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

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A Correction to this article was published on 26 November 2019

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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.

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Change history

  • 26 November 2019

    In the original article of Terakura et al., the COI disclosure were missing.

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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.).

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Authors and Affiliations

  1. Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan

    Seitaro Terakura, Makoto Onizuka, Yachiyo Kuwatsuka, Yukiyasu Ozawa, Koichi Miyamura & Yoshiko Atsuta

  2. Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Aichi, Japan

    Seitaro Terakura, Tomoki Naoe & Makoto Murata

  3. Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Japan

    Makoto Onizuka

  4. Division of Clinical Toxicology, Research and Education Center for Clinical Pharmacy, School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan

    Mariko Fukumoto

  5. Department of Advanced Medicine, Nagoya University Hospital, Nagoya, Japan

    Yachiyo Kuwatsuka

  6. Department of Hematology and Oncology, JA Aichi Konan Kosei Hospital, Konan, Japan

    Akio Kohno & Yoshihisa Morishita

  7. Department of Hematology and Oncology, Anjo Kosei Hospital, Anjo, Japan

    Yuichiro Inagaki & Masashi Sawa

  8. Department of HSCT Data Management/Biostatistics, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Yoshiko Atsuta & Ritsuro Suzuki

Authors
  1. Seitaro Terakura
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  2. Makoto Onizuka
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  14. Makoto Murata
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The Nagoya Blood and Marrow Transplantation Group

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Correspondence to Seitaro Terakura.

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12185_2019_2741_MOESM1_ESM.pdf

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

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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Terakura, S., Onizuka, M., Fukumoto, M. et al. Analysis of glutathione S-transferase and cytochrome P450 gene polymorphism in recipients of dose-adjusted busulfan-cyclophosphamide conditioning. Int J Hematol 111, 84–92 (2020). https://doi.org/10.1007/s12185-019-02741-8

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