Skip to main content

Advertisement

Log in

Alemtuzumab for the prevention and treatment of graft-versus-host disease

  • Progress in Hematology
  • Role of monoclonal antibodies for the prevention and treatment of graft-versus-host disease
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Alemtuzumab is a humanized monoclonal antibody against the CD52 antigen, which is expressed on the surface of various hematopoietic cells such as B and T lymphocytes, and has been widely used for preventing acute graft-versus-host disease (GVHD) in allogeneic stem cell transplantation (SCT). Administration of 100 mg alemtuzumab before transplantation has resulted in a low incidence of acute GVHD in HLA-matched and mismatched transplantation from either related or unrelated donors. However, because alemtuzumab could remain in the blood at the lympholytic level 1–2 months after transplantation, immune reconstitution was substantially delayed, leading to a high incidence of viral infection and relapse. A dose reduction of alemtuzumab was attempted in a reduced-intensity conditioning setting to facilitate immune reconstitution, and this resulted in earlier immune reconstitution, but the clinical benefits were unclear. The dose of alemtuzumab and the timing of its administration should be optimized to maximize the benefit of acute GVHD suppression and minimize the risk of infection and relapse. Another strategy to facilitate immune reconstitution and augment anti-tumor effects is donor cell infusion of T and NK cells. Although there is accumulating evidence regarding the use of alemtuzumab for acute GVHD prevention, information on the salvage treatment for steroid-refractory acute and chronic GVHD is still limited.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Ferrara JL, Levine JE, Reddy P, Holler E. Graft-versus-host disease. Lancet. 2009;373:1550–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hale G, Bright S, Chumbley G, Hoang T, Metcalf D, Munro AJ, et al. Removal of T cells from bone marrow for transplantation: a monoclonal antilymphocyte antibody that fixes human complement. Blood. 1983;62:873–82.

    CAS  PubMed  Google Scholar 

  3. Waldmann H, Hale G. CAMPATH: from concept to clinic. Philos Trans R Soc Lond B Biol Sci. 2005;360:1707–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Waldmann H, Polliak A, Hale G, Or R, Cividalli G, Weiss L, et al. Elimination of graft-versus-host disease by in vitro depletion of alloreactive lymphocytes with a monoclonal rat anti-human lymphocyte antibody (CAMPATH-1). Lancet. 1984;2:483–6.

    Article  CAS  PubMed  Google Scholar 

  5. Hale G, Xia MQ, Tighe HP, Dyer MJ, Waldmann H. The CAMPATH-1 antigen (CDw52). Tissue Antigens. 1990;35:118–27.

    Article  CAS  PubMed  Google Scholar 

  6. Xia MQ, Tone M, Packman L, Hale G, Waldmann H. Characterization of the CAMPATH-1 (CDw52) antigen: biochemical analysis and cDNA cloning reveal an unusually small peptide backbone. Eur J Immunol. 1991;21:1677–84.

    Article  CAS  PubMed  Google Scholar 

  7. Watanabe T, Masuyama J, Sohma Y, Inazawa H, Horie K, Kojima K, et al. CD52 is a novel costimulatory molecule for induction of CD4+ regulatory T cells. Clin Immunol. 2006;120:247–59.

    Article  CAS  PubMed  Google Scholar 

  8. Dyer MJ, Hale G, Hayhoe FG, Waldmann H. Effects of CAMPATH-1 antibodies in vivo in patients with lymphoid malignancies: influence of antibody isotype. Blood. 1989;73:1431–9.

    CAS  PubMed  Google Scholar 

  9. Rebello PR, Hale G, Friend PJ, Cobbold SP, Waldmann H. Anti-globulin responses to rat and humanized CAMPATH-1 monoclonal antibody used to treat transplant rejection. Transplantation. 1999;68:1417–20.

    Article  CAS  PubMed  Google Scholar 

  10. Cull GM, Haynes AP, Byrne JL, Carter GI, Miflin G, Rebello P, et al. Preliminary experience of allogeneic stem cell transplantation for lymphoproliferative disorders using BEAM-CAMPATH conditioning: an effective regimen with low procedure-related toxicity. Br J Haematol. 2000;108:754–60.

    Article  CAS  PubMed  Google Scholar 

  11. Rizzieri DA, Koh LP, Long GD, Gasparetto C, Sullivan KM, Horwitz M, et al. Partially matched, nonmyeloablative allogeneic transplantation: clinical outcomes and immune reconstitution. J Clin Oncol. 2007;25:690–7.

    Article  CAS  PubMed  Google Scholar 

  12. Hale G, Rebello P, Brettman LR, Fegan C, Kennedy B, Kimby E, et al. Blood concentrations of alemtuzumab and antiglobulin responses in patients with chronic lymphocytic leukemia following intravenous or subcutaneous routes of administration. Blood. 2004;104:948–55.

    Article  CAS  PubMed  Google Scholar 

  13. Morris EC, Rebello P, Thomson KJ, Peggs KS, Kyriakou C, Goldstone AH, et al. Pharmacokinetics of alemtuzumab used for in vivo and in vitro T-cell depletion in allogeneic transplantations: relevance for early adoptive immunotherapy and infectious complications. Blood. 2003;102:404–6.

    Article  CAS  PubMed  Google Scholar 

  14. Khouri IF, Albitar M, Saliba RM, Ippoliti C, Ma YC, Keating MJ, et al. Low-dose alemtuzumab (Campath) in myeloablative allogeneic stem cell transplantation for CD52-positive malignancies: decreased incidence of acute graft-versus-host-disease with unique pharmacokinetics. Bone Marrow Transplant. 2004;33:833–7.

    Article  CAS  PubMed  Google Scholar 

  15. Chakraverty R, Orti G, Roughton M, Shen J, Fielding A, Kottaridis P, et al. Impact of in vivo alemtuzumab dose before reduced intensity conditioning and HLA-identical sibling stem cell transplantation: pharmacokinetics, GVHD, and immune reconstitution. Blood. 2010;116:3080–8.

    Article  CAS  PubMed  Google Scholar 

  16. Oshima K, Kanda Y, Nakahara F, Shoda E, Suzuki T, Imai Y, et al. Pharmacokinetics of alemtuzumab after haploidentical HLA-mismatched hematopoietic stem cell transplantation using in vivo alemtuzumab with or without CD52-positive malignancies. Am J Hematol. 2006;81:875–9.

    Article  CAS  PubMed  Google Scholar 

  17. Kottaridis PD, Milligan DW, Chopra R, Chakraverty RK, Chakrabarti S, Robinson S, et al. In vivo CAMPATH-1H prevents graft-versus-host disease following nonmyeloablative stem cell transplantation. Blood. 2000;96:2419–25.

    CAS  PubMed  Google Scholar 

  18. Chakraverty R, Peggs K, Chopra R, Milligan DW, Kottaridis PD, Verfuerth S, et al. Limiting transplantation-related mortality following unrelated donor stem cell transplantation by using a nonmyeloablative conditioning regimen. Blood. 2002;99:1071–8.

    Article  CAS  PubMed  Google Scholar 

  19. Mead AJ, Thomson KJ, Morris EC, Mohamedbhai S, Denovan S, Orti G, et al. HLA-mismatched unrelated donors are a viable alternate graft source for allogeneic transplantation following alemtuzumab-based reduced-intensity conditioning. Blood. 2010;115:5147–53.

    Article  CAS  PubMed  Google Scholar 

  20. Kanda Y, Oshima K, Asano-Mori Y, Kandabashi K, Nakagawa M, Sakata-Yanagimoto M, et al. In vivo alemtuzumab enables haploidentical human leukocyte antigen-mismatched hematopoietic stem-cell transplantation without ex vivo graft manipulation. Transplantation. 2005;79:1351–7.

    Article  CAS  PubMed  Google Scholar 

  21. Barge RM, Starrenburg CW, Falkenburg JH, Fibbe WE, Marijt EW, Willemze R. Long-term follow-up of myeloablative allogeneic stem cell transplantation using Campath “in the bag” as T-cell depletion: the Leiden experience. Bone Marrow Transplant. 2006;37:1129–34.

    Article  CAS  PubMed  Google Scholar 

  22. von dem Borne PA, Starrenburg CW, Halkes SJ, Marijt WA, Fibbe WE, Falkenburg JH, et al. Reduced-intensity conditioning allogeneic stem cell transplantation with donor T-cell depletion using alemtuzumab added to the graft (‘Campath in the bag’). Curr Opin Oncol. 2009;21 Suppl 1: S27–9.

    Google Scholar 

  23. Buyck HC, Prentice HG, Griffiths PD, Emery VC. The risk of early and late CMV DNAemia associated with Campath use in stem cell transplant recipients. Bone Marrow Transplant. 2010;45:1212–9.

    Article  CAS  PubMed  Google Scholar 

  24. Chakrabarti S, Mackinnon S, Chopra R, Kottaridis PD, Peggs K, O’Gorman P, et al. High incidence of cytomegalovirus infection after nonmyeloablative stem cell transplantation: potential role of Campath-1H in delaying immune reconstitution. Blood. 2002;99:4357–63.

    Article  CAS  PubMed  Google Scholar 

  25. Chakrabarti S, Mautner V, Osman H, Collingham KE, Fegan CD, Klapper PE, et al. Adenovirus infections following allogeneic stem cell transplantation: incidence and outcome in relation to graft manipulation, immunosuppression, and immune recovery. Blood. 2002;100:1619–27.

    Article  CAS  PubMed  Google Scholar 

  26. Chakrabarti S, Milligan DW, Pillay D, Mackinnon S, Holder K, Kaur N, et al. Reconstitution of the Epstein–Barr virus-specific cytotoxic T-lymphocyte response following T-cell-depleted myeloablative and nonmyeloablative allogeneic stem cell transplantation. Blood. 2003;102:839–42.

    Article  CAS  PubMed  Google Scholar 

  27. Perez-Simon JA, Kottaridis PD, Martino R, Craddock C, Caballero D, Chopra R, et al. Nonmyeloablative transplantation with or without alemtuzumab: comparison between 2 prospective studies in patients with lymphoproliferative disorders. Blood. 2002;100:3121–7.

    Article  CAS  PubMed  Google Scholar 

  28. Rizzieri DA, Dev P, Long GD, Gasparetto C, Sullivan KM, Horwitz M, et al. Response and toxicity of donor lymphocyte infusions following T-cell depleted non-myeloablative allogeneic hematopoietic SCT from 3–6/6 HLA matched donors. Bone Marrow Transplant. 2009;43:327–33.

    Article  CAS  PubMed  Google Scholar 

  29. Peggs KS, Thomson K, Hart DP, Geary J, Morris EC, Yong K, et al. Dose-escalated donor lymphocyte infusions following reduced intensity transplantation: toxicity, chimerism, and disease responses. Blood. 2004;103:1548–56.

    Article  CAS  PubMed  Google Scholar 

  30. Cobbold M, Khan N, Pourgheysari B, Tauro S, McDonald D, Osman H, et al. Adoptive transfer of cytomegalovirus-specific CTL to stem cell transplant patients after selection by HLA-peptide tetramers. J Exp Med. 2005;202:379–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Peggs KS, Verfuerth S, Pizzey A, Khan N, Guiver M, Moss PA, et al. Adoptive cellular therapy for early cytomegalovirus infection after allogeneic stem-cell transplantation with virus-specific T-cell lines. Lancet. 2003;362:1375–7.

    Article  PubMed  Google Scholar 

  32. Orti G, Lowdell M, Fielding A, Samuel E, Pang K, Kottaridis P, et al. Phase I study of high-stringency CD8 depletion of donor leukocyte infusions after allogeneic hematopoietic stem cell transplantation. Transplantation. 2009;88:1312–8.

    Article  PubMed  Google Scholar 

  33. Amrolia PJ, Muccioli-Casadei G, Huls H, Adams S, Durett A, Gee A, et al. Adoptive immunotherapy with allodepleted donor T-cells improves immune reconstitution after haploidentical stem cell transplantation. Blood. 2006;108:1797–808.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Roy DC, Lachance S, Kiss T, Cohen S, Busque L, Fish D, et al. Haploidentical stem cell transplantation: high doses of alloreactive-T cell depleted donor lymphocytes administered post-transplant decrease infections and improve survival without causing severe GVHD. Blood (ASH annual Meeting Abstracts). 2009;114:512.

    Google Scholar 

  35. Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science. 2002;295:2097–100.

    Article  CAS  PubMed  Google Scholar 

  36. Ruggeri L, Mancusi A, Capanni M, Urbani E, Carotti A, Aloisi T, et al. Donor natural killer cell allorecognition of missing self in haploidentical hematopoietic transplantation for acute myeloid leukemia: challenging its predictive value. Blood. 2007;110:433–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hsu KC, Keever-Taylor CA, Wilton A, Pinto C, Heller G, Arkun K, et al. Improved outcome in HLA-identical sibling hematopoietic stem-cell transplantation for acute myelogenous leukemia predicted by KIR and HLA genotypes. Blood. 2005;105:4878–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Prasad VK, Chen D, Broadwater G, Reinsmoen NL, Clark A, Chao NJ, et al. Differential impact of inhibitory and activating killer Ig-Like receptors and HLA ligand on outcomes of transplantation for myeloid and lymphoid malignancies. Blood (ASH annual Meeting Abstracts). 2008;112:Abstract 3255.

  39. Rizzieri DA, Storms R, Chen DF, Long GD, Yang Y, Nikcevich DA, et al. Natural killer cell enriched donor lymphocyte infusions from a 3–6/6 HLA matched family member following non-myeloablative allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2010;18:1107–14.

    Article  Google Scholar 

  40. Schnitzler M, Hasskarl J, Egger M, Bertz H, Finke J. Successful treatment of severe acute intestinal graft-versus-host resistant to systemic and topical steroids with alemtuzumab. Biol Blood Marrow Transplant. 2009;15:910–8.

    Article  CAS  PubMed  Google Scholar 

  41. Gomez-Almaguer D, Ruiz-Arguelles GJ, del Carmen Tarin-Arzaga L, Gonzalez-Llano O, Gutierrez-Aguirre H, Cantu-Rodriguez O, et al. Alemtuzumab for the treatment of steroid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant. 2008;14:10–5.

    Article  CAS  PubMed  Google Scholar 

  42. Martinez C, Solano C, Ferra C, Sampol A, Valcarcel D, Perez-Simon JA. Alemtuzumab as treatment of steroid-refractory acute graft-versus-host disease: results of a phase II study. Biol Blood Marrow Transplant. 2009;15:639–42.

    Article  CAS  PubMed  Google Scholar 

  43. Malladi RK, Peniket AJ, Littlewood TJ, Towlson KE, Pearce R, Yin J, et al. Alemtuzumab markedly reduces chronic GVHD without affecting overall survival in reduced-intensity conditioning sibling allo-SCT for adults with AML. Bone Marrow Transplant. 2009;43:709–15.

    Article  CAS  PubMed  Google Scholar 

  44. Ruiz-Arguelles GJ, Gil-Beristain J, Magana M, Ruiz-Delgado GJ. Alemtuzumab-induced resolution of refractory cutaneous chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2008;14:7–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgement

J.K. is a Research Fellow of the Japan Society for the Promotion of Science.

Conflict of interest

The authors have no financial disclosures relevant to this manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to David A. Rizzieri.

About this article

Cite this article

Kanda, J., Lopez, R.D. & Rizzieri, D.A. Alemtuzumab for the prevention and treatment of graft-versus-host disease. Int J Hematol 93, 586–593 (2011). https://doi.org/10.1007/s12185-011-0802-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-011-0802-2

Keywords

Navigation