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:

Conditioning Regimens

Reduced-toxicity conditioning with fludarabine and treosulfan prior to allogeneic stem cell transplantation in multiple myeloma

Bone Marrow Transplantation volume 39, pages 389–396 (2007)Cite this article

Abstract

In recent years, reduced-intensity conditioning (RIC) regimens before allogeneic stem cell transplantation (SCT) are increasingly used in patients not eligible for conventional conditioning. We did a retrospective, multicenter analysis to assess the feasibility of conditioning with fludarabine and treosulfan before allogeneic SCT in multiple myeloma patients. Thirty-four patients with a median age of 51.5 years were included in the analysis. All patients underwent myeloablation after conditioning followed by stable engraftment, and 29 of 31 evaluable patients (94%) showed early complete hematopoietic chimerism. Non-hematological toxicities were limited and encompassed mainly fever in neutropenia and infections. Grade II–IV acute and chronic graft-versus-host disease was observed in 33 and 39%, respectively. With a median follow-up of 708 days (range 60–1729 days), the median progression-free survival was 180 days. The treatment-related mortality was 10% on day 100 and 25% after 1 year. The median overall survival has not yet been reached. Our data indicate that conditioning with fludarabine and treosulfan before allogeneic SCT is feasible in intensively pretreated multiple myeloma patients and leads to stable engraftment and complete hematopoietic chimerism. Randomized trials are warranted to determine if this approach might be incorporated in an algorithm of multiple myeloma treatment.

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. Gahrton G, Tura S, Ljungman P, Belanger C, Brandt L, Cavo M et al. Allogeneic bone marrow transplantation in multiple myeloma. European Group for Bone Marrow Transplantation. N Engl J Med 1991; 325: 1267–1273.

    Article  CAS  Google Scholar 

  2. Corradini P, Voena C, Tarella C, Astolfi M, Ladetto M, Palumbo A et al. Molecular and clinical remissions in multiple myeloma: role of autologous and allogeneic transplantation of hematopoietic cells. J Clin Oncol 1999; 17: 208–215.

    Article  CAS  Google Scholar 

  3. Gahrton G, Tura S, Ljungman P, Blade J, Brandt L, Cavo M et al. Prognostic factors in allogeneic bone marrow transplantation for multiple myeloma. J Clin Oncol 1995; 13: 1312–1322.

    Article  CAS  Google Scholar 

  4. Badros A, Barlogie B, Siegel E, Cottler-Fox M, Zangari M, Fassas A et al. Improved outcome of allogeneic transplantation in high-risk multiple myeloma patients after nonmyeloablative conditioning. J Clin Oncol 2002; 20: 1295–1303.

    Article  Google Scholar 

  5. Crawley C, Lalancette M, Szydlo R, Gilleece M, Peggs K, Mackinnon S et al. Outcomes for reduced-intensity allogeneic transplantation for multiple myeloma: an analysis of prognostic factors from the chronic leukaemia working party of the EBMT. Blood 2005; 105: 4532–4539.

    Article  CAS  Google Scholar 

  6. Giralt S, Aleman A, Anagnostopoulos A, Weber D, Khouri I, Anderlini P et al. Fludarabine/melphalan conditioning for allogeneic transplantation in patients with multiple myeloma. Bone Marrow Transplant 2002; 30: 367–373.

    Article  CAS  Google Scholar 

  7. Kroger N, Sayer HG, Schwerdtfeger R, Kiehl M, Nagler A, Renges H et al. Unrelated stem cell transplantation in multiple myeloma after a reduced-intensity conditioning with pretransplantation antithymocyte globulin is highly effective with low transplantation-related mortality. Blood 2002; 100: 3919–3924.

    Article  CAS  Google Scholar 

  8. Lokhorst HM, Wu K, Verdonck LF, Laterveer LL, van de Donk NW, van Oers MH et al. The occurrence of graft-versus-host disease is the major predictive factor for response to donor lymphocyte infusions in multiple myeloma. Blood 2004; 103: 4362–4364.

    Article  CAS  Google Scholar 

  9. Tricot G, Vesole DH, Jagannath S, Hilton J, Munshi N, Barlogie B . Graft-versus-myeloma effect: proof of principle. Blood 1996; 87: 1196–1198.

    CAS  PubMed  Google Scholar 

  10. Banna GL, Aversa S, Sileni VC, Favaretto A, Ghiotto C, Monfardini S . Nonmyeloablative allogeneic stem cell transplantation (NST) after truly nonmyeloablative and reduced intensity conditioning regimens. Crit Rev Oncol Hematol 2004; 51: 171–189.

    Article  Google Scholar 

  11. Schetelig J, Bornhauser M, Kiehl M, Schwerdtfeger R, Kroger N, Runde V et al. Reduced-intensity conditioning with busulfan and fludarabine with or without antithymocyte globulin in HLA-identical sibling transplantation – a retrospective analysis. Bone Marrow Transplant 2004; 33: 483–490.

    Article  CAS  Google Scholar 

  12. Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G 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  Google Scholar 

  13. Keating MJ . Fludarabine phosphate in the treatment of chronic lymphocytic leukemia. Semin Oncol 1990; 17 (Suppl 8): 49–62.

    CAS  PubMed  Google Scholar 

  14. Gahrton G . Progress in hematopoietic stem cell transplantation in multiple myeloma. Curr Opin Hematol 2005; 12: 463–470.

    Article  Google Scholar 

  15. Michallet M, Bilger K, Garban F, Attal M, Huyn A, Blaise D et al. Allogeneic hematopoietic stem-cell transplantation after nonmyeloablative preparative regimens: impact of pretransplantation and posttransplantation factors on outcome. J Clin Oncol 2001; 19: 3340–3349.

    Article  CAS  Google Scholar 

  16. Gropp M, Meier W, Hepp H . Treosulfan as an effective second-line therapy in ovarian cancer. Gynecol Oncol 1998; 71: 94–98.

    Article  CAS  Google Scholar 

  17. Schmittel A, Scheulen ME, Bechrakis NE, Strumberg D, Baumgart J, Bornfeld N et al. Phase II trial of cisplatin, gemcitabine and treosulfan in patients with metastatic uveal melanoma. Melanoma Res 2005; 15: 205–207.

    Article  CAS  Google Scholar 

  18. Fichtner I, Becker M, Baumgart J . Antileukaemic activity of treosulfan in xenografted human acute lymphoblastic leukaemias (ALL). Eur J Cancer 2003; 39: 801–807.

    Article  CAS  Google Scholar 

  19. Meinhardt G, Dayyani F, Jahrsdorfer B, Baumgart J, Emmerich B, Schmidmaier R . Treosulfan is an effective inducer of cell death in myeloma cell lines and primary myeloma cells from patients. Br J Haematol 2003; 122: 892–899.

    Article  CAS  Google Scholar 

  20. Beelen DW, Trenschel R, Casper J, Freund M, Hilger RA, Scheulen ME et al. Dose-escalated treosulphan in combination with cyclophosphamide as a new preparative regimen for allogeneic haematopoietic stem cell transplantation in patients with an increased risk for regimen-related complications. Bone Marrow Transplant 2005; 35: 233–241.

    Article  CAS  Google Scholar 

  21. Scheulen ME, Hilger RA, Oberhoff C, Casper J, Freund M, Josten KM et al. Clinical phase I dose escalation and pharmacokinetic study of high-dose chemotherapy with treosulfan and autologous peripheral blood stem cell transplantation in patients with advanced malignancies. Clin Cancer Res 2000; 6: 4209–4216.

    CAS  Google Scholar 

  22. Casper J, Knauf W, Kiefer T, Wolff D, Steiner B, Hammer U et al. Treosulfan and fludarabine: a new toxicity-reduced conditioning regimen for allogeneic hematopoietic stem cell transplantation. Blood 2004; 103: 725–731.

    Article  CAS  Google Scholar 

  23. Casper J, Knauf W, Blau I, Ruutu T, Volin L, Wandt H et al. Treosulfan/fludarabine: a new conditioning regimen in allogeneic transplantation. Ann Hematol 2004; 83 (Suppl 1): 70–71.

    Google Scholar 

  24. Ritchie DS, Seymour JF, Roberts AW, Szer J, Grigg AP . Acute left ventricular failure following melphalan and fludarabine conditioning. Bone Marrow Transplant 2001; 28: 101–103.

    Article  CAS  Google Scholar 

  25. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 1995; 15: 825–828.

    CAS  Google Scholar 

  26. Lee SJ, Vogelsang G, Flowers ME . Chronic graft-versus-host disease. Biol Blood Marrow Transplant 2003; 9: 215–233.

    Article  CAS  Google Scholar 

  27. Jones RJ, Lee KS, Beschorner WE, Vogel VG, Grochow LB, Braine HG et al. Venoocclusive disease of the liver following bone marrow transplantation. Transplantation 1987; 44: 778–783.

    Article  CAS  Google Scholar 

  28. Blade J, Samson D, Reece D, Apperley J, Bjorkstrand B, Gahrton G et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol 1998; 102: 1115–1123.

    Article  CAS  Google Scholar 

  29. Valcarcel D, Martino R, Caballero D, Mateos MV, Perez-Simon JA, Canals C et al. Chimerism analysis following allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning. Bone Marrow Transplant 2003; 31: 387–392.

    Article  CAS  Google Scholar 

  30. Griskevicius L, Gaughan U, Cancparo R, Nilsson C, Hassan M . The myeloablative and immunosuppressive properties of treosulfan in mice. ASH Annual Meeting 2001. Orlando, USA, Abstract number 5022.

  31. Westerhof GR, Ploemacher RE, Boudewijn A, Blokland I, Dillingh JH, McGown AT et al. Comparison of different busulfan analogues for depletion of hematopoietic stem cells and promotion of donor-type chimerism in murine bone marrow transplant recipients. Cancer Res 2000; 60: 5470–5478.

    CAS  PubMed  Google Scholar 

  32. Ploemacher RE, Westerhof GR, Blokland I, Baumgart J, Down JD . Treosulfan as an Alternative Conditioning Agent in Bone Marrow Transplantation. Bone Marrow Transplant 2000a; 25 (Suppl 1): 421.

    Google Scholar 

  33. Sjoo F, Hassan Z, Abedi-Valugerdi M, Griskevicius L, Nilsson C, Remberger M et al. Myeloablative and immunosuppressive properties of treosulfan in mice. Exp Hematol 2006; 34: 115–121.

    Article  Google Scholar 

  34. Weissert R, Wiendl H, Pfrommer H, Storch MK, Schreiner B, Barth S et al. Action of treosulfan in myelin-oligodendrocyte-glycoprotein-induced experimental autoimmune encephalomyelitis and human lymphocytes. J Neuroimmunol 2003; 144: 28–37.

    Article  CAS  Google Scholar 

  35. Ploemacher RE, Johnson KW, Rombouts EJC, Etienne K, Westerhof GR, Baumgart J et al. Addition of treosulfan to a nonmyeloablative conditioning regimen results in enhanced chimerism and immunologic tolerance in an experimental allogeneic bone marrow transplant model. Biol Blood Marrow Transplant 2004; 10: 236–245.

    Article  CAS  Google Scholar 

  36. Bornhauser M, Thiede C, Schuler U, Platzbecker U, Freiberg-Richter J, Helwig A 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  Google Scholar 

  37. Massenkeil G, Nagy M, Lawang M, Rosen O, Genvresse I, Geserick G et al. Reduced intensity conditioning and prophylactic DLI can cure patients with high-risk acute leukaemias if complete donor chimerism can be achieved. Bone Marrow Transplant 2003; 31: 339–345.

    Article  CAS  Google Scholar 

  38. Nagler A, Slavin S, Varadi G, Naparstek E, Samuel S, Or R . Allogeneic peripheral blood stem cell transplantation using a fludarabine-based low intensity conditioning regimen for malignant lymphoma. Bone Marrow Transplant 2000; 25: 1021–1028.

    Article  CAS  Google Scholar 

  39. Lamba R, Abella E, Kukuruga D, Klein J, Savasan S, Abidi MH et al. Mixed hematopoietic chimerism at day 90 following allogenic myeloablative stem cell transplantation is a predictor of relapse and survival. Leukemia 2004; 18: 1681–1686.

    Article  CAS  Google Scholar 

  40. Perez-Simon JA, Caballero D, Diez-Campelo M, Lopez-Perez R, Mateos G, Canizo C et al. Chimerism and minimal residual disease monitoring after reduced intensity conditioning (RIC) allogeneic transplantation. Leukemia 2002; 16: 1423–1431.

    Article  CAS  Google Scholar 

  41. Maloney DG, Molina AJ, Sahebi F, Stockerl-Goldstein KE, Sandmaier BM, Bensinger W et al. Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood 2003; 102: 3447–3454.

    Article  CAS  Google Scholar 

  42. Bensinger WI, Buckner CD, Anasetti C, Clift R, Storb R, Barnett T et al. Allogeneic marrow transplantation for multiple myeloma: an analysis of risk factors on outcome. Blood 1996; 88: 2787–2793.

    CAS  PubMed  Google Scholar 

  43. Gahrton G, Svensson H, Cavo M, Apperly J, Bacigalupo A, Bjorkstrand B et al. Progress in allogenic bone marrow and peripheral blood stem cell transplantation for multiple myeloma: a comparison between transplants performed 1983–93 and 1994–8 at European Group for Blood and Marrow Transplantation centres. Br J Haematol 2001; 113: 209–216.

    Article  CAS  Google Scholar 

  44. Hunter HM, Peggs K, Powles R, Rahemtulla A, Mahendra P, Cavenagh J et al. Analysis of outcome following allogeneic haemopoietic stem cell transplantation for myeloma using myeloablative conditioning--evidence for a superior outcome using melphalan combined with total body irradiation. Br J Haematol 2005; 128: 496–502.

    Article  CAS  Google Scholar 

  45. Schetelig J, Kroger N, Held TK, Thiede C, Krusch A, Zabelina T et al. Allogeneic transplantation after reduced conditioning in high risk patients is complicated by a high incidence of acute and chronic graft-versus-host disease. Haematologica 2002; 87: 299–305.

    PubMed  Google Scholar 

  46. Attal M, Harousseau JL, Facon T, Guilhot F, Doyen C, Fuzibet JG et al. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med 2003; 349: 2495–2502.

    Article  CAS  Google Scholar 

  47. Child JA, Morgan GJ, Davies FE, Owen RG, Bell SE, Hawkins K et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 2003; 348: 1875–1883.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Mr H Goeldner (Medizinische Klinik III, Charité – Campus Benjamin Franklin, Berlin), Mrs L Vahle (Abteilung für Hämatologie und Onkologie, Klinik und Poliklinik für Innere Medizin der Universität Rostock), Mrs H Kassubek (Abteilung für Hämatologie und Onkologie, Klinikum der Universität Regensburg), Mrs H Boenig (Universitätsklinikum Würzburg) and Mr Dr L Kraut (Klinik für Knochenmarktransplantation und Hämatologie/Onkologie GmbH, Idar-Oberstein) for their thorough data documentation. We also thank Dr J Weirowski for her valuable grammatical and stylistic proofreading of the manuscript. Part of the abstract has been demonstrated at the annual meeting of EBMT 2006 (Hamburg, Germany). The work has been financially supported by medac GmbH (Hamburg, Germany).

Author information

Authors and Affiliations

  1. Medizinische Klinik III (Hämatologie, Onkologie und Transfusionsmedizin), Charité – Campus Benjamin Franklin, Berlin, Germany

    M Schmidt-Hieber, I W Blau, U Keilholz, O Marinets, L Uharek & E Thiel

  2. Klinik für Knochenmarktransplantation, Universitätsklinikum Essen, Essen, Germany

    R Trenschel & D W Beelen

  3. Abteilung für Hämatologie und Onkologie, Klinikum der Universität Regensburg, Regensburg, Germany

    R Andreesen

  4. Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany

    G Stuhler & H Einsele

  5. Medizinische Klinik II, Universitätsklinikum Tübingen, Tübingen, Germany

    L Kanz

  6. Klinik für Knochenmarktransplantation und Hämatologie/Onkologie GmbH, Idar-Oberstein, Germany

    A A Fauser

  7. Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland

    L Volin & T Ruutu

  8. Onkologische Schwerpunkpraxis, Singen, Germany

    T Fietz

  9. Onkologische Schwerpunktpraxis Bethanien, Frankfurt/Main, Germany

    W Knauf

  10. Institut für medizinische Statistik, Charité – Campus Benjamin Franklin, Berlin, Germany

    W Hopfenmüller

  11. Abteilung für Hämatologie und Onkologie, Klinik und Poliklinik für Innere Medizin der Universität Rostock, Rostock, Germany

    M Freund & J Casper

Authors
  1. M Schmidt-Hieber
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I W Blau
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R Trenschel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R Andreesen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G Stuhler
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. H Einsele
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. L Kanz
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. U Keilholz
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. O Marinets
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. D W Beelen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. A A Fauser
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. L Volin
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. T Ruutu
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. L Uharek
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. T Fietz
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. W Knauf
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. W Hopfenmüller
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. E Thiel
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. M Freund
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. J Casper
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M Schmidt-Hieber.

Appendix

Appendix

The following centers participated in this investigation:

Medizinische Klinik III (Hämatologie, Onkologie und Transfusionsmedizin), Charité – Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany; Abteilung für Hämatologie und Onkologie, Klinik und Poliklinik für Innere Medizin der Universität Rostock, Ernst-Heydemann-Str. 6, 18057 Rostock, Germany; Klinik für Knochenmarktransplantation, Universitätsklinikum Essen, Hufelandstr. 55, 45122 Essen, Germany; Abteilung für Hämatologie und Onkologie, Klinikum der Universität Regensburg, Franz-Joseph-Strauss-Allee 11, 93042 Regensburg, Germany; Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Klinikstr. 6-8, 97070 Würzburg, Germany; Medizinische Klinik II, Universitätsklinikum Tübingen, Ottfried-Müller-Str. 10, 72076 Tübingen, Germany; Klinik für Knochenmarktransplantation und Hämatologie/Onkologie GmbH, Dr.-Ottmar-Köhler-Str. 2, 55743 Idar-Oberstein, Germany; Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schmidt-Hieber, M., Blau, I., Trenschel, R. et al. Reduced-toxicity conditioning with fludarabine and treosulfan prior to allogeneic stem cell transplantation in multiple myeloma. Bone Marrow Transplant 39, 389–396 (2007). https://doi.org/10.1038/sj.bmt.1705605

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1705605

Keywords

This article is cited by

Search

Advanced search

Quick links