COMMENTARY

In Lymphoma, Chemo Challenged by New Classes, New Combinations

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

Disclosures

December 15, 2015

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Bruce D. Cheson, MD: Welcome to Medscape Oncology from the American Society of Hematology (ASH) 57th Annual Meeting in Orlando, Florida. I'm Bruce Cheson, deputy chief of hematology/oncology and head of hematology at Georgetown University Hospital's Lombardi Comprehensive Cancer Center. With me is my old friend, Ian Flinn, director of blood cancer research at the Sarah Cannon Cancer Research Institute in Nashville, Tennessee. Minnie Pearl.

Ian W. Flinn, MD, PhD: The one and only.

Dr Cheson: The one and only. How are you doing?

Dr Flinn: I'm well.

Standard Regimen Challenged

Dr Cheson: This is a thought-provoking meeting for us lymphoma people. We've gotten so used to our standard old nonspecific chemotherapy regimens. We're kind of comfortable with them. Bendamustine plus rituximab (BR) has become a standard for most patients. But now, that is being challenged. We had two studies. We had the Alliance trial, and we had Nathan Fowler's study of rituximab and lenalidomide, the so-called R-squared frontline treatment, which led to the RELEVANCE randomized trial of R-squared vs R-chemo. Let's say that that is positive. Where do we go from there?

Dr Flinn: I think it's a great question because there are so many other therapies that are being developed. Let's say that the RELEVANCE trial does come out to be positive. Will that then be the de facto new king? Will that unseat BR as frontline therapy?

I think you have to take into the equation some of these other regimens that are now coming out that we hope might have fewer side effects and are more targeted without the chemotherapy background like R-squared—perhaps ibrutinib and rituximab. There are data here at ASH this week being presented from the frontline studies with ibrutinib and rituximab. To me, they were very, very different from what I was expecting.

Dr Cheson: Yes, me too. Different is a nice term.

Dr Flinn: I thought it was not going to be as good as it was, in the sense that ibrutinib in the refractory patient population previously had a very surprisingly low response rate.

Dr Cheson: Yes, but the 28% that Nancy Bartlett presented last year has been updated. It's a small number of patients; there were eight of them. The response rate at a higher dose was about 55%, but they were small numbers.

Dr Flinn: In this series,[1] they are seeing almost a 30% complete response (CR) rate. That's nothing like what you would see with R-squared, although I think we still have to figure out R-squared, too, in a phase 3 type of a trial. But you're right, we are comparing phase 2 with phase 2. Even in the phase 2 setting, the R-squared data were very, very encouraging, with very high CR rates. In the ibrutinib-rituximab study[1], the CR rates were 30% or slightly less than that, so it's not quite the same. It's certainly not a home run. Are people going to take that forward in select patient populations that you don't think can deal with chemotherapy? You can imagine it. You can imagine a role for that, but it's certainly not a home run.

Dr Cheson: Well, you could add another drug. We did R-squared plus ibrutinib frontline. Chaitra Ujjani from my institution led this Alliance study.[2] If we knew then what we know now, we might not have done the trial because how are you going to beat R-squared data by adding another drug? What we found was an amazing frequency of rash, some of them severe. That's why you've got to put these drugs together in a clinical trial. Even though they're all out there, if you throw them together...

Dr Flinn: Right. Why do you think that was? Just the one more agent? Have you had ibrutinib rashes like that with rituximab?

Dr Cheson: No, we haven't. We've seen a lot of lenalidomide rashes but not of this frequency. Maybe it's the two rash-inducing drugs put together. But what we found, as you know, is that you can take a couple of relatively innocuous targeted drugs, throw them together, and get into trouble. There was the Syk inhibitor, 9973, plus idelalisib. There was R-squared and idelalisib. And other ones that should have been fine, but patients died in those studies. You really have to be careful. We have lots of new drugs out there. We have venetoclax, we have ACP-196, and we have ONO. We have this, that, and the other. The combinations and permutations are staggering. How do we pick which ones to test? That's what you do for a living.

Dr Flinn: I guess it's always encouraging when the single-agent data look really good. Then trying to incorporate them with regimens that don't have overlapping toxicity is the next process forward. It is more difficult when, perhaps, drugs have late onset of responses or work only in combination. That's the more difficult setting. I think the venetoclax story is very interesting. It's obviously a tremendous drug in chronic lymphocytic leukemia. How that will play out in lymphoma, both in the low-grade and the aggressive lymphoma settings, still needs to be seen. Some of those data will read out in the not-too-distant future.

Checkpoint Inhibitors in Hodgkin Lymphoma

Dr Cheson: There is a whole other class of drugs that has excited lymphoma folks probably even more than the solid tumor folks. And those are checkpoint inhibitors, the nivolumabs and pembrolizumabs and all of the other ones from the various companies. The Hodgkin lymphoma data are coming out at this meeting, a longer-term follow up.

Dr Flinn: I am very impressed by the checkpoint inhibitors in Hodgkin disease. And was it last year at this time that we first saw the data?

Dr Cheson: We went, "Holy!" Excuse me.

Dr Flinn: I think they're great as a salvage. But ultimately, if we're going to make a change in the natural history of these diseases, we'll have to figure out ways of bringing them earlier. In Hodgkin disease, that's not an easy scenario. Think about brentuximab vedotin replacing bleomycin in the frontline Hodgkin disease setting and how you would bring a checkpoint inhibitor earlier on. Maybe you'll get unforeseen toxicity. That was probably seen with brentuximab vedotin in the initial patients. It's a real challenge, especially in a disease where there's such a high cure rate.

Dr Cheson: Actually, we've got a study starting in a couple of weeks of brentuximab plus nivolumab for upfront Hodgkin disease in elderly patients and those who can't get ABVD [doxorubicin (Adriamycin), bleomycin, vinblastine, dacarbazine]. And yes, we're concerned about toxicities, and we're going to keep a close eye on patients, but I think we do have to continue to work towards a chemo-free world for our patients.

That's great in Hodgkin disease. But what about in non-Hodgkin lymphomas?

Dr Flinn: I think that those same studies are being done. Single agents and a variety of different immunologically active agents are in the design phase and are being combined with, say, the bispecifics or with rituximab, trying to get away from a chemotherapy backbone. To me, that makes all the sense in the world. I don't know about you, but my patients come in saying, "I'd really rather not have chemotherapy."

Dr Cheson: You betcha.

Dr Flinn: "If you can come up with a different regimen, then I'm all yours."

Dr Cheson: Right now, we've got studies at our place, and there are plenty of studies around the country of Bruton tyrosine kinase (BTK) inhibitors and phosphoinositide 3-kinase (PI3K) inhibitors plus checkpoint inhibitors. Again, as you alluded to before, we've got to do this cautiously because we're going to run into some surprises.

Dr Flinn: That's a good point. We're studying idelalisib in combination with rituximab as part of an upfront clinical trial. Of course, in CLL, there has been a lot of toxicity, so we're doing this very carefully with a small number of patients and making sure that there isn't an adverse event signal with liver function tests. You can imagine that that might also be difficult. That might be a difficult combination, particularly with combining it with a checkpoint inhibitor, if one of the side effects is mostly immunologically mediated. Then sort of goosing the fire there might be hard.

Dr Cheson: Yes. There was an abstract[3] at these meetings in CLL with idelalisib upfront, getting more toxicity upfront than they saw in the relapse setting. When the patient is more immunocompetent, who knows what we're going to run into? That's a lot of what we are going to hear about CLL at this meeting.

Large Cell Lymphoma

But there are some interesting large cell lymphoma data as well. R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] has been the standard for decades. Some people never knew a time before R-CHOP. What we've learned is that diffuse large B-cell lymphoma is a collection of diseases. The biggest two are the activated B-cell (ABC) and the germinal center B-cell (GCB) subsets. We found out that there are some drugs that are preferentially active in the ABC type, which used to be the worse of the two for outcome. They are bortezomib, lenalidomide, and ibrutinib.

So the next logical step for that population was R-CHOP plus or minus one of those drugs. And we have a study[4] from this meeting. Is this a proof-of-concept study? Was it a success? Was it a failure? Ian, let us know.

Dr Flinn: I suspect you're referring to the bortezomib and R-CHOP study,[4] where patients with the ABC phenotype were randomly assigned to receive R-CHOP plus or minus bortezomib. What we're seeing is a negative study. I think it was probably a huge disappointment for many, many people. Perhaps bortezomib wasn't the greatest agent. Maybe there are better agents. But it would have been nice, even just as a proof of concept, if that had read out as a positive so that we could improve upon things.

There were plenty of phase 2 data to suggest that that might be good. There are plenty of phase 2 data to suggest that adding lenalidomide to R-CHOP would help that same group of patients. I hope we're not disappointed in the phase 3 results.

Dr Cheson: And ibrutinib, too.

Dr Flinn: Yes, exactly.

Dr Cheson: Ibrutinib had a 40% response rate in the relapse setting.

Dr Flinn: Exactly. So I'll keep my fingers crossed that the whole field isn't going down with this one.

Dr Cheson: The question is: Are we doing it wrong? We just think that that's how you do it. You take the standard regimen, and you add this new drug. You just kind of throw it in there. There's got to be a better way to do it. We need some kind of biomarkers to tell us how to do this.

Dr Flinn: Yes, I agree that if we could drive it by biomarkers, that would be a great help. Trying to look in the relapse setting, developing from them, and then moving to the frontline is always a challenge unless you're talking about niche populations like the elderly Hodgkin disease patients that we're afraid to give ABVD to. But the average patients with large-cell lymphoma, bring them in, and then think about the 60%-70% overall cure rate. Find a group of those patients who have a very low cure rate, perhaps the double-hit lymphoma patients, and maybe start from the beginning and not just add on to what we've been doing in the past.

Dr Cheson: Yes, the double hits are a particular challenge. As you know, R-CHOP is not great therapy for them. There are drugs in the pipeline targeting BCL2 and targeting MYC, but it will be a challenge.

Cellular Therapies

We also heard some interesting data on cellular therapies for a variety of lymphomas. Everybody's patients are coming in saying, "I want that CAR T-cell thing. Give it to me. Give it to me." We heard some provocative data this morning.

Dr Flinn: We sure did. We heard the experiences of a couple of different centers on large-cell lymphoma or lymphoma in general. Stephen Schuster from the University of Pennsylvania brought forward their experience.[5] We heard from Fred Hutchinson Cancer Research Center about their experience in lymphoma as well.[6] Each used a slightly different regimen, looking at whether it matters what chemotherapy you give before the regimen, the dose of the cells that are given, and some of the management issues and side effects afterward.

What I think we all know—and we've been learning more and more as we hear about CAR T cells—is that they are a highly effective therapy for a select group of patients. These are patients who, frankly, probably have to get a transplant. They're in that kind of health. Many are ending up in the intensive care unit, 40% or more with cytokine release syndrome. There is some interesting neurologic toxicity that sounds like it runs its course and, for most people, it's a temporary phenomenon.

Dr Cheson: It's a little scary.

Dr Flinn: It's scary the first time you see it. And it's scary to the patient every time they see it.

Dr Cheson: Yes. It's not quite ready to play in Peoria.

Dr Flinn: Yes. I would say that.

Dr Cheson: But maybe we'll get there. As I have discussions with my patients, I'll say, "You've got relapsed follicular lymphoma." And they say, "What about CAR T cells?" I go over the potential risks and say that you've got to get chemotherapy. "Or," I say, "I can give you a pill like idelalisib."

Dr Flinn: I'm hoping that some of these logistic issues and side effects get worked out. We're really in infancy in this area. The notion of proof of principle of being able to tap into the immune system and having durable remissions in some of these patients with very, very aggressive lymphomas is quite exciting. But being able to do it safely in a reproducible manner for the average patient is the key.

Dr Cheson: And we're in a world where there's a whole gaggle of drugs coming out that are pills, and they're very effective, and we can combine them. And checkpoint inhibitors. There are lots of new and exciting drugs that we've heard about. We've talked about some. There were some antibody drug conjugate data that were interesting. It's a new world. We're not seeing many more plain old chemotherapy studies, fortunately for us and fortunately for our patients.

Interesting meeting, interesting times, lots more for us to do.

Dr Flinn: Absolutely.

Dr Cheson: This is Bruce Cheson signing off for Medscape Oncology from the ASH Annual Meeting in Orlando with my good friend, Ian Flinn. Thank you, Ian, for joining me in this. And thank you to our viewers for your attention. We'll be seeing you again soon on Medscape.

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