Ask the GVHD Experts

Speakers: Saurabh Chhabra MD, MS, Medical College of Wisconsin; Najla El Jurdi MD, Stem Cell Transplant Clinic, University of Minnesota; Jackie Foster MPH, RN, OCN, Jason Carter Clinical Trials Program, Be The Match®;  John Galvin MD, MPH, University of Illinois Medical Center; Mark Juckett MD, University of Wisconsin Hospital and Clinics

Recorded October 12, 2019 at the National GVHD Patient Summit

Presentations: 28 minutes; Q&A: 32 minutes

Highlights of Presentation:

• Clinical trials are important in advancing our knowledge in how to prevent and treat diseases such as GVHD
• The Jason Carter Clinical Trials Program, offered by Be The Match® helps patients find clinical trials for GVHD
• Studies are focusing on novel ways to treat GVHD such as fecal transplants, skin grafts and placental membrane bandages

Key Points:

06:34   What is the difference between phase 1, phase 2 and phase 3 clinics trials?

13:26   Factors to consider when deciding whether to participate in a clinical trial

15:37   The Jason Carter Clinical Trials Program helps transplant and GVHD patients find clinical trials:

23:38   What is our microbiome and why it is important in GVHD?

24:38   Exposure to chemotherapy and/or radiation can upset the patient's normal, healthy biome and let bad bacteria grow and contribute to GVHD; A fecal transplant can restore a healthy biome to the patient

26:21   Skin grafts from the patient's donor are being studied as a possible treatment for skin GVHD

27:28   Using placenta membranes as bandages may be effective for skin ulcers caused by GVHD

37:32   Cyclophosphamide after transplant significantly decreases the incidence of GVHD

41:47  Clinical trials using Jakafi or Ruxolitinib are showing promise for lung GVHD

51:11  Can someone with bad GVHD have another transplant to replace the donor’s immune system?

Transcript of Presentation:

00:00  Introductions:  Welcome, everyone. This is a lightning round and ask the transplant experts. We're going to begin the day with introducing our panelists. We're honored to have these transplant experts who are ready to respond to your questions about health concerns after transplant.

With us are Dr. Najia El Jurdi. She's an assistant professor of medicine at the division of hematology oncology and transplantation. And a staff physician at the Blood and Marrow Transplant Clinic and surgery center in Minneapolis, Minnesota.

We also have Dr. John Galvin. Assistant Professor in the Department of clinical medicine at the University of Illinois Cancer Center, where he heads the GVHD clinic.

Also with us today, is Jackie Foster. The manager of the Jason Carter Clinical Trials Program and patient education, at the National Marrow Donor Program, Be The Match®.

And down on the end, we have Dr. Saurabh Chhabra, an Associate Professor of Medicine at the division of hematology/oncology, and a member of the Blood and Marrow Transplant and Cellular Therapy Program at Froedtert and Medical College of Wisconsin.

We will begin the session with three brief presentations about clinical trials and exciting research being conducted, to help patients with GVHD. We will begin with Dr. Galvin, who'll explain clinical trials. He has a seven-minute roughly, presentation. And then we'll go on to Miss Foster, and she'll explain how you can find a clinical trial that's right for you. Then Dr. El Jurdi will tell us about some exciting clinical trials currently taking place, and a novel approach to treating GVHD. All

02:06 [Dr. Galvin]  There are exciting new treatment on the horizon to treat GVHD: Thank you so much for the introduction. I think it was great that we have this session to talk about clinical trials because, we didn't really have a lot of clinical trials to offer in the past. But in the last five years, it's become an exciting time to be a transplant physician specializing in GVHD, because not only new, exciting drugs have come to the clinic, but also, just some more of an innovative type of approach to graft-versus-host disease.

And so, it's an exciting time and it's exciting for our patients. Because as all of you know, either caregivers or patients that are here, there isn't a long list of options once you've been treated for years. And so, it's very exciting for us as providers, but also for patients, to think that there's new things that can offer us potential at treating and reversing the effects of GVHD. Let's see if my slides will come up soon, or maybe it's just there. There we go.

So, I just wanted to give a very basic 'what you need to know'. Because I think, there's a lot of lingo that we use as providers, like phase one, phase two, and all of those things. We forget that it's not common parlance in the community.

03:34  What is the purpose of clinical trials: So, why do we do clinical trials? It's the safest way for testing a new drug. Even though drugs are available, and we can write prescriptions for them, and they may already be FDA approved, it's best to do it in a clinical trial setting so we can really assess the safety of it. Because sometimes, we can think it's working if we just treat a couple of patients. But you really need a structured trial to see if it's working better than the standard of care.

And we can learn about GVHD. Sometimes, we are surprised by the results that it works in some people, or at some sites, but not others. And that teaches us about the disease. So, it's very important to study new treatments on a clinical trial.

04:24  Enrolling in a clinical trial is voluntary and you can stop participation at any time: And remember, as you approach clinical trials, or if you seek out a clinical trial, if you're on the fence, it is always your decision, it's always voluntary, and you can decide to stop it anytime. And usually, whoever's consenting you will remind you of that as well. And this is always part of the ethics of consenting someone.

It will never affect your decision to say yes or no, it won't give you better or worse care. You won't upset anybody. But it's great to be at a medical center, or living near a medical center, that can offer these type of options. Like I mentioned, you always have the right to stop at any time.

05:14  Clinical trials are sponsored by the government, medical centers, networks of medical centers and pharmaceutical companies: So who supports clinical trials? Who's benefiting? Well, we design clinical trials for the benefit of the patients, and they're funded by multiple sources. So the government is a major sponsor of most clinical trials, both for cancer treatment and for complications like graft-versus-host-disease. So, you see these government agencies like the NIH, the NCI, and Department of Defense.

Also, medical centers have sometimes funding to support a clinical trial. And then when a lot of academic centers work together, they form networks. So, transplant, BMT, has a clinical trials network, and many different cancer societies and cancer alliances have clinical trial networks which support or help organize the infrastructure needed for a clinical trial. Some clinical trials are also supported in part by foundations.

And of course, there's pharmaceutical companies and biotech, which are some of the largest supporters of trials, obviously, for their own drugs that they're trying to learn about, and to potentially get FDA approval for. So, let me roll out these phases here.

06:34  What's the difference between phase 1, phase 2 and phase 3 clinics trials: So you've heard of these terms, phase one, phase two, phase three, either as a participant or just hearing about trials in general. But there is actually a real reason we call them these phases.

Preclinical or Phase 0 trials are clinical trial determine if a drug can be formulated so that it can be givenn to patients: In the early phases of a trial, actually, before we even are allowed to offer it to people, there's a lot of pre-clinical research done. Sometimes animals, sometimes in a petri dish, often both.

And then there's some very early tests to see if it can be formulated in an appropriate way to be given to a patient. And those are called pre-clinical and phase zero studies.

07:18  Phase 1 and Phase 2 clinical trials test whether it is safe to give a drug to patients, and the maximum safe dosage: The phase one and phase two are referred to as early phase studies. And those are really to assess for toxicity. Meaning that, okay, we know that this drug might help graft-versus-host disease, but we have to make sure it doesn't cause other side effects. And we need to know at what dose is it safe to give this medication.

And so, that's when we're learning about not just, is this working? It's really, is this causing any side effects? And so, is it safe? So, safety is the primary objective in phase one, and always in phase two as well.

07:57  Phase III clinical trials test whether a drug of therapy actually works: Phase three is usually really, to answer that very important question, is of efficacy. Meaning that, does this actually work as well as the standard of care. So, for graft-versus-host disease, does it work as well as steroids or other second line or third line treatments.

08:20  Phase 4 clinical trials test for long-term safety of the drug or therapy: So after medication is approved by the FDA, it's followed in what they call phase four, which is a long term safety [study]. Sometimes, even though the phase one, two and three might have offered information about hundreds to maybe thousands of patients, you sometimes don't really learn about long term effects of a drug until you watch it for five years or more. Maybe even 10 years. And that's that phase four data that the FDA is following.

And you've always heard about drugs much later, when they've already been marketed and approved, get pulled off the market, because of a toxicity that wasn't really realized until years later. And that's because, all of these medications are being monitored in phase four setting. So, we never stop monitoring the effects of medications that get approved.

09:15  Phase 1 clinical trials test how much drug is needed to get the desired effect without any toxic side effects: So, the general outline of a phase one is that you start at a very low dose. And then you go up to make sure you get the most effect for what you think your target dose is, without any toxicity. Safety, like I already mentioned.

Usually, it's a very small number of patients needed to determine this. And it's usually done just at one center typically, depending on how rare the condition is. GVHD is fairly rare. So, phase ones may be done at a few different centers. But you'll often see a phase one done at one large center or multiple medium to small centers. So, safety is the main reason for a phase one. Very important to do.

10:01  Phase 2 trials look at both safety and whether the drug works: Phase two is, once we are comfortable with the safety of the drug, we use a phase two to find out if it works. But we're still looking at safety at that new dose. So phase one might have helped us pick the dose that's safe. And then looking at that dose in a larger number of people, we're still assessing for safety. And then hopefully, we're learning something about the treatment that can tell us if it's working.

So, it definitely requires more people, and often takes a longer time to finish. And it also may require multiple centers for rare diseases, like graft-versus-host disease.

So phase two, if it's not at a very large center, you might have several centers throughout the country that are participating. And usually, starting at phase two, usually, there's a company involved. They're thinking about FDA approval. So, the design of that phase two, and certainly if there's going to be a phase three, the structure of it is given, the FDA has had inputs on it. Because they want certain information from that trial to help them decide whether or not to approve it.

Sometimes in Phase 2 trials, patients are randomized to receive the investigational drug or standard therapy: And sometimes, beginning in the phase two, there's a randomization. And that means that even though you signed up for a trial, you don't get to decide exactly what your treatment is. It could be the treatment, the investigational treatment, or not. And so, certainly, this is commonly done in phase three trials, but often done in phase two. Especially if they're looking for an FDA approval with phase two information.

11:53  Phase 3 clinical trials answer the question "Is this drug or therapy better than standard care?": So, if it worked well in phase two, and everyone's happy, and they have the investments they need to do a much larger phase three, this is where you're really at answering that question. Does this work as well as what we're already using? So, for all diseases that are a standard, or there's common drugs that we use. And the question in the phase three, is whether or not this is better than the standard. Or, is this going to reach a significant response rate to impress the FDA to approve the treatment.

Phase 3 clinical trials randomize patients to receive the new drug or therapy, or the standard therapy, and involve a large number of patients: So, this is where you have randomization. Sometimes you have blinding, meaning that you'll never know whether or not you got the treatment or not. And this is all to make the data as high quality as possible, so the FDA can make the best judgment of whether or not to approve this treatment.

Usually, in order to get really good data, you need very large numbers of patients. So phase three, studies are often done at a number of places. Sometimes, up to 100 different centers will be involved, if you have enough centers that are treating that specific disease. And sometimes, these are global as well. Meaning that, they're at centers in Europe or throughout the world. It can last a very long time, depending how rare the disease is.

13:26  Factors to consider when deciding whether to participate in a clinical trial:  So, should you consider signing up? This is a discussion with you and your transplant or graft-versus-host disease doctor. So, there definitely will be benefits and risks.

There may be travel involved in participating in a clinical trial: So, depending on the trial, unlike when you might see your doctor every month or every three months or something like that, often a trial will require you to come visit more often. So, there's travel considerations.

Often, the things that are done on a trial, need to be done at that medical center that's running the trial. So, there's travel concerns, time concerns. There might be extra tests that the doctor would not have normally done. So, these are factors that even though you might want to sign up, you need to think about it. And so, asking those questions is important.

Certainly, and this is a discussion you'll have with your doctor and your treatment team, is to, whether or not, if there's other options. And you might want to talk to other people who are on the trial, and considering the same things you are. I know that there's a time crunch here. So, I'm going to go through some of these risks.

14:50  You will get a detailed consent form before enrolling in a clinical trial: Any clinical trial that you sign up for, the provider has to go through all the potential risks and the potential benefits. And usually, you'll take that consent home and go over it very closely, before you come back and sign it. So, I don't want to get us off schedule. So, I'll leave it there.

15:11  All right. Our next presenter, thank you, Dr. Galvin, is Jackie Foster. And she'll explain a little bit more about clinical trials.

15:21  [Ms. Foster] Hi, everyone. Thanks for being here this afternoon. So, I work at Be The Match. And I'm the manager of the relatively new program that exists really, to help you and your family find and join clinical trials.

15:37  Jason Carter Clinical Trials Program helps transplant and GVHD patients find clinical trials: So in 2017, we launched the Jason Carter Clinical Trials Program. This is a free program, offered by Be The Match, to help anyone with a blood cancer, blood disorder or complication of transplant, find and join clinical trials. So that means, we have support and resources for people with AML, multiple myeloma, sickle cell disease or GVHD, who are looking and interested in joining a clinical trial.

So, there's three main components, and I'll just briefly talk through what we have to offer. The first is our one on one help. So you'll see, there's myself and my colleague, Anna DeSalvo, up there. If you call or email us, you're talking to me or Anna. We work over the phone and by email with patients and their family members, to help them figure out what might be a clinical trial option for them.

So there might be 30 clinical trials for GVHD in their area, and we can help them narrow down a good list to maybe bring to their doctor. And maybe even come up with some questions to ask their doctor about the clinical trial. And sometimes, we even help people connect with the researcher who's leading the clinical trial. So, we can do all of that with you and your family over the phone.

We also offer through our website, there's a search tool, which I'll talk through in the next few slides. And then a financial grant.

16:59  How to search for clinical trials on the Jason Carter Clinical Trials website:  So, the website for the program is jasoncarterclinicaltrialsprogram.org.  This is actually, a program started in 2017. It was funded by the Carter family. And so, that's where the name comes from. And you can go to jasoncarterclinicaltrialsprogram.org/GVHD to see specifically, the GVHD trials. Or you can go just to jcctp.org and find all of the trials.

So, if you go onto the website, you'll see on the left side of the screen here, this is just a screenshot walking through how to search. The left side is the search criteria. So you could enter in GVHD and you could enter in your age. You can enter in whether you had a previous transplant or not. You could limit the search location. So I put in within 100 miles of the Chicago area. And you can identify if you're interested in phase one, two or three, or all those types of trials. And it pulls up 12. And so, I looked, checked this morning and it's still 12.

Some of them are for GVHD, some of them are to prevent GVHD. Some of them are for chronic GVHD. But you'll see the list on the right side there. The first one on there, for example, is a drug in combination with steroids to treat chronic GVHD. And it lists the ages that can join, 18 and older. The phase, this is a phase three trial that's open in six locations. It has the clinical trial number, the national clinical trial number, that's the NCT number there. And then it has just one sentence to describe what the purpose is.

So this one, is to find out if this drug, in combination with steroids, is safe and works better to treat chronic GVHD, compared to standard treatment with steroids alone. So if you click on the name of the trial, it will actually bring up a little bit more information. So this is what it looks like. That's the same information. I'm showing a different trial right now. Here's a drug to treat GVHD of the eye. This is in two locations. And if you scroll down, it has the clinical trial goal. And if you keep scrolling, it has very brief inclusion exclusion criteria.

So, this information, we pulled from the federal clearinghouse clinicaltrials.gov. And we translated it for you into more simple language. It still can be pretty complicated, so that's why it's helpful to have myself and Anna available by phone and email. But we narrow it down, trim it down and focus it in to help you, and be a little bit more simple. And so for this trial, if you're 18 years or older, have GVHD of the eyes, have not had the treatment before, and agreed to have other standard tests done to see if you could be in the trial, you may be eligible to join.

And then it briefly describes the tests and treatments. So this one, for example, is a randomized trial where somebody would be randomized to get either the standard care plus this experimental drug, or the standard care plus placebo. And they wouldn't know. They and their doctor would not know. And if you just keep scrolling, you'll see the contact information.

So Dr. Jain, who I think was a speaker here this morning, he's the contact for this, and it pulls up the nearest locations where it's recruiting. There's two locations in the Chicago area. And so, you can figure out the contact information for this trial.

And then a nice thing about this too, is you can save the trial. So if you create an account on the website, it's pretty simple. It's not a lot of inform, we don't really request information from you to create an account, just your name and email. And you can create an account and you can save this and share it with your doctor, if you're interested in this one. Or add notes or share it with a family member.

You can also save your search. So if you've set up the search and you're like, "These 12 trials aren't that great for me. I don't really like any of these trials that are available. But I really want to keep my eyes out for anything that might be opening." You can save your search and then it can actually, you'll name it. So here, I named it Chicago GVHD. And then we can just automatically email you when there are new trials that match your search criteria.

20:51  Jason Carter Clinical Trials Program offers travel assistance to patients participating in clinical trials: And the final aspect of the program that's great for patients and families, is the travel assistance grants. So this grant is a grant that is up to $2,000, to help people pay for travel and housing needed to get to a clinical trial. So there's some criteria, there's an application and that you have to meet the criteria. Some of it is financial income criteria. And then minimum travel requirements. Like, you either have to fly someplace, or you have to drive 300 or more miles in a month to participate in the trial. Or pay $150 or more a month for gas and parking and all that sort of stuff.

And then that's our contact information. So, if you're interested in clinical trials for GVHD, you want some help figuring out what might be a good option for you. Or you're interested in this travel grant, please feel free to reach out, and we're happy to help you. Thanks.

21:48  All right. Great. Our next presenter is Dr. El Jurdi. And she's going to tell us about some exciting clinical trials that are currently taking place.

21:57 [Dr. El Jurdi]  Thank you. It's really a pleasure to be here today. And I thank the organizers for being able to talk to patients and their families, about new and exciting therapies for GVHD. Rather, non conventional therapies for GVHD. I have no conflicts of interest. And all the therapies I'm discussing today are still within clinical trials, so they're not FDA-approved yet.

I will start by defining the microbiome and microbiome-based therapies for prevention and treatment of graft-versus-host disease, and that's mostly acute graft-versus-host disease. And then I'll move on to focus on skin chronic GVHD.

22:37  There are more factors than the donor’s T-cells that contribute to GVHD:  Historically, we have only looked at donor T-cells as the cause of GVHD: So, as this audience knows very well, GVHD is a complex disease that affects many different organs. For many years, we've been focusing on the donor cells, specifically the T cells, that attack the recipient organs and causes a lot of tissue inflammation and damage. But we now know that this is not the only aspect of GVHD that we need to think of, when coming up with new therapies. And we now know also, that GVHD has to be approached from many different angles to come up with new and more beneficial therapies for our patients.

So, what are the other components of that puzzle that we're missing when we're only looking at those donor T cells? Well, we're certainly missing the damage component. And how can we promote our own body's ability to heal after this damage and inflammation happens? And how about the microbiome? Well, that's certainly an important piece of the puzzle that we now have a much better understanding of.

23:38  What is our microbiome and why it is important in GVHD: So, what is the microbiome? And what is the microbiota that we've been talking a lot about? Not just in GVHD, but also other aspects of medicine.

So the microbiome refers to all the microbes, all the bugs essentially, that coexist with us normally since we're born. Right? And so, that refers to many different components of that. That could be the bacterial component, the fungal component, the viruses. So, many different bugs contribute altogether, to this microbiome.

And in fact, it's really interesting to know that there are 10 times more of these bugs that coexist with us, than all of the human body’s cells combined. So they must be doing something, right? And a lot of research has shown that, when we have more of a diverse or healthy microbiome, that maintains human health. And when that balance is disrupted, when there's an imbalance in that component, that contributes to a lot of disease states, including graft-versus-host disease.

24:38  Exposure to chemotherapy and/or radiation can upset the patient's normal, healthy biome and let bad bacteria grow and contribute to GVHD: We know, in patients undergoing transplantation, they get exposed to a lot of chemotherapy, a lot of radiation, a lot of antibiotics. And that disrupts that microbiome balance. So, we go from a more diverse and healthy microbiome to a state where there's an overgrowth or dominance of one of those bad bacteria. And these bad components can cross through a damaged gut, because of all the chemotherapy and radiation, into the bloodstream. And therefore, can contribute to that inflammation as part of graft-versus-host disease.

25:13  A fecal transplant is the way to restore a healthy biome to the patient: So, how do we fix that? The fix is rather simple. We have to find donors for good and healthy microbiome and restore that. And that doesn't mean the original stem cell donor, but any person that could be a healthy donor for that diverse microbiome. That still has the good microbiome, that still has the good bacteria. Right? So, these are patients that are not exposed to the chemotherapy, they're not exposed to the radiation. They haven't seen all the damage that our patient has seen.

We process this poop, essentially. Right? And then we make it either in pill forms or enemas, and give them back to patients. So, that's being studied in clinical trials across the country. And that's being thought of as either a preventative strategy for example, where we are, at Minnesota, where we're giving it early o, before the patient develops graft-versus-host disease, to keep that microbiome diverse and healthy. Or after that, when patients have GVHD, and that's given as a therapeutic intervention, again, within a clinical trial.

So, moving on to another major concern for our patients, as you know, we talked about earlier today, is the skin chronic graft-versus-host disease. That could be very difficult to treat. And it's the most common presentation for a chronic GVHD.

So one approach that we're using, again, within a clinical trial, is that we're going back to that donor, the healthy donor, stem cell donor. We're taking a very, very, very superficial skin graft using this machine, essentially, that removes a very superficial component of the skin. No blood involved, decreased risk of infection. And then taking that skin graft from the donor, back to the recipient, where there are skin ulcers that are not healing with conventional therapies.

And what we've seen in case reports, and hopefully we'll continue to see, is that there's improvement in skin GVHD. Not just at that particular site, where we reapplied the donor's skin graft, but also in other sites. So there is more of that global improvement of the skin.

27:28  Using placenta membranes as bandages for skin ulcers caused by GVHD is being studied:  Another non-conventional way that we're treating skin ulcers is using placenta membranes. So the placenta, as some of you might remember, is that coating or covering that covers the human baby before birth. So, that membrane contains a lot of good proteins and cytokines, that when applied to that skin ulcer in chronic GVHD patients, promotes healing, decreases the inflammation locally. And decreases scar formation, as you can see, with one of our patients here.

So, these are some of the very few examples of non-conventional ways that we're approaching GVHD within clinical trials. So again, we're rethinking that old immune suppression model where we add more and more steroids, and more and more immune suppressive therapies to our patients with a lot of side effects, as this audience knows very well.

And also, it's really important to focus on how can we prevent GVHD, both acute and chronic, so that we can improve the outcomes for our patients. And as we touched upon, we have to figure out ways to promote tissue healing, after that inflammation happens from graft-versus-host disease. Thank you.

28:53 [Moderator] All right. So now, we're going to enter our second part of the session, and I have a few housekeeping items. I ask you to keep your questions brief, so that everyone has an opportunity to ask questions. And if you have a lengthy question, the experts will be happy to talk with you either later today, or we could get the email questions answered also.

Please raise your hand, and our volunteers will bring the microphone to you. We have two volunteers helping with that. And all right, I guess now the lightning round begins. We'll take questions from the audience. Who's got a question?

29:33  Is there is a correlation between where injections are given in the body and skin GVHD: Thank you. I've been in quite a few studies, as many as I could get into, and as time allowed. And one of the studies I was in, I had abdominal injections, rather than taking pills for the next five years for the remaining remission.

My GVHD is basically, where these injections were sited. Has there been any relationship shown between injection sites and GVHD? Dr. Holton and the University of Minnesota hospital, so help me out on this. The injections were to help me remain in remission from my AML plus FLT3 three.

30:48  [Juckett]: So I can make a comment about that. So, following a stem cell transplant, an allogenic transplant, a new immune system has to put itself back together. And an immune system is very complex where there's a part that is the attacking side, there's another part that is the command and control. There's another part that regulates the immune system. And early on, none of these pieces are there. And so you have, the army might be there, but the command and control is not.

And so in that setting, when there are events that lead to injury or inflammation, which could be a viral infection, it could be a sunburn, it could be an injection, anywhere where there's injury, you may get this, what we'll call an abnormal immune response, which is really what GVH is, that affects that particular area. So, it may not reflect the treatment per se, or the medicine I should say. It may not reflect the medicine per se, but it might reflect the injury from the needle. And I think, there may be analogous stories in the audience of other people, who have had similar experiences.

32:11  Anybody over on this side? Over here? Any questions over here, on this side of the room?

32:24  Is midastaurin a good drug to take after transplant for AML FLT3 if you have GVHD?: I had a question. So I had AML FLT3 and skin GVHD now, severe sclerotic. Tried a bunch of stuff. not clinical trials at this point. But my oncologist doesn't want me to go on a targeted midastaurin and those type of FLT3 inhibitors, or targeted drugs because of my active GVHD. He's concerned that where my immune system's at, the immune suppressants, wouldn't play well for me with the midastaurin-type drugs. But I'm concerned with the aggressiveness and the nature of FLT3.. I haven't asked anybody else, but what's your thoughts on that? I mean, the benefit versus the risk? If I made myself clear with that roundabout question.

33:18 [Dr. Juckett] I can make a comment about that. I think, without knowing your particular situation, when people have graft-versus-host disease, it can become very complex very quickly. Because in addition to the effects on your body that the GVH has, typically, there are two three four, maybe five or six new medicines, medicines to treat the GVH. Medicines to prevent infection, medicines to protect the bones.

And in that setting, adding an additional medicine like midastaurin, which I'm going to say, is a little bit of a messy medicine, there's a lot of interactions, there's significant toxicity. And I think that I can imagine a situation where the risk of the medicine may seem higher than the potential benefit, particularly after a transplant. We're still not exactly sure where something like that may play. We really don't know the role of a medicine like midastaurin after transplantation, right now.

34:24 [Dr. Chhabra] I completely agree with Dr. Juckett. I would make only one point. And that is at this point, we don't have a drug that is approved as maintenance for FLT3 AML patients. There is a clinical trial that's ongoing, that's being conducted by the Blood and Marrow Transplant Clinical Trials Network. So, we'll see what the results of that trial show in the end.

Midastaurin itself, is not a great drug for maintenance. Because as you take it, over time, the half-life, or the time the drug is in the system, it goes down. So for that reason, it's not a great drug for maintenance. And your oncologist might also be thinking that patients who have chronic GVHD, they have graft versus leukemia effect, and they are less likely to have the disease coming back.

35:27  Are there any new drugs on the horizon that will soon be available for GVHD?: Hello. A question. With all the clinical trials that are going on, consider a horse race. Okay? Are there any that as we, rounding the bend coming home, do you see anything in sight that will help the people in this room? I mean, you're ongoing, ongoing, ongoing, but are we crossing the finish line on any of them that might help?

35:51 [Dr. Galvin] Yeah. I think my panelists would agree that we've seen, at our conferences that we go to, we're pretty excited about at least a couple. I would say there's one that's gotten the most attention called KDO25. But yeah, certainly. And I think that's where when I mentioned, at the beginning, it's an exciting time to be treating chronic GVHD, and trying to prevent acute GVHD because actually, we've seen some progress in the last five years or so.

36:28 [Dr. Juckett] I'll echo that. I think up until just a couple of years ago, there were zero drugs approved to treat chronic GVH. And so, now there's one. There's another drug approved to treat acute GVH. And I think that, I would agree with the sentiment. There's a lot of interest now, in people that develop and study these medications to get into this.

Some of the problem has been, for years, it was very confusing really, to understand how a group of GVH patients could be assessed in a way that you could determine what worked. And so, a lot of work through the National Institute of Health, beginning in 2004, and again, just a handful of years ago, helped refine that. So that now, people that do these studies can really say, "Here's the way things are today. Let's start this medicine and then let's reassess how things are down the road, and understand for sure, whether a drug is really effective or not.

37:32 [Dr. Chhabra] The recent practice of giving patients cyclophosphamide after transplant has significantly decreased the incidence of GVHD: I will take it one step backwards, actually. I would say, prevention is better than cure. And we've seen that the effects of post-transplant cyclophosphamide has been terrific. The incidence of chronic graft-versus-host disease has gone down significantly, with that. There are a lot of trials that are going on in that direction. We'll have to wait for the results of the trial. But we are very excited, very enthusiastic about the role of post-transplant cyclophosphamide.

38:10  Is there any test that can predict if a patient will respond well to a drug before enrolling in a clinical trial? Yeah. It's good to see MCW represented here. One of the questions that I have, I've gone through and I don't want to offend any sponsors here, of different drugs and things like that, ut I've gone through five, maybe six lines of treatments at this point, and I know that that can disqualify me to certain studies.

But I keep moving on to the next one, to the next one. I mean, at what point in time ... Is that a good path to keep taking? Just go, well, let's try the new one, let's try the new one. And is there a test out there based on my physicality, what drug would be the most effective for me? I'm sorry, just shooting fish in a barrel type of thing.

39:06  [Dr. Chhabra] That is a million dollar question. We need a biomarker. So we need a test that can tell us what's the prognosis from the very beginning. And we can, if we have a drug that targets that particular biomarker. Unfortunately, we don't have it at this point.

39:31 [Dr. Juckett] One other thing that I would add is that, even though you've seen a lot of systemic treatment, meaning a treatment for your whole body, what we're learning about chronic GVHD and what you see some of these new studies coming out, is focusing on specific sites. Whether it's ocular GVHD, cutaneous GVHD, gastrointestinal GVHD. And what we're realizing is that, especially in the setting of chronic GVHD, the sites are unique. And the biology and the way GVHD presents and continues is unique. And so, I think what we're starting to see is treatments being studied that are very specific for those sites. And so, even though you may have been exposed to a few five or six lines, we're going to have a little bit more tailored approach to where your GVHD is happening.

40:28  Are there any new, promising therapies on the horizon for lung GVHD?: Just wondering specifically, with regards to lung GVHD. Are you excited about anything coming up in that area? The one that's pretty, not a good thing.

40:41 [Dr. Juckett] I think I can make a comment about that. As was just alluded to, we don't yet know how best to target organs. And there's a lot of interest right now, in determining specific biomarkers. So, a marker of your biology that can tell us that's the problem, so we're going to choose this medicine.

And so unfortunately, we are shooting fish in a barrel, a comment that was made earlier. And that's true for lung GVH as well. The agents that we use to treat somebody's whole body, all can be effective for lung. It's a harder type of GVH to treat. But all of these that are currently being studied, the medicines that have been studied do have a role. And we obviously, hope to learn more as time goes on. Nothing specific.

41:47  [Dr. Chhabra] Clinical trials using Jakafi or Ruxolitinib are showing promise for lung GVHD: If I may. So, there is a clinical trial going on with the use of Ruxolitinib or Jakafi. And there are actually, several trials going on at the same time with not just Jakafi, but also other JAK inhibitors. And I have case reports to talk about, patients who did not respond to other drugs. I've seen some good responses. But again, it's just my experience. We'll have to wait for more data.

42:20 [Dr. Galvin] Also, specifically, since you mentioned lung GVHD, there have been a couple of new drugs that have been approved for a interstitial pulmonary fibrosis, which are being studied in pulmonary GVHD as well. And so, we don't know yet. We can't make any conclusions.

But we often see advances in other areas, whether it's pulmonary or in rheumatology, and a lot of the drugs, JAK inhibitors is a good example, were already FDA approved for rheumatology and hematology. And so, using these drugs for GVHD is exciting, because we know that they already worked for similar diseases in rheumatology. And so, as new drugs come from rheumatological diseases, they're be tested likely for GVHD as well.

43:13  Jason Carter Clinical Trials Program is helpful: Actually, I had a question and a comment. And that woman on GVHD of the lungs had my question. My comment is, I just want to thank Be The Match again. I did go through the Jason Carter clinical trial program for both the study at NIH and also for the drug KDO25. They were incredibly helpful. Your website is great. The Carters have made huge contributions for clinical trial. So, I thank you. It is a bag of hope when you can wrap up a clinical trial or start it. It's like a big bag of hope. So anyways, thank you. That's the comment.

44:15  Are there ways to improve donor selection so that people with "perfectly matched" donors don't get GVHD?: Oh, okay. Well, I guess I'm up. I've got a question about genetic markers. Is it possible to test, after a transplant, test for more genetic markers? I'll just give a brief precis of what happened to me.

I had a donor who was a 10 out of 10 match for the factors they were testing for. And yet, I almost died because I had such an acute case of GVHD. I still have a lot of GVHD. Is it possible to go back and retest for more markers? Are they doing that at all, in order to try to find what is causing this exactly? And it was my younger brother, perfect candidate.

But where did the DNA go wrong? Or is that even a meaningful question after this stem cell transplant has already occurred? So, that could lead in a lot of different directions. But, I'll just see if anyone has anything to say on that.

45:34 [Dr. Juckett] I can make one comment about that. I think that the typing, people focus on the typing. And if you think about yourself and your brother, the typing is one part of what leads to GVH. And so, this typing is the way cells communicate with each other. Think of it as a barcode. But there's a lot more about your brother and you that are not matched. You're not the same, you're not identical. And so, all those other things between the two of you that are not identical, can all be sources of what's basically, a rejection episode.

So, this is an example of where the typing only gets us so far. And so, even with perfect typing, there will still be a graft-versus-host disease. And, what it amounts to is, if we look at a group of people with perfect donors who are typed, and everything matches, we'll simply have less risk. But within that group of people, unfortunately, there's still going to be some people where some difference exists that still leads to GVH that we can't assess for, today.

46:56 [Dr. Galvin] And we need that difference to prevent the cancer from coming back as well. So, we don't know the magic mismatches that we need to prevent cancer from coming back. Graft versus tumor, we call it. Or to avoid, to prevent graft versus host. Because there's probably so many of them. I mean, we're only looking at I don't know if it was 6 or 10 or 12 for you, that we look at. When you think about it, 10 is a very small number compared to the rest of the mismatches that exist. And some are very important, some have caused GVHD.

47:38  [audience member] I'm glad to hear you use the word magic, because it's how it seems sometimes.

47:48  [Dr. Chhabra] There is new technology on the horizon to more precisely match donors and patients: If I can make one comment, it's about a clinical trial, or actually a study. So, we think 12 out of 12 match is a perfect match. How we define one match is by looking at the gene itself and giving it a name. There's a new technology called next generation sequencing that reads the entire piece of DNA. And this new technology was used in UK. And they found out of 890 patients, who were part of a perfect 12 out of 12 match, it turned out 29% patients were actually not a 12 out of 12 match, when they use a new technology. So it's possible, as the technology has gotten better, we will find better matches in the future.

48:36  Are there new drugs on the horizon to treat GVHD in the mouth?: I have GVHD in a lot of places, but the worst place is my mouth. And nobody can seem to help me with this. My salivary glands aren't functioning well. And my dentist, doctor, thinks that I have nerve damage. Is there anything that can be done to help that? I can't eat at all. I mean, I can't taste. The taste is terrible. And I've done the [inaudible 00:49:12], I've done Tacrolimus. I've done 15 million different things. I've been on Prednisone forever. And I'm finally off of it, because it just didn't do anything. Is there anything coming out for problems in your mouth?

49:29 [Dr. Chhabra] I think, if I can have the audacity to say this, I think it's hard to say any or give any meaningful advice without knowing the entire history, in this forum. But I would say with regards to taste sensation, it's often that transplant patients, or those who have chronic GVHD, have zinc deficiency. And so, zinc level, if it is checked properly, and the supplementation is started, might help with the taste sensation.

50:07 [Dr. Galvin] I think you bring up an important point, about how they might be able to treat one part of your GVHD, but not another. I'm not sure if sometimes, skin, we can do a good job on treating with different treatments. But we're left with one part, one site that's causing a lot of symptoms. And it just shows us that the immune system acts differently at different sites.

So, it is an area that certain ... I know, at our College of Dentistry, they're working on that as well, with their oral GVHD clinic. And I know they have, I'm not sure what's available at the NIH, but they have an oral GVHD clinic there as well. But it's an area that we, especially as internist training, we don't learn a lot about the dental and oral biology and pathology. But it's an area that definitely needs more attention.

51:11 If someone has bad GVHD, can they have another transplant to replace the donor’s immune system? Yeah. I'm just piggybacking off of the gentleman in the front. But, in cases where you had seemingly a perfect match for the allogenic transplant, have there been any studies or any research into potentially, if somebody is hit with a really bad case of GVHD, chronic GVHD, potentially looking at other donors to potentially, perform another transplant? Or maybe potentially storing and reverting back to the original stem cells that the patient had in the first place, at all?

51:52 [Dr. Juckett] I know at least a couple of episodes where that was tried. And part of the problem with looking at a second transplant for somebody with bad GVH is that, I think as everyone in the room can appreciate, going through a transplant is a harrowing, awful and potentially dangerous treatment.

And so, when in the settings, where we think about the risk of a procedure versus the potential benefits, this is clearly a situation where we know the risk of a second transplant is very high. It's very unclear whether there would be any benefit in that setting. So, I think we would all hope that we would have, at a minimum, a much safer option. And obviously, one that maybe worked better.

52:51 [Dr. Chhabra] I completely agree. I think it's a risky procedure. And unfortunately, not many patients are in that situation. Most of the patients are older with chronic GVHD with multiple medications, health issues. And the only time I've heard about, or thought about this procedure, is for a patient who had lymphoma. And his bone marrow was clear before he had the transplant. And we still had his stem cells saved, and very few patients are in that situation.

53:38  How close together should extracorporeal photopheresis (ECP treatments be given?: With ECP treatments, is there any advantage to having the treatments spread out at more even intervals? Doctors suggested we can do them back to back, one afternoon and the next morning. But it seems to me it might be advantageous to spread those out in more equal intervals. What is your thoughts on that?

They have two treatments a week. Is there any advantage to have say, Monday to Thursday, instead of Wednesday afternoon, Thursday morning, back-to-back?

54:15 [Dr. Galvin] The only reason it's done that way is because, on the original clinical trial way back, a long time ago, they did a certain amount, and they required two days. So, I don't think it matters in terms of the proximity of those days during that week. It could be a Monday and Thursday or a back-to-back. And so, unless my colleagues here, feel differently, there really isn't a benefit to where those days fall within the week.

54:46 [Dr. Chhabra] If I can make a quick comment. I usually leave it to my patients, because it's about convenience. We are planning to have them undergo ECP for three to six months, at least. I prefer going more than six months, actually 12 months. So, it's about convenience. And whatever works for my patients, I let them do it.

And we don't know if there's a particular regimen that works best. In fact, there was a clinical trial which was done by the Blood and Marrow Transplant Clinical Trials Network, where they tried to compare three different types of therapies for patients with chronic GVHD. One of the arms or the groups, was patients who were supposed to get steroids for the phases. And actually, the trial closed early because they couldn't find patients for the trial. So, it's about convenience. And whatever works for the patients, I'm all for it.