Approaches to Frontline Therapy for Patients With Mantle Cell Lymphoma: Part 2

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 second video of the series, the members of the panel review the available data and discuss choices of frontline therapy for 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 move on to the second part of our discussion, in which we'll be discussing frontline treatment for mantle cell lymphoma. So maybe before we get into kind of logistics of treatment, or what we're using for treatment, let's just talk a little bit about when you first are seeing that patient with mantle cell lymphoma, how are you thinking about first-line therapy, in terms of what is your aim or your goal with first-line therapy?

Jia Ruan: I'm happy to share how we approach that. It's very individualized. We want to take each individual patient's needs into consideration because at the end of the day, we have to discuss with the patient that it's a rare condition and it's great treatment, but we cannot say that this is curable. We'd like to achieve the best possible remission, but in the meantime, we like to sustain their quality of life, and also make sure that they have excellent organ function reserve so that as newer treatments start streamlining, that they would be in great shape later on, should there be a need to continue to be a good candidate for subsequent therapy.

Traditionally, I think that there's chemoimmunotherapy, and because of that, intensity seems to be a very important factor in determining which pathway for patient to take. But now that we know that they are effective therapies that moderate in terms of intensity, so they become more widely applicable to a lot of patients.

In our practice, we prioritize clinical trials because we feel that the advancement of novel therapy really has changed the care, the landscape, and outcomes for our patients. So wherever possible, if there's a well-designed clinical trial, we like to follow the protocol, and try to provide therapy induction and maintenance and get to the best response and try to keep patients in maintenance therapy.

Outside the context of clinical trials, we do a lot of bendamustine-rituximab-based (BR) chemoimmunotherapy, because I think for standard risk mantle cell lymphoma patients, the response rate and also progression-free survival (PFS) plus rituximab maintenance has been really very excellent. They have a good balance of effectiveness and also side effects and toxicity profiles. 

There is 1 subgroup of patients, as we discussed earlier, which is high-risk, that could be high Ki-67, TP53 patients. We have to think carefully as to what to offer as initial therapy. Sometimes with chemoimmunotherapy, if they're young and fit patients, one could consider using a backbone incorporating high-dose cytarabine such as the European Mantle Cell Lymphoma Network, the R-CHOP, DHAP, or DHAX-based regimen. And more recently, there is incorporation of a BTK inhibitor into that particular backbone so we're contemplating how to adapt to those new data.

But in summary, I think with the majority of the patients with mantle cell lymphoma, we generally treat them outside the context of clinical trials with bendamustine-rituximab-based induction, and maybe adding rituximab maintenance. Then if there's clinical trials available, we always prioritize participation in those trials.

Kami Maddocks: Great. Dr Patel, can you maybe just walk us through how you view the goals of first-line therapy for mantle cell lymphoma and then maybe your treatment approach?

Krish Patel: Yeah, I'd be happy to. I think much like Dr Ruan outlined, I think this is very personalized. Maybe starting with those high-risk patients and patients that have TP53 aberrations, we know unfortunately they don't seem to be overcome by high-intensity therapy approaches. These are patients that I really think are important to be treated on clinical trials, but also to avoid therapies that are going to be toxic without a potential of long-term benefit. These might be patients that, if we can't get them on a trial, we try to potentially treat with novel targeted therapies that might incorporate things like BTK inhibitors, because we know biologically they may be active in that setting and not necessarily limit our chance for other therapies down the road.

For the standard-risk patients, much like Dr Ruan shared, we also tend to use predominantly bendamustine-based therapy. I think this reflects partly the fact that most patients with mantle cell lymphoma are older and may have some comorbidities, and so we want to maybe limit some of the toxicities that might be included in platinum- or cytarabine-containing chemotherapy regimens, or anthracycline-based regimens. 

And then for the young patients, at least historically at our institution, we have approached their treatment with a bit more intensive therapy for a longer initial remission, and use regimens that contain cytarabine and anthracycline followed by consolidated autologous transplant. I think as Dr Ruan mentioned, that is perhaps changing a bit now with recent data, for example, from the TRIANGLE study, which shows perhaps the advantage of consolidative transplant is not as great in an era where patients may have access to BTK inhibitors as part of frontline therapy, so that may be changing a bit for the younger and fitter patient. But I think very much the goal is to provide balance between the longest possible remission, and the least toxic therapy that we can offer.

Kami Maddocks: Great. So you both kind of touched on a little bit, mostly the TRIANGLE data, but do you think there's a role for BTK inhibitors in frontline treatment of mantle cell lymphoma, and how do you look at that, only with the TRIANGLE data? Or what are your thoughts now, and where we're moving?

Jia Ruan: We're a big believer in applying novel agents including BTK inhibitors, or maybe even before that, we tried the lenalidomide-based rituximab combination and we really came away so impressed with a novel agent alone, if you applied early and kind of judicially and generate a program where you can combine efficacy and minimize toxicity. I think yes, indeed. The question is, where do you combine? Should this be chemotherapy-free, or free of conventional chemotherapy, but just a combination of novel agents alone, or novel agents in combination with a chemoimmunotherapy backbone?

I think the best data or the most impressive data so far, the TRIANGLE data where people are talking about indeed, for younger fit patient who can tolerate the TRIANGLE-based backbone, generate the best PFS in finite duration of therapy, but that's in the context of autologous stem cell transplant as consolidation. I feel like the TRIANGLE study was well-designed in terms of looking at different arms where the outcome is quite well elucidated, although you have to wait for long-term follow-up in terms of efficacy and safety data. The addition of the BTK inhibitor to the backbone of the TRIANGLE seems to be generating a better progression-free survival, and also the standard arm of having the autologous stem cell transplant does not seem to wane out compared with the arm without bone marrow transplant. I thought that was very provocative in a positive way. But we like to see how that's translating or at least with the trial data, how do they evolve?

For the majority of the patients who are not a candidate for, or do not want to be treated with intensive backbone or autologous stem cell transplant, then the question is really should we incorporate that into a BR-based backbone versus just a novel combination alone? The conclusion for the BR-based backbone is not definitive at this point. We have the SHINE data, where there's no difference in terms of response rate or subpopulation with TP53 or [minimal residual disease] MRD. The toxicity data may be more so in the ibrutinib-BTK-containing arm. A question is, shall we do that sequentially, or only as needed, versus upfront in combination? We’re waiting to see if other BTK inhibitors might be doing a better job in terms of combining, but I think hopefully that we would have more data coming out to help us decide one way or the other.

Kami Maddocks: Great. Dr Patel, any additional thoughts on the role of BTK inhibitors in the frontline setting?

Krish Patel: I wanted to highlight an important point Dr Ruan made, which was that the TRIANGLE study was done in younger patients, so it’s important for us to recall that was a trial where we had selected for patients who could tolerate intensive approach, and really trying to understand whether the transplant component is needed, in addition to do we get more for adding a BTK inhibitor to intensive chemotherapy? And I also am impressed by that data, but I do think its applicability is probably smaller than we anticipate, because again, most patients are older. I think I’m excited about the potential for BTK inhibitors in the frontline for younger, fitter patients.

The question I have is, which BTK inhibitor? Ibrutinib has more toxicities than second-generation BTK inhibitors and we don’t yet have data from intensive therapy approaches with combination of second-generation inhibitors, although the NCCN guidelines now do list that as a potential consideration. But I think in older patients I actually have a very opposite feeling, which is that, so far, the data has not really clearly given us an advantage in older patients. 

As Dr Ruan nicely highlighted, in the SHINE trial, the combination of at least ibrutinib, a less selective inhibitor, did lead to more toxicities. This is something that we need to be cautious of and recognize where we have a different population in these 2 trials. I would try to generally incorporate a BTK inhibitor for my younger, fitter patients, and I think at least at this point, my approach would be different in older patients unless they were high-risk molecular and potentially being treated on a trial or something of that sort.

Kami Maddocks: Great. And before we move on, I want to quickly touch on one last thing. In discussion part 1 we mentioned indolent mantle cell lymphoma, and also leukemic non-nodal mantle cell lymphoma. If there are patients that you don’t treat at diagnosis, what do those patients look like and how do you follow them?

Jia Ruan: They’re less common, but I would say that it’s still sizable in our practice. Maybe 20% to 30% of those patients are watch-and-wait. More of them are having less of a nodal presentation. So indeed, like what Dr Patel mentioned before, it's a lot of leukemic, maybe splenomegaly, and we've seen patients maybe 5 or 10 years ago misdiagnosed with atypical [chronic lymphocytic leukemia] (CLL), and at the end of the day, they tend to be indolent mantle cell lymphoma. 

There's also a small cohort in our practice that we follow if they have some lymphadenopathy. They could be more indolent nodal patients where we watch and wait, and all of those watch-and-waits tend to be relative. I would say now nodal patients perhaps have a more protracted watch-and-wait, but there's still a small proportion that has some lymphadenopathy, but we watch for 3, 6 and 9 [months] or maybe a year, and then the treatments become elective, and efficacy and low toxicity become a priority for those patients.