Evolving and Future Treatments for Follicular Lymphoma
SAN FRANCISCO – Treatment for follicular lymphoma (FL) continues to evolve, according to a US Department of Veterans Affairs (VA) hematologist-oncologist, as second-line regimens emerge but the withdrawal of a recently approved agent complicates the picture.
“The future for our understanding and treatment of follicular lymphoma remains bright,” said Gerald Hsu, MD, PhD, of the University of California at San Francisco and the San Francisco VA Health Care System, during a presentation at the March Association of VA Hematology/Oncology (AVAHO) regional meeting on lymphoma.
By the Numbers
About 16,500 people in the US are diagnosed with FL each year. The median age of diagnosis is 64 years, and the 5-year survival rate from 2015-2021 was 89.0%, according to the National Cancer Institute.
FL is slow-growing and indolent, Hsu said.
“[That] means that we tend to see patients who are older when they are diagnosed,” he added. “They tend to live a long time, and they’re not usually curable.”
A better understanding of the biology of FL has allowed for the development of new markers and ways of measuring residual disease, Hsu said. Additional insight may allow clinicians to identify which patients could benefit most from specific therapies.
Frontline Options
Hsu highlighted the VA Oncology Clinical Pathway for FL, which offers step-by-step guidance regarding therapy and was updated in March 2026. “It walks you through the pathway, but it’s not something that you are beholden to,” he said.
If the patient has classic FL grades 1-3A, is not at risk of transformation to aggressive lymphoma, is not in stage 1 or continuous stage lymphoma, and is indicated for therapy, the guideline recommends lenalidomide plus rituximab (R2 or R-Len) or rituximab-bendamustine (R-Benda).
“There’s a lot of data to support R-Benda,” Hsu said, pointing to a pair of studies with large numbers of patients with FL. The 2013 StiL trial tracked > 500 patients with indolent or mantle cell lymphoma (46% high risk). Those on R-Benda displayed better progression-free survival (PFS) than those taking the combination rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; hazard ratio [HR], 0.61).
In a 5-year update of the BRIGHT trial, which enrolled > 500 patients with indolent or mantle cell lymphoma (9% high risk), the R-Benda group had better PFS than patients on R-CHOP or rituximab plus cyclophosphamide, vincristine, and prednisone (HR, 0.61).
R2 is a somewhat newer regimen, Hsu said. Data from the 2018 RELEVANCE study (> 1000 patients) found R2 to be nonsuperior to 3 rituximab-plus-chemotherapy regimens but with a lower rate of grade 3-4 neutropenia (32% vs 50% for the other regimens).
However, R2 is “not an FDA-approved regimen in the frontline because it did not demonstrate superiority” over other treatments, Hsu said.
Selecting the Right Therapy
Which therapy is best? It’s a bit of a wash, Hsu said.
He noted that R2, R-Benda, and another therapy that’s not yet in the VA pathway (R-CHOP) appear to be noninferior to one another, although R-Benda has the edge. R2 is better regarding neutropenia risk, although it lacks FDA approval.
“I think about these 3 regimens as appropriate and good,” Hsu said. “It’s nice having 3 wonderful regimens.”
Hsu highlighted the importance of complete remission (CR) as a goal. He pointed to a 2022 analysis of > 5,200 patients that showed progression within 24 months greatly boosted the risk of death vs no-progression (HR, 3.03). Progression within 24 months also lowered estimated 5-year overall survival to 71%.
“Timing really does matter,” Hsu said. “We often worry about transformation to diffuse large B-cell in patients who relapse, particularly this early.”
Second-Line Therapy Options
Two regimens have recently achieved National Comprehensive Cancer Network Category 1 preferred status in the second-line setting, Hsu said, although neither appears in the VA pathway.
One is tafasitamab plus R2, which was shown to extend median PFS to 22.4 months vs 13.9 months for R2 alone in the 2026 inMIND study (HR, 0.43), but without an overall survival benefit.
The other therapy is epcoritamab plus R2: Data from the 2026 EPCORE FL-1 study showed an overall response rate (ORR) of 95% for the combination vs 79% for R2 alone and an estimated 16-month PFS of 85.5% for the combination vs 40.2% for R2.
Hsu cautioned about the adverse event profile for community infusion centers. The combination carried higher rates of grade ≥ 3 infections (33% vs 16%) and neutropenia (69% vs 42%) compared with R2 alone. However, grade ≥ 3 cytokine release syndrome was absent.
“Stay alert to higher risk for infections and neutropenia here,” Hsu said.
Beyond Second Line: Biospecifics and CAR-T
The biospecifics mosunetuzumab and epcoritamab are now FDA-approved for patients who have relapsed ≥ 2 times. Mosunetuzumab showed ORR of 78% and CR rate of 60% in a 2025 study, while epcoritamab monotherapy showed ORR of 82% and CR of 63% in a 2024 study.
Mosunetuzumab had a 2.2% rate of cytokine release syndrome and a 4.4% rate of immune effector cell-associated neurotoxicity syndrome; epcoritamab had 0% rates of both.
“Think of these 2 options as getting you to the same place, potentially, but maybe with slightly different rates of toxicity,” Hsu said.
Meanwhile, CAR-T therapy has shown “impressive results for the right patient,” Hsu said.
Tazemetostat Withdrawn
Hsu noted that tazemetostat, an EZH2 inhibitor that was FDA-approved for relapsed/refractory FL with EZH2 mutations and patients with FL and no satisfactory alternative options, was withdrawn from the market by Eisai in March 2026. The cause of withdrawal was increased rates of secondary hematologic malignancies.
Meanwhile, patients enrolled in the ongoing SYMPHONY-1 trial will be switched to R2.
The withdrawal was “unfortunate,” Hsu said, “but the concept is important. Identifying new targets for therapy and developing those is how we make progress.”