Selective BTK inhibition improves bendamustine therapy response and normalizes immune effector functions in chronic lymphocytic leukemia

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has been shown to be highly effective in patients with chronic lymphocytic leukemia (CLL) and is approved for CLL treatment. Unfortunately, resistance and intolerance to ibrutinib has been observed in several studies, opening the door for more specific BTK inhibitors. CC‐292 (spebrutinib) is a BTK inhibitor with increased specificity for BTK and less inhibition of other kinases. Our in vitro studies showed that CC‐292 potently inhibited B‐cell receptor signaling, activation, proliferation and chemotaxis of CLL cells. In in vivo studies using the adoptive transfer TCL1 mouse model of CLL, CC‐292 reduced tumor load and normalized tumor‐associated expansion of T cells and monocytes, while not affecting T cell function. Importantly, the combination of CC‐292 and bendamustine impaired CLL cell proliferation in vivo and enhanced the control of CLL progression. Our results demonstrate that CC‐292 is a specific BTK inhibitor with promising performance in combination with bendamustine in CLL. Further clinical trials are warranted to investigate the therapeutic efficacy of this combination regimen. What's new? B‐cell receptor (BCR) signaling plays a pivotal role in chronic lymphocytic leukemia (CLL). BTK inhibitor ibrutinib has been shown to be highly effective in patients, but resistance and intolerance have also been observed. Here, the authors demonstrate that the more specific CC‐292 disrupts BCR signaling and inhibits tumor cell activation, proliferation, and chemotaxis in vitro. In mice, CC‐292 reduces tumor load and normalizes tumor‐associated expansion of T cells and monocytes while not affecting T cell function. Combination of CC‐292 and bendamustine impairs CLL cell proliferation and normalizes immune cell composition, which overcomes microenvironment‐mediated chemoresistance and enhances control of CLL progression.