The evolving frontline management of CLL: are triplets better than doublets? How will we find out?

Abstract Frontline therapy for chronic lymphocytic leukemia (CLL) has substantially advanced in the previous decade. While monotherapy with a Bruton's tyrosine kinase (BTK) inhibitor is an excellent option for many patients, combination therapies are of high clinical interest as they can induce deep responses and durable remissions, and in many cases allow discontinuation of therapy. There are several doublet therapies that are currently in clinical use. These include combinations of BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib) or BCL2 inhibitors (venetoclax) with anti-CD20 monoclonal antibodies, and combinations of BTK and BCL2 inhibitors. While BTK inhibitors with anti-CD20 monoclonal antibodies still typically require indefinite therapy, combinations involving the BCL2 inhibitor venetoclax have allowed for successful therapy discontinuation. Triplets, which combine all 3 of these paradigms, are of interest especially for patients with higher-risk disease. While triplets have been mainly studied in single-arm trials with excellent outcomes, comparative data to doublets are limited. In this article, we outline the doublet and triplet regimens that have been evaluated in CLL as well as the data from trials comparing doublets and triplets.