Overcoming Treatment Resistance for Patients With CLL

Thomas Kipps, MD, PhD

While progress has been made regarding individualized treatment approaches and prolonged overall survival within the chronic lymphocytic leukemia (CLL) space, there is a growing need for new approaches due to the emergence of point mutations.

According to Kipps, TP53 aberrations decrease a patient's length of survival. Because of this, patients should be treated using the combination of a targeted therapy and an inhibitor in the B-cell receptor pathway. These can consist of a Bruton tyrosine kinase inhibitor (BTK) or B-cell lymphoma 2 (BCL2) inhibitor.

Some new agents, like the BCL2 inhibitor venetoclax (Venclexta) and the BTK inhibitor ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa), have added to the treatment landscape of CLL in tremendous ways. These agents have proven to be effective and can be administered to patients for prolonged periods of time.

However, experts need more clarification when deciding which regimen should be used for certain patients in the front-line. To address this question, Thomas Kipps, MD, PhD, presented about the latest updates and treatment approaches to address patients with CLL who have mutations or deletions during a plenary session at the Annual Meeting of the Society of Hematologic Oncology (SOHO 2022).

In an interview with Targeted Oncology^TM, Kipps, distinguished professor of medicine and Evelyn and Edwin Tasch Chair in Cancer Research, UC San Diego Moores Cancer Center, explained the new treatment options and challenges being faced in the CLL space.

What can you tell us about resistance in CLL?

[The key question] is, how do we meet the challenge of resistance to some of the newer targeted therapies for chronic lymphocytic leukemia? We live in a very exciting time right now with the advent of small molecules that can target proteins inside the leukemia cell and that are critical for the survival of the cell. This has opened the way for what we call targeted therapy. It's been a game changer in terms of replacing chemotherapy or chemoimmunotherapy for the treatment of patients with this disease.

Like with every advance, we have to also acknowledge our failures, and some patients may do extremely well with these medications and for the most part, that's the majority. However, we do have patients who ultimately may become refractory and then may have disease progression after being on the drugs for a while. so we have to figure out what is the reason for this and identify some of the risk factors that are associated with the tendency to progress on these newer targeted therapies.

Can you explain the growing importance of this topic?

I think it aroused a lot of attention because this is a growing problem. With the success that we have, patients are living longer. But then we have to come up with the next answer to the problem that patients may have, either through intolerance or resistance to these targeted therapies. I covered the broad topics of inhibitors of the B-cell receptor signaling complex. This is a very important complex on the surface of the leukemia cell. Like any B cell, this complex is critical for the survival and the stimulation of the B-cell. If you block the signaling of the B-cell by targeting enzymes in that pathway, it does compromise the ability of the leukemia cell to actually grow. This has been an important advance for the treatment of patients with this disease.

During SOHO 2022, we covered the topic of what we call brutinibs. These are a growing list of small molecules which can target the enzyme BTK. They come in 2 basic flavors, 1 where you have the small molecule being able to form a chemical bond with BTK. That takes out BTK and the cell has to make more BTK in order to get that enzyme used again. The other flavor is to have a non-covalent inhibitor. That's 1 that is reversible. The reason for this is that the covalent inhibitors may only exist a short time in the blood supply, but they can target the enzyme and take it out for the duration whereas the reversible inhibitors have a longer half-life in the body and therefore, act over a longer period.

I think most of the therapies have been directed at the covalent inhibitors because of their noted success heralded by the drug ibrutinib, which has really been a game changer. This drug has shown itself to be superior to both aggressive chemoimmunotherapy as well as other forms of treatment. Patients may have a long, disease-free survival, provided they stay on the drug for a period of time.

Can you discuss some of the data that has been reported with these agents in CLL?

In looking over the data, we identified certain features that could be associated with the tendency to develop resistance to these drugs. Among them are prior chemo immunotherapies, which I caution, it shouldn't be that you reserve these targeted therapies for later. First try chemotherapy with your patients because you can mitigate the effectiveness of these drugs going forward. The other important changes are in a protein called tp53, which is a protein that acts to kill the cell if it detects genetic lesions caused by DNA damage. This gene is oftentimes lost in the setting of chemotherapy, such that it is no longer effective in killing the leukemic cell. It seems for some reason that we still don't quite understand that when you have this defect in this protein, the patients have a natural history to have a shorter progression-free survival if they stay on this drug.

We've also identified other factors which associate with the tendency for resistance at the expression of unmutated antibody genes. Although if the patients are being treated with these drugs, it doesn't seem to influence their progression-free survival, but could influence their tendency to recur if the patient should stop therapy. There's an additional drug called acalabrutinib that has been approved. This drug also has the same mechanism of action but there are differences in terms of some of the adverse events that you might have with ibrutinib vs acalabrutinib. Then, there's a new agent called acalabrutinib that seems to have equal activity. Now we can pick and choose and it's nice to have choices for your patients because sometimes we find intolerance to 1 drug, and you can get by with using a different drug. We've had patients who don't tolerate 1 of these BTK inhibitors that tolerate the other drugs well, so they can stay on the drug, which is important if they're going to maintain a long progression-free survival.

This category of drug is influenced by changes in the leukemia cell that you can get where you have mutations in the protein that's being targeted. That mutation prevents that drug from forming a chemical bond with BTK. That limits the effectiveness of these drugs and patients can make progress on therapy. Fortunately, we're also seeing the development of a new category of brutinibs, which are the non-covalent inhibitors. They do not appear to be affected by this mutation because they don't have to form this chemical bond. We're looking forward to the release of the studies that will have the comparison of these newer BTK inhibitors with ibrutinib and other BTK inhibitors that have been approved so that we can decide as to whether they are equal in efficacy and have the same safety profile as these drugs. It's an exciting time because with the advent of these agents, we can have long-term remissions.

What can you discuss about the use of BCL2 inhibitors in this space?

BCL2 is pivotal to the leukemia cell. CLL cells express high levels of BCL2, and it's counterbalanced by another protein. We can inhibit BCL2, and that allows for the proteins that will kill the cell to take over. The cells can undergo lysis quickly. In the early studies, we remarked how quickly the cells were dying, and noted that there could be problems with tumor lysis, so we had to work on adopting strategies where we stratified the dosing, and patients started with a very small dose and then ramped up. If we do this and recognize what patients are at risk, namely those patients with a high tumor burden, we can safely start therapy with this important category of drug.

This drug is also well tolerated when we get on the maintenance dose of 400 mg a day. We find that it can induce deep remission such that we can't find any leukemia cells in the marrow, even if we look with very sensitive techniques, including genetic sequencing, or flow cytometry, which we typically use to detect 1 cell in 10,000. We can get down below that limit and morphologically not see any evidence of leukemia in the bone marrow. This is exciting because it raises the prospect of doing a fixed duration therapy rather than continuous therapy.

Can you discuss some of the ongoing trials in this space?

A number of trials have been using fixed duration therapy with either venetoclax by itself or with anti CD20 antibodies. More recently, there's a combination of using venetoclax with these BTK inhibitors, notably, ibrutinib. Now there are studies going on with acalabrutinib and soon, zanubrutinib. What it shows is that the combination therapy can affect very high rates of clearance of detectable disease in both the blood and the marrow, and a high proportion of patients bordering on 60%-80%, depending on the combination. We are in the middle of conducting an important study, CAPTIVATE [NCT02910583] study, which looks at the ability to treat with 1 year of venetoclax therapy that follows 3 months of ibrutinib. Then you add venetoclax and stop therapy after a total of 15 months. We're looking at the outcome and we've had very good success. Many patients achieved complete remissions or excellent remissions without detectable minimal residual disease [MRD]. We're now following those patients and we're seeing how the outcome is.

We also have an interesting cohort of patients which are MRD driven that go through the same treatment regimen, but then the RSS for MRD. If we can't find it, they may be put into 1 category where they are without detectable disease, both in the blood and the marrow. Then the patients are then randomized to receive either ibrutinib or a placebo, they don't know what they're getting. We're following up on these patients and seeing how they do. The early analysis indicates after a year when we're monitoring for early recurrence of this MRD, we can't find evidence of MRD in either group of patients, which to me indicates that at least for the year after stopping therapy, adding Ibrutinib to a maintenance regimen is not required. Of course, longer term follow-up is necessary.

The other interesting group is 1 that we couldn't really determine the MRD status, and that was because they had partial responses. We did a deep dive into looking at MRD in those patients. About 2/3 had detectable disease, 1/3 had absence of MRD These patients were stratified and received either ibrutinib or ibrutinib and venetoclax. The early results are indicating that when you add ibrutinib, you're not really increasing over time the level of MRD, with a few exceptions. When you add ibrutinib with venetoclax, we're seeing further increases in the proportion of patients who can eradicate MRD. These are very interesting studies because they addressed important questions. Can we get away with fixed duration therapy? Is it necessary, at least for some patients, to add a maintenance therapy either with a BTK inhibitor, or together with a BCL2 inhibitor? I think this is going to be important to be able to address how we manage all our patients, because not all patients are the same.

We also address this important category because even with all our targeted therapies, when you throw them together, we hit a plateau where patients are able to have the disease eradicated beyond detection, but we only go about 75%-80% at maximum. There's still that 20% that has residual disease, and we know that a proportion of those patients, about half, may progress even if we continue with the single-agent venetoclax therapy. We're trying to figure out what those patients are like phenotypically. Often, the genetic complexity is there and there's something driving genomic instability in these cells, which makes them more likely to develop resistance to therapy.

What are your recommendations for treatment after resistance? What data supports those therapies?

There are many reasons for resistance to therapy and I covered 1 of the topics which is mutations in the cell that can affect the proteins that are being targeted by the targeted therapy. If you have those mutations, it can limit the activity of the drug. However, we do have to face the issue that we're all human, and sometimes patients may not be as compliant as they should be in taking the medications. We also know that there may be a request to stop the drug because of intolerance. There are many adverse events with some of these drugs that if they're continued over time which can reduce the compliance that patients may have to continue these drugs. That has to be firmly addressed. There's also the issue of cost which we have to address to make sure that these are provided to patients without breaking the bank. The other aspect is long therapies or continuous therapy with the brutinibs or BTK inhibitors. Patients may want to get 1 and done and have fixed duration therapy.

We have to figure out what is the basis for the patient getting off drugs. Is it due to the compliance? Is it due to toxicity? Is it due to cost or is it due to the fact that they've developed mutations that make the drug not effective? In the case of the BTK inhibitors, we know that the covalent inhibitors are affected by a specific mutation and BTK at position 481, which when it happens, prevents the drug from binding and forming a chemical bond with BTK. If you interchange between the different drugs, you're not going to have success in treating that patient. Ibrutonib does have some activity against the cells that have this mutation in them, although the cells may be coming up, but you can keep patients almost in check. Some of the newer anti BTK's such may be less effective in holding down that clone. Sometimes we can buy time by switching over to ibrutinib if you don't have access to the noncovalent inhibitors. I think that if you do have such resistance, you have to look at either these third generation BTK inhibitors such as the noncovalent inhibitors, or perhaps to try a venetoclax-based regimen that could be effective, along with an anti CD20.