Current landscape of frontline and relapsed follicular lymphoma trials Open Access

Follicular lymphoma (FL) is the most prevalent indolent B-cell non-Hodgkin lymphoma (B-NHL) worldwide, representing ∼20% of all NHL cases. In the United States, ∼14 000 new cases are diagnosed annually, making it a relevant concern for patients and health care providers.^1,2 Historically, FL has been considered incurable despite advances in treatment; however, some patients do achieve prolonged disease control. FL follows a relapsing-remitting course, with continuous patterns of recurrence and progressively shorter periods of disease control after each line of treatment.³ In addition, its high heterogenicity with varying clinical behavior makes management particularly nuanced.

Over the past 2 decades, the treatment landscape for FL has evolved significantly, particularly since the introduction of rituximab and other novel therapies. Rituximab marked a ground-breaking advance, but it is no longer a singular solution.⁴ Today, new therapeutic approaches are being explored, including novel immunotherapies, cellular therapies, and targeted therapies that aim to selectively eliminate cancer cells while minimizing damage to healthy tissues. There is growing discussion around the potential curability of FL, challenging the traditional view of the disease as incurable. Despite the broadening array of treatment options, determining the optimal sequence of therapies for FL remains a major challenge for clinicians, particularly for relapsed or refractory (R/R) FL.

In this review, we explore the current landscape of FL therapies, focusing on ongoing phase 3 trials that may provide clearer guidance on the most effective treatment strategies moving forward.

For limited-stage FL, defined as stage I or contiguous stage II, 24 Gy of local radiotherapy (RT) is associated with durable remission and is considered the standard of care (SOC).⁵ The Follicular Radiotherapy Trial (FoRT), which compared 24 Gy to 4 Gy in the frontline setting among 548 patients, demonstrated that lower dose of 4 Gy resulted in inferior local progression-free survival (PFS), with an estimated 3-year PFS difference of 19.8%.⁶ This finding suggests that reducing the radiation dose compromises local disease control and spurred interest in combining systemic therapy with RT in this patient population.

Building on the FoRT study concept, the FORTplus (NCT05045664) trial aims to evaluate whether the use of a more potent CD20 monoclonal antibody (mAb) can allow for a reduction in total RT dose.⁷ This multicenter study randomizes patients with limited-stage disease to receive either 24 Gy RT plus rituximab or 4 Gy RT plus obinutuzumab. The primary end point is complete remission rate (CRR), with PFS and overall survival (OS) as secondary end points. Obinutuzumab, considered a more potent CD20 mAb, may potentially offset the effects of reduced radiation dosing Table 1.

The GABEZO, multicenter phase 3 study (NCT05929222) is currently comparing 24 Gy RT alone against 24 Gy RT plus 8 doses of obinutuzumab for patients with limited-stage FL.⁸ With PFS as the primary end point, this trial aims to evaluate the benefits of adding systemic therapy. The trial will assess the potential immunosuppression toxicity from obinutuzumab, as well as the impact of an extended treatment duration on quality of life (QOL; 6 months for the combination arm compared with the 5-week course for 24 Gy RT).

Whereas the FORTplus study assesses the feasibility of reducing RT doses with a more potent CD20 mAb, the GABEZO study evaluates the effect of adding systemic therapy to RT. Both these trials will provide valuable insight on ways to limit RT toxicity, while preventing local and distant recurrence, and define the best strategies in managing limited-stage FL.

Low tumor burden FL is defined as patients with noncontiguous stage II or advanced stages who do not meet the Groupe d'Etude des Lymphomes Folliculaires criteria. The current SOC includes watchful waiting (W&W), and rituximab monotherapy with or without short-term maintenance.⁹ A randomized 1:1:1 study of rituximab induction vs rituximab maintenance (RM) vs W&W in this population demonstrated longer time to next treatment in the RM group without OS benefit.¹⁰ At 10-years follow-up, 29% of patients in the W&W group remained free of treatment. Rituximab retreatment approach is supported by the RESORT study.¹¹ Another study revealed similar response durability between short-term RM (4 weekly rituximab doses followed by 4 doses every 2 months) and long-term RM (4 weekly rituximab doses followed by every 2 months up to 5 years) supporting the use of short-term maintenance.¹² These observations underscore the excellent survival experienced by most patients with low tumor burden FL and the need to prioritize safe therapies. This sets a high bar for future therapies to replace current SOC, both in terms of efficacy and toxicity considerations.

A study in early development of rituximab suggested that vitamin D (Vit-D) deficiency impaired rituximab-mediated cellular cytotoxicity and Vit-D substitution might enhance the efficacy of rituximab.¹³ A pooled prospective evaluation on Vit-D levels of patients with FL enrolled in clinical trials revealed that low serum Vit-D levels are associated with inferior survival outcome.¹⁴ With that in mind, ILyAD, a phase 3, randomized, double-blind, placebo-controlled study examined the combination of rituximab with Vit-D, in patients with indolent lymphoma.¹⁵ Overall, 67% of 206 patients had low tumor burden FL. Although Vit-D supplements increased serum Vit-D level without added toxicity, there was no event-free survival benefit.

Based on the aforementioned studies, it appears that a bottleneck has been reached in terms of maximizing the use of CD20 mAb, whether through earlier treatment initiation, prolonged treatment duration, or addition of Vit-D. To address this, significant interest in the field shifted toward the use of novel therapies.

In recent years, bispecific antibodies made significant strides in the treatment of aggressive and indolent R/R B-NHL, such as diffuse large B-cell lymphoma (DLBCL) and FL.^16—18 Several pivotal studies of CD3×CD20 bispecific antibodies demonstrated high efficacy in heavily pretreated FL.^19—21 However, activation of T cells can lead to unique adverse events (AEs), such as cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS).

Mosunetuzumab, a CD3×CD20 bispecific antibody, demonstrated efficacy in the third-line R/R setting, with 60% CRR and a median PFS of 24 months in its phase 2 trial for patients with FL with ≥3 previous lines.¹⁹ The phase 2 MorningSun trial (NCT05207670) supported mosunetuzumab use in the frontline setting for patients with low tumor burden FL.²² Thirty patients were enrolled and the complete metabolic response rate was 83%. Low incidences of CRS (grade 1-2, 43%) and ICANS (grade 1, 7%) were observed. To build upon this concept, SWOG 2308 (NCT06337318), a multicenter phase 3 study compared rituximab monotherapy (8 doses: 4 weekly during induction followed by 5 cycles of rituximab every 8 weeks) with mosunetuzumab (for 8 cycles).²³ With PFS as the primary end point, this study aimed to challenge the concept of long-term cure by offering highly effective therapy while the tumor burden remains low but at the cost of potential added toxicity. Although mosunetuzumab is considered one of the safer bispecific antibodies, unique bispecific antibody toxicity remained. For patients with low tumor burden, it is crucial to carefully balance the benefits and risks to justify the use of more potent therapy.

For patients with high tumor burden FL, chemoimmunotherapy (CIT) are considered the SOC at front line, as demonstrated by the BRIGHT and StiL trials.^24,25 Although the RELEVANCE study revealed that rituximab-lenalidomide (R2) is as effective as CIT,²⁶ frontline R2 is not approved by US Food and Drug Administration/European Medicines Agency, but received compendium approval based on National Comprehensive Cancer Network recommendation.²⁷ Obinutuzumab was more efficacious over rituximab in the GALLIUM study.²⁸ However, ∼15% to 20% of patients experience disease progression within 24 months (POD24), which is associated with higher mortality risk.²⁹ Consequently, several ongoing frontline phase 3 clinical trials intend to address this unmet need.

A phase 1b/2 study (NCT04246086), combines mosunetuzumab with lenalidomide for untreated high disease burden FL, showed an impressive CRR of 82%.³⁰ This is followed by the MORNINGLYTE trial (NCT06284122), which compares mosunetuzumab-lenalidomide with CIT in the frontline setting. Both arms contain maintenance anti-CD20 with total treatment duration up to 30 months.³¹ PFS is the primary end point. In heavily pretreated R/R FL, PFS remains a meaningful indicator of disease control. Because FL progression is heterogeneous, patients with low tumor burden relapses may be monitored with regular assessments rather than initiating immediate next-line therapy. Time to next treatment may better reflect real-world practice, but it is influenced by both physician and patient decisions regarding when to initiate subsequent therapy. The application of Groupe d'Etude des Lymphomes Folliculaires criteria remains somewhat arbitrary, highlighting the need for more standardized criteria to inform treatment initiation and retreatment decisions, potentially incorporating the use of biomarkers to improve consistency and precision. In the FL frontline setting, PFS does not necessarily correlate well with OS, as shown by StiL, GALLIUM, and PRIMA trials.^25,28,32 Hence, OS end point remained important because it captures efficacy and short- and long-term toxicities of a certain treatment. As an indolent disease, newly diagnosed FL has a 10-year OS rate of >80%, necessitating long follow-up periods to detect meaningful difference in OS.^32,33 Although various treatment regimens may yield similar OS outcomes, therapies that provide longer treatment-free survival may be more appealing from a patient’s perspective.

Epcoritamab, another CD3×CD20 bispecific antibody, showed efficacy with 63% CRR and 18-month PFS of 49% in its phase 2 study of third-line FL.²⁰ EPCORE FL-2 (NCT06191744), is a phase 3 frontline trial comparing epcoritamab-R2 against CIT/R2.³⁴ This trial has dual primary end points: PFS and complete response rate at 30 months (CR30). Although CR30 is well validated in the CIT setting as an earlier surrogacy for PFS, it may require further validation in non-CIT settings.³⁵ Meanwhile, CR30 surrogacy was established during computed tomography scan era, but positron emission tomography (PET) scan is considered gold standard for response assessment these days.³⁶ Secondary end points for this trial include QOL outcomes, patient reported outcomes (PRO) according to Common Terminology Criteria for Adverse Events, and minimal residual disease (MRD) negativity rate. PRO according to Common Terminology Criteria for Adverse Events allows additional dimensions to detect AEs because we know underreporting of AE from health care provider is common. Unlike the MORNINGLYTE trial, rituximab was included in the experimental arm of this trial. The study suggested that some bispecific antibodies appear combinable with CD20 mAB because they target different epitopes, do not compete for Fc-γ receptors, and induce potent target-cell killing at low occupancy rates.³⁷ Although epcoritamab targets a different CD20 epitope (7D8) compared with rituximab, mosunetuzumab targets the same epitope (2H7).

A third CD3×CD20 bispecific antibody, odronextamab, was introduced to the FL treatment landscape based on the ELM-2 trial, which reported CRR of 73% and median PFS of 20.7 months in the third-line setting.²¹ The OLYMPIA-1 trial (NCT06091254) is comparing odronextamab monotherapy against CIT in frontline FL.³⁸ CR30 is the primary end point, and multiple QOL assessments as secondary end points (Table 2). Without lenalidomide partnership in this trial, efficacy and toxicity assessment solely depends on single-agent odronextamab.

The OLYMPIA-2 trial (NCT06097364) study on frontline FL therapy comprises 3 arms: odronextamab-CHOP (cyclophosphamide, doxorubicin, Oncovin [vincristine], and prednisone)/ CVP (cyclophosphamide, vincristine sulfate, and prednisone), odronextamab-CHOP/CVP with odronextamab maintenance, and rituximab-CHOP with RM.³⁹ Primary and secondary end points are the same as in OLYMPIA-1. OLYMPIA-2 will provide insights into the role of bispecific antibody maintenance in bispecific antibody–based induction regimens.

Although plenty of treatments are focusing on targeting CD20 using mAbs and bispecific antibodies, FL tumor cells do express CD19 universally. This spurred the clinical interest in targeting both CD20 and CD19, to improve further the efficacy. AZD0486 is a novel immunoglobulin G4 (IgG4) fully human CD3×CD19 bispecific antibody that was recently reported to be effective in R/R FL (NCT04594642).⁵⁷ The SOUNDTRACK-F1 (NCT06549595) frontline phase 3 trial is comparing AZD0486 plus rituximab against CIT, with PFS as the primary end point.⁴⁰ Although CD20 antibodies do not appear to affect the efficacy of subsequent CD3×CD20 bispecific antibodies, first-generation CD3×CD19 bispecific antibodies blinatumomab, and B-cell maturation antigen bispecific antibodies, raised concerns regarding T-cell exhaustion for subsequent chimeric antigen receptor T-cell (CAR-T) therapy with the same target.^61-63 At the same time, translational data demonstrated that, in contrast to the continuous exposure associated with blinatumomab infusion, intermittent dosing of bispecific antibodies, with treatment-free intervals, promotes T-cell expansion rather than exhaustion.⁶³ These findings suggest that dosing strategies may significantly influence T-cell fitness and therapeutic outcomes. Future mature clinical data will be crucial to clarify the role of intermittent dosing anti-CD19 bispecific antibodies and their potential impact on the efficacy of subsequent CD19-targeted CAR-T therapies.

CIT has remained SOC in frontline FL, but tolerability can be challenging in patients who are unfit. Efforts to reduce its toxicity while maintaining efficacy through a response-adapted approach are being explored in the FIL-FOLL19 trial (NCT05058404).⁴¹ In this trial, patients receive 4 cycles of CIT induction, followed by PET scan and MRD assessment using BCL2/IgH rearrangement in the peripheral blood. Patients with PET CR and MRD negativity are randomized to either the standard arm (2 additional cycles of CIT, totaling 6) or the experimental arm, which omits further CIT. The primary end point is PFS, with QOL as one of the secondary end points. This trial recalls the FOLL12 study, which used a response-adapted approach to determine postinduction treatment strategies.⁶⁴ In FOLL12, the response-adapted arm showed an inferior PFS compared with the standard RM arm, with 3-year PFS of 72% vs 86%, respectively (P < .001).

As previously highlighted in the FOLL12 study, the practicality of using peripheral blood BCL2/IgH rearrangement as MRD assessment in the FOLL19 trial poses challenges, including technical limitations and lower sensitivity. These factors may limit the applicability of this approach in real-world settings. Conversely, circulating tumor DNA (ctDNA) offers a promising alternative, with the potential to overcome these limitations through improved sensitivity and broader clinical feasibility.

ctDNA, also known as tumor-derived cell-free DNA, is released into the peripheral blood by tumor cells after biological processes of apoptosis, proliferation, and necrosis. Next-generation sequencing–based immunoglobulin sequencing, which identifies and tracks unique disease-associated immunoglobulin sequences (IgH, IgK, and IgL) in blood or bone marrow samples, best known as clonoSEQ commercially, is currently being explored in various B-cell malignancies.^65-67 This method proved highly tumor specific, with a low background error rate but limited by the total input DNA. This impairs the performance of the assay when ctDNA levels are low. At a single point at end of treatment (EOT), the sensitivity to detect relapses was ∼30%.⁶⁷ 

In contrast, a different MRD detection platform using the phased variant enrichment and detection sequencing (PhaseED-seq), has shown utility in detecting and quantifying ctDNA at levels as low as 1 part per million.⁶⁸ This method takes advantage the proximity of single-nucleotide variants in the BCL genome, and detects and tracks multiple somatic variants located on the same cell-free DNA molecule. This resulted in higher sensitivity, translated to more reliable detection of EOT MRD of up to 80% to 90%.^69,70 Several studies in DLBCL have demonstrated that PhaseED-seq correlates strongly with EOT disease status, offering superior sensitivity and specificity compared with PET scans.^70-72 Early data suggest that ctDNA could also be useful in the field of FL, predict time to first treatment in untreated patients, and assess treatment response and outcomes.^73,74 However, data on MRD in FL using either clonoSEQ or PhaseED-seq in FL remains limited compared with DLBCL. The recognition and understanding of ctDNA in DLBCL has improved over years, leading to its recommendation by the National Comprehensive Cancer Network guidelines as an EOT assessment modality for patients with DLBCL with positive PET scans, when a biopsy is not feasible.²⁷ 

Standing at the forefront of these exciting frontline phase 3 trials, there is hope that we may finally answer the longstanding question of curing FL, without compromising toxicity and QOL. Several important questions remain to be addressed: can we treat without chemotherapy? Are rituximab or lenalidomide essential partners for CD3×CD20 bispecific antibodies? What is the role of maintenance in bispecific antibody therapy? Can we revive response-adapted treatment approaches in FL?

Autologous anti-CD19 CAR-T therapies have been a breakthrough for B-NHL, including FL. These genetically engineered T cells recognize CD19 on B cells and initiate cytotoxic antitumor activity independent of major histocompatibility complex (MHC) presentation.⁷⁵ Although this MHC independence is a key advantage, it also limits CAR-T ability to recognize intracellular tumor-associated antigen, which require MHC-mediated presentation.

Three CAR-T products, axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel), are approved for R/R FL in the third-line setting. Axi-cel, which uses a CD28 costimulatory domain, showed high efficacy in the ZUMA-5 trial (FL cohort: CRR, 79%; median PFS, 57 months) but with notable toxicity (grade ≥3 CRS, 6%; grade ≥3 ICANS, 15%). Tisa-cel and liso-cel, both using 4-1BB domains, demonstrated strong efficacy with lower toxicity. In the ELARA trial (median 4 previous lines), tisa-cel achieved a CRR of 68% and 3-year PFS of 53%, with no grade ≥3 CRS and only 1% ICANS. In TRANSCEND FL (≥2 previous lines), liso-cel reported a CRR of 94% and 2-year PFS of 73%, with 1% grade ≥3 CRS and 2% ICANS. These results support the growing role of CAR-T therapy in R/R FL, with ongoing trials aiming to further optimize outcomes Table 3.

The ZUMA-22 trial (NCT05371093) is an ongoing phase 3 study examining axi-cel in comparison with SOC for patients with R/R FL who have had at least 2 previous lines of treatment.⁴² Notably, this study permits the inclusion of patients with POD24 in the second-line setting. Primary end point is PFS, with secondary end points including various QOL assessments. Importantly, this study incorporate transition into a long-term follow-up study lasting up to 15 years from randomization, which will provide valuable insights into the long-term effects of CAR-T therapy Table 4.

For tisa-cel, the LEDA trial (NCT05888493), building on the findings of the ELARA study, is comparing tisa-cel with SOC for patients with FL with at least 2 previous lines of treatment.⁴³ Unlike ZUMA-22, this trial does not include a separate cohort for patients with POD24 in the second-line setting, which may influence the clinical positioning of tisa-cel, particularly if axi-cel gains approval for use in this high-risk subgroup.

The planned phase 3 TRANSFORM FL trial (NCT06313996) will compare liso-cel with SOC in the second-line setting, with PFS as the primary end point, and PFS-2 (defined as the time from start of current therapy to disease progression or death on next line of therapy) among the secondary end points.⁴⁴ PFS-2 is an interesting end point, because it assesses the impact of second-line anti-CD19 CAR-T therapy on subsequent lines of treatment. Although all the aforementioned anti-CD19 CAR-T studies allow SOC relapsed regimens as control arms, these are limited to either Bendamustine-Rituximab (BR)/R-CHOP or R2 therapy.

Although CD3×CD20 bispecific antibodies are being explored in first-line trials, there are ongoing phase 3 trials evaluating their use in the R/R setting. The CELESTIMO trial (NCT04712097) compares mosunetuzumab-lenalidomide with R2 in the second-line setting.⁴⁵ The primary end point is PFS. Practical application of this trial may be influenced by results from frontline bispecific antibody trials. Similarly, the EPCORE FL-1 trial (NCT05409066) is investigating epcoritamab plus R2 against R2 in second line.⁴⁶ This trial adopts a finite epcoritamab treatment duration, with maximum 12 cycles of epcoritamab-R2. This provides insight into the durability and feasibility of retreatment, as well as facilitate comparison with other bispecific antibodies. Finally, the OLYMPIA-5 trial (NCT06149286) is a phase 3 study comparing odronextamab-lenalidomide with R2 in the second line, with PFS as the primary end point, with multiple QOL secondary end points.⁴⁷ It will be interesting to see how these 3 CD3×CD20 bispecific antibodies challenge the current second-line space, which is predominantly occupied by R2.

Because of its epigenetic alterations, FL often harbors enhancer of Zeste homolog (EZH2) mutations.⁷⁶ Tazemetostat, an EZH2 inhibitor, is approved for use in R/R FL, showing efficacy in both EZH2-mutated and wild-type patients.⁵⁸ The overall response rate ranges from 35% to 69%, with median PFS of ∼11 to 14 months. Tazemetostat is an oral therapy with favorable toxicity profile. A phase 3 trial, SYMPHONY-1 (NCT04224493), is comparing R2-tazemetostat with R2-placebo.⁴⁸ Tazemetostat or placebo is administered for 2 years, with PFS as the primary end point. This study, by including a placebo arm, provides valuable insights into the toxicity differences between doublet and triplet combinations. It also separates patients into cohorts based on their EZH2 mutation status, allowing for a more granular understanding of efficacy.

In the ROSEWOOD study, obinutuzumab and zanubrutinib (ZO) offered a synergistic effect in R/R FL.⁴⁹ The MAHOGANY trial (NCT05100862) is a phase 3 study comparing ZO with R2 in patients with R/R FL.⁷⁷ Zanubrutinib is administered continuously until progression, whereas lenalidomide in the R2 arm is limited to 12 cycles. PFS is the primary end point, with QOL measurement among the secondary end points. It is important to consider the differences in treatment duration and anti-CD20 partner when interpreting the results. Nevertheless, ZO may be an attractive option for patients who are unfit or frail, given its favorable oral administration route after obinutuzumab induction.

Unlike traditional immunomodulatory drugs, cereblon E3 ligase modulators (CELMods) have been designed to have improved potency and selectivity, leading to greater antitumor activity and lesser side effects. Several CELMods, such as golcadomide and iberdomide, are now being investigated in several B-cell malignancies.^59,60,78 GOLSEEK-4 (NCT06911502) is a phase 3 trial that compares the efficacy and safety of golcadomide in combination with rituximab against investigator choice (R2 or CIT) in patients with R/R FL who received at least 1 previous line of CD20 mAb and alkylating agent.⁵⁰ The primary end point is PFS, with MRD data and QOL assessment among the secondary end points. In contrast to the other aforementioned R/R FL phase 3 bispecific antibodies and targeted therapies, this study aims to question the role of lenalidomide in the second line and beyond. Lenalidomide is known to be myelosuppressive and prothrombotic, with potential dermatologic and gastrointestinal side effects, which sometimes affect patient QOL and tolerability.

The AUGMENT study established the important role of 12 cycles of R2 as a second-line treatment for R/R FL.⁷⁹ Recently, the inMIND study (NCT04680052) demonstrated that the addition of tafasitamab, a CD19 mAb, to R2 significantly improved PFS compared with R2 alone in patients with R/R FL.⁵⁴ Notably, R2 has become a common control arm in several ongoing phase 3 trials for relapsed disease, including studies evaluating bispecific antibodies, tazemetostat, and zanubrutinib. This consistent use of R2 as a comparator provides a valuable benchmark for cross-trial comparisons, enabling better assessment of the relative efficacy of emerging therapies.

Unlike CELESTIMO and OLYMPIA-5, the EPCORE FL-1 trial excludes anti-CD20 monotherapy as a previous line of treatment. This means that all enrolled patients have had at least 1 line of anti-CD20 in combination with chemotherapy, reflecting a potentially higher-risk cohort, including those who experienced POD24 after CIT.⁸⁰ 

Several large-scale trials, such as SYMPHONY-1 and CELESTIMO, have rapidly advanced from small phase 1 studies to large, randomized phase 3 trials. Although this accelerated development is welcomed, there is a concern that such rapid progression may overlook or underestimate potential toxicities, particularly the less well-characterized immune-related AEs associated with bispecific antibodies.

Earlier use of CAR-Ts in DLBCL allows better T-cell fitness with promising outcome (eg, ZUMA-12, ZUMA-7).^81,82 However, in FL, this approach may result in a shorter time interval between frontline bendamustine exposure and CAR-T apheresis. A study indicated that bendamustine exposure <9 months before CAR-T apheresis had a detrimental effect on CAR-T efficacy.⁸³ Although the impact of previous bendamustine on bispecific antibody efficacy is less pronounced, this is based on limited number of retrospective cases.^84,85 As these trials unfold, we will gain valuable insights into the best strategies for positioning CAR-Ts in FL.

With insights gained from the ongoing trials, there is growing potential to better define the optimal second-line treatment for high-risk patients with R/R FL, particularly those experiencing POD24. Although POD24 is widely recognized as a high-risk event, its current definition has limitations; it may encompass patients with transformed LBCL as well as those with persistent indolent FL. A study demonstrated differences in survival outcome based on histology at the time of progression.⁸⁶ An added layer of heterogeneity stems from the variable feasibility of obtaining biopsies from the most suspicious sites at each relapse. These challenges contribute to variability in baseline risk among patients with POD24 enrolled in R/R FL trials, potentially confounding the interpretation of outcomes. As such, there is an urgent need for more precise a priori biomarkers to enhance risk stratification and guide individualized treatment selection.

Although we are excited and eager to hear the outcomes of these trials, it is important to note that their results may not be directly applicable to patients who are frail or those who are unfit for CIT or lenalidomide as part of the control arms. For older adults, incorporating geriatric assessments into the inclusion criteria could help address this issue, providing a more standardized and objective approach to patient recruitment.⁸⁷ 

Given the long and evolving course of FL, incorporating patients’ values and preferences is essential for shared decision-making.⁸⁸ A qualitative study found that patients with FL prefer a holistic, individualized approach that accounts for lifestyle, side effect concerns, and treatment burden.⁸⁹ Other studies highlight that physicians and patients may prioritize different factors: while both value life expectancy and disease control, patients are often more willing to trade some disease control for simpler administration, lower toxicity, and fewer monitoring visits.^90,91 As efficacy differences between active therapies narrow, PROs related to toxicity and QOL are becoming increasingly important. Going forward, the key differentiator in treatment selection may be the option that offers the lowest toxicity and best QOL outcomes.⁹² Unfortunately, there is currently a lack of standardization in QOL assessments across various clinical trials particularly FL-specific QOL scale, even within the same therapeutic area. This complicates meaningful comparisons between treatment arms using disease-specific measures.

Lastly, although CAR-Ts, bispecific antibodies, and targeted therapies are poised to affect the future treatment landscape of lymphoma, health care disparities remain a critical challenge. This includes practice variations between community-based and academic centers, and low- to middle-income countries’ accessibility to novel therapies. Given the rising costs of novel therapies, well-designed cost-effectiveness studies are essential to justify their use in earlier-line treatments.

With numerous antilymphoma strategies being tested in ongoing phase 3 trials, the future of FL treatment is exciting. We hope to establish a refined SOC that meets the diverse needs of patients, including the potential for a cure, minimizing toxicity, and maintaining a high QOL. As science often unfolds, the results from these trials will likely raise new questions. Careful methodological evaluation and thoughtful discussion will be crucial in guiding future studies, enabling the practice of personalized medicine tailored to each patient’s needs.

Figures on graphical abstract were created with BioRender.com.

Contribution: L.C.K.N and C.C designed the research, summarized the data, and wrote and approved the manuscript.

Conflict-of-interest disclosure: C.C. reports consultancy with, and have received honoraria from Bristol Myers Squibb, AbbVie, Genentech/Roche, and Genmab; received research funding from Genmab, Gilead, and Genentech; and reports a leadership role with the American Society of Hematology and the Lymphoma Research Foundation. L.C.K.N. declares no competing financial interests.

Correspondence: Carla Casulo, Medicine, University of Rochester Medical Center, 601 Elmwood Ave, Box 704, Rochester, NY 14642; email: carla_casulo@urmc.rochester.edu.