Treating Patients With Relapsed/Refractory Mantle Cell Lymphoma: Part 3

In this expert roundtable series, Kami Maddocks, MD, The Ohio State University, Columbus, Ohio, leads a 5-part roundtable panel discussion on updates in mantle cell lymphoma with Jia Ruan, MD, PhD, Weill Cornell Medicine, New York, New York, and Krish Patel, MD, Swedish Cancer Institute, Seattle, Washington.

In the third video of the series, the members of the panel review the available data and discuss options for treating patients with relapsed/refractory mantle cell lymphoma. 

Transcript:

Kami Maddocks: Welcome to Oncology Learning Network. My name is Kami Maddocks from the Ohio State University James Comprehensive Cancer Center, and I will be moderating today's discussion on mantle cell lymphoma. I am joined today by a distinguished panel of experts in treating mantle cell lymphoma. 

Let's go ahead and move on to discussion number 3 and talk about the approach to treating relapsed/refractory mantle cell lymphoma. Most patients with mantle cell lymphoma can go through more than 1 relapse during the lifetime of their disease. But let's just start with initial relapse. How do you approach looking at treatment for a patient the first time they relapse?

Krish Patel: In general, relapse is a little bit different than at diagnosis in the sense that mantle cell lymphoma is a genomically-unstable disease. We tend to see patients at relapse sometimes have more aggressive biology, or sometimes even more aggressive clinical features. There's enrichment in acquisition of tumor suppressor mutations like ATM and P53. These are things that generally mean that most patients at relapse will usually be treated rather than observed. In this situation, I think covalent BTK inhibitors have become a very, I think, widely accepted standard therapy. There are now 2 currently approved in the US by the FDA, acalabrutinib and zanubrutinib. Both are highly selective. Both have a very good balance between efficacy and toxicity and tolerability.

My initial approach in most patients at relapse is a covalent BTK inhibitor. For patients that maybe had high-risk disease at diagnosis, those patients that had P53 aberrations, or maybe had blastoid morphology, things of that nature, those patients can also be well-served by BTK inhibitors, but their overall durability of response tends to be lower. Those are patients where I may at least discuss with the patient the potential option for CAR T-cell therapy. At least in the US, the label indication for CAR T-cell is any patient with relapsed/refractory mantle cell. So that might be a population where potentially CAR T-cell therapy could be beneficial. Although, at least to this point, all the trials of CAR T-cell therapy have been done in patients who have had a covalent BTK inhibitor.

Kami Maddocks: Great. Dr Ruan, how do you look at initial relapse?

Jia Ruan: I think it's important to also look at the sequence of their treatment strategy. For somebody who obviously previously had no novel agency exposure, then options are plenty in the sense you could start with doublet combinations, or sometimes even a triplet combination, based on the available data. 

For a lot of our patients, if they started with BTK-inhibitor-based induction, then I feel like when they relapse, I do feel some pressing need to think hard and quickly, knowing that they tend to have higher-risk mutations and the interval of making a decision might be shortened. I generally keep them on a BTK inhibitor while sorting out what needs to be done next. I do agree that we try to activate the CAR T-cell option because it's now FDA-approved for people who can tolerate it, and are medically accessible to this type of treatment.

And now that we also have non-covalent BTK inhibitors, I also discuss that option, as a bridge, if they could get on the non-covalent BTK inhibitor onto CAR T or other means of clinical trials, or if they were just not CAR T candidate, if they're not physically strong enough or fit enough to move onto CAR T. We've seen those patients, especially because they did so well previously with novel agents-based induction. I think that one has to be thinking about the sequence of events. And we also try to make clinical trials in the relapsed/refractory setting available for patients as well.

Kami Maddocks: Does your initial therapy impact your decision, both in terms of what a patient has been treated with and their initial response to that therapy or with the availability of BTK inhibitors in the second-line setting? Do you feel like that's the choice, as long as they haven't had it in the first line, for most patients?

Jia Ruan: I would agree with that statement where with BTK inhibitors, I would definitely prioritize them as second-line therapy if they have not been exposed in the frontline setting. In fact, there is literature coming out that if you use them earlier, instead of waiting for third and fourth line, use them in the second line, the relapsed setting, the durability or the mileage that one can get out of remission is quite remarkable. 

We're talking about next generation, the overall response rate 70, 80%, [with] 30, 40% [complete response] (CR). I want to say that maybe the durability is up to 2 years. Those are remarkable data even in the context of previous chemoimmunotherapy. I don't recall that any of those chemo [treatments] would be able to achieve that particular mileage. I think it's very important to have them as a second-line option.

Krish Patel: I would agree. I think assuming patients have not had a BTK inhibitor in the frontline. That would be my choice. I do think duration of response is an interesting question. We have seen in other lymphomas that patients that have an initial remission that's less than 2 years after frontline therapy in mantle cell lymphoma unfortunately have worse outcomes. So that's another maybe way of identifying patients that are at high risk for poor outcomes. And again, like we have mentioned, those are patients probably that would most likely benefit from being treated on clinical trials or consideration of approaches like CAR T-cells, which tend to work as well in high-risk patients as they do in standard risk patients.

Kami Maddocks: Great. When you start a patient on a covalent BTK inhibitor, how are you thinking about duration of treatment? Are you treating the patient as long as they're responding? Are you looking for a CR, and if they don't have CR, you're thinking about taking them to a different therapy? Does it depend on the patient disease risk factors? What does that kind of decision-making look like?

Krish Patel: That's a great, and tough, question. I think as Dr Ruan mentioned, overall responses are very good, somewhere around 80% with covalent BTK inhibitors. About half of patients will have a complete response by, say, a PET scan or a CT scan, and those patients do tend to have more durable outcomes. I think for the patients that have early complete responses, I think my goal is usually to continue the BTK inhibitor for as long as they are tolerating it well. 

For the patients that might have partial responses, I do tend to watch those patients very closely, and some patients will plateau a response and then maintain it for some time, so there's still the potential for durability. I don't necessarily switch at that point, but I probably have a higher threshold to repeat a response assessment, or if we're seeing some clinical change that is starting to suggest to us that we've lost that plateau and it's not going to deepen over time, then I'm fairly quick to change gears in those patients.

I think the other thing I tell all my patients when they start covalent BTK inhibitors is that for any reason at all, if they start to have disease progression, we don't want to stop the drug until we have a plan in place for the next line of therapy. I think this is maybe an important thing for patients to be empowered with that knowledge, so that if things happen and perhaps they get lost in follow-up or for any reason that they understand even if the drug appears not to be working for them anymore, it is much better to continue it, and then make a plan, than to just stop the medicine.

Kami Maddocks: I think you've both mentioned CAR T-cell therapy. How do you look at making a decision if a patient's a candidate for this? And I think you probably have both said it enough that we feel like that's probably what you're thinking about as a potential next therapy option post-covalent-BTK, but you've also alluded to that this is an older patient population. Can you talk a little bit about patient fitness for CAR T, and the reality of that?

Jia Ruan: I want to say that in our institution and perhaps in many other institutions as well, I've seen people going through CAR T at fairly advanced age group. They could certainly go to 70 if they are really fit with good organ reserve. I think it's biological age, and also organ reserve. We've had some cases, which is very uncommon, if they were to have fairly significant chronic renal disease and other things at a relatively young-ish age that still present some significant burden to crossover to the CAR T. It really depends. 

I think that if somebody has progressed on the BTK and you're trying very hard to come up with very effective solutions which would provide some durability as a next step, I think very highly of CAR T because the data is fairly immature at this point, and we have the capacity and resource to perform CAR T therapy. Now that we have the non-[covalent]–BTK inhibitor, I think that we continue to think very highly of CAR T.

I do sometimes consider doing the non-covalent BTK as a bridge if somebody who suddenly become a very symptomatic relapse and progression on the BTK. And also, I feel like the other scenario is success of mobilizing for CAR T, right? That's a practical issue. There are patients who previously maybe due to other therapy, could not very effectively get immobilized, getting enough healthy T-cells to generate CAR T. That was a significant problem, I think. Now that we have the non-[covalent]-BTK inhibitor, at least we have a bridge as a backup or as alternative for those patients. I think it's fairly complex, but we try to mobilize multiple pathways and try to prioritize for our patients.