Advances in the Management of Relapsed/Refractory CLL and Richter Transformation

ABSTRACT The management of relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), particularly when patients have double‐refractory CLL with progression after both covalent Bruton's tyrosine kinase inhibitors (BTKi) and venetoclax, as well as Richter Transformation (RT) remain significant clinical challenges. These patients face poor outcomes, necessitating novel treatment approaches. Recently approved therapies such as a non‐covalent BTKi and CAR‐T cells provide new options, while BTK degraders and bispecific antibodies are showing early promise in clinical trials. For RT, venetoclax‐based chemoimmunotherapy combinations may increase rates of complete response, but remain inadequate for many, highlighting the need for novel therapeutic approaches. This review synthesizes recent advancements in R/R CLL and RT treatment, discussing approved therapies, investigational agents, and combination strategies aimed at improving outcomes in these high‐risk populations.