Maintenance Therapy and MRD Testing in Follicular Lymphoma
Panelists: Ian W. Flinn, MD, PhD, Sarah Cannon Research Institute; Nathan H. Fowler, MD, The University of Texas MD Anderson Cancer Center; Ajay K. Gopal, MD, FACP, Seattle Cancer Care Alliance; Scott Huntington, MD, MPH, MSc, Yale University School of Medicine
Ian W. Flinn, MD, PhD: Talk about maintenance therapy, right? I mean, I feel like for like a decade, we—or more, maybe—most of my patients chose to have maintenance therapy because of the promise of an improved progression-free survival ultimately translating into overall survival, and that really hasn’t happened. The GALLIUM study improves progression-free survival PFS, but it’s with maintenance, and I’m sort of getting away from rituximab maintenance in that same patient population. So, let’s talk about your approach to maintenance overall, and then, if you were to use maintenance, does that affect how you’d start the chemotherapy? Does it, and do we now have—we just talk about—rituximab subcutaneous? It’s certainly more convenient. A lot of decisions and factors might affect the front-line therapy. Ajay, what? Lead us off here.
Ajay K. Gopal, MD, FACP: I mean, on the topic of maintenance, exactly—the pendulum has swung back and forth, I think, as we have not seen overall survival improvements. And there are 3 large trials. There’s longer follow-up with the PRIMA trial, significantly improved progression-free survival. There’s the BRIGHT trial after bendamustine—improves progression-free survival. And then the MAINTAIN trial shows that if you give 4 years of maintenance versus 2 years, you get more PFS. But we’ve all learned the hard way of chronic B-cell depletion, low-grade infections, sometimes significant infections, and sometimes patients requiring IVIG [intravenous immunoglobulin], and without a translation into improved overall survival. In general, I don’t give maintenance. There might be rare patients that have a lesion that’s in a critical place and I don’t want to have to scan them every 2 months to make sure things aren’t progressing. But in general, I don’t give maintenance for that reason.
In addition, with a different setting, the RESORT trial did not show that you got more mileage out of maintenance versus retreat. So with all those points, I generally don’t give maintenance.
Ian W. Flinn, MD, PhD: How about this: You know there’s the data set that shows that in patients with maintenance after chemo, that in 10 years, a substantial number of patients—I mean, it’s a large amount of patients—don’t require therapy; they haven’t progressed or needed therapy. Does that factor into your decisions at all or?
Ajay K. Gopal, MD, FACP: Well, I generally do sit down with patients and say, “Here are our options: We can stop; we can do maintenance; we can actually give ibritumomab tiuxetan if we want to.” That’s approved, as well, for consolidation—a radioimmunoconjugate.
I present the pros and cons, but I think most of my patients prefer to not have to keep coming in for treatment.
Ian W. Flinn, MD, PhD: Nathan, how do you think about it?
Nathan H. Fowler, MD: So, I do have also an issue with the lack of an overall survival benefit suggesting that in the long term, and most of these patients are going to, hopefully, live a long, long, long time. Rituximab is beneficial, but the timing—it may not really matter. And we now have long-term follow-up of chemotherapy backbone trials at The University of Texas MD Anderson Cancer Center, some of these 20, 25 years out. And there is this portion of patients—although it’s a minority—about 30% of patients never relapse following front-line therapy. At least today I don’t know who those patients are, and so it’s back to this argument we have about a lot of diseases.
Do you expose the majority to potentially more toxicity to benefit a minority when you may be able to salvage that minority with subsequent lines of therapy? So I tend to individualize this, as Ajay mentioned, in patients maybe who are very high risk for relapse. Patients who present with very bulky disease where PFS, to me, may translate into a survival benefit. Again, this is somewhat extrapolation, but for patients who are really high risk for relapse, patients who are only in a PR [partial response], I’ll add maintenance.
And the cohort that I think maybe we don’t think about enough is elderly patients who may only tolerate 1 line of chemotherapy backbone—so patients that are in their 80s, where PFS really matters, right? And so if I can get them a 10-year PFS, this is great, because I don’t know what their performance status is going to be like in 10 years. And so I tend to kind of edge these patients towards consideration of maintenance in a CR [complete response].
Ian W. Flinn, MD, PhD: Someone mentioned earlier the concern about combining perhaps obinutuzumab with bendamustine and some of the infectious complications and other complications. We know from the BRIGHT trial—and it wasn’t really known—there wasn’t a…big data set of rituximab used after a bendamustine-based approach. We knew it from R-CHOP [rituximab, cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate (Oncovin), and prednisone] and those and that type of chemotherapy. But Brad Kahl, MD, presented data about a year ago suggesting from the BRIGHT Trial that there really didn’t seem like rituximab used after bendamustine seemed to be fairly safe. If you’re worried about that, maybe you take some comfort in this.
I guess the other question that comes up—and you know that sounds like we’re not all using a lot of maintenance rituximab now—but in the data from the STILL group, looking at 4 versus 2 years, if you were to do it, would you use 2 years, would you use 4 years?
Scott Huntington, MD, MPH, MSc: Yeah, I mean, so I’m in agreement that for the majority of patients, we talk about maintenance, but I’m not really an advocate as much for the maintenance unless, like in the obinutuzumab trial, I’m worried about transformation and some indolent component. Perhaps maintenance could help in that subselect group.
In terms of the data on duration of maintenance, I think follicular lymphoma is pretty well defined, that 2 years probably has the best safety efficacy profile. The SAC data 2 versus 5—there was really no change in PFS. There were increased toxicity, infectious complications. So, at least with follicular lymphoma, 2 years, if we’re going to do maintenance, I think is reasonable. That’s in contrast to mantle cell lymphoma. There are some data for 3 years—even indefinite, perhaps—in elderly patients treated with R-CHOP following maintenance. But I think if you’re going to do anti-CD20 in follicular lymphoma, 2 years is probably the time to stop.
Ian W. Flinn, MD, PhD: I want to go back to an earlier discussion about MRD testing—so, data from the GALLIUM trial, MRD testing, association with improvement in progression-free survival. But is this ready for prime time? Are you doing it outside of clinical trial?
Nathan H. Fowler, MD: No.
Ian W. Flinn, MD, PhD: If you were, how would you do It?
Nathan H. Fowler, MD: So, for us, the short answer is no. I mean, we’ve looked at several different ways to look at MRD, and Mary Ann Anderson, MBBS, was I think one of the first folks to look at BCL2 negativity following fludarabine-based regimens. And there was a suggestion that patients that begin BCL2 negative had longer progression-free survival. Unfortunately, there are also patients who will not achieve MRD and have great long-term outcomes, as well as patients who have a return of BCL2 and don’t relapse. So I think at least with that data, I don’t typically use this in clinical practice. I think BCL2 is probably the most common way we look at MRD in follicular lymphoma. And for me, because it doesn’t really change what I do in clinical practice, I hate to say it, but I don’t check it in the majority of patients outside of a clinical trial.
I think there are some really neat data coming out looking at circulating tumor DNA—looking at very low levels of abnormal clones in the peripheral blood for follicular lymphoma, coming from Stanford and other places—that maybe will have a better MRD marker in the future, but at least today, I don’t think that that’s really common to check.
Ian W. Flinn, MD, PhD: And even if you did, I mean, what you would do with the data in terms of, are you going to give an extra cycle with chemotherapy?I mean, maybe that is OK. Maybe you would use a maintenance approach, but we don’t know today that that’s the right approach, right?
Ajay K. Gopal, MD, FACP:Yeah, I would agree. I think we don’t to do with the data. We need to have an actionable marker that it’s going to change our practice.
Ian W. Flinn, MD, PhD: I like that term—“actual marker.”