The noncovalent BTK/ITK inhibitor vecabrutinib can block wild-type and C481S-mutant BTK in preclinical models. Vecabrutinib has immunomodulatory effects similar to those of ibrutinib in the murine Eμ-TCL1 model. Treatment with a combination of vecabrutinib and venetoclax leads to prolonged survival of Eμ-TCL1 mice. Illustration created with BioRender.com.