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.