Secondary Cancers after Transplant

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Secondary Cancers

Presented April 22, 2021

Presenter: Peter McSweeney MD, ChB, Colorado Blood Cancer Institute at Presbyterian St. Luke's Medical Center

Presentation is 34 minutes followed by 18 minutes of Q & A

Summary: Secondary cancers sometimes occur after a bone marrow, stem cell transplant or cord blood transplant. Frequent screening can help detect secondary cancers early when treatment  is most effective. Lifestyle modifications can also reduce the risk of developing certain cancers after transplant.

Highlights:

• Secondary cancers are relatively uncommon, but an important problem after a bone marrow, stem cell transplant or cord blood transplant.
• The risk of developing a secondary cancer increases over time 
• Transplant recipients should get a long-term survivorship plan from their transplant team that describes the type and frequency of cancer screenings the patient will need after transplant, and which doctors will be responsible for doing the screenings.

Key Points:

(07:05)      Patients who had a stem cell  transplant with donor cells (an allogeneic transplant) have twice the risk of developing another cancer than the general population.

(09:35)      The most common secondary cancers after a transplant with donor cells (allogeneic transplant) are lung, breast, colorectal and prostate cancer as well as melanoma.

(10:04)       A type of lymphoma called post-transplant lymphoproliferative disorder (PTLD) occasionally occurs after a stem cell transplant using donor cells (allogeneic transplant).

(11:36)       The risk of developing a second cancer after an autologous stem cell transplant (transplant using your own cells) depends on  the patient’s age and type of cancer at the time of transplant, pre-transplant therapies, whether the patient was treated with radiation, how the stem cells were collected, and  the type of maintenance therapy given to the patient after transplant.

(15:42)      The risk of developing a myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) after an autologous stem cell transplant is five to 10 times higher than among people who did not have a transplant.

(13:49)       Multiple myeloma patients who receive lenalidomide (Revlimid®) as maintenance therapy after a stem cell transplant have an increased risk of developing a secondary cancer, but the survival benefit of taking lenalidomide outweighs the risk of a second cancer.

(17:47)        Cancer screening guidelines for patients who received a bone marrow or stem cell transplant as a child differ from recommendations for adults

(19:45)        Several factors affect the outcome after a secondary cancer including the type of cancer, age at diagnosis, stage of disease, whether it is localized, and avaialble treatments.

(21:44)        There are steps that patients can take to reduce the risk of developing a new cancer after a stem cell transplant.

(27:04)        Young women and girls who received radiation as part of their cancer treatment should begin screening for breast cancer at age 25 or 8 years after transplant, whichever comes earlier.

Note:  During this presentation, when the speaker uses the terms BMT or bone marrow transplant, he is referring to bone marrow, peripheral blood stem cell and cord blood transplants

Transcript of Presentation:

(00:01) [Lynne Spina]  Introduction.

Welcome to the workshop, Secondary Cancers. It is my pleasure to introduce to you our speaker, Dr. Peter McSweeney. Dr. Mcsweeney is the Director of Cellular Therapeutics at the Colorado Blood Cancer Institute at Presbyterian St. Luke's Medical Center in Denver, where he is a member of the Lymphoid, Transplant, Autoimmune and Long-Term Follow-Up Groups. Dr. McSweeney has over 30 years of experience in the field of blood and marrow transplantation.

Originally from New Zealand, he moved to the United States in 1979 and trained in bone marrow transplantation at the Fred Hutchinson Cancer Research Center in Seattle before moving to Colorado.

Dr. McSweeney helped develop the CAR T-cell therapy program at Colorado Blood Cancer Institute, and now focuses his research on allogeneic transplantation, lymphoma and CAR T-cell therapies for lymphoid malignancies. Please join me in welcoming Dr. Mcsweeney.

(01:24) [Peter McSweeney]  With an increasing number of patients surviving a stem cell transplant long-term, monitoring for secondary cancers becomes more important. All right. Well, good afternoon and good morning everybody, depending on where you are. It's a real honor to be speaking at this symposium and I thank the organizers for including me in it. The symposium has been about survival and wellness, and transplants of course are more available nowadays. We're treating older patients, they're safer, the results are improving. There are many more people becoming long-term survivors.

The need for a good follow-up has increased. Part of this follow-up is monitoring for secondary cancers after transplant, and these are cancers that are not the original cancer, but new ones that develop afterwards. We'll talk about some of the factors relevant to that as we go through the talk.

This talk is to provide knowledge that will empower you to look after your health in the future. I want to just make a clarification point before we go further that the terms bone marrow transplant and stem cell transplant will be used interchangeably in this talk and effectively mean the same thing. These are the subjects here that I'm going to try and cover.

(02:38)  The size and quality of studies about secondary cancers after transplant vary considerably. Now, one of the issues in trying to prepare such a presentation is what do we really know about the subject? One of the things that became very clear is there are many different studies, and they don't always say the same thing. Some of them are very big studies, some are smaller, more focused studies from individual institutions. There are varying durations of follow-up, and so one of the questions is how good is the data?

Another important concept is when we talk about risk of cancer, that risk needs to be measured against what the risk is in the population for somebody's age and young people, of course, would be expected to have a lower baseline risk of cancer. The important question has become has it got the potential as a problem to affect life expectancy, and what are the things that may contribute to the development of this?

(03:29)  Several factors, not related to transplant, can increase the risk of a secondary cancer. These are general factors that promote cancer development as a general rule, not specific to transplant. They include immune deficiency, aging, exposure to various what we call carcinogenic substances or organisms, such as viruses. You're familiar with smoking, alcohol, and sun exposure. Then there's this issue of genetic predisposition. If so, is it weak or strong?

(03:55)  A variety of factors contribute to the the risk of developing a secondary cancer after transplant. Then what we're really talking about here is treating individuals with cancer, providing therapies which are given most frequently to treat the underlying cancer. This involves the use of drugs before and after transplant and in some cases, radiation therapy.

These are some of the factors that may affect the cancer risk after transplant:  

• underlying disease and therapies actually given before the transplant;
• whether one's using a donor transplant or using one's own stem cells;
• drugs that may be given to prevent graft-versus-host disease after doing transplant;
• the presence and extent of graft-versus-host disease
• if one develops new viral infections or reactivation of viral infections
• the use of radiation
• the use of stronger or weaker conditioning regiments before transplant.
• Then, what might be quite important, is whether or not maintenance therapies are given after transplant.

(04:47)  A story about a patient who developed a secondary cancer after transplant. We're going to start initially with dealing with donor or allogeneic transplants. We'll start with a patient story and this is a 64 year-old gentleman whom I know quite well. I just saw him in the last few days. He was originally diagnosed with lymphoma in 2004, at 47, and this was complicated by the development of what is called a myelodysplastic syndrome, which was actually a chemotherapy-induced cancer of the bone marrow when he was 54 in 2011.

Both cancers were present when he went to an allogeneic, or donor transplant from a sibling. The remission of both diseases was obtained, but the MDS, myelodysplastic syndrome came back again a few months later. We were able to treat this effectively by tapering his immune suppressant medication, giving him some chemotherapy.

What happened after that was he developed what we call chronic graft-versus-host disease, which is a reaction against the body from the donor, and this occurred and has continued on for years since the transplant. This has gradually got better and now the doses of his medications have been lowered, but he's been experiencing very frequent skin cancers and scaly patches on the skin, and visits the dermatologist every two to three months or so to take care of this.

These have been mainly precancerous lesions, some squamous cell cancers, and also a malignant melanoma that required a major surgery on his head.

 In his mouth, he had chronic graft-versus-host disease, and ultimately developed a small nodule on the tongue that had to be removed. For me as a physician, it's been hard to tell when looking at the skin and in the mouth what's really going on. The difference between inflammation and an early development of cancers.

He remains disease free which is great. He has regular checkups for GVHD, and he needs constant monitoring by dermatology. He has regular oral medicine visits and fortunately, there's been no recurrence of the underlying diseases for which he underwent the transplant.

This is an example of somebody who's had multiple cancers develop, who needs careful monitoring for the longer term after his transplant.

(07:05)   Patients who had a transplant with donor cells (an allogeneic transplant) have twice the risk of getting another cancer, compared to the general population. The risk increases over time. What do we know about second cancers after a donor transplant? The biggest information blocks is from the international bone marrow transplant registry close to 29,000 cases, and their findings were that cancers occurred in roughly two times the expected rate of the general population with the highest excess found in lip, salivary gland, tongue, and bone, soft tissue and liver.

Now, what they did find is the risk for most solid tumors increased over time and is increased with a risk with presence of concurrent graft-versus-host disease for younger patients who had had radiation exposure.

(07:53)  A study found that 3% of patients who had a transplant with a donor cells (alllogeneic transplant) developed a second cancer during the 20 years after transplant.  This is a graph that shows us information and if you look out at about 20 years, they found that about 3% of the patients had developed cancer as defined in the study.

One of the things about the study is it did not include blood cancers, which are not highly prevalent after doing the transplant, but would have contributed a bit to this. They did find that the younger patients were particularly affected by prior radiation exposure, and that if you look at the graphs, you can see that it still goes up many, many years after the transplant. The implication of that is that a long-term follow-up in screening is going to be very important for patients of this type of therapy.

 (08:39) Just to put in perspective, the question I alluded to about what is the real data here, there was a recent report from the University of Helsinki that looks at their own data, but also reviewed the literature and found that it being reported to range from 1% to 11% secondary cancers at 10 years, and 2% to 12% at 15 years, which is a big, big difference amongst the studies.

In their own study of about 1200 patients, they found that 3.2% of patients at five years, 8.7% at 10 years and close to 14% at 15 years were the numbers they came up with the biggest excess in melanoma, skin cancer, mouth cancers, and thyroid cancer. There's a little bit of reconciliation between the different data sources.

(09:35) The most common cancers that develop after a transplant using donor cells (allogeneic transplant) are lung, breast, colorectal, and prostate cancers and melanoma. The European Registry found that the most common solid cancers - and when we talk about a solid cancer, I'm referring to something that isn't a blood cancer, such as a lymphoma or leukemia - they found that the most common cancers are these five shown here. The finding of lung, breast, colorectal and prostate were not surprising, they’re common cancers seen in the community anyway. Melanoma is probably disproportionately increased after transplants.

 (10:04)  A type of lymphoma called post-transplant lymphoproliferative disorder (PTLD) occasionally occurs after a transplant using donor cells (allogeneic transplant). There is an odd type of cancer that occurs after certain donor transplants called a post-transplant lymphoproliferative disorder. This presents as a lymphoma that is a growth in the lymph nodes, usually in the first year or two after transplant and it is directly associated with the growth of the mononucleosis virus in the blood.

It's been associated with transplants that involve more intense immunosuppression. This may be treatable, and we monitor for it by measuring the amount of virus in the blood after transplant.

(10:56)  An autologous stem cell transplant (transplant using your own cells) is most often used to treat patients with multiple myeloma, non-Hodgkin lymphoma and Hodgkin lymphoma. All right. Now I'm going to move on to autologous transplants which are transplants using your own cells. Now the biggest population of autologous transplant recipients by far is the multiple myeloma population. That's illustrated in this graph from 2018 showing transplants in the United States in 2018. The green bars are autologous transplants, the blue ones are donor transplants.

You can see the groups that tend to have autologous transplants are multiple myeloma, non-Hodgkin lymphoma and the Hodgkin's lymphoma. We'll focus primarily on those patients in the next few slides.

 (11:36)  The risk of developing a second cancer after a transplant using your own cells (autologous transplant) depends on the patient’s age and type of cancer at the time of transplant, pre-transplant therapies, whether the patient was treated with radiation, how the stem cells were collected, and the type of maintenance therapy given to the patient after transplant. Risk factors for developing a secondary cancer after autologous transplant have been studied, and these are the factors we think are potentially important in a given patient, age, the type of cancer one is being treated for, pre-transplant therapies given, the way the stem cells are collected, and how easy it is to get them, and then the use of post-transplant therapies that might be given to try and improve the outcome of the transplant. Then if the patient has been treated with radiation at any point either before the transplant, after the transplant, or with the transplant itself.

(12:13)  The risk of a second cancer in multiple myeloma patients who receive a stem transplant is similar to the risk for myeloma patients who do not undergo a transplant. Now, I'm going to focus on these next few slides on multiple myeloma. This was a big study reported out of California recently which looked at patients with multiple myeloma who had either undergone transplant or not undergone transplant. You can see the numbers of the two groups there. When they looked at the number of patients with solid tumors, 3.6% of patients developed this at five years and 6.7% at 10 years. Blood cancers occurred in 1.3% at five years and 2.7% at 10 years. Those numbers aren't necessarily so important in themselves. They suggest a relatively small risk overall. When they looked at this data, they found the transplant population did not have more of these solid tumors. There was a slight increase in the blood cancers, but overall, there was very little effect on survival of patients.

(13:08)  Multiple myeloma patients treated with Revlimid after transplant have a slightly increased the risk of developing a secondary cancer, but the survival benefits of the medication outweigh the risks. They made the point in their study that they did not include the effects of Revlimid maintenance because of the timeframe of the study.

Now that's an important question, and Revlimid maintenance has become a standard therapy to give after transplant. It's really been a very important addition to the transplant because two large studies show that it was superior to placebo, both in terms of preventing or slowing relapses and improving survival, but they did find a signal of increased secondary malignancies in the patients who were getting the Revlimid.

It's been concluded by many investigators in the field, as summarized in the statement here, that lenalidomide, which is Revlimid, increased the risk of a second primary cancer, but the survival benefits outweigh this risk.

Now, just to give you an idea what those numbers might be, this study was updated several years ago with an average follow-up of seven and a half years. They did actually find that the risk of a secondary cancer was close to 14% in the Revlimid arm versus 4.2% in the placebo arm and in particular, the blood cancers were seen in 7.8% of the Revlimid versus 1.3% of the placebo. I've certainly seen a number of those cases, and one of the unusual leukemias we see in this group is acute lymphoblastic leukemia.

This is an important finding which means that we need safer maintenance therapy for myeloma patients and certainly, there are some studies going on to look at new things, but it does mean that if you have myeloma, you've been treated with Revlimid maintenance, you need to stay in close contact with your doctor over the years in terms of follow-up and monitoring.

(15:02)  Patients undergoing an autologous stem cell transplant have an increased risk of developing myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).  Now, one of the biggest concerns about autologous transplants is the development of what we call myelodysplastic syndromes and acute myeloid leukemia after the transplants, and these arise as a result of marrow damage from prior cancer therapy, or the transplant itself. It's not really seen very often after donor transplants.

Unfortunately, these particular diseases tend to have what we call high-risk genetic features and are harder to treat than the same diseases that occur naturally. They tend to occur in the first five years or so after the transplants.

This table here summarizes one study which looked at the risk of these problems, and this compares three disease groups; non-Hodgkin's lymphoma, Hodgkin's lymphoma, and multiple myeloma. If you look at the bottom line there at the 10-year follow-up mark, they saw 4% of Hodgkin's patients, 6% of non-Hodgkin's patients, and 3% of myeloma patients developing this problem. This was a 5% to 10% increase on the background risk of normals in the same age groups.

(16:21)  Treatment for these depends on the health of the patient, or the prior therapies that have been given. It might include supportive care if someone is in poor general health. It might include treatment with regular therapy which may be suppressive, but not curative. Then under optimal circumstances, we will usually try and cure this type of problem by performing an allogeneic transplant. The best outcomes are seen when we can get the immature cells, the blasts down to low levels before we do a transplant.

(16:56)  Maintenance therapies after an autologous transplant can sustain remissions but may promote secondary cancers. Now, there's a tendency to use maintenance therapies more and more after transplant, and I've just put a few examples of these up on the slide. The idea is that these increase the chances of cure or sustain the remission longer and examples include rituximab, antibody therapy given after autologous transplants for the condition called mantle cell lymphoma; this drug called brentuximab for Hodgkin's disease and so forth. We don't know if any of these really are a problem in the same way that Revlimid is, but one of the potential drawbacks is that they do weaken the counts, they may suppress the immunity, and there's some theoretical risk of promoting new cancer development. All of these post-transplant therapies need to be followed and studied in order to give us a good idea of what's happening in this area.

(17:47)  Pediatric transplant patients differ from adults in their risk for secondary cancers. Now, one of the areas that may be different to what I've talked about is the area of pediatric transplantation, and the reason is that there are different diseases and different protocols than the large bulk of the transplants that we've talked about so far.

For example, neuroblastoma is one of the more common transplanted diseases in children and in the allogeneic setting, there are immune deficiencies and enzyme deficiencies that are not generally seen in adults, or at least adults are not transplanted for those because they take place and have their effects much earlier in life. This involves exposure to toxic therapies earlier in life while the child is still growing, and there are potential for more effects on fertility and hormonal development.

(18:36) Some of these children may have a greater predisposition to cancer due to their underlying genetic makeup, and it's been found that certainly solid tumors can occur very late after these transplants. Again, this speaks to the need for perhaps different screening protocols in the younger patients and beginning at an earlier age than one might be anticipating for the general population, or even the transplant population as a whole.

(19:04)  Now this is a slide from a recent study that looked at individuals or pediatric transplant recipients who had lived out to two years, and it followed what happened thereafter. About 15% of those patients still had a recurrence of their disease, and another 15% died of complications of their transplant, which is I think somewhat anticipated.

(19:32) Overall, about 6% of patients going through these transplants at a very young age had new cancers as a cause of mortality beyond this 2-year mark, so that's sobering.

(19:45)  Several factors affect the outcome after a secondary cancer. What is the outcome of the secondary cancers? Similar to cancers in any setting, the outcomes depend on a number of factors, such as the type of cancer, the age diagnosis, the stage of diagnosis, whether it's localized or not, whether it can be removed surgically or by radiotherapy, and then what are the drug therapies available for treating. Important things in the transplant setting are the presence of longer-term comorbidities, such as ongoing infections and graft-versus-host disease, as well as one's general health.

(20:21) Outcomes of a post-transplant secondary cancer are best in patients who develop breast, cervical, thyroid or prostate cancer, or melanoma.  There have been some studies that have looked at outcomes of secondary cancers after going through a transplant. This is a summary of one of those studies. This is from the European Registries, and this showed that the best results were in these diseases shown on the left hand side. These are cancers that are typically more superficial, or more detectable with examination and screening. Intermediate survival seen in the middle column, a disease that by and large. Some degree quite surgically treatable if you catch them at the right time. In the west were cancers that we typically have a lot of problems with in the general population and are typically very hard to cure.

(21:06) A study from Japan that looked at the same question noted a couple of things, and that was that the age of cancers developing was younger than that of the general population. - that's not surprising because of the use of transplant in the younger age groups - and the outcomes of treatment were somewhat worse than the general population after an allogeneic transplant. Understanding that this is a potentially important consequence of going through transplants, which are still somewhat crude treatments, even though they've got a lot of science and technology associated with them.

(21:44)   Frequent screening can catch cancers early when they are most easily treated.. What can you do to help yourself and reduce the risk of cancers after transplant? If you think of cancer as a multi-step process, there may actually be opportunity for intervening before it develops. You can either prevent it, or delay it developing by some of the activities that you could undertake. Screening is important for detecting early stages of cancer or cancer at a treatable stage and naturally, we all believe that early detection leads to a better chance of curing a disease.

(22:23): This is one of those cancer prevention slides that you can find online very easily. It gives you general guidance on healthcare protection. Obvious things that you probably already know, but I'll just reiterate; avoid smoking, avoid sun, watch your diet, watch your weight, and be physically active, practice safe sex, and avoid risky behaviors, get the immunizations that are recommended for you after transplant. This does include human papilloma virus and hepatitis, and know your family history because this may have implications for your future health.

 (23:05) There's a very detailed study summarized on this slide here. You can find that for yourself if you want to go through it. It has a lot of detail on screening, and it compares recommendations from a number of groups, including the American Cancer Society, the National Comprehensive Cancer Network, and it also included Consensus recommendations from groups of experts in Europe and internationally. You want to talk to your transplant physicians and other team members about what you should be doing for screening. I'm going to use some of the information from that paper and summarize it in some of the subsequent slides.

(23:48)  Symptoms of cancer. Just very simply, I think a lot of you are very familiar with the type of symptoms that might be associated with cancer. These are not necessarily, of course, specific for cancer, but they are symptoms that, if they persist, would be important to report to your own physicians, and they would then work with you to decide what evaluation should be undertaken.

(24:15)  The risk of skin cancer after a stem cell transplant can be reduced by avoiding sun exposure and using sun screens. Skin cancers, the first cancer I'm going to talk about. My anecdotal experiences, these are actually quite prevalent after transplants and it may be because I live at high altitude where there's a lot of sunshine. I'm not sure of that at this stage. In my experience, this is the commonest thing I see. I'm really very concerned about getting my patients to dermatology and taking care of these at an early stage, because I have seen several instances where skin cancers have progressed to be very severe problems.

(24:53) Prevention of skin cancers may be possible through sun avoidance and sunscreen use. Early detection helps to take off and eliminate pre-cancerous or lesions or early skin cancers. These can be more aggressive and come up quite frequently in some patients, particularly those with chronic graft-versus-host disease. They're also quite hard to detect for the average physician. Your dermatologist is much better at seeing these.

(25:26)     The University of Helsinki published a study recently, and I was looking at this. It's one of the few studies after transplant that has focused on skin cancers, because usually these are usually left out of the big other post-transplant secondary cancer studies. They found that skin cancers occurred in about 2.6% of the allogeneic transplant population versus 0.9% of the background population, with the commonest being a basal cell carcinoma.

(26:02)  Four types of skin cancer can occur after a stem cell transplant. The various common skin cancers are shown on this current slide. The actinic keratosis is more of a pre-cancerous lesion. It should be treated when it's found. These other three are the commoner types of skin cancer. The squamous and basal cell are typically surgically managed and so is the malignant melanoma, but the malignant melanoma has that name because it can spread internally and become almost untreatable once it does so. It's very important to catch this before it gets to a what we call metastatic stage throughout the body.

(26:39)   In the Helsinki study, they found that the risk of melanoma was about five times that of the general population. Now, I looked at the weather over there, and I think they have a lot less sunshine than a lot of places in the United States. It may be a higher risk in some parts of this country which have high sun exposure.

(27:04)  Patients with graft-versus-host disease should see a dentist regularly, and then an oral medicine specialist if the examination suggests mouth cancer. Now, these photographs illustrate findings in the mouth that we encounter as donor transplant physicians from time to time, and these are actually pictures of graft-versus-host disease, but they're actually quite difficult to monitor. It's hard to tell when a change has occurred to towards a pre-cancerous or cancerous problem. The best way to keep an eye on this is to have my patients have a regular visit with a dentist, and then see an oral medicine specialist if there's anything concerning rising out of those visits.

(27:43)  Women who have had a stem cell transplant should be screened for breast cancer. Young women and girls who had radiation as part of their cancer treatment should start breast cancer screening at age 25, or 8 years after exposure, whichever comes earlier. Now, breast cancer has been a frequent cancer amongst women, and we hear a lot about breast cancer screening. In terms of how to follow after transplant, we break down patients roughly into an average risk group, that is those who've just gone through a transplant without any particular high risk factors, and depending on the time the transplant would dictate the frequency and nature of the follow-up. On the younger patients, an exam every one to three years. Once you hit 40, annual clinical breast exam and a mammogram.

(28:18) An important group of young patients is young woman or girls who have been exposed to radiation for treatment of their cancer, or total body radiation in their transplant. It's recommended that they start follow up much earlier either at the age of 25 or eight years after exposure radiation, whichever comes first and certainly no later than 40 years of age. This type of follow-up is a little more involved, exams, mammograms, and breast MRI at a young age.

(28:52)  The HPV vaccine can help prevent cervical cancer. Cervical cancer is of course cancer there's frequent screening for in the general population. This involves pelvic exams and cervical smears. The HPV vaccine is available as prevention in younger patients, and we try and get that into our patients after transplant. One of the things we do have a little bit of a difficulty with is getting insurance to pay for vaccinations in the older female group.

(29:21)   Liver cancer is uncommon after a stem cell transplant. Liver cancer is not a particularly frequent cancer in my experience, but one of the things we do know is that it's facilitated by certain exposures. Cirrhosis is a step on the way to liver cancer, which may be promoted by excessive alcohol intake, or getting viral infections from either hepatitis A or B. Hepatitis C can be treated. Hepatitis B, we routinely vaccinate for after transplant.

And then another potentially important exposure is too much iron in the liver that can frequently eventuate after going through a transplant and having low blood counts. We look hard for iron overload and treat it when it's present.

(30:10)  Screening for colon cancer should begin between 45 and 50 years of age and continue until age 75. Colon cancer is a common cancer treated by surgery and of course, at an early stage is often curable. The main tests for screening are colonoscopy, doing a sigmoidoscopy, and stool blood and DNA testing. It's generally recommended that someone gets their first colonoscopy between 45 and 50 years of age. This age was lowered recently in some of the expert organization recommendations, and screenings should continue up to the age of 75.

(30:46)  The main risk for lung cancer is smoking. Getting patients to stop smoking after a stem cell transplant can be difficult. Lung cancer is historically a very important cancer numerically, and it's also a very hard one to cure. The emphasis in screening here is to try and identify it before it develops to an incurable problem.

(31:02) Now, I think you all know that smoking is the main risk factor for lung cancer, although not everybody who develops this has been a smoker. Many patients will have had CT scans that might identify nodules during their treatment course and may have follow up CAT scans to determine if anything unusual is going on. There are some recommendations from the pulmonary experts on screening for lung cancer, which involve the use of low dose CT scans of the chest. The two main groups that they recommend this for are patients who are 55 years or older and have greater than a 30-pack year history of smoking, and then a slightly younger group which is 50 and have greater than 20-year history of smoking with some additional risk factors.

(31:55)  Now smoking is a difficult problem for us to deal with as physicians, because some folks will go straight back to the cigarettes after we discharged from hospital, even if they've been in there for a long time. We know that when we've got other things promoting cancer, it'd be something to definitely not be doing.

We obviously try a number of things, such as drugs and patches to try and prevent patients from smoking and help them stop continuing, but I can tell you that it's a very difficult problem for some of our patients.

32:37  In terms of trying to deal with this somewhat nebulous problem of what's my risk of cancer and how do I try and avoid getting this problem, this is probably something one needs to discuss in some detail with one's physician about how you'll be followed up.

(33:00)  Stem cell transplant recipients should have a personalized survivorship plan that details the type of long-term cancer screening that is needed, and who will do which tests and exams.  There's obviously post-transplant planning for follow-up that covers a number of different topics, such as general healthcare maintenance, vaccines. With cancer screening, I think it's important to delineate who's going to be responsible cancer screening and to find a plan based on risk factors, important participants, a primary care physician who may assume a lot of this role, a gynecologist.

Then the oncologists and bone marrow transplant physicians, in my experience, aren't actually doing the screening themselves, but they're recommending follow-up plans and interfacing with the other physicians here. Now one of the things is this follow-up should continue for many, many years, or basically indefinitely after transplant and there's a lot of mobility in patients after transplant. One has to tie in with new physicians and try and get a plan going with a new physician when you move location.

(33:59)  Summary of presentation: In summary, secondary cancers are a relatively uncommon, but important problem after transplants. After autologous transplants, you are more likely to see marrow disorders. This is sometimes suggested by dropping of the blood counts. After allogeneic transplants, we see more in the way of what we call solid tumors. This risk increases over time, especially for solid tumors and may not actually have a period where one completely escapes this risk. This tells us that long-term follow-up with screening and early detection is very important and may help avoid risks associated with going through the transplant that could develop many years down the road.

(34:45) With that, I'd like to thank you for your attention and I'd be happy to try and answer any questions.

Question and Answer Session

(34:54) [Lynne Spina]  Thank you Dr. McSweeney for this informative presentation. I will now take questions. As a reminder, if you have a question, please type it into the chat box on the lower left hand corner of your screen.

(35:10) Our first question is, "My husband had prostate cancer, AML is the secondary cancer. Are there studies of tertiary cancers?"

(35:25) [Peter McSweeney] We don't really use that term to describe those, so I'd answer that that's not really a much of a concept. There may be multiple different secondary cancers. As he's treated for AML, of course he may be considering through a transplant to try and get rid of that.

(35:51) [Lynne Spina] Thank you. Do you recommend yearly skin checks or every six months?

(36:01) [Peter McSweeney] It depends on the circumstances. For low risk situations, I think annual is probably adequate. If you're somebody who's had an allogeneic transplant with graft-versus-host disease, I think more frequent. Then again, if you've actually started develop skin cancers in that circumstance, then even more frequently than that.

(36:21) [Lynne Spina] Thank you. I am scheduled for early June to have a stem cell transplant and have postponed my mammogram because I have a Hickman port in my chest. Should I wait to undergo a mammogram until after the transplant and if so, until when or should I get the mammogram before the transplant?

(36:46) [Peter McSweeny] That's a question that I think you should discuss with your physician and without knowing your medical history and when you had your last one, that would be difficult to answer. I don't think there is any great downside to having the mammogram done. I don't know how interpretable. Of course, it would be if the line is right there, it may create some imaging difficulties. Yeah, obviously have your breast exams done to see if there's anything obvious going on and post-transplant, if the line is an issue for the mammogram, then you can obviously do that as soon as your line is removed after the transplant.

(37:26) [Lynne Spina] This question refers to autologous transplants. Does the way that stem cells are collected affect risk of secondary cancers?

(37:45) [Peter McSweeney] It's very hard to tell the answer to that question nowadays, because almost everybody is collecting peripheral blood stem cells, but the issue of whether the use of say Mozobil as an extra drug over and above the GCSF, I think it's a little bit unclear. What we do know is that if you struggle to collect enough stem cells and you don't easily hit your target, you're probably at a little bit higher risk of getting problems after the transplant.

 (38:19)  [Lynne Spina] Thank you. Dr. McSweeney, we've received a couple questions about time out from transplants that secondary cancers could appear, and you've mentioned it in your presentation, especially as it relates to studies that have done and also in your summary slide, but I think if you could refer because there's a lot of people that are saying, "Well, is it more frequent after 10 years? How about five years, after six years?" I'm wondering if there's something you can say about this quantitative number that's on people's minds that might maybe calm their concerns, or maybe address specifically in a way that they can just look for early detection.

(39:11) [Peter McSweeney] Can you see the slide that I just put up? Is it showing the graph after transplant? Is that showing up?

(39:19) [Lynne Spina] Yes.

(39:20) [Peter McSweeney] Okay, so that addresses that. You can see that at 10 years in this study, the risk was 1% to 2%, or probably less than 2%, and then it's steadily accumulating. The risk doesn't look like it's necessary going up early in the transplant. The data later out suggests a possible slight increase in risk or the likelihood of developing, but if you see those dotted lines there, they're what we call confidence intervals and they show that there's a bit of uncertainty around that data. One of the things about people going through transplants nowadays, they're being treated somewhat differently to the folks in the study. Of course, the longest follow-up in these studies is from transplants done 20 or more years ago. Actually in this study, it's probably now 40 years ago. The slope of this should give you a little bit of a guide to that question.

(40:29) [Lynne Spina] Can you comment on that as it relates to autologous transplants because we've had a question or two on that too?

(40:37) [Peter McSweeney] Yeah. Well the autologous transplants tend to peak a little bit earlier and go down again, because you have this greater propensity to the marrow disorders. They tend to occur within five years of the transplant, and then be less prevalent later on. I did show you the study from California with the myeloma patients, where the solid tumor risk was not really different to the population not getting a transplant that was prior to the development of maintenance therapy. I haven't seen a really good graph for autologous transplant patients getting maintenance therapy.

(41:24) [Lynne Spina]  Okay. Thank you. I just thought it was worth addressing again because of the concern out there. I just wanted to make sure.

(41:50): "I am six years post BMT and now currently 80 years out on a CAR T study. Does this increase my chances of other cancers?"

(42:08) [Peter McSweeney]  I can't answer that question from any data. I think it doesn't yet to my mind reduce the chances given the additional therapies you've had and the increased suppression of immune system that goes along with the CAR T therapy.

(42:25) [Lynne Spina] Okay. Next question, how much sun exposure should be avoided in order to not develop secondary cancers and using sunscreen and wearing clothes that protect your skin from direct sunlight, is that good enough?

(42:43) [Peter McSweeney] I don't think anybody really has quantitated the amount of sunshine that is safe or unsafe. What I recommend or what our program recommends is that patients just indefinitely take care of some protection with sunscreens and protective clothing. I don't think it we have enough very specific information to refine it to a better answer. I'm sorry.

(43:12) [Lynne Spina] Okay. How dangerous are indoor skylights in terms of UV causing skin cancer? This person's home has a lot of skylights solar too. They've had some basal cell and later relapses. Should they remove all of the skylights? They also have a lot of windows, so would blinds help open?

(43:43) [Peter McSweeney] Gee, that's a tough question. I'd be reluctant to try and tell you what to do there, but I think you'd have to use your own judgment as to how much sun exposure you're getting from those skylights and windows. I can tell you that there have been some patients who I've recommended they wear their sun protection inside during the daytime if I think there are very high risk of skin cancer problems.

(44:13) [Lynne Spina] Thank you. Are you at a higher risk of contracting a second cancer if a patient has had both an autologous and an allogeneic transplant?

(44:30) [Peter McSweeney] That's a really good question, and I don't think I've seen any report that looks at that question. Again, I would say that one just has to do one's best with post-transplant screening. The issue here is that there's just more cumulative effects on your body from the more therapy you've had, and that probably is adverse in this regard.

(45:00) [Lynne Spina] All right, thank you. Is there any point in having an HPV vaccine if you're in your late 50s, monogamous, and have had reactivation a genital wart after 30 years due to immunosuppression?

(45:16) [Peter McSweeney] That's a really good question, and I've had patients who I've thought should be vaccinated at an older age. I don't think there's any downside to these vaccines at that age. I just don't have any data and when we've tried to vaccinate with HPV vaccines in older patients would sometimes hit a snag with the insurance not approving it. There is some potential for theoretical for benefit I think, but there isn't any study data that I've seen that answers that question.

(45:55) [Lynne Spina] Thank you. "I am post allogeneic transplant for MDS, 2018. I am toxic from transfusions receiving phlebotomies, iron overload in liver found on an MRI. Am I more at risk for liver cancer or GVHD of the liver?"

(46:22) [Peter McSweeney] That's a really good question. We haven't seen a lot of good data that says that iron overload after transplant is as much of a precipitant for liver cancer as it might be in patients with a natural iron overload called hemochromatosis. I do try and unload my patients who have excess iron in their tissues through phlebotomy just as you're undertaking, but I don't know that I've seen something I can specifically attribute liver cancer to this problem after transplant. I haven't seen reports that really point to this, but the risk is theoretical because of the potential for chronic liver damage from the iron.

(47:12) [Lynne Spina] Okay. Next question, "I never smoked, but was exposed to secondhand smoke in the job with poorly ventilated lab with chemicals. I'm 14 years post CMML and MDS. Do I ask for a lung CA screening?

(47:40) [Peter McSweeney] Yeah, that's difficult to answer because again, there's not much data on secondhand smoking risk this far out from your transplant in the... so I think you should probably talk that over with your local pulmonary specialist if you're concerned about that. I don't have a strong recommendation for you.

(48:03) [Lynne Spina] Okay. Next question, "My daughter had a BMT at age seven, including total body irradiation. Should she start breast cancer screening eight years later at age 15?"

(48:19) [Peter McSweeney] Based on the recommendations out there for follow-up and pediatric cancer treated patients, the answer is yes.

(48:29) [Lynne Spina] Okay. "At age 68, medical community drops Pap smears. Do I cite exception to that based on family history or diagnosis of cancer?"

(48:48) [Peter McSweeney] That I'm a little unsure of because I'm not an expert on monitoring cervical cancer. I think you should talk that over with your gynecologist and get their input on that one.

(49:13) [Lynne Spina] Okay, and the next question is does SCC appear where you previously had breast cancer?

(49:24) [Peter McSweeney] I think you're referring to the surgical site. If you are, I'm not aware of a particular association with that.

(49:36) [Lynne Spina] Yeah. "After an autologous transplant for diffuse large B cell NHL, at age 72, my husband was diagnosed with follicular NHL one-year post transplant. He started a treatment plan of protection every two months for a 2-year period. What should he be watching out for now?"

(50:06) [Peter McSweeney] That's an interesting development because some of us would probably view that the follicular lymphoma may have been present before the transplant and may have actually led to the diffuse large B cell lymphoma. I would be surprised if this was a true secondary cancer. I think that's probably going to be manageable just the way our usual follicular lymphoma would be and with the usual follow-up for that situation, something to talk over a little more detail with your oncologist.

(50:42) [Lynne Spina] Okay, thank you. This will be our last question. How do you screen or diagnose MDS?

(50:52) [Peter McSweeney] It's formally diagnosed by doing a bone marrow biopsy and looking at the makeup of the cells and doing genetic testing and chromosome testing on the bone marrow. In terms of screening and just having some concern about this is a possibility in keeping an eye on the blood counts and whether they are remaining within the normal range after you transplant is the simplest and most basic way. We don't routinely screen by doing bone marrow biopsies because of that risk, but if the count start to change in the wrong direction, then that's an indicator to do it.

(51:34) [Lynne Spina] Okay. I see that we actually have another minute left, and I'm going to ask one more question. Does Revlimid at a minimal dosage have a less chance of developing secondary cancers

(51:51) [Peter McSweeney] I haven't seen any trial data that answers that question. When Revlimid is given at a lower dose, it's usually because the patient's blood counts can't tolerate the higher dose and if we're talking about the maintenance setting. I can't tell you from anything I've seen whether that's protective or not

(52:14) [Lynne Spina] Closing. Okay. Well, that'll wrap up the session right now, and I would like to say on behalf of BMT InfoNet and our partners, thank you Dr. McSweeney for your very helpful remarks. There's been as you can see so much interest in this topic, and thank you the audience for your excellent questions. Have a great day.