360
Views
17
CrossRef citations to date
0
Altmetric
Review

The clinical use of DNA methyltransferase inhibitors in myelodysplastic syndromes

, , , &

References

  • Brunning RD, Orazi A, Germing U, Al E. Myelodysplastic syndromes/neoplasms, overview. In: Swerdlow SH, Campo E, Harris NL, et al. editors. WHO classification of tumours of hematopoietic and lymphoid tissues. 4th edition. IARC Press; Lyon, France: 2008. p-88-90
  • Sekeres MA. Epidemiology, natural history, and practice patterns of patients with myelodysplastic syndromes in 2010. J Natl Compr Canc Netw 2011;9(1):57-63
  • Ma X. Epidemiology of myelodysplastic syndromes. Am J Med 2012;125:S2-5
  • Zeidan AM, Gore SD, Padron E, Komrokji RS. Current state of prognostication and risk stratification in myelodysplastic syndromes. Curr Opin Hematol 2015;22(2):146-54
  • Faltas B, Zeidan A, Gergis U. Myelodysplastic syndromes: toward a risk-adapted treatment approach. Exp Rev Hematol 2013;6(5):611-24
  • Zeidan AM, Smith BD, Komrokji RS, Gore SD. Prognostication in myelodysplastic syndromes: beyond the International Prognostic Scoring System (IPSS). Am J Med 2013;126(4):e25
  • Greenberg P, Cox C, Lebeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997;89(6):2079-88
  • Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood 2012;120(12):2454-65
  • Harris NL, Jaffe ES, Diebold J, et al. The World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues. Report of the Clinical Advisory Committee meeting, Airlie House, Virginia, November, 1997. Ann Oncol 1999;10(12):1419-32
  • Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 2009;114(5):937-51
  • Zeidan AM, Lee JW, Prebet T, et al. Comparison of the prognostic utility of the revised International Prognostic Scoring System and the French Prognostic Scoring System in azacitidine-treated patients with myelodysplastic syndrome. Br J Haematol 2014;166(3):352-9
  • Zeidan AM, Linhares Y, Gore SD. Current therapy of myelodysplastic syndromes. Blood Rev 2013;27(5):243-59
  • 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(10):2429-40
  • Fenaux P, Mufti GJ, 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(3):223-32
  • 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(8):1794-803
  • Lübbert M, Suciu S, Baila L, et al. 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 2011;29(15):1987-96
  • Zeidan AM, Gore SD. Should elderly patients with higher-risk myelodysplastic syndromes undergo allogeneic hematopoietic stem cell transplantation? Exp Rev Hematol 2013;6(5):539-42
  • Cedar H, Bergman Y. Epigenetics of haematopoietic cell development. Nat Rev Immunol 2011;11(7):478-88
  • Itzykson R, Fenaux P. Epigenetics of myelodysplastic syndromes. Leukemia 2014;28(3):497-506
  • Kim TK, Gore SD, Zeidan AM. Epigenetic therapy in acute myeloid leukemia: current and future directions. Semin Hematol 2015; In press
  • Quesnel B, Guillerm G, Vereecque R, et al. Methylation of the p15(INK4b) gene in myelodysplastic syndromes is frequent and acquired during disease progression. Blood 1998;91(8):2985-90
  • Jeong M, Goodell MA. New answers to old questions from genome-wide maps of DNA methylation in hematopoietic cells. Exp Hematol 2014;42(8):609-17
  • Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 1999;99(3):247-57
  • Goll MG, Bestor TH. Eukaryotic cytosine methyltransferases. Annu Rev Biochem 2005;74:481-514
  • Okano M, Xie S, Li E. Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nat Genet 1998;19(3):219-20
  • Figueroa ME, Abdel-Wahab O, Lu C, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function and impair hematopoietic differentiation. Cancer Cell 2010;18(6):553-67
  • Ley TJ, Ding L, Walter MJ, et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med 2012;363(25):2424-33
  • Walter MJ, Shen D, Shao J, et al. Clonal diversity of recurrently mutated genes in myelodysplastic syndromes. Leukemia 2013;27(6):1275-82
  • Walter MJ, Ding L, Shen D, et al. Recurrent DNMT3A mutations in patients with myelodysplastic syndromes. Leukemia 2011;25(7):1153-8
  • Bejar R, Stevenson KE, Caughey BA, et al. Validation of a prognostic model and the impact of mutations in patients with lower-risk myelodysplastic syndromes. J Clin Oncol 2012;30(27):3376-82
  • Miller CA, Wilson RK, Ley TJ. Genomic landscapes and clonality of de novo AML. N Engl J Med 2013;369(15):1473
  • Russler-Germain DA, Spencer DH, Young MA, et al. The R882H DNMT3A mutation associated with AML dominantly inhibits wild-type DNMT3A by blocking its ability to form active tetramers. Cancer Cell 2014;25(14):442-54
  • Ribeiro AF, Pratcorona M, Erpelinck-Verschueren C, et al. Mutant DNMT3A: a marker of poor prognosis in acute myeloid leukemia. Blood 2012;119(24):5824-31
  • Shivarov V, Gueorguieva R, Stoimenov A, Tiu R. DNMT3A mutation is a poor prognosis biomarker in AML: results of a meta-analysis of 4500 AML patients. Leuk Res 2013;37(11):1445-50
  • Ko M, Huang Y, Jankowska AM, et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature 2010;468(7325):839-43
  • Itzykson R, Kosmider O, Renneville A, et al. Prognostic score including gene mutations in chronic myelomonocytic leukemia. J Clin Oncol 2013;31(19):2428-36
  • Abdel-Wahab O, Mullally A, Hedvat C, et al. Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood 2009;114(1):144-7
  • Yamazaki J, Taby R, Vasanthakumar A, et al. Effects of TET2 mutations on DNA methylation in chronic myelomonocytic leukemia. Epigenetics 2012;7(2):201-7
  • Malcovati L, Papaemmanuil E, Ambaglio I, et al. Driver somatic mutations identify distinct disease entities within myeloid neoplasms with myelodysplasia. Blood 2014;124(9):1513-21
  • Cazzola M, Della Porta MG, Malcovati L. The genetic basis of myelodysplasia and its clinical relevance. Blood 2013;122(25):4021-34
  • Song SJ, Ito K, Ala U, et al. The oncogenic microRNA miR-22 targets the TET2 tumor suppressor to promote hematopoietic stem cell self-renewal and transformation. Cell Stem Cell 2013;13(1):87-101
  • Kosmider O, Gelsi-Boyer V, Slama L, et al. Mutations of IDH1 and IDH2 genes in early and accelerated phases of myelodysplastic syndromes and MDS/myeloproliferative neoplasms. Leukemia 2010;24(5):1094-6
  • Jin J, Hu C, Yu M, et al. Prognostic value of isocitrate dehydrogenase mutations in myelodysplastic syndromes: a retrospective cohort study and meta-analysis. PLoS ONE 2014;9(6):e100206
  • Yen KE, Bittinger MA, Su SM, Fantin VR. Cancer-associated IDH mutations: biomarker and therapeutic opportunities. Oncogene 2010;29(49):6409-17
  • Bies J, Sramko M, Fares J, et al. Myeloid-specific inactivation of p15Ink4b results in monocytosis and predisposition to myeloid leukemia. Blood 2010;116(6):979-87
  • Figueroa ME, Skrabanek L, Li Y, et al. MDS and secondary AML display unique patterns and abundance of aberrant DNA methylation. Blood 2009;114(16):3448-58
  • Will B, Zhou L, Vogler TO, et al. Stem and progenitor cells in myelodysplastic syndromes show aberrant stage-specific expansion and harbor genetic and epigenetic alterations. Blood 2012;120(10):2076-86
  • Jiang Y, Dunbar A, Gondek LP, et al. Aberrant DNA methylation is a dominant mechanism in MDS progression to AML. Blood 2009;113(6):1315-25
  • Shen L, Kantarjian H, Guo Y, et al. DNA methylation predicts survival and response to therapy in patients with myelodysplastic syndromes. J Clin Oncol 2010;28(4):605-13
  • Marcucci G, Silverman L, Eller M, et al. Bioavailability of azacitidine subcutaneous versus intravenous in patients with the myelodysplastic syndromes. J Clin Pharmacol 2005;45(5):597-602
  • Cashen AF, Shah AK, Todt L, et al. Pharmacokinetics of decitabine administered as a 3-h infusion to patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Cancer Chemother Pharmacol 2008;61(5):759-66
  • Van Groeningen CJ, Leyva A, O’brien AM, et al. Phase I and pharmacokinetic study of 5-aza-2’-deoxycytidine (NSC 127716) in cancer patients. Cancer Res 1986;46(9):4831-6
  • Mahfouz RZ, Jankowska A, Ebrahem Q, et al. Increased CDA expression/activity in males contributes to decreased cytidine analog half-life and likely contributes to worse outcomes with 5-azacytidine or decitabine therapy. Clin Cancer Res 2013;19(4):938-48
  • Rius M, Stresemann C, Keller D, et al. Human concentrative nucleoside transporter 1-mediated uptake of 5-azacytidine enhances DNA demethylation. Mol Cancer Ther 2009;8(1):225-31
  • Pastor-Anglada M, Cano-Soldado P, Molina-Arcas M, et al. Cell entry and export of nucleoside analogues. Virus Res 2005;107(2):151-64
  • Lee T, Karon M, Momparler RL. Kinetic studies on phosphorylation of 5-azacytidine with the purified uridine-cytidine kinase from calf thymus. Cancer Res 1974;34(10):2482-8
  • Jasielec J, Saloura V, Godley LA. The mechanistic role of DNA methylation in myeloid leukemogenesis. Leukemia 2014;28(9):1765-73
  • Li LH, Olin EJ, Buskirk HH, Reineke LM. Cytotoxicity and mode of action of 5-azacytidine on L1210 leukemia. Cancer Res 1970;30(11):2760
  • Santi DV, Norment A, Garrett CE. Covalent bond formation between a DNA-cytosine methyltransferase and DNA containing 5-azacytosine. Proc Natl Acad Sci USA 1984;81(22):6993-7
  • Ghoshal K, Datta J, Majumder S, et al. 5-Aza-deoxycytidine induces selective degradation of DNA methyltransferase 1 by a proteasomal pathway that requires the KEN box, bromo-adjacent homology domain, and nuclear localization signal. Mol Cell Biol 2005;25(11):4727-41
  • Aimiuwu J, Wang H, Chen P, et al. RNA-dependent inhibition of ribonucleotide reductase is a major pathway for 5-azacytidine activity in acute myeloid leukemia. Blood 2012;119(22):5229-38
  • Hollenbach PW, Nguyen AN, Brady H, et al. A comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines. PLoS One 2010;5(2):e9001
  • Yang AS, Doshi KD, Choi SW, et al. DNA methylation changes after 5-aza-2’-deoxycytidine therapy in patients with leukemia. Cancer Res 2006;66(10):5495-503
  • Daskalakis M, Nguyen TT, Nguyen C, et al. Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-Aza-2’-deoxycytidine (decitabine) treatment. Blood 2002;100(8):2957-64
  • Stresemann C, Bokelmann I, Mahlknecht U, Lyko F. Azacytidine causes complex DNA methylation responses in myeloid leukemia. Mol Cancer Ther 2008;7(9):2998-3005
  • Stresemann C, Lyko F. Modes of action of the DNA methyltransferase ihibitors azacytidine and decitabine. Int J Cancer 2008;123(1):8-13
  • Lund K, Cole JJ, Vanderkraats ND, et al. DNMT inhibitors reverse a specific signature of aberrant promoter DNA methylation and associated gene silencing in AML. Genome Biol 2014;15(8):406
  • Almstedt M, Blagitko-Dorfs N, Duque-Afonso J, et al. The DNA demethylating agent 5-aza-2’-deoxycytidine induces expression of NY-ESO-1 and other cancer/testis antigens in myeloid leukemia cells. Leuk Res 2010;34(7):899-905
  • Goodyear O, Agathanggelou A, Novitzky-Basso I, et al. Induction of a CD8+ T-cell response to the MAGE cancer testis antigen by combined treatment with azacitidine and sodium valproate in patients with acute myeloid leukemia and myelodysplasia. Blood 2010;116(11):1908-18
  • Gang AO, Frøsig TM, Brimnes MK, et al. 5-Azacytidine treatment sensitizes tumor cells to T-cell mediated cytotoxicity and modulates NK cells in patients with myeloid malignancies. Blood Cancer 2014;4:e197
  • Li X, Mei Q, Nie J, et al. Decitabine: a promising epi-immunotherapeutic agent in solid tumors. Expert Rev Clin Immunol 2015;11(3):363-75
  • Coral S, Parisi G, Nicolay HJ, et al. Immunomodulatory activity of SGI-110, a 5-aza-2’-deoxycytidine-containing demethylating dinucleotide. Cancer Immunol Immunother 2013;62(3):605-14
  • Costello RT, Leclercq A, Treut TL, et al. Effects of 5-azacytidine on natural killer cell activating receptor expression in patients with refractory anemia with excess of blasts. Leuk Res Rep 2015;4(1):15-17
  • Goodyear OC, Dennis M, Jilani NY, et al. Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML). Blood 2012;119(14):3361-9
  • Stübig T, Badbaran A, Luetkens T, et al. 5-azacytidine promotes an inhibitory T-cell phenotype and impairs immune mediated antileukemic activity. Mediators Inflamm 2014;2014:418292
  • Costantini B, Kordasti SY, Kulasekararaj AG, et al. The effects of 5-azacytidine on the function and number of regulatory T cells and T-effectors in myelodysplastic syndrome. Haematologica 2013;98(8):1196-205
  • Kornblith AB, Herndon JEN, 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(10):2441-52
  • Lyons RM, Cosgriff TM, Modi SS, et al. Hematologic response to three alternative dosing schedules of azacitidine in patients with myelodysplastic syndromes. J Clin Oncol 2009;27(11):1850-6
  • García-Delgado R, De Miguel D, Bailén A, et al. Effectiveness and safety of different azacitidine dosage regimens in patients with myelodysplastic syndromes or acute myeloid leukemia. Leuk Res 2014;38(7):744-50
  • Sekeres MA, Maciejewski JP, Doneley DW, et al. A study comparing dosing regimens and efficacy of subcutaneous to intravenous azacitidine (AZA) for the treatment of myelodysplastic syndromes (MDS). ASH Annual Meeting Abstracts 2009;114(22):3797
  • Sekeres MA, Cutler C. How we treat higher-risk myelodysplastic syndromes. Blood 2014;123(6):829-36
  • Prebet T, Sun Z, Figueroa ME, et al. Prolonged administration of azacitidine with or without entinostat for myelodysplastic syndrome and acute myeloid leukemia with myelodysplasia-related changes: results of the US Leukemia Intergroup trial E1905. J Clin Oncol 2014;32(12):1242-8
  • 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(Suppl 1):21-9
  • Silverman L, Holland JF, Demakos E, Al E. Azacitidine in myelodysplastic syndromes: CALGB studies 8421 and 8921. Ann Hematol 1994;68:A12 (abstr)
  • Garcia-Manero G, Gore SD, Cogle C, et al. Phase I study of oral azacitidine in myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia. J Clin Oncol 2011;29(18):2521-7
  • Garcia-Manero G, Savona M, Gore SD, et al. Hematologic response to oral azacitidine (CC-486) in subjects with WHO-defined RAEB-1 or RAEB-2 myelodysplastic syndromes (MDS). Blood 2013;21:abstract 1554
  • Available from: https://Clinicaltrials.Gov/Ct2/Show/Nct02281084 PSaaODF
  • Available from: https://Clinicaltrials.Gov/Ct2/Show/Nct01566695 NIPFL-MaSC
  • Wijermans PW, Krulder JW, Huijgens PC, Neve P. Continuous infusion of low-dose 5-Aza-2’-deoxycytidine in elderly patients with high-risk myelodysplastic syndrome. Leukemia 1997;11(1):1-5
  • Wijermans P, Lübbert M, Verhoef G, et al. Low-dose 5-aza-2’-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multicenter phase II study in elderly patients. J Clin Oncol 2000;18(5):956-62
  • Available from: http://Www.Nccn.Org NGFTTOMS
  • Kantarjian H, Oki Y, Garcia-Manero G, et al. Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 2007;109(1):52-7
  • Steensma DP, Baer MR, Slack JL, et al. 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 2009;27(23):3842-8
  • 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(11):1410-16
  • Wells RA, Leber B, Zhu NY, Storring JM. Optimizing outcomes with azacitidine: recommendations from Canadian centres of excellence. Curr Oncol 2014;21(1):44-50
  • Gore SD, Fenaux P, Santini V, et al. A multivariate analysis of the relationship between response and survival among patients with higher-risk myelodysplastic syndromes treated within azacitidine or conventional care regimens in the randomized AZA-001 trial. Haematologica 2013;98(7):1067-72
  • Silverman LR, Fenaux P, Mufti GJ, et al. Continued azacitidine therapy beyond time of first response improves quality of response in patients with higher-risk myelodysplastic syndromes. Cancer 2011;117(12):2697-702
  • Voso MT, Breccia M, Lunghi M, et al. Rapid loss of response after withdrawal of treatment with azacitidine: a case series in patients with higher-risk myelodysplastic syndromes or chronic myelomonocytic leukemia. Eur J Haematol 2013;90(4):345-8
  • Rüter B, Wijermans PW, Lübbert M. Superiority of prolonged low-dose azanucleoside administration? Results of 5-aza-2’-deoxycytidine retreatment in high-risk myelodysplasia patients. Cancer 2006;106(8):1744-50
  • Lee JH, Lee KH, Lee JH, et al. Decreased incidence of febrile episodes with antibiotic prophylaxis in the treatment of decitabine for myelodysplastic syndrome. Leuk Res 2011;35(4):499-503
  • Merkel D, Filanovsky K, Gafter-Gvili A, et al. Predicting infections in high-risk patients with myelodysplastic syndrome/acute myeloid leukemia treated with azacitidine: a retrospective multicenter study. Am J Hematol 2013;88(2):130-4
  • Summary of product characteristics: Vidaza 25 mg/mL powder for suspension for injection. Available from: http://www.ema.europoa.eu/docs
  • Approved labeling dacogen (decitabine) for injection. Available from: http://www.accessdata.fda.gov
  • Douvali E, Papoutselis M, Vassilakopoulos TP, et al. Safety and efficacy of 5-azacytidine treatment in myelodysplastic syndrome patients with moderate and mild renal impairment. Leuk Res 2013;37(8):889-93
  • Batty GN, Kantarjian H, Issa JP, et al. Feasibility of therapy with hypomethylating agents in patients with renal insufficiency. Clin Lymphoma Myeloma Leuk 10;3(205):10
  • Malcovati L, Hellström-Lindberg E, Bowen D, et al. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood 2013;122(17):2943-64
  • Gerds AT, Gooley TA, Estey EH, et al. Pretransplantation therapy with azacitidine vs induction chemotherapy and posttransplantation outcome in patients with MDS. Biol Blood Marrow Transplant 2012;18(8):1211-18
  • Damaj G, Duhamel A, Robin M, et al. Impact of azacitidine before allogeneic stem-cell transplantation for myelodysplastic syndromes: a study by the Société Française de Greffe de Moelle et de Thérapie-Cellulaire and the Groupe-Francophone des Myélodysplasies. J Clin Oncol 2012;30(36):4533-40
  • Thanarajasingam G, Kim HT, Cutler C, et al. Outcome and prognostic factors for patients who relapse after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2013;19(12):1713-18
  • De Lima M, Giralt S, Thall PF, et al. Maintenance therapy with low-dose azacitidine after allogeneic hematopoietic stem cell transplantation for recurrent acute myelogenous leukemia or myelodysplastic syndrome: a dose and schedule finding study. Cancer 2010;116(23):5420-31
  • Platzbecker U, Wermke M, Radke J, et al. Azacitidine for treatment of imminent relapse in MDS or AML patients after allogeneic HSCT: results of the RELAZA trial. Leukemia 2010;26(3):381-9
  • Bolaños-Meade J, Smith BD, Gore SD, et al. 5-azacytidine as salvage treatment in relapsed myeloid tumors after allogeneic bone marrow transplantation. Biol Blood Marrow Transplant 2011;17(5):754-8
  • Czibere A, Bruns I, Kröger N, et al. 5-Azacytidine for the treatment of patients with acute myeloid leukemia or myelodysplastic syndrome who relapse after allo-SCT: a retrospective analysis. Bone Marrow Transplant 2010;45(5):872-6
  • Graef T, Kuendgen A, Fenk R, et al. Successful treatment of relapsed AML after allogeneic stem cell transplantation with azacitidine. Leuk Res 2007;31(2):257-9
  • Jabbour E, Giralt S, Kantarjian H, et al. Low-dose azacitidine after allogeneic stem cell transplantation for acute leukemia. Cancer 2009;115(9):1899-905
  • Kim SY, Cho SG, Cho BS, et al. Azacytidine treatment after discontinuation of immunosuppressants in patients with myelodysplastic syndrome and relapse after allo-SCT at a single center. Bone Marrow Transplant 2010;45(8):1375-6
  • Lübbert M, Bertz H, Wäsch R, et al. Efficacy of a 3-day, low-dose treatment with 5-azacytidine followed by donor lymphocyte infusions in older patients with acute myeloid leukemia or chronic myelomonocytic leukemia relapsed after allografting. Bone Marrow Transplant 2010;45(4):627-32
  • Schroeder T, Czibere A, Platzbecker U, et al. Azacitidine and donor lymphocyte infusions as first salvage therapy for relapse of AML or MDS after allogeneic stem cell transplantation. Leukemia 2013;27(6):1229-35
  • Schroeder T, Rachlis E, Bug G, et al. Treatment of acute myeloid leukemia or myelodysplastic syndrome relapse after allogeneic stem cell transplantation with azacitidine and donor lymphocyte infusions-a retrospective multicenter analysis from the german cooperative transplant study group. Biol Blood Marrow Transplant 2015;21(4):653-60
  • Schmid C, Labopin M, Nagler A, et al. Donor lymphocyte infusion in the treatment of first hematological relapse after allogeneic stem-cell transplantation in adults with acute myeloid leukemia: a retrospective risk factors analysis and comparison with other strategies by the EBMT Acute Leukemia Working Party. J Clin Oncol 2007;25(31):4938-45
  • Schmid C, Labopin M, Nagler A, et al. Treatment, risk factors, and outcome of adults with relapsed AML after reduced intensity conditioning for allogeneic stem cell transplantation. Blood 2012;119(6):1599-606
  • Mitchell M, Gore SD, Zeidan AM. Iron chelation therapy in myelodysplastic syndromes: where do we stand? Expert Rev Hematol 2013;6(4):397-410
  • 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(24):3895-905
  • Tobiasson M, Dybedahl I, Holm MS, et al. Limited clinical efficacy of azacitidine in transfusion-dependent, growth factor-resistant, low- and Int-1-risk MDS: Results from the nordic NMDSG08A phase II trial. Blood Cancer 2014;4:e189
  • Filì C, Malagola M, Follo MY, et al. Prospective phase II Study on 5-days azacitidine for treatment of symptomatic and/or erythropoietin unresponsive patients with low/INT-1-risk myelodysplastic syndromes. Clin Cancer Res 2013;19(12):3297-308
  • Falantes J, Delgado RG, Calderón-Cabrera C, et al. Multivariable time-dependent analysis of the impact of azacitidine in patients with lower-risk myelodysplastic syndrome and unfavorable specific lower-risk score. Leuk Res 2015;39(1):52-7
  • Falantes JF, Calderón C, Márquez Malaver FJ, et al. Clinical prognostic factors for survival and risk of progression to acute myeloid leukemia in patients with myelodysplastic syndromes with <10% marrow blasts and non-unfavorable cytogenetic categories. Clin Lymphoma Myeloma Leuk 2013;13(2):144-52
  • Garcia-Manero G, Jabbour E, Borthakur G, et al. Randomized open-label phase II study of decitabine in patients with low- or intermediate-risk myelodysplastic syndromes. J Clin Oncol 2013;31(20):2548-53
  • Fenaux P, Mufti GJ, Hellström-Lindberg E, 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(4):562-9
  • Santini V, Prebet T, Fenaux P, et al. Minimizing risk of hypomethylating agent failure in patients with higher-risk MDS and practical management recommendations. Leuk Res 2014;38(12):1381-91
  • Borthakur G, Ahdab SE, Ravandi F, et al. Activity of decitabine in patients with myelodysplastic syndrome previously treated with azacitidine. Leuk Lymphoma 2008;49(4):690-5
  • Braun T, Cherait A, Berthon C, et al. Treatment With Decitabine (DAC) After Azacitidine (AZA) Failure In High Risk Myelodysplastic Syndrome (MDS) and Advanced Chronic Myelomonocytic Leukemia (CMML). Blood 2013;122:21
  • Komrokji RS, Apuri S, Al Ali N, et al. Evidence for selective benefit of sequential treatment with azanucleosides in patients with myelodysplastic syndromes (MDS). J Clin Oncol 2013(Suppl):abstr 7113
  • Prébet T, Gore SD, Esterni B, et al. Outcome of high-risk myelodysplastic syndrome after azacitidine treatment failure. J Clin Oncol 2011;29(24):3322-7
  • Duong VH, Bhatnagar B, Zandberg DP, et al. Lack of objective response of myelodysplastic syndromes and acute myeloid leukemia to decitabine after failure of azacitidine. Leuk Lymphoma 2015;56(6):1718-22
  • 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(2):403-11
  • Zeidan AM, Lee JW, Prebet T, et al. Platelet count doubling after the first cycle of azacitidine therapy predicts eventual response and survival in patients with myelodysplastic syndromes and oligoblastic acute myeloid leukaemia but does not add to prognostic utility of the revised IPSS. Br J Haematol 2014;167(1):62-8
  • Momparler RL, Momparler LF, Samson J. Comparison of the antileukemic activity of 5-AZA-2’-deoxycytidine, 1-beta-D-arabinofuranosylcytosine and 5-azacytidine against L1210 leukemia. Leuk Res 1984;8(6):1043-9
  • Voso MT, Santini V, Fabiani E, et al. Why methylation is not a marker predictive of response to hypomethylating agents. Haematologica 2014;99(4):613-19
  • Meldi K, Qin T, Buchi F, et al. Specific molecular signatures predict decitabine response in chronic myelomonocytic leukemia. J Clin Invest 2015;125(5):1857-72
  • Bejar R, Lord A, Stevenson K, et al. TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood 2014;124(17):2705-12
  • Traina F, Visconte V, Elson P, et al. Impact of molecular mutations on treatment response to DNMT inhibitors in myelodysplasia and related neoplasms. Leukemia 2014;28(1):78-87
  • Cluzeau T, Dubois A, Jacquel A, et al. Phenotypic and genotypic characterization of azacitidine-sensitive and resistant SKM1 myeloid cell lines. Oncotarget 2014;5(12):4384-91
  • Valencia A, Masala E, Rossi A, et al. Expression of nucleoside-metabolizing enzymes in myelodysplastic syndromes and modulation of response to azacitidine. Leukemia 2014;28(3):621-8
  • Wu P, Geng S, Weng J, et al. The hENT1 and DCK genes underlie the decitabine response in patients with myelodysplastic syndrome. Leuk Res 2015;39(2):216-20
  • Duong VH, Lin K, Reljic T, et al. Poor outcome of patients with myelodysplastic syndrome after azacitidine treatment failure. Clin Lymphoma Myeloma Leuk 2013;13(6):711
  • Jabbour E, Garcia-Manero G, Batty N, et al. Outcome of patients with myelodysplastic syndrome after failure of decitabine therapy. Cancer 2010;116(16):3830-4
  • Jabbour EJ, Garcia-Manero G, Strati P, et al. Outcome of patients with low-risk and intermediate-1-risk myelodysplastic syndrome after hypomethylating agent failure: A report on behalf of the MDS Clinical Research Consortium. Cancer 2015;121(6):876-82
  • Zeidan AM, Gore SD, Komrokji RS. Higher-risk myelodysplastic syndromes with del(5q): is sequential azacitidine-lenalidomide combination the way to go? Expert Rev Hematol 2013;6(3):251-4
  • Zeidan AM, Faltas B, Douglas Smith B, Gore S. Myelodysplastic syndromes: what do hospitalists need to know? J Hosp Med 2013;8(6):351-7
  • Jabbour E, Garcia-Manero G. Deacetylase inhibitors for the treatment of myelodysplastic syndromes. Leuk Lymphoma 2015;56(6):1205-12
  • Follo MY, Finelli C, Mongiorgi S, et al. Synergistic induction of PI-PLCβ1 signaling by azacitidine and valproic acid in high-risk myelodysplastic syndromes. Leukemia 2011;25(2):271-80
  • Issa JP, Garcia-Manero G, Huang X, et al. Results of phase 2 randomized study of low-dose decitabine with or without valproic acid in patients with myelodysplastic syndrome and acute myelogenous leukemia. Cancer 2015;121(4):556-61
  • Platzbecker U, Germing U. Combination of azacitidine and lenalidomide in myelodysplastic syndromes or acute myeloid leukemia-a wise liaison? Leukemia 2013;27(9):1813-19
  • Sekeres MA, Tiu RV, Komrokji R, et al. Phase 2 study of the lenalidomide and azacitidine combination in patients with higher-risk myelodysplastic syndromes. Blood 2012;120(25):4945-51
  • Platzbecker U, Braulke F, Kündgen A, et al. Sequential combination of azacitidine and lenalidomide in del(5q) higher-risk myelodysplastic syndromes or acute myeloid leukemia: a phase I study. Leukemia 2013;27(6):1403-7
  • Garcia-Manero G, Daver NG, Borthakur G, Al E. Phase I study of the combination of 5-azacitidine sequentially with high-dose lenalidomide in higher-risk myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). Blood 2011;118:1122
  • Sekeres MA, Othus M, List AF, et al. Randomized phase II study of azacitidine combined with lenalidomide or with vorinostat vs. azacitidine monotherapy in higher-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML): North American Intergroup Study SWOG S1117. 56th ASH Annual Meeting and Exposition. 2014
  • Dinardo CD, Daver N, Jabbour E, et al. A Final Report: Phase I/II Study of Sequential Azacitidine and Lenalidomide in Patients with Higher-Risk Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML). 56th ASH Annual Meeting and Exposition. 2014
  • Finelli C, Clissa C, Follo MY, et al. Addition of Lenalidomide (LEN) to azacitidine (AZA) (combined vs sequential treatment) in high-risk myelodysplastic syndromes (MDS): a randomized phase II multicenter study. ASH abstract 2014
  • Kantarjian HM, Giles FJ, Greenberg PL, et al. Phase 2 study of romiplostim in patients with low- or intermediate-risk myelodysplastic syndrome receiving azacitidine therapy. Blood 2010;116(17):3163-70
  • Greenberg PL, Garcia-Manero G, Moore M, et al. A randomized controlled trial of romiplostim in patients with low- or intermediate-risk myelodysplastic syndrome receiving decitabine. Leuk Lymphoma 2013;54(2):321-8
  • Svensson T, Chowdhury O, Garelius H, et al. A pilot phase I dose finding safety study of the thrombopoietin-receptor agonist, eltrombopag, in patients with myelodysplastic syndrome treated with azacitidine. Eur J Haematol 2014;93(5):439-45
  • Ornstein MC, Mukherjee S, Sekeres MA. More is better: Combination therapies for myelodysplastic syndromes. Best Pract Clin Haematol 2015;28(1):22-31
  • Issa JP, Roboz G, Rizzieri D, et al. Abstract LB-214: Interim results from a randomized Phase 1-2 first-in-human (FIH) study of PK/PD guided escalating doses of SGI-110, a novel subcutaneous (SQ) second generation hypomethylating agent (HMA) in relapsed/refractory MDS and AML. Cancer Res 2012;72
  • Chuang JC, Warner SL, Vollmer D, et al. S110, a 5-Aza-2’-deoxycytidine-containing dinucleotide, is an effective DNA methylation inhibitor in vivo and can reduce tumor growth. Mol Cancer Ther 2010;9(5):1443-50
  • Yoo CB, Jeong S, Egger G, et al. Delivery of 5-aza-2’-deoxycytidine to cells using oligodeoxynucleotides. Cancer Res 2007;67(13):6400-8
  • Kantarjian HM, Roboz GJ, Rizzieri DA, Al E. Results from the dose escalation phase of a randomized phase 1–2 first-in-human (FIH) study of SGI-110, a novel low volume stable subcutaneous (SQ) second generation hypomethylating agent (HMA) in patients with relapsed/refractory MDS and AML. Blood (ASH Annual Meeting Abstracts) 2012;120:abstract 414
  • Garcia-Manero G, Ritchie EK, Walsh K, et al. First Clinical Results of a Randomized Phase 2 Dose-Response Study of SGI-110, a Novel Subcutaneous (SC) Hypomethylating Agent (HMA), in 102 Patients with Intermediate (Int) or High Risk (HR) Myelodysplastic Syndromes (MDS) or Chronic Myelomonocytic Leukemia (CMML). 56th ASH Annual Meeting and Exposition. 2014
  • Lee EJ, Zeidan A. Genome sequencing in myelodysplastic syndromes: can molecular mutations predict benefit from hypomethylating agent therapy? Expert Rev Hematol 2015;8(2):155-8
  • Zeidan AM, Komrokji RS. There’s risk, and then there’s RISK: The latest clinical prognostic risk stratification models in myelodysplastic syndromes. Curr Hematol Malig Rep 2013;8:351-60
  • Zeidan AM, Prebet T, Saad Aldin E, Gore SD. Risk stratification in myelodysplastic syndromes: is there a role for gene expression profiling? Expert Rev Hematol 2014;7(2):191-4
  • Zeidan AM, Kharfan-Dabaja MA, Komrokji RS. Beyond hypomethylating agents failure in patients with myelodysplastic syndromes. Curr Opin Hematol 2014;21(2):123-30
  • Yang H, Bueso-Ramos C, Dinardo C, et al. Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia 2014;28(6):1280-8

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.