BRIGHT Shines Light on R-Bendamustine in Lymphoma

Bruce D. Cheson, MD; Ian W. Flinn, MD, PhD


January 08, 2013

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Bruce D. Cheson, MD: Hello. I'm Bruce Cheson, Deputy Chief of Hematology-Oncology and Head of Hematology at Georgetown University Hospital and the Lombardi Comprehensive Cancer Center in Washington, DC. Welcome to this edition of Medscape Oncology Insights from the 2012 annual meeting of the American Society of Hematology (ASH) in Atlanta. Joining me today is my old friend, Dr. Ian Flinn, Director of Hematologic Malignancies Research at the Sarah Cannon Research Institute in Nashville, Tennessee.

Along Came Bendamustine

For decades the treatment of patients with follicular low-grade mantle cell lymphoma included regimens such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), R-CVP (rituximab, cyclophosphamide, vincristine, and prednisone) and R-fludarabine-based treatments. Then along came bendamustine. A couple of months ago I went to the 50th anniversary celebration of this drug in the town of Jena in the east of Germany. It is changing how we treat patients. It has taken over a large chunk of the initial management of patients with these diseases.

At this meeting, you are presenting the results of the BRIGHT trial,[1] for which we have been waiting a long time and anticipating the results. Can you tell us what the BRIGHT trial is and what your findings were?

BRIGHT: Bendamustine vs Standard Chemo

Ian W. Flinn, MD, PhD: The BRIGHT trial is a large, phase 3 randomized trial with more than 400 patients, looking at the combination of bendamustine and rituximab vs some of the standard therapies (R-CHOP and R-CVP). Those were considered the standard therapy arms. Patients on this trial were randomly assigned to receive either bendamustine and rituximab or the investigator's choice of R-CHOP or R-CVP. The primary objective of this trial was noninferiority. They wanted to make sure that bendamustine wasn't worse than those standard therapies. That objective of the trial was met. It was clearly noninferior in terms of complete response rate, as judged by an independent review committee. The investigators judged response and the independent review committee confirmed it. But an independent review committee also found that the combination of bendamustine and rituximab achieved noninferiority to the standard arm in terms of complete remission.

Dr. Cheson: There were 2 standard therapies, and based on a number of trials that have come out in recent years in Italy[2] and elsewhere, R-CHOP is pretty solidly superior to R-CVP. Did you analyze the data to look at rituximab-bendamustine (R-B) vs R-CVP and R-B vs R-CHOP?

Dr. Flinn: The trial is not powered to do that. Clearly, the magnitude of response depends on how you dive down into the populations where there was low-grade lymphoma or mantle cell lymphoma. Some of the responses differed according to that, but it looks like the magnitude of response was probably greater compared with R-CVP than it was compared with R-CHOP. Although we talk about R-B being noninferior, in every group the complete remission rate in R-B compared with the standard arm -- any way you divide it up -- was always numerically higher. So, there are some subgroups of patients in whom it was perhaps superior, but in aggregate it was noninferior. There wasn't any subgroup that I could find that didn't benefit from R-B, or at least that was a reasonable option.

Dr. Cheson: There is efficacy, and there is toxicity. One would think that R-CHOP would be more toxic than R-B. What were your results?

Toxicity Differences: Some Surprises

Dr. Flinn: The patterns of toxicity were different in the standard arm vs the R-B arm. We saw about the same amount of nausea and vomiting with R-B as we did with R-CHOP, perhaps even a little bit more in some patients. There were differences, and that was a surprise to me.

Dr. Cheson: Did you premedicate these patients? Was there a standard protocol or was it ad-hoc?

Dr. Flinn: It was left up to the investigators, but when we went back and looked at this in every way we could, even with the use of 5-HT3 antagonists, it was the same with the cycles and with the first dose. The use of antiemetics and the intensity of the antiemetics was the same across both arms. As we are talking about toxicity profiles, there were some differences, of course. Because we are using vincristine, you might imagine that people who received R-CHOP or R-CVP would have more constipation. That was true. There was a good deal more neuropathy in the patients in the standard arm. Alopecia, of course, is worse in patients who receive R-CHOP than in those who received R-B. That came out in the data.

Dr. Cheson: What about neutropenia and infections, which are a big concern?

Dr. Flinn: Neutropenia was worse in the R-CHOP arm than it was in the R-B arm. Not just a little, but there was a clinically relevant increase in grade 3 or worse neutropenia in patients who received R-CHOP, despite the fact that there was greater use of myeloid growth factors (granulocyte colony-stimulating factors). Their use was higher in the R-CHOP arm than in the patients who received R-B, and they still had more neutropenia.

From an infection standpoint, it seems that there were a few more opportunistic infections in patients who received R-B than in patients who received R-CHOP or R-CVP. There was a little bit more febrile neutropenia in patients who received R-CHOP.

Dr. Cheson: We have talked about efficacy and toxicity, but what about the time-dependent endpoints -- progression-free survival, for example? I know it's way too early for overall survival, but do you have any information on progression-free or event-free survival?

Dr. Flinn: We have been pretty careful to not promise people too much in this area, but we have looked at progression-free survival. At this point with very immature data, the events are basically the same.

Dr. Cheson: What is the median follow-up at this point?

Dr. Flinn: It's about 18 months at this point, maybe 2 years.

BRIGHT vs StiL: What Gives?

Dr. Cheson: For years now we have been watching presentation after presentation of the StiL data from Germany,[3]which was the first trial to directly compare R-CHOP with R-B. We have been seeing significantly higher complete remission rates, fewer infections, less neutropenia, less toxicity, less nausea and vomiting, and progression-free survivals that are quite different. We are not seeing this in the BRIGHT study. I know that the StiL data are still unpublished as of a few days ago. What do you think the difference is?

Dr. Flinn: I have no firsthand knowledge of the StiL data, but my understanding is that these were set up as very different types of trials to begin with. The StiL study was designed to answer a scientific question of one drug vs the other. But it didn't have all the monitoring that we now have for trials that are designed for registration purposes. There are issues with gathering toxicity data. If you are doing a trial for a cooperative group, the amount of data that you are capturing and the granularity and intensity of those data are probably going to be less than if you have a monitor coming into your office once a week and checking everything. They are 2 different purposes. It doesn't mean that one is better than the other, but the purposes of the trials are different. That probably explains some of the differences in toxicities that we are seeing between the 2 studies.

I can't comment on progression-free survival at this point because we don't have any data on progression-free survival right now. It's very short and it looks the same. In terms of remission rate, we do have an independent response committee that is looking at the radiology and the clinical notes. It was interesting to me when I looked at it that there was discordance between what the review committee thought and what the investigators thought. That is not surprising. That's why you have the review committee. Maybe that explains some of the differences.

Dr. Cheson: The German study was basically a private practice study -- a group of investigators who got together to conduct the study, but they were in a community setting. This one had academic centers and community centers and was more carefully scrutinized.

We will be waiting for your time-dependent endpoints, but in the meantime, let's say that I show up in your office. I say, "Dr. Flinn, I have follicular lymphoma. I am newly diagnosed. I have advanced-stage disease. How should I be treated?"

The BRIGHT Message: A Lot of Options

Dr. Flinn: I can tell you what I do, and the message that we take from the BRIGHT study is that there are a lot of good options, and R-B is a good option. People can be very comfortable. I tend to use a lot of bendamustine and rituximab. That's my practice. Personally, I like to avoid anthracycline and avoid the neuropathy. Most patients would like to avoid alopecia. From this study there was a greater incidence of nausea than I had expected, so I'm going to be more careful about making sure people get maximum prophylaxis and treatment for nausea.

Dr. Cheson: In my practice, one is not surprised by your data because this is what we see routinely. We give ondansetron and other drugs regularly, and there is still a lot of nausea. Something that never came out in the StiL study was fatigue. It was never mentioned. Did you see a lot of fatigue?

Dr. Flinn: We looked at a variety of quality-of-life measures. Dr. Burke is going to present those data as well.[4] It did look as though there were some advantages from a quality-of-life standpoint in terms of cognitive function and so forth that favored the R-B arm.

Dr. Cheson: Where do we go from here?

Dr. Flinn: That's a great question. Are the next studies going to build on a backbone of bendamustine and rituximab? Are we going to add new agents to this regimen? That's a very reasonable step forward. Some people are still concerned about the long-term toxicity from bendamustine and rituximab. Is there a difference? Opportunistic infections are greater. A greater degree of lymphopenia occurs with R-B, so how will that play out? I'm very comfortable with this regimen and it's a great backbone to build upon.

Dr. Cheson: Are there any patient characteristics, such as bulky disease, high Follicular Lymphoma International Prognostic Index, marginal zone lymphoplasmacytic mantle cell, in which R-B or R-CHOP stood out as being superior?

Dr. Flinn: In patients with mantle cell lymphoma, the complete remission rate was substantially greater with R-B. The magnitude of difference was higher in those patients than it was in the R-CHOP and R-CVP arm. About one third of the patients with mantle cell lymphoma who were treated were treated with R-CVP. That is clearly an inferior treatment, but there is still a substantial difference between R-B and R-CHOP in mantle cell lymphoma. So, I'm very comfortable using that regimen there as well.

Dr. Cheson: Good. We will be looking forward to seeing your presentation and hearing some interesting discussion. I'm sure there will be a lot of debate of BRIGHT vs StiL for months to come until we can see the data and analyze them carefully, but it certainly was a yeoman's effort and you are to be congratulated for getting the study done. I would like to thank you, Ian. And thank you for joining us for this edition of Medscape Oncology Insights. This is Bruce Cheson from ASH 2012 in Atlanta.


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