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Next Steps in MCL Include Frontline Trials of BTK Inhibitors

Brandon Scalea
Published: Tuesday, Sep 04, 2018

Simon Rule, MD
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.

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.

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

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.

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.

Is BTK inhibition being tested outside the relapsed setting?

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.

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