Double refractory chronic lymphocytic leukemia: clinical scenarios and therapeutic strategies.

Despite its typically indolent course in most patients, chronic lymphocytic leukemia (CLL) can relapse or become refractory to the two main classes of drugs commonly used: covalent BTK inhibitors and BCL2 inhibitors. This review outlines the potential reasons for discontinuation of these drug classes, defines the concepts of double exposure (DE) and double refractoriness (DR), delineates the possible treatment sequences leading to DR, summarizes the poor prognosis of this patient subgroup, and describes the approved, investigational, and less optimal therapeutic alternatives for the management of this population. Finally, three illustrative clinical vignettes of patients with DE/DR CLL are presented, including case analysis and practical management recommendations, as well as teaching points.