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Analysis of glutathione S-transferase and cytochrome P450 gene polymorphism in recipients of dose-adjusted busulfan-cyclophosphamide conditioning

  • Seitaro TerakuraEmail author
  • Makoto Onizuka
  • Mariko Fukumoto
  • Yachiyo Kuwatsuka
  • Akio Kohno
  • Yukiyasu Ozawa
  • Koichi Miyamura
  • Yuichiro Inagaki
  • Masashi Sawa
  • Yoshiko Atsuta
  • Ritsuro Suzuki
  • Tomoki Naoe
  • Yoshihisa Morishita
  • Makoto Murata
  • The Nagoya Blood and Marrow Transplantation Group
Original Article
  • 103 Downloads

Abstract

Sporadic incidence of veno-occlusive disease (VOD) continues to occur, despite achievement of recommended busulfan (BU) concentrations after real-time BU dose adjustment. To explore the potential influence of glutathione S-transferase (GST) and cytochrome P450 (CYP) genotypes on plasma BU concentration, subsequent VOD, and transplant outcome, we assessed the polymorphisms of multiple GST and CYP genes. Fifty-five patients were included (median age 38 years; range 21–67). Of these, 49 received dose-adjusted BU/CY therapy. Twenty-six patients received transplants from human leukocyte antigen-identical siblings, 26 from unrelated donors. The GSTA1*A/*A genotype was significantly associated with lower BU first-dose area under curve (AUC1st). We found that patients with higher AUC1st showed a significantly higher serum total bilirubin during the first month after transplantation, but this was not necessarily associated with subsequent development of VOD. We further analyzed a possible association of GST and CYP polymorphisms and VOD development, and found none of the polymorphisms investigated was associated with VOD incidence. Regarding transplant outcomes, GSTM1-positive patients showed lower relapse rates and better overall survival in multivariate analyses. These results suggest that a GSTM1-positive genotype in patients receiving BU/CY conditioning protects against relapse of hematological malignancies after allogeneic hematopoietic stem cell transplantation.

Keywords

Busulfan Cyclophosphamide Glutathione S-transferase Drug concentration Area under curve 

Notes

Acknowledgements

This work was supported by Grants from the Japan Society for the Promotion of Science (JSPS) KAKENHI (18K08351 to S.T. and 18K08321 to M.M.).

Compliance with ethical standards

Conflict of interest

The authors declare there is no conflict of interest.

Supplementary material

12185_2019_2741_MOESM1_ESM.pdf (43 kb)
Supplementary file 1 Figure S1 Comparisons of first dose AUC of BU according to GSTM1 and GSTT1 genotypes stratified with GSTA1 genotype. (A) GSTA1*A/*A patients and (B) GSTA1*A/*B and *B/*B patients. One-way ANOVA. NS, not significant (PDF 43 kb)
12185_2019_2741_MOESM2_ESM.pdf (40 kb)
Supplementary file 2 Figure S2 Impact of first dose AUC and BU-dose modification to the maximum total-bilirubin during first month after stem cell transplantation. (A) First dose AUC, (B) BU-dose modification. Mann-Whitney U test. **P<0.01, *P<0.05, NS, not significant (PDF 40 kb)

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Copyright information

© Japanese Society of Hematology 2019

Authors and Affiliations

  • Seitaro Terakura
    • 1
    • 2
    Email author
  • Makoto Onizuka
    • 1
    • 3
  • Mariko Fukumoto
    • 4
  • Yachiyo Kuwatsuka
    • 1
    • 5
  • Akio Kohno
    • 6
  • Yukiyasu Ozawa
    • 1
  • Koichi Miyamura
    • 1
  • Yuichiro Inagaki
    • 7
  • Masashi Sawa
    • 7
  • Yoshiko Atsuta
    • 1
    • 8
  • Ritsuro Suzuki
    • 8
  • Tomoki Naoe
    • 2
  • Yoshihisa Morishita
    • 6
  • Makoto Murata
    • 2
  • The Nagoya Blood and Marrow Transplantation Group
  1. 1.Department of HematologyJapanese Red Cross Nagoya First HospitalNagoyaJapan
  2. 2.Department of Hematology and OncologyNagoya University Graduate School of MedicineNagoyaJapan
  3. 3.Department of Hematology and OncologyTokai University School of MedicineIseharaJapan
  4. 4.Division of Clinical Toxicology, Research and Education Center for Clinical Pharmacy, School of Pharmaceutical SciencesKitasato UniversityTokyoJapan
  5. 5.Department of Advanced MedicineNagoya University HospitalNagoyaJapan
  6. 6.Department of Hematology and OncologyJA Aichi Konan Kosei HospitalKonanJapan
  7. 7.Department of Hematology and OncologyAnjo Kosei HospitalAnjoJapan
  8. 8.Department of HSCT Data Management/BiostatisticsNagoya University Graduate School of MedicineNagoyaJapan

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