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Graft-Versus-Host Disease

Risk factors and prognosis of hepatic acute GvHD after allogeneic hematopoietic cell transplantation

Abstract

Hepatic acute GvHD (aGvHD) is associated with high mortality owing to poor response to immunosuppressive therapy. The pathogenesis of hepatic aGvHD differs from that of other lesions, and specific risk factors related to pre-transplant liver conditions should be determined. We conducted a cohort study by using a Japanese transplant registry database (N=8378). Of these subjects, 1.5% had hepatitis C virus Ab (HCV-Ab) and 9.4% had liver dysfunction (elevated transaminase or bilirubin levels) before hematopoietic cell transplantation (HCT). After HCT, the cumulative incidence of hepatic aGvHD was 6.7%. On multivariate analyses, HCV-Ab positivity (hazard ratio (HR), 1.93; P=0.02) and pre-transplant liver dysfunction (HR, 1.85; P<0.01), as well as advanced HCT risk, unrelated donors, HLA mismatch and cyclosporine as GvHD prophylaxis, were significant risk factors for hepatic aGvHD, whereas hepatitis B virus surface Ag was not. Hepatic aGvHD was a significant risk factor for low overall survival and high transplant-related mortality in all aGvHD grades (P<0.01). This study is the first to show the relationship between pre-transplant liver conditions and hepatic aGvHD. A prospective study is awaited to validate the results of this study and establish a new strategy especially for high-risk patients.

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References

  1. Holtan SG, Pasquini M, Weisdorf DJ . Acute graft-versus-host disease: a bench-to-bedside update. Blood 2014; 124: 363–373.

    CAS  Article  Google Scholar 

  2. Hahn T, McCarthy PL Jr, Zhang MJ, Wang D, Arora M, Frangoul H et al. Risk factors for acute graft-versus-host disease after human leukocyte antigen-identical sibling transplants for adults with leukemia. J Clin Oncol 2008; 26: 5728–5734.

    Article  Google Scholar 

  3. Nagafuji K, Matsuo K, Teshima T, Mori S, Sakamaki H, Hidaka M et al. Peripheral blood stem cell versus bone marrow transplantation from HLA-identical sibling donors in patients with leukemia: a propensity score-based comparison from the Japan Society for Hematopoietic Stem Cell Transplantation registry. Int J Hematol 2010; 91: 855–864.

    Article  Google Scholar 

  4. Flowers ME, Inamoto Y, Carpenter PA, Lee SJ, Kiem HP, Petersdorf EW et al. Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria. Blood 2011; 117: 3214–3219.

    CAS  Article  Google Scholar 

  5. Jagasia M, Arora M, Flowers ME, Chao NJ, McCarthy PL, Cutler CS et al. Risk factors for acute GVHD and survival after hematopoietic cell transplantation. Blood 2012; 119: 296–307.

    CAS  Article  Google Scholar 

  6. Kanda J, Saji H, Fukuda T, Kobayashi T, Miyamura K, Eto T et al. Related transplantation with HLA-1 Ag mismatch in the GVH direction and HLA-8/8 allele-matched unrelated transplantation: a nationwide retrospective study. Blood 2012; 119: 2409–2416.

    CAS  Article  Google Scholar 

  7. Romee R, Weisdorf DJ, Brunstein C, Wagner JE, Cao Q, Blazar BR et al. Impact of ABO-mismatch on risk of GVHD after umbilical cord blood transplantation. Bone Marrow Transplant 2013; 48: 1046–1049.

    CAS  Article  Google Scholar 

  8. Harris AC, Ferrara JL, Levine JE . Advances in predicting acute GVHD. Br J Haematol 2013; 160: 288–302.

    CAS  Article  Google Scholar 

  9. Norton J, al-Saffar N, Sloane JP . Adhesion molecule expression in human hepatic graft-versus-host disease. Bone Marrow Transplant 1992; 10: 153–156.

    CAS  PubMed  Google Scholar 

  10. Akpek G, Boitnott JK, Lee LA, Hallick JP, Torbenson M, Jacobsohn DA et al. Hepatitic variant of graft-versus-host disease after donor lymphocyte infusion. Blood 2002; 100: 3903–3907.

    CAS  Article  Google Scholar 

  11. Tuncer HH, Rana N, Milani C, Darko A, Al-Homsi SA . Gastrointestinal and hepatic complications of hematopoietic stem cell transplantation. World J Gastroenterol 2012; 18: 1851–1860.

    Article  Google Scholar 

  12. Strasser SI, Myerson D, Spurgeon CL, Sullivan KM, Storer B, Schoch HG et al. Hepatitis C virus infection and bone marrow transplantation: a cohort study with 10-year follow-up. Hepatology 1999; 29: 1893–1899.

    CAS  Article  Google Scholar 

  13. Nakasone H, Kurosawa S, Yakushijin K, Taniguchi S, Murata M, Ikegame K et al. Impact of hepatitis C virus infection on clinical outcome in recipients after allogeneic hematopoietic cell transplantation. Am J Hematol 2013; 88: 477–484.

    Article  Google Scholar 

  14. McDonald GB, Frieze D . A problem-oriented approach to liver disease in oncology patients. Gut 2008; 57: 987–1003.

    CAS  Article  Google Scholar 

  15. Sakamoto S, Kawabata H, Kanda J, Uchiyama T, Mizumoto C, Kondo T et al. Differing impacts of pretransplant serum ferritin and C-reactive protein levels on the incidence of chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Int J Hematol 2013; 97: 109–116.

    CAS  Article  Google Scholar 

  16. Atsuta Y, Suzuki R, Yoshimi A, Gondo H, Tanaka J, Hiraoka A et al. Unification of hematopoietic stem cell transplantation registries in Japan and establishment of the TRUMP System. Int J Hematol 2007; 86: 269–274.

    Article  Google Scholar 

  17. Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 2005; 106: 2912–2919.

    CAS  Article  Google Scholar 

  18. Arai Y, Yamashita K, Mizugishi K, Watanabe T, Sakamoto S, Kitano T et al. Serum neutrophil extracellular trap levels predict thrombotic microangiopathy after allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2013; 19: 1683–1689.

    CAS  Article  Google Scholar 

  19. Giralt S, Ballen K, Rizzo D, Bacigalupo A, Horowitz M, Pasquini M et al. Reduced-intensity conditioning regimen workshop: defining the dose spectrum. Report of a workshop convened by the center for international blood and marrow transplant research. Biol Blood Marrow Transplant 2009; 15: 367–369.

    Article  Google Scholar 

  20. 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.

    CAS  Article  Google Scholar 

  21. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J et al. 1994 consensus conference on acute GVHD grading. Bone Marrow Transplant 1995; 15: 825–828.

    CAS  Google Scholar 

  22. Teshima T, Itoh M, Inoue M, Kato K, Taniguchi S, Miyamura K et al. Guideline for hematopoietic cell transplantation - GVHD. In: Differential diagnosis of aGVHD. Tokyo, Japan: Japanse Society for Hematopoietic Cell Transplantation, 2008, pp 24–27.

    Google Scholar 

  23. Gooley TA, Leisenring W, Crowley J, Storer BE . Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med 1999; 18: 695–706.

    CAS  Article  Google Scholar 

  24. Iacobelli S, Committee ES . Suggestions on the use of statistical methodologies in studies of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 2013; 48 (Suppl 1): S1–37.

    Article  Google Scholar 

  25. Gray RJ . A class of κ-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 1988; 16: 1141–1154.

    Article  Google Scholar 

  26. Fine JP, Gray RJ . A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999; 94: 496–509.

    Article  Google Scholar 

  27. Hogan WJ, Maris M, Storer B, Sandmaier BM, Maloney DG, Schoch HG et al. Hepatic injury after nonmyeloablative conditioning followed by allogeneic hematopoietic cell transplantation: a study of 193 patients. Blood 2004; 103: 78–84.

    CAS  Article  Google Scholar 

  28. McDonald GB . Hepatobiliary complications of hematopoietic cell transplantation, 40 years on. Hepatology 2010; 51: 1450–1460.

    Article  Google Scholar 

  29. Robin M, Porcher R, de Castro R, Fisher G, de Latour RP, Ribaud P et al. Initial liver involvement in acute GVHD is predictive for nonrelapse mortality. Transplantation 2009; 88: 1131–1136.

    Article  Google Scholar 

  30. Shaheen MA, Idrees M . Evidence-based consensus on the diagnosis, prevention and management of hepatitis C virus disease. World J Hepatol 2015; 7: 616–627.

    Article  Google Scholar 

  31. Veldt BJ, Heathcote EJ, Wedemeyer H, Reichen J, Hofmann WP, Zeuzem S et al. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Ann Intern Med 2007; 147: 677–684.

    Article  Google Scholar 

  32. Stift J, Baba HA, Huber E, Federmann B, Fischer HP, Schmitt-Graeff A et al. Consensus on the histopathological evaluation of liver biopsies from patients following allogeneic hematopoietic cell transplantation. Virchows Arch 2014; 464: 175–190.

    Article  Google Scholar 

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Acknowledgements

We would like to thank all the physicians and data managers at the centers who contributed valuable data on transplantation to the Japan Society for Hematopoietic Cell Transplantation (JSHCT), the Japan Marrow Donor Program (JMDP), the Japan Cord Blood Bank Network (JCBBN) and Transplant Registry Unified Management Program. We also thank the members of the Data Management Committees of JSHCT, JMDP, JCBBN and Transplant Registry Unified Management Program for their assistance. We also thank Dr Fumiaki Nakamura in the University of Tokyo for his critical advice for statistical analyses. This study was supported by research funding from the Ministry of Education, Science, Sports and Culture in Japan to TK.

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Correspondence to T Kondo.

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Arai, Y., Kanda, J., Nakasone, H. et al. Risk factors and prognosis of hepatic acute GvHD after allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 51, 96–102 (2016). https://doi.org/10.1038/bmt.2015.205

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