Dr. John Byrd discusses current and emerging strategies for managing double-class-refractory chronic lymphocytic leukemia (CLL) in community settings. He emphasizes the importance of distinguishing resistance from intolerance to BTK inhibitors through clinical history and molecular testing. Data from the BRUIN trial support the use of pirtobrutinib in select patients, while newer agents, including BTK degraders and bispecific antibodies, offer promising potential. Collaboration with CLL specialists is encouraged to guide therapy sequencing and access advanced treatments such as CAR T-cell therapy.