Ajay Gopal, MD, Seattle Cancer Care Alliance

 One of the most exciting aspects of taking care of folks with follicular lymphoma is seeing how rapidly the field is advancing. I look back to more than 20 years ago when I started my training, we didn't have much in our hand. Rituximab was just becoming available, and now we have so many options that I reviewed.

Looking forward, I’m also really encouraged about what we're going to have to offer patients. For the rare circumstances where follicular lymphoma is a life-threatening situation, I'm hopeful that were going to have treatments such as something called CAR [chimeric antigen-receptor] T-cells. These are cellular immunotherapies, these are ways to reprogram ones immune cells, and it does offer the potential of cure, of eradicating it.

Now, it is a pretty intensive therapy and it comes with risk. But as we learn how to do it more safely and understand which patients might most benefit from this, I suspect this will be expanded. This lifelong treatment approach might not be the case for folks, we can just get rid of it, and folks can move on with their life. I don't think we're quite there yet, but I think we will be getting there for many patients in the appropriate situations.

I think at the other end of the spectrum, we're going to develop more therapies that have even lower toxicity. We have a clinical trial studying a dose of one pill a week, a very low toxicity therapy that's worked quite well as the initial treatment. And many of us in the field are working on ultra-low toxicity therapies, to say how can we make this like managing hypertension, where you can have a pill that has very few side effects, or like managing high cholesterol, and make it into this problem that is not a major problem for folks.

Those are ends of the spectrum. For serious situations, we will have a way to get rid of it and try to reduce the risk with things like CAR T-cells or something else called bispecific antibodies where we can attach the immune cell to the tumor cell by giving an intravenous infusion. Then at the other end of the spectrum, we will have low toxicity therapies to treat this like high cholesterol.

I would like to close by saying these are very exciting times in terms of our options for folks with follicular lymphoma. When you have this historical perspective about how much has changed and how much is changing, I am so gratified about how we are able to help our patients who suffer with this diagnosis. We still have a lot of work to do. I would encourage everyone to not be bashful about asking about options and asking about reaching out to see someone who specializes in this area because these are complicated decisions and don't typically need to be rushed.

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The Future of Follicular Lymphoma Management

Quality of life is a very important consideration. There are many cancers where they are imminently life threatening and we have to be extremely aggressive in treating them to prevent them from being fatal. But follicular lymphoma in most cases does not shorten one's life. And that really brings us back to quality of life. We don't want to sacrifice longevity necessarily, but quality of life is a very important consideration. And I talked to patients about this. Much of this is really in the eye of the beholder.

But because we have so many options, we can tailor treatments to patients' preferences in terms of quality of life. Some folks would prefer to have a shorter duration but higher intensity treatment that might give them time off therapy. This might be an approach using chemotherapy, for example, which might give them time off therapy. Other folks might say, “Well, I don't mind chronic therapy that might go for years and years, even if I have some low-level side effects. I just don't want higher side effects, even if it's for a shorter period.”

That might lend people toward taking one of these oral therapies that go on indefinitely. So quality of life is a major part of the discussion in terms of the life strategy or management strategy for treating folks with follicular lymphoma.

Part of this is emphasizing that we want our patients to be empowered, to feel they can ask questions, to ask detailed questions about, “Well, it's a pill, but pills have side effects, too. What would I expect in terms of side effects,” and share their preferences with their provider. I think if treatment is being offered, it's important to understand what are the other options? Are there any clinical trial options?

Is there someone you might refer the patient to if their provider does not see lots of folks with follicular lymphoma, to get an opinion to make sure we're on the right track? And I think particularly in follicular lymphoma, where there are many options, where folks generally do well, and where it's mostly a nonurgent situation, it's not a split decision where someone has to come in and say, “Oh, this scan looks worse. You have to start this other therapy tomorrow.”

That's rarely the case in follicular lymphoma. There's plenty of time to think about it, to review different options, weigh the pros and cons, seek out second opinions, and make sure that you're on the track that's right for you.

Managing Quality of Life in R/R Follicular Lymphoma

I want to emphasize that things are evolving rapidly, and this is where it's important to, in real time, meet with someone, consult with someone who is an expert in the area. But as of now, in terms of approved options, there are standard chemotherapy-type options that are approved, drugs like bendamustine or other chemotherapies, if someone hasn’t had those therapies before. There are monoclonal antibodies like rituximab or obinutuzumab.

And particularly if folks have had long remissions off these treatments, they can be very effective again. There are some more novel options for first relapse, and this includes drug called lenalidomide, which is a pill therapy, and it's often given with rituximab, which is IV [intravenous]. And there was recently a study for folks who had had primarily one prior therapy and had rituximab that worked, comparing this combination to just rituximab, and it appeared to be superior in terms of lengthening the remission.

This is a relatively gentle therapy. I don't want to minimize it, everything has side effects and some folks have more than others. But that's a relatively new approval in this space for folks who have had one prior therapy. As we move down the list in terms of options, there are other classes of drugs that are novel agents. There is a whole class of drugs called the PI3 [phosphatidylinositol-3] kinase inhibitors, and there are three that are approved.

The first one approved is a drug called idelalisib, and this is approved for after two prior therapies for follicular lymphoma. This is also a pill, and everything has unique side effects and efficacy profiles. The initial study was in a tough situation of folks where both chemotherapy and rituximab had not worked in terms of garnering approval for this treatment. You will still have to be monitored closely by your physician, and side effects can be diarrhea, rash, rarely some lung issues.

There have been two other approvals since that time in this class of drug for folks who have had two prior treatments. One is another pill called duvelisib, which is quite similar to idelalisib, similar side effect profile, similar approval. And then there's an IV version called copanlisib, which has a little bit different side effect profile, a little less of the diarrhea issue, a little more high blood pressure and high blood sugar issue.

And it is IV. But some folks might prefer IV and some folks might prefer a pill form. These are very complicated discussions that need to be had with your provider. I want to make sure we don't forget a drug that has been approved for some time, and is quite simple. It's a drug called ibritumomab tiuxetan, which is a long word, and I hesitate to use brand names here, but the brand name is a lot shorter.

It's called Zevalin, and it's basically a radioactively labeled rituximab-type drug. It’s just one treatment infusion and quite short and simple. Also, it can be quite effective. Then to round things out, there was an approval just in the last few weeks of something called tazemetostat. Now this is a really interesting drug, this is a pill. And this is a drug in which the efficacy is based on the molecular signature of the tumor.

This is the first situation in follicular lymphoma where we can do a specialized test to see if there's a mutation present that will drive how well this drug will work. In many of my patients who are in tough situations, we're sending them molecular tests now to see. Now unfortunately, it’s only about one in five who we expect to have that special mutation. It is approved.

You don't have to have that mutation, but the drug works a lot better if you have this specific EZH2 mutation. That's a new drug, another pill, quite well-tolerated, and molecularly driven. So you can see this is a complicated situation. And I haven't even started talking about clinical trials. These give you access treatments that you couldn't otherwise get, and they're typically provided for free by the studies.

I'm going to talk a little more about clinical trials. I think a common question I get from my patients is, why would they be interested in a clinical trial? I first emphasize that I am more than happy to be their provider. I think most of us in academia, we're happy to take care of folks who are interested in clinical trials and those who are less interested in clinical trials. There's by no means a requirement for that.

But all these agents that I just reviewed, they were available in clinical trial before they were actually available commercially. And it does provide an opportunity, and I think you want to speak with someone who understands what the appropriate clinical trials are for you to get some of treatments before they are widely available. I think of the treatment of follicular lymphoma as really, as I said, a life strategy or chess match.

You want to make sure you do the right move first, and you want to still have lots of moves in reserve. I say to my patients who are interested in trials that agents that are FDA approved are always going to be there. But the clinical trial options come and go as the trial is opened and then closed. For those who are interested in trials, it gives them more moves, more options, more menu items to try get them to that finish line of a life well lived with the least side effects and lymphoma under control.

Obviously I do clinical trials, so I have a perspective on that. But it does potentially provide more options, the appropriate clinical trials.

Novel Agents for R/R Follicular Lymphoma Management

One characteristic regarding follicular lymphoma is, even though most will have a normal lifespan, it's a very difficult lymphoma to eradicate. It's really more of a chronic problem. It's to some degree one might even say a nuisance lymphoma that can cause symptoms, that needs to be dealt with over time, even if it's not typically life-threatening in most folks. When we get the initial treatment, the expectation is, unfortunately, that in most people, it's probably going to come back at some point.

And if it does recur, we ask the same questions. Is it bothering someone? Is there a reason to do something about it because really, there are no data to say that if it's not causing problems, that there is reason to treat. So we really ask those same questions. Is there a reason to do something about it? And then we look at factors such as, how bad is it causing problems or creating symptoms? Is it affecting organ functions? How long was it since the initial remission?

Did you get a really long remission after your first therapy or was it relatively short? And really, it's not rocket science that if you had a shorter remission, that's usually more problematic than if you had a longer remission. And then we also look at what was the first therapy you had. If you had a short remission after a really strong therapy, that’s something we take a lot more seriously than if you had a longer remission after really gentle therapy.

That would be the best-case scenario. And we put all those factors together and, of course, have the patient be a part of the decision-making to discuss the approaches, discuss clinical trial approaches. I obviously have a certain perspective here in an academic medical center, but these are complex decisions that don't need to be rushed typically. I often encourage folks to seek out expert opinions in treatment of lymphomas to help in the decision-making, even if the experts may not be the ones actually treating you, but help to guide treatment.

One question is, do we talk about what happens at relapse at the time of first diagnosis? This field is rapidly evolving. There are therapies that are being approved and new options and new data coming out almost on a month-by-month basis, or certainly, each year there are new approvals in this area. So I speak in general terms about overall strategy. I talk to patients about how this is really a life strategy.

How do we get patients to that finish line, whatever that might be, in terms of a life well lived with the least amount of side effects, the least amount of hassle, and the maximum quality of life and longevity? So I speak in general terms usually at the beginning and say that if that time comes, or when that time comes that we need to talk about relapsed disease, we'll talk about more specifics based on the state of the art at that time.

Ajay Gopal, MD, Seattle Cancer Care Alliance

The Future of Follicular Lymphoma Management

Managing Quality of Life in R/R Follicular Lymphoma

Novel Agents for R/R Follicular Lymphoma Management

Progression in R/R Follicular B-Cell Non-Hodgkin Lymphoma

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