5-Year Follow-Up Confirms Efficacy of Frontline Bendamustine Plus Rituximab in MCL, iNHL

Ian W. Flinn, MD, PhD

The BRIGHT study compared the safety and efficacy of bendamustine plus rituximab (BR) versus R-CHOP or R-CVP in patients with indolent non-Hodgkin lymphoma (iNHL) and mantle cell lymphoma (MCL).

In the phase III, open-label, non-inferiority study, 447 patients were randomized to receive BR, RCHOP, or R-CVP. The median follow-up was 65 months for BR and 64.1 months for R-CHOP/R-CVP.

5-year updated results of this study were presented at this year’s ASCO annual meeting, with progression-free survival (PFS), event-free survival (EFS), and overall survival (OS) being compared using a stratified long-rank test.

Results for the overall population showed that the 5-year PFS rate was 65.5% (95% CI, 58.5-71.6) for BR versus and 55.8% (95% CI, 48.4-62.5) for R-CHOP/R-CVP. The 5-year OS rate was 81.7% (75.7-86.3) versus 85% (79.3-89.3), respsectively.

The hazard ratio (HR) for PFS was 0.61 (95% CI, 0.45-0.85; P = .0025), HR for EFS was 0.63 (95% CI, 0.46-0.84; P = .0020), and HR for OS was 1.15 (0.72-1.84; P = .5461), comparing BR vs R-CHOP/R-CVP.

Although similar results were found in iNHL and MCL, the stronger effect was observed in patients with MCL. In patients with MCL, BR reduced the risk of progression or death by 60% (HR, 0.40; 95% CI, 0.21-0.75; P= .0035), whereas in patients with iNHL, the reduction was 30% (HR, 0.70; 95% CI, 0.49-1.01; P = .0582)

OncLive: Please provide an overview of this follow-up analysis.

What has been observed 5 years later?

In an interview with OncLive, lead author Ian W. Flinn, MD, PhD, director, Blood Cancer Research Program, principal investigator, Sarah Cannon Research Institute, discussed the 5-year update of the BRIGHT study.Flinn: The BRIGHT trial is a randomized phase III trial in patients with previously untreated low-grade lymphoma and MCL. It was a study that starting in 2009 and it is a randomized trial comparing BR to R-CHOP or R-CVP. The basic design of the study was once patients were deemed eligible, their treating physician chose a standard chemotherapy for R-CHOP or R-CVP. And then they were randomized…to receive that standard chemotherapy or BR. Our study was initially designed to be a noninferiority trial so, the primary endpoint of the trial was complete remission rate, which was judged by an independent review committee. In 2014, we published that it was noninferior; the complete remission rate was 31% with BR versus 25% for the standard chemotherapy. That clearly met the noninferiority endpoint of the trial. During this year's ASCO, we updated those results for the event-free survival and the time to event analysis such as OS and PFS and duration of response.

These results showed that it’s very consistent that there was superiority to BR in regards to PFS, EFS and duration of response. But, we did not see a difference in OS between the 2 arms, which looked very similar.

What does this update mean for the treatment landscape?

There were some unexpected results—it looked like there was increase in second malignancies in patients treated with BR. When we dove down into that in more detail, we found that a lot of these second malignancies were actually skin cancer, such as squamous cell carcinoma of the skin and basal cell carcinoma of the skin. So, when you excluded those, it was really just progression of the underlying disease. We found that while that it is no longer statistically significant, there was still, numerically, an increase in the number of malignancies that we need to understand. I think that BR in the last 5 years has become the standard frontline therapy for many patients in the United States. It is interesting to talk to people around the world, as they do not always necessarily share our perspective. There are regional variations of whether BR, R-CHOP, or R-CVP is used, but in the United States, I think it'll remain BR.

This data confirmed many previous thoughts toward this regimen, especially if you did not like R-CHOP or R-CVP. So, I think this regimen is here to stay for a while.

Are there any efforts toward adding in more agents to this regimen?

The next steps are primed to get away from the nondiscriminatory, cytotoxic chemotherapy and go toward more targeted therapies in the future.That is an interesting approach, and people have tried that. First of all, low-grade lymphoma is a very difficult disease to study in terms of OS, and even though this study was not geared to look at OS, there really was not a trend toward improvement. One of the reasons was, thankfully, because people live many years, and if you progress on BR you can then go get R-CHOP or R-CVP. There are some problems with crossover of these things. Which is a good problem to have here, but it makes challenges in designs that are based on OS in low-grade lymphoma.

What would you like community oncologists to know about this BR regimen?

I think it would be great if we could get away from chemotherapy, or adding drugs onto this regimen. Right now, drugs such as PI3-kinase inhibitors—because of the toxicities profiles that we have seen—have been hard to move to the frontline. So, there is not an obvious new addition to BR to improve things. We may have to start from scratch with some new regimens.The toxicity profile is what we reported in our initial publication in 2014, and there is increased hypersensitivity reaction. I think to many people’s surprise, there is actually a fair amount of nausea with BR and there was lymphocytopenia.

The good news for BR is that on the R-CHOP and R-CVP side, [there were] increased incidents of neutropenia, peripheral neuropathy, and alopecia.

Flinn I, van der Jagt R, Chang JE, et al. First-line treatment of iNHL or MCL patients with BR or R-CHOP/R-CVP: Results of the BRIGHT 5-year follow-up study. J Clin Oncol 35, 2017 (suppl; abstr 7500).