2429–2440.PubMedCrossRefGoogle Scholar
  13. 13.
    Silverman LR, Holland JF, Weinberg RS, et al. Effects of treatment with 5-azacytidine on the in vivo and in vitro hematopoiesis in patients with myelodysplastic syndromes. Leukemia. 1993;7:21–29.PubMedGoogle Scholar
  14. 14.
    Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol. 1982;51:189–199.PubMedGoogle Scholar
  15. 15.
    Silverman LR, McKenzie DR, Peterson BL, et al. Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. J Clin Oncol. 2006;24:3895–3903.PubMedCrossRefGoogle Scholar
  16. 16.
    Kornblith AB, Herndon JE 2nd, Silverman LR, et al. Impact of azacytidine on the quality of life of patients with myelodysplastic syndrome treated in a randomized phase III trial: a Cancer and Leukemia Group B study. J Clin Oncol. 2002;20:2441–2452.PubMedCrossRefGoogle Scholar
  17. 17.
    Fenaux P, Mufti GJ, Hellström-Lindberg E, et al. Azacitidine prolongs overall survival compared with conventional care regimens in older adult patients with low bone marrow blast count (20–30%) acute myeloid leukemia. J Clin Oncol. 2009;28:562–569.PubMedCrossRefGoogle Scholar
  18. 18.
    Rowe JM, Neuberg D, Friedenberg W, et al; Eastern Cooperative Oncology. A phase 3 study of three induction regimens and of priming with GM-CSF in older adults with acute myeloid leukemia: a trial by the Eastern Cooperative Oncology Group. Blood. 2004;103:479–485.PubMedCrossRefGoogle Scholar
  19. 19.
    Santini V, Fenaux P, Mufti GJ, et al. Management and supportive care measures for adverse events in patients with myelodysplastic syndromes treated with azacitidine. Eur J Haematol. 2010;85:130–138.PubMedGoogle Scholar
  20. 20.
    Fenaux P, Bowen D, Gattermann N, et al. Practical use of azacitidine in higher-risk myelodysplastic syndromes: an expert panel opinion. Leuk Res. 2010;34:1410–1416.PubMedCrossRefGoogle Scholar
  21. 21.
    Thépot S, Itzykson R, Seegers V, et al. Azacytidine (AZA) as first line therapy in AML: results of the French ATU program. Blood (ASH Annual Meeting Abstracts). 2009;114:843.Google Scholar
  22. 22.
    Itzykson R, Thépot S, Recher C, et al. Azacytidine in refractory or relapsed AML after intensive chemotherapy (IC): results of the French ATU program. Blood (ASH Annual Meeting Abstracts). 2009;114:1054.Google Scholar
  23. 23.
    Itzykson R, Thépot S, Quesnel B, et al. Prognostic factors for response and overall survival in 282 patients with higher-risk myelodysplastic syndromes treated with azacitidine. Blood. 2011;117:403–411.PubMedCrossRefGoogle Scholar
  24. 24.
    Grövdal M, Karimi M, Khan R, et al. Maintenance treatment with azacytidine for patients with highrisk myelodysplastic syndromes (MDS) or acute myeloid leukaemia following MDS in complete remission after induction chemotherapy. Br J Haematol. 2010;150:293–302.PubMedCrossRefGoogle Scholar
  25. 25.
    Gardin C, Prébet T, Bouabdallah K, et al. A phase II study of post-remission therapy with azacitidine (AZA) in patients with AML post-MDS and highrisk MDS: a GFM group study. Blood (ASH Annual Meeting Abstracts). 2009;114:844.Google Scholar
  26. 26.
    Soriano AO, Yang H, Faderl S, et al. Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome. Blood. 2007;110:2302–2308.PubMedCrossRefGoogle Scholar
  27. 27.
    Nand S, Godwin J, Smith S, et al. Hydroxyurea, azacitidine and gemtuzumab ozogamicin therapy in patients with previously untreated non-M3 acute myeloid leukemia and high-risk myelodysplastic syndromes in the elderly: results from a pilot trial. Leuk Lymphoma. 2008;49:2141–2147.PubMedCrossRefGoogle Scholar
  28. 28.
    Raza A, Mehdi M, Mumtaz M, Ali F, Lascher S, Galili N. Combination of 5-azacytidine and thalidomide for the treatment of myelodysplastic syndromes and acute myeloid leukemia. Cancer. 2008;113:1596–1604.PubMedCrossRefGoogle Scholar
  29. 29.
    Silverman LR, Verma A, Odchimar-Reissig R, et al. A phase I/II study of vorinostat, an oral histone deacetylase inhibitor, in combination with azacitidine in patients with the myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Initial results of the phase I trial: a New York Cancer Consortium. J Clin Oncol. 2008;26(suppl.). Abstract 7000.Google Scholar
  30. 30.
    Jabbour E, Giralt S, Kantarjian H, et al. Low-dose azacitidine after allogeneic stem cell transplantation for acute leukemia. Cancer. 2009;115:1899–1905.PubMedCrossRefGoogle Scholar
  31. 31.
    Vigil C, Cortes J, Kantarjian H, Garcia-Manero G, Lancet E, List A. Hypomethylating therapy for the treatment of acute erythroleukemia patients. Blood (ASH Annual Meeting Abstracts). 2009;114:2069.Google Scholar
  32. 32.
    Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006;106:1794–1803.PubMedCrossRefGoogle Scholar
  33. 33.
    National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology. Myelodysplastic Syndromes. V.2.2010. Available at: http://www.nccn.org/professionals/physician_gls. Accessed January 30, 2011.

Copyright information

© Springer Healthcare 2011

Authors and Affiliations

  1. 1.Department of HematologyHospital General Universitario Gregorio MarañónMadridSpain

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