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 2

Ibrutinib inhibits CLL cell birth and permits increased CLL cell death.

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Ibrutinib inhibits CLL cell birth and permits increased CLL cell death. ...
(A) 2H2O enrichment data from the plasma of CLL patients (n = 30), showing enrichment of 2H2O during the first 4 weeks of ingestion, followed by dilution of 2H2O during the washout phase, which fits an exponential decay model. (B) Percentage of 2H enrichment in the DNA of peripheral blood CLL cells from the 30 CLL patients studied was measured and converted into a fraction (f) of newly divided cells, as described in Methods. Data are plotted for the first 12 weeks of the study, comprising the first 4 weeks of labeling, followed by washout. (C) After starting ibrutinib therapy, there is a plateau in the proportion of labeled CLL cells, indicating an arrest of CLL cell birth based on the absence of dilution in f (the fraction of previously divided, labeled CLL cells) by newly divided, unlabeled CLL cells. (D) The increase in ALC before the start of ibrutinib therapy is due to birth rates that are higher than death rates (see F). (E) After the start of ibrutinib, the ALC initially increases briefly, due to redistribution lymphocytosis and then continuously declines. (F) Calculated birth and death rates before start of ibrutinib therapy (pre-dose) and after the start of ibrutinib therapy (post-dose) demonstrate profound inhibition of CLL proliferation in addition to accelerated CLL cell death and ALC clearance after the start of ibrutinib.