A Review of Treatment Options in CLL

Carrie Lenneman, MD, MSCI: Hello, and thank you for joining this OncLive® webinar titled: “Updates in CLL: A Closer Look at Adverse Events.” I’m Carrie Lenneman, an associate professor at and the director of cardio-oncology program at the University of Alabama at Birmingham. I’m joined by Dr. Farrukh Awan, an associate professor in the department of internal medicine and the director of the lymphoid malignancy program at [The University of Texas] Southwestern Medical Center. The treatment of chronic lymphocytic leukemia [CLL] continues to evolve as we learn how to incorporate new agents and improve our use of established therapies. Through our discussion, we hope to accomplish the following objectives: review the role of BTK inhibitors in the management of chronic lymphocytic leukemia, take an in-depth look at the adverse events associated with BTK inhibitors, especially with a focus on cardiotoxicity, obtain insight on strategies for monitoring and management and the potential impact on subsequent therapy selection, and discuss the role of advanced practice practitioners, nurses, and other medical professionals in the care of patients with CLL. Let’s begin. Dr. Awan, let’s review the available standard-of-care treatment options for CLL.

Farrukh Awan, MD: Thank you, Carrie. Thank you for this opportunity. I want to thank everyone who’s taking the time out to join us. CLL has gone through a lot of changes. Recently, there’s been a huge advance in the field. We’ve had many new drugs that have come out, which has changed the way we manage the disease compared with even a few years ago. The disease prognosis has changed our diagnostic processes and molecular markers—a lot has changed in the field. That’s very exciting for patients, but it’s also very challenging for practitioners to stay abreast with what’s happening. This is a great opportunity to discuss these issues and discuss recent developments, the good and bad that come with it. There’s been mostly good, but 1 thing that has happened in the last few years has been that chemotherapy is pretty much irrelevant for the vast majority of patients with CLL. Most of us stopped using chemotherapy a while ago, and more patients aren’t being treated with chemotherapy.

In some of the new studies that have come up—I don’t want to get into too many specifics of every trial that has been done in the last few years and reported in the last few years because then we’ll be just talking about those—there have been a few important messages coming out from these trials consistently. One such message is with the BTK inhibitors, which has been the major advance in the field. It has been systematically compared with existing chemotherapy options, and it has been clearly shown now that for older patients, ibrutinib with or without rituximab—because it’s debatable whetherrituximab adds to the efficacy of ibrutinib—ibrutinib is better than bendamustine and rituximab in the frontline setting. There’s very little doubt about the utility of ibrutinib in the untreated setting for patients who are 70 or older.

Similarly, ibrutinib was also compared head to head with FCR [fludarabine, cyclophosphamide, rituximab] chemotherapy for younger patients in the ECOG trial. Within a few years, we’ve already shown a survival advantage, which is almost getting to the point where it’s getting more significant. It’s very hard to demonstrate a survival advantage in patients with CLL. The purists say, “I’m not going to change the way I practice because none of your therapies has improved survival.” The follow-up is very short and it will be very difficult if everyone is eventually going to be treated with BTK inhibitor to demonstrate a survival advantage, so we have to have a surrogate end point to determine our outcomes. That’s why if progression-free survival is a surrogate, ibrutinib was clearly shown to be better in that setting.

Acalabrutinib is a second-in-class drug that was approved. These are all first-generation BTK inhibitors, which are irreversible BTK inhibitors. Acalabrutinib was also very active in the phase 1 setting. We have 4-year follow-up data from the ELEVATE TN study, which is the study of acalabrutinib in the treatment-naïve setting. It was also clearly shown to be better than the existing obinutuzumab chlorambucil and the 4-year outcomes look very promising. Outside the BTK space we have to talk about venetoclax. That’s a very relevant molecule and compound that’s being used a lot in patients with CLL because this is the only option we have for a time-defined treatment. Venetoclax-based treatments have shown very exciting responses. Durability depth has all been shown with all 3 of those agents, and they’re all approved for use in patients with untreated CLL and also for relapsed CLL. The field has moved along nicely. We have 2 major classes: the BTK inhibitors and the BCL2 inhibitors. They have different mechanisms of action, so they can be used 1 after the other, depending on which way you want to go.

It also raises a bunch of questions. One is that we’re treating CLL as we would treat hypertension or diabetes. You have chronic suppressive therapy, and you suppress the cancer for as long as possible in the case of BTK inhibitors. In the case of BCL2 inhibitors, it’s on-off therapy, which can potentially go on for years. But in the case of the BTK inhibitors, you have to continue therapy until patients progress or they have to stop because of toxicity. That raises new challenges because we have to deal with life. We have to deal with surgeries. We have to deal with hip replacements, knee replacements, and the long-term toxicity of drugs. We’ll be talking mostly about adverse events and what we’ve learned from that.

There’s a third drug, which is in the same first-generation BTK inhibitor space and is already approved for Waldenström [macroglobulinemia]. That’s zanubrutinib. It’s looking very promising. We do expect that it will be available for use in all patients with CLL in the future. It has a different toxicity profile from ibrutinib and acalabrutinib. Which is going to be clearly better than either 1? We have preliminary data that suggest that with the ibrutinib-zanubrutinib combination, zanubrutinib appears to have a better outcome in patients with CLL, although those are still early results, so we have to have more follow-up of that ALPINE study, which is very exciting and was recently presented. Zanubrutinib is looking very promising as a relevant option for patients who may not be considered candidates for ibrutinib or acalabrutinib. All 3 drugs are fascinating and very active in the BTK space, and we already know that venetoclax on the BCL2 side is also very attractive.

There’s also a growing body of data that suggest that if you become intolerant to 1 agent, you can move to another agent in the same class. If you have intolerance to ibrutinib, you can move to acalabrutinib. If you’re intolerant to acalabrutinib, you might be able to go to 1 of those 2 agents. In the future, when it gets approved, we’ll have zanubrutinib. These are all exciting probabilities. If you have a true progression on BTK inhibitors, unfortunately, if you do become resistant to 1 agent, there are obviously resistance mechanisms that people have. We’ve described them in the past. If you become resistant to 1 agent in the class, then you won’t respond to another agent in the same class. This is very clear. That’s the distinction right there. Patients who are truly progressing on a BTK inhibitor should not get another BTK inhibitor. Patients who are intolerant of a BTK inhibitor because of whatever toxicity would be perfectly reasonable candidates for another BTK inhibitor in the same class. That summarizes 10 years of data in 5 minutes.

Carrie Lenneman, MD, MSCI: That’s a great review of the FDA-approved BTK inhibitors. Thank you for talking about the emerging BTK inhibitors, especially with zanubrutinib, which is very exciting.

This transcript has been edited for clarity.