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Pharmacokinetically guided, once-daily intravenous busulfan in combination with fludarabine for elderly AML/MDS patients as a conditioning regimen for allogeneic stem cell transplantation

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Abstract

The efficacy of pharmacokinetically (PK) guided, once-daily administration of busulfan (BU) was evaluated in elderly patients with acute myeloid leukemia/myelodysplastic syndrome (AML/MDS). Twenty-one patients (median age 61) received 30 mg/m2 fludarabine for 6 days and BU for 4 days, starting from 3.2 mg/m2 and subsequently adjusted to the target area under the curve (AUC) of 6000 µmol-min/L. The median AUC of day 1 (AUC1), AUC4, and their average were 4871.3, 6021.0, and 5368.1 µmol-min/L, respectively. Veno-occlusive disease/sinusoidal obstructive syndrome (VOD/SOS) occurred in five patients (24%) but all recovered well. Four patients (20%) had non-infectious pulmonary complications (NIPCs). Patients with high AUC1 had frequent gastrointestinal adverse events, but similar incidence of VOD/SOS and NIPCs. Two-year overall survival (OS), non-relapse mortality (NRM), and relapse rates were 44.4%, 28.6%, and 29.1%, respectively. Patients with high AUC1 had significantly high NRM (57.1% vs. 14.3%, P = 0.04) and inferior OS (14.3% vs. 60.1%, P = 0.002), while patients with high AUC4 had a significantly low relapse rate (8.3% vs. 55.6%, P = 0.02). In conclusion, once-daily BU and a PK-guided dose intensification were beneficial for reducing relapse in elderly patients with AML/MDS. However, caution should be exercised as rapid BU dose elevation may contribute to NRM.

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Acknowledgements

The authors thank our patients and their families who have shared their experiences with us, and Editage (www.editage.com) for English language editing.

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Authors and Affiliations

  1. Department of Hematology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan

    Chikako Ohwada, Kensuke Kayamori, Yutaro Hino, Nagisa Oshima-Hasegawa, Tomoya Muto, Shokichi Tsukamoto, Shio Mitsukawa, Yusuke Takeda, Naoya Mimura, Tohru Iseki, Chiaki Nakaseko & Emiko Sakaida

  2. Blood and Marrow Transplant Center, Chiba University Hospital, Chiba, Japan

    Chikako Ohwada, Kensuke Kayamori, Yutaro Hino, Nagisa Oshima-Hasegawa, Tomoya Muto, Shokichi Tsukamoto, Shio Mitsukawa, Yusuke Takeda, Naoya Mimura, Tohru Iseki & Emiko Sakaida

  3. Department of Hematology, International University of Health and Welfare Narita Hospital, Narita, Japan

    Chikako Ohwada & Chiaki Nakaseko

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

    Shingo Yamazaki, Takaaki Suzuki & Itsuko Ishii

  5. Department of Hematology, Aoba Municipal Hospital, Chiba, Japan

    Katsuhiro Shono, Masahiro Onoda & Akira Yokota

  6. Department of Transfusion Medicine and Cell Therapy, Chiba University Hospital, Chiba, Japan

    Shio Mitsukawa, Naoya Mimura & Tohru Iseki

  7. Division of Hematology-Oncology, Chiba Cancer Center, Chiba, Japan

    Masahiro Takeuchi

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  1. Chikako Ohwada
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  2. Shingo Yamazaki
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Correspondence to Chikako Ohwada.

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Ohwada, C., Yamazaki, S., Shono, K. et al. Pharmacokinetically guided, once-daily intravenous busulfan in combination with fludarabine for elderly AML/MDS patients as a conditioning regimen for allogeneic stem cell transplantation. Int J Hematol 114, 664–673 (2021). https://doi.org/10.1007/s12185-021-03188-6

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  • DOI: https://doi.org/10.1007/s12185-021-03188-6

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