Leukemia cell proliferation and death in chronic lymphocytic leukemia patients on therapy with the BTK inhibitor ibrutinib

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Abstract

BACKGROUND. Ibrutinib is an effective targeted therapy for patients with chronic lymphocytic leukemia (CLL) that inhibits Bruton’s tyrosine kinase (BTK), a kinase involved in B cell receptor signaling.

METHODS. We used stable isotopic labeling with deuterated water (²H₂O) to measure directly the effects of ibrutinib on leukemia cell proliferation and death in 30 patients with CLL.

RESULTS. The measured average CLL cell proliferation (“birth”) rate before ibrutinib therapy was 0.39% of the clone per day (range 0.17%–1.04%); this decreased to 0.05% per day (range 0%–0.36%) with treatment. Death rates of blood CLL cells increased from 0.18% per day (average, range 0%–0.7%) prior to treatment to 1.5% per day (range 0%–3.0%) during ibrutinib therapy, and they were even higher in tissue compartments.

CONCLUSIONS. This study provides the first direct in vivo measurements to our knowledge of ibrutinib’s antileukemia actions, demonstrating profound and immediate inhibition of CLL cell proliferation and promotion of high rates of CLL cell death.

TRIAL REGISTRATION. This trial was registered at clinicaltrials.gov (NCT01752426).

FUNDING. This study was supported by a Cancer Center Support Grant (National Cancer Institute grant P30 CA016672), an NIH grant (CA081554) from the National Cancer Institute, MD Anderson’s Moon Shots Program in CLL, and Pharmacyclics, an AbbVie company.

Authors

Jan A. Burger, Kelvin W. Li, Michael J. Keating, Mariela Sivina, Ahmed M. Amer, Naveen Garg, Alessandra Ferrajoli, Xuelin Huang, Hagop Kantarjian, William G. Wierda, Susan O’Brien, Marc K. Hellerstein, Scott M. Turner, Claire L. Emson, Shih-Shih Chen, Xiao-Jie Yan, Dominik Wodarz, Nicholas Chiorazzi