BTK inhibitors are a treatment option in both the frontline and relapsed settings of chronic lymphocytic leukemia (CLL). In clinical research, several BTK inhibitors have demonstrated survival advantages compared with traditional chemoimmunotherapy regimens. However, the optimal sequence of therapies in these treatment settings for CLL has yet to be determined.

Three covalent BTK inhibitors currently have US Food and Drug Administration (FDA) approval for treating CLL. Ibrutinib was the first to be approved, followed by acalabrutinib and then zanubrutinib. Ibrutinib, acalabrutinib, and zanubrutinib are FDA approved for the initial treatment of CLL and for previously treated CLL. Both acalabrutinib and zanubrutinib tend to have fewer cardiovascular side effects compared with ibrutinib.

Ibrutinib, acalabrutinib, and zanubrutinib all bind to BTK covalently and permanently. Due to their overlapping mechanisms of action, in the case of resistance, it is not helpful to switch between them; patients will likely only get 1 of these drugs and will not go through all 3 of them, unless they develop intolerance to 1. In cases of intolerance, switching to a different covalent BTK ihibitor is frequently successful. The question of how to individualize initial treatment with BTK inhibitors based on patient and disease characteristics is an extremely important one, and it has several layers to it. The first is identifying which patients could benefit the most. I like to consider their disease characteristics, comorbidities, and preferences. Choosing subsequent treatment depends on what drugs were received previously and whether patients developed resistance to prior treatment.

TP53 mutations and del(17p) seem to be the highest-risk features that we see with CLL, even in this current era of targeted agents. To maximize the progression-free survival for patients with high-risk features during frontline therapy, I very strongly consider BTK inhibitors for my patients with del(17p) if they are not participating in a clinical trial. However, due to the risk of bleeding, hypertension, atrial fibrillation, and other side effects from BTK inhibitors, there are some patients for whom these agents are less suitable. Therefore, even in patients with high-risk CLL, I do not think that it is a good idea to use BTK inhibitor therapy if they are taking warfarin, for example, or have uncontrolled atrial arrhythmias. While BTK inhibition might be a little more effective for their CLL, it is certainly not better for them as a person. For those with well-controlled hypertension or atrial fibrillation, I have no issue using BTK inhibitors. I have even combined them with oral anticoagulants other than warfarin.

Patient preference is another important consideration when selecting treatment with a BTK inhibitor. BTK inhibitors are an indefinite treatment. Patients take them until they either experience disease progression or become intolerant. While most patients prefer a finite therapy, there are some who want treatment that is ongoing and do not want to finish treatment. Many patients may also prefer the convenience of BTK inhibitors compared with venetoclax plus obinutuzumab, which requires visits for infusions and ramp-up dosing. These considerations can make a big difference in selecting a BTK inhibitor, and I believe that it is very important to think through all of them when deciding on the initial treatment.

Another BTK inhibitior, pirtobrutinib, is noncovalent and has accelerated approval from the FDA for CLL that was previously treated with a covalent BTK inhibitor and a BCL-2 inhibitor. I think that pirtobrutinib is a very exciting drug for the group of patients who have been exposed to both covalent BTK inhibitors and venetoclax. There are concerns about whether covalent BTK inhibitors will work after pirtobrutinib, so, at this point, I would caution anyone against using it instead of a covalent BTK inhibitor in the frontline setting outside of a clinical trial.