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Second-Generation BTK Inhibitors for CLL

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Published on September 3, 2021

What Are Second-Generation BTK Inhibitors?

The approval of the first BTK inhibitor was a game changer for the treatment of CLL. In this video, Jacqueline Claudia Barrientos, MD, MS, of Northwell Health gives an overview of second-generation BTK inhibitors, their side effect profile, and how they differ from first-generation BTK inhibitors. Dr. Barrientos also discusses recently approved therapies, the status of those still in clinical trials, and the questions CLL patients should be asking their medical teams to improve outcomes.

Support for this series has been provided by Janssen Oncology and Pharmacyclics LLC. Patient Power maintains complete editorial control and is solely responsible for program content.

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Transcript | Second-Generation BTK Inhibitors for CLL

Dr. Barrientos:
My name is Jacqueline Barrientos. I work at the CLL Research and Treatment Program in Long Island, New York. It's part of the Northwell Health system.

So as you all may be aware, ibrutinib (Imbruvica) was a first-in-class oral BTK inhibitor, Bruton's tyrosine kinase inhibitor, that changed the way that we treat our patients with CLL, both in frontline and in relapsed/refractory disease. The issue is that over time we realized that many of our patients develop toxicities that did not allow them to continue on therapy. The most commonly seen that were worrisome for the patients and for the physicians were bleeding events, arrhythmias, and also a hypertension, which usually develops after several years. So, it's for this reason that many investigators looked into other novel compounds that might have more specificity against the BTK inhibitor and maybe be more tolerable. And so recently at ASCO 2020, which is the major American Society of Clinical Oncology meeting where we present our data, the long-term follow-up data was shown.


What Is the Difference Between First-Generation and Second-Generation BTK Inhibitors?

Between a second-generation BTK inhibitor called acalabrutinib (Calquence) against ibrutinib, which is the first-in-class therapy that was approved by the FDA. And what it showed was that it not only was non-inferior, meaning they both had the same time in remission or progression-free survival. But in addition to that, the patients that were treated with acalabrutinib, they were able to have less events of hypertension, less events of cardiac arrhythmias, less events of bleeding events, and less diarrhea and other naggy symptoms, like for example, joint pain. So that is the first second-generation BTK inhibitor that has been approved for CLL. There's another drug called zanubrutinib (Brukinsa) that is still in clinical development. And currently, the data that has been presented was the EHA, or the European Hematology Association meeting in 2021, where the investigator showed the data comparing zanubrutinib against ibrutinib. It's another second-generation BTK inhibitor. It's not yet approved for CLL, it's undergoing FDA review for that purpose. And it showed that in certain patients, like patients that had 17p deletion, it seemed to have a faster response which was a primary endpoint for the study, the overall response rate.

It seemed to also have a faster response rate for all the other prognostic markers of patients with CLL disease. Now having said that, the caveat with that study said that's a very slow time that has been followed up, and as such, many of the side effects that I'm mentioning occur over time. And there wasn't that much difference. It just seemed to be better tolerated in terms of bleeding events and other toxicities. However, I would think that we would need longer follow-up data to understand where zanubrutinib will come into the arriving pattern for CLL patients, or patients with CLL. But we're in any case very excited. There was another small publication abstract presented as a poster form at EHA for patients that were treated with ibrutinib and/or with acalabrutinib. And they couldn't tolerate the other drug, and they were salvaged with zanubrutinib. Many of the patients were able to tolerate the drug. So, the more options that we have for patients, it's the better. I welcome all the second-generation BTK inhibitors.

What Is the Process for Starting or Stopping a Treatment Regimen for CLL?

So, under what conditions can we safely stop a drug such as ibrutinib, or acalabrutinib, or zanubrutinib? These drugs were developed in a way that currently, they're being taken indefinitely until progression of disease or the development of toxicities that do not allow the patients to continue on the drug. Now, what we have seen in our data frontline of patients that were in the study e1912, that they received ibrutinib and rituximab (Rituxan) frontline, and this study was comparing against chemotherapy, a regimen called FCR at the time. What we found out was that even in patients that had to stop for another reason, like for example, they developed a toxicity and they had to stop the ibrutinib, many of them were able to still be in remission for a while. So, it doesn't mean that if you stop, you're going to relapse the next day. The majority of patients won't do that. There are, however, some patients that will have a more aggressive form of the disease. And particularly patients with the 17p deletion, who usually traditionally, from what we know from the clinical trials, these patients will require continuous daily dosing.


Why Is Minimal Residual Disease (MRD) Testing Important?

So as of right now, there's a technology called detection of MRD or also known as minimal residual disease. The testing of MRD is in evolution. Right now, we're trying to understand how and when to use it, and how it correlates to the outcomes. We know, for example, with a drug such as the Bcl-2 inhibitor venetoclax (Venclexta), if you actually test for undetectable MRD and there is no evidence of MRD, meaning there's no CLL cells in one in 10,000 lymphocytes, these patients will be in remission for much longer time. This is the closest that you can get to a cure. Now, the reason why this is not standardized is because there are some testing laboratories that only do one in 10,000 lymphocytes. And there are some other studies that are currently in research only, that do one in 10,000, one in 100,000 and one in 1,000,000.

So, the depth of the detection will change the way and the outcomes that you can expect. Of course, if you cannot detect one cell in a million, it means that likelihood of relapsing is extremely low. Now we have seen that with a drug such as venetoclax because those drugs can achieve undetectable MRD. Importantly to know is that BTK inhibitors such as ibrutinib, acalabrutinib, and zanubrutinib, have never shown to be able to achieve undetectable MRD, both in the bone marrow and in the peripheral blood, as monotherapy. There are new clinical trials ongoing, particularly the combination of ibrutinib with venetoclax was recently presented at ASCO and at EHA, both in young patients and in older patients with the diagnosis of CLL. And it shows that there was actually a significant amount of patients that were able to achieve undetectable MRD. How does this correlate into medical practice? We are still trying to understand.

The data from the CAPTIVATE study, which is the frontline use of ibrutinib for three months to debulk or making sure that the CLL gets smaller tumor burden, and then the addition of venetoclax with a combined therapy of ibrutinib with venetoclax for 12 months. What it showed is after those 12 months of combined therapy, if you stop two years later, 95% of the patients with be in remission. Which, a lot of people when the data showed up said, "Hey, what are we waiting for? Why don't we all embrace this regimen?" And the truth is that we, as investigators of CLL, we're very encouraged by this promising new regimen, but we still want to know what happens longer time.


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