Advances in Frontline Therapy for CLL

Nicole Lamanna, MD: There has been a very rapid shift in therapies for CLL [chronic lymphocytic leukemia]. There have been many new approvals. BTK [Bruton tyrosine kinase] inhibitors, which now include ibrutinib as well as acalabrutinib, have been approved in front line and relapsed, plus or minus a CD20 monoclonal antibody. Zanubrutinib is not approved for CLL; that’s another BTK inhibitor that recently got approved for mantle cell lymphoma. Stay tuned; there are lots of data in CLL as well, so we’re awaiting the approval of zanubrutinib in CLL. Of course, recently we had the venetoclax BCL2 inhibitor in combination with obinutuzumab, and that’s also now approved in the front line. There are many options for our patients with chronic lymphocytic leukemia in the untreated patient setting. In frontline therapy, there different options to discuss with them.

In the relapsed setting, of course, there are more therapies, including PI3 kinase inhibitors, which are approved in the relapsed setting so patients have multiple options of therapies. In the relapsed setting, of course, part of that will be dependent upon therapies they might have gotten in the front line: Did they have any toxicities to those therapies? What are their disease characteristics now? There are different things we can talk about that play into how we choose now that we have multiple therapeutic options for our CLL patients.

The survival for CLL, given these novel agents, has dramatically improved, and that’s an important point for patients to take home. These novel agents have drastically improved the survival for patients with CLL. There are still some important things to consider when we look at patients for treatment and their prognostic markers, including their cytogenetics and fluorescence in situ hybridization, will help guide selecting the therapy. Also, there are differences in their prognosis based on some of their features, and the immunoglobulin heavy-chain variable region gene mutational status is also an important feature that we check on patients.

The reason we consider these factors important is because selection of therapies is really based on some of these markers. If somebody has a 17p or a TP53 mutation, you’re going to go to a novel agent, and that is very important. Thankfully the survival of those individuals has dramatically improved as well compared with the era of chemoimmunotherapy. We all would agree that for patients with a 17p or a TP53 abnormality, these are patients who should receive a novel agent. Our longest data happens to be with BTK inhibitors in this subgroup, but certainly there are data for venetoclax-based combinations as well in this poor prognostic group of patients. That’s an important factor to know about prior to treating your patient because you would select, and let’s say chemoimmunotherapy or chemoimmunotherapy alone is not an option here—meaning you’re on a clinical trial that combines chemoimmunotherapy plus a novel agent. That would be fine, but it has to be a novel agent for patients with that feature.

Also, when we look at unmutated patients, certainly we’re going to move away from chemoimmunotherapy for unmutated folks as well. Again, checking the mutational status is important and knowing that because then you might decide to say we’re not doing chemoimmunotherapy. Remember, some of our patients who may otherwise seemingly have what we think is a good prognostic marker, like a 13q deletion, if they are unmutated, we would not give them chemoimmunotherapy. We would put those folks to a novel agent or a novel agent plus. Prognostic markers are still very important to obtain in our patients.

Remember, patients can change their chromosomal abnormalities if they have had therapy already in the front line. You’re going to want to check them again prior to their next subsequent therapy. If they now acquire a 17p or a TP53 mutation, that would be important to note. Prognostic markers are important, and we need to utilize them to learn more, particularly knowing that the patients have done so much better and their survival has improved dramatically and are akin to better players. That’s important. Getting these data is important, but they also help us select therapies for our patients given the multiple therapies we now have for our CLL patients.

Transcript Edited for Clarity