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FAQs: Chemo-Free Agents for FL
FAQs: Chemotherapy-Free Treatments for Follicular Lymphoma

Released: January 07, 2025

Expiration: January 06, 2026

Caron Jacobson
Caron Jacobson, MD
Peter Martin
Peter Martin, MD
Sonali M. Smith
Sonali M. Smith, MD, FASCO
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Key Takeaways
  • There are many new chemotherapy-free options for patients with follicular lymphoma.
  • Using bispecific antibodies requires patient education and coordination with an experienced center.
  • The risk of ICANS (neurotoxicity) is low with bispecific agents compared to CAR T-cell therapies.

In this commentary, Sonali M. Smith, MD, FASCO, Caron Jacobson, MD, and Peter Martin, MD, address clinical questions posed by the audience during the recent symposium titled “A Game Changer for Follicular Lymphoma: Mastering Use of Precision Therapies as Part of a Chemo-Free Treatment Paradigm” held during the ASH 2024 annual meeting.

What are the key barriers to utilizing bispecific antibodies, and how do you educate your patients and their families about treatment with these agents?

Caron Jacobson, MD: Epcoritamab and mosunetuzumab are CD20 x CD3 bispecific antibodies with FDA approval for use in patients with relapsed/refractory (R/R) follicular lymphoma (FL). With either of these bispecific antibodies, treatment needs to be initiated with a step-up dosing phase. 

Educating patients and their families about what to expect when they are about to initiate treatment with a bispecific antibody is incredibly important. For instance, cytokine release syndrome (CRS) is a potential toxicity of bispecific antibodies that usually occurs in the first cycle of treatment. Patient education becomes a real issue if patients do not have a strong support network with which they can share the information provided. Patients, together with their support systems, need to be able to recognize when they are experiencing a side effect of treatment such as a fever. It is of great importance for them to know what the symptoms of the potential side effects are. They need to know what their first steps should be after observing symptoms and whom to call at that critical moment. CRS primarily occurs in the first month of treatment or soon after the maximal dose of the bispecific antibody has been administered. Of note, CRS is not uncommon but the rate of severe CRS with bispecific antibodies is typically low.

Patients who are about to start treatment with a bispecific antibody should be empowered to be able to recognize the associated symptoms. Those who live far away from the treatment center need to follow a set protocol as soon as they start to experience these side effects. Patients and their caregivers should know what the proper care is so that they are able to advocate for themselves if they need to present themselves to a nearby community practice or emergency center when these symptoms occur.

Peter Martin, MD: Epcoritamab is administered by subcutaneous injection and mosunetuzumab is administered as an intravenous infusion. Both epcoritamab and mosunetuzumab are associated with serious and potentially fatal infections, and both have been associated with neurologic toxicities including immune effector cell–associated neurotoxicity syndrome. Fortunately, these are quite rare.

Due to the practical issues associated with the use of these agents, including the initial step-up dosing needed to administer these bispecific antibodies, it may be necessary for patients who choose to receive treatment with a bispecific antibody to start their treatment at a larger cancer center before returning to their smaller, local oncology center that may have less experience with using bispecific antibodies. These practical barriers remain challenging, especially in the community practice setting.

Sonali M. Smith, MD, FASCO: I agree that it can be complicated to set expectations and be able to appropriately monitor for and manage the associated toxicities, particularly with the initial administration of these bispecific antibodies.

Do you think bispecific antibodies have a role in the frontline management of FL, and if so, should there be a maintenance phase?

Caron Jacobson, MD: At my institution and others, there are several ongoing investigator-initiated trials of a bispecific antibody in the first-line setting (NCT05783609, NCT05783596, NCT06112847, NCT05410418). If the results are promising, the use of  bispecific antibodies in the frontline FL setting would mean a chemotherapy-free treatment for these patients, which could be a very attractive option for many patients. Given the incurable nature of FL, a priority of any treatment is time-limited therapy; so, maintenance therapy is unlikely to be attractive to many patients and their physicians. Most of my patients would prefer a time-limited therapy over an indefinite treatment.

Peter Martin, MD: I am excited about the potential use of frontline bispecific antibodies for patients with FL. However, there is never going to be a “one-size-fits-all” approach for patients with FL. Although there may be a scenario where a bispecific antibody is appropriate in the frontline setting, bispecific antibodies will not be appropriate for every patient in the frontline. There will still be options for single-agent rituximab and chemotherapy in this setting.

In general, I prefer time-limited therapy for my patients with FL receiving bispecific antibodies because I have some concerns about the longer-term risks of infections with these agents.

Sonali M. Smith, MD, FASCO: The randomized phase III SWOG- S2308 trial is investigating the effectiveness of mosunetuzumab vs rituximab for patients with previously untreated FL with a low tumor burden (NCT06337318). The results from this trial will provide more information about patients with untreated FL who stand to benefit more from the upfront use of a bispecific antibody.

How do you choose among the available treatment options for your patients with R/R FL in the third- or later-line setting?

Caron Jacobson, MD: For patients with FL who have progressed on first- and second-line treatments, my preferred treatment option is a T-cell directed therapy, either a bispecific antibody or a CAR T-cell therapy. Other options include tazemetostat, an EZH2 inhibitor, and zanubrutinib in combination with obinutuzumab. In this setting, the choice between a bispecific antibody and a CAR T-cell therapy will depend on the characteristics of the individual patient. Patients who are very risk-averse may shy away from CAR T-cell therapy with the risk of CRS and ICANS as well as the need to stay near the treating center for a month or more with a caregiver. If a patient has preexisting cytopenias, CAR T-cell therapy may not be the treatment of choice and a bispecific antibody may be preferred. For patients who desire to receive treatment that has a high potential for the longest duration of remission, where he/she can be off therapy for as long as possible without frequent visits to the oncologist, CAR T-cell therapy would be my preferred option.  Of note, some of the patients treated in 2010 on the first single agent CAR T-cell studies at the National Cancer Institute and the University of Pennsylvania were still in remission at Year 10, suggesting that CAR T-cells may cure a subset of patients with FL. To determine whether patients will ultimately be cured with a bispecific antibody or CAR T-cell therapy requires much longer follow-up of the pivotal studies.

The data with the use of a CAR T-cell  therapy for patients with disease progression or relapse of FL within 2 years of frontline chemoimmunotherapy (POD24) are very compelling. For patients with POD24, I would highly recommend a CAR T-cell therapy over a bispecific antibody.

Sonali M. Smith, MD, FASCO: I agree. However, the rate of survival is significantly reduced for patients with FL who require third- or later-line therapy.

Peter Martin, MD: As with any line of therapy, context is key. Important questions need to be answered before choosing third- or later-line treatment: What were the prior therapies? How did the patient tolerate and respond to them? What are the goals with the next line of therapy? We have managed to do really well with existing, fairly unsophisticated approaches for the past few decades. It is even better now that we have more therapeutic options so that we can better match the right treatment to the situation at hand, taking into account the complexity and variability presented by each and every person with FL.

Your Thoughts?
What questions do you have about the newer chemotherapy-free treatment options for your patients with R/R FL? Answer the polling question and join the conversation in the discussion box below. 

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