The Evolving Landscape in Mantle Cell Lymphoma - Episode 5

BTK Inhibitors for Relapsed Mantle Cell Lymphoma

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John P. Leonard, MD: I want to ask Tycel about the role of BTK [Bruton tyrosine kinase] inhibitors in general. We’re going to spend time going through a lot of the individual data in the next few minutes, but why does a BTK inhibitor work so well in mantle cell lymphoma? We know it works in CLL [chronic lymphocytic leukemia]. We know it works in mantle cell and Waldenström macroglobulinemia; not so much in follicular lymphoma, less in large cell. What about mantle cell makes this a good target?

Tycel Jovelle Phillips, MD: Mantle cell lymphoma is probably as close as we can get to CLL without being CLL. It’s a very close cousin, and both are very highly dependent on the B-cell receptor. We do know from all these preclinical studies and research that BTK is essential to B-cell signaling. That probably makes it quite sensitive to ibrutinib. This has given us responses and established itself in most situations as the go-to agent in first relapse in most of these patients. Especially with some of the data that we’ll touch on later showing the responses tend to be much improved the earlier we use it. I really think it’s revolutionizing change how we treat mantle cell lymphoma patients, especially in the relapsed/refractory setting.

Compare it with some of the data we have from bortezomib and lenalidomide—granted, those trials of those patients were heavily pretreated with chemotherapy prior to going on to those studies. But it’s really changed the way we look at mantle cell lymphoma, with some of the changes we’ve made up front contributing to the improvement of overall survival that we’re seeing in our patient population.

John P. Leonard, MD: Andy, ibrutinib was and has been around for a while. We have some data, and good long-term data, which is 1 of the good parts about ibrutinib. Obviously we have other newer agents with different profiles have come along. What’s your general sense as we look at the pooled data and the longer-term data with ibrutinib? How do you think of it in mantle cell lymphoma?

Andrew D. Zelenetz, MD, PhD: If you can call it that, it’s the grandfather of the BTK inhibitors. It has been around for a while. We do have some prolonged follow-up. We have follow-up with medians of 4 and 5 years. And so this is really mature. We have an idea of how ibrutinib works in this disease. One of the things that’s really important, and Tycel touched on it, is that it really matters when you give it. If you give it for the third, fourth, or fifth relapse, you know it works. It’s usually transient, but if you use it in second line of the pulled data, the progression-free survival exceeds 2 years. And we get a pretty good complete response rate, a radiographic complete response rate of nearly 60%.

The median progression-free survival, as I said, is 25 months, but the median overall survival actually hasn’t been reached as of the pulled analysis from Simon Rule that was published. However, the flip side is it is the drug, in my opinion, that has the most adverse effects. We see the bruising, we see diarrhea, we see rash; some are off-target effects. We’re seeing the cardiac adverse effects, which are really significant with an atrial fibrillation rate of 6% to 10%.

We see increasing hypertension at least through the first 12 to 18 months; maybe it plateaus after that. But we know a lot about the drug. We know how to manage the adverse effects. We can keep people on the drug for a long time. It’s a little easier to keep people on some of the newer agents, but certainly there’s a lot of comfort with ibrutinib because people have used it for a long time in mantle cell and in CLL.

John P. Leonard, MD: We’ll talk about the choices among different options. But generally speaking, when in a patient’s course with mantle cell would you go to a BTK inhibitor?

Andrew D. Zelenetz, MD, PhD: Outside a clinical trial, where we would consider in select patients to do it up front, I would do it at first relapse. Like CLL, the genetic background still makes a difference. Yes, TP53 mutant, or a TP53 aberrant mantle cell lymphoma, will unequivocally respond to ibrutinib. But if you look at TP53 aberrant versus nonaberrant, that progression-free survival is inferior for the aberrant cases. Maybe that’s 1 of the reasons why using it in second line is better, because we have a smaller proportion of patients who have the adverse genetic factors.

Transcript Edited for Clarity