Background
Phase III, open-label RCT. 1,030 patients with previously untreated advanced-stage follicular lymphoma (grades 1–3a, high tumor burden). Tested rituximab + lenalidomide (R², chemotherapy-free) versus rituximab + investigator-choice chemotherapy (R-CHOP, R-CVP, or R-bendamustine), each followed by rituximab maintenance.
Interventions and follow up
Arm A: Rituximab 375mg/m² IV + lenalidomide 20mg PO days 2–22 q28d × 6 cycles, then lenalidomide 10mg days 2–22 × 12 additional cycles; rituximab maintenance q8w × 12 doses
Arm B: Rituximab + chemotherapy (investigator's choice: CHOP, CVP, or bendamustine) for 6–8 cycles; rituximab maintenance q8w × 12 doses
Primary endpoint: CR/CRu rate at 120 weeks and progression-free survival
Median follow-up: ~10 years (final analysis)
Arm B: Rituximab + chemotherapy (investigator's choice: CHOP, CVP, or bendamustine) for 6–8 cycles; rituximab maintenance q8w × 12 doses
Primary endpoint: CR/CRu rate at 120 weeks and progression-free survival
Median follow-up: ~10 years (final analysis)
Results
10-year PFS: 46.4% vs 46.6%, HR 1.03, 95% CI 0.84–1.27 — not significant
10-year OS: 82.4% vs 81.1% — not significant
CR rate at 120 weeks: 48.0% vs 53.0% — not significant
POD24 rate: 18.6% vs 20.2%
Median PFS (both arms): ~110 months
10-year OS: 82.4% vs 81.1% — not significant
CR rate at 120 weeks: 48.0% vs 53.0% — not significant
POD24 rate: 18.6% vs 20.2%
Median PFS (both arms): ~110 months
Adverse events
Hematologic/infectious (R² vs R-chemo): Grade ≥3 AEs 71% vs 78%; grade ≥3 neutropenia 52% vs 55%; grade ≥3 infections 17% vs 19%.
Secondary malignancies: SPMs 2.11 vs 1.92 per 100 patient-years — numerically higher with R² but not statistically significant.
Secondary malignancies: SPMs 2.11 vs 1.92 per 100 patient-years — numerically higher with R² but not statistically significant.
Conclusions
R² achieved equivalent 10-year PFS and OS compared to R-chemoimmunotherapy in frontline advanced FL, establishing R² as a validated chemotherapy-free alternative with comparable long-term efficacy and acceptable toxicity.
Key Limitations
The R² arm demonstrated only equivalence, not superiority, and CR rates were numerically lower. Long treatment duration (18 months of lenalidomide) versus shorter chemoimmunotherapy induction. Numerically higher SPM rate warrants monitoring. Lenalidomide requires REMS and is not approved for frontline FL in the US (only the R/R setting). GALLIUM showed PFS superiority of G-chemo over R-chemo, but no direct comparison of G-chemo versus R² exists.
Clinical Context
RELEVANCE demonstrates that R² is a legitimate chemotherapy-free option for frontline FL achieving equivalent long-term outcomes to chemoimmunotherapy. ESMO recognizes R² as an alternative frontline option, though it is not FDA-approved in the frontline setting (only R/R FL). For patients wishing to avoid chemotherapy, R² or watch-and-wait are the main options. POD24 remains the key adverse prognostic factor regardless of regimen.