Dr. Carrie Kitko and survivor, Whitney Davis
We are so thankful to have our first speaker here with us, Dr. Carrie Kitko, Dr. Kitko joined the Vanderbilt pediatric hematology oncology program as the medical director of the pediatric stem cell transplant in June, 2015. She had previously worked at the University of Michigan initially as a clinical fellow in 2003, and then was appointed to a lecturer position in 2006 and promoted to assistant professor in 2009. During her time at Michigan, she developed a translational research focus on graft versus host disease. She has concentrated her research focus on GVHD diagnosis, treatment and prevention. She is currently serving as a co-chair of the GVHD working committee of the Center for International Blood and Marrow Transplant Research (CIBMTR). She has been serving as a chair of the GVHD strategy group for the Pediatric Transplantation and Cellular Therapy Consortium (PTCTC). At Vanderbilt, Dr. Kitko serves as the lead investigator for the Mount Sinai acute GVHD international consortium. This consortium has furthered GVHD biomarker discovery and has brought innovative clinical trials to our patients that allow for biomarker directed GVHD prevention and treatment. Recently, Dr. Kitko led working group IIA of the NIH consensus development project on criteria for clinical trials and chronic graft versus host disease, the 2020 clinical implementation and early diagnosis working group report. This was recently published in the Journal of Transplantation and Cellular Therapy last year. In other words, we have brought you someone who knows GVHD well, to speak to you today on this topic. Thank you for joining us today, Dr. Kitko,
Well, thank you very much for the invitation. I’m really pleased to be able to talk to this group today. Hopefully I can provide some sort of background information with regard to where things are at present with lung GVHD and maybe even some insight into where things might be going in the future. I just wanted to briefly touch on how do we know if a patient has acute GVHD versus chronic GVHD. So as many of you know, because you’ve all been through this before, our acute GVHD is the type of graft versus host disease that we see early after the transplant. It usually only affects the skin, the liver and the gut, whereas chronic GVHD happens later post-transplant and can occur in virtually every organ in the body. And the lungs are one of those target spots. We used to say that everything that happened before day 100 was acute and everything that happened after day 100 was chronic, but that’s really not the case. And as we recognized, the two diseases really do look different. So you should diagnose, is it acute or is it chronic based on the symptoms that you see in front of you and not necessarily what day the patient is after their transplant. With that in mind, how do we figure out that somebody has lung GVHD specifically? It can be very challenging to physicians taking care of these patients, because our patients commonly have pulmonary symptoms. Those symptoms are very common after transplant, our patients are also prone to infections, often respiratory illnesses that can also complicate matters as well.
One of the things that was helpful is that the NIH consensus projects have really helped define very strict criteria to help us sort out when patients have chronic GVHD. This is helpful so that when a patient with chronic GVHD is seen at any transplant center it means the same thing. So, if the patient is at Stanford or if the patient is in Boston or at the University of Michigan, that we’re all using the same language and the same criteria to make that diagnosis. On the flip side, it’s hard to sometimes really meet these exact definitions. And what do I mean by “to make the diagnosis of lung GVHD”? We look typically at our patient’s pulmonary function tests. If you remember, you all probably had to have those PFT’s done as you went into transplant, and you probably had several after transplant, and those tests show us how much air is moving into and out of the lungs.
And when we look at the different values, when we get those reports back, it can help us figure out are the patient’s lungs healthy, or are they not healthy? And if they’re not healthy, in what way are they not healthy? The strictest definition of lung GVHD is that we should look for an obstructive defect. So that immune system has turned itself on and unfortunately is attacking the small airways of the lungs, specifically the small bronchioles, but not the very end of the airways, which are the alveoli. You get this sort of obstruction, if you will, around that small airway so that the air can get all the way to the alveoli, but it’s hard for the air to get back out. So that’s what we mean by an obstructive defect. And when I’m looking at somebody’s pulmonary function tests, if you’re looking at your report, that’s the FEV1, or the forced expiratory volume in the first second.
We also look for declines in the FEV1 one more than the FVC, or forced vital capacity. Declines in the forced vital capacity tend to be more of a restrictive nature. And again, one of the challenges of making the diagnosis is that our patients often have a mixed picture. They don’t have a purely obstructive defect or a purely restrictive defect. They’re usually somewhere in the middle, which can make it sometimes hard to feel a hundred percent confident, just looking at pulmonary function studies, to be able to classify the type of of lung problem that the patients have. So then we also look to other ways of, of assessing the lungs, and the best way to get additional tests additional information is to get is a CT scan of the lungs. In the CT we actually get images when a patient is taking a big deep breath in, and then they get images again of the lungs as they’ve taken a full exhalation.
And so, we tried to blow out as much air as possible. And when you compare those two pictures of the lungs that we’ve gotten with the CT scan, you can actually see what we call air trapping on the CT scan, which can help support that diagnosis of lung GVHD. There are also associated findings like bronchiectasis, or larger airways than would be anticipated. So that can also be seen on the CT scan and can help sort of nail down that, yes, I really do think my patient is suffering from lung GVHD. And finally, for me, one of the most challenging things that’s in these NIH consensus criteria to make the diagnosis is that the patient cannot actively have an infection. And that makes good sense. If you, you know, recovered from a cold for the first several weeks after you’ve had a cold, you might be coughing more, you might be more short of breath, but the further out you get from that cold that you start feeling better, you’re breathing more easily again.
You don’t want to confuse just a post-infectious issue with something like lung GVHD, where, you know, you’re going be adding on new treatments. But again, in our patients after transplant, it can be very challenging because they can get recurrent infections. It’s hard to get that window where they’re not actually fighting an infection. In addition, we know that there’s data that sometimes a viral infection or any type of infection actually might be a trigger for the development of lung GVHD. It’s like the immune system went to help fight the infection, but then it got turned on and looked at the lungs and decided that they looked different and then started their attack. So no evidence of infection for me can sometimes be a real challenge to then tease out if the patient has GVHD or just consequences of having frequent infections.
Let’s say that I have the perfect patient and they meet the perfect diagnostic criteria. Well, what can I do for them is to try and treat their GVHD. Treatment for lung GVHD is based on what other symptoms the patient is having. It’s not just the lungs, but other sites of disease as well, like the eyes or the mouth or skin rashes as just some examples. These patients are probably going to be on steroids. Steroids are still, after several decades, our frontline treatment for GVHD. But steroids, I’m sure this audience knows, have a lot of side effects that are unpleasant. And we do like to try and find sort of minimum dose of steroids to help keep these symptoms under control. And again, one of the questions I know that has been posed is, are the changes reversible that happen to the lungs.
And unfortunately, most of these changes that we see, we think of as scarring. We are trying to prevent further progression, but we have a hard time with most of our known therapies of actually reversing that scar tissue once it’s formed. So that is also a real challenge for us. We do have some evidence to support use of some less toxic therapies other than steroids. For example FAM therapy, is a triple combination of fluticasone, which is an inhaled steroid, Azithromycin, and Montelukast. Fluticasone is sort of the equivalent, if you’ve had your skin rashes from GVHD, putting on a topical steroid cream directly on the skin. Fluticasone is that same idea, but directed toward the lungs. Then three times a week azithromycin. So, it’s an antibiotic, but on that schedule of Monday, Wednesday, Friday, it actually has some anti-inflammatory properties that we think are quite helpful for the lungs.
And then montelukast is the last one. And so that’s a medicine that targets macrophages, which we also think are important for how that fibrosis developing in the lungs. So that triple therapy with the FAM definitely has helped many people. There was a study out of the NIH that had shown that it definitely did seem to help stabilize many patients with lung function decline. So that FEV1 stopped decreasing in many patients. Generally speaking this combination is a very well tolerated therapy. I think most of us, if we’re worried our patient is developing some lung GVHD or early declines in their pulmonary function, we have a pretty low threshold for starting the FAM therapy. Our goal often with patients with lung GVHD is to sort of stop the progression of disease, but we have a difficult time reversing the disease.
Some of the potential good news is that we now have more tools in our toolkit. There are now three FDA approved agents for chronic GVHD, which we did not previously have. These target different areas of the immune system. And so they might work for one patient, but not the next patient. The first that was FDA approved several years ago, about three years ago now, was ibrutinib. This targets B Cells. I personally, I have not seen a lot of patients have massive improvement if they have lung GVHD with ibrutinib, but it’s certainly possible. And it could be worth a try if you have not been on it before. Ruxolitinib has been more recently FDA approved and this medicine blocks the production of some the cytokines or the proteins that are revving up those immune cells.
And so by sort of taking the foot off the gas, if you will, then hopefully the, the immune system sort of down regulates itself and is not quite as inflammatory. Again, there were some patients on the initial study that did have lung GVHD and did see some improvement in a few of the patients that had lung disease on that study. But I think the most promising agent that we have available to us right now is a medicine called Belumosudil (KD025 Clinical name). And so this is a medicine that targets a protein called ROCK2. And it probably doesn’t matter what ROCK2 stands for, but how it works, which is by two different mechanisms. So one mechanism that drug works on is trying to sort of reset the balance of some of those immune cells. So both T and B lymphocytes are important for chronic graft versus his disease.
But in particular, what we see in our chronic GVHD patients is that the T-cell ratio of the T-cells that are revved up and are attacking the body are enhanced compared to the, what we call the regulatory T- cells. I kind of think of them as the police officer cell, if you will. They sort of go and, and find those ones that are revved up and say “you don’t need to be so active.” And so what this medicine Belumosudil does is it kind of flips that ratio. So it turns off those reactive cells and, and helps improve the number of those regulatory T-cells. But I think the coolest thing about this new drug is that it’s actually involved directly in the fibrotic pathway. For the first time might have an agent that actually does have some ability to potentially reverse some of that fibrosis that we see in our patients.
So for me, that’s a really exciting development and potentially a way forward for our patients that we might have a new agent. Other things that I think are important to focus on are, are supportive care, which for our patients can be every bit as important as the actual immune suppression that they’re on. Our patients with lung GVHD can struggle on a day to day basis with getting short of breath and having a hard time doing their normal activities. I think equally important and, and problematic for our patients is the increased risk of infection because if they get another pulmonary infection, we can often see further decline in their pulmonary function. So really trying to make sure that we’ve optimized their antimicrobial prophylaxis strategy. Making sure that they’re on the right drugs to help prevent mold infections, making sure they’re on the right medicines to prevent particular bacterial infections and making sure as best as we can, that their vaccines are up to date.
Now that is sometimes a bit of a double edge sword. Cause if you’re on immune suppression to treat your GVHD you might not be able to respond to your vaccines as well as we would like. So it’s, you know, sort of a balance, but I certainly recommend that my patients get their as many vaccines as they can and test their response and give extra boosters if we have to. And this would include making sure that my patients get the COVID vaccine as well. I think another piece is making sure that our patients are plugged into physical therapy, sometimes even pulmonary rehab. I think trying to sort of let the body, you know, almost like reset the thermostat, if you will. If you have some lung damage, there’s ways of improving your stamina to be able to accommodate for the fact that your lungs might not be as healthy after you were pre-transplant.
And then I think I will just end with a few minutes on some of the future directions, things that I know that we’re working on. We would love to be able to diagnose lung GVHD earlier and to be able to have reliable signs or symptoms that we know, okay, the patient isn’t very symptomatic yet, or hopefully isn’t even having any symptoms, but there’s these subtle signs that I can point to and say, I know this person is at high risk and potentially intervene. There are ongoing natural history history studies at several places where they are following the patients staring before the transplant and following them very frequently through the first year to try and see if we can figure out what some of those early indicators might be.
Some of this involves more frequent pulmonary function tests, even something called a handheld spirometer. It’s like a piece of equipment that the patient can be doing at home measuring that forced expiratory volume at one second (FEV1), so that we can potentially catch some of those changes early. The sort of downstream effect is even if I find that early sign, what could I do as my intervention? What drug would you want to expose your patient to that isn’t too toxic, but also could potentially have benefit. FAM therapy might be an option starting that combination earlier as patients are starting to show declines in their FEV 1. But maybe there’s something, another medicine out there, that we could think about. Somebody also asked about biomarkers. Biomarkers are great.
I will say they are much further ahead in our research efforts, even including them clinical trial design and eligibility in our acute GVHD treatment trials. Chronic GVHD by its nature is just, it involves more organs. It can look very different from patient to patient. They have not reached the same significance where I can use them yet to direct my patient’s therapy. But again, we’ve incorporated frequent blood draws into these natural history studies, and my hope is that two or three years from now, if we have this talk again, I can be talking about advances in chronic GVHD biomarkers that we are now able to use to help guide our patients’ treatment. And then finally, one more agent that has not yet FDA approved, but there are clinical trials ongoing with a medicine called axatilimab. So this is a medicine that actually blocks very specific macrophages. And it’s often the macrophages, that’s a type of white blood cell, that is in our tissues. They sort of go from the bloodstream and migrate into the various tissues. And once they’re there, they are often the driver of promoting the fibrotic environment that we see in the lung and in the skin, for example. And so we’ve had patients on this medicine axatilimab and have seen improvements in both lung function and skin findings as well. So again, I think we’re finally seeing some agents that rather than just slamming the immune system and leaving our patients vulnerable to infections as a way of just essentially stopping the progression of disease, I feel like we’re finally seeing some agents that might actually target what our patients care most about. Can you make me better? Can you actually improve my lung function? So I’m here today to say I’m more hopeful today that we might actually be making good progress in that area. And so that, that was what I had planned on chatting about for now. Jennifer Gillette, Facilitator.
Thank you so much, Dr. Kitko. I learn something every day and I just learned a lot from you. Thank you so much. Now we are going to hear from Whitney Davis, who is not only a survivor of MDS, but she also has lung GVHD. She will share her story and experience, and hopefully you will learn a tip or two. Thanks for joining us, Whitney. Whitney Davis
Absolutely. Thank you for the invitation and for allowing me to do this. As she said, my name is Whitney. I’m 34 years old. I had my transplant when I was 29 years old. I was diagnosed with a thing called MDS. It was very new to me. I had never heard about it. Didn’t really know what it entailed. That’s when they explained to me that I would have to have a stem cell transplant. They said it wasn’t, IF it turns into leukemia, it was WHEN it turns into leukemia. I waited about eight months until I was able to get my transplant. Everything went well. I was only in the hospital for roughly 20 days afterwards. I got to go home with my family, be with my daughter, and then I started having symptoms of acute graft versus host.
I was originally diagnosed with it in my gut. Very soon after being and diagnosed with my gut. It was in my sinuses. I started randomly having seizures that I’d never had before. They didn’t know if it was graft versus host or if it was a complication of the transplant. And then from my skin and my sinuses and my gut, it moved into lungs, which I wasn’t diagnosed with that until about a year later. I had hip surgery due to a complication from the steroids causing my hips to collapsed. And when I started coming out of my anesthesia, my oxygen wouldn’t get above 80. They put me in the hospital that night trying to get my oxygen up. They weren’t sure what was going on. And I kind of told them, I was like, you know, I’m used to it running about 89, 90.
I wasn’t really familiar that that was low. So from that point I stayed the night in the hospital and then I was recommended to go do a PFT. So when I did the PFT, my FEV1 came back, I believe in the forties. They said that it looked like I had an obstruction. They weren’t sure what was going on. And I actually got put on the combination of drugs that Dr. Kitko had talked, FAM therapy. I stayed on that for roughly about six months. I started getting really short of breath. I just started having a lot of complications with breathing. So they gave me albuterol and told me to do the breathing treatments and to use inhalers twice a day as needed. That helped me for just a little bit. I also had a complication that apparently came from my surgery was I had blood clot in my legs.
So I went to the hospital one night. My oxygen was in the seventies. I don’t remember most of the nights, but I do know that my oxygen stayed between 65 and 70 that night in the emergency room. At that point, they decided to do a chest CT, and they said that it looked like I had ground glass granules in my lungs. They kept thinking that I had COVID. I spent two weeks on a ventilator. And after that, they proceeded to do 13 COVID tests on me thinking that it was just coming back negative. My lung function when I was in the hospital dropped down to 15% and they were still trying to go with the diagnosis of COVID. They really didn’t want to go with the graft versus host of the lung. They wanted to do more tests since there had been a recent infection. So I spent 45 days in the hospital. My lung function, or my lung O2 stats had finally got to where they were staying between 90 and 92. They finally let me go home. When I went home, I was on oxygen 24 /7. Basically, the only time I came off of it was to take a shower and get ready for my day. At this point, we did another PFT and my FEV 1 had dropped down to around 30. At that point we went and did another CT of the lung, and I still have the ground glass granules in there. They were like, maybe you have an infection let’s test for one. I went through, I did sputum cultures. I did another CT. So all in all, I had four CTS that all came back looking the same.
I went back and did one more FVC, and that’s when they officially said, we’re going to have to call it. It is what it is. You have the graft versus host of your lungs. At this point, I was taken off work full time. I was still on oxygen, full time and life just got to the point to where it was just really unbearable. I was recommended to actually see Dr. Kitko from my oncologist in Memphis and going to her was fantastic. She recommended that I tried the Belumosudil and after trying that my experience with it has been great. I lost about 50 pounds of fluid that was on me. My skin has returned back to normal. (00:30:13): I’m no longer on oxygen and I am back at work full time. So it has, has been excellent. This all was something that was very, very hard for me. I have a young child and my husband, they are my support system. My mother also lives close by. I didn’t know what to do. I didn’t how to explain to my daughter that I was only getting sicker. Some things that I did that helped me cope with this was I would write, I would write letters to what I was angry about. “Dear lungs, today, you know, I have felt like this today. You have made me feel the lowest of lows. I absolutely hate you.” I would just get it out. You can talk to people all day long, but if they don’t understand what you go through, then sometimes the advice is kind of hard to take in.
So I guess coping for me, writing the letters to the part of it that I was very angry about. And then I just tried to surround myself with the most positive people that I could if I had anyone in my life that was negative, you know, it was one of those things that I had to move on from and just really make sure that I was always around someone positive going through and doing daily Bible versus, and inspirations and joining groups of other people who are like us who have the same complications that we’re able to talk with and talk through. I have more friends on social media that have been through the exact same thing that I have then I have friends in real life. And it’s just because it’s easy to talk to, to them. It’s easy to explain what’s going on when you’re mad about it, you know, they understand what you’re going through. So just for me, like I said, talking about it was, was the biggest way that I was able to cope with it.