DR NASTOUPIL: We think that the microenvironment of follicular lymphoma is crucially important. And, if you can augment that, you can have improved efficacy. And so that was the whole notion behind lenalidomide/rituximab. Can you enhance the NK cells, the T cells, direct them at the follicular lymphoma cells? And based on our Phase II studies, the response rates were quite high. Complete response rate was over 85%, and it appeared to be durable. And there was a multicenter study that showed very similar results.

There’s a lot of heterogeneity in terms of the dosing strategies with lenalidomide and rituximab in terms of how many times you dose with rituximab. What is the duration of therapy? And there’s also some differences in the baseline characteristics, in that a third of our patients in our Phase II study were technically of low tumor burden and may have been suited for observation.

So the RELEVANCE study was a large international, multicenter Phase III study where to be eligible all patients had to have been of high tumor burden, generally based on the GELF criteria. So these are patients that you typically think of needing chemoimmunotherapy in the front-line setting. And so it was a head-to-head comparison of either R-CHOP, BR or R-CVP versus lenalidomide and rituximab.

And the dosing strategy was essentially more intensive lenalidomide until you achieved a complete response, which was usually assessed around six months. And then you could then transition to a maintenance lenalidomide, which was a lower dose, for a duration of 18 months of lenalidomide. And then it was up to 30 months of rituximab therapy, considering 24 months of maintenance, like you would do after front-line chemoimmunotherapy.

So the primary endpoint is progression-free survival. And as you might imagine, we would expect that to be long. So the study’s still ongoing. The enrollment was completed some time ago. We’re still waiting to hear the results. If we don’t hear the results for some time, that’s generally good news in our minds, because that means that the lenalidomide/rituximab is probably just as good — it may not be inferior. There clearly are early stopping rules. We have heard nothing in terms of efficacy at this point. We still have patients coming in for follow-up routinely. And so I do think that we’re all anxiously awaiting the results.

Kind of one of the questions you asked earlier, which I think is still a very important question, how do we choose therapy? How do we sequence therapy? Which patients would you prefer to use lenalidomide/rituximab in the front-line setting, or would you rather hold that to the relapsed setting where they’re starting to fail chemotherapy? I think those are clearly unanswered questions.

I hope from these large studies we will have correlatives that will help us maybe predict or risk stratify patients better than we currently do, because I think that’s what we’re lacking right now in follicular lymphoma. We don’t know who’s going to be that early progresser, who’s chemosensitive, who is not.

DR LOVE: How about the thought if the study ends up showing equivalent efficacy, you would choose R² because of tolerability?

DR NASTOUPIL: So that’s a great question. So I used to at least pitch to patients that this was a non-chemotherapy approach — it’s going to be well-tolerated. So if you look closely, it’s not — the head-to-head comparison will answer the question which is better tolerated. But lenalidomide and rituximab have pretty high incidence of fatigue, myalgias, fever and cytopenias. So it’s not infrequent to have a Grade 3/4 neutropenia.

What’s striking about it, at least in our experience, is the side-effect intensity seems to be greater in the first few months and then tends to stabilize or improve over time. And it’s unclear if patients become accustomed to the side-effect profile and they don’t report it or don’t seem to be bothered by it or if it really does get easier over time. I don't know the answer to that.

But the first 2 months with lenalidomide and rituximab, it’s not a free lunch. So we have quite a bit of fever. We do see rashes. We do see myalgias. Neutropenia is not infrequent. Fortunately, despite the Grade 3/4 neutropenias, we’ve not seen much in the way of infections. So I do think it’s a different safety profile than what we generally see with chemotherapy-based approaches, but it does have side effects and unique side effects that warrant discussing with patients in management.

What I don’t know is, if you have very proliferative tumors or high tumor burden, do you need chemotherapy in that setting versus lenalidomide and rituximab? We generally do see slower time to response with the immune therapy approaches than what we generally see with chemotherapy. And so that may be a question that’s answered with this front-line study. If you have a patient who comes in and they’re very high tumor burden, do you need chemotherapy to stabilize them faster? I don't know the answer to that.