 Welcome to the section of CURE Expert Connections

. This is a program that is focused on improving and understanding the lives of patients with follicular lymphoma. My name is Dr. Venugopal. I’m from the Rush University Medical Center. I am a professor of medicine, and I direct the section of hematology. Today I’m joined by Jennifer Garson, physician assistant, from the section of hematology, as well as one of our patients, Mr. Gerald Koch, who has follicular lymphoma, who is going to share with us his story of the disease and what he went through and how he’s doing.

 So maybe we can talk about non-Hodgkin lymphoma in general. As you know, it is one of the more common cancers. And follicular lymphoma is the low-grade subtype of non-Hodgkin lymphoma, which is the most common low-grade B-cell lymphoma and also the second most common non-Hodgkin lymphoma.

I think in 2018 about 75,000 new patients were diagnosed in the United States. And about 20 percent to 30 percent of these patients had follicular lymphoma. And follicular lymphomas are diseases that can go for a long time, sometimes even without treatment. That’s why if you look at the prevalence—that is, the number of patients alive, the total non-Hodgkin lymphoma &mdash; it comes to about 700,000 patients at any time, at least based on the 2015 statistics.

Maybe let’s talk about the risk factors that are involved in follicular lymphoma. There are many factors starting with, for example, age.

 So generally our patients do present older in age. The median age of a follicular lymphoma diagnosis is anywhere from early 60s to mid-70s, with our median patients being in their mid-60s. We generally do see a male predominance in non-Hodgkin follicular lymphomas.

 So we do see older patients, usually males. As far as family risk, there’s really not a hereditary link, but I think more and more, we’re finding genetic variance within families that are associated with these non-Hodgkin lymphomas, especially the low-grade lymphomas.

 I agree completely, yeah. So it is not like in breast cancer, where you can define the risk of a patient getting breast cancer based on family history. But in non-Hodgkin lymphoma we don’t have a pattern like that. Although we do see in some families that there’s an increased number of incidents. But there is no genetic pathway that is yet established. Other risk factors—including environmental factors, exposure, prolonged exposure to toxins and even fertilizers&mdash; have been mentioned, but nothing has been scientifically proven.

In terms of the risk stratification of the patient, in the clinic usually we use a certain scoring system. One is called FLIPI, or F-L-I-P-I. It is a prognostication system in which we take several factors, like the patient’s age, the number of lymph nodes and the size of the lymph nodes, and put them together, and we can classify them into low and high risk. And based on that we can make decisions on treatment choice and can give the patient an approximate prognosis in terms of what is the likely survival.

So these are things that help us in everyday practice in the clinic, helping patients to understand their disease and understand what is coming up in their life with respect to the disease.

 And I think one of the hardest things from a provider’s standpoint with low-grade lymphomas—and you may agree or disagree, I don’t know&mdash;is that there’s such diversity, not just in how our patients present but in our patients in general, as far as where they are in their lives, what their quality of life is at the point that they present with us, and their comorbidities, which can add to the challenges.

 You’re absolutely right. Particularly comorbidity can be a major factor in deciding what is the appropriate treatment. And that leads us to some of the new developments we have in this area, whereas unlike in the past we only had chemotherapy, which, as you know, causes significant adverse effects. And therefore, the option of chemotherapy is restricted to people who are otherwise healthy and younger. Whereas now we have options other than chemotherapy. The new agents, biological agents, which we can apply to older patients and patients with comorbidity.

Considerations in the Diagnosis of Follicular Lymphoma

 So today we are joined by Mr. Gerald Koch, who has a diagnosis of follicular lymphoma, and he has been kind enough to come and share with us some of the stories related to his diagnosis. Gerry, can you tell us something about how you were diagnosed? What were your symptoms that led you to the doctor, and what did the doctor talk to you about? And what are the tests that he recommended? Just take us through the story if you can.

 It was back in 2011. I had some back issues over the years, and I went into a doctor’s office to see what I could possibly do about relieving some of my back symptoms. I had an MRI [magnetic resonance imaging] and was shocked beyond belief when I received a phone call—actually, my wife received a phone call&mdash;that said that I had cancer and I needed to contact my doctor and go further. I contacted a doctor at MacNeal Hospital, and I was diagnosed with follicular lymphoma. I started a six-month treatment with Treanda and Rituxan, once a month for six months and then many months of maintenance afterward. And after the six treatments my cancer was gone.

 So going back to the initial diagnosis. You started with backache; that’s what you said. So you went and had a scan. I’m assuming they did a biopsy of the tumor, correct?

 I see. Did they tell you what the diagnosis was, what kind of lymphoma it was at that point?

 They told me it was follicular lymphoma, stage 4. I really had never heard of follicular lymphoma, so there was a lot I didn’t understand at first. But gradually I came to learn exactly what it was I had and what we were going to do about treating it.

 Did they do any other tests as part of the staging, like a bone marrow biopsy?

 Yes, I had a bone marrow biopsy. Very painful but necessary.

 Right. Yeah, so the bone marrow biopsy is usually part of the staging to find out, No. 1, what the stage is. And No. 2, we had to make sure that if the bone marrow has lymphoma, at the end of treatment we had to make sure that he was clean before we called him in complete remission. So that’s the purpose of doing the marrow.

 OK, so the doctor met with you and talked to you about the results of each of the tests, right?

 Did they say that your bone marrow has lymphoma?

 So that’s the reason why they mentioned stage 4. Once the follicular lymphoma involves bone marrow, it is stage 4. Obviously, it’s an advanced disease.

So you got started on treatment. How did you feel when you started treatment based on the information that you received from the doctor about the potential adverse effects? How did you feel?

 Well, I was a little apprehensive at first. The adverse effects weren’t as serious because I guess some people have different reactions. My biggest adverse effect from the first treatment was a little fatigue, a little nausea after the first day. I would generally take an anti-nausea pill, for just one day, and that kind of went away. I felt pretty good for the rest of the month until it was time to go back the next month.

 Were you able to work through the treatment?

 I took off work because of the risk factors from infection. I’m a police officer, so I’m around a lot of people who might carry disease. I’m around a lot of people who get sick a lot, and my doctor felt it best that I remove myself from that situation. So I was off for the eight months that I was being treated.

 And did you have to interrupt treatment for any reason?

 No, I pretty much went to six months with no problems at all.

 OK. And so you went for six months of treatment, that is six cycles of treatment.

 And at the end of that, the doctor probably did some tests to find out how your cancer is doing, right?

 He told me there was no evidence of cancer, I believe, after the third treatment. As I said though, for a year afterward, I did go in for maintenance treatment.

 So maintenance treatment means you were taking just rituximab every two months, right?

 And how long did you take the maintenance treatment?

 Two years is usually standard. And then what happened? After the maintenance, did you stop the treatment?

 Stopped treatment, but I was still seeing my doctor. And it was after a scan, I believe, that the doctor said that the lymphoma was reappearing. And that’s when I was referred to you at Rush [University Medical Center], and that’s where I’ve been ever since.

 Right. At that time did you go through more tests?

 I went through some more tests. Eventually I was put on a clinical trial treatment. I was on that for several months. That ended up not working out as planned. There was progression of the lymphoma. I was then put on another oral treatment that I was on for about a month, and I had a bad reaction with my liver, so they took me off that. And it was about 10 months later that I started my current treatment.

 So the treatment that Mr. Koch initially went through is a combination of bendamustine and rituximab, which is one of the commonly used first-line treatments for follicular lymphoma. It is very effective, and it also has much fewer adverse effects than the R-CHOP [rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone] chemotherapy that we used to do in the past. But subsequently there was a trial comparing the two, which clearly showed that the benefits are the same with much less toxicity. That is why this combination, which Gerry got, has become standard first-line treatment outside a clinical trial.

And after the first six months of treatment it is appropriate to keep the patient on a maintenance with rituximab, and usually we give it for two years. And after that we watch the patient, as was done in Gerry’s case. Unfortunately, the disease came back, which, as you know, in follicular low-grade lymphoma the disease responds well to treatment but has a tendency to come back. But fortunately we have many good options now, so when they come back with the relapse, we are able to keep them back in the remission and keep the quality of life.

It’s also important to know that when there is suspicion of relapse, the disease coming back, it’s always a good idea to do a biopsy again. One, we want to make sure it is lymphoma; and two, we want to make sure that the lymphoma has not changed. Sometimes low-grade lymphoma can change and become aggressive lymphoma, for which the treatment is quite different. That’s why a biopsy is very important, and that was the appropriate thing to do.

So then you went through a clinical trial—and clinical trials, as you know, are always the best way to get new medications even before FDA approves them&mdash;and that is exactly the reason why the doctor offered this approach. Gerry and his wife went through the research and found out exactly what the drug means and what are the adverse effects, and you know it was an informed decision on their part to participate in that. And he started the pill. Unfortunately, it didn’t work very well. So then he stopped the research trial and they put him on a drug that was at that time FDA approved.

And as Gerry said, after taking that pill for some time, he had significant problems with his liver function, so the drug has to be stopped. And then, subsequently, we started him on another drug that is a PI3 [phosphatidylinositol 3] kinase inhibitor.

Gerald's Journey Through Follicular Lymphoma

 So Gerry went through a first-line treatment. As I mentioned before, it’s the standard of care—bendamustine and rituximab in combination. And he responded well. But as we know with the nature of this disease, the response didn’t last long. And that’s why he had to look for other options, which brings us to the discussion of second-line treatment. What are the second-line treatment options in patients with follicular lymphoma?

There are standard-of-care drugs, including combination chemotherapy like R-CHOP [rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone], which, as I mentioned before, has significant side effects. Or you could look for novel drugs, and that is what he did. The novel agents mostly work through pathways and proteins on the surface of the cancer cells, so that you inhibit the cancer cell, or destroy the cancer cell, by working through inhibiting those pathways that the cancer cell depends on.

An example is a BTK, or Bruton tyrosine kinase pathway. Another example is a PI3 [phosphatidylinositol 3] kinase, which is the pathway that many cancer cells depend on significantly for their survival. So if you cut off the PI3 kinase pathway with their medication, you should be able to cut down the growth of the cancer and kill the cancer cell. Specifically, the cancer cell without affecting the normal cells. And that’s the beauty of using these targeted agents.

So the drug that Gerry used, the pill, is a PI3 kinase inhibitor. And unfortunately, that pill gave him some significant adverse effects with the liver disease. Do you remember what exactly happened? What was your symptom, Gerry, at that time?

 I went in for a checkup, and the blood test revealed that the level of liver enzymes, I believe, was in the thousands, and it should have been much lower. I believe it was the night before I went to the doctor. I noticed a change in my ability to taste food. And that progressed for the next several months until that went away. But I was immediately removed from that medication. I spent a couple of nights at Rush [University Medical Center] and was observed, and it was as I said, several months before I received a normal taste with food and drink. And at that point, other than my numbers going up, I didn’t have any other effects that I can remember. It was just the taste. That was the worst.

 Exactly. So what happened was, when he was put on this medication, he did have increased liver function abnormality. That means the liver was getting damaged from the medication, which is a known side effect of that drug. The PI3 kinase medications that inhibit the PI3 kinase pathway can cause hepatitis or liver inflammation, colitis or inflammation of the bowel, and pneumonitis or inflammation of the lung. These are side effects.

But there are several PI3 kinase inhibitors. Some of the names are idelalisib, copanlisib, duvelisib, and buparlisib. These are all PI3 kinase inhibitors. They’re all drugs that kill cancer cells by inhibiting the PI3 kinase pathway. The beauty is that the side effects vary among these drugs because the pathway is inhibited based on certain parts of the molecular setting, like delta, alpha, gamma. Depending on which part is inhibited, the side effects can vary.

That’s the reason Gerry was able to get another treatment with the same pathway inhibitor. So the treatment he is getting now is also a PI3 kinase inhibitor, but it has much fewer side effects on the liver as well as the lungs and the colon, and that is why he has been able to tolerate the treatment, so far, well. Can you tell me about experience with the current treatment?

 I am currently treated three times a month. Every week on Wednesday, I go for an infusion, and then I have one week off. My side effects are fairly minimal, I guess. I get a little fatigue and have some gastrointestinal issues, but nothing I can’t handle. Probably the biggest thing is the fact that I’ve got to go there every week. I’m there for about three, four hours. It’s just every week I’ve got to be there, and that is a little annoying at times, but that’s what I’ve got to do to treat my disease.

 Yeah, thank you. So I think it is also important to note that you know the point I mentioned before—that as a patient you should work with your provider, whether it’s a doctor or a physician assistant or a nurse practitioner, and look at options at each point. When Gerry had difficulties with the first PI3 kinase inhibitor drug, we talked about the different options. But then we thought, another use of another PI3 kinase would be concerning because if it is the same class of drug, can it also cause liver dysfunction?

But based on the studies and the information we had at that point, the chance of liver disease from this drug, even though it is working in the same pathway, appeared to be much less. And that’s why Gerry and his wife also did the research and finally said, “We are willing to try that, even though there is a risk.” And he tried, and did well. So I think the point again worth emphasizing is that you need to work with your doctor and look at all your options and select your treatment. In many things in life, we have to take some risk to get the benefit, and that is exactly what Gerry went through, and he made the correct decision. So I think what I would emphasize again is the point that as a patient, you try to get as much information as possible about your disease and your options and then work with the doctor and make that decision. Are you happy that you made that decision, at least at this point?

 I am happy, and I hope to continue the reduction in my cancer cells. It’s not gone yet, but it looks like we’re going that way.

Managing Gerald Through a Relapse of Follicular Lymphoma

 One of the conversations that comes up a lot with patients is…our experience with some of these newer, novel agents. And for Gerry it was a very difficult conversation to come back in and talk about another PI3 [phosphatidylinositol 3] kinase inhibitor after he had such a bad experience landing in the hospital with idelalisib. And one of the things we talked about are the different side effects associated with each of these different PI3 kinase inhibitors. And I know there’s always a lot of apprehension for patients when they have a bad experience with one drug to kind of jump in and be agreeable for another drug that may cause potentially similar side effects. So there was always a lot of discussion about how the mechanism of action is different with these drugs, especially the one he’s on now, and what we would expect as far as side-effect profile.

Currently Gerry is on a drug called copanlisib, which is an infusional type of PI3 kinase inhibitor. And the side-effect profile is a little bit different than the one that he had been on previously and had trouble with. The biggest side effects that we were going to be experiencing with this, we thought, were going to be transient hypertension and high blood sugars.

And so, Gerry was kind of the perfect patient to put on this drug because he doesn’t have a lot of comorbidities. He has not experienced a lot of uncontrolled hypertension, he doesn’t have diabetes. And so we weren’t expecting to see any real significant side effects from that standpoint. But again, with this drug, we can see some of that hepatotoxicity or liver toxicity that he had seen with the idelalisib, as well as some of the pneumonitis and colitis, even though it’s a lot less with this particular drug. I think from the patient perspective, it’s kind of a lot of reassurance from our end of things moving into this.

 For Gerry, one of the big drawbacks to this was that it was an infusional therapy versus an oral therapy. And so for a gentleman who is working the night shift and has a great quality of life at this point, it’s a really hard sell sometimes to say, “Can you come in once a week and do this?” Especially within our first cycle of treatment, we were very cautious in administering this drug to him, knowing that some of these side effects can peak at about five hours into the infusion. So if you remember way back when…about 16 cycles ago.

 We used to spend a lot of time together in the clinic. For about three weeks he was spending his entire Wednesday with us because we were monitoring him, even though the infusion was only an hour long. So I think there’s a lot of buy-in from the patient that we have to get in order to use some of these newer treatments, especially when they’re infusional. Any concerns going into this new drug?

 I was a little apprehensive, but you guys reassured me that you think that this was the right path for me to take. And after the first treatment I’m like, “Hey, I can do this.” And once again, the biggest negative to this treatment I’m on now is the time commitment. Every Wednesday I’ve got to go in there for three weeks, so you’ve got to kind of plan your schedule around that. And as I said, I work nights, and sometimes I have to go in the morning, sometimes I could schedule the afternoon. But that’s the biggest thing right now. Luckily, I don’t have any severe side effects. You know, you think of cancer and people losing their hair, and throwing up, and all that other stuff that you hear about, especially from years past. I haven’t experienced any of that, so that’s the most positive part of it. The time commitment — if I could get rid of that, I’d be home-free.

 We’re working on it. We really are working on it. The unfortunate thing with indolent lymphoma is that this is more of a chronic disease. And after first-line treatment, our duration of response dramatically decreases with each line of therapy. So I know from Gerry’s standpoint, he maybe feels at this point that we’re always jumping from treatment to treatment to treatment without a lot of breaks in between. As I said, one of the big components in making patients understand why and what we’re doing is to really outline the mechanism of action, the side-effect profile, and how we can best manage that to keep their quality of life as best as they want it to be at that point.

Preparing Patients for PI3K Infusion-Based Therapy

 We’ve talked a lot about Gerry’s story and how he’s been treated and more about the hematologic side of this. And one of the things we always work with is our multidisciplinary team. So with Gerry, for instance, just in patients who have relapsed or refractory disease, it’s always important not just to get another tissue sample but to sit with a group of experts essentially. And at Rush [University Medical Center] we have a lymphoma comprehensive clinic, and it’s where Dr. [Parameswaran] Venugopal, some of our other hematology attendings, as well as our advanced practice providers — our radiation oncologists, our pathologists, our radiologists &mdash; can all sit down and have a discussion about where a patient has been as far as diagnosis, where they are at the current time and what our plan is to get them to the next best treatment or remission event.

So it involves not just hematology. We look at all the other areas to help us make decisions. And then sometimes, just like with Gerry’s case, we have to bring in some experts from outside of hematology. For instance, when Gerry was on idelalisib and his liver enzymes went up so much, we brought him into the hospital. We had our liver experts come in and give us their opinion on the best way to treat him at that point. So it’s not always just about hematology. It’s involving kind of every other discipline and getting our patients the best care that we can.

One of the other conversations that Gerry and I have had over the past couple of months is we had a CT [computed tomography] scan that showed some pulmonary nodules after he had an infection. And from our standpoint we said, “Well, you’re just getting over an infection, so let’s repeat a scan. But if these nodules become more numerous or are getting bigger, let’s get our pulmonary team involved. Let’s get the experts on the chest in here and take a look at these lungs and see what else we need to do to make sure that he’s getting the best care.”

It’s not always just about the one discipline. You sometimes have to involve some other areas. And that extends into our nutrition department. Sometimes it can be our social workers, our psychologists, just to coordinate all the care that these patients need, especially as they are treated more and more frequently and for longer periods of time.

We talk a lot about the multidisciplinary approach on our end of it. But from your end, there’s a lot that goes into making sure that you’re doing well, and it’s not just you as an individual. It seems that you’ve got a pretty good support network that’s helping you through this.

 I do. I’ve got my wife, Kelly, who goes to most of my treatments with me, sits there with me during the infusions, gets me something to eat, makes sure I have something to read and gets me whatever I need. So that’s been great. My family at home, they kind of — you know, when I get my infusion, I come home, and a lot of times I’m tired. I work midnights, so a lot of times I work the night before, and then I’ve got to be there early in the morning, and I get my treatment. So the kids kind of know to give me some space. But the support I get at the hospital is great. The doctors, the nurses, everyone I encounter there are genuinely concerned for my well-being, and it shows through the work that they do.

Multidisciplinary Management of Follicular Lymphoma

 Any advice I could provide for anyone else going through the same situation? First off, you’ve got to listen to your doctor. I was kind of shocked when I was first diagnosed. I didn’t have anyone in my family who had been diagnosed with cancer before. I did some research on it, wanted to learn about it. I wanted to learn about the treatment options and the survivability. When I went through my first treatment, everything went well. There was always talk about getting a second opinion. We discussed that. I was referred to a doctor, and it was the same. Then we talked about treatment options. And as Dr. Venugopal said, I went with what was a pretty common treatment at the time. I had the support of my wife, my family. It wasn’t a problem to take off work, so I didn’t have to worry about that.

Take care of yourself, eat right and listen to what your body is saying. I didn’t have many side effects, so I can’t offer too much on that. But after the first treatment, it was offered to me to go on a clinical trial, and I was told that clinical trials are beneficial and that maybe you get access to drugs that other people might not, who aren’t participating in a trial, that you have access to, and there’s always new stuff coming out. I wouldn’t discount that. My clinical trial did not work out. However, it doesn’t mean that it won’t work out for someone else. So everyone reacts differently, I guess. And it didn’t work for me, but perhaps other people will have better results.

 Yeah, I think that it is important to know what Gerry went through because I think one of the things I particularly liked in my interactions with Gerry and his wife is that each time they listened to me first, but then they did their own research. They talked to others, read about it and then would come back and ask questions. So it is a combined effort, not just the doctor coming in telling you, “This is the best treatment.” I think this is the way every patient with lymphoma, or other cancer, should be thinking and should also think about trying to get a second opinion. That doesn’t mean that you don’t trust your doctor. It’s always a good idea to get a second opinion.

And also, try to educate yourself about the disease and the options. There may be more than one option. And then, of course, you have to believe in your doctor. And that belief comes out of your own research, and then the relationship you have with your doctor is very important. And Gerry had not only the determination to get through this but also wonderful support from his family, so he was able to go through what occurred and get the best results out of them. So that’s what I would encourage you to do. Get a second opinion, and try to learn about the disease and your options before agreeing for a treatment.

Practical Advice for Patients With Newly Diagnosed FL

 You know follicular lymphoma, low-grade follicular lymphoma, has truly become a chronic disease. You can keep it under control and maintain the patient’s quality of life. But unfortunately the disease has a tendency to come back, as Gerry was alluding to. And of course the good thing is that there are newer treatments, which work in totally different ways, so that every time it comes back there is something different we can do, which, again, controls the disease.

Gerry mentioned something, that it’s not curable. Well, follicular lymphoma, low-grade follicular lymphoma, is considered not curable except with a treatment called stem cell transplantation. And that, too, should be a donor transplant, a transplant from a donor. Now, you may ask why that is not being done more commonly? The main reason is, first, of course you have to get an appropriate donor. And even if you get a donor, allogeneic stem cell transplantation is associated with significant risk in terms of even dying from the procedure, and also, long-term morbidity, which means the patients can have reactions that can last very long, like graph versus host disease. If you’re taking medications for a long time just across the immune system, there are short-term and long-term side effects from that procedure. And typically for that procedure you have to be in the hospital for at least one month to get intensive chemotherapy and sometimes radiation. So because it is so intense and is associated with potential for including mortality, that’s the reason why nowadays, particularly with the advent of new medications, we do not recommend stem cell transplantation in the first or second line, or even in the third line. But that certainly is a treatment option, which is considered standard of care.

The other treatment option for the future is something called CAR-T, which stands for chimeric antigen receptor T-cell therapy. In simple words, you know we all have lymphocytes in our body. There are B lymphocytes and T lymphocytes. And the T lymphocytes in our body are supposed to eliminate the bad cells from our body. It is part of our immune system. What happens is cancer cells find ways of avoiding the attack by T cells. So now there are methods by which you can take the patient’s normal T cells from the blood and train it, manipulate it genetically and put it back into the patient so that those T cells, which are the patient’s own T cells, circulate and find the cancer cells and kill them, one by one. And they stay there. They keep killing them like a serial killer.

So this is called CAR-T therapy, which is probably going to be the most fascinating treatment. It’s FDA approved only in another type of lymphoma. But in follicular lymphoma, it is not yet approved. There’s a good possibility in the future that disease also will be included. So that certainly is exciting if you don’t need to do any medication or chemotherapy, and you just train your own cells to treat the cancer.

 I have heard about that. You told me about that several months ago. That would be great. Very promising.

 Right, absolutely. The other group of treatment options I want to mention is like the treatment you are getting, Gerry. You combine one pathway with a drug that is attacking another pathway. As you can imagine, if you have a cancer cell, it may be depending on more than one pathway to survive. We may be attacking just one pathway with one drug, and if you combine it with a different drug, you may be able to cut down both the pathways, and the cancer cell kill will be even better.

So those are trials that are going on, combining drugs like what Gerry is getting along with other drugs, which increases the likelihood of putting patients into remission, keeping them in longer remission, which is, in other words, cure. So there’s a lot of hope, and we need to be educated. The physicians, providers and the patients need to be educated and should be aware of these changes, so that we can apply that and give the opportunity to the patient to get the best care.

With that, I’ll stop here. I want to thank Gerry and my colleague Jennifer for coming and participating in this program. And, of course, I want to thank the CURE Expert Connections

 program for organizing this. This is absolutely a wonderful program for educating the patient. And as I said again and again, informing the patient about the options of treatment and educating them is the best way we can help take care of their disease. Thank you.

Improving the Outlook of Patients with Follicular Lymphoma

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