Management of Relapsed and/or Refractory Chronic Lymphocytic Leukemia.

Covalent Bruton's tyrosine kinase inhibitors (cBTKis), including acalabrutinib and zanubrutinib, and the BCL2 inhibitor venetoclax are currently sequenced in both front-line and relapsed and/or refractory (R/R) chronic lymphocytic leukemia (CLL). A newer challenge is the management of patients with R/R CLL after exposure to both a cBTKi and BCL2 inhibitor. Herein, we review the management of R/R CLL following prior treatment with chemoimmunotherapy, cBTKi, and venetoclax-based therapy. We review treatment options for "double exposed" CLL including venetoclax retreatment, pirtobrutinib, and CAR T-cell therapy with lisocabtagene maraleucel. Emerging treatment options include agents in clinical trials such as BTK degraders and bispecific antibodies.