Drug-related toxicities can be burdensome for patients with chronic lymphocytic leukemia (CLL), even for those receiving targeted agents. Adverse events are a major reason for discontinuing targeted agents and are reported more often in real-world treatment than in clinical trials.

There has been a paradigm shift in the treatment of patients with CLL. Over the last decade, we have been using targeted treatments more often than traditional chemotherapy or chemoimmunotherapy. As these treatments were called “targeted treatments,” it was felt that they would not have any toxicities at all. Unfortunately, that has not been the case. There are unique toxicities associated with the use of targeted agents that clinical practitioners need to be aware of.

The 4 broad classes of targeted agents that are currently approved by the US Food and Drug Administration (FDA) for the management of CLL include BTK inhibitors, BCL-2 inhibitors, PI3K inhibitors, and CAR T-cell therapy, specifically the recently approved lisocabtagene maraleucel, with BTK and BCL-2 inhibitors being the most commonly used. Within the category of BTK inhibitors, several covalent BTK inhibitors and 1 noncovalent BTK inhibitor are FDA approved. In general, the toxicity profile is similar across all BTK inhibitors, although the frequency of adverse events differs. Different toxicities are encountered with BCL-2 inhibitors.

Bleeding complications are common with BTK inhibitors and typically manifest as bruising under the skin, gum bleeding, or other minor bleeding issues. In a small proportion of cases, severe bleeding has been reported, particularly with the concurrent use of anticoagulants or antiplatelet drug use. There is a boxed warning on the use of BTK inhibitors among patients taking warfarin, and their concurrent use is not recommended. Other toxicities of BTK inhibitors include hypertension, atrial fibrillation, and ventricular arrhythmias. These are some of the more difficult-to-manage complications. There are also many “nuisance” effects of BTK inhibitors, including muscle aches, muscle spasms, brittle nails, and skin rashes. Most of these are minor and can be managed by dose reduction.

As I mentioned previously, the frequency of each of these adverse events is variable. Many patients receiving the newer covalent BTK inhibitors, which include zanubrutinib and acalabrutinib, experience fewer adverse events than they do with ibrutinib, such as a lower risk of atrial fibrillation. Head-to-head comparison studies exist between acalabrutinib and ibrutinib and between zanubrutinib and ibrutinib. However, no head-to-head comparison studies are available between acalabrutinib and zanubrutinib. For reasons of both safety and efficacy, I typically use either zanubrutinib or acalabrutinib over ibrutinib, as supported by data from the head-to-head trials. Unique toxicities of acalabrutinib include headache occuring within the first few weeks of use, which is easily managed with the use of acetaminophen and/or caffeine.

Pirtobrutinib was granted FDA accelerated approval in the relapsed/refractory setting after a covalent BTK inhibitor and a BCL-2 inhibitor stop working. It is the only noncovalent BTK inhibitor with an FDA indication in CLL, so, in my practice, I reserve pirtobrutinib for that situation. Based on current data, pirtobrutinib appears to be associated with a low rate of adverse events, including atrial fibrillation and hypertension, although follow-up is relatively short for pirtobrutinib at this time.

Venetoclax is the only currently FDA-approved BCL-2 inhibitor for the management of CLL. One of its most consequential toxicities is the occurrence of tumor lysis syndrome. Therefore, it is important to follow the package insert, which says that patients should receive 5-week ramp-up dosing with careful monitoring and prophylaxis. Venetoclax can also cause febrile neutropenia. The risk of this complication is anywhere from 3% to 5%, and some patients—particularly older individuals—are more prone to this complication. Another possible adverse event is diarrhea, which is modifiable by altering the dose of venetoclax.