CAR T-Cell Therapy Selection in Follicular Lymphoma Requires Careful Consideration

As lisocabtagene maraleucel (Breyanzi; liso-cel) recently joined the list of FDA-approved CAR T-cell therapies for the treatment of patients with relapsed or refractory follicular lymphoma who received at least 2 prior lines of systemic therapy, there is not a standardized answer regarding which agent clinicians should select in the third-line setting, as several factors influence this decision, according to Francisco Hernandez-Ilizaliturri, MD.^1,2

Findings from the phase 2 TRANSCEND-FL trial (NCT04245839), which supported the May 2024 approval of liso-cel in this patient population, showed that patients who received the agent (n = 94) achieved an overall response rate of 95.7% (95% CI, 89.5%-98.8%). Additionally, at a median follow up of 16.8 months (95% CI, 16.3-17.0), the median duration of response was not reached (NR; 95% CI, 18.04-NR).²

“We have many options to treat patients with follicular lymphoma and more than ever we need to individualize treatment selection. We need to be aware of the distinct mechanism of action of each option,” Hernandez-Ilizaliturri said in an interview with OncLive®. “We also need to [continue to] learn about the activity, but it’s also very important to be aware of the short-term and long-term toxicities of each treatment, and how to treat patients because at the end of the day those [factors] are going to be the foundation that we’re going to use to select an option for a given patient. It’s important to have knowledge of all of these areas. Every treatment that you select is going to be a good treatment, but the key is how do you match the patient that you’re seeing in the clinic with the best option for that patient?”

In the interview, Hernandez-Ilizaliturri, detailed factors that influence treatment selection for patients with relapsed or refractory follicular lymphoma and also highlighted the potential of pirtobrutinib (Jaypirca) in this space. Hernandez-Ilizaliturri is the director of Lymphoma Research, head of the Lymphoma Translational Research Laboratory, a professor of oncology, and an associate professor in the Department of Immunology at Roswell Park Comprehensive Cancer Center in Buffalo, New York.

OncLive: How has the FDA approval of liso-cel following 2 prior therapies shifted the treatment landscape for patients with follicular lymphoma?

Hernandez-Ilizaliturri: Liso-cel is another commercially available CAR T-cell therapy targeting CD19. It was previously approved for patients with relapsed/refractory large B-cell lymphoma and now is approved for patients with B-cell malignancies, especially indolent lymphomas and chronic lymphocytic leukemia [CLL]. It’s another tool that we have to control relapsed/refractory B-cell lymphomas and the activity is consistent with what we have [observed] with other CAR T-cell therapies. What is interesting about liso-cel is the safety profile, as cytokine release syndrome and neurotoxicities appear to be less severe and less frequent. That will encourage use in patients, especially in those with comorbidities.

How do you select between the multiple CAR T-cell therapies available in follicular lymphoma?

That [decision] is going to vary from institution to institution, [and] it depends on what product each organization has been working with. We [also] have to look at the therapy’s safety profile because, depending on the patient we have in front of us, we may favor 1 product vs another.

There are other factors that may influence the selection of the CAR T-cell product, [such as] the manufacturing time; some early CAR T-cell products [in development] have a shorter turnaround that is more suitable for patients who need a quick treatment. In addition, patients who may have less tumor burden, but have comorbidities, could favor a CAR T-cell product that has a longer manufacturing time [because] they may have a ‘safer profile.’

There is not a generalized answer to what would be the [best] product to choose. The age of the patient, comorbidities, tumor burden, and time in which you have to use treatment are variables that influence [decisions, and another factor is] what’s available at the institution where the patient will be treated. The training that the health care staff needs to undergo to administer each of those CAR T-cell products [is a consideration too].

How do these factors help inform treatment decisions in the second- or third-line settings of follicular lymphoma?

I tend to divide these factors into patient-related factors which has to do with age, comorbidities, organ function, [and other] factors, [such as] how fast the follicular lymphoma is growing [and] what the grade [of disease] is—grade 1 or grade 2 may be slightly different than grade 3A and certainly much different than 3B, which is now considered a high-grade lymphoma. Then, we have toxicities from prior treatment, which are treatment-related factors. What was the prior therapy and resulting adverse effects and how severe are [they]? We can [consider these factors] together to select the best next line of treatment for a given patient.

When I talk to patients with follicular lymphoma, I also try to, if possible, spread the intervals in which chemotherapy drugs are being administered because chemotherapy agents in contrast with targeted therapies have more off-target toxicities that can lead to permanent organ damage, [such as] cardiac toxicity, peripheral neuropathy, or, more concerning, myelodysplasia or secondary leukemias. In general, an ideal sequence of treatment is some form of chemoimmunotherapy in the first-line setting and then in the second- and third-line setting [we] try to tap into targeted agents to further increase that time in which patients are not exposed to chemotherapy drugs.

It’s now more important than ever to incorporate a patient’s interests and preferences into decision making because some treatments have logistics that can affect the [treatment] preference. There are patients who are keen to stay close to home to receive therapy or not spend too much time in the hospital seeing doctors. There are patients, on the other hand, who want to get done with treatment sooner [rather] than stay indefinitely on a treatment or stay for a long period of time. It’s very important to have these discussions with patients and caregivers.

What is the potential for the non-covalent BTK inhibitor pirtobrutinib and what could it potentially mean for the follicular lymphoma treatment paradigm?

Pirtobrutinib is emerging as another treatment [option] for patients with not only mantle cell lymphoma and CLL, but also for those with marginal [zone] and follicular lymphomas. It is another tool that we can use to treat patients, especially those who are in intolerant to a prior BTK inhibitor or are developing resistance to a covalent BTK inhibitor.

We have data on zanubrutinib [Brukinsa] in combination with obinutuzumab [Gazyva] which showed that the [combination] is active and well tolerated in patients with follicular lymphoma in the third-line setting; having pirtobrutinib available is another good therapeutic strategy. Those treatments may be more desirable in patients who are 75 years old or above, where having a more specific agent with less of an off-target effect may prove to be effective and safe.

It’s important to highlight that follicular lymphoma continues to be a disease that is primarily diagnosed in patients above the age of 65 and a significant number of patients, thankfully, will only require 2 lines of therapy during the time that they have lymphoma. There is a small group of patients who will require a third-line [treatment] and beyond; those are the patients who [have disease that is] a challenge for any oncologist [to treat].

References

1. Oncology (cancer) / hematologic malignancies approval notifications. FDA. June 26, 2024. Accessed July 12, 2024. bit.ly/4a9JHIt
2. FDA grants accelerated approval to lisocabtagene maraleucel for follicular lymphoma. FDA. May 15, 2024. Accessed July 12, 2024. bit.ly/462f86E