Treatment Challenges for R/R MCL

Transcript: Ian Flinn, MD: What do you think are the next and biggest challenges that we face right now in mantle cell lymphoma?

Bijal Shah, MD: The biggest challenge is still the proliferative patient, and that becomes especially relevant for the BTK [Bruton tyrosine kinase] inhibitors. We’re going to be using them earlier, whether it’s at first relapse, or as trials emerge, in the first line. We’re going to see these proliferative relapses, and we need to have some way of managing that disease. Many of us have used venetoclax around the table, and it certainly can provide benefits to some patients. However, is that a bridge to a transplant? Are we still talking about allogeneic stem cell transplant? Again, how are we going to effectively rescue the patient? R-BAC [rituximab plus bendamustine and cytarabine] is another treatment that’s gotten a bit of attention because of its highly toxic but active profile in this space.

I think we’re really struggling with what to do for these very proliferative patients. I think all of us around the table have been in the position of having given all of the above and now sitting on the patient. I’m very hopeful for what CAR [chimeric antigen receptor] T-cell therapy might provide. The data that [Michael] Wang, [MD,] will be presenting at this ASH [American Society of Hematology] 2019 annual meeting are very encouraging and may be one potential approach that we can take. I would say that independent of BTK refractoriness, those proliferative, highly aggressive patients are desperate for new therapies.

Ian Flinn, MD: That’s well said. The highly proliferative, pleomorphic, and blastoid variants are almost separate diseases in terms of how you manage these patients and require urgent care. You had a lot of experience with using lenalidomide. Do you use it predominantly in the front line? Do you use it in a relapsed setting in combination with a CD20 monoclonal antibody? What’s your CD20 monoclonal antibody of choice?

Bijal Shah, MD: LEN/Rituxan [lenalidomide, rituximab] is still what I do….

Ian Flinn, MD: In the front line or the second line?

Bijal Shah, MD: In the frontline setting. The LEN/OBI data—this is lenalidomide and obinutuzumab data—presented in follicular lymphoma were very interesting. I’ve done it once in a patient who was having tremendous difficulty tolerating rituximab. It works. We’re seeing MRD [minimal residual disease] eradication with [lenalidomide, rituximab], but also in this particular [lenalidomide], obinutuzumab patient. There is one question that I can’t answer, because we haven’t really compared rates of disease eradication. If we’re seeing more rapid MRD clearance, that may mean less time on lenalidomide before we can move to a maintenance approach. For me, that’s compelling. That’s meaningful. I think that’s something we need to think a lot harder about. What do these MRD findings mean?

In particular, can we begin to employ an approach like the Nordic group did, where if you’re MRD-negative, we watch, and if you’re MRD-positive in this post-autologous transplant setting, you get 4 weekly doses of rituximab and continue to follow patients with that pattern trying to keep them in remission? I think they showed upward of 9-1/2 to 10 years of remission-free survival in that trial, which is amazing.

In terms of [lenalidomide, rituximab] in the relapsed setting, I do use it. I feel like you have to be cognizant of what the last therapy was. If I have a patient who has just completed bendamustine, rituximab, who has very little in the way of T-cells—meaning they’re profoundly lymphopenic—I don’t know that I can depend on the immunomodulatory effects of the lenalidomide. It is not a very cytotoxic drug. Most of what I’m seeing in terms of the benefit is immunomodulatory.

Ian Flinn, MD: Javier, Bijal just talked a lot about MRD and how that might be a good end point. Do you get MRD testing in mantle cell lymphoma on clinical patients, on-trial or off-trial? Do you try to drive your patients toward that? If the goal were MRD-negativity, then you might have a strong argument toward these very intense therapies like transplant.

Javier Munoz, MD, FACP: Absolutely. The beauty of many of the trials that we have discussed today is that many of them are actually analyzing MRD as one of the variables that they are looking at. As we said, one of the unmet needs that we have for mantle cell lymphoma is that many therapies, at this point, are prescribed until progression of disease. We need to do better, and a way of doing better would be to find a finite duration of therapy, perhaps sequencing multiple agents or combining agents that would be synergistic. Instead of waiting for relapsed/refractory disease to develop, or for mutations to be acquired, perhaps we should prevent them by combining smart novel therapies that make sense.

Ian Flinn, MD: In both the relapsed and in the frontline setting?

Javier Munoz, MD, FACP: Yes, and some of the trials are exploring MRD, both in frontline and relapsed/refractory disease. The disclaimer is that this is not, at this point, standard of care. However, it’s something that I embrace and something that I like to do with my own patients.

Ian Flinn, MD: Tycel, if we’re going to advance therapy for patients with mantle cell lymphoma and we’re talking about unmet needs, that could easily change over time. A lot of the time, the natural history of most diseases that we treat is that things start out in the relapsed setting and they move to the frontline setting. Is that where we’re going in terms of BTK inhibitors or other targeted therapies?

Tycel Jovelle Phillips, MD: It seems like we’re there now. As Bijal correctly said, there are a multitude of ongoing trials looking at BTK inhibitors up front. Some are comparing it to chemotherapy, while some are being added to chemotherapy. Some of these other novel agents are being moved up front. As you pointed out, when things work in a relapsed/refractory setting, the first thing we want to do is throw them up front because we assume we’ll get better outcomes and responses. The key for some of these novel drugs is that we’re assuming that we’re giving a better toxicity profile, compared with standard chemotherapy.

I think we’re living in that era now. As some of these trials mature and produce data, we’ll see if there’s really a role for BTK inhibitors up front, what life is like for these patients when they relapse, and how that is impacting some of the long-term survival gains we feel we’ve made with mantle cell lymphoma. Our discussions with patients now are, “In 3 or 5 years, we hope to have you alive 10 years and beyond.” If we are moving some of these drugs up and shortening it, then we need to reevaluate how we’re staggering these medications.

Ian Flinn, MD: Right. As the conversation goes in a lot of diseases, are you better off combining the agents, or is it a sequential approach? I think, as you say, only time will tell.

Transcript Edited for Clarity