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Impact of Venetoclax Exposure on Clinical Efficacy and Safety in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia

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Abstract

Background

Venetoclax is a selective, potent, first-in-class B-cell lymphoma-2 inhibitor that restores apoptosis in cancer cells and has demonstrated efficacy in a variety of hematological malignancies.

Objective

The objective of this research was to characterize the relationship between venetoclax exposures and efficacy and safety in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).

Methods

A total of 272 and 338 patients from four clinical studies were pooled for the exposure–efficacy and exposure–safety analyses, respectively. Demographics, baseline disease characteristics, and select co-medications were evaluated for their impact on efficacy (lymphocytes, tumor size, objective response [OR]) and safety (neutropenia and infection).

Results

Higher venetoclax concentrations led to a more rapid decrease in lymphocyte counts and tumor size, which translated into patients more rapidly achieving OR. The 17p deletion somatic mutation was not identified, in any of the analyses, to affect the responsiveness of patients to venetoclax. Model-based simulations of lymphocyte counts and tumor size estimated an OR rate (ORR) of 84.8 % (95 % confidence interval 81.5–88.0 %) at a venetoclax dosage of 400 mg daily, with minimal increase in ORR at higher doses. The safety analyses of the adverse events (grade 3 or higher) of neutropenia and infection indicated that higher average venetoclax concentrations were not associated with an increase in adverse events.

Conclusions

The exposure–response analyses indicated that a venetoclax dosage regimen of 400 mg daily results in a high (>80 %) probability of achieving OR in R/R CLL/SLL patients, with minimal probability of increasing neutropenia or infection with higher exposures.

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Acknowledgments

The authors thank the patients who participated in this trial and their families; the study coordinators and the support staff at the clinical sites; and AbbVie and Genentech venetoclax team members. They also thank Allison Kitten, an employee of AbbVie, for her thoughtful revision of the manuscript organization.

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Authors and Affiliations

  1. Abbvie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA

    Kevin J. Freise, Aksana K. Jones, Doerthe Eckert, Sven Mensing, Shekman L. Wong, Rod A. Humerickhouse, Walid M. Awni & Ahmed Hamed Salem

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  1. Kevin J. Freise
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Corresponding author

Correspondence to Kevin J. Freise.

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Funding

This study was supported by AbbVie in collaboration with Genentech/Roche. Venetoclax (ABT-199/GDC-0199) is being developed in collaboration between AbbVie and Genentech. AbbVie and Genentech provided financial support for the study and participated in the design, study conduct, and analysis and interpretation of data, as well as the writing, review and approval of the manuscript.

Conflict of interest

Kevin J. Freise, Aksana K. Jones, Doerthe Eckert, Sven Mensing, Shekman L. Wong, Rod A. Humerickhouse, Walid M. Awni, Ahmed Hamed Salem are employees of AbbVie and may own stock.

Ethical approval

The studies were conducted in accordance with Good Clinical Practice guidelines and ethical principles that have their origin in the Declaration of Helsinki. All study protocols and amendments were approved by the Institutional Review Boards at each site.

Informed consent

Written informed consent was obtained from each patient before any study-related procedures were performed.

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Freise, K.J., Jones, A.K., Eckert, D. et al. Impact of Venetoclax Exposure on Clinical Efficacy and Safety in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia. Clin Pharmacokinet 56, 515–523 (2017). https://doi.org/10.1007/s40262-016-0453-9

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  • DOI: https://doi.org/10.1007/s40262-016-0453-9

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