Could BTK Combinations Become the New Standard of Care for MCL?

Simon Rule, MD

Simon Rule, MD

In newly diagnosed patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL), BTK inhibition has become more widely used over the past 10 to 15 years, according to Simon Rule, MD. However, outside of the R/R MCL group, high-dose cytarabine-based regimens are still the standard of care. Looking forward in the space, BTK inhibitors may take over the frontline setting, while chemotherapy is used in second line.

“If I were to predict the future, it will be a BTK combination across the board. Then, we'll use minimal residual disease [MRD] to assess whether we need to do anything else. We'll then use MRD negativity probably to decide whether we should stop treatment or not. In my mind right now, it's hard to see anything other than a BTK combination,” said Rule.

What physicians already know is that BTK inhibitors are highly active in patients with MCL. Therefore, even patients who traditionally have poor prognoses may benefit from these combinations. For example, elderly patients who are not fit for chemotherapy. In the second-line setting, young or fit patients may also benefit from BTK inhibition.

Ongoing studies are looking at BTK inhibitors in the frontline setting in combination with bendamustine or cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (CHOP)-based chemotherapy and rituximab (Rituxan) maintenance. The findings to date show high response rates and increased progression-free survival, Rule noted.

In an interview withTargeted Oncology, Rule, professor of hematology, Department of Hematology, Plymouth University Peninsula of Medicine and Dentistry, gave an overview of the standard of care for MCL, which he recently presented at the 2019 SOHO Annual Meeting.

TARGETED ONCOLOGY: Can you provide an overview of your presentation on the frontline therapy for MCL?

Rule: I think the standard frontline therapy for MCL is well established now, worldwide. All the guidelines are similar. We start with the young and fit patients and broadly speaking, that's 65 years and under. That's where most of the trials have been done. Standard of care there would be high-dose cytarabine-based regimen followed by an autologous stem cell transplant, followed by rituximab maintenance. There is a range of different high-dose cytarabine-based regimens. I don't believe any regimen is better than the others. Whatever you're comfortable with, that's what you should use. The exception would be the hyper-CVAD regimen, which isn't consolidated with a transplant. It's a slightly different approach and not something I would do. High-dose cytarabine is the key.

For the majority of patients, this is a disease of older people and the median age at presentation in my country is 72. It's probably very similar [in the United States]. You get them on to immunochemotherapy and then either bendamustine or a CHOP-based regimen. There are a number of those. I think bendamustine/rituximab is probably the most widely used regimen worldwide. CHOP still has a place there. Then, that's followed by maintenance in certain situations.

What's odd with MCLs is that if you use a CHOP-based regimen and you use maintenance afterward, you see a big benefit. If you use a bendamustine-based regimen and you use maintenance afterward, you get no benefit. If you look at the relative efficacy of those regimens, like CHOP/rituximab followed by rituximab maintenance, you'll probably get just as good an outcome as you would if you used bendamustine/rituximab, with or without maintenance. It probably doesn't matter what you use, but you are going to have to sequence your therapies.

Incorporating bortezomib (Velcade) or bortezomib into CHOP/rituximab frontline is beneficial and improves overall survival. That's a very old study now. I think if you were to do that today you might use the bortezomib slightly differently, certainly subcutaneously. That seems to benefit these patients, and if you add maintenance, you get an even better benefit. It's a good regimen, and I think for people using bendamustine frontline, that's something you may want to think about following a BTK inhibitor, which has become standard of care in relapse now.

That's the young patients and the older patients. Then, 10% to 15% of patients are frail, elderly patients. There's no real standard of care there. Broadly speaking, you're going to use some kind of chemotherapy, but you can certainly use something else, like a lenalidomide (Revlimid)-based treatment. But, it’s not going to work very well. It won't be very well tolerated. Then, you going to try and shift them onto a BTK inhibitor. It's probably that frail, elderly group that will benefit the most from frontline use of these new drugs.

TARGETED ONCOLOGY: Are there any subgroups of patients that don’t respond to these standards of care?

Rule: There are a couple of caveats. For the young and old, we know that if you have a p53-mutated MCL—that's about 6% to 8% of patients—you're going to do badly. It doesn't matter what chemotherapy you use. You're going to do badly and BTK inhibitors don't work very well. For young patients in that situation, I do allogeneic stem cell transplantation as my first consolidation. To me, that's the only long-term outcome that’s possible in that group of patients. For our older patients, you don't have much right now in the frontline, but there's evolving evidence that BTK combinations might be active there.

That's the standard of care as far as treatment is concerned. There is, of course, the watch-and-wait method. Almost one-third of patients you can watch initially and not treat. It's difficult to predict who those patients are. We've got a big study in the UK looking at that right now. Immediate therapy is not needed in this disease if the patient is asymptomatic. That's an important thing to remember.

TARGETED ONCOLOGY: Can you expand on the watch-and-wait method and what has been shown so far in the UK study?

Rule: We have what’s called a biobank, and it's a registration study for newly diagnosed patients with MCL, and there are no exclusion criteria. The idea is to capture everybody. We have almost 600 patients in that biobank now. We're collecting disease, blood, marrow, and germline DNA. We've got ethics to do whatever we like in that group of patients. We're just following a cohort of patients, but within that study, we're suggesting if the patient is asymptomatic, has low-volume disease, etc., then [they should get] watch and wait.

We have a prospective study now with patients being watched versus patients being immediately treated. The premise of that is we're hoping to find a proper biomarker. There isn't a biomarker now that tells you if [a patient is] indolent or not. The only way you can tell if the patient is indolent is to leave them alone. I’m defining indolent as untreated for 2 years. You can't argue that it's anything other than indolent disease. We've got a lot of patients and we’re going to take this group of patients and we’re going to do all sorts of analyses and compare them with the people who require immediate therapy and see if we can find some kind of discriminating factor.

There's no real clinical thing that helps predict if you're indolent. The obvious things are if a patient has symptoms, a high LDH, or a high Ki-67, you're not going to watch. [These are symptoms that require therapy.] The one thing that stands out that I've seen consistently throughout my career, and it’s a bit odd, is that women have more indolent-behaving disease. There's a higher proportion of women that you can watch and wait than men, but I have no idea why that's the case.

It's an ongoing study. We've almost closed recruitment now, and we will have over 600 patients total, and it's a nice cohort to follow. The beauty of it is there's no retrospective looking at patients who've behaved in an indolent way. It's all prospective.

In the UK right now, in that study, just under 25% of patients are being watched at 1 year. It's much higher than people think.

TARGETED ONCOLOGY:How has frontline therapy for MCL evolved in the past few years and how do you see it evolving in the future?

Rule: The major advances have been the acknowledgment that high-dose cytarabine is key and then the widespread adoption of rituximab in combination with chemotherapy in a maintenance setting.

Unlike other lymphomas, in mantle cell, rituximab improves survival, not just when you add it to chemotherapy but also when you use it in maintenance. It's an important component of therapy. That's where we are.

Where we're moving is away from chemotherapy. BTK inhibitors are highly active drugs. There are small studies looking at them in the frontline, particularly in combination with rituximab, and they show high response rates and good progression-free survival at the moment.

We've got a study in the UK right now, which is a frontline study for elderly patients randomized between ibrutinib (Imbruvica), rituximab, and chemotherapy (CHOP or bendamustine). That's got 260 patients in the trial right now. This trial is going to tell us whether we can use chemotherapy-free regimens rather than chemotherapy in the frontline. That should finish recruitment next year at 400 patients. I think that's going to be the trial that will show that you don't need to give chemotherapy frontline in that elderly group of patients.

Then, what's going to happen is that we're going to incorporate drugs together with ibrutinib, particularly venetoclax (Venclexta). That combination looks highly active in every situation. If I were to predict the future, it will be a BTK combination across the board. Then, we'll use MRD to assess whether we need to do anything else. We'll then use MRD negativity probably to decide whether we should stop treatment or not. In my mind right now, it's hard to see anything other than a BTK combination. Chemotherapy won't become a thing of the past because it does work, particularly in young patients. But, it will be reserved for the post-BTK space, I think.

TARGETED ONCOLOGY:What are your thoughts on zanubrutinib and the FDA's decision to give it a priority review?

Rule: I've used 5 BTK inhibitors now in MCL and they all work. They all buy into the same place and have the same activity, in my view. But, they have different [adverse] effect profiles. I think it's a good thing that we have more than one BTK drug available or becoming available. I'm pleased that more [of these drugs] are coming into the space.

One would hope, although I am skeptical, that if you have more than one player that might lead to some kind of pressure on price and make these drugs more widely available for patients. In Europe, we only have ibrutinib at the moment. We don't have acalabrutinib (Calquence) like in the United States, and zanubrutinib is further down the track. It's good to see more drugs coming along, it can only be good for patients.

TARGETED ONCOLOGY:What are your thoughts on the recent phase I and II data for vorinostat (Zolinza)/cladribine/rituximab showing a high overall response rate in patients with newly diagnosed MCL? How could these data impact the field?

Rule: Cladribine is a good drug. It may be slightly better than fludarabine. If you go back 10 or 15 years, fludarabine/cyclophosphamide is highly active in MCL. If you give that combination with rituximab, we showed in the UK that you increase survival. Purine analog—based treatments are very effective.

I'm not convinced that cladribine together with vorinostat makes things go any further. This is chemotherapy-based treatment. Cladribine and fludarabine have long-term toxicities that we don't particularly need. It does affect blood counts, and some elderly patients struggle with that. You do see higher response rates with many chemotherapy regimens, and I don't think that's the future. I think that is interesting and it's what we were doing 10 years ago.

You might say vorinostat is padding something, but I'm not convinced that's the way things are going. I think it's all about BTK inhibitors, and BCL-2 combinations right now.

TARGETED ONCOLOGY:Can you discuss how CAR T-cell therapy plays a role in the treatment of MCL?

Rule: CAR T-cell therapy is the big thing we're waiting to see. We're going to see this data at ASH this year and we're hoping that it will be a contributing treatment. My view is that it's probably going to have a place post-BTK. That's where the disease is harder to get control of. It may well replace allogeneic stem cell transplant. I think we need to see long-term data that proves that it's curing people because we do cure people with allogeneic stem cell transplantation. If it replaces that modality, it's going to be a good thing because we don't like the toxicity associated with it, particularly graft-versus-host disease.