Ian W. Flinn, MD, PhD: I think the choice of treatment also is affected by the first-line therapy, and personally, I’m reluctant to go back to bendamustine-based therapy if I’ve given them front line. I just worry about the stem cell toxicity. I’m pretty sure it’s a stem cell poison. So, would you switch? Is that a place where you would go to R-CHOP [rituximab (Rituxan) with cyclophosphamide, doxorubicin, vincristine, and prednisone]? Or I guess we’re going to talk about R-squared and other treatment options in second line, but what’s your thinking with that? And can you also talk about transplant? I mean, are you transplanting anybody these days?

Ajay K. Gopal, MD, FACP: Yeah. So, those are all very good questions. So, really, I agree with you. I am concerned about the cumulative marrow toxicity of bendamustine. I guess in theory, if somebody had had a very long remission to a bendamustine/rituximab-based regimen, maybe I would consider it. But it would be really quite the exception, would apply the same criteria. If there’s any concern for transformation, I would typically go with an R-CHOP—based approach.

And to addressing the question of transplant—we’ll talk about R-squared, it sounds, like in a moment—I usually think about that for those who, probably not further than third line, and you have to be, obviously, a relatively fit transplant candidate, and typically those…are the patients who relapse early.

So if I have a young patient who relapses early, I sit down and I say, “OK, here are some options. We probably just don’t want to give you chemotherapy and leave you alone, or you can do something novel. Or if we’re going to give you chemoimmunotherapy, we’re going to use that as a bridge to something else.” And, when you think about autotransplant, there are old data obviously showing a survival advantage with autotransplant in the prerituximab era.

But there was a more recent analysis from the German group retrospective with all the caveats of comparing nontransplanted versus transplanted patients. But they tried to compare patients that…were transplant candidates, and they had chemo-sensitive disease. And they looked at those who had responding disease to their salvage chemotherapy after early progression, and then they compared those that went to transplant versus those that didn’t, again with caveats of retrospective data. But there was a 20% overall survival benefit to autotransplant in that population. So it’s not randomized phase III data, but it is a consideration for folks who want to be aggressive.

Ian W. Flinn, MD, PhD: OK. How about allotransplant?

Ajay K. Gopal, MD, FACP: Yeah, I think it’s probably a little early for allo at that point in the disease course. That’s usually reserved for folks who we are really not able to control with novel therapies or auto. I think that the risk of morbidity and mortality with allo—even though we’re a lot better than we used to be, it’s still pretty high.

Ian W. Flinn, MD, PhD: We’re sort of getting into the era of CAR Ts [chimeric antigen receptor T cells] and other things, and so it’s unclear how that’s going to change that, but it’s certainly an interesting question. OK, Nathan, so you’ve gotten someone into a second remission. Unfortunately, that patient’s relapsed, and now we’re talking third-line therapy. I think that maybe you can even—maybe it’s simpler, maybe it’s more complex, the treatment decisions.

Nathan H. Fowler, MD: So, it’s interesting. I think the simple cases are the ones where, unfortunately, things have not gone as well as we liked. These are patients that are Rituxan refractory, patients that are progressing in short order after their second line of therapy. They’re now looking for a novel agent. I think PI3-kinase inhibitors are very effective in this setting. Patients that again are relapsing early, as I mentioned—or sorry, as Ajay mentioned—I would be thinking about sending to autotransplant or something. Unfortunately, in the third line, if patients have progressed in short order, none of the available agents are probably going to lead to a long-term remission. So I guess what I’m getting at is in third line, I’m already thinking about fourth line, because whatever I’m doing is probably only going to hold the disease for an average of around a year.

Now, that’s very different than a patient who’s in the third line who has had several year remissions with each prior line. Then it’s a little more complex, and I’m looking at the performance status. Should we just give them obinutuzumab as a single agent or radiate a solitary node if we can’t do something else? Again, I think there are lots of options for patients who have done well, and the kind of irony is that for patients that have not done as well, it’s somewhat limited, and we’re going after novel treatment or clinical trial, usually, in that setting.

Transcript Edited for Clarity