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

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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.

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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).

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Author notes

  1. Hiroyoshi Nakamura

    Present address: International University of Health and Welfare Mita Hospital, Tokyo, Japan

Authors and Affiliations

  1. Department of Hematology and Oncology, Shizuoka Children’s Hospital, Shizuoka, Japan

    Takayuki Takachi

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

    Takayuki Takachi & Keizo Horibe

  3. Department of Hematology and Oncology, Saitama Children’s Medical Center, Saitama, Japan

    Yuki Arakawa & Katsuyoshi Koh

  4. Department of Pharmacy, Chiba University Hospital, Chiba, Japan

    Hiroyoshi Nakamura

  5. Department of Nutrition and Health, Faculty of Psychological and Physical Science, Aichi Gakuin University, Nisshin, Japan

    Tomoyuki Watanabe

  6. Department of Pediatric Oncology, National Cancer Center Hospital, Tokyo, Japan

    Yuki Aoki

  7. Department of Hematology/Oncology for Children and Adolescents, Sapporo Hokuyu Hospital, Sapporo, Japan

    Junjiro Ohshima

  8. Department of Pediatrics, Aomori Prefectural Central Hospital, Aomori, Japan

    Yoshihiro Takahashi

  9. Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Japan

    Masahiro Hirayama

  10. Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan

    Takako Miyamura

  11. Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Chuo, Japan

    Kanji Sugita

  12. Department of Pediatrics, Ehime University Graduate School of Medicine, Toon, Japan

    Eiichi Ishii

  13. Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan

    Shuki Mizutani

  14. Division of Leukemia and Lymphoma, Children’s Cancer Center, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan

    Daisuke Tomizawa

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  1. Takayuki Takachi
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  2. Yuki Arakawa
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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.

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Correspondence to Daisuke Tomizawa.

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Takachi, T., Arakawa, Y., Nakamura, H. et al. Personalized pharmacokinetic targeting with busulfan in allogeneic hematopoietic stem cell transplantation in infants with acute lymphoblastic leukemia. Int J Hematol 110, 355–363 (2019). https://doi.org/10.1007/s12185-019-02684-0

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  • DOI: https://doi.org/10.1007/s12185-019-02684-0

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