Emerging Treatment Strategies for Patients With MCL

Simon Rule, MD, PhD

Simon Rule, MD, PhD

BTK inhibitors, such as ibrutinib (Imbruvica), are now emerging in the frontline setting for the treatment of patients with mantle cell lymphoma (MCL); However, it is questionable whether these agents are necessary in the first-line for young, fit patients who typically do well with standard of care treatment, said Simon Rule, MD, PhD.

“There is a lot of excitement about new drugs, obviously, and the odd thing I think with MCL is that these new drugs, if we’re thinking about the frontline setting, are going to be far more valuable for the older, frailer patient population where chemotherapy doesn’t work as well, than in the younger population, where it works really well,” he said.

Several clinical trials are investigating the use of BTK inhibitors in the frontline setting for these older, frail patients who don’t see as much benefit from chemotherapy. Rule, a professor of hematology at Plymouth University Medical School in the United Kingdom, is currently leading a trial exploring frontline treatment with ibrutinib plus rituximab versus bendamustine/rituximab or CHOP/rituximab in patients over 60 who are ineligible for transplant. Rule said even if the combination proves to be equally as effective as chemotherapy in older patients, it will almost certainly be a less toxic option.

In an interview withTargeted Oncology,Rule discussed the treatment options available for younger, fit patients with MCL, including the watch-and-wait approach and BTK inhibitors. He also highlighted several clinical trials supporting these strategies, as well as other ongoing trials aiming to advance the treatment landscape for the older patient population.

TARGETD ONCOLOGY: Could you discuss the current management strategies for younger patients with MCL?

Rule:Worldwide, I think it is pretty well established that for younger patients who need treatment, it’s a high dose cytarabine-based regimen, usually followed by a transplant, followed by rituximab maintenance. That’s fairly standard. There are a number of different ways you can give the high dose cytarabine. I don’t think there is anything to say that one way is better than the other. I think the approach here, invented in Houston, the hyper-CVAD, is becoming less and less fashionable. I think the good reason for that is because it’s quite toxic and includes drugs that probably don’t have much of a role in this disease, particularly high dose methotrexate. Nonetheless, pioneering high dose cytarabine is what that regimen did and that has been a key thing for these patients.

TARGETED ONCOLOGY: Are there any drug regimens in development that look promising?

Rule:Of course, the drugs that have made a big impact in the disease are the BTK inhibitors. The question is, in a young patient situation, do you actually need these drugs in the frontline setting? The outcomes are actually pretty good when we use high dose cytarabine and patients are off drugs with a normal quality of life. When they relapse, because everybody relapses, that’s when we tend to introduce these novel therapies.

There’s a trial ongoing in Europe right now taking a high dose cytarabine regimen. There are 3 arms in the trial. One is the standard, which is the chemotherapy followed by transplant with maintenance. There are 2 experimental arms, 1 incorporating ibrutinib into that algorithm and the third one drops the autograft, so if you incorporate ibrutinib in the frontline, do you need the autologous stem cell transplant at all? That’s a big study, and it will take quite a few years to recruit, but it’s going to challenge the conventional paradigm of do you need transplant? That’s something for the future.

I think it is difficult right now in a young patient group to switch to anything other than the conventional chemotherapy. One of the things that I always say when I give talks about this disease is don’t forget that chemotherapy works. There is a lot of excitement about new drugs, obviously, and the odd thing I think with MCL is that these new drugs, if we’re thinking about the frontline setting, are going to be far more valuable for the older, frailer patient population where chemotherapy doesn’t work as well, than in the younger population, where it works really well. Don’t forget chemotherapy and be cautious in getting involved with new drugs early, particularly in patients with a good prognosis, which is usually the younger patients.

TARGETED ONCOLOGY: Can you talk about the watch-and-wait approach in MCL?

Rule:I’ve been watching and waiting MCL for a long, long time, for well over a decade. I think people thought I was mad when I was doing it to start, but now I think it is quite well established. Watching and waiting does not disadvantage patients. If patients are asymptomatic with low-volume disease, it is the right thing to do. There is no advantage in treating someone early at diagnosis if they are well. That seems completely counterintuitive. You’ve got an aggressive cancer that’s incurable, why wouldn’t you treat it straight away? Well the answer is that when you treat this disease, it’s inevitably relapses, and when it relapses, it’s often a harder disease to manage, so putting that off as long as possible probably makes patients live longer.

We have a study in the UK now where we have essentially a watch-and wait-trial. It’s actually labeled as a biobank. Any newly diagnosed patient with MCL in the UK goes on the biobank, we collect baseline material, and if they need treatment, they get treatment, and we’re just following them for survival. Those that are clinically eligible for a watch-and-wait approach, [are patients who are] well, low-volume disease, normal blood count, [and] the clinician and the patient are happy to watch and be watched.

We have over 400 patients on that now. We’ve just looked at patients who have been registered for over a year, almost 150, maybe 200 actually. When we do that, we find that 40% are being watched to start with, which is miles higher than I thought it was going to be. Of that 40%, nearly 30% are still being watched at a year. This indolent group is actually far more common than anybody ever thought because you don’t know if somebody is indolent unless you leave them alone. If you treat everybody, you will never know that these people exist.

The whole point of the biobank is to, in retrospect, try to find a biomarker because all the biomarkers that have been used, and SOX11 is a good example, have been from highly selected groups of patients who retrospectively were found to have a good outcome. SOX11 works very well in leukemic patients, but not at all in nodal patients, which is the majority.

We will have patients that we know are indolent because they have been watched for 2 years. That’s going to be my definition of truly indolent. We will have patients who were treated straight away, and we will have to compare with all the biological material that what we have to find some kind of biomarker. That is the goal.

The question then arises, and this is the question I get asked not infrequently, is if you’ve got somebody that you’ve watched and waited them and you’ve watched them for a couple of years, when you do treat them, do you treat them any differently than somebody who presents in a more aggressive way? You can argue that 1 of 2 ways. You can either say biologically It’s not behaving so aggressively so you don’t need to treat them so aggressively, or your argument could be that if you treat them exactly the same way, you might get a better outcome. My approach is the latter, so I treat everybody the same at the point of their treatment.

One of the things I am hoping we will be able to pick out of this population that we are going to follow is we will look at outcomes of patients treated immediately with the standard treatments, CHOP and bendamustine, and see how durable they are. Then we will look at patients who we watch for a couple years who have indolent disease, then treat them the exact same way to see whether their remission duration was longer, because that will determine whether we need to do things differently. I think 1 of the challenges is actually truly defining that group of patients and then look at different treatment approaches.

TARGETED ONCOLOGY: There has been some discussion of putting BTK inhibitors upfront recently. What are your thoughts on that?

Rule:It’s the obvious thing to do. We know that the earlier we use BTK inhibitors in the relapse setting, the better the outcome. First relapse, you get the best benefit from a BTK inhibitor. It seems logical to using them in the frontline would be better still. Bearing in mind what I said about younger patients, older patients are a whole different ballgame. Chemotherapy for younger, fitter patients works very well, but the older the patient, the less fit the patient, the less benefit you will get from chemotherapy because you can’t deliver what you want to deliver. It makes sense and there are 3 trials of note.

The SHINE trial, which is the frontline Janssen registration study, [investigated] bendamustine/rituximab, plus or minus ibrutinib in a placebo-controlled fashion. That trial finished a couple of years ago and we are still waiting for the outcomes. This suggests to me that the control arm, bendamustine/rituximab, did much better than anybody thought it would, which I guess isn’t a surprise because people get used to managing these treatments. We are waiting for that, however, it has chemotherapy in both arms.

The trial I am running in the UK is a frontline trial of ibrutinib plus rituximab versus bendamustine and rituximab or CHOP/rituxumab. It’s chemotherapy versus non-chemotherapy in a patient group who are over 60 [and are] transplant-ineligible. That’s asking the question of do you need chemotherapy at all? We know from what Michael Wang, MD, has done here in Houston that ibrutinib in the frontline looks very active. That’s been in young patients, so I am taking it into older patients where it’s a bit more needed. It’s going to be a 400-patient study. There is about 150 [patients enrolled] already. We’re looking at progression-free survival, and all things you would expect us to look at. Even if it is as good as chemotherapy, it’s going to be less toxic, almost certainly. To me, that’s the obvious study to do.

The final study, which is ongoing in Europe, is a trial in the young, fit patients, where they are incorporating ibrutinib into that sort of standard of care and seeing whether you need the transplant or not. That’s looking at the young patient group, but as I said the older, frailer group of patients are the ones that get the most benefit.

I’m currently looking at 1 of the newer BTK inhibitors in the older, frail population, just using it as a single agent. To me, that makes perfect sense. I think the older the patient, the more you should be using these frontline, but I would not be surprised at all if they are in frontline treatment algorithms relatively soon. Maybe not across the board, but certainly in the older population.

TARGETED ONCOLOGY: Could you also discuss the Nordic trial and how that may impact the field?

Rule:I think 1 of the things that has emerged reasonably recently is that we recognize a group of patients that do really badly. The Nordic group looked atP53mutations, not deletions. Mutations were the things that predicted for a really bad outcome. These are young patients in the Nordic trials, so young, fit patients receiving high dose cytarabine, having an autograft, and basically, their survival with theP53mutations is under 2 years. They do really badly. We also know this group of patients don’t do very well with BTK inhibitors, so we recognize this group of young patients with bad outcomes. They are usually the blastoid patients, the highly proliferative ones who struggle getting into remission in the first place.

My approach to that group of patients is to do allogeneic stem cell transplantation, and I think it again comes back to what I said about the excitement with new drugs. You forget about all the things that work. An allogeneic stem cell transplantation offers potential cure for these patients. We do use it in a relapse setting for very young, fit patients. Certainly, my approach in a young patient who either has a blastoid presentation, because they are going to be theP53-mutated arm, is I will do an upfront allogeneic stem cell transplant.

We have in press right now a publication from a study in the UK where we did upfront allografting in MCL patients. It’s 5-year follow-up, and there’s an 80% survival at 5 years. We’re looking forP53mutations right now, because we didn’t know that at the time of the study, we were just looking at how applicable that was. This was pre-BTK inhibitors. I don’t think that challenges, and in fact, I say it in the paper, that we don’t suggest this challenges the conventional treatment which is autologous stem cell transplant, but I think it gives you good evidence that it’s a safe thing to do upfront. To take those [high-risk] patients and do an allograft, this is evidence that supports doing that. We are looking right now at historical material in those 25 patients to see if any of them areP53-mutated patients, because if they are long-term responders, I think that would validate the kind of approach I’m suggesting.

The other thing from that group is that we know the combination of ibrutinib plus venetoclax works very well in that mutated group. We know that from the publication in theNew England Journal of Medicinefrom our Melbourne colleagues looking at that combination in relapsed/refractory MCL. In those that wereP53-mutated, 50% got a complete response, so we know perhaps while ibrutinib isn’t very good, the combination probably is. Maybe for older patients, that might be an approach we would like to do.

My mantra, which has been drilled into me from being a young doctor, is never do a test unless you’re going to act on the results of it. There would been no point in doing aP53analysis, because what were you going to do? I think in the younger patients now, you have evidence to take a bad behaving disease and do something different. With older patients, we’re still not entirely sure what to do with it. Now it confirms a bad prognosis, but how will that affect the way we treat them? We are not entirely sure right now. It helps us, but I think that’s a group we need to focus on.

TARGETED ONCOLOGY: What is the takehome message for the management of younger patients?

Rule:[There are] a couple of things. One, just because you’re young, if you’re asymptomatic, you can still watch. I have a patient diagnosed in his early 50s, untreated for 12 years, and presented with nodal disease. It happens. If a patient is asymptomatic, I suggest you watch and you might be surprised. You will not disadvantage a patient.

If they need treating, I would personally now be looking at aP53mutation. If they are mutated, think about a far more aggressive strategy, because you probably won’t get them into remission and autograft is not going to work, neither is ibrutinib. Think about an early allogenic stem cell option. That’s 8% to 10% of patients. For the majority, use what is your favored high dose cytarabine regimen, but use rituximab maintenance afterwards.