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3L+ RR FL FAQs
Novel Targeted Therapies in Relapsed/Refractory Follicular Lymphoma: Experts Answer Frequently Asked Questions

Released: January 29, 2024

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Key Takeaways
  • Current targeted therapy options in the management of R/R FL in the 3L setting and beyond include the small-molecule inhibitor tazemetostat, anti-CD19 CAR T-cell therapy (axicabtagene ciloleucel, tisagenlecleucel), and bispecific T-cell engager therapy (mosunetuzumab-axgb).
  • How best to sequence these therapies remains an open question; specific patient and disease factors must be considered to individualize therapy for each patient (eg, fitness, comorbidities, prior therapies, disease burden, and patient preference).
  • Because of a risk for CRS and ICANS, which require early identification and specialized care, special considerations for receipt of T-cell–mediated therapies are caregiver availability and distance to treatment facility.
  • Based on clinical guidelines, trial data, and expert recommendations, tazemetostat can be used in the management of R/R FL in the 3L setting and beyond, irrespective of EZH2 mutation status.

The management of relapsed/refractory (R/R) follicular lymphoma (FL) is continuing to evolve, especially sequencing of therapy in the third-line (3L) setting and beyond. In this commentary, Peter Martin, MD; Sonali Smith, MD, FASCO; and Julie Vose, MD, MBA, answer clinical questions posed by the audience at a recent live satellite symposium held during the ASH 2023 annual meeting.

What is the optimal approach to sequencing therapies in the 3L setting for R/R FL?

Sonali Smith, MD, FASCO:
There is not one right answer to the question of how best to sequence therapies in patients with R/R FL. For newly diagnosed FL, many patients will receive chemoimmunotherapy with an anti-CD20 antibody (rituximab or obinutuzumab) and often bendamustine as the chemotherapy backbone followed by second-line lenalidomide plus rituximab. Then, for 3L therapy, one needs to look at all of the remaining options in the context of patient and disease characteristics, including observation, anti-CD20 antibody monotherapy, chemoimmunotherapy that has not yet been used, and the newer targeted therapy options we have in our toolbox today.

Peter Martin, MD:
I agree. With almost every other disease, you start with the most effective treatment possible and then move on from there, but because FL has an indolent nature and relapsing and remitting course, you instead start with an easy therapy and then go on to the next easy therapy, and so on—for example, I still use a lot of single‑agent rituximab. This leads to considerable heterogeneity in treatment patterns for FL across lines of therapy.

Sonali Smith, MD, FASCO:
We also must consider that with each successive therapy, duration of response and progression-free survival (PFS) get shorter and shorter, as was shown in the National LymphoCare Study, so by the time a patient with R/R FL gets to 3L therapy, median PFS can be shorter than 2 years. Two types of relapse are particularly challenging: (1) early progression of disease (ie, POD24)—and there are questions as to whether transplant might have a role here—and (2) double-refractory FL, where there is progression of disease within 6 months to both alkylating agents and rituximab. Getting these patients back into remission can be very challenging. Furthermore, the risk of transformation is lifelong for all of these patients and increases with the number of relapses.

Along with considering time to relapse on the most recent therapy, whether the patient has a high or low tumor burden and whether the patient is symptomatic should be considered when choosing the next therapy for someone whose disease has progressed. It is also very important to practice shared decision-making with our patients.

What do you consider when choosing between a bispecific antibody and CAR T-cell therapy in the management of 3L R/R FL?

Julie Vose, MD, MBA:
Currently, 2 CD19-directed CAR T-cell therapies, axicabtagene ciloleucel and tisagenlecleucel, and 1 CD20/CD3-directed bispecific antibody, mosunetuzumab-axgb, are approved by the FDA for 3L therapy in patients with R/R FL.

When deciding whether to use these T-cell–mediated therapies in the 3L setting for R/R FL, several patient and disease factors must be considered. For CAR T-cell therapy, age itself is not an exclusion; rather, a patient must be fit and in good health, including passing cardiac, renal, and liver function tests to make sure that they are healthy enough for CAR T‑cell therapy. Which prior therapies a patient has received, and how recently, will affect whether CAR T-cell therapy can be given. For example, recent receipt of bendamustine by a patient (ie, within ~2 months vs 2 years) can have a negative impact on the collection of functional T-cells. Furthermore, if a patient receiving CAR T-cell therapy has a high disease burden, they may need bridging therapy after apheresis, as it takes several weeks for the CAR T-cell therapy to be manufactured. Because bispecific antibodies are an off-the-shelf product, these considerations related to T-cell manufacturing are not a concern.

Furthermore, the availability of a reliable caregiver is critical for patients receiving either CAR T-cell therapy or a bispecific antibody. This person needs to be with the patient around the clock to monitor for signs of cytokine-release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). Being in the vicinity of the oncology center is also a consideration, as T-cell–mediated therapies currently are administered inpatient, and some of the potential complications, such as CRS and ICANS, require specialized care not available at your average emergency department.

For CAR T-cell therapy, our center requires patients to stay within the immediate area for 28 days, although some may spend the first 10 days after infusion inpatient. For bispecific antibodies, we typically have patients stay in the immediate vicinity for 24 hours, as the risk for CRS is earlier than with CAR T-cell therapy.

Peter Martin, MD:
We have struggled quite a bit at my center with the issue of patients who have received bispecific antibody therapy being outside of the hospital setting—and potentially outside of the immediate area—when CRS occurs. The first patient I gave mosunetuzumab to experienced grade 2 CRS very early on and was 1.5 hours away from the city. I felt helpless at the time because he went from his home to a nearby emergency department that did not have tocilizumab (the primary anticytokine drug we use to treat CRS) or an oncologist. They started him on dexamethasone, and within a day, he was fine. This experience led me to consider sending these patients home with a prescription for steroids.

At our institution, we now send all patients home with a prescription for dexamethasone and provide detailed patient education. Having patients call us right away if they have any hint of a fever, at all, and having them take steroids and acetaminophen has worked for us. However, if a patient is experiencing CRS, they should have someone drive them in for care or call an ambulance.

Sonali Smith, MD, FASCO:
We also give patients receiving bispecific antibody therapy a lot of information to take home and make sure they have a caregiver with them, and we have given some patients a prescription for steroids.

The decision between CAR T-cell therapy and bispecific antibody therapy also involves a lot of shared decision-making. I have had patients choose CAR T-cell therapy instead of a bispecific antibody because they preferred to be in the hospital during the time of the highest risk, whereas with the bispecific antibody they would have had to go back and forth for treatment.

Julie Vose, MD, MBA:
Individual patient discussions about T-cell–mediated therapies are going to become even more nuanced as additional bispecific antibodies gain approval for R/R FL because some of them are time limited, whereas others require ongoing therapy.

Is testing for EZH2 mutations required to use the EZH2 inhibitor tazemetostat in the treatment of patients with R/R FL?

Sonali Smith, MD, FASCO:
Tazemetostat is an oral, small-molecule EZH2 inhibitor that is approved by the FDA for 2 indications: (1) adult patients with R/R FL who have an EZH2 mutation and who have received ≥2 prior systemic therapies and (2) adult patients with no other satisfactory treatment options. The Cobas EZH2 Mutation Test is an FDA-approved companion diagnostic, and several next-generation sequencing (NGS) panels are available that include EZH2 mutations, including the in-house NGS panel I use.

However, clinical guidelines recommend tazemetostat for R/R FL irrespective of EZH2 mutation status in the 3L setting and beyond. Based on the phase II study data showing a response regardless of EZH2 mutation status—objective response rate was 35% with a median duration of response of 13 months in 49 patients with wild-type EZH2—I do not think EZH2 testing is necessary to use this drug.

Julie Vose, MD, MBA:
I think it is important to remember that it can take 10-14 days to get NGS test results back, depending on whether it was done in‑house, and that delay may be an issue. With that in mind, why test if patients without an EZH2 mutation potentially could respond to tazemetostat?

Peter Martin, MD:
I agree. We also have an in-house NGS panel available, but I do not always check the EZH2 mutation status in patients I treat with tazemetostat. For the reasons mentioned, if the patient is a good fit for the drug, I am not concerned about their EZH2 mutation status.

Your Thoughts?
What challenges have you experienced when treating patients with R/R FL with these novel targeted therapies? Answer the polling question and join the conversation in the discussion box below.

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Which of the following targeted therapies approved for the management of R/R FL in the 3L setting and beyond have you used in clinical practice? Please select all that apply.

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