Transcript:William G. Wierda, MD, PhD: Moving on to frontline therapies for patients who need treating, let's talk a little bit first about chemoimmunotherapy. We have a lot of chemoimmunotherapy data. There's a lot of experience with chemoimmunotherapy. It's a highly effective treatment. I'd like to know from Dr. O'Brien what your thoughts are on first-line chemoimmunotherapy. What are the relevant regimens? Who are they appropriate for?

Susan M. O’Brien, MD: The more myelosuppressive regimens would be FCR and BR. And we do have the German randomized trial data that suggest clearly that FCR produces a better progression-free survival. But there are some costs associated with that in that it also produces more myelosuppression and infections. So, I think there's been a tendency in older patients, where you think that they can still take that kind of a regimen, perhaps you give them BR because there is less myelosuppression. If you have really older patients, I think you sometimes go to chlorambucil-based regimens.

Historically, it was just single-agent. But now we have plenty of data with antibodies clearly showing that, in pretty much any lymphoid-disease chemotherapy, that when you add an antibody, you do better. So that's true when you add rituximab, obinutuzumab, or ofatumumab to chlorambucil. So, the common theme is that our standard frontline regimens are chemotherapy-based, but with the addition of an antibody. And the question is, is that going to change with some of the new agents that we're going to talk about? But I think people make decisions, again, similar to the first question you asked me, based on age, comorbidity, how myelosuppressive you think that the patient can be brought down to.

We all know that if a 66-year-old gets pneumonia and winds up hospitalized, versus a 50-year-old, they're probably going to be a lot more deconditioned. You may have to delay the next cycle of chemotherapy, etc, etc. So the point being that you have to take all that into consideration when you choose your regimen. But up until now, again, this is changing with the B-cell receptor inhibitors. I think the biggest complication of our therapies has been the risk for myelosuppression and infection—with any of those regimens really—just less so perhaps with chlorambucil. But they're all chemotherapy, and they're all myelosuppressive.

Alessandra Ferrajoli, MD: Susan, in this setting you, do you want to go back to prognostic factors and discuss immunoglobulin heavy-chain mutation status? What kind of weight does it have on your decision for frontline?

Susan M. O’Brien, MD: This is something that's obviously getting discussed a lot in advisory boards that we've all been to. We know, based on the randomized trial of ibrutinib versus chlorambucil, that in the market, we have better outcomes with ibrutinib. Perhaps it’s not surprising to anyone that this will probably soon get an FDA indication. Now the question really is, how broad or narrow will the label be? Because the trial eligibility was only over age 65. But sometimes the FDA does give broader eligibility approval than just the trial eligibility. So that remains to be seen.

But certainly, at least in older patients, I think that's going to be ibrutinib. I'm not sure the prognostic factors matter much in the sense of, again, we're not worried about 10- and 20-year outcomes perhaps in a 75-year-old. Where it is going to matter is if they have a very broad label—and even though the comparator in that trial was chlorambucil, which I think any of us would use in a fit 60-year-old patient. Then the question becomes, well, are you going to give up FCR/BR and go straight to ibrutinib because it's easier? And that's a little more controversial, I think. First of all, there are two intergroup trials that are looking at this, comparing BR to an ibrutinib-based regimen or FCR. And I believe the BR trial, in fact, has just reached accrual. But it's going to take a while for those trials to read out.

So the point is, and I think this is what Alessandra was getting to is, let's say tomorrow ibrutinib had a full approval, no age restriction. Is there any subset where I would not want to use it? Yes, there is. And that's based on data from the Germans, from the Italians, and the FCR data clearly showing that there are long-term plateaus on the progression-free survival curve with FCR. And we're talking about the MD Anderson data, which has the longest follow-up: 10 to 14 years. And when the analysis was done, what's clear is that the vast majority of those patients are mutated and, in particular, have trisomy 12.

So are those people cured? I personally think they are. But let's say for a minute they're not. Well, they got six months of chemotherapy, and 12 years later they still don't have any disease. And they're not on a pill that they have to take the rest of their life. So this is becoming, I think, a very controversial topic. On the other hand, this is going to make for long discussions with the patient. And I think some patients, even if you give them that data, are going to want to select chemotherapy because they want six months of therapy and then to be done. Or they're going to say, ‘I just don't want chemotherapy.’ And then they're going to say, ‘I want ibrutinib.’ So this is, I think, an area where we're going to be struggling a bit.

Transcript Edited for Clarity