Anas Younes, MD: Once you have failed R-CHOP, bendamustine/idelalisib—which is approved—and lenalidomide plus or minus rituximab, there are really no other agents on record that you can use outside of clinical trials. There are multiple agents being used in the context of clinical trials, like antibody drug conjugates; the BCL-2 inhibitor, venetoclax; the BTK inhibitor, ibrutinib, and other BTK inhibitors; and immuno-oncology drugs, like checkpoint inhibitors alone or in combination. But all these are in the context of clinical trials outside of the major 4 treatment strategies that most people use first.

Bruce Cheson, MD: Since almost all patients with follicular lymphoma eventually relapse, they require a series of subsequent treatment options. What those options are depends on the initial therapy. If you received R-CHOP up front, you can’t get that again, and the next regimen might be R-bendamustine or something else. In contrast, if you got BR up front, we really don’t have data on the efficacy of R-CHOP in that setting—but it is a potential option. After that, what do you do? What do you do for third-line and subsequent lines of therapy? There are some drugs that are approved by the FDA in this context. There is Y-90-ibritumomab tiuxetan, or Zevalin, a radioimmunotherapy that was popular 10 years ago, but is virtually unused anymore in the United States for a variety of reasons.

More recently, there has been idelalisib, the PI3 kinase inhibitor that is a highly effective pill. You take 1 pill twice a day. The response rate is around 60%, and the median progression-free survival is almost a year. That’s cool. But if a patient is not eligible to receive that drug, if there are reimbursement issues, or if they’ve taken it and they relapse, you need something else. What do you do? There’s really nothing that is generally used. People have their own preferences. One possibility is rituximab and lenalidomide, the R2 regimen, which we first developed over a decade ago. We published data in relapsed follicular lymphoma of R2 versus lenalidomide alone and showed that that response rate was much higher. The progression-free survival was about twice as long with R2 compared with lenalidomide alone. So, it is a treatment option. Our study was in relapsed patients. Other studies are being conducted in refractory patients.

The critical therapy, the most important therapy for patients in this setting, is a clinical trial, because without clinical trials, we’re not going to be able to develop these new drugs and bring them to the market so that our patients can benefit. So, once you get out to that point in time, there really isn’t a standard beyond the few drugs that I mentioned.

Anas Younes, MD: Ideally, you would want to use these targeted agents more than chemotherapy agents in patients who may not be fit for intensive chemotherapy. But some of these agents are not without side effects. The current label for idelalisib is for the double-refractory setting, but you can use it after at least 2 lines of therapy regardless of if you’re double-refractory. That’s where I think idelalisib comes to mind initially, when you fail 2 prior regimens. But in elderly patients who could not tolerate chemotherapy, like an 80-something-year-old person who exhausted options and cannot tolerate chemotherapy—you give them rituximab and then they failed rituximab—I think idelalisib comes to mind as a good agent. It can induce response rate in about 54% or 55% of patients that could last more than a year. So, I think that would be an option.

Transcript Edited for Clarity