Annals of Hematology

, Volume 94, Issue 2, pp 275–282 | Cite as

Early CMV replication and subsequent chronic GVHD have a significant anti-leukemic effect after allogeneic HSCT in acute myeloid leukemia

  • Ji Eun Jang
  • Soo Jeong Kim
  • June-Won Cheong
  • Shin Young Hyun
  • Yun Deok Kim
  • Yu Ri Kim
  • Jin Seok Kim
  • Yoo Hong MinEmail author
Original Article


Early cytomegalovirus (CMV) replication (eCMV) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been suggested as an independent factor that reduces leukemia relapse risk. We retrospectively analyzed 74 patients with acute myeloid leukemia (AML) who underwent allo-HSCT between August 2006 and September 2012. All recipients were CMV seropositive. In 52 patients, eCMV occurred at a median of 35 days (range, 11–92) after allo-HSCT. Univariate analysis revealed that the factors associated with a reduction in the 5-year cumulative incidence of relapse (CIR) included the first complete remission status at allo-HSCT, non-adverse cytogenetics and molecular abnormalities, pre-transplant serum ferritin level <1,400 mg/dL, chronic graft-versus-host disease (cGVHD), and eCMV. In sub-group analysis, according to the existence of eCMV and cGVHD, those with both eCMV and cGVHD showed the lowest 5-year CIR (P < 0.003). Patients with both eCMV and cGVHD had the best outcome for leukemia-free survival (LFS) (P < 0.001) and OS (P < 0.001). In the CMV-seropositive population, the presence of eCMV in combination with cGVHD had a significant positive effect on LFS and OS after allo-HSCT. When eCMV preceded cGVHD, the relapse rate after allo-HSCT was significantly reduced in patients with AML. Therefore, we suggest that it is critical to have an immunological understanding of the graft-versus-leukemia effect in this setting.


Cytomegalovirus Chronic GVHD Hematopoietic stem cell transplantation Relapse 


Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

277_2014_2190_MOESM1_ESM.pdf (157 kb)
ESM 1 (PDF 156 kb)


  1. 1.
    Boeckh M, Nichols WG, Papanicolaou G, Rubin R, Wingard JR, Zaia J (2003) Cytomegalovirus in hematopoietic stem cell transplant recipients: current status, known challenges, and future strategies. Biol Blood Marrow Transplant 9:543–558PubMedCrossRefGoogle Scholar
  2. 2.
    Boeckh M, Nichols WG (2004) The impact of cytomegalovirus serostatus of donor and recipient before hematopoietic stem cell transplantation in the era of antiviral prophylaxis and preemptive therapy. Blood 103:2003–2008PubMedCrossRefGoogle Scholar
  3. 3.
    Boeckh M, Gooley TA, Myerson D, Cunningham T, Schoch G, Bowden RA (1996) Cytomegalovirus pp 65 antigenemia-guided early treatment with ganciclovir versus ganciclovir at engraftment after allogeneic marrow transplantation: a randomized double-blind study. Blood 88:4063–4071PubMedGoogle Scholar
  4. 4.
    Lonnqvist B, Ringden O, Ljungman P, Wahren B, Gahrton G (1986) Reduced risk of recurrent leukaemia in bone marrow transplant recipients after cytomegalovirus infection. Br J Haematol 63:671–679PubMedCrossRefGoogle Scholar
  5. 5.
    Behrendt CE, Rosenthal J, Bolotin E, Nakamura R, Zaia J, Forman SJ (2009) 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 15:54–60PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Elmaagacli AH, Steckel NK, Koldehoff M, Hegerfeldt Y, Trenschel R, Ditschkowski M, Christoph S, Gromke T, Kordelas L, Ottinger HD, Ross RS, Horn PA, Schnittger S, Beelen DW (2011) 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 118:1402–1412PubMedCrossRefGoogle Scholar
  7. 7.
    Green ML, Leisenring WM, Xie H, Walter RB, Mielcarek M, Sandmaier BM, Riddell SR, Boeckh M (2013) CMV reactivation after allogeneic HCT and relapse risk: evidence for early protection in acute myeloid leukemia. Blood 122:1316–1324PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Ito S, Pophali P, Co W, Koklanaris EK, Superata J, Fahle GA, Childs R, Battiwalla M, Barrett AJ (2013) CMV reactivation is associated with a lower incidence of relapse after allo-SCT for CML. Bone Marrow Transplant. doi: 10.1038/bmt.2013.49 Google Scholar
  9. 9.
    Hermouet S, Sutton CA, Rose TM, Greenblatt RJ, Corre I, Garand R, Neves AM, Bataille R, Casey JW (2003) Qualitative and quantitative analysis of human herpesviruses in chronic and acute B cell lymphocytic leukemia and in multiple myeloma. Leukemia 17:185–195PubMedCrossRefGoogle Scholar
  10. 10.
    Weiden PL, Flournoy N, Thomas ED, Prentice R, Fefer A, Buckner CD, Storb R (1979) Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts. N Engl J Med 300:1068–1073PubMedCrossRefGoogle Scholar
  11. 11.
    Horowitz MM, Gale RP, Sondel PM, Goldman JM, Kersey J, Kolb HJ, Rimm AA, Ringden O, Rozman C, Speck B et al (1990) Graft-versus-leukemia reactions after bone marrow transplantation. Blood 75:555–562PubMedGoogle Scholar
  12. 12.
    Ringden O, Ruutu T, Remberger M, Nikoskelainen J, Volin L, Vindelov L, Parkkali T, Lenhoff S, Sallerfors B, Ljungman P et al (1994) A randomized trial comparing busulfan with total body irradiation as conditioning in allogeneic marrow transplant recipients with leukemia: a report from the Nordic Bone Marrow Transplantation Group. Blood 83:2723–2730PubMedGoogle Scholar
  13. 13.
    de Lima M, Couriel D, Thall PF, Wang X, Madden T, Jones R, Shpall EJ, Shahjahan M, Pierre B, Giralt S, Korbling M, Russell JA, Champlin RE, Andersson BS (2004) Once-daily intravenous busulfan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS. Blood 104:857–864PubMedCrossRefGoogle Scholar
  14. 14.
    Chunduri S, Dobogai LC, Peace D, Saunthararajah Y, Quigley J, Chen YH, Mahmud N, Hurter E, Beri R, Rondelli D (2008) Fludarabine/i.v. BU conditioning regimen: myeloablative, reduced intensity or both? Bone Marrow Transplant 41:935–940PubMedCrossRefGoogle Scholar
  15. 15.
    Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, Martin P, Chien J, Przepiorka D, Couriel D, Cowen EW, Dinndorf P, Farrell A, Hartzman R, Henslee-Downey J, Jacobsohn D, McDonald G, Mittleman B, Rizzo JD, Robinson M, Schubert M, Schultz K, Shulman H, Turner M, Vogelsang G, Flowers ME (2005) 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 11:945–956PubMedCrossRefGoogle Scholar
  16. 16.
    Seo S, Cho Y, Park J (2009) Serologic screening of pregnant Korean women for primary human cytomegalovirus infection using IgG avidity test. Korean J Lab Med 29:557–562PubMedCrossRefGoogle Scholar
  17. 17.
    Dazzi F, Goldman JM (1998) Adoptive immunotherapy following allogeneic bone marrow transplantation. Annu Rev Med 49:329–340PubMedCrossRefGoogle Scholar
  18. 18.
    Bukowski JF, Warner JF, Dennert G, Welsh RM (1985) Adoptive transfer studies demonstrating the antiviral effect of natural killer cells in vivo. J Exp Med 161:40–52PubMedCrossRefGoogle Scholar
  19. 19.
    Lopez-VergÃs S, Milush JM, Schwartz BS, Pando MJ, Jarjoura J, York VA, Houchins JP, Miller S, Kang S, Norris PJ, Nixon DF, Lanier L (2011) Expansion of a unique CD57+NKG2Chi natural killer cell subset during acute human cytomegalovirus infection. Proc Natl Acad Sci U S A 108:14725–14732CrossRefGoogle Scholar
  20. 20.
    Della Chiesa M, Falco M, Podesta M, Locatelli F, Moretta L, Frassoni F, Moretta A (2012) Phenotypic and functional heterogeneity of human NK cells developing after umbilical cord blood transplantation: a role for human cytomegalovirus? Blood 119:399–410PubMedCrossRefGoogle Scholar
  21. 21.
    Foley B, Cooley S, Verneris MR, Pitt M, Curtsinger J, Luo X, Lopez-Verges S, Lanier LL, Weisdorf D, Miller JS (2012) Cytomegalovirus reactivation after allogeneic transplantation promotes a lasting increase in educated NKG2C+ natural killer cells with potent function. Blood 119:2665–2674PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Muntasell A, Vilches C, Angulo A, Lopez-Botet M (2013) Adaptive reconfiguration of the human NK-cell compartment in response to cytomegalovirus: a different perspective of the host-pathogen interaction. Eur J Immunol 43:1133–1141PubMedCrossRefGoogle Scholar
  23. 23.
    Ringden O, Pavletic SZ, Anasetti C, Barrett AJ, Wang T, Wang D, Antin JH, Di Bartolomeo P, Bolwell BJ, Bredeson C, Cairo MS, Gale RP, Gupta V, Hahn T, Hale GA, Halter J, Jagasia M, Litzow MR, Locatelli F, Marks DI, McCarthy PL, Cowan MJ, Petersdorf EW, Russell JA, Schiller GJ, Schouten H, Spellman S, Verdonck LF, Wingard JR, Horowitz MM, Arora M (2009) The graft-versus-leukemia effect using matched unrelated donors is not superior to HLA-identical siblings for hematopoietic stem cell transplantation. Blood 113:3110–3118PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Storb R, Gyurkocza B, Storer BE, Sorror ML, Blume K, Niederwieser D, Chauncey TR, Pulsipher MA, Petersen FB, Sahebi F, Agura ED, Hari P, Bruno B, McSweeney PA, Maris MB, Maziarz RT, Langston AA, Bethge W, Vindelov L, Franke GN, Laport GG, Yeager AM, Hubel K, Deeg HJ, Georges GE, Flowers ME, Martin PJ, Mielcarek M, Woolfrey AE, Maloney DG, Sandmaier BM (2013) Graft-versus-host disease and graft-versus-tumor effects after allogeneic hematopoietic cell transplantation. J Clin Oncol 31:1530–1538PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Boeckh M, Leisenring W, Riddell SR, Bowden RA, Huang ML, Myerson D, Stevens-Ayers T, Flowers ME, Cunningham T, Corey L (2003) Late cytomegalovirus disease and mortality in recipients of allogeneic hematopoietic stem cell transplants: importance of viral load and T-cell immunity. Blood 101:407–414PubMedCrossRefGoogle Scholar
  26. 26.
    Pajand O, Ziyaeyan M, Mousavi S, Fatolahzadeh B, Hojabri Z, Bahador A, Abdossamadi Z (2008) Comparison of antigenemia assay and semiquantitative polymerase chain reaction test for monitoring active cytomegalovirus infection in allogeneic hematopoietic cell transplant recipients. Exp Clin Transplant 6:149–154PubMedGoogle Scholar
  27. 27.
    Jang JE, Hyun SY, Kim YD, Yoon SH, Hwang DY, Kim SJ, Kim Y, Kim JS, Cheong JW, Min YH (2012) Risk factors for progression from cytomegalovirus viremia to cytomegalovirus disease after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 18:881–886PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Ji Eun Jang
    • 1
  • Soo Jeong Kim
    • 1
  • June-Won Cheong
    • 1
  • Shin Young Hyun
    • 2
  • Yun Deok Kim
    • 1
  • Yu Ri Kim
    • 1
  • Jin Seok Kim
    • 1
  • Yoo Hong Min
    • 1
    Email author
  1. 1.Division of Hematology, Department of Internal MedicineYonsei University College of MedicineSeoulSouth Korea
  2. 2.Division of Hematology–Oncology, Wonju College of MedicineYonsei UniversityWonjuSouth Korea

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