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Personalized pharmacokinetic targeting with busulfan in allogeneic hematopoietic stem cell transplantation in infants with acute lymphoblastic leukemia

  • Takayuki Takachi
  • Yuki Arakawa
  • Hiroyoshi Nakamura
  • Tomoyuki Watanabe
  • Yuki Aoki
  • Junjiro Ohshima
  • Yoshihiro Takahashi
  • Masahiro Hirayama
  • Takako Miyamura
  • Kanji Sugita
  • Katsuyoshi Koh
  • Keizo Horibe
  • Eiichi Ishii
  • Shuki Mizutani
  • Daisuke TomizawaEmail author
Original Article

Abstract

Individual busulfan (BU) dosing based on pharmacokinetic (PK) data is preferable for hematopoietic stem cell transplantation (HSCT) conditioning, but information on BU PK in infants is scarce. We report BU PK data on HSCT conditioning for infants with KMT2A-gene-rearrangement-positive acute lymphoblastic leukemia (MLL-r ALL). Infants showed wide variation in BU PK indices, such as clearance (CL) and volume of distribution (Vd) value, which are distributed more widely among those who received oral, rather than intravenous (IV), BU. Because the steady state concentration (Css) fluctuates readily in infants, dose re-adjustment based on PK at the initial administration was important even if the initial dose was determined by a PK test. HSCT can be performed safely within the Css range of 600–900 ng/mL per dose, although it was difficult to fit within the therapeutic index of BU. The clinical outcome of engraftment, graft-versus-host disease, adverse events, including sinusoidal obstruction syndrome, and survival did not correlate with the BU PK data, which paradoxically suggests that remaining within this Css range helped minimize transplant-related toxicities, while securing engraftment in infants with MLL-r ALL.

Keywords

Busulfan Pharmacokinetics Hematopoietic stem cell transplantation Infant KMT2A 

Notes

Acknowledgements

This work was supported in by a Grant for Clinical Cancer Research from the Ministry of Health, Labour and Welfare of Japan (H23-GanRinsho-Ippan-014 and H26-GanRinsho-Shitei-068), a Grant for Practical Research for Innovative Cancer Control from the Japan Agency for Medical Research and Development (AMED) (17ck0106382s0101 and 18ck0106436h0001), and a Grant from the National Center for Child Health and Development (30-1).

Author contributions

Contributions: TT, YA, YA, JO, YT, MH, TM, KS, KK, EI, and DT participated actively in the study conception and design; HN was responsible for the busulfan pharmacokinetic study; TT, YA, and DT reviewed the data analysis and interpretation and were the main author of the manuscript; TW conducted the statistical analysis; TM, KH, EI, SM, and DT contributed to the financial and administrative support of the study; and all authors contributed to the conduct of the trial and were involved in the review of the results and the final approval of the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

12185_2019_2684_MOESM1_ESM.docx (2.6 mb)
Supplementary material 1 (DOCX 2631 kb)

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Copyright information

© Japanese Society of Hematology 2019

Authors and Affiliations

  • Takayuki Takachi
    • 1
    • 2
  • Yuki Arakawa
    • 3
  • Hiroyoshi Nakamura
    • 4
    • 5
  • Tomoyuki Watanabe
    • 6
  • Yuki Aoki
    • 7
  • Junjiro Ohshima
    • 8
  • Yoshihiro Takahashi
    • 9
  • Masahiro Hirayama
    • 10
  • Takako Miyamura
    • 11
  • Kanji Sugita
    • 12
  • Katsuyoshi Koh
    • 3
  • Keizo Horibe
    • 2
  • Eiichi Ishii
    • 13
  • Shuki Mizutani
    • 14
  • Daisuke Tomizawa
    • 15
    Email author
  1. 1.Department of Hematology and OncologyShizuoka Children’s HospitalShizuokaJapan
  2. 2.Clinical Research CenterNational Hospital Organization, Nagoya Medical CenterNagoyaJapan
  3. 3.Department of Hematology and OncologySaitama Children’s Medical CenterSaitamaJapan
  4. 4.Department of PharmacyChiba University HospitalChibaJapan
  5. 5.International University of Health and Welfare Mita HospitalTokyoJapan
  6. 6.Department of Nutrition and Health, Faculty of Psychological and Physical ScienceAichi Gakuin UniversityNisshinJapan
  7. 7.Department of Pediatric OncologyNational Cancer Center HospitalTokyoJapan
  8. 8.Department of Hematology/Oncology for Children and AdolescentsSapporo Hokuyu HospitalSapporoJapan
  9. 9.Department of PediatricsAomori Prefectural Central HospitalAomoriJapan
  10. 10.Department of PediatricsMie University Graduate School of MedicineTsuJapan
  11. 11.Department of PediatricsOsaka University Graduate School of MedicineSuitaJapan
  12. 12.Department of Pediatrics, Faculty of MedicineUniversity of YamanashiChuoJapan
  13. 13.Department of PediatricsEhime University Graduate School of MedicineToonJapan
  14. 14.Department of Pediatrics and Developmental BiologyTokyo Medical and Dental UniversityTokyoJapan
  15. 15.Division of Leukemia and LymphomaChildren’s Cancer Center, National Center for Child Health and DevelopmentTokyoJapan

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