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Relationship between achievement of major molecular response or deep molecular response and nilotinib plasma concentration in patients with chronic myeloid leukemia receiving first-line nilotinib therapy

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Abstract

Purpose

We evaluated the plasma exposure and response relationships of nilotinib for patients with newly diagnosed chronic myeloid leukemia (CML) in real-world practice.

Methods

For the 26 patients enrolled in this study, at 3, 6, 12, and 24 months after nilotinib administration, the trough plasma concentrations (Ctrough) of nilotinib were analyzed. The relationships between nilotinib Ctrough and the molecular response to nilotinib treatment at each point (each n = 26) were evaluated.

Results

Median nilotinib Ctrough values were significantly higher in patients with a major molecular response (MMR) at 3 months than in patients without an MMR (809 and 420 ng/mL, respectively; P = 0.046). Based on the area under the receiver-operating characteristic curve, the threshold value of the nilotinib Ctrough at 3 months for predicting MMR achievement was 619 ng/mL at the best sensitivity (71.4%) and specificity (77.8%). Patients with a nilotinib Ctrough of above 619 ng/mL had a significantly shorter time to achievement of a deep molecular response (DMR; 9.0 and 18.0 months, respectively; P = 0.020) and higher rates of DMR by 2 years in Kaplan–Meier plots (P = 0.025) compared with that in patients with a nilotinib Ctrough of less than 619 ng/mL.

Conclusion

For patients with newly diagnosed CML, the nilotinib dose may be adjusted using a Ctrough of above 619 ng/mL as the minimum effective concentration, i.e., the lowest concentration required for MMR or DMR achievement within a shorter time, during early stages after beginning therapy to obtain faster and deeper clinical responses.

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Funding

This work was supported by a grant (no. 20K07150) from the Japan Society for the Promotion of Science, Tokyo, Japan.

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Authors and Affiliations

  1. Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita, Japan

    Natsuki Fukuda, Yumiko Akamine, Maiko Abumiya & Masatomo Miura

  2. Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan

    Saori Takahashi, Tomoko Yoshioka, Yoshihiro Kameoka & Naoto Takahashi

  3. Clinical Research Promotion and Support Center, Akita University Hospital, Akita, Japan

    Saori Takahashi & Yoshihiro Kameoka

  4. Department of Pharmacokinetics, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan

    Masatomo Miura

Authors
  1. Natsuki Fukuda
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Correspondence to Masatomo Miura.

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Conflict of interest

N.T. declares research funding, honoraria, and speaker’s fees from Novartis, Otsuka; research funding and honoraria from Astellas; research funding from Pfizer; and honoraria from Asahikasei, Ono, Kyowa Kirin, Mochida. The other authors declare no conflicts of interest.

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Fukuda, N., Akamine, Y., Abumiya, M. et al. Relationship between achievement of major molecular response or deep molecular response and nilotinib plasma concentration in patients with chronic myeloid leukemia receiving first-line nilotinib therapy. Cancer Chemother Pharmacol 89, 609–616 (2022). https://doi.org/10.1007/s00280-022-04419-1

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