International Journal of Hematology

DOI: 10.1007/s12185-019-02684-0 Pages: 355-363

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

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

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

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

4. Chiba University Hospital, Department of Pharmacy

5. International University of Health and Welfare Mita Hospital

6. Aichi Gakuin University, Department of Nutrition and Health, Faculty of Psychological and Physical Science

7. National Cancer Center Hospital, Department of Pediatric Oncology

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

9. Aomori Prefectural Central Hospital, Department of Pediatrics

10. Mie University Graduate School of Medicine, Department of Pediatrics

11. Osaka University Graduate School of Medicine, Department of Pediatrics

12. University of Yamanashi, Department of Pediatrics, Faculty of Medicine

13. Ehime University Graduate School of Medicine, Department of Pediatrics

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

15. Children’s Cancer Center, National Center for Child Health and Development, Division of Leukemia and Lymphoma

Correspondence to:
Daisuke Tomizawa
Tel: +81-3-3416-0181
Email: tomizawa-d@ncchd.go.jp

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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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