Azacitidine in the management of patients with myelodysplastic syndromes

Therapeutic Advances in Hematology

Volumn 3, Issue 6, 2012, Pages 355-373

  Khan, Cyrus ^a   Pathe, Neeta ^a   Fazal, Salman ^a   Lister, John ^a   Rossetti, James M ^a  

^a WESTERN PENNSYLVANIA HOSPITAL   (United States)

Author keywords

acute myeloid leukemia; azacitidine; methylation; myelodysplastic syndromes

Indexed keywords

5 AZA 2' DEOXYCYTIDINE; ANTINEOPLASTIC AGENT; AZACITIDINE; CYTARABINE; DEOXYCYTIDINE; DNA METHYLTRANSFERASE; ENTINOSTAT; ETANERCEPT; FLUCYTOSINE DEOXYRIBOSIDE; GEMTUZUMAB OZOGAMICIN; LENALIDOMIDE; MOCETINOSTAT; ZEBULARINE;

ACUTE GRANULOCYTIC LEUKEMIA; AREA UNDER THE CURVE; BONE MARROW SUPPRESSION; CANCER PROGNOSIS; CANCER REGRESSION; CANCER SURVIVAL; CHRONIC MYELOMONOCYTIC LEUKEMIA; CYTOPENIA; CYTOTOXICITY; DEHYDRATION; DIARRHEA; DNA METHYLATION; DONOR LYMPHOCYTE INFUSION; DRUG BIOAVAILABILITY; DRUG DNA BINDING; DRUG EFFICACY; DRUG HALF LIFE; DRUG SAFETY; DRUG USE; ECCHYMOSIS; EVENT FREE SURVIVAL; FOLLOW UP; FOOD AND DRUG ADMINISTRATION; GENE EXPRESSION; HEMATOLOGIC MALIGNANCY; HEMATOPOIESIS; HEMATOPOIETIC STEM CELL; HUMAN; INJECTION SITE ERYTHEMA; LIVER TOXICITY; MULTIPLE CYCLE TREATMENT; MYELODYSPLASTIC SYNDROME; NAUSEA; PATIENT COMPLIANCE; PRIORITY JOURNAL; REVIEW; TREATMENT DURATION; TREATMENT OUTCOME; TUMOR MICROENVIRONMENT; VOMITING; WILD TYPE;

EID: 84993782377     PISSN: 20406207     EISSN: 20406215     Source Type: Journal    
DOI: 10.1177/2040620712464882     Document Type: Review

References (78)

1. Abdulhaq H. Rossetti J. (2007) The role of azacitidine in the treatment of myelodysplastic syndromes. Expert Opin Invest Drugs 16: 1967–1975.
2. Appelbaum F. Anderson J. (1998) Allogeneic bone marrow transplantation for myelodysplastic syndrome: outcomes analysis according to IPSS score. Leukemia 12(Suppl. 1): 25–29.
3. Bejar R. Levine R. Ebert B. (2011) Unraveling the molecular pathophysiology of myelodysplastic syndromes. J Clin Oncol 29: 504–515.
4. Cataldo V. Cortes J. Quintas-Cardama A. (2009) Azacitidine for the treatment of myelodysplastic syndrome. Exp Rev Anticancer Ther 9: 875–884.
5. Champion C. Guianvarc'h D. Senamaud-Beaufort C. Jurkowska R. Jeltsch A. Ponger L. et al. (2010) Mechanistic insights on the inhibition of c 5 DNA methyltransferases by zebularine. PloS ONE 5: e12388.
6. Cheson B. Bennett J. Kantarjian H. Pinto A. Schiffer C. Nimer S. et al. (2000) Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood 96: 3671–3674.
7. Chitambar C. Libnoch J. Matthaeus W. Ash R. Ritch P. Anderson T. (1991) Evaluation of continuous infusion low-dose 5-azacytidine in the treatment of myelodysplastic syndromes. Am J Hematol 37: 100–104.
8. Costa R. Abdulhaq H. Haq B. Shadduck R. Latsko J. Zenati M. et al. (2011) Activity of azacitidine in chronic myelomonocytic leukemia. Cancer 117: 2690–2696.
9. de Angelo D. Stone R. (2005) Myelodysplastic Syndromes: Biology and Treatment, Vol. 1, 4th ed. Philadelphia, PA: Churchill Livingstone.
10. de Lima M. Giralt S. Thall P. de Padua Silva L. Jones R. Komanduri K. et al. (2010) Maintenance therapy with low-dose azacitidine after allogeneic hematopoietic stem cell transplantation for recurrent acute myelogenous leukemia or myelodysplastic syndrome. Cancer 116: 5420–5431.
11. Fandy T. Herman J. Kerns P. Jiemjit A. Sugar E. Choi S. et al. (2009) Early epigenetic changes and DNA damage do not predict clinical response in an overlapping schedule of 5-azacytidine and entinostat in patients with myeloid malignancies. Blood 114: 2764–2773.
12. Fenaux P. Mufti G. Hellstrom-Lindberg E. Santini V. Finelli C. Giagounidis A. et al. (2009) 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 10: 223–232.
13. Field T. Perkins J. Huang Y. Kharfan-Dabaja M. Alsina M. Ayala E. et al. (2010) 5-Azacitidine for myelodysplasia before allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 45: 255–260.
14. Garcia R. de Miguel D. Bailen A. González J. Sanz G. Falantes J. et al. (2009) Different clinical results with the use of different dosing schedules of azacitidine in patients with myelodysplastic syndrome managed in community-based practice: effectiveness and safety data from the Spanish Azacitidine Compassionate Use Registry. Blood (ASH Annual Meeting Abstracts) 114: abstract 2773.
15. Garcia-Manero G. Assouline S. Cortes J. Estrov Z. Kantarjian H. Yang H. et al. (2008 a) Phase 1 study of the oral isotype specific histone deacetylase inhibitor MGCD0103 in leukemia. Blood 112: 981–989.
16. Garcia-Manero G. Gore S. Cogle C. Ward R. Shi T. Macbeth K. et al. (2011) Phase I study of oral azacitidine in myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia. J Clin Oncol 29: 2521–2527.
17. Garcia-Manero G. Kantarjian H. Sanchez-Gonzalez B. Yang H. Rosner G. Verstovsek S. et al. (2006) Phase 1 / 2 study of the combination of 5-aza-2’-deoxycytidine with valproic acid in patients with leukemia. Blood 108: 3271–3279.
18. Garcia-Manero G. Shan J. Faderl S. Cortes J. Ravandi F. Borthakur G. et al. (2008 b) A prognostic score for patients with lower risk myelodysplastic syndrome. Leukemia 22: 538–543.
19. Garcia-Manero G. Stoltz M. Ward M. Kantarjian H. Sharma S. (2008 c) A pilot pharmacokinetic study of oral azacitidine. Leukemia 22: 1680–1684.
20. Gardin C. Prebet T. Bouabdallah K. Caillot D. Guerci A. Raffoux E. et al. (2009) A phase II study of post-remission therapy with azacitidine (AZA) in patients with AML post-MDS and high-risk MDS: a GFM group study. Blood (ASH Annual Meeting Abstracts) 114: abstract 844.
21. Glover A. Leyland-Jones B. Chun H. Davies B. Hoth D. (1987) Azacitidine: 10 years later. Cancer Treat Rep 71: 737–746.
22. Goldberg J. Gryn J. Raza A. Bennett J. Browman G. Bryant J. et al. (1993) Mitoxantrone and 5-azacytidine for refractory / relapsed ANLL or CML in blast crisis: a leukemia intergroup study. Am J Hematol 43: 286–290.
23. Gore S. Baylin S. Sugar E. Carraway H. Miller C. Carducci M. et al. (2006) Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res 66: 6361–6369.
24. Greenberg P. Cox C. LeBeau M. Fenaux P. Morel P. Sanz G. et al. (1997) International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89: 2079–2088.
25. Greenberg P. Tuechler H. Schanz J. Sanz G. Garcia-Manero G. Sole F. et al. (2012) Revised International Prognostic Scoring System (IPSS-R) for myelodysplastic syndromes. Blood 120: 2454–2465.
26. Grinblatt D. Narang M. Malone J. (2008) Treatment of patients with low-risk myelodysplastic syndromes receiving azacitidine who are enrolled in AVIDA, a longitudinal patient registry. Blood (ASH Annual Meeting Abstracts) 112: abstract 1646.
27. Grovdal M. Karimi M. Khan R. Aggerholm A. Antunovic P. Astermark J. et al. (2010) Maintenance treatment with azacytidine for patients with high-risk myelodysplastic syndromes (MDS) or acute myeloid leukaemia following MDS in complete remission after induction chemotherapy. Br J Haematol 150: 293–302.
28. Gryn J. Zeigler Z. Shadduck R. Lister J. Raymond J. Sbeitan I. et al. (2002) Treatment of myelodysplastic syndromes with 5-azacytidine. Leuk Res 26: 893–897.
29. Gurion R. Vidal L. Gafter-Gvili A. Belnik Y. Yeshurun M. Raanani P. et al. (2010) 5-Azacitidine prolongs overall survival in patients with myelodysplastic syndrome – a systematic review and meta-analysis. Haematologica 95: 303–310.
30. Hagemann S. Heil O. Lyko F. Brueckner B. (2011) Azacytidine and decitabine induce gene-specific and non-random DNA demethylation in human cancer cell lines. PloS ONE 6: e17388.
31. Haq B. Rossetti J. Kramer W. Latsko J. Jasthy S. Lister J. et al. (2006) Response and tolerability of a 5-day azacytidine schedule in patients with myelodysplastic syndromes. J Clin Oncol (Meeting Abstracts) 24(18 Suppl.): 16532.
32. Hollenbach P. Nguyen A. Brady H. Williams M. Ning Y. Richard N. et al. (2010) A comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines. PloS ONE 5: e9001.
33. Holsinger A. Ramakishnan A. Storer B. (2007) Therapy of myelodysplastic syndrome with azacitidine given in combination with etanercept: a phase II study. Blood (ASH Annual Meeting Abstracts) 110: 1452.
34. Itzykson R. Kosmider O. Cluzeau T. Mansat-De Mas V. Dreyfus F. Beyne-Rauzy O. et al. (2011) Impact of TET 2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias. Leukemia 25: 1147–1152.
35. Jiang Y. Dunbar A. Gondek L. Mohan S. Rataul M. O'Keefe C. et al. (2009) Aberrant DNA methylation is a dominant mechanism in MDS progression to AML. Blood 113: 1315–1325.
36. Juvvadi R. Rossetti J. Shadduck R. Kaplan R. Kennedy M. Kramer W. et al. (2007) Response to azacitidine in patients with myelodysplastic syndrome with marrow fibrosis. J Clin Oncol (Meeting Abstracts) 25(18 Suppl.): 7089.
37. Kantarjian H. Issa J. Rosenfeld C. Bennett J. Albitar M. DiPersio J. et al. (2006) Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer 106: 1794–1803.
38. Kim D. Lee J. Park Y. Kim S. Choi Y. Lee S. et al. (2012) Feasibility of hypomethylating agents followed by allogeneic hematopoietic cell transplantation in patients with myelodysplastic syndrome. Bone Marrow Transplant 47: 374–379.
39. Kornblith A. Herndon J. Silverman L. Demakos E. Odchimar-Reissig R. Holland J. et al. (2002) 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 20: 2441–2452.
40. Kumar A. List A. Hozo I. Komrokji R. Djulbegovic B. (2010) Decitabine versus 5-azacitidine for the treatment of myelodysplastic syndrome: adjusted indirect meta-analysis. Haematologica 95: 340–342.
41. Leone G. Teofili L. Voso M. Lubbert M. (2002) DNA methylation and demethylating drugs in myelodysplastic syndromes and secondary leukemias. Haematologica 87: 1324–1341.
42. Lin K. Reljic T. Kumar A. Lancet J. List A. Komrokji R. (2010) Poor outcome of patients with myelodysplastic syndrome (MDS) after azacitidine treatment failure. Blood (ASH Annual Meeting Abstracts) 116: abstract 2913.
43. List A. Fenaux P. Mufti G. Hellstrom-Lindberg E. Gore S. Bennett J. (2008) Effect of azacitidine on overall survival in higher-risk myelodysplastic syndromes (MDS) without complete remission. J Clin Oncol 26: 7007.
44. Lubbert M. Suciu S. Baila L. Ruter B. Platzbecker U. Giagounidis A. et al. (2011) Low-dose decitabine versus best supportive care in elderly patients with intermediate- or high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy: final results of the randomized phase III study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group. J Clin Oncol 29: 1987–1996.
45. Lyons R. Cosgriff T. Modi S. Gersh R. Hainsworth J. Cohn A. et al. (2009) Hematologic response to three alternative dosing schedules of azacitidine in patients with myelodysplastic syndromes. J Clin Oncol 27: 1850–1856.
46. Malcovati L. Germing U. Kuendgen A. Della Porta M. Pascutto C. Invernizzi R. et al. (2007) Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J Clin Oncol 25: 3503–3510.
47. Marcucci G. Silverman L. Eller M. Lintz L. Beach C. (2005) Bioavailability of azacitidine subcutaneous versus intravenous in patients with the myelodysplastic syndromes. J Clin Pharmacol 45: 597–602.
48. McCredie K. Bodey G. Burgess M. Gutterman J. Rodriguez V. Sullivan M. et al. (1973) Treatment of acute leukemia with 5-azacytidine (NSC-102816). Cancer Chemother Rep 57: 319–323.
49. Michaelis L. Shafer D. Barton K. (2009) Azacitidine and low-dose gemtuzumab ozogamicin for the treatment of poor-risk AML and MDS including relapsed refractory disease. Blood (ASH Annual Meeting Abstracts) 114: 1034.
50. Murakami T. Li X. Gong J. Bhatia U. Traganos F. Darzynkiewicz Z. (1995) Induction of apoptosis by 5-azacytidine: drug concentration-dependent differences in cell cycle specificity. Cancer Res 55: 3093–3098.
51. Musto P. Maurillo L. Spagnoli A. Gozzini A. Rivellini F. Lunghi M. et al. (2010) Azacitidine for the treatment of lower risk myelodysplastic syndromes : a retrospective study of 74 patients enrolled in an Italian named patient program. Cancer 116: 1485–1494.
52. Nimer S. (2008) MDS: a stem cell disorder – but what exactly is wrong with the primitive hematopoietic cells in this disease? Hematol Am Soc Hematol Educ Program 43–51.
53. Peterson B. Collins A. Vogelzang N. Bloomfield C. (1981) 5-Azacytidine and renal tubular dysfunction. Blood 57: 182–185.
54. Prebet T. Gore S. Esterni B. Gardin C. Itzykson R. Thepot S. et al. (2011) Outcome of high-risk myelodysplastic syndrome after azacitidine treatment failure. J Clin Oncol 29: 3322–3327.
55. Prebet T. Gore S. Sun Z. Greenberg P. Juckett M. Malick L. et al. (2010 a) Prolonged administration of azacitidine with or without entinostat increases rate of hematologic normalization for myelodysplastic syndrome and acute myeloid leukemia with myelodysplasia-related changes: results of the US Leukemia Intergroup Trial E1905. Blood (ASH Annual Meeting Abstracts) 116: 601.
56. Prebet T. Sun Z. Ketterling R. Hicks G. Beach C. Greenberg P. et al. (2010 b) A 10 day schedule of azacitidine induces more complete cytogenetic remissions than the standard schedule in myelodysplasia and acute myeloid leukemia with myelodysplasia-related changes: results of the E 1905 US Leukemia Intergroup Study. Blood (ASH Annual Meeting Abstracts) 116: 4013.
57. Ravandi F. Issa J. Garcia-Manero G. O'Brien S. Pierce S. Shan J. et al. (2009) Superior outcome with hypomethylating therapy in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome and chromosome 5 and 7 abnormalities. Cancer 115: 5746–5751.
58. Raza A. Mehdi M. Mumtaz M. Ali F. Lascher S. Galili N. (2008) Combination of 5-azacytidine and thalidomide for the treatment of myelodysplastic syndromes and acute myeloid leukemia. Cancer 113: 1596–1604.
59. Rossetti J. Shadduck R. Thatikinda C. (2007) Low dose azacitidine for relapse of MDS / AML after unrelated donor blood peripheral stem cell transplantation. Blood (ASH Annual Meeting Abstracts) 110: 5034.
60. Runde V. de Witte T. Arnold R. Gratwohl A. Hermans J. van Biezen A. et al. (1998) Bone marrow transplantation from HLA-identical siblings as first-line treatment in patients with myelodysplastic syndromes: early transplantation is associated with improved outcome. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 21: 255–261.
61. Ruter B. Wijermans P. Lubbert M. (2004) DNA methylation as a therapeutic target in hematologic disorders: recent results in older patients with myelodysplasia and acute myeloid leukemia. Int J Hematol 80: 128–135.
62. Saiki J. Bodey G. Hewlett J. Amare M. Morrison F. Wilson H. et al. (1981) Effect of schedule on activity and toxicity of 5-azacytidine in acute leukemia: a Southwest Oncology Group Study. Cancer 47: 1739–1742.
63. Santini V. Fenaux P. Mufti G. Hellstrom-Lindberg E. Silverman L. List A. et al. (2010) Management and supportive care measures for adverse events in patients with myelodysplastic syndromes treated with azacitidine. Eur J Haematol 85: 130–138.
64. Schroeder T. Czibere A. Kroger N. Platzbecker U. Bug G. Rieger K. et al. (2010) Azacitidine (Vidaza(R), Aza) and donor lymphocyte infusions (DLI) in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) relapsing after allogeneic hematopoietic stem cell transplantation (HSCT): interim-analysis from the AZARELA-Trial (NCT-00795548). Blood (ASH Annual Meeting Abstracts) 116: 1294.
65. Sekeres M. List A. Cuthbertson D. Paquette R. Ganetzky R. Latham D. et al. (2010) Phase I combination trial of lenalidomide and azacitidine in patients with higher-risk myelodysplastic syndromes. J Clin Oncol 28: 2253–2258.
66. Seymour J. Fenaux P. Silverman L. Mufti G. Hellstrom-Lindberg E. Santini V. et al. (2010) Effects of azacitidine compared with conventional care regimens in elderly (>/= 75 years) patients with higher-risk myelodysplastic syndromes. Crit Rev Oncol Hematol 76: 218–227.
67. Shen L. Kantarjian H. Guo Y. Lin E. Shan J. Huang X. et al. (2010) DNA methylation predicts survival and response to therapy in patients with myelodysplastic syndromes. J Clin Oncol 28: 605–613.
68. Silverman L. Demakos E. Peterson B. Kornblith A. Holland J. Odchimar-Reissig R. et al. (2002) Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol 20: 2429–2440.
69. Silverman L. Fenaux P. Mufti G. Santini V. Hellstrom-Lindberg E. Gattermann N. et al. (2011) Continued azacitidine therapy beyond time of first response improves quality of response in patients with higher-risk myelodysplastic syndromes. Cancer 117: 2697–2702.
70. Silverman L. Holland J. Weinberg R. Alter B. Davis R. Ellison R. et al. (1993) Effects of treatment with 5-azacytidine on the in vivo and in vitro hematopoiesis in patients with myelodysplastic syndromes. Leukemia 7(Suppl. 1): 21–29.
71. Silverman L. McKenzie D. Peterson B. Holland J. Backstrom J. Beach C. et al. (2006) 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 24: 3895–3903.
72. Steensma D. (2009) The changing classification of myelodysplastic syndromes: what's in a name? Hematol Am Soc Hematol Educ Prog 645–655.
73. Steensma D. Baer M. Slack J. Buckstein R. Godley L. Garcia-Manero G. et al. (2009) Multicenter study of decitabine administered daily for 5 days every 4 weeks to adults with myelodysplastic syndromes: the alternative dosing for outpatient treatment (ADOPT) trial. J Clin Oncol 27: 3842–3848.
74. Thepot S. Itzykson R. Seegers V. Raffoux E. Quesnel B. Chait Y. et al. (2010) Treatment of progression of Philadelphia-negative myeloproliferative neoplasms to myelodysplastic syndrome or acute myeloid leukemia by azacitidine: a report on 54 cases on the behalf of the Groupe Francophone des Myelodysplasies (GFM). Blood 116: 3735–3742.
75. Troetel W. Weiss A. Stambaugh J. Laucius J. Manthei R. (1972) Absorption, distribution, and excretion of 5-azacytidine (NSC-102816) in man. Cancer Chemother Rep 56: 405–411.
76. Vigil C. Martin-Santos T. Garcia-Manero G. (2010) Safety and efficacy of azacitidine in myelodysplastic syndromes. Drug Des Dev Ther 4: 221–229.
77. Vogler W. Miller D. Keller J. (1976) 5-Azacytidine (NSC 102816): a new drug for the treatment of myeloblastic leukemia. Blood 48: 331–337.
78. Voso M. Santini V. Finelli C. Musto P. Pogliani E. Angelucci E. et al. (2009) Valproic acid at therapeutic plasma levels may increase 5-azacytidine efficacy in higher risk myelodysplastic syndromes. Clin Cancer Res 15: 5002–5007.