Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Reduced Intensity Conditioning Regimens

Reduced-intensity stem cell transplantation from an HLA-identical sibling donor in patients with myeloid malignancies

Bone Marrow Transplantation volume 33, pages 891–900 (2004)Cite this article

Summary:

The purpose of this study was to evaluate the feasibility and efficacy of allogeneic hematopoietic stem cell transplantation with a reduced-intensity regimen (RIST) in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). In all, 36 patients (median age 55 years) underwent RIST from an HLA-matched related donor between September 1999 and December 2002. The diagnoses included AML (n=14), leukemia evolving from MDS (n=10), and MDS (refractory anemia with excess blasts n=6, refractory anemia n=6). The RIST regimen consisted of purine analog (cladribine or fludarabine)/busulfan, with or without antithymocyte globulin. The regimen was well tolerated, and 34 patients achieved durable engraftment and most achieved remission after RIST. A total of 17 patients developed grade II–IV acute GVHD, and 27 developed chronic GVHD. Eight patients relapsed, and five of them received antithymocyte globulin (ATG) as part of the preparative regimen. A total of 12 patients died (four disease progression, six transplantation-related complications, and two others). Estimated 1-year disease-free survival (DFS) in low- and high-risk groups was 85 and 64%, respectively. We conclude that RIST can be performed safely in elderly patients with myeloid malignancies, and has therapeutic potential for those who fail conventional chemotherapy. In view of the significant association between GVHD or ATG and DFS, defined management of GVHD following RIST should become a major target of clinical research.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Keating MJ, Kantarjian H, Smith TL et al. Response to salvage therapy and survival after relapse in acute myelogenous leukemia. J Clin Oncol 1989; 7: 1071–1080.

    Article  CAS  PubMed  Google Scholar 

  2. 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: 2326–2331.

    Article  CAS  PubMed  Google Scholar 

  3. Germing U, Gattermann N, Strupp C et al. Validation of the WHO proposals for a new classification of primary myelodysplastic syndromes: a retrospective analysis of 1600 patients. Leuk Res 2000; 24: 983–992.

    Article  CAS  PubMed  Google Scholar 

  4. World Health Organization. Pathology and Genetics. Tumours of Hematopoietic and Lymphoid Tissues. World Health Organization: Geneva, 2001.

  5. Heaney ML, Golde DW . Myelodysplasia. N Engl J Med 1999; 340: 1649–1660.

    Article  CAS  PubMed  Google Scholar 

  6. Bortin MM, Truitt RL, Rimm AA, Bach FH . Graft-versus-leukaemia reactivity induced by alloimmunisation without augmentation of graft-versus-host reactivity. Nature 1979; 281: 490–491.

    Article  CAS  PubMed  Google Scholar 

  7. Horowitz MM, Gale RP, Sondel PM et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood 1990; 75: 555–562.

    CAS  PubMed  Google Scholar 

  8. Anderson JE, Gooley TA, Schoch G et al. Stem cell transplantation for secondary acute myeloid leukemia: evaluation of transplantation as initial therapy or following induction chemotherapy. Blood 1997; 89: 2578–2585.

    CAS  PubMed  Google Scholar 

  9. Biggs JC, Horowitz MM, Gale RP et al. Bone marrow transplants may cure patients with acute leukemia never achieving remission with chemotherapy. Blood 1992; 80: 1090–1093.

    CAS  PubMed  Google Scholar 

  10. Giralt S, Estey E, Albitar M et al. Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. Blood 1997; 89: 4531–4536.

    CAS  PubMed  Google Scholar 

  11. Slavin S, Nagler A, Naparstek E et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 1998; 91: 756–763.

    CAS  PubMed  Google Scholar 

  12. Giralt S . Non-myeloablative stem cell transplantation in myeloid leukemias – The M.D. Anderson Cancer Center experience. In: Giralt S, Slavin S (eds.). Non-myeloablative Stem Cell Transplantation (NST). Darwin Scientific Publishing Limited: Oxfordshire, 2000; pp 59–72.

    Google Scholar 

  13. Giralt S, Thall PF, Khouri I et al. Melphalan and purine analog-containing preparative regimens: reduced-intensity conditioning for patients with hematologic malignancies undergoing allogeneic progenitor cell transplantation. Blood 2001; 97: 631–637.

    Article  CAS  PubMed  Google Scholar 

  14. Saito T, Kanda Y, Kami M et al. Therapeutic potential of a reduced-intensity preparative regimen for allogeneic transplantation with cladribine, busulfan, and antithymocyte globulin against advanced/refractory acute leukemia/lymphoma. Clin Cancer Res 2002; 8: 1014–1020.

    CAS  PubMed  Google Scholar 

  15. Przepiorka D, Weisdorf D, Martin P et al. 1994 consensus conference on acute GVHD grading. Bone Marrow Transplant 1995; 15: 825–828.

    CAS  PubMed  Google Scholar 

  16. Sullivan KM, Agura E, Anasetti C et al. Chronic graft-versus-host disease and other late complications of bone marrow transplantation. Semin Hematol 1991; 28: 250–259.

    CAS  PubMed  Google Scholar 

  17. Kanda Y, Mineishi S, Saito T et al. Long-term low-dose acyclovir against varicella-zoster virus reactivation after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2001; 28: 689–692.

    Article  CAS  PubMed  Google Scholar 

  18. Pizzo PA . Management of fever in patients with cancer and treatment-induced neutropenia. N Engl J Med 1993; 328: 1323–1332.

    Article  CAS  PubMed  Google Scholar 

  19. Kanda Y, Mineishi S, Saito T et al. Response-oriented preemptive therapy against cytomegalovirus disease with low-dose ganciclovir: a prospective evaluation. Transplantation 2002; 73: 568–572.

    Article  CAS  PubMed  Google Scholar 

  20. Thiede C, Florek M, Bornhauser M et al. Rapid quantification of mixed chimerism using multiplex amplification of short tandem repeat markers and fluorescence detection. Bone Marrow Transplant 1999; 23: 1055–1060.

    Article  CAS  PubMed  Google Scholar 

  21. Bearman S, Appelbaum FR, Buckner C et al. Regimen-related toxicity in patients undergoing bone marrow transplantation. J Clin Oncol 1988; 6: 1562–1568.

    Article  CAS  PubMed  Google Scholar 

  22. Cheson BD, Cassileth PA, Head DR et al. Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol 1990; 8: 813–819.

    Article  CAS  PubMed  Google Scholar 

  23. Bornhauser M, Thiede C, Schuler U et al. Dose-reduced conditioning for allogeneic blood stem cell transplantation: durable engraftment without antithymocyte globulin. Bone Marrow Transplant 2000; 26: 119–125.

    Article  CAS  PubMed  Google Scholar 

  24. Childs R, Clave E, Contentin N et al. Engraftment kinetics after nonmyeloablative allogeneic peripheral blood stem cell transplantation: full donor T-cell chimerism precedes alloimmune responses. Blood 1999; 94: 3234–3241.

    CAS  PubMed  Google Scholar 

  25. Grochow LB, Jones RJ, Brundrett RB et al. Pharmacokinetics of busulfan: correlation with veno-occlusive disease in patients undergoing bone marrow transplantation. Cancer Chemother Pharmacol 1989; 25: 55–61.

    Article  CAS  PubMed  Google Scholar 

  26. Grever M, Leiby J, Kraut E et al. A comprehensive phase I and II clinical investigation of fludarabine phosphate. Semin Oncol 1990; 17 (5 Suppl. 8): 39–48.

    CAS  PubMed  Google Scholar 

  27. Piro LD, Carrera CJ, Carson DA, Beutler E . Lasting remissions in hairy-cell leukemia induced by a single infusion of 2-chlorodeoxyadenosine. N Engl J Med 1990; 322: 1117–1121.

    Article  CAS  PubMed  Google Scholar 

  28. Cheson BD, Vena DA, Foss FM, Sorensen JM . Neurotoxicity of purine analogs: a review. J Clin Oncol 1994; 12: 2216–2228.

    Article  CAS  PubMed  Google Scholar 

  29. Antin JH, Ferrara JL . Cytokine dysregulation and acute graft-versus-host disease. Blood 1992; 80: 2964–2968.

    CAS  PubMed  Google Scholar 

  30. Storb R, Deeg HJ, Whitehead J et al. Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia. N Engl J Med 1986; 314: 729–735.

    Article  CAS  PubMed  Google Scholar 

  31. Morishima Y, Morishita Y, Tanimoto M et al. Low incidence of acute graft-versus-host disease by the administration of methotrexate and cyclosporine in Japanese leukemia patients after bone marrow transplantation from human leukocyte antigen compatible siblings; possible role of genetic homogeneity. The Nagoya Bone Marrow Transplantation Group. Blood 1989; 74: 2252–2256.

    CAS  PubMed  Google Scholar 

  32. Hiraoka A, Ohashi Y, Okamoto S et al. Phase III study comparing tacrolimus (FK506) with cyclosporine for graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation. Bone Marrow Transplant 2001; 28: 181–185.

    Article  CAS  PubMed  Google Scholar 

  33. Martin P, Nash R, Sanders J et al. Reproducibility in retrospective grading of acute graft-versus-host disease after allogeneic marrow transplantation. Bone Marrow Transplant 1998; 21: 273–279.

    Article  CAS  PubMed  Google Scholar 

  34. Bunn D, Lea CK, Bevan DJ et al. The pharmacokinetics of anti-thymocyte globulin (ATG) following intravenous infusion in man. Clin Nephrol 1996; 45: 29–32.

    CAS  PubMed  Google Scholar 

  35. Chopra R, Chakraverty R, Chakrabartu S et al. Non-myeloablative conditioning limits transplant related mortality in patients who have previously failed high dose treatment. Blood 2000; 96: 553a.

    Google Scholar 

  36. McSweeney PA, Niederwieser D, Shizuru JA et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 2001; 97: 3390–3400.

    Article  CAS  PubMed  Google Scholar 

  37. Khouri IF, Saliba RM, Giralt SA et al. Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: low incidence of toxicity, acute graft-versus-host disease, and treatment-related mortality. Blood 2001; 98: 3595–3599.

    Article  CAS  PubMed  Google Scholar 

  38. Leith CP, Kopecky KJ, Godwin J et al. Acute myeloid leukemia in the elderly: assessment of multidrug resistance (MDR1) and cytogenetics distinguishes biologic subgroups with remarkably distinct responses to standard chemotherapy. A Southwest Oncology Group study. Blood 1997; 89: 3323–3329.

    CAS  PubMed  Google Scholar 

  39. Hamaki T, Kami M, Tanimoto T et al. Allogeneic hematopoietic stem cell transplantation using reduced-intensity conditioning (RIST) for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Int J Hematol 2002; 76 (Suppl. 1): 16.

    Google Scholar 

  40. Fujimaki K, Fujisawa S, Aotsuka N et al. Feasibility of early tapering and discontinuation of cyclosporine to intensify the graft-versus-leukemia effect in patients with advanced hematologic neoplasms. Rinsho Ketsueki 2001; 42: 680–684.

    CAS  PubMed  Google Scholar 

  41. Lowenberg B, Downing JR, Burnett A . Acute myeloid leukemia. N Engl J Med 1999; 341: 1051–1062.

    Article  CAS  PubMed  Google Scholar 

  42. Oka Y, Tsuboi A, Elisseeva OA et al. WT1 as a novel target antigen for cancer immunotherapy. Curr Cancer Drug Targets 2002; 2: 45–54.

    Article  CAS  PubMed  Google Scholar 

  43. Fontaine P, Roy-Proulx G, Knafo L et al. Adoptive transfer of minor histocompatibility antigen-specific T lymphocytes eradicates leukemia cells without causing graft-versus-host disease. Nat Med 2001; 7: 789–794.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Hematopoietic Stem Cell Transplant Unit, National Cancer Center Hospital, Tokyo, Japan

    T Hamaki, M Kami, S-W Kim, Y Onishi, Y Kishi, N Murashige, A Hori, R Kojima, M Sakiyama, O Imataki, Y Heike, R Tanosaki, K Tobinai & Y Takaue

  2. Department of Hematology, JR Tokyo General Hospital, Tokyo, Japan

    S Masuo

  3. Department of Hematology, Toranomon Hospital, Tokyo, Japan

    S Miyakoshi & S Taniguchi

Authors
  1. T Hamaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Kami
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S-W Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Y Onishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Y Kishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. N Murashige
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A Hori
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. R Kojima
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M Sakiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. O Imataki
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Y Heike
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. R Tanosaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. S Masuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. S Miyakoshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. S Taniguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. K Tobinai
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Y Takaue
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M Kami.

Additional information

The authors belong to Tokyo Stem-cell Transplantation (SCT) Consortium

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hamaki, T., Kami, M., Kim, SW. et al. Reduced-intensity stem cell transplantation from an HLA-identical sibling donor in patients with myeloid malignancies. Bone Marrow Transplant 33, 891–900 (2004). https://doi.org/10.1038/sj.bmt.1704477

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1704477

Keywords

This article is cited by

Search

Advanced search

Quick links