Introduction

Follicular lymphoma (FL) is the most common form of indolent non-Hodgkin lymphoma, characterized by a chronic relapsing-remitting course and clinical heterogeneity. While most patients respond well to frontline immunochemotherapy, the disease remains incurable, and outcomes in the relapsed/refractory (R/R) setting vary and are often suboptimal.^1,2

One of the most significant challenges in managing FL is the early progression of disease, particularly within 24 months of initial immunochemotherapy (POD24). Approximately 20% of patients relapse within this period, and this subgroup is associated with a poor prognosis.^2,3 Beyond POD24, additional challenges with FL include the lack of robust prognostic tools, the absence of validated predictive biomarkers, and the risk of transformation into more aggressive lymphomas. Treatment-related toxicity also remains a concern, which is especially relevant for older patients or those with comorbidities.⁴ Collectively, these factors underscore the need for more effective and tolerable treatment options.

In recent years, several novel therapeutic strategies have reshaped the treatment landscape for R/R FL. These include targeted therapies, CAR T-cells, and bispecific antibodies (BsAbs). To date, the U.S. Food and Drug Administration (FDA) has approved three CAR T-cell products for patients with R/R FL after two or more prior lines of therapy: lisocabtagene maraleucel (liso-cel), tisagenlecleucel (tisa-cel), and axicabtagene ciloleucel (axi-cel).⁵ While CAR T-cell therapy offers the potential for durable responses, its use remains limited due to lengthy manufacturing times, toxicity concerns, and patient-specific factors. To overcome some of these limitations, bispecific antibodies have emerged as a promising off-the-shelf alternative, providing immediate availability, a favorable safety profile, and encouraging clinical activity in R/R FL.⁵

Bispecific antibodies: off-the-shelf immunotherapy

Bispecific antibodies work by engaging CD3-positive T-cells with CD20-positive B-cells, redirecting immune responses to malignant cells.⁴ This dual-targeting mechanism enables T-cell-mediated cytotoxicity without the need for prior cell collection or genetic modification.⁶ Mosunetuzumab, the first BsAb approved in this setting in 2022, demonstrated an overall response rate (ORR) of 80% and a complete response (CR) rate of 60% in heavily pretreated patients in the Phase II open-label, multicenter, multi-cohort GO29781 trial (NCT02500407).⁷ In 2024, epcoritamab also gained accelerated approval by the FDA for adults with R/R disease after two or more prior lines of therapy based on findings from the open-label, multi-cohort, multicenter, single-arm EPCORE NHL-1 trial (NCT03625037).⁸ Odronextamab is currently also under review by the FDA.⁵

Given the excitement surrounding BsAbs in this disease setting, these agents are also being explored in combination with other targeted therapies (e.g. lenalidomide, BTK inhibitors, EZH2 inhibitors) as well as standard-of-care regimens such as R2 (lenalidomide-rituximab).⁵ Some trials of interest include the EPCORE FL-1 trial (NCT05409066) evaluating subcutaneous epcoritamab in combination with R2 in patients with R/R FL, the OLYMPIA-5 trial (NCT06149286) evaluating odronextamab in combination with lenalidomide versus R2, and the CELESTIMO trial (NCT04712097) evaluating mosunetuzumab in combination with lenalidomide versus R2. Other combinations being explored include epcoritamab plus tazemetostat (NCT06575686) and epcoritamab in combination with zanubrutinib and rituximab (NCT06563596).⁵ Results from these trials are eagerly awaited.

Conclusion

The treatment landscape in R/R FL is undergoing rapid transformation. BsAbs stand out as a particularly promising class of agents, offering off-the-shelf availability and demonstrating encouraging responses. Their ease of administration and rapid accessibility may significantly broaden the therapeutic window for patients who are ineligible for or unable to access CAR T-cell therapy. As BsAbs continue to integrate into clinical practice, they have the potential not only to improve patient outcomes but to redefine the treatment paradigm, including the possibility of earlier-line use. Future efforts should focus on optimizing combination approaches, minimizing toxicity, identifying predictive biomarkers, and expanding access.

References

The Lymphoma Channel on VJHemOnc is supported by AstraZeneca, BMS, Johnson & Johnson, Takeda, and Galapagos.

The supporters have no influence over the production of the content.