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Post-Transplant Events

A prospective randomized study using N-acetyl-L-cysteine for early liver toxicity after allogeneic hematopoietic stem cell transplantation

Bone Marrow Transplantation volume 41, pages 785–790 (2008)Cite this article

Abstract

Allogeneic hematopoietic stem cell transplantation (ASCT) and its conditioning with chemoradiotherapy often results in liver toxicity, the most severe form being veno-occlusive liver disease (VOD). N-acetyl-L-cysteine (NAC), an antioxidant glutathione precursor, may provide protection from liver toxicity. Patients with elevated bilirubin (>26 mmol/l) and/or elevated (ALT) (>1.4 μkat/l) and/or aspartate aminotransferase (AST) (>1.4 μkat/l) levels were randomized to treatment with NAC or no treatment. Among 522 transplanted patients, 160 were included in the trial. NAC was given, 100 mg/kg per day, as a 6-h i.v. infusion until normalization of bilirubin, ALT and AST values. Maximum bilirubin level was the same in patients randomized to NAC (n=72) or controls (n=88). Increase and recovery of ALT and AST were the same in patients randomized to NAC or controls. There were two patients in the NAC group who developed VOD, as compared to three of the controls. To conclude, NAC does not improve liver toxicity after ASCT.

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References

  1. Chyka PA, Butler AY, Holliman BJ, Herman MI . Utility of acetylcysteine in treating poisonings and adverse drug reactions. Drug Saf 2000; 22: 123–148.

    Article  CAS  PubMed  Google Scholar 

  2. Harrison PM, Keays R, Bray GP, Alexander GJ, Williams R . Improved outcome of paracetamol-induced fulminant hepatic failure by late administration of acetylcysteine. Lancet 1990; 335: 1572–1573.

    Article  CAS  Google Scholar 

  3. Bonanomi L, Gazzaniga A . Toxicological, pharmacokinetic and metabolic studies on acetylcysteine. Eur J Respir Dis Suppl 1980; 111: 45–51.

    CAS  PubMed  Google Scholar 

  4. Sekharam M, Trotti A, Cunnick JM, Wu J . Suppression of fibroblast cell cycle progression in G1 phase by N-acetylcysteine. Toxicol Appl Pharmacol 1998; 149: 210–216.

    Article  CAS  PubMed  Google Scholar 

  5. Colombo A, Ranheim E, Fong T, Kipps T . CD40 signaling in B cells involves reactive oxygen intermediates and induces activation of NF-kB. Blood 1994; 84 (Suppl 1): 511.

    Google Scholar 

  6. Ringden O, Remberger M, Lehmann S, Hentschke P, Mattsson J, Klaesson S et al. N-acetylcysteine for hepatic veno-occlusive disease after allogeneic stem cell transplantation. Bone Marrow Transplant 2000; 25: 993–996.

    Article  CAS  PubMed  Google Scholar 

  7. Sjoo F, Aschan J, Barkholt L, Hassan Z, Ringden O, Hassan M . N-acetyl-L-cysteine does not affect the pharmacokinetics or myelosuppressive effect of busulfan during conditioning prior to allogeneic stem cell transplantation. Bone Marrow Transplant 2003; 32: 349–354.

    Article  CAS  PubMed  Google Scholar 

  8. Ruutu T, Eriksson B, Remes K, Juvonen E, Volin L, Remberger M et al. Ursodeoxycholic acid for the prevention of hepatic complications in allogeneic stem cell transplantation. Blood 2002; 100: 1977–1983.

    Article  CAS  Google Scholar 

  9. Carreras E . Veno-occlusive disease of the liver after hemopoietic cell transplantation. Eur J Haematol 2000; 64: 281–291.

    Article  CAS  PubMed  Google Scholar 

  10. Jones RJ, Lee KS, Beschorner WE, Vogel VG, Grochow LB, Braine HG et al. Venoocclusive disease of the liver following bone marrow transplantation. Transplantation 1987; 44: 778–783.

    Article  CAS  PubMed  Google Scholar 

  11. McDonald GB, Sharma P, Matthews DE, Shulman HM, Thomas ED . Venocclusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors. Hepatology 1984; 4: 116–122.

    Article  CAS  Google Scholar 

  12. Shulman HM, Hinterberger W . Hepatic veno-occlusive disease—liver toxicity syndrome after bone marrow transplantation. Bone Marrow Transplant 1992; 10: 197–214.

    CAS  PubMed  Google Scholar 

  13. Holler E, Kolb HJ, Moller A, Kempeni J, Liesenfeld S, Pechumer H et al. Increased serum levels of tumor necrosis factor alpha precede major complications of bone marrow transplantation. Blood 1990; 75: 1011–1016.

    CAS  PubMed  Google Scholar 

  14. Remberger M, Ringden O . Increased levels of soluble interleukin-2 receptor in veno-occlusive disease of the liver after allogenic bone marrow transplantation. Transplantation 1995; 60: 1293–1299.

    Article  CAS  PubMed  Google Scholar 

  15. Remberger M, Ringden O . Serum levels of cytokines after bone marrow transplantation: increased IL-8 levels during severe veno-occlusive disease of the liver. Eur J Haematol 1997; 59: 254–262.

    Article  CAS  PubMed  Google Scholar 

  16. Shulman HM, Gown AM, Nugent DJ . Hepatic veno-occlusive disease after bone marrow transplantation. Immunohistochemical identification of the material within occluded central venules. Am J Pathol 1987; 127: 549–558.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Schaffer M, Aldener-Cannava A, Remberger M, Ringden O, Olerup O . Roles of HLA-B, HLA-C and HLA-DPA1 incompatibilities in the outcome of unrelated stem-cell transplantation. Tissue Antigens 2003; 62: 243–250.

    Article  CAS  PubMed  Google Scholar 

  18. Ringden O, Remberger M, Runde V, Bornhauser M, Blau IW, Basara N et al. Peripheral blood stem cell transplantation from unrelated donors: a comparison with marrow transplantation. Blood 1999; 94: 455–464.

    CAS  PubMed  Google Scholar 

  19. Ringden O, Remberger M, Svahn BM, Barkholt L, Mattsson J, Aschan J et al. Allogeneic hematopoietic stem cell transplantation for inherited disorders: experience in a single center. Transplantation 2006; 81: 718–725.

    Article  PubMed  Google Scholar 

  20. Ringden O, Ruutu T, Remberger M, Nikoskelainen J, Volin L, Vindelov L et al. A randomized trial comparing busulfan with total body irradiation as conditioning in allogeneic marrow transplant recipients with leukemia: a report from the Nordic Bone Marrow Transplantation Group. Blood 1994; 83: 2723–2730.

    CAS  Google Scholar 

  21. Hentschke P, Barkholt L, Uzunel M, Mattsson J, Wersall P, Pisa P et al. Low-intensity conditioning and hematopoietic stem cell transplantation in patients with renal and colon carcinoma. Bone Marrow Transplant 2003; 31: 253–261.

    Article  CAS  Google Scholar 

  22. Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 1998; 91: 756–763.

    CAS  PubMed  Google Scholar 

  23. Niederwieser D, Maris M, Shizuru JA, Petersdorf E, Hegenbart U, Sandmaier BM et al. Low-dose total body irradiation (TBI) and fludarabine followed by hematopoietic cell transplantation (HCT) from HLA-matched or mismatched unrelated donors and postgrafting immunosuppression with cyclosporine and mycophenolate mofetil (MMF) can induce durable complete chimerism and sustained remissions in patients with hematological diseases. Blood 2003; 101: 1620–1629.

    Article  CAS  PubMed  Google Scholar 

  24. Remberger M, Svahn BM, Hentschke P, Lofgren C, Ringden O . Effect on cytokine release and graft-versus-host disease of different anti-T cell antibodies during conditioning for unrelated haematopoietic stem cell transplantation. Bone Marrow Transplant 1999; 24: 823–830.

    Article  CAS  Google Scholar 

  25. Ringden O, Remberger M, Persson U, Ljungman P, Aldener A, Andstrom E et al. Similar incidence of graft-versus-host disease using HLA-A, -B and -DR identical unrelated bone marrow donors as with HLA-identical siblings. Bone Marrow Transplant 1995; 15: 619–625.

    CAS  Google Scholar 

  26. Storb R, Deeg HJ, Fisher L, Appelbaum F, Buckner CD, Bensinger W et al. Cyclosporine v methotrexate for graft-v-host disease prevention in patients given marrow grafts for leukemia: long-term follow-up of three controlled trials. Blood 1988; 71: 293–298.

    CAS  PubMed  Google Scholar 

  27. Svahn BM, Remberger M, Myrback KE, Holmberg K, Eriksson B, Hentschke P et al. Home care during the pancytopenic phase after allogeneic hematopoietic stem cell transplantation is advantageous compared with hospital care. Blood 2002; 100: 4317–4324.

    Article  CAS  PubMed  Google Scholar 

  28. Remberger M, Naseh N, Aschan J, Barkholt L, LeBlanc K, Svennberg P et al. G-CSF given after haematopoietic stem cell transplantation using HLA-identical sibling donors is associated to a higher incidence of acute GVHD II–IV. Bone Marrow Transplant 2003; 32: 217–223.

    Article  CAS  PubMed  Google Scholar 

  29. Lundgren G, Wilczek H, Lonnqvist B, Lindholm A, Wahren B, Ringden O . Acyclovir prophylaxis in bone marrow transplant recipients. Scand J Infect Dis Suppl 1985; 47: 137–144.

    CAS  PubMed  Google Scholar 

  30. Kaplan EL, Meier P . Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481.

    Article  Google Scholar 

  31. 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.

    Article  CAS  Google Scholar 

  32. Tolar J, Orchard PJ, Bjoraker KJ, Ziegler RS, Shapiro EG, Charnas L . N-acetyl-L-cysteine improves outcome of advanced cerebral adrenoleukodystrophy. Bone Marrow Transplant 2007; 39: 211–215.

    Article  CAS  PubMed  Google Scholar 

  33. Wang X, Kanel GC, DeLeve LD . Support of sinusoidal endothelial cell glutathione prevents hepatic veno-occlusive disease in the rat. Hepatology 2000; 31: 428–434.

    Article  CAS  PubMed  Google Scholar 

  34. Hagglund H, Remberger M, Klaesson S, Lonnqvist B, Ljungman P, Ringden O . Norethisterone treatment, a major risk-factor for veno-occlusive disease in the liver after allogeneic bone marrow transplantation. Blood 1998; 92: 4568–4572.

    CAS  PubMed  Google Scholar 

  35. Hassan Z, Ljungman P, Ringden O, Winiarski J, Nilsson C, Aschan J et al. Pharmacokinetics of liposomal busulphan in man. Bone Marrow Transplant 2001; 27: 479–485.

    Article  CAS  PubMed  Google Scholar 

  36. Ringden O, Barrett AJ, Zhang MJ, Loberiza FR, Bolwell BJ, Cairo MS et al. Decreased treatment failure in recipients of HLA-identical bone marrow or peripheral blood stem cell transplants with high CD34 cell doses. Br J Haematol 2003; 121: 874–885.

    Article  PubMed  Google Scholar 

  37. Paulin T, Ringden O, Lonnqvist B . Faster immunological recovery after bone marrow transplantation in patients without cytomegalovirus infection. Transplantation 1985; 39: 377–384.

    Article  CAS  PubMed  Google Scholar 

  38. Paulin T, Ringden O, Nilsson B, Lonnqvist B, Gahrton G . Variables predicting bacterial and fungal infections after allogeneic marrow engraftment. Transplantation 1987; 43: 393–398.

    Article  CAS  PubMed  Google Scholar 

  39. Eapen M, Horowitz MM, Klein JP, Champlin RE, Loberiza Jr FR, Ringden O et al. Higher mortality after allogeneic peripheral-blood transplantation compared with bone marrow in children and adolescents: the Histocompatibility and Alternate Stem Cell Source Working Committee of the International Bone Marrow Transplant Registry. J Clin Oncol 2004; 22: 4872–4880.

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank the Staff and Centre for Allogeneic Stem Cell Transplantation for compassionate and competent care of the patients. We thank Inger Hammarberg for secretarial help. This study was supported by grants from the Swedish Cancer Society (0070-B06-20XBC), the Children's Cancer Foundation (06/094), the Swedish Research Council (K2006-32X-05971-26-1), the Cancer Society in Stockholm, the Cancer and Allergy Foundation and Karolinska Institutet.

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Authors and Affiliations

  1. Centre for Allogeneic Stem Cell Transplantation, Karolinska University Hospital Huddinge, Stockholm, Sweden

    L Barkholt, M Remberger, Z Hassan, K Fransson, B Omazic, B-M Svahn, H Karlsson, J Mattsson & O Ringdén

  2. Division of Clinical Immunology, Karolinska University Hospital Huddinge, Stockholm, Sweden

    L Barkholt, M Remberger, K Fransson, H Karlsson, J Mattsson & O Ringdén

  3. Section of Hematology, Sahlgrenska University Hospital, Göteborg, Sweden

    M Brune

  4. Department of Laboratory Medicine, Experimental Cancer Medicine, Karolinska Institutet, Stockholm, Sweden

    M Hassan

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  1. L Barkholt
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Correspondence to O Ringdén.

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Barkholt, L., Remberger, M., Hassan, Z. et al. A prospective randomized study using N-acetyl-L-cysteine for early liver toxicity after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 41, 785–790 (2008). https://doi.org/10.1038/sj.bmt.1705969

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