Final RELEVANCE Data Affirm R2 as Chemo-Free Alternative in Untreated FL

According to the final analysis of the phase 3 RELEVANCE trial (NCT01476787; NCT01650701) published in Blood, the chemotherapy-free combination of lenalidomide (Revlimid) plus rituximab (Rituxan), known as R2, produced 10-year efficacy comparable to rituximab-based immunochemotherapy in patients with previously untreated advanced follicular lymphoma (FL).¹

At a median follow-up of 118.2 months, the median progression-free survival (PFS) by independent review committee assessment was 110.6 months with R2 compared with 102.8 months with immunochemotherapy, a difference that did not reach statistical significance (P =.80). The corresponding 10-year PFS rates were 46.4% and 46.6% with R2 and immunochemotherapy, respectively.

Median overall survival (OS) and median time-to-next-lymphoma-treatment (TTNLT) were not reached in either treatment group at the time of this analysis. The 10-year OS rates were 82.4% with R2 and 81.1% with immunochemotherapy, and the 10-year TTNLT rates were 62.2% with R2 and 66.3% with immunochemotherapy.

Safety Profile and Second Primary Malignancies

The long-term safety analysis showed no new safety signals with either regimen after a decade of follow-up. Grade 5 treatment-emergent adverse events occurred in 15 patients (1.5%) across the study population.

Second primary malignancies (SPMs) were reported in 164 patients, accounting for 207 total events; this included 79 patients (15.6%) in the R2 group and 85 patients (16.9%) in the immunochemotherapy group. Most SPMs were solid tumors. Nonmelanoma skin cancers occurred in 22 patients (4.3%) in the R2 group and 32 patients (6.4%) in the immunochemotherapy group. The cumulative incidence of SPMs across both arms was 2.11 cases per 100 patient-years (95% CI, 1.80-2.46), with no statistically significant difference between treatment groups.

Histologic transformation to a more aggressive lymphoma subtype remained uncommon in long-term follow-up. Among patients who had not transformed within the first 24 months, only 9 transformation events occurred afterward, 3 in the R2 group and 6 in the immunochemotherapy group.

A total of 87 deaths occurred in each of the 2 study groups, with the investigators noting that most deaths were attributable to lymphoma progression and to SPMs.

About the RELEVANCE Trial and Clinical Context

The global, randomized, open-label RELEVANCE trial enrolled 1030 adults with previously untreated grade 1 to 3a FL, randomly assigning 513 patients to R2 and 517 patients to immunochemotherapy.^2,3 Immunochemotherapy regimens included investigator's choice of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); rituximab plus bendamustine (R-B); or rituximab plus cyclophosphamide, vincristine, and prednisone (R-CVP).

RELEVANCE was designed to evaluate whether a chemotherapy-free immunomodulatory approach could match the efficacy of standard immunochemotherapy induction, an approach that has been a mainstay of frontline FL treatment given consistent, durable responses reported in the years following the introduction of rituximab-based regimens. The trial's primary end points at the time of initial reporting included the complete response, confirmed or unconfirmed, rate at 120 weeks and PFS by independent review.

The investigators concluded that this 10-year follow-up confirms R2 as a durable, chemotherapy-free alternative to immunochemotherapy for patients with previously untreated advanced FL, with comparable long-term efficacy and a comparable long-term safety profile, including rates of SPMs, between the 2 approaches.

“The final analysis of RELEVANCE confirmed the absence of differences in efficacy outcomes between R2 and [immunochemotherapy] and the lack of new safety concerns, positioning R2 as a valid chemo-free alternative for patients with previously untreated, advanced FL,” study authors Gower et al concluded.¹ “We believe these 10-year follow-up results constitute a benchmark for long-term expectations and comparisons with new promising chemo-free combinations currently tested in the frontline setting of FL.”

The findings thus add to the long-term evidence base for chemotherapy-free induction strategies in FL and may inform discussions of frontline regimen selection for this patient population, particularly in weighing the toxicity profiles associated with cytotoxic chemotherapy backbones against those of immunomodulatory approaches.

Findings From the RELEVANCE Trial in Follicular Lymphoma

REFERENCES

1. Gower N, Feugier P, Westin J, et al. Lenalidomide plus rituximab for previously untreated advanced follicular lymphoma: the 10-year RELEVANCE trial analysis. Blood. 2026;147(25):3061-3068. doi:10.1182/blood.2026033126

2. Combined Rituximab and Lenalidomide Treatment for Untreated Patients With Follicular Lymphoma (RELEVANCE). ClinicalTrials.gov. Updated May 14, 2025. Accessed July 21, 2026. https://clinicaltrials.gov/study/NCT01476787

3. A Phase 3 Open Label Randomized Study to Compare the Efficacy and Safety of Rituximab Plus Lenalidomide (CC-5013) Versus Rituximab Plus Chemotherapy Followed by Rituximab in Subjects With Previously Untreated Follicular Lymphoma (RELEVANCE). ClinicalTrials.gov. Updated September 25, 2025. Accessed July 21, 2026. https://clinicaltrials.gov/study/NCT01650701