Current and emerging treatment strategies for follicular lymphoma: A written recap

In this Managed Healthcare Executive K-Cast video series, Christina Poh, M.D., discusses the treatment landscape for follicular lymphoma, from active surveillance through newer immune-based combinations and the sequencing decisions. Poh is an associate clinical professor in the Division of Lymphoma and director of the T Cell Lymphoma Program at City of Hope Los Angeles.

A common but manageable disease

Follicular lymphoma is one of the most common types of indolent, or slow-growing, non-Hodgkin lymphoma, Poh explained, accounting for roughly 20% to 30% of all non-Hodgkin lymphomas. Although it is uncommon compared with cancers such as breast, lung or colorectal cancer, it represents a substantial share of the lymphomas oncologists see regularly. Patients are typically diagnosed in their 60s or 70s, though it also occurs in younger patients, Poh said. The presentation varies, she said, with some patients noticing painless, enlarged lymph nodes, whereas others have abdominal or chest lymphadenopathy found incidentally on imaging, with no symptoms at all.

Unlike an aggressive lymphoma, for which treatment is often urgently required, many patients with newly diagnosed follicular lymphoma do not need immediate therapy and can be safely monitored with active surveillance until the disease becomes symptomatic, Poh said, adding a cautionary note that “indolent doesn’t mean benign.” Follicular lymphoma is generally considered incurable with conventional therapy; patients often cycle through multiple rounds of treatment and remission over their lifetimes, and there is a risk of transformation into a more aggressive lymphoma, Poh said. Managing follicular lymphoma means balancing disease control, quality of life, treatment toxicity, and the cumulative burden and cost of multiple lines of therapy, she commented.

Active surveillance and the case for radiation

For early-stage disease, one of the most important considerations is that not every patient needs immediate treatment, Poh said. Because follicular lymphoma is indolent, an asymptomatic patient with a low tumor burden may see no immediate benefit from exposing themselves to the toxicities of systemic therapy. Studies have shown that in appropriately selected patients, delaying treatment until there is a clinical indication does not compromise overall survival, she noted. Active surveillance, Poh stressed, is not undertreatment but an appropriate management strategy.

Radiation is a different calculation. For patients with truly localized stage 1 or contiguous stage 2 disease, particularly when all of the disease can be safely encompassed in one radiation field, radiation can offer excellent local control and a long remission, since follicular lymphoma is highly sensitive to radiation. The choice between radiation and observation depends on the extent and location of disease, lymph node size, whether the lymphoma is causing symptoms or threatening an organ, and the patient’s age, health and preferences, Poh said, adding that the potential long-term effects of radiation matter more for younger patients or disease located near a critical organ.

When symptoms signal it's time to treat

The shift from an asymptomatic, low-burden state to more advanced or symptomatic disease is what drives the decision to treat, Poh said, not simply the fact that the lymphoma is growing. The symptoms include fever, night sweats, weight loss, significant or progressive lymphadenopathy, bone marrow involvement severe enough to cause cytopenias or disease that threatens the function of an important organ.

For patients with very limited, stage 1 disease, radiation can again offer real benefit, but most symptomatic patients have diffuse, advanced disease that calls for systemic therapy, Poh said. There is no single best regimen for every patient; the goal is an effective treatment that minimizes toxicity and avoids unnecessary intensity. Patients with relatively low tumor burden who need treatment because they have become symptomatic often start with an anti-CD20 antibody such as rituximab or obinutuzumab, sometimes combined with chemotherapy or a targeted agent. Patients with higher tumor burden or more aggressive features usually move to a combination regimen that includes an anti-CD20 antibody plus chemotherapy or other targeted therapies for more rapid and deeper disease control. Poh noted that chemotherapy-free approaches are increasingly used. Rituximab combined with lenalidomide is now an established frontline option with good disease-control outcomes, Poh said, and can be attractive for patients for whom minimizing chemotherapy-related toxicity matters most.

What drives the frontline treatment choice

Selecting among frontline regimens requires looking beyond efficacy alone, Poh said, since many current treatments produce good response rates. The more useful question to ask is which treatment strikes the right balance of disease control, toxicity, convenience and value for a given patient, she said. Factoring in toxicity may be especially important for patients who are older or for those with significant comorbidities who may not tolerate chemotherapy well, Poh said. For them, avoiding myelosuppression, infections or other chemotherapy-related complications can outweigh incremental efficacy gains.

Administration burden is another issue for clinicians and patients to consider, Poh said. Treatment varies by how often patients need to come to an infusion center, whether it is administered intravenously or orally, how much lab monitoring is required, and how treatment affects a patient's ability to work or maintain daily quality of life. Cost is part of the conversation as well, Poh said, and not just a particular drug’s acquisition cost but supportive medications, monitoring, potential hospitalizations and managing complications. Poh also discussed trade-offs; for example, an oral medication may mean fewer infusion visits but introduce its own adherence or coverage challenges. Because follicular lymphoma is a chronic disease likely to require multiple lines of therapy, Poh said clinicians don't want to use every option up front. “The best frontline regimen isn’t necessarily the most intensive or the least expensive one,” she said, but rather, the regimen that provides appropriate disease control for that patient at that time while minimizing toxicity, treatment burden and overall cost.

Building on rituximab-lenalidomide: Tafasitamab and epcoritamab

In the relapsed or refractory setting, there has been considerable interest in building on the established rituximab-lenalidomide combination by adding newer immune-based therapies such as tafasitamab or epcoritamab, Poh said, that engage the immune system through an additional mechanism to deepen and extend response. The phase 3 InMIND study, which added tafasitamab, a monoclonal antibody targeting CD19, to rituximab and lenalidomide, significantly improved progression-free survival compared with rituximab and lenalidomide alone. Similarly, the phase 3 EPCORE FL-1 study evaluated epcoritamab, a CD3-CD20 bispecific antibody, in combination with rituximab and lenalidomide and also showed a substantial improvement in progression-free survival.

These approaches are particularly attractive for patients with relapsed or refractory disease who need treatment but would prefer to avoid traditional chemotherapy, and for patients with higher-risk disease, Poh said, including those with disease refractory to a prior anti-CD20 antibody or that relapsed within 24 months of initial treatment, populations in which the studies showed these therapies performed well. Both regimens start intensively and taper over time. Tafasitamab is given intravenously weekly for the first three cycles, then every other week through cycle 12, with lenalidomide taken orally for 21 days of each 28-day cycle and rituximab given for the first five cycles. Epcoritamab uses a weekly step-up dosing schedule in the first cycle to mitigate cytokine release syndrome risk, continues weekly through cycles 2 and 3, then moves to once every four weeks through cycle 12. The heavier early-visit schedule can help allow, Poh said, closer monitoring of higher-tumor-burden patients for toxicity before the regimen eases up. Both regimens are fixed duration, running up to a year rather than continuing indefinitely.

Weighing added efficacy against added complexity

Adding another active agent to rituximab and lenalidomide can improve progression-free survival, but that benefit comes with more toxicity and treatment complexity, Poh said, and "more treatment doesn't automatically mean better treatment for every patient." Tafasitamab adds another intravenous therapy, with additional infusions and potential infusion-related or immune-mediated toxicities. Epcoritamab, as a bispecific antibody, entails a risk of cytokine release syndrome, requiring additional monitoring and step-up dosing early in treatment. Increased cytopenia or infection risk are considerations with both.

When discussing these options with patients, Poh said she tries to frame the benefit in concrete rather than purely statistical terms, including how much additional disease control a patient might expect, and what they are giving up to achieve it. The patient’s goals should be weighed into treatment decisions. For someone with high-risk or rapidly progressive disease who needs a deeper, more durable response, the added treatment burden may be well worth it, she said. For someone with lower-risk disease, significant comorbidities, or who lives too far away for frequent monitoring, a simpler regimen may make more sense. Shared decision-making is essential, Poh said, so patients understand not just the potential gain but the side effects, clinic time, monitoring and cost that come with it. The goal, she said, is “the right amount of treatment to achieve that meaningful disease control while preserving their quality of life.”

Sequencing therapy is patient-specific

There is no single algorithm for sequencing therapy in relapsed or refractory follicular lymphoma, Poh said. The right sequence depends on when a patient relapses, which treatments they previously received, how aggressive the disease appears to be, and which options a clinician wants to preserve for later. An early relapse — progression within 24 months of initial treatment — is generally considered high-risk disease and points toward a strategy that aims for a deeper, more durable response, she said. A later relapse, especially in a patient who was sensitive to prior therapy, allows more flexibility, and a rituximab-lenalidomide-based combination can be attractive as an effective chemotherapy-free approach, with an agent such as tafasitamab or epcoritamab added to further increase efficacy if warranted, Poh said.

Because tafasitamab and bispecific antibodies engage the immune system through different mechanisms — tafasitamab targeting CD19, epcoritamab targeting CD20 and CD3 to bring T cells into contact with lymphoma cells — there is a rationale for using either one first, Poh said. “We don't actually have data to say which one should come first,” she said.

Beyond the second line, the treatment choices broaden to include bispecific antibody monotherapy, chimeric antigen receptor-T cell therapy and other available targeted approaches, depending on a patient's prior treatment and fitness. The goal, Poh said, is to match the intensity of treatment to the biology of the disease and the patient's preferences while preserving options for later.

Making it a manageable chronic disease

With the advances in the treatment of follicular lymphoma, Poh said the field is moving away from a uniform approach toward more individualized strategies that weigh efficacy and durability alongside toxicity, patient age, comorbidities, disease burden, pace of relapse and prior therapies. Because the disease often requires multiple lines of treatment, sequencing remains a central question, and operational treatment burden matters increasingly, since more complex regimens can affect a patient's ability to stay on therapy and maintain quality of life. Total cost of care, including drug acquisition, administration, monitoring, supportive care and management of complications, must also be considered, she said, with an eye toward picking “the right treatment for the right patient at the right time.”

Poh said this is “a very exciting era in follicular lymphoma,” with multiple relatively effective treatment options now available, giving clinicians and patients real latitude in selecting therapy. New drugs and additional targeted immune-based therapies continue to be developed and approved, she said, and the key to answering the outstanding sequencing questions will be multicenter, real-world studies that clarify how these treatments perform for patients outside of clinical trials. The ultimate goal, Poh said, is to turn follicular lymphoma into a manageable chronic disease while maintaining and improving patients' quality of life.