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Early human cytomegalovirus reactivation is associated with lower incidence of relapse of myeloproliferative disorders after allogeneic hematopoietic stem cell transplantation

Bone Marrow Transplantationvolume 53pages14501456 (2018) | Download Citation


Conflicting results have been reported regarding the association between early cytomegalovirus (CMV) reactivation and relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This prompted us to evaluate the impact of CMV reactivation on outcomes of 155 consecutive adult patients transplanted in our institution. In our study, CMV reactivation did not affect cumulative incidence (CI) of relapse in patients with lymphoproliferative disorders. However, the CI of relapse in patients with myeloproliferative disorders (AML and MPN) was 37% (95% CI, 21–53) in patients without CMV reactivation as opposed to 17% (95% CI, 9–28) in patients with CMV reactivation (p = 0.03). An important correlation between CMV reactivation and relapse was found in patients with MPN; the CI of relapse was 50% (95% CI, 12–80) in patients without CMV reactivation as opposed to only 7% (95% CI, 0–27) in patients with CMV reactivation (p = 0.02). A substantial reduction of relapse in myeloproliferative disorders associated with CMV reactivation was confirmed by multivariate analysis (HR 2.73; 95% CI, 1.09–6.82, p = 0.03) using time-dependent covariates for high-risk disease, older age, RIC conditioning, ATG, grade II–IV acute, and chronic GVHD. To our knowledge, we are the first to show an association of CMV reactivation with relapse reduction in MPN patients. This putative virus vs myeloproliferation effect warrants further research.

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  1. 1.

    Boeckh M, Nichols WG. The impact of cytomegalovirus serostatus of donor and recipient before hematopoietic stem cell transplantation in the era of antiviral prophylaxis and preemptive therapy. Blood. 2004;103:2003–8.

  2. 2.

    Boeckh M, Nichols WG, Papanicolaou G, Rubin R, Wingard JR, Zaia J. Cytomegalovirus in hematopoietic stem cell transplant recipients: current status, known challenges, and future strategies. Biol Blood Marrow Transplant. 2003;9:543–58.

  3. 3.

    Ljungman P, Hakki M, Boeckh M. Cytomegalovirus in hematopoietic stem cell transplant recipients. Infect Dis Clin North Am. 2010;24:319–37.

  4. 4.

    Ljungman P, de la Camara R, Cordonnier C, Einsele H, Engelhard D, Reusser P, et al. Management of CMV, HHV-6, HHV-7 and Kaposi-sarcoma herpesvirus (HHV-8) infections in patients with hematological malignancies and after SCT. Bone Marrow Transplant. 2008;42:227–40.

  5. 5.

    Boeckh M, Ljungman P. How I treat cytomegalovirus in hematopoietic cell transplant recipients. Blood. 2009;113:5711–9.

  6. 6.

    Broers AE, van Der Holt R, van Esser JW, 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;95:2240–5.

  7. 7.

    Lonnqvist B, Ringden O, Ljungman P, Wahren B, Gahrton G. Reduced risk of recurrent leukaemia in bone marrow transplant recipients after cytomegalovirus infection. Br J Haematol. 1986;63:671–9.

  8. 8.

    Kollman C, Howe CW, Anasetti C, Antin JH, Davies SM, Filipovich AH, et al. Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age. Blood. 2001;98:2043–51.

  9. 9.

    Ljungman P, Brand R, Einsele H, Frassoni F, Niederwieser D, Cordonnier C. Donor CMV serologic status and outcome of CMV-seropositive recipients after unrelated donor stem cell transplantation: an EBMT megafile analysis. Blood. 2003;102:4255–60.

  10. 10.

    Behrendt CE, Rosenthal J, Bolotin E, Nakamura R, Zaia J, Forman SJ. Donor and recipient CMV serostatus and outcome of pediatric allogeneic HSCT for acute leukemia in the era of CMV-preemptive therapy. Biol Blood Marrow Transplant. 2009;15:54–60.

  11. 11.

    Farina L, Bruno B, Patriarca F, Spina F, Sorasio R, Morelli M, et al. The hematopoietic cell transplantation comorbidity index (HCT-CI) predicts clinical outcomes in lymphoma and myeloma patients after reduced-intensity or non-myeloablative allogeneic stem cell transplantation. Leukemia. 2009;23:1131–8.

  12. 12.

    Schmidt-Hieber M, Labopin M, Beelen D, Volin L, Ehninger G, Finke J, et al. CMV serostatus still has an important prognostic impact in de novo acute leukemia patients after allogeneic stem cell transplantation: a report from the Acute Leukemia Working Party of EBMT. Blood. 2013;122:3359–64.

  13. 13.

    Elmaagacli AH, Steckel NK, Koldehoff M, Hegerfeldt Y, Trenschel R, Ditschkowski M, et al. Early human cytomegalovirus replication after transplantation is associated with a decreased relapse risk: evidence for a putative virus-versus-leukemia effect in acute myeloid leukemia patients. Blood. 2011;118:1402–12.

  14. 14.

    Jang JE, Kim SJ, Cheong JW, Hyun SY, Kim YD, Kim YR, et al. Early CMV replication and sub- sequent chronic GVHD have a significant anti-leukemic effect after allogeneic HSCT in acute myeloid leukemia. Ann Hematol. 2015;94:275–82.

  15. 15.

    Green ML, Leisenring WM, Xie H, Walter RB, Mielcarek M, Sandmaier BM, et al. CMV reactivation after allogeneic HCT and relapse risk: evidence for early protection in acute myeloid leukemia. Blood. 2013;122:1316–24.

  16. 16.

    Mariotti J, Maura F, Spina F, Roncari L, Dodero A, Farina L, et al. Impact of cytomegalovirus replication and cytomegalovirus serostatus on the outcome of patients with B cell lymphoma after allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2014;20:885–90.

  17. 17.

    Yanada M, Yamamoto K, Emi N, Naoe T, Suzuki R, Taji H, et al. Cytomegalovirus antigenemia and outcome of patients treated with pre-emptive ganciclovir: retrospective analysis of 241 consecutive patients undergoing allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2003;32:801–7.

  18. 18.

    Jeljeli M, Guérin-El Khourouj V, Porcher R, Fahd M, Leveillé S, Yakouben K, et al. Relationship between cytomegalovirus (CMV) reactivation, CMV-driven immunity, overall immune recovery and graft-versus-leukaemia effect in children. Br J Haematol. 2014;166:229–39.

  19. 19.

    Manjappa S, Bhamidipati PK, Stokerl-Goldstein KE, DiPersio JF, Uy GL, Westervelt P, et al. Protective effect of cytomegalovirus reactivation on relapse after allogeneic hematopoietic cell transplantation in acute myeloid leukemia patients is influenced by conditioning regimen. Biol Blood Marrow Transplant. 2014;20:46–52.

  20. 20.

    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 HLA-matched sibling donors. Transplantation. 1974;18:295–304.

  21. 21.

    Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005;11:945–56.

  22. 22.

    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;15:1628–33.

  23. 23.

    Klein JP, Rizzo JD, Zhang MJ, Keiding N. Statistical methods for the analysis and presentation of the results of bone marrow transplants. Part 2: Regression modeling. Bone Marrow Transplant. 2001;28:1001–111.

  24. 24.

    Scrucca L, Santucci A, Aversa F. Regression modeling of competing risk using R: an in depth guide for clinicians. Bone Marrow Transplant. 2010;45:1388–95.

  25. 25.

    Fine JP. A proportional hazards model for subdistribution of a competing risk. JASA. 1999;94:496–509.

  26. 26.

    Bao X, Zhu Q, Xue S, Hu X, Ma X, et al. Cytomegalovirus induces strong antileukemic effect in acute myeloid leukemia patients following sibling HSCT without ATG-containing regimen. Am J Transl Res. 2016;8:653–61.

  27. 27.

    Teira P, Battiwalla M, Ramanathan M, Barret J, Ahn KW, Chen M, et al. Early CMV reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis. Blood. 2016;127:2427–38.

  28. 28.

    Takenaka K, Nishida T, Asano-Mori Y, Oshima K, Ohashi K, Mori T, et al. Cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation is associated with a reduced risk of relapse in patients with acute myeloid leukemia who survived to day 100 after transplantation: The Japan Society for Hematopoietic Cell Transplantation Transplantation-related Complication Working Group. Biol Blood Marrow Transplant. 2015;2008:e2016.

  29. 29.

    Ito S, Pophali P, CO W, Koklanaris EK, Superata J, Fahle GA, et al. CMV reactivation is associated with a lower incidence of relapse after allo-SCT for CML. Bone Marrow Transplant. 2013;48:1–4.

  30. 30.

    Hermouet S, Sutton CA, Rose TM, Greenblatt RJ, Corre I, Garand R, et al. Qualitative and quantitative analysis of human herpesviruses in chronic and acute B cell lymphocytic leukemia and in multiple myeloma. Leukemia. 2003;17:185–95.

  31. 31.

    Fletcher JM, Prentice HG, Grundy JE. Natural killer cell lysis of cytomegalovirus (CMV)-infected cells correlates with virally induced changes in cell surface lymphocyte function-associated antigen-3 (LFA-3) expression and not with the CMV- induced down-regulation of cell surface class I HLA. J Immunol. 1998;161:2365–74.

  32. 32.

    Della Chiesa M, Falco M, Podesta M, Locatelli F, Moretta L, Frassoni F, et al. Phenotypic and functional heterogeneity of human NK cells developing after umbilical cord blood transplantation: a role for human cytomegalovirus? Blood. 2012;119:399–410.

  33. 33.

    Foley B, Cooley S, Verneris MR, Pitt M, Curtsinger J, Luo X, et al. Cytomegalovirus reactivation after allogeneic transplantation promotes a lasting increase in educated NKG2Cþ natural killer cells with potent function. Blood. 2011;119:2665–74.

  34. 34.

    Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science. 2002;295:2097–2100.

  35. 35.

    Venstrom JM, Pittari G, Gooley TA, Chewning JH, Spellman S, Haagenson M, et al. HLA-C-dependent prevention of leukemia relapse by donor activating KIR2DS1. N Engl J Med. 2012;367:805–16.

  36. 36.

    Hiwarkar P, Gaspar HB, Gilmour K, Jagani M, Chiesa R, Bennett-Rees N, et al. Impact of viral reactivations in the era of pre-emptive antiviral drug therapy following allogeneic haematopoietic SCT in paediatric recipients. Bone Marrow Transplant. 2013;48:803–8.

  37. 37.

    Sousa H, Boutolleau D, Ribeiro J, Teixeira AL, Pinho Vaz C, Campilho F, et al. Cytomegalovirus infection in patients who underwent allogeneic hematopoietic stem cell trans- plantation in Portugal: a five-year retrospective review. Biol Blood Marrow Transplant. 2014;20:1958–67.

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Author information


  1. Department of Hematology, University Hospital Centre, Zagreb, Croatia

    • Zinaida Peric
    • , Nadira Durakovic
    • , Alen Ostojic
    • , Lana Desnica
    • , Ranka Serventi-Seiwerth
    •  & Radovan Vrhovac
  2. School of Medicine, University of Zagreb, Zagreb, Croatia

    • Zinaida Peric
    • , Jonas Wilson
    • , Nadira Durakovic
    • , Ivana Marekovic
    •  & Radovan Vrhovac
  3. Department of Microbiology, University Hospital Centre, Zagreb, Croatia

    • Violeta Rezo Vranjes
    •  & Ivana Marekovic


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The authors declare that they have no conflict of interest.

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Correspondence to Zinaida Peric.

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