Chemotherapy-Free Regimen Comparable to Rituximab-Chemotherapy as Front-Line Therapy for Follicular Lymphoma

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IN PATIENTS with previously untreated advanced follicular lymphoma, the chemotherapy-free combination of rituximab (Rituxan) plus lenalidomide (Revlimid), the so-called R-squared (R2) regimen, yielded outcomes as good as those in patients who received standard rituximab-chemotherapy, in the interim analysis of the phase III RELEVANCE trial.1 The hope, however, was that the chemotherapy-free regimen would have been better. 

“At a median follow-up of 37.9 months, superiority for R2 over rituximab-chemotherapy was not established for both co-primary endpoints,” said Nathan Hale Fowler, MD, of The University of Texas MD Anderson Cancer Center, Houston. 

“At a median follow-up of 37.9 months, superiority for R2 over rituximab-chemotherapy was not established for both co-primary endpoints.”
— Nathan Hale Fowler, MD

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The similar efficacy of R2 to rituximab-chemotherapy, however, positions this novel immunomodulatory approach as “a plausible new first-line option for patients with follicular lymphoma requiring treatment,” Dr. Fowler said at the 2018 ASCO Annual Meeting. 

The international open-label study compared the chemotherapy-free regimen with rituximab plus one of several chemotherapy choices. It is reportedly the first multicenter, international, open-label, randomized phase III trial of R2 vs rituximab-chemotherapy followed by rituximab maintenance in previously untreated patients with advanced follicular lymphoma requiring systemic treatment. 


THE RELEVANCE trial enrolled 1,030 patients with primarily grade 1 or 2, high–tumor burden, newly diagnosed follicular lymphoma. Patients were randomized to receive rituximab-chemotherapy (regimen by physician’s choice) or R2. The co-primary endpoint was complete remission and complete remission unconfirmed at 120 weeks as well as progression-free survival. 

The R2 arm received rituximab for 6 cycles, continued in responders for 12 additional cycles, and lenalidomide for 6 to 12 cycles, continued in responders for a total of 18 cycles. The control arm included three possible regimens: R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone), given to 72% of this arm; rituximab plus bendamustine (BR), given to 23%; or R-CVP (rituximab plus cyclophosphamide, vincristine, prednisone), given to 5%. This arm received the chemotherapy plus rituximab, followed by another 12 cycles of maintenance rituximab. The total treatment duration was 120 weeks. 

In the intent-to-treat analysis, by central review, complete remission and complete remission unconfirmed at 120 weeks was achieved in 48% of the R2 arm and 53% of the rituximab-chemotherapy arm (P = .13). The best overall response rate (which included partial responses) was 84% for R2 and 89% for rituximab-chemotherapy. Three-year progression-free survival was 77% and 78%, respectively (hazard ratio = 1.10; P = .48). Although overall survival is immature, 94% of patients in both arms were alive at 3 years, Dr. Fowler reported. 

The R2 and rituximab-chemotherapy regimens did reveal some different toxicities, although treatment discontinuations were similar between the arms and were mostly due to disease progression and toxicity. Patients who received rituximab-chemotherapy had more grade 3 or 4 neutropenia (31% vs 8%), febrile neutropenia (7% vs 2%), and use of growth factors (68% vs 23%) and more nausea, vomiting, neuropathy, and alopecia. Patients treated with R2 had more grade 3 or 4 cutaneous toxicity (7% vs 1%) and more tumor flare and diarrhea. 

DISCLOSURE: Dr. Fowler has served as a consultant or advisor to AbbVie, Celgene, and Merck and has received research funding from AbbVie, Celgene, Janssen, and Roche. 


1. Fowler NH, et al: RELEVANCE. 2018 ASCO Annual Meeting. Abstract 7500. Presented June 3, 2018. 

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