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Graft-versus-host Disease

Salvage therapy with everolimus reduces the severity of treatment-refractory chronic GVHD without impairing disease control: A dual center retrospective analysis

Bone Marrow Transplantation volume 49, pages 1412–1418 (2014)Cite this article

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Abstract

Chronic GVHD (cGVHD) remains the most important cause of late non-relapse mortality post allogeneic hematopoietic SCT (HSCT). Although first-line treatment of cGVHD with steroids is well established, evidence for second-line treatment remains limited. Here, we report a dual center retrospective analysis of the off-label salvage treatment of steroid-refractory cGVHD with everolimus. Out of 80 patients with a median age of 50 (17–70) years, 14 (17%) suffered from mild, 39 (49%) from moderate and 27 (34%) from severe cGVHD. At the final analysis, median follow-up after introduction of everolimus was 724 (14–2205) days. Thirty-four patients (43%) required the addition of further immunosuppression during everolimus-based therapy. Global NIH Severity Score improved in 34 patients (43%), remained stable in 37 patients (46%) and worsened in 9 patients (11%). The total sum of Global NIH Severity Scores in all patients assessable was significantly reduced after treatment with everolimus (P<0.0001). Most frequent grade 3/4 toxicities included infections (n=30) and thrombocytopenia (n=15). There was a single case of relapse. Everolimus-based salvage treatment of refractory cGVHD results in significant improvement of the NIH Severity Score without impairing control of the malignant disease. Finally, these preliminary results demand further verification in prospective trials.

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References

  1. Copelan EA . Hematopoietic stem-cell transplantation. New Engl J Med 2006; 354: 1813–1826.

    Article  CAS  PubMed  Google Scholar 

  2. Appelbaum FR . Hematopoietic-cell transplantation at 50. New Engl J Med 2007; 357: 1472–1475.

    Article  CAS  PubMed  Google Scholar 

  3. Gooley TA, Chien JW, Pergam SA, Hingorani S, Sorror ML, Boeckh M et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. New Engl J Med 2010; 363: 2091–2101.

    Article  CAS  PubMed  Google Scholar 

  4. Gratwohl A, Baldomero H, Gratwohl M, Aljurf M, Bouzas LF, Horowitz M et al. Quantitative and qualitative differences in use and trends of hematopoietic stem cell transplantation: a Global Observational Study. Haematologica 2013; 98: 1282–1290.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Pasquini MC, Wang Z, Horowitz MM, Gale RP . 2010 report from the Center for International Blood and Marrow Transplant Research (CIBMTR): current uses and outcomes of hematopoietic cell transplants for blood and bone marrow disorders. Clin Transpl 2011; 2010: 87–105.

    Google Scholar 

  6. Sutherland HJ, Fyles GM, Adams G, Hao Y, Lipton JH, Minden MD et al. Quality of life following bone marrow transplantation: a comparison of patient reports with population norms. Bone Marrow Transplant 1997; 19: 1129–1136.

    Article  CAS  PubMed  Google Scholar 

  7. Lee SJ, Klein JP, Barrett AJ, Ringden O, Antin JH, Cahn JY et al. Severity of chronic graft-versus-host disease: association with treatment-related mortality and relapse. Blood 2002; 100: 406–414.

    Article  CAS  PubMed  Google Scholar 

  8. Pavletic SZ, Fowler DH . Are we making progress in GVHD prophylaxis and treatment? Hematology Am Soc Hematol Educ Program 2012; 2012: 251–264.

    PubMed  Google Scholar 

  9. Wood WA, Chai X, Weisdorf D, Martin PJ, Cutler C, Inamoto Y et al. Comorbidity burden in patients with chronic GVHD. Bone Marrow Transplant 2013; 48: 1429–1436.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Weiden PL, Flournoy N, Sanders JE, Sullivan KM, Thomas ED . Antileukemic effect of graft-versus-host disease contributes to improved survival after allogeneic marrow transplantation. Transplant Proc 1981; 13: 248–251.

    CAS  PubMed  Google Scholar 

  11. Sullivan KM, Weiden PL, Storb R, Witherspoon RP, Fefer A, Fisher L et al. Influence of acute and chronic graft-versus-host disease on relapse and survival after bone marrow transplantation from HLA-identical siblings as treatment of acute and chronic leukemia. Blood 1989; 73: 1720–1728.

    CAS  PubMed  Google Scholar 

  12. 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 

  13. Rezvani K, Yong AS, Savani BN, Mielke S, Keyvanfar K, Gostick E et al. Graft-versus-leukemia effects associated with detectable Wilms tumor-1 specific T lymphocytes after allogeneic stem-cell transplantation for acute lymphoblastic leukemia. Blood 2007; 110: 1924–1932.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hilgendorf I, Wolff D, Nogai A, Kundt G, Hahn J, Holler E et al. Chronic graft versus host disease but not the intensity of conditioning has impact on survival after allogeneic hematopoietic stem cell transplantation for advanced hematological diseases. Onkologie 2012; 35: 487–492.

    Article  PubMed  Google Scholar 

  15. Arora M . Therapy of chronic graft-versus-host disease. Best Pract Res Clin Haematol 2008; 21: 271–279.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Inamoto Y, Flowers ME, Lee SJ, Carpenter PA, Warren EH, Deeg HJ et al. Influence of immunosuppressive treatment on risk of recurrent malignancy after allogeneic hematopoietic cell transplantation. Blood 2011; 118: 456–463.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Akpek G, Zahurak ML, Piantadosi S, Margolis J, Doherty J, Davidson R et al. Development of a prognostic model for grading chronic graft-versus-host disease. Blood 2001; 97: 1219–1226.

    Article  CAS  PubMed  Google Scholar 

  18. Devillier R, Castagna L, Gonzague L, El-Cheikh J, Furst S, Faucher C et al. TLI in refractory chronic GVHD. Bone Marrow Transplant 2013; 48: 854–858.

    Article  CAS  PubMed  Google Scholar 

  19. Akpek G, Lee SM, Anders V, Vogelsang GB . A high-dose pulse steroid regimen for controlling active chronic graft-versus-host disease. Biol Blood Marrow Transplant 2001; 7: 495–502.

    Article  CAS  PubMed  Google Scholar 

  20. Wolff D, Schleuning M, von Harsdorf S, Bacher U, Gerbitz A, Stadler M et al. Consensus Conference on Clinical Practice in Chronic GVHD: Second-Line Treatment of Chronic Graft-versus-Host Disease. Biol Blood Marrow Transplant 2011; 17: 1–17.

    Article  PubMed  Google Scholar 

  21. Couriel DR, Saliba R, Escalon MP, Hsu Y, Ghosh S, Ippoliti C et al. Sirolimus in combination with tacrolimus and corticosteroids for the treatment of resistant chronic graft-versus-host disease. Br J Haematol 2005; 130: 409–417.

    Article  CAS  PubMed  Google Scholar 

  22. Jurado M, Vallejo C, Perez-Simon JA, Brunet S, Ferra C, Balsalobre P et al. Sirolimus as part of immunosuppressive therapy for refractory chronic graft-versus-host disease. Biol Blood Marrow Transplant 2007; 13: 701–706.

    Article  CAS  PubMed  Google Scholar 

  23. Abouelnasr A, Roy J, Cohen S, Kiss T, Lachance S . Defining the role of sirolimus in the management of graft-versus-host disease: from prophylaxis to treatment. Biol Blood Marrow Transplant 2013; 19: 12–21.

    Article  CAS  PubMed  Google Scholar 

  24. Chapman TM, Perry CM . Everolimus. Drugs 2004; 64: 861–872 discussion 873-864.

    Article  CAS  PubMed  Google Scholar 

  25. Sanchez-Fructuoso AI . Everolimus: an update on the mechanism of action, pharmacokinetics and recent clinical trials. Expert Opin Drug Metab Toxicol 2008; 4: 807–819.

    Article  CAS  PubMed  Google Scholar 

  26. Sanchez-Fructuoso AI, Ruiz JC, Perez-Flores I, Gomez Alamillo C, Calvo Romero N, Arias M . Comparative analysis of adverse events requiring suspension of mTOR inhibitors: everolimus versus sirolimus. Transplant Proc 2010; 42: 3050–3052.

    Article  CAS  PubMed  Google Scholar 

  27. Rodriguez-Moreno A, Ridao N, Garcia-Ledesma P, Calvo N, Perez-Flores I, Marques M et al. Sirolimus and everolimus induced pneumonitis in adult renal allograft recipients: experience in a center. Transplant Proc 2009; 41: 2163–2165.

    Article  CAS  PubMed  Google Scholar 

  28. Vitko S, Margreiter R, Weimar W, Dantal J, Kuypers D, Winkler M et al. Three-year efficacy and safety results from a study of everolimus versus mycophenolate mofetil in de novo renal transplant patients. Am J Transplant 2005; 5: 2521–2530.

    Article  CAS  PubMed  Google Scholar 

  29. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer 2010; 116: 4256–4265.

    Article  CAS  PubMed  Google Scholar 

  30. Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. New Engl J Med 2012; 366: 520–529.

    Article  CAS  PubMed  Google Scholar 

  31. Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E et al. Everolimus for advanced pancreatic neuroendocrine tumors. New Engl J Med 2011; 364: 514–523.

    Article  CAS  PubMed  Google Scholar 

  32. Platzbecker U, von Bonin M, Goekkurt E, Radke J, Binder M, Kiani A et al. Graft-versus-host disease prophylaxis with everolimus and tacrolimus is associated with a high incidence of sinusoidal obstruction syndrome and microangiopathy: results of the EVTAC trial. Biol Blood Marrow Transplant 2009; 15: 101–108.

    Article  CAS  PubMed  Google Scholar 

  33. Jedlickova Z, Burlakova I, Bug G, Baurmann H, Schwerdtfeger R, Schleuning M . Therapy of sclerodermatous chronic graft-versus-host disease with mammalian target of rapamycin inhibitors. Biol Blood Marrow Transplant 2011; 17: 657–663.

    Article  CAS  PubMed  Google Scholar 

  34. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 2005; 11: 945–956.

    Article  PubMed  Google Scholar 

  35. Linhares YP, Pavletic S, Gale RP . Chronic GVHD: Where are we? Where do we want to be? Will immunomodulatory drugs help? Bone Marrow Transplant 2013; 48: 203–209.

    Article  CAS  PubMed  Google Scholar 

  36. Martin PJ, Inamoto Y, Carpenter PA, Lee SJ, Flowers ME . Treatment of chronic graft-versus-host disease: Past, present and future. Korean J Hematol 2011; 46: 153–163.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Keller F, Wiesner S, Bunjes D, Hartmann B, Schmitt M . Safety and efficacy of everolimus after kidney and hematopoietic stem cell transplantation. Ann Transplant 2012; 17: 52–58.

    PubMed  Google Scholar 

  38. Armand P, Gannamaneni S, Kim HT, Cutler CS, Ho VT, Koreth J et al. Improved survival in lymphoma patients receiving sirolimus for graft-versus-host disease prophylaxis after allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning. J Clin Oncol 2008; 26: 5767–5774.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kirken RA, Wang YL . Molecular actions of sirolimus: sirolimus and mTor. Transplant Proc 2003; 35: 227S–230S.

    Article  CAS  PubMed  Google Scholar 

  40. Recher C, Beyne-Rauzy O, Demur C, Chicanne G, Dos Santos C, Mas VM et al. Antileukemic activity of rapamycin in acute myeloid leukemia. Blood 2005; 105: 2527–2534.

    Article  CAS  PubMed  Google Scholar 

  41. Mielke S, Lutz M, Schmidhuber J, Kapp M, Ammer J, Einsele H et al. Salvage therapy with everolimus reduces the severity of treatment-refractory chronic graft-versus-host disease without impairing disease control: A dual center experience. Blood (ASH Annual Meeting Abstracts) 2012; 120: 4173.

    Google Scholar 

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Acknowledgements

We wish to thank our patients participating in this study. Parts of this work have been presented at the annual meeting of the American Society for Hematology (ASH) in Atlanta 2012.41 This work contains parts of the doctoral theses of JS and ML. We also thank Judy Peng, PhD, for critical reading of the manuscript.

Author contributions

SM and DW designed the study, provided patient care, analyzed data and wrote the paper; ML: collected and analyzed data, created figures and wrote the paper; JS: collected and analyzed data and contributed to the manuscript; DD and JA provided patient care and contributed to the manuscript; EH designed the study, provided patient care and contributed to the manuscript; MK, GUG and HE provided patient care and contributed to the manuscript.

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Author notes

  1. S Mielke and M Lutz: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine II, Allogeneic Stem Cell Transplantation Section, Würzburg University Medical Center, Würzburg, Germany

    S Mielke, M Lutz, M Kapp, H Einsele & G U Grigoleit

  2. Department of Internal Medicine III, Regensburg University Medical Center, Regensburg, Germany

    J Schmidhuber, D Ditz, J Ammer, E Holler & D Wolff

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  1. S Mielke
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Correspondence to S Mielke.

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Competing interests

SM received honoraria and travel grants from Novartis, Germany. DW and EH received research funding from Novartis, Germany. ML, JS, MK, DD, JA, HE and GUG declare no conflict of interest.

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Mielke, S., Lutz, M., Schmidhuber, J. et al. Salvage therapy with everolimus reduces the severity of treatment-refractory chronic GVHD without impairing disease control: A dual center retrospective analysis. Bone Marrow Transplant 49, 1412–1418 (2014). https://doi.org/10.1038/bmt.2014.170

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