The Evolving Role of BTK Inhibitors in Treating Chronic Lymphocytic Leukemia - Episode 4

CLL Frontline Options

April 16, 2020

Ian Flinn, MD:We should also talk a little about decision factors. There are other options that we can use, particularly in the frontline setting for our patients with CLL [chronic lymphocytic leukemia]. What factors do we think about in terms of using a BTK [Bruton tyrosine kinase] inhibitor, or perhaps a venetoclax, or even chemoimmunotherapy? I must confess, I don’t use a lot of chemoimmunotherapy anymore, although I’m sure there are exceptions to that rule for patients where that’s still important.

When I think about using a BTK inhibitor instead of venetoclax or chemoimmunotherapy, I’m not sure that some of the traditional agnostic factors necessarily sway me. Of course, if someone has ap53mutation, then we know that chemoimmunotherapy is just really not indicated. It’s hard to do that. But comparing it with venetoclax-based therapies, such as venetoclax-obinutuzumab which is a frontline regimen, we don’t have enough data in terms of which is the best therapy in those 2 different scenarios. I confess, I get a little worried about patients withp53mutations in using a time-limited therapy. I’m not sure my concern is rational, but I think we do need more data, and there are certainly trials ongoing examining that. How do you make that decision?

Jan A. Burger, MD, PhD:I agree. I think there’s a bit of uncertainty now with the availability of venetoclax to really make that decision. In general, everybody agrees that we’re moving the vast majority of patients away from chemoimmunotherapy to the new agents. We could still make the point that chemoimmunotherapy has some role, or should at least be discussed with young, fit patients who areIGHVmutated, where we saw in long-term analysis of the FCR [fludarabine, cyclophosphamide, rituximab] data that there is a fraction—about half of these patients—who have long-term survival and are still in remission beyond 10 years. For those patients, I still bring it up as an option, but many patients are going to opt against it, especially because of the concern of secondary AML [acute myeloid leukemia] and MDS [myelodysplastic syndrome], which is a valid concern and which has bad prognosis.

I think the general trend is to move to the new agents. Then you have, in the frontline setting, BTK inhibitors available, and now more recently you have venetoclax, obinutuzumab available. How do you make that choice since we don’t have comparative trials, at least not now. My decision is usually a case-by-case decision where you usually go with the BTK inhibitors—at least I do, based on long-term data and a lot of clinical trial data with the BTK inhibitors. Venetoclax is, for many patients, somewhat inconvenient because you have to dose escalate in the first 4 weeks. You have to monitor closely for tumor lysis, so that makes it a bit more complicated, at least in the beginning.

On the other hand, what favors the venetoclax approach is you get a limited-duration treatment, and that can be an advantage because some patients don’t want to be on the treatment where you have to say, “Well, it’s going to be several years until we have a better solution if you go with a BTK inhibitor.” So there are pros and cons, and you can also argue if a patient has a history of atrial fibrillation or right now has atrial fibrillation or other cardiac arrhythmia issues and has a high risk for fungal infection—which is something we could also discuss, which is an emerging concern with BTK inhibitors for maybe a small group of high-risk patients—then sometimes you may lean more toward venetoclax-based treatment, based on concerns around BTK inhibitor adverse effects.

In my opinion right now, because we don’t have comparative study data, it’s a case-by-case decision where you will really have to look closely at risks of each patient for developing problems, adverse effects, with each of these agents. That’s how I would approach it. There will be a study that’s going to help us with that which is the CLL17 trial by the German CLL Study Group, which is going to compare ibrutinib with venetoclax-obinutuzumab versus ibrutinib plus venetoclax. But until we have those data, many years are going to pass, and until then we’re going to be in this situation where we have great treatments. They are all good choices, but there are certain nuances for each patient where we can take patient preferences and certain risks for developing complications into account. That’s how I would go about it.

Ian Flinn, MD:I really use a very similar approach in taking it, having a discussion with patients. Some of it’s very practical—as you mentioned, the patient comes in for the ramp-up that’s all involved with venetoclax. It’s harder, especially older patients coming to the clinic that often. On the other hand, when you should outline that it’s a time-limited therapy where it’s for a year, then many people are willing to make that. But as you mentioned, fortunately we’re in a great position.

Both approaches—a BTK approach versus a venetoclax approach—are really fantastic therapies. We’re in a period of equipoise: I really don’t know which is better, and both are reasonable. But the field is moving forward, and we’re now moving on to even more effective regimens, either by adding a BTK inhibitor with venetoclax or the third drug, obinutuzumab, or a variety of scenarios there. Anyway, it’s an interesting time. We didn’t talk about TLS [tumor lysis syndrome] risk. There aren’t that many patients who I can’t manage with TLS risk as an outpatient, either by starting with obinutuzumab or debulking them. But it’s a rare day that you can’t manage that effectively for an outpatient, so that really doesn’t make my decision that I can’t manage them as an outpatient.

Jan A. Burger, MD, PhD:That’s a good point you’re bringing up. In the early clinical trials with venetoclax, we used to admit patients to the hospital for TLS monitoring if patients were considered high risk. But we’ve learned, we use precautions if we debulk patients prior to increasing venetoclax that I think the vast majority of patients can be managed outpatient. There’s only concern that we would have to admit most of these patients if they are high risk. That’s not so much a concern anymore.

Transcript edited for clarity.