New Study Supports “R2” Regimen in Previously Untreated Follicular Lymphoma

The combination of lenalidomide and rituximab, known as the R2 regimen, improved progression-free survival (PFS), time to next treatment (TTNT), and complete response (CR) rates in patients with previously untreated follicular lymphoma (FL), compared with rituximab alone, according to a study published in Blood. Toxicity with the R2 regimen was higher than with rituximab alone, however.

Long-term results have shown that frontline, single-agent rituximab allowed a substantial proportion of patients to defer chemotherapy “without compromising outcomes,” wrote Emanuele Zucca, MD, from the Oncology Institute of Southern Switzerland, and colleagues. “Rituximab alone may still be considered as a benchmark for the evaluation of novel chemotherapy-free regimens,” they noted.

In this randomized, phase II study, Dr. Zucca and co-authors compared outcomes between patients who received rituximab alone or a short duration of R2 (delivered over 6 months rather than 12 months, as previously studied).

Patients eligible for the study had symptomatic FL (grade 1-3A with CD20 expression) that required systemic therapy due to the presence of at least one of the following:

  • symptomatic enlarged lymph nodes, spleen, or other lymphoma manifestations
  • bulky disease (longest diameter ≥6 cm)
  • clinically significant progression of any tumor lesion over >6 months
  • B symptoms
  • hemoglobin <100 g/L or platelets <100×109/L
  • clinically significant progressive decrease in hemoglobin or platelet count due to lymphoma

Patients were randomized to receive intravenous rituximab 375 mg/m2 on day 1 of weeks 1–4 (n=77) or rituximab in addition to lenalidomide 15 mg/day administered 14 days prior to the first rituximab administration and until 14 days after the last (n=77).

People whose disease responded to treatment in the rituximab monotherapy group underwent a repeated regimen on day 1 of weeks 12–15; responders in the R2 group received treatment for up to 18 weeks.

The results suggest that R2 and other strategies should be further explored, despite the costs of novel targeted agents.

At 23 weeks of follow-up, the rate of CR or CR unconfirmed (CRu; primary endpoint) appeared higher in the combination arm compared with the single-agent rituximab arm. This benefit was observed in the entire intent-to-treat population (36% vs. 25%; p=0.056) and the per-protocol population (40% vs. 27%; p=0.055), as well as among patients >70 years old (33% vs. 8%; p=0.027).

PFS, a secondary endpoint, also was improved in patients who received the lenalidomide-rituximab combination: At 30-month follow-up, the PFS rate was 42% in the R2 group, compared with 19% in the rituximab group (p=0.001). This relationship persisted at four years of follow-up, with a median PFS of 5.0 versus 2.3 years in the R2 and rituximab groups (hazard ratio = 0.6; 95% CI 0.38-0.97; p=0.035).

Patients in the R2 group also appeared to experience a longer duration of CR/CRu (median = not reached vs. 3.0 years; p=0.055) and a longer TTNT (median = not reached vs. 2.1 years; p=0.003).

Seven patients in each arm died during follow up; the most common causes of death in the rituximab group were lymphoma-related (n=4) and cardiac events (n=2). In the R2 group, six patients died due to lymphoma and one due to an accident.

However, there was no difference between the two groups in terms of overall survival (OS) at four years (91% vs. 90%; p value not reported).

The incidence of any-grade adverse events (AEs) appeared to be higher in the R2 group (100% vs. 91%; p value not reported). “Fatigue, diarrhea, and skin rash were more common in the combination arm; however, these side effects were mostly grade 1-2,” the authors reported.

Grade ≥3 AEs also appeared to occur more frequently in the R2 arm (56% vs. 22%; p value not reported). The most common of these was neutropenia (23% vs. 7%; p value not reported). Overall, there were no treatment-related deaths in either arm.

A total of 14 patients in the overall cohort discontinued treatment due to toxicity, and Dr. Zucca noted that a higher proportion of patients in the rituximab monotherapy group discontinued therapy due to insufficient response at week 10 (21% vs. 4%, respectively; p value not reported).

A limitation of the study was the inclusion of only patients across Europe with symptomatic disease, which could affect the generalizability of the results. The authors also noted that the short duration of treatment and the early assessment of response represent other potential limitations.

The researchers concluded that R2 regimens might offer an alternative to standard immuno-chemotherapy and that “the acceptable and manageable toxicity and the excellent OS in both arms suggest that chemotherapy-free strategies should further be explored even if the costs of novel targeted agents remain an important unsolved issue, particularly when OS is apparently unaffected by the treatment.”

The authors report relationships with Roche and Celgene, the respective manufacturers of rituximab and lenalidomide.


Zucca E, Rondeau S, Vanazzi A, et al. Short regimen of rituximab plus lenalidomide in follicular lymphoma patients in need of first-line therapy. Blood. 2019 May 17. [Epub ahead of print]