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Leveraging Hypomethylating Agents for Better MDS Therapy

  • Terrence J. Bradley
  • Justin M. Watts
  • Ronan T. Swords
Myelodysplastic Syndromes (M Savona, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Myelodysplastic Syndromes

Abstract

Purpose of Review

Myelodysplastic syndrome (MDS) is a clinically and molecularly heterogeneous disease, which primarily occurs in older adults. Although hypomethylating agents have survival benefit and are the current standard of care, many MDS patients will not garner a response from therapy. For those who do respond, most responses are not durable, and the only hope for a cure is allogeneic stem cell transplant. New therapies to improve outcomes are urgently needed.

Recent Findings

Clinical trials combining standard hypomethylating agents with novel experimental agents are underway in an effort to improve clinical outcomes in MDS patients. Several of these small molecules have demonstrated the ability to augment the response rates of hypomethylating agents alone, including complete remission rates, in both the front line and refractory settings.

Summary

Combination approaches utilizing hypomethylating agents and novel-targeted therapies have demonstrated the ability to improve response rates in MDS patients in both the front line and salvage settings, and thus may change the standard of care.

Keywords

Myelodysplastic syndrome Acute myeloid leukemia Hypomethylating agents Isocitrate dehydrogenase Immunotherapy Pevonedistat 

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

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

  1. 1.
    Sekeres MA, Cutler C (2018) How we treat higher-risk myelodysplastic syndromes 123:829–837.Google Scholar
  2. 2.
    Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, 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;10:223–32.CrossRefGoogle Scholar
  3. 3.
    Kantarjian H, Issa J-PJ, Rosenfeld CS, Bennett JM, Albitar M, DiPersio J, et al. Decitabine improves patient outcomes in myelodysplastic syndromes. Cancer. 2006;106:1794–803.CrossRefGoogle Scholar
  4. 4.
    Silverman LR, McKenzie DR, Peterson BL, Holland JF, Backstrom JT, Beach CL, 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.CrossRefGoogle Scholar
  5. 5.
    Swords RT, Kelly KR, Smith PG, Garnsey JJ, Mahalingam D, Medina E, et al. Brief report inhibition of NEDD8-activating enzyme : a novel approach for the treatment of acute myeloid leukemia. Blood. 2010;115:3796–800.CrossRefGoogle Scholar
  6. 6.
    Swords RT, Erba HP, Deangelo DJ, et al. Pevonedistat (MLN4924), a first-in-class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 study. Br J Haematol. 2015;169:534–43.CrossRefGoogle Scholar
  7. 7.•
    Swords RT, Watts J, Erba HP, et al. Expanded safety analysis of pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukemia and myelodysplastic syndromes. Blood Cancer J. 2017;7:1–4 The results of this study merited the study of pevonedistat in combination with other active agents, including HMAs.CrossRefGoogle Scholar
  8. 8.
    Visconte V, Nawrocki ST, Espitia CM, et al. Comprehensive quantitative proteomic profiling of the pharmacodynamic changes induced by MLN4924 in acute myeloid leukemia cells establishes rationale for its combination with azacitidine. Leukemia. 2015;30:1190.CrossRefGoogle Scholar
  9. 9.
    Smith PG, Traore T, Grossman S, Narayanan U, Carew JS, Lublinksky A, et al. Azacitidine/decitabine synergism with the NEDD8-activating enzyme inhibitor MLN4924 in pre-clinical AML models. Blood. 2011;118:578–LP-578.Google Scholar
  10. 10.
    Swords RT, Coutre S, Maris MB, et al. Pevonedistat, a first-in-class NEDD8-activating enzyme (NAE) inhibitor, combined with azacitidine, in patients with AML. Blood. 2018;131:blood-2017-09-805895.CrossRefGoogle Scholar
  11. 11.•
    Konopleva M, Pollyea DA, Potluri J, et al. Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov. 2016;6:1106–17 Demonstrated that venetoclax was biologically active in patients with AML, and suggested that priming was needed with HMAs and other low-dose chemotherapy combinations.CrossRefGoogle Scholar
  12. 12.
    Pollyea DA, Dinardo CD, Thirman MJ, Letai A, Wei AH, Jonas BA, 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;34:7009.CrossRefGoogle Scholar
  13. 13.
    DiNardo CD, Pollyea DA, Jonas BA, et al. Updated safety and efficacy of venetoclax with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2017;130:2628 LP-2628.Google Scholar
  14. 14.
    DiNardo CD, Pratz KW, Letai A, et al. Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol. 2018;19:216–28.CrossRefGoogle Scholar
  15. 15.
    DiNardo CD, Rausch CR, Benton C, et al. Clinical experience with the BCL2-inhibitor venetoclax in combination therapy for relapsed and refractory acute myeloid leukemia and related myeloid malignancies. Am J Hematol. 2018;93:401–7.CrossRefGoogle Scholar
  16. 16.
    Wei A, Strickland SA, Roboz GJ, et al. Phase 1/2 study of venetoclax with low-dose cytarabine in treatment-naive, elderly patients with acute myeloid leukemia unfit for intensive chemotherapy: 1-year outcomes. Blood. 2017;130:890 LP-890.CrossRefGoogle Scholar
  17. 17.
    Rausch CR, DiNardo CD, Kadia T, et al. Results of off-label venetoclax use in combination with low-intensity chemotherapy in patients with relapsed and refractory myeloid malignancies. Blood. 2017;130:1356 LP-1356.Google Scholar
  18. 18.
    Zhao S, Guo J, Zhao Y, Fei C, Zheng Q, Li X, et al. Chidamide, a novel histone deacetylase inhibitor, inhibits the viability of MDS and AML cells by suppressing JAK2/STAT3 signaling. Am J Transl Res. 2016;8:3169–78.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Quintás-Cardama A, FPS S, Garcia-Manero G. Histone deacetylase inhibitors for the treatment of myelodysplastic syndrome and acute myeloid leukemia. Leuk Off J Leuk Soc Am Leuk Res Fund UK. 2011;25:226–35.Google Scholar
  20. 20.
    Schaefer EW, Loaiza-Bonilla A, Juckett M, DiPersio JF, Roy V, Slack J, et al. A phase 2 study of vorinostat in acute myeloid leukemia. Haematologica. 2009;94:1375–82.CrossRefGoogle Scholar
  21. 21.
    Abaza YM, Kadia TM, Jabbour EJ, Konopleva MY, Borthakur G, Ferrajoli A, et al. Phase 1 dose escalation multicenter trial of pracinostat alone and in combination with azacitidine in patients with advanced hematologic malignancies. Cancer. 2017;123:4851–9.CrossRefGoogle Scholar
  22. 22.
    Prebet T, Sun Z, Figueroa ME, Ketterling R, Melnick A, Greenberg PL, 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.CrossRefGoogle Scholar
  23. 23.
    Blum W, Klisovic RB, Hackanson B, Liu Z, Liu S, Devine H, et al. Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. J Clin Oncol. 2007;25:3884–91.CrossRefGoogle Scholar
  24. 24.
    Soriano AO, Yang H, Faderl S, et al. Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic retinoic acid in acute myeloid leukemia and myelodysplastic syndrome. Blood. 2007;110:2302 LP-2308.CrossRefGoogle Scholar
  25. 25.
    Kirschbaum M, Gojo I, Goldberg SL, Bredeson C, Kujawski LA, Yang A, et al. A phase 1 clinical trial of vorinostat in combination with decitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome. Br J Haematol. 2014;167:185–93.CrossRefGoogle Scholar
  26. 26.
    How J, Minden MD, Brian L, Chen EX, Brandwein J, Schuh AC, et al. A phase i trial of two sequence-specific schedules of decitabine and vorinostat in patients with acute myeloid leukemia. Leuk Lymphoma. 2015;56:2793–802.CrossRefGoogle Scholar
  27. 27.
    Silverman LR, Verma A, Odchimar-Reissig R, Cozza A, Najfeld V, Licht JD, et al. A phase I/II study of vorinostat, an oral histone deacetylase inhibitor, in combination with azacitidine in patients with the myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Initial results of the phase I trial: a New York Cancer Consorti. J Clin Oncol. 2008;26:7000.CrossRefGoogle Scholar
  28. 28.
    Luger SM, O’Connell CL, Klimek V, Cooper MA, Besa EC, Rossetti JM, et al. A phase II study of mocetinostat, an oral isotype-selective histone deacetylase (HDAC) inhibitor, in combination with 5-azacitidine in patients with myelodysplastic syndrome (MDS). J Clin Oncol. 2013;31:7116.Google Scholar
  29. 29.
    Garcia-Manero G, Berdeja JG, Komrokji RS, Essell J, Lyons RM, Maris M, et al. A randomized, placebo-controlled, phase II study of pracinostat in combination with azacitidine (AZA) in patients with previously untreated myelodysplastic syndrome (MDS). Blood. 2015;126:911 LP-911.Google Scholar
  30. 30.
    Garcia-Manero G, Montalban-Bravo G, Berdeja JG, Abaza Y, Jabbour E, Essell J, et al. Phase 2, randomized, double-blind study of pracinostat in combination with azacitidine in patients with untreated, higher-risk myelodysplastic syndromes. Cancer. 2017;123:994–1002.CrossRefGoogle Scholar
  31. 31.
    Garcia Manero G, Atallah E, Khaled SK, et al. A phase 2 study of pracinostat and azacitidine in elderly patients with acute myeloid leukemia (AML) not eligible for induction chemotherapy: response and long-term survival benefit. Blood. 2016;128:100 LP-100.Google Scholar
  32. 32.
    DiNardo CD, De Botton S, 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 LP-725.Google Scholar
  33. 33.
    Stein EM, Fathi AT, DiNardo CD, et al. Enasidenib (AG-221), a potent oral inhibitor of mutant isocitrate dehydrogenase 2 (IDH2) enzyme, induces hematologic responses in patients with myelodysplastic syndromes (MDS). Blood. 2016;128:343 LP-343.Google Scholar
  34. 34.•
    Stein EM, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2018;130:722–32 Changed the standard of care for this subtype of IDH2-mutated myeloid malignancies.CrossRefGoogle Scholar
  35. 35.•
    DiNardo CD, Stein EM, de Botton S, et al (2018) Durable remissions with Ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med NEJMoa1716984. Will change the standard of care for IDH1-mutant myeloid malignancies. Google Scholar
  36. 36.
    DiNardo CD, Stein AS, Fathi AT, et al. Mutant isocitrate dehydrogenase (mIDH) inhibitors, enasidenib or ivosidenib, in combination with Azacitidine (AZA): preliminary results of a phase 1b/2 study in patients with newly diagnosed acute myeloid leukemia (AML). Blood. 2017;130:–639 LP-639.Google Scholar
  37. 37.
    Jelinek T, Mihalyova J, Kascak M, Duras J, Hajek R. PD-1/PD-L1 inhibitors in haematological malignancies: update 2017. Immunology. 2017;152:357–71.CrossRefGoogle Scholar
  38. 38.
    Abedin S, Platanias LC. PD1 and PDL1 upregulation and survival after decitabine treatment in lower risk MDS. Leuk Lymphoma. 2017;58:764–5.CrossRefGoogle Scholar
  39. 39.
    Garcia-Manero G, Tallman MS, Martinelli G, Ribrag V, Yang H, Balakumaran A, et al. Pembrolizumab, a PD-1 inhibitor, in patients with myelodysplastic syndrome (MDS) after failure of Hypomethylating agent treatment. Blood. 2016;128:345 LP-345.Google Scholar
  40. 40.
    Berger R, Rotem-Yehudar R, Slama G, Landes S, Kneller A, Leiba M, et al. Phase i safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin Cancer Res. 2008;14:3044–51.CrossRefGoogle Scholar
  41. 41.
    Garcia-Manero G, Daver NG, Montalban-Bravo G, et al. A phase II study evaluating the combination of nivolumab (Nivo) or ipilimumab (Ipi) with azacitidine in Pts with previously treated or untreated myelodysplastic syndromes (MDS)1. (2016) A Phase II Study. Blood. 2016;128:344 LP-344.Google Scholar
  42. 42.
    Daver N, Garcia-Manero G, Basu S, et al. Nivolumab (Nivo) with azacytidine (AZA) in patients (pts) with relapsed acute myeloid leukemia (AML) or frontline elderly AML. Blood. 2017;130:1345 LP-1345.Google Scholar
  43. 43.
    Kaushik S, Liu F, Veazey KJ, et al. Genetic deletion or small-molecule inhibition of the arginine methyltransferase PRMT5 exhibit anti-tumoral activity in mouse models of MLL-rearranged AML. Leukemia. 2017;32:499.CrossRefGoogle Scholar
  44. 44.
    Pérez-Salvia M, Esteller M, Erez-Salvia MP, Esteller M, Pérez-Salvia M, Esteller M. Bromodomain inhibitors and cancer therapy: from structures to applications. Epigenetics. 2017;12:323–39.CrossRefGoogle Scholar
  45. 45.
    Wang Z, Dove P, Shamas-Din A, et al. The highly potent bromodomain (BRD) inhibitor FV-281 displays preclinical efficacy in acute myeloid leukemia (AML). Blood. 2015;126:1364 LP-1364.Google Scholar
  46. 46.
    Forero-Torres A, Rosen S, Smith DC, et al. Preliminary results from an ongoing phase 1/2 study of INCB057643, a bromodomain and extraterminal (BET) protein inhibitor, in patients (pts) with advanced malignancies. Blood. 2017;130:4048 LP-4048.Google Scholar
  47. 47.
    Lee MG, Wynder C, Schmidt DM, McCafferty DG, Shiekhattar R. Histone H3 lysine 4 demethylation is a target of nonselective antidepressive medications. Chem Biol. 2006;13:563–7.CrossRefGoogle Scholar
  48. 48.
    Schenk T, Chen WC, Göllner S, Howell L, Jin L, Hebestreit K, et al. Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nat Med. 2012;18:605–11.CrossRefGoogle Scholar
  49. 49.
    Zeidner JF, Karp JE. Clinical activity of alvocidib (flavopiridol) in acute myeloid leukemia. Leuk Res. 2015;39:1312–8.CrossRefGoogle Scholar
  50. 50.
    Bogenberger J, Whatcott C, Hansen N, Delman D, Shi CX, Kim W, et al. Combined venetoclax and alvocidib in acute myeloid leukemia. Oncotarget. 2017;8:107206–22.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Terrence J. Bradley
    • 1
  • Justin M. Watts
    • 1
  • Ronan T. Swords
    • 1
  1. 1.Sylvester Comprehensive Cancer CenterUniversity of Miami Miller School of MedicineMiamiUSA

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