Ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor, may impair natural killer cell cytotoxic activity, potentially through off-target inhibition of IL-2–inducible kinase (ITK), an in vitro study suggests. The study findings were published online in Haematologica.

Ibrutinib is widely used in chronic lymphocytic leukemia (CLL), and while studies have investigated the effects of BTK inhibitors on natural killer cell function, the results to date have been conflicting. Because studying the effects of ibrutinib on natural killer cell repertoire and function in CLL patients is difficult due to the often high B-cell tumor burden among these patients, the study researchers investigated these effects in patients with mantle cell lymphoma instead.

The study researchers showed in cell culture that exposure to an ITK inhibitor lead to suppression of natural killer cell cytotoxicity, suggesting that ITK is important for natural killer cell cytotoxic activity.

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In vitro experiments confirmed that zanubrutinib and ibrutinib both inhibit BTK but also showed they inhibit interleukin-2-inducible kinase (ITK) too, though zanubrutinib was 20-fold less potent against ITK. “Zanubrutinib is therefore an equally potent, but more selective inhibitor of BTK than ibrutinib in vitro,” the study authors wrote.

In vitro experiments revealed that ibrutinib “severely” suppressed natural killer cell activation and target-cell killing, whereas zanubrutinib did not. An additional set of experiments showed that ibrutinib, but not zanubrutinib, “significantly” suppressed cytotoxic activity of natural killer cells, a finding that is consistent with off-target ITK inhibition.

“Our findings demonstrate the differential effects of first- and second-generation BTK inhibitors ibrutinib and zanubrutinib on NK [natural killer] cell function, highlighting the need for careful consideration of the most appropriate combination therapies when using this class of drugs to treat blood cancers,” the study authors concluded.


Flinsenberg TWH, Tromedjo CC, Hu N, et al. Differential effects of BTK inhibitors ibrutinib and zanubrutinib on NK cell effector function in patients with mantle cell lymphoma [published online June 6, 2019]. Haematologica. doi: 10.3324/haematol.2019.220590