A History of Targeted Therapy Development and Progress in Novel–Novel Combinations for Chronic Lymphocytic Leukemia (CLL)

SIMPLE SUMMARY: The treatment landscape for CLL has changed dramatically since the advent of targeted therapies. Studies have shown clear progression-free survival (PFS) benefit of these agents, as well as overall survival (OS) benefit in some instances, when compared with chemoimmunotherapy (CIT). Building on these successes, novel–novel combinations, including doublets and triplets, are under development with study designs exploring fixed and depth-of-response-driven durations. Further studies will be needed to elucidate the relative contributions of agents more clearly in these combinations and the optimal approach when using novel–novel combinations. ABSTRACT: Over the last 10 years, the traditional treatment paradigms for CLL have been upended as the use of traditional chemoimmunotherapy regimens has declined in favor of novel targeted therapies. Targeted therapies have become the new standard of care in CLL given their superior progression-free survival (and overall survival, in some cases) when compared with chemoimmunotherapy, as well as their improved toxicity profiles. Targeted agents are FDA approved for the treatment of CLL including ibrutinib, acalabrutinib, zanubrutinib, and venetoclax. Importantly, as opposed to traditional chemotherapy regimens, the benefits of these targeted therapies appear to be consistent regardless of high-risk mutational status. In this review, we discuss the pivotal CLL studies of the last decade and the data supporting doublet and triplet novel–novel combinations. We explore the use of new surrogate end points for PFS/OS in targeted therapies such as undetectable minimal residual disease (uMRD) and their potential role in minimizing toxicity by permitting earlier treatment discontinuation. We also highlight areas that warrant further exploration and future studies that may help address some of these key questions.