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Evaluation of infliximab as second-line treatment of acute graft versus host disease -validating response on day 7 and 28 as predictors of survival

Bone Marrow Transplantation volume 53, pages 844–851 (2018)Cite this article

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Abstract

Several immunosuppressive drugs have been proposed for second-line treatment of steroid-refractory acute graft versus host disease (aGvHD) after allogeneic hematopoietic stem cell transplantation. However, the studies on these drugs are small, retrospective, uncontrolled and use different endpoints. Therefore, it remains unknown which treatment is superior. We retrospectively evaluated 68 consecutive patients treated with infliximab for aGvHD. We adhered to recently proposed guidelines for aGvHD trials and thus evaluated response on day 7 and 28. Furthermore, we assessed the composite endpoint 6 months freedom from treatment failure (6MFTF). The majority of patients had grade III-IV aGvHD. We found that 41 patients (60%) responded on day 7 and 31 patients (46%) on day 28. Twenty-four patients (35%) achieved 6MFTF. The main reasons for failure within 6 months were death (n = 31) or additional immunosuppression (n = 16). By six and 24 months, 44 and 34% of the patients were alive respectively. Patients with response to infliximab on day 7 and 28 had significantly higher overall survival (OS) probability than non-responders. We show that response on day 7 and 28 identifies high and low risk groups. Patients who fail to respond should be identified early and offered alternative therapy.

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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 Transpl. 2012;18:1150–63.

    Article  Google Scholar 

  2. Martin PJ, Inamoto Y, Flowers MED, Carpenter PA. Secondary treatment of acute graft-versus-host disease: a critical review. Biol Blood Marrow Transpl. 2012;18:982–8.

    Article  Google Scholar 

  3. Martin PJ. Study design and endpoints in graft-versus-host disease. Best Pract Res Clin Haematol. 2008;21:357–72.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Martin PJ, Bachier CR, Klingemann H-G, McCarthy PL, Szabolcs P, Uberti JP, et al. Endpoints for clinical trials testing treatment of acute graft-versus-host disease: a joint statement. Biol Blood Marrow Transpl. 2009;15:777–84.

    Article  CAS  Google Scholar 

  5. Sengsayadeth S, Savani BN, Jagasia M, Goodman S, Greer JP, Chen H, et al. Six-month freedom from treatment failure is an important end point for acute GVHD clinical trials. Bone Marrow Transpl. 2014;49:236–40.

    Article  CAS  Google Scholar 

  6. Inamoto Y, Martin PJ, Storer BE, Mielcarek M, Storb RF, Carpenter PA. Response endpoints and failure-free survival after initial treatment for acute graft-versus-host disease. Haematologica. 2014;99:385–91.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Remberger M, Ringden O, Markling L. TNF alpha levels are increased during bone marrow transplantation conditioning in patients who develop acute GVHD. Bone Marrow Transpl. 1995;15:99–104.

    CAS  Google Scholar 

  8. Korngold R, Marini JC, De Baca ME, Murphy GF, Giles-komar J. Role of tumor necrosis factor alpha in graft-versus-host disease and graft-versus-leukemia responses. Biol Blood Marrow Transpl. 2003;303:292–303.

    Article  Google Scholar 

  9. Choi SW, Stiff P, Cooke K, Ferrara JLM, Braun T, Kitko C, et al. TNF-inhibition with etanercept for graft-versus-host disease prevention in high-risk HCT: lower TNFR1 levels correlate with better outcomes. Biol Blood Marrow Transpl. 2012;18:1525–32.

    Article  CAS  Google Scholar 

  10. Hamadani M, Hofmeister CC, Jansak B, Phillips G, Elder P, Blum W, et al. Addition of Infliximab to standard acute graft-versus-host disease prophylaxis following allogeneic peripheral blood cell transplantation. Biol Blood Marrow Transpl. 2008;14:783–9.

    Article  Google Scholar 

  11. Alousi AM, Weisdorf DJ, Logan BR, Bolan J, Carter S, Difronzo N, et al. Etanercept, mycophenolate, denileukin, or pentostatin plus corticosteroids for acute graft-versus-host disease: a randomized phase 2 trial from the Blood and Marrow Transplant Clinical Trials Network. Blood. 2009;114:511–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Uberti JP, Ayash L, Ratanatharathorn V, Silver S, Reynolds C, Becker M, et al. Pilot trial on the use of etanercept and methylprednisolone as primary treatment for acute graft-versus-host disease. Biol Blood Marrow Transplant. 2005;11:680–7.

    Article  PubMed  CAS  Google Scholar 

  13. Levine JE, Paczesny S, Mineishi S, Braun T, Choi SW, Hutchinson RJ, et al. Etanercept plus methylprednisolone as initial therapy for acute graft-versus-host disease. Blood. 2008;111:2470–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Couriel DR, Saliba R, de Lima M, Giralt S, Andersson B, Khouri I, et al. A phase III study of infliximab and corticosteroids for the initial treatment of acute graft-versus-host disease. Biol Blood Marrow Transpl. 2009;15:1555–62.

    Article  CAS  Google Scholar 

  15. Gatza E, Braun T, Levine JE, Ferrara JLM, Zhao S, Wang T, et al. Etanercept plus topical corticosteroids as initial therapy for grade one acute graft-versus-host disease after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transpl. 2014;20:1426–34.

    Article  CAS  Google Scholar 

  16. Herve BP, Flesch M, Tiberghien P, Wijdenes J, Racadot E, Bordigoni P, et al. Phase I-II Trial a Monoclon Anti-Tumor Necrosis Factor. Blood. 1992;79:3362–8.

  17. Kobbe G, Schneider P, Rohr U, Fenk R, Neumann F, Aivado M, et al. Treatment of severe steroid refractory acute graft-versus-host disease with infliximab, a chimeric human/mouse antiTNFalpha antibody. Bone Marrow Transpl. 2001;28:47–9.

    Article  CAS  Google Scholar 

  18. Rivkina AM, Stump LS. Infliximab in graft-versus-host disease. Am J Health Syst Pharm. 2002;59:1271–5.

    PubMed  CAS  Google Scholar 

  19. Yamane T, Yamamura R, Aoyama Y, Nakamae H, Hasegawa T, Sakamoto C, et al. Infliximab for the treatment of severe steroid refractory acute graft-versus-host disease in three patients after allogeneic hematopoietic transplantation. Leuk Lymphoma. 2003;44:2095–7.

    Article  PubMed  CAS  Google Scholar 

  20. Patriarca F, Sperotto A, Damiani D, Morreale G, Bonifazi F, Olivieri A, et al. Infliximab treatment for steroid-refractory acute graft-versus-host disease. Haematologica. 2004;89:1352–9.

    PubMed  CAS  Google Scholar 

  21. Couriel D, Saliba R, Hicks K, Ippoliti C, de Lima M, Hosing C, et al. Tumor necrosis factor-alpha blockade for the treatment of acute GVHD. Blood. 2004;104:649–54.

    Article  PubMed  CAS  Google Scholar 

  22. Sleight BS, Chan KW, Braun TM, Serrano A, Gilman A L. Infliximab for GVHD therapy in children. Bone Marrow Transpl. 2007;40:473–80.

    Article  CAS  Google Scholar 

  23. Pidala J, Kim J, Field T, McBride A, Kharfan-Dabaja M, Perkins J, et al. Infliximab for managing steroid-refractory acute graft-versus-host disease. Biol Blood Marrow Transpl. 2009;15:1116–21.

    Article  CAS  Google Scholar 

  24. Rao K, Rao A, Karlsson H, Jagani M, Veys P, Amrolia PJ. Improved survival and preserved antiviral responses after combination therapy with daclizumab and infliximab in steroid-refractory graft-versus-host disease. J Pediatr Hematol Oncol. 2009;31:456–61.

    Article  PubMed  CAS  Google Scholar 

  25. Yang J, Cheuk DKL, Ha SY, Chiang AKS, Lee TL, Ho MHK, et al. Infliximab for steroid refractory or dependent gastrointestinal acute graft-versus-host disease in children after allogeneic hematopoietic stem cell transplantation. Pediatr Transpl. 2012;16:771–8.

    Article  CAS  Google Scholar 

  26. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 consensus conference on acute GVHD grading. Bone Marrow Transpl. 1995;15:825–8.

    CAS  Google Scholar 

  27. MacMillan ML, DeFor TE, Weisdorf DJ. The best endpoint for acute GVHD treatment trials. Blood. 2010;115:5412–7.

    Article  PubMed  CAS  Google Scholar 

  28. Saliba RM, Couriel DR, Giralt S, Rondon G, Okoroji G-J, Rashid A, et al. Prognostic value of response after upfront therapy for acute GVHD. Bone Marrow Transpl. 2012;47:125–31.

    Article  CAS  Google Scholar 

  29. Levine JE, Logan B, Wu J, Alousi AM, Ho V, Bolaños-Meade J, et al. Graft-versus-host disease treatment: predictors of survival. Biol Blood Marrow Transpl. 2010;16:1693–9.

    Article  Google Scholar 

  30. Marty FM, Lee SJ, Fahey MM, Alyea EP, Soiffer RJ, Antin JH, et al. Infliximab use in patients with severe graft-versus-host disease and other emerging risk factors of non-Candida invasive fungal infections in allogeneic hematopoietic stem cell transplant recipients: a cohort study. Blood. 2003;102:2768–76.

    Article  PubMed  CAS  Google Scholar 

  31. García-Cadenas I, Rivera I, Martino R, Esquirol A, Barba P, Novelli S, et al. Patterns of infection and infection-related mortality in patients with steroid-refractory acute graft versus host disease. Bone Marrow Transpl. 2017;52:107–13.

    Article  CAS  Google Scholar 

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Acknowledgements

Supported by unrestricted grants from the Novo Nordisk Foundation (NNF15OC0014158) and the Danish Cancer Society.

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Authors and Affiliations

  1. Department of Hematology, National University Hospital, Rigshospitalet, Denmark

    Marietta Nygaard, Niels Smedegaard Andersen, Gitte Olesen, Ida Marie Schjødt, Carsten Heilmann & Henrik Sengeløv

  2. Department of Clinical Microbiology, National University Hospital, Rigshospitalet, Denmark

    Claus Ernst Moser

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  1. Marietta Nygaard
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  2. Niels Smedegaard Andersen
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Correspondence to Marietta Nygaard.

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Nygaard, M., Andersen, N.S., Moser, C.E. et al. Evaluation of infliximab as second-line treatment of acute graft versus host disease -validating response on day 7 and 28 as predictors of survival. Bone Marrow Transplant 53, 844–851 (2018). https://doi.org/10.1038/s41409-018-0099-3

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