Immunochemotherapy is still the frontline gold standard for patients with follicular lymphoma (FL). The RELEVANCE trial showed that lenalidomide, an immunomodulatory agent, plus rituximab (R2) provided similar efficacy to rituximab plus chemotherapy (R-chemo) in patients with advanced-stage, previously untreated FL. After six years of follow-up, R2 continued to show comparable, durable efficacy and safety vs. R-chemo, providing an acceptable chemo-free alternative in this setting.
Although immunochemotherapy remains the frontline gold standard for patients with follicular lymphoma (FL) needing systemic therapy, FL has shown to be immune-responsive to non-chemotherapy regimens. Lenalidomide is an immunomodulatory agent with multiple properties, including altering the production of cytokines and increasing T-cell co-stimulation and natural killer cell cytotoxicity. The RELEVANCE trial showed that the combination of lenalidomide with rituximab (R2) provided similar efficacy to rituximab plus chemotherapy (R-chemo) in patients with advanced-stage, previously untreated FL. However, toxicity and efficacy data were still needed in the long-term follow-up. After six years of follow-up, these data are now presented.
The multicentre, open-label, RELEVANCE phase III trial enrolled with grade 1-3a, previously untreated FL. Patients were randomised 1:1 to rituximab plus lenalidomide (R2) or R-chemo (investigator’s choice of rituximab + cyclophosphamide, doxorubicin, vincristine, and prednisone, rituximab + bendamustine, or rituximab + cyclophosphamide, vincristine, and prednisone), followed by maintenance rituximab. Coprimary endpoints were confirmed/unconfirmed complete response (CR/CRu) at 120 weeks and progression-free survival (PFS). Post hoc exploratory analyses on survival from a risk-defining event (Landmark approach) according to progression of disease within two years of first-line therapy (POD24) were performed. Survival from a risk-defining event was from the time of POD24 or from two years after random assignment for the non-POD24 reference group.
From December 2011 through November 2014, 1,030 patients were randomly assigned to R2 (N= 513) or R-chemo (N= 517). Median follow-up was 72 months. The results for the coprimary endpoints were similar to those of the first analysis. Overall response rate (ORR) in the R2 and R-chemo groups was 61% vs. 65%, with CR/CRu rates of 48% vs. 53% (p= 0.10). PFS did not differ significantly (HR[95%CI]: 1.03[0.84-1.27]; p= 0.78) and median PFS was not reached in either group. Six-year PFS rates in the R2 and R-chemo groups were 60 vs. 59%, respectively. Median overall survival (OS) was not reached in either group. Six-year OS was estimated to be 89% in both groups. Similarly, event-free survival and time to next antilymphoma treatment did not differ significantly between the groups. Overall response after progression was 61% and 59%, and 5-year estimated survival rate after progression was 69% and 74% in the R2 and R-chemo groups, respectively. The cumulative incidence of transformation at six years in the R2 and R-chemo groups was 4.4% and 3.3%, and transformation rates per year were 0.68% and 0.45%. The efficacy of R2 continued to be independent of conventional prognostic factors, including disease stage, Follicular Lymphoma International Prognostic Index score, bulky disease, and age. In patients with POD24, 5-year survival was similar in both groups (59% vs. 60%, p= 0.97). The overall safety profile in both groups was consistent with the first interim analysis and no new safety signals were detected. Secondary primary malignancies occurred in 11% and 13% (p= 0.34) in R2 and R-chemo groups. Death from lymphoma was higher in the R2 (N= 29) vs. R-chemo group (N= 17), but death from other causes was higher in the R-chemo group (6 vs. 13), particularly death from cardiac disorder
After a longer follow-up of six years, R2 continues to show comparable, durable efficacy and safety vs. R-chemo in previously untreated patients with FL. Therefore, R2 demonstrates to be an acceptable, long-term, chemo-free alternative to R-chemo on the basis of immunomodulation in this setting.
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. 2022;40(28):3239-45.