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Post-Transplant Events

A randomized controlled trial of plasma real-time PCR and antigenemia assay for monitoring CMV infection after unrelated BMT

Bone Marrow Transplantation volume 45, pages 1325–1332 (2010)Cite this article

Abstract

Preemptive therapy is the standard strategy for preventing CMV disease after allogeneic hematopoietic SCT. In this study, unrelated BMT recipients were randomly assigned to a plasma real-time PCR group or an antigenemia group to compare the value of these monitoring tools for CMV reactivation. Ganciclovir (GCV) was started at 5 mg/kg/day when PCR reached 300 copies per ml or when antigenemia reached three positive cells per two slides. A total of 88 patients were randomized into the antigenemia group (n=45) or the PCR group (n=43). A significantly higher number of patients reached the threshold in the antigenemia group than in the PCR group (73.3 vs 44.2%, P=0.0089). However, only three patients (one in the antigenemia group and two in the PCR group) developed early CMV disease. These patients exclusively had colitis and were successfully treated with GCV or foscarnet. The median number of antigenemia-positive cells at the start of GCV was 47 in the PCR group. These findings suggest that antigenemia assay with the current cutoff was too sensitive and led to unnecessary use of GCV. However, the appropriateness of the threshold may be different by the methodology used, and therefore, it is difficult to generalize.

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References

  1. Goodrich JM, Bowden RA, Fisher L, Keller C, Schoch G, Meyers JD . Ganciclovir prophylaxis to prevent cytomegalovirus disease after allogeneic marrow transplant. Ann Intern Med 1993; 118: 173–178.

    Article  CAS  PubMed  Google Scholar 

  2. Winston DJ, Ho WG, Bartoni K, Du Mond C, Ebeling DF, Buhles WC et al. Ganciclovir prophylaxis of cytomegalovirus infection and disease in allogeneic bone marrow transplant recipients. Results of a placebo-controlled, double-blind trial. Ann Intern Med 1993; 118: 179–184.

    Article  CAS  PubMed  Google Scholar 

  3. Boeckh M, Gooley TA, Myerson D, Cunningham T, Schoch G, Bowden RA . Cytomegalovirus pp65 antigenemia-guided early treatment with ganciclovir versus ganciclovir at engraftment after allogeneic marrow transplantation: a randomized double-blind study. Blood 1996; 88: 4063–4071.

    CAS  PubMed  Google Scholar 

  4. Boeckh M, Ljungman P . How we treat CMV in hematopoietic cell transplant recipients. Blood 2009; 113: 5711–5719.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ljungman P, Reusser P, de la Camara R, Einsele H, Engelhard D, Ribaud P et al. Management of CMV infections: recommendations from the infectious diseases working party of the EBMT. Bone Marrow Transplant 2004; 33: 1075–1081.

    Article  CAS  PubMed  Google Scholar 

  6. Kanda Y, Mineishi S, Saito T, Seo S, Saito A, Suenaga K et al. Pre-emptive therapy against cytomegalovirus (CMV) disease guided by CMV antigenemia assay after allogeneic hematopoietic stem cell transplantation: a single-center experience in Japan. Bone Marrow Transplant 2001; 27: 437–444.

    Article  CAS  PubMed  Google Scholar 

  7. Kanda Y, Mineishi S, Saito T, Saito A, Ohnishi M, Niiya H 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 

  8. Einsele H, Ehninger G, Hebart H, Wittkowski KM, Schuler U, Jahn G et al. Polymerase chain reaction monitoring reduces the incidence of cytomegalovirus disease and the duration and side effects of antiviral therapy after bone marrow transplantation. Blood 1995; 86: 2815–2820.

    CAS  PubMed  Google Scholar 

  9. Boeckh M, Gallez-Hawkins GM, Myerson D, Zaia JA, Bowden RA . Plasma polymerase chain reaction for cytomegalovirus DNA after allogeneic marrow transplantation: comparison with polymerase chain reaction using peripheral blood leukocytes, pp65 antigenemia, and viral culture. Transplantation 1997; 64: 108–113.

    Article  CAS  PubMed  Google Scholar 

  10. Kanda Y, Chiba S, Suzuki T, Kami M, Yazaki Y, Hirai H . Time course analysis of semi-quantitative PCR and antigenaemia assay for prevention of cytomegalovirus disease after bone marrow transplantation. Br J Haematol 1998; 100: 222–225.

    Article  CAS  PubMed  Google Scholar 

  11. Mori T, Okamoto S, Watanabe R, Yajima T, Iwao Y, Yamazaki R et al. Dose-adjusted preemptive therapy for cytomegalovirus disease based on real-time polymerase chain reaction after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2002; 29: 777–782.

    Article  CAS  PubMed  Google Scholar 

  12. Gerna G, Lilleri D, Caldera D, Furione M, Zenone Bragotti L, Alessandrino EP . Validation of a DNAemia cutoff for preemptive therapy of cytomegalovirus infection in adult hematopoietic stem cell transplant recipients. Bone Marrow Transplant 2008; 41: 873–879.

    Article  CAS  PubMed  Google Scholar 

  13. Lilleri D, Gerna G, Furione M, Bernardo ME, Giorgiani G, Telli S et al. Use of a DNAemia cut-off for monitoring human cytomegalovirus infection reduces the number of preemptively treated children and young adults receiving hematopoietic stem-cell transplantation compared with qualitative pp65 antigenemia. Blood 2007; 110: 2757–2760.

    Article  CAS  PubMed  Google Scholar 

  14. Verkruyse LA, Storch GA, Devine SM, Dipersio JF, Vij R . Once daily ganciclovir as initial pre-emptive therapy delayed until threshold CMV load > or=10000 copies/ml: a safe and effective strategy for allogeneic stem cell transplant patients. Bone Marrow Transplant 2006; 37: 51–56.

    Article  CAS  PubMed  Google Scholar 

  15. 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 

  16. Kanda Y, Mineishi S, Nakai K, Saito T, Tanosaki R, Takaue Y . Frequent detection of rising cytomegalovirus antigenemia after allogeneic stem cell transplantation following a regimen containing antithymocyte globulin. Blood 2001; 97: 3676–3677.

    Article  CAS  PubMed  Google Scholar 

  17. Kurihara T, Hayashi J, Ito A, Asai T . CMV antigenemia assay using indirect ALP-immunostaining in bone marrow transplant recipients. Transplant Proc 1996; 28: 1750–1753.

    CAS  PubMed  Google Scholar 

  18. Tanaka Y, Kanda Y, Kami M, Mori S, Hamaki T, Kusumi E et al. Monitoring cytomegalovirus infection by antigenemia assay and two distinct plasma real-time PCR methods after hematopoietic stem cell transplantation. Bone Marrow Transplant 2002; 30: 315–319.

    Article  CAS  PubMed  Google Scholar 

  19. Asano-Mori Y, Kanda Y, Oshima K, Watanabe T, Shoda E, Motokura T et al. Pharmacokinetics of ganciclovir in haematopoietic stem cell transplantation recipients with or without renal impairment. J Antimicrob Chemother 2006; 57: 1004–1007.

    Article  CAS  PubMed  Google Scholar 

  20. Asano-Mori Y, Kanda Y, Oshima K, Kako S, Shinohara A, Nakasone H et al. Clinical features of late cytomegalovirus infection after hematopoietic stem cell transplantation. Int J Hematol 2008; 87: 310–318.

    Article  CAS  PubMed  Google Scholar 

  21. Mori T, Mori S, Kanda Y, Yakushiji K, Mineishi S, Takaue Y et al. Clinical significance of cytomegalovirus (CMV) antigenemia in the prediction and diagnosis of CMV gastrointestinal disease after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2004; 33: 431–434.

    Article  CAS  PubMed  Google Scholar 

  22. Boeckh M, Woogerd PM, Stevens-Ayers T, Ray CG, Bowden RA . Factors influencing detection of quantitative cytomegalovirus antigenemia. J Clin Microbiol 1994; 32: 832–834.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Gerna G, Revello MG, Percivalle E, Morini F . Comparison of different immunostaining techniques and monoclonal antibodies to the lower matrix phosphoprotein (pp65) for optimal quantitation of human cytomegalovirus antigenemia. J Clin Microbiol 1992; 30: 1232–1237.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Grundy JE, Ehrnst A, Einsele H, Emery VC, Hebart H, Prentice HG et al. A three-center European external quality control study of PCR for detection of cytomegalovirus DNA in blood. J Clin Microbiol 1996; 34: 1166–1170.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Gerna G, Percivalle E, Torsellini M, Revello MG . Standardization of the human cytomegalovirus antigenemia assay by means of in vitro-generated pp65-positive peripheral blood polymorphonuclear leukocytes. J Clin Microbiol 1998; 36: 3585–3589.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Verschuuren EA, Harmsen MC, Limburg PC, van Der Bij W, van Den Berg AP, Kas-Deelen AM et al. Towards standardization of the human cytomegalovirus antigenemia assay. Intervirology 1999; 42: 382–389.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Mrs Aki Tanihara, who was involved in the data management. This research was supported by a Grant-in-Aid for Scientific Research from the Ministry of Health, Labor and Welfare.

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Authors and Affiliations

  1. Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama, Japan

    Y Kanda

  2. Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan

    T Yamashita

  3. Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan

    T Mori

  4. Division of Hematology, Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan

    T Ito

  5. Division of Hematology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan

    K Tajika

  6. Department of Hematology and Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan

    S Mori

  7. Division of Hematology, Saiseikai Maebashi Hospital, Maebashi, Japan

    T Sakura

  8. Division of Hematology, Ehime Prefectural Central Hospital, Matsuyama, Japan

    M Hara

  9. Department of Hematology, Dokkyo Medical University School of Medicine, Tochigi, Japan

    K Mitani

  10. Department of Hematology and Oncology, University of Tokyo, Tokyo, Japan

    M Kurokawa

  11. Medicine and Biosystemic Science, Kyushu University School of Medical Science, Fukuoka, Japan

    K Akashi & M Harada

  12. NHO Ohmuta National Hospital, Fukuoka, Japan

    M Harada

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  1. Y Kanda
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Correspondence to Y Kanda.

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Kanda, Y., Yamashita, T., Mori, T. et al. A randomized controlled trial of plasma real-time PCR and antigenemia assay for monitoring CMV infection after unrelated BMT. Bone Marrow Transplant 45, 1325–1332 (2010). https://doi.org/10.1038/bmt.2009.337

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  • DOI: https://doi.org/10.1038/bmt.2009.337

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