Treating Mantle Cell Lymphoma: Role of BTK Inhibition - Episode 14
Lauren C. Pinter-Brown, MD: My personal experience in treating mantle cell lymphoma with ibrutinib has been great. Most of the patients who I have, or many of the patients who I have now who are being treated, are those I described earlier. Patients who perhaps received hyper-CVAD [cyclophosphamide/ vincristine/doxorubicin/dexamethasone] or the Nordic regimen in an autotransplant, and they’re so frightened about relapsing. But now, 8 or 10 years later, to be able to tell them that they don’t have to necessarily have the same experience, that they could take a pill every day, is a wonderful thing to be able to tell people, and they look so relieved. And in combination with that, I have the ability to tell them that there are other drugs like this so that their experience doesn’t have to be duplicated.
Eduardo Sotomayor, MD: In terms of my personal experience with ibrutinib, I think the most important message for the physicians is it’s a new class of drug. It’s not conventional chemotherapy. So we understand mechanism of action. We are understanding better the mechanism of resistance; we have a safety profile that you need to be aware of in order to try to identify which patients are going to benefit the most with this treatment with less exposure to adverse effects. Three years of follow-up data show that it’s a treatment that is tolerated by a significant portion of patients, not all, but those patients who are receiving and tolerating treatment at 1 year probably are going to be patients who will continue tolerating treatment.
Now, where the field is moving is also in understanding how long we need to keep this treatment: 1 year, 2 years, 3 years. The good news is that in other diseases, there are data that if you achieve very good response, in some cases, no evidence of minimal residual disease, you can safely stop ibrutinib in other settings. Still, these are clinical trials, but what we are going to be seeing in the future is that we are going to start talking about a limited number of months or years of ibrutinib therapy.
Bijal D. Shah, MD: I’m happy to describe my personal experience with ibrutinib and acalabrutinib in mantle cell lymphoma. The first thing that I need to make sure I comment on is that our patients may be of higher risk than what other groups are seeing. And I say that because median duration of ibrutinib in our group is going to be somewhere around 6 months or so before patients either progress or prove intolerant. Whereas, in talking to my colleagues both in Europe and also at other major centers in the United States, they’re seeing median durations closer to a year, where 50% of their patients are still on ongoing ibrutinib a year after starting.
What is it that’s unique about our patients? We are making a concerted effort now to sequence our patients when they present, not just when they relapse. And what we’re finding is a lot more p53 mutation than we had expected. So going back to what I was saying before where 17p deletions may not be as predictive, I do think the point mutations are a bad thing. And particularly if you combine that with proliferative disease, that can be challenging to overcome with just ibrutinib.
The other thing that we have observed is the frequency of noncanonical NF [nuclear factor]—kappa B mutations is also quite high, and many of them are preexisting. So it’s not something that we’re selecting for with our therapy per se. It’s something that’s there before we give the ibrutinib. And so of the last 50 or so patients, I think 30 carried a p53 point mutation in our series, just to give you a sense of what we’re seeing as we sequence patients. And so that’s probably more reflective of why we’re not seeing patients on therapy for longer at our center.
A better question is, “What’s unique about Moffitt?” It is possible that it’s just referral bias. Patients are sent to us with shorter remissions from frontline therapy, and we’re of course going to see those because I think physicians recognize, “Hey, if I’m getting 6 months before someone progresses after a frontline regimen, I probably need to get them to Moffitt to figure out how to fix this.” So some of it’s that. Some of it is, I think, related to an accumulation of p53 point mutations in people who are older, and I say this purely as a hypothesis. But we do see in acute lymphoblastic leukemia, for example, that in those over the age of 65, there seems to be a higher frequency of p53 mutation relative to those under the age of 65. And so there may be something unique just about the age of the patients as they’re coming to us. I want to reiterate the median age of mantle cell is 68, so it’s not to say that 65 is a cut point; it’s just to say these are some of the things that I’m trying to grasp, trying to better understand in terms of the patients that we see.
Transcript Edited for Clarity