Ian Flinn, MD: Let’s turn to the lenalidomide-and-rituximab regimen. This was relatively recently, FDA approved in the United States, and there’s several different data sets. What are your thoughts on this?

Lori A. Leslie, MD: Lenalidomide and rituximab, commonly referred to as R², is recently FDA approved. Though it has been on NCCN [National Comprehensive Cancer Network] Guidelines and used in practice in follicular lymphoma much longer than the recent approval, based on 2 large studies. The MAGNIFY phase III study looked at patients with follicular and marginal zone lymphoma and a few patients with mantle cell lymphoma as well, who all got R² [lenalidomide, rituximab] induction, which was then randomized to R² [lenalidomide, rituximab] maintenance versus R [rituximab] maintenance with a high overall response rate at end of treatment, and a large portion of patients achieving a CR [complete response].

The safety data from that and the efficacy data mostly are from the AUGMENT study, which is a phase III study looking at R² [lenalidomide, rituximab] versus rituximab monotherapy. These patients had to be previously exposed to rituximab but had to be rituximab sensitive, so appropriate for R [rituximab] monotherapy as an option versus MAGNIFY rituximab-refractory, in which patients were allowed. It’s 2 slightly different populations, but all are common patients we see in the relapsed setting.

The primary outcome of AUGMENT was progression-free survival [PFS], showing a benefit of about 39 months in R² [lenalidomide, rituximab] versus 14 in R [rituximab] alone. That made sense to me—just adding an extra agent, your PFS is longer. But I think what was very interesting to me about the AUGMENT study is some of the exploratory secondary end points, including PFS2—how long you respond to the subsequent line of therapy after either R² [lenalidomide, rituximab] or R [rituximab], also favoring R²[lenalidomide, rituximab]. And then in the follicular lymphoma subgroup, there was a secondary end point of overall survival that did favor R²[lenalidomide, rituximab].

Though hypothesis-generating, it makes me wonder that in a patient otherwise appropriate for rituximab monotherapy, adding immunomodulation with lenalidomide or a similar agent earlier in the course of therapy is changing the biology of the disease, the biology of the microenvironment in a way that may change that patient’s story moving forward. So longer term follow-up from those studies will be very important to figure out sequencing.

Ian Flinn, MD: Is it commonly used in Italy, the R² [lenalidomide, rituximab] regimen?

Pier Luigi Zinzani, MD, PhD: We are waiting for the EMA [European Medicines Agency] approval. There are treatments like lenalidomide and then anti-CD20s, like rituximab. It’s very important to use a treatment without a combination of chemotherapy. There is a different toxicity, but psychologically I think it’s very important. The data from AUGMENT are really very interesting.

Ian Flinn, MD: John, we haven’t talked about the RELEVANCE trial in the frontline setting. We had a long discussion there about how to pick frontline, but no one talked about—well, I’m going to give someone R² [lenalidomide, rituximab]. That trial basically showed equivalence in the frontline setting to chemoimmunotherapy. Your group has done a lot of work with lenalidomide in combination with rituximab in mantle cell lymphoma and other diseases. What do you use it in frontline?

John Leonard, MD: In follicular lymphoma occasionally, but it’s not particularly common. I think the challenge is the equivalence. The AUGMENT study has a clear superiority to single-agent rituximab. For the patient, by whatever criteria you would have used in giving single-agent rituximab, you have a reason potentially to give the combination. I think that you know in the up-front setting the issue is, most individuals are getting bendamustine-based treatment, and I think the data are less compelling. That said, it’s certainly a reasonable option, and from the standpoint of giving a patient an option that isn’t chemotherapy, it’s reasonable. But at the end of the day most individuals will either get up-front single-agent rituximab in my practice, or they’ll get a bendamustine-based treatment.

Pier Luigi Zinzani, MD, PhD: The RELEVANCE study was a negative study at the end of the day. But there was a real demonstration that a regimen like R² [lenalidomide, rituximab] present the same results in terms of CR rate, overall response rate, progression-free survival, and overall survival when you compare with the combination of chemoimmunotherapy like CHOP [cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone] plus rituximab, bendamustine plus rituximab, or CVP [cyclophosphamide, vincristine, prednisone] plus rituximab. I think this is very important. This could be the first step for the future, to increase the possibility to use a chemotherapy-free regimen in the treatment of follicular lymphoma.

Ian Flinn, MD: It was technically a negative study published in the New England Journal of Medicine. A lot of individuals interpreted it just as you did, that it’s essentially the same in terms of outcomes that we can measure so far. But it probably hasn’t gotten a lot of uptake in the United States in terms of frontline therapy. Back to guidelines: are you allowed to use this regimen even in the frontline or in relapsed?

John Gribben, MD, DSc: As Pier Luigi said, we’re expecting EMA approval imminently, so it’s not licensed in Europe. Unlike in the United States—where if something is in the NCCN Guidelines, it tends to be used—in Europe, if a drug is not licensed, it you probably will never get reimbursement. Under those circumstances, it’s very, very difficult to use. There have been patients we’ve gotten compassionate use for in their particular circumstances and used it.

Once it is approved, and it’s only going to be approved in the relapsed setting, it’s almost a pity that the company didn’t actually go that little step further and just do some more patients on, because we could have probably gotten a license on equivalence. But because they went for the license on superiority, it wouldn’t succeed. In the relapsed setting, once it’s approved it represents a very attractive, as I already said, chemotherapy-free approach. And we’ve already talked before about the fact that we would still be using single-agent rituximab in that setting. The demonstration of R² [lenalidomide, rituximab]—giving not just the progression-free but even looking from a subset an overall survival advantage—means I expect it would be used and often be replacing rituximab monotherapy in that setting. I think it will even replace lots of chemotherapy regimens in the second-line setting, for individuals looking to move away from a chemotherapy relapse.

Ian Flinn, MD: Lori, do you think this perhaps represents a sort of coalescence of treatment options or choices in the second-line follicular lymphoma? For many years it’s been very hard to be dogmatic about—and it still is, frankly—whether you should do this or do that in that sequence. If you’re using chemoimmunotherapy up front, whatever your favorite chemoimmunotherapy, for the 80% of individuals who aren’t the early progressors, does R² [lenalidomide, rituximab] represent the standard second option for patients? Or is that too far?

Lori A. Leslie, MD: I think it’s a standard option for many patients. It’s increasingly complicated to determine a standard of care in up-front and relapsed settings. It’s hard to say it’s the standard of care in those patients. One good thing about the regimen is you really can give it in all degrees of renal dysfunction, and in relapsed/refractory follicular lymphoma older patients, that’s a common problem too. But I still think we have no idea in terms of what algorithm is ideal. Maybe some big data in the future that can help real-world evidence of sequencing and what to do and how individuals respond or do overall with a longer-term big picture will be helpful to help more define that.

John Leonard, MD: One of the things that we’ve all said is that the majority of our patients are getting bendamustine-based chemotherapy up front. When that patient relapses, you can give single-agent rituximab, you can give lenalidomide-rituximab, or you can give CVP [cyclophosphamide, vincristine, prednisone] or CHOP [cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone]—based treatment. And so there are 1000 different paths patients can follow, but probably the most common path is a relapse several years after bendamustine-based chemotherapy with or without maintenance.

It’s a choice of R² [lenalidomide, rituximab] versus R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone] or O-CHOP [obinutuzumab, cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone]. To me, I think if the patient hasn’t transformed, why would you want to use CHOP [cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone]? For the same reasons we don’t want to use it up front, we don’t want to use it at first relapse. A large fraction of those patients relapsed from bendamustine-based treatment are going to get R² [lenalidomide, rituximab] second line, at least with what we currently have available.

Transcript Edited for Clarity