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:

Cell Procurement

Individual patient data meta-analysis of allogeneic peripheral blood stem cell transplant vs bone marrow transplant in the management of hematological malignancies: indirect assessment of the effect of day 11 methotrexate administration

  • W Bensinger1 na1
  • on behalf of the Stem Cell Trialists' Collaborative Group

Bone Marrow Transplantation volume 38, pages 539–546 (2006)Cite this article

Abstract

The effects of immunosuppressive regimens on the outcomes of patients with hematological malignancies undergoing allogeneic stem cell transplantation remain uncertain. We conducted an individual patient data meta-analysis using data from nine randomized trials comparing allogeneic peripheral blood stem cell (PBSCT) transplants to bone marrow (BMT) transplants, focusing on the administration of three vs four doses of methotrexate (MTX) as part of a regimen for graft-versus-host-disease (GVHD) prophylaxis which included cyclosporine. Six trials containing 573 patients prescribed four doses of MTX while three trials containing 534 patients prescribed three doses of MTX. Four doses of MTX conferred a statistically significant survival advantage, resulting in death odds ratio (OR) 0.67 (CI 0.52–0.88) (P=0.0036) for recipients of PBSC compared to BM; with three doses, there was no statistically significant difference. In the four-dose studies relapse rates were 36.6% among recipients of BM compared to 19.2% among recipients of PBSC (P=0.0015). The rates of relapse in the three dose studies were 26% for both PBSC and BM. We hypothesize that the fourth dose of MTX provides extra immunosuppression among BM recipients resulting in a reduced anti-leukemic effect. This hypothesis can only be proved or disproved by a prospective, randomized trial.

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
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Gratwohl A, Baldomero H, Horisberger B, Schmid C, Passweg J, Urbano-Ispizua A . Current trends in hematopoietic stem cell transplantation in Europe. Blood 2002; 100: 2374–2386.

    Article  CAS  PubMed  Google Scholar 

  2. Korbling M, Anderlini P . Peripheral blood stem cell versus bone marrow allotransplantation: does the source of hematopoietic stem cells matter? Blood 2001; 98: 2900–2908.

    Article  CAS  PubMed  Google Scholar 

  3. Bensinger WI, Clift R, Martin P, Appelbaum FR, Demirer T, Gooley T et al. Allogeneic peripheral blood stem cell transplantation in patients with advanced hematologic malignancies: A retrospective comparison with marrow transplantation. Blood 1996; 88: 2794–2800.

    CAS  PubMed  Google Scholar 

  4. Bensinger WI, Deeg HJ . Blood or marrow? (Commentary). Lancet 2000; 355: 1199–1200.

    Article  CAS  PubMed  Google Scholar 

  5. Early Breast Cancer Trialists Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomized trials. Lancet 1998; 352: 930–942.

  6. Stewart LA, Clarke MJ . Practical methodology of meta-analyses (overviews) using updated individual patient data. Cochrane Working Group. Stat Med 1995; 14: 2057–2079.

    Article  CAS  PubMed  Google Scholar 

  7. Stem Cell Trialists' Collaborative Group. Allogeneic peripheral blood stem-cell compared with bone marrow transplantation in the management of hematologic malignancies: an individual patient data meta-analysis of 9 randomized trials. J Clin Oncol 2005; 23: 5074–5087.

  8. Morton J, Hutchins C, Durrant S . Granulocyte-colony-stimulating factor (G-CSF)-primed allogeneic bone marrow: significantly less graft-versus-host disease and comparable engraftment to G-CSF-mobilized peripheral blood stem cells. Blood 2001; 98: 3186–3191.

    Article  CAS  PubMed  Google Scholar 

  9. Vigorito AC, Azevedo WM, Marques JF, Azevedo AM, Eid KA, Aranha FJ et al. A randomised, prospective comparison of allogeneic bone marrow and peripheral blood progenitor cell transplantation in the treatment of haematological malignancies. Bone Marrow Transplant 1998; 22: 1145–1151.

    Article  CAS  PubMed  Google Scholar 

  10. Vigorito AC, Marques Junior JF, Aranha FJ, Oliveira GB, Miranda EC, de Souza CA . A randomized, prospective comparison of allogeneic bone marrow and peripheral blood progenitor cell transplantation in the treatment of hematologic malignancies: an update. Haematologica 2001; 86: 665–666.

    CAS  PubMed  Google Scholar 

  11. Couban S, Simpson DR, Barnett MJ, Bredeson C, Hubesch L, Howson-Jan K et al. A randomized multicenter comparison of bone marrow and peripheral blood in recipients of matched sibling allogeneic transplants for myeloid malignancies. Blood 2002; 100: 1525–1531.

    Article  CAS  PubMed  Google Scholar 

  12. Schmitz N, Beksac M, Hasenclever D, Bacigalupo A, Ruutu T, Nagler A et al. Transplantation of mobilized peripheral blood cells to HLA-identical siblings with standard-risk leukemia. Blood 2002; 100: 761–767.

    Article  CAS  PubMed  Google Scholar 

  13. Blaise D, Kuentz M, Fortanier C, Bourhis JH, Milpied N, Sutton L et al. Randomized trial of bone marrow versus lenograstim-primed blood cell allogeneic transplantation in patients with early-stage leukemia: a report from the Société Française de Greffe de Moelle. J Clin Oncol 2000; 18: 537–571.

    Article  CAS  PubMed  Google Scholar 

  14. Cornelissen JJ, van der Holt B, Petersen EJ, Vindelov L, Russel CA, Hoglund M et al. A randomized multicenter comparison of CD34(+)-selected progenitor cells from blood vs from bone marrow in recipients of HLA-identical allogeneic transplants for hematological malignancies. Exp Hematol 2003; 31: 855–864.

    Article  CAS  PubMed  Google Scholar 

  15. Heldal D, Tjonnfjord GE, Brinch L, Albrechtsen D, Egeland T, Steen R et al. A randomised study of allogeneic transplantation with stem cells from blood or bone marrow. Bone Marrow Transplant 2000; 25: 1129–1136.

    Article  CAS  PubMed  Google Scholar 

  16. Clarke M, Stewart L . Obtaining individual patient data from randomised controlled trials. In: Egger M, Smith GD, Altman DG (eds). Systemic Reviews in Health Care Meta-analysis in Context. London: BMJ, 2001.

    Google Scholar 

  17. Powles R, Mehta J, Kulkarni S, Treleavan J, Millar B, Marsden J et al. Allogeneic blood and bone-marrow stem-cell transplantation in haematological malignant diseases: a randomised trial. Lancet 2000; 355: 1231–1237.

    Article  CAS  PubMed  Google Scholar 

  18. Bensinger WI, Martin PJ, Storer B, Clift R, Forman SJ, Negrin R et al. Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers. N Engl J Med 2001; 344: 175–181.

    Article  CAS  PubMed  Google Scholar 

  19. Sahovic E . Allogeneic peripheral blood vs bone marrow transplant in hematologic malignancies: a randomized controlled trial. Personal communication 2002.

  20. Myeloma Trialists' Collaborative Group. Interferon as therapy for multiple myeloma: an individual patient data overview of 24 randomized trials and 4012 patients. Br J Haematol 2001; 113: 1020–1034.

  21. Early Breast Cancer Trialists' Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 1998; 352: 930–942.

  22. Mahmoud H, Fahmy O, Kamel A, Kamel M, El Haddad A, El Kadi D . Peripheral blood vs bone marrow as a source for allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 1999; 24: 355–358.

    Article  CAS  PubMed  Google Scholar 

  23. Storb R, Deeg HJ, Pepe M, Appelbaum FR, Anasetti C, Beatty P et al. Methotrexate and cyclosporine versus cyclosporine alone for prophylaxis of graft-versus-host disease in patients given HLA-identical marrow grafts for leukemia: Long-term follow-up of a controlled trial. Blood 1989; 73: 1729–1734.

    CAS  PubMed  Google Scholar 

  24. Sullivan KM, Weiden PL, Storb R, Witherspoon RP, Fefer A, Fisher L et al. Influence of acute and chronic graft-versus-host disease on relapse and survival after bone marrow transplantation from HLA-identical siblings as treatment of acute and chronic leukemia. Blood 1989; 73: 1720–1728.

    CAS  PubMed  Google Scholar 

  25. Nordlander A, Mattsson J, Ringden O, Leblanc K, Gustafsson B, Ljungman P et al. Graft-versus-host disease is associated with a lower relapse incidence after hematopoietic stem cell transplantation in patients with acute lymphoblastic leukemia. Biol Blood Marrow Transplant 2004; 10: 195–203.

    Article  PubMed  Google Scholar 

  26. Horowitz MM, Gale RP, Sondel PM, Kersey J, Kolb HJ, Rimm AA et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood 1990; 75: 555–562.

    CAS  PubMed  Google Scholar 

  27. Johnston A, Gudjonsson JE, Sigmundsdottir H, Ludviksson BR, Valdimarsson H . The anti-inflammatory action of methotrexate is not mediated by lymphocyte apoptosis, but by the suppression of activation and adhesion molecules. Clinical Immunology 2005; 114: 154–163.

    Article  CAS  PubMed  Google Scholar 

  28. Oehler VG, Radich JP, Storer BS, Blume KG, Chauncey T, Clift R et al. Randomized trial of allogeneic related bone marrow transplantation versus peripheral blood stem cell transplantation for chronic myeloid leukemia. Biol Blood Marrow Transplant 2005; 11: 85–92.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

Funding source: Main funding for this project was provided by the NHI/NHLBI Grant # 1R01HL71650–01 (Drs Djulbegovic and Bensinger) and in part by The Jose Carreras Foundation Against Leukemia, NCI CA18029, CA18221 (Dr Bensinger), the Swiss National Research Foundation, and the French Ministry of Health (Programme Hospitalier de Recherche Clinique 1996) (Dr Gratwohl) and a grant from the Ligue Nationale de Lutte Contre le Cancer (Dr Blaise).

Author information

Author notes

  1. W Bensinger: See Appendix A for full list.

Authors and Affiliations

  1. Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    W Bensinger

Authors
  1. W Bensinger
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

on behalf of the Stem Cell Trialists' Collaborative Group

Corresponding author

Correspondence to W Bensinger.

Appendix

Appendix

Members of Stem Cell Trialists' Collaborative Group (in alphabetical order):

  1. 1

    Mahmoud al-Jurf – Department of Medicine, King Faisal Specialist Hospital & Research Center, Riyadh, Kingdom of Saudi Arabia

  2. 2

    Claudio Annasetti, H. Lee Moffitt Cancer Center & Research Institute, University of South Florida, Tampa, USA

  3. 3

    Jane F. Apperley – EBMT – Department of Haematology, Faculty of Medicine, Imperial College, Hammersmith Hospital, London, United Kingdom

  4. 4

    Roy Baynes – Amgen, Thousand Oaks, California, USA

  5. 5

    William I. Bensinger – Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

  6. 6

    Didier Blaise – France – Unite de Transplantation et de Therapie Cellulaire (UTTC), Institut Paoli-Calmettes, Marseille and French society of transplantation (SFGM-TC), France

  7. 7

    Mike Clarke – UK Cochrane Center

  8. 8

    Ed Colcol – Department of Oncology, Section of Adult Hematology/BMT, King Faisal Specialist Hospital and Research Center Health Care System, Riyadh, Saudi Arabia

  9. 9

    Jan J Cornelissen – Department of Hematology, Daniel den Hoed Cancer Center, Rotterdam, The Netherlands

  10. 10

    Stephen Couban – Canadian Bone Marrow Transplant Group, Department of Medicine, Dalhousie University and Queen Elizabeth II Health Sciences Centre, Halifax, NS, Canada

  11. 11

    Corey Cutler – Dana Farber Cancer Institute, Boston, MA, USA

  12. 12

    Benjamin Djulbegovic – H. Lee Moffitt Cancer Center & Research Institute, University of South Florida, Tampa, USA (PI for the NIH/NHLBI grant # 1R01HL71650-01)

  13. 13

    Alois Gratwohl – Kantonsspital, Basel, Switzerland

  14. 14

    Dag Heldal – Medical Department, Rikshospitalet University Hospital, 0027 Oslo, Norway

  15. 15

    Robert K Hills University of Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, UK

  16. 16

    Iztok Hozo – Department of Mathematics, Indiana University, Gary, IN, USA

  17. 17

    Mathieu Kuentz, MD; Department of Hematology, Hopital Henri Mondor, Creteil and French society of transplantation (SFGM-TC), France

  18. 18

    Ambuj Kumar – H. Lee Moffitt Cancer Center & Research Institute, University of South Florida, Tampa, USA

  19. 19

    Jeffrey H. Lipton-Princess Margaret Hospital, Toronto, Canada

  20. 20

    Eliana CM Miranda- Bone Marrow Transplantation Unit, State University of Campinas, Brazil

  21. 21

    Mohamad Mohty – France – Unite de Transplantation et de Therapie Cellulaire (UTTC), Institut Paoli-Calmettes, Marseille Marseille and French society of transplantation (SFGM-TC), France

  22. 22

    James Matcham, Amgen, Thousand Oaks, California, USA

  23. 23

    James Morton – Bone Marrow Transplant Unit, Royal Brisbane Hospital, Herston, Australia

  24. 24

    Tony Panzarella – Canadian Bone Marrow study group – Princess Margaret Hospital, Toronto, Ontario, Canada

  25. 25

    Ray Powles – Royal Marsden Hospital, Sutton, UK

  26. 26

    Sue Richards, Clinical Trial Service Unit, Oxford University, UK

  27. 27

    Entezam Sahovic – Department of Oncology, Section of Adult Hematology/BMT, King Faisal Specialist Hospital and Research Center Health Care System, Riyadh, Saudi Arabia

  28. 28

    Norbert Schmitz – Abteilung Hämatologie, AK St. Georg, Germany

  29. 29

    David R. Simpson, North Shore Hospital, Takapuna, Auckland, New Zealand

  30. 30

    Bhawna Sirohi – Royal Marsden Hospital, Sutton, UK

  31. 31

    Heloisa P Soares – H. Lee Moffitt Cancer Center & Research Institute, University of South Florida, Tampa, USA

  32. 32

    Carmino A de Souza – Bone Marrow Transplantation Unit, State University of Campinas, Brazil

  33. 33

    B Van der Holt – Department of Hematology, Daniel den Hoed Cancer Center, Rotterdam, The Netherlands

  34. 34

    Afonso C Vigorito – Bone Marrow Transplantation Unit, State University of Campinas, Brazil

  35. 35

    Keith Wheatley University of Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, UK

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bensinger, W., on behalf of the Stem Cell Trialists' Collaborative Group. Individual patient data meta-analysis of allogeneic peripheral blood stem cell transplant vs bone marrow transplant in the management of hematological malignancies: indirect assessment of the effect of day 11 methotrexate administration. Bone Marrow Transplant 38, 539–546 (2006). https://doi.org/10.1038/sj.bmt.1705488

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1705488

Keywords

This article is cited by

Search

Advanced search

Quick links