Chemotherapy-Free Combination Shows Efficacy in Untreated Follicular Lymphoma

The randomized, global, phase III RELEVANCE trial showed that a regimen of lenalidomide and rituximab (R2) had similar safety and efficacy to a rituximab-based chemotherapy regimen (R-chemo) in patients with previously untreated follicular lymphoma (FL).

This is the first randomized trial to demonstrate the efficacy of a chemotherapy-free regimen in this setting, lead author Nathan Hale Fowler, MD, from the University of Texas MD Anderson Cancer Center, noted during his presentation at the 2018 ASCO Annual Meeting.

“For most patients with low-grade, grade 1-3a FL, rituximab plus chemotherapy results in very good responses and prolonged progression-free survival (PFS),” Dr. Fowler noted. “However, most of these patients are still at risk of relapse and remissions are shorter with each subsequent line of therapy.”

The RELEVANCE trial was designed as a superiority study evaluating R2 and R-chemo (including rituximab plus CHOP, bendamustine, or CVP) in 1,030 patients with advanced, previously untreated FL. Participants were randomized 1:1 to receive:

  • R2: lenalidomide 20 mg/day plus rituximab 375 mg/m2 (n=513)
  • R-chemo (control arm): investigator choice of R-CHOP, R-bendamustine, or R-CVP (n=517)

In the R2 arm, lenalidomide dose was lowered to 10 mg/day if patients achieved complete response (CR). Participants in each arm received maintenance therapy with rituximab 375 mg/m2 every eight weeks for up to one year.

Baseline characteristics were “fairly well balanced” between both arms, Dr. Fowler said, with similar incidence of bulky disease (42% and 38%), high-risk Follicular Lymphoma International Prognostic Index (FLIPI) score (49% and 48%), and B symptoms (27% and 26%).

As of May 31, 2017 (data cutoff), more than half of patients in each cohort completed treatment: 69 percent in the R2 cohort and 71 percent in the R-chemo cohort.

After a median follow-up of 37.9 months (range not reported), superiority for the chemotherapy-free regimen over chemotherapy-containing regimens was not established for both co-primary endpoints: CR/CR unknown (CRu) and PFS. See TABLE for all efficacy outcomes.

Interim results showed PFS was “nearly identical” between the two arms, and prespecified subgroup analyses found that this finding persisted regardless of age, sex, disease stage, or FLIPI score.

Almost all patients reported some treatment-emergent adverse events (99% in R2 and 97% in R-chemo). While the authors reported that the regimens were tolerable, with 8 percent and 3 percent discontinuing treatment due to toxicity, they noted that patients in the R-chemo arm experienced more neutropenic events:

  • grade 3/4 neutropenia: 160 (32%) and 252 (50%)
  • febrile neutropenia: 11 (2%) and 34 (7%)

In addition, patients in the R2 arm had higher incidence of grade 3/4 rash, likely attributable to lenalidomide (7% and 1%).

Reports of secondary primary malignancies were similar: 7 percent in the R2 arm and 9 percent in the R-chemo arm.

“These results show that R2, an immunomodulatory approach, is a potential first-line option for patients with FL,” Dr. Fowler concluded, adding that the survival data of this analysis was immature and requires longer follow-up. The reliance on physician’s choice of chemotherapy in the R-chemo arm also may have confounded the findings.

The corresponding authors report financial support from AbbVie, Genentech, Celgene, Merck, Roche, Janssen, Bristol-Myers Squibb, and Gilead Sciences.


Fowler NH, Morschhauser F, Feugier P, et al. RELEVANCE: Phase III randomized study of lenalidomide plus rituximab (R2) versus chemotherapy plus rituximab, followed by rituximab maintenance, in patients with previously untreated follicular lymphoma. Abstract #7500. Presented at the 2018 American Society of Clinical Oncology Annual Meeting, June 3, 2018; Chicago, IL.

TABLE. Primary Efficacy Results
  R2 (n=513) R-Chemo (n=517) p Value
Complete response (CR)/CR unknown at 120 weeks
By IRB 48% 53% 0.13
By investigators 55% 58% 0.38
Hazard ratio for progression-free survival (PFS)
R2 vs. R-chemo by IRB 1.10 (95% CI 0.85-1.43) 0.48
R2 vs. R-chemo by investigators 0.94 (95% CI 0.73-1.22) 0.63
Rates of survival
2-year PFS 84% 87%
3-year PFS 77% 78%
3-year overall survival 94% 94%
R2 = lenalidomide plus rituximab; R-chemo = rituximab plus chemotherapy; IRB = investigational review board