Transcript:William G. Wierda, MD, PhD: I wonder if we could talk a little bit about idelalisib and PI3 kinase inhibitors. Rick, you have a lot of experience with idelalisib. I wonder if you could give us your thoughts on where you think it fits in, how we manage patients with CLL, and some of the things that we need to think about when we have patients that we're starting on idelalisib, and monitoring them on idelalisib.

Richard R. Furman, MD: Idelalisib is another B-cell receptor antagonist that has shown incredible efficacy in the treating of patients with CLL. And one of the things that's most important with these B-cell receptors, and so what I'm saying applies to ibrutinib as well as idelalisib, is the ability of these agents to work regardless of prognostic markers. So, we're really talking about the 17p deleted patients still having a potentially good outcome with idelalisib. So I think these agents really are dramatic for their effect.

Now, with regard to idelalisib and the initiation of its therapy, we do see, as we talked about earlier, diarrhea, bruising, atrial fibrillation, and hypertension with ibrutinib. With idelalisib, we do see an early diarrhea that's often a mild diarrhea, but we do see very late inflammatory colitis, which is very important for physicians to be aware of, because at least for the late diarrhea you certainly want to intervene quickly. Whereas with the early diarrhea, often that's one that can be controlled with anti-motility agents.

The other thing that's important to keep in mind is the transaminitis. So what's really important is the transaminitis always seems to occur between week 4 and 12. And if you make it through week 12 without the transaminitis, you're going to be okay. And the transaminitis is never associated with a hyperbilirubinemia. So, if a patient does have hyperbilirubinemia, you really do need to seek out other potential causes of transaminitis and not just attribute it to the idelalisib. And likewise, if it occurs later in the disease, that is something that should also prompt investigation. So, we've had a couple of late episodes of transaminitis in the studies, but those were often patients who developed Richter's that was involving the liver or something along those lines. Other than that, there is a potential propensity for an increased risk for autoimmunity. But the drug itself is otherwise really well tolerated.

William G. Wierda, MD, PhD: The pivotal trial that I believe you were an author on was in combination with rituximab. Is there a substantial amount of data with monotherapy idelalisib or is it predominantly used in combination?

Richard R. Furman, MD: There are substantial data with monotherapy, mostly from the very large phase I/II study that was done early on. Most of the subsequent phase III data has always been in combination. And an intriguing finding about idelalisib in combination with rituximab in treatment-naive patients, and this was a study that was led by Susan O'Brien and Steve Coutre, actually suggested that there might be more diarrhea with the anti-CD20 combination. So there's still a lot we need to learn about mitigating the side effects of these new agents.

William G. Wierda, MD, PhD: There's a late-breaking abstract that Andy Zelenetz is reporting at this meeting with a combination of bendamustine, rituximab, and idelalisib. Maybe you could comment a little bit about that, and particularly in regard to the toxicities that were seen with that combination as opposed to with the pivotal trial.

Richard R. Furman, MD: It's interesting. We did have a few very bad outcomes early on before we learned a little bit about the combination of bendamustine with idelalisib. And it's unclear to me whether or not the question of allopurinol plus bendamustine also factored in. So, we saw a great deal of rash and even desquamating rash in some of the early combinations. And one of the things I like about these data is it seems that if you are careful and avoid the allopurinol, you really do mitigate a lot of those adverse effects.

Now the data are actually intriguing, because if you really can maximally deplete the clone very quickly, it really has the potential for a very good long-term outcome. And so, I think that it's a no brainer that adding the idelalisib to the chemotherapy is going to improve the effects of the chemotherapy. But the interesting aspect would be whether or not the improvement is such that we could really actually use that to shorten the duration of therapy of the BCR antagonist.

Alessandra Ferrajoli, MD: Do you think the difference in the frequency and intensity of diarrhea between the treatment-naive patient and the relapsed patient will guide where this agent is used more?

Richard R. Furman, MD: I think there are going to be a lot of things regarding the guidance of where these agents are. One of the things that I think is always important to keep in mind is that the FDA-approved indications are often very specific. But these FDA-approved indications aren't recommendations, and we still need to do data-driven medicine that's best for our patients. I certainly use idelalisib, not just in the patients that we studied in the pivotal study, but really in anyone in an attempt to avoid chemotherapy. And I think that one of the important questions is when to actually sequence them and when to choose one or the other. And those are data that we really just don't know. And I think looking at the toxicity profiles would be the best way to assess which one to choose.

Transcript Edited for Clarity