Safeguard Your Health from Late Complications after a Transplant Using Donor Cells

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Safeguard Your Health from Late Complications after a Transplant Using Donor Cells

Saturday, April 30, 2022

Presenter: Minoo Battiwalla, MD, MS, Director for Outcomes Research and leader of the Survivorship Program for the Sarah Cannon Blood Cancer Network

Presentation is 36 minutes with 22 minutes of Q & A.

(This workshop was made possible, in part, by support from Pharmacyclics, an AbbVie Company, Janssen Biotech, Inc., and Gamida-Cell)

Summary:  The number of stem cell transplants performed is increasing, which means more people are concerned about ongoing complications or late effects after transplant. This presentation reviews potential late effects after a stem cell transplant (hematopoietic cell transplant) using donor cells (aka allogeneic transplant).

Highlights:

• Some late effects are potentially lethal but preventable; others are non-lethal but problematic and may require ongoing treatment.   

• Transplant patients have much higher risk of secondary cancers, so prevention and screening are essential for transplant survivors.

• Survivorship clinics or programs at the transplant center can be very valuable for transplant recipients. If your center does not have a survivorship program available, request an individualized survivorship plan from your transplant team that describes your treatment history, potential late effects, and  testing and monitoring to catch potential problems early.

Key Points:

(05:49): Late effects five years after transplant now occur in about 80% of recipients.

(07:25): The chemotherapy and/or radiation received before transplant, genetic factors and disruption of normal immune system functions can lead to late effects after transplant.

(08:32) Graft-vs-host-disease (GVHD) is the most common late effect in the first three years after a transplant using donor cells.

(11:25): Infections continue to be a risk two or more years after transplant.

(13:41): Vaccinations, including childhood vaccinations and COVID vaccines as soon as three  months after transplant are currently recommended.

(19:49) Because transplant recipients have a higher risk of developing cancer than the general population, monitoring is important life-long.

(19:22): Transplant recipients have an increased risk of developing heart and blood vessel problems after transplant.

(21:27): Lung problems can develop after transplant due to smoking, vaping, infection and/or graft-versus-host disease (GVHD).

(23:39): Other non-lethal problems include bone, endocrine, hormonal and metabolic issues.

(28:35): A healthy life style and exercise are important.

(34:21): Transplant survivors need to practice good health, know their treatment history, be aware of future risks, and ask questions.

Transcript of Presentation:

(00:01): [Michelle Kosik]   Introduction. Hello. My name is Michelle Kosik. Welcome to the workshop, Safeguarding Your Health from Late Complications after a Transplant Using Donor Cells. I'd like to thank Pharmacyclics, an AbbVie Company, Janssen Biotech, Inc., and Gamida-Cell who helped to make this workshop possible.

(00:23): It is my extreme pleasure to introduce Dr. Minoo Battiwalla. Dr. Battiwalla is a stem cell transplant physician at the Sarah Cannon Transplant and Cellular Therapy Program at TriStar Centennial Medical Center in Nashville, Tennessee. He is also the director for Outcomes Research and leads the Survivorship Program for the Sarah Cannon Blood Cancer Network. Dr. Battiwalla chairs the steering committee of the National Institutes of Health Late Effects Initiative and co-chairs the Cardiovascular and Metabolic Committee. He is a well-known expert on the topic of late effects after stem cell transplantation and has published extensively on the topic. Please give me a warm welcome in welcoming Dr. Battiwalla.

(01:13): [Dr. Minoo Battiwalla]      Overview of Talk.     Thank you very much for that introduction, Michelle. I want to welcome the 1,800 global registrants from 28 countries to this conference to celebrate a second chance at life. Safeguarding your health after an allogeneic transplant, which is the transplant from a donor, is going to be the focus of my talk. I consider survivorship the scientific art of maximizing health after cancer treatments. It is my distinct privilege to be able to speak to you today. I have no financial disclosures to make.

(02:03): What I will discuss today are long-term and late survivorship issues in allogeneic stem cell transplantation. Why are we talking about this today? Because cure is not enough and there's a growing emphasis on the quality, and not just the sheer quantity, of survivorship after these transplant treatments.

(02:37): It is important to understand when problems occur, because they occur in very unique timeframes. And complications which occur in the first few months, may never pop up again. Whereas entirely different complications could happen years and even decades after the transplant.

(02:59): It is important to be aware of the broad spectrum of the health problems that our transplant survivors may face. Some of them are also potentially lethal; so it's important to recognize them early. Huge challenges. How do we effectively deliver care to our survivors in a timely fashion, especially when they are geographically distributed, sometimes many miles and different states from the original transplant center? I want to touch upon all of this today.

(03:44): Stem cell transplantation is a rapidly growing field and survivorship rates are increasing. As you know, the field of stem cell transplantation has been rapidly growing. Over the years, there has been a massive increase in transplantation because of growing efficacy, and more safety, the more patients are surviving and are living longer. This justifies a shifted emphasis towards protecting and safeguarding your health.

(04:08): By one calculation in 2020, we had about 250,000 transplant survivors. By 2030, we should easily double that number. Sixty percent of transplant survivors are autologous transplant recipients and 40% are allogeneic, the focus of today's talk. Sixty percent are aged between 18 to 59, but that also leaves at the tails a large number of very young individuals and much older individuals, both of whom have special needs.

(04:46): Now if you look at the graphic on the right, you'll notice in the top panel, the number of survivors is rapidly growing. If you look at the graphic at the bottom, over time post-transplant, especially when the transplant is done for blood cancer, the risk of relapse diminishes over time. As time goes on, there's a very high likelihood of cure.

(05:16): On the other hand, we have an overlapping population that's growing health problems and these can impact the quality of survivorship. Consequently, we can only wish that all our transplant survivors are as fit, healthy, happy, and youthful as the participants in a reality TV show, but that is often not the case.

(05:49): However late effects five years after transplant occur in 80% of recipients. Survivorship might give you a cure, but it might come at a tremendous cost. Consider that about 40% of childhood cancer survivors have severe illnesses or might even die of such illnesses. Eighty percent of transplant recipients will have one or more late effects at five years after transplants. Even if you're cured, the five-year life expectancy is significantly lower than a comparable general healthy population.

(06:25): We have this conundrum shown in the middle graphic, where you have a sick patient who transforms into a possibly vulnerable survivor with that sword of Damocles always looming over one's future. How can one deal with this? It's important to recognize the spectrum of problems. Long term and late effects impacts all domains of health. While the focus is primarily on all the physical problems that you can have, one should understand that a holistic view of health includes consideration of sexual, emotional, psychosocial, as well as the impact of financial toxicity.

(07:25): What causes late effects after transplant? You may ask, "Why do long term and late effects occur?" There are basically three reasons. The first reason is, of course, there's this toxicity from the conditioning regimen, the chemo or the radiation that you may have received. This is, of course, piling on top of all the other cancer treatments you may have received before the transplant. A second consideration is an overlap with pre-transplant or an individual's genetic predisposition to getting some problems including their prior general health. Last and what is unique to the allogeneic transplant setting is the impact of immune dysregulation particularly chronic graft-versus-host disease which, as we shall see later, accelerates all the late effects that we expect to see after the transplant.

(08:32) Graft-versus-host-disease (GVHD), infections and relapse are the most common late effect in the first three years after transplant. From the transplant physician standpoint, we can mentally visualize distinct, but variable timeframes for complications. In the first few years after the transplant, typically first three years after the transplant, our focus as physicians is on treating graft-versus-host disease, both acute and chronic graft-versus-host disease, which burn out over time. There's also the risk of early infections and the risk of malignancy recurring.

(09:10) Three or more years after transplant, a different set of complications become more common. But over time, these will fade away and then you have a different set of complications. Some of them are shown here: impact on thyroid hormones, as well as other hormonal problems; fertility; bone loss; eye problems; lung problems; cardiovascular problems; and new malignancies. These have variable times of onset. Sometimes, the risk continues to increase over time as we expect even with the general aging.

(09:47): Then for very long term survivors, maybe 20, 30 years and beyond, there are many questions which are left unanswered. Will there be stem cell exhaustion? Will there be accelerated aging in general? Could there be neurodegeneration? We don't know the answers to all these questions, but these are areas of intense research.

(10:09): Some late effects are potentially lethal but largely preventable; others are non-lethal but problematic. Today for you, I would like to give you a focus on some of the key late effects, as I see them in our patients. The box on the left shows potentially lethal late effects, which are largely preventable, but you need to know about them in order to prevent them: infections, second cancers, heart and vascular issues, and lung problems. At the minimum, you should pay a lot of attention to these.

(10:43): Then on the right hand graphic, you will see non-lethal, but problematic problems. Issues such as endocrine and metabolic, we will discuss some of these: bone health, sexuality; fertility; iron overload; impact on general health, brain problems, such as chemo-brain; and mental and emotional problems. Graft-versus-host disease is like that inflammatory background fire, which fuels all of these and exacerbates all these problems.

(11:25): Infections continue to be a risk two or more years after transplant. I will first focus on some of the key late effects, which could possibly impact survival. Infections are always treatable and almost definitely preventable in many cases. It is a shame that patients continue to lose their lives after infection after an allogeneic transplant. Bearing in mind that the key point in their immune deficiency is very early post-transplant. A lethal infectious complication many years later is clearly preventable.

(12:09):This study from the International Transplant Registry shows that if you survived more than two years after transplant, you are still at risk for infections for over the next 10 years. Yes, adults have it worse than children. What are the causes of these late fatal infections? They're surprisingly not the typical opportunistic infections. They are all the common infections: bacterial, fungal, viral, and multiple infections.

(12:45): Several strategies can prevent infections. What can we do about it? Well, infections can easily be prevented. All of the transplant patients are on these prophylactic or preventative antimicrobials. These can be antifungals like the azoles; antivirals like acyclovir; anti-PCP and toxoplasma drugs such as Bactrim; and antibacterial penicillin for some patients who have chronic graft-versus-host disease. I often find that patients will prematurely stop these prophylactic drugs. These often need to be taken for at least months and sometimes many years after a transplant. They're very safe for the long run and can give us a huge umbrella of safety.

(13:41): Vaccinations, including against COVID, are crucial. The next strategy is vaccination. The allogeneic transplant will wipe out your immunologic memory against all the childhood diseases and you will need to resume all your childhood shots. The key point is not if to give; it has to be done. The key point is when to start. The strongest data is for protection from COVID and influenza by vaccination. Here, perfection is the enemy of the good. The general recommendation is regardless of whether or not you're on immunosuppression, at three months after the transplant, you should start getting COVID and flu shots. Whereas you have the luxury of time to wait for at least six months after the transplant and being off systemic immunosuppression before starting all the other routine childhood vaccines.

(14:49): Transplant patients have much higher risk of secondary cancers, so prevention and screening are key. Secondary cancers are I will now focus on second cancers or subsequent neoplasms. There is a threefold higher risk of another cancer after transplant. The graphic shows that stem cell transplant survivors have far higher rates of second cancers compared to what is expected for the untransplanted population for their age. This can be an entirely different cancer. It's related to cumulative doses of all the chemotherapy and radiation that the survivor has received. These can, unfortunately, occur with a latency of a decade or longer. This can happen long after you have severed your connection with the transplant center and hopefully outlived your transplant physicians.

(15:51):  Ways to protect against skin cancer. How do we manage this? Well, prevention, prevention, prevention. These are strong recommendations for our transplant survivors. Skin is the most vulnerable organ. I can personally attest to a patient of mine, who was a truck driver, who did not believe in sun protection, and would drive with one arm outside his cab and with the other arm inside. I personally had to remove 17 skin malignancies from the arm, which was dangling outside the cab exposed to the sun versus none on the arm, which was protected. Now our patients need annual dermatologic skin exams even if you do not reside in the Sun Belt. Sunscreen is your friend. Please use broad-spectrum sunscreen, which covers both UVA as well as UVB, with a very high SPF, a minimum of 30. Avoid peak sun. Wear sunglasses, hats, and sun-protective clothing. Trips to the beach are certainly possible if you follow these guidelines.

(17:15): Thyroid cancer just requires an annual physical examination.

(17:19): Mouth and throat cancer are also very common and this is the primary reason you need to have a dental exam at least every six months, not so much as to keep your teeth healthy, but also to look for oral cancers. HPV vaccination greatly reduces the risk of oral cancers and that is part of the vaccination strategy.

(17:43): Protect against lung cancer. The lungs are one of your most vulnerable organs. If you've ever been a tobacco smoker or user or vaper, you have to stop it. It's a big no-no after transplants. There are recommendations derived from the general population for using low-dose screening CT scans for high-risk patients.

 (18:12): Protect against breast cancer. The breasts are a vulnerable organ, especially if you have received radiation for any reason. There are recommendations for clinical breast examination, mammography, and occasionally MRI based upon your transplant characteristics.

(18:30): Protect against gynecologic cancers. Gynecologic cancers, particularly cervical dysplasia, is often triggered by a rampant human papillomavirus. The annual HPV testing and HPV vaccination should be performed as part of an annual gynecologic examination even if you are postmenopausal.

(18:540): Protect against throat cancer. Esophageal screening is only if you have difficulty swallowing.

(19:00): Protect against colorectal cancer.  All people over the age of 45 to 50 will need colorectal cancer screening, whether you've had a transplant or not. Hopefully, stringent adherence to these preventable conditions will make a big difference in allowing you to live a longer and healthy life.

(19:22): Transplant recipients are at risk of developing late heart and blood vessel problems. I want to talk about cardiac and blood vessel issues. There are three groups of problems affecting our transplant survivors here. The first is cardiac dysfunction, which is a pump failure, where the heart fails to pump well. This is typically seen in the younger population and those who have received certain kinds of drugs, chemo drugs and/or radiation.

(19:49) Arterial disease is linked to underlying inflammation. It can happen in the coronary vessels leading to premature heart attacks, but also in the vessels, which feed the brain leading to early strokes. Of course, peripheral vascular disease.

(20:07): Transplant recipients are three times more likely to develop high blood pressure, diabetes and other metabolic problems than the general population. Then potentiating all this are metabolic disorders, which are also increased in our transplant population with a threefold higher risks in hypertension, diabetes, cholesterol problems, and obesity. Understand that all of these results in a cumulative risk of future cardiovascular events, which are much higher than the general population. The events will occur earlier. According to one study, the first heart attack occurred 14 years earlier than the general population. This risk is permanent and tends to increase with time after transplant.

(20:52): Screening for heart and metabolic problems is important long-term. How do we prevent this? Well, screening. Once things are stabilized at six months to 12 months after transplant, you need to start screening for all the preventable cardiac risk factors. Correct blood pressure, cholesterol, diabetes, overweight, smoking. In select cases, we will do echocardiograms. In people who are vulnerable, we'll also be taking a closer look at your heart with EKGs and stress testing, and CT angiograms.

 (21:27): Lung problems can develop after transplant due to smoking, vaping, infection and/or graft-versus-host disease (GVHD). The next vulnerable organ is your lung. Please, please, please, if you have not heard it before, stop all smoking or vaping. Infections are a common problem here. Get vaccinated and seek medical attention early if you have any pulmonary symptoms. Although graft-versus-host disease is going to be covered extensively in another workshop, I want to emphasize that lung injury from graft-versus-host disease is the killer form of chronic graft-versus-host disease. I want to emphasize that it is frequently misdiagnosed even by transplant doctors and professionals as infections or pneumonias. It is often recognized at a point where it is too late.

(22:22):There are two patterns of lung GVHD. One is cryptogenic organizing pneumonia, which occurs early. It resembles infectious pneumonia in terms of presenting with fever and cough and breathlessness, and will show up with infiltrates on a CT scan, but it is not an infection. After rapidly ruling out infection, it is very easily treated with steroids, but for a long course of treatment.

 (22:53): On the other hand, a different form of lung GVHD, which affects the airways, is called bronchiolitis obliterans. This is silent early. By the time symptoms occur, too much damage has been done and it is absolutely irreversible at that point. This is why if there is any evidence of chronic graft-versus-host disease, we recommend serial pulmonary function testing every three months for the first five years. If you don't have graft-versus-host disease, then serial pulmonary function testing should be performed every six to 12 months.

(23:39): Bone damage is common after a stem cell transplant. Now we'll move on to some of the non-lethal problems, which consume a lot of our attention. Bone damage is common. It takes two patterns. The first on the left is a loss of bone mineral density. You've heard of terms like osteoporosis, which is the higher grade and osteopenia, which is the lower grade. The normal bone will appear hollowed out. This is often treated with vitamin D, calcium, exercise, et cetera, et cetera. Avascular necrosis is a different pattern. It presents with severe pain and joint fractures because the bone underneath the cartilage dies. If you look at the graphic, you'll see that the regular smooth contour has been replaced with irregular contour, with bone rubbing against bone. It is severely painful and ends up requiring joint replacements.

(24:41): Endocrine, hormonal, and metabolic issues are very common [after transplant]. Low levels of thyroid hormones are very common and most patients would end up requiring... I shouldn't say most, but many patients will end up requiring lifelong supplementation. Threefold higher risk of diabetes, high cholesterol. Sex hormones are universally diminished resulting in premature ovarian n failure. This can, of course, impact sexuality, but can also give you fatigue. There can be genitourinary changes, especially vaginal changes and pain, and symptoms of premature menopause. Men will suffer from erectile dysfunction and loss of libido. Infertility is very common, but maybe avoided if you have received the very reduced-intensity transplants. What do we do about it? For ovarian failure, I strongly recommend hormone replacement therapy up to the age of natural menopause. Whereas for men, they will all have low testosterone. In my experience, testosterone supplementation really does not provide any clinical benefits.

(26:07): Ongoing fatigue is common after transplant.  There are many other general health issues, which persist for a long time. Here are some tips. Fatigue is common. Try and identify the underlying medical cause. You need to treat pain. Reduce workload to part time. Exercise to build up strength and endurance, and strategic naps to recharge your batteries. Sleep disturbance is also very common and cognitive behavioral therapy might help. Sleep hygiene is also important. Muscle cramping is a common issue. Hydration and tonic water can help.

(26:51): Memory loss, changes in the way you think, difficulty finding words and difficulty with organization, sometimes called chemo brain, may occur after transplant. There are mental health challenges. A very unique issue in many malignancy survivors, particularly transplant survivors, is fogginess in the brain. It is colloquially referred to as chemo-brain and it is characterized by short-term memory loss, reduced thinking, word-finding difficulties, slight diminution in executive functions. It can improve, but might take a year to five years after the transplant. There's cognitive rehab and certain medications might help, but this requires the guidance of a competent neurologist.

(27:37): Dry eyes, cataracts and dry mouth common after transplant.  Eyes are very commonly affected. Dry eyes and premature cataracts demand annual eye examinations and lots of things can be done about them.The mouth is also an area for attention. Dry mouth, cavities, risk of oral malignancies require regular dental examinations.

(27:37): Transplant recipients should be monitored for kidney and liver problems, such as iron overload.  Kidneys, you should have an annual urine/protein check. Protect your liver by avoiding alcohol. Iron overload from cumulative blood transfusions will sometimes require phlebotomy; that is a little bit of blood-letting until the iron levels come down in the body.

(28:17): Chemotherapy-induced neuropathy can occur after transplant. Neuropathy related to cumulative chemotherapy. It's important to see a neurologist and get good foot care. There are some medications for neuropathy. The pain and discomfort does diminish over time. There is hope for improvement.

(28:35): A healthy life style and exercise is important. My recommendation for all our patients is to adopt a healthy lifestyle. Many patients ask about diet. A healthy, balanced diet including at least five daily servings of fruits and vegetables is important. Multivitamins. Please avoid iron, and aggressive supplementation of calcium and vitamin D were indicated. These will help with the diabetes, the weight, osteoporosis, cholesterol, as well as your heart health.

(29:08): Exercise is important; not just for weight reduction, but because weight-bearing builds up your bones and reduces the risk of osteoporosis. I also strongly recommend stretching or yoga exercises because stiffness of the joints is exceedingly common. You must get at least one exercise session every day. These help with your bones, with fatigue, with your brain, and your flexibility. Infections. Get used to hand washing and using your little hand-sanitizing wipes all the time.

(29:48): Sleep hygiene is important and can help with your overall fatigue. Stop nicotine, moderate your alcohol intake. Please establish lifelong specialist care: gynecologist, dental, eye, and skin.

(30:12): Survivorship clinics or programs or individualized survivorship plans can be very helpful. How do we bring it all together? We know that simple screening and prevention can greatly improve survivor health. We, at Sarah Cannon across our Blood Cancer Network, have addressed the special needs of our survivors by creating a dedicated survivorship clinic. Many transplant centers will also have models such as ours. At our center, at the heart of coordinating all of this is a dedicated long term follow-up transplant coordinator, who will take information from the primary care physicians from consultants and coordinate visits with the transplant physicians, as well as the transplant nurse practitioner. The transplant physicians tend to focus on the acute critical issues. They will focus on cancer control, graft-versus-host disease, sometimes infections. These will be routine visits as clinically indicated. Whereas our survivorship nurse practitioner or physician assistant will focus on milestone visits. These are very long visits taking at least an hour to conduct. We conduct these milestone visits at day 100, six months and annually, and integrate information from all the consultants that you see. We then sit together as a group and provide final recommendations.

(32:04): Transplant recipients who don’t have access to a survivorship clinic can request an individualized survivorship care plan. This is obviously extremely laborious and not a model that is available to many transplant survivors, some of whom might be present on this call. If you are a transplant survivor and you do not have access to a survivorship clinic, what can you do? Well, one solution, which is being rapidly adopted in our transplant field, is individualized survivorship care plans. This is a relatively recent development in the field. This is a document and we give it to our patients to carry home with them as a passport to take to their referring physicians, to their consultants, and then they return home. It's something as an enduring document. We give it at day 100 and update it from time to time.

(33:09): This document lists the transplant therapy they received: the chemo, the radiation. Pre- GVHD: How was it prevented? Did GVHD occur? Recommended treatments, which are based upon the patient's age, their chemo, whether or not they got radiation, and their sex. This is another way you can protect your health without having to attend a survivorship clinic.

(33:45): BMT InfoNet and Be The Match can provide helpful survivorship information. Yes, this is complicated, but you are not alone. There are many organizations, which seek to help such as the organization which created this symposium [BMT InfoNet]. Another good source for documentation and help is the National Marrow Donor Program, which is now known as Be The Match. They have a very active survivorship support program, which they administer via phone app, website, as well as telephone support. Those links will be available to you.

(34:21): Transplant survivors need to practice good health, know their treatment history, be aware of future risks, and ask questions. In conclusion, late effects are common and frequent. You must commit to long term follow-up. Multidisciplinary care is complicated, but meaningful. Survivorship clinics and individual survivorship care plans are really helpful. Please take responsibility for your health. Practice good health, know your treatment, understand the complications you have endured, be aware of future risk, and ask questions.

(35:01): What I provided was a overview of survivorship after allogeneic transplants. There are other workshops covering individual organ systems and problems. As part of our symposium, please make a note of these and feel free to attend the ones which are very relevant to you. There is also an entirely different set of programs devoted to graft-versus-host disease, which as I've alluded to, really accelerates and aggravates all the problems that we see. With that, I will end the didactic portion of this talk. I would be very happy to take your questions. Once again, I'm absolutely amazed at the journey and the courage that our survivors show. I want to wish you all the best. Thank you.

(36:05): [Michelle Kosik]  Q & A. Incredible presentation. Thank you, Dr. Battiwalla, for all of this information. I know we've got a plethora of questions for you. We're now going to go ahead and move to the question portion. As a reminder, if you have a question, please go ahead and type it into the chat box on the lower left hand corner of your screen.

(36:27): Our first question is: Do we have any knowledge if any specific vaccines would lead to an increased risk of graft-versus-host that is post allogeneic transplant?

(36:40): [Dr. Minoo Battiwalla] There is absolutely no evidence, even anecdotal, that vaccinations incite, aggregate or worsen graft-versus-host disease. Instead, the preponderance of evidence suggests that vaccination saves lives and should be given.

(37:04): [Michelle Kosik] Thank you. Our next question is: Are there certain chemotherapies that are linked to an increased risk of cardiac dysfunction?

(37:14): [Dr. Minoo Battiwalla]   Yes. Radiation as part of the transplant and the group of chemotherapy drugs called anthracyclines, and specific alkylating agents named cyclophosphamide can cause heart problems.

(37:36): [Michelle Kosik]  Thank you. Oh, this is a great question. Do you recommend getting Shingrix vaccine before discontinuing the use of acyclovir?

(37:47): [Dr. Minoo Battiwalla] Yes. In our practice, we overlap acyclovir until both doses of the Shingrix vaccine are given. I think this is a terrific practice. I would never stop the acyclovir unless I have both doses of Shingrix under the belt.

(38:15): [Michelle Kosik]  Excellent. The lung injuries with graft-versus-host disease you are describing in your presentation, they are both non-infectious. Correct?

(38:28): [Dr. Minoo Battiwalla]  Absolutely. These are non-infectious inflammatory reactions induced by donor immune cells directly or indirectly attacking different parts of the lung. But yes, they do look like infections.

(38:49): [Michelle Kosik]  Exactly. The next question is When you mentioned diabetes, are you speaking of type 1 or type 2?

(39:00); [Dr. Minoo Battiwalla]  Very good question. The type of diabetes that we see after transplant is exclusively type 2 diabetes. That is where there's insulin resistance and it goes together with many other metabolic issues. Type 1 diabetes refers to reduced production of insulin from a destroyed pancreas; that is not what we see after a transplant.

(39:30): [Michelle Kosik]  We have a very smart audience. I got to tell you. I'm reading some of these questions, Dr. Battiwalla , and they're pretty incredible. What is the reduced-intensity transplant and when is it indicated? What are the risks versus benefits? This is a long one. Let's just talk about what a reduced-intensity transplant is first and when is it indicated, and then I can continue on with the rest of the questions.

(39:56): [Dr. Minoo Battiwalla]  Well, the choice of transplant conditioning regimen should be left to your transplant physician; that's something I strongly believe. We can use higher intensity regimens in patients who are younger, who have an aggressive disease, which would require such intensity. For patients who are either older or who have comorbidities such as, let us say, a bad heart or lungs, or maybe having a second transplant or have a disease which is not that aggressive, we could get away with a reduced-intensity transplants. Often the choice is forced on us because of considerations such as age and disease. The benefit also with reduced-intensity transplant is that there is less chemo or radiation used and there are fewer side effects. However, the usual downside of using reduced-intensity conditioning is that there is a potentially higher risk of relapse of malignancy. This is a complicated calculation, which transplant centers will use to determine what is the best conditioning regimen for you.

(41:29): [Michelle Kosik]  Wonderful. There is another question that asks if [Do] all women end up on hormone replacement therapy and I believe your recommendation was that you strongly recommended it. Do you want to take that a little further?

(41:44): [Dr. Minoo Battiwalla] Yes. All women who are below the age of natural menopause, which in the United States is early 50s, deserve to get hormone replacement therapy for the following reasons. One is that it mimics your natural body hormonal status up to that point. Second, it protects your bones and your heart. I can't emphasize this enough. There's a lot of data which suggests that hormone replacement protects your heart health. There are side effects from hormone replacement. And if you would not qualify for hormone replacement therapy for reasons such as a tendency towards blood clotting or other very rare syndromes, then maybe you may have to skip that. But otherwise, I strongly believe it's the most healthy thing we can do to maintain the health of our female survivors. But it's also important to stop it at the age of natural menopause.

(42:56): [Michelle Kosik]   Oh, I like this question. Can you speak about the newly approved graft-versus-host disease drug, Rezurock?

(43:09): [Dr. Minoo Battiwalla]  That's a complicated question. I will say that we've gone from an era where we had nothing but steroids, which seem to help, and our standard GVHD drugs like tacrolimus, cyclosporine, which were used for treatment of chronic graft-versus-host disease. Now we have three FDA approved drugs: Imbruvica, which is ibrutinib; Jakafi, which is ruxolitinib; and Rezurock, which is belumosudil. All of these probably have a benefit in chronic graft-versus-host disease.

Rezurock is somewhat interesting because it acts by a different mechanism than the other agents. In my anecdotal experience, it may help with some of the more stubborn forms of chronic graft-versus-host disease. I think the primary benefit from all three of these newly approved drugs is that it gives us the confidence to avoid using steroids long term, which is a huge, huge problem for our patients.

(44:35): [Michelle Kosik]  Thank you. Is the sensation of a tight band around your chest an indication of possible lung graft-versus-host disease?

(44:49):[ Dr. Minoo Battiwalla]  I actually have two patients currently who have that sensation. No, it could be skin graft-versus-host disease occurring really as a tight sclerodermatic band around the chest. We have seen that very often. Yes, anything inside the lung might potentially give you that feeling. Neurologic problems from spinal compression, let us say, osteoporotic spinal fracture could also give you a band sensation. There's clearly many possibilities here, which deserve medical attention. Please bring this to the attention of your physician.

(45:36): [Michelle Kosik ] Our next question is: What causes iron overload?

(45:42): [Dr. Minoo Battiwalla] Iron overload in our patients is typically related to either excessive red cell transfusions. Each unit of red cells that you have been transfused contains about 50 milligrams of iron and which is delivered directly into your bloodstream. In contrast, every day that you eat, even if you eat a regular diet with red meat, you get about 1 to 2 milligrams of iron. Over time, if you get 20 to 30 units of red cells with every transplant, you're likely to get heavily iron overloaded. This can cause some health problems, which is why at around three to six months after transplant, many centers will measure your iron levels and determine if a little bit of blood-letting called phlebotomy will help rapidly bring your iron levels under control.

(46:41): Transfusional iron overload is the commonest cause of excessive iron buildup in your body. Of course, there are genetic syndromes like hemochromatosis, et cetera, and if those occur in conjunction with transfusion iron overload, that can be really quite serious. But most patients will not have that. Very interesting question. Oh, yes. The other corollary to all of this is that if you have iron overload, it's important not to take many forms of multivitamins, which also have iron supplementation. We usually recommend avoiding the women's health vitamins, which all have iron, and going for the men's health vitamins, which lack iron.

(47:36): [Michelle Kosik] That's really important. Thank you for that addition. One of our questions is... I have chronic graft-versus-host to the eyes and mouth. I had a PFT [pulmonary function test] at the two-year mark. Currently at 4.5 years, trying to wean off final immunosuppressant. How often should PFT test be performed on me?

(48:02): [Dr. Minoo Battiwalla]  Very good question. If your immunosuppression is being weaned off, it means that your chronic GVHD is slowly burning out. It is very unlikely that you will develop new areas of chronic graft-versus-host disease. I would suggest continuing doing three-monthly lung function tests up to about five years after the transplant. Then switching to maybe six months for another year or two and then stopping all together if everything looks good.

(48:46): [Michelle Kosik]  Next question is: Are secondary cancers influenced by the original cancer treated with BMT? In other words, are second cancers more common in survivors who had a specific cancer type?

(49:05): [Dr. Minoo Battiwalla]  Generally not. I'm sorry. I can't give you a more specific answer than that ... but there's a lot of interest in how these cancers arise. It's a confluence of either your genetic predisposition, which gave you the first cancer in the first place. Then all the chemo and radiation, and other toxic treatments you have received, then combined with the inflammatory environment of graft-versus-host disease. Immunodeficiencies which allow certain oncogenic viruses like HPV to thrive. All of these act together and can tickle the genome of your normal tissue and drive additional cancers.

(50:09): [Michelle Kosik]  Wonderful. How do you mentally deal with the constant setbacks? I seem to be in a cycle of one step forward and two steps back. It's hard for me to stay positive all the time.

(50:23): [Dr. Minoo Battiwalla]  Congratulations. You are a great dancer of the transplant tango. It's two steps forward, one step back. But the important thing is that you are moving forward. As time goes on, a lot of these problems will just cease to exist and the risk will completely fade away. I've had patients who have fought for their lives and have ultimately gone on to run marathons. As long as the general tendency is positive, it's worth fighting for because a lot of these problems are often solvable and will improve in time. My recommendation is have a sense of optimism, have trust in your healthcare providers, seek the attention that you need. Some of these treatments are going to be prolonged, but the future will be bright.

(51:40): [Michelle Kosik]  I think psychosocial team within your transplant team can also be a wonderful, wonderful asset to help support our patients.

For muscle cramping. Oh. Yes, sir. For muscle cramping, tonic water is mentioned as possibly helping. How does it help? Is it the quinine?

(52:04): [Dr. Minoo Battiwalla]  Bingo. Yes, quinine.

(52:10): [Michelle Kosik]  A magic ingredient. What is the single best thing that we can do to decrease our chances of those late complications? Weight control, nutrition, regular exercise, or just a combination of all of them?

(52:32): [Dr. Minoo Battiwalla]  As somebody who tries very hard to keep off the excess pound, I can tell you that no single intervention will work. Everybody needs to do all of these.

(52:49):  [Michelle Kosik]  Excellent. One of our viewers said, "I had my vaccinations at the one year mark after transplant. I was still on tacrolimus and sirolimus. Now three years later, I am still on tacrolimus and now Jakafi. Do I need to have all of my vaccinations repeated? If so, when?"

(53:17): [Dr. Minoo Battiwalla] Very good question. Sometimes, we are forced to give vaccinations and hope for the best because perfection is the enemy of the good. In your case, you're still on systemic immunosuppression. I would wait until the systemic immunosuppression, tacro, sirolimus are completely stopped. Then actually draw titers, which are looking at the antibodies against these vaccines, and see which vaccines you need re-immunization against. It's very safe to wait at this point. That's all I would do; wait for a year or two. Then specifically re-vaccinate against the vaccines which have failed to take.

(54:08): [Michelle Kosik]  All right. We're nearing the end of our Q&A. I will take a couple more questions. "I have chronic graft-versus-host for 11 years now. What does the data say about this? Can I ever become free of chronic GVHD?"

(54:26): [Dr. Minoo Battiwalla]  Without knowing the specifics of your case, it would be wrong for me to comment. But one consideration is that the underlying inflammation may have actually ceased and what you're left with is permanent battle scars. If you have a burn and you get fibrosis, similar features happen after chronic GVHD has affected an organ. You might be left with some permanent sequelae, which may not respond to anti-inflammatory therapy. Distinguishing between what is permanently lost versus active graft-versus-host disease, I think that's something which needs to be very carefully considered. It is very unusual, as you allude to, to have active inflammatory graft-versus-host disease 11 years after transplant. Most likely, it is inactive at the point.

(55:42): [Michelle Kosik]  Terrific. Wow! Congratulations. We have an 18-year survivor asking a question. She has a few long-term side effects, but she can't find a doctor to address these issues in San Antonio, Texas. Do you have any ideas on where she could look to find centers in San Antonio, Texas?

(56:02): [Dr. Minoo Battiwalla]  Well, our colleagues at Methodist Hospital would be very happy to help you out. We have a very active transplant program there in San Antonio. Please check them out.

(56:15): [Michelle Kosik]  Have a wonderful long term follow-up or survivorship work group. I think that sounds like a great idea. This will be our last question. We are at the end of our presentation. The final question is: I received a stem cell transplant from 100% matched donor. Why do I have chronic graft-versus-host disease?

(56:50): [Dr. Minoo Battiwalla]  That is a wonderful question. Unfortunately, even with a HLA identical transplant, there's enough immunologic disparity at non-HLA loci that is at areas which are not tissue matched. There are definitely going to be differences. These are what will trigger graft-versus-host disease. Yes, you can have life-threatening graft-versus-host disease despite a full match. I'm sorry that this is something that has happened to you, but there is a known mechanism.

(57:42): [Michelle Kosik] Closing. On behalf of BMT InfoNet and our partners, I'd like to thank you, Dr. Battiwalla, for your incredible presentation. You have given us so much information. Many accolades in the question, in the chat boxes thanking you for your informative presentation. I'd like to thank the audience for your excellent questions and your engagement in this presentation. Please enjoy the rest of the symposium.

(56:50): [Dr. Minoo Battiwalla]  That is a wonderful question. Unfortunately, even with a HLA identical transplant, there's enough immunologic disparity at non-HLA loci that is at areas which are not tissue matched. There are definitely going to be differences. These are what will trigger graft-versus-host disease. Yes, you can have life-threatening graft-versus-host disease despite a full match. I'm sorry that this is something that has happened to you, but there is a known mechanism.

(57:42): [Michelle Kosik] Closing. On behalf of BMT InfoNet and our partners, I'd like to thank you, Dr. Battiwalla, for your incredible presentation. You have given us so much information. Many accolades in the question, in the chat boxes thanking you for your informative presentation. I'd like to thank the audience for your excellent questions and your engagement in this presentation. Please enjoy the rest of the symposium.