Post-Treatment Survivorship

Post-Treatment Survivorship - 9.29.25 - Transcript

Participants:    

• Dr. Trent Wang, Sylvester Cancer Center, University of Miami     
• Dr. Evan C Chen, Dana Farber Cancer Institute
• Marla O’Keefe, BMT Infonet (webinar partner)
• Lindsey Whyte, Leukemia Research Foundation

- Hello, and thank you so much for joining us for the second webinar of Leukemia Research Foundation's Leukemia Awareness Month series. Today we're pleased to be co-hosting the program with BMT Infonet on post-treatment survivorship. In a moment, I will be introducing my co-host Marla O'Keefe and our esteemed speakers, Dr. Evan Chen from Dana-Farber in Boston, and Dr. Trent Wang from Sylvester Cancer Center in Miami. My name is Lindsey Whyte and I'm the Director of Programs & Partnerships at the Leukemia Research Foundation. I'd like to take a moment to acknowledge the supporters of this program. They are AstraZeneca, Autolus, Rigel, Astellas, AbbVie, and Novartis. We're very grateful to them for their support.

- The Leukemia Research Foundation's mission is to cure leukemia through innovative research funding and to support patients and families. The Foundation has raised almost $100 million in support of our mission since our founding in 1946 and has funded research grants to over 750 investigators worldwide. Our support programs for leukemia patients and their loved ones include information and resources, education programs and financial assistance, and a directory of helpful organizations and resources on our website. Marla, would you like to speak briefly about BMT INFONET and the programs that you have for patients and caregivers?

- Thank you, Lindsey. For those of you that are not familiar with BMT Infonet, we are a nonprofit agency that provides resource information and emotional support to patients and their care partners before, during and after bone marrow or stem cell transplants and CAR T-cell therapy. We have peer support programs. If someone is going through treatment and they want to talk to someone else who has been through the same treatment, we can connect them. We have webinars, we have online support groups, we have a variety of programs. So please take a look at our website to learn more and do not hesitate to call us if you have any questions or need any help. We're happy to be a part of this today. Thank you.

- Wonderful. Thank you. We appreciate the partnership. For today's program I'm just going to go through a few nuts and bolts about today's program. Everyone will be muted throughout the program, but you are welcome to submit questions through the Q & A box, which you can find at the bottom of the screen in Zoom. And a very important note that if you want your question to be anonymous, you have to click that little button there, the little box that says anonymous. Otherwise people will see your name or potentially your name or other identifying information. If you already submitted a question through your registration, we have those questions and I've shared them with the speakers and we will try to get to as many of them as we can. And sometimes we've grouped them so your question may be similar to someone else's. So after today's program, you will be sent a brief evaluation through email and we would love it if you would just complete that short survey just so that we can get some feedback. This helps us improve our future programs. Also, this program will be recorded and sent to participants or the link to it will be sent to all registrants for the program and it will also be available on our website.

- First, I'd like to introduce Dr. Evan Chen. Dr. Chen is a clinical investigator and attending physician in the adult leukemia program at Dana-Farber Cancer Institute. He attended Stanford University School of Medicine and completed internal medicine residency at Massachusetts General Hospital and Medical Oncology Fellowship at Dana-Farber Cancer Institute. His research interest is in the development of novel therapies for advanced myeloid neoplasms such as acute leukemias and myelodysplastic syndromes with a focus on cell therapies and epigenetic approaches. Dr. Chen, thank you so much for joining us today. Now Marla's going to introduce Dr. Wang.

- Thank you. Dr. Trent Wang is an associate professor of clinical medicine in the division of transplantation and cellular therapy at the University of Miami Sylvester Comprehensive Cancer Center. His clinical focus has been treating patients with blood cancers who require an allogeneic stem cell transplant or other cellular therapies. Dr. Wang's research focuses on complications of allogeneic stem cell transplantation. He conducts interventional behavioral and retrospective studies of graft versus host disease, infectious transplant complications and transplant survivorship. He also studies the outcomes of immune effector cell therapies such as CAR T cells for various oncologic indications. Thank you both for joining us.

- Okay, so I'm going to allow Dr. Chen to take over the slides because he's going to talk briefly about some considerations, a little bit about sort of the logistics of immunotherapy treatments and also considerations for post-transplant or post treatment. So Dr. Chen, please take it away.

- Yeah, fabulous. Yeah, thanks everyone for having Trent and I. It's really our privilege to be here. I just want to confirm, can you see my title slide here and see? Does that look good? Great. Okay. So as Lindsey and Marla introduced, our focus very much is on answering questions and being of the best help we can be, but it's also important I think, just to get us on the same page. So that's our, that's our intention with these slides here. So we just saw these, so you know, immunotherapy just to start by acknowledging that this term really is pretty loosely used throughout a lot of oncology. And so immunotherapy used in one context that you may hear may be different from the way we use it here. Immunotherapy encompasses a lot of things that basically harness the immune system to fight cancer. And for us in leukemias, blinatumomab is one such example which binds your own T cells to then bring next to your leukemia cells and cause the leukemia cells to be killed. You can also have CAR T cells where your own T cells are taught to bind and kill, again, leukemia cells. And these are the products that you may come across Brexu-cel, Obe-cel, but immunotherapy for others might also encompass antibody drug conjugates where you have antibodies attach to chemotherapy and it's the chemotherapy that kills the leukemia cells. And then finally, in a lot of oncology immunotherapy might involve checkpoint inhibitors which are really not really used in our field of cancer. And this is essentially where your cancer cell may have a "don't kill me" signal that if you block then leads to your T-cells' ability to kill your cancer cells. So again, all of this falls under immunotherapy, but checkpoint inhibitors really are not so relevant to our types of conditions. And even antibody drug conjugates, I think I would leave out of this leaving I think our focus here on just blinatumomab and CAR T cells.

- Also very briefly, the treatment journey of acute myeloid leukemia and acute lymphoblastic leukemia, I wish to just briefly review. For AML we broadly divide this into intensively treated or less intensively treated folks and intensively treated folks are where you may encounter those terms such as induction and consolidation. The these stepwise rounds of chemotherapy usually leading to a bone marrow transplant with the intention generally of trying to cure someone of the condition. For those getting less intensive treatment, usually they're unable to go to transplant due to older age or other health issues. And as such, the treatment tends to be a gentler version that is repeated for as long as possible and for as long as tolerated. Acute lymphoblastic leukemia, again, we broadly divide them into two categories, Philadelphia chromosome positive and Philadelphia chromosome negative. The structure of the treatment journey is also a bit different for those that are pH positive, as we say, it's the basis of tyrosine kinase inhibitor plus steroids and potentially plus chemo. If you're Philadelphia chromosome negative, you receive several rounds of multi-agent chemotherapy that all vary depending on the specific regimen given. So I don't, I don't even give them a name here, but there's many rounds of this. Both paths coalesce onto blinatumomab consolidation now and also are in a state where we are not so sure if everyone still needs a bone marrow transplant or a long-term remission, AKA potential cure given how well blinatumomab has served us in the second step of these treatments.

- Alright, and then finally to bring us just on the same page about some of the terms we might use in the session. Toxicities that are CRS or ICANS, these stand for cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. It's a mouthful. So we just use the acronyms. Cytokine release syndrome typically within the first two weeks has to do with fever, which I'll get into in the next slide. ICANS usually all about mental confusion, difficulty with speech and worst case scenarios, seizures and coma. These are the two predominant symptoms that we think about when we think about immunotherapies. This I also just display as referenced to show you that for CRS we do grade them based on severity and the grades range from 1, 2, 3, 4. And the things we pay attention to are fever, blood pressure and oxygen levels. If your grade one let me take a step back, any grade requires a fever. So CRS is really, the backbone of this side effect is fevers. And if you have low blood pressure or low oxygen levels to various degrees, then you start climbing up on the grade. And then finally is ICANS, which is the sort of the neurologic toxicity of immunotherapy. The premise of grading ICANS rests on what we call the ICE score. It's a series of 10 things we ask folks multiple times throughout the day, things like what is a month, year, where are you? What's the name of the city? Name three objects, follow commands, write a sentence, count backwards by 10. When folks develop neurotoxicity, it can manifest in difficulties accomplishing these tasks. And the score we give them out of 10 then allows us to then again, grade the neurotoxicity and grading ultimately matters because it lets us determine the most appropriate treatment based on the toxicity grade. Alright, and I'll turn it over to Dr. Wang.

- Thanks so much. I'm going to present just two slides on what allogeneic stem cell transplant is and some of the major issues we deal with afterwards. But essentially allogeneic stem cell transplantation is important because it sometimes is the only curative treatment for relapse or refractory blood cancer such as leukemia or other bone marrow failure states. It is however not recommended for everyone. The benefit of this treatment must outweigh the sometimes substantial risks. The benefit of transplant is that it does reduce the risk of relapse compared to no transplant and it can provide recovery of bone marrow function in bone marrow failure transplant does so by using a graft versus leukemia immunotherapy effect, Dr. Chen will know that, where the donor's immune system is installed into the recipient's body and can start surveilling and eliminating threats such as cancer cells that it can now detect. However, the risks include weakening of the immune system, which leads to infections. Chemotherapy and radiation therapy can also injure organs and off-target damage from the new immune system, which is called graft versus host disease can cause issues as well.

- So the journey starts with a pre-transplant period, which Dr. Chen described sometimes intensive or not to get a patient into remission. And remission is a key in blood cancers because it gives the immune system time to get stronger and do its job. And in cases where remission cannot be achieved, sometimes the relapse rates are a little bit higher. During the pre-transplant period we start a workup for stem cell transplant in the appropriate patients. And this includes finding a donor, evaluating recipient fitness, how strong they are for transplant, social support and figuring out other logistics. Sometimes people live very far from transplant centers for example. Once a patient is determined to be a good candidate and the patient is interested in transplant and all the pre-transplant tests and bureaucratic hurdles are cleared, then the patient is admitted to the hospital for about three to four weeks, which is that second box of HCT itself. This includes about up to a week of chemotherapy or radiation to prime the body to receive the new cells but also to hit the cancer cells one more time. Then the stem cell infusion is administered usually very much like a blood transfusion, but you're getting a bag of stem cells instead of just red blood cells. And then you stay in the hospital for about another two or three weeks to allow the new immune system to start growing.

- During this time in the hospital there's initiation of a few new immunosuppressant drugs, we're watching for infection, we're giving blood transfusions. And then, when we have the white blood cells recover with the donor cells, this is called engraftment and starts the next phase of treatment, which is the post-transplant care, which is often chockfull of outpatient follow ups and medications and survivorship issues. So the success of transplant is ultimately variable and unpredictable. The factors at the very top are some of the individual specific risks that we may or may not have the ability to modify, but they definitely play a part. Next slide please.

- In the first a hundred days after transplant, patients are often taking many medications and they're at risk of infection and this is also the time that acute GVHD tends to show itself. So sometimes the signs and symptoms of acute GVHD can be confusing and difficult to differentiate from other symptoms. But when we do see it, it's often the initial sign that the new bone marrow system and the immune system is working. So it's not necessarily a bad thing. The manifestations for acute GVHD that we're looking for are skin- this could be a rash. In the GI tract, this could be nausea, easy fullness, poor appetite or diarrhea, and sometimes liver enzyme changes on laboratory review. There's other possible features of acute GVHD, but these are the main ones that we look for. And when they do develop treatment, depends on how severe it is. If the acute GVHD is mild, we give some creams or we might just watch it. If it is significant, we can give immune suppressants to dampen the immune system response from the donor, the classic one being prednisone or a corticosteroid. And this often works well but it can increase the risk of infection and lead to other complications as well. After day 100, we start looking for a different form of GVHD called chronic GVHD. And this is clinically a different entity which manifests with different organs involved including the skin, mouth, sores or redness, eye dryness and much more. And when identified chronic GVHD symptoms and features will often last for years instead of just days or weeks, which can be the case in acute. The management is generally the same. We use immune suppressants or supportive therapies. It's about balancing the risk of the GVHD damage to the body with the risks of the treatment for that GVHD, which can, you know, increase the risk of infections and cause other side effects.

- So I did include a few points on the right that I wanted to emphasize. Specialized care is often required just because these are very sometimes rare manifestations and the diagnosis can be challenging. The management is always, is rarely straightforward I should say. There's a lot of balance required to control the symptoms without overdoing it. And we always have to watch the quality of life. You know, patients always ask will the symptoms ever go away? And the answer is yes, given a long enough period of time there is tolerance that develops, but we have to keep you safe during that long period of time, which can be many, many years. And then while we're waiting these many, many years, the rest of your body is still carrying on as it was. So health maintenance is still important. Watching for your cardiovascular health, your endocrine health, doing your cancer screenings, and keeping up with your mental health and support. Okay, that's it. Thank you.

- Great, thank you so much both of you. Actually, if you could leave this slide up, I just wanted to point out on our website we have some information but I know that BMT Infonet, which Marla shared earlier also has quite a bit of information and videos. And then I also wanted to share this resource, KnowGVHD, which is specifically for post-transplant patients and caregivers. There's a lot of really great information on that website as well. So thank you for sharing that. And I think we can stop sharing the slides now and go into the q & a and we will start with some questions that were submitted by the people who registered in advance and submitted their questions. But I also wanted to point out that, at the bottom of everyone's screen, there's a little box that says Q & A and that's where you would click there to submit a question. And when you submit it, if you want it to be anonymous, please do click that little, click the little button that's, there's like a little square and I think you just say anonymous.

- So we're going to start with questions that are focused on symptoms, both the long- and the short-term symptoms. We had a few that were submitted in advance. So, let's see, in one case there was an AML patient that said is continued lack of energy to be expected a year after treatment ends? And I don't believe that that specific patient indicated if they had a transplant or if they had chemo. And then another patient said, is pain and fatigue a lifelong side effect of the stem cell transplant? So I would ask you both to kind of take the concept of pain and fatigue, both on the side of the transplant but also on the side of chemo and other treatments just to kind of talk about that please.

- Sounds good. And maybe Dr. Wang, I'll start just because the pre-transplant sections feels more natural to, to begin with here. So this is assuming that someone does not go to a transplant. In these scenarios, our goal always is for folks to feel better. That really is a priority- to live longer and feel better. So when folks do not feel better, we have to reevaluate I think our goals of treatment. Could it be, as we always consider in these situations, that the fatigue is from the treatment itself or from the leukemia that may not be adequately controlled? I think that's the first distinction to be made. And that often may involve a bone marrow biopsy to clarify whether the leukemia's still there in the bone marrow or not. Assuming that it's not the leukemia being the reason for ongoing fatigue, then we are at liberty to adjust the treatment to find a better balance between controlling the leukemia and supporting your symptoms and level of energy. The challenge always with treatment is that the harder we hit the leukemia, the harder we sort of affect the rest of the body as well. And so sometimes if the leukemia is well controlled, we might say, well, why don't we take our foot off the gas pedal a little bit with the treatment? And more specifically how that might look, might be perhaps longer breaks in between rounds of chemotherapy or it could be a dose reduction so you get less chemotherapy each cycle. Again, of course to be balanced with making sure that the leukemia is still controlled. So I would say my answer to the question of whether fatigue is expected, you know, it can occur, but we would want to actively work to improve it. And the methods I described are the ways we do so.

- Thanks Dr. Chen. As for the post-transplant perspective, I think it's as wide open as telling your doctor “I'm tired” and people who didn't get a transplant, we have to make sure that number one, we're not missing anything big like what Dr. Chen was indicating. After transplant with every passing month, the chance of relapse generally decreases one year later, you know, the chance of relapse is fairly small. Two years later, even smaller. But we like that. So although it is small, we still consider what Dr. Chen mentioned and we have to ensure that there's nothing going on that might be a recurrence of the cancer, for example. Fatigue and pain might be the body's way of telling us that something's wrong. You know, many times we can find out why, sometimes we can't. But in a post-transplant survivor, we need to make sure that there's no active infection going on, including running tests through the blood and maybe imaging if there's signs or symptoms that point to that. But we also have to make sure that there's no evidence of the chronic form of graft versus host disease. These are, you know, systemic states that can cause a lot of drain of the body's resources and as a result people don't feel quite like themselves. So there's a lot of medical testing that we usually need to do to evaluate a patient who complains about fatigue or pain. And then finally we have to also, you know, recognize the psychiatric component of it, making sure that we do depression screens and evaluating the entire patient because fatigue and loss of interest can be one of the first signs of clinical depression. Sometimes people just take a little bit longer to recover from their therapy and there may be absolutely nothing wrong, we just need to give it more time. But, but like I said, there's a lot of other things that we need to rule out first before we chalk it up to that.

- Great, thank you so much. I wanted to ask a question. There was a specific question from a Hairy Cell leukemia patient, and of course I don't have it in front of me here, but it's

- No worries, Lindsey. I think the, was the question about sort of symptoms after treatment?

- That's right. It was symptoms after chemo for an HCL patient.

- So hairy cell leukemia, I would say on the whole fatigue after treatment would be a little less expected just because the treatment for hairy cell leukemia for the most part is very discreet. There's a clear endpoint to it without necessarily needing a transplant with its lasting side effects. And the treatment usually is chemotherapy and now, more recently with rituximab for eight doses or so and then it's all done. So I think ongoing fatigue would have me searching for other potential contributors and I think that's always something worth remem.. and I say “remembering” not because it's your burden to do so, it's ours to think on your behalf. Other reasons for fatigue. Fatigue is one of the most common symptoms that Dr. Wang and I encounter and I always remind folks to keep the common causes in mind. How is the sleep going, sleep apnea, checking for thyroid levels, nutritional, vitamin, all those sorts of things. Not to say that that hasn't been done. I'm presuming that has potentially been looked at already, but in these situations where I would think the chemo itself is not the likely culprit, you know, what else could it be? I would speak with your primary care physician and other members of your health provider team.

- Great, thank you. And the other piece of that question was what do I look for in case of recurrence?

- Yes. So recurrence for hairy cell leukemia can come in several parts and we usually consider all parts together to see if the entire picture requires treatment to be resumed. These parts are your blood counts and or specifically your red blood cell numbers or your hemoglobin, your platelets, and in your neutrophil count, not necessarily your white count, but your neutrophils, which are a subset, a subtype of your white cells. We also look for, you know, generally how you're feeling, fatigue, weight loss, night sweats, and then whether your spleen might be enlarged as well. Just one or the other is not necessarily enough to push the need to treat, but it's the constellation and the severity of each of these that would sort of be added up together. So monitoring is key.

- Great, thank you. Okay, so we're going to move into when a transplant is done and it either is not successful or a patient relapses. So we have quite a few questions on that topic. So the first one is, why do transplants fail?

- Yeah, that's a difficult question to answer and the subject of a lot of investigation right now. As I alluded to earlier, one of the main reasons that transplant fails is because we weren't able to eliminate the leukemia or whatever the transplant was for before going into the transplant and that the cells were just growing in the background and the kinetic growth of the cells outpaces what the immune system can do in terms of taking care of it after transplant. So then sometimes early by day 30 to day 100 after transplant we detect evidence of it. So that's just because we weren't able to clear it as well. Sometimes transplants fail late because the leukemia cells have kind of adapted and mutated to figure out its way around the new immune system and kind of cloaked itself better. And then this subclone grew out and they made more and more of themselves that the leukemia, you know, did not recognize and was not able to eliminate. So that is another form of transplant failing in terms of relapse? I'm assuming the question was in reference to relapse because I guess it could also fail with regards to toxicities and graft versus host disease, but those are, you know, two of the major reasons we see cancer returning after a transplant. And there are strategies that are being worked on to reduce that- different ways of doing the transplant, different therapies to kind of heighten the graft versus leukemia effect without increasing damage to the patient's body. There's different maintenance regimens where we might start cancer specific therapies after transplant even without evidence that the cancer is there. We do that sometimes in cases of AML or we have very high risk or we have a easily targeted mutation that has a therapy which doesn't add too much side effects. So, you know, it's being studied but they do fail too much. That is for sure.

- Dr. Chen, how about on the immunotherapy or CAR T cell side? Do you have any

- In terms of treatment failure? Yeah, in general the starting point in our field is that transplant is viewed as the only potentially curative approach for most of our conditions and it's essentially the ultimate form of immunotherapy. And so from that starting point, not many of us assume that blinatumomab or the CAR T-cell therapies when they were first being developed would be curative in and of themselves. And Blinatumomab has shown that to be the case. It is a bridge to something more long-lasting in terms of treatment. It itself is not curative. CAR T-cells though are starting to surprise us, I think. And I think that's where the future will tell us whether CAR T-cell therapies might actually be long-lasting on their own without a subsequent transplant for certain folks. How do I, how do we identify those folks who will be long-term responders? I think we're working on that. Why are some long-term responders doing so well versus others? We're also looking into that. So at the moment though, we generally don't quite yet assume that other immunotherapies other than transplant are really curative on its own.

- Okay, great. And then on the relapse side, so there we have several questions regarding relapse. Let's start with this general one. What percentage of allogeneic bone marrow transplantees for ALL remain relapse free? I'm not sure if you happen to have those statistics on the top your mind.

- Yeah, I'll take this one for, for now. It's highly variable based on the specifics going into transplant, you know, whether they're Philadelphia positive or negative, whether there's a presence of certain mutations that confer higher risk or not, whether or not just before transplant we detect any evidence of the leukemia, which is called measurable disease. All of those things can impact what we gauge as the benchmark for success. But in general, the cure rate for an ALL patient is somewhere in the 30 to 60% range based on what we just mentioned with transplant.

- That's the cure rate, not the relapse rate.

- Right. That's a cure rate that, sorry. Okay. So that means, you know, at three or five years, let's say that the chance of still being in remission without evidence of leukemia somewhere in 30 to 60% range.

- Right. Okay. And what, so you, you've touched on this before and I just want to make sure that everyone is clear in this. There's certain treatments that are ongoing depending on the patient and depending on their kind of kind of biomarkers or genetics and, but there's also this concept of maintenance treatment. So I wonder if you could just talk a little bit about, you know, what kind of, what are the expectations going forward post-transplant for patients and you know, how does that differ depending on, you know, what the patient's kind of characteristics are on the genetics side and other factors?

- So I guess the question is about maintenance and you know, when do we do maintenance and in which specific patients? In general maintenance is not standard after bone marrow transplant? It is not. We tend to use it when we feel someone has a higher than average risk or if the chance is there because of a clinical trial and we're trying to see if this might be better. But so far most of the large clinical trials we have, they don't have results yet or they haven't, you know, far beyond shown that maintenance wins. However, it's still used commonly as the example is given in, in AML if you have a FLT3 mutation, we actually have several pills that can be fairly well tolerated after transplant and the data in, you know, fairly small groups of patients under a hundred patients show that people who get the pill, they have a much higher likelihood of staying in remission at one or two years than people who didn't get the pill. So in those cases, the maintenance makes sense to try. The other circumstance where we sometimes try maintenance is if we detect small amounts of the leukemia cells after transplant and we're nervous that the immune system is not going to recover fast enough to handle it. So then we might start some low intensity therapies to try to control that as we give the new bone marrow time. Just as examples.

- Okay. We did receive one question online. Marla, do you want to read that one?

- Sure. This person asked, they are a 30 year BMT transplant survivor with TBI [total body irradiation] and they want to know if they need to be concerned about the amount of radiation they received during their lifetime?

- That's a great question. The answer is yes. Yes, because ultimately any form of treatment, whether it's chemotherapy and especially radiation in high doses can add to the cumulative DNA damage that our body has taken and as a result you're at higher risk of developing not only, you know, long-term damage to organs but also the increased risk of developing another type of cancer on your body. So what is recommended is making sure that the endocrine organs are doing well, that the cardiovascular health is good because radiation can affect both of those and doing cancer screenings as recommended. If the patient is a female, we usually do mammograms at a much earlier age after radiation, otherwise you would follow, for the most part, standard cancer screenings that the primary care doctors recommend, including colonoscopies and skin screenings, that kind of stuff. It also depends on the degree of graft versus host disease that is present because that that is a separate independent risk factor for developing different types of other cancers if you've had it for a long time.

- Okay. So back to the relapse topic. This question is maintenance treatment to treat high risk AML- AZA/Venetoclax put the patient into CR1 and had BU/FLU conditioning with transplant; no MRD after 10 AZA/VEN cycles; still recommend going for 24 AZA/VEN cycles four weeks apart? It's a very specific person's situation.

- So I take it this individual has gone through transplant

- It seems that way. Lemme see if there's additional

- Bu/Flu conditioning.

- Yeah, I mean these kinds of decisions and, and I'll let Dr Chen comment as well, are made in conjunction with the patient and the treating leukemia doctor. If the transplant doctor is a separate one, sometimes they do both. But like I mentioned, if this was a high-risk leukemia for one reason or another and I was very nervous about the cancer coming back early, I would institute some kind of maintenance. I'm not sure that VEN/AZA maintenance is better than another, you know, type of maintenance for example. But these are fairly individualized decisions. Dr. Chen,

- It just says that. Yeah, says “please talk about your experience and knowledge of reduced relapse rates and cure with Venetoclax and Azacitidine monthly maintenance.” Yeah, and it's a caregiver of someone with AML.

- I found the question as well and whether there was a preceding transplant matters a lot here because, as Dr. Wang says, if this is a post-transplant scenario, then the choice of maintenance really can be quite variable, very individualized and often based on preliminary early sorts of data in the field. So there's, it's rare to have a consensus on what the most ideal maintenance is. And in general, a choice of further venetoclax maintenance post-transplant, I would say is uncommon to my knowledge. And it sounds as if the dosing here is also less typical than what we would do for leukemia before transplant, which is where venetoclax has been approved. So sorry to say difficult to answer this question from what we know.

- Okay. I'm going to ask a question about long-term side effects that have been seen as a result of being treated with blinatumomab. I -you might have touched on this previously, but that was one of the

- Sure, yeah. Happy to address this. So on the whole blinatumomab is felt to not have too many long-lasting side effects. It's an antibody-based sort of molecule. It doesn't last very long in your body, which is why when it's given to you, it's given to you continuously. That's one of the reasons. One side effect that we did a study here at Dana-Farber looking at is occasionally your white blood cells might be low actually from blinatumomab, neutropenia might come about. That might raise some risks of infection. But this is a risk that's really, again, during treatment and generally after blinatumomab, we don't find it to have long lasting side effects in general.

- Okay. Let's see. Can you talk a little bit, you, Dr. Wang, you mentioned already a little bit of concern about secondary cancers or you maybe alluded to it. Can you talk a little bit about other health conditions after chemotherapy, radiation treatment and or transplant for this person is specifically NHL and ALL?

- Yeah, I guess this kind of touches on the general survivorship issues after transplant. All cancer centers generally have kind of a set of guidelines that we've put together based on what data is out there regarding what is at increased risk. So for example, here at six months and at one year, we have a certain number of things that we have to check. Whether it's your endocrine function with your thyroid, your blood sugar screening, your skin checks, colonoscopies, all of those become very important after transplant for everyone with or without graft versus hosts disease. Just because of the cumulative effects of therapy that you've received. Any cumulative effect of inflammation, which could be from graft versus host disease. It's hard to give a general thought on it just because it's fairly complex and detailed. But, you want to look at your cardiovascular health, your risk of a heart attack, your risk of a stroke relating to cholesterol and blood pressure. Those are important things. Your thyroid function, your pancreatic function and your blood sugar, your secondary health screenings with cancer screenings as well. Oral cancer screening is one that's underdiscussed in my opinion, especially with people with oral graft versus host disease for more than, you know, a few years, three to five years I think is when we start seeing these cases of oral cancer. So I've been recommending a lot of patients to see the dentist or the OMFS [Oral and Maxillofacial Surgery] team, certain ENTs also do cancer screenings in the mouth. That's one of my areas of focus when I see patients for survivorship.

- Well you actually anticipated the next question that I had on my list, which was specifically about prevention and screenings. So we got that one taken care of. Thank you. And I just want to remind everyone, if you do have a question for the speakers, please submit it in that little chat box at the bottom of the screen. I just, I'm going to float this one by you both. There's one that is my 31-year-old daughter has the TP53 marker. Can you tell me more about this? And this is an ALL patient or caregiver of an ALL patient.

- I can start here with at least the pre-transplant implications of P53. So P53 in general is a worrisome mutation when we do find it. But the degree of worry really varies based on the type of blood cancer in which it's seen in ALL, P53 is noteworthy but not quite as high risk to the significant extent as it would be in AML. In ALL what we need to do if we do see a P53 mutation is to check if the chromosomes, if you might recall, those are the X's and Y, you know, and such from high school biology. We need to make sure that there aren't a lot of changes to the chromosomes big picture because P53 often comes, can come along with a lot of abnormalities at the chromosome level. And when we see the combination of the two - P53 with complex karyotype as we put it, or a hypodiploid state, these are all more technical terms that is worrisome for higher risk ALL. What that would tell me as a leukemia doc is that this is likely someone who would probably be better served with the maximal therapy that we can provide. What would that mean? That would mean probably intensive chemo for a young individual of age 30. We would give a pediatric inspired, pretty intensive type of chemotherapy. We would follow it up with blinatumomab to really push the levels of leukemia low. And then I would have a discussion with colleagues like Dr. Wang to say, hey, you know, based on the response so far and the genetic risk, should we consider a bone marrow transplant to follow all of that up? So if you, if you recall to my patient journey picture for ALL, the bone marrow transplant was a question mark, but in this situation it's less of a question mark. I think we would really think about it.

- Okay, great. And then the second half of that person's, they also said they would love to join a support group with caregivers who have gone through recovering stem cell kind of supporting someone who has had a stem cell transplant. So Marla, I'm wondering, do you have resources on your, or referrals on your website? I know we have some information but we typically refer people to Imerman Angels, but I was wondering if you also have some information?

- Thanks, Lindsey. We, you know, the support group thing is difficult, you know, because the transplant community is so dispersed. We also have a one-on-one peer support program where if someone before, during and after the treatment that someone's going through, they can reach out to us and we can pair them either with a another survivor or a care partner or even a donor if they want to speak to someone. We do, we've also been for a number of years, we have online support groups for patients that are post-transplant living with GVHD, their care partners post-transplant living with GVHD and we just recently started a CAR T-cell therapy support group. We also have a support group for young adults. I think it's age like 19 to 39 maybe that meets once a month. And we also have a support group for parents of pediatric patients. But these all focus, you know, with a lean towards GVHD except for the CAR T-cell therapy. It's hard. I mean we always tell, ask people, you know, we tell people to, you know, go back to their social work at the transplant program and see if they can, you know, help with some resources. Because it's hard to find support groups. Maybe your local, you know, cancer wellness center or one of those kind of places might have something as well. It's tough though.

- Yeah. And I know in the Midwest we have a pretty good presence of Gilda's Clubs so that's another option, potentially. So, you know, if that person wanted to reach out to me directly, I think I may have the contact information I can follow up on. It's a great question and so important.

- Sorry, I'd like to also make a pitch for when Marla was mentioning support groups that were available, but actually, you know, the University of Miami and BMT Infonet and Mass General are running a study. This project is called Horizons and it's focused on patients with GVHD symptoms. But essentially it's a group intervention through telehealth, through Zoom where we have a group of patients with a clinician and a, you know, a psychiatrist or some kind of behavioral health expert and, and they walk through a certain curriculum together. And, and you know, so far, I've been a part of these groups. Patients seem to really love it, loved it so far. We have this study as a multicenter thing going on in within the next year. I think we'll be starting sessions. So if you wanted to Google it I do think there will be an avenue for BMT Infonet people to get added onto this study. So they're definitely a major part of this. So just to pitch it 'cause we're running it here at Miami. https://www.clinicaltrials.gov/study/NCT06910969

- Sounds good. Thank you. And we can try and share that link maybe in the chat. In the meantime, what are some symptoms of graft versus host in the eyes? What should we be looking out for to prevent or if issues are developing?

- Yeah, graft versus host disease of the eyes is generally a chronic manifestation. It's rare as an acute one. So usually we see it after three to six months when immune suppression is being tapered to try to stop it in transplant recipients. What patients notice is that there might be a feeling of a foreign body like sand in the eyes. The eyes might be dry, they might be red or irritated and then they get some relief initially from lubricating eyedrops, like over the counter stuff just to keep them moist. There isn't so much data established in terms of reducing the risk of developing it. Although if you ask the ophthalmologists here, they will push medication such as cyclosporine because rationally cyclosporine inhibits immune system cells from coming to the eye surface. So maybe it can reduce the likelihood of developing it, but we don't really have concrete data on that. And some people don't like cyclosporine eyedrops because it tends to burn a little bit. The best thing to do is just look for those symptoms of dry eye or feeling like something is there, if the eyes are red a lot and see the ophthalmologist early because it can be from other things. Sometimes we have other glands that become a little bit sleepy in the eyes. Sometimes they can fix things by removing little eyelashes that might be irritating the eye. There's a lot of things that can be done for it.

- Great. And you know, while we're on the topic of kind of side effects of medications, there were a couple of questions about the steroid medications and can you talk a little bit about side effects or things that can come about when you're taking prednisone or some other things and how can people kind of mitigate that? And then one other question was, how often do side effects interfere specifically with the treatment?

- Yeah, I'll take the prednisone question. Prednisone is one of the most effective therapies we have for any toxicity of immunotherapy, especially GVHD. It works very fast, it tends to work very well and people have variable reactions to it within their body. In the first one or two weeks, people are very happy they suddenly got this burst of energy, but they might have difficulty with sleep. It might make them a little bit jittery. Some people, you know, if they've had a history of depression or bipolar, they can actually get into a manic episode from it. So it definitely affects them psychologically. In terms of physically, after about two weeks is when we start looking for some of the more long-term physical side effects. This can include the blood sugars going up. It can include weight gain and change in the appearance of one's face and body. I mean, it can cause other things. More importantly, infections in the long term. There's a whole bunch of steroid side effects. They're also difficult to use because oftentimes we prescribe them in in different doses that are tapering. As another pitch, we're actually working on a steroid app that's focused on educating about steroid side effects as well as, you know, giving you a way to input the doses that you're supposed to take appropriately. I hope to have this app out soon to help patients, but it's definitely one of the most complicated drugs.

- Okay. Thanks. Anything to add, Dr. Chen?

- Not about the prednisone, but Lindsey, do you mind reminding me the second part of that question? It was

- Uh oh - I clicked away. Let's see, how often do side effects interfere with the treatment was the second piece?

- Yeah, I can speak about that in the pre-transplant scenario and the answer is quite frequently. The chemo, again, as it tries to get rid of the leukemia cells, also inadvertently gets rid of your healthy cells. And so we have to find that balance. Often the side effects then are from low blood counts leading to fatigue, low platelets leading to bruising, bleeding, and then low white cells leading to infections. And for individuals with a lot of those complications, we might have to say that the risks outweigh the benefits of pushing forward with treatment. And a lot of times we take a little bit of a break.

- Okay. I'm going to suggest that we tackle this one. What is the life expectancy of someone who has had a second cord blood transplant 17 years after the first one and is now 65 years old?

- Oh, this one's a hard question because second transplants are already fairly rare, but in general, the long-term survival of second transplant is not as good as the first one. However, 17 years after the first transplant is an incredibly good risk factor. So I don't know. If you ask statistics, it's probably under 30% long-term survival after a second transplant. But not everyone is 17 years after the first. So, you know, give and take.

- And here's one that I think would kind of good like right before we start wrapping things up. Which key behaviors, medications, or treatments impact survival the most?

- I'm trying to think of where to start with the question because that's a broad one. It's an important one. I would say broadly speaking, to start, what impacts treatment outcomes the most is achieving response. Remission is the key here. We meaning driving the leukemia to very low levels. And that is, in part, because then you're controlling the leukemia and suppressing it, but also setting yourself up for the next step to come. And whether that's transplant or CAR T, blinatumomab, what have you. Now if you take a step further, what are the factors that lead to a successful remission, right? How do I get my chances of success remission to be as high as it can be? A lot of that depends on the biology of your diagnosis, the genetics of your diagnosis, what mutations are altered and so forth. And that unfortunately is a bit beyond, certainly beyond your control. And I wouldn't wish anyone to feel that they are responsible for the genetics in any way. And additionally dependent a bit on how strong you are, how fit you are as an individual to get the chemotherapy that can sometimes be very intensive. And that part is a bit in your control. So I would say if we walk backwards from there, probably what, what we can do best for ourselves is to just, you know, look after yourselves in other health aspects at all times. Go to your primary care. This is all straightforward, intuitive things, but they really do matter when you know the hammer is dropped and we need to start treatment for something as serious as leukemia.

- Great. Okay, well I think we're just about out of time. So Marla, was there anything that I missed that you'd like to add or should we start wrapping things up a little?

- I think we're, I think we're good.

- Okay. I'm going to just share the screen real quick because I wanted to once again acknowledge our supporters of the event. So once more thank you to our sponsors. But most importantly, thank you so much to our speakers, Dr. Chen and Dr. Wang. Really appreciate your insights on this. I think it was a great program, answered lots of questions and we hope that everyone will just kind of stay tuned for future programs. I will also put out a shout-out for our next webinar, which will be taking place on October 27th. And it is on the topic of Your Care Team. And so this is actually something that's very, very much relevant for patients who are in, particularly in inpatient, who have multiple members of the care team who can help them as they kind of prepare for and receive their stem cell transplant and are recovering, they can benefit from the various members of the care team to kind of support them. And so with that, I'll just hand it off to Dr. Chen and Wang for any final closing thoughts?

- No, just a big thank you to Lindsey, Marla, and to all in attendance to Dr. Wang as well. We're here to help. The journey is long, don't hesitate to reach out.

- Agreed. Thank you.

- Thank you Marla, thank you so much for partnership on this and we look forward to future events. Okay, thanks everyone for participating. Bye-bye.

- Bye.