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Post-Transplant Events

Cytochrome P450 2C19 loss-of-function polymorphism is associated with an increased treatment-related mortality in patients undergoing allogeneic transplantation

Abstract

The polymorphic gene expression of CYP2C19 causes individual variability in drug metabolism and thereby in pharmacologic and toxicologic responses. We genotyped 286 patients and their donors for the CYP2C19 gene who underwent allogeneic transplantation for various diseases and analyzed their outcome. Patients were classified as: poor metabolizers (PMs; 3.1%), intermediate metabolizers (IMs; 24.5%) and extensive metabolizers (EMs; 72.5%). Patients genotyped as PMs had significant higher hepato- and nephrotoxicities compared to IMs or EMs. Maximum bilirubin and serum creatinine levels measured after transplant were approximately twofold higher than those of EMs or IMs. The increased toxicity resulted in an increased 4-year estimate for transplant-related mortality (TRM) with 50±18.6% for PMs compared to 25.1±3.7% for EMs (P<0.018) and 22.7 ±5.6% for IMs (P<0.042), whereas no significant influence for relapse rate, overall survival or incidence of acute graft-versus-host disease grade 2–4 were found between the groups. Multivariate analysis including all potential factors that might influence TRM confirmed that the genotype of CYP2C19 is an independent factor, which influenced TRM significantly. These results suggest that genotyping for CYP450 2C19 can help to identify patients with higher risk for TRM.

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References

  1. Daly AK . Pharmacogenetics of the major polymorphic metabolizing enzymes. Fundam Clin Pharmacol 2003; 17: 27–41.

    Article  CAS  Google Scholar 

  2. Desta Z, Zhao X, Shin JG, Flockhart DA . Clinical significance of the cytochrome P4502C19 genetic polymorphism. Clin Pharmacol Ther 2005; 77: 40.

    Google Scholar 

  3. Timm R, Kaiser R, Lotsch J, Heider U, Sezer O, Weisz K et al. Association of cyclophosphamide pharmacokinetics to polymorphic cytochrome P4502C19. Pharmacogenomics J 2005; 5: 365–373.

    Article  CAS  Google Scholar 

  4. Griskevicius L, Yasar U, Sandberg M, Hidestrand M, Eliasson E, Tybring G et al. Bioactivation of cyclophosphamide: the role of polymorphic CYP2C enzymes. Eur J Clin Pharmacol 2003; 59: 103–109.

    Article  CAS  Google Scholar 

  5. Ishida Y, Goto Y, Kondo T, Kurata M, Nishio K, Kawai S et al. Eradication rate of Helicobacter pylori according to genotypes of CYP2C19, IL-1B, and TNF-A. Int J Med Sci 2006; 3: 135–140.

    Article  CAS  Google Scholar 

  6. Kawabata H, Habu Y, Tomioka H, Kutsumi H, Kabayashi N, Oyasu K et al. Effect of different proton pump inhibitors, differences in CYP2C19 genotype and antibiotic resistance on the eradication rate of Helicobacter pylori infection by a 1-week regimen of proton pump inhibitor, amoxicillin and clarithromycin. Aliment Pharmacol Ther 2003; 17: 259–265.

    Article  CAS  Google Scholar 

  7. Miki I, Aoyama N, Sakai T, Shirasaka D, Wambura CM, Maekawa S et al. Impact of clarithromycin resistence and CYP2C19 genetic polymorphism on treatment efficacy of Helicobacter pylori infection with lansoprazole- or rabeprazole-based triple therapy in Japan. Eur J Gastroenterol Hepatol 2003; 15: 27–33.

    Article  CAS  Google Scholar 

  8. Kropp S, Lichtinghagen R, Winterstein K, Schlimme J, Schneider U . Cytochrome p-450 2D6 and 2C19 polymorphisms and length of hospitalization in psychiatry. Clin Lab 2006; 52: 237–240.

    CAS  PubMed  Google Scholar 

  9. Mikus G, Schöwel V, Drzewinska M, Rengelshausen J, Ding R, Riedel KD et al. Potent cytochrome P4502C19 genotype-related interaction between voriconazol and the cytochrome P4503A4 inhibitor ritonavir. Clin Pharmacol Therap 2006; 80: 126–135.

    Article  CAS  Google Scholar 

  10. Hulot J-S, Bura A, Villard E, Azizi M, Remones V, Goyenvalle C et al. Cytochrome P4502C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 2006; 108: 2244–2247.

    Article  CAS  Google Scholar 

  11. Ottinger HD, Ferencik S, Beelen DW, Lindemann M, Peceny R, Elmaagacli AH et al. Hematopoietic stem cell transplantation: contrasting the outcome of transplantations from HLA-identical siblings, partially HLA-mismatched unrelated donors. Blood 2003; 102: 1131.

    Article  CAS  Google Scholar 

  12. Elmaagacli AH, Peceny R, Steckel N, Trenschel R, Grosse-Wilde H, Schaefer UW et al. Outcome of transplantation of highly purified peripheral blood CD34+ cells with T-cell add-back compared with unmanipulated bone marrow or peripheral blood stem cells from HLA-identical sibling donors in patients with first chronic phase chronic myeloid leukemia. Blood 2003; 101: 446.

    Article  CAS  Google Scholar 

  13. Thomas ED, Storb R, Clift RA, Fefer A, Johnson L, Neiman PE et al. Bone marrow transplantation. N Engl J Med 1975; 292: 895.

    Article  CAS  Google Scholar 

  14. Maniatis T, Fritsch EF, Sambrook J . Molecular Cloning. A Laboratory Manual. Cold Spring Harbor Laboratory Press: Harbor, NY, USA, 1982.

    Google Scholar 

  15. Kaplan EL, Meier P . Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481.

    Article  Google Scholar 

  16. Cox DR . Regression models and life-tables. J R Stat Soc 1972; 34: 187.

    Google Scholar 

  17. Luo H-R, Poland RE, Lin K-M, Wan YJY . Genetic polymorphism of cytochrom P4502C19 in Mexican Americans: a cross-ethnic comparative study. Clin Pharmacol Ther 2006; 80: 33–40.

    Article  CAS  Google Scholar 

  18. Halling J, Petersen MS, Damkier P, Nielsen F, Grandjean P, Weihe P et al. Polymorphism of CYP2D6, CYP2C19, CYP2C9 and CYP2C8 in the Faroese population. Pharmacogenetics 2005.

  19. Elmaagacli AH, Koldehoff M, Hindahl H, Steckel NK, Trenschel R, Peceny R et al. Mutations in innate immune system NOD2/CARD 15 and TLR-4 (Thr399Ile) genes influence the risk for severe acute GVHD in patients who underwent an allogeneic transplantation. Transplantation 2006; 81: 247–254.

    Article  CAS  Google Scholar 

  20. Boucher HW, Groll AH, Chiou CC, Walsh TJ . Newer systemic antifungal agents: pharmacokinetics, safety and efficacy. Drugs 2004; 64: 1997–2000.

    Article  CAS  Google Scholar 

  21. Ikeda Y, Umemura K, Kondo K, Sekiguchi K, Miyoshi S, Nakashima M . Pharmacokinetics of voriconazole and cytochrome P4502C19 genetic status. Clin Pharmacol Ther 2004; 75: 587–588.

    Article  CAS  Google Scholar 

  22. Wilkinson GR . Drug metabolism and variability among patients in drug response. N Engl J Med 2005; 352: 2211–2221.

    Article  CAS  Google Scholar 

  23. Andersson T, Flockhart DA, Goldstein DB, Goldstein DB, Huang SM, Kroetz DL et al. Drug-metabolizing enzymes: evidence for clinical utility of pharmacogenomic tests. Clin Pharmacol Ther 2005; 78: 559–581.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Christiane Schary, Melanie Kroll, Silke Gottwald and Ines Riepenhoff (all Essen, Germany) for their excellent technical assistance with PCR analyses. This work was supported by grants from Deutsche Krebshilfe 70-3093-El4 and Kulturstiftung Essen (05 032 Elmaagacli).

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Correspondence to A H Elmaagacli.

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Elmaagacli, A., Koldehoff, M., Steckel, N. et al. Cytochrome P450 2C19 loss-of-function polymorphism is associated with an increased treatment-related mortality in patients undergoing allogeneic transplantation. Bone Marrow Transplant 40, 659–664 (2007). https://doi.org/10.1038/sj.bmt.1705786

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