Factors Impacting the Development and Selection of Targeted Therapies for Patients With CLL

In this interview with the Journal of Clinical Pathways, Matthew S. Davids, MD, speaks about the latest targeted therapies for treating CLL, the challenges in developing these treatments, and how they are being used in the community oncology setting.

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

I'm Dr Matthew Davids, and I'm the director of clinical research for the Division of Lymphoma at Dana-Farber Cancer Institute. I’m also an associate professor of medicine at Harvard Medical School. My own clinical practice and research interests focus on CLL, and over the last 15 years or so I've been involved with helping to develop some of the new targeted therapies that are now approved and in development for CLL.

What are the current challenges for developing targeted therapies for CLL?

There are a number of challenges still in terms of developing targeted therapies for patients with CLL. One is that we have a lot of existing targeted therapies now, between BTK inhibitors, a very good BCL2 inhibitor, and other mechanisms. For many patients with CLL, they can do well just with these agents. This is particularly true for our older patients, but there are still a lot of opportunities to develop drugs in CLL. This is the case for our younger patients where we really don't know what the long-term outcomes are with these targeted therapies beyond 10 years or so, which is the longest follow up we have with ibrutinib.

There are other opportunities in terms of subsets of patients; for example, those with high genetic risk CLL. This includes patients with deletion of 17p by FISH [fluorescence in situ hybridization] and also with TP53 mutation. These are patients—even with the existing targeted therapies—where the progression-free survival tends to be shorter, especially with our time-limited therapies. Developing novel combinations to achieve durable response with a time-limited regimen is an excellent goal for these patients.

Finally, another challenge in CLL right now is patients who develop Richter syndrome. This is when CLL transforms into an aggressive lymphoma. The current treatments are unfortunately quite poor, so there are a lot of opportunities in this area as we continue to develop drugs for CLL.

As more patients with CLL are treated with BTK inhibitors, what are your observations regarding long-term outcomes and side effects? How do you monitor and manage these effects to ensure optimal patient care?

We're fortunate in CLL to now have four BTK inhibitors that are US Food and Drug Administration (FDA) approved for this disease, including three of the covalent inhibitors (ibrutinib, acalabrutinib, and zanubrutinib) and the non-covalent inhibitor, pirtobrutinib. Now we have the longest term follow up with ibrutinib. We've had reports of 10 years median follow-up, and the long-term outcomes with this drug are really excellent. So median, progression-free survival, for example, in the RESONATE-2 trial in the frontline setting with Ibrutinib monotherapy is about 9 years. However, what we find in the real world is that a lot of patients who have comorbidities don't tolerate ibrutinib as well, particularly from a cardiovascular standpoint.

We do see high rates of discontinuation with that drug due to toxicity. That is where the newer drugs acalabrutinib and zanubrutinib, which are more selective BTK inhibitors, when compared head to head to ibrutinib are better tolerated. So, those have become our drugs of choice when we're using BTK inhibitors, particularly in the frontline setting, but also in the relapse setting with Pertebrutinib. It's a newer drug. It seems to be very well tolerated.

We don't have as long term follow up at this point, but certainly the initial data look very good. We need to be mindful that even with the more selective inhibitors, we do still sometimes see cardiovascular toxicities that need to be managed. We need to monitor blood pressure and sometimes add antihypertensives. If it's not well controlled the more selective inhibitors do have some risk of atrial fibrillation as well. So, we need to counsel patients about being mindful of symptoms like palpitations, and if so, investigating further and potentially anticoagulating and rate controlling those patients.

There are also some more pesky side effects, like arthralgia and rash, that can pop up. These can usually be managed with brief dose holds things like steroids or nonsteroidal anti-inflammatory drugs (NSAIDs), and sometimes by resuming at a dose reduction. Those are some of the ways that we can keep patients on BTK inhibitors. They have been developed so far as continuous treatment, so we do need to be mindful of managing side effects in the longer term. On the other hand, as we look to the future of CLL therapy. We have a number of BTK inhibitor-based time-limited regimens, and that's exciting to be able to derive a lot of the benefit from the BTK inhibitors without necessarily needing to be on them long term.

What are some of the factors impacting the selection of therapy for CLL in the community setting?

There is a lot of use of single agent BTK inhibitors, especially in the community setting, given as a continuous treatment. In large part, that is because it is a pretty straightforward approach. You start the drugs and there is relatively minimal monitoring that is required, and patients can do well on them for a very long period of time. There is nothing wrong with that strategy. Though, increasingly, we've been using time-limited therapies that are venetoclax-based. This has rolled out first in academic centers, but it is picking up now in terms of use in the community. This is a bit of a more cumbersome regimen at the beginning, particularly the obinutuzumab infusions which can lead to infusion-related reactions as well as taking up chair time for these long infusions. The venetoclax ramp up is a bit challenging in terms of getting labs back in a timely fashion and checking them later in the day, after patients start each of the new doses in the 5-week ramp up.

But these are challenges that can be overcome, and I encourage community oncologists to try to get experience with venetoclax-based therapy in CLL. It is a highly effective treatment and has the major advantage of being time limited. We expect to have the first approval of a BTK plus venetoclax-based combination in the US soon. This will likely be acalabrutinib with venetoclax. Although this will still have some of the cumbersomeness of the ramp up with venetoclax, it does get rid of the infusions with obinutuzumab, so we'll have our first all oral time-limited targeted therapy in CLL. That's going to be a great option in the community setting, and a great option for our patients.

How can clinical pathways help oncologists with decision-making when treating patients with CLL?

Pathways are particularly helpful now in CLL as we have a growing range of different treatment options, and it is a bit different than it was even just a few years ago. We used to kind of divide patients up by their age and different genetic markers like TP53 status. Those are still important factors, but now a number of other things go into the treatment decision, particularly frontline treatment. This includes patient comorbidities. What specific issues do they have? For example, do they have more cardiovascular comorbidities? In which case we might be trying to avoid BTK inhibitors. Do they have significant renal dysfunction where we might be more worried about tumor lysis risk with venetoclax, and we might opt more for a BTK inhibitor race strategy.

Then we have patient preference as well, which is important. Some patients don't mind the idea of adding on a pill to their regimen and continuing it long term. Other patients like the idea of time-limited therapy, even if it's a little bit more intensive at the beginning. Pathways can help to navigate through these different preferences and comorbidities and take into account the genetic factors. For example, one thing that I always like to mention is that it is useful in CLL to check the immunoglobulin heavy-chain variable (IGHV) mutational status. This can be either unmutated, which is a more steadily progressive form of CLL, or mutated, which is the more indolent form of the disease because this doesn't change over time. You can check it at diagnosis and you'll know it for the lifetime of the patient.

What we're finding is that with our time-limited venetoclax-based regimens, patients with unmutated IGHV tend to have a bit of a shorter, progression-free survival compared to patients with mutated IGHV. Why is that important? Well, if we're on the fence about one treatment or another, that is often something that will sway me. For example, a patient who is trying to decide between time-limited venetoclax–obinutuzumab or a continuous BTK inhibitor if they have mutated IGHV, I'll lean toward venetoclax–obinutuzumab because that is where we've seen long-term remissions—upwards of 75% of patients still alive and progression-free after 6 years. Whereas patients with unmutated IGHV tend to have about a median 6-year progression-free survival, so still very good with venetoclax–obinutuzumab. But they can see potentially even longer remissions with continuous BTK inhibitor-based therapy. So again, for a patient on the fence, I might lean more toward a continuous BTK inhibitor for patients with unmutated IGHV. Pathways are helpful here, and they'll continue to evolve as more treatment options come online for our patients with CLL.