Insights on BTK Inhibitors as Frontline Treatment for Chronic Lymphocytic Leukemia

In this interview, Danielle Brander, MD, associate professor of medicine and director at the Duke Cancer Institute, discusses the latest National Comprehensive Cancer Network (NCCN) guidelines for chronic lymphocytic leukemia (CLL) treatment and the efficacy of BTK inhibitors as monotherapy in the frontline treatment of CLL.

Please introduce yourself by stating your name, title, organization, and relevant professional experience.

Hi, my name is Danielle Brander. I'm an associate professor of medicine and director of the CLL and Lymphoma Clinical Research Program at the Duke Cancer Institute and Duke Health System in Durham, North Carolina.

What are some of the latest NCCN guidelines for the treatment of CLL?

The NCCN guidelines—which are periodically updated as more data becomes available—are a great resource tool for CLL,  from diagnosis to management, and for first treatment, second treatment or relapses, and for instances where CLL transforms (Richter's transformation). The guidelines provide additional highlights in regard to supportive care and health maintenance, such as vaccinations or for patients that may have frequent infections in hypogammaglobulinemia.

Updates are always highlighted at the beginning of the guidelines. I'll draw attention to one area of recent interest, which is addition of anti-CD20 antibodies to the treatment of CLL, including novel agents such as BTK inhibitors and the BCL2 or anti-apoptotic inhibitor, venetoclax. In the frontline setting there have been a number of trials that have looked at the combination of BTK inhibitor with anti-CD20 antibody. When BTK inhibitor was combined with rituximab, historically the first and really for many years only used anti CD20 antibody, there didn't appear to be a difference in progression-free survival between a BTK inhibitor, namely ibrutinib with rituximab or without rituximab.

However, more recently, when combined with the newer generation obinutuzumab anti-CD20 antibody, we see greater efficacy. A four-am study looked at patients receiving first treatment for their CLL either with chemo-immunotherapy with a triplet combination (which I won't talk about) but had two arms that were venetoclax plus rituximab or venetoclax plus obinutuzumab. And interestingly, even in the frontline setting, the patients who received venetoclax plus obinutuzumab had superior outcomes, whereas those who received venetoclax plus rituximab did not. We draw from that data not only in the frontline setting where venetoclax already was combined with obinutuzumab, but in the relapsed and refractory setting where at least when the drug was first developed, venetoclax was combined with rituximab.

To summarize, we need to consider that not all anti-CD 20 antibodies are the same. One of the important NCCN guideline updates highlights that in the frontline setting when combining a BTK inhibitor, not just venetoclax with an anti-CD 20 antibody, obinutuzumab is preferred. This is also true in the relapsed refractory setting for venetoclax, although historically it was combined with rituximab, especially in cases of either re-treatment or other circumstances with prior rituximab approval. Consider that the preferred pathway in the relapsed refractory setting with venetoclax is also obinutuzumab.

Why do you recommend BTK inhibitors as monotherapy in the frontline treatment of CLL?

In the frontline setting there are a number of good treatment options for patients with CLL/SLL, and I try to individualize this conversation to consider patient-specific factors, whether there are other comorbidities, what other medications they are taking, and disease-specific factors such as if there are high-risk changes, deletion of 17p or TP53 mutations being the highest risk. I also consider the available regimens themselves. How they are given and how patients are monitored are very different. Right now, between BTK inhibitors, either as monotherapy or with anti-CD20 vs venetoclax in the frontline setting, there's no head-to-head studies to say one of these treatment approaches is superior to the other. Therefore of those three categories, individualizing treatment for a given patient is very important without that head-to-head data saying for everyone it's superior.

But in terms of patients where I want to consider BTK as the preferred approach, one of the main ones would be patients with deletion 17p or TB53 aberrations. BTK inhibitors are given continuously, meaning patients who start those treatments continue them unless they run into issues with not tolerating the medication or it becomes resistant. And so, for this highest risk disease, I prefer BTK inhibitors because I prefer that constant clonal suppression vs frontline fixed duration therapy. That being said, of course patients can have other reasons to tip away from BTK inhibitors, such as their comorbidities or concurrent medications. It's not that patients with TP53 aberrations can never receive venetoclax therapy, but given the diagnosis of CLL is often in later decades of life and given some venetoclax regimens can be risked for tumor lysis, particularly bulky disease or if patients have baseline poor renal function, we need to be thoughtful about both time commitment and resources to do oral regimens; these include BTK inhibitors monotherapy vs venetoclax and obinutuzumab, which is time limited but requires the infusions of the obinutuzumab and all the tumor lysis monitoring while venetoclax is being ramped up.

For many patients, fortunately, BTK monotherapy as we see in long-term 10-year follow-up of ibrutinib and now ongoing longer follow-up of second generation covalent BTKs that are very well tolerated (zanubrutinib and acalabrutinib), can control their disease for a long period of time. And adding in combinations isn't necessarily going to benefit them vs adding risk. But again, we're fortunate to have different options and the ability to individualize for a given patient.

Can you briefly discuss the A041202 study and how the findings support the use of BTK inhibitors vs chemotherapy for CLL?

This is an important frontline study that had three arms, meaning patients with first treatment of their CLL randomized either to chemo-immunotherapy, which in this trial was what was considered the gold standard for older patients or those with comorbidities, bendamustine and rituximab vs ibrutinib vs ibrutinib plus rituximab. And in this study with ongoing long follow-up, there's superior progression-free survival for either of the ibrutinib arms vs chemo-immunotherapy. And therefore, as an important frontline study was one of the important ones to lay the groundwork to show superiority of targeted agents, namely ibrutinib in this case, though other BTK inhibitors have followed similar approaches.

First is chemo-immunotherapy and this was across all risk groups. We've talked a little bit about the highest risk group, which is TP53 operations where we already know that chemo-immunotherapy is inferior. But if you think of other common high-risk groups, namely immunoglobulin heavy-chain variable region gene (IGHV) unmutated, you can see a significant difference between using targeted agents vs chemotherapy. But even those with favorable risk disease such as IGHV-mutated or patients with favorable fluorescence in situ hybridization (FISH) characteristics, there was a benefit to using targeted agents. As discussed previously, ibrutinib plus rituximab did not appear to be superior to ibrutinib by itself. However, again, we need to be cautious that rituximab is not the same as other anti-CD20 antibodies, namely obinutuzumab. So, the conclusions of the study should not be that BTK inhibitors never benefit from the addition of the newer anti-CD20 antibodies.