Managing Relapsed/Refractory Follicular Lymphoma: Overview and Unmet Needs

This article was sponsored by AbbVie Inc. Kami Maddocks is a paid consultant for AbbVie Inc.

Follicular lymphoma (FL) is the second most common subtype of non-Hodgkin lymphoma (NHL), accounting for approximately 20% of NHL cases globally.^1,2 This indolent B-cell malignancy often is characterized by a slow but relapsing course, with a portion of patients observed following diagnosis before requiring treatment.^2-4 The disease often responds well to initial therapy, such as immunotherapy alone or in combination with chemotherapy or immunomodulator therapy; however, FL is incurable, and patients often experience multiple relapses.^3-5 Patients can experience increasingly aggressive or refractory disease that requires multiple lines of treatment over decades.^3,5

Although the disease is often manageable, its treatment for each successive relapse tends to be associated with reduced response duration, therapy-related toxicities, and treatment resistance.^3,5,6 The disease trajectory in relapsed/refractory (R/R) FL underscores a growing unmet need for chemotherapy-free regimens that address the evolving biology of resistance and provide improved durable disease control while maintaining tolerability.⁷ These approaches should offer longer overall survival (OS) and progression-free survival (PFS), extended time off treatment, and flexibility to individualize therapy and preserve quality of life (QOL).^3,4,7

Relapsed/Refractory FL

Frontline chemoimmunotherapy achieves high initial response rates in FL, but most patients ultimately relapse.^4,7,8 With each successive line of treatment, the duration of response and PFS tend to decline as a result of evolving tumor biology, emerging resistance, and the cumulative burden of prior therapies.^5-7 This pattern reflects the biologic heterogeneity of R/R FL and underscores the need for more durable, tolerable treatment strategies that improve long-term remissions with manageable toxicity.^7,9

Increasingly, the depth of response following frontline therapy has emerged as a meaningful prognostic factor. Patients who fail to achieve complete remission (CR) or complete metabolic remission (CMR) after induction are more likely to experience early relapse and inferior long-term outcomes.^4,10,11 Findings from 2 pivotal trials suggest that maintenance therapy benefits patients broadly; however, achievement of a deeper remission—particularly CMR or CR—is prognostically favorable and may serve as a surrogate marker for prolonged PFS.^10,11 In a 13-year follow-up of the GITMO–IIL trial (NCT00435955), achieving a CR was strongly associated with superior long-term outcomes in FL, with 13-year OS estimates of 77.0% in patients who achieved CR versus 36.8% in those without CR. The estimated 13-year disease-free survival was also higher among patients who achieved CR, with more than half (57.9%) remaining free of disease.¹²

The SCHOLAR-5 retrospective study results demonstrated that for patients with R/R FL, response rates declined with each successive line of therapy. At the third line of treatment, the ORR was 68.3%, with 43.9% achieving CR. By the fifth or later line, the ORR fell to 37.2% and the CR fell to 21.5%. Duration of benefit also was shorter in later lines: median PFS at the third line was 11 months and 3.9 months in the fifth or later lines. Median OS also declined with subsequent lines.⁹ These results suggest that it becomes harder to achieve deep and lasting remissions in later lines of treatment; further, there is a need to maximize disease control in earlier lines of therapies and to develop therapies that provide more durable responses in later lines of therapy.⁹

Quality of Life Concerns in Managing R/R FL

Given the indolent but relapsing nature of FL, many patients live for decades with the disease. In the R/R setting—in which repeated lines of therapy are common—preserving QOL is a critical treatment objective.^13-15 Cumulative toxicities, extended time on treatment, and chemotherapy-related burdens can significantly impair physical, psychological, and functional well-being.^13,14 In response, contemporary management increasingly emphasizes the need for patient-centered approaches that prioritize fixed-duration regimens, chemotherapy-sparing strategies, and therapies with favorable safety profiles.^7,15-17 The incorporation of QOL metrics into clinical trials and routine care is essential to ensure that treatment decisions align with patient preferences and long-term survivorship goals.^14,15

R/R FL Treatment Landscape

Despite FDA approval of multiple therapies, there is no universally accepted standard of care for R/R FL, which leads to heterogeneous treatment patterns across clinical practice settings.⁹ Current R/R FL treatments include a broad range of options such as immunochemotherapy, anti-CD20 monotherapy, and immunomodulator or targeted therapies with or without anti-CD20 therapies. These treatments have demonstrated efficacy, but responses often are not durable.^9,18 Two more recent therapeutic classes have contributed to the R/R FL treatment landscape: chimeric antigen receptor (CAR) T-cell therapies and bispecific antibodies (BsAbs).

CAR T-cell therapy involves genetically modifying autologous T cells to express receptors targeting CD19 on malignant B cells.¹⁹ This personalized approach has demonstrated deep and durable responses in FL, including in patients with heavily pretreated disease, refractory disease, and those with progression of disease within 24 months.¹⁹ However, widespread adoption of cellular therapies, such as CAR T-cell therapy, may be limited due to several logistical and systemic challenges. These include access being limited to certified treatment centers, delays in manufacturing and delivery of autologous products, and the requirement for intensive monitoring during and after infusion due to risks of cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity (ICANS).^7,19-23 The recent elimination of risk evaluation and mitigation strategy programs for select CAR T-cell therapies may reduce administrative burden and facilitate broader access for some patients.^23,24 Reimbursement complexities and insurance-related hurdles remain significant barriers, particularly outside of major academic centers.^16,20,22 Despite its potential for disease control, CAR T-cell therapy has historically been applied in the R/R setting after 2 or more lines of prior systemic therapy, with earlier treatment strategies focusing on approaches that are more accessible, scalable, and tolerable.^16,23

The use of BsAbs offers an off-the-shelf therapy option.²³ By simultaneously engaging CD3 on T cells and CD20 on B cells, BsAbs redirect T-cell cytotoxicity toward B-cells.²³ Used for patients with R/R disease, BsAbs have demonstrated high response rates and durable remissions in clinical trials.^16,25 Toxicities of note include CRS and ICANS, which are mostly grade 1 and 2 adverse events (AEs) but can be serious, life-threatening or fatal, and require monitoring and access to qualified health care facilities and providers.^16,25,26 Strategies like step-up dosing and subcutaneous administration help to mitigate these CRS and ICANS toxicities.^23,30 Other AEs to be aware of include infections, neutropenia, anemia, lymphopenia, hypophosphatemia, fatigue, and diarrhea.^16,25,26

As these treatment modalities continue to evolve, their integration into clinical practice must be guided by individual patient needs, disease biology, prior treatment history, and access considerations.^16,19 Optimal sequencing and combination strategies remain active areas of investigation aimed at improving long-term outcomes in R/R FL.^16,19,23

Conclusion

R/R FL presents a complex and evolving clinical challenge marked by biologic heterogeneity, diminishing response durations with successive therapies, and the absence of a universally accepted standard of care. Although typically indolent, FL in the relapsed setting can adopt a more aggressive course, resulting in poorer outcomes and increasingly difficult management. Conventional therapies, while initially effective, often fail to provide durable disease control in R/R settings, and cumulative toxicities can further compromise long-term QOL. Novel chemotherapy-free treatments offer promising new avenues for achieving sustained remission while maintaining tolerability across a broad range of patients, potentially reducing treatment-related toxicity without sacrificing efficacy. As the treatment landscape advances, clinicians must navigate increasing complexity in selecting therapy and sequencing, tailor approaches to a broad range of individual patient needs, and prioritize efficacy, tolerability, accessibility, and patient-centered outcomes. Addressing unmet needs in R/R FL will require continued innovation and integration of QOL considerations into both clinical trials and routine care.

Dr Maddocks is a professor of clinical internal medicine in the division of hematology at The Ohio State University in Columbus.

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