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Current Hematologic Malignancy Reports

, Volume 10, Issue 3, pp 329–333 | Cite as

Preparing Patients With Myelodysplastic Syndrome for Transplant When Is Pre-transplant Cytoreductive Therapy Appropriate?

  • Martin Wermke
  • Silke Gloaguen
  • Uwe Platzbecker
Myelodysplastic Syndromes (D Steensma, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Myelodysplastic Syndromes

Abstract

To date, the only treatment option with curative potential for patients suffering from myelodysplastic syndromes (MDS) is allogeneic stem cell transplantation (allo-SCT). However, patient selection for this procedure as well as the choice of the appropriate pre-transplant regime remain challenging. This review discusses both intensive chemotherapy and hypomethylating agents (HMAs) as debulking strategies. Current evidence on the use of AML-like intense chemotherapy suggests that this represents a valuable option especially in fitter and younger MDS patients with aggressive disease, whereas HMAs seem especially indicated in patients presenting with certain mutations and less proliferative disease in order to bridge them to transplant. The actual need for pre-transplant cytoreduction strongly depends on donor availability and disease progression: upfront allo-SCT might be considered for patients with slowly progressing MDS if a donor is readily available. Common to the data discussed in this review is their retrospective nature, making clear recommendations in terms of debulking strategy difficult. Prospective randomized trials are required to explicitly answer this question in the future.

Keywords

Myelodysplastic syndromes Pre-transplant cytoreductive therapy Allogeneic stem cell transplantation 

Notes

Compliance with Ethics Guidelines

Conflict of Interest

The authors declare that they have no competing interests.

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

  1. 1.
    Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120(12):2454–65.PubMedCentralCrossRefPubMedGoogle Scholar
  2. 2.
    Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89(6):2079–88.PubMedGoogle Scholar
  3. 3.
    Fenaux P, Mufti GJ, Hellstrom-Lindberg E, 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(3):223–32.PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Lübbert M, Suciu S, Baila L, 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(15):1987–96.CrossRefPubMedGoogle Scholar
  5. 5.
    Passweg JR, Baldomero H, Peters C, et al. Hematopoietic SCT in Europe: data and trends in 2012 with special consideration of pediatric transplantation. Bone Marrow Transplant. 2014;49(6):744–50.PubMedCentralCrossRefPubMedGoogle Scholar
  6. 6.
    Sorror ML, Maris MB, Storb R, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005;106(8):2912–9.PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    Sorror ML, Storb RF, Sandmaier BM, et al. Comorbidity-age index: a clinical measure of biologic age before allogeneic hematopoietic cell transplantation. J Clin Oncol. 2014;32(29):3249–56.CrossRefPubMedGoogle Scholar
  8. 8.
    Estey E, de Lima M, Tibes 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.CrossRefPubMedGoogle Scholar
  9. 9.
    Cutler CS, Lee SJ, Greenberg P, et al. A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood. 2004;104(2):579–85.CrossRefPubMedGoogle Scholar
  10. 10.
    Alessandrino EP, Porta MGD, Malcovati L, et al. Optimal timing of allogeneic hematopoietic stem cell transplantation in patients with myelodysplastic syndrome. Am J Hematol. 2013;88(7):581–8.PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Yakoub-Agha I, de La Salmonière P, Ribaud P, 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
  12. 12.
    Warlick ED, O'Donnell PV, Borowitz M, et al. Myeloablative allogeneic bone marrow transplant using T cell depleted allografts followed by post-transplant GM-CSF in high-risk myelodysplastic syndromes. Leuk Res. 2008;32(9):1439–47.PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    de Witte T, Suciu S, Peetermans M, et al. Intensive chemotherapy for poor prognosis myelodysplasia (MDS) and secondary acute myeloid leukemia (sAML) following MDS of more than 6 months duration. A pilot study by the Leukemia Cooperative Group of the European Organisation for Research and Treatment in Cancer (EORTC-LCG). Leukemia. 1995;9(11):1805–11.PubMedGoogle Scholar
  14. 14.
    Parker JE, Pagliuca A, Mijovic A, et al. Fludarabine, cytarabine, G-CSF and idarubicin (FLAG-IDA) for the treatment of poor-risk myelodysplastic syndromes and acute myeloid leukaemia. Br J Haematol. 1997;99(4):939–44.CrossRefPubMedGoogle Scholar
  15. 15.
    de Witte T, Suciu S, Verhoef G, et al. Intensive chemotherapy followed by allogeneic or autologous stem cell transplantation for patients with myelodysplastic syndromes (MDSs) and acute myeloid leukemia following MDS. Blood. 2001;98(8):2326–31.CrossRefPubMedGoogle Scholar
  16. 16.
    Scott BL, Storer B, Loken MR, Storb R, Appelbaum FR, Deeg HJ. Pretransplantation induction chemotherapy and posttransplantation relapse in patients with advanced myelodysplastic syndrome. Biol Blood Marrow Transplant. 2005;11(1):65–73.CrossRefPubMedGoogle Scholar
  17. 17.
    Seifert H, Mohr B, Thiede C, et al. The prognostic impact of 17p (p53) deletion in 2272 adults with acute myeloid leukemia. Leukemia. 2009;23(4):656–63.CrossRefPubMedGoogle Scholar
  18. 18.
    Rücker FG, Schlenk RF, Bullinger L, et al. TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. Blood. 2012;119(9):2114–21.CrossRefPubMedGoogle Scholar
  19. 19.
    Devillier R, Mansat-De Mas V, Gelsi-Boyer V, et al. Role of ASXL1 and TP53 mutations in the molecular classification and prognosis of acute myeloid leukemias with myelodysplasia-related changes. Oncotarget. 2015;6(10):8388–96.PubMedCentralPubMedGoogle Scholar
  20. 20.
    Thol F, Damm F, Lüdeking A, et al. Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia. J Clin Oncol. 2011;29(21):2889–96.CrossRefPubMedGoogle Scholar
  21. 21.
    Shen Y, Zhu Y, Fan X, et al. Gene mutation patterns and their prognostic impact in a cohort of 1185 patients with acute myeloid leukemia. Blood. 2011;118(20):5593–603.CrossRefPubMedGoogle Scholar
  22. 22.
    Kornblith AB, Herndon JE, Silverman LR, et al. Impact of azacytidine on the quality of life of patients with myelodysplastic syndrome treated in a randomized phase III trial: a Cancer and Leukemia Group B study. J Clin Oncol. 2002;20(10):2441–52.CrossRefPubMedGoogle Scholar
  23. 23.
    Silverman LR, Fenaux P, Mufti GJ, et al. Continued azacitidine therapy beyond time of first response improves quality of response in patients with higher-risk myelodysplastic syndromes. Cancer. 2011;117(12):2697–702.PubMedCentralCrossRefPubMedGoogle Scholar
  24. 24.
    Wermke M, Schmidt A, Middeke JM, et al. MRI-based liver iron content predicts for nonrelapse mortality in MDS and AML patients undergoing allogeneic stem cell transplantation. Clin Cancer Res. 2012;18(23):6460–8.CrossRefPubMedGoogle Scholar
  25. 25.
    Prébet T, Gore SD, Esterni B, et al. Outcome of high-risk myelodysplastic syndrome after azacitidine treatment failure. J Clin Oncol. 2011;29(24):3322–7.CrossRefPubMedGoogle Scholar
  26. 26.
    Gerds AT, Gooley TA, Estey EH, Appelbaum FR, Deeg HJ, Scott BL. Pretransplantation therapy with azacitidine vs induction chemotherapy and posttransplantation outcome in patients with MDS. Biol Blood Marrow Transplant. 2012;18(8):1211–8.PubMedCentralCrossRefPubMedGoogle Scholar
  27. 27.
    Damaj G, Duhamel A, Robin M, et al. Impact of azacitidine before allogeneic stem-cell transplantation for myelodysplastic syndromes: a study by the Société Française de Greffe de Moelle et de Thérapie-Cellulaire and the Groupe-Francophone des Myélodysplasies. J Clin Oncol. 2012;30(36):4533–40.CrossRefPubMedGoogle Scholar
  28. 28.
    Traina F, Visconte V, Elson P, et al. Impact of molecular mutations on treatment response to DNMT inhibitors in myelodysplasia and related neoplasms. Leukemia. 2014;28(1):78–87.CrossRefPubMedGoogle Scholar
  29. 29.
    Bejar R, Lord A, Stevenson K, et al. TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood. 2014;124(17):2705–12.PubMedCentralCrossRefPubMedGoogle Scholar
  30. 30.
    Müller-Thomas C, Rudelius M, Rondak I, et al. Response to azacitidine is independent of p53 expression in higher-risk myelodysplastic syndromes and secondary acute myeloid leukemia. Haematologica. 2014;99(10):e179–81.PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    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(7):751–5.CrossRefPubMedGoogle Scholar
  32. 32.
    Middeke JM, Fang M, Cornelissen JJ, et al. Outcome of patients with abnl(17p) acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation. Blood. 2014;123(19):2960–7.CrossRefPubMedGoogle Scholar
  33. 33.
    Bejar R, Stevenson KE, Caughey B, et al. Somatic mutations predict poor outcome in patients with myelodysplastic syndrome after hematopoietic stem-cell transplantation. J Clin Oncol. 2014;32(25):2691–8.CrossRefPubMedGoogle Scholar
  34. 34.
    Pan R, Hogdal LJ, Benito JM, et al. Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia. Cancer Discov. 2014;4(3):362–75.PubMedCentralCrossRefPubMedGoogle Scholar
  35. 35.
    Platzbecker U, Wermke M, Radke J, et al. Azacitidine for treatment of imminent relapse in MDS or AML patients after allogeneic HSCT: results of the RELAZA trial. Leukemia. 2012;26(3):381–9.PubMedCentralCrossRefPubMedGoogle Scholar
  36. 36.
    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):3361–9.CrossRefPubMedGoogle Scholar
  37. 37.
    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(6):1280–8.PubMedCentralCrossRefPubMedGoogle Scholar
  38. 38.
    Lown RN, Shaw BE. Beating the odds: factors implicated in the speed and availability of unrelated haematopoietic cell donor provision. Bone Marrow Transplant. 2013;48(2):210–9.CrossRefPubMedGoogle Scholar
  39. 39.
    Luznik L, O'Donnell PV, Symons HJ, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008;14(6):641–50.PubMedCentralCrossRefPubMedGoogle Scholar
  40. 40.
    Damaj G, Mohty M, Robin M, et al. Upfront allogeneic stem cell transplantation after reduced-intensity/nonmyeloablative conditioning for patients with myelodysplastic syndrome: a study by the société française de greffe de moelle et de thérapie cellulaire. Biol Blood Marrow Transplant. 2014;20(9):1349–55.CrossRefPubMedGoogle Scholar
  41. 41.
    Oran B, Kongtim P, Popat U, et al. Cytogenetics, donor type, and use of hypomethylating agents in myelodysplastic syndrome with allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2014;20(10):1618–25.CrossRefPubMedGoogle Scholar
  42. 42.
    Schmid C, Schleuning M, Ledderose G, Tischer J, Kolb H. Sequential regimen of chemotherapy, reduced-intensity conditioning for allogeneic stem-cell transplantation, and prophylactic donor lymphocyte transfusion in high-risk acute myeloid leukemia and myelodysplastic syndrome. J Clin Oncol. 2005;23(24):5675–87.CrossRefPubMedGoogle Scholar
  43. 43.
    Saure C, Schroeder T, Zohren F, et al. Upfront allogeneic blood stem cell transplantation for patients with high-risk myelodysplastic syndrome or secondary acute myeloid leukemia using a FLAMSA-based high-dose sequential conditioning regimen. Biol Blood Marrow Transplant. 2012;18(3):466–72.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Martin Wermke
    • 1
  • Silke Gloaguen
    • 1
  • Uwe Platzbecker
    • 1
  1. 1.Medizinische Klinik IUniversitätsklinikum „Carl-Gustav-Carus“DresdenGermany

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