Transcript:Lauren C. Pinter-Brown, MD: The availability of drugs like ibrutinib has been effective for 2 populations of patients probably the most. One of those is the population of patients who were treated 8 or 10 years ago, when the outlook for mantle cell was very, very poor, and they got extremely aggressive treatment. To be able to offer them treatments that are so less intrusive with a good expectation of a long response really represents a big change. As well as for those patients who are frailer and may not have been able to tolerate even intermediate or minimal kinds of chemotherapy, it offers a way for them to be treated that is tolerable.

Eduardo Sotomayor, MD: Ibrutinib is a targeted agent that is going to inhibit the Bruton tyrosine kinase [BTK] pathway, which is extremely important for the survival of proliferation of malignant B cells. I remember the day that ibrutinib data were presented at one of these ASH [American Society of Hematology] meetings and then published in the New England Journal of Medicine. And to me it changed the landscape of how we treat mantle cell lymphoma. So remember, we used to say mantle cell lymphoma is the most aggressive incurable disease that we need to treat aggressively with more chemotherapy and keep at it. And suddenly here we have an oral agent, a pill. They take 4 pills a day, and you’re able to see fantastic responses. I have seen complete response in patients with mantle cell lymphoma for whom I was running out of options. And here we are with an oral agent.

But also the message that I want to send is: When we have oral agents that work, we get all excited. But we need to be careful about the adverse effects associated with this novel type of agent because although they are not conventional chemotherapy, they have their own subset of adverse effects that we need to be aware of.

Bijal D. Shah, MD: The mechanism of action of ibrutinib is going to be BTK driven. Now, with that, I’m going to pause and tell you what that means. It’s tempting to say that by blocking B-cell receptor signaling, you’re provoking apoptosis or cell death in any of its various forms. But that’s actually less commonly seen. I think more often what we see is lymphocyte egress. We see mantle cell lymphoma literally being expelled from the nodal compartment, from the splenic compartment, into the peripheral blood. And with that, essentially death by neglect over time. And I think that is just as important, the mechanism of B-cell receptor inhibitors, as any potential apoptosis or cell death you may see.

The lymphocyte egress is not an easy thing to explain. There appears to be—to borrow a term from my colleague—inside-out and outside-in signaling through adhesion molecules, the integrins that influence homing and retention within the nodal compartments. And you can block that with ibrutinib. But we always joke around, and it almost becomes a philosophical debate at times when we’re chatting and discussing. “So tell me again, how does ibrutinib kill cells?” I want to say that it should make sense, but it doesn’t, because why would a cancer cell care that the B-cell receptor is blocked. Isn’t that intrinsic to B-cell survival to have BTK? And if that were the case, then I would ask you some very hard questions. Why do we see B-cell recovery over time in spite of the BTK inhibitors? Why do we see some patients who convert from PR [partial response] to CR [complete response] over time, as their B cells are recovering? It gets much, much more challenging than to simply say, “Hey, yeah, we blocked the B-cell receptor. We challenged the identity of what it is to be a B cell, so it committed suicide.” Maybe in some but probably not in the majority.

Transcript edited for clarity.