Ask the Pediatric Transplant Experts

Learn about medical and learning issues your child may face after transplant.

Ask the Pediatric Transplant Experts

July 11, 2020  Part of the Virtual Celebrating a Second Chance at Life Survivorship Symposium 2020


  • Kenneth Cooke MD, Director, Pediatric Blood and Marrow Transplantation Program, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
  • Leslie Lehmann MD, Clinical Director, Pediatric Hematopoietic Stem Cell Transplant Program, Dana-Farber Boston Children's Cancer and Blood Disorders Center
  • Marybeth Morris Ed.M., School Psychologist/Educational Specialist, Dana-Farber Boston Children's Cancer and Blood Disorders Center

60 minutes of Q&A.

Summary: A panel of pediatric transplant experts answer patient questions about medical, emotional, social and learning issues children and young adults may face after transplant.


  • Children may not grow at a normal rate after a bone marrow transplant. Growth hormones may be needed to spur growth.
  • Executive function issues are common in pediatric transplant bone marrow transplant survivors and can affect their ability to start a task, plan and organize their work, recall details, see a task through to completion, multi-task and control impulses. Parents can seek accomodations at school to help their child succeed academically.
  • A bone marrow transplant can affect when a child goes through puberty and may cause infertility.

Specific questions addressed are highlighted in the transcript below.

Transcript of Question and Answer Session

00:00 [Moderator]

Welcome you to the "Ask the Pediatric Transplant Experts" workshop. My name is Sue Stewart, and I will be your moderator today.

Today, we're honored to have a panel of distinguished experts who are ready to respond to your questions about your child's health after transplant. With us are Dr. Kenneth Cooke. Dr. Cooke is the director of pediatric blood and marrow transplantation at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.

Also, with us today is Dr. Leslie Lehmann. Dr. Lehman is the clinical director of the pediatric stem cell transplant program at the Dana-Farber Cancer Institute Boston Children's Hospital.

And finally, with is us Marybeth Morris. Ms. Morris is a school psychologist with an expertise in assessment, special education, and neurocognitive late effects of transplant. She works with patients and families at the stem cell transplant program at Dana-Farber Boston Children's Hospital.

So, we'll begin with our first question. "Can you summarize the major complications pediatric survivors might face long-term after transplant? Are they any different than issues adult survivors face?" Dr. Cooke, would you like to start?

01:21     [Dr. Lehmann] Yep. Perfect.

01:22     [Dr. Cooke] Sure, I'd be delighted. So, thank you Susan for inviting me to participate, and thank all of you who are out there listening to this presentation. So, this is an excellent question, as the number of transplants that we're doing for pediatric patients continues to increase year after year. Dr. Lehmann, I, all of our colleagues are forever paying attention to long-term side effects and complications that our survivors may face. The first question, regarding whether they're different than adult survivors, I would say, generally speaking, you could probably clump most of the them together. Yes, I think the answer to that is yes. There are going to be some specific things to pediatric patients.

For example, I would probably say there's at least four categories of areas that we're going to be paying most attention to. The first is growth and development: physical growth and cognitive development. And, as one could imagine, the younger the patient is at the time of transplant, the bigger the impact a transplant, and the medications used for that transplant procedure, may have on the development, the cognitive development, of that particular patient.

I would also think about fertility issues. I would think about the concerns regarding second cancers as a patient grows older. And then finally, I think we always pay attention to specific organ late effects, whether that would be the lung, the kidney, the liver, the heart, et cetera.

So, I do think they are many times comparable to that, what we follow in our adult survivors. But from a growth and development perspective, we certainly are going to want to pay attention to linear growth. How is that patient doing, growing in height, growing in weight, and specifically, how are they doing in terms of cognitive development? How are they doing in school? Are they progressing along okay? Can we identify issues related to, perhaps, challenges with learning, that we can intervene at an early time point to keep our patients on track?

Fertility is a big issue. I think as we have made advances in fertility preservation, not only prior to transplant procedures, but our efforts to improve the ability to allow female patients to mother children and male patients to father children. I think we're going to have a greater and greater likelihood that we can preserve fertility. But this is something we're certainly going to want to pay attention to. We're going to also want to pay attention to whether our patients are developing sexually, in a way that is commensurate with their age. Sometimes, this would involve the use of supplemental hormones, like estrogen replacement or sometimes testosterone replacement, if need be. But these are going to be items that we will pay particularly attention to as our patients grow older.

Issues with secondary cancers are always an issue, particularly if radiation has been involved in one way, shape, or form. And as I mentioned earlier, specific follow up with respect to organ function. We spend a lot of time following pulmonary function as our kids get older. Cardiac function is also very important. We can do this by non-invasive means, including pulmonary function tests and eco-cardiography and tests of that nature. And some of that will also be guided by whether or not a patient had acute toxicity in any one of those target organs during the transplant procedure. Hopefully, that was a quick summary for the person who presented that question.

05:31     [Moderator] Thank you, Dr. Cooke. Dr. Lehmann, perhaps you can answer this next question. "Why do some patients get radiation as part of their treatment and others do not? And do those who only get chemotherapy have a higher chance of relapse?"

05:46     [Dr. Lehmann] That is also a great question. And thank you all for being here today. So, over in the beginning, everybody got radiation back in the beginning of transplant in the late 70s and early 80s. And the research field on has done a really nice job by doing studies to show who does and doesn't need radiation. And currently, it's based almost exclusively on your underlying disease for which you're being transplanted. And so, if you're being transplanted for a benign disease, in pediatrics it's relatively common, thalassemia sickle cell disease, et cetera, immunodeficiency radiation would virtually never be used. Or, if so, it would be very low dose radiation. Currently, with the most recent studies, it does appear that using radiation for ALL, acute lymphocytic leukemia, does decrease the risk of relapse compared to non-radiation regimens. Although, there is an open study through the BMT Pediatric Consortium looking at whether some children with ALL could avoid radiation and still have an equivalent risk of relapse.

07:00     [Moderator] Thank you. Ms. Morris, perhaps you can take this next question. "My 12-year-old son has been out of school for all of fifth grade due to the transplant. We're starting to see some executive functioning problems show up. What kind of testing, if any, should I get for him, and what sort of help can I ask for him when he returns to school?"

07:26     [Ms. Morris] Sure, I can certainly answer that. And that's a great question. We see executive functioning challenges commonly in this population. And for those on the call that may not be familiar, executive functions are skills that help with task initiation and seeing through a task. So, for example, managing time, attending, switching focus, planning and organizing, recalling details, inhibiting impulses and self-regulation, and multi-tasking kind of come under that umbrella of executive functioning skills. And they develop over time in any individual, usually into the early 20s, and sometimes a little bit longer, particularly for boys. It is a buzzword we hear a lot in schools. Schools are becoming more familiar with executive functioning deficits. And I want to caution parents, particularly at the age this particular child is, and being that he is a boy, schools will often say, "That's boys, and these skills are emerging over time." But because it is a vulnerability in this population, I certainly would recommend exploring it further and pursuing an evaluation.

There's two ways you can go about that. One is a school-based evaluation and requesting that through the special education department in your school. One of the caveats of that is schools don't necessarily have the testing materials to dive deep into looking at specific areas of executive functioning. So, my recommendation would be to look for a neuro-psychological evaluation. Ideally would be hospital-based but could certainly be at a community testing center that's familiar with transplant or late effects. And that should be covered by insurance. Sometimes it takes some working with the medical team as well as the neuropsychologist to get that covered.

But in terms of having that done, the outcome of that would be two potential areas where your son could be provided with supports at school. One would be accommodations through a Section 504 plan. And accommodations are designed to level the playing field, if you will. So, students who have executive functioning, giving them the accommodations so that they can perform equally to their more typically developing peers. Some accommodations for executive functioning ... And again, you'll get more specific answers based upon the results of an evaluation. But some may be extended time, assistance breaking down tasks, helping with organizing information, either external organization of materials or internally organizing information in your mind.

But for some students who are struggling more significantly, specific and explicit instruction around executive functioning skills can also be helpful. And that's something that would generally come through an individualized education program, or IEP. So, you would want to take the results of an evaluation to your special ed department at your school district, and they would determine based on the results and recommendations, what your individual child is eligible for in the school system.

10:49     [Moderator] Thank you. Dr. Cooke, perhaps you can take this next question. "My daughter was 7 at the time of transplant and just turned 11 years old. My questions about physical growth and development. After radiation and chemo for transplant, is it always expected that their physical growth will be lagging, in that they will need some sort of intervention, like an injection, to stimulate growth? She's certainly short compared to other kids at her age, at this point, but we aren't sure what to expect. She sees endocrinology, but this hasn't been discussed yet."

11:22     [Dr. Cooke] So, this is, again, another terrific question, and I think dovetails nicely with the first question, that really got us to put in general terms, what are some of the major complications that our pediatric survivors may face long-term after transplant. And as I tried to touch upon before, growth and development is certainly one. I suppose, "is it always expected?" I think we anticipate that this is going to be an issue, and this is why we really pay close attention to it. Life is all about expectations. At least when I counsel families, I will mention this, that there is an expectation that this may occur. It doesn't necessarily mean that it's going to occur the majority of the time.

But what we don't to do is actually lose sight of this and potentially lose sight of a window of opportunity to do something to augment growth, if it in fact, it is lagging. So, we will follow growth closely, as you guys probably all know. We rarely give up our transplant patients. My guess is Dr. Lehmann is still seeing some patients that we both may have taken care of 25 years ago, in one way, shape or form. So, whether or not it's with your pediatrician or with a long-term follow up clinic, or whether that care is ultimately transitioned, we are going to pay attention to growth. If there is a plateau in growth, that generally will trigger a workup that could look at how the bones are, in fact, aging in association with chronologic age. This is perfect if you've already been in contact with an endocrinologist, because there are certain hormone levels that can be checked. And then, it can be determined based upon anticipated overall height. That comes, also, from parental height estimates, whether or not your son or daughter would be a candidate to have some hormonal supplementation to augment growth.

So, getting back to the specific question: "Is it expected?" I think it's at least anticipated, which means we are going to pay attention to it. I would probably still say it's going to be the smaller group of patients rather than the majority that actually have to have some type of intervention to augment growth. But certainly, we'll pay attention to this in all of our patients.

13:57     [Moderator] Thank you. Dr. Lehmann, perhaps you can answer this question. "I'd like to know if it's reasonable to expect all cell lines to return to their normal baseline two years after transplant. Is it possible that cell lines will continue to grow, albeit slowly? My child is two years post-allogeneic transplant and is often moderately neutropenic, which worries me, even though he has good immune function and chimerism."

14:26     [Dr. Lehmann] Thank you. That's a very intriguing question, and I would also love to hear Ken's perspective on this. So, we see this not uncommonly, and it's either, it will be a small decrement in one of the cell lines, sometimes platelets, with the platelet count that's three quarters of normally, or mild neutropenia, as you say in the question. And it always should prompt a full evaluation, which it looks like your providers have done in terms of chimerism. Sometimes, we do a bone marrow, but the chimerism may be the most important thing, looking for other sources of neutropenia, which can be an ongoing infection. Its most often medication related. Although, it sounds like not. Two years out, it wouldn't be in that case. But things like Bactrim or acyclovir can certainly depress the count.

And then sometimes, we are just left with someone who runs a slightly lower than normal neutrophil count. And it's starred on the lab printout, which always is a cause of concern for parents. And for us, too, but I have, over the years, accumulated a group of these patients who seem to do brilliantly. I have not seen that there's been any more complications, either in terms of infection or the neutropenia being a sign of something worse, than with patients who have a normal neutrophil count.

The only thing I will say, having looked it up recently for a similar patient like this, is that African-American women run lower neutrophil counts, and so, if the donor were an African-American woman or female, either as a sibling or as an unrelated donor, that may be part of it. And presumably, other groups may run slightly lower neutrophil counts than the standard public, which was based mostly on northern European patients.

So, it definitely happens, and I have not seen it to identify a group at particular risk of a complication far after transplant. And Ken, have you seen it, as well?

16:26     [Dr. Cooke] Yes. I think these are great questions. And sometimes, not bad questions to have. If everything else is going great, and there's just a slight decrement in one of the cell lines, that really means that we're in pretty good shape if this is the focus. But that's okay. These are questions that families have, and we want to be able to address. But I would agree with you. So long as the workup has been complete, that we know these are donor cells, that the bone marrow otherwise looks healthy, that immune system and function is recovered and robust, I agree completely, Leslie, with your approach, there.

17:11     [Moderator] Thank you, Dr. Cooke. Maybe you want to follow up with this question, as well: "When should we screen our child for secondary cancers after transplant? And when should my daughter start getting mammograms?"

17:25     [Dr. Cooke] Yes. So, this is a great question. And we have to think about, what secondary cancers are we concerned with? So, some of this is going to be, was there some type of genetic predisposition that may have been identified in the patient or in the family, even prior to the first underlying reason for the bone marrow transplant? And if that is the case, then, many times, families will have genetic counselors in the search and surveillance for secondary cancers, maybe more intense and may occur earlier. Otherwise, I must say, I will call a friend and ask Dr. Lehmann if she has some thoughts on this. In terms of actual timing for some of these things, we're always going to want to do good skin exams. No question that mammography is going to be important for women, particularly if they have had additional radiation. For example, sometimes patients will have had lymphoma, Hodgkin's disease or otherwise, of the chest. And a female patient may have had radiation to the thoracic area that could have scatter or direct impact on the breast tissue. That is certainly going to trigger a sooner, and probably more aggressive, surveillance practice for secondary breast cancers.

Similarly, if there was other targeted radiation, even above what one would get for total body radiation, those areas will be watched more carefully for skin cancers, for bone cancers, et cetera. But Leslie, what are your thoughts about this excellent question?

19:09     [Dr. Lehmann] Yeah. No, I agree totally. The majority of cancers, secondary cancers, are skin cancers. And so, we recommend a yearly dermatologic exam, and our pediatric dermatologist works with families to help them identify something that could be worrisome in this time between the exams. And then, for the other ones, long-term follow up clinics are changing the recommendations. But by and large, other than mammograms, people have not recommended scopes, endoscopies, or something like that, unless, as Dr. Cooke said in the beginning, your bone marrow transplant happened in the context of a more global cancer predisposition syndrome.

19:56     [Moderator] All right. Thank you. I'm not sure whether this is for Ms. Morris or one of the two doctors. I'll just throw it out there. "Is it possible to experience neurological late effects after long-term use of immunosuppressants, such as methylprednisolone, tacrolimus, MMF, or even after R or ETG? Our nine-year-old son is two years post-transplant, and we're trying to understand if that could still be a factor contributing to some of his current issues, complaints. He's been successfully off all meds for a year."

20:40     [Ms. Morris] I'm going to have to pass that on to the doctors. I'm not as familiar with all of the different treatments that were mentioned in that. So, I don't feel as though I'm equipped to answer that question.

20:50     [Moderator] Dr. Lehmann and then Dr. Cooke?

20:52     [Dr. Lehmann] I can answer. So, in general, the side effects for medication should be mostly gone by this time after transplant. The main ones that cause side effects that you mentioned are the tacrolimus and its sister, cyclosporine, which can cause peripheral neuropathies. And those can actually linger for several months after they've been discontinued, but I personally would be surprised if they were staying on two years before. The ETG that you mentioned, or the MMF, they really don't have long-term neurologic side effects in terms of either peripheral neuropathies, like tingling or weakness, or more central things, like changes in [inaudible 00:21:36] or strokes. They should not be associated with the medications. And I would also like Ken to chime in if he has a different experience of this.

21:47     [Dr. Cooke] No, I agree, Leslie. The other things to comment on is that medications like tacrolimus and cyclosporine in addition could sometimes cause a fairly scary but relatively rare complication known as PRES, which can present with seizures, can present with loss of cognitive function, usually transient. Usually occurs in the setting of high blood pressure and some other things going on. So, that can happen acutely. In my experience, the effects of that are usually short-lived, as well, as Dr. Lehmann said.

Other things that can, however, I think impact more longer-term for these cognitive essential neurologic function would be if your son or daughter had leukemia and required, for example, multiple intrathecal injections in chemotherapy. That sometimes can have longer-term neurologic effects, as could radiation specifically to the brain. Sometimes, that is delivered as what we would call a cranial boost, in addition to total body radiation. So, those are the things that pique my interest in terms of long-term follow up of cognitive function. But as Dr. Lehmann said, I think the rest of these immune suppressant drugs, at least once they are off, are not, in my experience, associated with neurologic toxicity in the long term.

23:18     [Moderator] All right. Thank you, Dr. Lehmann. Maybe you can address, there's two questions that are along the same line. First is, "Generally, what is the outcome for reproductive health for girls after transplant? My daughter was seven at the time of transplant, and this wasn't discussed, and I didn't think to ask." And another person also asks, "My eight-year-old daughter had an allogeneic transplant for acute lymphocytic leukemia in March of this year. Will she have her period early? What are her options for having a baby later in life? And how do you recommend telling her about her infertility?"

23:56     [Dr. Lehmann] Maybe Ms. Morris can address the telling her.

23:58     [Ms. Morris] I'm happy to.

24:00     [Dr. Lehmann] Let me give a general overview and then see if Ken wants to add anything, and then we can go from there. So, I think of the female reproductive system as having two parts. And the way I think of it, at least, is that they're almost disjoined. And so, one job of the ovaries is to produce hormones, and that's estrogen, primarily, obviously.

And the job of those hormones, as most people know, is one, to help you go through puberty if you're pre-pubertal. So, it's what makes your breasts grow, and what makes you get secondary sexual characteristics. And then, secondly, during the rest of your adult womanhood, they're what keep you pre-menopausal. So, keep you from having vaginal atrophy and keep your bones strong and do a ton of things. And so, many, many people who got a full transplant, many women, will not make enough estrogen when they get to this period of time when they would either go through puberty or, if they're through puberty, don't make enough estrogen to keep themselves pre-menopausal during the years until they would be expected to through menopause.

And so, that is a very important complication. It's a very important thing that the providers and the parents follow. And so, probably Dr. Cooke and I vary a little bit in how we do it. Every program is slightly different, but at some point in time, when puberty should come or could be coming, we send our female patients to an endocrinologist to test all sorts of blood levels from the pituitary, to see whether the patient is, in fact, making the hormones that would begin the process of puberty. And if that isn't true, they can supplement those hormones so that the patient can go through puberty, develop breasts, develop secondary sex characteristics, and be a sexually functional adult female. And that is a tricky thing to do. I would never do it. I would have an endocrinologist do it. To get adequate breast development, you need to have some progesterone and some estrogen, and I feel that it's out of my area of specific expertise. So, I always use a pediatric endocrinologist who has experience with this kind of thing.

So, that's sort of part one. Part two that the ovaries do is that they have eggs that allow you to have a genetic child down the road. And so, for many transplants that are either not as strong, or some children will make enough estrogen, but they still will be infertile, because they won't have enough eggs that they are able to produce to make a biologic child. And so, for that, there's no standard to guarantee that for children at this point in time. There's a lot of research being done on this, and we offer ovarian cryopreservation. It still is not a standard practice, although it's becoming one. And these guidelines keep changing. And so, a female child can have a piece of ovary preserved before transplant and then re-implanted down the road, stimulated, and the hope is that that would then allow an egg to be retrieved, and then, through in-vitro fertilization, generate a biologic child.

There are already in place, you can get an egg if you're pubertal and freeze it, or freeze an embryo, but those are not for little girls, of course. And so, at this point in time the field is changing so rapidly, there may be ways that, when these two young children are grown, that there may be actual ways to retrieve eggs that were previously thought not to be viable, or to figure out how to get genetic material from a patient that acts like an egg. But those have not come yet. The field really moves very, very quickly.

For telling the child, and again, I'll let other people share their opinions, I first of all ask the parents if they want me to tell the child with them present, or they want to tell the child. And some parents feel that it comes better from a medical provider, and some parents want a more private conversation. And I certainly would frame it in the light of, at the time we were doing what we could do to give you the best chance of a long and healthy life, we made the decisions we had to make at the time. The field is still evolving, and we will help you explore options for the next decade, so that hopefully there will be some other opportunities. Also, adoption, of course. And many of our transplant survivors, a fertilized egg could be placed into their uterus, and they would be able to carry that baby to term, usually. There's some complications around that, too. I'll stop there.

29:05     [Moderator] All right. Dr. Morris, or Marybeth, do you want to address the how to tell a child? Or do you have anything else to add there?

29:15     [Ms. Morris] I wish that I had a universal answer for how to tell any child, but it really depends on the individual child, based on maturity level, based on where your child is in terms of coming to terms with her medical history, what her understanding is. My recommendation, I think as a parent you certainly know your child best, but also, as a parent, you have a lot of feelings invested in this process, as well. My recommendation would be to talk with her individual medical providers. And also, if your cancer center or treatment center has a psychosocial clinician on staff, try to engage with that person so that he or she can get to know your child and help give you specific recommendations based on your individual child. I think it's really hard to have a one-size-fits-all answer to that question.

30:11     [Moderator] All right. Dr. Cooke, perhaps you can answer this question: "Our daughter had her transplant in 2018. Her related donor is in his late 30s and had chickenpox when he was young. Would it make sense for my daughter and the donor to get the non-live Shingrix vaccine?"

30:32     [Dr. Cooke] These are really provocative questions, right? We're always thinking about, how do we need to retrain this new donor immune system? How much of the donor immunity is actually transferred, not only immediately after transplant, but in the months to years that follow? There are a couple of things that can guide us in this regard. We certainly could follow, there's antibody tests that we can do for chickenpox or varicella to demonstrate whether or not someone has circulating immunity to that particular virus. So, that would be a good place to start.

If, despite the fact the donor had chickenpox, if after transplant, looking for the varicella antibodies was in fact negative, then that would actually certainly prompt me to re-vaccinate that patient early using the upfront varicella zoster vaccine. And then, with respect to the later vaccine, I think that is something that is also still to be at least considered because many times immunity, even if robust at one point, will wane later. So, I think that is in part why people end up getting, as we get older, the booster vaccine to prevent shingles, because sometimes this immunity can wane with time if, in fact, the body is not re-challenged with the virus. Leslie, do you have anything to add to that?

32:12     [Dr. Lehmann] No. As you probably know, live vaccines aren't approved to be given until two years after transplant, for autologous and allogeneic transplant. And that's the upfront vaccine that Dr. Cooke was talking about. People haven't really studied this new vaccine in post-transplant recipients, but down the road, it should be a safe thing to have when they got to the appropriate risk category to need that vaccine. But at two years after transplant, currently every transplant recipient, regardless of [inaudible], should get the varicella vaccine.

32:49     [Moderator] All right. Thank you, Dr. Lehmann. Maybe you can follow up with this question: "My daughter was first diagnosed with Hodgkin lymphoma in January 2016, at the age of 16 years old. She had chemotherapy followed by an autologous transplant in 2018. My question is, are there any treatment options other than an allogeneic stem cell transplant, in case she relapses?"

33:17     [Dr. Lehmann] That's an evolving question for sure. And currently, there's lots of treatment options. One would be, if she were to relapse, to have another autologous transplant, and that certainly has been done with some successes and some concerns about having enough stem cells, and are the stem cells that are being collected damaged by the prior chemotherapy and the first transplant and the salvage chemotherapy?

The most standard approach in general for another relapse has been an allogeneic transplant in a young person, as this woman is. And that's where the most data exists, because it's what's been done for the longest period of time. There are definitely new therapies for Hodgkin's disease, and at this point, it's not clear. Antibody-mediated therapies, such as brentuximab being the one that comes most to mind ... People are in general, today, a little anxious, I think, about saying that they would replace the need for transplant. But it's being looked at completely. And perhaps in a year, there would be a study that said that you didn't definitively need a second transplant if it were to recur. Ken, do you have any other thoughts on that?

34:35     [Dr. Cooke] Yeah. I think this is an emerging field, as you said, Leslie. The other group of medications that are now being considered, particularly for Hodgkin's lymphoma, are what are called checkpoint inhibitors. So, these are these cool medications that have been used to re-turn on the patients' immune systems, so that it can effectively eradicate tumors. Now, these medications are being used now for patients with lung cancer, colon cancer, melanoma, et cetera, et cetera. And now, I think one was recently approved for its use in Hodgkin's lymphoma, particularly when it is [inaudible 00:35:20]. So, many times, these medications are now being used in conjunction with some of the antibody therapy that Dr. Lehmann just mentioned. They're being introduced even up front to see whether or not they can replace some standard chemotherapy, but this is, again, a rapidly evolving field in terms of advancing our ability to control cancer and minimize toxicity. So, certainly after an auto-transplant, if it was a relapse, these medications could be used to get a patient back into remission.

I think in the end, another transplant, our institution would certainly favor an allogeneic transplant in that setting, likely using what we would call a reduced-intensity conditioning regiment. So, there'd be actually much less chemotherapy, and the toxicity associated with that delivered, and we would then rely on the donor immune system to help keep that patient in remission after the second transplant. So, I guess the real answer here is, fortunately, let's keep our fingers crossed and prayers up that the autologous transplant is successful.

36:37     [Dr. Cooke] But if in fact something happens, there are several options that are on the table to get your child back into remission and then to keep her there in the future.

36:52     [Moderator] All right. Ms. Morris, I think this is a question that you might be able to answer: "My teen son has a lot of fatigue after transplant and is not doing well in school. The workload is too much for him, and he is just shutting down. How do I motivate him to continue on?"

37:10     [Ms. Morris] Sure. I'm happy to answer that. I hear that question, and I guess, to me, it brings a lot more questions. I think the question of, how much of this is fatigue, how much of this may be missed school and therefore gaps in learning and kind of getting back into the routine of school, and also whether or not there may be some cognitive effects of treatment that are impacting learning. So, I think my initial answer would be to meet with the school team and request a 504 plan, accommodation plan. Your son may or may not already have that plan. Sometimes those are developed during treatment, more medically based.

But to include some support for academics, such as prioritizing assignments on the focus of the quality of work versus the quantity. So, in other words, reducing that workload for him, eliminating busywork, setting a time limit for homework. Oftentimes, teenagers have hours of homework at night. With fatigue and processing, things may not come as easily to him. So, shortening that time, talking to the team about a set amount of time that he can do what he's able to complete in that time, but not going beyond that. Modifying his assignments and assessments. And then perhaps providing some individualized support at school. So, if there is gaps in learning, which we often see, particularly in math, when there is missed school time due to transplant, some of those building blocks of math gets missed. So, even though it may not be a learning deficit, because he has missed out on some aspect of instruction, things may be more challenging.

So, initially, I would think that looking for some accommodations such as that. The other piece, when thinking about fatigue, trying to either shorten the school day ... If it's high school, generally what we recommend is scheduling so that the bulk of the academic classes are either at the beginning of the day, where your child may have the most energy, so that he's able to be on target for a certain portion of the day. And maybe the latter half of the day, he either comes home to rest or has less heavy classes, more elective type things.

Or, if your child is one that would do better with sleeping in and having more of those academic-heavy classes at the end of the day, that's also an accommodation you can consider. Additionally, if you continue to have concerns beyond whether or not your child is becoming fatigued and overwhelmed, looking at having an evaluation, either school-based, or, again, a psychological evaluation, to determine whether or not there's some underlying deficits that may need some more specialized support may be helpful to explore, as well.

39:51     [Moderator] All right. Thank you. Dr. Lehmann, perhaps you can take this one: "My daughter will be undergoing a haplo transplant later this month, using the alpha-beta T-cell depletion technique. I'm unable to find much research on this new technique. What are its advantages and disadvantages?" And perhaps for the rest of the listeners, Dr. Lehmann, you can explain what T-cell depletion is.

40:15     [Dr. Lehmann] So, in any transplant that's not autologous, when you're getting a transplant from somebody other than yourself or an identical twin, the T-cell, which is a type of lymphocyte that's in the donor, are primed to attack the patient when you put them in from the donor because they see the patient as different. And the least worrisome scenario for that is a matched sibling donor, where the patient and donor share a lot of components of the immune system, and they're seen as less different. But the further you go from that to unrelated donors or haploidentical donors, the more of a problem it becomes. And so, Dr. Cooke has done so much work on this for the length of his career that these T-cells in the graft from the donor are wanting to attack the patient, and you need to address that problem in some way. So, for example, in matched sibling donor, for most people they will just use medications like cyclosporine or tacrolimus methotrexate, and that will be enough for those T-cells to be quiet enough that they don't cause major problems.

When you become more different from your donor, you need a stronger approach. And one of the early approaches that we've tried was to take the T-cells out of the graft. So, you harvest the donor by bone marrow or periphery, and then you remove those T-cells. And a lot of that early work came from [inaudible 00:41:50] and then has sort of become global. And you take all of them out, and you get very, very little graft versus host disease, or the T-cells attacking the patient, when you do that. But there seemed to be lots of problems with that approach, primarily that it's sometimes hard to get the graft to be accepted by the patient because the T-cells help drive in the graft, and also, T-cells are what keep all of us sitting here safe from chickenpox reactivation and EBD and CMD and all sorts of viruses, and these patients had a lot of problems with serious viral infection. And then last, they perhaps had a greater chance of relapse as well, if they were being transplanted for a leukemia process.

And so, now, probably 10-ish years ago, longer than that, people noticed that there were two categories of T-cells. There were alpha-beta T-cells, and there were gamma-delta T-cells. And that the alpha-beta T-cells seemed to be more of a problem in terms of causing graft versus host disease. And for years, we didn't have the technology to do it, but now we have the technology where we can take out the alpha-beta T-cells but leave in the gamma-delta T-cells. And the hope by that approach is that the gamma-delta T-cells will both help get the graft in and also protect against infections, and that getting out the alpha-beta T-cells will decrease the risk of graft versus host disease.

And that has been shown in some very nice publications. The one I can remember of the top of my head is a doctor named Frank Locatelli from Italy, has done a lot of work in this. Ken may know other people who have done work, as well. And so, with haplo transplants, when the donor is only a half-match, compared to a sibling where they're sort of a full match, not identical, but they match in the important places that we'd look at for matching, that is a reasonable method to try to decrease the risk for graft versus host disease but not increase the risk of infection. Ken, did you want to add anything to that?

43:56     [Dr. Cooke] Yeah. That happens to be one of the few approaches that have made this half-match transplant an approach that has really transformed our ability to break down donor barriers to transplant availability across the globe. Right? So, when Dr. Lehmann and I were training together, you pretty much had to have a full match in your family. You could go to the unrelated donor registries, but it was still sometimes challenging, if you didn't have a full match sibling, to actually find a suitably matched donor. There has been progress made over the course of time. The use of cord blood is something that has really expanded donor availability. But now, half-match transplant is something that is being done across the globe, and one of the way to allow this to be done safely is to take this portion of T-cells, as Dr. Lehmann said, the alpha-beta T-cell types, out of the graft. They are the ones that are believed to be more rigorously in this graft versus host reaction.

Our center takes a different approach. We actually move two doses of a very common chemotherapy known as Cytoxan, that is usually delivered before the transplant. We give two of those doses after the transplant, strategically placed on day three and four after the transplant is actually infused. That, too, is very effective at mitigating this graft versus host disease process. So, it is another one of the two major ways to make haploidentical a safe and effective method for treating patients with both malignant and non-malignant disorders.

45:52     [Moderator] All right. Thank you. Dr. Lehmann, I'll pose this one to you: "At what point should we be transitioning our child to a doctor who cares for adult patients? What do we need to tell the adult care doctor about our son's transplant history?"

46:11     [Dr. Lehmann] That is a million dollar question with no right answer. I would say a couple things. One is, each center has its own practice about this, and there's multiple ways to do it. So, way number one is that the patients would be followed by their pediatric transplant team forever. And I think that used to be the way it was done, as Dr. Cooke alluded to earlier, that we sort of followed them forever and then involved adult physicians as needed.

Another way that we do, and I'm not sure what's used at Hopkins, is we have a survivor's clinic, and they have gathered ... So, it's housed within pediatrics. And they see bone marrow transplant patients as well as oncology patients that are deemed survivors, usually your close to five years off therapy, or after transplant. And they have enrolled a bunch of adult providers that can provide car for these patients. And so, the stem cell transplant doctor, the pediatric stem cell transplant doctor, sees the patient, and then the patient is seen by an adult cardiologist, and adult psychologist, insurance people, and adult pulmonologist, et cetera. And so, that, in a way, is a little bit, perhaps, a melding of both worlds, but the center needs to get these adult providers' credentials or have a relationship with a group of adult providers.

The third way is to actually transition the person over to an adult provider, and that's if there's an adult BMT program where you go. Then, that would be also a very reasonable way, in which case your pediatric stem cell transplant provider would provide a summary, would usually have a conversation by phone, if not by email, as the care transitioned. And so, I don't really think much of the burden would have to be on you to provide that transition of care.

48:22     [Moderator] Okay. Thank you very much. I'm stepping in for Sue here. I have a question: "Do pediatric patients have a higher than normal risk for heart disease, stroke, and diabetes?" Dr. Cooke, you want to take that first?

48:40     [Dr. Cooke] Sure, absolutely. This gets back to that theme of survivorship and things that we have to keep our eyes on as our pediatric transplant recipients continue to grow and thrive over the course of time. Now, we talked about the importance of focusing in on several target organs like the heart, like the lungs, like the kidneys, and we have talked also about the CNS. So, what I know for certain is that there is an increased risk of cardiac issues. And that can either be heart failure ... If a patient has had radiation to the chest, their risk for cardiovascular or coronary artery disease actually does go up. So, certainly keeping an eye on cardiac long-term effects is going to be key.

I would also imagine that diabetes could be an issue, particularly if your son or daughter has received long courses of steroids, either for their initial therapy, say for acute lymphoblastic leukemia, or if they had a complication like graft versus host disease or anything like that, that does reek havoc on the body's ability to regulate insulin. We do know that even in the short term, being on steroids can cause high blood sugar and sometimes need more insulin.

Now, if there is ongoing problems with the pancreas or just residual injury, I would imagine that could be an issue moving forward. And then finally, the question was heart and then stroke. So, this is what I will say. I don't know this for certain. It wouldn't surprise me if there was an increased risk in pediatric long-term transplant survivors, but I don't know this for sure. But the reason why I say this wouldn't surprise me is because the lining of the blood vessels, called endothelial cells, are known to be injured during the transplant process, either by chemotherapy or by many of the complications that occur early after transplant. And some of this is, the reason why, whether it's coronary arteries or cerebral arteries, the arteries that feed the brain, if the lining of those cells is scuffed up in any way, to me that would set the stage for issues that could predispose to stroke going on. So, I don't want to speak with absolute confidence.

Maybe Dr. Lehmann, you have more information about that. But certainly heart, and my guess would be endocrine and the possible increase of stroke versus patients who have not had transplants would not surprise me.

51:33     [Dr. Lehmann] I agree totally. And one of the follow up things that should happen ... And the other thing is, cyclosporine and tacrolimus can cause what we call dyslipidemia. It can affect your cholesterol and your high-density lipoproteins, and all of that. And so, having good "metabolic" follow-ups to make sure that the cholesterol channel is normal after transplant would be part of good, routine transplant care.

52:03     [Moderator] All-righty. Dr. Lehmann, maybe I can follow up with you on this question: "For pediatric patients post-transplant with the FLT3 mutation, they recommend an inhibitor, in our case NEXAVAR, for one year after transplant. But the adult recommendation is two or more years. In which category would a 20 year old fall: the pediatric recommendation or the adult?"

52:27     [Dr. Lehmann] That's really hard, and I'm sure no-one has an exact right answer for that, unless Ken knows. What we do, we use it for a year, and I think if we're treating a 20 year old, we would call them a pediatric patient. We sometimes transplant 25 year olds, and I honestly don't know whether we would then say that that was an adult patient. And we follow routinely to make sure that there's no evidence of any mal recurrence with bone marrows at nodal points, as well. And we usually get a bone marrow before we stop therapy. I think there's concern about side effects in those FLT3 inhibitors. And back to the first question, are those side effects more prominent in organs that are developing instead of organs that are developed? But it would be hard to make a firm recommendation. I would definitely do it for at least a year. Ken, I don't know what your program does.

53:23     [Dr. Cooke] Yeah. I agree, Leslie. This is an open-ended question. I think it's a hard question to answer because the answer is not steadfast at the moment. There's an ongoing trial for sure that would include young adults, I'm certain a 20-year-old, that is being run through what is called the Bone Marrow Transplant Clinical Trial Network. And believe it or not, this is as trial wherein some patients get the drug sorafenib, or NEXAVAR, and some people don't. So, there's a lot of excitement that post-transplant maintenance is where the future lies, and I agree with that. So, one could argue, and many have, how could you run a trial wherein not everyone is getting the drug? I think there are many questions that still remain to be answered, including the duration of therapy. Does everyone need to get the therapy? We do know that transplant will cure a significant percent of patients, even with FLT3 AML. We're trying to improve that, of course, but we know for certain which patients need to get the medication.

And again, it gets back to the question. If so, how long, and how does one account for side effects that may occur with that particular medication or with its cousins? There are other inhibitors that are also used for the same mutation, the FLT3 mutation. So, I agree with Dr. Lehmann. It's a hard question to answer because I don't think the answer is truly available yet. But I would like to reassure the person who offered the question that we are actively working on this, and I think we should know some time in the near future. Can we identify patients who will benefit, and, if so, what is the optimal duration of therapy to try to optimize survival in these patients who have this particular mutation?

55:24     [Moderator] All right. And Dr. Cooke, since you're on the subject, I'm going to follow up with a related question: "Do you recommend that someone who is two years post-transplant and is on sorafenib get the MMR shot while they're still taking sorafenib? Does it make sense to wait until after the inhibitor is done, and, if so, how long?"

55:44     [Dr. Cooke] Dang it. I was hoping I was going to escape that question. I think this gets back to what Dr. Lehmann and I were talking about before, about the use of certain vaccines at two years post. That would include the varicella vaccine and the MMR vaccine. So, we're at that point when the questioner is saying we're about two years out. We want to make sure that it's both safe and effective, right? If you're on continued medication, this is not necessarily immune suppressant, but I don't know that anyone knows for certain what impact it would have on the ability of the vaccine to be effective. I don't necessarily think it would make it any less safe, but I don't have a great answer for that. I think it's a terrific question, and it segues perfectly with the one that we just tried to answer in terms of duration of therapy. I would probably vote to wait until the sorafenib is completed. I don't know how long I would necessarily, but ... Leslie, what would your advice be?

56:52     [Dr. Lehmann] Yeah. It's definitely not known. These are opinions now, not things that are known. MMR, measles, mumps, rubella, are relatively uncommon. And I totally agree with Ken that I can't think of a reason that it would make it more dangerous, but it may make it that the body doesn't make as good levels of protection against those. So, if someone were stopping the pre-inhibitor in another month, I would wait until they were off, wait another one or two months, and then vaccinate them. But that would be an individual decision.

57:32     [Dr. Cooke] Yeah, I agree. It's more of an opinion at this point than anything based on solid fact. That's for certain.

57:39     [Moderator]  All right we'll need to end the presentation with one final question, which I think [Ms. Morris] can answer: "My 20 year old daughter lives independently but struggles a bit in college. Do colleges provide any help for students who have poor organization skills as a result of transplant?"

57:59     [Ms. Morris] The short answer is maybe. It depends. Private colleges who don't accept federal funding are not legally obligated to. Any college, which, most fall into this category, even private schools, that do accept federal funding would be legally obligated to provide accommodations for students with a documented disability. That being said, I've never come across a school that has not had some sort of services available to students, whether that be formalized through the disability office or through an academic support center.

My recommendation would be for your daughter to reach out to both the disability office and the academic support center at her school to find out what's available to her. The scope of what's available varies significantly from school to school. Some have very organized programs, while others are a little more dependent on the student. She may have to have an evaluation within the last three years that documents an organization disability, although some schools, because it's the result of a medical treatment, may accept a letter from her oncologist.

So, my recommendation would be for her to start there, with the academic support office and the disability office, to see what's available to her. And then, they can walk her through the process of how to obtain those services, what is available to her, and then how to alert each professor. She's really going to need to do a lot of that on her own, which differs from what she may have had in high school. But it's a great test of her self-advocacy skills, and I'm sure that either of those offices would be able to support her in the process of obtaining the support that she requires.

59:41     [Moderator] Thank you. And with that, we will need to end this session. I want to thank all of our presenters for their very helpful remarks. And I want to thank you, the audience, for your excellent questions.



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