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Graft-Versus-Host Disease

Induction of graft versus malignancy effect after unrelated allogeneic PBSCT using donor lymphocyte infusions derived from frozen aliquots of the original graft

Abstract

To evaluate safety and efficacy of donor lymphocyte infusions (DLI), derived from frozen aliquots of the original G-CSF-stimulated graft after allogeneic PBSCT from unrelated donors, data of 121 patients with hematological malignancies treated with DLIs were retrospectively analyzed. Indications for PBSCT were AML/myelodysplastic syndrome (n=63/8), ALL (n=17), lymphoma (n=13), multiple myeloma (n=10) and myeloproliferative syndrome (n=10). Reasons for DLI were hematological relapse (n=81), molecular and/or cytogenetic relapse (n=5), mixed chimerism (n=22) and prophylactic DLI in high-risk patients (n=13). DLIs were well tolerated with no acute adverse reactions. DLI-induced acute-type GvHD (aGvHD) was observed in 19 patients and chronic-type GvHD (cGvHD) developed in 14 patients. Three patients died of GvHD complications. DLI induced CR, complete chimerism or PR in 34 patients; 24 patients had stable disease, 50 patients progressed and 13 patients were not evaluable for response. Objective response was more obvious for molecular relapse (5/5) or mixed chimerism (14/22) compared with hematological relapse (13/81). Median survival after first DLI was 10.4 months (95% confidence interval: 4.4–26.0). Cryopreserved G-CSF-stimulated DLI, derived from allogeneic grafts are safe and immunoreactive, and can be applied early in case of mixed chimerism and molecular or cytogenetic relapse.

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References

  1. Savani BN, Mielke S, Reddy N, Goodman S, Jagasia M, Rezvani K . Management of relapse after allo-SCT for AML and the role of second transplantation. Bone Marrow Transplant 2009; 44: 769–777.

    Article  CAS  PubMed  Google Scholar 

  2. Levine JE, Braun T, Penza SL, Beatty P, Cornetta K, Martino R et al. Prospective trial of chemotherapy and donor leukocyte infusions for relapse of advanced myeloid malignancies after allogeneic stem-cell transplantation. J Clin Oncol 2002; 20: 405–412.

    Article  CAS  PubMed  Google Scholar 

  3. Kolb HJ, Mittermuller J, Clemm C, Holler E, Ledderose G, Brehm G et al. Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 1990; 76: 2462–2465.

    CAS  PubMed  Google Scholar 

  4. Kolb HJ, Schattenberg A, Goldman JM, Hertenstein B, Jacobsen N, Arcese W et al. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood 1995; 86: 2041–2050.

    CAS  PubMed  Google Scholar 

  5. Slavin S, Naparstek E, Nagler A, Ackerstein A, Kapelushnik J, Or R . Allogeneic cell therapy for relapsed leukemia after bone marrow transplantation with donor peripheral blood lymphocytes. Exp Hematol 1995; 23: 1553–1562.

    CAS  PubMed  Google Scholar 

  6. Riddell SR, Murata M, Bryant S, Warren EH . T-cell therapy of leukemia. Cancer Control 2002; 9: 114–122.

    Article  PubMed  Google Scholar 

  7. Schmid C, Labopin M, Nagler A, Bornhauser M, Finke J, Fassas A et al. Donor lymphocyte infusion in the treatment of first hematological relapse after allogeneic stem cell transplantation in adults with acute myeloid leukemia: a retrospective risk factors analysis and comparison with other strategies by the EBMT Acute Leukemia Working Party. J Clin Oncol 2007; 25: 4938–4945.

    Article  CAS  PubMed  Google Scholar 

  8. Lee JH, Lee KH, Kim S, Seol M, Kim SH, Kim WK et al. Combination chemotherapy of intermediate-dose cytarabine, idarubicin, plus etoposide and subsequent mobilized donor leukocyte infusion for relapsed acute leukemia after allogeneic bone marrow transplantation. Leuk Res 2001; 25: 305–312.

    Article  CAS  PubMed  Google Scholar 

  9. Choi SJ, Lee JH, Kim S, Seol M, Lee YS, Lee JS et al. Treatment of relapsed acute myeloid leukemia after allogeneic bone marrow transplantation with chemotherapy followed by G-CSF-primed donor leukocyte infusion: a high incidence of isolated extramedullary relapse. Leukemia 2004; 18: 1789–1797.

    Article  CAS  PubMed  Google Scholar 

  10. Collins Jr RH, Shpilberg O, Drobyski WR, Porter DL, Giralt S, Champlin R et al. Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol 1997; 15: 433–444.

    Article  PubMed  Google Scholar 

  11. Tomblyn M, Lazarus HM . Donor lymphocyte infusions: the long and winding road: how should it be traveled? Bone Marrow Transplant 2008; 42: 569–579.

    Article  CAS  PubMed  Google Scholar 

  12. Alyea EP . Modulating graft-versus-host disease to enhance the graft-versus-leukemia effect. Best Pract Res Clin Haematol 2008; 21: 239–250.

    Article  CAS  PubMed  Google Scholar 

  13. Raiola AM, Van Lint MT, Valbonesi M, Lamparelli T, Gualandi F, Occhini D et al. Factors predicting response and graft-versus-host disease after donor lymphocyte infusions: a study on 593 infusions. Bone Marrow Transplant 2003; 31: 687–693.

    Article  CAS  PubMed  Google Scholar 

  14. Verdonck LF, Petersen EJ, Lokhorst HM, Nieuwenhuis HK, Dekker AW, Tilanus MG et al. Donor leukocyte infusions for recurrent hematologic malignancies after allogeneic bone marrow transplantation: impact of infused and residual donor T cells. Bone Marrow Transplant 1998; 22: 1057–1063.

    Article  CAS  PubMed  Google Scholar 

  15. Simula MP, Marktel S, Fozza C, Kaeda J, Szydlo RM, Nadal E et al. Response to donor lymphocyte infusions for chronic myeloid leukemia is dose-dependent: the importance of escalating the cell dose to maximize therapeutic efficacy. Leukemia 2007; 21: 943–948.

    Article  CAS  PubMed  Google Scholar 

  16. Kim JG, Sohn SK, Kim DH, Lee NY, Suh JS, Lee KS et al. A pilot study of cytoreductive chemotherapy combined with infusion of additional peripheral blood stem cells reserved at time of harvest for transplantation in case of relapsed hematologic malignancies after allogeneic peripheral blood stem cell transplant. Bone Marrow Transplant 2004; 33: 231–236.

    Article  CAS  PubMed  Google Scholar 

  17. Sohn SK, Baek JH, Kim DH, Jung JT, Kwak DS, Park SH et al. Successful allogeneic stem-cell transplantation with prophylactic stepwise G-CSF primed-DLIs for relapse after autologous transplantation in mantle cell lymphoma: a case report and literature review on the evidence of GVL effects in MCL. Am J Hematol 2000; 65: 75–80.

    Article  CAS  PubMed  Google Scholar 

  18. Sohn SK, Jung JT, Kim DH, Lee NY, Seo KW, Chae YS et al. Prophylactic growth factor-primed donor lymphocyte infusion using cells reserved at the time of transplantation after allogeneic peripheral blood stem cell transplantation in patients with high-risk hematologic malignancies. Cancer 2002; 94: 18–24.

    Article  CAS  PubMed  Google Scholar 

  19. Marks R, Potthoff K, Hahn J, Ihorst G, Bertz H, Spyridonidis A et al. Reduced-toxicity conditioning with fludarabine, BCNU, and melphalan in allogeneic hematopoietic cell transplantation: particular activity against advanced hematologic malignancies. Blood 2008; 112: 415–425.

    Article  CAS  PubMed  Google Scholar 

  20. Grullich C, Bertz H, Spyridonidis A, Muller CI, Finke J . A fludarabine, thiotepa reduced toxicity conditioning regimen designed specifically for allogeneic second haematopoietic cell transplantation after failure of previous autologous or allogeneic transplantation. Bone Marrow Transplant 2008; 41: 845–850.

    Article  CAS  PubMed  Google Scholar 

  21. Bertz H, Potthoff K, Finke J . Allogeneic stem-cell transplantation from related and unrelated donors in older patients with myeloid leukemia. J Clin Oncol 2003; 21: 1480–1484.

    Article  PubMed  Google Scholar 

  22. Wasch R, Reisser S, Hahn J, Bertz H, Engelhardt M, Kunzmann R et al. Rapid achievement of complete donor chimerism and low regimen-related toxicity after reduced conditioning with fludarabine, carmustine, melphalan and allogeneic transplantation. Bone Marrow Transplant 2000; 26: 243–250.

    Article  CAS  PubMed  Google Scholar 

  23. Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA 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  PubMed  Google Scholar 

  24. Sairafi D, Remberger M, Uhlin M, Ljungman P, Ringden O, Mattsson J . Leukemia lineage-specific chimerism analysis and molecular monitoring improve outcome of donor lymphocyte infusions. Biol Blood Marrow Transplant 2010; 16: 1728–1737.

    Article  CAS  PubMed  Google Scholar 

  25. Wasch R, Bertz H, Kunzmann R, Finke J . Incidence of mixed chimaerism and clinical outcome in 101 patients after myeloablative conditioning regimens and allogeneic stem cell transplantation. Br J Haematol 2000; 109: 743–750.

    Article  CAS  PubMed  Google Scholar 

  26. Klingebiel T, Bader P . Delayed lymphocyte infusion in children given SCT. Bone Marrow Transplant 2008; 41 (Suppl 2): S23–S26.

    Article  PubMed  Google Scholar 

  27. le Coutre P, Kreuzer KA, Massenkeil G, Baskaynak G, Zschieschang P, Genvresse I et al. Autologous peripheral blood stem cell transplantation of stem cells harvested in imatinib-induced complete cytogenetic remission: an example of in vivo purging in CML. Leukemia 2003; 17: 2525–2526.

    Article  CAS  PubMed  Google Scholar 

  28. Kolb HJ, Schmid C, Barrett AJ, Schendel DJ . Graft-versus-leukemia reactions in allogeneic chimeras. Blood 2004; 103: 767–776.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank I Matt for data management and the staff of BMT Unit Löhr for patient care.

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Correspondence to J Finke.

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Hasskarl, J., Zerweck, A., Wäsch, R. et al. Induction of graft versus malignancy effect after unrelated allogeneic PBSCT using donor lymphocyte infusions derived from frozen aliquots of the original graft. Bone Marrow Transplant 47, 277–282 (2012). https://doi.org/10.1038/bmt.2011.45

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