Ian W. Flinn, MD, PhD: All right, Ajay, let’s move on to figuring out what to do when someone relapses. First we’ve got to figure out who’s at high risk for this. Are there things that we can use clinically to determine risk of relapse? And then I guess, what constitutes a high-risk patient after they relapse?

Ajay K. Gopal, MD, FACP: Right. So, as we talked a little bit a moment ago, these are the same patients we think about for potentially putting on maintenance therapy—patients who still have a positive PET [positron emission tomography] scan at the end of therapy, partial remission patients. There are emerging data regarding MRD [minimal residual disease]—we don’t know what to do with it. We also use the FLIPI [Follicular Lymphoma International Prognostic Index] score a little bit to predict. There were some data presented at the last ASH [American Society of Hematology] meeting by Carla Casulo, MD, and colleagues from so-called FLASH Study, where they took data from a variety of clinical trials and used that to predict the 24-month progression of disease, and they found some additional factors in addition to the FLIPI score. Unfortunately, it was bad to be male. If you had a poor performance status, that was also not surprisingly a risk factor for early progression, as well as an elevated beta-2 microglobulin.

I think the challenge with all these things is that it doesn’t necessarily tell us what to do next. It makes us worry a little more, and maybe we may scan someone a little more frequently and bring them in a little more often to the clinic, but it doesn’t really guide our therapy.

Regarding what is considered early, that same group, Casulo and colleagues, defined this progression of a disease at 24 months, as there appeared to be a cut point in terms of folks who have a better outcome if you don’t have early progression versus those that have an early outcome. Fortunately, 80% of the people did not relapse within 24 months. So the vast majority of patients—and I really like to tell my patients this, because I think it’s pretty exciting to say, “You have an 80% chance you’re going to do well—and for 20% to say, “We need to get a little more serious about treating your lymphoma.”

Ian W. Flinn, MD, PhD: It’s really a dramatic difference. I mean, those curves are very wide. I mean, it’s impressive that such a simple thing as when you relapsed after front-line therapy is going to predict such a powerful predictor of survival.

So there are these data with using natural killer cells at baseline. I mean, I think it’s interesting, but people with lower natural killer [NK] cell numbers and function are not going to do as well, but I personally haven’t used that. Is that something you’re doing or you think we should be doing?

Ajay K. Gopal, MD, FACP: I think that’s really a research setting. It was noted in the GALLIUM trial, as well as the GOYA trial, that there was some correlation with low NK cells at baseline. And I guess the hypothesis there, when you have an ADCC [antibody-dependent cell-mediated toxicity]—optimized antibody like obinutuzumab, maybe that makes a difference. But I think it’s really a research question at this point.

Nathan H. Fowler, MD: And we’ve seen that therapy probably matters with [regard] to some of these biomarkers. You know there’s been a lot of work looking at the level of tumor macrophages and NK cells and T cells and, interestingly, that the ability to predict outcome often depends on the treatment patients received prior to getting that biopsy. So it’s hard to know: Would these NK cell levels mean anything if you use something other than obinutuzumab: I mean, I agree with you, Ajay, that it’s still a research question. It would be nice to see if these markers hold true across different types of treatment.

Ian W. Flinn, MD, PhD: That’s a really important point. OK, Scott, now, the patient’s relapsed, you know, may be symptomatic or not symptomatic. What’s driving your treatment decisions? Are they the same as when you…the front-line therapy? Are you waiting till the watching and waiting? Are you diving right in? And then…what matters? What factors into what therapy you decide at that point?

Scott Huntington, MD, MPH, MSc: Yeah, that’s a great question. So in terms of timing of progression to treatment, it is very broad. Right? So in clinical trials, they might be doing more frequent scanning than I would typically do in a routine clinical practice. And you can note that for, say, GALLIUM, the PFS [progression-free survival] is very different from the time of next treatment. And so some patients may actually do very well for months, if not years, between an actual progression event based on CT [computed tomography] criteria and clinical progression. And so for me, time to next treatment is actually a nice thing to see in clinical trials. It gives us an idea of what patients…that’s an important measure for quality and what patients are really desiring.

When patients symptomatically progress, that’s when we select a second-line therapy, and it’s really, what did you get in the first-line setting? How long ago did you get it? And how are you doing at this moment in terms of other comorbidities, other factors in their life?

And so typically, if patients have a nice long duration of remission from immunochemotherapy in the front-line setting, I’m often giving another round of therapy in the second line, and in that situation, usually using rituximab first line; perhaps obinutuzumab is the backbone upon relapse. If patients do not have many years of remission following front-line therapy, then I’m typically using a more novel agent. Clinical trials are incredibly important for those patients. We have the intergroup study looking for early progressors, those patients progressing within 2 years of front-line therapy. And so those are the patients that we really need to work hard on to improve the outcomes of follicular lymphoma. It’s 80%, they’re going to be doing well. It’s really that 20%, whether it’s primary progressive follicular or oftentimes a transformation event that’s occurring in those patients.

Ian W. Flinn, MD, PhD: So, Nathan, I thinkI remember having a conversation one time where maybe you don’t wait quite as long on the second-line therapy as the front-line therapy to start treating someone again. Did I remember correctly? And if that’s true, is it for all patients or early relapsers?

Nathan H. Fowler, MD: So some of this—and I think Scott alluded to this a little bit, as well as Ajay—would kind of depend on the time of relapse. There are patients who—if you’re asking if I use GELF [Groupe d’Etude des Lymphomes Folliculaires] criteria to determine whether they should start next line treatment—actually, I don’t do it as much in the second line. As I mentioned earlier on…, there is a percentage of patients that are probably cured with front-line therapy, although a small number.

But if patients progress, especially if they progress in short order, I think that they’re declaring that this disease is a little more troublesome, and I often will treat earlier. I think there is some evidence, especially with things like rituximab, that treating patients at lower bulk leads to higher CR [complete response] rates. And so I generally don’t wait till they get bulky and symptomatic in the relapsed setting, again, with the hope that if the disease is beginning to declare itself, I can change that natural history by intervening a little bit earlier.

Transcript Edited for Clarity