RELEVANCE, a phase 3 trial, compared the R2 regimen in the upfront setting in advanced follicular lymphoma with rituximab and chemotherapy combination (including CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone], CVP [cyclophosphamide, vincristine, prednisone], and bendamustine).7 Efficacy outcomes were similar between the comparators and R2 was noninferior. MAGNIFY, a phase 3b trial involving rituximab-sensitive and rituximab-refractory patients with previously treated follicular lymphoma and MZL, demonstrated an overall response rate of 73%, complete response rate of 45%, and median PFS of 36 months in patients who received the R2 regimen and who entered a plan to receive maintenance with rituximab.8
The AUGMENT trial was conducted at 97 centers in the United States and 14 Asian and European countries; it enrolled 358 patients, 82% of whom had a follicular lymphoma, between February 13, 2014 and January 26, 2017. The study was well conducted. The R2 regimen was compared to the often used second-line therapy of rituximab alone, and 1:1 randomization was done with stratification factors of prior rituximab use, marginal versus follicular histology, and time lapse of less than or greater than 2 years since last therapy. A limitation of this study is that it selected individuals with a better prognosis, as the study patients were not rituximab refractory and 57% had received only a single prior therapy.
As observed in other R2 regimen trials in follicular or marginal zone lymphomas, the most common adverse reactions (occurring in at least 20% of patients) were neutropenia, fatigue, and constipation. These were manageable with dose adjustments and interruptions, and, in the opinion of authors, did not take away from the overall benefits seen.
The authors acknowledge that a limitation of this study was a lower assessment of median PFS in both arms by investigators than by independent reviewers. The independent review committee assessed PFS for R2 at 39.4 months, whereas investigators assessed it at 25.4 months. The median PFS benefit remained at 14.1 months by both methods of assessment. This may highlight the differences of radiographic measurements in a central setting versus at individual centers.
Histologic transformation to a higher-grade aggressive lymphoma occurred in 2 patients in the R2 arm and 10 patients in the placebo/rituximab arm. After transformation, 1 patient in the R2 arm and 6 in the placebo plus rituximab arm died. A plausible mechanism for this variation has not been provided. If confirmed across a wider population, this may be one of the most significant benefits of the R2 regimen.