Venetoclax Retreatment in Chronic Lymphocytic Leukemia is biologically rational and clinically effective

Venetoclax therapy has evolved from continuous monotherapy to fixed-duration (FD) and measurable residual disease (MRD)-guided combination regimens in frontline and relapsed/refractory chronic lymphocytic leukemia (CLL). Compared with continuous therapy, FD regimens are associated with a lower incidence of emergence of BCL2 mutations and distinct mechanisms of relapse, supporting the rationale for investigating venetoclax-based combination retreatment strategies. In this review, we summarize the key studies for venetoclax rechallenge and discuss the available clinical evidence. To date, ten abstracts or published manuscripts have reported on venetoclax retreatment, as continuous monotherapy or with FD/MRD guided combinations with anti-CD20 monoclonal antibodies (rituximab, obinutuzumab) or covalent Bruton tyrosine kinase inhibitors (ibrutinib, acalabrutinib). Patient and disease characteristics were heterogeneous across studies, with a substantial proportion of patients with high-risk disease (IGHV-unmutated or del17p/TP53 mutations). The median time off venetoclax following initial therapy ranged from 9 to 90 months. Reported overall response rates to retreatment ranged from 72% to 100%, and undetectable MRD rates in peripheral blood from 32% to 92%. Median progression-free survival, when available, ranged from 23 to 58 months. Optimal patient selection remains to be defined, but the depth of the initial venetoclax response and time to progression from last venetoclax exposure may predict rechallenge efficacy and are incorporated in new clinical trial criteria allowing previous FD venetoclax treatment.