Two phase III trials published in December 2025—BRUIN CLL-313 and BRUIN CLL-314—delivered clinically consequential results for chronic lymphocytic leukemia, with pirtobrutinib positioned as a noncovalent option. Experts in the coverage urged caution on how treatments should be sequenced. The piece framed CLL as being at a regulatory and clinical crossroads, where the next standard of care could depend less on single-agent activity and more on optimal ordering relative to existing BTK inhibitor and other backbone regimens. For clinicians and biotech strategy teams, the signal is that late-line dynamics and real-world adoption will hinge on guidance for treatment sequences rather than only on aggregate efficacy.