Late Effects after a Transplant Using Donor Cells (Allogeneic Transplant)

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Late Effects after a Transplant Using Donor Cells (Allogeneic Transplant)

April 17, 2021

Presenter: Catherine Lee, MD, Assistant Professor of Medicine in Division of Hematology/BMT, Huntsman Cancer Institute, University of Utah Health

Presentation is 32 minutes long with 20 minutes of Q & A.

Summary: The number of long-term survivors of hematopoietic cell transplants (bone marrow, stem cell, and cord blood) is dramatically increasing. However, up to two thirds of survivors report at least one chronic health condition as a late effect of treatment.  This presentation describes these effects and interventions to treat them.

Highlights:

• Late effects may arise from pre-transplant exposures, cancer treatment itself, graft-versus-host disease, or a patient’s inherent risk factors.
• Transplant survivors have about triple the risk of developing secondary cancers that can affect many different parts of the body.
• Fatigue is the most common late effect among survivors, and it can arise from many causes. Interventions include exercise, improved sleep, treating pain, and cognitive and behavioral therapy.

Key Points:

(04:07) “Long term” effects begin during treatment whereas “late effects” were absent or not clinically obvious during treatment but appear thereafter.

(05:26) Late effects can impact physical, emotional and spiritual health and have a significant impact on a survivor’s overall well-being.

(08:31) Damaged DNA. and prolonged inflammation, and immune dysfunction can all be triggers for late effects.

10:55) Transplant survivors have an increased risk of cardiac effects like coronary artery disease and cardiomyopathy.

(13:23) Secondary cancers can affect the skin, thyroid, mouth, neck, breast, cervix, and esophagus.

(14:59) There are screening recommendations for each of these cancers that may lead to early detection and treatment.

(18:25) Bone disorders may arise from steroids and radiation. Interventions include bone scans, weight-bearing exercises, and monitoring calcium and vitamin D levels.

(25:22) Neurocognitive changes such as memory loss often appear posttransplant but can improve and return to normal within one to five years after transplant.

(27:47) Additional late effects may affect the eyes, mouth, kidneys, or liver.  Peripheral neuropathy is also a very common late effect of chemotherapy and radiation.

(29:39) High quality survivorship may require multiple specialists. Patients should know their treatment risks and be pro-active in addressing them.

Transcript of Presentation:

(00:00) [Michelle Kosik]     Introduction. Good morning. My name is Michelle Kosik and welcome to the workshop: Late Effects after a Transplant Using Donor Cells. It is my pleasure to introduce Dr. Catherine Lee. Dr. Lee is an assistant professor of medicine in the Division of Hematology/BMT at the University of Utah's Huntsman Cancer Institute. She specializes in adult autologous and allogeneic stem cell transplantation and directs the chronic graft-versus-host disease long-term follow-up program. Dr. Lee's research includes clinical trials for chronic GvHD, intervention to improve access to high-quality BMT care and optimizing the health of post-transplant patients. Please join me in welcoming Dr. Lee.

(00:50) [Catherine Lee]     Overview of talk. Hello, everyone. Thank you so much for your participation in the 2021 Celebrating a Second Chance of Life Survivorship Symposium. My name is Dr. Lee, Catherine Lee, and I am from the Huntsman Cancer Center at the University of Utah in Salt Lake City where I perform bone marrow transplantation and cellular therapies such as CAR-T therapy for adult patients. I'm the physician-champion for our BMT long-term follow-up program which focuses on providing medical and supportive care for survivors of transplant and cellular therapies. I would like to thank the organizers for inviting me to give this presentation on late effects after a transplant using donor cells.

(01:29) So today's agenda today is to discuss the following. First, I'm going to talk about current trends in survivorship. Next, focus on why survivorship is important. Thirdly, we'll then delve into the medical late effects with the focus on screening, prevention and treatment. And lastly, we'll summarize how to thrive after a donor transplant or an allogeneic transplant.

(02:00) The number of transplant survivors is dramatically increasing. So, transplant survivors are gathering force. In 2010, there were approximately 110,000 transplant survivors in the United States. The number of transplant survivors increased by 2.5 times in 2020 and is estimated to increase by five times by the year 2030. Approximately 60% of the survivors are recipients of autologous transplantation and 40% of allogeneic transplantation. By 2030, 60% of transplant survivors will be between the ages of 18 to 59. Additionally, we have started to see a growing number of survivors who receive chimeric antigen receptor T cell therapy for diffuse large B-cell lymphoma and acute lymphoblastic leukemia and they will also become an important survivor population.

(02:52) So continuing survivor trends, but also discussing why survivorship is important. Well, despite improvements in long-term survival due to improved transplantation techniques and supportive care, many survivors suffer from negative long-term effects of this otherwise curative therapy. Survival could come with the price.

(03:14) But two thirds of transplant survivors report at least one chronic health condition. Approximately 66% of patients of BMT survivors report at least one chronic health condition compared to 39% of healthy siblings. 79% of survivors have a non-malignant late effect at five years after bone marrow transplantation, so they have a late effect that is not a cancer late effect. Life expectancy among five-year survivors remains 30% lower compared to the general population. So that means there is work to be done to improve these outcomes in our transplant survivors.

Now let us turn our attention to the physical, medical and psychosocial effects of allogeneic transplant. However first, we should differentiate between long-term effects and late effects of treatment.

(04:07) Distinguishing long-term versus late effects. So long-term effects are characterized by symptoms that began while undergoing treatment and they can linger for months or even years. Some examples of medical long-term effects are fatigue, neuropathy and other pain syndromes, premature menopause, infertility, chemo brain, cataracts, sexual dysfunction, anxiety, depression.

(04:36) Medical late effects are toxicities that were absent or not clinically obvious at the end of cancer treatment but show after treatment has ended. Some common late effects of allogeneic transplant are cardiovascular disorders such as coronary artery disease and congestive heart failure, secondary cancers, bone diseases such as osteopenia and osteoporosis, endocrine disorders such as diabetes, thyroid and low sex hormones, chronic graft-versus-host disease, neurocognitive impairments, infertility, lung disorders, kidney diseases, liver diseases and infections. These late effects can begin a few months after treatment has ended or years later.

(05:26) Late effects impact physical, emotional and spiritual health. Medical late effects can have a significant impact on a survivor's well-being and affect individuals' physical health, emotional and spiritual health and as well relationships. Late effects can take a toll on premature aging, cognitive issues, physical symptoms, disabilities and can ultimately cause loss of job, financial problems, disabilities, separations and divorce, suicidal thoughts for some survivors and you may have experienced some of these consequences that I have listed here.

(06:00) Late effects may arise from pre-transplant exposures and initial treatment.  Well, after many years of research, we have begun to understand why late effects develop after donor transplantation. It begins with the individual's pre-transplant exposures and comorbidities. Examples of pre-transplant exposures and comorbidities include a history of smoking and or alcohol, exposure to chemicals or radiation. To occupational work or obesity or high blood pressure present before the cancer diagnosis. These baseline exposures or habits could contribute to chronic medical conditions late after transplant. Fortunately, some can be reversed during the transplant journey.

(06:35) They may also arise from chemotherapy, radiation, and steroids to prepare for transplant. As we move on, the patient is diagnosed with cancer and begins cancer treatments or the primary treatments usually with chemotherapy with or without radiation. These treatments in themselves not only injure and kill cancer cells, but they can injure healthy cells such as the heart which may result in clinical changes down the road. Sometimes high doses of corticosteroids such as prednisone or dexamethasone or some that you may be familiar with, are used with these treatments and long exposure to the steroids can cause high sugar levels or injure the bone.

(07:07) When the patient moves forward to bone marrow transplant, more chemotherapy and possibly radiation is used as part of the bone marrow transplant conditioning regimen. This again not only helps the transplant to work but can also damage organs of the body.

(07:22) Late effects may arise from graft-versus-host disease. After transplant, several complications can occur which may affect long-term health. One of the most important complications is graft-versus-host disease, a syndrome where the donor cells attack the patient's own organs and can cause organ injury and inflammation. The condition itself and the treatments used to control graft-versus-host disease can damage the body and cause long-term health problems. Other exposures during transplant such as to infections or medications can also potentially affect different organs.

(07:53) Patients’ inherent risk factors also  play a role. Lastly, throughout the continuity of a cancer diagnosis and its treatments are the patient's inherent risk factors for the development of late effects. A patient's genetic predisposition, lifestyle factors such as diet and exercise, age and gender may influence the development of late medical effects. For example, a 45-year-old male who has a family history of heart disease and early age heart attacks among males in the family, may be at a higher risk of developing coronary artery disease after transplant compared to a 65-year-old female who has a healthy lifestyle and no history of heart disease in the family.

(08:31) Damaged DNA and prolonged inflammation, immune dysfunction can trigger late effects. Well, what leads to these medical late effects. We know some of the biological mechanisms leading to medical late effects after transplant. Damage to the DNA in the cells directly from chemotherapy or radiation causes the cell to not function properly and can lead to cell damage and death. When enough cell damage and death has occurred within an organ, the organ may not work as well as it used to be. One example of this is the heart. I like to use a heart as an example many times because I feel that everyone knows that the heart is a very important organ. When enough cells are injured in the heart, the heart cannot pump as well and may not be able to push blood to the rest of the organs efficiently.

(9:13) In addition to direct damage to the DNA and cells from chemotherapy, radiation, other medications, prolonged inflammation such as graft-versus-host disease and immune dysfunction can also injure organs, delay the healing process and make patients vulnerable to infections.

(09:34) As I mentioned about two slides ago, we know that recognizing an individual's baseline risk factors is so important in determining how to prevent or intervene on late effects. We need to consider the patient's past medical history which include past and current medical problems. We need to look at the family medical history for a history of cancer syndromes, early heart disease or diabetes. We need to look at the patient's occupational exposures to chemicals, to sun exposure and other airway irritants. Lifestyle factors are also very important to know and are very specific to certain individual. This includes activity and exercise, habits, diet, sleep, social supports and the patient's own coping and resiliency. Again habits, we need to know the patient's smoking history, alcohol, any alcohol use or illicit drug use.

(10:34) And now we are going to review some key medical effects that occur after transplant. We will focus on the following including heart disease, secondary cancers, bone disorders, endocrine disorders, lung disorders, iron overload, neurocognitive changes, fatigue, sexual dysfunction and infertility and others.

(10:55) Transplant survivors have an increased risk of cardiac effects. So moving on to cardiac effects. So we know that BMT survivors have about a 1.4 to 3.5 times higher risk of heart disease compared to the general population. Complications that I mentioned before, the two main complications that we look for are coronary artery disease and cardiomyopathy or a heart failure. Risk factors include certain chemotherapy. Particularly anthracyclines. And examples of these are medications called doxorubicin or idarubicin.

(11:25) Radiation to the chest or to the total body which is sometimes used in preoperative regimen for bone marrow transplant, having any graft-versus-host disease, exposure to high-dose steroids or having baseline risk factors such as high blood pressure, abnormal cholesterol levels, diabetes, being obese or having significant history of alcohol, smoking habits or having an inactive lifestyle are risk factors for these cardiac complications.

(11:57) Interventions and screening for cardiac effects. Interventions include controlling the blood pressure, controlling cholesterol and diabetes, controlling weight and diet, promoting exercise, stopping any use of smoking or alcohol, excessive use of smoking or alcohol and possibly having a health or wellness coach and being in support groups, are very excellent interventions for preventing cardiac late effects.

(12:26) Screening tests may include an EKG or an echocardiogram and possibly a cardiac stress test. Here in our program, we calculate the Framingham Risk Score which estimates a 10-year chance of having a heart attack. If a patient is found to have an elevated risk score, we send our patients to one of our cardiology colleagues who's very interested in heart health after bone marrow transplantation.

(12:58) Transplant survivors have triple the risk of secondary cancers. Next, we'll focus on the secondary cancers that can occur after transplant. So BMT survivors have a three times higher risk of another cancer occurring after transplant. This can be a solid tumor such as blood cancer or skin cancer or could be another blood cancer that was different from the cancer for which the transplant was performed. The risk of that particular cancer depends on the exposure.

(13:23) Possible secondary cancers include skin, thyroid, and oropharyngeal cancers. So, risk factors for key secondary cancers. For skin cancers, we know that having acute and chronic graft-versus-host disease, being on long-term immunosuppression medications or being exposed to high doses of total body irradiation, having a transplant at a young age or having fair skin, are key risk factors.

(13:45) For the thyroid cancer, having total body irradiation, being female or having chronic graft-versus-host disease have been reported risk factors for thyroid cancer.

(13:54) For oropharyngeal, having sustained chronic graft-versus-host disease, being on prolonged immunosuppression, having any local radiation to the mouth-neck area, being male, having a history of tobacco use and having a positive history of human papillomavirus are risk factors for oropharyngeal cancer.

(14:17)  Potential secondary cancers also include breast, cervical and esophageal cancers. Breast cancer, being exposed to total body irradiation prior to age 30, having a history of radiation to the chest or having a family history of breast cancer are risk factors.

(14:27) For cervical cancer, chronic graft-versus-host disease, having human papillomavirus and being as well on prolonged immunosuppression are risk factor for cervical cancer.

(14:39) For esophageal, chronic graft-versus-host disease and being on prolonged immunosuppression has been reported as risk factors and for therapy-related myelodysplastic syndrome or acute myeloid leukemia, prior chemotherapy or radiation are the usual causes of having these secondary cancers.

(14:59) There are screening recommendations for potential secondary cancers. So the cancer screening recommendations are listed here for some of these cancers. For skin cancer, we recommend routine skin exam at least annually. For patients who are found to actually have either squamous cell skin cancer or melanoma or basal cell cancer, their dermatologist may recommend more frequent skin exams.

(15:25) We recommend for the whole survivorship population, broad spectrum sunscreen use and the bottle should say that there's protection against UVA and UVB. We also recommend avoiding peak sun hours, wearing sunglasses, hats and other protective clothing. And there is also a detergent called SunGuard, which can be purchased at usual CVS, Walgreens pharmacies where it's a detergent that can be thrown into your laundry and essentially acts as sort of a sunblock on clothes.

(16:03) For thyroid cancer, we recommend an annual physical exam.

(16:07) For oral pharyngeal cancer, the recommendations include having an exam, a physical exam every six to 12 months depending on the patient's risk factors, a dental exam at least every six months, encourage smoking and alcohol cessation, so stopping any tobacco use or alcohol use and vaccination against human papillomavirus as indicated.

(16:34) For lung cancer, the recommendations follow the recommendations for the general population which is screening with low dose CT scan or a CAT scan for high-risk groups and you can read here what these high risk groups are. We also encourage stopping any tobacco products use.

(16:56) For breast cancer for our transplant survivors who are between age 20 to 40 years, a clinical breast exam every one to three years. After age 40, female should receive an annual clinical breast exam and they should also receive an annual mammogram. And for those patients who receive total body irradiation or radiation to the chest, these females should start undergoing clinical breast exam, an annual mammogram or an annual breast MRI at age 25 years or starting eight years after radiation whichever comes first, but no later than age 40.

(17:34) And for cervical cancer, it is important to continue your annual Pap tests and HPV DNA tests until recommended to stop by your gynecologist and as well human papillomavirus vaccination is indicated for those in high-risk groups.

(17:51) For esophageal cancer, we recommend symptom-based screening which includes endoscopy for patients who have severe GERD syndromes or acid reflux symptoms or who have difficulty swallowing.

(18:06) And for colorectal cancer starting at age 50, we recommend having a fecal occult blood or fecal immunochemical test once a year or undergoing sigmoidoscopy or a special type of CAT scan of the colon every five years or having a colonoscopy every 10 years.

(18:25) Bone disorders may arise after transplant due to steroids and radiation. Moving on to bone health and bone disorders. So we know that BMT survivors have a 20% incidence of osteoporosis by two years post-transplant. Majority of the bone loss occurs within three to six months after transplant. So complications include osteoporosis or osteopenia, this means very weak bones. Some patients can have compression fractures or bone fractures and some patients have avascular necrosis. This is essentially areas of the bone that are dying.

(18:55) Risk factors, the most common culprits of this are steroids, high doses and prolonged use of steroids to help treat GvHD. Graft-versus-host disease in itself is a risk factor for bone disorders, low hypogonadism or low estrogen, low testosterone levels. Radiation is also a culprit, prolonged immunosuppression, low vitamin D levels are a risk factor and we try to supplement low vitamin D levels, having a sedentary lifestyle and as well as age, race and smoking are risk factors.

(19:37) Interventions can help with bone disorders. So interventions include increasing physical activity, particularly having weight-bearing exercises included in your exercise, repleting calcium and vitamin D levels, offering bisphosphonates for those who have severe bone disease and offering hormone replacement therapy. Screening tests include checking vitamin D levels, having a bone density scan or bone X-ray every one to two years and checking parathyroid level in some patients.

(20:11) Endocrine disorders including diabetes may also occur. So moving on to endocrine disorders, complications include having a low thyroid function otherwise known as hypothyroidism. Symptoms of hypothyroidism usually include being fatigued, feeling cold, having dry skin, noticing weight gain or having signs of depression. Risk factors can include radiation therapy and some chemotherapy treatments. Intervention, the main intervention is replacing thyroid hormone. Screening tests include thyroid hormone levels, checking TSH level and a free T4 level.

(20:48) Another common endocrine disorder is diabetes. Symptoms of diabetes sometimes there are none. Otherwise, some patients will have increased thirst, they may have frequent urination, they may report feeling fatigued and some patients may complain of having blurry vision. Risk factors, again, the main risk factor is long-term use of steroids for cancer treatment or for graft-versus-host disease. Interventions include optimizing diet and exercise and using insulin or oral medication for the treatment of diabetes. Screening tests to diagnose diabetes include the hemoglobin A1C test and checking glucose levels.

(21:31) And third, endocrine disorder that is often seen is something called hypogonadism. This is essentially where there are low sex hormones and leading to sexual dysfunction. Symptoms can include having low sex drive, being fatigued, women having vaginal changes and pain, ovarian failure and men having complaints of erectile dysfunction. Risk factors include radiation to the pelvic area, the testes or the spine and the brain. Total body irradiation is also a culprit and having high doses of chemotherapy can be a risk factor.

(22:07) Interventions for endocrine disorders. Interventions include hormone replacement when safe, testosterone placement for certain symptoms and we want to make sure that for men, the PSA level is checked. PSA stands for prostate specific antigen, as sub testosterone replacement can elevate the PSA levels and be a risk factor for prostate cancer. Sometimes a referral to endocrine gynecology and neurology is appropriate and so these are things to keep in mind. Screening tests include checking hormone levels such as estradiol, follicular-stimulating hormone, luteinizing hormone, morning testosterone levels and free testosterone levels.

(22:48) Lung disorders and interventions. Moving on to lung disorders. Typical complications, the main complication is bronchiolitis obliterans syndrome and recurrent lung infections and fibrosis. Risk factors include chest radiation, total body irradiation, chemotherapy and again any history of smoking or other lung diseases. And chronic graft-versus-host disease is a risk factor for long-term lung disorders.

(23:18) Interventions include pulmonary rehabilitation, exercise, again, stopping smoking, making sure that you receive the appropriate immunizations to prevent infections and receiving intravenous immunoglobulin are very important interventions. Screening tests include serial or interval pulmonary function tests and CAT scan imaging of the chest.

(23:48) Iron overload and interventions. Iron overload is another late effect of transplant, and this is a syndrome when too much iron may be stored in organs including the bone marrow or the liver or this spleen and sometimes the heart. Symptoms of iron overload include fatigue, muscle and joint pain, abdominal pain and too much iron in the organs can cause damage. And as I said before, this usually happens to the liver, the pancreas, the heart and the endocrine system and patients will then end up having organ specific symptoms.

(24:24) Risk factors, the main risk factors in the transplant world are frequent blood transfusions. Some patients will have genetic susceptibility to having iron overload and it's through questioning the patient and performing certain genetic tests that we would determine this.

(24:43) Interventions include removing the iron either through phlebotomy, such as... And what that is essentially is donating blood, it's similar to like donating blood where we just take blood out of the patients or giving medication called chelators to help bind the iron. Screening tests include lab tests such as ferritin and transferrin saturation level. If these are elevated or if there is suspicion of iron overload, an MRI of the liver called a T2 Star MRI can be very useful for quantifying iron deposition in the liver and the heart.

(25:22) Neurocognitive changes such as memory loss have several causes and interventions. So neurocognitive changes are often very common after transplant. Symptoms include short-term memory loss, slow thinking, word-finding difficulty, learning impairment and executive function impairment. It typically declines around 80 days after transplant but it can return to pre-transplant levels at the one-year mark and it may continue to improve one to five years after transplant. I believe there's another presentation on cognitive health after transplant, so for those interested, that would be a great presentation to listen to.

(25:59) Risk factors for neurocognitive changes include brain radiation and chemotherapy including systemic or intravenous chemotherapy or chemotherapy given intrathecally or directly into the central nervous system. Immune dysfunction can cause neurocognitive changes as well as drug toxicity, steroids, again. Certain infections, infections that are found in the central nervous system can cause these neurocognitive changes and critical illness often causes delirium and neurocognitive changes later on.

(26:31) Interventions include rehabilitation. For some patients who report trouble focusing or feeling that they could use help with attention, we sometimes can prescribe Methylphenidate or Modafinil to help with energy and fatigue related to this.

(26:50) Fatigue is the most common late effect among survivors. And then moving on to fatigue. This is the most common concern among survivors. Risk factors include stress, anxiety, depression, pain, treatment-related effects, poor sleep, deconditioning, poor nutrition and dehydration and there are other many other causes fatigue.

(27:08) So how do we intervene on this? Well, we treat any underlying medical cause of fatigue. Exercise has been shown to help improve fatigue levels. Sleep could be very important in improving fatigue, relaxation techniques have been shown to be very useful, treating any pain syndrome can alleviate fatigue. Cognitive and behavioral therapy, again has also been shown in clinical trials to be useful and referral to supportive oncology, a palliative care could be very useful in terms of assessing fatigue and offering interventions.

(27:47) Additional late effects may affect the eyes, mouth, kidneys, or liver. Other late effects which we'll summarize here include ocular effects. Premature cataracts and dry eye syndrome are common after transplant. Interventions include protecting the eye from the sun, so wearing sunglasses. And again, we recommend having at least an annual eye exam.

(28:06) Oral late effects including having dry mouth and cavities. So important here is having a routine dental exam, cleaning, routine X-rays and having routine fluoride treatment. There is a toothpaste called PreviDent 5000 which is a prescription toothpaste that needs to be prescribed by a dentist or a physician. But essentially this is a toothpaste that works very well in some of my patients who complain of dry mouth. So again, the name of that toothpaste is called PreviDent 5000, it's made by Colgate.

(28:41) Chronic kidney dysfunction, it can sometimes happen after transplant and what needs to be done is to check the urine protein and possibly referral to a kidney doctor may be necessary.

(28:54) Liver complications after transplant include having a fatty liver, scarring in the liver otherwise known as cirrhosis or having hepatitis of the liver. So prevention techniques include avoiding any alcohol and improving diet and exercise and checking for any viral etiologies of hepatitis after transplant.

(29:14) Peripheral neuropathy is a common late effect. Peripheral neuropathy is very common associated with chemotherapy and radiation. For patients who have this and who may not have good sensory feeling on their feet, it would be wise to see a foot doctor once a year and to have a foot exam to examine for any wounds or ulcers that you may not necessarily be aware of.

(29:39) High quality survivorship may require multiple specialists. So, I want to highlight here that high-quality survivorship care can take a village of experts to meet each survivors’ unique physical, social, psychosocial and spiritual needs. Specialists may include all of these: cardiology, pulmonary expert and endocrinology, mental health professional, physical and occupational therapy, neurology, sexual health experts, fertility experts, supportive oncology and palliative care, social workers and primary care physicians. These are essentially your partners in having you thrive in your after-transplant life.

(30:21) Patients should know their treatment risks and be pro-active in addressing them. So in summary, I just like to make the following points. Medical late effects commonly occur after a donor transplant. Know your treatment and the risk of the treatments that you received. Be informed and ask your healthcare providers questions, don't be afraid to ask questions. Actively own your health and follow recommendations for prevention and intervention and ultimately commit to lifelong follow-up.

(30:52) Some resources from Be the Match. So with that, let me make you aware of this resource from Be The Match of the National Marrow Donor Program. It's a mobile application that contains after transplant guidelines for patients who received allogeneic transplant and includes information about what care should be focused on and given a key checkup time points such as a six month and the one-year checkup. And also has a chronic GvHD symptom checker and the ability to set reminders for appointments. You can search for transplant guidelines in the App Store to download. These guidelines are also available online and in print form and here is a website where you can go to get more information about this app.

(31:34) Lastly, I'd like to inform you of a work-in-progress being done by the National Marrow Donor Program to help improve quality of life for BMT survivors who do not otherwise receive or have access to comprehensive survivorship care. The goal of this group effort is to create and examine the effectiveness of a virtual survivorship program which includes the following elements. So individualized survivorship care plans, scheduled follow-up appointment with a nurse practitioner, a clinical consultation service, help with care coordination, access to critical resources and then ultimately an evaluation of the program's impact on the patient's quality of life. So this is currently in the works right now, once it is out in some of the transplant programs, I encourage you to ask your physician if it's available at your program. Now we can move on to questions.

(32:33) [Michelle Kosik]      Q & A. Thank you, Dr. Lee for this excellent presentation. We will now take questions. As a reminder, if you have questions, please type them in the chat box on the lower left-hand corner of your screen.

(32:46) And our first question is: I'm 14 years-post allogeneic T cell-depleted transplant. I have read some disconcerting news regarding COVID and immunocompromised vaccinated people. I'm hearing conflicting reports regarding COVID vaccine effectiveness in this situation. What are your thoughts?

(33:09) [Catherine Lee]      Yeah, this is a common concern, this is a great question, it's a very appropriate question. So I will say that right now in the transplant community, we don't have enough scientific data yet to really understand the impact and efficacy of the COVID vaccines on our transplant survivors. There is a big initiative and it may have already started where many other transplant centers are collecting blood samples from patients and collecting information on patients. And the goal is for the transplant programs to come together to share the information and to study how COVID affects highly-immunocompromised patients, such as a transplant patients and to also study the impact of the COVID vaccine on our transplant survivors. So that research is ongoing right now and hopefully over the next year, we'll start having preliminary data which will mature over the next couple of years.

(34:21) I will say that according to expert recommendations, according to all the transplant guidelines, American Society of Transplantation and Cellular Therapies, we recommend our highly-immunocompromised patients to receive the COVID vaccine. At our center, we recommend the Moderna and the Pfizer vaccines, the mRNA vaccines over the other existing vaccines. There are certain populations of patients such as those with graft-versus-host disease on high-dose immunosuppressive therapy such as steroids, who we may delay vaccines because we do not feel that they may have most robust response to vaccines. So we wait until those patients, the GvHD becomes a little bit more quiescent or has lower doses of Prednisone and immunosuppression before we vaccinate. So and this may be where the conflicting results are coming from, even within the BMT survivor population, we have very different patients.

(35:29) [Michelle Kosik]     Perfect. The next question is: I am 28 years out from my BMT and I've experienced just about every medical challenge possible. Is my graft-versus-host disease playing a part in these medical challenges and can I expect more issues from it?

(35:51) [Catherine Lee]      A wonderful question. Based on what I'm being told and obviously I am not looking at your own medical records right now, so it's very difficult for me to nail the specifics, but we know that patients who have long-standing active graft-versus-host disease and who have been exposed to long treatments of immunosuppression medications including steroids or other drugs such as tacrolimus or cyclosporine can have many late effects or long-term complications of graft-versus-host disease and its treatments. Some of the complications are difficult to completely eradicate. Some other complications, we can prevent further complications from happening.

(36:47) So for example of that latter example, osteoporosis. So patients who develop osteoporosis or weak bones because of graft-versus-host disease and its treatments, we try to prevent further long-term sequelae such as fractures or osteonecrosis and the way we do this is by making sure patients are supplemented on vitamin D, calcium, making sure they get bisphosphonates, making sure that they get appropriate physical therapy, they have optimum exercise curriculum including weight-bearing therapies. So that complication can be managed with our current interventions.

(37:33) It's difficult for me to say what other complications can occur without really understanding your medical history, infections. Recurrent infections are pretty common in patients who have long standing graft-versus-host disease and who continue to have graft-versus-host disease, particularly if patients are still under receiving immunosuppressive treatment, so recurrent infections are very common. I think what's very important is to really target those late effects that you might be having now and to prevent further damage down the road. So if you could talk to your provider and focus on bone health, prevention of secondary cancers, prevention of heart disease, these are some very high yield areas where you could prevent further negative consequences down the road.

(38:29) [Michelle Kosik]      Thank you, Dr. Lee. The next question: I had a stem cell transplant in 2014, I've been very lucky and I've done well. I have had many skin cancers and extreme pain in my neck, hands, arms and shoulders when this person's muscles are being used. Is that a common thing?

(38:52) [Catherine Lee]      Yes, so I will say skin cancers are quite common particularly if you have certain risk factors such as you're fair skinned. You might be out and if you're not using any protective clothing or sunblock and you're exposed to intense sun here in Utah, because we're at a higher altitude, our patients are a little bit more at risk for skin cancers. So skin cancers are common after transplant, as well as muscle aches and joint aches. Sometimes the treatment for skin cancers which oftentimes is surgery or radiation and sometimes chemotherapy, can lead to joint aches and muscle aches and nerve pain. So it can be tied into the skin cancer and its treatment.

(39:50) Oftentimes as well though, the muscle aches, the joint aches could be occurring due to a different reason and that should be evaluated. One should look at vitamin D levels because low vitamin D levels can often make someone have muscle aches and joint aches. Another common cause that sometimes overlooked is iron overload. Having too much iron can cause muscle aches and joint aches. And then hopefully you're being evaluated for any possible graft-versus-host disease because sometimes graft-versus-host disease is a disease of the skin and the underlying fascia can also lead to muscle aches and joint aches and nerve sensitivity. So while skin cancers in their treatments can be linked to these muscle complaints, you definitely want to evaluate for other causes.

(40:46) [Michelle Kosik]      Our next question is: I am 35 years post-transplant and I have had avascular necrosis in my joints due to prednisone. Is there a treatment and is it reversible? Is hyperbaric treatment an option?

(41:02) [Catherine Lee]      Oh, that's a very interesting question. So if you've already had osteonecrosis, I don't know the... Again, I'm not reading your chats, I don't know the extent of your osteonecrosis. I'm not sure if you have required surgery and joint replacement but oftentimes for patients who have had severe osteonecrosis in the hip, surgery is usually necessary with joint replacement. Other than surgery, again, if you're not at that point, making sure that your calcium and vitamin D levels are repleted is very important, making sure that you're receiving bisphosphonates treatment is very important. And then again, exercise, weight-bearing exercises can be useful. So while osteonecrosis is not necessarily reversible, there are interventions which can be done to prevent further damage.

(42:02) Now, the second part of the question, hyperbaric oxygen chambers. So hyperbaric oxygen chambers these days based upon my knowledge, and I actually had to look this up for a patient the other day, is at least at the University of Utah in our other medical hospitals here in Utah, hyperbaric oxygen chambers are being really used for wound-healing, mainly wound-healing. Of course, research is going on where hyperbaric oxygen is being tested for other indications such as traumatic brain injury. I have not heard yet about hyperbaric oxygen and its applicability for osteoporosis or avascular necrosis. But there is another presentation I believe on bone health, so that is a great place to ask the expert that question.

(43:04) [Michelle Kosik]      Thank you. Is it common for IgG levels to remain lowered post-transplant?

(43:13) [Catherine Lee]       Yes. And so typically, depending how far you are in transplant, we typically see low immunoglobulin G levels and what we define as low immunoglobulin G levels is a level 400 or less. Some institutions use 500 as a threshold. We can see low immunoglobulin levels, normally up to one year in patients who are not having any graft-versus-host disease or other complications. So immunoglobulin G is usually the one we check. Immunoglobulin levels are produced from B-lymphocytes. When B-lymphocytes mature into plasma cells, plasma cells are the cells that will make these immunoglobulin antibodies that help patients fight against infection or prevent infection.

(44:07) Now some patients who received therapies that eradicate the B-lymphocytes, and a common drug is called rituximab, they will have prolonged low immunoglobulin G levels and that's because the B-lymphocytes are not there anymore. And after the medication such as rituximab is finished, it can take approximately at least six months for those B-lymphocytes to recover and to start making those immunoglobulin levels again. So yes, naturally after transplant, immunoglobulin levels are low. Without complications such as graft-versus-host disease or any other type of treatment, immunoglobulin levels will usually normalize by the one-year mark for patients who have immune dysfunction such as graft-versus-host disease or received B cell-depleting who like rituximab, those immunoglobulin levels will remain lower. And for those patients who have recurrent infections, those patients who receive IVIg or intravenous immunoglobulins to help bring that level back up.

(45:16) [Michelle Kosik]      That's a great response, thank you, Dr. Lee. There are a lot of questions on wanting to define prolonged immunosuppression and defining what is high-dose steroids usage and specifically one of our audience members asked, is one milligram of tacrolimus two times a day, a moderate dose after three years since transplant?

(45:49) [Catherine Lee]      Yeah, great question. So kind of trying to summarize all my answers for this. So prolonged immunosuppression, so in a, okay, I'll call it a normal allogeneic transplant. Once a patient reaches the day 100 mark and their bone marrow biopsy looks clear and that there's no evidence of disease and there's no evidence of graft-versus-host disease, most transplant physicians will start tapering off the immunosuppression so that most patients are off their immunosuppression by six to nine months after transplant as long as there is no evidence of graft-versus-host disease showing up. So that's the normal. So definitely by one year, most patients who've had uncomplicated transplant, will be off their immunosuppression.

(46:39) Now what we mean by prolonged immunosuppression are really patients because chiefly of graft-versus-host disease, they need to be on prolonged treatment with tacrolimus, sirolimus, cyclosporine or they are receiving high-dose steroids. And how we define high-dose steroids is usually a prednisone dose or another steroids with an equivalent prednisone dose of 20 milligrams per day or higher for at least two weeks. And sometimes some people will use three months as the kind of a threshold as prolonged steroid use. So typically, in the graft-versus-host disease world, most our patients are on prednisone doses of 60 to 100 milligrams per day or even sometimes twice a day for at least eight weeks and then they start tapering very slowly over the next three to six months.

(47:34) So all those patients have now received high doses of prolonged steroid exposure and these patients are typically on therapeutic doses of tacrolimus for many months. Now as the GvHD becomes quiescent or inactive, most patients immunosuppression will start to be tapered and tacrolimus, again, we'll also be tapered over time. Each patient is very different, their metabolism of tacrolimus is very different among patients. So a one milligram twice a day dose for one patient could lead to a level of two or possibly not even be detected in one patient, whereas a dose of one milligram twice a day, could lead to a tacrolimus level of 10 or higher and another patient.

(48:28) So it's hard to say that in general, what the dose of one milligram twice a day is, it really just depends on the trough level that is detected in you when you're on tacrolimus. The most important in terms of tacrolimus effect on late effects, is seeing whether Tacrolimus is causing... Some of the toxicity of Tacrolimus include having high blood pressure and later on injury to the kidneys. So if there is evidence that a patient's kidney function is starting to decline and the patient is on tacrolimus, this should be investigated if the tacrolimus is causing the kidney issues. And the most definitive way of doing that is a kidney biopsy but other measures, non-invasive measures could be done first such as looking at protein and creatinine levels in the urine and a referral to a kidney doctor could be useful. So that's just one example of a toxicity due to tacrolimus.

(49:34) [Michelle Kosik]     Nice, robust response Dr. Lee, thank you. And now this will be our last question for this session. Are you seeing COVID shots escalating GVHD flares? What is being done to help with those that are at risk?

(49:50) [Catherine Lee]      This is a great question. So I run a GvHD clinic, I have been recommending my patients who have inactive or quiet, quiescent, a quiet GvHD and who are on minimal doses of immunosuppression - so that's a prednisone dose less than 20 milligrams or no prednisone or a very low dose tacrolimus, a dose for that patient -. I am recommending these patients to go get the COVID vaccine. For my other GvHD patients who have very active GvHD and who are on high-dose prednisone and therapeutic doses of calcineurin inhibitor, we are waiting. And the primary concern is that is because we just don't think the patient will be able to mount a good response against the vaccine. And also we are concerned about the vaccines effect on the patient's GvHD just in case some patients are able to mount an immune response against the vaccine and may also sort of incite or put some gasoline on the GvHD fire.

(51:00) In practice, I have seen a mixed picture. I have had a couple of patients who've come to me after their COVID vaccine who didn't have active GvHD at the time of the vaccine but who presented with symptoms of a GvHD flare after their vaccine, mainly after the second dose, but sometimes after the first dose. Can I say that this was caused by the vaccine? No, not with just the couple of handful of patients that I've seen this happen. It's an observation, it's something that I'm taking note of and I think many other transplant centers, we will be pooling our data together and comparing these observations. So definitely, we do not recommend, again, the vaccine where patients who have active GvHD on high-dose immunosuppression, we would still recommend it for patients who have inactive GvHD and on none or low immunosuppression.

(52:08) Because of benefits, because again, the benefits of the COVID vaccine, protecting the patient against the COVID infection, we think is much higher than the risk.

(52:19) [Michelle Kosik]      Closing. Wonderful, thank you for that. On behalf of BMT InfoNet and our partners, thank you Dr. Lee for your very helpful remarks and thank you the audience for your excellent questions.