Introduction: Follicular lymphoma (FL) is the most common indolent B-cell non-Hodgkin lymphoma. In most cases, it presents as asymptomatic, advanced-stage disease (stage III-IV). The GELF criteria are widely used to define treatment indications. For patients with high tumor burden and/or symptoms, immunochemotherapy (ICT) followed by rituximab maintenance (R-M) is the standard of care. Although FL has historically been considered incurable, long-term data from studies such as PRIMA, one-third of advanced FL patients treated with ICT/R-M remained relapse-free at 10 years and introduced the concept of “functional cure.” This study aims to analyze the outcomes of advanced FL patients treated with ICT/R-M at two academic centers from Argentina with long-term follow-up.

Materials and Methods: This is a retrospective study including patients diagnosed with advanced-stage FL treated with ICT and R-M between January 2010 and January 2025 at two high-complexity academic centers. The primary endpoint was progression-free survival (PFS), and secondary endpoints included overall survival (OS) and treatment-related toxicity. Patients who initiated R-M were included regardless of completion. Kaplan-Meier curves and log-rank tests were used for survival analysis. Univariate and multivariate analyses were performed using Cox regression.

Results: A total of 122 patients were included, with complete data available for 108. Median age was 62 years (range: 32–84), and 60% were female. FLIPI distribution was low (15%), intermediate (28%), and high (57%). ICT regimens included R-CHOP-21 (66%), BR (22%), R-CVP (8%), and R-miniCHOP (4%). Median age by regimen was R-CHOP: 57, BR: 70 and R-CVP: 71. GELF criteria were met in 51% of cases. Complete response was achieved in 96% of patients, with 3% reaching CR during R-M. One treatment-related death occurred due to septic shock. Relapse occurred in 22 patients (18%), 7 classified as POD24. Eight, underwent salvage therapy with high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation, 7 of whom were POD24.

At a median follow-up of 60 months, 5-year OS was 90% (95% CI: 83.3–97.5) and PFS 82.6% (95% CI: 74.6–91.5). Seventeen patients (13%) remain in CR ≥10 years, 24 (19%) ≥8 years, and 39 (31%) ≥6 years post-treatment. Five-year OS by regimen was: R-CHOP 99%, BR 80% and R-CVP 60%, with significant OS differences between R-CHOP/BR vs R-CVP (p<0.001). No statistically significant differences in PFS were observed among regimens. PFS in GELF-positive vs GELF-negative patients was 82% and 83.1% respectively (p=NS). Among POD24 vs non-POD24 patients, 5-year OS was 33% vs 93% (p<0.001). Overall mortality was 13% (17 patients), with 6 death attributed to disease progression.

Post-treatment hypogammaglobulinemia (IgG <500 mg/dL) occurred in 17%. In multivariate analysis, hypogammaglobulinemia (HR=4,35; IC95%: 0,79–23,9; p=0,091), secondary neoplasms (HR=1,79; IC95%: 0,25–12,8; p=0,561), and heart failure (HR=3,67; IC95%: 0,32–42,6; p=0,299) did not significantly impact OS.

Conclusions: ICT followed by R-M significantly improved PFS and OS compared to historical pre-rituximab data. A substantial proportion of patients remain in long-term remission without relapse or further treatment. Treatment-related mortality was <5%. R-CHOP/R-M showed the best PFS and OS outcomes, though potential age-related selection bias exists. Early treatment without GELF criteria did not improve outcomes. POD24 remains a strong negative prognostic factor. Hypogammaglobulinemia was the most relevant long-term adverse event but did not impact OS. In summary, ICT/R-M has significantly improved the prognosis of advanced FL, with many patients achieving what may be considered a “functional or even definitive cure”.

Keywords: Follicular Lymphoma, funcional cure, survival, hypogammaglobulinemia

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2025
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