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:

Graft-Versus-Host Disease

Effect of acute and chronic GVHD on relapse and survival after reduced-intensity conditioning allogeneic transplantation for myeloma

Bone Marrow Transplantation volume 47, pages 831–837 (2012)Cite this article

Abstract

We evaluated the effect of acute and chronic GVHD on relapse and survival after allogeneic hematopoietic SCT (HSCT) for multiple myeloma using non-myeloablative conditioning (NMA) and reduced-intensity conditioning (RIC). The outcomes of 177 HLA-identical sibling HSCT recipients between 1997 and 2005, following NMA (n=98) or RIC (n=79) were analyzed. In 105 patients, autografting was followed by planned NMA/RIC allogeneic transplantation. The impact of GVHD was assessed as a time-dependent covariate using Cox models. The incidence of acute GVHD (aGVHD; grades I–IV) was 42% (95% confidence interval (CI), 35–49%) and of chronic GVHD (cGVHD) at 5 years was 59% (95% CI, 49–69%), with 70% developing extensive cGVHD. In multivariate analysis, aGVHD (⩾grade I) was associated with an increased risk of TRM (relative risk (RR)=2.42, P=0.016), whereas limited cGVHD significantly decreased the risk of myeloma relapse (RR=0.35, P=0.035) and was associated with superior EFS (RR=0.40, P=0.027). aGVHD had a detrimental effect on survival, especially in those receiving autologous followed by allogeneic HSCT (RR=3.52, P=0.001). The reduction in relapse risk associated with cGVHD is consistent with a beneficial graft-vs-myeloma effect, but this did not translate into a survival advantage.

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

Similar content being viewed by others

References

  1. Aschan J, Lonnqvist B, Ringden O, Kumlien G, Gahrton G . Graft-versus-myeloma effect. Lancet 1996; 348: 346.

    Article  CAS  PubMed  Google Scholar 

  2. Lokhorst HM, Schattenberg A, Cornelissen JJ, van Oers MH, Fibbe W, Russell I et al. Donor lymphocyte infusions for relapsed multiple myeloma after allogeneic stem-cell transplantation: predictive factors for response and long-term outcome. J Clin Oncol 2000; 18: 3031–3037.

    Article  CAS  PubMed  Google Scholar 

  3. 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 

  4. Verdonck LF, Lokhorst HM, Dekker AW, Nieuwenhuis HK, Petersen EJ . Graft-versus-myeloma effect in two cases. Lancet 1996; 347: 800–801.

    Article  CAS  PubMed  Google Scholar 

  5. Le Blanc R, Montminy-Metivier S, Belanger R, Busque L, Fish D, Roy DC et al. Allogeneic transplantation for multiple myeloma: further evidence for a GVHD-associated graft-versus-myeloma effect. Bone Marrow Transplant 2001; 28: 841–848.

    Article  CAS  PubMed  Google Scholar 

  6. Bruno B, Rotta M, Patriarca F, Mattei D, Allione B, Carnevale-Schianca F et al. Nonmyeloablative allografting for newly diagnosed multiple myeloma: the experience of the Gruppo Italiano Trapianti di Midollo. Blood 2009; 113: 3375–3382.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Barlogie B, Kyle RA, Anderson KC, Greipp PR, Lazarus HM, Hurd DD et al. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321. J Clin Oncol 2006; 24: 929–936.

    Article  CAS  PubMed  Google Scholar 

  8. Bjorkstrand BB, Ljungman P, Svensson H, Hermans J, Alegre A, Apperley J et al. Allogeneic bone marrow transplantation versus autologous stem cell transplantation in multiple myeloma: a retrospective case-matched study from the European Group for Blood and Marrow Transplantation. Blood 1996; 88: 4711–4718.

    CAS  PubMed  Google Scholar 

  9. Facon T, Mary JY, Hulin C, Benboubker L, Attal M, Pegourie B et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet 2007; 370: 1209–1218.

    Article  CAS  PubMed  Google Scholar 

  10. 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  PubMed  Google Scholar 

  11. 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  PubMed  Google Scholar 

  12. Bruno B, Rotta M, Patriarca F, Mordini N, Allione B, Carnevale-Schianca F et al. A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med 2007; 356: 1110–1120.

    Article  CAS  PubMed  Google Scholar 

  13. Garban F, Attal M, Michallet M, Hulin C, Bourhis JH, Yakoub-Agha I et al. Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma. Blood 2006; 107: 3474–3480.

    Article  CAS  PubMed  Google Scholar 

  14. Rosinol L, Perez-Simon JA, Sureda A, de la Rubia J, de Arriba F, Lahuerta JJ et al. A prospective PETHEMA study of tandem autologous transplantation versus autograft followed by reduced-intensity conditioning allogeneic transplantation in newly diagnosed multiple myeloma. Blood 2008; 112: 3591–3593.

    Article  CAS  PubMed  Google Scholar 

  15. Krishnan A, Pasquini M, Ewell M, Stadtmauer EA, Edwin PAI, Antin JH et al. Tandem Autologous Hematopoietic Stem Cell Transplants (AuHCT) with or without Maintenance Therapy (auto-auto) Versus Single AuHCT Followed by HLA Matched Sibling Non-Myeloablative Allogeneic HCT (auto-allo) for Patients with Standard Risk (SR) Multiple Myeloma (MM): Results From the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0102 Trial. ASH Annual Meeting 2010; 116: 41 (abstract).

    Google Scholar 

  16. 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  PubMed  Google Scholar 

  17. Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant 2009; 15: 1628–1633.

    Article  PubMed  PubMed Central  Google Scholar 

  18. 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  PubMed  Google Scholar 

  19. Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 1974; 18: 295–304.

    Article  CAS  PubMed  Google Scholar 

  20. 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: 204–217.

    Article  CAS  PubMed  Google Scholar 

  21. Crawley C, Iacobelli S, Bjorkstrand B, Apperley JF, Niederwieser D, Gahrton G . Reduced-intensity conditioning for myeloma: lower nonrelapse mortality but higher relapse rates compared with myeloablative conditioning. Blood 2007; 109: 3588–3594.

    Article  CAS  PubMed  Google Scholar 

  22. Rotta M, Storer BE, Sahebi F, Shizuru JA, Bruno B, Lange T et al. Long-term outcome of patients with multiple myeloma after autologous hematopoietic cell transplantation and nonmyeloablative allografting. Blood 2009; 113: 3383–3391.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ringden O, Hermans J, Labopin M, Apperley J, Gorin NC, Gratwohl A . The highest leukaemia-free survival after allogeneic bone marrow transplantation is seen in patients with grade I acute graft-versus-host disease. Acute and chronic leukaemia working parties of the European Group for Blood and Marrow Transplantation (EBMT). Leuk Lymphoma 1996; 24: 71–79.

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  25. Ringden O, Labopin M, Gluckman E, Reiffers J, Vernant JP, Jouet JP et al. Graft-versus-leukemia effect in allogeneic marrow transplant recipients with acute leukemia is maintained using cyclosporin a combined with methotrexate as prophylaxis. Acute leukemia working party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 1996; 18: 921–929.

    CAS  PubMed  Google Scholar 

  26. 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 

  27. Weiden PL, Sullivan KM, Flournoy N, Storb R, Thomas ED . Antileukemic effect of chronic graft-versus-host disease: contribution to improved survival after allogeneic marrow transplantation. N Engl J Med 1981; 304: 1529–1533.

    Article  CAS  PubMed  Google Scholar 

  28. Carlens S, Aschan J, Remberger M, Dilber M, Ringden O . Low-dose cyclosporine of short duration increases the risk of mild and moderate GVHD and reduces the risk of relapse in HLA-identical sibling marrow transplant recipients with leukaemia. Bone Marrow Transplant 1999; 24: 629–635.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA76518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases; a Grant/Cooperative Agreement 5U01HL069294 from NHLBI and NCI; a contract HHSH234200637015C with Health Resources and Services Administration (HRSA/DHHS); two Grants N00014-06-1-0704 and N00014-08-1-0058 from the Office of Naval Research; and grants from AABB; Aetna; American Society for Blood and Marrow Transplantation, Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Astellas Pharma US, Inc.; Baxter International, Inc.; Bayer HealthCare Pharmaceuticals; Be the Match Foundation; Biogen IDEC; BioMarin Pharmaceutical, Inc.; Biovitrum AB; BloodCenter of Wisconsin; Blue Cross and Blue Shield Association; Bone Marrow Foundation; Buchanan Family Foundation; Canadian Blood and Marrow Transplant Group; CaridianBCT; Celgene Corporation; CellGenix, GmbH; Centers for Disease Control and Prevention; Children's Leukemia Research Association; ClinImmune Labs; CTI Clinical Trial and Consulting Services; Cubist Pharmaceuticals; Cylex, Inc.; CytoTherm; DOR BioPharma, Inc.; Dynal Biotech (an Invitrogen Company); Eisai, Inc.; Enzon Pharmaceuticals, Inc.; European Group for Blood and Marrow Transplantation; Gamida Cell, Ltd.; GE Healthcare; Genentech, Inc.; Genzyme Corporation; Histogenetics, Inc.; HKS Medical Information Systems; Hospira, Inc.; Infectious Diseases Society of America; Kiadis Pharma; Kirin Brewery Co., Ltd.; The Leukemia and Lymphoma Society; Merck and Company; The Medical College of Wisconsin; MGI Pharma, Inc.; Michigan Community Blood Centers; Millennium Pharmaceuticals, Inc.; Miller Pharmacal Group; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Nature Publishing Group; New York Blood Center; Novartis Oncology; Oncology Nursing Society; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; Pall Life Sciences; Pfizer, Inc.; Saladax Biomedical, Inc.; Schering Corporation; Society for Healthcare Epidemiology of America; Soligenix, Inc.; StemCyte, Inc.; StemSoft Software, Inc.; Sysmex America, Inc.; THERAKOS, Inc.; Thermogenesis Corporation; Vidacare Corporation; Vion Pharmaceuticals, Inc.; ViraCor Laboratories; ViroPharma, Inc.; and Wellpoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense or any other agency of the US Government. Olle Ringdén is supported by grants from the Swedish Cancer Society, the Children's Cancer Foundation, the Swedish Research Council, the Cancer Society in Stockholm, and Karolinska Institutet.

Author information

Authors and Affiliations

  1. Department of Clinical Immunology, Karolinska University Hospital, Stockholm, Sweden

    O Ringdén & M Remberger

  2. Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI, USA

    S Shrestha, M-J Zhang & P N Hari

  3. Department of Statistics, University of Sao Paulo, Sao Paulo, Brazil

    G T da Silva

  4. Mayo Clinic, Rochester, MN, USA

    A Dispenzieri

  5. Department of Hematology and Oncology, Baylor College of Medicine, Houston, TX, USA

    R Kamble

  6. Department of Hematology, South Texas Veterans Health Care Systems, San Antonio, TX, USA

    C O Freytes

  7. Department of Hematology and Oncology, Celgene Corporation, Summit, NJ, USA

    R P Gale

  8. Department of Haematology, Royal Prince Alfred Hospital, Institute of Haematology, Camperdown, New South Wales, Australia

    J Gibson

  9. Department of Medicine, Princess Margaret Hospital, Toronto, Ontario, Canada

    V Gupta

  10. The Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    L Holmberg

  11. Department of Medicine, University Hospitals Case Medical Center, Cleveland, OH, USA

    H Lazarus

  12. Roswell Park Cancer Institute, Buffalo, NY, USA

    P McCarthy

  13. Department of Medicine, Dartmount-Hitchcock Medical Center, Lebanon, NH, USA

    K Meehan

  14. Department of Internal Medicine, University Hospital Maastricht, Maastricht, The Netherlands

    H Schouten

  15. Angelica Ocampo-Fundaleu, Buenos Aires, Argentina

    G A Milone

  16. Department of Medicine, Emory University Hospital, Atlanta, GA, USA

    S Lonial

Authors
  1. O Ringdén
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Shrestha
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G T da Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M-J Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A Dispenzieri
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M Remberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R Kamble
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. C O Freytes
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. R P Gale
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. J Gibson
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. V Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. L Holmberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. H Lazarus
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. P McCarthy
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. K Meehan
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. H Schouten
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. G A Milone
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. S Lonial
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. P N Hari
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P N Hari.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ringdén, O., Shrestha, S., da Silva, G. et al. Effect of acute and chronic GVHD on relapse and survival after reduced-intensity conditioning allogeneic transplantation for myeloma. Bone Marrow Transplant 47, 831–837 (2012). https://doi.org/10.1038/bmt.2011.192

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2011.192

Keywords

This article is cited by

Search

Advanced search

Quick links