In the phase III RELEVANCE trial reported in The New England Journal of Medicine by Franck Morschhauser, MD, PhD, of The University of Lille, Centre Hospitalier Universitaire Lille, France, and colleagues, no difference in the complete response rate or interim progression-free survival was found between rituximab (Rituxan)/lenalidomide (Revlimid) vs rituximab/chemotherapy in newly diagnosed advanced follicular lymphoma.1 The adverse-event profiles differed between the two regimens. Dr. Morschhauser and Nathan H. Fowler, MD, of The University of Texas MD Anderson Cancer Center, contributed equally to this article in The New England Journal of Medicine.
In the open-label trial, 1,030 patients from 137 sites in Australia, Belgium, Canada, France, Germany, Italy, Japan, Portugal, Spain, and the United States were randomized between December 2011 and November 2014 to receive rituximab plus lenalidomide (n = 513) or rituximab plus investigator’s choice of chemotherapy (n = 517). In the chemotherapy group, 372 patients (72%) received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; 117 (23%) received rituximab/bendamustine; and 28 (5%) received rituximab, cyclophosphamide, vincristine, and prednisone. Randomization was stratified by Follicular Lymphoma International Prognostic Index (FLIPI), age (≤ 60 vs > 60 years), and lesion size (≤ 6 vs > 6 cm).
The total treatment duration was 120 weeks for both study groups. Treatment with rituximab plus lenalidomide consisted of 18 cycles of the 2 drugs followed by rituximab maintenance therapy every 8 weeks for 1 year. Treatment with rituximab plus chemotherapy consisted of the rituximab-based regimens followed by maintenance rituximab every 8 weeks for 2 years. The primary endpoints were complete response (confirmed or unconfirmed) at 120 weeks and progression-free survival (first interim analysis) on independent review committee assessment in the intent-to-treat population.
For the rituximab/lenalidomide group vs the rituximab/chemotherapy groups, the median age was 59 years in both (16% vs 15% aged > 70 years); 51% in both were female; the Eastern Cooperative Oncology Group performance status was 0 or 1 in 97% in both; 94% vs 92% had Ann Arbor stage III or IV disease; 42% vs 38% had bulky disease; the disease grade was 1 or 2 in 85% vs 86%; and the FLIPI score was 0 or 1 in 15% in both, 2 in 36% vs 37%, and 3 to 5 in 49% vs 48%.
After a median follow-up of 37.9 months, confirmed or unconfirmed complete response at 12 weeks was observed in 48% (confirmed in 28%) of the lenalidomide/rituximab group vs 53% (confirmed in 33%) of the rituximab/chemotherapy group (P = .13). On investigator assessment, the rate of confirmed or unconfirmed complete response was 55% vs 58% (P = .38). The overall response rate was 61% vs 65%, respectively.
The interim 3-year rate of progression-free survival on independent review was 77% vs 78% (hazard ratio [HR] = 1.10, P = .48). On investigator assessment, 3-year progression-free survival was 77% vs 78% (HR = 0.94, P = .63). No signifcant differences between rituximab/lenalidomide and rituximab/chemotherapy were observed in the subgroup analysis for either complete response rate or progression-free survival, including analysis by FLIPI scores of 0 to 1, 2, or 3 to 5; age ≤ 60 and > 60 years; or lesion size. Overall survival data were immature at the time of analysis; 3-year overall survival was 94% vs 94% (HR = 1.16, 95% confidence interval = 0.72–1.86).
Adverse events of any grade that were more common in the rituximab/lenalidomide group included cutaneous reactions (43% vs 24%), diarrhea (37% vs 19%), rash (29% vs 8%), abdominal pain (15% vs 9%), myalgia (14% vs 6%), muscle spasms (13% vs 4%), and tumor flare reaction (6% vs < 1%). Adverse events of any grade that were more common in the rituximab/chemotherapy group included anemia (89% vs 66%), fatigue (29% vs 23%), nausea (42% vs 20%), vomiting (19% vs 7%), peripheral neuropathy (16% vs 7%), leukopenia (10% vs 4%), febrile neutropenia (7% vs 2%), and alopecia (9% vs 1%). The rate of thromboembolic events of any grade was similar in the two groups.
Among patients with previously untreated follicular lymphoma, efficacy results were similar with rituximab plus lenalidomide and rituximab plus chemotherapy.— Franck Morschhauser, MD, PhD, and colleagues
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Grade 3 or 4 adverse events occurred in 65% of the rituximab/lenalidomide group vs 68% of the rituximab/chemotherapy group. Grade 3 or 4 cutaneous reactions were more common in the rituximab/lenalidomide group, whereas grade 3 or 4 neutropenia was more common in the rituximab/chemotherapy group. The incidence of infection was higher in the rituximab/chemotherapy group. Febrile neutropenia requiring hospitalization occurred in 2% of the rituximab/lenalidomide group vs 5% of the rituximab/chemotherapy group, and growth factor was used in 23% vs 68%, respectively.
Second primary cancers occurred in 7% vs 10% of patients. Death occurred in 37 patients (23 attributed to lymphoma) vs 29 patients (10 attributed to lymphoma). The death of one patient in each group was considered related to study treatment.
The investigators concluded: “Among patients with previously untreated follicular lymphoma, efficacy results were similar with rituximab plus lenalidomide and rituximab plus chemotherapy (with both regimens followed by rituximab maintenance therapy). The safety profile differed in the two groups.” ■
DISCLOSURE: The study was funded by Celgene. Dr. Morschhauser has received honoraria from Celgene, AbbVie, Roche/Genentech, Gilead Sciences, Bristol-Myers Squibb, and Janssen; and is a consultant/advisor for Bristol-Myers Squibb, Gilead Sciences, Celgene, and Roche/Genentech. For full disclosures of the other study authors, visit www.nejm.org.
1. Morschhauser F, Fowler NH, Feugier P, et al: Rituximab plus lenalidomide in advanced untreated follicular lymphoma. N Engl J Med 379:934-947, 2018.
Jonathan W. Friedberg, MD, MMSc
We have seen remarkable progress in the outcomes of patients with advanced-stage follicular lymphoma over the past 2 decades.1 Recent manuscripts and presentations describing long-term follow-up of randomized trials comparing various chemotherapy platforms...!-->!-->