Additional Relevant Details ARQ 531 is a potent inhibitor of BTK with promising activity both in vitro and in vivo. • Multi-targeted inhibition of cytokine, chemokine, and BCR pathways by ARQ 531 decreases activation, migration, and viability of CLL cells. • Unlike ibrutinib, ARQ 531 inhibits activation of C481S mutated BTK variants and maintains cytotoxicity in ibrutinib resistant clones. • ARQ 531 demonstrates remarkable efficacy in an in vivo TCL1 adoptive transfer model, improving survival to a greater extent than ibrutinib and restoring granulocyte production. • These data warrant transition of ARQ 531 into clinical trials.