Dual-targeted regimens for the frontline treatment of CLL

The treatment landscape of chronic lymphocytic leukemia (CLL) has evolved considerably over the past decade due to the development of effective novel agents with varying mechanisms of action, including Bruton tyrosine kinase (BTK) and B-cell lymphoma 2 (BCL2) inhibitors. Extrapolating upon the success of anti-CD20-directed chemoimmunotherapy, a dual-targeted approach has been explored in treatment-naive patients with CLL. Anti-CD20 monoclonal antibody combinations with BTK inhibitors as well as BCL2 inhibitors have demonstrated superiority over traditional cytotoxic chemoimmunotherapy regimens such as fludarabine, cyclophosphamide, and rituximab; bendamustine-rituximab; and obinutuzumab-chlorambucil. Impressive clinical benefit is seen in both younger and older patients, those with comorbidities, and, most importantly, those with poor prognostic features. Given this success, combinations of BTK inhibitors and venetoclax have been explored in clinical trials. These dual-targeted regimens provide remarkable efficacy while allowing for an all-oral approach and fixed duration of treatment. Current investigations under way are evaluating the utility of a triplet approach with the addition of obinutuzumab in comparison to a doublet approach.