Your Lungs and Chronic GVHD

Presenters:

• Guang-Shing Cheng MD,  Fred Hutchinson Cancer Research Center
• Iskra Pusic MD, Siteman Cancer Center at Barnes Jewish Hospital

This is a video of the workshop presented at the 2019 GVHD Patient Summit.

Presentation: 38 minutes, followed by 22 minutes Q&A

Summary: Fourteen to 15% of patients who develop chronic graft-versus-host disease after transplant develop bronchiolitis obliterans syndrome (BOS), a common manifestation of lung GVHD. Outcomes are best in patients diagnosed and properly treated early in the course of the disease.

Highlights:

• Lung problems that can occur after transplant include bronchiolitis obliterans syndrome (BOS), interstitial lung disease, cryptic organizing pneumonia, neuromuscular lung disease, pleural disease and problems caused by skin sclerosis which can affect the chest wall and make it hard to breathe.
• Symptoms of bronchiolitis obliterans may not appear until the disease has progressed extensively
• Treatment for bronchiolitis obliterans syndrome usually does not reverse the disease, but may stop it from getting worse.

Key Points:

08:32:    Bronchiolitis obliterans syndrome affects the small airways that lead to air spaces in the lungs. 

12:22:    Symptoms of bronchiolitis obliterans syndrome include shortness of breath and cough.

13:45:    Bronchiolitis obliterans syndrome is diagnosed by pulmonary function tests and CT scans.

18:33:    Risk factors for bronchiolitis obliterans syndrome include chronic GVHD in other parts of the body, low immunoglobulin, lung problems prior to transplant, chemotherapy, radiation to the lungs and viral infections

23:38:    Most patients with bronchiolitis obliterans syndrome do not improve lung function after the diagnosis is made, but the disease tends to remain stable after diagnosis and treatment.

25:16:    Early diagnosis of lung GVHD may improve outcomes.

26:35:    Two year survival after a diagnosis of BOS is about 70%.  Five year survival is about 40%

28:38:    Corticosteroids and bronchodilator are the mainstay of therapy for most patients with lung GVHD

30:53  Long-acting prednisone is not effective in reversing decline from lung GVHD

38:40:    Pulmonary rehab can improve quality of life in patients with lung GVHD

Transcript

00:00 [moderator] Introduction of Speakers:  Let me introduce Dr. Guang-Shing Cheng, and Dr. Iskra Pusic. Dr. Cheng is an Associate Member of Fred Hutchinson Research Cancer Center, and also an Associate Professor at the University of Washington in Seattle. She's a member of the Division of Pulmonary, Critical Care and Sleep Medicine. Her research has been concentrating in early detection and the management of complications of the lung, for those patients who have undergone pulmonary transplantation, and especially correlation with infectious diseases.

Dr. Pusic is an Assistant Professor at Washington University. She's an Associate Professor of Medicine in the Division of Oncology. She is leading their chronic graft versus host disease clinic, and she's a member also of the NIH, National Institutes of Health GVHD study group. Please join me in welcoming Dr. Cheng.

01:19  [Dr. Cheng] Thank you very much Dr. Rodriguez for that kind introduction. It really is an honor for me to be here. I'm a pulmonologist as Dr. Rodriguez mentioned. My practice is very unique. I am embedded within the cancer center. My practice, I see exclusively patients with cancer and cancer survivors.

It is a great honor to be at this event, because every day I'm inspired by survivors such as yourself. This talk is really for you, for the patients that have come under my care for their lung problems, who have inspired me with their resilience. We're going to talk about your lungs and chronic graft versus host disease. What I'm going to try to cover today, is really what actually constitutes GVHD of the lung? How does it happen? Who is at risk for developing lung GVHD?

02:19  Outline of Talk: The first part of the talk is a little bit technical. I'll try to get through that so that we can talk more about the treatment strategies and, really, the approach to living with lung GVHD.

02:36  Lung problems in survivors of stem cell transplantation is actually a fairly significant problem, that is now being more and more recognized by the medical community. The incidence of late noninfectious pulmonary complications is probably hovering between 15 and 20%. What I mean by late, meaning people who have survived the early part, the first three months of their transplant, and now are in their survivorship. Noninfectious meaning, all the problems that can happen that are actually not related to an infectious pneumonia, which is actually still quite frequent in this population.

03:19  There have actually been studies that have looked at, actually it was a very good study out of the Hutch, that looked at survivors of stem cell transplant even compared to survivors of other malignancies, had more respiratory problems during the course of their survivorship. Compared to all other organ systems in their body, including cardiovascular, kidneys, gastrointestinal, second only to infectious complications. Breathing problems are really a big issue, and sometimes under reported issue for survivors of transplant.

03:59  What is the spectrum of lung disease in survivors? Well, what I have listed here are the specific names of these entities that you may hear. Bronchiolitis obliterans syndrome, I think many of you are familiar with this.

There are different manifestations of lung disease depending on where in the respiratory system is affected. In addition to bronchiolitis obliterans, we have interstitial lung diseases, and some of you might have already experienced something called organizing pneumonia, which is part of this rubric.

You can have lung problems due to weakness of your breathing system, so neuromuscular lung disease. You can have pleural disease, that's lining of your lungs and your chest. Some people have fluid in their lungs called pleural effusions. Then you can also have pulmonary vascular disease. Your lungs has a very rich circulation, separate from the circulation in the rest of your body. That circulation sometimes can be affected by blood clots, by changes in the blood vessels.

05:16  Bronchiolitis obliterans is a manifestation of GVHD:  What is actually due to graft versus host disease? Well, it's fairly clear that bronchiolitis obliterans is a manifestation of graft versus host disease. This often presents with a so-called obstructive pattern on your pulmonary function tests.

Bronchiolitis obliterans can happen in patients who've never gotten transplant. We see it also in patients who have gotten lung transplantation. It's an uncommon condition in children who have had infections, and in some individuals who have been exposed to chemicals. Bronchiolitis obliterans in and of itself as an entity, is not really specific to stem cell transplant. But we do see it now, our understanding of it comes from transplant patients.

What are the types of lung disease that might be due to chronic GVHD?

As I had mentioned, interstitial lung disease, which again is not unique to transplant patients, but sometimes tend to crop up. Specifically an entity called cryptogenic organizing pneumonia, or organizing pneumonia. This shows up differently than bronchiolitis obliterans, is generally more treatable. Does show up as a so-called restrictive pattern on your pulmonary function test, and has some chest imaging findings.

Pleural disease, so this is also... Sometimes I do see survivors with these chronic effusions, or fluid in the lungs, that really with lots and lots of investigation I cannot attribute to anything else except for their chronic GVHD. I think that chronic GVHD can show up in the lining of the lungs in this way, but it's very difficult to prove.

But in any case, these are manifestations of lung disease that can be due to, I think can be due to a chronic GVHD.

There are definitely lung problems that can be due to the effects of other aspects of chronic GVHD. Specifically, sometimes patients who have severe skin sclerosis, it can definitely affect the chest wall. Your chest needs to be able to move for you to breathe. I actually do see that with some degree of regularity.

Many patients, and many of you I'm sure have been on prednisone for quite a long time. Prednisone itself I think can contribute to neuromuscular weakness, that then contributes to not being able to breathe quite as well.

08:32 The difference between bronchiolitis obliterans syndrome and cryptogenic organizing pneumonia:  Now back to bronchiolitis obliterans syndrome, versus cryptogenic organizing pneumonia. I want to mention this because sometimes there's confusion about these two entities.

From a medical point of view, an anatomic point of view, organizing pneumonia affects the small airspaces, the alveoli. Whereas bronchiolitis obliterans affects the very small airways. The small airways lead to the air spaces. They're pathologically different.

However, they sometimes do happen simultaneously in the same person. Or somebody can get organizing pneumonia first, be treated, and then ultimately develop bronchiolitis obliterans.

Just one more word about organizing pneumonia, it's often misdiagnosed as infectious pneumonia. It is treated with prednisone, and for the most part the majority of people with this condition do respond, and can recover from this.

These are also CT scans of individuals who have been affected with organizing pneumonia. It shows up as these patches or these so-called infiltrates of stuff in the lungs. These are inflammatory infiltrates that you do not see, you shouldn't see in somebody with just bronchiolitis obliterans.

10:09  How does bronchiolitis obliterans syndrome (BOS) actually happen? We don't entirely know, but we hypothesize that there's some insult that you inhale, whether it's a virus or a toxin or if you have reflux disease. If you're aspirating some acid from your stomach, that goes down into your airways and your small airways are very sensitive. These inhaled triggers can cause acute inflammation, and in the context of your graft, these really hyper active cells that you have from your transplant, chronic inflammation happens around the small airways.

Then something happens where immune response is irregular or dysregulated, if you will, that leads to fibrosis around the airways, and within the airways. Fibrosis is not like inflammation. Fibrosis is very hard to treat, is generally considered not reversible. This fibrosis, it squeezes down the small airways leading to what we call airflow obstruction, and hence shortness of breath.

11:29  What does bronchiolitis obliterans syndrome look like? What does it look like on a pathologic specimen? Well, this is an airway that's been obliterated by fibrous material. The particular stain, you can see this is actually a stain of the airway lining, epithelium, that's actually been disrupted, and it's filled up with this fibrous material. Every airway is associated with, accompanied by a blood vessel. This looks normal, but this is definitely not normal.

12:22  Symptoms of bronchiolitis obliterans syndrome:  If you can imagine your small airways, what leads to your air sacks get closed up, air can't leave, and then you feel very breathless. Sometimes the symptoms can also manifest with cough, there's a lack of oxygen.

If you can imagine that if you can't breathe out, and I'm sure some of you feel this, that when you are trying to exert yourself, it's like you're already starting from a hyperinflated lung. Trying to take another deep breath on lungs that are already full of air that can't get out, that's very challenging. Any questions to this point that we can?

12:55 How often does bronchiolitis obliterans syndrome occur?  Okay. Some basic facts about BOS. How often does it occur? Probably 14, 15% of patients with chronic GVHD will be affected by this. Among all allogeneic transplant patients, probably around five or six percent, it depends on where you get your transplant. I know in Europe, in France it's closer to 10%.

13:15  When does bronchiolitis obliterans syndrome occur after transplant?:  When is it diagnosed? Generally later in the course of survivorship, between six months and up to five years. But the vast majority of cases are recognized between one and two and a half years. It generally is diagnosed after somebody's already had other manifestations of GVHD like the skin.

13:45 How is bronchiolitis obliterans syndrome diagnosed? Well, we do pulmonary function tests. We might want to get a CT scan. Sometimes a bronchoscopy or a biopsy is required to make this diagnosis. Some of you might have already experienced that. A bronchoscopy is a procedure where a long thin tube with a camera at the end of it, we go down into your airways, take some washings and biopsies.

I just wanted to show this. This is our pulmonary function laboratory setup. When I'm talking about pulmonary function tests or PFTs, this is what I'm referring to. Actually this is my nurse practitioner Maggie Guerrero, she's kind enough to demonstrate for me. She's performing spirometry which is basically the blowing maneuver. I'm sure you may have experienced this. There's a technician there, and this is Janet our PFT technician here, coaching Maggie to blow.

Spirometry is very essential. It's measuring how much you can blow within a specific period of time. It's a forced maneuver. Maggie is sitting in this device called a body box or it's body plug, plethysmography is the technical term. That actually measures your lung volumes.

Then what do we see on our spirometry?  What we see is that, what we're looking at is this forced expository volume in the first second. You're asked to blow out hard and fast, as hard and fast as you can. This maneuver that shows you what you blow out in the first second is most representative of how your airways are doing. You can see in a patient who has bronchiolitis obliterans, they are so obstructed that what they blow out in the first second is really reduced. Instead of this nice flow of air with your exhalation, it's all scooped out. That's an indication of the air flow limitation.

Your CT scan might show what we call air trapping, or dilated large airways. This is an example of a patient with... We're looking at your FEV one predicted.

How is your FEV one doing compare to what it should be for your height and age? This individual, this patient had an FEV one of 66% of what was considered normal for her. She has these, it might be a little hard to appreciate, but she has some areas where it looks like it's very dark. That's the air that is trapped in that piece of lung that can't get out. Therefore, it looks like there's not very much there. As opposed to in contrast to somebody with organizing pneumonia, they have all sorts of patches and stuff. That's not the case in bronchiolitis.

This is a dear patient of mine who had very, very impaired lung function. She had developed something what we call bronchiectasis, where you have dilated airways. Sometimes if it's so severe, your airways, your larger airways become dilated because the lung is pulled outwards by the fibrosis.These are some findings that you can have on CT scan.

17:26 National Institutes of Health definition of BOS:  The NIH has come up with a definition of BOS, under their chronic GVHD rubric. Just to briefly review it is a little bit technical, but what we want to see is some evidence of airflow obstruction by the spirometry. Evidence of air flow decline, meaning that your FEV one has declined by a specific amount. In the absence of an infection, so pneumonias and colds and viral infections can also cause airflow decline. Airflow decline in and of itself is not specific. It can mean a number of things. In the absence of an active infection. Then of course the CT scan findings can be very helpful. Then if you also have chronic GVHD in another organ with these PFT findings, if you will, then it's very suggestive of bronchiolitis.

18:33  Risk factors for bronchiolitis obliterans syndrome: Who gets BOS? As I mentioned, patients with chronic GVHD. Low immunoglobulin has been associated with this. Immunoglobulin meaning the factors that your B cells make to fight off infection. I think this is suggestive of low immunoglobulin being a risk factor for actually respiratory infections.

Potential risk factors. Lung problems before transplant. Some patients might go into transplant already with some lung injury. If you've smoked before, or if you had asthma at one point in your life. It's possible that we've never been able to really nail that down. I know more and more people get transplant even though their lungs might not be perfect at the time of transplant.

19:28  A lot of people have gotten chemotherapy and multiple treatments before they get their transplant. Lungs are often damaged by the heavy chemotherapy that people have for their hematologic malignancies.

Radiation for sure is a risk factor for earlier kinds of lung injury after transplant and could be also for later.

But I think viral infections, and I highlight this because there's just this increasing body of evidence to suggest that viral infections even occurring early after transplant, and throughout survivorship. Either early cytomegalovirus, or systemic viral infections, and then respiratory cold viruses. There's a panel of respiratory cold viruses, have been shown to be a risk factor for people developing lung GVHD. This is something that we're actually, it's a line of active research in my program, and other people at the Hutch.

Why is this important? Because if we know that somebody has a viral infection post-transplant, maybe this might be somebody who ought to be monitored more frequently, or be a candidate for some preemptive treatment.

Right now how do we figure out who has BOS? Or how do we make the diagnosis? Well, it really depends on the pulmonary function test. There are definitely recommendations for routine monitoring with PFT after transplant. But these recommendations are not uniformly followed at every center. I think it depends center to center.

21:36  Patients with a high risk for developing bronchiolitis obliterans syndrome should be carefully monitored after transplant:  There's definitely a recommendation for patients who are high risk to be monitored every three months during that period of high risk. I would consider high risk being somebody who has active chronic GVHD, on systemic immunosuppressive therapy.

But again, we haven't completely defined who is at high risk, and so it depends on center to center. It is the thing where a pulmonary function test, you do have to make an appointment, go into the lab, get it done. Sit there have somebody yell at you for a couple of minutes. Anyway, so it is in some places perceived to be a nuisance and inconvenience, but it is noninvasive. It is really the best way to detect the disease early.

22:29  Clinical trial using handheld spirometry device that can be used at home to track lung function:  Meanwhile, how do we get around this concept? This inconvenience of getting these frequent pulmonary function tests every three months.

I am running a trial to look at handheld spirometry. These little devices that people can take home. They're about yea big, they can fit in your pocket. They're connected, they're Bluetooth enabled to your smartphone. Where patients who are high risk can do them once a week, or however often they want, in the comfort of their own home.

The data basically gets sent to a cloud, and then I'm able to look at patient's lung function on a weekly basis from my computer. This is something we're trying out, and I think hopefully this will help us figure out who’s at high risk. At what point when we see lung function decline is the right time to intervene. Stay tuned for that.

23:38: What is the prognosis for patients with lung GVHD?  Okay, so now I get this question from my patients a lot. What is the prognosis of lung GVHD? There are a couple of factors here, things that I just want to bring up. Lung function in terms of will your lung function get better? For the most part, I show this graph to, this is an analysis that I did actually with Dr. Pusic also.

We looked at a cohort of patients with bronchiolitis obliterans who were diagnosed at this time. I looked back at how fast did lung function decline? At what point did they decline? Basically found that once somebody recognizes it, once your doctor says, "Okay, I think this is what you have", patients get started on treatment, and generally things are fairly stable after that.

Now what does that mean exactly? Does that mean it was the treatment that stopped you from declining? That's possible. But it's also quite possible that by the time you were symptomatic, the damage had already been done. Most patients do not improve their lung function after the diagnosis is made. However, you can see that if we look back at the lung function measurements that were done before diagnosis, in order to have decline, you had to have started from something normal to go down to that decline.

25:16  Early diagnosis of lung GVHD may improve outcomes:  If it is the case that we can stop lung function decline with our treatment, then why don't we get people up here, so that their lung function is more like 70% as opposed to 40% when they're diagnosed? Now that really is a function of the monitoring.

There are some patients who do improve with treatment. In my experience, in my clinic, those are the patients who we recognize much earlier through screening. They may or may not be symptomatic.

Respiratory infections, so you might get diagnosed with bronchiolitis, so then things stabilize. But once you have lung disease, you are predisposed to getting respiratory infections. I think the respiratory infections, there are some individuals who tend to have a lot of respiratory infections, some individuals who do not.

The individuals who have more repeated bouts of pneumonias or bronchitis that need treatment, their lung function tends to drop over time.

26:35  The two most common causes of death in patients with BOS are, a severe infection, or respiratory failure from the primary lung disease itself. Overall survival, so two year survival in somebody who's been diagnosed with BOS is about 70%. Five year survival is about 40%. Those are the most recent estimates from my analysis, and other centers. Much better than what has been historically reported in the earlier days of transplant. But I do want to shed some hope that patients can survive many years even with poor lung function. I think a lot of that has to do with your general lung health, avoiding infections, treating exacerbating causes, and maintaining your overall strength.

27:43  First line management at least at my center is this so-called FAM + LABA. That's fluticasone, which is an inhaled corticosteroid. Budesonide is often used. LABA means long-acting beta-agonist. Azithromycin, I put this in brackets because we are now deciding if this is actually appropriate in stem cell transplant patients. Then montelukast this is leukotriene inhibitor, which is often used in allergic asthma.

Many of the treatments that we have for BOS are really derived from our experience as pulmonologists in treating other chronic lung diseases, such as asthma or COPD, or even cystic fibrosis, and also from the lung transplantation population.

28:38  Corticosteroids and bronchodilator are the mainstay of therapy for most patients with GVHD. I do want to mention that inhaled corticosteroid and bronchodilator are a combination. This should be the mainstay of therapy for most patients with pulmonary GVHD.

There are a number of them and you may be familiar with them. These combinations make it easier to take all in one inhaler. The one I like to use is Symbicort, which is budesonide and formoterol. There's also Advair. These are very common meds in patients with asthma also. Dulera is another. Dulera and Breo are more recent ones that also I think work equally well.

What you end up on a lot of the times depends on what your insurance is going to pay for. Symbicort I do have to mention that this was actually tested in a randomized controlled trial in France, in patients with bronchiolitis obliterans after stem cell transplant. My colleague Anne Bergeron, Dr. Bergeron showed that Symbicort actually helped improve lung function a little bit at one month. I do tend to use this.

Advair is also quite good. The other agents that can be used are ones that we also use for patients with emphysema or chronic obstructive pulmonary disease. These are often the long-acting muscarinic agents. Like the LABAs, you might hear the term LAMA, these are also, they try to dilate your airways and help air flow with that. Tiotropium or Spiriva is one that we've had a lot of experience with, is generally a very good drug once a day. Umeclidium or Incruse is another one that's cropped up. There are a bunch of combination drugs that combine the long-acting muscarinics with the long-acting beta-agonist. That have come out on the market in the last three or four years.

30:53  Long-acting prednisone is not effective in reversing decline from lung GVHD: What about prednisone? If I diagnose somebody with new onset bronchiolitis, it's the first recognition, I might use a short course of prednisone like a couple of weeks. But long-acting prednisone really has never been shown to be effective in reversing the decline that occurs. Either way, I try to get people off of the prednisone within four to six weeks if I'm going to use it for this indication.

The point of the prednisone is really if there is a component of inflammation. If things have not gone fully fibrotic yet, then that's what the prednisone is treating, is actually treating the inflammation. If there is fibrosis, that is actually something that is very difficult to treat that I'm not actually treating with the prednisone. I know a lot of my patients are on corticosteroids for other manifestations of their GVHD.

Often I allow the oncologist to dictate the prednisone for their skin or their eyes or what have you, but not necessarily for the lungs. For the lungs, two weeks of high dose steroids is more than enough. In addition to the inhaled agents in the montelukast.

32:21  Treating sinus disease is important:  Definitely, definitely want to treat exacerbating factors, like infections I mentioned before, sinus disease. Sometimes pulmonologists we like to call sinusitis asthma of the nose. Because whatever happens up here in your sinuses, definitely always ends up in your airways. It causes cough among other things, and could serve as trigger for worsening airflow obstruction.

32:48  Managing aspiration and reflux is important:  Aspiration and reflux, after a certain age, our esophagus gets relaxed, we lie down, we're not even aware of it.  Stuff comes up into our mouths, and then it gets aspirated while we're sleeping. We don't even realize it, because your trachea and your esophagus are really close together. Your windpipe and your gullet are neighbors. We do want to treat aspiration.

I do advise patients to sleep with their head slightly elevated, whether that's through pillows, or by simply just raising the support of the bed, the head of the bed.

Then environmental things. I mean, obviously no smoking, no vaping, definitely not. Avoiding places, allergens that might serve as a trigger, especially if you're somebody who already had asthma or is sensitive to certain inhaled substances.

33:55:  Study of azithromycin for lung GVHD:  Now, this is a very frequently asked question as of late, should I be taking azithromycin for lung GVHD?

I want to mention this because the FDA actually put out a warning in response to this trial. Dr. Bergeron in France, she conducted a trial looking at azithromycin. Azithromycin is an antibiotic. Many of you might be familiar with this. It's generally considered to be very safe. In lung transplant patients, it has been shown to decrease the risk of bronchiolitis obliterans, when given as a preventative medicine, as a prophylactic medicine.

This study tested the use of azithromycin given right up front at the time of transplant for a year to see if that would reduce the incidence of lung GVHD. What happened was that what it showed, was that the incidence of lung GVHD did not go down, but that the incidence of relapse, hematologic relapse actually went up in the group that got azithromycin.

That's why the FDA and the European Medicine Agency decided to put out a warning that this medicine should not be given for prevention of bronchiolitis.

Is that a concern? Is that relevant to patients with already established bronchiolitis obliterans syndrome? The setting in which is azithromycin is given is quite different.

Most patients with lung GVHD are diagnosed quite some time after their transplant, when the risk of relapse has gone down. It's not down to zero but has gone down. Other things are more likely to affect your survival. Right now it's not entirely clear, but I have to say that there are about to be published some manuscripts that suggest azithromycin given for bronchiolitis obliterans syndrome, specifically after stem cell transplant, is not associated with relapse.

Does it actually provide benefit? Now that's another question. What are the pros and cons of using this? We don't think there's any evidence for relapse in bronchiolitis, but we'll see in the next couple of months as these studies start coming out. It potentially reduces infectious exacerbations because, and we've seen this in patients with asthma and cystic fibrosis and chronic obstructive pulmonary disease. It's generally well tolerated.

Cons, of course, risk of relapse early post-transplant. You might reduce the tumor surveillance, and it is associated with arrhythmias. We really have not shown any effect on improving lung function whatsoever.

36:57  If lung function gets worse, what should a patient do?  What if my lung function gets worse? That's another frequently asked question.

Well, one is we want to investigate the exacerbating factors. Is there an infection? Is there sinus disease? Is there reflux?

There are second line treatments that can be tried. ECP, Ruxolitinib, which is also known as Jakafi, which some of you might have already experienced that. Then ibrutinib of course is approved for second line treatment of GVHD.

There are, indeed, a number of agents being tested right now specifically for BOS. I just put this up here as a kind of a reference, I want to point out specifically I'm doing this trial in Ruxolitinib. Pirfenidone and nintendanib are actually lung specific agents. These are anti-fibrotic agents that have been approved for idiopathic pulmonary fibrosis. These are specifically anti-fibrotic agents that I think are potentially very, can be helpful.

Then of course supportive care, supplemental oxygen. Airway clearance if you tend to have a lot of infectious exacerbations, airway clearance is very helpful. Pulmonary rehabilitation, this generally helps build up your strength and the prevention of infections. Lung transplantation for lung GVHD, and maybe we'll get into this more during the Q & A session. It is possible even for if you've already had a transplant it can be done, but in select patients. But there is a risk of getting bronchiolitis obliterans again.

38:40  Then, lastly, I'll just leave you with this idea of living with your lung GVHD as a survivor. Inhaled corticosteroids I think are the mainstay. Pulmonary rehab I think definitely improves your quality of life. You want to avoid infections as well as other exacerbating factors. A lot of it is if this is the primary thing that's affecting your life, it's a partnership between you, your oncologist and a pulmonologist that you feel comfortable with. With that I think I will open it up for questions.

39:18 [moderator] Thank you Dr. Cheng for a fantastic, fantastic presentation. Now we're going to open the floor for questions. I want to remind everybody that this session is being recorded for those who are not able to attend physically. If you have any question, please try to use the microphone.

39:51 [audience]  How to find a GVHD pulmonologist:  I'm at the University of Michigan. I think with most hospitals, they don't have like a GVHD pulmonologist. When I go to a pulmonologist, would you suggest one that has a background in CF or what would you suggest?

40:10 [Cheng] I know this is complicated because there are very few pulmonologists who see a lot of this. The question was, "If I'm at a center who doesn't have a specific lung GVHD pulmonologist, who should I go to?" If your center has a lung transplantation program, a lot of those doctors are familiar with bronchiolitis obliterans. That would be a good first choice. After that, somebody who has specific interest in chronic obstructive pulmonary disease might be a good pulmonologist to connect with. It really just depends on the interest of the pulmonologist, and how, for the vast majority of pulmonologists, some will never see a case of this in their lifetime. Those who manage chronic patients will probably see this at some point.

Your transplant physician might know a pulmonologist to recommend maybe somewhere nearby

 41:46  We can repeat the question.

41:50  [audience] Would my BOS improve? I've had it for four years, and I've gone from ibrutinib, to Jakafi to imatinib, to Ofev, and to a clinical trial of KD025. I kind of been around the block. You had one slide up there, and it said if you increase your immuno, is that the IGG? [Inaudible 00:42:15]

42:15  [Cheng] I think the question is, "If I increase my immunoglobulins, will my BOS improve?" I don't think so. Very few things help improve BOS or your lung function. I think what we are giving now is meant for reducing, is preventing decline. The point of the immunoglobulins is if you have low immunoglobulin, particularly immunoglobulin G, you may benefit from getting that replaced in order to reduce your risk of a pulmonary infection.

43:00  [audience] It's based on infection then.

43:02  [Cheng] Yes. Not with a lot of evidence per se, but the biology of it is this is why we think that that puts one at risk for worse lung function.

43:13  [audience] Okay, and then you also had a chart that said that you went out three years for the longevity for BOS. Then you also talked about five years equals 40%. Then what? Do you have anything longer than that?

43:29  [Cheng] Like a 10 year survival? I haven't done that. I haven't done that analysis. It's probably around 20%.

43:41  [audience] Okay thank you.

43:46  [audience]  What about the role of the cardiovascular exercise? Is there any benefit or link between that and any of these factors?

43:55  [Cheng]  The question is, "What is the role of cardiovascular exercise?" That is part of what pulmonary rehab is about. Pulmonary rehab, and it depends on the program that's available where you are. They provide exercises to help you cope with your breathlessness. Then also it is in part cardiovascular, because you are put through exercises, and the point is that you're strengthening other parts. You might not necessarily be able to improve your lung function per se, but you're strengthening the other parts of your body that are involved in breathing and oxygen transport.

Your heart, if you have a healthy heart that's better in general. I think it can be very hard for patients who are breathless to feel like they can get up and move, but actually strengthening these little exercises have been shown to be beneficial. Not only for quality of life, but actually people do improve their lung function a little bit in so far as the spirometry is an effort dependent test, meaning you actually need strength to blow.

45:02 [Pusic] We definitely also recommend it at our institution, I believe that most large institutions that have large pulmonary departments will have ability to do pulmonary and cardiovascular rehab for such people.

45:21  [audience]  Pulmonary rehab helped survivor:  I'm a 12 year survivor with BOS. Put me in your next study. I've been through the photophoresis, which was miraculous. That was a couple years after transplant. I transplanted in 07. That really was helpful for me.

In 2017, I got a pneumonia where they found bacterial, fungal and viral infiltrates. I went from about a 50% FEV one, down to 30, and went to a different pulmonologist after being in and out of the hospital. He says, "You're at the point of no return. You'll be on oxygen unless we can bring you up, or you can get up."

I went to pulmonary rehab for the second time in this 12 years. Worked my tail off, and I've gotten up to 46%, so it can happen. I have been on the FEM protocol for about 10 years. I'm questioning azithromycin only because I want to reduce the pills I'm on, so that was an interesting point. But I don't know what LABA is, and wonder if that is something I ought to look into.

47:05 [Cheng] What is LABA:  Okay, LABA means long... The question is, "What is LABA?" LABA is long-acting beta-agonist. It's a bronchodilator. It's simply for symptomatic relief. It's something we use in patients with asthma, and sometimes chronic obstructive pulmonary disease due to smoking. I think that it can be useful early on in patients with milder disease that has an airway, kind of a reactive airway component. Not everybody has that. If you do not feel symptomatically better with it, then I would just drop it. It's not necessarily for everybody. We do try it.

47:56  [audience]  With regards to the LABA, do you ever use nebulized steroids and LABA in advancing BOS or? Somebody has suggested that as potentially taking it by inhaler, but they said maybe nebulization might be better to get it further deep down.

48:12 [Cheng] The question is using nebulized corticosteroids as opposed to inhaled. It really is just a simply a matter of delivery. If there are some patients who have a hard time using the inhaler properly, or there are some formulations that are specifically made like the HFA formulation, made for better delivery. Nebulization may or may not help for some individuals. Yes, I have tried that in people who don't really tolerate the canister setup.

48:54 [audience] But there haven't been any particular studies to compare one versus the other?

48:55  [Cheng] No.

48:56  [audience] Those who can use the inhalers. You mentioned that lung transplantation and BOS might be available for a certain select patients. Who are those patients?

49:07 [Cheng] The question is, "Who would lung transplant be good for?" Really it has to be somebody who you're going to die within two years if you don't get a lung transplantation. Your lung disease is so bad that your life is really limited by it.

Generally, you need to be free of your malignancy at least five years. Two is pushing it, but most centers these days are requiring five years. You can't be on a whole lot of prednisone. You can't have other organ GVHD [crosstalk 00:49:50]. Other things, good social support. You've demonstrated compliance.

Lung transplantation is a very... Lungs are very, very rare scarce resource. A lot of the programs are very, very strict. It has been done multiple times in Seattle around the nation, in Europe. In fact, they published a large paper discussing this. Well, there's no real strict age cutoff, it definitely helps if you are younger, and you don't have have kidney disease, you don't have heart disease, etcetera.

50:47 [Pusic] It's a somewhat difficult decision to make for your physicians, for your pulmonologist, for your transplant physician, because you have to be doing bad from your lung, but overall not so bad that you wouldn't tolerate another transplant. This is still another very serious procedure that can be devastating. It's very hard to decide when you really want to go that route-

51:20 [audience] Has it generally been found to be beneficial? 100 patients, would 50 benefit and 50 not? Is there any...

51:29 [Cheng] Okay, so the question is, "Has lung transplantation been found to be beneficial?" I'll give you a sense of the stats.

50% of patients who get lung transplant, all comers develop BOS again by five years. The five year survival for lung transplant lags behind all the other organ transplants. Right now it's about 55 to 60%.

Is it beneficial for individual patients? Yes. There are definitely patients who have, they were clearly declining from their GVHD related lung disease, or transplant related lung disease, who got new lungs, and are now living a full, able to do what they can do. But, those are patients who really had only one problem, which was their lungs. They do tend to be younger patients who were very fit to begin with.

52:30 [moderator] We have time for one more question.

52:32 [Pusic] There is one little tragic, interesting thing we don't have time to go into. But from lung transplant, you can also develop a form of GVHD, which is completely a different story. This procedure has its own toxicities.

52:51 [audience] Have you come across or had patients that have had Gleevec as a treatment for their GVHD in their lungs?

53:01 [Pusic] Particularly in the lungs?

53:02 [audience] Yeah.

53:03 [Cheng] Well we have used Gleevec. There has been a study a couple of years ago comparing Gleevec and another medicine called rituximab. During the time we did have patients who had lung involvement. Gleevec is thought to be sometimes beneficial in people who have skin fibrosis, and there is a thought that it could be beneficial in people-

53:30 [audience] I've had it used, but when I changed insurance, one lot of insurance will pay for it, the other ones won't because they're saying it's used for a purpose that it was not originally authorized by whatever the FDA approved yes. It's worked for me so far.

53:48 [Pusic] It's still I think individual. In some people it worked, in some people it doesn't. I can't say that it always works.

53:58  In my experience your physician can appeal to the insurance company, if he can certify that and send some papers usually insurance companies-

54:13  [audience] Is there something called like an orphan drug?

54:13 [Pusic] Yes.

54:13 [Pusic] Yeah, there is.

54:13  Sometimes that's possible. Sometimes drug companies are willing to do it on a compassionate use kind of basis.

54:21  Thank you, Dr. Cheng, Dr. Pusic. It has been a wonderful presentation.