Extracorporeal Photopheresis: A Treatment for Some Patients with Graft-versus-Host Disease (GVHD)

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Extracorporeal Photopheresis (ECP): A Treatment for Some Patients with Graft-versus-Host Disease (GVHD) 

Monday, April 29, 2024

Presenter: Molly Gallogly MD, PhD, University Hospitals Seidman Cancer Center

Presentation is 23 minutes long with 23 minutes of Q & A.

Summary:  Graft-versus-host disease (GVHD) is a common complication after a stem cell transplant. Extracorporeal photopheresis (ECP) can be an effective treatment for certain types of GVHD. This presentation explains how ECP works and its potential benefits for patients with significant GVHD.

Highlights:

• ECP is a type of light therapy that's performed on blood cells that are removed from the body, exposed to ultraviolet light, and then returned.
• ECP can be an appropriate treatment for patients with moderate-to-severe GVHD that has not responded to steroid therapy.
• ECP is most effective in patients diagnosed with acute GVHD that affects the skin. Response rates are lower for patients with chronic GVHD but it has shown some effectiveness in patients whose chronic GVHD affects the skin, mouth, GI tract or liver.

Key Points:

(05:42): There are two types of GVHD: acute and chronic. Acute GVHD primarily attacks the skin, stomach, intestines, and/or the liver. Chronic GVHD affects additional organs including the mouth, eyes, lung, musculoskeletal symptoms and blood cells.

(06:58): Steroids are typically the first line of treatment for GVHD.

(07:25): If steroids fail to control GVHD, patients are given one of two FDA-approved drugs to treat the steroid-refractory GVHD.

(08:10): If second line therapy fails, ECP is one treatment that patients may be offered.

(10:18): ECP interrupts the attack by donor immune cells on healthy organs by changing the level of chemicals called cytokines that cause inflammation. It also affects the level of immune cells that cause GVHD.

(10:57): The effectiveness of ECP is difficult to evaluate for several reasons.

(12:47): Reported response rates to ECP for patients with acute GVHD are about 60% . For chronic GVHD patients,, reported response rates range from roughly 33%-75%, depending on a number of factors.

(14:27): The frequency and duration of ECP vary by hospital or clinic administering the therapy.

(14:56): Typical ECP appointments can take up much of the day to complete the process.

(21:12): ECP is a relatively safe form of treatment for GVHD because it does not significantly increase infection risks, decrease blood counts or create drug interactions.

Transcript of Presentation:

(00:02): [Jon Stawowy]:   Introduction. Hello and welcome to the workshop Extracorporeal Photopheresis or ECP: A Treatment for Some Patients with Graft-versus-Host Disease. My name is Jon Stawowy, and I'll be your moderator today.

(00:17): It's my pleasure to introduce today's speaker, Dr. Molly Gallogly. Dr. Gallogly is assistant professor in the Department of Medicine and a member of the Immune Oncology Program at University Hospitals Seidman Cancer Center in Cleveland, Ohio. Dr. Gallogly spearheaded and serves as a director of a multidisciplinary graft-versus-host disease, or GVHD, outpatient clinic, which provides focused care and offers clinical trial enrollment to patients with GVHD.

(00:56): She is currently investigating the efficiency of two cellular therapies: extracorporeal photopheresis, or ECP, and mesenchymal stem cell infusion to treat steroid refractory and high-risk GVHD. Please join me welcoming Dr. Gallogly for her presentation.

(01:34): [Dr. Molly Gallogly]:  Overview of Talk. All right, thanks so much. I wanted to thank BMT InfoNet for inviting me to speak and thank you all for being here.

(01:42): Just to say a little bit more about Seidman, the cancer center that I work in is affiliated with University Hospitals in Cleveland, Ohio, and as part of the Case Comprehensive Cancer Center. At Seidman, we do about 50 allo-transplants per year and over 100 total cell therapy infusions per year. And as Jon mentioned, I run a specialized clinic focused on the evaluation and treatment of GVHD with my nurse practitioner colleague, Linda Baer.

(02:11): And today, I'll be focusing on extracorporeal photopheresis, or ECP, for the treatment of graft-versus-host disease. My hope is that during this talk, we'll review how ECP works to understand how it differs from other treatments for graft-versus-host disease and identify who might benefit from ECP. We'll start doing that by reviewing how graft-versus-host disease develops. We'll review the usual approach to graft-versus-host disease treatment and see where ECP fits in. Then we'll talk more specifically about how ECP works and the pros and cons of ECP treatment.

(02:56): Our bone marrow is like a factory where stem cells become different types of blood cells. So, I always like to review how GVHD works before talking about GVHD treatment. And understanding GVHD requires understanding of the bone marrow and how it's affected by stem cell transplantation. So, the bone marrow serves as a factory for our circulating blood cells. The red cells, the white cells and the platelets that are shown in the figure. All these cells that circulate in our bloodstream developed from stem cells, which live and stay in the bone marrow.

(03:26): Stem cell transplants first require chemotherapy to kill original stem cells and blood cancer cells. I think of stem cells like version 1.0 of every blood cell. They serve as the basic model blood cell that can then specialize into becoming a grown-up red cell, white cell or platelets. So, when a transplant is performed, strong chemotherapy kills the stem cells that a patient is born with. And this can be beneficial because that strong chemotherapy is also capable of killing any leftover blood cancer cells that might be residing in the marrow. But unfortunately, it destroys the bone marrow supply of healthy stem cells.

(04:02): Donor cells are then transplanted to repopulate the bone marrow and protect against relapse. So, for patients who get a transplant to treat a blood cancer and they get their cells from a donor that is not themselves, the donor cells have two jobs. One is to repopulate the empty bone marrow and the second is to use its new immune cells to protect against the blood cancer relapse. And I'm going to explain that in a little more detail in the next couple of slides.

(04:31): This picture shows how the immune cells from the donor, which are shown in green, can attack a recipient's cancer cell, in pink. So, a specific type of white blood cell from the donor, which is called T-cells, or the green cell, they're able to recognize differences between themselves and the recipient cells. And when those recipient cells are cancer cells, like the pink cell, the donor immune cell can destroy them and that can basically prevent relapse of the blood cancer. Unfortunately, the recipient's own immune cells, which are shown in blue, do not have that same ability.

(05:15): Donor T-cells attack cancer cells but sometimes they also attack the recipient’s health tissues and organs; this is graft-versus-host disease (GVHD). In an ideal world, donor T-cells are only supposed to destroy cancer cells for the recipient. They should not attack the recipient's normal cells, which are shown here in blue, who happen to be innocent bystanders in this process. However, if the donor T-cells do attack the recipient's healthy tissues and organs, that is a situation called graft-versus-host disease.

(05:42): Acute GVHD primarily involves the skin, the stomach, the intestines, or the liver. So, as you may be aware, graft-versus-host disease can occur at any time after stem cells engraft, which means they enter the bone marrow and start to grow. In general, graft-versus-host disease that occurs within the first a hundred days of transplant is considered acute and it primarily involves the skin, the stomach, the intestines, or the liver.

(06:06): Chronic GVHD affects additional organs including the mouth, eyes, lung, musculoskeletal symptoms and blood cells. On the other hand, graft-versus-host disease that occurs after 100 days is generally referred to as chronic and it affects many more organ systems, as shown in the figure. And this may include the mouth, the eyes, the lungs, the musculoskeletal system, even the blood cells themselves.

(06:28): Prophylaxis is routinely used to prevent GVHD. So, all patients who receive their stem cells from another person, receive some kind of intervention to prevent graft-versus-host disease. Either a medication or the cells themselves are manipulated before they're given to the patient. The prevention intervention is called prophylaxis, and some of the common medications that are used for graft-versus-host disease prophylaxis are shown at the bottom of this pyramid in the dark blue.

(06:58): If GVHD still develops, steroids are typically used. If graft-versus-host disease develops despite the prophylaxis, we generally add steroids. And depending on the severity of the GVHD symptoms, we might add just a topical steroid, like a steroid cream to the skin, or we might do pills like prednisone or we may give IV infusions like methylprednisolone. So, the steroids come in multiple formulations.

(07:25): If steroids are ineffective, second line treatments are available. If the graft-versus-host disease symptoms do not improve with steroids or if they recur while the steroids are being lowered or tapered, then we will add what we call a second line treatment. There are three current FDA-approved medications to treat steroid refractory graft-versus-host disease. One for acute GVHD and three for chronic GVHD.

(07:50): In general, the FDA-approved agents are used first after steroids. And if those second line agents don't work or a patient doesn't tolerate them, then many other treatments may be considered, and one of those many treatments is ECP.

(08:10): If second line treatments are ineffective against GVHD, extracorporeal photopheresis (ECP) may be used. It’s light therapy performed on blood cells that are removed and then returned to the body. So, let's talk about ECP. We can kind of break it down. We can break down the words to get the meaning. So, extra means outside, corporeal means the body, photo refers to light, and phoresis is an actual procedure where blood is removed from the body, it's manipulated and then it's returned to the body again. So, if we had to define ECP, we could say it's a light therapy that's performed on blood cells that are removed from the body and then returned.

(08:43): How does ECP work? A patient is connected to a special machine called an apheresis machine, and that connection can be through a regular IV in their arm or they may be connected through a special port. When the apheresis procedure starts, whole blood is removed from the patient and then the blood cells themselves are separated. So, in particular there's a special population of white cells, which includes the T-cells, which we talked about earlier. Those cells are kind of pulled and removed from the rest of the blood and the rest of the blood gets returned to the patient.

(09:23): In ECP, T-cells are exposed to ultraviolet light and then returned to the patient. These immune cells that have been separated out are then incubated with a light sensitizer, and that's a chemical called 8-methoxypsoralen. And then the blood sensitizer mixture is exposed to ultraviolet light. This damages the DNA of the cells, and the treated blood cells are returned to the patient through either another IV in the other arm or the same port.

(09:57): Our current understanding of ECP is not perfect and we only understand some of the ways that it helps to stop the inflammation in graft-versus-host disease. In the big picture, it stops the war of the donor immune cells on the healthy recipient organs. In the more detailed picture, research has shown that it does that in multiple ways.

(10:18): ECP interrupts the attack by donor immune cells on healthy organs in several ways. One is that it changes the levels of chemicals called cytokines that can increase inflammation. It also changes the balance of immune cells that contribute to graft-versus-host disease compared to the immune cells that are what we call tolerant, which means they kind of make peace between themselves and the recipient. So, the immune cells that contribute to the inflammation, those levels go down. And the immune cells that make peace with the recipient, those increase, and overall the balance goes more towards tolerance than inflammation.

(10:57): The effectiveness of ECP is difficult to evaluate for several reasons. So, is extracorporeal photopheresis effective? That question is hard to answer precisely, and that's because studies that are published on ECP can be difficult to apply to all GVHD patients. And there's several reasons. One is that the studies are small. The largest ones may be with 50 to 150 patients, but most of them are smaller, maybe 20 to 30 patients. There's always variation in the patients who are included and that might be their disease, their cancer that they had originally, what type of transplant they had, what kind of graft-versus-host disease prophylaxis they received, and how far out they are from transplant and what they might've already received for their graft-versus-host disease treatment. So, it's the very mixed population of patients.

(11:48): Another is that ECP schedules vary according to different centers. So, some patients would receive it twice a week, some three times a week, some two days in a row, some more spread out. And many of these studies don't compare ECP to another treatment, which makes it hard to know how it stacks up against other things. And then finally, most of these studies are retrospective in nature, which means that they were done by looking back at data that was collected over patients who already received the intervention.

(12:19): And the best quality studies for predicting how certain treatments will affect patients in the future, those are designed where the treatment plan is made before the study is done, and then you'll follow the patients through the treatment plan and look at their results that way. It's just a better-quality study. So, although the studies are imperfect, there are several publications that exist on ECP treatment.

(12:47): In general, for acute GVHD, the reported response rates are about 60% and higher. The best responses tend to occur in patients who have involvement of the skin. And in one study, starting the ECP earlier after the diagnosis of steroid refractory acute GVHD, was a little bit more effective than starting later. So, patients who started two weeks after versus three weeks after, had a little bit better responses.

(13:17): In chronic graft-versus-host disease, the reported response rates are a bit lower and more variable from about a third to three quarters. Among patients with graft-versus-host disease that's chronic, the better responses occurred in patients who have skin involvement, oral cavity involvement or GI or liver involvement. This is not to say that someone with lung GVHD for example, could not still benefit from ECP. It's just that among patients with all those different organ functions that are affected, the ones who responded best happen to have those organ manifestations.

(13:55): So, really, how helpful ECP could be for you can be sort of a tricky assessment that depends on publications, depends on other factors about you and what the transplant center may have available. So, your care team can probably compare ECP to other therapies, and there are pros and cons, to predict what treatment has the best balance of risks and benefits for you.

(14:27): Treatment schedules for ECP vary across clinics and usually taper down over time. So, how does this actually work for a patient? What is their experience like? The treatment schedule of ECP, the most standard one, is a twice a week schedule, although in a few studies there are three times a week schedules that have been published. Sometimes those twice a week visits are two days in a row and sometimes they're spread through the week to things easier for the patient. So, something like a Monday and Thursday or a Tuesday and Friday.

(14:56): Typical ECP appointments can take up much of the day to complete the process. Once a patient has a stable response or some improvement in their symptoms, then we start to decrease the frequency of the ECP. We go to weekly and then every two weeks and then stop. Probably every center has its own specific way of tapering down the ECP appointments. In a typical appointment, it does take a lot of the day. So, patients will come in, get their vital signs taken and their labs drawn, because sometimes in order to proceed with ECP, they may need an infusion of electrolytes or may need a blood transfusion. There are parameters for the safety of ECP that do require a certain red cell and platelets level.

(15:45): Usually, that does not keep patients from receiving it if their counts are low because we can give them transfusions ahead of time. But we always want to make sure that the patients meet criteria to treat before we start the procedure.

(15:57): Then they need their IV access established. So again, some patients can just use their regular veins, their peripheral IVs, to do the ECP and others cannot, and then they need a special port. This is different from a mediport unfortunately, it's a special port called a parallel port, that can withstand the pressure changes of the apheresis machine.

(16:19): Then IV access has to be established, and then if the patient ends up needing electrolytes or transfusions, we do that first and then there's the ECP procedure itself, which can take up to a couple of hours. So, that ends up taking most of the day for most patients.

(16:35): ECP treatments may continue for months or even years. In terms of how long does the treatment last, it could be four months to even years, depending on how helpful it is. If it works, great, it may be tapered over a couple of months once it starts to help and it can take weeks to make symptoms better. So, you add up the weeks to make things better and then a little bit of time for stable symptoms, and then several more weeks to wean off and you're already at months. And that's even if it works well.

(17:06): If it's not working great, we'll sometimes try to give it its best shot and really do for a couple of months to really make sure that we tried. And then if that doesn't work well, we may taper it off and try something different. For some patients who found it very helpful, they like to kind of stay on even every two weeks or so, just hoping that it's still adding a little bit to keeping their symptoms stable. And so the duration of treatment could be months to years. It's usually not shorter than that.

(17:40): ECP does not significantly increase infection risks or decrease blood counts. So, what are some of the pros and cons of ECP? One of the pros from a physician's standpoint is that when we're adding on treatments for patients with graft-versus-host disease, we want to be really careful and thoughtful about the risks of infection because almost every treatment for GVHD affects the immune system in some way, that will make a patient more susceptible to infection. And ECP as a procedure is not very immunosuppressive. It definitely affects the way that our immune cells function, as I've explained, but it doesn't tend to be associated with many additional infections. And so when we want to add it to other treatments or substitute it for other treatments, we don't worry quite as much about immunosuppression.

(18:29): It also doesn't decrease patient's blood counts. So, the red cells, white cells and platelets should remain about the same with the exception of some very tiny drops that can occur with the procedure itself. So, in comparison to other treatments, some of the treatments for graft-versus-host disease might affect counts significantly or a patient may be struggling with poor engraftment, where their blood counts are not too high, and those counts will not take a hit from going through ECP.

(19:01): ECP does not create drug interactions and can be given in or out of the hospital. Kind of like I talked about before, with low risk of infection, it's easy to add to other treatments. So, there aren't any drug-drug interactions that we need to think about or timing. If it's a pill, when do you take the pill, compared to other things. It doesn't add to anyone's pill burden because it's given through the IV. So, it can be added on fairly easily without worrying about interactions with other treatments.

(19:27): And it can also be given in or out of the hospital. And by that I mean if a patient comes in very sick and they're inpatient and they're admitted to the hospital, it can be started right then, at least in our center, it can. We can do ECP for patients who are hospitalized. Once the patients are discharged, we can then give the ECP in an outpatient setting. So, out of the hospital just means out of an outpatient setting. It doesn't mean at home. They still have to come to our infusion center and get their treatment there.

(19:56): But it's something that can be initiated in the hospital and then carried through to outpatient. Or if a patient is on ECP and they happen to get admitted for any particular reason, it can be continued inside the hospital, which is helpful for consistency.

(20:11): ECP may be inconvenient for some patients and may take some time to be effective. In terms of what are some of the drawbacks of ECP, it may be inconvenient depending on your schedule or your distance from your transplant center. So, I wrote, "may be," because I was going to say that it just is inconvenient, but some people don't find it terribly inconvenient. They don't mind coming in for their twice a week, but many people do hesitate to start ECP because they know that it's going to be two days of their week, every week for a long time.

(20:39): For patients who have smaller veins or more difficult IV access, they may need a dedicated port placed for ECP, which just introduces a small, but not zero risk, of things like poured infections or blood clots, things like that. It's another procedure to go through.

(20:59): Another drawback is that it can take time to work. Sometimes it's weeks to months before we really have a great sense of whether it's helpful or not, and that may not be available at every transplant center.

(21:12): ECP is appropriate for patients with moderate to severe GVHD. So, who might benefit from ECP? The patients that we consider for ECP should at least have moderate to severe symptoms of graft-versus-host disease. So, if they have just mild symptoms that don't require what we call systemic steroids, like steroids that are pills or IV, if it's something that can be treated with topical treatments or local treatments, it's usually not something where ECP is needed. It's usually something where the symptoms are, in our grading scale, considered to be moderate or severe.

(21:43): In general, we also consider patients who have not fully responded to steroids, and that's because if we could use steroids successfully, then it's a lot easier, most of the time, than bringing in someone for such an extensive, kind of involved treatment. So, if we can get away with our usual therapy, then we would always do that first.

(22:02): It's important that the patient has the right type of IV access. Again, if peripheral IVs don't work, they may need to have a port placed. And then there are pros and cons to that. They do have to meet the laboratory criteria for the procedure when they come in. And again, this is usually not a big issue, but again, if someone's counts are low, we need to make sure that we can transfuse them to make the procedure safe. And then of course, the ECP needs to be available at their center.

(22:33): Before I ask for questions, I just wanted to acknowledge the support at our center. The director of the Cell Therapy Program at Seidman is Dr. Van Besien. My GVHD clinic could not function without Linda Bear, the nurse practitioner that I work with. And then this is a picture of some of our fantastic apheresis nurses in our apheresis center, and of course the patients and their caregivers. And I would be happy to take questions.

Question and Answer Session

(23:05): [Jon Stawowy]:  Thank you, Dr. Gallogly, for this excellent presentation. Right now, we're going to go into the question-and-answer session.

(23:29): So, we have some in there already. And the first question is, "What is the success rate of patients who have had ECP? The doctor's arranging for you to have this treatment? Because I have chronic GVHD, my skin, my arms are very tight and painful. I've been doing two other treatments to help it, but not seeing results in a timely manner."

(23:57): [Dr. Molly Gallogly]:   Okay, yeah, that's a great question. It's a difficult one to answer. I think the hardest question to answer about ECP is how likely it is to work, and I think that's because I try to make all my predictions based on data, and like we kind of talked about, the publications all have a little bit of their limitations.

(24:18): But what I would say from the literature that's available and my own experience and our center's experience, I would say probably odds are that there will be a response. But I know it sounds like it's probably hard to wait because the symptoms are so bothersome and I'm not sure how much time has been allowed for the other treatments, but it definitely could take a couple of weeks, even a couple of months, to really know for sure.

(24:46): So, I would recommend giving it its best shot by trying for at least a couple of months before deciding that it may not be successful. And I absolutely, truly do hope that it is.

(25:01): [Jon Stawowy]:   Thank you. "What research is going on regarding ECP and lung GVHD?"

(25:11): [Dr. Molly Gallogly]:  I'm not aware of any active trials that are being done locally. I don't know if there might be something focused on lung GVHD and ECP, maybe nationally or internationally. I think it's a really good question because lung GVHD is so challenging to treat. And among all of the treatments for graft-versus-host disease, it tends to be the organ that responds the least out of almost anything else. And so it's definitely highlighting a really important challenge.

(25:46): I do know, and it's sort of interesting to think about, we do ECP in our center for patients who have had lung transplants and they're undergoing rejection of their transplant through... which is a completely different situation, but we know that in those patients, there can be some benefit. And so what that has in common with lung GVHD is it's involving inflammation in the lungs by one immune system against another organ. So, it's encouraging to know that there's some role there and that it can be effective there.

(26:21): It also, I think, highlights the fact that we don't have a lot of studies that will take one organ and look at all the different ways you could treat that organ with a graft-versus-host disease. We have a lot of studies that are centered on what is the treatment, and then we put all the GVHD patients who are all very different from each other, kind of into that same group. And so I think that it can be very hard to know what is best for each organ that's affected when we're looking at these large groups, and it's not based on the organ itself, but it's something that I could certainly look into to see if there are any active studies that I may not be aware of.

(27:05): [Jon Stawowy]:   Thank you. Next question is, "What are the factors that influence the use of a port versus IV access?"

(27:15): [Dr. Molly Gallogly]:  So, usually it's based on whether an IV is easily placed. So, if you need an IV for IV fluid infusion or something like that, if in general it's really uncomfortable or difficult to get that IV placed, then most likely it will be uncomfortable or difficult to get the IV placed for ECP.

(27:38): We do a dedicated vein assessment prior to starting ECP where our apheresis nurses will evaluate a patient, examine their veins, and try to determine whether a port is needed. We try whenever we can to not use a port, but I would say that a majority of the time, patients do end up needing one, which is probably just because their veins have been accessed so many times for so many reasons by that point.

(28:06): Occasionally, someone will start without a port, but after a couple of treatments, they find that it's getting harder and harder and that they do need a port. So, it's really just based on how easy is it to start an IV, and then does that change over time.

(28:23): [Jon Stawowy]:   Thank you. You mentioned that ECP is kind oflike the third line of treatment after the second line of drugs either fail or aren't effective anymore. Are those drugs stopped before you go into ECP treatment or are they used together sometimes?

(28:47): [Dr. Molly Gallogly]: That's a great question. They can be, for sure, continued and there's different ways to handle that situation. So, if we feel that those medications have not worked well and we want to add ECP, there's sort of two ways to do that.

(29:10): One is just start the ECP and then taper that drug down or at least give the ECP a little bit of a chance to work before that drug goes away. That might be done in a situation where the patient is tolerating the drug fine, but we're just not so sure if it's working. And that way, we let the ECP take over, we let the ECP help the patient, and then we feel safer and more comfortable taking away the other medicine.

(29:36): In other situations, if we think that one of the second line medications either was harmful or is very difficult to tolerate, or maybe it was only given for a short time and we decided that there was a reason that it couldn't be continued, maybe a safety reason or a tolerability reason, then we kind of want to just take that off quickly and switch to ECP.

(30:00): I think what I'm saying is that when we're not sure how helpful the second line treatment has been, we tend to keep it on to be on the safe side until we know ECP is working, and then we kind of try to sneak it away and have the body not notice. But if that second line treatment is something that we feel we really need to get someone off quickly for safety reasons, then we might do that faster.

(30:20): And it's okay to continue... If someone's on a second line treatment that we think is helping, but maybe, say, it helped in some organs but not another, we may just add the ECP to try to get to that other organ. And again, like we talked about, there's usually not much additional toxicity when you add ECP on top of something that you're already getting. So, it doesn't tend to add a lot of increased medical risk.

(30:49): [Jon Stawowy]: Thank you. Next question, "What are the factors that help making the decision for when to lead off of ECP?"

(31:04): [Dr. Molly Gallogly]:  Great question. So, one would be, is it working? So, if a patient has been on for... I'll usually give a couple of months before I try to make a determination if it's helping or not. If there's really no change in someone's symptoms and it's been at least a few months, then it's really a risk-benefit question. Am I really helping someone by suggesting that they go through this when after a couple of months we're not seeing any improvement? So, one would be just a lack of improvement. That would be one reason to think about just stopping.

(31:38): Another would be if someone has improved and stabilized them for a while. So, the moment they improve probably isn't the time that you want to back off on the treatment, just like anything else that we combine together for graft-versus-host disease. Once someone has improved, we usually try to keep them on for a while to make sure symptoms are truly stable and better, and then start to slow down after that.

(32:02): We have a standard operating procedure for our ECP about when to think about tapering down, and it could be... It's probably different for every center, but it's sort of like a helpful reminder, "Hey, don't forget to taper down if things are working well." I'm just trying to look at it right now to see if I can find it because I have it pulled up in front of me, but I don't see it right in front of me, and it probably does vary... Oh yeah, sorry. We give four months to sort of declare a response. And then if at four months we're not seeing an improvement, then we will start to taper.

(32:59): And then the other factor could be tolerance. So, for some reason it's difficult to tolerate, it becomes inconvenient or impossible to come in, if there's an issue with a port or the IV access, that could be another reason to decide to taper down. So, either, I guess in a nutshell, if we're worried that there is no response, if there has been an adequate response and we think it's held on for enough time, or if there's a practical reason that we can't continue.

(33:28): [Jon Stawowy]:  Okay, thank you. The next question is kind of a follow-up, "I've been doing ECP for over a year along with Rezurock, and the last few months I've had increased tightness of my skin and fascia. Is there a point where starts losing efficiency and it's time to move on to something else?"

(33:51): [Dr. Molly Gallogly]:  That's also a great question. I think that just like any other intervention, there can be a point where an intervention doesn't help as much anymore. So, just like a medication or something like that, the efficacy can change.

(34:12): Yes, it's possible to have basically graft-versus-host disease progressing, despite being on a treatment that has worked well for a period of time. So, I think when we think about it on our side, we blame the graft-versus-host disease more than a failure of the treatment. But I guess the answer is yes. So, unfortunately for graft-versus-host disease, one of the reasons it's so tricky is that it can sort of find ways to progress when we feel like we're doing everything right or feel like we're doing everything we can.

(34:42): So, unfortunately it will be possible to still have some progression. And then your doctor can figure out with you how to handle that. Do you want to take something away? Do you want to add something? If you do take something away, which one would you pick and what the strategy should be moving forward?

(35:06): [Jon Stawowy]:  Thank you. Next question, "Can you speak more about the special port? In the past I required heparin because of a DVT from the PICC line. Does the special port also run the same risk of DVT?"

(35:25): [Dr. Molly Gallogly]:  Yes, unfortunately. The risk is very low, but is not zero. So, any port that is put into your body is associated with some small risk of cloud or infection.

(35:40): [Jon Stawowy]:  Thank you. Next question is, "With the damage to DNA cells that are returned to the body, does that increase the risk of developing secondary blood cancers or anything like that?"

(35:55): [Dr. Molly Gallogly]:  That's a really good question. And actually as I said it, I felt a little bad. It's probably more than just damaging the DNA itself in the cells. There's a variety of organelles and other parts of the cell that can be injured. But still, to address your question specifically, not that we know of. It's a really great question.

(36:17): I think what happens to most of the cells after they go through that process and that damage, is most of them end up dying. And something I think is really interesting about ECP is that it's not just that we take out these actively inflammatory cells and just kill them and leave them outside the body. It's not like we're just removing them, but somehow giving back these dying cells is sending some kind of a signal to the rest of the immune system to just settle down.

(36:52): And I almost think of it like you're bringing back wounded soldiers and the donors T-cells look at all these wounded soldiers and they think, "Oh my gosh, we got to back off. We're getting beaten." And then everything sort of settles. So, there's no association that has been published, or at least to my knowledge that I'm aware of any kind of secondary cancers. But I do think it's very interesting that the damage tends to just kill the cell, but then once the cell comes back in, that's what really tells the body that it needs to change its strategy.

(37:33): [Jon Stawowy]:  Thank you. Next question, "Does ECP increase the risk of skin cancer because of the soreness component?"

(37:47): [Dr. Molly Gallogly]: Again, not that I'm aware of. I'm not aware of any associated risks of cancer. I think probably the reason that it would not be affecting the skin would be that that methoxypsoralen is only affecting the blood cells in the circulation, and as long as they're... I don't think that that circulating blood is reaching the skin. But again, no reports that I am aware of in terms of secondary malignancy. But based on the number of questions, I'd be happy to look into that a little bit more because it's making me curious.

(38:30): [Jon Stawowy]:  Thank you. Next question, "I received ECP twice a week for over 30 treatments now, and I have severe pulmonary GVHD. Can I ask about having weekly treatments?"

(39:04): [Dr. Molly Gallogly]:   Okay. If it's helping, then going down from twice a week to weekly is reasonable. If it's not helping, then probably doing less would not be helpful. So, I'm not sure if I caught that detail, but that would be my answer based on the information that was given.

(39:25): [Jon Stawowy]:   Okay. I know you touched on this a bit. What is the average length in time for treatments in months and years?

(39:42): [Dr. Molly Gallogly]:  Oh, okay. Oh, boy. I would just go on my own experience. I don't know if there's a study about that, so I would just have to say that overall, I would say most of our patients would be in the six months to a year range, with a few being less usually because we either decide it's not working or the patient can't continue for a particular reason. There aren't many who do it for more than a year. So, I think that's my best average based on my own experience.

(40:19): [Jon Stawowy]:   Okay. Thanks. Two more questions. The first one is, "Do you have knowledge of patients with AML extramedullary sarcomas being actively treated with azacytidine and Venetoclax, and what are the issues?"

(40:55): [Dr. Molly Gallogly]:  Is that the question? I'm thinking. I don't think that I do personally, but if that person wants to contact me and they have a question that I can help with, I might be able to direct them to someone who can. It sort of depends on what the question is because it doesn't sound like it's maybe a graft-versus-host question or an ECP question, but I'm happy to try to help find the answer to the question.

(41:26): [Jon Stawowy]:  Okay, perfect. "Is ECP currently being approved by insurance? Is it still in test and are other new studies going on?"

(41:46): [Dr. Molly Gallogly]:  So yes, it is approved by insurance. I don't think I've had any trouble getting insurance approval for patients, whether it's for acute or chronic graft-versus-host disease. There's still some trials being done on ECP, but it's not an area where there are very many active trials at any given time.

(42:08): And I don't know the answer exactly why that would be, except that most patients and centers probably prefer a treatment that's a little bit easier to administer and a little bit better understood. And ECP is probably the most involved and inconvenient treatment that exists. And so it's not one that we're really pushing a lot to figure out how we could maybe optimize it because at the end of the day, most people would probably rather have a pill or an infusion or something like that.

(42:45): So yes, there are a few studies that are open at any given time, but I wouldn't say it's an area of extremely active investigation right now.

(42:58): [Jon Stawowy]:  Okay. I have a follow-up question. The question is, "I get ECP twice every other week. Should I get treatments every week as opposed to the that we asked before?"

(43:14): [Dr. Molly Gallogly]:  I'm not familiar with data for that schedule. It's not a schedule that we do here. It doesn't mean it's wrong, by any means. It could be that institution standard of care. So, I guess I don't know. If it is working, I would say stick with what's working. If it seems like it may not be working as well as you'd like, then that would be something to discuss with your doctor, whether changing the frequency might make things a little bit better.

(43:43): [Jon Stawowy]:  Okay. Thank you. One more question came in, "I have severe GVHD in my lungs  (BOS).  High doses of prednisone has not worked. I tried pirtenidine , but that did not work as well. You think photopheresis could help?"

(44:05): [Dr. Molly Gallogly]:  It's possible. Again, what's tricky with lung GVHD, it's so challenging, and I really just want to respect that. We've definitely had situations where patients with lung graft-versus-host disease have a response to ECP. There's a meta-analysis that I'm just pulling up right now. Meta-analysis is a study that tries to take all the studies that exist and pull together the results to try to make it a little bit more predictive for most people.

(44:47): In that meta-analysis, the response rate in lung GVHD was close to 50%. But I have to say that in my own experience, it's not been quite that good. I would say that it's certainly worth considering, especially if other things have not helped. And maybe, again, depending a little bit on what you've already tried and what other options there are, there's something that seems like it has a greater likelihood of helping, maybe go for that first. But it's not unreasonable to consider it. I certainly wouldn't rule it out to say the response rate is not fantastic, but it's not zero either. So, I would say I would definitely keep it on the list of things to consider.

(45:34): [Jon Stawowy]:  Closing. Okay. Thank you. That was our last question. Do you have anything else you'd like to add?

(45:40): [Dr. Molly Gallogly]:  I just want to thank everyone for being here and the questions that you asked. I made a couple of notes to see if I can follow up on some of the questions and hopefully get you guys a little bit better answers to some of them.

(45:54): [Jon Stawowy]: Well, thank you. Well, on behalf of BMT InfoNet and our partners, I'd like to thank Dr. Gallogly for a very helpful and interesting presentation.

(46:07): [Dr. Molly Gallogly]: Thank you.

(46:09): [Jon Stawowy]:  BMT InfoNet, if we can help you in any way.