Real-world evidence is valuable in understanding why patients discontinue treatment with BTK inhibitors for chronic lymphocytic leukemia (CLL). The most common reason for discontinuation is adverse events, particularly atrial fibrillation and hypertension. Newer BTK inhibitors may have fewer cardiovascular effects and are promising for patients who are at risk of these complications.

Our knowledge of real-world factors associated with BTK inhibitor discontinuation in CLL has evolved. When the initial trials with BTK inhibitors were conducted more than 10 years ago, it was rare for a patient to come off a BTK inhibitor. I think that this is because the drugs were being used in second, third, fourth, or even later lines of therapy, and patients were feeling so miserable before they went on BTK inhibitor therapy that they felt much better after treatment. We did not understand that there were a number of adverse events that were low grade but still important, even though they were a less likely reason for treatment discontinuation in later lines of therapy.

As the BTK inhibitors started to roll out earlier in the course of the disease, especially now that they are being used in the frontline setting, we realized that there are a number of adverse events associated with treatment discontinuation. These include more serious cardiovascular effects, such as atrial fibrillation, but we also see hypertension and some lower-grade toxicities, such as arthralgias, myalgias, and diarrhea. I think that patients who are receiving BTK inhibitors in the frontline setting are less likely to tolerate these adverse events compared with those who are receiving BTK inhibitors in later lines of therapy.

We know from a number of data sets, including the work of Dr Anthony R. Mato and colleagues, that patients frequently do not stay on BTK inhibitors in the real world because of adverse events. He reported early discontinuations in his initial study on ibrutinib, and subsequent studies have reported similar data. This has also been reflected in our clinical practice.

There are some factors that we know put patients at higher risk for adverse events. A history of atrial fibrillation certainly increases the risk of developing atrial fibrillation on a BTK inhibitor. I think that this is true with any cardiovascular concern, including hypertension. It is harder to know why some patients experience myalgias and arthralgias that become nagging. Still, patients who are receiving frontline BTK inhibitors seem to have more adverse events than those receiving them in the second line.

Another factor that has become clear is that older patients have a much higher incidence of cardiovascular adverse events than younger patients. That makes sense because older patients are more prone to them in general. The good news is that the newer covalent BTK inhibitors have been shown to have fewer cardiovascular adverse events leading to treatment discontinuation. That said, patients may still experience other side effects, including arthralgias and bruising. The available data that we have on the noncovalent BTK inhibitor pirtobrutinib suggest that it has fewer adverse events, including cardiovascular adverse events, than the covalent BTK inhibitors. However, we need longer follow-up to be 100% sure about the adverse event rate. It took us a long time to reach a firm understanding of the adverse-event profile of the covalent BTK inhibitors because adverse events can take a while to develop.