Advanced search

Vol 9, No 2 (2018)
Review paper
Published online: 2018-08-17

open access

View PDF (Polish) Download PDF file
Page views 764
Article views/downloads 1663
Get Citation

Connect on Social Media

Connect on Social Media

Role of drugs influencing epigenetic mechanisms in acute myeloid leukemia treatment

Kamil Wiśniewski1, Joanna Góra-Tybor1
DOI: 10.5603/Hem.2018.0014
Hematologia 2018;9(2):110-122.

Abstract

Currently, two DNA methyltransferase inhibitors, azacitadine and decitabine, are the epigenetic agents used for AML treatment. As a result of DNA hipomethylation, these DNA methyltransferase inhibitors contribute to the reactivation of methylation silence tumor suppressor genes. Azacitadine and decitabine can increase life expectancy of older patients precluded from intensive chemotherapy. New studies are being conducted in order to determine the use of azacitadine and decitabine in prevention and treatment of AML relapse after allogeneic hematopoietic stem cell transplantation. The present paper manifests the mechanism of action of hypomethylating drugs, as well as provides a brief overview of some clinical trials concerning the use of azacitadine and decitabine in AML. The article also discusses some potential epigenetic drugs that are undergoing clinical trials.

Keywords: acute myeloid leukemiaDNA methylationhypomethylating agentsazacitadinedecitabine

Article available in PDF format

View PDF (Polish) Download PDF file

References

  1. Oran B, Weisdorf DJ. Survival for older patients with acute myeloid leukemia: a population-based study. Haematologica. 2012; 97(12): 1916–1924.
    CrossRefPubMed
  2. Burnett A, Wetzler M, Löwenberg B. Therapeutic advances in acute myeloid leukemia. J Clin Oncol. 2011; 29(5): 487–494.
    CrossRefPubMed
  3. Klepin HD. Elderly acute myeloid leukemia: assessing risk. Curr Hematol Malig Rep. 2015; 10(2): 118–125.
    CrossRefPubMed
  4. Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007; 128(4): 683–692.
    CrossRefPubMed
  5. Esteller M. Epigenetics in cancer. N Engl J Med. 2008; 358(11): 1148–1159.
    CrossRefPubMed
  6. Pleyer L, Burgstaller S, Girschikofsky M, et al. Azacitidine in 302 patients with WHO-defined acute myeloid leukemia: results from the Austrian Azacitidine Registry of the AGMT-Study Group. Ann Hematol. 2014; 93(11): 1825–1838.
    CrossRefPubMed
  7. Bhatnagar B, Duong VuH, Gourdin TS, et al. Ten-day decitabine as initial therapy for newly diagnosed patients with acute myeloid leukemia unfit for intensive chemotherapy. Leuk Lymphoma. 2014; 55(7): 1533–1537.
    CrossRefPubMed
  8. Falkenberg KJ, Johnstone RW. Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat Rev Drug Discov. 2014; 13(9): 673–691.
    CrossRefPubMed
  9. Nebbioso A, Clarke N, Voltz E, et al. Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells. Nat Med. 2005; 11(1): 77–84.
    CrossRefPubMed
  10. Nassereddine S, Lap CJ, Haroun F, et al. The role of mutant IDH1 and IDH2 inhibitors in the treatment of acute myeloid leukemia. Ann Hematol. 2017; 96(12): 1983–1991.
    CrossRefPubMed
  11. 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): 225–231.
    CrossRefPubMed
  12. Damaraju VL, Mowles D, Yao S, et al. Role of human nucleoside transporters in the uptake and cytotoxicity of azacitidine and decitabine. Nucleosides Nucleotides Nucleic Acids. 2012; 31(3): 236–255.
    CrossRefPubMed
  13. Qin T, Jelinek J, Si J, et al. Mechanisms of resistance to 5-aza-2'-deoxycytidine in human cancer cell lines. Blood. 2009; 113(3): 659–667.
    CrossRefPubMed
  14. Li LH, Olin EJ, Buskirk HH, et al. Cytotoxicity and mode of action of 5-azacytidine on L1210 leukemia. Cancer Res. 1970; 30(11): 2760–2769.
    PubMed
  15. Van Rompay AR, Norda A, Lindén K, et al. Phosphorylation of uridine and cytidine nucleoside analogs by two human uridine-cytidine kinases. Mol Pharmacol. 2001; 59(5): 1181–1186.
    PubMed
  16. Momparler RL, Derse D. Kinetics of phosphorylation of 5-aza-2'-deoxyycytidine by deoxycytidine kinase. Biochem Pharmacol. 1979; 28(8): 1443–1444.
    PubMed
  17. Qin T, Castoro R, El Ahdab S, et al. Mechanisms of resistance to decitabine in the myelodysplastic syndrome. PLoS One. 2011; 6(8): e23372.
    CrossRefPubMed
  18. Galmarini CM, Thomas X, Graham K, et al. Deoxycytidine kinase and cN-II nucleotidase expression in blast cells predict survival in acute myeloid leukaemia patients treated with cytarabine. Br J Haematol. 2003; 122(1): 53–60.
    PubMed
  19. Eliopoulos N, Cournoyer D, Momparler RL. Drug resistance to 5-aza-2'-deoxycytidine, 2',2'-difluorodeoxycytidine, and cytosine arabinoside conferred by retroviral-mediated transfer of human cytidine deaminase cDNA into murine cells. Cancer Chemother Pharmacol. 1998; 42(5): 373–378.
    CrossRefPubMed
  20. 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): 938–948.
    CrossRefPubMed
  21. Karahoca M, Momparler RL. Pharmacokinetic and pharmacodynamic analysis of 5-aza-2'-deoxycytidine (decitabine) in the design of its dose-schedule for cancer therapy. Clin Epigenetics. 2013; 5(1): 3.
    CrossRefPubMed
  22. Savona MR, Odenike O, Amrein PC, et al. Results of first in human (FIH) phase 1 pharmacokinetic (PK) guided dose-escalation study of ASTX727, a combination of the oral cytidine deaminase inhibitor (CDAi) E7727 with oral decitabine in subjects with myelodysplastic syndromes (MDS). Blood. 2015; 126: abstract.
  23. Tsai CT, Yang PM, Chern TR, et al. AID downregulation is a novel function of the DNMT inhibitor 5-aza-deoxycytidine. Oncotarget. 2014; 5(1): 211–223.
    CrossRefPubMed
  24. 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): 6993–6997.
    PubMed
  25. Christman JK. 5-Azacytidine and 5-aza-2'-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy. Oncogene. 2002; 21(35): 5483–5495.
    CrossRefPubMed
  26. Stresemann C, Lyko F. Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int J Cancer. 2008; 123(1): 8–13.
    CrossRefPubMed
  27. 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): 4727–4741.
    CrossRefPubMed
  28. 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): 5229–5238.
    CrossRefPubMed
  29. Derissen EJB, Hillebrand MJX, Rosing H, et al. Quantitative determination of azacitidine triphosphate in peripheral blood mononuclear cells using liquid chromatography coupled with high-resolution mass spectrometry. J Pharm Biomed Anal. 2014; 90: 7–14.
    CrossRefPubMed
  30. Jansen RS, Rosing H, Wijermans PW, et al. Decitabine triphosphate levels in peripheral blood mononuclear cells from patients receiving prolonged low-dose decitabine administration: a pilot study. Cancer Chemother Pharmacol. 2012; 69(6): 1457–1466.
    CrossRefPubMed
  31. Liu Z, Marcucci G, Byrd JC, et al. Characterization of decomposition products and preclinical and low dose clinical pharmacokinetics of decitabine (5-aza-2'-deoxycytidine) by a new liquid chromatography/tandem mass spectrometry quantification method. Rapid Commun Mass Spectrom. 2006; 20(7): 1117–1126.
    CrossRefPubMed
  32. 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.
    CrossRefPubMed
  33. Santini V. Azacitidine: activity and efficacy as an epigenetic treatment of myelodysplastic syndromes. Expert Rev Hematol. 2009; 2(2): 121–127.
    CrossRefPubMed
  34. Choi SiHo, Byun HM, Kwan JM, et al. Hydroxycarbamide in combination with azacitidine or decitabine is antagonistic on DNA methylation inhibition. Br J Haematol. 2007; 138(5): 616–623.
    CrossRefPubMed
  35. Christman JK, Mendelsohn N, Herzog D, et al. Effect of 5-azacytidine on differentiation and DNA methylation in human promyelocytic leukemia cells (HL-60). Cancer Res. 1983; 43(2): 763–769.
    PubMed
  36. Mund C, Hackanson B, Stresemann C, et al. Characterization of DNA demethylation effects induced by 5-aza-2'-deoxycytidine in patients with myelodysplastic syndrome. Cancer Res. 2005; 65(16): 7086–7090.
    CrossRefPubMed
  37. Wong YF, Jakt LM, Nishikawa SI. Prolonged treatment with DNMT inhibitors induces distinct effects in promoters and gene-bodies. PLoS One. 2013; 8(8): e71099.
    CrossRefPubMed
  38. Shen L, Kantarjian H, Guo Yi, et al. DNA methylation predicts survival and response to therapy in patients with myelodysplastic syndromes. J Clin Oncol. 2010; 28(4): 605–613.
    CrossRefPubMed
  39. 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): 5495–5503.
    CrossRefPubMed
  40. Fandy TE, Herman JG, Kerns P, et al. 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. 2009; 114(13): 2764–2773.
    CrossRefPubMed
  41. 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): 2957–2964.
    CrossRefPubMed
  42. Maegawa S, Gough SM, Watanabe-Okochi N, et al. Age-related epigenetic drift in the pathogenesis of MDS and AML. Genome Res. 2014; 24(4): 580–591.
    CrossRefPubMed
  43. Zhu ZZ, Hou L, Bollati V, et al. Predictors of global methylation levels in blood DNA of healthy subjects: a combined analysis. Int J Epidemiol. 2012; 41(1): 126–139.
    CrossRefPubMed
  44. Saiki JH, McCredie KB, Vietti TJ, et al. 5-azacytidine in acute leukemia. Cancer. 1978; 42(5): 2111–2114.
    PubMed
  45. Karon M, Sieger L, Leimbrock S, et al. 5-Azacytidine: a new active agent for the treatment of acute leukemia. Blood. 1973; 42(3): 359–365.
    PubMed
  46. 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): 2429–2440.
    CrossRefPubMed
  47. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. International Vidaza High-Risk MDS Survival Study Group. 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): 223–232.
    CrossRefPubMed
  48. Arber DA, Brunning RD, Brunning A. et al. Acute myeloid leukaemaia with myelodysplastic-related changes. In: Swerdlow SH, Campo E, Harris NL. et al. ed. WHO classifi cation of tumors of haematopoietic and lympohoid tissues. 4th edn. International Agency for Research on Cancer, Lyon 2008.
  49. Silverman LR, McKenzie DR, Peterson BL, et al. Cancer and Leukemia Group B. 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): 3895–3903.
    CrossRefPubMed
  50. 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): 562–569.
    CrossRefPubMed
  51. Silverman LR, Fenaux P, Mufti GJ, et al. The effects of continued azacitidine (AZA) treatment cycles on response in higher-risk patients (Pts) with myelodysplastic syndromes (MDS). Blood. 2008; 112: 227.
  52. Dombret H, Seymour JF, Butrym A, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015; 126(3): 291–299.
    CrossRefPubMed
  53. 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): 1067–1072.
    CrossRefPubMed
  54. Cabrero M, Jabbour E, Ravandi F, et al. Discontinuation of hypomethylating agent therapy in patients with myelodysplastic syndromes or acute myelogenous leukemia in complete remission or partial response: retrospective analysis of survival after long-term follow-up. Leuk Res. 2015; 39(5): 520–524.
    CrossRefPubMed
  55. Kantarjian H, O'Brien S, Cortes J, et al. Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome:. Cancer. 2006; 106(5): 1090–1098.
    CrossRef
  56. Cashen AF, Schiller GJ, O'Donnell MR, et al. Multicenter, phase II study of decitabine for the first-line treatment of older patients with acute myeloid leukemia. J Clin Oncol. 2010; 28(4): 556–561.
    CrossRefPubMed
  57. Blum W, Garzon R, Klisovic RB, et al. Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine. Proc Natl Acad Sci USA. 2010; 107(16): 7473–7478.
    CrossRefPubMed
  58. Kantarjian HM, Thomas XG, Dmoszynska A, et al. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012; 30(21): 2670–2677.
    CrossRefPubMed
  59. Sureda A, Bader P, Cesaro S, et al. Indications for allo- and auto-SCT for haematological diseases, solid tumours and immune disorders: current practice in Europe, 2015. Bone Marrow Transplant. 2015; 50(8): 1037–1056.
    CrossRefPubMed
  60. Bejanyan N, Weisdorf DJ, Logan BR, et al. Survival of patients with acute myeloid leukemia relapsing after allogeneic hematopoietic cell transplantation: a center for international blood and marrow transplant research study. Biol Blood Marrow Transplant. 2015; 21(3): 454–459.
    CrossRefPubMed
  61. Ruutu T, de Wreede LC, van Biezen A, et al. European Society for Blood and Marrow Transplantation (EBMT). Second allogeneic transplantation for relapse of malignant disease: retrospective analysis of outcome and predictive factors by the EBMT. Bone Marrow Transplant. 2015; 50(12): 1542–1550.
    CrossRefPubMed
  62. 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): 754–758.
    CrossRefPubMed
  63. 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): 3361–3369.
    CrossRefPubMed
  64. Choi J, Ritchey J, Prior JL, et al. In vivo administration of hypomethylating agents mitigate graft-versus-host disease without sacrificing graft-versus-leukemia. Blood. 2010; 116(1): 129–139.
    CrossRefPubMed
  65. Santourlidis S, Trompeter HI, Weinhold S, et al. Crucial role of DNA methylation in determination of clonally distributed killer cell Ig-like receptor expression patterns in NK cells. J Immunol. 2002; 169(8): 4253–4261.
    PubMed
  66. Craddock C, Labopin M, Robin M, et al. Clinical activity of azacitidine in patients who relapse after allogeneic stem cell transplantation for acute myeloid leukemia. Haematologica. 2016; 101(7): 879–883.
    CrossRefPubMed
  67. Schroeder T, Rautenberg C, Haas R, et al. Hypomethylating agents after allogeneic blood stem cell transplantation. Stem Cell Investig. 2016; 3(2): 84–150.
    CrossRefPubMed
  68. Steinmann J, Bertz H, Wäsch R, et al. 5-Azacytidine and DLI can induce long-term remissions in AML patients relapsed after allograft. Bone Marrow Transplant. 2015; 50(5): 690–695.
    CrossRefPubMed
  69. Tessoulin B, Delaunay J, Chevallier P, et al. Azacitidine salvage therapy for relapse of myeloid malignancies following allogeneic hematopoietic SCT. Bone Marrow Transplant. 2014; 49(4): 567–571.
    CrossRefPubMed
  70. Schroeder T, Rachlis E, Bug G, 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): 1229–1235.
    CrossRefPubMed
  71. 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): 627–632.
    CrossRefPubMed
  72. Schroeder T, Czibere A, Platzbecker U, 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): 872–876.
    CrossRefPubMed
  73. Ganguly S, Amin M, Divine C, et al. Decitabine in patients with relapsed acute myeloid leukemia (AML) after allogeneic stem cell transplantation (allo-SCT). Ann Hematol. 2013; 92(4): 549–550.
    CrossRefPubMed
  74. Singh SN, Cao Q, Gojo I, et al. Durable complete remission after single agent decitabine in AML relapsing in extramedullary sites after allo-SCT. Bone Marrow Transplant. 2012; 47(7): 1008–1009.
    CrossRefPubMed
  75. El-Cheikh J, Massoud R, Fares E, et al. Low-dose 5-azacytidine as preventive therapy for relapse of AML and MDS following allogeneic HCT. Bone Marrow Transplant. 2017; 52(6): 918–921.
    CrossRefPubMed
  76. 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): 5420–5431.
    CrossRefPubMed
  77. Craddock C, Jilani N, Siddique S, et al. Tolerability and clinical activity of post-transplantation azacitidine in patients allografted for acute myeloid leukemia treated on the RICAZA Trial. Biol Blood Marrow Transplant. 2016; 22(2): 385–390.
    CrossRefPubMed
  78. Pusic I, Choi J, Fiala MA, et al. Maintenance therapy with decitabine after allogeneic stem cell transplantation for acute myelogenous leukemia and myelodysplastic syndrome. Biol Blood Marrow Transplant. 2015; 21(10): 1761–1769.
    CrossRefPubMed
  79. Oshikawa G, Kakihana K, Saito M, et al. Post-transplant maintenance therapy with azacitidine and gemtuzumab ozogamicin for high-risk acute myeloid leukaemia. Br J Haematol. 2015; 169(5): 756–759.
    CrossRefPubMed
  80. Griffiths EA, Choy G, Redkar S, et al. SGI-110: DNA methyltransferase inhibitor oncolytic. Drugs Fut. 2013; 38(8): 535–543.
    PubMed
  81. Yoo CB, Jeong S, Egger G, et al. Delivery of 5-aza-2'-deoxycytidine to cells using oligodeoxynucleotides. Cancer Res. 2007; 67(13): 6400–6408.
    CrossRefPubMed
  82. Kantarjian HM, Roboz GJ, Kropf PL, et al. Guadecitabine (SGI-110) in treatment-naive patients with acute myeloid leukaemia: phase 2 results from a multicentre, randomised, phase 1/2 trial. Lancet Oncol. 2017; 18(10): 1317–1326.
    CrossRefPubMed
  83. Roboz G, Kantarjian H, Yee K, et al. Dose, schedule, safety, and efficacy of guadecitabine in relapsed or refractory acute myeloid leukemia. Cancer. 2017; 124(2): 325–334.
    CrossRef
  84. Schneider-Stock R, Ocker M. Epigenetic therapy in cancer: molecular background and clinical development of histone deacetylase and DNA methyltransferase inhibitors. IDrugs. 2007; 10(8): 557–561.
    PubMed
  85. Dokmanovic M, Clarke C, Marks PA. Histone deacetylase inhibitors: overview and perspectives. Mol Cancer Res. 2007; 5(10): 981–989.
    CrossRefPubMed
  86. Witt O, Deubzer HE, Milde T, et al. HDAC family: what are the cancer relevant targets? Cancer Lett. 2009; 277(1): 8–21.
    CrossRefPubMed
  87. Christiansen AJ, West A, Banks KM, et al. Eradication of solid tumors using histone deacetylase inhibitors combined with immune-stimulating antibodies. Proc Natl Acad Sci USA. 2011; 108(10): 4141–4146.
    CrossRefPubMed
  88. Noureen N, Rashid H, Kalsoom S. Identification of type-specific anticancer histone deacetylase inhibitors: road to success. Cancer Chemother Pharmacol. 2010; 66(4): 625–633.
    CrossRefPubMed
  89. Scott GK, Mattie MD, Berger CE, et al. Rapid alteration of microRNA levels by histone deacetylase inhibition. Cancer Res. 2006; 66(3): 1277–1281.
    CrossRefPubMed
  90. Bose P, Grant S. Rational combinations of targeted agents in AML. J Clin Med. 2015; 4(4): 634–664.
    CrossRefPubMed
  91. Shao W, Growney JD, Feng Y et al. Potent anticancer activity of the pan-deacetylase inhibitor panobinostat (LBH589) as a single agent in in vitro and in vivo tumor models. In: 99th American Association of Cancer Research.
  92. Wahaib K, Beggs AE, Campbell H, et al. Panobinostat: A histone deacetylase inhibitor for the treatment of relapsed or refractory multiple myeloma. Am J Health Syst Pharm. 2016; 73(7): 441–450.
    CrossRefPubMed
  93. Giles F, Fischer T, Cortes J, et al. A phase I study of intravenous LBH589, a novel cinnamic hydroxamic acid analogue histone deacetylase inhibitor, in patients with refractory hematologic malignancies. Clin Cancer Res. 2006; 12(15): 4628–4635.
    CrossRefPubMed
  94. DeAngelo DJ, Spencer A, Bhalla KN, et al. Phase Ia/II, two-arm, open-label, dose-escalation study of oral panobinostat administered via two dosing schedules in patients with advanced hematologic malignancies. Leukemia. 2013; 27(8): 1628–1636.
    CrossRefPubMed
  95. Tan P, Wei A, Mithraprabhu S, et al. Dual epigenetic targeting with panobinostat and azacitidine in acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood Cancer J. 2014; 4: e170.
    CrossRefPubMed
  96. Ocio EM, Herrera P, Olave MT, et al. PETHEMA Group. Panobinostat as part of induction and maintenance for elderly patients with newly diagnosed acute myeloid leukemia: phase Ib/II panobidara study. Haematologica. 2015; 100(10): 1294–1300.
    CrossRefPubMed
  97. Byrd JC, Marcucci G, Parthun MR, et al. A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia. Blood. 2005; 105(3): 959–967.
    CrossRefPubMed
  98. Klimek VM, Fircanis S, Maslak P, et al. Tolerability, pharmacodynamics, and pharmacokinetics studies of depsipeptide (romidepsin) in patients with acute myelogenous leukemia or advanced myelodysplastic syndromes. Clin Cancer Res. 2008; 14(3): 826–832.
    CrossRefPubMed
  99. Gojo I, Jiemjit A, Trepel JB, et al. Phase 1 and pharmacologic study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemias. Blood. 2007; 109(7): 2781–2790.
    CrossRefPubMed
  100. Quintás-Cardama A, Santos FPS, Garcia-Manero G. Histone deacetylase inhibitors for the treatment of myelodysplastic syndrome and acute myeloid leukemia. Leukemia. 2011; 25(2): 226–235.
    CrossRefPubMed
  101. Ley TJ, Miller C, Ding Li, et al. Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013; 368(22): 2059–2074.
    CrossRefPubMed
  102. Patel JP, Gönen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012; 366(12): 1079–1089.
    CrossRefPubMed
  103. Marcucci G, Maharry K, Wu YZ, et al. IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol. 2010; 28(14): 2348–2355.
    CrossRefPubMed
  104. Lu C, Ward PS, Kapoor GS, et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature. 2012; 483(7390): 474–478.
    CrossRefPubMed
  105. Gross S, Cairns RA, Minden MD, et al. Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J Exp Med. 2010; 207(2): 339–344.
    CrossRefPubMed
  106. Reitman ZJ, Parsons DW, Yan H. IDH1 and IDH2: not your typical oncogenes. Cancer Cell. 2010; 17(3): 215–216.
    CrossRefPubMed
  107. Fathi AT, DiNardo CD, Kline I, et al. AG221-C-001 Study Investigators. Enasidenib in mutant relapsed or refractory acute myeloid leukemia. Blood. 2017; 130(6): 722–731.
    CrossRefPubMed
  108. DiNardo CD, de Bo, Stein EM, et al. Ivosidenib (AG-120) in mutant IDH1 AML and advanced hematologic malignancies: results of a phase 1 dose escalation and expansion study. Blood. 2017; 130: 725.

About cookies

Necessary cookies

Allways active

These cookies are necessary for the proper display and operation of the website. Blocking them may cause the website to malfunction.

Analytical cookies

As part of our website, we use analytical tools, such as Google Analytics, that allow us to verify website traffic. These tools may require the use of cookies.

Community cookies

These are cookies associated with the social networks we use. Accepting them will allow us to associate your visit to the site with our social media profiles.

Marketing cookies

These are cookies responsible for carrying out advertising and marketing activities - consenting to their use will allow us to target you with advertisements based on your previous activities within our website.

Hematology in Clinical Practice

About Via Medica Advertising
Bookstore (Ikamed) TVMed
News
Copyright © 2023 Via Medica Regulations Cookie policy Privacy policy Legal Notice