Treatment After Progression in Follicular Lymphoma

John M. Burke, MD:A patient’s prior therapy history absolutely has a major impact on what treatment choice is made in the relapsed setting. It’s interesting to note that many patients with follicular lymphoma never need treatment in relapsed disease. That is even though we think of follicular lymphoma as perhaps not being a curable disease; many patients receive only 1 line of therapy, perhaps half. Perhaps only a half of the patients ever even need second-line therapy or thereabouts—even less need third-line therapy, maybe a third, depending on what study you look at. That’s good news for patients that they don’t necessarily need additional lines of therapy, even though we think of this as not being a curable disease in most patients.

Their prior therapy has a major impact on what therapy you’re going to choose for second- or third-line therapy or beyond. For example, someone who’s had CHOP [cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone] chemotherapy as their backbone we know is not going to get CHOP as the next line of therapy because there’s only so much doxorubicin the heart can take. I think also another factor is if they received lenalidomide and rituximab as their first line of therapy, well, maybe incorporation of chemotherapy as the second line of therapy might be a good strategy—something the patient hasn’t seen before. It is important when you’re choosing a line of therapy for relapsed disease to look at what the patient’s been treated with before and how they did with it, how they tolerated it, and what efficacy that treatment had. It’s possible to repeat bendamustine. So, if a patient received bendamustine many years ago and had a long remission, that is a choice that could be repeated.

What are the options? I think chemoimmunotherapy remains an option and oftentimes, the choice that’s made is what drug did they not get before that we could try again. For example, if they received R-CHOP [rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone] before, you could use bendamustine and rituximab or bendamustine and obinutuzumab in the relapsed situation. That would be 1 major option. Similarly, if they received bendamustine and obinutuzumab before, R-CHOP could be a reasonable second-line option.

Another category is lenalidomide and rituximab, and that is now an FDA-approved indication for lenalidomide in patients with relapsed follicular lymphoma. A third category of drugs is the PI3 [phosphoinositide 3]-kinase inhibitors. There are 3 of those on the market for patients with relapsed follicular lymphoma—idelalisib, duvelisib, and copanlisib. Also, radioimmunotherapy is often a forgotten underappreciated modality that can be used in patients with relapsed follicular lymphoma. So I would say those are the main categories of agents that can be used for patients and again can be chosen on an individual basis, based on a lot of factors including what they received before, functional status, comorbidities, personal preference, and so forth.

Should their initial duration of response affect the choice of second-line therapy or third-line therapy and if so, how? If, for example, a patient has the median 10-year remission in response to chemoimmunotherapy plus maintenance, then that’s a good long remission. But does that mean that the patient should definitely undergo chemoimmunotherapy in the second-line setting? It doesn’t have to. Certainly, many patients who have long remissions, while that might lead you to think that chemotherapy is a good modality for the cancer, they’re also 10 years, 15 years older than they were when they underwent chemotherapy the first time around.

Certainly, using a nonchemotherapy combination, such as lenalidomide and rituximab in that situation would be very reasonable. So it’s certainly not the only factor. On the other hand, if the patient has a very short duration of remission—let’s say they receive R-CHOP and they relapse within a couple of months or within a year of completing their R-CHOP—you certainly can wonder whether chemotherapy is the right choice in that patient and whether you want to go with that or use a novel strategy. That’s a patient who has an unfavorable prognosis in whom you’re going to be thinking about alternative mechanisms of action—you’re going to be thinking about stem cell transplant. The duration of response can factor into your decision, but it’s certainly not the only factor.

I think there’s an ongoing SWOG trial now that’s addressing that very question as to what the best therapy is for a patient who relapses within 2 years of their initial treatment. That’s a trial that has 3 arms to it, and patients can receive either chemoimmunotherapy that they didn’t receive before or lenalidomide plus an anti-CD20 antibody, obinutuzumab, or a PI3-kinase inhibitor plus an anti-CD20 antibody. I think the design of that trial tells us that we don’t know what the best treatment is for someone who relapses within 24 months of their initial therapy. Is it more chemotherapy? Is it a targeted drug with a PI3-kinase inhibitor, or is it the immunomodulatory drug—lenalidomide in combination with CD20? It’s a great question and trial with an unknown answer right now.

Transcript edited for clarity.