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Pharmacokinetics and immunological outcomes of alemtuzumab-based treatment for steroid-refractory acute GvHD

Bone Marrow Transplantation volume 51, pages 1153–1155 (2016)Cite this article

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There is currently no standardized approach for the treatment of steroid-refractory acute GvHD (SR-aGvHD).1, 2 Alemtuzumab has been shown to have clinical activity in a number of small prospective and retrospective studies, but optimal doses remain unknown and survival remains poor, with deaths from both GvHD and infection contributing.3, 4, 5, 6, 7, 8 Critically, very little is known about alemtuzumab's pharmacokinetics and pharmacodynamics in this context, and therefore dosing is empirical, ranging from 10–50 mg in the first week, with or without repeat dosing at 10–30 mg every 1–4 weeks.3, 4, 5, 6, 7 In order to better define the clinical outcome and develop a rational approach to alemtuzumab dosing in SR-aGvHD, we conducted a phase II clinical study in which we incorporated weekly pharmacokinetics and immunological monitoring.

This study was opened at the Royal Brisbane and Women’s Hospital (RBWH), Royal Melbourne Hospital and Westmead Hospital, all in Australia. The primary end point was overall survival at 6 months post alemtuzumab. The secondary end points were aGvHD response, infection rate and incidence of chronic GvHD. The study was approved by the human research ethics committee at the RBWH and registered on the Australian New Zealand Clinical Trials Registry (ACTRN12613000288729). The target enrollment was 16 patients based on a 6-month overall survival of 50% for SR-aGvHD treated with anti-thymoglobulin (ATG)-based therapy at the RBWH.9 Regrettably, however, the study was closed after the enrollment of four patients as access to alemtuzumab was prevented by a new pharmaceutical supplier within the context of their repurposing development.

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References

  1. Martin PJ, Rizzo JD, Wingard JR, Ballen K, Curtin PT, Cutler C et al. First- and second-line systemic treatment of acute graft-versus-host disease: recommendations of the American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transplant 2012; 18: 1150–1163.

    Article  Google Scholar 

  2. Deeg HJ . How I treat refractory acute GVHD. Blood 2007; 109: 4119–4126.

    Article  CAS  Google Scholar 

  3. Meunier M, Bulabois CE, Thiebaut-Bertrand A, Itzykson R, Carre M, Carras S et al. Alemtuzumab for severe steroid-refractory gastrointestinal acute graft-versus-host disease. Biol Blood Marrow Transplant 2014; 20: 1451–1454.

    Article  CAS  Google Scholar 

  4. 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: 910–918.

    Article  CAS  Google Scholar 

  5. Schub N, Gunther A, Schrauder A, Claviez A, Ehlert C, Gramatzki M et al. Therapy of steroid-refractory acute GVHD with CD52 antibody alemtuzumab is effective. Bone Marrow Transplant 2011; 46: 143–147.

    Article  CAS  Google Scholar 

  6. 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: 10–15.

    Article  CAS  Google Scholar 

  7. 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: 639–642.

    Article  CAS  Google Scholar 

  8. Khandelwal P, Lawrence J, Filipovich AH, Davies SM, Bleesing JJ, Jordan MB et al. The successful use of alemtuzumab for treatment of steroid-refractory acute graft-versus-host disease in pediatric patients. Pediatr Transplant 2014; 18: 94–102.

    Article  CAS  Google Scholar 

  9. Kennedy GA, Butler J, Western R, Morton J, Durrant S, Hill GR . Combination antithymocyte globulin and soluble TNFalpha inhibitor (etanercept) +/- mycophenolate mofetil for treatment of steroid refractory acute graft-versus-host disease. Bone Marrow Transplant 2006; 37: 1143–1147.

    Article  CAS  Google Scholar 

  10. 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  Google Scholar 

  11. 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: 948–955.

    Article  CAS  Google Scholar 

  12. Rebello P, Hale G . Pharmacokinetics of CAMPATH-1H: assay development and validation. J Immunol Methods 2002; 260: 285–302.

    Article  CAS  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: 404–406.

    Article  CAS  Google Scholar 

  14. Mould DR, Baumann A, Kuhlmann J, Keating MJ, Weitman S, Hillmen P et al. Population pharmacokinetics-pharmacodynamics of alemtuzumab (Campath) in patients with chronic lymphocytic leukaemia and its link to treatment response. Br J Clin Pharmacol 2007; 64: 278–291.

    Article  CAS  Google Scholar 

  15. Zhang X, Tao Y, Chopra M, Ahn M, Marcus KL, Choudhary N et al. Differential reconstitution of T cell subsets following immunodepleting treatment with alemtuzumab (Anti-CD52 monoclonal antibody) in patients with relapsing–remitting multiple sclerosis. J Immunol 2013; 191: 5867–5874.

    Article  CAS  Google Scholar 

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Acknowledgements

GRH is supported by an NHMRC Australian Fellowship and SKT is supported by an NHMRC Early Career Fellowship.

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Authors and Affiliations

  1. Bone Marrow Transplant Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia

    S-K Tey, S Vuckovic, A Varelias, J P Martins, S Olver, L Samson, G A Kennedy & G R Hill

  2. Department of Haematology and Bone Marrow Transplantation, Royal Brisbane and Women’s Hospital, Butterfield St, Brisbane, Queensland, Australia

    S-K Tey, E Sturgeon, J Leach, J Avery, M Nakagaki, J P Butler, C Curley, A J Morton, S T Durrant, G A Kennedy & G R Hill

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  1. S-K Tey
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Correspondence to S-K Tey.

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Tey, SK., Vuckovic, S., Varelias, A. et al. Pharmacokinetics and immunological outcomes of alemtuzumab-based treatment for steroid-refractory acute GvHD. Bone Marrow Transplant 51, 1153–1155 (2016). https://doi.org/10.1038/bmt.2016.83

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