Triplet regimens for frontline treatment of CLL—Great company or just a crowd?

Abstract Standard frontline treatment of chronic lymphocytic leukemia (CLL) is with fixed‐duration venetoclax‐based doublets or indefinite covalent Bruton tyrosine kinase inhibitor (BTKI). Although these approaches achieve excellent results, venetoclax doublets have diminished efficacy in high‐risk biological subgroups, and indefinite covalent Bruton tyrosine kinase inhibitor (cBTKI) is associated with cumulative cardiovascular and infectious toxicity. Triplet regimens for treatment of CLL involve simultaneous use of cBTKI, venetoclax, and anti‐CD20 monoclonal antibody. Three major frontline Phase 3 trials (CLL‐13/GAIA, AMPLIFY, and A041702) have demonstrated higher rates of undetectable minimal residual disease (uMRD) and longer remissions with triplets than doublets, particularly in patients with IGHV‐unmutated (IGHV‐U) disease. However, this comes at the cost of increased infectious toxicity, particularly with COVID‐19, and thus has translated into a variable impact on progression‐free survival (PFS) and, to‐date, no overall survival (OS) benefit. Although there are promising Phase 2 data for triplets in patients with TP53 aberrant or relapsed disease, the heterogeneity of treatment duration/MRD definition, lack of control arm, and potential increased toxicity make it premature to use triplets in these groups. We recommend considering triplets in treatment naïve CLL patients with IGHV‐U, TP53 wild type, anticipated low incidence/good tolerance of Gr ≥ 3 infection (<70 years old, no major comorbidity and fully immunized) who are well informed and prioritize maximal time off therapy at the expense of increased short‐term logistical complexity. Future triplet research should focus on randomized trials in specific genomic subgroups, incorporating novel agents (e.g., non‐covalent BTKI, BTK degrader, and next‐generation BCL2 inhibitors) and new ways of adapting treatment duration to maximize efficacy and minimize toxicity.