Novel combination approaches with targeted agents in frontline chronic lymphocytic leukemia

Targeted therapies have revolutionized the frontline treatment landscape for patients with chronic lymphocytic leukemia (CLL) and have largely displaced a reliance on chemoimmunotherapy when treating this disease. Multiple randomized trials have documented the efficacy of oral therapy with the Bruton tyrosine kinase inhibitors ibrutinib and acalabrutinib (and zanubrutinib, pending a supplemental new drug application in CLL), as well as BCL2 inhibition using venetoclax. In this review, the authors highlight novel therapeutic strategies for using these agents in combination, either as doublet therapy or as triplet therapy, with anti-CD20 antibodies. First, the current treatment landscape is outlined, and the data are reviewed for continuous and time-limited therapeutic approaches, which constitute the current standard of care. Then, more recent reports are described from phase 2 and 3 studies exploring different combination strategies of Bruton tyrosine kinase and BCL2 inhibition for treatment-naive patients. In addition, relevant differences are emphasized between patient characteristics (e.g., patient fitness and the presence of high-risk disease features) and study methodology (e.g., dosing schedule, randomization, and assessment of measurable residual disease) across trials. Finally, the authors revisit the currently available data for these approaches in the context of ongoing studies and future planned trials, evaluating their potential impact on the frontline treatment landscape for CLL in the years to come.