Secondary Cancers After Transplant
Saturday, April 29, 2023
Presenter: Alison Loren MD, MSCE, Hospital of the University of Pennsylvania
The presentation is 32 minutes long followed by 26 minutes of Q & A.
Bone marrow transplant survivors have an increased risk of developing a second or “secondary” cancer later in life. This video discusses risk factors for developing a secondary cancer, cancers most frequently seen after transplant and monitoring and testing that should be done periodically to catch second cancers early when they are easiest to treat. (Throughout the talk, "bone marrow transplant" refers both to bone marrow transplants and stem cell transplants, as well as cord blood transplants.)
- Stem cell transplant survivors have a higher risk than the general population of developing certain cancers many years after transplant
- The type of cancer that transplant survivors are at risk of developing varies depends on the type of transplant the patient received - whether it was an autologous transplant, using the individual's own blood stem cells, or an allogeneic transplant , using someone else's blood stem cells. These risks apply to both pediatric and adult recipients of transplants.
- Lifelong screening for secondary cancers is essential. Leading a healthy lifestyle can reduce your risk of getting a secondary cancer.
(03:52): Transplant outcomes are improving.
(07:23): The risk of getting a secondary cancer after a bone marrow transplant is four to 11-fold higher than the general population.
(08:05): There are three groups of secondary cancers that can occur after transplant: therapy-related blood cancers, lymphomas and solid tumors.
(08:36): Therapy-related cancers after transplant include acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) which typically occur early after transplant.
(08:54): Lymphomas - post-transplant lymphoproliferative disorders (PTLD) - also tend to occur within a year or two after transplant, and not later. They occur almost exclusively in patients who had a transplant using donor cells.
(09:07): The risk of developing a solid tumor after transplant rises over time and never really plateaus.
(12:51): As many as 8% of patients who received some of the riskier forms of transplants can go on to develop post-transplant lymphoproliferative disorder (PTLD).
(13:49): Understanding the big difference between “relative risk “and “absolute risk” is important. Although a "relative risk" can be four times higher than the general population, the actual number of patients who develop a second cancer can be quite small.
(14:32): The risk of developing a solid tumor cancer after transplant seems to be a little bit higher in transplants using donor cells (allogeneic), as compared to transplants using the patient’s own cells (autologous), with the exception of autologous transplants having a therapy-related blood cancer risk, which is 20-fold higher than the general population.
(15:34): Other risk factors for developing a solid tumor cancer after a bone marrow transplant include radiation as part of the treatment; younger ages when receiving radiation therapy; chronic graft-versus-host disease; infections with certain viruses like HPV, which can cause cervical cancer or penile cancer; and hepatitis viruses, which can cause hepatic cancers.
(30:45): It's highly recommended that you discuss with your transplant team the necessary screening for secondary cancers you should receive after transplant. Ensuring that you schedule and complete your screening on time is crucial. Pay attention to the importance of these tests, as the risks associated with your transplant never truly vanish. Even years after your transplant, it remains vital to prioritize these tests.
Transcript of Presentation:
(00:01): [Marla O'Keefe]: Good afternoon. Welcome to the workshop Secondary Cancers after Transplant. My name is Marla, and I will be your moderator for this workshop.
(00:10): Speaker Introduction. I am pleased to introduce today's speaker, Dr. Alison Loren. Dr. Loren is the Chief of Hematology/Oncology and Professor of Medicine at Perelman School of Medicine at the University of Pennsylvania. She is also the Director of the Blood and Marrow Transplant and Cellular Therapy Program at Abramson Cancer Center. Dr. Loren specializes in hematologic malignancies or blood cancers, and her clinical and research interests focus on outcomes after transplant, fertility preservation and pregnancy after transplant, and long-term survivorship. Please join me in welcoming Dr. Loren.
(00:53): [Dr. Alison Loren]: Thank you very much. It's great to be here, and I appreciate the BMT InfoNet Survivorship Symposium and the entire team who put this wonderful workshop together. And it's an honor to be here and speak to all of you, the bravest and strongest people I have ever met. And I get so much out of caring for my transplant patients every day, and I thank all of you for all you've taught me.
(01:21): What is a secondary cancer? I will talk to you a little bit today about the issue of developing cancers after your bone marrow transplant and just a little bit of terminology. What we will be talking about today is what we call a second cancer or secondary cancer. These cancers occur months or years after a bone marrow or stem cell transplant. And they are different from the one for which the transplant is performed. So, if the transplant was done for a certain type of blood cancer, like acute myeloid leukemia, and that same cancer comes back after the transplant, we call that a relapse. But if a person develops a different cancer after transplant, we call that a second cancer.
(02:06): People who have had hematopoietic cell transplants - aka bone marrow, stem cell or cord blood transplants - are at an increased risk of developing another cancer, mainly because of the effects of high-dose chemotherapy, radiation, immune suppression, and also certain infections that can occur after transplant. And there may be certain genetic predispositions that make people more likely to develop their first cancer as well as the second cancer.
(02:39): Experiencing a second cancer after a bone marrow transplant is common. I want to emphasize a few key points in this presentation. Firstly, it's crucial to understand that experiencing a second cancer after a bone marrow transplant is common. However, the type of cancer that may occur [varies] depending on the type of transplant received - whether it was an autologous transplant using the individual's blood stem cells or an allogeneic transplant using someone else's blood stem cells. These risks apply to both pediatric and adult recipients of transplants.
(03:10): Screening for secondary cancers and lifestyle choices after a bone marrow transplant affect the risk for, and outcome after, a secondary cancer. It's important to know that there are things you can do about these risks. Screening and prevention are essential and make a huge difference in long-term outcomes after transplant. And in addition to making sure that you stick with your screening recommendations, it's also important to know that there are lifestyle choices that you can make that will reduce your chances of getting another cancer.
(03:34): Research is underway to understand why some people develop second cancers after transplant, so we can develop personalized approaches to reduce the risk. And lastly, it's important for you to know that there's a lot of research going on in this area. For example, we need to understand why some people develop cancers after transplant while others don't. And we hope that what we learn can help personalize our approaches to reduce the risks for our transplant recipients.
(03:52): So, one piece of great news to share is that transplant outcomes are improving. And here I'm showing you some data from a study that was published almost 15 years ago, comparing patients who received transplants in an earlier era, in the 90s, to patients who had transplants just ten years later from the 2003 to 2007 timeframe. And you can see, in the first panel, that patients who received their transplant in the nineties were more likely to die from transplant-related complications as compared to patients transplanted more recently.
(04:33): And then reflecting that the likelihood of surviving a transplant is significantly higher in patients who received transplants more recently. So that's great news. However, we still see that people who survive transplants don't live as long as those who have yet to have transplants. And this graph demonstrates this strikingly.
(04:55): This study looked at patients at least two years after their transplant and followed them over time. Again, as you can see in the first two lines, these are women and men who live in the United States, and you can see that their likelihood of being alive 20 or 25 years after the initial time point is still pretty high, greater than 90, or 95%.
(05:19): Whereas of people who received donor transplants or allogeneic bone marrow transplants, only about 75% were still alive 25 years after their transplant. Now, that's a great outcome in some respects because, as you all know, patients who receive transplants typically receive them for life-threatening illnesses that they otherwise would not have survived even one year, let alone 25. But at the same time, we're losing many lives in that timeframe, this gap between people who were not transplanted and those who were transplanted. And we'd like to understand that a little bit better.
(05:57): This is another depiction of a similar concept. Essentially this shows the likelihood of dying per year. And you can, of course, see that people who have not had bone marrow transplants, which is this bottom dotted line, have a pretty low chance of dying at any given time, whereas people who have survived five years or more after a bone marrow transplant are much more likely to die from some illness. And I will break that down in a moment. But essentially, you can see that having undergone a bone marrow transplant still puts you at high risk of dying from complications.
(06:34): And why do people die after bone marrow transplants? It's still a heterogeneous group of causes. For donor and autologous transplants, the relapse or recurrence of the original cancer for which the transplant was performed is the most significant cause of death. You can see that graft-versus-host disease is an important concern for people who receive donor bone marrow transplants.
(06:59): Five to 10% of people transplanted with stem cells from a donor (allogeneic transplant) die from a second cancer. Up to 25% of patients who are transplanted with their own stem cells (autologous transplant) die from a second cancer. Again, highlighting the importance of second cancers, five to 10% of people who received donor transplants die from second cancer. And in people who receive autologous transplants, it can be as much as a quarter of people dying from second cancers. So it's an important problem that we need to understand and try to work on preventing.
(07:23): So in general, second cancers after a bone marrow transplant are a significant risk. The risk of getting another cancer [after transplant] is between four and 11-fold higher compared to the general population.
(07:36): In one study, the BMT Sibling Survivorship study, which compares transplant survivors to their siblings, 7.5% of transplant survivors developed another cancer as opposed to 1.6% of their sibling controls. So even within the same family, there's a higher risk. And the risk continues to rise, so even 15 years after a donor transplant, the cancer risk is still significant.
(08:05): There are three groups of secondary cancers that can occur after transplant: therapy-related blood cancers, lymphomas and solid tumors. We typically break these types of cancers into three main groups because they differ. One group of second cancers is known as therapy-related blood cancers. Another group of cancers is lymphomas, which are related to the transplant and immune suppression itself. And then the third group is what we call solid cancers. And these are cancers of the organs like the breast, colon or skin, or cervical. So they are different kinds of cancers in different groups of patients.
(08:36): Therapy-related cancers after transplant include acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) which typically occur early after transplant. So I will talk about them individually. And the most important thing you can see in this slide is that for people who develop MDS or AML, these are the therapy-related blood cancers that typically happen early after transplant, and then the risk sort of levels off by five years after transplant.
(08:54): Lymphomas also tend to occur within a year or two after transplant, and not later. And that's similar to lymphomas. These post-transplant lymphoproliferative disorders, or PTLD, also tend to occur very early within the first one, maybe two years after transplant, but not at all afterward.
(09:07): The risk of developing a solid tumor after a bone marrow transplant steadily rises over time. But solid tumors steadily rise over time, and they never really plateau. So, as much as 4% of patients who have received a transplant, at 20 years, will have developed another tumor.
(09:22): The therapy-related blood cancers typically include blood cancers known as myelodysplastic syndrome or MDS and acute myeloid leukemia or AML. Many of you in the audience will recognize these cancers because these are also very common reasons why people receive donor bone marrow transplants. These conditions can be triggered or caused by exposure to certain agents, such as chemotherapy and radiation. For example, people who have received autologous transplants - people who have received a transplant using their own blood cells - have typically received a lot of chemotherapy and radiation before getting their transplant. And so, the presumption is that their blood stem cells may have become more likely to go on to develop these therapy-related blood cancers.
(10:13): As I highlighted before, these typically occur pretty early after the transplant up until about five years, with a cumulative incidence around 2% at ten years. And as I mentioned, radiation exposure. And in the older days, we used a drug called etoposide, that is not frequently used anymore, to help mobilize or stimulate the blood stem cells. And this is one of the reasons that people who received high doses of etoposide as a mobilizing agent to collect the stem cells are at higher risk.
(10:46): In contrast, lymphomas, which are known as post-transplant lymphoproliferative disorders when they occur in this context, almost exclusively occur in recipients of donor bone marrow transplants (allogeneic transplant). And as I mentioned, these typically occur quite early after the transplant. They are nearly all driven by a virus known as Epstein Barr Virus, which is a virus that is in the herpes family of viruses and is the virus that causes mono (]mononucleosis). Some of you may have heard of this virus before. This is thought to be caused by the EBV virus, which lives in B-cells, which are a type of white blood cell. That EBV infection of B-cells seems to drive the B-cell to overgrow or proliferate in people who have not had bone marrow transplants, who have a normally functioning T-cell population.
(11:41): Patients who have impaired T-cell function have an increased risk of developing a lymphoma after a stem cell transplant. T-cells are another form of immune cell. If they're working right, those T-cells can block that B-cell proliferation and prevent this type of cancer from occurring. But people who have impaired T-cell function, such as those who have had donor bone marrow transplants or solid organ transplants (liver, heart, lung, and kidney transplants) can get this.
(12:05): People who have had T-cell depletion, as a preparation for their transplants, either using antibodies like ATG or Campath or T-cell depletion as part of graft engineering, where it's a CD34 or a stem cell selected graft: people who have received umbilical cord blood transplants; people who have an immune deficiency as a reason for getting the transplant - this is more often in children; people who have had mismatched or unrelated donors because the degree of immune suppression is usually greater; and similarly, people who have significant graft-versus-host disease, again, who needs a lot of immune suppressive therapy; those are the people who are more likely to develop post-transplant lymphoproliferative disorders.
(12:51): These are not uncommon. As many as 8% of patients who have received some of the riskier forms of transplants can go on to develop post-transplant lymphoproliferative disorder (PTLD). In the old days, when I was training, these were very serious problems that patients often succumbed to. In good news, we've learned a lot about these disorders, and we are learning how to surveil and monitor for these and to treat them, often with a medication known as rituximab (Rituxin®), which will prevent a full-blown lymphoma from forming. So, we've made a lot of progress in understanding and treating this condition.
(13:34): I think the biggest challenge is the risk of solid tumors. And I want to emphasize here that I will show you some numbers that are a bit scary and offer significantly increased risks of getting these different kinds of cancers after a transplant.
(13:49): There is a difference between the “absolute risk” of getting a second cancer after transplant, and the “relative risk”. Recognizing a big difference between relative and absolute risks is important. This will sound shocking to this audience, but cancers are not terrifically common year-to-year. And so, a twofold or a 30-fold increase may still be a small percentage increase, but it is still relatively uncommon, and the risks are still much higher than the average person. So keep that in mind as we review these numbers; while they are striking, important, and have major health risks, there's no cause for panic. And again, there are things you can do to help mitigate your risks.
(14:32): The risk of developing a solid tumor after transplant is higher among patients who were transplanted with donor bone marrow or stem cells (allogeneic transplant), than among patients transplanted with their own cells (autologous transplant). So the risks of solid tumor occurrences, second cancers seem to be a little bit higher in donor transplants, allogeneic transplants, as compared to autologous transplants, with the exception of autologous transplants having this therapy-related blood cancer risk, which is 20 fold higher. Remember that these myeloid cancers are uncommon in the general population. So this 20-fold increased risk
(15:05): You can see that people who have received allogeneic transplants have about a twofold risk of developing some solid cancer. And it's about a 1.4-fold risk for people who have received autologous transplants for cancers other than these blood cancers.
(15:19): As I mentioned, the cumulative risk is significant and increases over time. There's no plateau; it never levels off. So even if you're 35 years after your transplant, you still need to pay attention to these risks.
(15:34): Other risk factors for developing a solid tumor after a bone marrow transplant include radiation, age at the time of radiation, chronic graft-versus-host disease and certain infections. People who have received radiation, people who have chronic graft-versus-host disease, with the attendant immune suppression that engenders, as well as the inflammation that it tends to cause; people who are at younger ages when they receive their radiation therapy; people who have infections with certain viruses like HPV, which can cause cervical cancer or penile cancer and hepatitis viruses, which can cause hepatic cancers; are all at increased risk.
(16:04): It also seems that the reason for the transplant might influence the risk of getting second cancer. People with transplants for acute leukemia seem to be at higher risks, for instance, than people with severe aplastic anemia, which is not considered a cancerous condition. And so whether that has to do with the intensity of the therapy that people received before their transplant, how the transplant was done, or maybe genetic predisposition somehow to cancers in general, we're still trying to understand that.
(16:34): The risk of developing a secondary cancer after transplant is still significant even if you don't receive radiation as part of your transplant preparation. This study focused only on patients who received chemotherapy-based conditioning with busulfan and cyclophosphamide. You can see that patients who received their transplant for AML or CML still had about a 3% incidence of some solid cancer 15 years after the transplant.
So, it's not just about the radiation, although radiation is certainly the most significant risk factor. And mainly if you are young when you receive radiation therapy, you can have a significant risk of non-squamous cell cancer. Squamous cell cancers typically are cancers of the epidermis like the skin, the mouth, or the cervix, whereas non-squamous cell cancers are all the other cancers - breast, GI, etc. Radiation is most strongly associated with rare cancers like thyroid, bone, soft tissue, sarcomas, central nervous system tumors like brain cancer, breast and melanoma - a non-squamous cell skin cancer.
(17:45): Chronic graft-versus-host disease increases the risk of squamous cell cancers in the mouth, vaginal area and on the skin. The presence of chronic graft-versus-host disease mainly influences, conversely, the risk of squamous cell cancers, and again, that's largely thought to be related to this sort of inflammatory environment of chronic GVHD. And those of you with chronic GVHD certainly can attest that skin, mouth, and vaginal areas in women are significantly affected. And so, if you can imagine a lot of inflammation and cell turnover, that probably is why there's a lot higher risk of squamous cell carcinomas in those areas in patients with chronic GVHD.
(18:20): For some reason, men have a higher risk of skin cancer. We don't understand that. Reduction in T-cells seems to increase the risk of melanoma, and it does seem that people who receive very intensive conditioning regimens (myeloablative conditioning) may be at a higher risk than reduced-intensity transplants. A recent publication suggests that people who have received reduced-intensity transplants may have risks that more closely mimic the general population. But I still think that those are people who need our close attention. I'm unsure, I would check out if you had a reduced-intensity transplant. I think there's still a lot to be learned there.
(19:05): What are the risks of getting lung cancer, liver cancer, thyroid cancer, breast cancer or oral cancer after a bone marrow transplant? This is just an example of the increased risk people have after transplants. So these numbers reflect the fold increase over the general population. So, for instance, the risk of lung cancer. For people who have received busulfan/cytoxan conditioning before the transplant, the chance of getting lung cancer is 2.6 times that of the general population. And as you can see, these are not very common cancers. Liver cancer, and thyroid cancer, are not particularly common. And so, their risks are significantly increased because of the exposures associated with transplants. But even so, breast cancer risk is still elevated. Oral cavity cancers are elevated. This is one of the reasons I'm always harassing my patients to see the dentist. I always look in their mouths, but it's sometimes hard to see back there. And dentists can be an important way to surveil these cancers.
(20:04): Radiation can increase the risk of developing a brain tumor after a bone marrow transplant in children, although the risk is still small. Some recent data about children and central nervous system or brain tumors that it's important to be aware, again, remembering that brain tumors are very, very uncommon. So a 30 to 33 -fold increased risk is only about a five to 10% chance of getting a brain tumor, but that's significantly higher than the general population, in which these tumors are quite rare. So we are learning that radiation exposure and the presence of cancer in the central nervous system before transplant - for instance, patients with acute lymphoblastic leukemia (ALL) who had leukemia in their spinal fluid - seemed to be at the highest risk for developing this type of cancer.
(20:51): Children are also at increased risk even if they've had an autologous transplant. We're starting to understand that, because these kids were transplanted when they were so young, developing solid cancer five years or ten years after their transplant means they're only 18 or 19 or 20 or 25 years old when they're developing these second cancers that are typically cancers are diseases of an older population. So it is a significantly increased risk because cancers are so rare in these young patients.
(21:30): There are probably genetic predispositions that influence the risk of developing a second cancer after a bone marrow transplant. We're starting to learn, based mainly on Dr. Bhatia's work and others, that there are probably genetic predispositions to the risk of certain cancers. So genetic risks may increase the chance of developing cancer. For example, for people with genetic problems in their ability to repair damaged DNA, there's genetic variability in how we metabolize chemotherapy. Some people seem less able to metabolize the chemo as quickly, so it hangs around for longer, and maybe that causes an increased risk for cancer down the line.
(22:09): Some studies demonstrate that a certain part of the chromosomes known as telomeres may be affected by treatment, which can specifically increase the risk of thyroid cancer. And more recently, we're starting to learn more about a genetic tool called polygenic risk scores, which can help us better focus on increased risk - patients at risk for breast, thyroid, or central nervous system cancers.
(22:37): And so what can we do about this? We're actively trying to figure out safer ways to do transplants. And everybody in this presentation is aware of our efforts to reduce the toxicity of the therapies we're offering. But in the meantime, and for those of you who have already had your transplant, which I suspect is most of you, what can you do about this moving forward?
(23:01): The first step in reducing the risk of developing a second cancer after a bone marrow transplant is to know your risks. Well, number one is to be aware of your risks. I've already mentioned that if you've had radiation as part of your treatment, your risks are higher, and you need to be aware of that. To prevent skin cancer, it is recommended that you see a dermatologist every year and have them check you out from head to toe. And in particular, if you have graft-versus-host disease of the skin, this is essential. The risk cannot be overstated. It would help if you had yourself checked out every year.
(23:30): Bone marrow transplant survivors have an increased risk of thyroid cancer, so an annual thyroid exam and ultrasound is appropriate. Thyroid cancer is rare cancer, but it is significantly increased in these populations, especially people who have received radiation. So an annual thyroid exam or an ultrasound is appropriate. Checking thyroid blood tests does not necessarily exclude thyroid cancer. Somebody should lay their hands on your thyroid gland; it sits in your neck just below your Adam's apple. Somebody should examine that every year, or you can do it. And if you feel a little lump, that's important to report.
Some people prefer thyroid ultrasounds, especially if they already have thyroid nodules. It can be hard to know whether they're cancerous or not. An ultrasound can tell the difference. Thyroid nodules are common; they are often benign and don't need any intervention. So that can be a helpful tool to distinguish those nodules.
(24:24): Transplant survivors should have a good dental exam at least every six to 12 months I already mentioned the importance of a good dental exam at least every six to 12 months. Many people, after transplant, have dental issues anyway because of the reduction in saliva production and the dry mouth. And so many of my patients will see their dentist three times a year because of that. It's also good to ensure they get a good exam.
(24:45): There is an increased risk of cancer of the esophagus, and at this time, there are no screening recommendations, but certainly, I would have a very low threshold to have an upper endoscopy done if there are any symptoms pertaining to the esophagus such as, heartburn or difficulty swallowing. It's a very safe procedure that can be done in the same session as a colonoscopy. I think there's a minimal downside to looking there, if you have any symptoms or concerns.
(25:15): Bone marrow transplant survivors should have a screening for colon cancer starting at age 45, or younger if you have a relative who had colon cancer. Many of you are probably aware that the incidence of colon cancer seems to be increasing in younger people. And several groups have revised their colonoscopy screening guidelines to age 45 rather than 50. So if you've had radiation, if you've had chronic GVHD, if you have relatives who have colon cancer, I would strongly recommend a colonoscopy starting at age 45 or younger. If you have a colon cancer relative - affected relatives who were younger when they had their diagnosis - and you can individualize these recommendations with either your transplant physician or your gastroenterologist.
(25:54): For bone marrow transplant survivors who are age 50 or older and have smoked more cigarettes more than 30 pack year s- a screening chest CT is appropriate. Lung cancer screening. We couldn't figure this out for a long time, but it turns out that there is a survival benefit to screening certain people with a smoking history. This is independent of the bone marrow transplant. If you are over 50 years old and have smoked for more than 30 pack years (calculated by multiplying the number of packs smoked per day by the number of years smoked), then you meet the criteria. For example, smoking three packs daily for ten years equals 30 pack years.
Similarly, smoking one pack a day for 30 years also equals 30 pack years. A transplant is a risk factor for people who meet these criteria or in our patients. And so, for our patients, it would be at age 50 or older and 20 pack years when a screening chest CT is appropriate. And there are some pretty detailed guidelines around these recommendations in various thoracic publications. Your transplant physician should be able to familiarize themselves with these pretty easily.
(26:55): Breast cancer screening is incredibly important, particularly for people who have had total body radiation, certain kinds of chemotherapy and are younger at the time of transplant. The recommendation is to start screening eight years after the treatment is completed or at age 25, whichever is earlier, but not later than age 40. And there are emerging data that breast MRIs will be helpful screening tools for people who have had radiation to the chest. There are a number of publications that support this. However, breast MRIs are expensive, and insurance companies sometimes balk at paying for them. I would strongly urge you to have a conversation with your transplant doctor about it and make sure they understand that your insurance company understands that you are at high risk for breast cancer. And this is for both recommended mammograms and MRIs because they provide complementary information and should be done annually.
(27:49): Cervical cancer screening is crucial, especially for post-transplant women with vaginal GVHD. Unfortunately, while screening recommendations for cervical cancer have become less frequent among the general population, there is no evidence to support less frequent Pap smears for this group.There's emerging evidence that many women are not appropriately screened. Fewer than 40% of patients are getting appropriate Pap smear screening. And women with GVHD who are at the highest risk are 50% less likely to be screened. That may well be due to the stenosis that can occur in the vagina, which makes vaginal exams very uncomfortable, but it's still essential to try. So I strongly urge women post-transplant to ensure they still see a gynecologist or a provider who can do Pap smears.
(28:48): There are no specific screening recommendations for these other cancers that I've lifted here listed here, but I will highlight that there's a significant gap in our understanding of risk for female genital tract cancers. And this is an area that we need to understand better.
(29:04): Lifestyle changes you can make to reduce your risk of developing a secondary cancer. Then I mentioned a few things you can do for yourself. Be healthier. Don't smoke. Use sunscreen SPF 30, or higher, and reapply it every one to two hours. Follow a healthy lifestyle with as few processed foods as possible, low fat, high protein, lots of whole grains, and fruits and vegetables. Make sure you get some exercise every day. This is also important for cardiovascular health, which I know you'll hear more about.
(29:31): Research is underway to better understand how to reduce the risk of a secondary cancer after a bone marrow transplant. We're trying to understand better how to mitigate these risks. And so, some future research directions we've identified in the field, are to understand the magnitude of risks for specific cancers and the interactions between traditional risk factors and transplant-related risk factors.
(29:51): We're trying to do some other tissue banking to study risks related to inflammatory markers or genetic characteristics to personalize our screening recommendations. We're trying to understand how well our risk reduction strategies are working and also make sure that, when appropriate, our patients are getting vaccinated against HPV and hepatitis B after their transplant to try to reduce their risks moving forward.
(30:20): So, to wrap up, although this is a tough conversation, no one should regret having a bone marrow transplant. Bone marrow transplants are lifesaving therapies. It is far from perfect, but it is the best treatment for many blood cancers and other severe diseases. It is still an excellent therapy even though it leaves us with a lot to work on.
(30:45): It's highly recommended that you discuss with your transplant team the necessary screening to undergo. Ensuring that you schedule and complete your screening on time is crucial. Pay attention to the importance of these tests, as the risks associated with your transplant never truly vanish. Even years after your transplant, it remains vital to prioritize these tests.
(31:03): One challenging area is understanding who owns this and who ensures all the testing is done. Is it going to be your transplant team? Is it your primary care doctor? Is it your gynecologist? Is it your gastroenterologist? Make sure that you know who's owning the job of ordering all these tests.
(31:21): And then lastly, as I mentioned, make sure that you take good care of yourself and make sure that you advocate for yourself. Only some providers are going to understand the special needs of transplant survivors. I'm sure many of you are already in a position of having to educate your healthcare teams about what transplant recipients need for their health moving forward. Don't be shy about that. It is a long road, but hopefully, it ends in a great place for all of you. And I will stop now, and I'm happy to take questions.
Questions and Answer Session
(31:59): [Marla O'Keefe]: Thank you, Dr. Loren, for this excellent presentation. We have a number of questions here, so we'll now begin the question-and-answer session.
(32:17): Our first question is, "Can Cologuard suffice for a colonoscopy?"
(32:23): [Dr. Alison Loren]: That is a great question. So Cologuard is very good at catching cancers but not pre-cancers. There is a whole spectrum of pre-cancerous abnormalities that can happen in the colon that may or may not show up on Cologuard. I have heard gastroenterologists say is that they want to know about their patient's risk before they have cancer. So yes, a Cologuard is a good screening test for picking up cancers, but it's not as good for pre-cancers. And so, I would prefer a colonoscopy. If it's Cologuard or nothing, I'll take the Cologuard, but I think a colonoscopy is a much more comprehensive test that identifies pre-cancers.
(33:14): [Marla O'Keefe]: Okay, thank you. The next question is, how does familial cancer history affect your risk for developing secondary cancers?
(33:25): [Dr. Alison Loren]: The question regarding cancer risks within families is worth $64,000, but unfortunately, there is no clear answer. However, some familial cancer risks can be tested for, such as BRCA. So, if someone has a known BRCA mutation, their screening and management would be handled similarly to any other BRCA carrier.
(33:59): But there are these more nebulous situations where there's, for instance, lots and lots of prostate cancer in somebody's family but no known gene we can identify. In those areas. It has to be a conversation between the patient and their team to understand, 'Are there additional screening tests or additional considerations that we need to be mindful of?' For example, I have many patients for whom I will order a PSA simply because they have five male relatives who had prostate cancer in their forties, so I think they should be screened even though there's no known link between prostate cancer and transplant.
(34:41): I think from the ‘how does it feel’ perspective, we all believe that those patients are probably at higher risk for cancers that run in their families, and maybe that risk is even higher because of the transplant. But we don't know, and this is a very active area of research that we're trying to understand. The whole field of genetic risk for cancer is at a turning point. The more we can test, the more we can understand, but it also adds many more questions. So yeah, that's a great question. I wish I had a better answer for you other than it matters, but we're still determining exactly how much or how to manage that increased risk.
(35:23): [Marla O'Keefe]: Thank you. Is breast cancer an issue for male survivors as well?
(35:30): [Dr. Alison Loren]: That is another great question. It has not been studied to my knowledge. We do not recommend mammograms or ultrasounds for men for screening unless they are BRCA1 carriers. There is a risk for male breast cancer in specific genetic syndromes, but otherwise, for men, we don't know, actually, and I've not seen anything published about this. It is not part of routine screening to consider that. That said, men have mammary tissues, and if they're exposed to radiation, that certainly could be a risk, but we don't screen for it.
(36:13): [Marla O'Keefe]: Thank you. There are a couple of questions here about an annual breast mammogram or a 3D mammogram. Is that acceptable if I get a mammogram and an ultrasound, or do I need an MRI?
(36:29): [Dr. Alison Loren]: The data about ultrasounds for screening is controversial, and I would say that for all of the published studies we have, no one's looked at ultrasound as a screening option, so I would go with an MRI if you can. I would not rely on an ultrasound. I would go with an MRI.
(36:53): [Marla O'Keefe]: Okay. Are all of the comparisons allogeneic and autologous? Can I assume that if I had a haplo [haploidentical] transplant, that falls into the allogeneic group?
(37:09): [Dr. Alison Loren]: Yes, haplo transplants are considered allogeneic. Anything that's not yourself is considered allogeneic. So haplo, cord bloods, those are all allogeneic.
(37:19): [Marla O'Keefe]: Okay. Are blood or organ cancers more likely after transplant? Do I look to my primary care physician or oncologist for recommended screenings?
(37:35): [Dr. Alison Loren]: So I would say that if you've had a bone marrow transplant, you're very likely getting routine blood counts - what we call a CBC or a complete blood count - as part of your routine visits with your doctor. I do not think there's any additional screening that needs to happen other than that which is part of likely your routine cancer care.
(37:54): Attention should be paid to changes in the blood counts. Certainly, one blood count being off happens often, for many reasons, but if something abnormal happens, I recommend a closer follow-up, maybe two to four weeks later. And if those changes persist, then they may need additional evaluation. Unfortunately, this is not unfamiliar to this group; the best way to evaluate for blood cancer is to do a bone marrow biopsy. And so ultimately, if the blood count abnormalities persist, that's usually the next step.
(38:32): [Marla O'Keefe]: Okay, thank you. Do you think a colonoscopy needs to be done sooner if colon cancer was the cause of death of a parent?
(38:45): [Dr. Alison Loren]: That's a good question. Typically for colon cancer recommendations, this isn't my exact field. However, I believe colonoscopy is recommended starting ten years before the original diagnosis of the first-degree family member. So, for instance, if a parent was diagnosed with colon cancer at age 48, their first-degree relatives should be screened at age 38 regardless of their other history.
(39:14): I would probably stick with that or the more aggressive strategy. I don't think it matters at what age the parent died; it's more relevant at what age they were diagnosed and start ten years before. And then, after the first colonoscopy, the interval is usually based on what they find. So if there are pre-cancerous polyps or adenomas, they may have the person come back in one year or three years, or five years rather than the usual 10. But I think that is a more detailed conversation that a gastroenterologist can have with the patient after their first colonoscopy. So I hope that answers the question.
(39:52): [Marla O'Keefe]: Thank you. Let's see—next question. My mouth and tongue always stay irritated and sore, but my doctors and dentists say they don't see anything wrong. What would be the next step to try to figure out what's going on?
(40:11): [Dr. Alison Loren]: That's a good question. So, I'm glad it's been evaluated, and if they're looking around and they're not seeing anything, that's certainly reassuring. I would say that general irritation or sensitivity is often related to some graft-versus-host disease. If this is a person who's received a donor transplant,viral infections. like herpes can cause ulcers that might be causing a lot of pain and tenderness. But if it's just a generalized sort of diffuse irritation, cancers usually are painless, so wouldn't worry much about cancer. However, I might be worried about some inflammation related to graft-versus-host disease or even certain vitamin deficiencies, which are sometimes common after transplant when people aren't eating well.
(41:00): I might review it with the oncologist caring for you and see if they have any other thoughts. And then beyond a dentist, there's a medical specialty known as oral medicine. That might be another place to try. Try for a referral to a tertiary center with an oral medicine or oral surgery specialty for somebody to take a look. They can take biopsies, which sounds like little fun, but they can be useful. I suggest asking some more questions and getting a referral to somebody with subspecialty expertise in that area.
(41:35): [Marla O'Keefe]: Those are some good other options. Thank you. The next question is, Should a 70-year-old male with an allogeneic transplant get the HPV vaccination?
(41:47): [Dr. Alison Loren]: It is not recommended at this time for people who are over the age of 45. So the official answer is no, and I don't see any reason at this time.
(42:01): [Marla O'Keefe]: How long does an oncologist post-transplant generally follow patients?
(42:07): [Dr. Alison Loren]: That is another great question. That varies depending on the practices of your transplant center. So some large referral centers will refer the patient back to their primary oncologist at day 100, one year, or two years. And I think it speaks to this issue of survivorship, as well, who takes care of long-term cancer survivors in general. It's a difficult problem, and it's a good question to ask your transplant physician - what's their usual practice, and how do they manage patients moving forward?
(42:45): Although I may come across as possessive, I have my patients' best interests at heart. Even if they feel tired of visiting, I recommend seeing my transplant patients at least annually. However, if they cannot make it to Philadelphia, I provide them with a comprehensive list of required screening tests and potential risks. Additionally, I ensure that they have a diligent primary care physician who will prioritize their health needs.
(43:20): As I mentioned earlier, most of the studies that we recommend are basic primary care. They're largely things that most people should be doing. It's just extra important that transplant recipients do them. Most people, of course, don't follow general health advice, as we all know. And so for transplant survivors, it's just extra important to stick with those good primary care screening guidelines, plus the extra bells and whistles that I usually try to put into a referral note. There are medical references that outline in a lot of detail about what patients need after a transplant, so I'll often provide that reference to the primary care provider.
(44:01): And there are also a lot of variations in what a transplant physician is comfortable handling themselves versus not. For example, I am not a big fan of prescribing statins. I'm not a big fan of managing diabetes, nor a big fan of managing testosterone supplements myself. Those things are quite difficult for somebody who only sometimes does it. And so, I'll often rely on a primary care partner to help me with those things or a cardiology provider to help me because I want to work as a team and ensure the patient's getting the best care.
(44:37): So, you hit on a really sore point in our healthcare system where there can be gaps in who's managing what, which unfortunately requires you, the recipient, to manage and ensure that somebody's doing all of this. Having an engaged physician willing to have those conversations with you is key.
(44:57): [Marla O'Keefe]: That's a great answer, and I think your patients are very lucky that you're possessive. The next question is, I had one radiation treatment after my chemo before my transplant. Is that considered a risk for total body radiation? It was from my neck to my hips.
(45:14): [Dr. Alison Loren]: That's another important point and something I should have gotten into the weeds on in this presentation. But typically, low doses of radiation, which I suspect is what you had, if these numbers may be meaningful to you, 200 centigrade, 400 centigrade, those are low enough doses that we think probably it does not significantly increase the risk. However, higher doses are generally more than 800 centigrade, and the usual doses for myeloablative transplants are 1200 centigrade. So those people are definitely at increased risk.
(45:47): Your risk is probably not increased for lower dose recipients. But again, most of these screening and preventive practices are general population recommendations anyway, so it can be good to adhere to the basic screening guidelines for everyone.
(46:06): Thank you. The next question is whether Medicare will only pay for a Pap test every other year after 70, and I am 71. Do you have any suggestions on what I should do?
(46:18): You should write your member of Congress. And I'm only sort of joking about that. I think our healthcare system leaves a lot to be desired, as I'm sure you all, having been through it, would agree. So I think this is a really understudied area. So if you're a 71-year-old person who does not have HPV infection, who's had numerous normal Paps, has never had an abnormal Pap, and you're a long time after your transplant, and you don't have GVHD, it's probably okay to stick to population guidelines, but that's a lot of ifs, and it's just a guess. We don't really know the answer. And this is what I was highlighting at the end of my talk, which is that women's cancers are significant. Women's health, in general, is significantly understudied, and women's cancer risk is understudied, and women's cancer risk after bone marrow transplant, there is nothing, there's no data.
(47:21): If you're not super-duper low risk, your provider could appeal and say this is a special case and request coverage above and beyond what they normally cover. I don't know how flexible Medicare is about that.
(47:39): Another option is to try to work out a payment plan with your provider. If, for some reason, it needs to be done annually, and your provider is not able to get it authorized from Medicare, paying out of pocket sometimes is an option, although it can be quite costly. And so it's only an option for some.
(47:55): But it is a hole that we often have to deal with. I have a patient and I'm wrestling with her insurance to get a mammogram approved. It's just so frustrating. Would you rather pay for her breast cancer chemotherapy, or would you rather pay for the MRI? It's absolutely maddening. So I'm really serious about considering letting our elected representatives understand that the needs of cancer survivors are different and important, and there are lots and lots of you guys out there more and more every year, which is wonderful. However, we need to start accounting for that in our healthcare policy.
(48:38): [Marla O'Keefe]: Totally agree with you. Next question. If someone has reactivation of HPV post-transplant due to immunosuppression and steroids and is over 45, should that person have an HPV vaccination?
(48:55): [Dr. Alison Loren]: So that's a great question, and I will tell you I have had one or two patients like that, actually, including one who had an HPV-driven head and neck cancer, which I did not mention as a risk, but that is definitely something that can happen both after radiation and HPV. And I shared that person's care with one of our head and neck oncologists, and we did actually vaccinate them even though they were over 45. So, again, it might be a bit of a magician's trick to get it covered, but I think it's probably worth trying to get it done in that particular situation.
(49:36): [Marla O'Keefe]: Next question, how often should upper endoscopy and colonoscopy be done for total body irradiation (TBI) and graft-versus-host disease (GVHD) patients?
(49:45): [Dr. Alison Loren]: Another great question that we don't totally know the answer to. My practice has been, as I mentioned, have a very low threshold to send them. Certainly, if they're over 45 and I've never had a colonoscopy, I recommend an upper endoscopy and a colonoscopy if they have any upper GI symptoms. Depending on what is found, if there's nothing, if it's completely clean, an every-10-year evaluation is perfectly fine, only because we don't know any better. But this is another understudied area that we really need to learn about.
(50:23): One of my Penn colleagues is studying this. He has some research funding to look at long-term survivors of radiation to the chest and abdomen to understand cancer risks. So, the key difference is that the first screening test with upper endoscopy and colonoscopy, getting that done as promptly as possible. But if there are no concerning findings, is every ten years appropriate? We don't actually know, but the best information we have right now is to revert to normal screening guidelines if the scopes are clean.
(51:00): Marla O’Keefe: Thank you. Next question. If my original cancer was a lymphoma, do I have a higher risk of developing solid cancer?
(51:12): [Dr. Alison Loren]: Yes. I'm assuming you have received an autologous bone marrow transplant; usually, they're autologous for lymphoma, but not always. And so, the risk of solid tumors is increased in all transplant recipients, but the degree of risk is greater in transplant using donors versus a transplant using your own cells. The overall risk of a second cancer is about two-and-a-half-fold for people who received allogeneic transplants (with donor cells) and one-and-a-half-fold for people who have received autologous transplants.(using their own cells.
(51:56): [Marla O'Keefe]: What are the criteria for distinguishing the reception of an auto transplant versus an allo transplant, or why does a patient receive one over the other?
(52:06): [Dr. Alison Loren]: Right. That's an excellent question. People with cancers that respond well to chemotherapy and can be cured with it, such as myeloma and lymphoma patients, often receive autologous transplants. While autologous transplants may not be a cure for myeloma patients, they can significantly increase their life expectancy and reduce the risk of complications like fractures and kidney disease. However, with so many advanced and powerful therapies available today, the role of autologous transplants in treating myeloma remains uncertain.
(52:53): For lymphoma, it's also getting more complicated. Autologous transplant used to be the first choice for people who had relapsed lymphoma after an initial round of therapy, usually for people who have either Hodgkin disease or diffuse large B-cell lymphomas. But now, with CAR T-cells, the role of autologous transplant as the second line is being called into question. And CAR-T is now, as many of you know, an FDA-approved for second-line therapy for diffuse large B-cell lymphomas, although not for Hodgkin disease.. For Hodgkin disease, it still remains an important second-line choice.
(53:33): People who typically have cancers of the bone marrow itself, like acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, and myelofibrosis, we can't use that unhealthy bone marrow for a transplant. So those people need a new bone marrow entirely. They need somebody else's blood cells. So that typically is the way that we decide. But there are exceptions to all of those, like T-cell lymphomas. It's very controversial whether to do an autologous or an allogeneic, and it often depends on the disease, the patient's health, and the donor's options. And similarly, there are rare circumstances in acute myeloid leukemia where we might choose to do an autologous transplant using our own cells. So this is by no means a one size fits all answer, but a very general sense of how we make these decisions.
(54:29): [Marla O'Keefe]: Thank you. The next question is, Have you seen marked differences in treatment responses to secondary cancers from people who have transplants?
(54:40): [Dr. Alison Loren]: That's another really important question, and I would say that the answer is yes, which is why screening and prevention are so important. So I certainly do not need to tell this audience, after all you've been through, how therapy takes a lot out of you. And so it does get harder to get through, for instance, chemotherapy for breast cancer or colon cancer if you've already had a transplant. I think the toxicities are greater and getting through treatment is harder. I don't think we know if treatment is more or less effective, but I know it's harder on people. And so what that sometimes means is that the treatments have to be modified, reduced, or attenuated because the person can't tolerate them, which might impact how well they work.
(55:28): I think it is harder for people, once they've had a transplant, to go through treatments for other cancers. But I will tell you, I take care of a lovely patient who had a bone marrow transplant 25 years ago when she was 20 that included total body radiation, and she just recently had a breast MRI that revealed stage one cancer. And so all she needed was surgery and hormone therapy. Thank goodness. Otherwise, it might have been a much more serious situation that would've required higher-intensity therapies if we had not found it. So I think that's why we push people to adhere to these screening and preventive practices because if you can find it early, the likelihood of needing those risky therapies is much less.
(56:18): [Marla O'Keefe]: Thank you. And this will have to be our last question. What is the role of Rezurock® (belumosudil) in helping with chronic GVHD and, in turn, reducing the chances of secondary cancer?
(56:32): [Dr. Alison Loren]: So Rezurock® is the most recently FDA-approved therapy for chronic graft-versus-host disease. And it is a very effective form of treatment. I think the person is asking if you treat graft-versus-host disease, does the risk of cancer decrease? And if that's the question you're asking, that's another $64,000 question we don't know the answer to.
(56:59): It does stand to reason. You could argue it either way. You could say, well, if there's less inflammation and less damage to the organs, the skin, the mouth, then maybe there's a lower chance of cancer. But we also worry about immune suppression. All of these medications that treat GVHD ultimately lower our immune responses, which can predispose us to other cancers.
(57:25): I don't think it will be a straightforward yes or no, or up-down risk. I think it's complicated. And a lot of our endpoints for treating graft-versus-host disease have to do with symptoms. How is the person feeling? Is the range of motion improved? Are they feeling better? Are they able to do more physically? We're not asking questions about cancer risks and GVHD treatment. We should be. That's a great question and point, but we are still determining the answer.
(58:00): [Marla O'Keefe]: Okay. Unfortunately, on that, we will have to end it. On behalf of BMT InfoNet and our partners, I'd like to thank Dr. Loren for her very helpful presentation. And thank you, the audience, for your excellent questions.
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