Lenalidomide Plus Rituximab Represents Acceptable Chemo-Free Alternative for Untreated Advanced Follicular Lymphoma

The combination of lenalidomide and rituximab demonstrated durable safety and efficacy that was comparable to that achieved with rituximab plus chemotherapy in previously untreated patients with follicular lymphoma, according to 6-year data from the phase 3 RELEVANCE trial.

The combination of lenalidomide (Revlimid) and rituximab (Rituxan; R2) demonstrated durable safety and efficacy that was comparable to that achieved with rituximab plus chemotherapy in previously untreated patients with follicular lymphoma, according to 6-year data from the phase 3 RELEVANCE trial (NCT01650701) published in the Journal of Clinical Oncology.1

At a median follow-up of 72 months, R2 (n = 513) elicited an overall response rate (ORR) of 61% per independent review committee (IRC) review, with a complete response (CR) plus unconfirmed CR rate of 48% (95% CI, 44%-53%). The combination of rituximab and chemotherapy (n = 517) resulted in an ORR of 65% with a CR/CRu rate of 53% (95% CI, 49%-58%).

Progression-free survival (PFS) was not found to significantly differ between the R2 and rituximab/chemotherapy arms (HR, 1.03; 95% CI, 0.84-1.27; P = .78). With the additional follow-up since the interim analysis, the median PFS had not yet been reached in either group. The 6-year PFS rate in the investigative arm was 60% (95% CI, 55%-64%) vs 59% (95% CI, 54%-64%) in the control arm.

The median overall survival (OS) was also not reached in either arm; the estimated 6-year OS rate in both groups was 89%. Event-free survival and time to next anti-lymphoma treatment were also not found to significantly differ between the treatment arms.

“R2 provides an acceptable, long-term, chemotherapy-free alternative to rituximab/chemotherapy on the basis of immunomodulation in patients with advanced untreated follicular lymphoma in need of treatment,” Franck Morschhauser, MD, PhD, of Hospital Claude Huriez, and colleagues, wrote in a paper on the findings.

The multicenter, international, phase 3 trial enrolled patients with histologically confirmed, CD20-positive follicular lymphoma who were determined to be in need of treatment per Groupe d’Étude des Lymphomes Folliculaires criteria.2 Patients could not have received prior systemic treatment for their disease.

Study participants were randomly assigned 1:1 to rituximab/lenalidomide vs rituximab/chemotherapy followed by maintenance treatment with rituximab. Those in the control arm received investigator’s choice of 1 of 3 regimens: rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; rituximab and bendamustine; or rituximab, cyclophosphamide, vincristine, and prednisone.

Across the 2 arms (n = 1030), the median age was 59 years (range, 23-89), with 15% of patients older than 70 years of age. Moreover, 49% of patients were male, 67% had an ECOG performance status of 0, 93% had an Ann Arbor stage III to IV disease, 40% had bulky disease, and 85% had grade 1 or 2 disease. Regarding Follicular Lymphoma International Prognostic Index (FLIPI) score, 15% were low risk, 36% were intermediate risk, and 49% were high risk.

Ninety-nine percent of patients in the investigative arm and 97% in the control arm had received at least 1 dose of study drug; 69% and 71% of patients, respectively, completed the full 120 weeks of treatment. Thirty-one percent of those who received R2 prematurely discontinued treatment vs 29% of those who were given rituximab/chemotherapy. The most common reason for discontinuation was disease progression and toxicity.

Twelve percent of patients experienced relapse or disease progression within 24 months of initiation (POD24); this includes 67 patients in the R2 arm and 57 patients in the rituximab/chemotherapy arm.

Data from an exploratory analysis did not demonstrate significant differences between the 3 different rituximab/chemotherapy groups in terms of PFS by IRC or investigator assessment or with regard to OS.

Moreover, 206 patients received additional treatment following relapse; 107 of these patients were in the R2 arm and 99 were in the rituximab/chemotherapy arm. In the patients who received R2, the ORR was 61% vs 59% in those who received rituximab/chemotherapy; the CR/CRu rates in these groups were 37% and 45%, respectively. There was not a statistical significance observed between the group in terms of survival.

Data from subgroup analyses showed that the efficacy achieved with R2 in terms of PFS continued to be independent of conventional prognostic factors, including disease stage, FLIPI score, bulky disease, and age.

Early POD was linked with worse 5-year survival compared with a reference group at 59.5% (95% CI, 49.9%-67.8%) and 95.2% (95% CI, 93.3%-96.6%), respectively (P < .0001). In those with POD24, 5-year survival rates were reported to be comparable between the arms, at 59% and 60%, respectively (P = .9693).

No new safety signals were reported.

A total of 15 patients experienced at least 1 treatment-emergent toxicity that was grade 5; 9 occurred in the investigative arm and 6 occurred in the control arm. New grade 5 effects reported since the initial analysis of the trial were chronic obstructive pulmonary disease (n = 1) and adenocarcinoma of the colon (n = 2).

Moreover, those with second primary malignancies increased from 7% in 2017 to 11% in 2020 in the investigative arm; these rates jumped from 10% to 13% in the control arm (P = .34). The number of deaths increased from 66 in 2017 to 114.


  1. Morschhauser F, Nastoupil L, Feugier P, et al. Six-year results from RELEVANCE: lenalidomide plus rituximab (R2) versus rituximab-chemotherapy followed by rituximab maintenance in untreated advanced follicular lymphoma. J Clin Oncol. Published online August 10, 2022. doi:10.1200/JCO.22.00843
  2. Morschhauser F, Fowler NH, Feugier P, et al. Rituximab plus lenalidomide in advanced untreated follicular lymphoma. N Engl J Med. 2018;379(10):934-947. doi:10.1056/NEJMoa1805104