New Cancers after Transplant: Steps You Can Take to Reduce Your Risk

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New Cancers After Transplant: Steps You Can Take to Reduce Your Risk

Presenter:  Saro Armenian DO,MPH, Director, Center for Survivorship and Outcomes in the Hematologic Malignancies Research Institute, City of Hope Cancer Center

April 28, 2024

Presentation is 33 minutes followed by 27 minutes Q&A

This workshop was made possible, in part, by support from the William G. Pomeroy Foundation.

Summary:  New cancers can develop after a stem cell transplant using your own (autologous) or donor (allogeneic) stem cells.  This presentation describes what types of cancers may develop, risk factors and what you can do to reduce your risk of developing a secondary cancer,  

Key Points:

• Bone marrow/stem cell transplant survivors have a higher risk of developing a new cancer than the general population. These are called secondary cancers. 
• Risk factors for developing a secondary cancer after transplant include your age, disease for which you were transplanted, graft-versus-host disease (GVHD), type of transplant and the type of chemotherapy and radiation you received prior to, during and after transplant.
• Lifestyle modifications to reduce the risk of a secondary cancer include no tobacco use, skin protection from UV and sun exposure, maintaining a healthy diet, keeping a healthy weight, staying physically active, avoiding risky behaviors including excessive alcohol intake, and getting appropriate immunizations and revaccinations if needed.

Highlights:

(06:05): The risk of developing a new cancer after an allogeneic is twice the risk expected in the general population The highest relative risk is for skin, oral, bone and soft tissue cancers, as well as liver tumors.

(06:39): Solid tumor cancers seen most often after an allogeneic transplant are lung, breast, prostate, colorectal and melanoma

(07:26): A unique disorder that can occur during the first two after an allogeneic transplant is lymphoproliferative disorder.

(09:41): Radiation to the breast tissue is the biggest risk factor for developing breast cancer after treatment for lymphoma.

(10:56): Risk factors for new cancers after an autologous transplant depend on the patients age, type of cancer and treatments received prior to, during and after transplant.   

(11:50): Most autologous stem cell transplant survivors do not have a greater risk of developing a second cancer than the general population. However, a small subset will develop myelodysplastic syndrome (MDS) or acute myeloid leukemia after transplant.

(14:52): Many transplant survivors have other transplant-related health problems that limit their ability to receive treatment for a second cancer.

(16:30): While some risks for developing a second cancer are beyond a patient’s control, life-style modifications and aggressive screening for cancers can help reduce the risk.

(18:48): Potential signs and symptoms of a second cancer that should be evaluated by your doctor include new lumps, unusual fatigue, fevers and sweats, persistent cough, unexplained bleeding or bruising and skin sores and infections.  

(19:46): Skin cancer is common after a stem cell transplant and tends to be more aggressive than skin cancers seen in the general population. There are easy-to-follow guidelines that can help you check yourself for skin cancer.  

Transcript of Presentation

(00:01): [Michala O’Brien]:  Welcome. to the workshop, New Cancers After Transplant: Steps You Can Take to Reduce Your Risk. My name is Michala O’Brien and I will be your moderator for this workshop.

(00:11): Before we begin, I would like to thank the William G. Pomeroy Foundation whose support helped make this workshop possible.

(00:20): Introduction of Speaker. It's my pleasure to introduce today's speaker, Dr. Saro Armenian. Dr. Armenian is the Director of the Center of Survivorship Outcomes at the City of Hope Cancer Center in Duarte, California and past president of the Children's Oncology Group, Survivorship and Outcomes Committee. He is an internationally recognized physician-scientist, focused on improving the health outcomes of childhood and adult-onset cancer patients. Please join me in welcoming Dr. Armenian.

(00:54): [Dr. Saro Armenian]:  Good morning and good afternoon to many of you on the East Coast. Just want to say it's such a thrill and an honor to be here as part of the symposium. Hope you can hear me okay.

(01:06): Learning Objectives. I'm going to talk mostly today on new cancers after transplantation, both allogeneic and autologous transplant, with a large focus on preventive and proactive strategies for steps you can take to reduce your risk.

Hopefully, by the end of this workshop, you will be able to understand the potential secondary cancers that can occur after allogeneic and autologous transplant, and understand the incidence and risk of developing a second cancer after transplant.  As well, you will be able to understand the medical tests and exams that are needed, their timing, as well as strategies to reduce the risk and lifestyle modifications that can be facilitating strategies.

(0156): Risk factors for developing cancer in the general population include genetics, age, smoking, alcohol use, sun exposure and some viruses. Let's talk about, in general, the concept of cancer development in the general population outside of transplant. There are some well-established risk factors.

First, genetic predisposition for developing a cancer. This could be a family history or specific syndromes that individuals are born with, typically seen in childhood, such as issues with telomere shortening, that predispose someone for developing a cancer earlier than you would expect for the general population.

Normal aging itself clearly is the biggest risk factor of developing a cancer. Additionally,  well-established carcinogens such as smoking, alcohol, excessive alcohol use, prolonged sun exposure - in particular frequent sunburns - as well as specific viruses such as human papillomavirus (HPV) and Epstein-Barr virus (EBV) have been associated with cancers.  I'll talk about these a little bit later.

(02:50): Cancer treatment can increase the risk of new secondary cancer. But we also know that cancer treatments themselves and the specific exposures such as chemotherapy, radiation and prolonged immunosuppression can increase the risk of cancers as well as the immunodeficiency syndromes and disorders that individuals are born with. So that's the big umbrella, broad categories of factors that drive cancer risk.

(03:10): Risk factor for developing another cancer after transplant. Let's dive in a little bit more and talk about the specific risk factors for cancer after the transplant. These include graft-versus-host disease (GVHD), both acute as well as chronic, medications used to treat or even prevent graft-versus-host disease, underlying diseases and associated prior treatments.  Some cancer treatments or myelodysplastic management, and myelodysplastic disease itself can result in subsequent cancers and then transplant-related chemotherapy and radiation.

(03:47): We also have a higher risk from donor transplant, so own versus other stem cells, which I'll talk about.  Other risk factors result from maintenance therapies associated with transplant and new lifestyle risk factors that develop after transplant as a result of these therapies.  I’ll talk about how they drive transplant risk factors. So that's a broad category.

(04:08): Case example of a patient who developed a second cancer after a transplant using donor cells (allogeneic transplant).  I'll start with some case examples. First, focusing on patients who underwent an allogeneic transplant and why it matters to talk about subsequent cancers in this population.

(04:22): So you have a 47-year-old male with a history of acute lymphoblastic leukemia (ALL), who underwent a matched, unrelated bone marrow transplant, and who is now a three-year survivor.

(04:35): He presents to a survivorship clinic with a two-month history of a skin lesion on his forehead. A biopsy was performed after a referral to dermatology, and this patient ended up having a skin cancer. Specifically, squamous cell carcinoma.

(04:53): Some risk factors for developing squamous cell carcinoma after transplant. So what are the specific risk factors and relevant history for this patient? Well, the patient had male pattern baldness. The hair itself obviously protects from sun exposure and the forehead is a common place for these cancers to develop. He was non-Hispanic white. The more fair skinned you are, the higher the risk of skin cancer, compared to the general population.

(05:21): He's a construction worker, so he spent a lot of time outdoors, a risk factor for skin cancer in the general population.

(05:30) When you talk about transplant-related additional risk factors, he had received total body irradiation, which puts you at risk for skin cancer because radiation is a risk factor for skin cancer. He also developed graft-versus-host disease. Both the graft-versus-host disease as well as the management of the graft-versus-host disease, which in his case was use of CellCept for more than three months, so he had prolonged immunosuppression, are risk factors. The combination of all of these risk factors likely contributed to the development of skin cancer in this patient.

(06:05): The risk of developing a new cancer after a transplant with donor cells (allogeneic transplant) is twice what would be expected in the general population. What do we know about new cancers after allogeneic transplant? I'll talk about autologous transplant later. In general, the risk is twice what would be expected for the general population. It's important to contextualize this because cancer is an aging disease, so you always want to evaluate it in the context of relative to the general population. It’s about two times the risk compared to the general population. And in fact, with longer follow-up, and as our survivors get older, that general risk relative to the population increases with time.

(06:39): Solid tumor cancers seen most often after transplant are lung, breast, prostate, colorectal and melanoma. Specific to solid tumors, there's a higher risk of lung, breast, prostate, colorectal and melanoma. Essentially, what we're seeing is what we call a left shift. There is an earlier onset of various cancers that you would expect in the aging population, but you're seeing it earlier and a higher risk in our allogeneic transplant population.

(07:12): Graft-versus-host disease (GVHD) and exposure to radiation during treatment are the biggest risk factors for developing a second cancer after an allogeneic stem cell transplant.  What are the patient and transplant-specific risk factors? Obviously, older age as we discussed earlier, but then graft-versus-host disease and associated radiation exposure are the biggest drivers in this population.

(07:26): A unique disorder that can occur after an allogeneic transplant is lymphoproliferative disorder. Let's talk about a unique condition that we see often after allogeneic transplant, which is lymphoproliferative disorder. This typically presents in the first two years after transplant and it's associated with activation of the Epstein-Barr virus or EBV, which many of us harbor but is essentially dormant. Once someone is chronically immunosuppressed, that virus essentially emerges and it presents with lymphoma-type clinical characteristics, such as enlarged lymph nodes, fevers, weight loss, etc.

(08:00): What's interesting, in fact, is that because this is a dormant virus in all of us and it's typically kept at check based on your immune system, the more the immune system is suppressed after the transplant, the higher the risk of this EBV being activated and this lymphoproliferative disorder developing.

(08:18): Risk factors for individuals to develop lymphoproliferative disorders are patients who undergo T-cell depleted transplant where T-cells are not there as part of the graft, severe graft-versus-host disease, or cord blood stem cell source. The treatments are relatively straightforward. Oftentimes, they're responsive to Rituxan, which is an antibody-based therapy typically used for lymphoma. In some cases, chemotherapy is used.

(08:46): Case example of a person who developed breast cancer after a transplant using her own stem cells (autologous transplant). Let's talk about another patient scenario, which is a patient who underwent autologous transplant. This is a 32-year-old female with a history of Hodgkin’s lymphoma, diagnosed at 17 years of age. So now, nearly 15 years after her diagnosis, she was treated with six cycles of ABVD as well as chest radiation therapy because she had high-risk disease. She eventually relapsed and underwent an autologous stem cell transplant as a rescue, and was cured of her Hodgkin’s lymphoma. She is now a 15-year survivor.

(09:23): She feels a suspicious breast mass and presents to her physician for workup. Eventually a referral was made and a biopsy and imaging studies were done, and she's diagnosed with breast cancer at age 32.

(09:41): Radiation to the breast tissue is the biggest risk factor for developing breast cancer after treatment of lymphoma. Interestingly, when you think about breast cancer developing in a 32-year-old female, you think about family history and genetics, but this patient had no family history of breast cancer and her genetic workup was negative. But she did have a 10-pack-year smoking history, which is a risk factor. And the original site of disease, as you may recall, was the chest, or the mediastinum, where she received 20 Gy of involved nodal chest radiation therapy. In this case, it's panel B.

(10:15): What you'll see is that she received radiation to the mediastinum to control the lymphoma, but that also likely included the breast tissue. Radiation to the breast tissue is the biggest risk factor for developing breast cancer after treatment of lymphoma.

(10:30): She received conditioning chemotherapy with BEAM, which is a combination of drugs that is typically not associated with breast cancer. So based on this patient's history, it's really the 10-pack-year history of smoking as well as the radiation that she received that likely had the breast tissue in the radiation field, that put her at greatest risk.

(10:56): Risk factors for developing a second cancer after a stem cell transplant using your own cells (autologous transplant) include older age, type of cancer, and treatments received before, during and after transplant.   What do we know about new cancers after autologous transplant as general risk factors? Obviously, just like allogeneic transplant, older age at transplant and older acquired age put you at higher risk of developing new cancers. It's important to understand what the type of cancer was that somebody had, as well as the associated therapy. These were some treatments that were provided. The initial cancer puts you at high risk, and the classic example was the radiation for Hodgkin’s lymphoma and risk of subsequent breast cancer.

(11:28): Post-transplant therapies, including some maintenance therapies that are given for myeloma, which I'll talk about in a minute, may put someone at higher risk of cancers. Radiation therapy is a risk factor. I talked about it either being used for control of the underlying disease, which I mentioned for lymphoma, or used as part of the conditioning regimen, but this is less often for autologous transplant than it is for allogeneic transplant.

(11:50): For the most part, patients undergoing an autologous stem cell transplant for multiple myeloma do not have a greater risk of developing a second cancer than the general population. I'll briefly touch on myeloma. The reason I'm focused on that is because it's the most common indication in the United States or even worldwide at this point for autologous stem cell transplantation. Overall, there's no increase in second cancers in myeloma patients who had a transplant compared to those who did not have a transplant, which is reassuring. There's a 50% increased risk of leukemia/lymphoma diagnoses compared to the general population, so it's a very small subset, but the interesting thing is that new cancers that develop after myeloma typically do not impact overall mortality risk.

(12:31): There's a little bit of a caveat here. The fact is that myeloma is very difficult to completely cure. In fact, what an autologous transplant does for many individuals is that it essentially provides them prolonged periods of myeloma-free survival. So sometimes it's difficult to assess the impact of second cancers in this population when they may potentially succumb to the myeloma itself. There are some emerging concerns or signals around relevant maintenance therapy that are beginning to be explored in our group.

(13:07): A small subset of patient who had an autologous stem cell transplant for multiple myeloma or lymphoma develop myelodysplastic syndrome (MDS) which can lead to acute myeloid leukemia.  Another relative rare entity that can definitely happen after autologous transplant is myelodysplastic syndrome and acute myeloid leukemia. As I mentioned, many people are undergoing an autologous stem cell transplant for myeloma, but also for lymphomas. For these individuals, a certain small subset will develop myelodysplastic syndrome, which means abnormal bone marrow, and progression to acute myeloid leukemia.

(13:34): That may be due to marrow injury that may occur from prior cancer therapy, before the transplant, which increases after autologous transplant because they received chemotherapy for the transplant.  It's typically associated with alkylator chemotherapy exposure such as cytokine and ifosfamide, both as part of conditioning or pre-transplant. It’s also associated with topoisomerase inhibitors such as etoposide, as well as radiation exposure.

Myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), typically develop in the first five years after the transplant. Outcomes are generally poor unless additional more aggressive therapies are implemented such as anallogeneic transplant. For patients who develop MDS or AML after autologous transplant, typically the curative approach is to try to get to an allogeneic transplant.

(14:22): Outcomes after a secondary cancer vary depending on a the type and characteristics of the secondary cancer and patient age. What are the big factors in terms of outcomes after second cancers and what are the factors that impact outcomes? A lot of it depends on the type of cancer that they develop. Skin cancer outcomes are very different than pancreatic cancer outcomes.

(14:36): The age of the patient, the stage at the time of diagnosis and the extent of localization, these are risk factors that we would typically expect are similar for the general population as well. It also depends on the effectiveness of the drugs that you have at your disposal.

(14:52): Many transplant survivors have other health problems after transplant that limit their ability to receive treatment for a second cancers. And then the chronic health conditions. Many of our transplant patients have a number of comorbidities or chronic health conditions that develop after the transplant, and that may impact their ability to receive additional therapy for the treatment of their second cancers. Poor general health, poor organ function or ongoing graft-versus-host disease and associated immunocompromised status may prevent them from receiving additional immunosuppressive therapies.

(15:21): Overall, outcomes after treatment for a solid tumor that occurs after transplant are similar to the general population. There was a paper that looked at outcomes for solid tumors after transplantation. What they were able to do is categorize the various cancers that they saw in the large population-based study into favorable, intermediate and poor. There are no big surprises here. The ones that are favorable for the general population are also favorable for our transplant population. These include thyroid cancer, cervical cancer, prostate, breast and melanoma. Then the intermediate risk. Then you have the poor outcome cancer categories including pancreas, gastric, brain, which again generally have poor outcomes for the general population.

(16:03): When you look at these incidences of mortality - risk of death due to a second cancer - either breast, colorectal or lung cancer after transplant, what you'll see is that while breast is more likely to occur in this population, the overall mortality associated with it is much less than a rare cancer such as lung cancer, which has a higher mortality.

(16:30): While some risks for developing a second cancer are beyond a patient’s control, life-style modifications and aggressive screening for cancers can help reduce the risk. Let's get to the meat of the talk, which is, what can survivors do to reduce their risk of new cancers after transplant? These individuals are survivors and they had to undergo stem cell transplant because that was really the only curative approach for them. The goal is to reduce the factors that increase risk after transplantation because we know that the big hits that they receive are the treatments, the transplant and the pre-transplant exposure. You really want to minimize the second hit or the third hit risk factors that put you at risk for cancers. This would include lifestyle modification, which I'll talk about a bit, exercise, no smoking, and low alcohol intake.

(17:13): One strategy is to avoid risk factors. The other is to perform aggressive screening and close follow-up if you have these risk factors, whether they're treatment-related or otherwise. It's important to follow established guidelines for wellness, and increase surveillance that is personalized to the specific therapies that you received that put you at higher risk. Early detection is key to optimize outcomes associated with that diagnosis.

(17:39): Steps that can reduce the risk of developing a secondary cancer include no smoking, protecting skin from sun and UV radiation, maintaining a healthy diet and weight, physical activity and avoiding excessive alcohol intake. The general key takeaway messages about overall steps to prevent cancer. I would argue that these are applicable to the broader population and I'll get to more specific recommendations for our transplant patients. So, no tobacco use, skin protection from UV and sun exposure, maintain a healthy diet, keep a healthy weight, stay physically active and avoid risky behaviors including excessive alcohol intake.

(18:09): Make sure that you're getting appropriate immunizations based on your age and recommendations. If you're early in life, HPV vaccination is critical for prevention of cervical cancer, or penile cancer in males. It’s very important to get revaccinated with hepatitis vaccines, especially after allogeneic transplant, if you have not done so.

(18:30): Empower yourself with your own and family history. It's important to understand. Again, we're talking about multiple hits to your own biology that drive risk. If you have a family history combined with therapeutic exposures that put you at risk plus the transplant, you can imagine that those are issues that you need to be aware of.

(18:48): Potential signs and symptoms of a second cancer that should be evaluated by your doctor include new lumps, unusual fatigue, fevers and sweats, persistent cough, unexplained bleeding or bruising and skin sores and infections.  Any new lumps or bumps that you feel should be brought to your primary attending doctor. Unusual fatigue, fevers and sweats, prolonged sweats and night drenching sweats. Persistent cough, hoarseness and chest pain that is unexplained, so not associated with a virus or a flu. Easy bleeding or bruising that's unexplainable. Abdominal pain, loss of appetite and difficulty swallowing that typically persists for several weeks. New unexplained blood clots. Sores and skin infections which may be suggestive of immunocompromised status. Change in neurologic status, which would be really concerning for central nervous system (CNS) or brain cancers.

(19:35): I'm going to talk now specifically about individual cancers and steps you can take to prevent these types of cancers after transplantation.

(19:46): Skin cancer is common after a stem cell transplant and tends to be more aggressive than skin cancers seen in the general population.  Prevention and early detection are key.  Skin cancer. It's one of the most common post-transplant cancers. It's much more common in patients who underwent an  allogeneic versus an autologous transplant.

Prevention is key. Sun avoidance or high-SPF sunscreen is integral. It's important to have regular dermatologic visits to perform full body examination. We recommend at least once-a-year dermatology visits for patients who underwent allogeneic transplantation. Early detection is especially important to optimize outcomes.

(20:19): Compared to skin cancers in non-transplant populations, skin cancers in patients who are transplant survivors tend to be more aggressive.  This means it's very important to be engaged in aggressive screening and early detection and it's important to be aware of suspicious lesions.

(20:35): Photos of suspicious lesions that should be checked for skin cancer What do these suspicious lesions look like? I'm going to break it down across melanoma, - which is the most feared skin cancer - squamous cell carcinoma and basal cell carcinoma.

(20:46): Characteristics of melanoma. Melanoma. What are some of the hallmarks of melanoma that you should be worried about? We look at them as the ABCDEs of melanoma detection. On the top, we have normal. On the bottom, we have what a melanoma would look like.

Asymmetry is key. Borders are uneven typically. There are multiple colors as opposed to a single color within a lesion. They're typically larger than a quarter inch. Importantly, they're often changing in size, shape and color. These are the hallmarks of what you should be aware of for melanoma risk.

(21:22): Characteristics of squamous cell carcinoma. Squamous cell carcinomas are a little bit difficult to pick up, but typically they have this rough texture, this keratotic texture. While they are slow growing, they can sometimes grow over weeks. They have this weird shaped look. It looks like what I showed earlier with that patient, with this kind of scab-like look that just typically is not going to heal and go away.

(21:51): Basal cell carcinoma is not life-threatening and is often associated with sun exposure. Basal cell carcinomas are again difficult to pick up. A lot of times, they're associated with sun exposure, so they're going to be in places where there is a lot of sun exposure including the ear, the nose, the forehead and the top of the head for males who have male pattern baldness.

(22:08): I would be worried if there was an unexplained whitish scar area, there was a shiny bump, or there was a nodule or reddish patch, or an irradiated area - that is in an area where the patient may have received radiation. If they have persistent non-healing sores, that's really a red flag. A pink growth with slightly elevated, rolled borders with crusted indentation in the center, that again is another sort of suspicious lesion that you would worry about for basal cell carcinoma.

(22:39): Basal cell carcinomas are typically non-life-threatening. They can be excised in clinic as an outpatient procedure. Melanoma, on the other hand, is quite worrisome, so you should be aware.

(22:52): Easy-to-follow guidelines to check yourself for skin cancer. How does one check for skin cancer? These are the general guidelines that we have recommended from our colleagues. Step one. Gather a hand mirror, a hair dryer, two chairs or stools and a partner or a close friend that you feel comfortable having facilitate a full skin examination. Stand in front of a full-length mirror. Look at your whole face including your nose, lips, mouth, ears, and behind your ears. Use the hand mirror. Ask your partner to help you see. If you have a lot of hair, use a hair dryer by layer to check your scalp in the mirror, or use the hair dryer to move your hair aside.

(23:32): Check your hands. Start with your palms, back of your hands, look between your fingers and then under your fingernails. Take your shirt off and continue to look at your wrists and look at the front and back of your forearms. Stand in front of the full-length mirror, bend your elbow and check your upper arm and armpit and check the other side. For those of you who think I'm going too fast, no worries, you can download these slides.

(23:56): Finish undressing and check your neck, chest and front and upper body, including your stomach. Women should lift their breasts to see under skin folds to see if there are any suspicious lesions there. Use the hand mirror with the help of your partner to check your back. That's an area that's often missed and a lot of exposure happens there, including total body irradiation and sun exposure. Continue to use your hand mirror to look at your buttocks, back and the back of your legs.

(24:22): Lastly, sit down and prop your leg up on the stool to examine your groin area with a hand mirror. Check the front and sides of both legs, of both feet, between your toes, toenails, heels and the soles of your feet. Now this seems like a lot, but it really takes a few minutes to do all of these and it doesn't need to happen every day. Once every few months or so is more than reasonable. Plus a dermatologist should be helping you facilitate the screening annually at least.

(24:48): Oral cancers occur more often after an allogeneic transplant than an autologous transplant. Your dentist should routinely check your gums, tongue and under the tongue for suspicious lesions. Oral cancers. Typically, oral cancers happen after allogeneic transplant. They are associated with a history of graft-versus-host disease and it's imperative that having regular dental visits for comprehensive screens. So it's not just about your teeth when you visit the dentist, but it's also for the gums and tongue and below the tongue, so that if there are any suspicious lesions, they're picked up.

(25:12): There should be a low threshold for consultation with an oral surgeon if there are suspicious lesions. I've shown two. One on the bottom is a very excessive case of an oral cancer after allogeneic transplant. The one on the left at the top is actually one that probably would not have been picked up unless they went to the dentist. It’s Incredibly important that if you have a history of graft-versus-host disease, especially skin and oral graft-versus-host disease, that you are making sure that your primary care providers are aware of these suspicious lesions.

(25:42): Guidelines for breast cancer screening after transplant. What about breast cancer? We talked about this already a bit, but I'll just reiterate some of the key things that you could do to prevent and be more proactive. What are the risk factors? Prior chest radiation therapy that we discussed with that female in that case study, but also total body irradiation as part of allogeneic transplant.

(26:02): For female patients who receive radiation, whether it's total body irradiation (TBI) or chest radiation, starting at 25 years of age, or eight years after radiation exposure, whichever comes first, and no later than age 40, we recommend regular annual breast exams, and mammogram and breast magnetic resonance imaging (MRI) that are alternating every six months.

(26:32): Those are essentially the guidelines that are for individuals who have genetic predispositions, like the breast cancer gene (BRCA) mutations, like the Angelina Jolies of this world. It's really important that we are following the more aggressive guidelines for the general population. If you're at average risk, so you have not received any radiation exposures, then typically between 20 to 40 years of age, you follow the regular guidelines, which is clinical breast exam every one to three years and an annual exam and mammogram after 40 years of age.

(27:02): The biggest risk for cervical cancer in the general population and in the transplant population is HPV - human papillomavirus. It's important early in life that you receive the HPV vaccine for prevention of cervical cancer and penile cancer in males. In younger individuals, it’s important to undergo regular pelvic examinations with cervical smears and an annual PAP test and HPV DNA test as would be recommended for all transplant patients.

(27:33): Liver cancer is rare after transplant. Risk factors include excessive alcohol intake, liver damage due to chemotherapy or GHVD, and iron overload. For liver cancer, thankfully it's relatively rare. In the past, one of the highest risk factors was blood transfusions, but now with better screenings, those risk factors are much, much less. Nonetheless, we can vaccinate for many of these. For example, for hepatitis B, it's important to vaccinate and then to treat. Post-transplant, you can check titers and evaluate things, but most patients post-allotransplant will have to have their hepatitis B series repeated. Hepatitis C, there's no vaccination. You just treat.

(28:05): It's important to limit your alcohol intake. Cirrhosis itself is a risk factor for liver cancer.  This is not due to alcohol intake, but due to chemotherapy and graft-versus-host disease, where there can be substantial liver injury and damage in some individuals, although obviously not everybody.

(28:20): Iron overload associated with repeated blood transfusions could contribute to liver injury, and ultimately, if severe enough, to liver cancer. It's really important to identify abnormalities and blood markers of liver injuries, such as liver enzymes elevations, because if it's gone too far, then it's really difficult to treat.

(28:48): Gastrointestinal (GI) graft-versus-host disease and radiation to the abdomen increase the risk of colorectal cancer. Turning our attention to colorectal cancer. Clearly, it's one of those cancers that early colonoscopy has dramatically improved outcomes for the general population. It's really curable with surgery alone if picked up at an early stage.

(29:04): What are the transplant and cancer-specific risk factors for colorectal cancer? Gastrointestinal (GI) graft-versus-host disease and radiation to the abdomen put individuals at higher risk of colorectal cancer.

(29:22): What are the tests? Colonoscopy, sigmoidoscopy, and stool, blood and DNA testing.

It's recommended that the first colonoscopy should be performed at 45 years of age and individuals should be screened up to 75 years of age.

There may need to be more frequent or even earlier screening if individuals are at higher risk due to a genetic family history or for pediatric patients who are now adult survivors who were treated with abdominal radiation therapy when they were children for their primary cancer - that typically is for individuals with conditions such as Wilms tumor or neuroblastoma who then undergo autologous transplantation. These patients are also at higher risk.

(30:04): Lung cancer is relatively rare after transplant. The biggest risk is for smokers who received radiation during treatment. Finally, as far as cancers are concerned, lung cancer. Again, it's a relatively rare cancer after stem cell transplantation. Clearly, the biggest driver of risk is smoking, but as I mentioned, it's a multiple hit issue.

(30:21): The first hit, per se, is smoking, but if that individual who has an extensive smoking history then received radiation, whether it's TBI or chest radiation for the treatment of lymphoma, the combination of the two puts you at higher risk of developing lung cancer compared to the general population.

(30:47): What can we do to screen for early detection? Screening with low-dose computed tomography (CT) of the chest. Low-dose CT is very important because you want to minimize the amount of additional radiation exposure associated with the CT scanning. Low-dose CT scan of the chest is recommended for the following high-risk groups: more than 55 years old and more than 30-pack-year smoking history, or more than 50 years old and more than 20-pack-year history with another risk factor such as radiation exposure. For our transplant patients who receive TBI, have a smoking history, or receive chest radiation exposure, the screening starts earlier and there's a lower threshold based on pack-year history.

(31:31): I've just touched the tip of the iceberg. There are many resources that are at your disposal to provide you with more information about cancer screening and cancer prevention detection.  These include the BMT InfoNet, American Cancer Society, American Society of Clinical Oncology (ASCO) Guidelines, The Cancer Network and the Leukemia & Lymphoma Society. There are many patient-friendly and accessible resources that are readily available, but hopefully, this has just given you a broad overview of what the areas are to be worried about or be concerned about.

(32:07): Learning about the treatments you received before, during and after transplant can help you understand your personal risk for secondary cancers. Ultimately, what do we encourage our survivors to do? It's really important to learn about the treatments you received. Many of the factors that I mentioned were specific risk factors associated with either the transplant or the primary cancer. The more you are informed about those, the more you are armed with that information, the better you can help guide your primary care provider - where you may be a minority in that primary care provider's practice - for differential screening compared to the general population. It's important to get checkups focusing on health risks related to your cancer treatment.

(32:43): Develop a long-term follow-up plan with your healthcare team to prevent, detect and treat potential secondary cancers. Work with your healthcare providers to develop a long-term follow-up plan both in terms of your primary transplant doctor and your primary care physician, and make sure that they are personalized to the therapies that you received with your unique risk factors. Ultimately, it's important to make healthy choices, because clearly, the choices you make after transplant could have an impact on long-term cancer and other health risks as well. Ultimately, we believe, both at City of Hope and in the broader transplant community, that you are the most important member of the healthcare team. So the more proactive you are, the more informed you are, the better you will live your lives in complete health moving forward.

(33:21): I'm going to stop there and I'm happy to take questions from the audience. Thank you very much for your attention. If you would like to reach me, you can reach me sarmenian@coh.org, which is at City of Hope.

Question and Answer Session

(33:38): [Michala O’Brien]:  Thank you, Dr. Armenian, for this excellent presentation. We will now begin the Q&A session of this presentation. If you do have a question for Dr. Armenian, please use the chat box on the lower left side of your screen and you can type in a question. We will answer as many questions as possible. Let's see. Our first question is, "does GVHD itself leave you more open to secondary cancers or is it the steroid treatment that's causing the higher risk?"

(34:12): [Dr. Saro Armenian]:  It's a great question. It's actually the GVHD itself that is the biggest driver because there's a lot of cell proliferation that happens as part of the GVHD. If it's GI GVHD, the common areas that we worry about are colorectal, skin and oral mucous membranes cancer risks. The treatment of GVHD does increase the risk of certain cancers, so prolonged immunosuppression plus GVHD puts you at higher risk of skin cancer. Typically, the GVHD alone, irrespective of the immunosuppressive therapy, increases the risk. Also, the longer the GVHD course, the more severe it is, the more chronic it is, the higher the risk.

(35:05): [Michala O’Brien]:  Thank you. “Is there any data on the importance of family history of the donor stem cells or is that only pertinent for blood cancers?”

(35:14): [Dr. Saro Armenian]:  That's a great question. So you have two sets of donors. You have family and then you have matched sibling or haploidentical, etc. These are all family members where you know the history. Then you have matched unrelated donors. Typically, we know very little about the unrelated donor's family history for a variety of reasons. There's a lot of anonymity around the donation process. So I don't think anyone's really studied that, or if they have, I can't imagine that they've done it accurately because much of that information is not accessible.

(35:52): But I would say that while some of the risk factors could be transmitted to blood - so theoretically the risk factors for leukemia, lymphoma and myeloma - those may be transmitted through the host.  But there are additional tissue risk factors such as breast, colorectal or liver, etc. I would be very surprised if those risk factors would transmit from the donor. I think those are inherently the genes and the DNA that you're born with. Because typically at the organ-tissue level, it's difficult to replace the full DNA profile, whereas in the blood it's not.

(36:40): [Michala O’Brien]:  Okay, this patient wants to know - they've had 44 infusions of Rituxan between 2007 and 2014 prior to an allotransplant in 2014. "At what point will the secondary cancer risk diminish for me?"

(36:59): [Dr. Saro Armenian]:  I would say that for the Rituxan in itself, there isn't a lot of data for long-term cancers. It's something that we're watching. I would say that the second cancer risk really depends on the specific exposures and treatments associated with that allogeneic transplant. So if they received total body irradiation, if they had prolonged graft-versus-host disease, those are all risk factors that continue through the end of life. That's just something that's not going to go away. But like I said, the specific other types of cancers like myelodysplastic syndrome and AML that we would see as a second cancer or second marrow disorder, those are typically in the first five years. So it really depends.

(37:51): For solid tumors like skin, colorectal, breast, etc., those risks continue through end of life. For the blood cancers like AML, acute myeloid leukemia, as well as marrow disorders like MDS, typically that's in the first five years after a transplant.

(38:16): [Michala O’Brien]:  "Can you comment on donor-derived leukemia etiology and treatment using any donor stem cell source?"

(38:26): [Dr. Saro Armenian]:  Again, I can't really speak too much about the treatment because the treatment, from my understanding, is not very different if it's donor-derived versus de novo -  something that emerges out of nowhere. There's definitely this entity called donor-derived leukemias that we are aware of. It's very, very rare. And so I would say that it's an emerging area of interest where we're looking at specific genetic markers that may put you at risk, that may indicate this leukemic potential in the donor stem cells, which we can screen for, but these are all early, early studies. From my understanding, at this point, there really isn't too much of a difference in terms of the treatment strategies for a donor-derived leukemia versus the leukemia that derives outside the donor.

(39:25): [Michala O’Brien]:  "Can you comment on some concerns of Revlimid?"

(39:32): [Dr. Saro Armenian]:  Yeah, as I alluded to, we started using Revlimid as maintenance therapy relatively recently. In order for you to consistently be able to get a long-term signal on Revlimid on any kind of cancer, you really need a lot of data for it. What I would say is that there's an indication that there's a higher risk of leukemia-lymphoma in patients who receive Revlimid maintenance therapy. But as I mentioned, A, the data is still early, so we need to follow it with time. B, for whatever reason, patients don't die of these leukemias and lymphomas. The cause of death is typically the myeloma itself. So in a way there's a bit of a silver lining there that they're not necessarily as lethal, but I think there's much work to be done in this area.

(40:33): [Michala O’Brien]:  This is a question on breast cancer. The patient wants to know if they have a 3D mammogram, do they need to do an MRI as well with no bloodline family history of breast cancer?

(40:46): [Dr. Saro Armenian]:  Yeah, so depends on the age, to be honest with you. We generally prefer MRI. There hasn't been a lot of really good head-to-head comparisons of breast MRI versus 3D mammography in cancer survivors, in young cancer survivors. I think, generally speaking, there's a sense that 3D mammography is really good at detecting breast cancer in patients with dense tissue. But I would say that the gold standard as far as I'm aware is still going to be MRI, especially for younger individuals because of the density of the breast tissue that may not be fully picked up by the 3D or the 2D mammography. But again, 3D mammography is still a relatively new area that's being explored. We have colleagues that are doing these head-to-head comparisons. I would say we'll have more data probably in the next couple of years or so to help the guideline recommendations. But for now, the guidelines say standard mammography plus MRI, alternating every six months.

(42:00): [Michala O’Brien]:  "Can you comment on the safety and efficacy of intravenous immunoglobulin (IVIG) infusions?"

(42:10): [Dr. Saro Armenian]:  I'm not aware of any data of IVIG itself causing risk of subsequent cancers. There are people who've received it for many, many years for a variety of conditions that are not related to cancer like immunodeficiencies, etc., that people are born with. That said, I haven't done a recent extensive literature review on IVIG, so I'm just going based on I haven't come across anything. That's not to say that there isn't any data there, but I haven't come across it. It's not a big signal that we worry about.

(42:49): [Michala O’Brien]:  Okay. "How about any correlation between veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) in liver cancer?"

(42:56): [Dr. Saro Armenian]:  Yeah, there's definitely a signal there and I would say that it really depends on the health of the liver after someone has gone through VOD/SOS. Some people go through VOD/SOS at a relatively young age, for a short period of time, and then the liver health is quite normal afterwards and they're doing just fine. And others have ... If they have a prolonged course of VOD/SOS and there's sort of irreversible fibrosis and maybe even some early signs of cirrhosis, clearly that's your biggest risk factor for developing liver cancer. But liver cancers are relatively rare, and with the incidence of VOD and SOS declining through better management and early detection, I think it's probably not as much of an issue as it was probably 10, 20 years ago or so.

(43:51): But routine monitoring for liver enzymes and liver function with the primary care provider or with your oncologist or survivorship doctor is very important, especially if you have extensive history of VOD/SOS.

(44:08): [Michala O’Brien]:  The survivor is 63 years old and 15 months post-transplant for MDS. "What are some new cancers that I might watch for? I've had polyps removed four years ago. Any suggestions?"

(44:25): [Dr. Saro Armenian]:  It would be tough for me to ... If it's only MDS, I'm assuming that transplant itself was reduced intensity conditioning that did not involve total body irradiation and I'm also assuming that there wasn't any significant GVHD. So all those things assumed, I think the risk of subsequent cancers is probably very low. But, if total body irradiation was used, a patient had prolonged graft-versus-host disease, all the risk factors that we talked about, then those cancers like skin cancer, colorectal cancer, breast, all those things are worth monitoring. Maybe less on breast cancer.

(45:06): I think, with conventional reduced intensity conditioning with no additional radiation exposure, and no significant GVHD, the risk of subsequent cancers is probably very, very, very low. But again, there's issues like family history. Why did that person get MDS? So what are the risk factors for MDS? Could those risk factors for MDS also be risk factors for subsequent cancers? I don't know. I would need to get a bit more of a history on that person.

(45:37): [Michala O’Brien]:  "Dr. Armenian, you talked about allogeneic and autologous risk factors. Do any of these risk factors apply to chimeric antigen receptor (CAR) T-cell transplant survivors?"

(45:53): [Dr. Saro Armenian]:  We don't know. The reason why I say we don't know is because there are very few people who are walking around today who've only received CAR-T and no transplant. For many people, until recently, CAR-T was a bridge to transplant. So it's really difficult to differentiate between CAR-T-related exposures versus transplant. Now, there was a paper that recently came out that suggested that patients who received CAR-T therapy have a slightly higher risk of different cancers. People were specifically worried about a T-cell lymphoma, because you have these activated T-cells that you have engineered and the question was, would they then tick off and turn into lymphomas?

(46:34): We haven't seen that signal, but there is a broad concern that there may be higher risk of different cancers after CAR-T. I personally think that it's incredibly difficult to untangle from the transplant itself. There are three things to keep in mind. One, as I said earlier, CAR-T is rarely given without transplant or until recently it wasn't. So it's hard again to untangle the two. Number two, we don't have a large body of data from long-term survivors of CAR-T. We're talking about five, 10, 15 years out for us to truly be able to understand the epidemiology of various cancers in this population. So it's going to take some time for us to be able to see that. And then three, the signal is there. We are investigating, but it's way, way too early for us to comment on any CAR-T-associated cancers.

(47:35): [Michala O’Brien]:  "Can you comment on any advances, domestically or internationally, in the treatment of high-risk disease?"

(47:44): [Dr. Saro Armenian]:  High-risk, what kind? I'm not really following. High risk?

(47:50): [Michala O’Brien]: Maybe it's high-risk factors for new cancers, maybe that's a shorter question.

(47:59): [Dr. Saro Armenian]:  What I would say is that the transplant community, while it appears to be very big, it's actually not. The transplant scientists and investigators, especially those in the survivorship world, work very, very closely to develop guidelines. Evidence-based guidelines. These are international evidence-based guidelines that take into consideration the totality of available evidence as well as integration of emerging data into our recommendations. We're always doing, tweaking and refining what we consider is high-risk for developing the subsequent cancer. What we have learned over the last five to 10 years has informed the new generation of guidelines that have come out in this past year, and will likely inform our work moving forward. So I would say collaboration is key to our success and to our recommendations.

(49:00): [Michala O’Brien]:  "How often do you recommend colonoscopies?" This patient is 47 years old. They've only had one colonoscopy. They've had a transplant with TBI and they also have gut GVHD.

(49:20): [Dr. Saro Armenian]:  This person is how old?

(49:22): [Michala O’Brien]:  47.

(49:25): [Dr. Saro Armenian]:  Yeah, it depends on what their first colonoscopy showed. If the first colonoscopy was completely clean, and this is not going based on any guidelines whatsoever, personally, I would not wait a full 10 years until doing the next colonoscopy. I definitely would probably do it more frequently, maybe every five years or so. Again, these are areas that are emerging as an area of study. We have to do cost-effectiveness studies to look at different screening strategies, etc. for this population. But if I had got GVHD as well as TBI, I personally would not wait every 10 years, but that's again my own personal recommendation. It's not driven by hard data, but at the very least, we'd probably do it every five years or so.

(50:18): [Michala O’Brien]:  "How often should transplant survivors be tested for EBV?"

(50:22): [Dr. Saro Armenian]:  I would only do it if there was a suspicion, if there are lymph nodes that are enlarged or clinically ... Lymphoproliferative disorders are relatively rare. They can happen after allogeneic transplant. As I said, it's due to prolonged immunosuppression. After transplant, that will put you at risk, but I don't think that there's currently recommendations for routine surveillance and screening with EBV. Typically, these lymphoproliferative disorders are relatively easy to treat. You should just have a low threshold. If you feel a lump or a bump, obviously report it to your primary care physician. The further you are from your allogeneic transplant, the less likely that you will develop these lymphoproliferative disorders.

(51:17): [Michala O’Brien]:  "Can you recommend any checklist or care plans for long-term survivors of hematopoietic cell transplantation (HCT) with TBI, 15 years plus?" She's saying her needs seem to be different from those in the first five to 10 years, but it's hard for her to find clear guidelines.

(51:40): [Dr. Saro Armenian]:  Let’s start with just some of the general ones. For skin cancer, it's the most frequent cancer after allogeneic transplant, especially after TBI. So it's important that you have an annual dermatology visit to do a comprehensive head-to-toe evaluation looking for various skin cancers. It's also important for you to perform these exams more frequently yourself. At least once a month. If that's too much, then you can do it once every other month. But those are things that you should definitely be aware of.

(52:21): That's checklist number one. Everything else with the checklist depends on your own exposures.  So, depending on your age. If you are young when you receive total body irradiation and you're currently still in your early 40s, I think you should have a very low threshold to monitor for skin cancers. As I mentioned, it depends on what the exposures are. So graft-versus-host disease of the GI tract, you should screen for colorectal cancer. Those are the big three that you should really be worried about. Everything else could probably be picked up as part of routine annual evaluations with your primary care physician. Definitely having an annual physical with comprehensive evaluation of both laboratory and physical examinations is probably the best thing you could do for yourself.

(53:18): [Michala O’Brien]:  This patient was diagnosed with breast cancer six years after a bone marrow transplant for leukemia. "Can the breast cancer treatment wake up the leukemia?"

(53:27): [Dr. Saro Armenian]:  That's a very interesting question. No, it typically does not. But that said, the treatments associated with the breast cancer could put individuals at higher risk of developing leukemia and AML. For example, Robin Roberts from Good Morning America had breast cancer and then eventually developed a type of a leukemia called AML. So we do see that. I think you just have to have some conversations with your oncologist. If you've already had the treatment, I wouldn't worry about your initial leukemia coming back, but within the first five years or so after your breast cancer treatment, you should have a low threshold for ... You should have at least annual complete blood counts (CBCs) done to check your blood counts, etc. And if your platelets are dropping, hemoglobin is dropping, white counts dropping, then you should have a low threshold for additional workup from there.

(54:24): [Michala O’Brien]:  Okay. This survivor is 63 years old and first diagnosed when they were 57. They had T-cell, non-Hodgkin’s lymphoma, unspecified with one autologous and one allogeneic transplant. "Do you know which type of cancer people have been known to get after having T-cell lymphoma?"

(54:52): [Dr. Saro Armenian]:  Generally, it really depends on what the initial exposures were for the management of the T-cell lymphoma that led to the autologous and then the allogeneic transplant. I think we'd have to know what those were. It depends if there was any radiation used for the treatment of that lymphoma. I think I was able to broadly articulate what the risk factors were. I think I worry about being able to make specific recommendations. Does a history of T-cell lymphoma put you at risk for a subsequent type of cancer? Not the T-cell lymphoma itself. I think the main issue is just the treatments that you receive for it as well as the additional exposures afterward. I think those probably have to be personalized recommendations for follow-up based on what I've discussed today.

(55:50): [Michala O’Brien]:  "Are there any steps you could take to protect kidney function so you wouldn't possibly develop kidney disease after transplant?"

(56:03): [Dr. Saro Armenian]:  I think making sure that you're well hydrated is really, really important. If you have hypertension or borderline hypertension, then make sure that your blood pressure is well controlled. And ideally, if you can tolerate an angiotensin-converting enzyme (ACE) inhibitor that way, you can use an ACE inhibitor as a medication for both the management of the blood pressure as well as the kidney function. Those are the basic things that you could really do. Other than that, not too much.  Make sure that you're exercising regularly, and that you're doing regular checkups to monitor your creatinine as well. As I said, for anyone with a borderline hypertension, you want to make sure that that's under control with an ACE inhibitor, ideally, for some nephroprotection for the kidneys.

(56:55): If you have diabetes or elevated blood sugars, you want to make sure that that's well under control because nothing injures the kidney more than chronically elevated blood sugars and diabetes itself. So you want to make sure that that's under control as well.

(57:14): [Michala O’Brien]:  Okay. And this will have to be our last question. We are running out of time. "How does having a cord blood donor increase the risk of myeloproliferative illness?"

(57:31): [Dr. Saro Armenian]:  Yeah, I don't think that there's any data to suggest that cord blood transplant itself puts you at higher risk of proliferative disorders. I know I put that in one of the slides. I think the issue is that many of the patients with cord blood have to have prolonged immunosuppression as part of the cord blood treatment or the graft-versus-host disease that may develop afterwards. The one thing I'll just say is that just like T-cell depletion, the cord blood itself doesn't have a fully mature immune system just yet. So I think the idea there is that when you don't have a fully mature immune system or an immune system that does not mature as quickly as, let's say, a non-cord blood transplant, then that will allow for the dormant EBV to emerge in the individual. It's the same concept as you would get for T-cell depletion, plus, in addition, any GVHD, etc. that may develop afterwards.

(58:35): Those are the emerging concepts around that, but cord transplants are not used as often, especially these days. So again, we'll have to follow the larger data that moves forward.

(58:50): [Michala O’Brien]:  Well, on behalf of BMT InfoNet and our partners, I'd like to thank Dr. Armenian for a very helpful presentation today. And thank you the audience for your excellent questions. Please contact BMT InfoNet if we can help you in any way and enjoy the rest of the symposium.