Leukemia cell proliferation and death in chronic lymphocytic leukemia patients on therapy with the BTK inhibitor ibrutinib
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
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
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Clinical Research and Public Health Clinical trials Hematology

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

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

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Figure 5

Modeling and estimating CLL kinetics.

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Modeling and estimating CLL kinetics. (A) A 2-compartment mathematical m...
(A) A 2-compartment mathematical model (given by ordinary differential equations) was used to estimate CLL cell death rates in tissue and blood, according to previously established methods. CLL cells in the tissue are assumed to die with a rate d1 and redistribute to blood with a rate m. CLL cells in the blood are assumed to die with a rate d2. The parameter c is included to account for the observation that the rate of CLL cell decline during ibrutinib treatment slows down over time and converges to a plateau. In accordance with data, it is assumed that no meaningful amount of cell proliferation and homing occurs during therapy. (B) Two examples of the treatment responses to ibrutinib. Circles show measured ALC in the blood, and the line is the best model fit to the data. The top graph is a typical patient with “slow” disease clearance, with a pronounced lymphocytosis phase that lasts for about 3 weeks. The bottom graph is a typical “fast” responder, with limited lymphocytosis that only lasts for a few days and a subsequent rapid decline. (C) Distribution of tissue death rates of tumor cells among patients, separated according to M-CLL (blue) and U-CLL (red). Each symbol represents a patient. The death rate is expressed both as the average life span of CLL cells in a patient (left), and as the percentage of CLL cells that die per day (right). (D) Average tissue decline dynamics among patients with M-CLL (blue) and U-CLL (red), as predicted by the parameterized mathematical model. The computer simulation of the model was run for individual patients, and the predicted tissue sizes were averaged and plotted every 30 days. The tissue size before start of treatment is given by 100, and the other sizes are scaled accordingly. For the purpose of comparison to previous studies, we plotted the predicted 2D tissue size, which scales with the number of cells to the power of 2/3. Note that this assumes complete correspondence between tissue size shrinkage and the decline of cell numbers in tissue, which should be reasonably accurate for large tissue sizes. Deviations are expected at smaller tissue sizes.