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Overexposure to venetoclax is associated with prolonged-duration of neutropenia during venetoclax and azacitidine therapy in Japanese patients with acute myeloid leukemia

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Abstract

Purpose

An observational study was conducted to evaluate the pharmacokinetics of venetoclax and its impact on the efficacy and safety for Japanese patients with acute myeloid leukemia (AML) treated with venetoclax and azacitidine therapy.

Methods

The association between the plasma concentration, after the first cycle of azacitidine and venetoclax therapy, and the efficacy and safety was evaluated in 33 patients with untreated or relapsed/refractory AML.

Results

Full dose of venetoclax was administered to all patients. Venetoclax treatment was 28 day long in 82% of patients; the relative dose intensity of azacitidine was 82%. Trough concentration was significantly higher among patients with complete remission (CR) and CR with incomplete hematologic recovery (CRi) than those with the morphologic leukemia-free state and partial remission, and no response groups (P = 0.01). Median duration of grade 3 neutropenia was 28 days (range 8–46 days). Area under the concentration–time curve (AUC0–24) was significantly higher among patients with protracted grade 3 neutropenia (≥ 28 days) than those with a shorter duration (< 28 days) (P = 0.03); multivariate analysis revealed that a higher AUC0–24 was a significant predictor of a longer duration of neutropenia (odds ratio 54.3, P = 0.007).

Conclusion

Plasma concentrations of venetoclax were variable in Japanese patients with AML. Higher plasma concentrations were associated with CR/CRi and protracted grade 3 neutropenia. Therefore, it is essential to adjust the duration of venetoclax administration based on individual pharmacokinetic data to limit total drug exposure, reduce severe neutropenia, and achieve higher efficacy.

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Acknowledgements

We would like to thank Editage (www.editage.com) for English language editing.

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Authors and Affiliations

  1. Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita City, Akita, Japan

    Takahiro Kobayashi, Honami Sato, Wataru Kuroki, Isuzu Kobayashi, Yoshihiro Kameoka & Naoto Takahashi

  2. Department of Pharmacokinetics, Akita University Graduate School of Medicine, Akita, Japan

    Masatomo Miura

  3. Department of Pharmacy, Akita University Hospital, Akita, Japan

    Yayoi Fukushi

  4. Department of Internal Medicine, Yuri Kumiai General Hospital, Yurihonjo, Japan

    Wataru Kuroki

  5. Department of Hematology, Akita City Hospital, Akita, Japan

    Fumiko Ito

  6. Department of Hematology, Hiraka General Hospital, Yokote, Japan

    Kazuaki Teshima

  7. Department of Hematology, Nephrology and Rheumatology, Omagari Kousei Medical Center, Daisen, Japan

    Atsushi Watanabe

  8. Department of Hematology, Nephrology and Rheumatology, Noshiro Kousei Medical Center, Noshiro, Japan

    Naohito Fujishima

Authors
  1. Takahiro Kobayashi
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Contributions

Study design: T.K., Y.K., N.T.Patient enrollment: T.K., H.S., W.K., F.I., K.T., A.W., N.F., I.K.Measurement of plasma concentration of venetoclax and genoty**: M.M., Y.F.Collection and assembly of data: T.K., H.S.Data Analyses (including statistical): T.K., H.S., M.M.Manuscript writing: T.K., H.S.Final approval of the manuscript: All authors.

Corresponding author

Correspondence to Takahiro Kobayashi.

Ethics declarations

Ethics approval and informed consent

The multicenter prospective observational study was conducted in Akita prefecture, Japan. This study enrolled patients with AML who were judged ineligible for intensive chemotherapy by the attending physician. This study was conducted in accordance with the 1964 Helsinki Declaration and approved by the Ethics Committee of Akita University (August 6, 2021/No. 2696). Written informed consent was obtained from all participants before enrollment.

Conflict of interests

Naoto Takahashi received honoraria from Otsuka, Novartis, and received research funding from Otsuka, Novartis, Astellas, Asahikasei Pharma, and Ono Pharmaceutical.

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Kobayashi, T., Sato, H., Miura, M. et al. Overexposure to venetoclax is associated with prolonged-duration of neutropenia during venetoclax and azacitidine therapy in Japanese patients with acute myeloid leukemia. Cancer Chemother Pharmacol (2024). https://doi.org/10.1007/s00280-024-04673-5

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