Integrating venetoclax-based targeted and/or immune therapies for chronic lymphocytic leukemia

Venetoclax (VEN), a selective BCL-2 inhibitor and VEN-based combinations represent a cornerstone of modern chronic lymphocytic leukemia (CLL) management and allow deep remissions and fixed-duration, chemotherapy-free treatment options. Our narrative review aims to provide an overview of VEN-based targeted and immunotherapy combinations in both newly-diagnosed and relapsed/refractory CLL. We summarize pivotal clinical trials evaluating VEN in combination with anti-CD20 monoclonal antibodies, Bruton's tyrosine kinase inhibitors (BTKi), bispecific antibodies and chimeric antigen receptor (CAR) T-cells. The regimens we discuss in this paper achieved high overall response rates, durable progression-free survival, and substantial rates of undetectable minimal residual disease, often translating into prolonged treatment-free intervals. For instance, fixed-duration VEN–obinutuzumab/rituximab regimens demonstrated superiority over chemoimmunotherapy, while combinations of VEN with BTKi further improved depth of response and reduced resistance rates. MRD-guided strategies are discussed, their superiority over fixed-duration approaches, however, remains unproven. Emerging data on retreatment, sequencing strategies, dose optimization, and next-generation BTKi are also highlighted. We also identify current knowledge gaps because future studies directly comparing regimens and integrating MRD-driven decision-making will be critical to defining optimal therapeutic strategies. • Determining which treatment combination is most suitable for each patient group remains a key question in CLL. • Determining the optimal treatment dose and duration (i.e., number of cycles) continues to be an area of active investigation. Another important consideration when comparing different regimens is the route of administration. • Oral combinations offer several advantages over parenteral therapies, transforming CLL into a chronic disease managed with daily medication. • BTKi-Ven combinations are generally easier to administer and monitor than intravenous or subcutaneous anti-CD20 antibody–based combinations, such as VenO.