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.

  • Original Article
  • Published:

Stem Cells

Early recipient chimerism testing in the T- and NK-cell lineages for risk assessment of graft rejection in pediatric patients undergoing allogeneic stem cell transplantation

Leukemia volume 26, pages 509–519 (2012)Cite this article

Abstract

Timely diagnosis of impending graft rejection is crucial for effective therapeutic intervention after allogeneic hematopoietic stem cell transplantation (SCT). We have investigated the predictive potential of early leukocyte subset-specific chimerism for graft loss in children undergoing SCT. In total, 192 pediatric patients transplanted for the treatment of malignant and non-malignant diseases after reduced-intensity or myeloablative conditioning were investigated. Surveillance of lineage-specific chimerism was initiated upon first appearance of leukocyte counts amenable to cell sorting. Graft rejection occurred in 23 patients between 24 and 492 days post-transplant (median 63 days). The first chimerism analysis of T and NK cells performed at a median of 20 days after SCT identified three different risk groups that were independent from the conditioning regimen: recipient chimerism (RC) levels in T cells below 50% indicated a very low risk of rejection (1.4%), whereas high levels of RC (>90%) both in T and NK cells heralded graft loss in the majority of patients (90%) despite therapeutic interventions. RC >50% in T cells and ⩽90% in NK cells defined an intermediate-risk group in which timely immunotherapy frequently prevented rejection. Early assessment of T- and NK-cell chimerism can therefore be instrumental in the risk assessment and therapeutic management of imminent graft rejection.

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Schraml E, Daxberger H, Watzinger F, Lion T . Quantitative analysis of chimerism after allogeneic stem cell transplantation by PCR amplification of microsatellite markers and capillary electrophoresis with fluorescence detection: the Vienna experience. Leukemia 2003; 17: 224–227.

    Article  CAS  PubMed  Google Scholar 

  2. Lion T . Summary: reports on quantitative analysis of chimerism after allogeneic stem cell transplantation by PCR amplification of microsatellite markers and capillary electrophoresis with fluorescence detection. Leukemia 2003; 17: 252–254.

    Article  CAS  PubMed  Google Scholar 

  3. Thiede C, Bornhauser M, Oelschlagel U, Brendel C, Leo R, Daxberger H et al. Sequential monitoring of chimerism and detection of minimal residual disease after allogeneic blood stem cell transplantation (BSCT) using multiplex PCR amplification of short tandem repeat-markers. Leukemia 2001; 15: 293–302.

    Article  CAS  PubMed  Google Scholar 

  4. Watzinger F, Lion T, Steward C . The RSD code: proposal for a nomenclature of allelic configurations in STR-PCR-based chimerism testing after allogeneic stem cell transplantation. Leukemia 2006; 20: 1448–1452.

    Article  CAS  PubMed  Google Scholar 

  5. Antin JH, Childs R, Filipovich AH, Giralt S, Mackinnon S, Spitzer T et al. Establishment of complete and mixed donor chimerism after allogeneic lymphohematopoietic transplantation: recommendations from a workshop at the 2001 Tandem Meetings of the International Bone Marrow Transplant Registry and the American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transplant 2001; 7: 473–485.

    Article  CAS  PubMed  Google Scholar 

  6. Bader P, Niethammer D, Willasch A, Kreyenberg H, Klingebiel T . How and when should we monitor chimerism after allogeneic stem cell transplantation? Bone Marrow Transplant 2005; 35: 107–119.

    Article  CAS  PubMed  Google Scholar 

  7. Satwani P, Cooper N, Rao K, Veys P, Amrolia P . Reduced intensity conditioning and allogeneic stem cell transplantation in childhood malignant and nonmalignant diseases. Bone Marrow Transplant 2008; 41: 173–182.

    Article  CAS  PubMed  Google Scholar 

  8. Ozyurek E, Cowan MJ, Koerper MA, Baxter-Lowe LA, Dvorak CC, Horn BN . Increasing mixed chimerism and the risk of graft loss in children undergoing allogeneic hematopoietic stem cell transplantation for non-malignant disorders. Bone Marrow Transplant 2008; 42: 83–91.

    Article  CAS  PubMed  Google Scholar 

  9. Saito B, Fukuda T, Yokoyama H, Kurosawa S, Takahashi T, Fuji S et al. Impact of T cell chimerism on clinical outcome in 117 patients who underwent allogeneic stem cell transplantation with a busulfan-containing reduced-intensity conditioning regimen. Biol Blood Marrow Transplant 2008; 14: 1148–1155.

    Article  CAS  PubMed  Google Scholar 

  10. Michaelis L, Lin S, Joseph L, Artz AS, Kline J, Pollyea D et al. Chimerism does not predict for outcome after alemtuzumab based conditioning. Bone Marrow Transplant 2007; 40: 181.

    Article  CAS  PubMed  Google Scholar 

  11. Lim ZY, Pearce L, Ingram W, Ho AY, Mufti GJ, Pagliuca A . Chimerism does not predict for outcome after alemtuzumab-based conditioning: lineage-specific analysis of chimerism of specific diseases may be more informative. Bone Marrow Transplant 2008; 41: 587–588.

    Article  CAS  PubMed  Google Scholar 

  12. Khan F, Agarwal A, Agrawal S . Significance of chimerism in hematopoietic stem cell transplantation: new variations on an old theme. Bone Marrow Transplant 2004; 34: 1–12.

    Article  CAS  PubMed  Google Scholar 

  13. Mattsson J, Ringden O, Storb R . Graft failure after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2008; 14 (Suppl 1): 165–170.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Ho VT, Soiffer RJ . The history and future of T-cell depletion as graft-versus-host disease prophylaxis for allogeneic hematopoietic stem cell transplantation. Blood 2001; 98: 3192–3204.

    Article  CAS  PubMed  Google Scholar 

  15. Lion T . Chimerism testing after allogeneic stem cell transplantation: importance of timing and optimal technique for testing in different clinical–biological situations. Leukemia 2001; 15: 292.

    Article  PubMed  Google Scholar 

  16. Lion T, Daxberger H, Dubovsky J, Filipcik P, Fritsch G, Printz D et al. Analysis of chimerism within specific leukocyte subsets for detection of residual or recurrent leukemia in pediatric patients after allogeneic stem cell transplantation. Leukemia 2001; 15: 307–310.

    Article  CAS  PubMed  Google Scholar 

  17. Dubovsky J, Daxberger H, Fritsch G, Printz D, Peters C, Matthes S et al. Kinetics of chimerism during the early post-transplant period in pediatric patients with malignant and non-malignant hematologic disorders: implications for timely detection of engraftment, graft failure and rejection. Leukemia 1999; 13: 2059, 2060–2069.

    Article  CAS  PubMed  Google Scholar 

  18. Fritsch G, Witt V, Dubovsky J, Matthes S, Peters C, Buchinger P et al. Flow cytometric monitoring of hematopoietic reconstitution in myeloablated patients following allogeneic transplantation. Cytotherapy 1999; 1: 295–309.

    Article  CAS  PubMed  Google Scholar 

  19. Baron F, Sandmaier BM . Chimerism and outcomes after allogeneic hematopoietic cell transplantation following nonmyeloablative conditioning. Leukemia 2006; 20: 1690–1700.

    Article  CAS  PubMed  Google Scholar 

  20. Doney K, Loken M, Bryant E, Smith A, Appelbaum F . Lack of utility of chimerism studies obtained 2–3 months after myeloablative hematopoietic cell transplantation for ALL. Bone Marrow Transplant 2008; 42: 271–274.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Hoelle W, Beck JF, Dueckers G, Kreyenberg H, Lang P, Gruhn B et al. Clinical relevance of serial quantitative analysis of hematopoietic chimerism after allogeneic stem cell transplantation in children for severe aplastic anemia. Bone Marrow Transplant 2004; 33: 219–223.

    Article  CAS  PubMed  Google Scholar 

  22. Lion T, Watzinger F . Chimerism analysis following nonmyeloablative stem cell transplantation. Methods Mol Med 2006; 125: 275–295.

    CAS  PubMed  Google Scholar 

  23. Matthes-Martin S, Lion T, Haas OA, Frommlet F, Daxberger H, Konig M et al. Lineage-specific chimaerism after stem cell transplantation in children following reduced intensity conditioning: potential predictive value of NK cell chimaerism for late graft rejection. Leukemia 2003; 17: 1934–1942.

    Article  CAS  PubMed  Google Scholar 

  24. Miura Y, Tanaka J, Toubai T, Tsutsumi Y, Kato N, Hirate D et al. Analysis of donor-type chimerism in lineage-specific cell populations after allogeneic myeloablative and non-myeloablative stem cell transplantation. Bone Marrow Transplant 2006; 37: 837–843.

    Article  CAS  PubMed  Google Scholar 

  25. Zeiser R, Spyridonidis A, Wasch R, Ihorst G, Grullich C, Bertz H et al. Evaluation of immunomodulatory treatment based on conventional and lineage-specific chimerism analysis in patients with myeloid malignancies after myeloablative allogeneic hematopoietic cell transplantation. Leukemia 2005; 19: 814–821.

    Article  CAS  PubMed  Google Scholar 

  26. Bornhauser M, Thiede C, Platzbecker U, Jenke A, Helwig A, Plettig R et al. Dose-reduced conditioning and allogeneic hematopoietic stem cell transplantation from unrelated donors in 42 patients. Clin Cancer Res 2001; 7: 2254–2262.

    CAS  PubMed  Google Scholar 

  27. Mossallam GI, Kamel AM, Storer B, Martin PJ . Prognostic utility of routine chimerism testing at 2 to 6 months after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2009; 15: 352–359.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Fritsch G, Printz D, Stimpfl M, Dworzak MN, Witt V, Potschger U et al. Quantification of CD34+ cells: comparison of methods. Transfusion 1997; 37: 775–784.

    Article  CAS  PubMed  Google Scholar 

  29. Bader P, Kreyenberg H, Hoelle W, Dueckers G, Handgretinger R, Lang P et al. Increasing mixed chimerism is an important prognostic factor for unfavorable outcome in children with acute lymphoblastic leukemia after allogeneic stem-cell transplantation: possible role for pre-emptive immunotherapy? J Clin Oncol 2004; 22: 1696–1705.

    Article  PubMed  Google Scholar 

  30. Huisman C, de Weger RA, de Vries L, Tilanus MG, Verdonck LF . Chimerism analysis within 6 months of allogeneic stem cell transplantation predicts relapse in acute myeloid leukemia. Bone Marrow Transplant 2007; 39: 285–291.

    Article  CAS  PubMed  Google Scholar 

  31. Bader P, Niemeyer C, Willasch A, Kreyenberg H, Strahm B, Kremens B et al. Children with myelodysplastic syndrome (MDS) and increasing mixed chimaerism after allogeneic stem cell transplantation have a poor outcome which can be improved by pre-emptive immunotherapy. Br J Haematol 2005; 128: 649–658.

    Article  PubMed  Google Scholar 

  32. Kristt D, Stein J, Klein T . Frontiers of stem cell transplantation monitoring: capturing graft dynamics through routine longitudinal chimerism analysis. Isr Med Assoc J 2007; 9: 159–162.

    CAS  PubMed  Google Scholar 

  33. Childs R, Clave E, Contentin N, Jayasekera D, Hensel N, Leitman S et al. Engraftment kinetics after nonmyeloablative allogeneic peripheral blood stem cell transplantation: full donor T-cell chimerism precedes alloimmune responses. Blood 1999; 94: 3234–3241.

    CAS  PubMed  Google Scholar 

  34. Montero A, Savani BN, Kurlander R, Read EJ, Leitman SF, Childs R et al. Lineage-specific engraftment and outcomes after T-cell-depleted peripheral blood stem cell transplant with Flu/Cy/TBI conditioning. Br J Haematol 2005; 130: 733–739.

    Article  CAS  PubMed  Google Scholar 

  35. Schaap N, Schattenberg A, Mensink E, Preijers F, Hillegers M, Knops R et al. Long-term follow-up of persisting mixed chimerism after partially T cell-depleted allogeneic stem cell transplantation. Leukemia 2002; 16: 13–21.

    Article  CAS  PubMed  Google Scholar 

  36. Baron F, Baker JE, Storb R, Gooley TA, Sandmaier BM, Maris MB et al. Kinetics of engraftment in patients with hematologic malignancies given allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. Blood 2004; 104: 2254–2262.

    Article  CAS  PubMed  Google Scholar 

  37. Mohty M, Avinens O, Faucher C, Viens P, Blaise D, Eliaou JF . Predictive factors and impact of full donor T-cell chimerism after reduced intensity conditioning allogeneic stem cell transplantation. Haematologica 2007; 92: 1004–1006.

    Article  PubMed  Google Scholar 

  38. Girgis M, Hallemeier C, Blum W, Brown R, Lin HS, Khoury H et al. Chimerism and clinical outcomes of 110 recipients of unrelated donor bone marrow transplants who underwent conditioning with low-dose, single-exposure total body irradiation and cyclophosphamide. Blood 2005; 105: 3035–3041.

    Article  CAS  PubMed  Google Scholar 

  39. van Leeuwen JE, van Tol MJ, Joosten AM, Wijnen JT, Verweij PJ, Khan PM et al. Persistence of host-type hematopoiesis after allogeneic bone marrow transplantation for leukemia is significantly related to the recipient's age and/or the conditioning regimen, but it is not associated with an increased risk of relapse. Blood 1994; 83: 3059–3067.

    CAS  PubMed  Google Scholar 

  40. van Leeuwen JE, van Tol MJ, Joosten AM, Schellekens PT, van den Bergh RL, Waaijer JL et al. Relationship between patterns of engraftment in peripheral blood and immune reconstitution after allogeneic bone marrow transplantation for (severe) combined immunodeficiency. Blood 1994; 84: 3936–3947.

    CAS  PubMed  Google Scholar 

  41. Lamba R, Abella E, Kukuruga D, Klein J, Savasan S, Abidi MH et al. Mixed hematopoietic chimerism at day 90 following allogenic myeloablative stem cell transplantation is a predictor of relapse and survival. Leukemia 2004; 18: 1681–1686.

    Article  CAS  PubMed  Google Scholar 

  42. Goh RY, Cho SS, Song YJ, Heo K, Oh SY, Kim SH et al. Clinical utility of chimerism status assessed by lineage-specific short tandem repeat analysis: experience from four cases of allogeneic stem cell transplantation. Korean J Lab Med 2009; 29: 277–281.

    Article  CAS  PubMed  Google Scholar 

  43. Yoshimi A, Niemeyer CM, Bohmer V, Duffner U, Strahm B, Kreyenberg H et al. Chimaerism analyses and subsequent immunological intervention after stem cell transplantation in patients with juvenile myelomonocytic leukaemia. Br J Haematol 2005; 129: 542–549.

    Article  PubMed  Google Scholar 

  44. Willasch A, Hoelle W, Kreyenberg H, Niethammer D, Handgretinger R, Lang P et al. Outcome of allogeneic stem cell transplantation in children with non-malignant diseases. Haematologica 2006; 91: 788–794.

    PubMed  Google Scholar 

  45. Marks DI, Lush R, Cavenagh J, Milligan DW, Schey S, Parker A et al. The toxicity and efficacy of donor lymphocyte infusions given after reduced-intensity conditioning allogeneic stem cell transplantation. Blood 2002; 100: 3108–3114.

    Article  CAS  PubMed  Google Scholar 

  46. Gyger M, Baron C, Forest L, Lussier P, Lagace F, Bissonnette I et al. Quantitative assessment of hematopoietic chimerism after allogeneic bone marrow transplantation has predictive value for the occurrence of irreversible graft failure and graft-vs-host disease. Exp Hematol 1998; 26: 426–434.

    CAS  PubMed  Google Scholar 

  47. Lassaletta A, Ramirez M, Montero JM, Gonzalez-Vicent M, Balas A, Madero L et al. Full donor chimerism by day 30 after allogeneic peripheral blood progenitor cell transplantation is associated with a low risk of relapse in pediatric patients with hematological malignancies. Leukemia 2005; 19: 504–506.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. St Anna Children's Hospital, Vienna, Austria

    S Breuer, A Lawitschka, C Peters, G Mann & S Matthes-Martin

  2. Children's Cancer Research Institute, Vienna, Austria

    S Preuner, G Fritsch, H Daxberger, M Koenig, U Poetschger & T Lion

Authors
  1. S Breuer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Preuner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G Fritsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H Daxberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Koenig
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. U Poetschger
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A Lawitschka
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. C Peters
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. G Mann
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. T Lion
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. S Matthes-Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T Lion.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Breuer, S., Preuner, S., Fritsch, G. et al. Early recipient chimerism testing in the T- and NK-cell lineages for risk assessment of graft rejection in pediatric patients undergoing allogeneic stem cell transplantation. Leukemia 26, 509–519 (2012). https://doi.org/10.1038/leu.2011.244

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2011.244

Keywords

This article is cited by

Search

Advanced search

Quick links