Treatment Options for Follicular Lymphoma: Second Line and Beyond

Alexey Danilov, MD, PhD: What do you use for second-line therapy and beyond second line for patients with follicular lymphoma?

Tycel Jovelle Phillips, MD: In the second line, for the most part, a lot depends on duration of first remission and what we use in the frontline setting. We can reuse bendamustine and rituximab, even though a lot of people are hesitant to reuse that agent out of concern for what continual exposure of bendamustine will potentially still do. Specifically, to the lymphoid patient population. Obviously, it does have risks. There’s a high risk of infection, T-cell depletion, lymphoid depletion in general, and more prolonged times of recovery compared with what we see with R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] or R-CVP [rituximab, cyclophosphamide, vincristine, prednisone].

R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone], if it’s used up front, can be used in the second line. In patients for whom there’s concern for POD24 [progression of disease within 2 years], in some situations people are prone to try to use R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] or O-CHOP [oncovin, cyclophosphamide, doxorubicin, vincristine, prednisone], even though the POD24 data suggest that chemotherapy-immunotherapy isn’t necessarily the best choice in that situation. There’s a very limited utilization of R-CVP [rituximab, cyclophosphamide, vincristine, prednisone] in general. We’ve used it more in the COVID-19 era out of concern for lymphoid toxicity with bendamustine.

My most probable option in the second-line setting has been R2 [lenalidomide, rituximab] in these patients irrespective of the duration of response given it’s efficacy. If it’s a POD24 patient, I’m much more confident in that cause in some beneficial response vs some of those chemotherapy drugs we have available. Very seldom would it be Rituxan monotherapy, except in a patient with very low burden disease. Obviously, that’s something that just needs to cool off without a lot of concerns that the lymphoma is driving that person’s cancer.

Alexey Danilov, MD, PhD: In the third line, we have several agents approved that are not approved for the first or second line. Those would be 3 kinds of these PI3K inhibitors: copanlisib, duvelisib, and umbralisib. Duvelisib and umbralisib are oral agents, and copanlisib is used in IV [intravenous] formulation. Even more recently we got approval of tazemetostat. This agent is approved in patients who have an EZH2 mutation or who are EZH2 wild type but have no chance of treatment options. Interesting wording from the FDA.

Finally, some agents can be used for patients who received 3 prior therapies. Umbralisib is another PI3K inhibitor, and there’s anti-CD19 CAR [chimeric antigen receptor] T-cell therapy. CAR T-cell therapy has made significant headway in therapy for Hodgkin lymphoma. No exception is follicular lymphoma. In the ZUMA-5 study, responses were very high with this agent, with an oral response rate of 90%, a complete response rate of 60%, and a 1-year remission rate of 75%. A highly active agent in multiple-refractory follicular lymphoma. We certainly have a lot of exciting agents there. Dr Phillips, do you use PI3K inhibitors in your practice? Which mechanism of action do you rely on?

Tycel Jovelle Phillips, MD: I do use PI3K-delta inhibitors in my clinical practice. I’ll be honest: most of that has been through clinical trial participation recently. I have a few patients who I treat with idelalisib early on who, for some reason or another, came off the medication. But a few of these patients are still in remission 3 to 4 years after discontinuation. The mechanism action of the PI3K inhibitors is for the most part inhibition the delta isoform. Which is another pathway that up and down in the B-cell receptors. Some of the newest-generation delta inhibitors also inhibit some of the other isoforms, such as copanlisib, which also has inhibition of alpha. Then you have duvelisib, which has inhibition of gamma. Umbralisib which has casein 1 epsilon inhibition, which is unique from all the other ones that we’ve typically seen. Then you have some of the newer traditional ones that have pure delta inhibitors, such as zandelisib and parsaclisib. For the most part, when we look at indolent lymphomas and follicular lymphomas, we assume that most of the benefit is through inhibition of the delta isoform, with some contribution from other isoforms depending on the non-Hodgkin lymphoma subtype of an agent used at that point in time.

Transcript Edited for Clarity