<p>Real-world studies are an important source of information about treatments beyond what is observed in clinical trials. Real-world data on small-molecule drugs for chronic lymphocytic leukemia (CLL) are revealing more about the adverse-event and efficacy profiles of these agents.</p>

It is important to get beyond clinical trial data and study how small-molecule agents are being used in the real world, comparing drugs using large treatment or insurance databases. We are beginning to get real-world data that can help us choose between small-molecule therapies for patients with CLL. For example, real-world data have been important in determining the risk of adverse events. Specifically, real-world data on the rates of atrial fibrillation, hypertension, and infections have emerged for BTK inhibitors and should be used to drive the selection of BTK inhibitor therapy.

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Real-world studies have found that the next-generation BTK inhibitors acalabrutinib and zanubrutinib have improved safety outcomes compared with the first-generation BTK inhibitor ibrutinib. A study of patients with CLL or small cell lymphocytic lymphoma treated with single-agent acalabrutinib or single-agent ibrutinib found that the 3-year incidence of atrial fibrillation or flutter was 7.1% with acalabrutinib vs 14.7% with ibrutinib and that the rate of new-onset hypertension was 16.3% and 27.7%, respectively. These findings could mean that patients may continue acalabrutinib therapy longer, and being able to stay on a BTK inhibitor generally equates to longer progression-free survival.

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We have not yet learned whether it is better to start off with time-limited therapies that contain a BCL-2 inhibitor for 1 to 2 years or to use a BTK inhibitor continuously for as long as possible before transitioning to a BCL-2 inhibitor. This is where it gets complicated, and I feel that this is more of an art than a science-driven decision.

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Finally, recent real-world data have indicated that the racial disparities that have been observed in CLL survival rates appear to be driven by unequal access to care rather than by biological differences in disease presentation. I think that this is an important observation that we need to address.