Surviving the Cure: Late Effects after a Transplant Using Donor Cells (Allogeneic Transplant )

People who undergo a bone marrow/stem cell transplant using donor cells (allogeneic transplant) are often cured, but may have lingering or late-occuring side effects. 

Surviving the Cure: Late Effects after a Transplant Using Donor Cells (Allogeneic Transplant)

Presenter: Betty Hamilton, MD, Associate Professor, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University.

Many thanks to Sanofi for supporting this workshop.

This presentation lasts 38 minutes, followed by 19 minutes of Q&A.

Summary: Late effects after an allogeneic transplant (a transplant using donor cells) can affect the physical, psychological, and social well-being of survivors. Dr. Hamilton sheds light on the most common long-term effects and how they can best be managed to minimize complications. She also stresses the importance of ongoing survivorship care to ensure that survivors can live life to the fullest.

Key Points:

  • There is a significant burden of late and long-term effects of therapy after an allogeneic transplant, including chronic graft-versus-host disease (GVHD), cardiovascular complications and an increased risk for secondary cancers.
  • Improved screening, risk identification, and early treatment can help minimize long-term complications and side effects.
  • Maintaining a healthy lifestyle, including regular exercise, a well-rounded diet, and ongoing survivorship medical care can improve outcomes in patients who have had an allogeneic transplant.


(02:35): There are currently 200,000 transplant survivors in the United States. This number is expected to grow to over half a million by 2030. In a large BMT survivor study, 66% of patients reported at least one chronic health condition. 18% reported severe conditions. 

(08:58): Physical symptoms, psychological well-being, social functioning, and environmental factors are all factors that can affect the quality of life in transplant survivors.

(13:54): Previous chemotherapy and radiation, GVHD, medications, hormone changes, and chronic inflammation all contribute to late effects after transplant.

(16:47): A multidisciplinary team of specialists is required to best care for transplant survivors with late effects of therapy.

(18:08): Cardiovascular disease and metabolic syndrome are common late effects of therapy. Metabolic syndrome can affect up to 50% of post-transplant patients, and those with metabolic disease are 2-3 times more likely to develop cardiovascular disease.

(21:39): Maintaining a healthy lifestyle, including proper diet and regular exercise, can help prevent the development of accelerated cardiovascular disease.

(23:40): Secondary cancers are a potential long-term effect seen in transplant survivors. There is a 22% increased risk of a second cancer 30 years post-transplant.  GVHD is a common risk factor for the development of secondary cancers.

(26:31): An increased risk of infections is observed in transplant recipients. Older age, chronic GVHD, and unrelated donors are all risk factors. Infections can contribute to death late after transplant.

(27:56): Bone mineral density loss is observed in 50-75% of transplant survivors. Risk factors include older age, being female, low body weight, poor nutrition, and chronic kidney and liver disease. Low bone mineral density is linked to a higher risk of fractures.

(31:54): It is crucial to establish a survivorship care plan. Patients with low income, lack of insurance, and from racial minorities are at an increased risk of not receiving survivorship care.

(35:39): Multidisciplinary, formal survivorship visits at days 100 and one year can be helpful to screen and treat long-term effects.  

Transcript of Presentation

(00:01): [Jordan Sexton]:  Hi. Welcome to the workshop, Surviving the Cure: Late Effects after a Transplant using Donor Cells, Allogeneic Transplant. My name is Jordan Sexton and I will be your moderator for this workshop.

(00:12): Before we begin, I'd like to thank Sanofi whose support helped make this workshop possible.

(00:17): It's now my pleasure to introduce today's speaker, Dr. Betty Hamilton. Dr. Hamilton is an associate professor at the Cleveland Clinic Lerner College of Medicine at Case Western Reserve University. Her clinical and research interests focus on the treatment of hematological malignancies with allogeneic hematopoietic cell transplantation and improving outcomes after transplant, specifically in graft-versus-host disease, survivorship and late effects. Please join me in welcoming Dr. Hamilton.

(00:50): [Dr. Betty Hamilton]:  Thank you so much, Jordan, for that introduction. It's a real pleasure to be here today and I thank you for the invitation, for being able to give this talk about survivorship and late effects after transplant. As you mentioned, I am an associate professor of medicine. I'm an adult transplant physician at the Cleveland Clinic.

(01:14): Overview of Lecture. Okay, so this is an overview of what I'm going to be speaking about today. I'm going to start by just talking about survivorship as a growing field and give an overview of the numerous late effects that we see and that have been described in the literature. While the bulk of what I'll be talking about is focused on allogeneic transplant, that's regarding patients who have undergone a transplant from a donor, some of the data I'll be showing also comes from and includes some autologous transplant survivorship data as well.

(01:49): Then I will overview the burden of late effects and particularly the impact on patients and patient-centered outcomes. Again, really describing some of the data and literature that has been published. Within that context, I will discuss the need, why we need survivorship care, as well as why we need further understanding of these late effects and how to prevent or treat them with additional survivorship research.

(02:21): Then, lastly, I'm going to end by reviewing some approaches to survivorship care and just an example of how we care for patients at the Cleveland Clinic.

(02:35): There are currently 200,000 transplant survivors in the United States. This number is expected to grow to over half a million by 2030. As transplant strategies and the overall safety and efficacy of transplant has continued to improve over time, the number of transplant survivors have also continued to grow. Currently, there are an estimated 200,000 transplant survivors in the United States alone, which is a number that's estimated to be over half a million by 2030.

(02:56): Transplant survivors continue to remain at risk for long-term late effects long after the risk of their primary disease relapse decreases. These risks of late effects can vary quite a bit over time. Tracking and managing these can be quite challenging because they can occur after one transitions from the really close clinical care received by the transplant center back towards where they're receiving care closer to home.

(03:27): As transplant approaches have become safer, the demographic of the population of patients is changing, trending towards an older population. The populations of patients undergoing transplant has also been evolving over time. Again, as transplant approaches have become less toxic, safer and more efficacious, our patient demographics have also changed. These are data and graphs from the Center for International Blood and Marrow Transplant Research, which is a large registry of transplant data that is reported within the United States. As you can see on the bar graph on the left, we're transplanting over time an increasingly older and more comorbid population.

(04:07): On the right side, you can see that, particularly in older patients, age also comes with an increasing number of other medical issues or what we call comorbidities. Of course, this can all impact or complicate transplant complications as well as longer-term late effects.

(04:27): There now have been several studies which have demonstrated an increasing number of chronic health conditions that transplant recipients can experience. And throughout this talk, again, I'm going to be showing some data and research on what we know about late effects and survivorship. A lot of this data I will mention comes from a large cohort of patients I'll refer to as a BMT Survivor Study. This is a cohort of patients that included thousands of patients who received transplants between 1974 and 2014 and survived at least two years after their transplant. A part of this study, siblings of patients of patient were used as a control group.

(05:09): In a large BMT survivor study, 66% of patients reported at least one chronic health condition. 18% reported severe conditions.  This particular study that I'm showing here includes both allogeneic and autologous transplant survivors and demonstrates that really the prevalence of any chronic health condition can be quite high with up to 66% reporting to have at least one chronic health condition over time. 18% reported that they had very severe conditions, more than half reported that they had two or more conditions, and more than a third reported having three or more conditions.

(05:38): In addition, the rate of chronic health conditions continues to increase and particularly among allogeneic transplant survivors, this approach is over 70% at 15 years after transplant. And unfortunately, this can also translate into lower life expectancy compared to the general population.

(05:56): Cardiovascular disorders are the most common chronic illness observed in transplant survivors. This is a table from the same study showing the prevalence of specific chronic health conditions and its associated relative risks for transplant survivors compared to their sibling controls. Overall, transplant survivors were more likely to have cardiovascular issues, which included things like coronary artery disease, congestive heart failure and stroke, hearing or seeing impairments, gastrointestinal complications including the need for surgery and liver issues, hormonal or endocrine issues including diabetes and musculoskeletal problems including joint replacements.

(06:36): Chronic graft-versus host disease (GVHD) contributes to increased risk of chronic health conditions. As I'll continue to discuss and mention throughout, chronic graft-versus-host disease (GVHD), which can be a common late complication after allogeneic transplant, also can contribute significantly to the increased risk of chronic health conditions as well as the development of multiple chronic health conditions. As these numbers show, among transplant survivors, nearly three-quarters of patients with chronic GVHD report at least one chronic health condition and more than half have two or more conditions.

(07:10): The 10-year rate of severe chronic health conditions can approach about 50% among those with chronic GVHD and twice that of those without. And further, patients who are also on immunosuppressive therapy to treat GVHD, this further increases the risk. Survivors with chronic graft-versus-host disease are three to 11 times more likely to report things like severe cardiovascular, gastrointestinal, endocrine, ocular and musculoskeletal complications as seen here.

(07:44): Late effects after transplant has been recognized by the National Institute of health as a research priority. While there are a number of complications that often are focused upon early after transplant and are most often the focus within the first year of transplant, we now know that long-term survivors are really at increased risk for several other things including lung complications, eye hormonal, bone effects, and in particular, and increasing risk for cardiovascular diseases and second cancers. The importance of late effects after transplant really has been recognized over the last decade as a research priority by our national Institutes of Health or NIH.

(08:24): In 2015, the NIH convened several working groups of experts to address the research needs and best practices for late effects after transplant. This, of course, included working groups and specific key late effects like cardiovascular disease and second cancers. But also importantly, I wanted to highlight that a patient-centered outcomes working group was also convened to review the state of what quality of life and late effects looks like with the goal of identifying research gaps and opportunities within the transplant survivorship community.

(08:58): Physical symptoms, psychological well-being, social functioning, and environmental factors are all factors that can affect the quality of life in transplant survivors. This is just to introduce that it's well recognized that survivors continue to have poor quality of life. They have higher rates of symptoms like fatigue, sleep issues, pain, sexual dysfunction, cognitive dysfunction, emotional distress and financial toxicity. Psychosocial factors such as depression and emotional distress are reported as frequently impaired and as well in and of themselves associated with outcomes that negatively impact quality of life. Gaps identified include that we're still learning about interventions to improve outcomes and long-term survivals and there's a need to address more patient-centered outcomes and integration into survivorship care.

(09:45): Survivors with three or more late effects report that they have lower physical functioning, lower likelihood to return to work or school and higher likelihood of limitations on their usual activities. What about the patient perspective in late effects and survivorship? In general, there's a general positive perception of recovery back to baseline in transplant survivors by one year. But data also demonstrate that many long-term survivors still report several residual deficits. Survivors with three or more late effects report that they have lower physical functioning, lower likelihood to return to work or school and higher likelihood of limitations on their usual activities.

(10:14): The patient reported outcomes indicate that chronic GVHD has a negative impact on quality of life. This is more prevalent in survivors with active chronic GVHD. There have also been several studies that have evaluated the association of quality of life and symptoms of graft-versus-host disease. The Lee symptom score is a common patient-reported outcome or symptom scale that was developed within chronic GVHD that has shown that chronic GVHD is associated with significant symptom burdens and quality of life impairments. The symptoms can predict outcomes and specific measures such as depression which have also been studied and they've also been associated with hospitalizations in both acute and chronic graft-versus-host disease.

(10:54): Patients with more severe chronic GVHD have reported worse quality of life and higher symptom burden. They're more likely to be taking medications for pain, anxiety and depression. These studies have shown that patients with GVHD have significantly worse scores in quality of life in patients with chronic GVHD severe symptoms compared to those who have never developed GVHD or only have mild or even resolved symptoms. The study also demonstrated that up to 40% of patients with active chronic GVHD were unable to work due to health reasons compared to only 12% whose chronic GVHD had resolved and 15% who had never had chronic graft-versus-host disease.

(11:44): Multiple studies have reported that chronic GVHD significantly contributes to cognitive, physical, and work disabilities. Additional studies using direct patient reported data have shown similar findings. This was an online patient survey of patients with chronic GVHD. It was an online survey administered in 2020 to adult patients who reported that they had chronic GVHD within the previous five years. And the respondents of the surveys reported information regarding their demographics, their disease, work status, chronic GVHD symptoms and their impacts on activities of daily living.

(12:18): Based on these survey questions, disability was categorized into cognitive disability, physical disability and work disability as defined here. Things like patients who scored seven to 10 that was deemed as severe in regard to severe limitations to things like managing personal finances or social interactions or computer use. Severe physical disability was reporting severe limitations in things like dressing, eating, moving around the house, doing housework or getting outside the home and then work disability with any report of taking disability leave or leaving a job because of graft-versus-host disease.

(13:02): In this study, 47% of respondents reported severe cognitive disability while 67% reported severe physical disability and 63% reported some work disability. Really just highlighting the significant impact that chronic GVHD and subsequent late effects patients have in their lives long-term.

(13:25): Why do we think transplant survivors are an increase for all of these late effects? The biology of these post-transplant late effects is likely influenced by a lot of different factors. They're the baseline risk factors like genetic susceptibility, lifestyle and health behaviors that can contribute to some of the development of some chronic health conditions.

(13:54): Previous chemotherapy and radiation, GVHD, medications, hormone changes, and chronic inflammation all contribute to late effects after transplant. But additional factors specific to transplant also include tissue injury that has been induced by radiation and chemotherapy exposure, potential development of graft-versus-host disease, the medications or immunosuppressive treatment for graft-versus-host disease and just as part of the transplant. And effects of this such as hormonal changes, chronic inflammation and the development of new risk factors all contribute to the development of late effects. And in addition, we know that the immune system changes quite a bit and it's quite suppressed for a long time and medications can also all be implicated in the potential development of late effects as well as second cancers.

(14:46): Guidelines have been developed to identify risk factors, screening recommendations, and prevention practices for transplant survivors. What do we do about this? I just spent all these slides talking about that the significant burden of what we know about late effects. What do we do about it? Back in 2012, recommendations were published from several transplant organizations including the American Society of Transplant and Cellular Therapy, as well as several other international organizations. They convened to provide recommendations for the screening and preventative practices of survivors of transplant. This paper provided guidelines for identifying the risk factors, screening tests and possible preventative measures for several different organ systems and potential complications and this really served as a foundation for survivorship care across many institutions. Largely considered the standard of care after transplant.

(15:39): Most recently, these guidelines have been updated and was recently published this past February of this year. These updated guidelines are really a reflection of the clear recognition that survivorship and late effects field is growing rapidly. Not only with just the sheer number of survivors including survivors of newer therapies like cellular therapies, but it's also important to acknowledge the growing amount of data in the field regarding the recognition of late effects and specific populations that it may affect.

(16:15): This is just a little figure. If you do a search of research articles including looking up transplant and late effects, you can see over the last decade there's been a tremendous growth of research and data coming from the field basically tripling the number of citations of manuscripts that have previously occurred over the last three decades. Really just underscoring that this is a real recognition of the needs of recognizing late effects.

(16:47): A multidisciplinary team of specialists is required to best care for transplant survivors with late effects of therapy. This is just a summary of some of the late effects that can cause burden to patients. This of course can all be impacted in some ways with the development of chronic GVHD. What we really know and want to emphasize is that the care of the transplant patient, both short-term but also long-term requires a multidisciplinary team and collaboration to coordinate care and to recognize these late effects.

(17:18): Even as you can see throughout this great symposium and the numerous sessions, there are a number of different providers that are from different subspecialties. They have expertise in different specific late effects. I'm highlighting just a few here on more specific information that in the rest of the talk I'll highlight certain topics like second cancers, bone health, psychosocial health, cognitive health and infection.

(17:45): Over the next several slides I'm going to highlight a few key late effects that I think are important in particular to recognize and highlight. And I'm going to first highlight cardiovascular disease. Cardiovascular disease and metabolic syndrome.

(18:08): Cardiovascular disease and metabolic syndrome are common late effects of therapy. What is metabolic syndrome? This is the name for a group of risk factors that can increase the rate of heart disease and stroke. There are four factors that are included in metabolic syndrome and those include abdominal obesity, high cholesterol or what we call dyslipidemia, high blood sugar and high blood pressure.

(18:29): Metabolic syndrome can affect up to 50% of post-transplant patients. Those with metabolic disease are 2-3 times more likely to develop cardiovascular disease. Transplant patients are predisposed to develop metabolic syndrome and subsequent cardiovascular disease through several ways. Again, as one of the prior figures showed, the chemotherapy-related damage to tissues, hormonal dysfunction as well as immune-related changes and inflammatory changes.  These effects can impact and underlie the reason why patients are more at risk for metabolic syndrome. And in the general population, individuals with metabolic syndrome are two to three times more likely to develop cardiovascular disease than those without metabolic syndrome. Metabolic syndrome has been reported to occur in up to nearly 50% of patients post-transplant.

(19:16): Several studies have now also investigated the incidence of heart disease after transplant. This study again as I mentioned is from the Bone Marrow Transplant Survivor Study. It demonstrated that allogeneic transplant survivors were at two times higher odds of coronary heart disease compared to their siblings and several cardiovascular risk factors were identified. Some of those factors including the metabolic syndrome like diabetes, high blood pressure and high cholesterol, and that these factors are shown in the graph are significantly higher risk of developing heart disease.

(19:54): Metabolic syndrome, prior exposure to anthracycline chemotherapy or radiation, chronic GVHD, smoking, age and irregular heart rhythm all are risk factors for developing coronary artery disease. Other risk factors have also been identified from previous studies. These include prior exposure to certain type of chemotherapy called anthracyclines, radiation to the chest and also possibly graft-versus-host disease with its chronic inflammatory state.

(20:10): Again, data from the Bone Marrow Transplant Survivor Study took some of these risk factors and developed a nomogram or a calculator to help predict risk of coronary artery disease after transplant to help identify who these patients may be. And these risk factors included things like age, smoking, diabetes, high blood pressure, history of an irregular heart rhythm and radiation.

(20:39): That data has increasingly shown us that there are a number of important factors that increase the risk of heart disease, again, what do we do about screening and prevention of this? These are guidelines. I know the next couple slides are a little bit busy tables, but these are guidelines that have been adapted from our survivorship transplant guidelines as well as the most recent American College of Cardiology and Heart Association guidelines on the primary prevention of cardiovascular disease.

(21:12): I just want to point out some key practical points and the first and foremost is just recognition of what the definitions of metabolic syndrome are, what qualifies as abdominal obesity, high cholesterol, insulin resistance or elevated glucose as well as high blood pressure. And importantly, just the need to screen for these early and regularly assess the need for prevention or treatment.

(21:39): Maintaining a healthy lifestyle, including proper diet and regular exercise, can help prevent the development of accelerated cardiovascular disease. These are things that are part of normal general population guidelines as well with a real emphasis on maintaining a healthy lifestyle and physical activity as well as a healthy diet. Again, it is important to monitor blood pressure and screen for diabetes. Just again emphasizing the need for ... All these things happen after a transplant but don't forget, the general health maintenance and recognition that these things are also important.  They should be part of routine and early monitoring as part of survivorship care. This is important, of course, because these things can all be things that we know we can potentially help and intervene on and hopefully also prevent the development of accelerated cardiovascular disease.

(22:27): I also wanted to point out there's a lot of ongoing research as to what is the best way to even improve the screening and improve the identification of patients who may be at higher risk for cardiovascular disease. These are just graphs from two early studies, a small number of patients, but investigating the use of coronary artery calcium scores. These are things that you potentially hear of even again are sometimes used in general population screening and may be predictive as well and transplant survivors and more predictive than the standard cardiovascular risk scoring systems like the Framingham risk score.

(23:09): Studies are underway to identify interventions that may prevent cardiovascular disease in transplant survivors. There are also several studies beginning to test interventions to prevent cardiovascular disease with the early use of medications such as cholesterol medications, some of the newer diabetic medications. Also, the use of certain supplements with the addition of exercise. And again, these are just examples. It's important to note that this is all still in early stages of research and there's no standard approach, just highlighting that there's still a lot of active research that's happening.

(23:40): Secondary cancers are a potential long-term effect seen in transplant survivors. There is a 22% increased risk of a second cancer 30 years post-transplant.  I'm going to move away from cardiovascular disease and talk about another key late effect that I want to highlight briefly. It's subsequent second cancers. And why this is as important is that it's been reported in several studies that second cancers tend to increase with longer survivor, particularly in younger age groups.

(24:00): In this study of nearly 5,000 patients transplanted at the Fred Hutchinson Cancer Center in Seattle, there's an overall increasing rate of 22% of a subsequent second cancer in these patients at 30 years after transplant. And these are things that potentially could be screened for and prevented as well.

(24:24): As I have just shown, the incidence of second cancers continues to rise over time after transplant with follow up even up to 20 years. The graph here on the left just demonstrates that the age-standardized cancer rates in the general population for several different solid cancers. This is, again, not necessarily transplant survivors but general population with the most common being breast, lung, colorectal and cervical cancer. And while transplant recipients are still at risk for these cancers similar to the general population, there's also an increased risk of specific types of cancers and in particular those are skin cancers, oral cavity, thyroid, esophageal cancers and liver cancers.

(25:06): Again, the next two slides are tables, but these have been adapted from recommendations again from our survivorship guidelines and American Cancer Society, just highlighting that the solid cancers that have an increased incidence compared to the general population. Some risk factors that might increase the risk. Which of course may include radiation or graft-versus-host disease and just really most importantly, the need for routine screening like routine skin exams.

(25:39): GVHD is a common risk factor for the development of secondary cancers. There are no specific guidelines for screening for things like esophageal and liver cancer. And overall, just to emphasize also these rates are relatively low. It's just important to be aware of risk factors and symptoms. And as you can see, GVHD tends to be a common potential risk factor for several of these second cancers. And these four solid cancers are the most common solid tumors and they have the highest incidence in the general population.

(26:07): Again, these are general screening guidelines adapted from our survivorship guidelines and for additional details on second cancers, Dr. Saro Armenian gave this talk this past Sunday. That should be up to be able to review if you want more details about new cancers after transplants and things you can do to prevent or reduce the risk.

(26:31): An increased risk of infections is observed in transplant recipients. Older age, chronic GVHD, and unrelated donors are all risk factors. Infections can contribute to death late after transplant. I'm going to move on to briefly highlight the immune system and late infections. Several older studies have tried to investigate the immune system. I always tell my patients the immune system is very complex. It's often very hard to definitively measure this, but they measured levels of antibodies against certain vaccines and what their overall findings was that actually immunity and long-term survivors were normal or near normal 20 to 30 years after transplant.

(27:02): However, despite this there have been other studies that have shown that still with longer-term adult and pediatric transplant patients, infections can still be a contributor to late death. Older age, chronic GVHD and the use of unrelated donors were risk factors for these late infections.

(27:24): And then something just important to point out, 7% of these patients in this study had vaccine-preventable infections as well. So just highlighting the importance of routine post-transplant vaccinations. These are standardly recommended vaccines and their general timeline. And again, for more detailed information on managing infections after transplant and cellular therapies, Dr. Eric Dubberke will be giving a talk about this on Friday.

(27:56): Bone mineral density loss is observed in 50-75% of transplant survivors. Risk factors for this include older age, being female, low body weight, poor nutrition, and chronic kidney and liver disease. Low bone mineral density is linked to a higher risk of fractures. Bone health is also an important and potentially preventable late-effect post-transplant. Bone mineral density loss is very common among transplant survivors. It has a reported incidence of 50 to 75% after allogeneic transplant. The majority of bone loss actually has been found to occur within the first three to six months after transplant. Survivors with reduced bone mineral density are increased risk for what we call fragility fractures that can occur spontaneously or just even with minimal trauma and occur at a rate of about two to 8%.

(28:33): Baseline risks tend to be similar to the general population and include age, being female, hormonal changes or low hormone levels, low body weight, poor nutrition and chronic liver or kidney disease. Additional transplant risk factors can be associated with things like what the underlying disease for the transplant was like multiple myeloma as well as lack of physical activity, nutritional deficiency, hormone changes and steroid exposure.

(29:03): Patients at high risk for bone loss may be treated as early as day 100. Treatment may include Calcium, Vitamin D and Bisphosphate medications.  for This is an algorithm that we tend to use. It was adapted from guidelines recently published based on expert opinions from the American Society of Transplant and Cell Therapy. Really advocating for early management of bone health through the transplant, even including pre-transplant assessment of risk factors and a bone density scan. It might be challenging to consider treatment in certain patients prior to transplant just given timing, but at least this is just considering a much more proactive approach to consider treatment even early post-transplant at day 100 or at one-year.

(29:42): Screening for calcium and vitamin D deficiency is important and therapy most commonly consists of treatments with bone strengtheners such as Bisphosphonates. Other drugs such as hormonal therapies may be considered in specific situations, although overall there's not as much data in the transplant population. Again, for more information there's a talk by Dr. Sarah Keller from the Cleveland Clinic that was also given this past Sunday.

(30:13): Psychological impacts such as depression, anxiety and distress are often seen after transplant. While we often focus and as I just did over the last many slides, reviewing late effects of organ dysfunction, it's also important to note that of course there's significant psychosocial impacts that can occur after transplant. As mentioned previously, anxiety, depression, financial toxicity, and overall quality of life. Again, this is data from the BMT Survivorship Study which shows that anxiety, depression, and distress were all significantly higher in transplant survivors compared to their sibling controls.

(30:43): Things like using steroids as part of treatment were associated with more distress and lower household income and self-reported poor health along with chronic GVHD were also associated with an increased risk.

(31:02): There are a myriad of other late effects and symptoms that unfortunately just given time, we don't have a lot to go into detail but are recognized and as important symptoms to screen for and address. These include things like hormonal changes, changes in thyroid function, iron overload and peripheral neuropathy, neurocognitive dysfunction, muscle cramping, fatigue and anxiety. Again, there are several talks throughout the symposium that are speaking in more detail regarding some of these specific topics that are great to tune into.

(31:40): In my last few slides I'm going to talk about how we address survivorship care. And I think I went over, highlighting just why it's important to establish survivorship care and I want to just review historically what we know about how patients receive care.

(31:54): It is crucial to establish survivorship care. Patients with low income, lack of insurance, and from racial minorities are at an increased risk of not receiving survivorship care. This data is again from that Bone Marrow Transplant Survivorship Study cohort where adult patients who had survived at least two years after transplant. And what was found was that among patients who have survived over 20 years, only about 50% underwent routine checkups. Only about 37% reported BMT specific visits and only about 28% reported any cancer center visits at all. In contrast the presence of chronic health conditions and chronic GVHD of course increased the rate of needing healthcare and this also includes things like emergency visits and hospitalization. Things like lack of insurance, racial and ethnic minorities, they were associated with a lower prevalence of routine checkups and transplant center visits as well. And unfortunately, lower income also increased the odds of things like ER visits and highlighting that there's a real gap there.

(33:10): The study from Canada also investigated the rate of transplant survivors to their primary care physicians and their adherents to recommended preventative medicine interventions in the years post-transplant. They found that even though, before transplant up to 80% of patients had at least one visit with their primary care physician, by the fifth year of transplant, 36% did not see their primary care physician at all and the rates of routine health screening was really quite low.

(33:41): It's only 20 to 25% having a cholesterol screen, 20% with a diabetes screen, 30% had breast cancer screening and 17% had cervical cancer screening and only 20% had colon cancer screening. Really just a large gap in patients seeking care.

(34:03): It is important for survivors to establish and maintain a healthy lifestyle. Smoking, heavy alcohol intake and minimal exercise all contribute to poor outcomes.  Also, just emphasizing the importance of a healthy lifestyle. This study, again from the BTC survivors today also demonstrates that risky health behaviors such as smoking, heavy alcohol use and lower physical activity were all associated with worse outcomes.

(34:20): An evidence-based, flexible model of survivorship care is necessary to ensure the needs of post-transplant patients are met. How do we address all these needs? As part of that National Institutes of Health or NIH Late Effects initiative, they also convened a group to specifically address healthcare delivery. This is an ideal model or framework for patient- and caregiver-centered care. Really focusing on the patient, then caregiver, impacted by the survivorship experience.  This really called for being responsive to healthcare needs, models that were accessible and affordable that could be coordinated with local providers or a multidisciplinary team.  Also, it can be dynamic and adaptable as healthcare status can change over time. Of course, that survivorship should really be based on evidence and data that we know of high quality and individualized to patient specific exposures.

(35:18): Early assessment, identification and treatment of transplant related late effects is required. This is just an example of how we try to address some of the needs and how we currently approach some of our survivorship care, which is really focused on early assessments and early identification, both prior to transplant and during the transplant process to screen for late effects.

(35:39): Multidisciplinary, formal survivorship visits at days 100 and one year can be helpful for appropriate screening and treatment of long-term effects.   Patients who undergo their normal pre-transplant testing and workup, of course assess their organ function and their psychosocial support. But we also obtain several baseline assessments which we consider part of survivorship care to monitor changes post-transplant and at longer time points follow up. Formal survivorship visits with a provider are done at day 100 to include further screening a graft-versus-host disease evaluation, multidisciplinary care with nutrition and pharmacy and social work as well as specific evaluations for bone health, neurocognitive screening, physical functioning and metabolic syndrome evaluation. And each patient is provided a treatment summary and care plan at each time point.

(36:36): Goals of ongoing survivorship care include empowering and educating patients. Another formal survivorship visit's done at one year that again includes similar screening and evaluations and cancer screening and referrals to a team as needed. We try to do this based on what we know of the evidence and evidence-based guidelines. These are being updated with the 2023 ASTCT International Survivorship Guidelines. We know that not all care models can be like this. While we have the capability of providing the care at our center, we really emphasize that the goals for survivorship clinic are really to empower and educate you as patients in your own survivorship care and really any provider can potentially help and coordinate some of the survivorship care as well.

(37:29): Lastly, I just wanted to show some of the survivorship resources that are available and these are now supplements within our survivorship guidelines as part of the American Society of Transplant Cellular therapy. There's several links and I know BMT InfoNet also is included. This is a wonderful resource for patients, particularly in the transition of care returning to work or school as well as patient, partner and peer support. Again, these are now included in our ASTCT guidelines.

(38:07): In summary, we know that the number of transplant survivors continues to increase. We know that there's a significant burden of late effects including organ dysfunction, second cancers and a number of psychosocial late effects. There is active research that's ongoing to better understand and intervene on these. And I always advocate for survivorship care beginning early and taking a very patient-centered approach. With that, that's the end of my presentation and I'm happy to take any questions.

Question and Answer Session

(38:44): [Jordan Sexton]:  Wonderful. Thank you very much Dr. Hamilton. That was excellent. We're now going to begin the question-and-answer session. Our first question is where can survivors get help creating a care plan if our transplant center simply will not do it?

This person had a stem cell transplant in 2008 at a clinic that doesn't provide long-term follow-up care and they seem to be struggling in getting their healthcare teams on board with the current recommendations and have been considered a hypochondriac when they feel they're just trying to follow the guidelines that are provided.

(39:30): [Dr. Betty Hamilton]:  Yeah. I think we're hoping, I think as a community, and someone obviously who's interested in survivorship in their transplant community, really trying to disseminate what we know about survivorship and the importance of these survivorship care plans and screening It's an important question. I think there are a lot of resources out there now available. Some of the links that were on the slide and within our guidelines are survivorship care type templates. The National Marrow Donor program also is a resource where you can find more information about what a survivorship care plan looks like. There are also many centers. I know it can be very difficult to travel and find some of this information, but there are centers that will see patients for cancer survivorship or transplant survivorship even if you weren't a primary patient. There are potentially several options that are available.

(40:33): [Jordan Sexton]:  Excellent. Thank you. Okay, the next person says they are five months out from transplant for AML and a recent BM biopsy showed that cancer is coming back. There has been talk of a second transplant and they would like to know what is the success rate for second transplants. They're uncertain if they want to go through all of it again just to have it fail and they are 62 without any comorbidities.

(40:59): [Dr. Betty Hamilton]:  That's always challenging and I'm sorry that it seems like the disease is coming back so soon after the transplant. Unfortunately, there's a lot of factors that go into the success of a second transplant and obviously lots of different measures of success. I think those are questions that are probably best to talk with your primary team about just in terms of getting the best numbers and pros and cons. It's obviously not an ideal situation to have to go through a whole second transplant. It definitely can be successful, but there are a lot of different factors that impact the outcome of something like that.

(41:45): [Jordan Sexton]:  Thank you. And the next question is what are the types of GI issues you can have post-transplant that are not GVHD? This questioner is four years out and still has a lot of GI issues but also did CAR-T and Keytruda.

(42:01): [Dr. Betty Hamilton]:  Yeah. That can also be a challenge. Sometimes after a transplant, we always think about GVHD first, but sometimes the biopsy is just not consistent or symptoms are not consistent.

There's, unfortunately, a whole host of GI issues that cannot be GVHD but can still have symptoms related to it. I have patients who are very sensitive to certain foods become lactose intolerant. Sometimes they're almost like a neuropathy. Like their gut is slow and the transit of foods is not as fast as normal.

Sometimes patients actually have structural abnormalities like narrowing of certain areas. And sometimes it can be a little bit difficult to figure out and to definitively say exactly what it is, but they continue to have some of these symptoms. This is where when it becomes challenging, collaboration not only with your transplant team but a gastroenterologist or a specialist who is well tuned to seeing not only transplant patients but can think outside of that box as well.

(43:27): [Jordan Sexton]:  All right. Our next question asks if you could please comment on the effectiveness of the use of autologous serum tears for ocular GVHD. Should this be used regularly to prevent flares of eye GVHD and is acetylcysteine 10% compounded eyedrops useful for eye GVHD causing Filamentary Keratitis by breaking down the strands or filaments on the cornea eyes if GVHD is flaring?

(43:59): [Dr. Betty Hamilton]:  I'm not quite sure I can answer all those questions. Again, some of these specific organ GVHD questions, I work very closely with ophthalmologists and ocular specialists. I can say that autologous serum tears can be very effective in ocular GVHD. 

Although we've made great advances in how we treat GVHD, there's still no one medicine that fits all. Autologous serum tears, If you're able to get them, if you're at a center that can make them, often they're not covered by insurance, so if you can afford them, they can be very effective in treating GVHD. I guess by treating you will also prevent flares as well if you continue to use them. They're just another tool in the toolbox to treat GVHD.

In regard to the acetylcysteine drops, I will have to defer that question. I'm actually not as familiar with that specifically. And then I do say that we often see this keratitis type of stuff. Again, I defer to your ophthalmologists and exactly how they treat it, but I would say that when I have patients who have that it is typically associated with GVHD.

(45:24): [Jordan Sexton]:  Awesome. Okay. Next question comes from someone who would like to know if you could react to the COVID vaccination in post-transplant patients or any reaction to the COVID vaccination in post-transplant patients?

(45:37): [Dr. Betty Hamilton]:  Yeah. In general, as I said in my talk, there are many vaccine-preventable infections that occur and COVID has now become just like any respiratory virus. The flu virus, the RSV virus, several different viruses that we have vaccines for now that in general I recommend.

There is some conflicting data about whether some of these vaccines, of course particularly the COVID vaccine, if it can contribute to any flares in GVHD. I think that there's some conflicting data. It's possible that by boosting the immune system in a way it's also potentially causing the immune system to react and can react in a GVHD type of way.  It's all about risk-benefit, and we oftentimes discuss this individually with a patient, such as how controlled their GVHD is, what their risk of infections is, what type of safety, and other things that they use to try to stay safe, particularly during the respiratory viral season.

(46:56): [Jordan Sexton]:  Our next question comes from someone who says they lost the lining of their stomach a few days after their transplant. Can that eventually heal totally and if so, how long does it take?

(47:10): [Dr. Betty Hamilton]:  I'm not 100% sure what's meant by losing the lining. During transplant, the high doses of chemotherapy certainly can really cause a lot of damage and irritation, inflammation to the lining. I think most of the lining everywhere from our mouth down to our intestines are all lined by white cells and our chemotherapy and radiation we know gets rid of that. But our bodies and our stem cells, our white cells have a remarkable ability to recover. In that way we expect the gut to recover. As someone asked earlier, I think you can still have some late complications from that or late effects from that, whether the gut fully returns to normal in all cases, that's not always true, but most of the time I would expect any normal mucosal recovery.

(48:20): All right. Our next two questions are actually from two different people but they're relatively similar so I will lump them. It is how do we make sure that our other doctors are aware of our increased risks after BMT? I find that I need to inform my other doctors and as a follow-up, are there any best approaches to get primary care doctors more informed on this topic?

(48:44): [Dr. Betty Hamilton]:  That's a great question. I think just in survivorship care in general, cancer survivorship care, we're still trying to figure out what the best model is that can be really disseminated not only in large centers, but in smaller centers and more rural populations and areas where people are not as familiar with the literature.

There is, which is publicly accessible, a lot of literature that is out there that physicians and providers can kind of look up and see. I mentioned our 2023 updated society survivorship screening guidelines. Those are publicly available. There are also resources, some of the NMDP links, and other resources.

It unfortunately does sometimes take patient empowerment. It takes the patient to help inform and educate and guide that as well. Just like organizations like this in the symposium, these are available for providers to see. We all as providers continue to learn. I think there's no perfect answer. It's something that we're all still striving to disseminate this information and how to work best with primary care physicians and other providers.

(50:30): [Jordan Sexton]:  Cool. All right. And is it only possible for allogeneic transplant patients to get GVHD?

(50:42): [Dr. Betty Hamilton]:  I guess the short answer to is that yes. The three major cellular therapies that we do are allogeneic transplant and that's where we see most graft-versus-host disease. Autologous stem cell transplant, that's not really recognized that one can get GVHD. There are some rare case reports where people describe what we call autologous GVHD, but whether that's actually something is debated. And then similar in CAR-T, we don't see graft-versus-host disease in that setting unless someone's already had an allotransplant.

(51:26): [Jordan Sexton]:  This person was diagnosed with MDS at the age of 72 and received a donor marrow transplant 13 months ago without any side effects. Great news. Does having MDS make it more likely to get cancer again?

(51:42): [Dr. Betty Hamilton]:  No, not necessarily. There are some rare genetic predisposition syndromes that might increase risk of cancers, but no, not specifically the disease itself. It's just the exposure to chemo baseline risk factors, genetic risk factors, but not specifically the disease itself.

(52:06): [Jordan Sexton]:  Good deal. All right. And how often would you say are patients diagnosed with two types of leukemia simultaneously?

(52:18): [Dr. Betty Hamilton]:  Overall, very rare. There are certain leukemias that can't necessarily be defined and called undifferentiated or biphenotypic because they have characteristics of both. But in general, it's quite rare to have two different blood cancers. We do see it occasionally, though. If someone has a leukemia and then they have for example some low-grade myeloma process, those are just examples. We do occasionally, but overall, it's rare.

(52:59): [Jordan Sexton]:  Okay. This person says they're two and a half years out of BMT. Have you ever had anyone with experience on GVHD that affects their ability to walk? This person is currently unable to walk and feels as if their brain and feet are not listening to each other.

(53:20): [Dr. Betty Hamilton]:  It depends on why they're unable to walk. There are some manifestations of GVHD that can, and again rare, but can affect the nerves and can affect the muscles. And so those are uncommon or atypical manifestations of graft-versus-host disease. Oftentimes, it requires a pretty extensive evaluation. Again, collaboration, for example, with a neurologist or somebody who has a lot of expertise in the neuromuscular system to make sure that we're ruling out other causes is very important. There are some atypical manifestations that can affect the nerves and muscles that might be related. But again, other things need to be ruled out beforehand.

(54:19): [Jordan Sexton]:  Okay. We have a couple of dietary questions here. Will eating an anti-inflammatory diet make a difference in cardiovascular risk and do you have any thoughts on omega oils?

(54:32): [Dr. Betty Hamilton]:  I unfortunately don't have specific recommendations regarding specific supplements. I do think in general, yes. There's not much data for an anti-inflammatory diet, particularly within a transplant population. I think that probably if you look at all the data across several decades, probably the type of diet that has the most data in terms of cardiovascular health is the Mediterranean diet. I would say that we know that for the general population, abiding by these healthy lifestyles and increased physical activity can decrease cardiovascular risk.

(55:20): [Jordan Sexton]:  All right. We have about four minutes left, so we just have time for one more question here. This person has not been able to receive an MMR vaccine and they find it concerning that there have been measles outbreaks recently. Are you aware of any non-live vaccines being created or is there a possibility that the donor's immunity is sufficient, that the titers come back showing some immunity for measles?

(55:53): [Dr. Betty Hamilton]:  Yeah. This can be a challenging situation, particularly when again, like they said, when there are outbreaks. Again, it's all about risk-benefit and trying to use smart practices.  Certain populations that are not MMR vaccinated you want to avoid. Here in Ohio, I tell my patients who aren't vaccinated and don't have any titers to avoid the Amish community and things like that. But there are no inactivated vaccines that I'm aware of for MMR.

We do check titer, so antibodies against the measles, mumps or rubella. And we do consider that you're fairly protected if there's detectable antibodies. Now, what's interesting is that we actually don't know if those are donor antibodies or just recipient antibodies that have lingered. It's an interesting question. But if we can detect them, we do rely on that they're there and can provide protection. If you do have antibodies there, I would say that you're fairly protected.

(57:04): [Jordan Sexton]:  Awesome. Well, I think that has to be our last question, but I just want to thank you very much on behalf of BMT InfoNet and our partners. Thank you very much, Dr. Hamilton. This was an excellent presentation. And thank everyone in the audience for your excellent questions. We apologize if we weren't able to get to everybody. Please contact BMT InfoNet if we can help you in any way.

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