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Treatment of Hematologic Malignancies with DNA Hypomethylating Agents

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Epigenetic Therapy of Cancer

Abstract

The azanucleosides 5-azacytidine (5-aza, Vidaza) and its deoxyribonucleoside analog 5-aza-2′ deoxycytidine (decitabine), while first synthesized and shown to have/possess [besitzen] antileukemic activity in 1964, have only recently been approved for the treatment of myeloid neoplasias. Thus, they now provide a novel treatment standard for the mostly elderly patients with these diseases. Clinical development of clinically active low-dose schedules of these drugs has taken an arduous route, since for decades their in vivo mechanism of action (DNA hypomethylation) was not generally accepted. In turn, proof of their clinical activity even at low doses (together with the recent discovery of mutations of the DNMT3a gene in AML) has leaned credence to the fundamental role of DNA methylation abnormalities in cancer and the applicability of epigenetically active drugs to treat leukemias, preleukemias, and even solid tumors. This chapter provides a comprehensive overview of the clinical development of both drugs as single agents for MDS and AML and other hematopoietic malignancies. In addition, combination treatment with other epigenetically active agents is described, as well as innovative use before and after allogeneic blood stem cell transplantation.

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References

  • Al-Ali HK, Jaekel N, Junghanss C, Maschmeyer G, Krahl R, Cross M, Hoppe G, Niederwieser D (2012) Azacitidine in patients with acute myeloid leukemia medically unfit for or resistant to chemotherapy: a multicenter phase I/II study. Leuk Lymphoma 53:110–117

    CAS  PubMed  Google Scholar 

  • Al-Ameri AA, Kantarjian H, Malik A, Badoux X, Andreeff M, Quintas-Cardama A, Borthakur G (2010) Decitabine and gemtuzumab ozogamicin in patients with advanced myelofibrosis. Blood (ASH Annu Meet Abstr) 116:5061

    Google Scholar 

  • Blum W, Klisovic RB, Hackanson B, Liu Z, Liu S, Devine H, Vukosavljevic T, Huynh L, Lozanski G, Kefauver C, Plass C, Devine SM, Heerema NA, Murgo A, Chan KK, Grever MR, Byrd JC, Marcucci G (2007) Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. J Clin Oncol 25:3884–3891

    CAS  PubMed  Google Scholar 

  • Blum KA, Liu Z, Lucas DM, Chen P, Xie Z, Baiocchi R, Benson DM, Devine SM, Jones J, Andritsos L, Flynn J, Plass C, Marcucci G, Chan KK, Grever MR, Byrd JC (2010a) Phase I trial of low dose decitabine targeting DNA hypermethylation in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: dose-limiting myelosuppression without evidence of DNA hypomethylation. Br J Haematol 150:189–195

    CAS  PubMed Central  PubMed  Google Scholar 

  • Blum W, Garzon R, Klisovic RB, Schwind S, Walker A, Geyer S, Liu S, Havelange V, Becker H, Schaaf L, Mickle J, Devine H, Kefauver C, Devine SM, Chan KK, Heerema NA, Bloomfield CD, Grever MR, Byrd JC, Villalona-Calero M, Croce CM, Marcucci G (2010b) Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine. Proc Natl Acad Sci USA 107:7473–7478

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bogani C, Ponziani V, Guglielmelli P, Desterke C, Rosti V, Bosi A, Le Bousse-Kerdiles MC, Barosi G, Vannucchi AM (2008) Hypermethylation of CXCR4 promoter in CD34+ cells from patients with primary myelofibrosis. Stem Cells 26:1920–1930

    CAS  PubMed  Google Scholar 

  • Boivin AJ, Momparler LF, Hurtubise A, Momparler RL (2002) Antineoplastic action of 5-aza-2′-deoxycytidine and phenylbutyrate on human lung carcinoma cells. Anticancer Drugs 13:869–874

    CAS  PubMed  Google Scholar 

  • Borthakur G, Ahdab SE, Ravandi F, Faderl S, Ferrajoli A, Newman B, Issa JP, Katarjian H (2008) Activity of decitabine in patients with myelodysplastic syndrome previously treated with azacitidine. Leuk Lymphoma 49:690–695

    CAS  PubMed Central  PubMed  Google Scholar 

  • Borthakur G, Garcia-Manero G, Estrov Z, Konopleva M, Burger JA, Thomas DA, Kadia T, Williams B, George S, Kantarjian H (2009) Phase 2 study of decitabine and gemtuzumab ozogamicin in acute myelogenous leukemia and high-risk myelodysplastic syndrome – outcome in previously untreated patients. Blood (ASH Annu Meet Abstr) 114:1053

    Google Scholar 

  • Braun T, Itzykson R, Renneville A, de Renzis B, Dreyfus F, Laribi K, Bouabdallah K, Vey N, Toma A, Recher C, Royer B, Joly B, Vekhoff A, Lafon I, Sanhes L, Meurice G, Orear C, Preudhomme C, Gardin C, Ades L, Fontenay M, Fenaux P, Droin N, Solary E, on behalf of the Groupe Francophone des Myelodysplasies (2011) Molecular predictors of response to decitabine in advanced chronic myelomonocytic leukemia: a phase 2 trial. Blood 118:3824–3831

    CAS  PubMed  Google Scholar 

  • Cameron EE, Bachman KE, Myohanen S, Herman JG, Baylin SB (1999) Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat Genet 21:103–107

    CAS  PubMed  Google Scholar 

  • Cashen AF, Schiller GJ, O’Donnell MR, DiPersio JF (2010) Multicenter, phase II study of decitabine for the first-line treatment of older patients with acute myeloid leukemia. J Clin Oncol 28:556–561

    CAS  PubMed  Google Scholar 

  • Cheson BD, Bennett JM, Kantarjian H, Pinto A, Schiffer CA, Nimer SD, Löwenberg B, Beran M, de Witte TM, Stone RM, Mittelman M, Sanz GF, Wijermans PW, Gore S, Greenberg PL, World Health Organization (WHO) International Working Group (2000) Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood 96:3671–3674

    CAS  PubMed  Google Scholar 

  • Chowdhury S, Seropian S, Marks PW (2009) Decitabine combined with fractionated gemtuzumab ozogamicin therapy in patients with relapsed or refractory acute myeloid leukemia. Am J Hematol 84:599–600

    PubMed  Google Scholar 

  • Cornelison AM, Garcia Manero G, Kantarjian H, Ravandi F, Kadia T, Cortes J, O’Brien S, Borthakur G, Brandt M, Jabbour EJ (2010) Decitabine (DAC) can be safely reduced after achievement of best response in patients (pts) with myelodysplastic syndrome (MDS). Blood (ASH Annu Meet Abstr) 116:1858

    Google Scholar 

  • Craddock C, Quek L, Goardon N, Freeman S, Siddique S, Raghavan M et al (2013) Azacitidine fails to eradicate leukemic stem/progenitor cell populations in patients with acute myeloid leukemia and myelodysplasia. Leukemia 27(5):1028–1036

    CAS  PubMed  Google Scholar 

  • Czibere A, Bruns I, Kröger N, Platzbecker U, Lind J, Zohren F, Fenk R, Germing U, Schröder T, Gräf T, Haas R, Kobbe G (2010) 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 45:872–876

    CAS  PubMed  Google Scholar 

  • de Lima M, Giralt S, Thall PF, de Padua Silva L, Jones RB, Komanduri K, Braun TM, Nguyen HQ, Champlin R, Garcia-Manero G (2010) 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 116:5420–5431

    PubMed  Google Scholar 

  • Debusscher L, Marie JP, Dodion P, Blanc GM, Arrigo C, Zittoun R, Stryckmans P (1990) Phase-I-II trial of 5-aza-2′-deoxycytidine in adult patients with acute leukemia. In: Momparler RL, de Vos D (eds) 5-Aza-2′-deoxycytidine: preclinical and clinical studies. PCH, Haarlem, pp 131–142

    Google Scholar 

  • Fabre, Claire, Chermat, Fatsiha, Legros, Laurence, Park, Sophie, Dreyfus, Francois, Isnard, Francoise, Nowak, Florence, Marfaing, Anne, de Botton, Stephane, Noel, Marie-Pierre, Fruchart, Christophe, Prebet, Thomas, Vey, Norbert, Dartigeas, Caroline, Fenaux, Pierre (2006) Treatment of high risk MDS and AML Post-MDS with Azacytidine (AZA): preliminary results of the French ATU program. ASH Annual Meeting Abstracts 108:2664

    Google Scholar 

  • Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, Schoch R, Gattermann N, Sanz G, List A, Gore SD, Seymour JF, Bennett JM, Byrd J, Backstrom J, Zimmerman L, McKenzie D, Beach C, Silverman LR, International Vidaza High-Risk MDS Survival Study Group (2009) Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomized, open-label, phase III study. Lancet Oncol 10:223–232

    CAS  PubMed  Google Scholar 

  • Fenaux P, Mufti GJ, Hellström-Lindberg E, Santini V, Gattermann N, Germing U, Sanz G, List AF, Gore S, Seymour JF, Dombret H, Backstrom J, Zimmerman L, McKenzie D, Beach CL, Silverman LR (2010) Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol 28:562–569

    CAS  PubMed  Google Scholar 

  • Field T, Perkins J, Huang Y, Kharfan-Dabaja MA, Alsina M, Ayala E, Fernandez HF, Janssen W, Lancet J, Perez L, Sullivan D, List A, Anasetti C (2010) 5-Azacitidine for myelodysplasia before allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 45:255–260

    CAS  PubMed  Google Scholar 

  • García R, Arnar M, Luño E, Bargay J, Ma Mar Romero, Besalduch J, Amutio E, Garrido R, Carnicero F, Grupo Andaluz de Smd (2010) Efficacy and effectiveness of azacitidine in elderly patients with acute myeloid leukemia and blasts counts below 30%: experience of the Spanish registry. Blood (ASH Annu Meet Abstr) 116:4354

    Google Scholar 

  • Garcia-Manero G, Issa JP (2005) Histone deacetylase inhibitors: a review of their clinical status as antineoplastic agents. Cancer Invest 23:635–642

    CAS  PubMed  Google Scholar 

  • Garcia-Manero G, Daniel J, Smith TL, Kornblau SM, Lee MS, Kantarjian HM, Issa JP (2002a) DNA methylation of multiple promoter-associated CpG islands in adult acute lymphocytic leukemia. Clin Cancer Res 8:2217–2224

    CAS  PubMed  Google Scholar 

  • Garcia-Manero G, Bueso-Ramos C, Daniel J, Williamson J, Kantarjian HM, Issa JP (2002b) DNA methylation patterns at relapse in adult acute lymphocytic leukemia. Clin Cancer Res 8:1897–1903

    CAS  PubMed  Google Scholar 

  • Garcia-Manero G, Jeha S, Daniel J, Williamson J, Albitar M, Kantarjian HM, Issa JP (2003) Aberrant DNA methylation in pediatric patients with acute lymphocytic leukemia. Cancer 3:695–702

    Google Scholar 

  • Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B, Yang H, Rosner G, Verstovsek S, Rytting M, Wierda WG, Ravandi F, Koller C, Xiao L, Faderl S, Estrov Z, Cortes J, O’brien S, Estey E, Bueso-Ramos C, Fiorentino J, Jabbour E, Issa JP (2006) Phase 1/2 study of the combination of 5-aza-2′-deoxycytidine with valproic acid in patients with leukemia. Blood 108:3271–3279

    CAS  PubMed Central  PubMed  Google Scholar 

  • Garcia-Manero G, Couriel DR, Tambaro FP, Gabrail N, Nadeem A, Kadia T, Jabbour E, Borthakur G, Faderl S, Newsome W, Yang H, Chen K, Stein K, Kantarjian H (2009a) A phase II Randomized Bayesian Study of very low dose subcutaneous decitabine administered daily or weekly times three in patients with lower risk myelodysplastic syndrome (MDS). Blood (ASH Annu Meet Abstr) 114:119

    Google Scholar 

  • Garcia-Manero G, Yang H, Kuang SQ, O’Brien S, Thomas D, Kantarjian H (2009b) Epigenetics of acute lymphocytic leukemia. Semin Hematol 46:24–32

    CAS  PubMed  Google Scholar 

  • Garcia-Manero G, Thomas D, Rytting M, Zweidler-McKay PA, Yang H, Fang Z, Kuang S, Dara S, O’Brien S, Kantarjian HM (2009c) A phase 1 study of dose-dense 5-Aza-2′-deoxycitidine (decitabine) in relapse refractory acute lymphocytic leukemia (ALL). Blood (ASH Annu Meet Abstr) 114:2030

    Google Scholar 

  • Garcia-Manero G, Thomas DA, Rytting ME, O’Brien S, Franklin ARK, Borthakur G, Kwari M, Dara S, Yang H, Kantarjian H (2010) Final report of a phase I trial of decitabine with or without hyperCVAD in relapsed acute lymphocytic leukemia (ALL). Blood (ASH Annu Meet Abstr) 116:Abstract 867

    Google Scholar 

  • Garcia-Manero G, Gore SD, Cogle C, Ward R, Shi T, Macbeth KJ, Laille E, Giordano H, Sakoian S, Jabbour E, Kantarjian H, Skikne B (2011) Phase I study of oral azacitidine in myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia. J Clin Oncol 29(18):2521–2527

    CAS  PubMed Central  PubMed  Google Scholar 

  • Garcia-Manero G, Tambaro FP, Bekele NB, Yang H, Ravandi F, Jabbour E, Borthakur G, Kadia TM, Konopleva MY, Faderl S, Cortes JE, Brandt M, Hu Y, McCue D, Newsome WM, Pierce SR, de Lima M, Kantarjian HM (2012) Phase II trial of vorinostat with idarubicin and cytarabine for patients with newly diagnosed acute myelogenous leukemia or myelodysplastic syndrome. J Clin Oncol 30(18):2204–2210

    CAS  PubMed  Google Scholar 

  • Giagounidis AA (2007) Decitabine dosage in myelodysplastic syndromes. Blood 110:1082–1083

    CAS  PubMed  Google Scholar 

  • Goldberg SL, Steensma DP (2009) Myelodysplastic syndrome patients obtaining a cytogenetic response to outpatient decitabine experience improved hematological responses and longer survival: additional analyses from the ADOPT trial. Blood (ASH Annu Meet Abstr) 114:3817

    Google Scholar 

  • Gore SD, Weng LJ, Figg WD, Zhai S, Donehower RC, Dover G, Grever MR, Griffin C, Grochow LB, Hawkins A, Burks K, Zabelena Y, Miller CB (2001) Impact of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukemia. Clin Cancer Res 7:2330–2339

    CAS  PubMed  Google Scholar 

  • Gore SD, Weng LJ, Zhai S, Figg WD, Donehower RC, Dover GJ, Grever M, Griffin CA, Grochow LB, Rowinsky EK, Zabalena Y, Hawkins AL, Burks K, Miller CB (2002) Impact of prolonged infusions of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukemia. Clin Cancer Res 8:963–970

    CAS  PubMed  Google Scholar 

  • Gore SD, Baylin S, Sugar E, Carraway H, Miller CB, Carducci M, Grever M, Galm O, Dauses T, Karp JE, Rudek MA, Zhao M, Smith BD, Manning J, Jiemjit A, Dover G, Mays A, Zwiebel J, Murgo A, Weng LJ, Herman JG (2006) Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res 66:6361–6369

    CAS  PubMed  Google Scholar 

  • Grövdal M, Karimi M, Khan R, Aggerholm A, Antunovic P, Astermark J, Bernell P, Engström LM, Kjeldsen L, Linder O, Nilsson L, Olsson A, Holm MS, Tangen JM, Wallvik J, Oberg G, Hokland P, Jacobsen SE, Porwit A, Hellström-Lindberg E (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. J Haematol 150:293–302

    Google Scholar 

  • Hoshino K, Quintás-Cardama A, Yang H, Sanchez-Gonzalez B, Garcia-Manero G (2007) Aberrant DNA methylation of the Src kinase Hck, but not of Lyn, in Philadelphia chromosome negative acute lymphocytic leukemia. Leukemia 21:906–911

    CAS  PubMed  Google Scholar 

  • Iastrebner M, Jang JH, Nucifora E, Kim K, Sackmann F, Kim DH, Orlando S, Jung CW, Basquiera A, Klein G, Santini F, Bernard HI, Korin J, Taborda G (2010) Decitabine in myelodysplastic syndromes and chronic myelomonocytic leukemia: Argentinian/South Korean multi-institutional clinical experience. Leuk Lymphoma 12:2250–2257

    Google Scholar 

  • Issa J-PJ, Garcia-Manero G, Giles FJ, Mannari R, Thomas D, Faderl S, et al (2004) Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2′-deoxycytidine (decitabine) in hematopoietic malignancies. Blood 103(5):1635–40

    Google Scholar 

  • Issa JP, Gharibyan V, Cortes J, Jelinek J, Morris G, Verstovsek S, Talpaz M, Garcia-Manero G, Kantarjian HM (2005) Phase II study of low dose decitabine in patients with chronic myelogenous leukemia resistant to imatinib mesylate. J Clin Oncol 23:3948–3956

    CAS  PubMed  Google Scholar 

  • Jabbour E, Garcia-Manero G, Batty N, Shan J, O’Brien S, Cortes J, Ravandi F, Issa JP, Kantarjian H (2010) Outcome of patients with myelodysplastic syndrome after failure of decitabine therapy. Cancer 116:3830–3834

    CAS  PubMed  Google Scholar 

  • Jabbour E, Garcia-Manero G, Ravandi F, Faderl S, O’Brien S, Fullmer A, Cortes JE, Wierda W, Kantarjian H (2013) Prognostic factors associated with disease progression and overall survival in patients with myelodysplastic syndromes treated with decitabine. Clin Lymphoma Myeloma Leuk 13(2):131–138

    CAS  PubMed  Google Scholar 

  • Jones LC, Tefferi A, Idos GE, Kumagai T, Hofmann WK, Koeffler HP (2004) RARbeta2 is a candidate tumor suppressor gene in myelofibrosis with myeloid metaplasia. Oncogene 23:7846–7853

    CAS  PubMed  Google Scholar 

  • Kantarjian HM, Deisseroth A, Kurzrock R, Estrov Z, Talpaz M (1993) Chronic myelogenous leukemia: a concise update. Blood 82:691–703

    CAS  PubMed  Google Scholar 

  • Kantarjian HM, O’Brien SM, Estey E, Giralt S, Beran M, Rios MB, Keating M, De Vos D, Talpaz M (1997a) Decitabine studies in chronic and acute myelogenous leukemia. Leukemia 11(Suppl 1):35–36

    Google Scholar 

  • Kantarjian HM, O’Brien SM, Keating M, Beran M, Estey E, Giralt S, Kornblau S, Rios MB, De Vos D, Talpaz M (1997b) Results of decitabine therapy in the accelerated and blastic phases of chronic myelogenous leukemia. Leukemia 11:1617–1620

    CAS  PubMed  Google Scholar 

  • Kantarjian HM, O’Brien S, Cortes J, Giles FJ, Faderl S, Issa JP, Garcia-Manero G, Rios MB, Shan J, Andreeff M, Keating M, Talpaz M (2003) Results of decitabine (5-aza-2′-deoxycytidine) therapy in 130 patients with chronic myelogenous leukemia. Cancer 98:522–528

    CAS  PubMed  Google Scholar 

  • Kantarjian HM, Issa JP, Rosenfeld CS, Bennett JM, Albitar M, DiPersio J, Klimek V, Slack J, de Castro C, Ravandi F, Helmer R 3rd, Shen L, Nimer SD, Leavitt R, Raza A, Saba H (2006) Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer 106:1794–1803

    CAS  PubMed  Google Scholar 

  • Kantarjian HM, Oki Y, Garcia-Manero G, Huang X, O’Brien S, Cortes J, Faderl S, Bueso-Ramos C, Ravandi F, Estrov Z, Ferrajoli A, Wierda W, Shan J, Davis J, Giles F, Saba HI, Issa JP (2007a) Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 109:52–57

    CAS  PubMed  Google Scholar 

  • Kantarjian HM, O’Brien S, Shan J, Aribi A, Garcia-Manero G, Jabbour E, Ravandi F, Cortes J, Davisson J, Issa JP (2007b) Update of the decitabine experience in higher risk myelodysplastic syndrome and analysis of prognostic factors associated with outcome. Cancer 109(2):265–273

    CAS  PubMed  Google Scholar 

  • Kantarjian HM, Thomas XG, Dmoszynska A, Wierzbowska A, Mazur G, Mayer J, Gau J-P, Chou W-C, Buckstein R, Cermak J, Kuo C-Y, Oriol A, Ravandi F, Faderl S, Delaunay J, Lysák D, Minden M, Arthur C (2012) 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 30:2670–2677

    CAS  PubMed  Google Scholar 

  • Kirschbaum M, Gojo I, Goldberg SL, Kujawski L, Atallah E, Marks P, Gravio D, Pyle L, Rizvi S, Issa JP (2009) Vorinostat in combination with decitabine for the treatment of relapsed or newly diagnosed acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS): a phase I, dose-escalation study. Blood (ASH Annu Meet Abstr) 114:2089

    Google Scholar 

  • Kuang SQ, Tong WG, Yang H, Lin W, Lee MK, Fang ZH, Wei Y, Jelinek J, Issa JP, Garcia-Manero G (2008) Genome-wide identification of aberrantly methylated promoter associated CpG islands in acute lymphoblastic leukemia. Leukemia 8:1529–1538

    Google Scholar 

  • Kuendgen A, Strupp C, Aivado M, Bernhardt A, Hildebrandt B, Haas R, Germing U, Gattermann N (2004) Treatment of myelodysplastic syndromes with valproic acid alone or in combination with all-trans retinoic acid. Blood 104:1266–1269

    CAS  PubMed  Google Scholar 

  • Kuendgen A, Bug G, Ottmann OG, Haase D, Schanz J, Hildebrandt B, Nachtkamp K, Neukirchen J, Dienst A, Haas R, Germing U, Gattermann N (2011) Treatment of poor-risk myelodysplastic syndromes and acute myeloid leukemia with a combination of 5-azacytidine and valproic acid. Clin Epigenetics 2(2):389–399

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lee J-H, Jang JH, Park J, Park S, Joo Y-D, Kim Y-K, Kim H-G, Choi CW, Kim S-H, Park SK, Park E, Min YH (2011) A prospective multicenter observational study of decitabine treatment in Korean patients with myelodysplastic syndrome. Haematologica 96:1441–1447

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lübbert M (2000) DNA methylation inhibitors in the treatment of leukemias, myelodysplastic syndromes and hemoglobinopathies: clinical results and possible mechanisms of action. Curr Top Microbiol Immunol 249:135–164

    PubMed  Google Scholar 

  • Lübbert M, Wijermans P, Kunzmann R, Verhoef G, Bosly A, Ravoet C, Andre M, Ferrant A (2001) Cytogenetic responses in high-risk myelodysplastic syndrome following low-dose treatment with DNA methylation inhibitor 5-aza-2′-deoxycytidine. Br J Haematol 114:349–357

    PubMed  Google Scholar 

  • Lübbert M, Suciu S, Baila L, Rüter BH, Platzbecker U, Giagounidis A, Selleslag D, Labar B, Germing U, Salih HR, Beeldens F, Muus P, Pflüger KH, Coens C, Hagemeijer A, Schaefer HE, Ganser A, Aul C, de Witte T, Wijermans PW (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 Organization for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group. J Clin Oncol 29:1987–1996

    PubMed  Google Scholar 

  • Lübbert M, Rüter BH, Claus R, Schmoor C, Schmid M, Germing U, et al (2012) A multicenter phase II trial of decitabine as first-line treatment for older patients with acute myeloid leukemia judged unfit for induction chemotherapy. Haematologica 97(3):393–401

    PubMed Central  PubMed  Google Scholar 

  • Lyons RM, Cosgriff TM, Modi SS, Gersh RH, Hainsworth JD, Cohn AL, McIntyre HJ, Fernando IJ, Backstrom JT, Beach CL (2009) Hematologic response to three alternative dosing schedules of azacitidine in patients with myelodysplastic syndromes. J Clin Oncol 27:1850–1856

    CAS  PubMed  Google Scholar 

  • Maslak P, Chanel S, Camacho LH, Soignet S, Pandolfi PP, Guernah I, Warrell R, Nimer S (2006) Pilot study of combination transcriptional modulation therapy with sodium phenylbutyrate and 5-azacytidine in patients with acute myeloid leukemia or myelodysplastic syndrome. Leukemia 2:212–217

    Google Scholar 

  • Momparler RL, Rivard GE, Gyger M (1985) Clinical trial on 5-aza-2′-deoxycytidine in patients with acute leukemia. Pharmacol Ther 30:277–286

    CAS  PubMed  Google Scholar 

  • Mufti GH, Gore SD, Santini V, Fenaux P, Silverman LR, Hagemeijer A, Skikne B, Hellstrom-Lindberg E, Seymour JF, Beach CL, Backstrom J, Fernando I (2009) Influence of karyotype on overall survival in patients with higher-risk myelodysplastic syndrome treated with azacitidine or a conventional care regimen. Blood (ASH Annu Meet Abstr) 114:1755

    Google Scholar 

  • Musto P, Maurillo L, Spagnoli A, Gozzini A, Rivellini F, Lunghi M, Villani O, Aloe-Spiriti MA, Venditti A, Santini V, Ad Hoc Italian Cooperative Study Group on Azacitidine in Myelodysplastic Syndromes Acute Leukemias (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

    CAS  PubMed  Google Scholar 

  • Nand S, Godwin J, Smith S, Barton K, Michaelis L, Alkan S, Veerappan R, Rychlik K, Germano E, Stiff P (2008) 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 49:2141–2147

    CAS  PubMed  Google Scholar 

  • Odenike OM, Godwin JE, van Besien K, Huo D, Stiff PJ, Sher D, Klekowski N, Green M, Larson RA, Stock W (2006) Phase II study of decitabine in myelofibrosis with myeloid metaplasia. Blood (ASH Annu Meet Abstr) 108:4923

    Google Scholar 

  • Oki Y, Kantarjian H, Gharibyan V, Jones D, O’brien S, Verstovsek S, Cortes J, Morris GM, Garcia-Manero G, Issa JP (2007) Phase II study of low-dose decitabine in combination with imatinib mesylate in patients with accelerated or myeloid blastic phase of chronic myelogenous leukemia. Cancer 109:899–906

    CAS  PubMed  Google Scholar 

  • Petti MC, Mandelli F, Zagonel V, De Gregoris C, Merola MC, Latagliata R, Gattei V, Fazi P, Monfardini S, Pino A (1993) Pilot study of 5-aza-2′-deoxycytidine (decitabine) in the treatment of poor prognosis acute myelogenous leukemia patients: preliminary results. Leukemia 7:36–41

    PubMed  Google Scholar 

  • Pinto A, Zagonel V, Attadia V, Bullian PL, Gattei V, Carbone A, Monfardini S, Colombatti A (1989) 5-aza-2′-deoxycytidine as a differentiation inducer in acute myeloid leukaemias and myelodysplastic syndromes of the elderly. Bone Marrow Transplant 4(Suppl 3):28–32

    PubMed  Google Scholar 

  • Platzbecker U, Aul C, Ehninger G, Giagounidis A (2009) Reduction of 5-azacitidine induced skin reactions in MDS patients with evening primrose oil. Ann Hematol 89:427–428

    PubMed  Google Scholar 

  • Prebet T, Gore SD, Sun Z, Greenberg PL, Juckett M, Malick L, Smith MR, Paietta E, Czader M, Gabrilove J, Erba HP, Tallman MS (2010) 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 Annu Meet Abstr) 116:601

    Google Scholar 

  • Raffoux E, Cras A, Recher C, Boëlle PY, de Labarthe A, Turlure P, Marolleau JP, Reman O, Gardin C, Victor M, Maury S, Rousselot P, Malfuson JV, Maarek O, Daniel MT, Fenaux P, Degos L, Chomienne C, Chevret S, Dombret H (2010) Phase 2 clinical trial of 5-azacitidine, valproic acid, and all-trans retinoic acid in patients with high-risk acute myeloid leukemia or myelodysplastic syndrome. Oncotarget 1:34–42

    PubMed  Google Scholar 

  • Raj K, John A, Ho A, Chronis C, Khan S, Samuel J, Pomplun S, Thomas NS, Mufti GJ (2007) CDKN2B methylation status and isolated chromosome 7 abnormalities predict responses to treatment with 5-azacytidine. Leukemia 21:1937–1944

    CAS  PubMed  Google Scholar 

  • Ravandi F, Issa JP, Garcia-Manero G, O’Brien S, Pierce S, Shan J, Borthakur G, Verstovsek S, Faderl S, Cortes J, Kantarjian H (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

    CAS  PubMed Central  PubMed  Google Scholar 

  • Richel DJ, Colly LP, Kluin-Nelemans JC, Willemze R (1991) The antileukemic activity of 5-aza-2′-deoxycytidine (Aza-dC) in patients with relapsed and resistant leukemia. Br J Cancer 64:144–148

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ritchie EK, Arnason J, Feldman EJ, Gergis US, Mayer SA, Ippoliti C, Scandura JM, Roboz G (2009) Decitabine-based salvage therapy in adults with acute myeloid leukemia. Blood (ASH Annu Meet Abstr) 114:2063

    Google Scholar 

  • Rivard GE, Momparler RL, Demers J, Benoit P, Raymond R, Lin K, Momparler LF (1981) Phase I study on 5-aza-2′-deoxycytidine in children with acute leukemia. Leuk Res 5:453–462

    CAS  PubMed  Google Scholar 

  • Roman-Gomez J, Jimenez-Velasco A, Castillejo JA, Agirre X, Barrios M, Navarro G, Molina FJ, Calasanz MJ, Prosper F, Heiniger A, Torres A (2004) Promoter hypermethylation of cancer-related genes: a strong independent prognostic factor in acute lymphoblastic leukemia. Blood 10:2492–2498

    Google Scholar 

  • Roman-Gomez J, Cordeu L, Agirre X, Jimenez-Velasco A, San Jose-Eneriz E, Garate L, Calasanz MJ, Heiniger A, Torres A, Prosper F (2007a) Epigenetic regulation of Wnt-signaling pathway in acute lymphoblastic leukemia. Blood 8:3462–3469

    Google Scholar 

  • Roman-Gomez J, Jimenez-Velasco A, Barrios M, Prosper F, Heiniger A, Torres A, Agirre X (2007b) Poor prognosis in acute lymphoblastic leukemia may relate to promoter hypermethylation of cancer-related genes. Leuk Lymphoma 48:1269–1282

    CAS  PubMed  Google Scholar 

  • Rüter B, Wijermans PW, Lübbert M (2006) Superiority of prolonged low-dose azanucleoside administration? Results of 5-aza-2′-deoxycytidine retreatment in high risk myelodysplasia patients. Cancer 106:1744–1750

    PubMed  Google Scholar 

  • Rüter B, Wijermans P, Claus R, Kunzmann R, Lübbert M (2007) Preferential cytogenetic response to continuous intravenous low-dose decitabine (DAC) administration in myelodysplastic syndrome with chromosome 7 abnormalities. Blood 110:1080–1082

    PubMed  Google Scholar 

  • Sacchi S, Kantarjian HM, O’Brien S, Cortes J, Rios MB, Giles FJ, Beran M, Koller CA, Keating MJ, Talpaz M (1999) Chronic myelogenous leukemia in nonlymphoid blastic phase: analysis of the results of first salvage therapy with three different treatment approaches for 162 patients. Cancer 86:2632–2641

    CAS  PubMed  Google Scholar 

  • Schwartsmann G, Fernandes MS, Schaan MD, Moschen M, Gerhardt LM, DiLeone L, Loitzembauer B, Kalakun L (1997) Decitabine (5-aza-2′-deoxycytidine; decitabine) plus daunorubicin as a first line treatment in patients with acute myeloid leukemia: preliminary observations. Leukemia 11(Suppl 1):28–31

    Google Scholar 

  • Sekeres MA, List AF, Cuthbertson D, Paquette R, Ganetzky R, Latham D, Paulic K, Afable M, Saba HI, Loughran TP Jr, Maciejewski JP (2010) Phase I combination trial of lenalidomide and azacitidine in patients with higher-risk myelodysplastic syndromes. J Clin Oncol 28:2253–2258

    CAS  PubMed Central  PubMed  Google Scholar 

  • Shen L, Toyota M, Kondo Y, Obata T, Daniel S, Pierce S, Imai K, Kantarjian HM, Issa JP, Garcia-Manero G (2003) Aberrant DNA methylation of p57KIP2 identifies a cell cycle regulatory pathway with prognostic impact in adult acute lymphocytic leukemia. Blood 101:4131–4136

    CAS  PubMed  Google Scholar 

  • Silverman LR, Holland JF, Demakos EP (1994) Azacitidine (aza C) in myelodysplastic syndromes (MDS), CALGB studies 8421 and 8921. Ann Hematol 68:A12

    Google Scholar 

  • Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R, Stone RM, Nelson D, Powell BL, DeCastro CM, Ellerton J, Larson RA, Schiffer CA, Holland JF (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

    CAS  PubMed  Google Scholar 

  • Silverman LR, McKenzie DR, Peterson BL, Holland JF, Backstrom JT, Beach CL, Larson RA, Cancer and Leukemia Group B (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

    CAS  PubMed  Google Scholar 

  • Soriano AO, Yang H, Faderl S, Estrov Z, Giles F, Ravandi F, Cortes J, Wierda WG, Ouzounian S, Quezada A, Pierce S, Estey EH, Issa JP, Kantarjian HM, Garcia-Manero G (2007) 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 110:2302–2308

    CAS  PubMed  Google Scholar 

  • Steensma DP, Baer MR, Slack JL, Buckstein R, Godley LA, Garcia-Manero G, Albitar M, Larsen JS, Arora S, Cullen MT, Kantarjian H (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

    CAS  PubMed  Google Scholar 

  • Thépot S, Itzykson R, Seegers V, Recher C, Quesnel B, Delaunay J, Cluzeau T, Marfaing Koka A, Stamatoullas A, Chaury MP, Dartigeas C, Cheze S, Salanoubat C, Morel P, Plantier I, Taksin A, Marolleau JP, Pautas C, Wattel E, Isnard F, Sanhes L, Harel S, de Botton S, Chait Y, Uzunov M, Guerci A, Dahoun M, Vey N, Dombret H, Dreyfus F, Ades L, Fenaux P, Gardin C (2009) Azacytidine (AZA) as first line therapy in AML: results of the French ATU program. Blood (ASH Annu Meet Abstr) 114:843

    Google Scholar 

  • Uchida T, Kinoshita T, Nagai H, Nakahara Y, Saito H, Hotta T, Murate T (1997) Hypermethylation of the p15INK4B gene in myelodysplastic syndromes. Blood 90:1403–1409

    CAS  PubMed  Google Scholar 

  • Uy GL, Abboud CN, Cashen AF, DiPersio JF, Stockerl-Goldstein KE, Vij R, Westervelt P (2010) Phase I study of panobinostat plus decitabine in elderly patients with advanced MDS or AML. Blood (ASH Annu Meet Abstr) 116:1060

    Google Scholar 

  • van den Bosch J, Lübbert M, Verhoef G, Wijermans PW (2004) The effects of 5-aza-2′-deoxycytidine (decitabine) on the platelet count in patients with intermediate and high-risk myelodysplastic syndrome. Leuk Res 28:785–790

    PubMed  Google Scholar 

  • Vardiman JW, Harris NL, Brunning RD (2002) The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 100:2292–2302

    CAS  PubMed  Google Scholar 

  • von Hoff DD, Slavik M, Muggia FM (1976) 5-azacytidine. A new anticancer drug with effectiveness in acute myelogenous leukemia. Ann Intern Med 85:237–245

    Google Scholar 

  • Voso MT, Santini V, Finelli C, Musto P, Pogliani E, Angelucci E, Fioritoni G, Alimena G, Maurillo L, Cortelezzi A, Buccisano F, Gobbi M, Borin L, Di Tucci A, Zini G, Petti MC, Martinelli G, Fabiani E, Fazi P, Vignetti M, Piciocchi A, Liso V, Amadori S, Leone G (2009) Valproic acid at therapeutic plasma levels may increase 5-azacytidine efficacy in higher risk myelodysplastic syndromes. Clin Cancer Res 15:5002–5007

    CAS  PubMed  Google Scholar 

  • Wang JC, Chen W, Nallusamy S, Chen C, Novetsky AD (2002) Hypermethylation of the P15INK4b and P16INK4a in agnogenic myeloid metaplasia (AMM) and AMM in leukaemic transformation. Br J Haematol 116:582–586

    CAS  PubMed  Google Scholar 

  • Wijermans PW, Krulder JW, Huijgens PC, Neve P (1997) Continuous infusion of low-dose 5-aza-2′-deoxycytidine in elderly patients with high-risk myelodysplastic syndrome. Leukemia 11:19–23

    Google Scholar 

  • Wijermans PW, Lübbert M, Verhoef G, Bosly A, Ravoet C, Andre M, Ferrant A (2000) 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 18:956–962

    CAS  PubMed  Google Scholar 

  • Wijermans PW, Luebbert M, Verhoef G, Klimek V, Bosly A (2005) An epigenetic approach to the treatment of advanced MDS; the experience with the DNA demethylating agent 5-aza-2′-deoxycytidine (decitabine) in 177 patients. Ann Hematol 84(Suppl 1):9–17

    CAS  PubMed  Google Scholar 

  • Willemze R, Archimbaud E, Muus P (1993) Preliminary results with 5-aza-2′deoxycytidine (DAC)-containing chemotherapy in patients with relapsed or refractory acute leukemia. The EORTC Leukemia Cooperative Group. Leukemia 7(Suppl 1):49–50

    PubMed  Google Scholar 

  • Willemze R, Suciu S, Archimbaud E, Muus P, Stryckmans P, Louwagie EA, Berneman Z, Tjean M, Wijermans P, Döhner H, Jehn U, Labar B, Jaksic B, Dardenne M, Zittoun R (1997) A randomized phase-II study on the effects of 5-aza-2′-deoxycytidine combined with either amsacrine or idarubicin in patients with relapsed acute leukemia: an EORTC Leukemia Cooperative Group phase-II study. Leukemia 11(Suppl 1):24–27

    Google Scholar 

  • Yang H, Hoshino K, Sanchez-Gonzalez B, Kantarjian H, Garcia-Manero G (2005) Antileukemia activity of the combination of 5-aza-2′-deoxycytidine with valproic acid. Leuk Res 29:739–748

    CAS  PubMed  Google Scholar 

  • Yang H, Kadia T, Xiao L, Bueso-Ramos CE, Hoshino K, Thomas DA, O’Brien S, Jabbour E, Pierce S, Rosner GL, Kantarjian HM, Garcia-Manero G (2009) Residual DNA methylation at remission is prognostic in adult Philadelphia chromosome-negative acute lymphocytic leukemia. Blood 113:1892–1898

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zagonel V, Pinto A, Bullian PL, Sorio R, Gattei V, Curri G, De Rosa L, Attadia V, Monfardini S (1990) 5-aza-2′-deoxycytidine as a differentiation inducer in human hemopoietic malignancies: preliminary clinical report. In: Momparler RL, de Vos D (eds) 5-aza-2′-deoxycytidine: preclinical and clinical studies. PCH, Haarlem

    Google Scholar 

  • Zagonel V, Lo Re G, Marotta G, Barbare R, Sardeo R, Gattei V, De Angelis V, Montardinni S, Pinto A (1993) 5-aza-2′-deoxycytidine (decitabine) induces trilineage response in unfavorable myelodysplastic syndrome. Leukemia 7(Suppl 1):30–35

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Haematology and Central Haematology Laboratory, Inselspital, Bern, Switzerland

    Michael Daskalakis

  2. Cancer Research, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, VIC, 3002, Australia

    Tina E. Joeckel MD

  3. Department of Hematology/Oncology, University Medical Center Freiburg, University of Freiburg, Hugstetterstr. 55, Freiburg, D-79106, Germany

    Michael Lübbert MD, PhD

  4. Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University, Düsseldorf, Germany

    A. Kuendgen

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  2. Tina E. Joeckel MD
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  3. Michael Lübbert MD, PhD
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  4. A. Kuendgen
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  1. Department of Hematology/Oncology, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany

    Michael Lübbert

  2. Norris Comprehensive Cancer Center Urologic Cancer Res. Lab., University of Southern California Dept. Biochemistry & Molecular Biology, Los Angeles, California, USA

    Peter A. Jones

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Daskalakis, M., Joeckel, T.E., Lübbert, M., Kuendgen, A. (2014). Treatment of Hematologic Malignancies with DNA Hypomethylating Agents. In: Lübbert, M., Jones, P. (eds) Epigenetic Therapy of Cancer. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-38404-2_7

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