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

Fludarabine-based reduced intensity conditioning transplants have a higher incidence of cytomegalovirus reactivation compared with myeloablative transplants

Bone Marrow Transplantation volume 45, pages 849–855 (2010)Cite this article

Abstract

Two hundred and ten adult CMV seropositive patients undergoing myeloablative conditioning (MAC) [n=127] or reduced intensity conditioning (RIC) [n=83] transplants (HCT) were serially monitored for CMV reactivation and disease, using a qualitative polymerase chain reaction (PCR) followed by quantitation with pp65 antigen or quantitative PCR. CMV reactivation occurred in 53 RIC (63.9%) and 61 MAC (48%; P=0.03) transplants at a median of 47 days (range: 24–1977). Risk factors identified included acute GVHD (P=0.001), RIC regimen (P=0.03), unrelated donor (P=0.02), use of anti-thymocyte globulin/alemtuzumb (P=0.02) and use of bone marrow in MAC transplants (P=0.011). On multivariate analysis, RIC transplants and acute GVHD remained independent predictors. Treatment with antiviral drugs resulted in CMV negativity rates of 86.8% in MAC and 88.6% in RIC transplants. CMV disease occurred in 10.8% of RIC and 4.7% of MAC transplants (P=0.15). At a median follow-up of 26 months (range: 3–88), 48.1% of RIC and 50.3% of MAC transplants are alive. The higher incidence of CMV reactivation among RIC transplants suggests the need for novel prophylactic or pre-emptive strategies in this high-risk group of patients.

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

Similar content being viewed by others

References

  1. Antin JH . Reduced intensity stem cell transplantation. Hematology Am Soc Hematol Educ Program 2007; 2007: 47–54.

    Article  Google Scholar 

  2. Junghanss C, Boeckh M, Carter RA, Sandmaier BM, Maris MB, Maloney DG et al. Incidence and outcome of cytomegalovirus infections following nonmyeloablative compared with myeloablative allogeneic stem cell transplantation, a matched control study. Blood 2002; 99: 1978–1985.

    Article  CAS  PubMed  Google Scholar 

  3. Schetelig J, Oswald O, Steuer N, Radonic A, Thulke S, Held TK et al. Cytomegalovirus infections in allogeneic stem cell recipients after reduced-intensity or myeloablative conditioning assessed by quantitative PCR and pp65-antigenemia. Bone Marrow Transplant 2003; 32: 695–701.

    Article  CAS  PubMed  Google Scholar 

  4. Hill QA, Hill A, Collyns TA, Pearce RM, Cook G . Similar lymphocyte recovery and CMV reactivation profiles between reduced intensity conditioning with alemtuzumab and myeloablative allogeneic stem cell transplantation. Bone Marrow Transplant 2008; 41: 749–751.

    Article  CAS  PubMed  Google Scholar 

  5. Nachbaur D, Larcher C, Kircher B, Eibl G, Nussbaumer W, Gunsilius E et al. Risk for cytomegalovirus infection following reduced intensity allogeneic stem cell transplantation. Ann Hematol 2003; 82: 621–627.

    Article  PubMed  Google Scholar 

  6. Kalpoe JS, van der Heiden PL, Vaessen N, Claas EC, Barge RM, Kroes AC . Comparable incidence and severity of cytomegalovirus infections following T cell-depleted allogeneic stem cell transplantation preceded by reduced intensity or myeloablative conditioning. Bone Marrow Transplant 2007; 40: 137–143.

    Article  CAS  PubMed  Google Scholar 

  7. Chae YS, Sohn SK, Kim JG, Cho YY, Moon JH, Yang DH et al. Impact of alemtuzumab as conditioning regimen component on transplantation outcomes in case of CMV-seropositive recipients and donors. Am J Hematol 2008; 83: 649–653.

    Article  CAS  PubMed  Google Scholar 

  8. Chakrabarti S, Mackinnon S, Chopra R, Kottaridis PD, Peggs K, O’Gorman P et al. High incidence of cytomegalovirus infection after nonmyeloablative stem cell transplantation: potential role of Campath-1 H in delaying immune reconstitution. Blood 2002; 99: 4357–4363.

    Article  CAS  PubMed  Google Scholar 

  9. Mohty M, Mohty AM, Blaise D, Faucher C, Bilger K, Isnardon D et al. Cytomegalovirus-specific immune recovery following allogeneic HLA-identical sibling transplantation with reduced-intensity preparative regimen. Bone Marrow Transplant 2004; 33: 839–846.

    Article  CAS  Google Scholar 

  10. Nakai K, Kanda Y, Mineishi S, Saito T, Ohnishi M, Niiya H et al. Suspected delayed immune recovery against cytomegalovirus after reduced-intensity stem cell transplantation using anti-thymocyte globulin. Bone Marrow Transplant 2002; 29: 237–241.

    Article  CAS  PubMed  Google Scholar 

  11. Micklethwaite K, Hansen A, Foster A, Snape E, Antonenas V, Sartor M et al. Ex vivo expansion and prophylactic infusion of CMV-pp65 peptide-specific cytotoxic T-lymphocytes following allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2007; 13: 707–714.

    Article  CAS  PubMed  Google Scholar 

  12. Micklethwaite KP, Clancy L, Sandher U, Hansen AM, Blyth E, Antonenas V et al. Prophylactic infusion of cytomegalovirus-specific cytotoxic T lymphocytes stimulated with Ad5f35pp65 gene-modified dendritic cells after allogeneic hemopoietic stem cell transplantation. Blood 2008; 112: 3974–3981.

    Article  CAS  PubMed  Google Scholar 

  13. Meijer E, Dekker AW, Lokhorst HM, Petersen EJ, Nieuwenhuis HK, Verdonck LF . Low incidence of infectious complications after nonmyeloablative compared with myeloablative allogeneic stem cell transplantation. Transpl Infect Dis 2004; 6: 171–178.

    Article  CAS  Google Scholar 

  14. Oh SJ, Lee KH, Lee JH, Choi SJ, Kim WK, Lee JS et al. The risk of cytomegalovirus infection in non-myeloablative peripheral stem cell transplantation compared with conventional bone marrow transplantation. J Korean Med Sci 2004; 19: 172–176.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Nakamura R, Cortez K, Solomon S, Battiwala M, Gill VJ, Hensel N et al. High-dose acyclovir and pre-emptive ganciclovir to prevent cytomegalovirus disease in myeloablative and non-myeloablative allogeneic stem cell transplantation. Bone Marrow Transplant 2002; 30: 235–242.

    Article  CAS  PubMed  Google Scholar 

  16. Kline J, Pollyea DA, Stock W, Artz A, Rich E, Godley L et al. Pre-transplant ganciclovir and post transplant high-dose valacyclovir reduce CMV infections after alemtuzumab-based conditioning. Bone Marrow Transplant 2006; 37: 307–310.

    Article  CAS  PubMed  Google Scholar 

  17. Lamba R, Carrum G, Myers GD, Bollard CM, Krance RA, Heslop HE et al. Cytomegalovirus (CMV) infections and CMV-specific cellular immune reconstitution following reduced intensity conditioning allogeneic stem cell transplantation with Alemtuzumab. Bone Marrow Transplant 2005; 36: 797–802.

    Article  CAS  PubMed  Google Scholar 

  18. Busca A, Locatelli F, Barbui A, Ghisetti V, Cirillo D, Serra R et al. Infectious complications following nonmyeloablative allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis 2003; 5: 132–139.

    Article  CAS  PubMed  Google Scholar 

  19. Miller W, Flynn P, McCullough J, Balfour Jr HH, Goldman A, Haake R et al. Cytomegalovirus infection after bone marrow transplantation: an association with acute graft-v-host disease. Blood 1986; 67: 1162–1167.

    CAS  PubMed  Google Scholar 

  20. Ljungman P, Perez-Bercoff L, Jonsson J, Avetisyan G, Sparellid E, Aschan J et al. Risk factors for the development of cytomegalovirus disease after allogeneic stem cell transplantation. Haematologica 2006; 91: 78–83.

    PubMed  Google Scholar 

  21. Moss P, Khan N . CD8(+) T-cell immunity to cytomegalovirus. Hum Immunol 2004; 65: 456–464.

    Article  CAS  PubMed  Google Scholar 

  22. Kano Y, Shiohara T . Current understanding of cytomegalovirus infection in immunocompetent individuals. J Dermatol Sci 2000; 22: 196–204.

    Article  CAS  PubMed  Google Scholar 

  23. Ozdemir E, St John LS, Gillespie G, Rowland-Jones S, Champlin RE, Molldrem JJ . Cytomegalovirus reactivation following allogeneic stem cell transplantation is associated with the presence of dysfunctional antigen-specific CD8+ T cells. Blood 2002; 100: 3690–3697.

    Article  CAS  PubMed  Google Scholar 

  24. Ganepola S, Gentilini C, Hilbers U, Lange T, Rieger K, Hofmann J et al. Patients at high risk for CMV infection and disease show delayed CD8+ T-cell immune recovery after allogeneic stem cell transplantation. Bone Marrow Transplant 2007; 39: 293–299.

    Article  CAS  PubMed  Google Scholar 

  25. Lilleri D, Fornara C, Chiesa A, Caldera D, Alessandrino EP, Gerna G . Human cytomegalovirus-specific CD4+ and CD8+ T-cell reconstitution in adult allogeneic hematopoietic stem cell transplant recipients and immune control of viral infection. Haematologica 2008; 93: 248–256.

    Article  PubMed  Google Scholar 

  26. Ferrari V, Cacere CR, Machado CM, Pannuti CS, Dulley FL, Barros JC et al. Distinct patterns of regeneration of central memory, effector memory and effector TCD8+ cell subsets after different hematopoietic cell transplant types: possible influence in the recovery of anti-cytomegalovirus immune response and risk for its reactivation. Clin Immunol 2006; 119: 261–271.

    Article  CAS  PubMed  Google Scholar 

  27. Hakki M, Riddell SR, Storek J, Carter RA, Stevens-Ayers T, Sudour P et al. Immune reconstitution to cytomegalovirus after allogeneic hematopoietic stem cell transplantation: impact of host factors, drug therapy, and subclinical reactivation. Blood 2003; 102: 3060–3067.

    Article  CAS  PubMed  Google Scholar 

  28. Maris M, Boeckh M, Storer B, Dawson M, White K, Keng M et al. Immunologic recovery after hematopoietic cell transplantation with nonmyeloablative conditioning. Exp Hematol 2003; 31: 941–952.

    Article  CAS  PubMed  Google Scholar 

  29. Broers AE, van Der Holt R, van Esser JW, Gratama JW, Henzen-Logmans S, Kuenen-Boumeester V et al. Increased transplant-related morbidity and mortality in CMV-seropositive patients despite highly effective prevention of CMV disease after allogeneic T-cell-depleted stem cell transplantation. Blood 2000; 95: 2240–2245.

    CAS  PubMed  Google Scholar 

  30. Kröger N, Zabelina T, Krüger W, Renges H, Stute N, Kabisch H et al. Patient cytomegalovirus seropositivity with or without reactivation is the most important prognostic factor for survival and treatment-related mortality in stem cell transplantation from unrelated donors using pretransplant in vivo T-cell depletion with anti-thymocyte globulin. Br J Haematol 2001; 113: 1060–1071.

    Article  PubMed  Google Scholar 

  31. Winston DJ, Young JA, Pullarkat V, Papanicolau GA, Vij R, Vance E et al. Maribavir prophylaxis for prevention of cytomegalovirus infection in allogeneic stem cell transplant recipients: a multicenter, randomized, double-blind, placebo controlled, dose-ranging study. Blood 2008; 111: 5403–5410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mackinnon S, Thomson K, Verfuerth S, Peggs K, Lowdell M . Adoptive cellular therapy for cytomegalovirus infection following allogeneic stem cell transplantation using virus-specific T cells. Blood Cells Mol Dis 2008; 40: 63–67.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Haematology, Level II ICPMR, Westmead Hospital, Sydney, New South Wales, Australia

    B George, I Kerridge, G Huang, M Hertzberg, D Gottlieb & K Bradstock

  2. Department of Infectious Diseases, Level II ICPMR, Westmead Hospital, Sydney, New South Wales, Australia

    N Gilroy

Authors
  1. B George
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I Kerridge
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N Gilroy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Hertzberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D Gottlieb
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. K Bradstock
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B George.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

George, B., Kerridge, I., Gilroy, N. et al. Fludarabine-based reduced intensity conditioning transplants have a higher incidence of cytomegalovirus reactivation compared with myeloablative transplants. Bone Marrow Transplant 45, 849–855 (2010). https://doi.org/10.1038/bmt.2009.273

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2009.273

Keywords

This article is cited by

Search

Advanced search

Quick links