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Hypomethylating Agents as a Therapy for AML

  • Acute Myeloid Leukemias (H Erba, Section Editor)
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Abstract

Acute myeloid leukemia (AML) is predominantly a disease of older adults associated with poor long-term outcomes with available therapies. Used as single agents, hypomethylating agents (HMAs) induce only 15 to 25% complete remissions, but current data suggest that median OS observed after HMAs is comparable to that observed after more intensive therapies. Whether long-term cure may be obtained in some patients treated with HMAs is unknown. Combinations of HMAs to novel agents are now extensively investigated and attractive response rates have been reported when combining HMAs to different drug classes. The absence of reliable predictive biomarkers of efficacy of HMAs in AML and the uncertainties regarding their most relevant mechanisms of action hinder the rational design of the combinations to be tested in priority, usually in untreated older AML patients.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015;373:1136–52. Review.

    Article  PubMed  Google Scholar 

  2. Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368:2059–74.

    Article  Google Scholar 

  3. Dombret H, Gardin C. An update of current treatments for adult acute myeloid leukemia. Blood. 2016;127:53–61. Review.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Soshnev AA, Josefowicz SZ, Allis CD. Greater than the sum of parts: complexity of the dynamic epigenome. Mol Cell. 2016;62:681–94. Review.

    Article  CAS  PubMed  Google Scholar 

  5. Figueroa ME, Lugthart S, Li Y, et al. DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer Cell. 2010;17:13–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Delhommeau F, Dupont S, Della Valle V, et al. Mutation in TET2 in myeloid cancers. N Engl J Med. 2009;360:2289–301.

    Article  PubMed  Google Scholar 

  7. Mardis ER, Ding L, Dooling DJ, Larson DE, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med. 2009;361:1058–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ley TJ, Ding L, Walter MJ, et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med. 2010;363:2424–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ward PS, Patel J, Wise DR, et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2 hydroxyglutarate. Cancer Cell. 2010;17:225–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Patel JP, Gönen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366:1079–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Abdel-Wahab O, Levine RL. Mutations in epigenetic modifiers in the pathogenesis and therapy of acute myeloid leukemia. Blood. 2013;121:3563–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Jasielec J, Saloura V, Godley LA. The mechanistic role of DNA methylation in myeloid leukemogenesis. Leukemia. 2014;28:1765–73. Review.

    Article  CAS  PubMed  Google Scholar 

  13. Li S, Garrett-Bakelman FE, Chung SS, Sanders MA, et al. Distinct evolution and dynamics of epigenetic and genetic heterogeneity in acute myeloid leukemia. Nat Med. 2016. doi:10.1038/nm.4125.

    Google Scholar 

  14. Von Hoff DD, Slavik M, Muggia FM. 5-Azacitidine. A new anticancer drug with effectiveness in acute myelogenous leukemia. Ann Intern Med. 1976;85:237–45. Review.

    Article  Google Scholar 

  15. Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. 2002;20:2429–40.

    Article  CAS  PubMed  Google Scholar 

  16. Silverman LR, McKenzie DR, Peterson BL, et al. Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. J Clin Oncol. 2006;24:3895–903.

  17. 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;28:562–9.

    Article  CAS  PubMed  Google Scholar 

  18. Becker H, Suciu S, Rüter BH, et al. Decitabine versus best supportive care in older patients with refractory anemia with excess blasts in transformation (RAEBt)—results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group (GMDSSG). Ann Hematol. 2015;94:2003–13.

    Article  PubMed  Google Scholar 

  19. Lübbert M, Rüter BH, Claus R, et al. A multicenter phase II trial of decitabine as first-line treatment for older patients with acute myeloid leukemia judged unfit for induction chemotherapy. Haematologica. 2012;97:393–401.

    Article  PubMed  PubMed Central  Google Scholar 

  20. 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 U S A. 2010;107:7473–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. •• 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):2670–7. This phase 3 study led to EU registration of decitabine for use in older AML with more than 20% marrow blasts, if ineligible to intensive chemotherapy.

  22. •• 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;126:291–9. This phase 3 study established AZA as a new therapeutic option in older AML with more than 30% marrow blasts and WBC less than 15 G/L.

  23. de Vos D. Epigenetic drugs: a longstanding story. Semin Oncol. 2005;32:437–42. Review.

    Article  PubMed  Google Scholar 

  24. Lübbert M, Wijermans P, Kunzmann R, et al. Cytogenetic responses in high-risk myelodysplastic syndrome following low-dose treatment with the DNA methylation inhibitor 5-aza-2′-deoxycytidine. Br J Haematol. 2001;114:349–57.

    Article  PubMed  Google Scholar 

  25. 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;109:52–7.

    Article  CAS  PubMed  Google Scholar 

  26. Cashen AF, Schiller GJ, O’Donnell MR, DiPersio JF, et al. Multicenter, phase II study of decitabine for the first-line treatment of older patients with acute myeloid leukemia. J Clin Oncol. 2010;28:556–61.

    Article  CAS  PubMed  Google Scholar 

  27. Griffiths EA, Choy G, Redkar S, et al. SGI-110: DNA methyltransferase inhibitor oncolytic. Drugs Future. 2013;38:535–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Issa JP, Roboz G, Rizzieri D, et al. Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study. Lancet Oncol. 2015;16:1099–110.

    Article  CAS  PubMed  Google Scholar 

  29. Savona MR, Gore SD, Kolibaba KS, et al. CC-486 (oral azacitidine) monotherapy in patients with acute myeloid leukemia (AML). Blood. 2015;126:abstract 452.

    Google Scholar 

  30. Garcia-Manero G, Gore SD, Kambhampati S, et al. Efficacy and safety of extended dosing schedules of CC-486 (oral azacitidine) in patients with lower-risk myelodysplastic syndromes. Leukemia. 2016;30:889–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 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 683.

    Article  Google Scholar 

  32. Ebrahem Q, Mahfouz RZ, Durkin L, et al. Mechanisms of resistance to 5-azacitidine/decitabine in MDS-AML and pre-clinical in vivo proof of principle of rational solutions to extend response. Blood. 2015;126:abstract 678.

    Google Scholar 

  33. Thepot S, Itzykson R, Seegers V, et al. Treatment of progression of Philadelphia-negative myeloproliferative neoplasms to myelodysplastic syndrome or acute myeloid leukemia by azacitidine: a report on 54 cases on the behalf of the Groupe Francophone des Myelodysplasies (GFM). Blood. 2010;116:3735–42.

    Article  CAS  PubMed  Google Scholar 

  34. Maurillo L, Venditti A, Spagnoli A, et al. Azacitidine for the treatment of patients with acute myeloid leukemia: report of 82 patients enrolled in an Italian Compassionate Program. Cancer. 2012;118:1014–22.

    Article  CAS  PubMed  Google Scholar 

  35. • Thépot S, Itzykson R, Seegers V, et al. Azacitidine in untreated acute myeloid leukemia: a report on 149 patients. Am J Hematol. 2014;89:410–6. The results of this large retrospective study confirm the AZA-001 AML trial conclusions in real life.

  36. • 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;93:1825–38. The results of this large retrospective study confirm the AZA-001 AML trial conclusions in real life.

  37. Pleyer L, Burgstaller S, Stauder R, et al. Azacitidine in acute myeloid leukemia with >30% bone marrow blasts and <15 G/L white blood cell count: results from the Austrian Azacitidine Registry of the AGMT Study Group versus randomized controlled phase III clinical trial data. Blood. 2015;126:abstract 2515.

    Google Scholar 

  38. Ramos F, Thépot S, Pleyer L, et al. Azacitidine frontline therapy for unfit acute myeloid leukemia patients: clinical use and outcome prediction. Leuk Res. 2015;39:296–306.

    Article  CAS  PubMed  Google Scholar 

  39. Ivanoff S, Gruson B, Chantepie SP, et al. 5-Azacitidine treatment for relapsed or refractory acute myeloid leukemia after intensive chemotherapy. Am J Hematol. 2013;88:601–5.

    Article  CAS  PubMed  Google Scholar 

  40. Itzykson R, Thépot S, Berthon C, et al. Azacitidine for the treatment of relapsed and refractory AML in older patients. Leuk Res. 2015;39:124–30.

    Article  CAS  PubMed  Google Scholar 

  41. Gardin C, Itzykson R, Thépot S, et al. Frontline azacitidine (AZA) or intensive chemotherapy (ICTx) in older AML patients. J Clin Oncol. 2010;26:15s (suppl; abstract 6530).

  42. • Quintás-Cardama A, Ravandi F, Liu-Dumlao T, et al. Epigenetic therapy is associated with similar survival compared with intensive chemotherapy in older patients with newly diagnosed acute myeloid leukemia. Blood. 2012;120:4840–5. This retrospective single center comparison was the first to suggest that HMAs and intensive chemotherapy may lead to similar long-term outcomes for most older AML patients.

  43. Kadia TM, Thomas XG, Dmoszynska A, et al. Decitabine improves outcomes in older patients with acute myeloid leukemia and higher blast counts. Am J Hematol. 2015;90:E139–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Döhner H, Seymour JF, Butrym A, et al. Overall survival in older patients with newly diagnosed acute myeloid leukemia (AML) with >30% bone marrow blasts treated with azacitidine by cytogenetic risk status: results of the AZA-AML-001 study. Blood. 2014;124:621 [abstract].

    Article  Google Scholar 

  45. Seymour JF, Döhner H, Schuh AC, et al. Azacitidine (AZA) vs conventional care regimens (CCR) in patients with acute myeloid leukemia (AML) with myelodysplasia-related changes (MRC) in AZA-AML-001 per central review. Annual EHA Meeting 2016 [abstract 2016].

  46. Klco JM, Spencer DH, Lamprecht TL, et al. Genomic impact of transient low-dose decitabine treatment on primary AML cells. Blood. 2013;121:1633–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Itzykson R, Kosmider O, Cluzeau T, et al. Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias. Leukemia. 2011;25:1147–52.

    Article  CAS  PubMed  Google Scholar 

  48. Metzeler KH, Walker A, Geyer S, et al. DNMT3A mutations and response to the hypomethylating agent decitabine in acute myeloid leukemia. Leukemia. 2012;26:1106–7.

    Article  CAS  PubMed  Google Scholar 

  49. Emadi A, Faramand R, Carter-Cooper B, et al. Presence of isocitrate dehydrogenase mutations may predict clinical response to hypomethylating agents in patients with acute myeloid leukemia. Am J Hematol. 2015;90:E77–9.

    Article  CAS  PubMed  Google Scholar 

  50. DiNardo CD, Patel KP, Garcia-Manero G, et al. Lack of association of IDH1, IDH2 and DNMT3A mutations with outcome in older patients with acute myeloid leukemia treated with hypomethylating agents. Leuk Lymphoma. 2014;55:1925–9.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Coombs CC, Devlin S, Dixit S, et al. Response to hypomethylating agent therapy in acute myeloid leukemia based upon mutations in the DNA methylation pathway. Blood. 2015;126:abstract 2522.

    Article  Google Scholar 

  52. Tang L, Dolnick A, MacBeth KJ, et al. Impact of gene mutations in older patients with acute myeloid leukemia (AML) treated with azacitidine (AZA) or conventional care regimen (CCR). Annual ASH Meeting 2016 [abstract]. To be updated at the edited proof stage.

  53. Mims A, Walker AR, Huang X, et al. Increased anti-leukemic activity of decitabine via AR-42-induced upregulation of miR-29b: a novel epigenetic-targeting approach in acute myeloid leukemia. Leukemia. 2013;27:871–8.

    Article  CAS  PubMed  Google Scholar 

  54. Bally C, Adès L, Renneville A, et al. Prognostic value of TP53 gene mutations in myelodysplastic syndromes and acute myeloid leukemia treated with azacitidine. Leuk Res. 2014;38:751–5.

    Article  CAS  PubMed  Google Scholar 

  55. Desoutter J, Gay J, Berthon B, et al. Molecular prognostic factors in acute myeloid leukemia (AML) in patients receiving first line therapy with azacitidine (AZA). Blood. 2014;124:abstract 482.

    Google Scholar 

  56. Welch JS, Petti A, Miller CA, et al. Dynamic changes in clonal clearance with decitabine therapy in AML and MDS patients. Blood. 2015;126:abstract 689.

    Google Scholar 

  57. 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;22:385–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. 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;21:1761–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. de Lima M, Ravandi F, Shahjahan M, et al. Long-term follow-up of a phase I study of high-dose decitabine, busulfan, and cyclophosphamide plus allogeneic transplantation for the treatment of patients with leukemias. Cancer. 2003;97:1242–7.

    Article  PubMed  Google Scholar 

  60. Müller-Tidow C, Tschanter P, Röllig C, et al. Azacitidine in combination with intensive induction chemotherapy in older patients with acute myeloid leukemia: The AML-AZA trial of the Study Alliance Leukemia. Leukemia. 2016;30:555–61.

    Article  PubMed  Google Scholar 

  61. Soriano AO, Yang H, Faderl S, et al. Safety and clinical activity of the combination of 5-azacitidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome. Blood. 2007;110:2302–8.

    Article  CAS  PubMed  Google Scholar 

  62. Raffoux E, Cras A, Recher C, et al. 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. 2010;1:34–42.

    Article  PubMed  PubMed Central  Google Scholar 

  63. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. 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;32:1242–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Garcia-Manero G, Atallah E, Khaled SK, et al. Final results from a phase 2 study of pracinostat in combination with azacitidine in elderly patients with acute myeloid leukemia (AML). Blood. 2015;126:453.

    Google Scholar 

  66. Ramsingh G, Westervelt P, Cashen AF, et al. A phase 1 study of concomitant high-dose lenalidomide and 5-azacitidine induction in the treatment of AML. Leukemia. 2013;27:725–8.

    Article  CAS  PubMed  Google Scholar 

  67. Pollyea DA, Kohrt HE, Gallegos L, et al. Safety, efficacy and biological predictors of response to sequential azacitidine and lenalidomide for elderly patients with acute myeloid leukemia. Leukemia. 2012;26:893–901.

    Article  CAS  PubMed  Google Scholar 

  68. Narayan R, Garcia JS, Percival ME, et al. Sequential azacitidine plus lenalidomide in previously treated elderly patients with acute myeloid leukemia and higher risk myelodysplastic syndrome. Leuk Lymphoma. 2016;57:609–15.

    Article  CAS  PubMed  Google Scholar 

  69. Wei A, Tan P, Perruzza S, et al. Maintenance lenalidomide in combination with 5-azacitidine as post-remission therapy for acute myeloid leukaemia. Br J Haematol. 2015;169:199–210.

    Article  CAS  PubMed  Google Scholar 

  70. Chang E, Ganguly S, Rajkhowa T, et al. The combination of FLT3 and DNA methyltransferase inhibition is synergistically cytotoxic to FLT3/ITD acute myeloid leukemia cells. Leukemia. 2016;30:1025–32.

    Article  CAS  PubMed  Google Scholar 

  71. • Ravandi F, Alattar ML, Grunwald MR, et al. Phase 2 study of azacitidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood. 2013;121:4655–62. This single-center phase 2 study was the first to suggest that HMAs and a kinase inhibitor active on the FLT3-ITD mutation may lead to improved response.

  72. Muppidi MR, Portwood S, Griffiths EA, et al. Decitabine and sorafenib therapy in FLT-3 ITD-mutant acute myeloid. Leukemia. Clin Lymphoma Myeloma Leuk. 2015;15:S73–9.

    Article  PubMed  Google Scholar 

  73. Williams CB, Kambhampati S, Fiskus W, et al. Preclinical and phase I results of decitabine in combination with midostaurin (PKC412) for newly diagnosed elderly or relapsed /refractory adult patients with acute myeloid leukemia. Pharmacotherapy. 2013;33:1341–52.

    Article  CAS  PubMed  Google Scholar 

  74. Cooper BW, Kindwall-Keller TL, Craig MD, et al. A phase I study of midostaurin and azacitidine in relapsed and elderly AML patients. Clin Lymphoma Myeloma Leuk. 2015;15:428–432e2.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Strati P, Kantarjian H, Ravandi F, et al. Phase I/II trial of the combination of midostaurin (PKC412) and 5-azacitidine for patients with acute myeloid leukemia and myelodysplastic syndrome. Am J Hematol. 2015;90:276–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Borthakur G, Kantarjian HM, O’Brien S, et al. The combination of quizartinib with azacitidine or low dose cytarabine is highly active in patients (Pts) with FLT3-ITD mutated myeloid leukemias: interim report of a phase I/II trial. Blood. 2014;124:abstract 388.

    Google Scholar 

  77. Nand S, Godwin J, Smith S, Barton K, et al. Hydroxyurea, azacitidine and gemtuzumab ozogamicin therapy in patients with previously untreated non-M3 acute myeloid leukemia and high-risk myelodysplastic syndromes in the elderly: results from a pilot trial. Leuk Lymphoma. 2008;49:2141–7.

    Article  CAS  PubMed  Google Scholar 

  78. Nand S, Othus M, Godwin JE, et al. A phase 2 trial of azacitidine and gemtuzumab ozogamicin therapy in older patients with acute myeloid leukemia. Blood. 2013;122:3432–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Walter RB, Medeiros BC, Gardner KM, et al. Gemtuzumab ozogamicin in combination with vorinostat and azacitidine in older patients with relapsed or refractory acute myeloid leukemia: a phase I/II study. Haematologica. 2014;99:54–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. • Daver N, Kantarjian H, Ravandi F, et al. A phase II study of decitabine and gemtuzumab ozogamicin in newly diagnosed and relapsed acute myeloid leukemia and high-risk myelodysplastic syndrome. Leukemia. 2016;30:268–73. This phase 2 study suggests that the combination of DAC and gemtuzumab ozogamicin is tolerable and may lead to improved response.

  81. Fathi AT, Erba HP, Lancet JE, et al. SGN-CD33A plus hypomethylating agents: a novel, well-tolerated regimen with high remission rate in frontline unfit AML. Blood. 2015;126:abstract 454.

    Article  Google Scholar 

  82. Vasu S, He S, Cheney C, Gopalakrishnan B, et al. Decitabine enhances anti-CD33 monoclonal antibody BI 836858-mediated natural killer ADCC against AML blasts. Blood. 2016;12:2879–89.

    Article  Google Scholar 

  83. Daver N, Kantarjian HM, Garcia-Manero G, et al. Phase I/II study of vosaroxin and decitabine in newly diagnosed older patients (pts) with acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (MDS). Blood. 2015;126:abstract 461.

    Google Scholar 

  84. Mawad R, Becker PS, Hendrie P, et al. Phase II study of tosedostat with cytarabine or decitabine in newly diagnosed older patients with acute myeloid leukaemia or high-risk MDS. Br J Haematol. 2016;172:238–45.

    Article  CAS  PubMed  Google Scholar 

  85. Pollyea DA, Dinardo CD, Thirman MJ, et al. Results of a phase 1b study of venetoclax plus decitabine or azacitidine in untreated acute myeloid leukemia patients ≥ 65 years ineligible for standard induction therapy. J Clin Oncol, 2016; 34:(suppl; abstr 7009).

  86. Navada SC, Silverman LR, Hearn KP, et al. A phase II study of the combination of oral rigosertib and azacitidine in patients with myelodysplastic syndromes (MDS). Blood. 2015;126:abtract 910.

    Google Scholar 

  87. 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;34:899–905.

    Article  CAS  PubMed  Google Scholar 

  88. Cruijsen M, Hobo W, van der Velden WJ, et al. Addition of 10-day decitabine to fludarabine/total body irradiation conditioning is feasible and induces tumor-associated antigen-specific T cell responses. Biol Blood Marrow Transplant. 2016;22:1000–8.

    Article  CAS  PubMed  Google Scholar 

  89. Srivastava P, Paluch BE, Matsuzaki J, et al. Immunomodulatory action of SGI-110, a hypomethylating agent, in acute myeloid leukemia cells and xenografts. Leuk Res. 2014;38:1332–41.

    Article  CAS  PubMed  Google Scholar 

  90. Schumacher T, Bunse L, Pusch S, et al. A vaccine targeting mutant IDH1 induces antitumour immunity. Nature. 2014;512:324–7.

    Article  CAS  PubMed  Google Scholar 

  91. 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;28:1280–8.

    Article  CAS  PubMed  Google Scholar 

  92. Ørskov AD, Treppendahl MB, Skovbo A, et al. Hypomethylation and up-regulation of PD-1 in T cells by azacitidine in MDS/AML patients: a rationale for combined targeting of PD-1 and DNA methylation. Oncotarget. 2015;6:9612–26.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Dear AE. Epigenetic modulators and the new immunotherapies. N Engl J Med. 2016;374:684–6.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Hervé Dombret.

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Claude Gardin reports personal fees from Celegene and Sunesis.

Hervé Dombret reports grants and personal fees from Roche/Genentech, grants and personal fees from Amgen, personal fees from Pfizer, grants and personal fees from Ariad, personal fees from Novartis, personal fees from Celgene, grants and personal fees from Jazz Pharma., personal fees from Agios, personal fees from Sunesis, personal fees from Ambit (Daiichi Sankyo), personal fees from Karyopharm, grants and personal fees from Kite Pharma., personal fees from Menarini, personal fees from Astellas, personal fees from Janssen, personal fees from Servier, and personal fees from Seattle Genetics.

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This article is part of the Topical Collection on Acute Myeloid Leukemias

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Gardin, C., Dombret, H. Hypomethylating Agents as a Therapy for AML. Curr Hematol Malig Rep 12, 1–10 (2017). https://doi.org/10.1007/s11899-017-0363-4

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