Recent Advances in Chronic Lymphocytic Leukemia Treatment

Justin Taylor, MD, Assistant Professor, Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, answers a series of questions about recent advances in the treatment landscape for chronic lymphocytic leukemia.

Transcript:

My name is Justin Taylor. I'm an assistant professor and a physician at the Sylvester Comprehensive Cancer Center that's at the University of Miami Miller School of Medicine in Miami, Florida.

What is the current standard of care for chronic lymphocytic leukemia (CLL)?

Most patients with CLL, chronic lymphocytic leukemia, the first line of treatment, the standard options are either a Bruton's tyrosine kinase inhibitor, BTK inhibitor. We have ibrutinib and acalabrutinib approved. And then another option would be venetoclax, which is a BCL-2 inhibitor with an anti-CD20 antibody, typically obinutuzumab or some people can use rituximab.

How have screening measures and therapeutic options for CLL evolved in recent years?

We typically don't use chemotherapy any longer unless there's an unusual circumstance. So, I think that's the major shift to targeted therapies, that we're getting very good at using them and figuring out the best sequences to use the targeted therapies.

Are there any key publications, approvals, or data sets of note you’d like to mention?

One recent data set that was presented at the European Hematology Association meeting this summer was updates from CLL14. That was the phase 3 trial looking at venetoclax and obinutuzumab, the regimen I mentioned earlier. In frailer patients that were thought to be unfit for chemotherapy, comparing it to chlorambucil and obinutuzumab, and they presented the 5-year updates. So, patients received this treatment only for 1 year, fixed duration, so they had 4 years off therapy. And so, after even this much time, the patients treated with venetoclax and obinutuzumab are still doing better. There's a high rate of survival, as well as patients that are what we call minimal-residual-disease negative or MRD negative. So that's very encouraging, and I'm sure they'll continue to follow those patients even further to see what's the length of time one can get a benefit from that combination.

Please briefly describe any research you are currently conducting and the impact it has on detecting and treating CLL.

The research that I'm doing is more for the other class of drugs called the BTK inhibitors, Bruton's tyrosine kinase, and I mentioned that ibrutinib and acalabrutinib are approved, and there's other BTK inhibitors being studied. One of the newer generations of BTK inhibitors are noncovalent BTK inhibitors. And we did a study with a drug called pirtobrutinib, and there's others as well that are still in clinical trials as next-generation BTK inhibitors. And the goal of those is to be more safe, less side effects, as well as working against some of the resistance mechanisms from the first generation of BTK inhibitors. And so, our work focuses on identifying new mechanisms of resistance to this noncovalent class of BTK inhibitors.

So, unfortunately, despite all the successes of targeted therapies, one of the barriers is that resistance can occur to these treatments, necessitating a change of treatment. So, we are trying to see if we can learn more about the resistance in ways to either anticipate the resistance is going to occur or come up with new therapies if resistance does indeed occur.

Were any of the outcomes of your research particularly surprising?

We did detect some resistance mutations that occurred in BTK itself, and I guess that might not be surprising because that's the target of these drugs. However, these were all non-C481 mutations, and the most common mutation occurring in ibrutinib, for example, treatment is C481. So these were all different than previously described. And so, that was a little bit surprising. And as well as the mechanism of action of some of these, which is still something we're studying to completely figure out how they're working.

Do you (and any applicable co-investigators) intend to expand upon this research? If so, will you be incorporating any new interventions, end points, or patient populations?

The pirtobrutinib trial completed the phase 1 portion, which is where you find the safe dose, and it has moved on to phase 2, which is treating more patients with what's thought to be the most effective but safe dose. And so despite us reporting on some patients that had resistance, a majority of patients benefit from it. So it is moving forward in clinical trials. And one of the things that we're studying is combinations of BTK inhibitors such as pirtobrutinib with other drugs such as venetoclax. And so, can combining two of these very active drugs get more of an effect? And in essence, could that also prevent resistance from occurring?

And in a separate line of a study, we're looking at potential BTK degraders. These are also drugs that can be administered to patients. They're still in clinical trials, but instead of inhibiting the BTK function, they cause the BTK protein itself to get degraded or become unable to function just by not being present at all. So, it may be better than inhibiting, but we don't know because we don't know all the side effects. Those are still in phase 1 trials.

Aside from your own research, what upcoming therapies in the CLL space are you most excited about?

I mentioned our particular combinations we're studying, but other combinations are being looked at. And one particular study, I'm very excited to see the results, although it will be a long time before we have them because this study is just getting started, it's called CLL17. It's going to answer hopefully one of the major questions we have is comparing upfront BTK inhibitors, the first-generation ibrutinib compared to venetoclax and obinutuzumab directly to see what's the best or better upfront approach. They also have an arm that's the combination of ibrutinib and venetoclax. So again, whether combining them, two active drugs at the very beginning, is better than just treating with one drug and then keeping the other and treating with it later. So, it's going to be a long time until we know the results of that, but I think that's a major question that everyone has.

How do you personally encourage patients to enroll in clinical trials?

I encourage every patient to consider a clinical trial because at the moment that's where some of our best potential drug combinations and even single-drug agents are. Ultimately, we hope that these get FDA approved because they do look so promising. But at the moment we don't know, so we can't recommend it for everybody. But if somebody would be able to participate in a clinical trial and is interested, I always encourage them because you may be getting the drug of the future, so you might be 5 years in advance of where we're currently treating today. So, that's how I encourage patients.

What are some immediate action items that oncologists and other oncology health care professionals can employ to better meet the needs of these patients?

Along those lines, these drugs are oral medications. I didn't go through all that, but BTK inhibitors particularly can be taken just by mouth. The venetoclax is also oral, but again, that's typically paired with a CD20 antibody, which is given IV [intravenously]. But especially for the oral drugs, it's pretty easy for an oncologist to prescribe that to a patient and just have them go out the door. But I always encourage people to consider getting a second opinion. It's not that just starting on a BTK inhibitor is incorrect, or whatever treatment, it's more that you want to see a CLL expert to kind of make sure that based on everything we know, such as mutations and p53, IGHV [immunoglobulin heavy chain variable region gene] status, the whole picture is considered before starting that first therapy.

And then you can still be treated locally, close to home, with all the conveniences that come with that. But then at the time of, say, resistance, like some of the things that we're studying, then you have that expert to call back again and say, "This is the situation; what's the next treatment?" So, I always encourage that to have a second opinion on CLL. There are lots of treatments and so sometimes that's a good thing, but sometimes it can be confusing just as to what's the best treatment to go with at the first treatment and then also later decision points.

Is there anything else you’d like to add?

One thing that's exciting to me, even though I'm fairly early in my career, is that we're taught that CLL is not a curable disease except for maybe in stem cell transplant in some cases, but that's not commonly done because of all the side effects. However, now some people are starting to talk about cures with some of these therapies. I think we still have to see how long these last, and even with chemotherapy of the past remissions would last a long time, but were not indefinite. So, we're still not quite there, but at least people are discussing that, and it may be something on the horizon. So, I think for any CLL patients listening, it's an exciting time. It's an exciting time to be an oncologist that treats CLL patients, as well as a researcher.