Next Steps in MCL Include Frontline Trials of BTK Inhibitors

Simon Rule, MD, PhD

The promising activity BTK inhibitors have shown in patients with relapsed mantle cell lymphoma (MCL) has led to studies investigating these agents in the the frontline setting.

For example, the phase II ENRICH trial (NCT01880567) is investigating the combination of ibrutinib (Imbruvica) and rituximab (Rituxan) in elderly patients with newly diagnosed MCL, as well as in those with relapsed/refractory disease.

“This will be the ultimate test in seeing if we can have a truly chemotherapy-free regimen in an aggressive form of lymphoma,” said Simon Rule, MD, PhD.

Similarly, the BTK inhibitor acalabrutinib (Calquence) is also being tested in untreated patients with MCL. One phase I study is testing the safety and efficacy of the agent plus alternating cycles of bendamustine/rituximab (BR) and cytarabine/rituximab, to determine whether the addition of BTK inhibition will increase the complete response rate (NCT03623373).

Both BTK inhibitors, ibrutinib and acalabrutinib, are approved by the FDA as a treatment for patients with MCL who have received at least 1 prior line of therapy.

OncLive: What is the typical prognosis for a patient with MCL, and what is the current standard of care?

In an interview with OncLive^®, Rule, professor of Hematology at Plymouth University Medical School, United Kingdom, discussed the current and potential use of BTK inhibitors for the treatment of patients with MCL.Rule: The prognosis depends a little bit on whether you're looking at trial-related data or population-based data. The population-based data, of course, is a lot worse than the data we see in trials. The general prognosis is somewhere between 3 and 5 years. For the younger patients, it's clearly a lot better than that. It's a moving target because BTK inhibitors are going to make a huge difference, particularly in the relapsed setting. It is definitely improving, though.

You can see an improvement over the last decade, first with the incorporation of rituximab into chemotherapy regimens, and secondly with the widespread adoption of cytarabine-based treatment in younger patients. As BTK inhibitors become more widely used, there will be an improvement in overall survival as well. That sounds gloomy, but it is actually realistic. A lot of people seem to think the prognosis is better than that, but they're looking, of course, at trial data, which is always a highly selective group of patients.

As far as the standard of care is concerned, it depends on which patient group you are talking about. First, for young patients—by young, we mean under 65—you're going to be using a high-dose cytarabine-based regimen, followed by stem cell transplant, followed by rituximab maintenance. That would be standard of care. For the majority of patients—the average age we see this disease diagnosed is around 70—then you're looking at rituximab and chemotherapy and perhaps a bendamustine-based treatment. It depends very much on your personal preference.

Then there is the frail, elderly population, probably about 10% to 15% of patients, where you're going to struggle delivering any treatment at all. You [typically] treat them with a very gentle form of chemotherapy and maybe an antibody alone. When you relapse, I would like to say the standard of care is BTK inhibition. That's pretty much across the board. In a young patient, you would give them a BTK inhibitor to get the patient ready for a stem cell transplant—but this is very rare. For those who aren't fit or young enough for that therapy, you're likely going to use a BTK inhibitor with an antibody.

Is BTK inhibition being tested outside the relapsed setting?

For frailer patients, [this combination will be given] very early because they likely won't respond to what you give them in the frontline setting. There is a small group of patients where you actually don't want to treat their diagnosis, you want to just [observe]. It's an indolent group of patients; they are asymptomatic. You'll find that some of them will do reasonably well if they go untreated for a long period of time. Therefore, this is pretty much where we are today.The relapsed setting is where these agents are approved, so that's where we are confined right now. However, there are frontline trials going on. I'm involved with one in the United Kingdom where we are using ibrutinib plus rituximab versus chemotherapy. There are about 140 patients in that trial right now. There is also a frontline study testing bendamustine and rituximab in combination, with or without ibrutinib.

How has the implementation of rituximab maintenance therapy changed the treatment landscape?

You would want to use BTK inhibitors in the frontline setting, as I said, particularly in the frail and elderly patients. Unlike many new drugs, where they're first used in a younger and fitter population, BTK inhibitors should be used the other way around. This is especially true because for the younger patients, we see pretty good outcomes with cytarabine-based treatment. Right now, you wouldn't want to be using these drugs for that group in the frontline setting. However, of course, if they relapse, then BTK inhibitors could be prominent.It's been very interesting. Giving rituximab after a stem cell transplant should be the standard of care, and even in my country [United Kingdom] it's the standard of care. In the patients receiving rituximab and chemotherapy, there is a difference there. If you use frontline bendamustine, it makes no difference. It depends very much on the chemotherapy backbone you use.

What is the toxicity profile of a BTK inhibitor?

My personal preference is using CHOP in the frontline setting and using bendamustine following ibrutinib. I've found this is very effective. The biggest thing is how to sequence your therapies. If you use maintenance rituximab after CHOP, the outcomes are very good. If you look at the updated data from a European study of elderly patients, 70% were alive in 7 years. Bendamustine and rituximab is good, and it tends to have a better side effect profile.There is an easy bleeding and bruising issue. It's an aspirin-like effect. You do see quite significant bruising in a small percentage of patients and modest bruising in up to 50% of patients. The second-generation BTK inhibitors appear to have slightly less than that, although it remains a class effect. You have to be careful when you do a procedure on these patients; you must make sure to stop the drug and that it's washed out before you do anything. Ibrutinib has an issue with atrial fibrillation, and hypertension is starting to become apparent. There are cardiac issues in some patients who receive ibrutinib, but we don't seem to see this with the newer class of BTK inhibitors. Those are the major things.

What can be accomplished in the treatment paradigm over the next few years?

Diarrhea can also be an issue. We usually see this early on and it tends to be self-limiting. There are some aches and pains that patients tend to get if they're on the drug long term. This is more of an issue, though, for patients with chronic lymphocytic leukemia (CLL) than it is for those with MCL. We need to remind ourselves that this is the most active class of drugs we've ever seen, particularly in the lymphoma setting. A lot of patients, when we first started using ibrutinib, said they had no side effects whatsoever. For the most part, these are very well-tolerated drugs with mild side effects.We will have a better understanding of what we can combine ibrutinib with. We'll also have better long-term outcome data, particularly with the second-generation BTK inhibitors. Are they the same? Are they slightly better? We'll see some head-to-head data that will help us answer these questions.

The combination of ibrutinib with venetoclax (Venclexta) looks very promising in the MCL space, and we know it works well in CLL. We would like to see a little more data on that. Ideally, what we would like to learn is if we can stop treatment with these drugs. One of the challenges is the financial toxicity associated with expensive drugs over long periods of time. If we can actually stop therapy, that would be an accomplishment. Whether this cures anybody, that is obviously the ultimate goal. We will certainly have to wait and see, but it's an exciting time.