International Journal of Hematology

, Volume 95, Issue 1, pp 26–33 | Cite as

Combination strategies in myelodysplastic syndromes

Progress in Hematology Dysplastic myelopoiesis—from the second JSH International Symposium


The myelodysplastic syndromes (MDS) consist of an array of clonal hematological malignancies resulting from disorders of pluripotent hematopoietic stem cells. MDS is associated with a poor overall prognosis and patients are categorized as higher risk and lower risk on the basis of the International Prognostic Scoring System. Currently, lenalidomide, azacitidine, and decitabine are the only three FDA-approved drugs for MDS. Traditional therapies for MDS involve the administration of single agents providing either supportive measures or disease-modifying effects directed to slowing progression to acute myeloid leukemia (AML) and improving survival. Recently, however, there has been increasing evidence suggesting that the combination of drugs with different mechanisms of action offers substantial benefit in the form of diminished side effects, improved overall survival, and delayed progression to AML. Multiple studies indicate that when compared with traditional monotherapies, combining various medications with non-overlapping mechanisms of action and toxicities may result in significant benefit for patients with MDS. A variety of combination therapies with growth factors, DNA methytransferase inhibitors, histone deacetylase inhibitors, and immunosuppressant treatments provide encouraging data indicating that the successful future of MDS treatment rests in the combination of multiple treatments modalities to achieve improved clinical outcomes.


MDS Azacitidine Decitabine Lenalidomide Combination 


  1. 1.
    Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114:937–51.PubMedCrossRefGoogle Scholar
  2. 2.
    Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89:2079–88.PubMedGoogle Scholar
  3. 3.
    Garcia-Manero G, Fenaux P. Hypomethylating agents and other novel strategies in myelodysplastic syndromes. J Clin Oncol. 2011;29:516–23.PubMedCrossRefGoogle Scholar
  4. 4.
    Sekeres MA. Are we nearer to curing patients with MDS? Best Pract Res Clin Haematol. 2010;23:481–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Epling-Burnette PK, List AF. Advancements in the molecular pathogenesis of myelodysplastic syndrome. Curr Opin Hematol. 2009;16:70–6.PubMedCrossRefGoogle Scholar
  6. 6.
    Jiang Y, Dunbar A, Gondek LP, Mohan S, Rataul M, O’Keefe C, et al. Aberrant DNA methylation is a dominant mechanism in MDS progression to AML. Blood. 2009;113:1315–25.PubMedCrossRefGoogle Scholar
  7. 7.
    Rassool FV, Gaymes TJ, Omidvar N, Brady N, Beurlet S, Pla M, et al. Reactive oxygen species, DNA damage, and error-prone repair: a model for genomic instability with progression in myeloid leukemia? Cancer Res. 2007;67:8762–71.PubMedCrossRefGoogle Scholar
  8. 8.
    Komrokji RS, Sekeres MA, List AF. Management of lower-risk myelodysplastic syndromes: the art and evidence. Curr Hematol Malig Rep. 2011;6:145–53.PubMedCrossRefGoogle Scholar
  9. 9.
    Hellstrom-Lindberg E, Gulbrandsen N, Lindberg G, Ahlgren T, Dahl IM, Dybedal I, et al. A validated decision model for treating the anaemia of myelodysplastic syndromes with erythropoietin + granulocyte colony-stimulating factor: significant effects on quality of life. Br J Haematol. 2003;120:1037–46.PubMedCrossRefGoogle Scholar
  10. 10.
    Hellstrom-Lindberg E. Efficacy of erythropoietin in the myelodysplastic syndromes: a meta-analysis of 205 patients from 17 studies. Br J Haematol. 1995;89:67–71.PubMedGoogle Scholar
  11. 11.
    Kantarjian H, Giles F, List A, Lyons R, Sekeres MA, Pierce S, et al. The incidence and impact of thrombocytopenia in myelodysplastic syndromes. Cancer. 2007;109:1705–14.PubMedCrossRefGoogle Scholar
  12. 12.
    Gonzalez-Porras JR, Cordoba I, Such E, Nomdedeu B, Vallespi T, Carbonell F, et al. Prognostic impact of severe thrombocytopenia in low-risk myelodysplastic syndrome. Cancer. 2011;117(24):5529–37.PubMedCrossRefGoogle Scholar
  13. 13.
    Cruz R, Galili N, Khan GS, Raza A. Thrombocytopenia predicts for poor survival in patients with lower risk myelodysplastic syndromes (MDS). Blood (ASH annual meeting abstracts). 2010;110:Abstract 4021.Google Scholar
  14. 14.
    Kuter DJ, Bussel JB, Lyons RM, Pullarkat V, Gernsheimer TB, Senecal FM, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet. 2008;371:395–403.PubMedCrossRefGoogle Scholar
  15. 15.
    Kantarjian H, Fenaux P, Sekeres MA, Becker PS, Boruchov A, Bowen D, et al. Safety and efficacy of romiplostim in patients with lower-risk myelodysplastic syndrome and thrombocytopenia. J Clin Oncol. 2010;28:437–44.PubMedCrossRefGoogle Scholar
  16. 16.
    List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med. 2006;355:1456–65.PubMedCrossRefGoogle Scholar
  17. 17.
    Fenaux P, Giagounidis A, Selleslag D, Beyne-Rauzy O, Mufti G, Mittelman M, et al. A randomized phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients with Low-/Intermediate-1-risk myelodysplastic syndromes with del5q. Blood. 2011;118(14):3765–76.PubMedCrossRefGoogle Scholar
  18. 18.
    Sloand EM, Wu CO, Greenberg P, Young N, Barrett J. Factors affecting response and survival in patients with myelodysplasia treated with immunosuppressive therapy. J Clin Oncol. 2008;26:2505–11.PubMedCrossRefGoogle Scholar
  19. 19.
    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.PubMedCrossRefGoogle Scholar
  20. 20.
    Kantarjian H, Issa JP, Rosenfeld CS, Bennett JM, Albitar M, DiPersio J, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006;106:1794–803.PubMedCrossRefGoogle Scholar
  21. 21.
    Shen L, Kantarjian H, Guo Y, Lin E, Shan J, Huang X, et al. DNA methylation predicts survival and response to therapy in patients with myelodysplastic syndromes. J Clin Oncol. 2010;28:605–13.PubMedCrossRefGoogle Scholar
  22. 22.
    Lyons RM, Cosgriff TM, Modi SS, Gersh RH, Hainsworth JD, Cohn AL, et al. Hematologic response to three alternative dosing schedules of azacitidine in patients with myelodysplastic syndromes. J Clin Oncol. 2009;27:1850–6.PubMedCrossRefGoogle Scholar
  23. 23.
    Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R, 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.PubMedCrossRefGoogle Scholar
  24. 24.
    Kantarjian HM, O’Brien S, Huang X, Garcia-Manero G, Ravandi F, Cortes J, et al. Survival advantage with decitabine versus intensive chemotherapy in patients with higher risk myelodysplastic syndrome: comparison with historical experience. Cancer. 2007;109:1133–7.PubMedCrossRefGoogle Scholar
  25. 25.
    Lubbert M, Suciu S, Baila L, Ruter BH, Platzbecker U, Giagounidis A, et al. Low-dose decitabine versus best supportive care in elderly patients with intermediate- or high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy: final results of the randomized phase III study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group. J Clin Oncol. 2011;29:1987–96.PubMedCrossRefGoogle Scholar
  26. 26.
    Kantarjian HM, Giles FJ, Greenberg PL, Paquette RL, Wang ES, Gabrilove JL, et al. Phase 2 study of romiplostim in patients with low- or intermediate-risk myelodysplastic syndrome receiving azacitidine therapy. Blood. 2010;116:3163–70.PubMedCrossRefGoogle Scholar
  27. 27.
    Greenberg P, Garcia-Manero G, Moore MR, Damon LE, Roboz GJ, Wei H, et al. Efficacy and safety of romiplostin in patients with low or intermediate-risk myelodysplastic syndrome (MDS) receiving decitabine. Blood (ASH annual meeting abstracts). 2009;114:Abstract 1769.Google Scholar
  28. 28.
    Lyons RM, Larson RA, Kosmo MA, Gandhi S, Liu D, Chernoff M, et al. Randomized phase II study evaluating the efficacy and safety of romiplostim treatment of patients with low or intermediate risk myelodysplastic syndrome (MDS) receiving lenalidomide. Blood (ASH annual meeting abstracts). 2009;114:Abstract 1770.Google Scholar
  29. 29.
    Adler V, Yin Z, Fuchs SY, Benezra M, Rosario L, Tew KD, et al. Regulation of JNK signaling by GSTp. EMBO J. 1999;18:1321–34.PubMedCrossRefGoogle Scholar
  30. 30.
    Raza A, Galili N, Callander N, Ochoa L, Piro L, Emanuel P, et al. Phase 1-2a multicenter dose-escalation study of ezatiostat hydrochloride liposomes for injection (Telintra, TLK199), a novel glutathione analog prodrug in patients with myelodysplastic syndrome. J Hematol Oncol. 2009;2:20.Google Scholar
  31. 31.
    Raza A, Galili N, Smith S, Godwin JE, Boccia R, Myint H, et al. Phase 2 randomized multicenter study of extended dosing schedules of oral ezatiostat HCl (Telintra), a glutathione analog prodrug GSTP1-1 inhibitor, in low to intermediate-1 risk myelodysplastic syndrome (MDS). Blood (ASH annual meeting abstracts). 2010;116:Abstract 2910.Google Scholar
  32. 32.
    Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med. 2003;349:2042–54.PubMedCrossRefGoogle Scholar
  33. 33.
    Cameron EE, Bachman KE, Myohanen S, Herman JG, Baylin SB. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat Genet. 1999;21:103–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Gore SD, Baylin S, Sugar E, Carraway H, Miller CB, Carducci M, et al. Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res. 2006;66:6361–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Cheson BD, Bennett JM, Kantarjian H, Pinto A, Schiffer CA, Nimer SD, et al. Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood. 2000;96:3671–4.PubMedGoogle Scholar
  36. 36.
    Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, et al. Revised recommendations of the International Working Group for Diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol. 2003;21:4642–9.PubMedCrossRefGoogle Scholar
  37. 37.
    Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B, Yang H, Rosner G, Verstovsek S, et al. Phase 1/2 study of the combination of 5-aza-2′-deoxycytidine with valproic acid in patients with leukemia. Blood. 2006;108:3271–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Kuendgen A, Bug G, Ottmann OG, Haase D, Hildebrandt B, Habersang K, et al. Treatment of poor risk myelodysplastic syndromes and acute myeloid leukemia with a combination of 5-acacytidine ad valproic acid. Blood (ASH annual meeting abstracts). 2008;112:Abstract 3639.Google Scholar
  39. 39.
    Silverman LR, Verma A, Odchimar-Reissig R, LeBlanc A, Nejfeld V, Gabrilove JL, et al. A phase I trial of the epigenetic modulators vorinostat, in combination with azacitidine (azaC) in patients with the myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML): a study of the New York Cancer Consortium. Blood (ASH annual meeting abstracts). 2008;112:Abstract 3656.Google Scholar
  40. 40.
    Garcia-Manero G, Estey E, Jabbour E, Kadia T, Estrov Z, Cortes J, et al. Phase II study of 5-azacitidine and vorinostat in patients (pts) with newly diagnosed myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) not eligible for clinical trials because poor performance or presence of other comorbidities. Blood (ASH annual meeting abstracts). 2010;116:Abstract 604.Google Scholar
  41. 41.
    Garcia-Manero G, Yang A, Klimek V, Cortes J, Ravandi F, Newsome W, et al. Phase I/II study of MGCD0103, an oral istype-selective histone deacetylase (HDAC) inhibitor, in combination with 5-azacitidine in higher-risk myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) Blood. 2007;110:Abstract 444.Google Scholar
  42. 42.
    Di Croce L, Raker VA, Corsaro M, Fazi F, Fanelli M, Faretta M, et al. Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science. 2002;295:1079–82.PubMedCrossRefGoogle Scholar
  43. 43.
    Soriano AO, Yang H, Faderl S, Estrov Z, Giles F, Ravandi F, et al. 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. 2007;110:2302–8.PubMedCrossRefGoogle Scholar
  44. 44.
    Yang H, Hoshino K, Sanchez-Gonzalez B, Kantarjian H, Garcia-Manero G. Antileukemia activity of the combination of 5-aza-2′-deoxycytidine with valproic acid. Leuk Res. 2005;29:739–48.PubMedCrossRefGoogle Scholar
  45. 45.
    Prebet T, Gore SD, Sun Z, Greenberg PL, Juckett M, Malick L, et al. 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 annual meeting abstracts). 2010;116:Abstract 601.Google Scholar
  46. 46.
    Sekeres MA, List AF, Cuthbertson D, Paquette R, Ganetzky R, Latham D, et al. Phase I combination trial of lenalidomide and azacitidine in patients with higher-risk myelodysplastic syndromes. J Clin Oncol. 2010;28:2253–8.PubMedCrossRefGoogle Scholar
  47. 47.
    Sekeres MA, O’Keefe C, List AF, Paulic K, Afable M 2nd, Englehaupt R, et al. Demonstration of additional benefit in adding lenalidomide to azacitidine in patients with higher-risk myelodysplastic syndromes. Am J Hematol. 2011;86:102–3.PubMedCrossRefGoogle Scholar
  48. 48.
    Appelbaum FR. Antibody-targeted therapy for myeloid leukemia. Semin Hematol. 1999;36:2–8.PubMedGoogle Scholar
  49. 49.
    Jilani I, Estey E, Huh Y, Joe Y, Manshouri T, Yared M, et al. Differences in CD33 intensity between various myeloid neoplasms. Am J Clin Pathol. 2002;118:560–6.PubMedCrossRefGoogle Scholar
  50. 50.
    Sievers EL, Larson RA, Stadtmauer EA, Estey E, Lowenberg B, Dombret H, et al. Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol. 2001;19:3244–54.PubMedGoogle Scholar
  51. 51.
    Schiller GJ, Slack J, Hainsworth JD, Mason J, Saleh M, Rizzieri D, et al. Phase II multicenter study of arsenic trioxide in patients with myelodysplastic syndromes. J Clin Oncol. 2006;24:2456–64.PubMedCrossRefGoogle Scholar
  52. 52.
    Vey N, Bosly A, Guerci A, Feremans W, Dombret H, Dreyfus F, et al. Arsenic trioxide in patients with myelodysplastic syndromes: a phase II multicenter study. J Clin Oncol. 2006;24:2465–71.PubMedCrossRefGoogle Scholar
  53. 53.
    Sekeres MA, Maciejewski JP, Erba HP, Afable M, Englehaupt R, Sobecks R, et al. A phase 2 study of combination therapy with arsenic trioxide and gemtuzumab ozogamicin in patients with myelodysplastic syndromes or secondary acute myeloid leukemia. Cancer. 2011;117:1253–61.PubMedCrossRefGoogle Scholar
  54. 54.
    Borthakur G, Garcia-Manero G, Estrov Z, Konopleva M, Burger JA, Thomas D, et al. Phase 2 study of decitabine and gemtuzumab ozogamicin in acute myelogenous leukemia and high-risk myelodysplastic syndrome-outcome in previously untreated patients. Blood (ASH annual meeting abstracts). 2009;114:Abstract 114.Google Scholar
  55. 55.
    Selleri C, Sato T, Anderson S, Young NS, Maciejewski JP. Interferon-gamma and tumor necrosis factor-alpha suppress both early and late stages of hematopoiesis and induce programmed cell death. J Cell Physiol. 1995;165:538–46.PubMedCrossRefGoogle Scholar
  56. 56.
    Deeg HJ, Gotlib J, Beckham C, Dugan K, Holmberg L, Schubert M, et al. Soluble TNF receptor fusion protein (etanercept) for the treatment of myelodysplastic syndrome: a pilot study. Leukemia. 2002;16:162–4.PubMedCrossRefGoogle Scholar
  57. 57.
    Scott BL, Ramakrishnan A, Storer B, Becker PS, Petersdorf S, Estey EH, et al. Prolonged responses in patients with MDS and CMML treated with azacitidine and etanercept. Br J Haematol. 2010;148:944–7.PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2011

Authors and Affiliations

  1. 1.Leukemia Program, Department of Hematologic Oncology and Blood DisordersCleveland Clinic Taussig Cancer InstituteClevelandUSA

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