Transcript:William G. Wierda, MD, PhD: I wonder, Rick, if you can comment on what your treatment objectives are with managing patients with the small molecular inhibitors, particularly ibrutinib in this case. What do you look for? What do you want to achieve?

Richard R. Furman, MD: Well, right now in the absence of data identifying that it's safe to discontinue these agents, my goal is just progression-free survival. And one of the things that I think is very interesting, and very important to keep in mind when we discuss the data surrounding BCR antagonists, is this phenomenon of MRD-negative partial responses. We're collecting a lot of patients who have lymph nodes 2 to 2.5 cm in size radiographically. But their MRD status in the blood and bone marrow are negative. And so, ultimately, these would probably be CRs, but the data for how well they're going to do is going to show up in PFS.

Now, the important question will be whether or not these are patients who need to be on B-cell receptor antagonists forever, or whether or not discontinuing them at some point is actually feasible. And we do have some trials that are currently being undertaken, Peter Hillmen in the United Kingdom. We'll try to address that using MRD on three successive occasions over six months as the endpoint to deciding who to then randomize and discontinue versus continuing therapy.

So, for now, the ultimate endpoint always is going to be progression-free survival and improvement of side effects. And until we have more data, it's continuing the therapy indefinitely. One of the fortunate aspects that we see with these B-cell receptor antagonists is that we're not making our patients into excellent dysgammaglobulinemia patients; they're not developing the infections. They're not suffering from a shutdown of B-cell production. And that's a very interesting feature, arguing for differences between kinase dead mutants versus the absence of the structural protein. And these data come from the earlier studies with 1102 where we actually see fewer infections in patients the longer they're on ibrutinib. As we get more and more of those data, I think the comfort level with continuing the therapies long-term will improve.

William G. Wierda, MD, PhD: And what about hypogammaglobulinemia? Are patients receiving replacement for hypogammaglobulinemia, and is that improving with ibrutinib therapy?

Richard R. Furman, MD: So the hypogammaglobulinemia is really part of CLL. We talk about maybe 75% to 80% of CLL patients having hypogammaglobulinemia. The thing that I find very intriguing, and I really have to caution people on just using IVIG replacement therapy for hypogammaglobulinemic patients, is that I have some patients with IgG levels of 50 and 75 who have never had an infection and they're fine. And it intrigues me that patients with immunoglobulin levels of 500 can suffer tremendously from repeated infections. So I do use IVIG therapy based upon the clinical criteria that were published back in the 70s identifying life-threatening infections or recurrent symptomatic infections as the only indication, regardless of the immunoglobulin level.

Now, getting back to your question: what's interesting is we do see an increase in IgA levels, or we have seen this so far in the patients from the phase II ibrutinib data. And of course IgA, even though it's not that high in the blood, is the most turned over immunoglobulin since most of it gets secreted. And whether or not that little uptick that we see with IgA is one of the early signs of repair of the immune system remains to be seen.

William G. Wierda, MD, PhD: How about secretory IgA? Has anybody looked at secretory IgA?

Richard R. Furman, MD: I'm not aware of anyone looking at that yet.

William G. Wierda, MD, PhD: Dr. Ma, what about long-term side effects of ibrutinib patients? You'd spoke or mentioned about an increased risk for bleeding, some atrial fibrillation that has been seen. We're seeing patients now that have been on ibrutinib for several years. Are there things that we're worried about now long term, in terms of toxicity, other than the ones that you've mentioned already?

Shuo Ma, MD, PhD: It's interesting. So if you look at the three-year follow up on the phase II study of single-agent ibrutinib in relapsed refractory CLL, most of the concern, for example, for cytopenia and infection has declined over time, whereas the other risks, such as atrial fibrillation and bleeding, did not seem to increase over time. Those seem to have stayed steady. So I didn't see any increasing of any adverse events over time on any of those issues I mentioned before.

Alessandra Ferrajoli, MD: The frontline study on the early lead that is going to be presented of ibrutinib versus chlorambucil did mention that, especially in an elderly population, there tends to be an increase in blood pressure level. And, therefore (it's usually a grade 2 or 3), even if it's not to the point that you need to discontinue the ibrutinib therapy, you need to readjust, at times, your blood pressure medication. Some of the patients on ibrutinib tend to experience some weight gain, and that also needs to be seen in the context of making sure that their medications are properly adjusted.

Richard R. Furman, MD: I think the importance of talking about the long-term effects of ibrutinib are very important from the perspective that it looks like these are going to be therapies patients are going to be on long term. And in terms of the toxicities, we do see the bruising and we do see the bleeding almost immediately upon initiation of therapy. Fortunately, the diarrhea can often be mitigated by administering the pill at night before bedtime and not eating afterwards, or often it just resolves on its own after a couple of months of therapy.

What's interesting is we do see the emergence of atrial fibrillation, and it's still unclear whether or not there's a plateau. So whether or not this is something that's an early phenomenon: that once you're through a year of therapy you're going to not be at risk, or whether or not the risk will continually increase.

The bleeding does look like it actually gets better later on, and it could be because of the changes in the platelet count in terms of TEC kinase in BTK or because the improvement in the marrow allows for increased megakaryocyte production and larger platelets that can sort of compensate. Then it’s the emergence of hypertension. So, the later effects are intriguing, and we really don't have a mechanism, and it's going to be interesting to see what else might come down the road.

Transcript Edited for Clarity