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Ibrutinib, the first clinically approved Bruton’s tyrosine kinase (BTK) inhibitor, is an effective and widely used therapy for chronic lymphocytic leukemia (CLL). The significant homology between BTK and IL-2-inducible kinase (ITK) makes ITK an off-target kinase inhibited by ibrutinib. This may lead to unintended consequences, as ITK regulates T-cell development and effector function of natural killer (NK) cells. Indeed, ibrutinib has been shown to inhibit healthy donor NK-cell cytotoxic activity in vitro but, at the same time, potentiated NK-cell function in xenograft mouse models of B-cell lymphoma. Given these contrasting experimental findings, it remains unknown whether patient NK-cell effector function is adversely affected during ibrutinib therapy. A major obstacle to investigating NK-cell repertoire and function in patients with CLL is their typically high B-cell tumor burden, which makes phenotypic and functional analyses of circulating NK cells challenging. To overcome this obstacle, we investigated patients with mantle cell lymphoma (MCL) rather than CLL. MCL is an aggressive disease with median survival of 3-6 years. We recently reported the results of a clinical trial in which ibrutinib was used to treat patients with MCL, while a second clinical trial assessing the safety and optimal dose of a new generation BTK inhibitor, zanubrutinib (BGB3111), in B-cell malignancies including MCL has been completed (Tam et al., 2019, submitted manuscript). Since MCL patients typically have few circulating malignant B cells, we had a unique opportunity to compare peripheral NK-cell repertoire and function in the same patients before and after one month of monotherapy with ibrutinib or zanubrutinib. We found that the repertoire of NKcell ligands on B cells of MCL patients was essentially

Differential effects of BTK inhibitors ibrutinib and zanubrutinib on NK-cell effector function in patients with mantle cell lymphoma