Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Impaired thymopoiesis predicts for a high risk of severe infections after reduced intensity conditioning without anti-thymocyte globulin in double umbilical cord blood transplantation

Bone Marrow Transplantation volume 53, pages 673–682 (2018)Cite this article

Subjects

Abstract

Umbilical cord blood stem cell transplantation (UCBT) is associated with retarded hematopoietic recovery and immune reconstitution and a high infection-related morbidity and mortality, especially after conditioning including anti-thymocyte globulin (ATG). However, data on immune recovery, incidence of infections, and outcome in double UCBT (dUCBT) recipients receiving an ATG-free reduced intensity conditioning (RIC) are lacking. In this study, recovery of lymphocyte subsets, thymopoiesis, and its association with severe infections and clinical outcome was assessed in a group of 55 recipients of a dUCBT ATG-free RIC regimen. T cell recovery was severely protracted in the majority of patients. However, T cell receptor excision circle TREC+ T cells were detectable in 62% of patients at 3 months post-transplantation. A total of 128 common toxicity criteria grade 3−4 infections were observed in the first year post-transplantation. Non-relapse mortality at 12 months post-transplant was 16%, of which 78% infectious mortality. One-year overall survival was 73%. Patients who failed to recover thymopoiesis at 3 months post-transplantation were at a 3.3-fold higher risk of subsequent severe grade 3–4 infections.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Ballen KK, Gluckman E, Broxmeyer HE. Umbilical cord blood transplantation: the first 25 years and beyond. Blood. 2013;122:491–8.

    Article  CAS  Google Scholar 

  2. Rocha V, Labopin M, Sanz G, Arcese W, Schwerdtfeger R, Bosi A, et al. Transplants of umbilical-cord blood or bone marrow from unrelated donors in adults with acute leukemia. N Engl J Med. 2004;351:2276–85.

    Article  CAS  Google Scholar 

  3. Laughlin MJ, Eapen M, Rubinstein P, Wagner JE, Zhang MJ, Champlin RE, et al. Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia. N Engl J Med. 2004;351:2265–75.

    Article  CAS  Google Scholar 

  4. Szabolcs P, Niedzwiecki D. Immune reconstitution after unrelated cord blood transplantation. Cytotherapy. 2007;9:111–22.

    Article  CAS  Google Scholar 

  5. Barker JN, Scaradavou A, Stevens CE. Combined effect of total nucleated cell dose and HLA match on transplantation outcome in 1061 cord blood recipients with hematologic malignancies. Blood. 2010;115:1843–9.

    Article  CAS  Google Scholar 

  6. Barker JN, Krepski TP, DeFor TE, Davies SM, Wagner JE, Weisdorf DJ. Searching for unrelated donor hematopoietic stem cells: availability and speed of umbilical cord blood versus bone marrow. Biol Blood Marrow Transplant. 2002;8:257–60.

    Article  Google Scholar 

  7. Gluckman E, Rocha V, Boyer-Chammard A, Locatelli F, Arcese W, Pasquini R, et al. Outcome of cord-blood transplantation from related and unrelated donors. Eurocord Transplant Group and the European Blood and Marrow Transplantation Group. N Engl J Med. 1997;337:373–81.

    Article  CAS  Google Scholar 

  8. Barker JN, Weisdorf DJ, DeFor TE, Blazar BR, McGlave PB, Miller JS, et al. Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy. Blood. 2005;105:1343–7.

    Article  CAS  Google Scholar 

  9. Barker JN, Weisdorf DJ, DeFor TE, Blazar BR, Miller JS, Wagner JE. Rapid and complete donor chimerism in adult recipients of unrelated donor umbilical cord blood transplantation after reduced-intensity conditioning. Blood. 2003;102:1915–9.

    Article  CAS  Google Scholar 

  10. Barker JN, Weisdorf DJ, Wagner JE. Creation of a double chimera after the transplantation of umbilical-cord blood from two partially matched unrelated donors. N Engl J Med. 2001;344:1870–1.

    Article  CAS  Google Scholar 

  11. Somers JA, Braakman E, van der Holt B, Petersen EJ, Marijt EW, Huisman C, et al. Rapid induction of single donor chimerism after double umbilical cord blood transplantation preceded by reduced intensity conditioning: results of the HOVON 106 phase II study. Haematologica. 2014;99:1753–61.

    Article  CAS  Google Scholar 

  12. Storek J, Geddes M, Khan F, Huard B, Helg C, Chalandon Y, et al. Reconstitution of the immune system after hematopoietic stem cell transplantation in humans. Semin Immunopathol. 2008;30:425–37.

    Article  Google Scholar 

  13. Rufer N, Helg C, Chapuis B, Roosnek E. Human memory T cells: lessons from stem cell transplantation. Trends Immunol. 2001;22:136–41.

    Article  CAS  Google Scholar 

  14. Mackall CL, Granger L, Sheard MA, Cepeda R, Gress RE. T-cell regeneration after bone marrow transplantation: differential CD45 isoform expression on thymic-derived versus thymic-independent progeny. Blood. 1993;82:2585–94.

    CAS  PubMed  Google Scholar 

  15. Clave E, Lisini D, Douay C, Giorgiani G, Busson M, Zecca M, et al. Thymic function recovery after unrelated donor cord blood or T-cell depleted HLA-haploidentical stem cell transplantation correlates with leukemia relapse. Front Immunol. 2013;4:54.

    Article  Google Scholar 

  16. Wils EJ, van der Holt B, Broers AE, Posthumus-van Sluijs SJ, Gratama JW, Braakman E, et al. Insufficient recovery of thymopoiesis predicts for opportunistic infections in allogeneic hematopoietic stem cell transplant recipients. Haematologica. 2011;96:1846–54.

    Article  Google Scholar 

  17. Parody R, Martino R, Rovira M, Vazquez L, Vazquez MJ, de la Camara R, et al. Severe infections after unrelated donor allogeneic hematopoietic stem cell transplantation in adults: comparison of cord blood transplantation with peripheral blood and bone marrow transplantation. Biol Blood Marrow Transplant. 2006;12:734–48.

    Article  Google Scholar 

  18. Safdar A, Rodriguez GH, De Lima MJ, Petropoulos D, Chemaly RF, Worth LL, et al. Infections in 100 cord blood transplantations: spectrum of early and late posttransplant infections in adult and pediatric patients 1996-2005. Medicine (Baltimore). 2007;86:324–33.

    Article  Google Scholar 

  19. Komanduri KV, St John LS, de Lima M, McMannis J, Rosinski S, McNiece I, et al. Delayed immune reconstitution after cord blood transplantation is characterized by impaired thymopoiesis and late memory T-cell skewing. Blood. 2007;110:4543–51.

    Article  CAS  Google Scholar 

  20. Ruggeri A, Peffault de Latour R, Carmagnat M, Clave E, Douay C, Larghero J, et al. Outcomes, infections, and immune reconstitution after double cord blood transplantation in patients with high-risk hematological diseases. Transpl Infect Dis. 2011;13:456–65.

    Article  CAS  Google Scholar 

  21. Somers JA, Brand A, van Hensbergen Y, Mulder A, Oudshoorn M, Sintnicolaas K, et al. Double umbilical cord blood transplantation: a study of early engraftment kinetics in leukocyte subsets using HLA-specific monoclonal antibodies. Biol Blood Marrow Transplant. 2013;19:266–73.

    Article  CAS  Google Scholar 

  22. Broers AE, van der Holt B, Haze S, Braakman E, Gratama JW, Lowenberg B, et al. A comparison of postengraftment infectious morbidity and mortality after allogeneic partially T cell-depleted peripheral blood progenitor cell transplantation versus T cell-depleted bone marrow transplantation. Exp Hematol. 2005;33:912–9.

    Article  Google Scholar 

  23. Beije N, Versluis J, Kraan J, Gratama JW, Sleijfer S, Cornelissen JJ. Circulating endothelial cell enumeration demonstrates prolonged endothelial damage in recipients of myeloablative allogeneic stem cell transplantation. Haematologica. 2015;100:e246–9.

    Article  Google Scholar 

  24. Danby R, Rocha V. Improving engraftment and immune reconstitution in umbilical cord blood transplantation. Front Immunol. 2014;5:68.

    Article  Google Scholar 

  25. Niehues T, Rocha V, Filipovich AH, Chan KW, Porcher R, Michel G, et al. Factors affecting lymphocyte subset reconstitution after either related or unrelated cord blood transplantation in children—a Eurocord analysis. Br J Haematol. 2001;114:42–8.

    Article  CAS  Google Scholar 

  26. Tanaka J, Sugita J, Asanuma S, Arita K, Shono Y, Kikutchi M, et al. Increased number of CD16(+)CD56(dim) NK cells in peripheral blood mononuclear cells after allogeneic cord blood transplantation. Hum Immunol. 2009;70:701–5.

    Article  CAS  Google Scholar 

  27. Talvensaari K, Clave E, Douay C, Rabian C, Garderet L, Busson M, et al. A broad T-cell repertoire diversity and an efficient thymic function indicate a favorable long-term immune reconstitution after cord blood stem cell transplantation. Blood. 2002;99:1458–64.

    Article  CAS  Google Scholar 

  28. Kanda J, Chiou LW, Szabolcs P, Sempowski GD, Rizzieri DA, Long GD, et al. Immune recovery in adult patients after myeloablative dual umbilical cord blood, matched sibling, and matched unrelated donor hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2012;18:1664–76. e1

    Article  CAS  Google Scholar 

  29. Brown JA, Stevenson K, Kim HT, Cutler C, Ballen K, McDonough S, et al. Clearance of CMV viremia and survival after double umbilical cord blood transplantation in adults depends on reconstitution of thymopoiesis. Blood. 2010;115:4111–9.

    Article  CAS  Google Scholar 

  30. Ballen K, Mendizabal AM, Cutler C, Politikos I, Jamieson K, Shpall EJ, et al. Phase II trial of parathyroid hormone after double umbilical cord blood transplantation. Biol Blood Marrow Transplant. 2012;18:1851–8.

    Article  CAS  Google Scholar 

  31. Simpson D. T-cell depleting antibodies: new hope for induction of allograft tolerance in bone marrow transplantation? BioDrugs. 2003;17:147–54.

    Article  CAS  Google Scholar 

  32. Chung B, Barbara-Burnham L, Barsky L, Weinberg K. Radiosensitivity of thymic interleukin-7 production and thymopoiesis after bone marrow transplantation. Blood. 2001;98:1601–6.

    Article  CAS  Google Scholar 

  33. Mackall CL, Fleisher TA, Brown MR, Andrich MP, Chen CC, Feuerstein IM, et al. Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy. N Engl J Med. 1995;332:143–9.

    Article  CAS  Google Scholar 

  34. Jimenez M, Martinez C, Ercilla G, Carreras E, Urbano-Ispizua A, Aymerich M, et al. Reduced-intensity conditioning regimen preserves thymic function in the early period after hematopoietic stem cell transplantation. Exp Hematol. 2005;33:1240–8.

    Article  CAS  Google Scholar 

  35. Chao NJ, Liu CX, Rooney B, Chen BJ, Long GD, Vredenburgh JJ, et al. Nonmyeloablative regimen preserves “niches” allowing for peripheral expansion of donor T-cells. Biol Blood Marrow Transplant. 2002;8:249–56.

    Article  Google Scholar 

  36. Uhlin M, Sairafi D, Berglund S, Thunberg S, Gertow J, Ringden O, et al. Mesenchymal stem cells inhibit thymic reconstitution after allogeneic cord blood transplantation. Stem Cells Dev. 2012;21:1409–17.

    Article  CAS  Google Scholar 

  37. Chiesa R, Gilmour K, Qasim W, Adams S, Worth AJ, Zhan H, et al. Omission of in vivo T-cell depletion promotes rapid expansion of naive CD4+ cord blood lymphocytes and restores adaptive immunity within 2 months after unrelated cord blood transplant. Br J Haematol. 2012;156:656–66.

    Article  CAS  Google Scholar 

  38. Sauter C, Abboud M, Jia X, Heller G, Gonzales AM, Lubin M, et al. Serious infection risk and immune recovery after double-unit cord blood transplantation without antithymocyte globulin. Biol Blood Marrow Transplant. 2011;17:1460–71.

    Article  CAS  Google Scholar 

  39. Lindemans CA, Chiesa R, Amrolia PJ, Rao K, Nikolajeva O, de Wildt A, et al. Impact of thymoglobulin prior to pediatric unrelated umbilical cord blood transplantation on immune reconstitution and clinical outcome. Blood. 2014;123:126–32.

    Article  CAS  Google Scholar 

  40. Clave E, Busson M, Douay C, Peffault de Latour R, Berrou J, Rabian C, et al. Acute graft-versus-host disease transiently impairs thymic output in young patients after allogeneic hematopoietic stem cell transplantation. Blood. 2009;113:6477–84.

    Article  CAS  Google Scholar 

  41. Sairafi D, Mattsson J, Uhlin M, Uzunel M. Thymic function after allogeneic stem cell transplantation is dependent on graft source and predictive of long term survival. Clin Immunol. 2012;142:343–50.

    Article  CAS  Google Scholar 

  42. Weinberg K, Blazar BR, Wagner JE, Agura E, Hill BJ, Smogorzewska M, et al. Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation. Blood. 2001;97:1458–66.

    Article  CAS  Google Scholar 

  43. John AZ. Prevention of Cytomegalovirus Disease in Hematopoietic Stem Cell Transplantation. Clin Infect Dis. 2002;35(8):999–1004.

    Article  Google Scholar 

  44. Crystal LM, Terry JF, Ronald EG. Harnessing the biology of IL-7 for Therapeutic application. Nat Rev Immunol. 2011;11(5):330–342.

    Article  Google Scholar 

  45. Perales M-A, Goldberg JD, Yuan J, Koehne G, Lechner L, Papadopoulos EB, Young JW, Jakubowski AA, Zaidi B, Gallardo H, Liu C, Rasalan T, Wolchok JD, Croughs T, Morre M, Devlin SM, van den Brink MRM. Recombinant human interleukin-7 (CYT107) promotes T-cell recovery after allogeneic stem cell transplantation. Blood. 2012;120(24):4882–4891.

    Article  CAS  Google Scholar 

  46. Politikos I, Boussiotis VA. The role of the thymus in T-cell immune reconstitution after umbilical cord blood transplantation. Blood. 2014;124(22):3201–3211.

    Article  CAS  Google Scholar 

  47. Dudakov JA, Mertelsmann AM, O’Connor MH, Jenq RR, Velardi E, Young LF, Smith OM, Boyd RL, van den Brink MRM, Hanash AM. Loss of thymic innate lymphoid cells leads to impaired thymopoiesis in experimental graft-versus-host disease. Blood. 2017;130(7):933–942.

    Article  CAS  Google Scholar 

  48. Parent AV, Russ HA, Khan IS, LaFlam TN, Metzger TC, Anderson MS, Hebrok M. Generation of functional thymic epithelium from human embryonic stem cells that supports host T cell development. Cell Stem Cell. 2013;13(2):219–229.

    Article  CAS  Google Scholar 

  49. Sun X, Xu J, Lu H, Liu W, Miao Z, Sui X, Liu H, Su L, Du W, He Q, Chen F, Shi Y, Deng H. Directed differentiation of human embryonic stem cells into thymic epithelial progenitor-like cells reconstitutes the thymic microenvironment in vivo Cell Stem Cell. 2013;13(2):230–236.

    Article  CAS  Google Scholar 

Download references

Funding

The work described within this manuscript was performed within the framework of the TIPharma project D5-402.

Author information

Author notes

    Authors and Affiliations

    1. Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands

      Lucia E. Duinhouwer, Anita Rijken-Schelen, Judith Somers, Eric Braakman & Jan J. Cornelissen

    2. Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands

      Nick Beije & Cor H. Lamers

    3. Department of Hematology Erasmus MC Cancer Institute, HOVON Data Center, Rotterdam, The Netherlands

      Bronno van der Holt

    4. Sanquin Blood Supply, Rotterdam, The Netherlands

      Judith Somers

    Authors
    1. Lucia E. Duinhouwer
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Nick Beije
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Bronno van der Holt
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Anita Rijken-Schelen
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Cor H. Lamers
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Judith Somers
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Eric Braakman
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Jan J. Cornelissen
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Lucia E. Duinhouwer.

    Ethics declarations

    Conflict of interest

    The authors declare that they have no conflict of interest.

    Additional information

    Lucia E. Duinhouwer and Nick Beije contributed equally to this work.

    Electronic supplementary material

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Duinhouwer, L.E., Beije, N., van der Holt, B. et al. Impaired thymopoiesis predicts for a high risk of severe infections after reduced intensity conditioning without anti-thymocyte globulin in double umbilical cord blood transplantation. Bone Marrow Transplant 53, 673–682 (2018). https://doi.org/10.1038/s41409-018-0103-y

    Download citation

    • Received:

    • Revised:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1038/s41409-018-0103-y

    This article is cited by

    Search

    Advanced search

    Quick links