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 3

Peripheral blood cell counts, bone marrow infiltration, and survival during ibrutinib treatment.

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Peripheral blood cell counts, bone marrow infiltration, and survival dur...
(A) Median ALC (±SEM) before and after starting ibrutinib therapy (black arrow: start of labeling phase; gray arrow: start of ibrutinib therapy). The trend of the ALC shows a characteristic transient increase after the start of ibrutinib therapy due to redistribution of tissue CLL cells into the peripheral blood. (B) Redistribution lymphocytosis was seen only in patients with mutated IGHV (M-CLL, n = 11); in contrast, redistribution lymphocytosis was absent patients with unmutated IGHV (U-CLL, n = 17). (C) Median hemoglobin levels and (D) platelet counts (±SEM) normalize during ibrutinib therapy. The gray shaded areas indicate normal values. (E) There was a continuous improvement in bone marrow infiltration by CLL cells after starting ibrutinib therapy, indicated as the percentage of bone marrow lymphocytes that are displayed for each patient together with the median (±SEM, n = 29). (F) When comparing patients with M-CLL with patients with U-CLL, there was faster bone marrow clearance of leukemia cells in patients with U-CLL. (G) No progression events were seen in the entire patient population after a median follow-up of 26 months. (H) Only one CLL- and treatment-unrelated death occurred; the remaining patients are alive and almost all (27 of 30) continue on ibrutinib therapy. PFS, progression-free survival; OS, overall survival.