International Journal of Hematology

, Volume 110, Issue 3, pp 355–363 | Cite as

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


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.


Busulfan Pharmacokinetics Hematopoietic stem cell transplantation Infant KMT2A 



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)


  1. 1.
    Ciurea SO, Andersson BS. Busulfan in hematopoietic stem cell transplantation. Biol Blood Marrow Transpl. 2009;15(5):523–36.CrossRefGoogle Scholar
  2. 2.
    Takagi M, Ishiwata Y, Aoki Y, Miyamoto S, Hoshino A, Matsumoto K, et al. HLA haploidentical hematopoietic cell transplantation using clofarabine and busulfan for refractory pediatric hematological malignancy. Int J Hematol. 2017;105(5):686–91.CrossRefPubMedGoogle Scholar
  3. 3.
    Bolinger AM, Zangwill AB, Slattery JT, Risler LJ, Sultan DH, Glidden DV, et al. Target dose adjustment of busulfan in pediatric patients undergoing bone marrow transplantation. Bone Marrow Transpl. 2001;28(11):1013–8.CrossRefGoogle Scholar
  4. 4.
    Bartelink IH, Lalmohamed A, van Reij EM, Dvorak CC, Savic RM, Zwaveling J, et al. Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis. Lancet Haematol. 2016;3(11):e526–36.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Ansari M, Theoret Y, Rezgui MA, Peters C, Mezziani S, Desjean C, et al. Association between busulfan exposure and outcome in children receiving intravenous busulfan before hematopoietic stem cell transplantation. Ther Drug Monit. 2014;36(1):93–9.PubMedGoogle Scholar
  6. 6.
    Bartelink IH, Bredius RG, Belitser SV, Suttorp MM, Bierings M, Knibbe CA, et al. Association between busulfan exposure and outcome in children receiving intravenous busulfan before hematologic stem cell transplantation. Biol Blood Marrow Transpl. 2009;15(2):231–41.CrossRefGoogle Scholar
  7. 7.
    Vassal G, Michel G, Esperou H, Gentet JC, Valteau-Couanet D, Doz F, et al. Prospective validation of a novel IV busulfan fixed dosing for paediatric patients to improve therapeutic AUC targeting without drug monitoring. Cancer Chemother Pharmacol. 2008;61(1):113–23.CrossRefPubMedGoogle Scholar
  8. 8.
    Veal GJ, Nguyen L, Paci A, Riggi M, Amiel M, Valteau-Couanet D, et al. Busulfan pharmacokinetics following intravenous and oral dosing regimens in children receiving high-dose myeloablative chemotherapy for high-risk neuroblastoma as part of the HR-NBL-1/SIOPEN trial. Eur J Cancer. 2012;48(16):3063–72.CrossRefPubMedGoogle Scholar
  9. 9.
    Schechter T, Finkelstein Y, Doyle J, Verjee Z, Moretti M, Koren G, et al. Pharmacokinetic disposition and clinical outcomes in infants and children receiving intravenous busulfan for allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transpl. 2007;13(3):307–14.CrossRefGoogle Scholar
  10. 10.
    Ansari M, Huezo-Diaz P, Rezgui MA, Marktel S, Duval M, Bittencourt H, et al. Influence of glutathione S-transferase gene polymorphisms on busulfan pharmacokinetics and outcome of hematopoietic stem-cell transplantation in thalassemia pediatric patients. Bone Marrow Transpl. 2016;51(3):377–83.CrossRefGoogle Scholar
  11. 11.
    Okamoto Y, Nagatoshi Y, Kosaka Y, Kikuchi A, Kato S, Kigasawa H, et al. Prospective pharmacokinetic study of intravenous busulfan in hematopoietic stem cell transplantation in 25 children. Pediatr Transpl. 2014;18(3):294–301.CrossRefGoogle Scholar
  12. 12.
    Philippe M, Goutelle S, Guitton J, Fonrose X, Bergeron C, Girard P, et al. Should busulfan therapeutic range be narrowed in pediatrics? Experience from a large cohort of hematopoietic stem cell transplant children. Bone Marrow Transpl. 2016;51(1):72–8.CrossRefGoogle Scholar
  13. 13.
    Tomizawa D. Recent progress in the treatment of infant acute lymphoblastic leukemia. Pediatr Int. 2015;57(5):811–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Lu H, Rosenbaum S. Developmental pharmacokinetics in pediatric populations. J Pediatr Pharmacol Ther. 2014;19(4):262–76.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Savic RM, Cowan MJ, Dvorak CC, Pai SY, Pereira L, Bartelink IH, et al. Effect of weight and maturation on busulfan clearance in infants and small children undergoing hematopoietic cell transplantation. Biol Blood Marrow Transpl. 2013;19(11):1608–14.CrossRefGoogle Scholar
  16. 16.
    McCune JS, Bemer MJ, Barrett JS, Scott Baker K, Gamis AS, Holford NH. Busulfan in infant to adult hematopoietic cell transplant recipients: a population pharmacokinetic model for initial and Bayesian dose personalization. Clin Cancer Res. 2014;20(3):754–63.CrossRefPubMedGoogle Scholar
  17. 17.
    Koh K, Tomizawa D, Moriya Saito A, Watanabe T, Miyamura T, Hirayama M, et al. Early use of allogeneic hematopoietic stem cell transplantation for infants with MLL gene-rearrangement-positive acute lymphoblastic leukemia. Leukemia. 2015;29(2):290–6.CrossRefPubMedGoogle Scholar
  18. 18.
    Slattery JT, Sanders JE, Buckner CD, Schaffer RL, Lambert KW, Langer FP, et al. Graft-rejection and toxicity following bone marrow transplantation in relation to busulfan pharmacokinetics. Bone Marrow Transpl. 1995;16(1):31–42.Google Scholar
  19. 19.
    Nakamura H, Sato T, Okada K, Miura G, Ariyoshi N, Nakazawa K, et al. Population pharmacokinetics of oral busulfan in young Japanese children before hematopoietic stem cell transplantation. Ther Drug Monit. 2008;30(1):75–83.CrossRefPubMedGoogle Scholar
  20. 20.
    McDonald GB, Sharma P, Matthews DE, Shulman HM, Thomas ED. Venocclusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors. Hepatology. 1984;4(1):116–22.CrossRefPubMedGoogle Scholar
  21. 21.
    Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. Consensus conference on acute GVHD grading. Bone Marrow Transpl. 1994;15(6):825–8.Google Scholar
  22. 22.
    Eberly AL, Anderson GD, Bubalo JS, McCune JS. Optimal prevention of seizures induced by high-dose busulfan. Pharmacotherapy. 2008;28(12):1502–10.CrossRefPubMedGoogle Scholar
  23. 23.
    Hassan M, Ljungman P, Bolme P, Ringden O, Syruckova Z, Bekassy A, et al. Busulfan bioavailability. Blood. 1994;84(7):2144–50.PubMedGoogle Scholar
  24. 24.
    Palmer J, McCune JS, Perales MA, Marks D, Bubalo J, Mohty M, et al. Personalizing busulfan-based conditioning: considerations from the American Society for Blood and Marrow Transplantation Practice Guidelines Committee. Biol Blood Marrow Transpl. 2016;22(11):1915–25.CrossRefGoogle Scholar
  25. 25.
    Ansari M, Rezgui MA, Theoret Y, Uppugunduri CR, Mezziani S, Vachon MF, et al. Glutathione S-transferase gene variations influence BU pharmacokinetics and outcome of hematopoietic SCT in pediatric patients. Bone Marrow Transpl. 2013;48(7):939–46.CrossRefGoogle Scholar
  26. 26.
    Zwaveling J, Press RR, Bredius RG, van Derstraaten TR, den Hartigh J, Bartelink IH, et al. Glutathione S-transferase polymorphisms are not associated with population pharmacokinetic parameters of busulfan in pediatric patients. Ther Drug Monit. 2008;30(4):504–10.PubMedGoogle Scholar
  27. 27.
    Elhasid R, Krivoy N, Rowe JM, Sprecher E, Adler L, Elkin H, et al. Influence of glutathione S-transferase A1, P1, M1, T1 polymorphisms on oral busulfan pharmacokinetics in children with congenital hemoglobinopathies undergoing hematopoietic stem cell transplantation. Pediatr Blood Cancer. 2010;55(6):1172–9.CrossRefPubMedGoogle Scholar
  28. 28.
    Ansari M, Lauzon-Joset JF, Vachon MF, Duval M, Theoret Y, Champagne MA, et al. Influence of GST gene polymorphisms on busulfan pharmacokinetics in children. Bone Marrow Transpl. 2010;45(2):261–7.CrossRefGoogle Scholar
  29. 29.
    Srivastava A, Poonkuzhali B, Shaji RV, George B, Mathews V, Chandy M, et al. Glutathione S-transferase M1 polymorphism: a risk factor for hepatic venoocclusive disease in bone marrow transplantation. Blood. 2004;104(5):1574–7.CrossRefPubMedGoogle Scholar
  30. 30.
    Kashyap A, Wingard J, Cagnoni P, Roy J, Tarantolo S, Hu W, et al. Intravenous versus oral busulfan as part of a busulfan/cyclophosphamide preparative regimen for allogeneic hematopoietic stem cell transplantation: decreased incidence of hepatic venoocclusive disease (HVOD), HVOD-related mortality, and overall 100-day mortality. Biol Blood Marrow Transpl. 2002;8(9):493–500.CrossRefGoogle Scholar
  31. 31.
    Tomizawa D, Koh K, Sato T, Kinukawa N, Morimoto A, Isoyama K, et al. Outcome of risk-based therapy for infant acute lymphoblastic leukemia with or without an MLL gene rearrangement, with emphasis on late effects: a final report of two consecutive studies, MLL96 and MLL98, of the Japan Infant Leukemia Study Group. Leukemia. 2007;21(11):2258–63.CrossRefPubMedGoogle Scholar

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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