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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 Transplantation volume 53, pages 1450–1456 (2018)Cite this article

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Abstract

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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References

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

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

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

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Authors and Affiliations

  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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  1. Zinaida Peric
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Peric, Z., Wilson, J., Durakovic, N. et al. Early human cytomegalovirus reactivation is associated with lower incidence of relapse of myeloproliferative disorders after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 53, 1450–1456 (2018). https://doi.org/10.1038/s41409-018-0172-y

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