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Conditioning Regimens

Feasibility of conditioning with thymoglobulin and reduced intensity TBI to reduce acute GVHD in recipients of allogeneic SCT

Bone Marrow Transplantation volume 42, pages 723–731 (2008)Cite this article

Abstract

Murine studies using anti-T-cell antibodies for conditioning in allogeneic SCT demonstrate engraftment with low rates of GVHD. On the basis of this preclinical model, we conditioned 30 patients with advanced hematologic malignancies with rabbit antithymocyte globulin (ATG) and TBI, to reduce rates of fatal acute GVHD. Patients were enrolled in two sequential groups: cohort 1 received ATG 10 mg/kg in divided doses (days −4 to −1)+200 cGy TBI (n=16), and cohort 2 received ATG (days −10 to −7)+450 cGy TBI (n=14). Median donor blood chimerism for the combined group was 94, 93 and 93% in the first, second and third months after transplant. Only three developed grade II acute GVHD despite 43% of patients receiving unrelated donor transplants. One-year survival was 71±11 and 54±14%, respectively, in recipients of related and unrelated donor SCT. Donor lymphocyte infusions were needed in 12 patients for the management of relapse and for mixed donor–recipient chimerism in 4 patients. We conclude that 10 mg/kg ATG and TBI allows engraftment with a low risk of acute GVHD; however, further dose optimization of ATG is required to achieve a balance between GVHD and disease relapse.

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References

  1. Alyea EP, Kim HT, Ho V, Cutler C, DeAngelo DJ, Stone R et al. Impact of conditioning regimen intensity on outcome of allogeneic hematopoietic cell transplantation for advanced acute myelogenous leukemia and myelodysplastic syndrome. Biol Blood Marrow Transplant 2006; 10: 1047–1055.

    Article  Google Scholar 

  2. McSweeney PA, Niederwieser D, Shizuru JA, Sandmaier BM, Molina AJ, Maloney DG et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 2001; 97: 3390–3400.

    Article  CAS  PubMed  Google Scholar 

  3. Sorror ML, Maris MB, Storer B, Sandmaier BM, Diaconescu R, Flower C et al. Comparing morbidity and mortality of HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative and myeloablative conditioning: Influence of pretransplantation comorbidities. Blood 2004; 104: 961–968.

    Article  CAS  PubMed  Google Scholar 

  4. Baron F, Maris MB, Sandmaier BM, Storer BE, Sorror M, Diaconescu R et al. Graft-versus-tumor effects after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning. J Clin Oncol 2005; 23: 1993–2003.

    Article  PubMed  Google Scholar 

  5. Baron F, Sandmaier BM, Storer BE, Maris MB, Langston AA, Lange T et al. Extended mycophenolate mofetil and shortened cyclosporine failed to reduce graft-versus-host disease after unrelated hematopoietic cell transplantation with nonmyeloablative conditioning. Biol Blood Marrow Transplant 2007; 13: 1041–1048.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Horowitz MM, Gale RP, Sondel PM, Goldman JM, Kersey J, Kolb HJ et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood 1990; 75: 555–562.

    CAS  PubMed  Google Scholar 

  7. Rowlings PA, Przepiorka D, Klein JP, Gale RP, Passweg JR, Henslee-Downey PJ et al. IBMTR severity index for grading acute graft-versus-host disease: retrospective comparison with glucksberg grade. Br J Haematol 1997; 97: 855–864.

    Article  CAS  PubMed  Google Scholar 

  8. MacMillan ML, Weisdorf DJ, Wagner JE, DeFor TE, Burns LJ, Ramsay NK et al. Response of 443 patients to steroids as primary therapy for acute graft-versus-host disease: Comparison of grading systems. Biol Blood and Marrow Transplantation 2002; 8: 387–394.

    Article  CAS  Google Scholar 

  9. Sharabi Y, Sachs DH . Mixed chimerism and permanent specific transplantation tolerance induced by a nonlethal preparative regimen. J Exp Med 1989; 169: 493–502.

    Article  CAS  PubMed  Google Scholar 

  10. Wekerle T, Kurtz J, Ito H, Ronquillo JV, Dong V, Zhao G et al. Allogeneic bone marrow transplantation with co-stimulatory blockade induces macrochimerism and tolerance without cytoreductive host treatment. Nat Med 2000; 6: 464–469.

    Article  CAS  PubMed  Google Scholar 

  11. Nikolic B, Zhao G, Swenson K, Sykes M . A novel application of cyclosporine A in nonmyeloablative pretransplant host conditioning for allogeneic BMT. Blood 2000; 96: 1166–1172.

    CAS  PubMed  Google Scholar 

  12. Tomita Y, Sachs DH, Khan A, Sykes M . Additional monoclonal antibody (mAB) injections can replace thymic irradiation to allow induction of mixed chimerism and tolerance in mice receiving bone marrow transplantation after conditioning with anti-T cell mABs and 3-gy whole body irradiation. Transplantation 1996; 61: 469–477.

    Article  CAS  PubMed  Google Scholar 

  13. Finke J, Bertz H, Schmoor C, Veelken H, Behringer D, Wasch R et al. Allogeneic bone marrow transplantation from unrelated donors using in vivo anti-T-cell globulin. Br J Haematol 2000; 111: 303–313.

    Article  CAS  PubMed  Google Scholar 

  14. Storb R, Leisenring W, Anasetti C, Appelbaum FR, Buckner CD, Bensinger WI et al. Long-term follow-up of allogeneic marrow transplants in patients with aplastic anemia conditioned by cyclophosphamide combined with antithymocyte globulin. Blood 1997; 89: 3890–3891.

    CAS  PubMed  Google Scholar 

  15. Ringden O, Remberger M, Carlens S, Hagglund H, Mattsson J, Aschan J et al. Low incidence of acute graft-versus-host disease, using unrelated HLA-A-, HLA-B-, and HLA-DR-compatible donors and conditioning, including anti-T-cell antibodies. Transplantation 1998; 66: 620–625.

    Article  CAS  PubMed  Google Scholar 

  16. Mohty M, Boiron JM, Damaj G, Michallet AS, Bay JO, Faucher C et al. Graft-versus-myeloma effect following antithymocyte globulin-based reduced intensity conditioning allogeneic stem cell transplantation. Bone Marrow Transplantation 2004; 34: 77–84.

    Article  CAS  PubMed  Google Scholar 

  17. Crawley C, Szydlo R, Lalancette M, Bacigalupo A, Lange A, Brune M et al. Outcomes of reduced-intensity transplantation for chronic myeloid leukemia: an analysis of prognostic factors from the chronic leukemia working party of the EBMT. Blood 2005; 106: 2969–2976.

    Article  CAS  PubMed  Google Scholar 

  18. Lowsky R, Takahashi T, Liu YP, Dejbakhsh-Jones S, Grumet FC, Shizuru JA . Protective conditioning for acute graft-versus-host disease. N Engl J Med 2005; 353: 1321–1331.

    Article  CAS  PubMed  Google Scholar 

  19. Regan JF, Lyonnais C, Campbell K, Smith LV, Buelow R, US Thymoglobulin Multi-Center Study Group. Total and active thymoglobulin levels: effects of dose and sensitization on serum concentrations. Transpl Immunol 2001; 9: 29–36.

    Article  CAS  PubMed  Google Scholar 

  20. Waller EK, Langston AA, Lonial S, Cherry J, Somani J, Allen AJ et al. Pharmacokinetics and pharmacodynamics of anti-thymocyte globulin in recipients of partially HLA-matched blood hematopoietic progenitor cell transplantation. Biol Blood Marrow Transplant 2003; 9: 460–471.

    Article  CAS  PubMed  Google Scholar 

  21. Yu C, Storb R, Mathey B, Deeg HJ, Schuening FG, Graham T et al. DLA-identical bone marrow grafts after low-dose total body irradiation: effects of high-dose corticosteroids and cyclosporine on engraftment. Blood 1995; 86: 4376–4381.

    CAS  PubMed  Google Scholar 

  22. Sandmaier BM, Storb R . Nonmyeloablative therapy and hematopoietic cell transplantation for hematologic disorders. In: Blume K, Forman S, Appelbaum F (eds). Thomas' Hematopoietic Cell Transplantation. Blackwell Publishing: Malden, MA, USA, 2004, pp 1164–1176.

    Google Scholar 

  23. Storb R, Raff RF, Graham T, Appelbaum FR, Deeg HJ, Schuening FG et al. Marrow toxicity of fractionated vs single dose total body irradiation is identical in a canine model. Int J Radiat Oncol Biol Phys 1993; 26: 275–283.

    Article  CAS  PubMed  Google Scholar 

  24. Storb R, Raff RF, Appelbaum FR, Deeg HJ, Graham TC, Schuening FG et al. DLA-identical bone marrow grafts after low-dose total body irradiation: the effect of canine recombinant hematopoietic growth factors. Blood 1994; 84: 3558–3566.

    CAS  PubMed  Google Scholar 

  25. Nash RA, Schuening FG, Seidel K, Appelbaum FR, Boone T, Deeg HJ et al. Effect of recombinant canine granulocyte-macrophage colony-stimulating factor on hematopoietic recovery after otherwise lethal total body irradiation. Blood 1994; 83: 1963–1970.

    CAS  PubMed  Google Scholar 

  26. Storb R, Yu C, Wagner JL, Deeg HJ, Nash RA, Kiem HP et al. Stable mixed hematopoietic chimerism in DLA-identical littermate dogs given sublethal total body irradiation before and pharmacological immunosuppression after marrow transplantation. Blood 1997; 89: 3048–3054.

    CAS  PubMed  Google Scholar 

  27. Spitzer TR, McAfee S, Sackstein R, Colby C, Toh HC, Multani P et al. Intentional induction of mixed chimerism and achievement of antitumor responses after nonmyeloablative conditioning therapy and HLA-matched donor bone marrow transplantation for refractory hematologic malignancies. Biol Blood and Marrow Transplantation 2000; 6: 309–320.

    Article  CAS  Google Scholar 

  28. Dey BR, McAfee S, Colby C, Cieply K, Caron M, Saidman S et al. Anti-tumour response despite loss of donor chimaerism in patients treated with non-myeloablative conditioning and allogeneic stem cell transplantation. Br J Haematol 2005; 128: 351–359.

    Article  CAS  PubMed  Google Scholar 

  29. Mapara MY, Kim YM, Wang SP, Bronson R, Sachs DH, Sykes M . Donor lymphocyte infusions mediate superior graft-versus-leukemia effects in mixed compared to fully allogeneic chimeras: a critical role for host antigen-presenting cells. Blood 2002; 100: 1903–1909.

    Article  CAS  PubMed  Google Scholar 

  30. Kolb HJ, Gunther W, Schumm M, Holler E, Wilmanns W, Thierfelder S . Adoptive immunotherapy in canine chimeras. Transplantation 1997; 63: 430–436.

    Article  CAS  PubMed  Google Scholar 

  31. Klebanoff CA, Khong HT, Antony PA, Palmer DC, Restifo NP . Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy. Trends Immunol 2005; 26: 111–117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wrzesinski C, Restifo NP . Less is more: lymphodepletion followed by hematopoietic stem cell transplant augments adoptive T-cell-based anti-tumor immunotherapy. Curr Opin Immunol 2005; 17: 195–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Miller JS, Cooley S, Parham P, Farag SS, Verneris MR, McQueen KL et al. Missing KIR ligands are associated with less relapse and increased graft-versus-host disease (GVHD) following unrelated donor allogeneic HCT. Blood 2007; 109: 5058–5061.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Cooley S, McCullar V, Wangen R, Bergemann TL, Spellman S, Weisdorf DJ et al. KIR reconstitution is altered by T cells in the graft and correlates with clinical outcomes after unrelated donor transplantation. Blood 2005; 106: 4370–4376.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Penack O, Gentilini C, Fischer L, Asemissen AM, Scheibenbogen C, Thiel E et al. CD56dimCD16neg cells are responsible for natural cytotoxicity against tumor targets. Leukemia 2005; 19: 835–840.

    Article  CAS  PubMed  Google Scholar 

  36. Shilling HG, Guethlein LA, Cheng NW, Gardiner CM, Rodriguez R, Tyan D et al. Allelic polymorphism synergizes with variable gene content to individualize human KIR genotype. J Immunol 2002; 168: 2307–2315.

    Article  CAS  PubMed  Google Scholar 

  37. Shilling HG, McQueen KL, Cheng NW, Shizuru JA, Negrin RS, Parham P . Reconstitution of NK cell receptor repertoire following HLA-matched hematopoietic cell transplantation. Blood 2003; 101: 3730–3740.

    Article  CAS  PubMed  Google Scholar 

  38. Remberger M, Svahn BM, Mattsson J, Ringdén O . Dose study of thymoglobulin during conditioning for unrelated donor allogeneic stem-cell transplantation. Transplantation 2004; 78: 122–127.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We acknowledge the nurses, nurse practitioners and coordinators in the bone marrow transplant program at Loyola University. We also acknowledge Norma Neuswanger in the tissue typing laboratory at Loyola University and Dr John McCarty for his critical review of the manuscript.

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Authors and Affiliations

  1. Department of Internal Medicine, Bone Marrow Transplant Program, Stritch School of Medicine, Loyola University Medical Center, Maywood, IL, USA

    A Toor, T Rodriguez, M Bauml, J Norton, M Parthasarathy, C Petrowsky, S Smith & P Stiff

  2. Department of Microbiology & Immunology, Stritch School of Medicine, Loyola University Medical Center, Maywood, IL, USA

    H Mathews & S Shanti

  3. Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, USA,

    D Senitzer

  4. Department of Pathology, Stritch School of Medicine, Loyola University Medical Center, Maywood, IL, USA

    A Kini & B Bonilla

  5. Department of Radiation Oncology, Stritch School of Medicine, Loyola University Medical Center, Maywood, IL, USA

    N Mohideen

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  1. A Toor
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Correspondence to A Toor.

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Toor, A., Rodriguez, T., Bauml, M. et al. Feasibility of conditioning with thymoglobulin and reduced intensity TBI to reduce acute GVHD in recipients of allogeneic SCT. Bone Marrow Transplant 42, 723–731 (2008). https://doi.org/10.1038/bmt.2008.244

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  • DOI: https://doi.org/10.1038/bmt.2008.244

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