Advertisement

International Journal of Hematology

, Volume 99, Issue 5, pp 635–643 | Cite as

Multicenter study evaluating the impact of hypomethylating agents as bridging therapy to hematopoietic stem cell transplantation in myelodysplastic syndromes

  • Yundeok Kim
  • In-Ho Kim
  • Hyeong Joon Kim
  • Silvia Park
  • Kyoo-Hyung Lee
  • Soo Jeong Kim
  • Jung-Hee Lee
  • Dae-Young Kim
  • Sung-Soo Yoon
  • Yeo-Keoung Kim
  • Jun Ho Jang
  • Seon Yang Park
  • Jae-Sook Ahn
  • Chul Won Cheong
  • Je-Hwan Lee
  • June-Won Cheong
  • Korean Society of Hematology Acute myeloid Leukemia/Myelodysplastic Syndrome Working Party
Original Article

Abstract

Allogeneic hematopoietic stem cell transplantation (alloSCT) is currently the only curative treatment modality for myelodysplastic syndromes (MDS). The treatment paradigm for MDS has changed in recent years with the introduction of hypomethylating agents (HMAs). The present retrospective multicenter study was designed to assess the effects of pre-transplant HMA on transplant outcome and determine which patients would benefit most from this therapy. A total of 109 patients who received alloSCT at one of five institutions between 2007 and 2010 were enrolled in this study regardless of pre-transplant HMA therapy. 81 of the 109 patients enrolled were treated with HMA prior to alloSCT. 28 patients received alloSCT without HMA bridging. The distributions of WHO classification groups and IPSS scores were similar between the two groups (P = 0.752 and P = 0.265, respectively). Pre-transplant HMA did not affect OS (P = 0.244), and there were no differences in response to HMA therapy within the HMA-treated group. The cumulative incidence of NRM was not significantly different between the two groups (P = 0.500). However, for patients with a high blast count (>5 % of bone marrow at the time of diagnosis), pre-transplant HMA therapy had a NRM benefit (83.3 vs. 48.6 %, P = 0.014).

Keywords

Myelodysplastic syndrome Hypomethylating agent AlloSCT 

References

  1. 1.
    Cazzole M, Malcovati L. Myelodysplastic syndromes––coping with ineffective hematopoiesis. N Engl J Med. 2005;352(6):536–8.CrossRefGoogle Scholar
  2. 2.
    Schiffer CA. Clinical issues in the management of patients with myelodysplasia. Hematol Am Soc Hematol Edu Progr. 2006;1:205–10.Google Scholar
  3. 3.
    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(10):2429–40.PubMedCrossRefGoogle Scholar
  4. 4.
    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(8):1794–803.PubMedCrossRefGoogle Scholar
  5. 5.
    Seymour JF, Fenaux P, Silverman LR, Mufti GJ, Hellström-Lindberg E, Santini V, et al. Effects of azacitidine compared with conventional care regimens in elderly (≥75 years) patients with higher-risk myelodysplastic syndromes. Crit Rev Oncol Hematol. 2010;76(3):218–27.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Sierra J, Pérez WS, Rozman C, Carreras E, Klein JP, Rizzo JD, et al. Bone marrow transplantation from HLA-identical siblings as treatment for myelodysplasia. Blood. 2002;100(6):1997–2004.PubMedGoogle Scholar
  7. 7.
    Deeg HJ, Storer B, Slattery JT, Anasetti C, Doney KC, Hansen JA, et al. Conditioning with targeted busulfan and cyclophosphamide for hemopoietic stem cell transplantation from related and unrelated donors in patients with myelodysplastic syndrome. Blood. 2002;100(4):1201–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Estey E, de Lima M, Tibes R, Pierce S, Kantarjian H, Champlin R, et al. Prospective feasibility analysis of reduced-intensity conditioning (RIC) regimens for hematopoietic stem cell transplantation (HSCT) in elderly patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). Blood. 2007;109(4):1395–400.PubMedCrossRefGoogle Scholar
  9. 9.
    Leone G, Teofili L, Voso MT, Lübbert M. DNA methylation and demethylating drugs in myelodysplastic syndromes and secondary leukemias. Haematologica. 2002;87(12):1324–41.PubMedGoogle Scholar
  10. 10.
    Baylin SB, Herman JG, Graff JR, Vertino PM, Issa JP. Alterations in DNA methylating: a fundamental aspect of neoplasia. Adv Cancer Res. 1998;72:141–96.PubMedCrossRefGoogle Scholar
  11. 11.
    Herman JG. Hypermethylation of tumor suppressor genes in cancer. Semin Cancer Biol. 1999;9(5):359–67.PubMedCrossRefGoogle Scholar
  12. 12.
    Cooper DN. Eukaryotic DNA methylation. Hum Genet. 1983;64(4):315–33.PubMedCrossRefGoogle Scholar
  13. 13.
    Jones PA, Taylor SM. Cellular differentiation, cytidine analogs and DNA methylation. Cell. 1980;20(1):85–93.PubMedCrossRefGoogle Scholar
  14. 14.
    Ando T, Nishimura M, Oka Y. Decitabine (5-aza-2′-deoxycytidine) decreased DNA methylation and expression of MDR-1 gene in K562/ADM cells. Leukemia. 2000;14(11):1915–20.PubMedCrossRefGoogle Scholar
  15. 15.
    Ley TJ, Anagnou NP, Noguchi CT, Schechter AN, DeSimone J, Heller P, et al. DNA methylation and globin gene expression in patients treated with 5-azacytidine. Prog Clin Biol Res. 1983;134:457–74.PubMedGoogle Scholar
  16. 16.
    Gattei V, Aldinucci D, Petti MC, Da Ponte A, Zagonel V, Pinto A. In vitro and in vivo effects of 5-aza-2′-deoxycytidine (Decitabine) on clonogenic cells from acute myeloid leukemia patients. Leukemia. 1993;7(Suppl 1):42–8.PubMedGoogle Scholar
  17. 17.
    Corey C. Allogeneic hematopoietic stem-cell transplantation for myelodysplastic syndrome. Hematol Am Soc Hematol Edu Progr. 2010;2010:325–9.CrossRefGoogle Scholar
  18. 18.
    De Silva Padua L, de Lima M, Kantarjian H, Faderl S, Kebriaei P, Giralt S, et al. Feasibility of allo-SCT after hypomethylating therapy with decitabine for myelodysplastic syndrome. Bone Marrow Transpl. 2009;43(11):839–43.CrossRefGoogle Scholar
  19. 19.
    Field T, Perkins J, Huang Y, Kharfan-Dabaja MA, Alsina M, Ayala E, et al. 5-Azacitidine for myelodysplasia before allogeneic hematopoietic cell transplantation. Bone Marrow Transpl. 2010;45(2):255–60.CrossRefGoogle Scholar
  20. 20.
    Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006;108(2):419–25.PubMedCrossRefGoogle Scholar
  21. 21.
    Shulman HM, Sullivan KM, Weiden PL, McDonald GB, Striker GE, Sale GE, et al. Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients. Am J Med. 1980;69(2):204–17.PubMedCrossRefGoogle Scholar
  22. 22.
    Castro-Malaspina H, Harris RE, Gajewski J, Ramsay N, Collins R, Dharan B, et al. Unrelated donor marrow transplantation for myelodysplastic syndromes: outcome analysis in 510 transplants facilitated by the national marrow donor program. Blood. 2002;99(6):1943–51.PubMedCrossRefGoogle Scholar
  23. 23.
    Oran B, Giralt S, Saliba R, Hosing C, Popat U, Khouri I, et al. Allogeneic hematopoietic stem cell transplantation for the treatment of high-risk acute myelogenous leukemia and myelodysplastic syndrome using reduced-intensity conditioning with fludarabine and melphalan. Biol Blood Marrow Transpl. 2007;13(4):454–62.CrossRefGoogle Scholar
  24. 24.
    Yakoub-Agha I, de La Salmonière P, Ribaud P, Sutton L, Wattel E, Kuentz M, et al. Allogeneic bone marrow transplantation for therapy-related myelodysplastic syndrome and acute myeloid leukemia: a long-term study of 70 patients: report of the French Society of bone marrow transplantation. J Clin Oncol. 2000;18(5):963–71.PubMedGoogle Scholar
  25. 25.
    Anderson JE, Appelbaum FR, Fisher LD, Schoch G, Shulman H, Anasetti C, et al. Allogeneic bone marrow transplantation for 93 patients with myelodysplastic syndrome. Blood. 1993;82(2):677–81.PubMedGoogle Scholar
  26. 26.
    Sutton L, Chastang C, Ribaud P, Jouet JP, Kuentz M, Attal M, et al. Factors influencing outcome in de novo myelodysplastic syndromes treated by allogeneic bone marrow transplantation: a long-term study of 71 patients Société Française de Greffe de Moelle. Blood. 1996;88(10):358–65.PubMedGoogle Scholar
  27. 27.
    Runde V, de Witte T, Arnold R, Gratwohl A, Hermans J, van Biezen A, et al. Bone marrow transplantation from HLA-identical siblings as first-line treatment in patients with myelodysplastic syndromes: early transplantation is associated with improved outcome: Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transpl. 1998;21(3):255–61.CrossRefGoogle Scholar
  28. 28.
    Parmar S, de Lima M. Hematopoietic stem cell transplantation for myelodysplastic syndrome. Biol Blood Marrow Transpl. 2010;16(1 Suppl):S37–44.CrossRefGoogle Scholar
  29. 29.
    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(6):1133–7.PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Yahng Seoung-Ah, Yoon Jae-Ho, Shin Seung-Hwan, Lee Sung-Eun, Cho Byung-Sik, Lee Dong-Gun, et al. Response to pretransplant hypomethylating agents influences the outcomes of allogeneic hematopoietic stem cell transplantation in adults with myelodysplastic syndromes. Eur J Haematol. 2013;90(2):111–20.PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2014

Authors and Affiliations

  • Yundeok Kim
    • 1
  • In-Ho Kim
    • 2
  • Hyeong Joon Kim
    • 3
  • Silvia Park
    • 4
  • Kyoo-Hyung Lee
    • 5
  • Soo Jeong Kim
    • 1
  • Jung-Hee Lee
    • 5
  • Dae-Young Kim
    • 5
  • Sung-Soo Yoon
    • 2
  • Yeo-Keoung Kim
    • 3
  • Jun Ho Jang
    • 4
  • Seon Yang Park
    • 2
  • Jae-Sook Ahn
    • 3
  • Chul Won Cheong
    • 4
  • Je-Hwan Lee
    • 5
  • June-Won Cheong
    • 1
  • Korean Society of Hematology Acute myeloid Leukemia/Myelodysplastic Syndrome Working Party
  1. 1.Severance HospitalYonsei University College of MedicineSeoulKorea
  2. 2.Seoul National University HospitalSeoulKorea
  3. 3.Chonnam National University Hwasun HospitalJeollanamdoKorea
  4. 4.Samsung Medical CenterSungkyunkwan University School of MedicineSeoulKorea
  5. 5.Asan Medical CenterUniversity of Ulsan College of MedicineSeoulKorea

Personalised recommendations