Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Transplant Outcomes

Relationship between tacrolimus blood concentrations and clinical outcome during the first 4 weeks after SCT in children

Bone Marrow Transplantation volume 45, pages 1161–1166 (2010)Cite this article

Abstract

The relationship between tacrolimus concentration and acute GVHD is not well known, with few published data available for lower target levels. We hypothesized that lower levels of tacrolimus would correlate with higher incidence of acute GVHD and poorer prognosis. Receiver operator characteristic curves (ROC) were used to quantify tacrolimus blood levels as predictors of grade II–IV acute GVHD. A total of 97 pediatric patients with hematological malignancies met the study criteria. On the ROC, a cutoff of 7 ng/ml provided the best balance between sensitivity and specificity (62.8 vs 68.2%, respectively). Cumulative incidence of acute GVHD was 65.9% (range 58.5–73.3%) in patients with mean tacrolimus concentration of ⩽7 ng/ml and 34.8% (range 27.8–41.8%) in patients with mean tacrolimus concentration of >7 ng/ml (P=0.002). Incidence of non-relapse mortality (NRM) was higher in patients with tacrolimus of ⩽7 ng/ml (42.9%; range 35.6–50.2%) than in patients with tacrolimus of >7 ng/ml (28.3%; range 17.4–39.2%; P=0.008). This translated into better EFS in patients with tacrolimus of >7 ng/ml (48.9%; range 39.8–58.0%) than in patients with tacrolimus of ⩽7 ng/ml (31.8%; range 25.0–38.6%; P=0.031). Multivariate analysis showed that tacrolimus concentration was significantly associated with clinical outcomes. Mean whole-blood level of tacrolimus as continuous infusion should be maintained at ⩾7 ng/ml for pediatric patients.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Wingard JR, Nash RA, Przepiorka D, Klein JL, Weisdorf DJ, Fay JW et al. Relationship of tacrolimus (FK506) whole blood concentrations and efficacy and safety after HLA-identical sibling bone marrow transplantation. Biol Blood Marrow Transplant 1998; 4: 157–163.

    Article  CAS  PubMed  Google Scholar 

  2. Przepiorka D, Saliba R, Cleary K, Fischer H, Tonai R, Fritsche H et al. Tacrolimus does not abrogate the increased risk of acute graft-versus-host disease after unrelated-donor marrow transplantation with allelic mismatching at HLA-DRB1 and HLA-DQB1. Biol Blood Marrow Transplant 2000; 6: 190–197.

    Article  CAS  PubMed  Google Scholar 

  3. Morishima Y, Morishita Y, Tanimoto M, Ohno R, Saito H, Horibe K et al. Low incidence of acute graft-versus-host disease by the administration of methotrexate and cyclosporine in Japanese leukemia patients after bone marrow transplantation from human leukocyte antigen compatible siblings; possible role of genetic homogeneity. The Nagoya Bone Marrow Transplantation Group. Blood 1989; 74: 2252–2256.

    CAS  PubMed  Google Scholar 

  4. 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  PubMed  Google Scholar 

  5. Przepiorka D, Nash RA, Wingard JR, Zhu J, Maher RM, Fitzsimmons WE et al. Relationship of tacrolimus whole blood levels to efficacy and safety outcomes after unrelated donor marrow transplantation. Biol Blood Marrow Transplant 1999; 5: 94–97.

    Article  CAS  PubMed  Google Scholar 

  6. Nishida T, Hamaguchi M, Hirabayashi N, Haneda M, Terakura S, Atsuta Y et al. Intestinal thrombotic microangiopathy after allogeneic bone marrow transplantation: a clinical imitator of acute enteric graft-versus-host disease. Bone Marrow Transplant 2004; 33: 1143–1150.

    Article  CAS  PubMed  Google Scholar 

  7. Fujino M, Kim Y, Ito M . Intestinal thrombotic microangiopathy induced by FK506 in rats. Bone Marrow Transplant 2007; 39: 367–372.

    Article  CAS  PubMed  Google Scholar 

  8. Nakamae H, Yamane T, Hasegawa T, Nakamae M, Terada Y, Hagihara K et al. Risk factor analysis for thrombotic microangiopathy after reduced-intensity or myeloablative allogeneic hematopoietic stem cell transplantation. Am J Hematol 2006; 81: 525–531.

    Article  PubMed  Google Scholar 

  9. Oran B, Donato M, Aleman A, Hosing C, Korbling M, Detry MA et al. Transplant-associated microangiopathy in patients receiving tacrolimus following allogeneic stem cell transplantation: risk factors and response to treatment. Biol Blood Marrow Transplant 2007; 13: 469–477.

    Article  CAS  PubMed  Google Scholar 

  10. Przepiorka D, Blamble D, Hilsenbeck S, Danielson M, Krance R, Chan KW . Tacrolimus clearance is age-dependent within the pediatric population. Bone Marrow Transplant 2000; 26: 601–605.

    Article  CAS  PubMed  Google Scholar 

  11. Wong R, Shahjahan M, Wang X, Thall PF, De Lima M, Khouri I et al. Prognostic factors for outcomes of patients with refractory or relapsed acute myelogenous leukemia or myelodysplastic syndromes undergoing allogeneic progenitor cell transplantation. Biol Blood Marrow Transplant 2005; 11: 108–114.

    Article  PubMed  Google Scholar 

  12. Nakamura Y, Takeuchi H, Okuyama K, Akashi T, Jojima Y, Konno O et al. Evaluation of appropriate blood level in continuous intravenous infusion from trough concentrations after oral administration based on area under trough level in tacrolimus and cyclosporine therapy. Transplant Proc 2005; 37: 1725–1727.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by a grant from the Ministry of Health, Labour, and Welfare of Japan, Tokyo.

Author information

Authors and Affiliations

  1. Division of Hematology and Oncology, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan

    N Watanabe, K Matsumoto & K Kato

  2. Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan

    H Muramatsu & S Kojima

  3. Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan

    K Horibe

  4. Nagoya Nishi Clinic Hospital, Nagoya, Japan

    T Matsuyama

Authors
  1. N Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K Matsumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H Muramatsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K Horibe
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T Matsuyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S Kojima
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. K Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to N Watanabe.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Watanabe, N., Matsumoto, K., Muramatsu, H. et al. Relationship between tacrolimus blood concentrations and clinical outcome during the first 4 weeks after SCT in children. Bone Marrow Transplant 45, 1161–1166 (2010). https://doi.org/10.1038/bmt.2009.327

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2009.327

Keywords

This article is cited by

Search

Advanced search

Quick links