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Chimerism

Clinical relevance of serial quantitative analysis of hematopoietic chimerism after allogeneic stem cell transplantation in children for severe aplastic anemia

Summary:

Allogeneic stem cell transplantation (allo-SCT) is a well-established treatment modality for children with severe aplastic anemia (SAA). Treatment failures are rare and mostly caused by graft rejection. Increasing mixed chimerism represents a stage at the very beginning of graft rejection, where immunological intervention might be an effective prophylactic approach. To substantiate this, we: (1) monitored peripheral blood cells from children with SAA after allo-SCT and performed pre-emptive immunotherapy in patients with increasing MC. In all, 23/34 courses of 32 children with SAA after allo-SCT showed a complete chimerism (CC) throughout and 10/34 developed different types of mixed chimerism (MC). Altogether, 4/10 with MC spontaneously developed decreasing MC, 2/10 courses persisted with low proportions of autologous cells below 30% (stable-MC), 4/10 developed increasing MC and one patient showed an autologous recovery. All patients with CC, decreasing MC or stable MC remained in continuous complete remission (CCR). In all, 2/4 patients with increasing MC developed graft rejection. Based on these observations, 2/4 new patients with increasing MC received low-dose DLIs prophylactically, and remained in CCR without any GVHD. These results substantiate that low-dose DLI in children with SAA and increasing MC can prevent graft rejection with a calculable risk to induce severe GVHD.

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References

  1. Ball SE . The modern management of severe aplastic anaemia. Br J Haematol 2000; 110: 41–53.

    Article  CAS  Google Scholar 

  2. Mollee P, Woodward N, Durrant S et al. Single institution outcomes of treatment of severe aplastic anaemia. Intern Med J 2001; 31: 337–342.

    Article  CAS  Google Scholar 

  3. Hows JM, Marsh JC, Yin JL et al. Bone marrow transplantation for severe aplastic anaemia using cyclosporin: long-term follow-up. Bone Marrow Transplant 1989; 4: 11–16.

    CAS  Google Scholar 

  4. Margolis D, Camitta B, Pietryga D et al. Unrelated donor bone marrow transplantation to treat severe aplastic anaemia in children and young adults. Br J Haematol 1996; 94: 65–72.

    Article  CAS  Google Scholar 

  5. Bacigalupo A, Brand R, Oneto R et al. Treatment of acquired severe aplastic anemia: bone marrow transplantation compared with immunosuppressive therapy – The European Group for Blood and Marrow Transplantation experience. Semin Hematol 2000; 37: 69–80.

    Article  CAS  Google Scholar 

  6. McCann SR, Bacigalupo A, Gluckman E et al. Graft rejection and second bone marrow transplants for acquired aplastic anaemia: a report from the Aplastic Anaemia Working Party of the European Bone Marrow Transplant Group. Bone Marrow Transplant 1994; 13: 233–237.

    CAS  Google Scholar 

  7. Gomez JR, Garcia MJ, Serrano J et al. Chimerism analysis in long-term survivor patients after bone marrow transplantation for severe aplastic anemia. Haematologica 1997; 82: 588–591.

    CAS  PubMed  Google Scholar 

  8. Hill RS, Petersen FB, Storb R et al. Mixed hematologic chimerism after allogeneic marrow transplantation for severe aplastic anemia is associated with a higher risk of graft rejection and a lessened incidence of acute graft-versus-host disease. Blood 1986; 67: 811–816.

    CAS  Google Scholar 

  9. Lawler M, McCann SR, Gardiner N et al. Mixed chimerism predicts graft rejection following BMT for severe aplastic anaemia. Final report for the EBMT working party on SAA. Bone Marrow Transplant 1995; 15: 64a.

    Google Scholar 

  10. Casado LF, Steegmann JL, Pico M et al. Study of chimerism in long-term survivors after bone marrow transplantation for severe acquired aplastic anemia. Bone Marrow Transplant 1996; 18: 405–409.

    CAS  Google Scholar 

  11. Bader P, Beck J, Frey A et al. Serial and quantitative analysis of mixed hematopoietic chimerism by PCR in patients with acute leukemias allows the prediction of relapse after allogeneic BMT. Bone Marrow Transplant 1998; 21: 487–495.

    Article  CAS  Google Scholar 

  12. Beck JF, Klingebiel T, Kreyenberg H et al. Relapse of childhood ALL, AML and MDS after allogeneic stem cell transplantation can be prevented by donor lymphocyte infusion in a critical stage of increasing mixed chimerism. Klin Padiatr 2002; 214: 201–205.

    Article  CAS  Google Scholar 

  13. Bader P, Duckers G, Kreyenberg H et al. Monitoring of donor cell chimerism for the detection of relapse and early immunotherapeutic intervention in acute lymphoblastic leukemias. Ann Hematol 2002; 81 (Suppl 2): S25–S27.

    PubMed  Google Scholar 

  14. Fuhrer M, Burdach S, Ebell W et al. Relapse and clonal disease in children with aplastic anemia (AA) after immunosuppressive therapy (IST): the SAA 94 experience German/Austrian Pediatric Aplastic Anemia Working Group. Klin Padiatr 1998; 210: 173–179.

    Article  CAS  Google Scholar 

  15. Bader P, Holle W, Klingebiel T et al. Quantitative assessment of mixed hematopoietic chimerism by polymerase chain reaction after allogeneic BMT. Anticancer Res 1996; 16: 1759–1763.

    CAS  Google Scholar 

  16. Kreyenberg H, Holle W, Mohrle S et al. Quantitative analysis of chimerism after allogeneic stem cell transplantation by PCR amplification of microsatellite markers and capillary electrophoresis with fluorescence detection: the Tuebingen experience. Leukemia 2003; 17: 237–240.

    Article  CAS  Google Scholar 

  17. Lang P, Schumm M, Taylor G et al. Clinical scale isolation of highly purified peripheral CD34+ progenitors for autologous and allogeneic transplantation in children. Bone Marrow Transplant 1999; 24: 583–589.

    Article  CAS  Google Scholar 

  18. Schumm M, Lang P, Taylor G et al. Isolation of highly purified autologous and allogeneic peripheral CD34+ cells using the CliniMACS device. J Hematother 1999; 8: 209–218.

    Article  CAS  Google Scholar 

  19. Klingebiel T, Schlegel PG . GVHD: overview on pathophysiology, incidence, clinical and biological features. Bone Marrow Transplant 1998; 21 (Suppl 2): S45–S49.

    Google Scholar 

  20. Glucksberg H, Storb R, Fefer A et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 1974; 18: 295–304.

    Article  CAS  Google Scholar 

  21. Dufour C, Dallorso S, Casarino L et al. Late graft failure 8 years after first bone marrow transplantation for severe acquired aplastic anemia. Bone Marrow Transplant 1999; 23: 743–745.

    Article  CAS  Google Scholar 

  22. Boiron JM, Cotteret S, Cony-Makhoul P et al. Stable mixed chimerism without relapse after related allogeneic umbilical cord blood transplantation in a child with severe aplastic anemia. Bone Marrow Transplant 1998; 22: 819–821.

    Article  CAS  Google Scholar 

  23. Bader P, Klingebiel T, Schaudt A et al. Prevention of relapse in pediatric patients with acute leukemias and MDS after allogeneic SCT by early immunotherapy initiated on the basis of increasing mixed chimerism: a single center experience of 12 children. Leukemia 1999; 13: 2079–2086.

    Article  CAS  Google Scholar 

  24. Bader P, Beck J, Schlegel PG et al. Additional immunotherapy on the basis of increasing mixed hematopoietic chimerism after allogeneic BMT in children with acute leukemia: is there an option to prevent relapse? Bone Marrow Transplant 1997; 20: 79–81.

    Article  CAS  Google Scholar 

  25. Gardiner N, Lawler M, O'Riordan JM et al. Monitoring of lineage-specific chimaerism allows early prediction of response following donor lymphocyte infusions for relapsed chronic myeloid leukaemia. Bone Marrow Transplant 1998; 21: 711–719.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank all the participating centers and all colleagues who also included less than three patients into the study: Professor Dr B Kremens, University Children's Hospital Essen; Professor Dr C Niemeyer, University Children's Hospital Freiburg; Professor Dr A Reiter, University Children's Hospital Gießen; PD Dr KW Sykora, University Children's Hospital Hannover.

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Correspondence to P Bader.

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Hoelle, W., Beck, J., Dueckers, G. 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 33, 219–223 (2004). https://doi.org/10.1038/sj.bmt.1704337

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