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JCI Insight. 2017 Jan 26;2(2):e89904. doi: 10.1172/jci.insight.89904.

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

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Department of Leukemia, MD Anderson Cancer Center, Houston, Texas, USA.
KineMed Inc., Emeryville, California, USA.
Department of Diagnostic Radiology and.
Department of Biostatistics, MD Anderson Cancer Center, Houston, Texas, USA.
Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, California, USA.
Karches Center for Chronic Lymphocytic Leukemia Research, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York, USA.
Department of Mathematics and Department of Ecology and Evolutionary Biology, University of California, Irvine, Irvine, California, USA.


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 (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.

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