The prognostic impact of the cytomegalovirus serostatus in patients with chronic hematological malignancies after allogeneic hematopoietic stem cell transplantation: a report from the Infectious Diseases Working Party of EBMT

  • Martin Schmidt-HieberEmail author
  • Gloria Tridello
  • Per Ljungman
  • Malgorzata Mikulska
  • Nina Knelange
  • Didier Blaise
  • Gerard Socié
  • Liisa Volin
  • Nicole Blijlevens
  • Nathalie Fegueux
  • Ibrahim Yakoub-Agha
  • Edouard Forcade
  • Johan Maertens
  • Patrice Chevallier
  • Jakob Passweg
  • Jan Cornelissen
  • Nigel Russell
  • Charles Craddock
  • Jean Henri Bourhis
  • Tony Marchand
  • Péter Reményi
  • Jean Yves Cahn
  • Mauricette Michallet
  • Silvia Montoto
  • Nicolaus Kröger
  • Bertram Glaß
  • Jan Styczynski
Original Article


It has been shown recently that donor and/or recipient cytomegalovirus (CMV) seropositivity is associated with a significant overall survival (OS) decline in acute leukemia patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). We now analyzed the prognostic impact of the donor/recipient CMV serostatus in 6968 patients with chronic hematological malignancies who underwent allo-HSCT. Donor and/or recipient CMV seropositivity was associated with a significantly reduced 2-year progression-free survival (PFS, 50% vs. 52%, p = 0.03) and OS (62% vs. 65%, p = 0.01). Multivariate Cox regression analyses showed an independent negative prognostic impact of donor and/or recipient CMV seropositivity on PFS (HR, 1.1; 95% CI, 1.0–1.2; p = 0.03), OS (HR, 1.1; 95% CI, 1.0–1.2; p = 0.003), and non-relapse mortality (HR, 1.2; 95% CI, 1.0–1.3; p = 0.02). OS decline was strongest for CMV-seropositive recipients with a CMV-seronegative donor (HR, 1.2; 95% CI, 1.1–1.3), followed by CMV-seropositive patients with a CMV-seropositive donor (HR, 1.1; 95% CI, 1.0–1.2). Conversely, OS did not differ significantly between CMV-seronegative recipients allografted from a CMV-seropositive donor (HR, 1.0; 95% CI, 0.9–1.2) and patients with donor/recipient CMV seronegativity (p = 0.001 for the four groups together). Non-relapse mortality was also significantly (p = 0.01) higher for CMV-seropositive patients with a CMV-seronegative graft (HR, 1.2; 95% CI, 1.1–1.4) than for CMV-seropositive patients with a CMV-seropositive graft (HR, 1.1; 95% CI, 0.9–1.2) or CMV-seronegative recipients with a CMV-seropositive graft (HR, 1.0; 95% CI, 0.8–1.2). Donor and/or recipient CMV seropositivity still results in an OS decline in patients with chronic hematological malignancies who have undergone allo-HSCT. However, this OS decline seems to be lower than that described for acute leukemia patients previously.


Allogeneic hematopoietic stem cell transplantation Chronic hematological malignancies Cytomegalovirus Serostatus Survival 



M.S.H., G.T., P.L., M.Mik., and J.S. designed the research. M.S.H., G.T., P.L., M.Mik., N.K., D.B., G.S., L.V., N.B., N.F., I.Y.A., E.F., J.M, P.C., J.P., J.C., N.R., C.C., J.H.B., T.M., P.R., J.Y.C., M.Mic., S.M., N.K., B.G., and J.S. provided important clinical data and/or performed statistical analyses. M.S.H. wrote the first draft of the manuscript. All authors approved the final version of the manuscript. A complete list of contributors appears in the online data supplement.

The authors thank all allogeneic transplantation centers of the European Bone Marrow Transplantation group for reporting the data to this registry.

Compliance with ethical standards

Conflict of interest

I.Y.A received honorarium from Biotest and MSD Sharp & Dohme GmbH that commercialize anti-CMV drugs. The other authors declare that they have no conflicts of interest.

Ethical approval

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

According to EBMT policy, patients give informed consent for data reporting to the EBMT registry.

Supplementary material

277_2019_3669_MOESM1_ESM.docx (45 kb)
ESM 1 (DOCX 44.8kb)


  1. 1.
    Schmidt-Hieber M, Labopin M, Beelen D, Volin L, Ehninger G, Finke J, Socié G, Schwerdtfeger R, Kröger N, Ganser A, Niederwieser D, Polge E, Blau IW, Mohty M (2013) 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 122(19):3359–3364. CrossRefGoogle Scholar
  2. 2.
    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(6):881–886. CrossRefGoogle Scholar
  3. 3.
    Marty FM, Winston DJ, Rowley SD, Vance E, Papanicolaou GA, Mullane KM, Brundage TM, Robertson AT, Godkin S, Momméja-Marin H, Boeckh M (2013) CMX001 to prevent cytomegalovirus disease in hematopoietic-cell transplantation. N Engl J Med 369(13):1227–1236. CrossRefGoogle Scholar
  4. 4.
    Chemaly RF, Ullmann AJ, Stoelben S, Richard MP, Bornhäuser M, Groth C, Einsele H, Silverman M, Mullane KM, Brown J, Nowak H, Kölling K, Stobernack HP, Lischka P, Zimmermann H, Rübsamen-Schaeff H, Champlin RE, Ehninger G (2014) Letermovir for cytomegalovirus prophylaxis in hematopoietic-cell transplantation. N Engl J Med 370(19):1781–1789. CrossRefGoogle Scholar
  5. 5.
    Green ML, Leisenring W, Xie H, Mast TC, Cui Y, Sandmaier BM, Sorror ML, Goyal S, Özkök S, Yi J, Sahoo F, Kimball LE, Jerome KR, Marks MA, Boeckh M (2016) Cytomegalovirus viral load and mortality after haemopoietic stem cell transplantation in the era of pre-emptive therapy: a retrospective cohort study. Lancet Haematol 3(3):27–e127. Google Scholar
  6. 6.
    Marty FM, Ljungman P, Chemaly RF, Maertens J, Dadwal SS, Duarte RF, Haider S, Ullmann AJ, Katayama Y, Brown J, Mullane KM, Boeckh M, Blumberg EA, Einsele H, Snydman DR, Kanda Y, DiNubile MJ, Teal VL, Wan H, Murata Y, Kartsonis NA, Leavitt RY, Badshah C (2017) Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation. N Engl J Med 377(25):2433–2444. CrossRefGoogle Scholar
  7. 7.
    Broers AE, van der Holt R, van Esser JW, Gratama JW, Henzen-Logmans S, Kuenen-Boumeester V, Löwenberg B, Cornelissen JJ (2000) 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 95(7):2240–2245Google Scholar
  8. 8.
    Kröger N, Zabelina T, Krüger W, Renges H, Stute N, Schrum J, Kabisch H, Schafhausen P, Jaburg N, Löliger C, Schäfer P, Hinke A, Zander AR (2001) 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 113(4):1060–1071CrossRefGoogle Scholar
  9. 9.
    Nichols WG, Corey L, Gooley T, Davis C, Boeckh M (2002) High risk of death due to bacterial and fungal infection among cytomegalovirus (CMV)-seronegative recipients of stem cell transplants from seropositive donors: evidence for indirect effects of primary CMV infection. J Infect Dis 185(3):273–282. CrossRefGoogle Scholar
  10. 10.
    Yong MK, Ananda-Rajah M, Cameron PU, Morrissey CO, Spencer A, Ritchie D, Cheng AC, Lewin SR, Slavin M (2017) Cytomegalovirus reactivation is associated with increased risk of late-onset invasive fungal disease after allogeneic hematopoietic stem cell transplantation: a multicenter study in the current era of viral load monitoring. Biol Blood Marrow Transplant 23(11):1961–1967. CrossRefGoogle Scholar
  11. 11.
    Lönnqvist B, Ringdèn 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(4):671–679CrossRefGoogle Scholar
  12. 12.
    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(5):1402–1412. CrossRefGoogle Scholar
  13. 13.
    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(7):1316–1324. CrossRefGoogle Scholar
  14. 14.
    George B, Pati N, Gilroy N, Ratnamohan M, Huang G, Kerridge I, Hertzberg M, Gottlieb D, Bradstock K (2010) Pre-transplant cytomegalovirus (CMV) serostatus remains the most important determinant of CMV reactivation after allogeneic hematopoietic stem cell transplantation in the era of surveillance and preemptive therapy. Transpl Infect Dis 12(4):322–329. CrossRefGoogle Scholar
  15. 15.
    Ljungman P (2013) CMV: a warrior against leukemia? Blood 122(7):1101–1102. CrossRefGoogle Scholar
  16. 16.
    Teira P, Battiwalla M, Ramanathan M, Barrett AJ, Ahn KW, Chen M, Green JS, Saad A, Antin JH, Savani BN, Lazarus HM, Seftel M, Saber W, Marks D, Aljurf M, Norkin M, Wingard JR, Lindemans CA, Boeckh M, Riches ML, Auletta JJ (2016) Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis. Blood 127(20):2427–2438. CrossRefGoogle Scholar
  17. 17.
    Koldehoff M, Ross SR, Dührsen U, Beelen DW, Elmaagacli AH (2017) Early CMV-replication after allogeneic stem cell transplantation is associated with a reduced relapse risk in lymphoma. Leuk Lymphoma 58(4):822–833. CrossRefGoogle Scholar
  18. 18.
    Albano MS, Taylor P, Pass RF, Scaradavou A, Ciubotariu R, Carrier C, Dobrila L, Rubinstein P, Stevens CE (2006) Umbilical cord blood transplantation and cytomegalovirus: posttransplantation infection and donor screening. Blood 108(13):4275–4282. CrossRefGoogle Scholar
  19. 19.
    Mikulska M, Raiola AM, Bruzzi P, Varaldo R, Annunziata S, Lamparelli T, Frassoni F, Tedone E, Galano B, Bacigalupo A, Viscoli C (2012) CMV infection after transplant from cord blood compared to other alternative donors: the importance of donor-negative CMV serostatus. Biol Blood Marrow Transplant 18(1):92–99. CrossRefGoogle Scholar
  20. 20.
    Auner HW, Szydlo R, van Biezen A, Iacobelli S, Gahrton G, Milpied N, Volin L, Janssen J, Nguyen Quoc S, Michallet M, Schoemans H, El Cheikh J, Petersen E, Guilhot F, Schönland S, Ahlberg L, Morris C, Garderet L, de Witte T, Kröger N (2013) Reduced intensity-conditioned allogeneic stem cell transplantation for multiple myeloma relapsing or progressing after autologous transplantation: a study by the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 48(11):1395–1400. CrossRefGoogle Scholar
  21. 21.
    Stern M, de Wreede LC, Brand R, van Biezen A, Dreger P, Mohty M, de Witte TM, Kröger N, Ruutu T (2014) Sensitivity of hematological malignancies to graft-versus-host effects: an EBMT megafile analysis. Leukemia 28(11):2235–2240. CrossRefGoogle Scholar
  22. 22.
    Robinson SP, Boumendil A, Finel H, Schouten H, Ehninger G, Maertens J, Crawley C, Rambaldi A, Russell N, Anders W, Blaise D, Yakoub-Agha I, Ganser A, Castagna L, Volin L, Cahn JY, Montoto S, Dreger P (2016) Reduced intensity allogeneic stem cell transplantation for follicular lymphoma relapsing after an autologous transplant achieves durable long term disease control: an analysis from the Lymphoma Working Party of the EBMT. Ann Oncol 27:1088–1094. CrossRefGoogle Scholar
  23. 23.
    Martino R, Henseler A, van Lint M, Schaap N, Finke J, Beelen D, Vigouroux S, Alessandrino EP, Mufti GJ, Veelken JH, Bruno B, Yakoub-Agha I, Volin L, Maertens J, Or R, Leblond V, Rovira M, Kalhs P, Alvarez AF, Vitek A, Sierra J, Wagner E, Robin M, de Witte T, Kröger N (2017) Long-term follow-up of a retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic transplantation from matched related donors in myelodysplastic syndromes. Bone Marrow Transplant 52(8):1107–1112. CrossRefGoogle Scholar
  24. 24.
    Sullivan KM (1999) Graft-versus-host-disease. In: Thomas E, Blume K, Forman SJ (eds) Hematopoietic Cell Transplantation, 2nd edn. Blackwell Science, Boston, MA, pp 515–526Google Scholar
  25. 25.
    Ljungman P (2014) The role of cytomegalovirus serostatus on outcome of hematopoietic stem cell transplantation. Curr Opin Hematol 21(6):466–469. CrossRefGoogle Scholar
  26. 26.
    Ljungman P, Brand R, Hoek J, de La CR, Cordonnier C, Einsele H, Styczynski J, Ward KN, Cesaro S (2014) Donor cytomegalovirus status influences the outcome of allogeneic stem cell transplant: a study by the European group for blood and marrow transplantation. Clin Infect Dis 59(4):473–481. CrossRefGoogle Scholar
  27. 27.
    Ljungman P, Brandan R (2007) Factors influencing cytomegalovirus seropositivity in stem cell transplant patients and donors. Haematologica 92(8):1139–1142CrossRefGoogle Scholar
  28. 28.
    Bacigalupo A, Socié G, Hamladji RM, Aljurf M, Maschan A, Kyrcz-Krzemien S, Cybicka A, Sengelov H, Unal A, Beelen D, Locasciulli A, Dufour C, Passweg JR, Oneto R, Signori A, Marsh JCW (2015) Current outcome of HLA identical sibling versus unrelated donor transplants in severe aplastic anemia: an EBMT analysis. Haematologica 100(5):696–702. CrossRefGoogle Scholar
  29. 29.
    Nishihori T, Shaheen M, El-Asmar J, Aljurf M, Kharfan-Dabaja MA (2015) Therapeutic strategies for cytomegalovirus in allogeneic hematopoietic cell transplantation. Immunotherapy 7(10):1059–1071. CrossRefGoogle Scholar
  30. 30.
    Maffini E, Giaccone L, Festuccia M, Brunello L, Busca A, Bruno B (2016) Treatment of CMV infection after allogeneic hematopoietic stem cell transplantation. Expert Rev Hematol 9(6):585–596. CrossRefGoogle Scholar
  31. 31.
    Gor D, Sabin C, Prentice HG, Vyas N, Man S, Griffiths PD, Emery VC (1998) Longitudinal fluctuations in cytomegalovirus load in bone marrow transplant patients: relationship between peak virus load, donor/recipient serostatus, acute GVHD and CMV disease. Bone Marrow Transplant 21(6):597–605. CrossRefGoogle Scholar
  32. 32.
    Ganepola S, Gentilini C, Hilbers U, Lange T, Rieger K, Hofmann J, Maier M, Liebert UG, Niederwieser D, Engelmann E, Heilbronn R, Thiel E, Uharek L (2007) Patients at high risk for CMV infection and disease show delayed CD8+ T-cell immune recovery after allogeneic stem cell transplantation. Bone Marrow Transplant 39:293–299Google Scholar
  33. 33.
    van der Heiden PLJ, van Egmond HM, Veld SAJ, van de Meent M, Eefting M, de Wreede LC, Halkes CJM, Falkenburg JHF, Marijt WAF, Jedema I (2018) CMV seronegative donors: effect on clinical severity of CMV infection and reconstitution of CMV-specific immunity. Transpl Immunol 49:54–58. CrossRefGoogle Scholar
  34. 34.
    Verduyn Lunel FM, Raymakers R, van Dijk A, van der Wagen L, Minnema MC, Kuball J (2016) Cytomegalovirus status and the outcome of T cell-replete reduced-intensity allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 22(10):1883–1887. CrossRefGoogle Scholar
  35. 35.
    Ringdén O, Paulin T, Lönnqvist B, Nilsson B (1985) An analysis of factors predisposing to chronic graft-versus-host disease. Exp Hematol 13(10):1062–1067Google Scholar
  36. 36.
    Miller W, Flynn P, McCullough J, Balfour HH, Goldman A, Haake R, McGlave P, Ramsay N, Kersey J (1986) Cytomegalovirus infection after bone marrow transplantation: an association with acute graft-v-host disease. Blood 67(4):1162–1167Google Scholar
  37. 37.
    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(6):2003–2008. CrossRefGoogle Scholar
  38. 38.
    Yakoub-Agha I, Mesnil F, Kuentz M, Boiron JM, Ifrah N, Milpied N, Chehata S, Esperou H, Vernant JP, Michallet M, Buzyn A, Gratecos N, Cahn JY, Bourhis JH, Chir Z, Raffoux C, Socié G, Golmard JL, Jouet JP (2006) Allogeneic marrow stem-cell transplantation from human leukocyte antigen-identical siblings versus human leukocyte antigen-allelic-matched unrelated donors (10/10) in patients with standard-risk hematologic malignancy: a prospective study from the French Society of Bone Marrow Transplantation and Cell Therapy. J Clin Oncol 24(36):5695–5702. CrossRefGoogle Scholar
  39. 39.
    Hahn T, McCarthy PL, Zhang M-J, Wang D, Arora M, Frangoul H, Gale RP, Hale GA, Horan J, Isola L, Maziarz RT, van Rood JJ, Gupta V, Halter J, Reddy V, Tiberghien P, Litzow M, Anasetti C, Pavletic S, Ringdén O (2008) Risk factors for acute graft-versus-host disease after human leukocyte antigen-identical sibling transplants for adults with leukemia. J Clin Oncol 26(35):5728–5734. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Martin Schmidt-Hieber
    • 1
    Email author
  • Gloria Tridello
    • 2
  • Per Ljungman
    • 3
  • Malgorzata Mikulska
    • 4
  • Nina Knelange
    • 5
  • Didier Blaise
    • 6
  • Gerard Socié
    • 7
  • Liisa Volin
    • 8
  • Nicole Blijlevens
    • 9
  • Nathalie Fegueux
    • 10
  • Ibrahim Yakoub-Agha
    • 11
  • Edouard Forcade
    • 12
  • Johan Maertens
    • 13
  • Patrice Chevallier
    • 14
  • Jakob Passweg
    • 15
  • Jan Cornelissen
    • 16
  • Nigel Russell
    • 17
  • Charles Craddock
    • 18
  • Jean Henri Bourhis
    • 19
  • Tony Marchand
    • 20
  • Péter Reményi
    • 21
  • Jean Yves Cahn
    • 22
  • Mauricette Michallet
    • 23
  • Silvia Montoto
    • 24
  • Nicolaus Kröger
    • 25
  • Bertram Glaß
    • 26
  • Jan Styczynski
    • 27
  1. 1.Clinic for Hematology and OncologyCarl-Thiem-KlinikumCottbusGermany
  2. 2.Policlinico G.B. RossiVeronaItaly
  3. 3.Karolinska University HospitalStockholmSweden
  4. 4.DISSAL, Division of Infectious DiseasesUniversity of Genova and IRCCS Ospedale Policlinico San MartinoGenoaItaly
  5. 5.EBMT Data OfficeLeidenNetherlands
  6. 6.Institute Paoli CalmettesMarseilleFrance
  7. 7.Hopital St. LouisParisFrance
  8. 8.HUCH Comprehensive Cancer CenterHelsinkiFinland
  9. 9.Nijmegen Medical CentreRadboud UniversityNijmegenNetherlands
  10. 10.CHU LapeyronieMontpellierFrance
  11. 11.CHU de Lille, LIRIC, INSERM U995Université de LilleLilleFrance
  12. 12.CHU BordeauxService d’Hematologie et Therapie CellulaireBordeauxFrance
  13. 13.University Hospital GasthuisbergLeuvenBelgium
  14. 14.CHU NantesNantesFrance
  15. 15.University HospitalBaselSwitzerland
  16. 16.Erasmus MC Cancer InstituteRotterdamNetherlands
  17. 17.Nottingham UniversityNottinghamUK
  18. 18.Queen Elizabeth HospitalBirminghamUK
  19. 19.Gustave Roussy Institute de CancérologieVillejuifFrance
  20. 20.Centre Hospitalier Universitaire de RennesRennesFrance
  21. 21.St. Istvan & St. Laszlo HospitalBudapestHungary
  22. 22.CHU Grenoble Alpes GrenobleGrenobleFrance
  23. 23.Centre Hospitalier Lyon SudLyonFrance
  24. 24.Barts Health NHS Trust LondonSt Bartholomew’s HospitalLondonUK
  25. 25.University Hospital EppendorfHamburgGermany
  26. 26.Clinic for Hematology and Stem Cell TransplantationHELIOS Clinic Berlin-BuchBerlinGermany
  27. 27.Collegium Medicum UMKUniversity HospitalBydgoszczPoland

Personalised recommendations