Managing Your Respiratory Health after Transplant and CAR T-cell Therapy

[00:00] Moderator: Hello and welcome to the workshop Managing Your Respiratory Health After Transplant and CAR T Cell Therapy. 

My name is Jordan Sexton and I'll be your moderator for this session. 

[00:09] Before we begin, I'd like to thank Sanofi, whose support helped make this workshop possible. 

It's now my pleasure to introduce Dr. Joe Hsu. Dr. Hsu is an assistant professor in the Division of Pulmonary Allergy and Critical Care Medicine at Stanford University and director of the Stanford Lung GVHD Clinic. 

He has over 15 years of experience treating and studying bronchiolitis obliterans syndrome, BOS, in stem cell transplant and lung transplant recipients. His research focuses on pulmonary complications, including both infection and rejection after transplant, and he was the lead investigator on a recently completed STOP-BOS trial using pirfenidone for lung GVHD. 

Please join me in welcoming Dr. Hsu. 

[00:56] Dr. Hsu: Thank you, Jordan. First, I'd like to thank the organizers for inviting me, and as Jordan said, about 10 years ago, I started a clinic that's known as the Stanford Lung GVHD Clinic. This is a unique clinic in a way that we primarily see patients with pulmonary complications after bone marrow transplantation. From that clinic, as Jordan mentioned, we've been involved in new trials to develop antifibrotic drugs to treat bronchiolitis obliterans syndrome or BOS. 

[01:24] We've also been involved in pioneering new diagnostic techniques, and I'm going to talk to you about both those things today. 

I'm just thrilled to be here and talking to this group of people that are suffering from graft-versus-host disease. I just find the people with this condition to be so inspiring, having gone through blood cancers, having gone through the treatment, having gone through the rigors of transplant, and then to have this oftentimes incurable lung disease out of that, and I just really feel so much compassion for caring for those patients. 

[02:02] I want to start today by having a quote from Don Quixote, because this really typifies my mission in this disease to try to make sure that we diagnose the disease properly and also that we develop new treatments. 

 So, the quote is, 

“Perhaps to be too practical is madness. 

To surrender dreams, this may be madness. 

But maddest of all, to see life as it is and not as it should be.” 

This is where I was in 2017. I had this large patient population that were doing fine, but there was no drugs to treat them at that time. At that point, it was my Don Quixote moment where I essentially cold called Genentech, and I said, listen, you have a drug that you use to treat pulmonary fibrosis. This is the same process that we see within lung GVHD, and that was the onset of the trial that we're going to be talking about. 

[03:02] So today, just by introduction, I want to talk to you about the breath and what that actually means. But beyond the notion of breathing, I want to focus on how we really breathe. That actually gets down to how do we get oxygen into our bloodstream, get that oxygen moving forward and get it to the tissues so that you can have a good quality of life and focusing on the cardiopulmonary status with folks that have some type of lung GVHD. 

Then what we're going to do is we're going to talk about the specific problems that you can run into after transplant and also some more recent data of things that you can run into post CAR T and talk to you about some exciting treatments that have come down the line. Last time I was on this, giving this talk, there were really no treatments that were available, and it's exciting that we've come to a place, and I know Dr. Cutler has reviewed some of these treatments already, so we'll talk about specifically how it relates to BOS.  

We're going to talk about how to live with lung GVHD, and that really comes down to the cardiopulmonary status. 

[04:02] Then I think there's a lot of questions that happen around lung transplantation, so I want to make sure I address those as well.  

In terms of the learning objectives, I want to make sure that we understand the types of injuries that can happen after hematopoietic cells transplant. I want you to understand what the risk factors you have to watch out for, for developing pulmonary GVHD and other lung problems after transplant. 

How do you detect these things? Oftentimes it's very difficult to detect because there's a lot of disability that happens after transplant. In other words, like your fatigue after transplant and how can we track things to make sure that you don't develop lung GVHD and then talk to you about lung issues after CAR T therapy. 

When we think of the breath, the common thought is that it is getting oxygen in and getting that oxygen across that alveoli, which you can see here on the lower right, and into the bloodstream. That's the main focus, how is my saturation doing? What am I doing like that? 

But, breathing is much more complicated than that. It's also getting carbon dioxide out, and getting carbon dioxide out is actually one of the more significant things that happens to people as they progress through their lung disease, that it becomes a difficulty in exhaling the carbon dioxide. 

[05:24] When we think about that, we have to focus on the mechanics of breathing, and here the mechanics of breathing are much like a bellow. 

The main driver for our breath is the diaphragm. You can see the lower two arrows that represent the diaphragm and the diaphragm has to descend down into the abdomen. When you get into a situation where there's any abdominal contents that are pushing up on that diaphragm that just decreases the lung size.  

One of the conditions that we're going to talk about today is truncal sclerosis where the skin over the abdomen is so stiff that the diaphragm actually can't descend. Even though that's not a lung condition itself, it affects your respiratory mechanics. 

[06:01] In addition, your chest wall has to expand so, in that same condition, if you have truncal sclerosis and it involves a chest wall, then it's not going to let the lungs expand as they normally would. The lungs themselves, once again, are fine.  It's just that they're in a box, and they can't quite expand. 

The other conditions that we see that cause this same problem are fluid around the lungs or tightening around the lungs themselves. This is the kind of thing that we need to think about when we think about breathing itself. 

[06:34] However, the real question here is how do we actually get oxygen to our tissues so that we can get up, we can get around, we can have a good quality of life? 

That is a very complicated equation, which is known as the delivery of oxygen equation. But in that equation, it really takes into account other things than just the lungs. I want to focus on that and give you an analogy. 

The analogy that people use when they talk about oxygen delivery is one of a train trying to carry people from one station to the next. Here the people are actually the oxygen molecules. 

So, here you see the top of the graph, which is the lungs. This is the loading station, and this is where, obviously, people are focused on in terms of their breath. 

But what can be done in order to breathe better? 

[07:23] It starts with the blood. The blood is the car that actually carries the people, which are the oxygen. But really, it depends on having a good, strong heart. And this heart is the train that actually pushes things along. 

In fact, when you actually look at the equation itself, the heart plays a much bigger role than the lungs play in terms of getting oxygen to the tissues. So, we need to focus on getting people stronger. 

Then the other station is the tissues, and that's like the city where the people are being dropped off. The muscles have to also be very efficient in using oxygen and using as much oxygen as possible. 

So, for the longest time, when there were no treatments, this is what we focused on in the clinic is optimizing how we are exchanging oxygen to our tissues itself. I'm going to talk more about this later. 

[08:13] The other thing that I thought would be helpful to start, in terms of introducing this topic, is the pulmonary function test. So, the pulmonary function test is a variety of tests, but what we're looking at here is something known as spirometry. Spirometry essentially is determining the mechanics of how you breathe. 

What we have here on the far left is normal, right? And then the green line here at the top is actually your exhalation. 

How well can you blow air out? On the horizontal axis is volume on the vertical axis is flow. What we see in the obstructive patient in the middle graph is that the flow out of the lung becomes blocked, that's why it becomes more scooped in that flow diagram. 

You also see that the volume becomes bigger. What happened there is that the lungs are beginning to become hyperinflated. We're going to talk more about that as well. 

[09:08] The other condition that we see in spirometry and pulmonary function testing is a restrictive pattern. This restrictive pattern in the curve itself looks normal, but you'll see that the volume is much, much lower, and that's oftentimes what we're seeing on patients that have some restrictive lung disease. 

So, when we think about the landscape of lung complications that happen after transplant and CAR T therapy, you simply divide it into those that are restrictive diseases, which you see here in green, and those that are obstructive diseases, which I've labeled in purple. 

[09:44] Then there is this bronchiectasis entity, which is newly discovered form that's very prevalent after stem cell transplant and CAR T therapy, and we're going to talk about that as well.  

I've also  given you these dotted lines and these solid black lines. Here, the dotted lines represent diseases that are possibly associated with graft-versus-host disease. It's not to say that they are not graft-versus-host disease, but oftentimes these diseases can be caused by many other things. They don't carry that same moniker as, say, for example, bronchial asylbutarine syndrome has, where it is clearly associated with chronic graft-versus-host disease. 

[10:25] Moving on, I want to first start talking about the pneumonias. These are restrictive lung diseases because they take up space within the lung itself. 

When we think of pneumonia, we typically think of the typical infectious pneumonia, which is the thing that you can get when you're immune suppressed. But what we're seeing here on the CT scan, which is essentially cutting the body cross-sectionally, is that there's a this big white area on the left side of the figure. That is the pneumonia, the bacterial pneumonia that begins to take up space in the lungs, and as it begins to take up space in the lungs, it's no wonder that you become short of breath when you have a pneumonia. 

[11:09] Now, the other feature I just want to point out to you on the CT scan is that it's very, very dense. In other words, there's no patchiness that's happening here. So, it's basically taking up that whole section of the lungs.  

One of the conditions that somewhat mimics this issue is something called organizing pneumonia. Organizing pneumonia has many different names. It's sometimes called cryptogenic organizing pneumonia or COP. It's sometimes called bronchiolitis obliterans organizing pneumonia or BOOP. But I think the easiest way to term is organizing pneumonia. Organizing pneumonia, as opposed to infectious pneumonia, is relating to inflammatory conditions in the lungs. 

There's no bacteria that's causing pneumonia per se, but what happens essentially is that it can be associated with chronic graft-versus-host disease, it oftentimes is initiated by a viral infection. 

[12:03] It's not to say that you have a viral pneumonia, it's just that the viral infection heightens the immune system to begin to react to the lungs. Oftentimes what we see in this pneumonia is that in the tapering of your chronic graft-versus-host disease medications and you start to have a flare, that's oftentimes where the cardinal symptoms that we see before you develop an organizing pneumonia. 

It can present like an infection. It feels like a flu-like illness, and it is typified by shortness of breath. You can get very low-grade fevers with it, but one of the cardinal symptoms that I see when I see organizing pneumonia is something which is described as a chest pain. 

It's a chest pain that wants to come on when you take a big, deep breath. And that's called a pleuritic chest pain. People will sometimes describe that as a catch or a pinch when I'm taking my top breath, and that somewhat distinguishes it from an infectious pneumonia per se. 

It can be associated with a cough. But the thing about this type of pneumonia is that as opposed to using antibiotics to treat an infectious pneumonia, here you actually use corticosteroids like prednisone to treat this pneumonia. 

[13:11] The gentleman you're seeing here on the right is the gentleman that we're going to see CT scans of. He came in with a very severe case of organizing pneumonia that actually landed him in the ICU. He was treated, as we'll take a look, and here he is wearing a medal that he won from winning a 5K. So, what we expect from an organizing pneumonia is that it's treatable and that you should return to your baseline lung function.  

But unfortunately, what happens oftentimes is that when you get the next viral infection or if your GVHD is still poorly controlled, it can actually come back. That happens in about one-third of patients. 

So here is that CT scan of our patient, and you'll notice that the areas that are white on the CT scan are not as dense as I had shown you before. When we were looking at an infectious pneumonia. 

[14:06] In fact, there are multiple areas that seem to be spared, and those are circled in these red lines. What that is actually looking like is like it's looking like an atoll, and that's known as the atoll sign. This may be one of the radiographic features that  distinguishes an infectious pneumonia from an inflammatory pneumonia. 

[14:23] Now, because these are not the defining features of the radiograph, in other words, you might not see these features. This is oftentimes why we need to rule out infections with things like a bronchoscopy before we start to treat you because oftentimes it's a very different treatment. In other words, one is trying to immunosuppress; the other one is trying to kill the pathogen that's causing the infection, but as I said before it's very treatable This is actually his CT scan at six weeks follow-up and with corticosteroids it begins to go away.  

The next set of restrictive lung diseases that I'm going to focus on are things that begin to take up space around the lung. Here we have two disease entities. One is known as serositis and the other one is known as truncal sclerosis.  

[15:24] Serositis is an inflammation of the lining of the lung known as the pleural surface. You can think of it basically as that is becoming the target of the graft-versus-host disease. That essentially begins to create fluid that builds up around the lung itself, and you can see that in the red circles here where there are some fluid pockets that happen beneath the lung. This is a restriction because it begins to take up landscape within the chest wall. We often see, for example, when we see fluid around the lung, oftentimes it's attributed to the heart and the heart not squeezing well, but here the heart is usually normal. However, the heart can also be involved with this. And when the lining of the heart called the pericardium gets inflamed, then you can actually get fluid around the heart itself, so these patients will have fluid around the lungs, but also fluid around the heart.  

[16:24] In terms of treatment, this is also fairly amenable to treatment with corticosteroids such as prednisone. Sometimes you need drainage of this fluid collection, but generally with slow management, these fluid collections begin to resolve with corticosteroid treatment themselves. 

The other entity that causes restriction of the lungs is something known as truncal sclerosis, and this is when the skin from graft-versus-host disease becomes very stiff and tight. I think you can see pretty clearly on the right upper panel, when the abdomen becomes tight, it becomes a difficulty for the diaphragm to descend down into the lungs into the abdomen. That causes shortness of breath. 

[17:08] The shortness of breath will typically come on when you're lying flat., because when you're lying flat, your abdominal contents are pushed up into your lungs, and that's where the shortness of breath is derived from. You know, oftentimes people describe shortness of breath when they're bending over. This can be a slowly progressive problem for the respiratory status, but the lungs themselves are actually normal underneath that. We'll take a closer look at what that looks like. 

This is typically treated by treating the sclerosis of the skin. For example, extracorporeal photopheresis, or ECP, is effective for this, but there has been a new medication that has become even more effective, which is known as axatilimab. It can be actually quite remarkable. You can see quite dramatic responses when people do respond to axatilimab. In other words, their abdominal skin is getting softer, and then they can suddenly breathe much better. The critical piece here is that you have to maintain your cardiopulmonary status, so that when you finally have the resolution of your skin problem, then you're not having to deal with deconditioning that this situation can create. 

[18:21] Now we're going to shift gears here and move away from the restrictive lung diseases and now talk about one of the best-known diseases of lung GVHD, which is bronchiolitis obliterans syndrome, and bronchiolitis obliterans syndrome is known as an obstructive disease. 

This is a picture of the microscopic look of the airway that happens right before the balloon, the alveoli. This is so known as the terminal respiratory airway. On the left-hand side, you can see the normal situation where this stringy pink area is just nice and wide open. Around it, you're seeing this feathery, lacy appearance of tissue. And that's actually the balloons that actually exchange gas, the alveoli exchanges gas that has been caught in cross-section. 

On the right, you have a condition that's known as obliterative bronchiolitis. What's happening here is that the yellow circle is actually same equivalent area to the one that's on the left where it's now closed down. And that is where the GVHD wants to attack. 

[19:31] This person, unfortunately, had a viral infection in the setting of chronic GVHD and then had this rapidly progressive development of bronchiolitis obliterans syndrome.  

Bronchiolitis obliterans syndrome, as we can see here in the cartoon, is a progressive decrease in that airway that becomes more and more constricted. As it becomes more constricted, we can see this on the pulmonary function test, which is this middle graph. 

Just to orient you, the FEV1 is the forced expiratory volume in the first second. In other words, it's how fast can you blow air out of your lungs. You can see that before transplant, this person was sitting around 120% of the people, his same height and size. But then he suddenly begins to drop down and then has a very precipitous fall to the orange part where the BOS diagnosis is made. 

[20:29] This is one of the problems with our current diagnostic criteria. They have to drop into this very low place before we can call it BOS. In fact, we're gathering a group of experts in Geneva this fall to try to redefine this disease so that we can call it BOS when you've dropped down, say, 10 or 15 percent, rather than you're almost losing a third of your lung function. Unfortunately, when we lose lung function the morbidity begins to increase and then eventually mortality. 

[21:04] We see this condition in about 5% to 10% of all allogeneic transplants. It has a five-year survival of about 40% to 50%. Now, this survival is a very historic survival, and we are about to publish a manuscript that will look at more recent survival. It's actually come up from these numbers. So, I oftentimes tell my patients to watch out what they read about bronchiolitis obliterans syndrome on the internet.  

Unfortunately, as I mentioned before, late diagnosis is common. The problem is after transplant, you're dealing with so many things, including graft-versus-host disease, that people become naturally debilitated, and they become less active. As they become less active, this insidious narrowing of this airway becomes more difficult to parse out. In the clinic, we've been focusing on how we can diagnosis this earlier? Certainly, having pulmonary function tests on a regular basis is going to help you make sure that you don't develop this condition. 

[22:15] What do the pulmonary function tests look like when you develop bronchiolitis obliterans syndrome? So here, once again, that normal graph is on the left. Here on the right, you have that obstructive graph, and the yellow arrow essentially shows you what happens to the obstruction as the disease begins to progress. It becomes more and more and more difficult to blow air out. Like a balloon that you're inflating, but because the air can't get out because it's obstructive, the lungs become hyperinflated. And we took that and actually began to use that as a marker of how we can diagnose this disease. 

 In collaboration with Dr. Craig Galbán and Dr. Greg Yanik at University of Michigan, we started to see what we can do to begin to quantify the CT scans that people get and have this as our guide to diagnosing bronchiolitis obliterans syndrome. 

What this essentially is, is it's looking at a CT scan when you take a big deep breath in, and then it looks at the CT scan when you've blown out all the air, and it tries to determine the density of the lungs that happens during that expiratory phase. 

[23:31] This allows us to begin to grade the lungs. So, what we see here in green is normal lung, and you can see that here on the far left, that there's all green here. What we're now looking for with bronchiolitis obliterans syndrome is a yellow, which is known as air trapping or hyperinflation, or this red emphysema, which is basically severe hyperinflation. 

[23:56] What we're seeing here is that in the bronchiolitis obliterans syndrome lung, you have a lot of yellow area, and we went ahead and we designed an algorithm to look at this data and decide whether or not it could pick out bronchiolitis obliterans syndrome, and the algorithm actually outperformed our radiologists. We essentially see that we can't see this image just by our plain eyes, but the machine can actually pick up the changes in based on the expiratory cycle. 

[24:29] The purple here represents opacities in the lungs, and this is just a look at what organizing pneumonia will look like in the third panel here. So once again, it's that purple area that begins to take up space in the lungs, but it's very patchy, unlike the lobar pneumonia.  Then on the far right, you have a look at what truncal sclerosis looks like. 

[24:48] Here the lungs themselves are green. They're largely normal, but you're noticing that at the top here that there's a little bit of purple. That is the lung hitting the restriction of the skin and can't expand, and like a sponge that gets pushed down, it begins to fall down. You're also noticing that the lung size is very, very small. This really typifies what happens in truncal sclerosis where you basically have a restriction of the lungs. They can't expand, and therefore you're dealing with smaller lung sizes than usual. 

[25:28] The other thing that we've been working to pioneer is home spirometry. This is in collaboration with Fred Hutchinson Cancer Center and Guang-Shing Cheng. What we've shown is that the home spirometer, which hooks into your smartphone, is actually a very reliable way to monitor lung function. 

What we've been doing in our trial that's about to wrap up is trying to find an earlier diagnosis of bronchiolitis obliterans syndrome. Hopefully one day this will become standard of care. 

The next thing I want to do is talk a bit about treatment. You know, historically, we really didn't have a whole lot that we could use on people with bronchiolitis obliterans syndrome. The one thing that we did have was a regimen known as FAM, F-A-M. F stands for fluticasone, which is an inhaled corticosteroid. Oftentimes, this is a combination of medication that is sitting with a medication that helps open up the airway, known as a long-acting beta agonist. We also, in this regimen, use azithromycin, which you'll recognize as an antibiotic, but here we're using it as an anti-inflammatory.  And then interestingly, there's also montelukast, which is actually a medicine that works on the allergic side of the immune system. 

[26:46] The real exciting part of this is that there are a lot more types of treatments that fall into this immunosuppression antifibrotic category. I'm going to talk about four specifically, and then finally, we have shown that extracorporeal photopheresis can be helpful. It can be helpful, and it has been shown to be helpful in survival, but it is thought that that survival benefit was relating to being able to drop your prednisone earlier. 

I last gave this talk, this slide was almost blank, and now we have various drugs, ruxolitinib, belumosudil, axatilimab, and pirfenidone. 

[27:30] Here are the results of a prospective trial that was conducted in patients with two types of BOS. Group A was early BOS, in other words, BOS was diagnosed within six months, and group B was established BOS. This was to use ruxolitinib, which is also known as Jakafi, as a 10 milligram twice a day dose. They found that the overall response rate was around 35%, and that's what we're going to look at as consistent. 

Among the forms of graft-versus-host disease, lung graft-versus-host disease is the most difficult to treat, and these are patients that also failed multiple lines of therapy. 

 The one thing I want to point out is that the drug seemed to work mainly for people with mild to moderate disease. I mean, here you're seeing overall response rates around 40% for this NIH lung score of 1 and 2. Whereas for patients with more severe lung disease, it was not as effective. 

[28:40] The other drug that is relatively new is a drug called belumosudil. Belumosudil is an interesting drug because it actually is not only an immunosuppressant, but it is also antifibrotic, and here is the compounded results from the belumosudil trials. Similarly, what we saw here is it was very effective for people with newly diagnosed or mild bronchiolitis obliterans syndrome. 

It was somewhat less effective as the bronchiolitis obliterans syndrome began to progress and the pulmonary function test began to fall. It really wasn't that effective for people with very advanced disease. 

[29:22] Based on these trial results, Dr. Cutler, who just gave the talk, is currently running a trial to try to use belumosudil up front in patients with newly diagnosed BOS or Incipient BOS, and hopefully that will show some impact. Remember that this trial as well was people that had failed multiple lines of therapy, so hopefully using it up front will be somewhat helpful. 

[29:45] The next drug I want to talk about is a drug known as axatilimab. Axatilimab is also a medication that's somewhat immunosuppressant, but what it does is it shuts down a cell called a macrophage. The macrophage is a bit like the construction crew that begins to build the fibrosis, so it puts them to rest. 

What they found, interestingly, was that as opposed to the two drugs we've already mentioned, that people with more advanced disease, in other words, a very relatively low FEV1 or pulmonary function test, actually responded to this drug. I think that's really interesting. The other thing that is interesting is that the response came on fairly quickly. So, the median response time was around 2.6 months. This is among the drugs that become very interesting to think about starting if the disease is on the later stage. 

[30:49] The trial that I ran was the safety and tolerability preventative and for BOS, otherwise known as stop BOS. This, as I said before, was my Don Quixote moment where I was just not going to be satisfied with the status quo and really trying to move the needle. I enrolled 30 patients; it was an open label trial. That trial was successful at a year, but what we then did is extend the trial results to continue to treat patients for an additional four years. I'm going to show you the complete results here. 

Overall, what we found is that pirfenidone seemed to stabilize the pulmonary function test. What we're looking at here are the two pulmonary function test parameters, which are the top bar, the top green curve. The red here represents the pulmonary function tests that were happening before the trial, up to two years before the trial. Then the blue represents the people that were on trial. 

We were pretty happy because even though these people were progressive, they were able to stop the progression of their FEV1 fall overall. 

[31:56] When we looked more closely at our data, we saw something that was very surprising. There were certain people in the trial; that actually had a significant response and actually improved their pulmonary function test. This somewhat  argues against the notion that we have an irreversible situation here, that some people got much better on the drug, even though they had had BOS for several years. 

Overall, 41% of participants had an improvement, and many of those patients are still on pirfenidone today.  

From the trial, we now know that pirfenidone is safe and well-tolerated. As I mentioned, 41% of participants were responders to drugs. It interestingly had some off-target effects. In other words, people's livers got better. That was pretty much universal within the trial. Some people’s skin, their sclerotic skin got better. Then in terms of looking at patient-reported outcomes, the eyes and the mouth and physical function also improved. Because of this, Pirfenidone is actually now available through some insurance carriers, mainly Kaiser. 

We're really excited to be able to offer this drug to patients, whereas previously there were no drugs that would try to stabilize or maybe improve the lung function at this late stage. 

[33:23] We're going to move on from bronchiolitis obliterans syndrome, and now I want to talk to you about bronchiectasis. I actually already see in the chat that there's a question about infections post-CAR T, and I think this is one of the things that I really want to raise awareness about in this group. 

So, bronchiectasis is a disease that is caused by many different things. For example, cystic fibrosis is the classic form of bronchiectasis, but what we found in looking at our patients and in a group that was based out of France was that bronchiectasis is actually very, very common in patients with bronchiolitis obliterans syndrome. In our study, 50% of patients with BOS had bronchiectasis as well. This is somewhat common after hematologic malignancies. 

The symptoms of bronchiectasis are that chronic productive coughs, and if there are folks out there that have these symptoms, in other words, they are always producing quite a measurable quantity of mucus or sputum. These are people that go through frequent pneumonias, right? They see a lot of antibiotics, and they have oftentimes the pneumonias will show up in the same area. They have a lot of exacerbations, which essentially means that you bring in more sputum, and you need more antibiotics to treat this. 

[34:49] We've also found that it's actually fairly common after CAR T therapy. In our preliminary look at things, we see this in about 8% to 10% of our whole CAR T group. The reason that we think we see it is because one of the things that CAR T does is knock out your immunoglobulins. Having hypogammaglobulinemia is one of the more potent risk factors for the development of bronchiectasis. 

The thing about bronchiectasis is that it is treatable. 

What is bronchiectasis? Bronchiectasis, as opposed to BOS, is an enlarging of the airway, and when the airways get too big, they lose the cilia that line the airway. Then you have this image here on the right lower panel where the airway becomes lined with this thick, sticky mucus that can't get removed. 

What happens in that mucus is that bacteria and other organisms, like fungi, take up residence. They begin to so-called colonize that airway, and they build a little bit of a city in there. 

[35:59] You need to clear this stuff out of your airway, so we focus a lot on something known as airway clearance. Sometimes that is by inhaling salty water to make you cough deeply. Sometimes that's chest physiotherapy that shakes this mucus out, but you want to get this out of your airway. 

[36:21] If you have low IgG levels, sometimes IVIG can help. 

There was actually a new drug that is really exciting called brensocatib. This was approved for non-cystic fibrosis bronchiectasis, but in the few patients that I've used this on, you can see the amount of mucus that they produce on a daily basis literally begins to go away. 

The other thing that you can do to treat this condition by using inhaled antibiotics. This becomes a very targeted antibiotic therapy as opposed to the serial antibiotics that you would take as a pill that begins to create drug resistance. What becomes a problem for folks with bronchiectasis is repeated antibiotic use and eventually developing drug resistance. 

[37:06] Now that we've talked about the landscape of complications that happen after transplant and after CAR T, I want to talk to you and get back to that analogy of that train station and try to deliver the oxygen to the other station, which essentially is the muscles. 

When we look at this, we really want to focus on strengthening your heart function and improving your muscular efficiency. This is just to make the whole system run in a better way. Even though you have difficulties with the lungs, just by doing this alone, it can significantly improve your quality of life. 

This is an example of a person with moderate BOS, and I've seen this person for more than 10 years, and she is actually quite incredible. She can hike, she one time unwisely chose to swim in the kelp forest, but she leads a pretty active life. 

[38:00] The reason that she can lead this active life is that we've been focusing on this red line. This red line is something known as the DLCO. That is a measure of how well oxygen gets transported into the blood and carried off to the tissues by keeping yourself in a high cardiopulmonary status. We see here that she largely remains in a DLCO above 80%. 

Even though she has a mechanical obstruction of her lungs, because she's able to maintain her whole cardiopulmonary status, she's able to live with a decent quality of life. 

I actually have a young patient with an FEV1 as low as 18%, and that person has a DLCO that sits around 110%. He, in fact, actually can exercise in the gym for an hour and a half. 

[38:57] Now I want to conclude by addressing some of the questions that may come in around lung transplant, because I know that this becomes sometimes an option for folks. 

You know, I have done this for more than 20 years. I have sent a total of maybe three patients to receive a lung transplant, to give you a sense. 

But the question is, who can get a lung transplant? So, you have to be free from cancer for more than five years and have no serious infections. 

[39:25] The other question that comes up is, how long do patients actually survive after a lung transplant? Unfortunately, lung transplants, in general, have fairly poor survival. The median survival post-lung transplant is about five to seven years. Now certainly this is just a population number. I mean, I actually have a friend who had a lung transplant and she has been alive for more than 12 years. So take this with a bit of a grain of salt. 

The thing is that after having had a bone marrow transplant and then to have a lung transplant is a very difficult course. When Guang-Shing Cheng looked at this, she's a researcher from Fred Hutch, she found that the survival was only 49 months. 

[40:04] This really gets to the question of when do you know that you need a lung transplant? This is clearly a decision that has to happen between you and your physicians. 

For my patients, the thought about needing a lung transplant was essentially the notion that the world was becoming smaller and smaller, that they weren't able to get around, and they weren't able to have the quality of life that they wanted. 

In the few patients that I've had that went to lung transplant, almost universally they've said that they do not regret that decision, that when they did the lung transplant, the world got bigger, their quality of life got better. Even though the survival wasn't what we wanted, the quality of their life at that point was much, much improved. 

The difficult part of this is that if your lungs were recognized as foreign, then the transplanted lungs are likely also to be recognized as foreign. We are working on this. This is an active part of research, and hopefully, we can try to prevent this from happening in the future and improve outcomes in general. 

[41:17] In conclusion, surveillance is critical for maintaining lung function. You know, if you have chronic GVHD, the current recommendations are to have pulmonary function tests every three months, particularly while you're on systemic treatment. 

There are new diagnostic techniques that I've shown you. Home spirometry is going to be hopefully standard of care. 

We are now more and more centers are able to use this advanced CT scan that I showed you as well. 

Pulmonary problems are largely related to restriction. In other words, the lungs are too small or obstructed. There's mechanical difficulty in the lungs. 

BOS is extremely difficult to diagnose and treat, but we now have new treatments, and there are more treatments that are coming down the road. There are people that are actively looking at this, and we've developed this international group that is trying to develop clinical trials. 

There are more new treatments on the horizon. In my lab, we're working on small molecules that are much more potent than pirfenidone. 

Then living with BOS is about maintaining cardiopulmonary status. It's really about trying to stabilize lung function and maintain quality of life. 

[42:22] I want to conclude by acknowledging the people in my lab that have done all the work. You can see the group on the lower right. 

I also want to acknowledge my transplant colleagues, Dr. Laura Johnson, Sally Rye, acknowledge Genentech for being kind enough to allow us to use pirfenidone in our trial. 

The family up here is the Herd family. Ann unfortunately passed away, but Chris has been a stalwart funder for our research, as well as the NIH with my two grants that I have. 

I also want to acknowledge the Lung-GVHD consortium. This is a consortium that we started, a really grassroots effort that has really grown into something larger. I have alluded to meeting with international experts coming up in Geneva, Switzerland in the fall. 

In that meeting, the intention is to redefine bronchiolitis obliterans syndrome so we can diagnose it earlier, and we start medications earlier, to redefine what lung GVHD is. Many of those things that I showed you with dotted lines that weren't necessarily related to GVHD; we think they are and therefore should be open to GVHD-related treatments. 

[43:29] With that, I'd be happy to take any questions. 

[43:32] Moderator: Thank you very much, Dr. Hsu. That was an excellent presentation. We're going to take some questions now. If you have a question for Dr. Hsu, please type it into the question box on the lower left side of the screen. We have until 3:30 Eastern for this session, so we're going to try to answer as many questions as possible. 

Our first question is from someone who would like to know if you can touch on the role or place of exercise in all of this. 

Dr. Hsu: Yeah. I think exercise is absolutely essential. It becomes the cornerstone of what we try to do in clinic. In fact, I don't know if the group is familiar with Strava. Strava is a social media app where you're able to log your exercises and multiple of my patients participate in Strava, so I can see what their heart rates are doing. I can see what their walking pace is doing, and I can give them advice. But I think it absolutely is the central piece that no matter where you are in terms of treatment, you can always try to improve your quality of life by exercising. 

[44:31] Moderator: One person said that they heard the immunity of the lung comes from Peyer's patches in the gut. Would butyrate, I may be butchering that, I'm sorry, butyrate, maybe, supplementation helped to keep the lung and gut healthy? And thank you for this. 

[44:50] Dr. Hsu: This is actually an area of active research. We do know that the microbiome in the gut seems to want to influence the inflammation in the lungs. 

There haven't been any specific therapies that have tried to modulate that interaction, so there's nothing I can recommend per se, but it certainly is a place where we are looking to make sure that we try to understand that pathologic connection 

[45:22] Moderator: One person dealing with respiratory infections post-CAR T-cell therapy. What can they do to improve their immunity post-CAR T? 

[45:34] Dr. Hsu: Right. This is exactly what I'm talking about. The first thing that a person should do is to make sure that there's no structural problem that's causing the recurrent infections in the lungs. Certainly, avoiding viral infections and avoiding these kinds of things are important. But the thing is, we're seeing this so commonly that I would try to make sure that that person does not have bronchiectasis because that itself is not an immune problem. It's a structural problem where you can't get rid of the bacteria that want to reside inside the lungs. 

[46:14] Moderator: What's your current recommendation for the timing of pulmonary function tests in confirmed lung GVHD? 

[46:20] Dr. Hsu: Right. That's a great question. That's something that patients need to do better and can advocate for themselves and that we need to do better in the healthcare system. So, the current recommendations are as follows. 

When you, well, there are some people that would say that at day 100, you should just get a pulmonary function test, and what people have seen, not yet published data, is that it sometimes can be predictive for later problems down the road. 

In general, when you get diagnosed with chronic GVHD, it's a good time to get a baseline pulmonary function test, and then the guidelines essentially right now are to say that if you are on systemic immunosuppression for your chronic GVHD, that you should have a pulmonary function test every three months. 

Really, the importance of that is that when people fall with bronchiolitis obliterans syndrome, they fall pretty quickly.  What you want to try to do in all these cases is come to a diagnosis ASAP so that treatment can start as soon as possible before you develop that more difficult to treat lung fibrosis. 

[47:31] Moderator: If a bronchoscopy shows scarring on one of the lobes of the lung, could that have been caused by GVHD? And how can it be treated, if at all? 

[47:44] Dr. Hsu: So, there can be certain things, for example, like chest radiation that can cause these specific problems inside the specific area in the lungs. Sometimes you can get infections that can scar the airway, and that leads to bronchiectasis and the problems that we talked about before. 

The thing about lung GVHD, or let's say BOS specifically, you want to try to maintain your immune system, so it's not surveilling the lungs. 

For example, these frequent viral infections that people get. For the longest time we suspected it, now there's a publication out there that we now know it if you contract multiple viral infections, that greatly increases your risk for developing BOS. That is because the immune system starts to invade the lungs, and then while it's invading the lungs to fight the virus, it starts to notice that the resident tissue is also foreign and begins to attack that tissue. 

It's very important that the infections be dealt with. And yes, if you have a \ slow infection in the lungs, it certainly can increase your risk for lung GVHD. 

[49:06] Moderator: Is there a correlation with increased viral infections associated with worsening lung GVHD? Would the worsening of lung GVHD be because of the immune response, because of fibrosis, or both? 

[49:18] Dr. Hsu: That's a great question. That's similar to what I said in the last question. Yes, there is an association between viral infections, bacterial infections, lung GVHD, and BOS. The fibrosis aspect is happening a little bit more downstream. And so, these are the phases of disease. 

Phase one, we'll say that's the viral infection, so there's an injury to the lung in some way. 

Phase two, the part of the immune responds against the virus, but it's also an immune response against the patient. 

Then the GVHD begins to get set off. What that does is it brings these cells into the area, and this is what I said for axatilimab is that these macrophages, which are the construction team, begin to inappropriately try to deal with the damage. When they deal with the damage, it starts to release pro-fibrotic mediators. 

That is why the research that I've done is to focus on and prevent that last stage. The advantage of preventing that last stage is its non-immunosuppressant. 

It's this notion of all roads leading to Rome. Rome is the fibrosis. You have to prevent that from happening. That happens at a later stage after the injury, after the immune response. 

[50:46] Moderator: Is ECP effective for BOS with no skin GVHD? 

[50:52] Dr. Hsu: There are some studies that show it. In those studies, it was effective. It was mainly effective in terms of trying to lower the prednisone dose. Because of that, there was some signal on survival. 

[51:12] Moderator: Every spring this person gets a deep four-month-long bronchitis. They're five years post-allogeneic stem cell transplant. How do they know if it's an allergic reaction to mold or pollen or, in fact, BOS or bronchiectasis? They didn't have GVHD, but they have eye, skin, and mouth cGVHD now. They also previously had acute skin GVHD post-transplant. But do you have any recommendations or suggestions for what to ask their oncologist? 

[51:42] Dr. Hsu: Absolutely, that person should get a complete pulmonary function test. If they have the opportunity, they could also get one of these more advanced scans, the parametric response mapping scans. 

In that bronchitis, in that pulmonary function test, they should be treated with albuterol and see if they develop a change with albuterol, and that's not just going to be more indicative of asthma. You can actually get asthma from your donor if you didn't have it before. If someone describes that situation to me where it's mainly seasonal, it results in this persistence of bronchitis or a persistence of a cough, then that sounds like an asthma symptom to me. I would make sure that we rule that out first. 

Now, there can be people with bronchiolitis obliterans syndrome that do have a bit of an asthma phenotype, but that comes down to what the numbers are sitting and how the numbers will correct after you get the inhaler treatment. 

[52:52] Moderator: What are ground glass opacities on repeated CT scans post-autologous stem cell transplant? 

[52:59] Dr. Hsu: It depends on how close post-auto they were. Sometimes you can have a drug-induced so-called pneumonitis, which is inflammation of the lung tissue itself. The ground glass opacities are those, it presumes like inflammation that's happening in the lungs. There's, as you can imagine, a whole laundry list of possible causes. 

But post-autologous transplant, if it's an immediate post-auto, then I would be thinking about things like BCNU pneumonitis or some type of chemotherapy-induced reaction. 

[53:40] Moderator: Could you explain again what types of exercise should be done and what does the exercise do to help improve lung GVHD? 

[53:48] Dr. Hsu: The typical thing that I recommend for my patients is, first off, what they can tolerate. What I generally recommend is at least three times a week; you're doing a dedicated activity toward getting out there and being active. 

I think along those lines, pulmonary rehabilitation is quite good because it allows you to be under observation as you begin to find your footing and understand what activity makes you short of breath, and what activity you can tolerate. But the ideal place to be is 30 minutes at least three times a week. 

I would try to grade the exercise. Oftentimes I tell my patients that I want them to be not more than a 7 out of 10. 10 being like a full sprint, 7 being a place where you're exercising with attention. You can still talk if you had to, but you prefer not to. You want to stay in that zone so that you're actually making the most out of the exercise. 

How this works for lung GVHD is it tries to build the system around the lungs that helps support the difficulty in the lungs. As I mentioned before, people with very obstructive diseases are less than 20 percent. Sometimes if they can raise that diffusion capacity, the DLCO, with their fitness, then they can get past the mechanical obstruction. 

[55:23] Moderator: We're running out of time, so this is going to be our last question. But can pirfenidone actually improve FEV1s in patients with moderately severe BOS? 

[55:34] Dr. Hsu: We did see that. There were about 40% of patients that had some response. The median time from their BOS diagnosis was something like two years. It's certainly not a drug that we used up front. It was drug for people who had BOS already. 

I think there are certain people that will respond to pirfenidone. We don't quite understand why there are some people that respond and others that don't respond. But it definitely becomes a treatment avenue, particularly with those that have BOS already. 

[56:13] Moderator: Awesome. Well, thank you so much, Dr. Hsu, and thank you everyone for your great questions. Sorry, we didn't have time to make it to all of them. 

On behalf of BMT InfoNet and our partners, I'd like to thank you, Dr. Hsu, for your helpful remarks and someone in the Q&A actually called them very kind, informative and compassionate. So, thank you for that. 

Thank you again to the audience for attending and for excellent questions. And before you leave, please do stay online to complete a brief survey. 

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