Out of the Frying Pan and ...? Life after Transplant Using Donor Cells

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Out of the Frying Pan and ...?  Life after Transplant Using Donor Cells (allogeneic transplant)

Saturday, April 29, 2023

Presenter: Scott Rowley MD, FACP, MedStar Georgetown University Hospital

Presentation is 40 minutes long with 18 minutes of Q & A

Summary: Long-term health consequences of stem cell transplant using donor cells (an allogeneic transplant) are very real, although they affect a minority of patients and can often be treated effectively. This presentation reviews the most common problems following an allogeneic transplant and the therapies available to treat them.

(Please note that throughout this presentation, unless otherwise specified, the word "transplant" refers to bone marrow or stem cell transplants that use cells from a donor, not from the patient.)

Highlights: 

• Despite improvements, stem cell transplantation is associated with increased overall mortality and decreased life expectancy.  Causes of death after an allogeneic stem cell transplant (a transplant using cells from a donor)  include relapse, infections, secondary cancers, and heart disease.
• Stem cell transplant recipients can minimize post-transplant complications by receiving proper vaccinations, following cancer screening recommendations, and implementing lifestyle changes where appropriate.
• Caregivers are a crucial part of a successful transplant and follow-up care, but they often report social and psychological challenges like fatigue, sleep problems, depression, and anxiety arising from their role. Various interventions can help caregivers manage these challenges.

Key Points:

(06:12): Survival rates have improved for allogeneic stem cell transplant recipients, despite the fact that more older patients now undergo a transplant.

(09:35): Relapse is the primary cause of death after an allogeneic transplant, but is much less likely to occur once you're two years or more out after transplantation.

(10:18): Chronic GVHD is major concern after an allogeneic transplant.

(11:56): Organ damage as well as bone and joint damage can occur after an allogeneic transplant.

(12:27): Psychological and financial challenges are common after transplant.

(14:38): Transplant recipients may have up to double the relative risk of various medical problems compared to the general population, but these problems are still somewhat rare.

(20:36): Causes of death in transplant patients include relapse, infections, secondary cancers, and heart disease.

(21:00): Late fatal infections are a significant risk for transplant patients. Many can be prevented with vaccines or treated with antibiotics.

(27:55): Neurocognitive disorders may affect up to half of transplant recipients, particular soon after transplant.  Most transplant recipients recover from neurocognitive disorders with time.

(34:29): Transplant recipients should have a long-term survivorship plan that spells out recommended doctor visits, tests, scans, and screenings long-term after transplant.

Transcript of Presentation:

(00:01): [Michala O’Brien]:  Introduction. Welcome to the workshop, Out of the Frying Pan? Life After Transplant Using Donor Cells. My name is [Michala O’Brien]:  and I will be your moderator for this workshop.

(00:12): It's my pleasure to introduce you today to our speaker, Dr. Scott Rowley. Dr. Rowley is a professor of medicine and the Director of the Stem Cell Transplant and Cellular Immunotherapy Program at MedStar Georgetown University Hospital in Washington, DC. He is also the Medical Director of the Cellular Therapies Manufacturing Facilities at Hackensack University Medical Center in New Jersey. Dr. Rowley's research has focused on developing bone marrow graft processing and cryopreservation techniques.

(00:47): He served on the committee that wrote the standards for cell processing adopted by the Foundation for Accreditation of Cellular Therapy. He has also served on boards of the American Society for Transplantation and Cellular Therapy and the International Society for Chemotherapy and Graft Engineering. Please join me today in welcoming Dr. Rowley.

(01:14): [Dr. Scott Rowley]:  Overview of Talk. Thank you very much for the very kind introduction. I also want to thank BMT InfoNet, Susan Stewart, and her colleagues, for the opportunity to present to this group.

(01:29): My presentation today is an overview of late effects after allogeneic transplantation. And I gave a bit of a cute title to talk about out of the frying pan because we talk about various phases of transplantation, the initial hospital stay.

(01:45):  Up to half of people receiving allogeneic transplants will be admitted to the hospital for posttransplant complications and this usually happens within three months of transplant. I tell patients after they're discharged from the hospital, usually 12, 14, 18 days when they achieve engraftment, that now the work really starts because over the next several months there are many complications of transplantation that can arise, including infections as well as graft-versus-host disease and various complications. A third to half of people will be admitted to the hospital for some complication of allogeneic transplantation.

(02:10): But usually this settles down about three months after transplantation. People can return home if they're being transplanted at a distant facility or make the visits less often to the transplant program, if they have at a local transplant program as well.

(02:27): So, my presentation today will be an overview. It's an overview of survivorship. And basically, cancer survivorship is no longer a rare event.

(02:40): We're here focused on allogeneic transplantation and treatment of cancer, but there's been a considerable amount of survivorship research efforts and support going on across not just the United States, but also European countries and other countries as well. And from the moment of diagnosis, and for the balance of life, a person with cancer is a survivor. And there are quite a few people who are survivors. I'll show that in the subsequent slide.

(03:09): There are several possible late effects of transplant including secondary cancers, heart disease, and chronic graft-versus-host-disease (GVHD). But today what I want to do is address the late effects after allogeneic transplant. And at the conclusion of this presentation, I'd really like you to understand the long-term health risk after transplantation, particularly several primary health issues such as second cancers, heart disease and chronic graft-versus-host disease, and complications like that.

(03:33): We want you to be able to establish a proper long-term care plan with your physician, whether that be a transplant physician or, you're returning back home to your primary care physicians that have cared for you over the years. And we also want to address, time permitting, the care for your caregiver.

(03:50): Now, as I mentioned, cancer survivorship is no longer rare even. These are data from the United States and there's an estimated 18 million cancer survivors in the United States in 2022. The right-hand side shows that these are primarily people over the age of 65, because these cancers are primarily diseases of the older person. So, colon cancer, breast cancer, lung cancer, leukemia, myeloma. The diseases we transplant for are typically cancers of patients over 40 years of age.

(04:21): And you can see the orange segment of the graph, there are people over the age of 40 to 65. And the blue is the patients over the age of 65. So, we're dealing with lots and lots of people across the United States who are cancer survivors, not just the transplant patient, but also patients with other forms of cancers and other treatments.

(04:43): Allogeneic transplants have seen increasing survival rates over time. And we've seen this older age population in the United States transplantation as well. But let me just talk about the fact that we are seeing improved survival over time. I first became involved with transplantation at Johns Hopkins in 1981, so I'm involved in this field for about 40 years. And on the right-hand side, looking at the adult population, and just an aside here, I will be focusing primarily on adults. I'm an internist, not a pediatrician. So, on the right-hand side, age of patients who underwent transplantation over the age of 18 years. And you can see in the dark blue, 2001 to 2005, there was about a 30 to 40% probability of being alive at five years after allogeneic transplantation.

(05:34): If you look at five-year intervals, you can see that the survivorship rate continues to improve over time. And I would suspect that we're going to be over 60% with current data as transplant medicine continues to get better. So, we're seeing improved survival after allogeneic transplant as we get better at our treatments, our supportive care, and taking care of complications of transplantation, and this is going to directly result in more cancer survivors and more cancer caregivers. I do not want to forget about our caregivers as we go through this presentation today.

(06:12): Improving survival rates for allogeneic transplants have occurred even as older patients have received transplants. I mentioned that this improving survival is despite the fact we're treating older patients. In 1981, I sat with a woman who was 40 years of age and said, "You're kind of old for a transplant." And her response back to me was that she'd rather see her daughters get married than graduate from high school. So we went forward with the transplant.

(06:32): But what's happened over these decades is that we're able to deliver transplant medicine to older and older populations. And on the right-hand curve, you can see that about 20, 25% maybe approaching 30% of patients who undergo allogeneic transplantation are over the age of 65 now. And this is important because myeloma, leukemia, lymphomas are typically diseases of people who are over 60 years of age. And if you can't deliver transplant medicine to these people, then you are not treating a large population of people who might benefit from such treatment. So, there's been a real focus on being able to deliver transplant medicine to people of older ages.

(07:16): Older transplant patients are more likely to have comorbid health issues even before their transplant. But we also must look at the fact that older patients are more likely to have comorbid health issues such as high blood pressure, hyperlipidemia or cholesterol and triglycerides. They'd be more likely to have diabetes. They'd maybe be more likely to be obese, so the transplant teams have to be able to deal with a person who has other comorbid issues that we did not face when we were treating patients back in the 1980s.

(07:45): And this is shown here. The health issues that we are facing pre-diagnosis are a variety of different health issues. I just listed some of the common ones, high blood pressure, high cholesterol levels, high blood sugars, obesity, I mentioned these.

(08:01): We also have to deal with cancer-related complications. Bone damage, for example, is extremely common in patients with multiple myeloma. It's oftentimes how they present - a bone fracture, low back pain that just doesn't go away. And when they're evaluated, they find that they've had bone collapses or bone fractures.

(08:20): And we may have to deal with malnutrition. Even if somebody comes to transplantation with normal weight, they may be malnourished with loss of muscle mass. There can be organ damage as the result of the disease that they have, or the treatments that they received to try to get to remission.

(08:38): Additional health issues can arise after transplantation. And then, health issues that we face after transplantation. There are the treatment-related issues, such as heart disease, second cancer, ovarian failure, et cetera, et cetera. And preexisting health issues, you see on the left-hand side of the curve, may be exacerbated by transplantation.

(08:57): As we sit with patients, getting them ready for transplantation, we're looking at their comorbid health history where they have high blood pressure or high cholesterol or whatever, and try to develop a regimen that can bring them successfully through transplantation without a lot of treatment-related illnesses.

(09:19): Now, just to get a little bit on the morbid side here, let's talk about death after allogeneic transplantation. I've sat with many young physicians and said, "Okay, what is the primary problem with allogeneic transplantation?" They'll say, "graft-versus-host disease." And I'll say, "Wrong, it's relapse."

(09:35): Relapse is the primary cause of death after transplantation but is much less likely to occur once you're two years or more our after transplantation. The statistics I've heard is that 50% of all the relapses. that are likely to occur, will occur in the first year. And 50% of the next group of relapses will occur in the second year. So, you're up to 75%. And then it just becomes less and less common that you see relapses after two or three or more years after transplantation. Transplant programs are facing this. and are actively exploring consolidation or maintenance regimens after the transplant to reduce the risk of relapse.

(10:18): Chronic GVHD is another major concern after transplant. Chronic graft-versus-host disease is also a problem and is associated with an increased risk of ongoing infection and organ damage, both because of the suppression of the immune system, the recovery of the immune system, as well as the drugs that we use to treat chronic GVHD.

(10:34): And the current Holy Grail for transplant medicines is that we want our people to have both freedom of chronic GVHD and a very low risk of relapse. And so, a lot of the research that's going on in allogeneic transplantation now is looking for GRFS, GVHD and relapse-free survival.

(10:57): These are slides from the CIBMTR (Center for International Blood & Marrow Transplant Research). I don't know if people in this audience know, but all transplant programs in the United States are required, by law to submit data to a central database for every allogeneic transplant. And these data can be used to conduct research about questions of allogeneic transplantation.

(11:19): You can see in the lower right-hand corner that for patients who died after day 100, so still very early on, transplant relapse is the primary cause. That's the dark blue portion. There's a bit of a beige color that is GVHD, that'd be chronic GVHD at that point. And above that is infection 14%. Those two go together. So you can see, again, GVHD and relapse are the primary health issues or long-term health issues that we would see with after transplantation.

(11:52): And there'll be people who'll be talking about that as part of this symposium.

(11:56): Organ damage as well as bone and joint damage can occur after an allogeneic transplant. Cardiovascular disease, second cancers, there can be damage to lungs, liver, kidneys. There can be bone and joint damage, particularly with corticosteroid use, prednisone use.

(12:13): Oral health. People oftentimes have dry mouth after transplantation leading to loss of teeth if they don't have proper dental health care. There can be infections. There can be ocular complications, skin problems.

(12:27): Psychological and financial challenges are common after transplant. So, a variety of complications can occur after the treatment of cancer, not just transplantation. Other possible health issues that we see are well known after allogeneic transplantation, but also after other treatments. After cancer treatment, in general, there can be depression, or anxiety. An altered body image is very important.

(12:51): There can be changes in interpersonal relationships. How does a cancer survivor deal with friends and family members who have not had the experience of having cancer, and redevelop the interpersonal relationships that might have been changed by the fact that they are cancer survivors?

(13:07): There can be impacts on health and life insurance. You're very unlikely, as a cancer survivor, to be able to get a new life insurance policy. You may find that you have job lock. You can't get promotions, or you might have job loss. There'll be financial burdens. So, there are a variety of issues that are raised in cancer survivors.

(13:28): The concepts of relative risk and cumulative incidents are important in understanding posttransplant complications. Now I want to introduce a couple concepts. One is relative risk, and one is cumulative incidents. So relative risk is the likelihood that you will have a complication, as a transplant survivor, compared to a healthy individual.

(13:45): So this is a slide, published 20 years ago, and it looks at pediatric patients who are survivors of cancer treatments, not transplant, but cancer treatments. And the control group was a sibling, a brother or sister. So, you're dealing with a patient and a controlled population that have the same parents, grew up in the same house, grew up in the same neighborhood, have the same schooling, have the same financial resources.

(14:15): And if you look, for example, at the leukemia line, the second line down, you can see that the cancer patients would say that they were twice as likely, 2.2X, twice as likely, of having problems with general health; 3.8 times as likely of having functional impairment; 1.8 times as likely to have limitations in activity; and 1.7 times as likely to have problems with mental health.

(14:38): Transplant recipients may have up to double the relative risk of various medical problems occurring compared to the general population, but these problems are still somewhat rare. Now this sounds bad, that you're twice as likely to have a complication of something compared to your sibling. But a lot of these events are rare events. So, twice as likely of 1% is now 2%, which means that you're 98% likely not to have it. And so, when you start looking at relative risk, you have to look at your controlled population to see how likely it's occurring there.

(15:05): So here are the percentages. If you look at leukemia, yes, 9.6% of the survivors of leukemia treatment said that their general health was impaired; 9.3% said they had functional impairment; 8.6% had activity limitations; and 17.5% had mental health limitations. But if you look at the flip side of it, the glass half full side of it, that means that 90% of these patients are doing quite well after their treatment when they became adults.

(15:36): So, this is looking at the percentage of patients who develop limitations in their health versus their relative risk. Relative risk or twice as likely, but they're still small numbers. And we will see that throughout the data on the transplant here.

(15:53): Now, one of the things that we're facing as we get more and more sophisticated is trying to develop treatment plans for individual patients. And individual patients may have special needs.

(16:05): This is just a slide that's showing the racial proportions of patients undergoing allogeneic transplantation. Overwhelmingly this is a Caucasian population. But we do have racial and ethnic minorities that come through our treatment. But even in the Caucasian population, there are differences.

(16:24): Social determinants of health can also affect posttransplant quality of life. There's what we call the social determinants of health. And these include the economic stability of the patient and their family. Do they have access to education and quality? What's their access to healthcare and what's the quality of healthcare? Are you living three hours away from the city and your level three trauma centers and medical care centers? Or are you living in a city where it's just a taxi ride across town?

(16:50): What about your neighborhood environment? Are you living in an environment that has good water, good air? And certainly, the social community context, what's your supportive care available to you? And so, we, as transplant physicians, as we bring people to transplant and then send them back to their communities, we want to look at the whole needs of our patient, not just whether we took care of their leukemia.

(17:16): Now, I showed this slide earlier. I put asterisks on this. And actually, I think depression was on the lower right, that I didn't put an asterisk on, that I think it's being addressed also. But these are all health issues that are going to be specifically addressed through the six-day, seven-day symposium.

(17:32): So for example, Dr. Harris will be talking about graft-versus-host disease this afternoon and Dr. Lauren will talk about secondary cancers. We have a question-and-answer session tomorrow that's going to be talking about allogeneic transplantation. Thursday, we can talk about maintenance therapy, exercise, nutrition.

(17:51): So, a lot of these subjects will be talked throughout the symposium. So, I can't do any one of these justice in a limited timeframe here. But you will have other speakers who can present specific issues that you may be interested in.

(18:06): Now, let me go back to life expectancy. This is a slide of a study from a couple years ago, 2021. They looked at a 40-year population transplanted between 1974, which is when I graduated from high school and up to 2014. And they looked at patients who were alive two years after transplantation.

(18:32): They compared this to life table data from the Centers of Disease Control from the US government. They tried to find out what the life expectancy was for a person of the same sex and age and see how they compared in terms of their life expectancy. And what they found is that, over time there, has been a change in the patient populations undergoing transplantation.

(18:55): Over time, transplants for patients in their 60s and 70s have become much more common. I mentioned back in the 1980s, transplanting somebody over the age of 40 was pretty rare. It was pretty much a pediatric and young adult population with which we dealt. Now we're treating people in their 60s and 70s. There have been changes in the regiment that we use for transplantation, a variety of regimens.

(19:13): Changes in transplant methods and techniques have also improved over time. We have our maxis, our minis, our minis. We have changes in donor types. We can use unrelated donor transplants, mismatched family members, haploidentical donor transplants. And diseases have changed also. The chronic myelogenous leukemia used to be the number one reason why I came to work. And now, we have medications, oral medications, that control that disease quite nicely and we rarely see that disease. So there have been changes over time that transplant medicine has been studied and made available to people in the United States.

(19:45): Despite improvements, transplant is associated with increased overall mortality and decreased life expectancy by a number of measures. But what they did find was that there is an 8.8-fold increase overall mortality [compared to the control group]. It's highest at two to five years after transplant, the relative risk is 34-fold. But even 30 years after transplant, and again, these are people who are transplanted at a very young age, it's still a 5.4-fold increase in mortality.

(20:14): What they also found is that there was a decrease in life expectancy with about 8.7 years of life loss. So that means that if you're genetically going to live 90 years then you will live 83 years. And so, there are long-term effects of cancer treatment and possibly allogeneic transplantation.

(20:36): Causes of death in transplant patients include relapse, infections, secondary cancers, and heart disease. When they looked at the causes of death, they said relapse-related mortality was 12%. Again, these were people that were late after transplantation. But they did see other causes of death which we will address today, and those are infections, second cancer and heart disease, which were about 5 to 10% of the causes of death.

(21:00): Late fatal infections are a significant risk for transplant patients. Now let me go over those specific issues. So, health issues after transplantation, infectious diseases, late fatal infections. This is an analysis from the CIBMTR database: 10,000 adults, 5,000 pediatric patients. And they found that the infections were the cause of death for 31% of adults and 29% of children. But the probability of having an infectious death by 12 years after transplantation was 6% for adults and 2% for children.

(21:33): And the risk factors for fatal infections were older age; mismatched or unrelated donors, because of the wound to the immune system that comes from using mismatched donors; and chronic graft-versus-host disease, because its effect immune system recovery after transplant and the medications we use.

(21:55): Many transplant related infections are treatable with vaccines or antibiotics. But the good news is that many of these infections are vaccine or antibiotic preventable illnesses. The bad news, and this is an issue that I face with many people, I get this question about 'can I go on my bucket list, take the trip up the Amazon River' for example. And my answer to that is we have no way of knowing how robust your immune system is. And so that any travel outside of an area where you have good water supply, I would be very concerned about because I can't say to a person in my clinic that I know what their immune system will be like. So, there's always the risk of infections and we want to manage those risks.

(22:36): Second cancers like skin cancer are more likely in transplant recipients. What about second cancers? And, again, I'm going to give you the incidence ratio. This doesn't mean you're 7% likely to get it. It just means that compared to a healthy control, any skin cancer will be seven times more likely. We see a lot of those within the first year or two after transplantation, particularly squamous cell cancers and basal cell cancers. There's something about the immune system, that when it is suppressed, these cancers can arise.

(23:02): And we see this not just in transplantation, we also see it in treatment of autoimmune diseases, such as lupus or rheumatoid arthritis. Anytime you suppress the immune system, you can see some skin cancers arise. Fortunately, you detect them, you remove them, and you cure them. But other cancers such as thyroid cancer, mouth cancers can be seen with persistent GVHD or radiation therapy.

(23:27): Lung cancer really is tobacco use. As you can see, we're starting to see publications which say that the incidence of lung cancer is actually below the control group, 0.7%. And that's because we select patients preferably who do not have bad lungs coming to transplantation because of tobacco use.

(23:48): Breast cancer can be seen after transplantation, particularly in women who've had radiation therapy to the chest or younger age. We can see cancer of the cervix, a risk factor there is graft-versus-host disease.

(24:02): Colon cancer may or may not be increased. I have a mistake on the slide there, it's not five, it's 0.5 incidence ratio to 2.2%, but no specific risk factors reported and no specific risk factors for prostate cancer. Another common cancer in men after as we age. I won't say after transplantation, but as we age.

(24:26): Heart disease is more common in transplant recipients, especially if they have preexisting risk factors for heart disease and stroke. What about heart disease? Again, looking at the middle column, relative risk, a person who's had an allogeneic transplant is 2.7 times as likely to have a death from heart disease compared to a healthy control; is 1.4 times as likely to develop coronary artery disease and angina; is, 1.3 as likely to have a stroke.

(24:53): These risks go much higher if there are risk factors for heart disease and stroke. The risk factors are listed at the fourth bullet on the lower left-hand side of the slide here. Risk factors are high blood pressure, high lipid levels, cholesterol and triglycerides, diabetes, renal disease. And if you go to the far-right slide, you can see that the relative risk then really zooms if you have three of those risk factors. You have high blood pressure, high cholesterol, and diabetes, then your risk of stroke is very high.

(25:23): Transplant recipients are also at higher risk for metabolic syndrome.  Your risk of death from cardiovascular disease is 25 times the control group that doesn't have those issues. What is the likelihood, after transplantation, of seeing high cholesterol and high blood pressure and so forth? There's this illness called metabolic syndrome. It's a combination of high blood sugars, high blood pressure, high lipid levels, cholesterol, triglycerides, and abdominal fat. This is more common after transplantation than in patients who did not receive such treatment. The metabolic syndrome shown on the previous slide is associated with heart disease and death.

(26:13): I mentioned obesity as a risk factor here. Waist circumference, abdominal fat, is more informative than bone marrow index, your BMI.

(26:26): Loss of muscle mass and weight loss can also be complications of transplant. I mentioned earlier in the slides, the people that come to transplantation with loss of muscle. They're malnourished with loss of muscle mass. This can be seen even with normal weight. It's something we call sarcopenic obesity, where you lose your muscle mass, your muscles in your legs, your arms, your core muscles have been lost as a result of treatment or malnourishment, malnutrition as you go through treatment. But you can still come to transplantation with normal weight but an increase in body fat. So, you actually come to transplantation malnourished. And so, after transplantation there is a 2.3-fold increase in cholesterol levels or more risk to have a high blood cholesterol or blood triglycerides. You're two times more likely to have high blood pressure.

(27:15): These things come with aging, as well. I have to say that when I hit 70, I finally had to start my Lipitor for my high cholesterol levels and other medications for my prostate. They come with aging. But we also see that they increase with allogeneic transplantation. If you don't manage these risks, you can get an increased relative risk of coronary art disease, so that instead of being twice as likely to have heart disease, you're 12 times as likely, or as on the previous slide, even 25 to 30 times as likely to have heart disease.

(27:48): So, I'm laying out the groundwork of what we have to deal with after transplantation. I'll come to some slides as to how to manage these things.

(27:55): Neurocognitive disorders may affect up to half of transplant recipients, particular soon after transplant.  So neurocognitive disorders. I've had a lot of people complain about attention and concentration, particularly during the first three months after transplantation. And the domains that we talk about are attention, perceptual processing, learning, abstract thinking, motor function, emotions.

(28:18): Up to 58% of adult patients report that they have neurocognitive disorders. These data are limited for older patients, people in their 50s, 60s, and 70s, we don't know what's happening there yet. Studies need to be done.

(28:32): Most transplant recipients recover from neurocognitive disorders with time. The good news is most patients do recover to baseline in most of the domains, although many people will say they still have some mild symptoms at five years after transplant. I put some interventions in there, primarily to try to avoid medications. Try non-pharmaceutical interventions like weight loss, exercise, and good sleep hygiene to help improve the quality of life.

(29:04): Proper vaccination is crucial to minimizing posttransplant complications. So how do we prevent some of these things? So, one thing is proper vaccination. This grid is well-known in the transplant field. I know that there are political concerns in our country about vaccines and some people believe strongly in vaccines, some people don't. But these are our recommendations. You can see that starting at three months after transplant, we give a particular pneumonia vaccine called Prevnar13® and repeat that at six months, repeat it at 12 months. And then two years later we give a different vaccination for pneumonia.

(29:39): For people who are younger, the human papillomaviruses, we want to give this to both men and women because it not only prevents cervical cancer but can also prevent mouth cancer and throat cancer. Hepatitis B vaccines, the polio vaccines, the tetanus diphtheria vaccines, haemophilus meningococcal vaccines, whole series of vaccines.

(30:01): For people who are older and have had chicken pox, we give the recombinant shingles vaccine. If you've not had chicken pox and are younger patients, then we have to go with the live virus vaccine the Varivax® , first. But the live virus vaccines aren't given until at least two years after transplant if a person' is no longer being treated for graft versus those disease.

(30:26): Influenza vaccine, we recommend it every year. I've been getting my influenza vaccine every year for the past 40 years. I have no problems with it. I'm not addressing COVID vaccines. That's still shifting. We don't know what the answer's going to be there.

(30:43): Cancer screening for a variety of cancers is also highly recommended for transplant recipients. What about cancer screening? This is not specific to transplant. This is from the American Cancer Society, and they say, "Okay, we should be starting our colonoscopies or similar treatment for colon cancer at age 45. It used to be 50, but we're seeing colon cancer in younger people."

(31:02): Lung cancer is no specific screening unless you are a smoker, in which case, we would recommend low dose CT scans of the chest.

(31:10): Breast cancer, talk with your PCP if you've had radiation to the chest. Talk to your doctor. Talk with your oncologist. But starting at 45 years of age, you can see the annual mammograms. And the recommendations for cervical cancer and prostate cancer as well.

(31:31): Lifestyle changes can also reduce risks of posttransplant complications. Heart issues. There are a variety of tools to assess 10-year risk. When I started on my cholesterol medication, my internist did some magic on the internet and said, "Okay, your risk of developing heart disease over the next 10 years is X." I don't remember the number. So, there are a variety of tools to assess your risk. But you want to look at your dietary patterns and change your food, your diet, stay away from foods that might increase the risk of heart disease.

(32:00): Obesity, I mentioned, it does go back to BMI. But it really has to do with your abdominal girth; that's where the field of medicine is right now. Physical activity. I'm able to go to the YMCA and lift weights in a weight class twice a week. I have that opportunity and that'll help reduce my risk of cardiovascular disease. Watch for diabetes, watch your cholesterol, watch your blood pressure, avoid tobacco use. I put in here that no tobacco use has ever been shown to be beneficial to health.

(32:35): What about transitioning to general medical care? Is your transplant center your primary care team or do you have the benefit of a long-term clinic at your center or are you going back to your primary care physician? There are issues such as the distance from the transplant center, convenience, the medical expertise.

(32:54): Transplant teams should provide all medical care during the first several months posttransplant; then care can transition to primary care physicians. During the first three months after transplantation, I do not want an internist taking care of patients because of the drug-drug interaction. If a medication were to be started that I was not aware of, there could be other medications that I would need to adjust.

(33:08): And so, we try to provide all aspects of medical care during the first several months. But once people are free of many of the complications of allogeneic transplantation, we do offer the opportunity to go back to their local physician. It may be more convenient, parking might be easier, might be easier to get an appointment. But that's a personal decision for each individual patient.

(33:38): But how well are we doing here? How many people in this audience have visited their primary care physician over the past year? This is data from the University of Ottawa where there's less of an issue about health insurance keeping people from visiting their physicians. What they found was that pre-transplant, only about 17% of patients had visited a primary care physician. By five years after transplantation, only about a third, 36% of people, had visited their primary care physician. And what this translates into is a horrible result in terms of screening. Screening for the complications of transplantation. Looking at your cholesterol, 25% of people had a screening for cholesterol testing, 20% had diabetes screening, 30% had breast cancer screening.

(34:29): Transplant recipients should have long-term survivorship plans that spell out recommended doctor visits, tests, scans, and screenings. So that I think that we, as the medical care team, and the cancer survivors must be aware that there is a need to address long-term survivorship. So, for example, questions here: how often should you have a return visit? What follow-up tests, if any, should I have? How often will I need these tests? What symptoms should I watch for? If I develop any of these symptoms, whom should I call?

(34:56): And this, again, is not just transplant. This is from the general clinical oncology that says that failing to plan is planning to fail.

(35:05): How do we improve the quality of care for survivors? Patients should have written, ideally, a follow-up plan. But even a non-written follow-up plan if there's a good understanding of the likely cause of recovery from acute toxicities.

(35:19): What recommended cancer screening and other periodic testing should be done? What are the possible late and long-term effects of treatment? What are the impacts on your insurance, employment, financial consequences? What kind of ongoing health maintenance should I be involved in?

(35:36): Should I be receiving maintenance therapy? That'll be addressed by your primary oncologist, not your primary care physician. But should you be on maintenance therapy to reduce the risk of relapse? And you should be provided with a list of cancer-related resources and information. I have three slides at the end of my talk here that list just a short number of resources that you have.

(36:00): Caregivers are a crucial part of having a successful transplant and follow up care. Let me switch quickly for the next couple of minutes just to the caregiver. What do we know about the caregiver before and after transplantation? This is an extremely important issue because I will not take somebody to transplantation if they do not have a caregiver. I need to see that caregiver eye-to-eye. I need to be able to speak with that caregiver. I need to be able to know that the caregiver, who is going to be a member of my team and caring for the patient, is able, can do this care.

(36:27): Caregivers for transplant recipients report a number of social and psychological issues like fatigue, sleep problems, depression, and anxiety arising from their role. What we do know about caregivers is there's a fair amount of anxiety and depression that is present before transplantation and they may actually be higher in the caregiver than they are in the patient. Anxiety 46, 47% of caregivers report anxiety and depression, 16%. And these have to do with social support. Does the caregiver have support? Are they remotely located to a distant transplant program? How good are they at self-efficacy and coping with the caregiver burden? How much care are they required to give? What's the financial stability of the house?

(37:08): What do we know about caregivers? We now can recognize system clusters. These things go together. These clusters can occur as a group fatigue, sleep disturbance, depression, anxiety, cognitive difficulty, so-called chemo brain, you actually see in the caregivers as well. And it's probably a result of fatigue, sleep disturbance, poor nutrition, lack of exercise.

(37:30): We find that caregivers, who are lonely, have greater symptoms, and people who are much more self-sufficient will have lesser symptoms or fewer symptoms.

(37:40):There are intervention models that can help caregivers meet the social and psychological  challenges of caregiving. We can intervene. There are two intervention models. The one on the left, BMT-CARE was given during the first 60 days after transplant. The one on the right was given through the first 100 days after transplantation doing cognitive behavioral strategies, psychological counseling and so forth.

(37:59): And they find that they improve the caregiving burden, because of anxiety and depression, improve coping skills. And as a physician, when I see caregivers, I look to see that there is a good caregiver, but I also want to make sure that we have a caregiver team, that we're assessing our caregivers, that we have a good education system, that we're screening the caregivers for their needs as they go through the transplant course because they are team members.

(38:29): And just as I expect that the nurses and the doctors go home at night to get their sleep, I expect the caregivers to take care of themselves as well. Long-term, though, there are a lot of long-term caregiver issues as well. And you see it more in the women caregivers than the male partners.

(38:48): Caregivers report higher incidence of problems than control populations. Partners in patients reported worse sleep and sexual problems than control populations. They have worse fatigue. Both the caregivers and the patients report more cognitive dysfunction, the so-called chemo brain. They had worse impairments in mental health and depressive symptoms. But the caregivers, not the patients, reported they had lower social support, higher loneliness, and less satisfaction than in partnership than controls. So, these are issues that need to be addressed.

(39:16): I'm going to quickly sum up here. There are several caregiver issues. We're all probably going to be caregivers. My mother took care of my father during his pancreatic cancer. I have a brother taking care of my mother, now she's 94 years of age. For my in-laws, we were able to afford a caregiver in their house because they live in another part of the country.

(39:35): But there are several caregiver support programs out there. And just to give you these couple of slides here, you can look them up afterwards. But the caregivers have the right and actually have the duty to take care of themselves and to seek help, as they need it. to make sure they can continue to function as caregiver.

(39:55): Long-term health consequences of stem cell transplantation are very real, although they affect a minority of patients and can often be treated effectively. So, I want to sum up here with this: long-term health consequences of cancer and treatment are real. They're a minority of the patients, not a majority, but they are real. It is possible to establish a proper care plan to offset the risk of heart disease, infections, second cancers.

(40:11): And your caregiver also requires long-term support in recovering from the difficulty of going through a transplant and taking care of somebody that has cancer.

Question and Answer Session

(40:22): [Michala O’Brien]:  Thank you, Dr. Rowley, for this excellent presentation. We'll now begin the Q&A session. The first question is, "Tell us about why and when and how a person's blood can change from their O to the donor's B after transplant."

(40:53): [Dr. Scott Rowley]:  So allogeneic transplantation is organ transplantation. The bone marrow is an organ. It's an organ that you can't easily hold in your hands the way you can hold a heart or a lung or a kidney. This organ makes your blood. So, your blood is being made in the bone marrow. And in stem cell transplantation, you are actually receiving the hematopoietic or blood-forming stem cells from the donor.

(41:23): So, when these donor cells engraft, you are basically an identical twin with your donor in the bone marrow. The rest of you know. And we've had all sorts of comments made about, "Am I going to be like my donor?" "Am I going to have his personality or quirks or whatever?" But the answer is that no, your bone marrow will be the same as the donor. And the bone marrow makes the different cell lines, the white cells, red cells and platelets.

(41:54): And so, you'll make the red cells of the donor. This starts very early after transplantation, 7 to 12, 14 days later when we see engraftment. If we were to do a bone marrow at that point, we would see red cells being made as well. And they're going to be donor red cells.

(42:12): So, if your donor is a B and you are an O, your O cells will die off as your bone marrow dies off and the B cells will come up as the donor cells take over. Now, there are nuances here, you give a B cell graft to somebody who has O blood, are you going to see a transfusion reaction? And it's a possibility. We have ways of managing that and it's not really an issue that occurs during the first hour or so after the transplant, the actual infusion of cells.

(42:46): People who have a different blood type may take more red cell transfusions over time because the O person, their antibodies, because they will have anti-B will mow down the B red cells for a period of time. And so, somebody who's got a different blood type will take more red cell transfusions. But that wears off over time and I expect by 30, 40 days after transplantation, even those who have a different blood group will have donor red cells growing and become transfusion independent.

(43:19): So, it all has to do with the fact that the donor cells are going to grow up in there and you'll be making red cells, white cells and platelets that are equivalent to the donor itself.

(43:30): [Michala O’Brien]:  Okay, the second question is from a patient who's 18 months out of their allogeneic transplant, and they've suddenly started gaining a lot of weight. And their blood glucose levels are high, but they were very well controlled before the transplant. Does this eventually even out with the help from an endocrinologist?

(43:53): [Dr. Scott Rowley]:  Yes, it should even out. And it's going to require, though, an incredible amount of work because I think it's going to require not just management of medications, but also lifestyle changes as well. And so, there will have to be exercise as well as dietary changes as well as medication changes, especially if you are receiving certain medications, corticosteroids, for example, which wreak havoc with the ability to control blood sugar. But there are other medications such as cyclosporine that may have effects on blood glucose control as well. And then as you heal up from the transplant and are able to be weaned or tapered from these medications, that'll take a lot of the stress off but that metabolic syndrome that we see is more common after allogeneic transplant and is something that needs to be addressed. And you must work with your internist, your primary care physician, the nutritionist, and just focus on trying to get back to a good healthy body weight.

(44:58): [Michala O’Brien]:  Okay. This is a two-part question. "Do you need to be completely off immunosuppressants before vaccines are administered? And then, if you're having trouble getting off immunosuppressants after two years, what do you recommend?"

(45:13): [Dr. Scott Rowley]:  That's a two-part answer as well. So most of the vaccines on that grid are not live virus vaccines. And so, they can be given to a person without risk of inducing an infection. So, for example, if we give the Varivax®, the live chicken pox vaccine, to somebody who has a suppressed immune system, they can and oftentimes will develop chicken pox because they can't fight the virus. They can't control the virus.

(45:43): But on the other hand, the Prevnar13®, the Pneumovax vaccines, the tetanus vaccines, influenza vaccine, these are not live virus vaccines. And so, you cannot get illness from these vaccines. People talk about getting the flu vaccine, and they think the vaccine gave them the flu. Impossible. But a few years ago, I had the flu vaccine and I felt absolutely miserable. I said, "Now I know what people talk about." But it's a reaction to the flu vaccine. It's not the flu itself.

(46:16): And the next year I got my flu vaccine, and every year after that I've had my flu vaccine without that reaction. So, you can give the non-live virus vaccines to people who are early after transplant, three months, six months. You can give them to people who are on immunosuppression.

(46:34): But the other half of your question is what about the live virus vaccine? So the MMR vaccine, and for our younger patients who never had chickenpox and cannot get shingles vaccine, the Shingrix vaccine, you want to give them the Varivax®. Then we have a 2-1-8 rule. You want to be two years after transplantation and one year after being free of immunosuppression and at least eight months after IVIG, intravenous immunoglobulin.

(47:03): So that's a common so-called 2-1-8 rule because if you give the live virus vaccine to somebody who's on immunosuppression or early after transplantation, you run the risk that you're going to give them the disease.

(47:18): Fortunately, for a lot of these diseases, herd immunity comes to play. Now there are populations in our country, various neighborhoods, different populations that do not believe in vaccinations. And we see outbreaks of things such as chicken pox or measles. But for most of us, we're protected by the herd immunity. Most of the people in your community have received vaccinations. And so, it's very unlikely to see a very big outbreak of measles or chickenpox across your communities. You're protected by that. But no, we do not want to give these live virus vaccines early on after transplantation or while a person has immunotherapy.

(47:55): [Michala O’Brien]:  Okay. Here's another vaccination question. "Does Gardasil® vaccination help after you have human papillomavirus, and how often should you have PAP once you're diagnosed with HPV?

(48:11): [Dr. Scott Rowley]:  I don't have an answer for that. I mean, should we be vaccinating our older people? And that's a question, I think some transplant programs are giving the HPV or the Gardasil® vaccine to their older population with the idea that maybe the immune system will benefit from this. And certainly there are many different varieties of this virus. It's not just one virus. There are different families of COVID and different families of influenza that maybe, in theory at least, that the Gardasil® , the HPV vaccine, will help prevent some of the other viruses from taking hold.

(48:51): But I have not seen an answer to that question directly. I've only seen the hypothesis that maybe these people who have had HPV will benefit from this. I don't think the answer is there and I think that for the general population, as a whole, they would recommend against it.

(49:09): [Michala O’Brien]:  Okay. Thank you. "How can I help my kidneys recover from high creatinine over one year post transplant?"

(49:19): [Dr. Scott Rowley]:  There is no real way of helping the kidneys recover other than avoiding the insults. So, one of the easy insults is dehydration. You do not want to be dehydrated. You want to make sure that you’re well-hydrated. Another common insult is medications. There are various medications that are very damaging to kidneys. And your primary care physician, or any of your physicians, should be aware of your creatinine when they sit at their desk and write a prescription out for you, so that it's being addressed.

(49:56): You can put into your file with the pharmacy that you have an elevated creatinine, that your creatinine clearance, your kidney function is depressed, and they will be able to put that in your file and notify the physicians if there's a drug interaction or a concern about kidney function. But unfortunately, once kidneys have been damaged, they do not have recovery function.

(50:20): [Michala O’Brien]:  Okay. This person had an allotransplant 11 years ago and just recently was diagnosed with non-alcohol related cirrhotic liver. "What, if anything, can I tell my doctor to help in my treatment?"

(50:36): [Dr. Scott Rowley]:  That, as far as I know, is not related to the transplant other than the metabolic syndrome. Go back to metabolic syndrome of abdominal obesity, high blood pressure, high cholesterol, et cetera. And so, I don't know of any specific directions to the physicians caring for this person who has liver problems. I think that you just address it as you would the liver problem, not specific transplant.

(51:11): [Michala O’Brien]:  Okay. "Do you know of any maintenance therapies that are currently used to reduce the relapse rate during the first two years post BMT?"

(51:21): [Dr. Scott Rowley]:  We are learning a lot in this area. With the genetic testing that's now being done, AML is not, AML is not AML. We have FLT3 positive AML. We have NPM1 positive AML. We have IDH2 mutations. We're learning that cancers are very distinct from person to person. So once we learn that, now we start looking at can you target the cancer cell in some way?

(51:49): So, a FLT3 positive AML, there are certain drugs that specifically target that mutation. And so, we would give somebody with a FLT3 positive, or mutated AML, Sorafenib (Nexavar®) or one of the other drugs that target the FLT3. But we wouldn't give them a drug that would target IDH2 because that drug would not be effective and vice versa.

(52:15): So, it really depends upon the disease you have and how much do we know about that particular disease. Now, there are mutations that occur that we do not know how to target yet. But you can be certain that the scientists are working on that. The pharmaceutical companies can sell a lot of drugs if they have a treatment that can target a particular mutation for any of the diseases.

(52:39): [Michala O’Brien]:  Okay. "Can you please explain what happens when chimerism fails?

(52:47): [Dr. Scott Rowley]:  Well, there are a couple different forms of chimerism. What I focus primarily on, the lymphoid chimerism., is the real reason we do an allogeneic transplant, to actually put a new immune system in there. The stem cells are there to help the person recover from the high dose chemotherapy we might give. But the treatment of cancer is really just putting a new immune system in there.

(53:09): And so I'm looking specifically at the immune system of the donor, what we call CD3 chimerism and there's also CD34 chimerism, which is the stem cell. And that's more a measure of relapse versus non-relapse, who's in there, who's making the blood, the donor, the recipient. But the lymphoid chimerism is what we are looking for to give us a graft versus tumor effect.

(53:34): It can vary. I've seen somebody go all the way down to 0% and then claw his way back up to 50%. There is no uniform answer to that. Some doctors will reduce their immunosuppression and hopefully the donor cells will take over. And other doctors will increase the immunosuppression, hoping that the donor cells are less likely to be rejected by the recipient.

(53:57): But it is something that should be looked at because in my experience, a good robust donor immune system predicts for a lower risk of relapse after transplantation in both myeloid and lymphoid malignancies.

(54:15): [Michala O’Brien]:  "Is there any effort being made to update the standardized information that's given to patients regarding the treatment symptoms, et cetera of chronic GVHD?"

(54:28): [Dr. Scott Rowley]:  I don't know of any standard information. You will find, for example, the speakers giving talks about graft-versus-host disease as part of this symposium. But I don't know of anybody or any publications that are saying this is the proper treatment.

(54:44): Chronic graft-versus-host disease is a multi-organ disease. It affects the eyes, mouth, lungs, kidneys, skin, et cetera, and not everybody has the same presentation. It's important that, when people go back to primary care physicians, I still ask people to come back to see me intermittently because there may be skin changes that could be a second skin cancer or that might be GVHD that might not be recognized by a primary care physician, but that I would recognize immediately as a complication of transplantation.

(55:19): But there is no standard way of treating them. We're trying to avoid corticosteroids. So a lot of the treatments now that we're using for chronic GVHD, Ruxolitinib, Belumosudil, these are what we call "steroid sparing" agents because steroids wreak so much havoc.

(55:39): [Michala O’Brien]:  Okay. "Have you seen neuropathy as a long-term complication from transplant? Not just for multiple myeloma only, that's not attributed to chemotherapy."

(55:52): [Dr. Scott Rowley]:  I've seen some with tacrolimus. I had a surgeon who was having a very difficult time standing at the operating room table and we finally determined that the cause was tacrolimus and got him weaned off of that medication and his neuropathy got better. Other medications can cause neuropathy. I'm not certain there's any chronic graft-versus-host disease of the nervous system, but I would think that there can be a lot of this related to medications that are being used.

(56:27): It's a very difficult area. I mean, we have people with chronic neuropathies such as those who've had medications for myeloma, that can be very debilitated by neuropathy, and we don't have a good answer for that or good treatments for them.

(56:48): [Dr. Scott Rowley]:  I think I stopped my slides a little bit early. I want to mention to people, I'm just going to pop forward with a few slides here. Selected resources. Do know that these are in your slides that these are just a partial listing bone marrow transplant. BMT InfoNet has a wealth of information on transplantation. Caregiver support is another slide here. And then, legal and financial support. I just wanted to make sure you understand that these slides are available for you. But go ahead with the last question.

(57:16): [Michala O’Brien]:  Okay. Yes. The last question is, "How long do platelets take to recover after transplant?"

(57:27): [Dr. Scott Rowley]:  That's variable. They're usually slower than white cells. White cells come back first, platelets second and red cells third. We have people that may be platelet transfusion dependent for several weeks after transplantation. But I expect that most people will have platelet recovery by four weeks, five weeks after transplantation.

(57:50): If they remain platelet transfusion dependent, then we must look and see if there is a graft problem. So, that entails getting a bone marrow sample. And if we have good growth of the bone marrow, then they're being destroyed. And they're being destroyed in the peripheral blood, something we call ITP, idiopathic thrombocytopenia purpura. And we have ways of treating that.

(58:17): [Michala O’Brien]:  Closing. Well. Great. On behalf of BMT InfoNet and our partners, I'd like to thank Dr. Rowley for a very helpful presentation. And thank you, the audience, for your excellent questions. Please contact BMT InfoNet if we can help you in any way. And enjoy the rest of the symposium.