New therapies for relapsed/refractory chronic lymphocytic leukemia (CLL) have been studied in clinical trials, and 2 agents have received US Food and Drug Administration (FDA) accelerated approval in the past year. Our featured experts share their current clinical decision-making processes regarding the use of these novel agents in patients with relapsed/refractory CLL.

For me, the biggest considerations when caring for a patient with previously treated CLL are what agents they have already received and whether their CLL has become resistant to them. For example, someone who has never taken a BTK inhibitor has different treatment options than someone who has taken a BTK inhibitor and their CLL became resistant. If a patient stopped taking a BTK inhibitor due to an adverse event, that is a completely different consideration.

We have very good options for covalent BTK inhibition with ibrutinib, acalabrutinib, and zanubrutinib. Once a patient’s CLL becomes resistant to one of these agents, we either target a different mechanism, such as venetoclax for Bcl-2 inhibition, or choose a noncovalent BTK inhibitor. In people whose CLL has become resistant to both covalent BTK inhibitors and venetoclax, noncovalent BTK inhibition generally works. This is where some exciting developments come into play.

In addition to noncovalent BTK inhibitors, there are several other therapies, either FDA approved or in development, that can be effective. BTK degraders are really unique drugs that remove the BTK protein rather than inhibit it. Theoretically, they can be very useful, and preliminary data indicate that they may have a role in treatment when CLL cells have BTK mutations that escape other pharmacologic inhibitors. We are also currently gaining experience with using immunotherapies, including CAR T-cell therapy and bispecific antibodies. Overall, the options for patients with CLL are good and continue to improve. I am really excited about what these drugs will do for our patients, and I am hopeful that, as we gain more experience with using them, they might be used earlier in the disease course for even better benefit.

That was a very comprehensive response from Dr Rogers. I will add that managing double-refractory CLL (ie, refractoriness to both covalent BTK inhibition and Bcl-2 inhibition) is increasingly an unmet need in the clinic. We are seeing more and more patients who initially respond very well to these 2 classes of drugs but then, unfortunately, experience disease progression. I think that the field is moving toward answering pressing clinical questions for this group of patients.

Thankfully, we have 2 treatments that were recently granted accelerated approval by the FDA: pirtobrutinib and lisocabtagene maraleucel (liso-cel). Pirtobrutinib is a noncovalent BTK inhibitor that was approved last year, and liso-cel is a CAR T-cell therapy that was approved earlier this year. Both of these drugs represent true advances in our ability to help patients who have experienced disease progression on covalent BTK inhibitors and venetoclax. But, unfortunately, they are not home runs. We see patients continue to progress despite receiving these treatments.

That setting is where the next wave of research is currently ongoing with BTK degraders, bispecific antibodies, and CAR T-cell therapy combinatorial approaches to enhance its efficacy. All of these will hopefully continue to improve the benchmark that pirtobrutinib and liso-cel have recently set in the double-refractory space.

When we think about sequencing these drugs, we should remember that there was a reason for someone choosing their initial therapy. Understanding why venetoclax-based therapy or a BTK-based therapy was chosen as the first round of treatment can also affect subsequent treatment decisions. For example, maybe the patient is older and it was very difficult for them to come into the office for a venetoclax-based ramp-up. That might explain why the first-line treatment choice was made and would, perhaps, affect how we approach the choice of second-line therapy as well.

In addition, the cytogenetics and genomic rearrangements that a patient has may also affect our choice of second-line therapy. For instance, if a patient with del(17p) progresses on a BTK inhibitor, my expectations and choices for their second line of therapy might be different now that we have more than one choice after the initial treatment.