Contemporary Management of Relapsed or Refractory Chronic Lymphocytic Leukemia

Relapsed or refractory (RR) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) presents increasing therapeutic complexity in the era of targeted agents. Frontline use of covalent Bruton tyrosine kinase inhibitors (cBTKis) and venetoclax-based fixed-duration (FD) or minimal residual disease–guided regimens has led to deeper remissions, yet many patients will eventually require subsequent therapy. Management of first relapse should integrate clinical status, prior therapy, progression kinetics, and assessment for Richter transformation, along with genomic re-evaluation (particularly acquired resistance mutations and TP53 aberrations). Multiple effective options exist for relapsing disease. Second-generation cBTKi (acalabrutinib, zanubrutinib) continuous therapy provides durable disease control with improved tolerability over ibrutinib, whereas continuous venetoclax monotherapy or FD venetoclax-rituximab achieves high response rates and prolonged remission, with retreatment feasible for selected patients. Noncovalent BTKis (ncBTKis) such as pirtobrutinib offer meaningful activity in patients previously exposed to cBTKi. Cellular therapies, particularly lisocabtagene maraleucel, have demonstrated substantial efficacy in heavily pretreated patients, and allogeneic hematopoietic cell transplantation remains an option for select individuals with double-class refractory disease. Emerging therapies—including BTK degraders, next-generation BCL2 inhibitors, and bispecific antibodies—will likely reshape the therapeutic landscape for RR CLL/SLL. With broadening treatment options for RR CLL/SLL, optimal sequencing requires consideration of disease biology, depth and duration of prior response, comorbidities, toxicity profiles, patient preferences, and logistical factors. As therapeutic options expand, individualized treatment planning and clinical trial participation remain essential for improving outcomes in RR CLL/SLL.