Background
Phase III, double-blind, placebo-controlled RCT. 358 patients (295 with FL, 63 with MZL) with R/R indolent lymphoma who were not rituximab-refractory. Tested lenalidomide + rituximab (R²) versus placebo + rituximab as a chemotherapy-free salvage approach.
Interventions and follow up
Arm A: Lenalidomide 20mg PO days 1–21 q28d × 12 cycles + rituximab 375mg/m² IV weekly × 4 (cycle 1), then day 1 of cycles 2, 4, 6, 8 (5 total doses)
Arm B: Placebo PO days 1–21 q28d × 12 cycles + rituximab 375mg/m² IV (same schedule)
Primary endpoint: Progression-free survival (investigator-assessed, FL population)
Median follow-up: ~6 years (5-year update)
Arm B: Placebo PO days 1–21 q28d × 12 cycles + rituximab 375mg/m² IV (same schedule)
Primary endpoint: Progression-free survival (investigator-assessed, FL population)
Median follow-up: ~6 years (5-year update)
Results
Median PFS (FL): 39.4 vs 14.1 months, HR 0.46, 95% CI 0.34–0.62, P<.001
5-year OS (FL): HR 0.59, 95% CI 0.37–0.95, P=.03 — significant in 5-year update
ORR: 78.2% vs 52.8%; CR 34.0% vs 18.4%
MZL subgroup PFS: HR 0.69 — not statistically significant
5-year OS (FL): HR 0.59, 95% CI 0.37–0.95, P=.03 — significant in 5-year update
ORR: 78.2% vs 52.8%; CR 34.0% vs 18.4%
MZL subgroup PFS: HR 0.69 — not statistically significant
Adverse events
Hematologic/infectious (R² vs R-placebo): Grade 3–4 neutropenia 50% vs 13%; grade ≥3 infections 16.3% vs 8.4%; febrile neutropenia 3.9% vs 1.7%.
Other: Cutaneous reactions 5.0% vs 2.2%; treatment discontinuation due to AEs 11.6% vs 5.0%.
Other: Cutaneous reactions 5.0% vs 2.2%; treatment discontinuation due to AEs 11.6% vs 5.0%.
Conclusions
R² significantly improved PFS in R/R FL (median PFS 39.4 vs 14.1 months, HR 0.46), with an OS benefit emerging at 5-year follow-up (HR 0.59), establishing R² as a preferred chemotherapy-free option for non-rituximab-refractory R/R FL.
Key Limitations
Grade 3–4 neutropenia in 50% of patients — substantially higher than rituximab alone. The MZL subgroup (n=63) showed no significant PFS benefit, limiting extrapolation to MZL. Lenalidomide requires a REMS program and carries teratogenicity risk. The rituximab rechallenge design may limit benefit in patients with prior rituximab maintenance or refractory disease.
Clinical Context
The FDA approved lenalidomide (Revlimid) + rituximab for R/R FL and MZL in 2019, based on AUGMENT; EMA approval followed. R² is an ESMO-recognized preferred option for R/R FL in non-rituximab-refractory patients. With bispecifics (mosunetuzumab, epcoritamab) now available and showing impressive results, the role of R² may shift toward earlier lines or specific patient populations.