Take a Breath! Managing Breathing Problems after Transplant

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Take a Breath! Managing Breathing Problems after Transplant

Presenter: Greg Yanik, MD, Professor, Blood and Marrow Transplant Program, University of Michigan, Mott Children's Hospital

May 1, 2024

Presentation is 42 minutes, followed by 15 minutes of Q&A

Many thanks to Sanofi whose support  helped make this presentation possible.

Summary:  Chronic graft-versus-host disease (GVHD) is a common complication after a transplant using donor stem cells (allogeneic transplant) that target many organs, including the lungs. Learn who’s at risk of developing chronic GVHD in the lungs, how it affects breathing and therapies available to treat it.

Key Points

• Lung graft-versus-host disease (also called bronchiolitis obliterans or BOS) develops in 10% to 20% of patients who have chronic GVHD in other parts of their body.
• Risk factors for developing chronic lung GVHD include prior acute GVHD; a viral infection during the first three months after transplant that never resolves; and low pulmonary function prior to transplant.  
• Pulmonary function tests (PFTs) performed early after transplant are crucial to the diagnosis and successful treatment of lung GVHD.

Highlights

(03:36): Pneumonia simply means that there is inflammation or irritation in the lungs. Not all pneumonias are due to infection.

(05:07): If infectious pneumonia persists long enough, it can cause scarring in the lungs and lead to non-infectious pneumonia which then leads to more lung infections.

(08:05): Lung GVHD, typically occurs six to 12 months after transplant. It causes scarring that obstructs the  airways. Air can get into the lungs but can’t get back out.

(08:55): Lung GVHD is also called bronchiolitis obliterans or BOS. Symptoms include shortness of breath, chronic cough and fatigue.

(10:31): There are two types of GVHD: acute and chronic. Lung GVHD occurs in patients who have chronic GVHD, not acute GVHD.

(20:50): Early diagnosis of lung GVHD is critical. The survival rate for patients whose lung GVHD is caught early is over 90%. For those who are diagnosed later, after the lungs are very scarred, have a much lower survival rate.

(26:36): At-home, hand-held pulmonary function testing (PFT) is being studied to help catch lung GVHD early.

(29:00): New CAT scan technology color codes the lungs, making it easier to detect areas of damage and catch lung GVHD early.

(32:39): Current treatments for lung GVHD include inhaled steroids and FAM therapy..

(35:59): Exercise is one of the most powerful ways to combat breathing problems after transplant.

Transcript of Presentation

(00:01): [Steve Bauer]: Introduction of Speaker. Welcome to the workshop, “Take a Breath! Managing Breathing Problems after Transplant.”

(00:10): Before we begin, I'd like to thank Sanofi, whose support helped make this workshop possible.

(00:16): It is my pleasure to introduce Dr. Gregory Yanik. Dr. Yanik has been a faculty member in the blood and marrow transplant program at the University of Michigan since 1992. He is currently a professor in the blood and marrow transplant program at Mott Children's Hospital. Dr. Yanik has made major contributions in understanding acute and chronic lung injury post hematopoietic cell transplant. Please join me in welcoming Dr. Yanik.

(00:57): [Dr. Greg Yanik]: Overview of Lecture. Thank you and to everybody out there, it's truly a pleasure to be here. As Steve said, I'm Greg Yanik from the University of Michigan. If anybody is from the state of Michigan, I'm one of your blood brethren through and through, and we're a good group. As Steve said, I've been here for 30 years at the University of Michigan. Much of my focus has been on looking at acute lung injury, chronic lung injury.

(01:23): What I thought I would do with you today is try to take you into our minds and try to give you insight, that you ordinarily wouldn't have, in terms of thinking about the lungs. I'm going to actually teach you a little bit even how to read some of the pulmonary function tests, and see some of our chest X-rays and walk you some of the things that we as physicians think about. Hopefully this will help click with you and help you as you start thinking things through.

(01:55): I love this quote on this first slide. I've used it in several talks now. I think it is the essence of life, the quote from Francis Peabody. Quote's almost 100 years old now. Talking about that the real purpose and path to health and healing is to make joyful connections. Thus, I want to thank everybody here, everybody at BMT InfoNet, for the joyful connections I've made with your team and for all of you listening today.

(02:24): Quotations from patients with lung GVHD. But I'll start the talk with several other quotes. One of my good friends and colleagues in Seattle at the Fred Hutchinson Cancer Research Center, Guang-Shing Cheng, is a pulmonologist there. She recently did a focus group with patients in Seattle who had lung graft-versus-host disease, and she shared some of the quotes with me. If any of you have had graft-versus-host disease of the lungs, I'm sure you can relate to some of these quotes.

(02:55): "I need to breathe to live, but I also need to live to breathe." "I'm alive, but I've had so much loss." "If I had known I would get lung disease like this, I would rather have died from my AML." What you're hearing in these quotes that Dr. Cheng shared with me is quality of life. It's how lung dysfunction, lung problems, can impact your quality of life after transplant. Well, hopefully today I'll shed a little light on that and how we can actually predict some of these problems in advance, treat some of them and help patients' quality of life.

(03:36): Pneumonia simply means that there is inflammation or irritation in the lungs. Not all pneumonias are due to infection. If you can remember any slide that's going to be a little off the wall for you listening to this talk, it's going to be this slide right here, the third slide of my talk. It's entitled Pneumonia, Lung Disease and Transplant. Over 50% of patients will develop pneumonia at some point after transplant. Pneumonia can occur at any time whether in the first few months or many years after transplant. But here's the catch: Not all pneumonias are due to an infection.

(04:06): When you catch pneumonia, you think of having an infection causing the pneumonia. Us as transplantars, now I'm giving you insight into our mind. When we see pneumonia, we don't always see it as an infection. In fact, about half of all pneumonias that we see after transplant aren't infectious at all with no germs in the lungs. What does that mean in English? By definition, pneumonia simply means that there is inflammation or irritation in the lungs.

(04:35): For example, if you're going through transplant, you've got fluid in the lungs, some swelling in the lung tissue, irritation of the lung tissue that's making it hard to breathe, that can all be present in the lungs without having an actual infection present. To us, we're still going to call that pneumonia. So start getting into your mind, rethink your mind in terms of that: Pneumonia doesn't just mean infection. Pneumonia means inflammation in the lungs. It can be infection, but it can mean other things in the lungs.

(05:07): If infectious pneumonia persists long enough, it can cause scarring in the lungs and lead to non-infectious pneumonia which then lead to more lung infections. The lines between an infectious and a non-infectious type of pneumonia are often blurred, and here's what I mean. You can see some chest X-rays here. I'm going to show you the problems with these chest X-rays in a second. But let's just start with these bullet points. Patients who have an infectious pneumonia, if it goes on long enough, it may lead to a non-infectious pneumonia.

(05:36): Here's what I mean by that. If you have an infection in your lungs that persists long enough, eventually that inflammation from the infection will start turning into scar tissue, and now you'll get scar tissue in the lungs. We'll see that scar tissue on our chest X-ray or CAT scans. To us, we'll still see what looks like pneumonia, but there's no infection in the lungs any longer. The infection's gone. What's present now is scar tissue. So chronic infections in the lungs can actually lead to chronic scar tissue and scarring. It still looks like pneumonia to us though.

(06:11): On the other hand, flip it around. Patients with non-infectious pneumonia are often chronically infected. If you have scar tissue in your lungs or if your lungs are weak, this would be the correlate to somebody who has emphysema, for example. Somebody who's been a smoker all their life, for example, has emphysema. They often get infections in their lungs. The same thing can happen after transplant where you've got some chronic lung injury – let's just say scar tissue again – and that keeps germs in. The germs can't get out. So patients who have chronic scarring – chronic non-infectious types of pneumonia – are the same ones who then go on to get infections. The two go hand in hand. Infections lead to non-infectious types of pneumonia and chronic lung problems, and chronic lung problems then lead to more infections. The problem we face as physicians, and this is a sobering one, is we can't even tell which it is by looking at a chest X-ray or a CAT scan.

(07:07): So if you ask transplant physicians to look at these chest X-rays, the ones that the blue arrow is pointing at, and have us as physicians tell you, the patients, which had an infection in their lungs and which didn't, they couldn't tell you. At least without with any accuracy. Because in many of our situations, these non-infectious pneumonias can look just like an infectious pneumonia.

(07:34): So how can we start this process? We can start by defining what lung graft-versus-host disease (GVH or GVHD) is. What is it, how do we test for it and how do we treat it? By the way, in case you're curious, when we get chest X-rays that are ambiguous and we can't tell if it's an infection or not, we often do what's called bronchoscopy where we actually will take a periscope and put it into the patient's lungs to look down their lungs to see what we see; to get a sample of the fluid to see if there's any germs in it or not.

(08:05): Lung GVHD, typically occurs six to 12 months after transplant. It obstructs the  airways: air can get into the lungs but can’t get back out. It usually occurs between six to 12 months after transplant. Let's start by defining what lung GVHD is. Start with this: It's a form of chronic graft-versus-host disease. It's an obstructive airway disease that usually occurs between six to 12 months, but in most patients around a year out from transplant.

(08:26): What it actually means is that air can get into your lungs, but can't get back out. Your lungs are floppy. So you can inhale air but you don't have that strength in the lung tissue to force that air back out. The air you breathe then gets trapped. It's like stagnant water in a pond. The air gets stagnant in your lungs. Germs set in – chronic infections. Infectious pneumonia often then occurs.

(08:55): Lung GVHD is also called bronchiolitis obliterans or BOS. Symptoms include shortness of breath, chronic cough and fatigue. Symptoms from patients with lung GVH, shortness of breath, chronic cough, just fatigue. It's all those quotes you saw in my first slide that patients will feel and truly impacts quality of life. It develops in 10% to 20% of all patients with chronic graft-versus-host disease. We've done a lot of studies at the University of Michigan just to look to see how many patients will get lung GVH in general. It's about 5% of all patients who go through an allogeneic bone marrow transplant. Patients who go through an autologous bone marrow transplant, let's say for multiple myeloma or lymphoma, typically won't get this, but our allogeneic transplant recipients, there's about a 5% chance of getting this "lung GVH."

(09:40): The medical term for it that we as physicians use is called bronchiolitis obliterans syndrome. That's a mouthful. It was probably on the national spelling bee to spell it. But if you break down the words as I will in a couple of slides, you'll see that it's simple to figure out.

(09:59): Bronchioles are the smallest airways. Itis means inflammation. Bronchiolitis means inflammation of the smallest airways.

(10:07): Obliterans means they get obliterated, scarred down, fibrosed. So you get inflammation and fibrosis, or scarring, of the smallest airways in your lungs.

(10:18): This is a syndrome, meaning it occurs after transplant, again, in about 5% of patients where you get this band of scar tissue around the airways. Air can get through that band. It just can't get back out.

(10:31): There are two types of GVHD: acute and chronic. Lung GVHD occurs in patients who have chronic GVHD, not acute GVHD. When I think of lung GVH, when I think of GVH in general, I often think of a camel with two humps. The first hump is acute graft-versus-host disease. The second hump is chronic graft-versus-host disease. The X-axis here shows time so the peak onset of acute graft-versus-host disease is in the first three months after transplant, or the peak onset of chronic graft-versus-host disease is around a year after transplant.

(11:01): Acute GVHD causes massive inflammation. Acute graft-versus-host disease, I always view it like a roaring bonfire in patients. It's just this massive inflammation that patients will get – redness, inflammation, diarrhea, skin rashes, jaundice all occur with acute GVH. Chronic graft-versus-host disease on the other hand, I always view as a series of campfires. Problem is if you get a lot of campfires and they all coalesce, then you get one big fire.

(11:28): The chronic GVH comes on slowly, it comes on insidiously and it comes on as a series of patches of campfires here or there, but ultimately it can lead to a lot of chronic inflammation – and chronic inflammation in the body leads to scarring of the skin or, in the case of this talk, in the lungs. And when you see lung GVH is right here. That term bronchiolitis obliterans syndrome. The lung GVH occurs not with acute graft-versus-host disease, but with chronic.

(11:58): Researchers are looking at ways to predict who will get lung GVHD, the best way to treat it. There's been a lot of advances made in the past decade in terms of looking at lung GVHD. There have been new diagnostic techniques. I'll show you some of them today. I'm a member of collaborative teams at the University of Michigan, and we're blessed to be in partnership with a number of great medical centers. We're looking at lung injury work centers in Seattle, Stanford, MD Anderson, Emory, and Boston Dana-Farber. A number of other collaborative teams are also out there now looking at lung problems and lung disorders in transplant. We're looking at things that can predict who's going to get the lung GVH. The best treatment for lung GVH is to prevent it, and then if you start seeing it, really jump on it and get it treated before that fire gets out of control.

(12:45): A number of novel clinical trials are now being developed to treat patients with chronic graft-versus-host disease of the lungs or lung GVH. And then the biggest thing that I'd say has happened over the past decade has been just the support that we've had from a number of organizations like BMT InfoNet and a number of other organizations that have come together to help us in our search and mission to help patients with lung problems after transplant.

(13:11): Photographs of normal lungs and those with GVHD. So this slide here, again, I'm giving you insider trading information into what the lungs actually look like. I like giving talks in person rather than over video because if I was giving this slide right now in person, I'd be holding up a stalk of grapes. Think of the lungs like a grape stalk. The stalk's the airway. The branches off that stalk, which are going to a series of grapes. The grapes in this case are air sacs. The air sacs is where air gets transported from inside these air sacs into your body, into the blood vessels that bring air to the body.

(13:51): So literally think of your lungs as just thousands and thousands of these stalks and grapes hanging off them, each of these grapes being an air sac. And now if you go to this slide, on the far left-hand side, just imagine if we took a slice like slicing through bread through this grape stalk. You'd cut through a lot of grapes and you'd also cut through the stalk. So right here, I put it in yellow, is the air sac. That's called an alveolus. That's where air actually gets into this air sac and then the air, the oxygen can get transported into the body.

(14:32): This part in the center, that's the stalk on the grape stalk. This is a small airway or bronchial. This is what normally the lungs look like. So if you're to do a biopsy on you or I, this hopefully is what our lungs would look like, with these series of wide open spaces. The red lines are cells that delineate margins between the various air sacs and grapes in the lungs.

(14:59): But with graft-versus-host disease, what happens is eventually the stalk starts getting thickened and then the stalk gets so thickened that that airway literally starts becoming obliterated. And now air can barely get through, and if it can get through, it definitely cannot get back out. So the left-hand side shows what normally the lungs look like, and then the right-hand side shows what the lungs look like with lung GVHD.

(15:25): Risk factors for developing chronic lung GVHD include prior acute GVHD; a viral infection during the first three months after transplant that never resolves; and low pulmonary function prior to transplant.   At the University of Michigan, we have an extensive database. We recently looked at over a thousand patients to see who is at risk for getting lung GVH after a transplant, and here's a few factors that you should know as patients and caregivers. Patients who had that first hump on the camel, meaning patients who had a history of severe acute graft-versus-host disease, are more likely to get chronic graft-versus-host disease. They're also the ones more likely to get chronic graft-versus-host disease in the lungs themselves.

(15:54): It's the second bullet point though that I really caution people about. Patients who develop a viral infection – and that can even be something as simple as a cold, and/or pneumonia – within the first three months to 100 days after transplant. What happens is you catch this infection, your immune system is suppressed, and the infection – the germs – just kind of sit there. Oh, you feel better at some point, but the infection never truly goes away and just kind of lingers, almost like stewing, simmering like a fire just simmering on embers or a pot just simmering.

(16:29): And then all of a sudden you get to be a year out from transplant, and that chronic simmering of this infection in the lungs now starts leading to scar tissue in the airways, and now you get lung GVH. So we're particularly in tune at our center for patients who get viral infections in the first three months after transplant.

(16:47): And then the last bullet point, it almost goes without saying, but patients who come in with low lung function prior to transplant measured by a test called pulmonary function tests are the same ones who exit transplant with even worse lung function. Lungs don't get better going through transplant. If anything, they stay stable or get worse. So if you're already coming in low, those patients are at high risk getting lung GVHD.

(17:14): Pulmonary function tests (PFTs) are crucial to the diagnosis and treatment of lung GVHD. How is lung GVHD diagnosed? The National Institute of Health (NIH) initially put forth in 2005 criteria for diagnosing lung GVHD by Lisa Filipovich, and then they were modified in 2015 in a sentinel publication by Madan Jagasia of Vanderbilt. But the criteria really require what's called PFTs or pulmonary function tests.

(17:43): Here's the criteria, the next two bullet points. The main criteria is an FEV1 less than 75% predicted for age and size, and the FEV1 must have declined greater than 10% from baseline, meaning prior measurements. Well, if you're listening to this talk, you're probably thinking what the bleep does that even mean? Well, I'm now giving you insider trading information.

(18:04): When you get your PFTs done your transplant physician will pull up your PFT report. It's a big report with a lot of numbers on it. You can rest assured that he or she is quickly scanning that to look for this value, called FEV1.

(18:20): Pulmonary function tests measure FEV1: the volume of air that can forcibly be exhaled in one second.  So what does FEV1 mean? Well, I'll start showing you now. Most of you hopefully have had, if you had a transplant, pulmonary function tests. As one patient described it to me, it's like blowing out your brains. In fact, I decided to go do it myself just so I could see what our patients are going through and I can appreciate what patients go through. Man, the technologist having you do it just keeps saying, blow, blow, blow, blow until I felt like I was going to pass out. I don't know how you as patients can go through the same thing, but it is impressive.

(18:50): So PFTs, the main parameter that we as physicians look at again is called FEV1. FEV1 stands for forced expiratory volume in one second. What that means is it's the amount of air, the volume of air that you can forcibly exhale in one second. Okay. Everybody take a deep breath and blow out as hard as you can. How much air can you actually breathe out in one second when you forcibly exhale?

(19:17): So this is what we see as physicians. We'll see a curve that looks like this. The first part is just normal breathing. They call it tidal volume. The line goes up and down, up and down with every breath you take. That's just air going in and air going out. When you do the pulmonary function tests, what we're actually doing is exaggerating your tidal volume. You take those really deep breaths and really forcibly exhale, and now you see this. You take a deep breath, and that line goes way up to the top. It reaches a new peak, and then it goes way down as the technologist gets you to exhale as hard as you can, and then it bottoms out. And then it comes back up again the next time they ask you to do it.

(20:00): The FEV1 is the exhaled volume in one second. So as you come down that curve, right where that FEV1 in red is, we measure how much air you put out in liters, and now we know – based on your age and body size – what it should be. We know that for somebody, let's say my age and size, that I should be able to exhale, in one second, over three liters of air. If I can only exhale two liters, that means my lung capacity is going to be 67% of predicted. These are the numbers that we as physicians look at. This number is so incredibly key because of the next slide.

(20:50): Early diagnosis of lung GVHD is critical. The survival rate for patients whose lung GVHD is caught early is over 90%. For those who are diagnosed later after the lungs are very scarred have a much lower survival rate. In our center, we actually went back through a thousand plus patients and looked at all their pulmonary function tests, and looked to see how many actually met that NIH definition for lung GVHD. And then we looked to see when the physicians actually picked it up and actually even recognized that the patients met this criteria for lung GVHD. Meaning how sick were the patients by the time we saw it and then started treating them for it.

(21:19): There's three lines for you here: A green line, a blue line, and a red line. What the green line means is that we picked up the patients when the FEV1 was between 60 and 75%. Normally to be diagnosed with lung GVH, that FEV1 has to be under 75%. So the green line was where we caught patients early. They had just gotten under the 75%. They were in that 60 to 75% range. The blue line is patients that is a survival for patients that we didn't realize they had lung GVH until their FEV1 was 40 to 60%. And the red line is patients that we didn't realize they had lung GVH until their FEV1 was under 40%.

(22:08): This is a pretty sobering slide. In fact, at our center – and we look at these things all the time – the median or average FEV1 at the time that our medical team picks up lung GVHD is 57%. That means that in a center that's in tune to looking for lung GVH, most of the patients we're seeing are already on the blue line.

(22:32): Why is that critical? Because the horizontal axis here in this blue line is years of survival and then percent survival. If we can pick up the lung GVH early when you're on the green line, you can see the survival there for those patients is over 90%. If we don't pick up the lung GVH until there's so much scar tissue in the lungs that you're on the red line, you can see that the patient's survival there is much lower.

(22:56): So the key for us and for everybody listening to this talk, PFTs are critical because if you do develop GVH in the lungs, you want to make sure that it's caught when you're on the green line. In fact, if you see your transplant physicians and they say, "What did Dr. Yanik Talk about?" Say, "Well, if I'm going to get GVH, I want to be on the green line." The problem is we start treating when you've got all that inflammation and scar tissue around these bronchioles or airways. Well, we need to be treating when that inflammation is just starting out.

(23:33): We need to recognize who's at risk literally at the start of transplant. When Guang-Shing Cheng, my colleague, in Seattle, did that focus group that gave the quotes at the beginning of this talk, she actually had a questionnaire. I thought this one was particularly compelling. She had 54 patients that filled out surveys at three sites. FHCC is Fred Hutchinson Cancer Center in Seattle, Stanford and Geneva in Switzerland. We had 30 respondents, and the question was, ‘What aspect of BOS and lung complications after transplant should researchers focus on in order of importance?’ One being highest priority.

(24:19): Diagnosis and prevention was number one. I would rank that number one, too. Early diagnosis and prevention should be what we as researchers are focusing on. Picking these patients up before they get a lot of scar tissue in their lungs should be a key for us.

(24:44): All talks should have quotes from Woody Allen: “85% of success is just showing up.” So that's my recommendation for monitoring pulmonary function tests. Just get them done. Just get your PFTs done.

(24:59): How often should PFTs be performed? In 2020, the National Institute of Health came out with what's called a consensus development project. It was really just an NIH consensus panel of experts from around the country doing pulmonary transplant work. And final recommendation came out for how often pulmonary function tests should be done after transplant.

(25:25): Read the two bullet points. For those of you that had a transplant, ask yourself right now, are you following these guidelines? Is your physician asking you to follow these guidelines? The guidelines being have pulmonary function tests done prior to transplant, then every three months for the first year after transplant. For those patients who get chronic graft-versus-host disease, which can be about 40% of patients going through an allogeneic transplant, once the chronic GVHD is diagnosed, obtain pulmonary function tests every three months.

(26:03): Even at our own center that's in tune to looking for lung injury, I find that we often miss having patients meet this NIH recommendation for how often PFTs should be performed. One of the problems is the PFTs themselves. I mentioned that it's like blowing out your brains. For those of you that had PFTs done, it's a tough test to do. So are there alternatives to doing standard pulmonary function tests that we can do that can also tell us that we've got GVH of the lungs?

(26:36): At-home, hand-held pulmonary function testing (PFT) is being studied to help catch lung GVHD early. There's two things that I'd like to bring to your attention right now. Here's the first: PFT testing in your hands. This is an NIH funded study by Guang-Shing Cheng in Seattle. The patient will perform the PFT testing once a week at home. You could do the testing every day. You could do it every hour if you want to.

(26:59): On the lower right of this slide, the device is shown with the young lady holding it up to her mouth. You can see the white part that she inserts in the mouth, and then blows into it. It's a wireless Bluetooth enabled device, that black part that she's holding in her hand. As she breathes out, her exhaled volume, all of her pulmonary function tests are synced with the patient's smartphone. So if you have an iPhone or Android, you can actually see what your pulmonary function tests are. You can see your FEV1.

(27:30): Now, you know that an FEV1 is the forcible exhaled volume of air in one second, and it should be over 75%. Well, now you can actually see it and say “geez, I'm down to 65%. What happened?’ Imagine if you could do that in your own home without having to get these PFTs done. Imagine if you could see the result yourself, but better yet, this device not only allows you to see it, we see it as physicians. I've got a coordinator whose sole job right now at our center – her name is Maria – is to contact me: "Hey, Dr. Yanik. Mr. Jones just had a 10% drop in their FEV1. Should we bring them in to be seen? Should we contact your other colleague that's seeing them next week?" Meaning that these readings will come to us in real time whenever you do them.

(28:31): There's a large four center study in progress being done in Seattle, Stanford, MD Anderson and at the University of Michigan. We're looking at getting these devices from a foundation so that we can actually give them out to patients to start using; to start giving them training on how to do it. I think it can be a really powerful tool that you can have in your own hand that you could measure your lung volume and your lung function.

(29:00): New CAT scan technology color codes the lungs, making it easier to detect areas of damage and catch lung GVHD early. There's also new CAT scan (CT) technology. It's called PRM. PRM stands for parametric response mapping. This technology was developed at our center at the University of Michigan. It color codes the lungs so that you can see the areas of lung damage within the lungs themselves.

(29:26): If you've ever seen a CAT scan, they're black and white. You see areas that are horizontally black on a CAT scan, white are areas where you've got some type of thickening of tissue or pneumonia or something. Well, in our CAT scan technology called PRM at our center, we divide the lungs into various cubic segments called voxels. We'll look at the density of each of those segments, when a patient takes a deep breath, when they exhale, and then we know what's normal, we know what's abnormal, we know what we see with scar tissue, we know what we see with lung GVH and we color code everything. And now we can actually count it up even and we can quantitate it and say, for example, ‘hey, out of every 1000 cubes that we're looking at, 800 of them already have changes of lung GVH.’

(30:18): Then we can follow that with treatment on CAT scans. What you're seeing here where it says one year post-BMT, this is one of our patients. It was a 30-year-old male who had some mild lung symptoms, a little bit of shortness of breath, fatigue. We did pulmonary function tests on him and a CAT scan and both read as normal.

(30:36): We put the CAT scan through this PRM color coding and now you can see all these different colors. What do the colors mean? Well, green is normal. Yellow starts showing areas of air trapping or lung GVH setting in. Purple starts showing areas of thickened lungs where you can start getting scar tissue. Even though his pulmonary function test and CAT scan were both read as normal, when we did this color coding, his lungs were anything but normal.

(31:06): Then two years after transplant, by the time that the pulmonary function test actually got under 75% FEV1, the patient was diagnosed with lung GVH, and we repeated the CAT scan. His lungs are mostly yellow now. Red on the CAT scan means that you've really got severe air trapping, almost like emphysematous changes in the lungs going on. And this is the one the pulmonary function test just picked up that there could be lung GVHD. Here we're seeing a ton of yellow. And then five years after transplant, now these lungs were all yellow, a lot of red. Ultimately, this patient underwent a lung transplant just because the lungs weren't salvageable with any of our other therapies.

(31:49): This is a powerful tool. It's being studied in a research study. I gave this talk to another group several months ago and within a week or two after giving the talk, I started getting all these emails from folks around the country, "How can I get this done?" The technology is available at other centers. I can walk your physicians through some of it, but right now it's primarily being done as a research study to validate its utility at four sites: University of Michigan in Ann Arbor, Seattle, Stanford and MD Anderson. We're also bringing in Emory in Atlanta and Dana-Farber Cancer Center in Boston to partner with us to validate how well this technology works.

(32:39): Current treatments for lung GVHD include inhaled steroids and FAM therapy. Therapy for Lung GVHD. What about the therapy for lung GVHD? There's few randomized clinical trials, sadly enough, and most of the trials that have been out there involve 20, maybe 30 patients – not large numbers. There have been two trials that I would say have truly impacted care.

(32:58): Inhaled Steroids. One is a trial done by Anne Bergeron in Paris. It was published several years ago, looking at inhaled steroids. These would be the inhalers that you use that have steroids in them to help coat the lung tissue that's been irritated and inflamed from the GVH.

(33:14): FAM therapy. The other one is FAM therapy that another one of my good friends, Kirsten Williams in Atlanta at Emory, published back in 2016. I'd say FAM therapy has become the gold standard for the initial therapy for lung GVH.

(33:29): F stands for inhaled fluticasone. That's steroid, kind of like what Dr. Bergeron was using in Paris. A stands for azithromycin. Azithromycin or Zithromax®. It's actually an oral antibiotic, but it's also an anti-inflammatory agent that helps take down inflammation in the lungs. M is for Montelukast. Azithromycin and Montelukast are oral. The other name for Montelukast is Singulair. This is a powerful anti-inflammatory agent often used in patients with asthma. So it took a lot of the asthma therapy and developed this FAM, F-A-M, approach that Dr. Williams piloted. And I'd say that that FAM therapy has now become pretty much the gold standard, especially for patients with newly diagnosed lung GVH.

(34:15): What Studies are Currently Being Done for Lung GVHD? Clinicaltrials.gov is the FDA's website for what's being done right now. You'll see a number of studies out there. Starting from the far right of this slide, Steve Pavletic at the NIH has this novel drug called Alvelestat for treating lung GVH based on impacting enzymes that bring in neutrophils into the lungs. Neutrophils are blood cells that can cause lung damage.

Itacitnib by Amin Alousi at MD Anderson. Itacitnib is almost like ruxolitinib or Jakafi® if you're aware of these drugs as immune suppressant drugs for the lungs.

Pirfenidone, Joe Hsu has been piloting and he's got funding to study it. This is a drug that breaks down scar tissue, so this could be a wonderful drug if the studies pan out in lung GVH.

(35:13): A group in Switzerland has now piloted liposomal CSA – stands for cyclosporine. Cyclosporine is like tacrolimus, and it's an immune suppressant drug that you would inhale literally into your lungs if you had lung GVH. Kristen Huck also has a drug called nintedanib. Cass Myers in Cincinnati and Zach D. Philipp are looking at a drug called ruxolitinib or Jakafi to treat lung GVH. And Corey Cutler up in Boston at Dana-Farber has now got NIH funding to study a drug called belumosudil or Rezurock® for patients with lung GVHD. This is it though, as of a few months ago. These are all the trials that are out there for lung GVHD being done. There need to be a lot more.

(35:59): Exercise is one of the most powerful ways to combat breathing problems after transplant. Then just my last few slides, I just want to show you this. The power of exercise. I can't overstate this slide enough. The power of exercise. This is the actual PFT report that we as physicians see. Remember I said there's all these values on there, and what did we look at?

(36:22): This is a 50-year-old male at our center with chronic graft versus host disease, and the top red box is where the FEV1 is. It says ‘percent pred,’ percent predicted. That meant that his forced exhale volume in one second was only 52% of normal. Again, anything under 75% means you've got lung GVH. The bottom red box is one value I haven't told you. It's DLCO. DLCO is a fancy medical term for how well air or oxygen that you inhale can actually get through your lungs and into your bloodstream. For example, if your lungs are all scarred down, then the air you breathe can't get through the lungs.

(37:06): But what if the lungs are healthy but your blood vessels, say from atherosclerosis or other blood vessel damage, are all thickened and the air can't get into them? So the DLCO can be low in patients if you have lung problems or if you have blood vessel problems. So it's one thing to have a low FEV1, but you also want to look at the DLCO. Again, the DLCO measures your ability to transport air into the bloodstream.

(37:37): This patient’s first initial is T. When T. developed long GVH, he started bike riding. This was his pre-bike riding pulmonary function test. He had an FEV1 at 58% and a DLCO – The D stands for diffusion – of 77%. That means 70% of the air he was able to take in was able to get into the bloodstream compared to predicted for his age and size. How would you feel if you had that? Probably tired. Short of breath. So he took up bike riding.

(38:17): I was always amazed that somebody with an FEV1 at 58% could ride 20 miles, 30 miles, sometimes 40 miles a day, and he did it religiously. He's been doing it for many years now, and I recently did follow up pulmonary function tests on him. And after years of bike riding, his FEV1 hasn't gone up at all. In fact, it's gone down. But his diffusion number, his DLCO, has gone up to 107%. So he couldn't get rid of the scar tissue in his lungs, but he made his blood vessels so dang healthy that every molecule of oxygen he breathes in gets across into his body.

(38:57): He feels great mostly because he's exercised himself to the point of incredible health, maximizing his lung health, but really maximizing his blood vessel health. Thus the power of exercise for all of you who've got chronic graft versus host disease, or have had lung GVHD, I can't overstate it enough as evidenced by this patient. I smile every time I see him because he's my poster child for goodness. Still riding 20, 30, 40 miles a day on a bike. Amazing.

(39:33): The Circle of Health and Hope. If you've ever read the book, The Boy, the Mole, the Fox and the Horse by Charles Mackesy, it's a great book. It's a great quote there. It's a boy who's walking through the woods and across the terrain with a horse – obviously with a mole and a fox too – and he looks up to the horse and asks, "What's the bravest thing you've ever said?" "Help," said the horse.

(39:59): I want all of you to know that's really a circle of help. It's a circle of hope. And that it's a help that we all need to give hope. We as clinicians need help from you, the patients, to enroll in clinical trials to treat lung GVH. The researchers in our labs, our centers across the country, need us as clinicians to come up with ideas, to bring them patient samples and things that they can then study in their labs to look at lung complications. And then ultimately what the research has developed then comes back to the patients, you that are asking us for help. It's a circle of help. It's a circle of hope. And thus, "What's the bravest thing you've ever said?" asked the boy. "Help," said the horse. That's a tough thing, but I think each of us who are going through this recognize that saying ‘help’ is sometimes the wisest thing to do.

(41:09): I want to conclude by thanking everybody that listened to this talk today, to the BMT InfoNet, to the patients we serve. And I'm truly grateful and blessed to be able to be part of the lives and the care of those that I work with. I truly feel honored. I have the greatest job in the world. I want to thank the medical teams I work with and I want to thank all of you.

(41:35):  I want to end with a quote: "Happy are those who dream dreams and have paid the price to make them come true." For those of you that have gone through a bone marrow transplant, you've paid a price. I just hope that you still have your dreams and that we as researchers can help you fulfill them.

(41:54): By the way, the picture on the far right-hand side is not anybody who's gone through transplant. It's my son and his daughter. That's my first grandchild. I figure any talk that I can show off my granddaughter is a good excuse for me to show a picture of my cute granddaughter.

(42:12): With that, thank you and I'll take any questions.

Question and Answer Session

(42:20): [Steve Bauer]: Thank you, Dr. Yanik, for this excellent presentation. We will now begin the question and answer session. Our first question is, How useful is Belumosudil in a person who has lung GVHD for seven years? Any chance of improvement or only stability?

(42:52): [Dr. Greg Yanik]: Great question. And one of the questions can also be, ‘How do we measure response? How do we define success?’ The large Belumosudil trial that was published in patients that had lung GVHD found that it only helped the numbers with approximately 16% of patients. That may sound sobering, but to be honest with you, every one of us recognizes that it's a good drug. We just have to use it early. The key for us is getting PFTs done on patients, or those hand-held spirometry, or that CAT scan with that PRM or other techniques to diagnose that these patients’ lungs are starting to get sick and we need to treat early. So, if you're going to hope for improvement with Belumosudil, the key is to use it early. When you've already got established lung GVHD, then the responses are more likely going to be stability, meaning that your PFTs didn't get worse, your FEV1 was 50% and instead of going from 50% to 45% to 40% to 35%, drugs like Belumosudil kept it at 50%. That would be a marker for success. There are a number of drugs out there that we're looking at, and you saw some of them in that one slide.

(44:21): Belumosudil, Ruxolitinib, Itacitinib, Pirfenidone. I think the key for all those drugs is early use and early intervention before you get too much scar tissue in the lungs. Once you've got a lot of scar tissue – think of lung GVHD. I didn't talk about this, but think of long GVHD as two stages: First stage being inflammation, second stage being scar tissue. The drugs we use to treat inflammation are different than the drugs we use to treat scar tissue. So drugs like Belumosudil, Ruxolitinib, Itacitinib and some of the other ones, they're going to focus a lot on decreasing lung inflammation. But once you get the scar tissue, then those drugs hopefully will just help things keep stable, but they may not give you improvement. Now, one drug I mentioned, Pirfenidone, which was being studied at Stanford, that's a drug that's looking at scar tissue. That drug may actually be focusing on the second stage of development when we get that scar tissue. So to make a short answer long here, I would say if you've already got lung GVHD and you're using a drug like Belumosudil or some of the other agents we use, disease stability, just keeping a stable FEV1 is what we really look at.

(45:46): [Steve Bauer]: How often should someone have PFTs if they have not been diagnosed with GVHD? Should people who have had TBI have more frequent PFTs? If so, how frequent?

(46:03): [Dr. Greg Yanik]: That is a great question. I'd almost like to have the person in front of me to ask them how often have they had PFTs done right now. By the NIH recommendations, a PFT should be done every ... In fact, can I go back on the slides?

(46:27): [Referring to slide at (24:59)]: It says, ‘How often should PFTs be performed?’ This question gets to a hole in my slide. I said PFTs should be performed every three months for the first year after transplant. I didn't say what should be done after that. At our center, we recommend that PFTs be performed at 18 months. So once you're a year out, then you get PFTs at 18 months and 24 months after transplant, and then once a year through year five. That's what I recommend right now. So every three months for the first year and every six months in that second year, and then once a year for years three, four and five out from transplant. That's my typical recommendation.

(47:13): Once the chronic graft versus host disease has been diagnosed, then PFTs every three months. How long do you go with every three months? It kind of depends on the patient. Certainly for the first year or more after they're diagnosed, you should follow it. With patients once they get chronic GVHD, the average time it takes to getting a lung GVH or the lung manifestation of that is usually about six to 12 months later. So that first year from diagnosis of chronic GVHD is critical to keep following PFTs. But to answer the question, for patients who never get chronic GVHD, I recommend PFTs every three months for the first year, every six months for the second year, and then once a year for years three, four, and five after transplant.

(47:58): [Steve Bauer]: I have chronic cough and frequent bronchitis still three years after an autologous SCT. My chest X-ray is usually okay. What do you recommend next?

(48:11): [Dr. Greg Yanik]: That's a good question. So this is an autologous transplant. We recently published, in abstract form, that patients who have had autologous transplants, especially patients who've had them for lymphoma, have nearly a 20% incidence of getting some lung complications after that autologous transplant. And sometimes these lung complications can last for a long term. I actually would almost treat you as if we treat a lung GVH patient and I would say that you could be a good candidate for FAM therapy. The fluticasone, azithromycin and Montelukast if you haven't been on it already.

(49:00): The F in FAM is fluticasone. That's an inhaled steroid, so it's an inhaler that has steroids in it. It's different than some of the other inhalants that people take for asthma. The A, the azithromycin, is an anti-inflammatory antibiotic. And the M for Montelukast is an anti-inflammatory agent. I'd consider that. And very few transplant physicians even realize that roughly 20% of patients who get an autologous transplant can get some significant, almost chronic, lung complications after that. If you've had radiation of the chest or lungs, that's the really high-risk group for who's going to get these chronic lung complications. So if the person writing the question had, let's say lymphoma, and they had radiation to their chest that would hit the lungs, and then they had a transplant, that's a high-risk group for having chronic lung damage, scarring. I definitely would consider them probably if they're still symptomatic, for that FAM-type therapy.

(50:04): [Steve Bauer]: Will the flu cause lung GVHD to flare up?

(50:11): [Dr. Greg Yanik]: We're looking at that. I stated that patients who get viral infections, upper estuary infections, in the first three months after transplant have a higher risk for getting lung GVH 12 months later. We started looking at patients who had lung GVH. If they get a flu, what happens with their lung GVH? Does it all of a sudden get worse? We're not sure of that answer yet, but we're looking at a number of studies that are being done right now. Patients who do get influenza who have lung GVH, we typically – at least I will – treat them a little longer than I treat somebody normally for influenza. I also make sure one of the key factors in treating lung GVH is a blood test called Immunoglobulin G (IgG). IgG is your antibody level, and if you have chronic GVHD, it really would behoove your transplant physician not only to get a CBC on you when you come into clinic, but to get an IgG level.

(51:14): Patients who have low levels of IgG or antibody in their bloodstream are the ones who get these chronic infections. If you can keep that IgG level up – every center has their own cutoff, but our center is 400. If you can keep that IgG level up over 400, then you can cut down the number of lung infections, or the severity of them. So for the person who asked the question, if they already have chronic GVH or if they already have lung GVH and they get influenza, we're studying whether that will cause the lung GVH to worsen. We haven't seen that yet, but we're definitely wary of it. But what I really recommend in those patients is to make sure you keep your IgG antibody level – it's a blood test – up to prevent those lungs from getting worse.

(52:17): [Steve Bauer]: If a child had GVHD in lung and was treated and it subsided, could there be a change as an adult that it could return?

(52:28): [Dr. Greg Yanik]: That's a really interesting question, and you could take away the child part and just say, if any patient had developed lung GVHD and you got better with treatment, you had early recognition and you treated and it and got better, could it come back, let's say 10, 20 years later? In my own experience, that'd be highly unlikely. So, let's say you had a five-year-old child who had lung GVH and now they're 35, should they worry about the lung GVH coming back? I haven't seen that and I've been here at U of M for 30 years, so I've now been able to follow patients for a long time. But what I will admit is, as a child with GVH gets older, keeping them away from other lung irritants is key. Smoking, marijuana, any inhaled agent...vaping in particular.

(53:27): I always view it like rock crystallization of the lungs with vaping. So anything that you're going to smoke or inhale that could cause further irritation to the lungs as you get older. Maybe the GVH won't come back, but you've already got lungs that, let's say at five years old, the lungs have GVH, you've got some scar tissue there, and then if you keep adding more lung damage to them, you could worsen your lung function. The beauty of kids is that as they grow, their lungs will expand and grow too. So kids stand a better chance of getting through the side effects of lung GVH, at least the young kids, than does somebody who's 40 or 50 whose lungs obviously aren't growing anymore. Short answer, I haven't seen that lung GVH at age five comes back at age 35, but I do worry about other things that could worsen the lungs. Like smoking cigarettes, smoking marijuana, vaping, things like that.

(54:26): [Steve Bauer]: This will have to be our last question. I am 18 months post-transplant and still need oxygen at night. Can I recover?

(54:36): [Dr. Greg Yanik]: By the way, Steve, and everybody asking these questions, these are some of the best questions I've had asked of me in several years. I just appreciate the thoughtfulness of the questions. I mean, this question here, it's a heartfelt question. To answer your question, I need to see your PFTs. If your FEV1 is 20%, 30%, it's unlikely that your FEV1 can ever come back up to 40%, 50%, 60%. If your FEV1 though, is at 50%, 60%, there have been some trials that have improved lung function. We were part of a trial with a drug called a Etanercept years ago. Ken Cook, who's at Hopkins, and I actually did see in about a third of our patients, the drug of Etanercept did help lung function in patients with lung GVH, but it really helped those patients whose lungs weren't that severe. If you're on oxygen and your lungs are already in that 20%, 30% range on that PFT, you're just hoping for stability.

(55:52): I can't promise you that there's a drug out there that'll be a magic bullet that'd get that FEV1 up to 40%, 50%, 60% or higher. If you're at 50%, 60%, 70% and you're asking this question, then I'd say there's a chance. Really comes down to, think of those two stages I said: The first stage is inflammation, where you just have to put out the fire. The second stage is scar tissue, where now the fire's gone. You're left with scar tissue. If you're at the point where you're left with scar tissue, it's hard to recover a lot of lung function. So I guess go back, ask your transplant physician, say, "What's my FEV1?" He or she will look up at you and think, how do you know about this term? Because you've heard with this talk today, a lot of insider trading information. And sit down and ask your transplant physician, seriously, "Can I see my PFTs and what my FEV1 is and what the trajectory is?" If the trajectory of your FEV1 is that it's stable. Let's say it's been holding at 30%, that's good. But if it's going 75, 60, 50, 40, 30, 25, that's not good and that's a really worrisome sign to me that the trajectory continues to decline.

(57:09): [Steve Bauer]: On behalf of BMT InfoNet and our partners, I'd like to thank Dr. Yanik for his very helpful remarks on our questions. And thank you, the audience, for your excellent questions. Please contact BMT InfoNet if we can help you in any way.