William Wierda, MD, PhD: Any use for chemoimmunotherapy other than FCR [fludarabine, cyclophosphamide, rituximab] for young, fit, patients with mutated IGHV? People are still using BR [bendamustine, rituximab]. They're still using chlorambucil-obinutuzumab. I know what I think the answer to this question is, but I think it's important for people in the community who are seeing these patients to hear. What is the role for chemoimmunotherapy other than the specific example you gave about FCR?

John Burke, MD: I think for me, BR has little role in the upfront setting, if any, and the rationale there is that in the group that we really think benefits from FCR that I’ve described, we do not know that BR achieves the same benefits, so I would not use BR in that group. For everyone else, we have data from the Alliance A041202 study that ibrutinib achieves better progression-free survival. I see less of a role for BR as the initial therapy.

Likewise, chlorambucil-obinutuzumab have lost now in several trials to BTK [Bruton tyrosine kinase] inhibitors and venetoclax-obinutuzumab. Is there a role? If I play the devil's advocate for a minute, I will say that none of those treatments improved survival compared with BR or with obinutuzumab-chlorambucil. One can certainly make an argument that it's acceptable to start either of those chemoimmunotherapy combinations and then bring in the targeted agents later, if for some reason you were to want to do that.

It's just not putting your best foot forward. So for me, there's very little role for chemoimmunotherapy as initial therapy, other than what I described in young, fit patients.

William Wierda, MD, PhD: Dr Allan, a similar situation for you, do you base it on an individualized decision and have the patient’s input into the selection for first-line therapy as your major strategy?

John Allan, MD: Five years ago when ibrutinib was coming out, the decision-making was relatively easy. This conversation with our patients was relatively straightforward. It was: here are the data with chemotherapy, here are the emerging data with this BTK inhibitor, and here are the toxicity differences. When I have that conversation—I like to make decisions with my patients, I don't typically make the decision for them—I try to inform them as best I can.

Depending on how you spin it, you can make any approach attractive. Ultimately, in my belief, these novel therapies are the way to go. I think you spare a lot of toxicity and potential long-term toxicity. This conversation has now become very complicated and long, to where you do talk about—when you have that really low-risk patient who has been presented and may benefit long term from FCR—now we've got good data with ibrutinib, long-term, head-to-head. We also have venetoclax-obinutuzumab, which provides the attractive part of FCR, which is the fixed duration and potentially long-term benefit.

This conversation with my patients has gone from a relatively simpler 20-minute, 30-minute conversation to at least an hour-long conversation when you're talking about an initiation of treatment and all potential options, to inform them of what it is. By the end of it, our patients’ heads are spinning, and they need another week or two to think about it and come back with what's right for them.

I echo all of these issues that we’re facing. The future for us is moving toward these BTK-based and venetoclax, BCL2 inhibitor-based treatments. As time goes on, we're going to find the right patient for which drug, we just don't know what that is yet. We'll find that subgroup, we’ll be able to identify the best patient, and therefore our decision-making will be a little bit clearer and easier with true data behind it.

We'll be a little bit more confident when we say a decision for a fixed duration or continual therapy and things like that. Still, patient factors come into it. I tell them the options, and sometimes they ask what I would do. I give them my opinion, but for the most part, I’ve found our patients with CLL [chronic lymphocytic leukemia] are very educated. They're very informed about all these options. They know what they want coming into it as well.

Transcript Edited for Clarity