Secondary Cancers after Transplant

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Secondary Cancers after Transplant

Sunday, May 1, 2022

Presenter: Madhuri Vusirikala MD, Medical Director of the Long-Term Follow Up and Chronic Graft-versus-Host Disease Clinic at UT Southwestern Simmons Comprehensive Cancer Center Allogeneic Stem Cell Transplant Program.

Presentation is 30 minutes long with 25 minutes of Q & A.

Summary: Patients who have had a stem cell transplant have a higher risk of developing a second cancer than the general population. The risk of developing a second cancers increases over time. Life-long surveillance and testing is important to catch any second cancer early, when treatment is most effective.

Highlights:

• Secondary cancers are those that occur after a transplant and are different from the original cancer for which the patient received the transplant.
• Skin cancer is the most common secondary cancer after transplant. Many other types of cancer are also possible so preventative measures like regular screenings are highly recommended.
• The risk of second cancers increases over time, but the risk of fatal outcomes can be reduced by smoking cessation, sun protection and annual screenings for cancer.

Key Points:

(05:20): Patient-related factors that may increase the risk of developing a second cancer include age, family history, genetics, prior infection, and social history.

(06:36): Transplant-related factors that increase the risk of secondary cancers include total body irradiation, some types of chemotherapy, certain diagnoses, prolonged immunosuppression and graft-versus-host disease.

(07:46): Some of the maintenance therapies given to patients after transplant to reduce the risk of relapse can increase the risk of secondary cancers

(08:04): Viral infections and graft-versus-host-disease can predispose patients to secondary cancers. 

(08:30): Some diseases like lymphoma, CLL or Fanconi anemia increase the risk of developing a secondary cancer.

(13:34): Secondary cancers after a transplant using your own cells (autologous transplant) tend to be solid tumors and myelodysplastic syndrome/acute myeloid leukemia (MDS/AML).

(16:15): Secondary cancers that occur most often after a transplant using donor cells include solid tumors, and post-transplant lymphoproliferative disorders (PTLD). 

(18:09): The risk of developing a solid cancer after transplant increases with time.

(19:43): Secondary cancers account for about 5-10% of deaths among transplant recipients.

(22:02): Preventions strategies include not smoking, sun protection, and regular screening.

Transcript of Presentation:

(00:00): [Lynne Spina]    Introduction. Hello, my name is Lynne Spina. Welcome to the workshop, Secondary Cancers After Transplant. It is my pleasure to introduce to you our speaker, Dr. Madhuri Vusirikala. Dr. Vusirikala is a Professor of Internal Medicine in the Division of Hematology/Oncology at UT Southwestern Medical Center. She leads the Long-Term Follow Up and Chronic Graft-Versus-Host Disease Clinic, managing the complications commonly seen in patients after a transplant using donor cells. She focuses on bone health, cardiac health, and screening for secondary malignancies. Dr. Vusirikala's research interests include chronic graft-versus-host disease, allogeneic stem cell transplantation, and survivorship issues.

(01:04): [Dr. Madhuri Vusirikala] Overview of Talk. Good afternoon, good morning, good evening, everyone, depending on which part of the world you are. Welcome to today's workshop. Thank you for attending, and let's get started.

(01:17): So the topic of this workshop is Secondary Cancers After Stem Cell Transplant. The learning objectives of this symposium are primarily to understand that there can be secondary cancers following stem cell transplantation and understand the risk factors that may be responsible for the development of these secondary cancers after stem cell transplant. The strategies one can take to mitigate the risk of developing a secondary cancer after transplant - it could be from the patient aspect as well as the physician aspect. Then, of course, recommendations for screening of secondary cancers. As we all know, prevention is better than cure. And if we can identify or diagnose secondary cancers early, on or identify the risk factors and mitigate them, then we might be able to prevent these secondary cancers.

(02:15): For the purpose of this workshop, I do want to state that when I use the word stem cell transplant, I am using it synonymous with bone marrow transplant. The source [of cells] does not

(02:37): Some of the relevant topics that will be discussed in today's workshop are to understand what is the definition of a secondary cancer? What are the different types of secondary cancers? What are the risk factors that can lead to the development of these secondary cancers, the timing, et cetera? How can we reduce the risks of developing these cancers, as well as prevention strategies? Then what are the current recommendations for screening procedures for early detection of these cancers?

(03:08): So this is a slide I'm sure you guys have seen quite a bit over the last day and a half. This is the activity of stem cell transplantation over the years in United States based on the type of transplant. The green curve is for autologous stem cell transplant, and auto autologous meaning, for those who are not familiar with the word, a transplant done using one's own stem cells and not a different donor. Then the blue curve refers to allogeneic stem cell transplant activity, which is a transplant done using a donor's cells other than the patient. This donor could be a match related, could be a mismatch related, could be unrelated, or could be cord blood.

(03:58): Secondary cancers are those that occur after a transplant and are different from the original cancer. So what is the secondary cancers? These are cancers that occur after a stem cell transplant and are different from the original cancer or condition for which the transplant was done. Typically these cancers tend to occur about five years after the stem cell transplant has been performed. They're rare and it is real. They're responsible for about 5% to 10% of so-called late deaths after transplant.

(04:28): There are different types of secondary cancers. They can be solid tumors, the type we hear about, breast cancer, lung cancer, GI cancer, there can be cancers involving the bone marrow per se, and another unique condition known as post-transplant lymphoproliferative disorder, also known as PTLD. This is a disorder or cancer that is more often seen after solid organ transplant like liver transplant, lung transplants, but can be seen after bone marrow transplant. I will address that in slides coming up.

 (05:05): Several factors can increase the likelihood of developing a secondary cancer. There are several contributing factors that can be responsible for the development of secondary cancers. Some of those are patient-related and some of those are transplant-related, and as I tell my patients, something, I am causing as a physician.

(05:20): Patient-related factors include age, family history, genetics, prior infection, and social history. The patient-related contributing factors could be something that we can modify or something that we cannot modify. For example, age. Age is something ... It's there. There's nothing we can do about it. But we do know that as one gets older, the risk of secondary cancers, or any cancer for that matter, increases.

(05:39): There are certain family histories of cancer, and genetics play a role in development of the cancer. There are certain genetic conditions that the patient has, which increase the risk of secondary cancers. For example, Fanconi's anemia. Patients who have Fanconi's are at increased risk not just for bone marrow failure, but also secondary cancers.

(06:02): There are certain types of infections that one can develop as a result of the immune suppression from the stem cell transplant. These infections may be contributing to the development of the secondary cancer. This is something that is under our control and sometimes we can mitigate it.

(06:20): Social history is one of the most important things that we can alter. For example, smoking, alcohol consumption, sun exposure. These are things that a patient has in his or her hands and can reduce the risk caused by these factors.

(06:36): Transplant-related factors that can increase the risk of a secondary cancer include the type of radiation or chemotherapy given pre-transplant, patient’s diagnosis, and prolonged immunosuppression after transplant. Transplant-related factors that increase the risk for secondary cancers are radiation exposure, both as part of the transplant or before the transplant, [and] the chemotherapy and the type of chemotherapy that is given for the transplant and prior to the transplant.

(06:52): There are certain type of diagnoses and cancers that do increase the risk of cancer just by the presence of that cancer. For example, patients with lymphoma, irrespective of whether they get transplant or not, do have a slightly higher risk than the general population to develop other type of cancers.

(07:09): For those getting transplanted using a donor, allogeneic transplant, those do have an increased risk of secondary cancer development if they are on prolonged immune suppression. Then infections related to the transplant.

(07:27): Let's talk a little bit about the transplant-related factors. Chemotherapy and radiation that are given for the initial treatment of the disease can contribute to the cancer development. But the chemotherapy and radiation given for the actual transplant do also contribute to the development of cancer.

(07:46): Some maintenance therapies given to patients after transplant to reduce the risk of relapse can increase the risk of secondary cancers. In certain diseases, maintenance therapy is used after the transplant to reduce the risk of the primary cancer coming back. For example, multiple myeloma patients are placed on lenalidomide for maintenance post-transplant, and that does increase the risk of developing secondary cancers.

(08:04): Certain viral infections and graft-versus-host-disease can predispose patients to secondary cancers. Certain type of viral infections such as Epstein-Barr virus infection or human papilloma virus infection, do increase the risk of certain cancers. Graft-versus-host disease, which is a complication seen after allogeneic stem cell transplant, by itself can increase the risk of secondary cancers, but also the medications used for the treatment of graft-versus-host disease also predispose one to developing secondary cancers.

(08:30): Some diseases like lymphoma, CLL or Fanconi anemia increase the risk of developing a secondary cancer. Condition for which the transplant is performed. Just like I said earlier, patients with lymphoma, CLL, or those who have Fanconi's anemia, by virtue of the underlying disease, do have a higher risk of developing secondary cancers.

(08:45): So let's talk about secondary cancers that one can see after an autologous stem cell transplant. Autologous, again, just to remind you is the type of transplant that is done using the patient's own stem cells.

(08:59): So just to give you some background, autologous stem cell transplantation typically is performed for certain types of conditions or disorders. Those are primarily multiple myeloma, lymphomas, both Hodgkin and non-Hodgkin, certain type of germ cell tumors, both ovarian and testicular, and then autoimmune disorders. Now even though stem cell transplantation is not approved for autoimmune disorders, there are several clinical trials ongoing where these transplants are done for patients with advanced lupus, rheumatoid arthritis, and even multiple sclerosis. So we do end up seeing patients who have undergone stem cell transplantation for this diagnosis.

(09:43): So what are the factors contributing to risk of secondary cancers after an autologous transplant? Well, age is definitely one of them. We all know that as one gets older, the incidence of these underlying conditions and cancers increases. The type of cancer, again, lymphoma and CLL patients are at higher risk for developing secondary cancers.

(10:04): The treatments given prior to the transplant, the type of chemotherapy and/or radiation that is given prior to the transplant. Then, like we mentioned, lenalidomide or other type of post-transplant maintenance therapies do increase the incidence of secondary cancers.

(10:21): The risk of secondary cancers increases over time. So early on, I mentioned that the incidence of secondary cancers is not huge, but it is finite. So based on which clinical trial or study you look, at the incidence of secondary cancers after an autologous transplant at the five-year mark is about 4%. As we go farther down, about 15 years after autologous transplant, this incidence can go as high as 8% to 15%. This incidence continues to increase the longer you have survived your transplant.

(10:55): With autologous transplants, the risks are due to treatment before transplant rather than the transplant itself. So one question people often ask me is does the autologous transplant by itself increase the risk of cancer? There have been several clinical trials done both in multiple myeloma and lymphoma, and it appears that the risk of increased secondary cancer is due to the treatment given prior to the transplant rather than the transplant itself. In general, patients with lymphoma are at a higher risk of developing 

(11:25): So here is a clinical trial that was published in patients with Hodgkin disease. They looked at 1700 patients with Hodgkin disease. Then 1500 out of those 1700 had received conventional treatment. That means they did not get transplant. They just got chemotherapy and/or radiation. 200 patients out of this group underwent an autologous transplant. What they looked at is the incidence or the risk of developing a secondary cancer.

(11:53): So if you looked at the entire cohort of 1700 patients, the overall risk of developing secondary cancers after the 15-year mark was about 9%. But there was no difference in the secondary cancers between the two groups. The only thing that seemed to be contributing to the increased risk of secondary cancer was age. So those people who were older than 35 years of age did have a higher risk of developing a secondary cancer.

(12:24): This has been seen in myeloma patients, too. They're at risk of second cancers in myeloma patients who got lenalidomide or did not get lenalidomide. We all know that lenalidomide, an oral agent that is given after the transplant for multiple myeloma patients, does improve overall survival as well as progression-free survival. But exposure to lenalidomide, irrespective of the dose used, does increase the risk of secondary cancers. This is true even if the patient did not have a transplant.

(12:56): Again, there was a study that was published looking at 3,200 myeloma patients. The five-year risk of secondary cancers was 6.9% in patients who received lenalidomide as compared to 4.8% without. So it was also seen that those patients who'd received a type of chemotherapy called melphalan, in addition to the lenalidomide, had a higher risk of developing secondary cancers. So these are factors that one needs to take into consideration when making decisions regarding maintenance, or at least be very well-informed about it.

(13:34): Secondary cancers after autologous transplant tend to be solid tumors. The types of second cancers that are seen after autologous stem cell transplant, mostly solid tumors, are skin cancers, cancers of the oral cavity, brain cancers, bone cancers, cancers of the thyroid, and then female genital tract cancers, including uterine, cervix, and breast cancer. As I mentioned earlier, this risk continues to increase 15 years and beyond after the transplant.

(13:59): MDS/AML (myelodysplastic syndrome/acute myeloid leukemia) can also develop after an autologous stem cell transplant. There's another type of cancer that happens after autologous transplant, and that is called MDS/AML. MDS stands for myelodysplastic syndrome and AML stands for acute myeloid leukemia. The reason one develops this is due to damage to the bone marrow done from the chemo-radiation given for the treatment of the cancer before and during the stem cell transplant.

(14:24): It does seem to have a worse prognosis if you have developed MDS after a transplant, so-called treatment related MDS, as compared to somebody who had previously not received chemotherapy and developed MDS. The best treatment for this is allogeneic stem cell transplant. I do inform my patients that it is curable. So there is a treatment and there is a cure, potentially. The risk, again, just like any other cancer, continues to increase as time goes by. To give you an idea, the risk of developing MDS is only 1% at the 30-month mark but goes up to as high as 11.7% past the five-year mark. This continues to rise over the years after the transplant.

(15:11): Switching gears, let's talk about the secondary cancers that can happen after allogeneic transplant. Just as a reminder, allogeneic transplant is a transplant where we use donor cells.

(15:23): Risk factors for secondary cancers after a transplant using donor cells (allogeneic transplant) include total body irradiation, prolonged use of immunosuppressive drugs, graft-versus-host disease, advanced age, certain infections and genetic factors.  The risk factors for second cancers after allogeneic transplant include use of total body radiation, a frequently used modality as part of the regimen prior to the transplant, the so-called anti-rejection medicine drugs or immunosuppressive agents, development of chronic graft-versus-host disease, patients who are of advanced age, patients who develop infections, specifically EBV or HPV infections, underlying genetic predisposition, just like Fanconi's anemia, and then the intensity of the preparative regimen used for the transplant.

(15:59): This last item is a little controversial, depending on which clinical trial you look at. It has not been substantiated in large trials that the intensity of preparative regimen does impact, the type does.

(16:15): Second cancers that occur most often after a transplant using donor cells are solid tumor and post-transplant lymphoproliferative disorders (PTLD).  Again, looking at the different types of secondary cancers that happen after allogeneic transplant. These can be divided into two classes, The solid tumors, again, the risk is relatively low early on in the course of the transplant, about 1% to 2% or less than 2% at the five-year mark, going up to 2% to 6% by the 10-year mark, and as high as 4% to 15% by the 15-year mark post-transplant. MDS and AML. That is a little bit more frequently seen in the autologous setting, [and] is fairly rare after allogeneic transplants.

(16:53): The type of second cancers after the allogeneic transplant also includes PTLD or post-transplant lymphoproliferative disorder. This is the most common second cancer that can happen in the first year of the transplant. Remember I said that most secondary cancers happen the farther you go from transplant, and very rarely do you see second cancers early on in the transplant. This is one of those second cancers that can be seen real early in the transplant.

(17:21): The incidence is fairly low, and it all depends on the type of transplant, the conditioning regimen that is used, and the type of donor who's used for the transplant and can range between 0.2% to 11%. It has been shown that when you use very, very strong immune-suppressing chemotherapy and a process that is called T-cell depletion, where the T-cells from the actual stem cell graft is removed, that increases the risk of developing PTLD.

(17:51): The primary stimulus for PTLD is a type of viral infection called EBV or Epstein-Barr virus. It's typically arising from the donor cells. So this is not a type of cancer that arises from the host or the recipient cells. It is arising from the donor cells.

(18:09): The risk of developing a solid cancer after transplant increases with time. This is a graph of the incidence of second solid cancers after allogeneic transplant. As you can see that risk is only 1% by the five-year mark, about 1.5% to 2% by the 10-year mark. But as you go farther down, up to the 15-year mark, the incidence rises and continues to rise the farther you get. But also remember, if you are 25 years post-transplant, you're also older, and age by itself could be contributing to the risk of developing a second cancer.

(18:43): Rarely, secondary cancers in allogeneic transplants may be caused by the donor’s cells. Donor-derived second cancers is something that is unique to allogeneic stem cell transplant. We already talked about the PTLD or post-transplant lymphoproliferative disorder that happens in the first one year of the transplant. There's another condition called late-occurring lymphoma. It's different from PTLD because it is not associated with the EBV infection. [It] often occurs in patients who have severe, poorly controlled chronic graft-versus-host disease, and tends to have a relatively good prognosis with treatment.

(19:13): There's another condition called donor cell leukemia. Again, a very rare entity. In my 25 years of career, I've probably seen one or two such cases. It occurs over the course of the transplant, no clear cause, and it's presumed to be due to already damaged donor stem cells that developed additional mutations during the transplant process as a result of infections or medications that are given for the transplant.

(19:43): Secondary cancers account for 5-10% of deaths among transplant recipients. So what about outcomes of secondary cancers? Since secondary cancers account for about 5% to 10% of deaths among transplant recipients, it is important to know what the outcomes of individual cancers are. So a lot of it depends on the type of the cancer, the age of the patient, the fitness level of the patient. Is the patient going to be able to tolerate further treatment for this secondary cancer? And, of course, the stage at the diagnosis of cancer is very important. This is irrespective of whether you are a transplant survivor or otherwise never had any chemotherapy type of patient. Stage is very important. Then availability of effective treatments is naturally an important factor in the outcome of that secondary cancer.

(20:32): Here is a graph that shows the outcomes of secondary cancers in transplant survivors and non-transplant survivors. The solid black graph is transplant survivors and the gray or the lighter gray is the general public as seen in the SEER registry.

(20:55): From what we can see, for most of the cancers, the outcomes are fairly similar, except for a few. The lower GI tract, the central nervous system, lung, and liver seem to do slightly worse in the transplant survivors, but, overall, for thyroid, testicular cancer, melanoma, breast cancer, patients who have cancer as a result of transplant versus not, the outcomes are very similar. This could be because of the availability of good treatment options.

(21:31): Here, another slide just showing the outcomes of secondary cancers, the 10 to 15-year overall survival estimates are anywhere between 40% to 46% once a diagnosis of cancer is made. Survival is particularly poor, like I showed earlier, for cancers of the central nervous system, liver, and lung. The outcomes for male reproductive cancers, thyroid, breast, and skin, specifically melanoma, cancers are better and very similar to the general public.

(22:02): The risk of developing a secondary cancer can be reduced by not smoking, sun protection, and regular screening. So let's talk about prevention strategies. Well, obviously we can reduce the risk of cancers if we can reduce risk factors. So smoking cessation is very, very important. As we all know, smoking increases the risk of several types of cancers, but specifically lung cancer, too.

(22:20): Sun protection is very important because we know ultraviolet rays in the sun do increase risk for skin cancers, including melanoma. Reduce the risk of infections such as hepatitis C, HPV. Diet and exercise are very important to stay fit, as well as the reduced risk of cancers.

(22:39): Then regular screening is very important. There are recommended screening procedures that are part of the general recommendations for any patient. Self-examination is very important, especially of the skin, breast, and genitalia. Then early reporting of symptoms such as chronic cough that is not going away, bleeding from certain areas, pain or discomfort in certain areas, rashes, and weight loss that is not explained. So these are things that one needs to be very cognizant of and be constantly looking out for.

(23:18): Avoiding total body irradiation, choosing younger donors, and minimizing bone marrow damage also reduce risks of secondary cancers. As far as the treatment changes, that is what your provider or your treating physician can make, we try our best to avoid total body radiation wherever indicated. I always talk to patients about the risk-benefit ratio. If I feel the use of total body radiation is going to make a huge impact on the outcome of their transplant, only then do we use it. Reduce the exposure to certain type of chemotherapies. Then donor choices, younger donors versus older donors.

(23:49): And thorough screening of bone marrows for underlying mutations prior to an autologous transplant, especially those patients who have been what we call heavily pretreated. Patients who have had multiple lines of chemotherapy prior to their autologous transplant may possibly have had some damage to their bone marrow, and that might increase the risk of developing secondary AML or MDS after the transplant. So thorough screening is important.

(24:16): Cancer screening recommendations should be closely followed. These are some of the cancer screening recommendations created by the CIBMTR and the European Bone Marrow Transplant groups for recommendations of secondary solid cancer screening following a transplant. Then there is another document for which I have provided the link, which is CIBMTR guidelines for long-term follow up for transplant survivors. These do talk about secondary cancer screening.

(24:43): Skin cancer is the most common secondary cancer after transplant. I'm just going to end this talk by talking about some of the specific cancers. Let's talk about skin cancer. It is the most common secondary cancer after stem cell transplant and can include squamous cell cancer, basal cell carcinoma, as well as melanoma. The cumulative, that means the overall, incidence over a period of 20 years is about 6% for basal cell and 3% of squamous cell.

(25:07): What is important is regular skin exam for yourself, sun protection, as well as dermatology visits. I do recommend all my patients who are transplant survivors go and see a dermatologist at least once a year. But if they have reasons for abnormal findings on their exam or they have had prior skin cancers, these visits might need to be more frequent.

(25:35): Female transplant survivors of stem cell transplant are at an increased risk of developing breast cancer. Breast cancer. Female survivors of stem cell transplant are at an increased risk of developing breast cancer. Risk factors, of course, are younger age at diagnosis, increased time since transplantation. Like any other cancer, the farther you go from transplant, the risk of cancers does increase. Use of total body radiation, as well as radiation involving the chest and head and neck region where the breast could have been affected by the radiation. Annual mammograms and self-breast exams are very important. We all know if you can diagnose this cancer early on, you can have a better chance at cure and controlling it.

(26:20): Patients with chronic GVHD may develop oropharyngeal cancer. Head and neck cancers. Oropharyngeal cancer is most common and increased in patients with chronic graft-versus-host disease, especially involving the mouth, and long-term immunosuppressive drugs for those who have been on these drugs for more than two years. Radiation is another risk factor for developing these cancers, and the risk seems to be higher in men than women. Very important to avoid chewing tobacco or using tobacco products, and routine dental visits is very important. So we do recommend all our patients to have routine dental visits at least every three to six months so that they not only have good dental health, but also are screened for cancers inside the mouth.

(27:04): Patients with extensive GVHD or who have Fanconi anemia have a higher-than-normal risk of developing a GI cancer. GI cancer. Increased risk in patients with extensive chronic graft-versus-host disease, higher risk in patients with Fanconi's anemia.

 (27:13): Colorectal and cervical cancers may also occur. Colorectal cancer is also something that can be detected early. So we recommend routine colonoscopy starting the age of 50, if they are regular risk, that means they have no family history or they don't have underlying GI conditions, but earlier, at the age of 40, if they're high risk. Stool testing is recommended for some patients, if they fall into the regular risk category.

(27:39): Cervical cancer. HPV or human papilloma virus infection is an important risk factor. So routine gynecological exams and HPV vaccinations are recommended. HPV vaccinations are available and fairly safe and should be considered by all patients.

(27:59): Smoking cessation is important to reduce the risk of developing lung cancer. The last cancer I want to talk about is lung cancer. Tobacco use pre- and post-transplant increases the risk. Total body radiation is not considered a major risk factor but can contribute. In one clinical trial using busulfan and Cytoxan, a type of chemotherapy, showed a higher risk of lung cancer in survivors. But this has not been substantiated in larger studies, so I don't want to make a blanket statement.

(28:23): Smoking cessation is the most important thing one can do to reduce the risk of lung cancer. Then screening recommendations for lung cancer are not very clear in asymptomatic patients. There are no standardized recommendations. But if a patient has symptoms or has had lung GVHD, it is very clear

(28:45): Regular cancer screenings can help catch second cancers early when they are most easily treated. So long-term follow up in survivorship. Routine transplant and disease follow up, re-vaccinations for preventable infections is very, very important. Cancer screening such as mammograms, pap smears, dental exams, colonoscopy, prostate exam, and routine dermatology care are of utmost importance in identifying early cancers in post-transplant survivors.

(29:10): Secondary cancers are a rare but well-defined complication. So I would like to summarize saying that secondary cancers after stem cell transplant are rare, but a well-defined complication, and one needs to be aware so that they can be identified very early and taken care of. Solid tumors and post-transplant lymphoproliferative disorders are more common after allogeneic transplants. But bone marrow cancers such as MDS and AML are more common after the autologous transplants.

(29:37): The risk of secondary cancers increases over time but preventative strategies and routine screening can reduce the risk of fatal outcomes.  Risk continues to increase over the years after stem cell transplant, and there are multiple preventative strategies and routine screenings that are available to survivors to reduce the risk of fatal outcomes from the secondary cancers. With that, I will end my talk. I'm happy to take questions. Thank you for your attention.

Question and Answer Session

(29:58): [Lynne Spina] Thank you, Dr. Vusirikala, for this very excellent presentation. It was so informative, so comprehensive. Now we'll take questions.

(30:19): I'm going to start with a question about the all-important skin cancer. The question is, "Do I always need to apply sunscreen to prevent skin cancer, or are there certain UV levels that are safe enough to avoid having to wear sunscreen?"

(30:39): [Dr. Madhuri Vusirikala] That's a great question. So we do know that sun protection is very important to avoid skin cancer, irrespective of whether you have had a transplant or received chemotherapy. Everybody is at risk for increase in skin cancer the longer and more sun exposure they've had. Now there is really no data on the amount of sun exposure that has been considered safe. So I think having sun protection is always important.

(31:12): [Lynne Spina] Good to know. The next question, "How do numbers of infections connect with secondary transplants? Are there specific infections?" I think the person meant secondary cancers.

(31:27): [Dr. Madhuri Vusirikala] Right. So infections such as upper respiratory infections or pneumonias by themselves don't increase the risk of secondary cancers. It is very specific viral infections that increase the risk of cancers. Like I mentioned, Epstein-Barr virus infection increases the risk of PTLD and HPV infections increase the risk of cervical cancer, and so on.

(31:56): [Lynne Spina] Thank you. This next question has to do with colon cancer prevention. "Have you been using Cologuard as a screening tool?"

(32:06): [Dr. Madhuri Vusirikala] The answer is yes. I routinely recommend a colonoscopy for all my patients, but I have some patients who are very, very reluctant to have a colonoscopy. So I use Cologuard as a surrogate marker, especially if they are low risk, or should I say standard risk. That means they don't have a strong family history of cancers of the colon or the GI tract.

(32:32): [Lynne Spina] Very good to understand. Thank you. "If a person has had both an autologous and an allogeneic," so transplant with their own cells and one with donor cells, in addition, "is there likelihood of the secondary cancers much higher?"

(32:55): [Dr. Madhuri Vusirikala] Well, theoretically, yes, because you're having double exposure to the conditioning regimen and the chemotherapy. Of course, the reason for the transplant is important. But overall getting two different types of conditioning regimens, and then, of course, anti-rejection medicines and immunosuppressive medicines after the allogeneic transplant does increase the risk of secondary cancers as compared to somebody getting only one transplant.

(33:25): [Lynne Spina] Another reason to be diligent. So the next question is, "What is the definition of advanced age? Is it over 60, 65, 70, 50?"

(33:37): [Dr. Madhuri Vusirikala] That's a wonderful question. Honestly, I don't think there is a true definition of advanced age. What we do say is the older you are ... And there is really no cutoff, to be honest with you. We all know that as we age, we develop mutations as a result of exposure to all the carcinogens around us, and those mutations increase with every decade we live. But there is really no cutoff for so-called advanced age.

(34:13): [Lynne Spina] Okay. "So what are the most common specific genes that are associated with increased risk of secondary cancers in allogeneic transplants?"

(34:27): [Dr. Madhuri Vusirikala] So there are some types of underlying genetic abnormalities. For example, Fanconi's anemia, patients who have GATA2 mutations. They are at slightly higher risk of developing secondary cancers. Patients who have telomere abnormalities, they're called short telomere or telomere length abnormalities, those patients do tend to have higher risk of developing secondary cancers.

(34:53): Now for patients who have had auto autologous transplant, certain type of mutations such as RANKS1 and DNMT3A, T53, those type of mutations in the bone marrow increase the risk of developing MDS and AML.

(35:16): [Lynne Spina] Okay. This person had an allogeneic transplant in 2018 and they had iron overload from blood transfusions treated with phlebotomies. "I have excessive iron in my liver on the MRI. Am I more at risk for liver cancer?"

(35:38): [Dr. Madhuri Vusirikala] So the role of iron overload and risk of liver cancer has been studied in a condition called hemochromatosis. It has been shown in those patients that a high iron level in the liver does increase the risk of liver cancer.

(35:59): Now has that been substantiated in stem cell transplant? No, partly because we do treat our patients early on with phlebotomy. So there's no data suggesting that patients who have high iron after transplant are at an increased risk.

(36:16): Now if there's ongoing iron accumulation, there might be a slightly higher risk of chronic liver disease, but we clearly don't know whether they're at increased risk for liver cancer per se.

(36:32): [Lynne Spina] Thank you, doctor. "If there's no family history of breast cancer in a stem cell transplant patient, is the risk for development the same as someone who has family history but no stem cell transplant?"

(36:50): [Dr. Madhuri Vusirikala] Again, a great question. Nobody has really looked at that comparison. So it's very hard for me to tell you that it is equivalent. You have to look at several other factors. For example, if somebody had a transplant, did they have radiation as part of their transplant regimen? Did they have radiation before their transplant regimen? Those things could contribute in addition to the age of the patient. So there are so many more risk factors than just transplant versus no transplant and family history versus no family history.

(37:28): [Lynne Spina] Okay. Now this question circles back to your presentation when you touched upon infections. "Are donor cells tested for EBV and CMV prior to transplant?"

(37:41): [Dr. Madhuri Vusirikala] So the cells are not tested, but the donor is tested. So that's part of the donor evaluation. They're tested for EBV infections and CMV infections prior to the donation. But the cells themselves are not tested.

(38:00): [Lynne Spina] Okay. The next question is, "I was told that after 65, I did not have to have gynecological exams. However, being a survivor, should I continue to go for exams?"

(38:17): [Dr. Madhuri Vusirikala] So after the transplant, if you've had some pap smears and you don't have any HPV infections and you do not have any gynecological symptoms, then past the age of 65, you may not need those testing. But, again, it depends on what type of transplant you had. If you had an allogeneic stem cell transplant and have active graft-versus-host disease and are on immunosuppressive agents, there might be a benefit to doing a pap smear.

(38:47): [Lynne Spina] Okay. The next question, "Can you get HPV vaccine at the age of 43 after an allogeneic transplant and with GVHD?"

(39:03): [Dr. Madhuri Vusirikala] The answer is yes and no. So can you get the vaccine at the age of 40-plus? Yes, you can. But if you have active graft-versus-host disease and are on immunosuppressive therapy, there's a small chance that your immune system is not strong enough to mount a response to the vaccine.

(39:22): So it goes back to what your immune system is like. HPV vaccine is not a live vaccine, so it is safe to be given. But at the same time, if your immune system is extremely weak, the vaccine may not work.

(39:39): [Lynne Spina] Okay. "Is pancreatic cancer a risk in allogeneic transplant patients? Can you share any reports or statistics?"

(39:51): [Dr. Madhuri Vusirikala] Pancreatic cancer by itself is such a rare cancer. So is there an increased risk of pancreatic cancer after allogeneic transplant? There are no specific reports just looking at pancreatic cancer. But if you include pancreatic cancer as part of the GI cancers, yes, there is a slightly higher risk.

(40:16): [Lynne Spina] Okay. The next one, I think many GVHD patients would like to know the answer to this. How do you screen for lung cancer? I am not aware that I was screened for lung cancer, and I have lung GVHD."

(40:31): [Dr. Madhuri Vusirikala] So patients who have lung GVHD often get CT scans as part of their evaluation. What we typically use is high-resolution scans if there is change in their lung GVHD pattern or if there's change in their pulmonary function test. So those CT scans can be considered screening tools. Patients who have abnormal or new nodular findings, we do refer our patients to the pulmonologist for further testing.

(41:04): Is there any role for doing annual chest x-rays in chronic GVHD patients? The answer is maybe. It all depends on the patient. So if a patient has pretty severe lung GVHD requiring immunosuppressive therapy, I do recommend annual chest x-rays for those patients.

(41:27): [Lynne Spina] Thank you. This is, "I'm 73 years old, had an allogeneic stem cell transplant for AML. I am on tacrolimus and Jakafi three and a half years later. Should I still have pap smears?"

(41:50): [Dr. Madhuri Vusirikala] Yes. Yes. So the answer is, again, maybe. If you have chronic GVHD, and especially chronic GVHD of the vaginal area, then there might be a benefit to doing pap smears, because you are at a slightly higher risk of developing HPV infections being on immunosuppressive therapy. So it depends on what your previous pap smears were like and if you had HPV infection in the past three years. So those are the factors that'll help determine if you should continue to have pap smears or not.

(42:34): [Lynne Spina] Thank you. "Does extreme conditioning such as marathoning help or hurt the risk of secondary cancers?"

(42:47): [Dr. Madhuri Vusirikala] I don't think extreme anything is too good, but would it hurt? Probably not. So if your body is able to do that, I would say it does not necessarily increase the risk of secondary cancers per se.

(43:04): [Lynne Spina] Thank you. This question refers to the fact that you said that secondary cancers are higher after five years. This person wants to know, "For those people that do get secondary cancers before five years, are there some that are more prevalent in less number of years post-transplant?"

(43:29): [Dr. Madhuri Vusirikala] The only historically ... And based on the data that's available, the one that has been reported before the five-year mark is really PTLD. There's no specific cancer that we see a higher incidence of before the five-year mark. I think a lot of it depends on the patient and the treatment they have received and exposure they have received and, of course, family history. So if somebody has a family history of breast cancer, there might be just an inherent risk of developing breast cancer and the transplant might have precipitated it.

(44:07): [Lynne Spina] Thank you. "My stem cell donor was a 100% match. Does that lower the secondary cancer chance or risk?"

(44:18): [Dr. Madhuri Vusirikala] Great question. So a 100% match necessarily does not lower the risk of cancer by itself, but it reduces the risk of graft-versus-host disease. Chronic graft-versus-host disease by itself is a factor in increasing the risk of secondary cancers. So, indirectly, it actually lowers your risk because it reduces the chances of getting chronic graft-versus-host disease.

(44:49): [Lynne Spina] Next question, "When you indicate diet is a modifiable factor, do you advocate for less amount of sugar?"

(45:04): [Dr. Madhuri Vusirikala] I would say everything in moderation is okay. So starving yourself off sugar does not necessarily reduce the risk of cancers. But I would not be the type of person who would be having dessert with every meal either. So just everything in moderation would be the right thing to do. Now if you do have underlying pre-diabetic or diabetic conditions, which should impact your diet, for sure.

(45:35): [Lynne Spina] Thank you. This question relates to colonoscopies. "Once you do reach those ages you mentioned in your talk, how often do you recommend having a colonoscopy?"

(45:49): [Dr. Madhuri Vusirikala] So we do recommend colonoscopy at the age of 50, if you are standard risk, which means you don't have any strong family history, or you don't have underlying ulcerative colitis or Crohn's disease, that's considered standard risk. We recommend every 10 years. Now you do have a colonoscopy that shows some abnormality, the GI doctor might recommend doing that as early as two to three years or as early as five years. So that depends on the findings. For those who are high risk, the screening recommendations are starting at the age of 40.

(46:23): [Lynne Spina] Okay. "My MDS was derivative of two NH lymphoma treatments, chemo and radiation and an auto BMT. Does this increase my chance of a new cancer even more?"

 (46:51): [Dr. Madhuri Vusirikala] Okay. So autologous transplant by itself increases the risk of secondary cancers. Having one cancer does not preclude you from getting another one and having one does not increase the risk of developing another one.

(47:06): Now the etiology of developing MDS is very different from the etiology of solid tumors. So to answer your question, just because you have MDS as a result of the transplant does not necessarily increase the risk of another cancer. But having had a transplant and all the treatments for lymphoma and having a diagnosis of lymphoma does increase the risk of second cancers.

(47:35): [Lynne Spina] Thank you. "Why is it more prevalent to get, treatment-related AML from an auto transplant and not an allogeneic transplant?"

(47:46): [Dr. Madhuri Vusirikala] Yup. So with the autologous transplant, we are using the patient's own stem cells, and these stem cells have been exposed to prior chemotherapy for whatever condition they have, lymphoma or Hodgkin or multiple myeloma. So we're basically reintroducing stem cells in the autologous setting that have been exposed to prior chemotherapy.

(48:11): In the allogeneic setting on the other hand, we are using stem cells from a young healthy donor who has never had prior exposure to chemotherapy. Hence, those are more so-called cleaner cells that have never been exposed to chemicals. So, hence, the lower risk of MDS in the allogeneic setting.

(48:32): [Lynne Spina] Okay, good to know. "How does GVHD increase the risk of secondary cancers? How or why?"

(48:42): [Dr. Madhuri Vusirikala] Sure. I think there are two factors that are involved. As you know, chronic graft-versus-host disease is an inflammatory condition. Chronic inflammation and irritation of the tissue and cells does predispose them to mutate and cause cancerous conditions. It's more like having constant stress in that tissue. Then in addition, the treatment for chronic graft-versus-host disease, which is immunosuppressive drugs, also increases the risk of secondary cancers, either due to risk of infections or because of the presence of the drug itself.

(49:25): [Lynne Spina] All right. "How long is prolonged immunosuppression to increase the risk of CA, months versus years?"

(49:34): [Dr. Madhuri Vusirikala] I would say years. Most of the data that's out there typically say it's beyond two years.

(49:42): [Lynne Spina] Okay. "I'm on 0.5 milligrams of tacrolimus a day," I know I didn't say that right, "for mild ocular-oral GVF. ALT elevated less than five points, all else is normal. Is it best to be off the drug? I had angioimmunoblastic T-cell lymphoma. I had an allogeneic transplant in 2018."

(50:15): [Dr. Madhuri Vusirikala] I think that's a question to ask your treating transplanter. 0.5 milligrams of tacrolimus is a pretty low dose. The question is, is your graft-versus-host disease really active or not and if it is safe for you to come off your immunosuppression? So that's a question that you need to discuss with your transplant physician. I would hate to advise you not knowing your entire history.

(50:50): [Lynne Spina] Okay. "I developed MDS three years after breast cancer and had an allogeneic transplant. Does my risk for other secondary cancers increase more with two treatment routines already?"

(51:09): [Dr. Madhuri Vusirikala] Possibly, yes, especially if you received radiation for the breast cancer. That does slightly increase the risk of developing secondary cancer, just as a result of the radiation. That will also depend on how your allogeneic transplant is going, whether you are on chronic immunosuppression or not. But, overall, more chemo a body has been exposed to, it is cumulative and it does slightly increase your risk as compared to not having had any treatment for prior solid tumor. Then family history is also very important in situations like this.

(51:53): [Lynne Spina] This next question is, "How common is it to be able to avoid total body radiation in leukemias or lymphomas?"

(52:05): [Dr. Madhuri Vusirikala] So, again, the use of total body radiation is based on the disease for which you're undergoing transplant, as well as the type of donor that is being used. TBI or total body radiation is more frequently used in mismatched and haploidentical or half-match donor transplants because it is a very good immunosuppressive agent.

(52:31): If it is possible to avoid total body radiation, your treating physician will try to avoid it. But if the benefit of the total body radiation to make your transplant more successful is necessary, then you just have to use it in that situation. So that's a discussion you can have with your physician. There are sometimes patients choose not to do total body radiation based on its side effects, knowing that there might be a slightly worse outcome from the transplant itself. So it's not black and white. This is a discussion you can have with your transplant physician.

(53:14): [Lynne Spina] Okay, next question, "What risks are there if I had HPV warts before my autologous stem cell transplant one year ago?" This person is a male and 62 years old.

(53:30): [Dr. Madhuri Vusirikala] Yes, definitely, there is a risk during the immunocompromised state. So viral infections do tend to reactivate when your immune system is weak. Now the autologous transplant immune system does tend to recover faster than an allogeneic transplant. You should be vaccinated at some point for the HPV if it is under control. That's a discussion you need to have with your infectious disease doctor, as well as your transplant doctor. But if your immune system is recovered, the risk of HPV-related secondary cancers might not be too high. But if you had warts before, there is a risk now.

(54:17): [Lynne Spina] The next question is from a former smoker who writes, "What are the risks of secondary cancers if I get low-dose CT lung scan every year? I smoked for 45 years, but stopped before I actually found out I had MDS. I'm a six-year transplant survivor."

(54:40): [Dr. Madhuri Vusirikala] Okay. I think the data on radiation exposure as a result of CT scans is scant as ... What should I say? Factor causing lung cancer. So I don't think there is enough data to prove that radiation as a result of CT scans and x-rays increases the risk of lung cancer, even if you were a former smoker. But having said that, if the CT scans are not absolutely necessary, one might want to consider not doing them that frequently. It's, again, about risk-benefit ratio.

(55:18): [Lynne Spina] Closing. Yes. Thank you. Our hour is closing now, so I will have to have that one be our last question. So on behalf of BMT InfoNet and our partners, I'd like to thank you, Dr. Vusirikala, for your very helpful remarks. And thank you, audience. You had so many good questions. Please contact BMT InfoNet if we can help you in any way.