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

Franck Morschhauser, MD, PhD

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.

References

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