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refractory follicular lymphoma, with a 79% reduction in the risk of disease progression or death. However, this efficacy comes at the cost of substantially increased grade ≥3 adverse events, particularly infections, raising concerns about toxicity management, patient selection, and real-world applicability. While the regimen offers a promising chemotherapy-free option, unresolved questions regarding long-term survival, tolerability in older or comorbid populations, and access in resource-limited settings remain. Further research is needed to refine patient selection and optimize supportive care.The EPCORE FL-1 trial, published in The Lancet, establishes fixed-duration epcoritamab combined with lenalidomide and rituximab (R ² ) as superior to R ² alone in relapsed or refractory follicular lymphoma, achieving a 79% reduction in the risk of disease progression or death (hazard ratio 0•21, p<0•0001).¹ As the first phase 3 study to report on a bispecific antibody combination in this setting, these results position epcoritamab plus R ² as a potential new standard for second-line or subsequent therapy. However, while the efficacy signal is undeniable---complete response rate nearly doubling from 50% to 83%---the substantial increase in grade ≥3 adverse events (90% vs 68%) and infectious complications raises critical questions about patient selection, toxicity management, and real-world generalisability that warrant closer examination.The magnitude of benefit observed with epcoritamab plus R ² is The critical unanswered question is whether these toxicities will prove manageable in real-world populations less selectedin terms of general health status variablesthan trial participants. EPCORE FL-1 enrolled patients with median age 60--63 years, good performance status, and excluded those with significant comorbidities. Community oncology practices treating older adults with cardiovascular disease, renal impairment, or baseline cytopenias may encounter higher rates of treatment discontinuation or infectious mortality than reported here.Notably, 19% of epcoritamab-R² recipients discontinued treatment due to adverse events---primarily infections---raising concerns about whether less resilient patients can complete the intended 12-cycle course.Moreover, tolerability of the triplet may negatively affect relative dose intensity (RDI). The relationship between RDI of the triplet and its components and long-term efficacy outcomes (PFS, OS) should be evaluated during long-term follow-up. Despite subsequent salvage therapies, such analyses could yield valuable data to outline a baseline patient profile foreboding likely inadequate treatment tolerance.The open-label design, while acknowledging the obvious advantages in this context-simplifying logistics, enabling safe and timely management of immune toxicities, and avoiding placebo procedureswhile still maintaining scientific rigor when objective endpoints are used, introduces potential bias in adverse event reporting and subsequent therapy decisions. Although independent review committee assessment of primary endpoints mitigates efficacy bias, toxicity assessments remain ⁷ This discrepancy reflects inclusion of higher-risk patients in EPCORE FL-1---all required GELF criteria for active therapy, and 41% had POD24.It is critical to emphasise that AUGMENT excluded rituximab-refractory patients and did not mandate treatment by GELF criteria. The EPCORE FL-1 population, comprising patients with prior immunochemotherapy and high rates of POD24 and double-refractory disease, represents a significantly higher-risk group. This context is essential to prevent readers from undervaluing R ² in lower-risk relapsed settings.Comparisons with the recently reported inMIND trial, where tafasitamab plus R ² achieved a 57% risk reduction with lower complete response rates (45%) but also lower grade ≥ 3 infections (18%), highlight divergent benefit-risk profiles across CD19-directed and CD20-directed Additionally, the issue of grade 3B follicular lymphoma is highly relevant in another sense. While 3B FL patients are generally considered eligible for DLBCL regimens per guidelines and are typically excluded from trials like EPCORE FL-1, occult transformation can be unexpectedly high (76% in the Freeman retrospective analysis). ¹ ¹ A potential tissue sample reanalysis in the POD24 subgroup would be meaningful -though likely not feasible-with a re-evaluation of transformed FL versus true POD24 efficacy correlates. Whether epcoritamab-R ² can prevent or delay transformation events remains unknown, as event-free survival data were immature at analysis.From a global oncology equity perspective, epcoritamab-R ² presents challenges. Subcutaneous administration facilitates outpatient delivery, but requirements for CRS monitoring, infection prophylaxis, and management of prolonged cytopenias demand healthcare infrastructure not universally available. In low-resource settings where R² alone may already be inaccessible, adding a costly bispecific antibody risks widening disparities. Cost-effectiveness analyses will be essential to guide reimbursement decisions and prioritisation within national formularies.With upcoming regulatory HTA assessments, future EPCORE FL-1 cost-effectiveness models versus R ² , mosunetuzumab, tafasitamab-R ² , and CAR-T will commence.The observation that quality of life (FACT-Lym scores) was preserved during treatment provides some reassurance, but these data derive from highly selected trial participants with high baseline scores. Mean change analyses can mask significant deterioration experienced by patients who suffer serious adverse events, such as hospitalisations for infections.Future analyses should report the proportion of patients experiencing clinically meaningful deterioration, not merely average scores, to better capture the tolerability landscape. Thus, while the regimen did not lead to net QoL deterioration at the population level---likely due to the benefit of disease control---this finding should not be interpreted as uniform tolerability across all patients.Where does epcoritamab-R ² fit among emerging options? Compared with tafasitamab-R ² , it offers deeper responses but higher toxicity.Compared with CAR T-cell therapy---curative-intent but logistically Fourth, dedicated studies in bendamustine-exposed and older populations are needed to guide patient selection.For now, epcoritamab plus R² sets a new efficacy benchmark in relapsed follicular lymphoma. The challenge for clinicians will be translating this benefit to real-world patients while mitigating the accompanying toxicity burden---a balance that will define whether this regimen becomes universally adopted or reserved for carefully selected candidates.