Clinical outcomes of the chemo-free approach in relapsed/refractory follicular lymphoma: A network meta-analysis

Relapsed/refractory follicular lymphoma (R/R FL) remains a clinically challenging condition, with progressively declining benefit across consecutive lines of therapy. While anti-Cluster of Differentiation 20 (CD20) antibodies remain the therapeutic backbone, the optimal targeted or immune-based partner remains undefined. A systematic review and network meta-analysis (NMA) of 5 phase III and 1 phase II trials (2500 patients) evaluated seven anti-CD20-based combination strategies. Primary end-points were overall survival (OS) and progression-free survival (PFS); secondary end-points included objective response rate (ORR) and grade ≥3 adverse events. Treatments were ranked using surface under the cumulative ranking (SUCRA) values. Immune-activating strategies ranked highest across efficacy end-points. Epcoritamab plus rituximab (R²) achieved the top SUCRA rankings for OS, PFS and ORR, while tafasitamab plus R² consistently ranked second, with a better safety profile. R² alone showed intermediate efficacy and good tolerability, whereas zanubrutinib plus anti-CD20 demonstrated modest efficacy with lower toxicity. Bortezomib and copanlisib-based combinations ranked lowest for efficacy, with phosphoinositide 3-kinase (PI3K) inhibitor-based regimens showing the least favourable benefit-risk profile. Anti-CD20 monotherapy was the safest but least effective option. This NMA indicates that immune-centric, anti-CD20-anchored combinations represent the most effective chemotherapy-free strategies for R/R FL. Combinations incorporating anti-CD19 or CD20/CD3 bispecific antibodies appear to offer deeper disease control, particularly in high-risk and rituximab-refractory disease.