Rituximab Plus Lenalidomide Noninferior to Chemotherapy in Treatment-Naïve Follicular Lymphoma

Treatment with the chemotherapy-free combination of rituximab and the immunomodulatory agent lenalidomide (R2) was noninferior to the combination of rituximab and chemotherapy (R-chemo) in patients with previously untreated follicular lymphoma (FL), according to results from a phase III trial published in The New England Journal of Medicine.

Lead study author Franck Morschhauser, MD, PhD, of the University of Lille in France, told ASH Clinical News that these results represent a landmark in this disease setting. “There are multiple considerations for patients when comparing the results for first-line R2 with R-chemo plus rituximab maintenance for both,” he said. While each regimen was associated with different safety profiles, “R2 provides an alternative treatment option with a safety profile favoring patients who are unable to tolerate or unwilling to receive chemotherapy.”

The randomized, phase III RELEVANCE (Rituximab Lenalidomide versus Any Chemotherapy) trial enrolled 1,030 patients with histologically confirmed, CD20-positive FL (grade 1 to 3a) who had not received any prior systemic lymphoma treatment.

Participants were randomized 1:1 to one of two treatment arms:

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

In the R2 arm, the lenalidomide dose was lowered to 10 mg/day if patients achieved a complete response (CR) following six treatment cycles; patients who had a partial response (PR) after six cycles received lenalidomide 20 mg/day for three or six additional treatment cycles or until a confirmed or unconfirmed CR (CRu) was achieved. Participants in each arm received maintenance therapy with rituximab 375 mg/m2 every eight weeks for 12 cycles.

Baseline characteristics were similar between the R2 and R-chemo arms, with a similar incidence of bulky disease (42% and 38%), high-risk FL International Prognostic Index score (49% and 48%), and B symptoms (27% and 26%).

At a median follow-up of 37.9 months (range not reported), there was no significant difference between the two treatment groups for either of the co-primary endpoints (assessed by independent review committee):

  • CR/CRu at 120 weeks: 48% (n=247) for R2 vs. 53% (n=274) for R-chemo (p=0.13)
  • 3-year progression-free survival (PFS): 77% vs. 78% (hazard ratio [HR] = 1.10; 95% CI 0.85-1.43; p=0.48)

The investigator-assessed rates were similar:

  • CR/CRu at 120 weeks: 55% (n=283) vs. 58% (n=299; p=0.38)
  • 3-year PFS: 77% vs. 78% (HR=0.94; 95% CI 0.73-1.22; p=0.63)

At the three-year interim analysis, rates of overall survival also were the same between the two groups: 94 percent for R2 vs. 94 percent for R-chemo (HR=1.16; 95% CI 0.72-1.86; p value not reported).

The safety analysis included 507 patients in the R2 group and 503 in the Rchemo group, most of whom experienced at least one adverse event (AE; 99.8% and 99.0%, respectively). As Dr. Morschhauser noted, the safety profiles differed between the R2 and R-chemo groups: R2-treated patients experienced lower rates of grade 3/4 neutropenia (32% vs. 50%), grade 3/4 febrile neutropenia (2% vs. 7%), grade 3/4 leukopenia (2% vs. 6%), and upper respiratory tract infections (9% vs. 11%), while R-chemo–treated patients had a higher incidence of grade 3/4 cutaneous reactions (7% vs. 1%; p values not reported).

The investigators noted that the differences between lenalidomide-induced neutropenia and chemotherapy-induced neutropenia may be partly due to the biologic differences of the regimens’ mechanisms of action.

The authors added that “a higher percentage of the patients in the [R2] group than in the [R-chemo] group had AEs that led to dose reduction (36% vs. 14%), dose interruption (59% vs. 35%), or early discontinuation of trial treatment (11% vs. 3%; p values not reported).” In the R2 group, neutropenia was the most common reason for dose reduction (20%) and interruption (32%); neutropenia led to discontinuation in 1 percent of patients.

The study’s findings are limited by the follow-up time for time-to-event endpoints; the authors noted that “longer follow-up with more mature survival data will be needed to assess long-term outcomes.” The study was also unblinded.

“The RELEVANCE study is continuing to collect progression and survival data, as more mature data will be needed to fully characterize the benefit-to-risk profile of R2 versus R-chemo in this setting,” Dr. Morschhauser noted. “Additional analyses will be conducted to further characterize potential biomarkers and the immune-based mechanisms of action of R2 in patients, as well as potential differences between arms for other exploratory endpoints (e.g., minimal residual disease status).”

The authors report financial relationships with Celgene and LYSARC, which supported the study.


Morschhauser F, Fowler NH, Feugier P, et al. Rituximab plus lenalidomide in advanced untreated follicular lymphoma. N Engl J Med. 2018;379:934-47.