Issues for Parents of Pediatric Bone Marrow Failure Patients | Aplastic Anemia and MDS International Foundation

Issues for Parents of Pediatric Bone Marrow Failure Patients

An interview with David Margolis, MD

You can also watch this video >interview in our Online Learning Center

The following transcript is modified from an interview with Dr. David Margolis, a professor of pediatrics at the Medical College of Wisconsin and director of the Blood and Bone Marrow Transplant Program at Children's Hospital of Wisconsin in Milwaukee. You can also watch the video interview on our Online Learning Center.

INTERVIEWER: Is there a different approach to diagnosing and treating bone marrow failure in children compared to adults?

DR. MARGOLIS: Children and adults are different. I think that for children and adults, one needs to make sure that the diagnosis is correct. So you want to make sure that there is bone marrow failure, and you do that with a bone marrow aspirate and bone marrow biopsy. Then you want to make sure that they do not have an inherited bone marrow failure syndrome – a programming defect that causes your bone marrow to fail. And that needs to be differentiated or separated from an acquired bone marrow failure syndrome. So the younger you are, the more important it is to think about an inherited bone marrow failure syndrome. However, we have really learned over the last 5 to 10 years that even adults can have inherited bone marrow failure syndrome as their reason for marrow failure, so it needs to be thought about for both.

INTERVIEWER: How does a parent decide where to go for treatment?

DR. MARGOLIS: Well, I think it's really important to look at your options. I think that choosing a pediatric hematologist/oncologist is probably your first step. Children are not just little adults, so I think having somebody that is trained in pediatric hematology and oncology is important. Then, having a good relationship with your doctor, and your doctor hopefully having experience with this particular disease is important. I think it's really important for parents of children with aplastic anemia to realize that this is not cancer and aplastic anemia needs to be treated differently than a child with leukemia. Aplastic anemia is more rare than leukemia, and so working with your doctor and making sure that your doctor has experience with the disease is always helpful.

INTERVIEWER: How does a doctor decide if a child is a good candidate for a stem cell transplantation?

DR. MARGOLIS: We will call it a bone marrow transplant, for lack of a better word. You can get your blood stem cells from either bone marrow, cord blood, or peripheral blood, and there are risks and benefits to each of those approaches. I think that the first decision, and needs to be done very quickly, is does the child have an HLA matched brother or sister? That is something that should be checked for very quickly and hopefully you get results very quickly. Because if a child has been diagnosed with severe aplastic anemia and they have a sibling who is a match, I think that the data suggests that moving to a bone marrow transplant right then and there is in the child's best interest. So that's decision #1 – does my child have a matched sibling? If the patient does not have a matched sibling, then in general our recommendation is to go to immune suppression therapy with ATG and cyclosporine. When to have a bone marrow transplant after having immune suppressive therapy is very much based on risks, benefits, and the response one has to immune suppression. So what I would encourage a parent to do is to find out what their child's tissue typing is, what their unrelated donor search looks like and can we get an unrelated donor in the bullpen. Then, after a couple of months, you decide whether your child is responding to immune suppression or not. Then you sit down with a transplant doctor that has experience with alternative donor transplants for aplastic anemia and make those risk/benefit decisions on a case-by-case basis.

INTERVIEWER: What is the process of getting a bone marrow transplant?

DR. MARGOLIS: I view the transplant as four phases. The first phase is making sure you are a candidate for a bone marrow transplant. Are your organs healthy? Is your liver healthy? Are your kidneys healthy? Are your lungs healthy? Is your heart healthy? The next phase is what we call the conditioning phase, and that's the immune suppressive chemotherapy, immune suppressive therapy, and maybe radiation therapy, to get your body ready to accept the new immune system. The third part is the transplant itself. Very boring, very anti-climactic. It's just an infusion of blood progenitor cells through your IV that manages to get its way into the bone marrow. And the last part of the process is what I like to call "deal with it," and those are the side effects that go along with everything we just did in the conditioning phase and the bone marrow infusion phase. Those are side effects, some of them will be there only for a week or two, others will be there for your whole life, so that's the process in a nutshell.

INTERVIEWER: What are some of those side effects, both the short term and the long term of bone marrow transplant?

DR. MARGOLIS: The short-term side effects in the bone marrow transplant are very much the short-term side effects of the chemotherapy you received. The more chemotherapy we need to use, the more the side effects are. Infection, infection, infection. We worry about infections the most. Infections with bacteria, infections with virus, infections with fungi. Bleeding is a risk. And then, just toxicity from the chemotherapy. Do we hurt the heart? Do we hurt the lungs? Do we hurt the kidneys? Once the new bone marrow starts to grow, we worry about graft-versus-host disease, and that's the immune response that occurs between the donor immune cells and the new home. Sometimes, if you have a really well matched donor, you don't notice anything. At other times, even if you do have a well-matched donor with the things we can test for, the new donor says, "I'm not in Kansas anymore" and attacks. That's what we call graft-versus-host disease. That can be very mild, with a little bit of a skin rash, to very severe, which would be skin that looks like having burns and really bad, cramping diarrhea, and really bad liver problems.

Down the road, we worry about late side effects of the bone marrow transplant. Late side effects are those that we tend to see a year or 2 or 3 years after the transplant. That really depends on how the transplant was done. The less medicine or less poisons we need to use for the transplant, the less your late side effects are going to be. Those are the things you need to discuss with your doctor: What is the probability of sterility? What is the probability of kidney problems, liver problems, heart problems, and lung problems? Each different regimen has its own expected side effects.

INTERVIEWER: Aside from the bone marrow transplant, what are the other options for treating aplastic anemia?

DR. MARGOLIS: Immune suppression is the gold standard, and one can have immune suppression using ATG, cyclosporine, and prednisone. What I always recommend people look at is the NHLBI web site. Do a quick Google search on NHLBI and aplastic anemia, you'll find their Web site, and you can see what's being tested compared to that. There are other immune suppressants that have been utilized. Johns Hopkins has utilized cyclophosphamide, also known as Cytoxan, as an immune suppressant, so those are various options that one has for aplastic anemia.

INTERVIEWER: What is the process of getting treated with ATG and cyclosporine?

DR. MARGOLIS: In general, ATG either comes from a horse or a rabbit, and therefore has side effects of putting a protein in from one species into another. So, when one gets ATG, one worries about allergies. One worries about breathing difficulties, rashes, and fevers. So, we generally do ATG in the hospital, at least at our institution, and depending on which regimen you are using, it is 4 or 5 or 10 days. The gold standard is 4 days. After that, you're on prednisone for about 2 weeks. We use the prednisone really to try to minimize the side effects from the ATG. Then, the patient is on cyclosporine for 6 months, 12 months, a year. We use cyclosporine as the backbone of a long immune suppression regimen. The patient takes cyclosporine generally twice a day. If they can't tolerate the cyclosporine, maybe we'll use Prograf, which is a similar immune suppressing drug. We monitor people for the side effects of those drugs.

INTERVIEWER: How do doctors decide when it is time to get a second round of ATG?

DR. MARGOLIS: That's an excellent question. I really think that that ends up being an individual decision based on the patient, how old the patient is, how their initial course went, and what the other options are. Do they have a well-matched unrelated donor? Do they not have a well-matched unrelated donor? How did they do with their first round of immune suppression? So those are the issues that need to be brought to the table. When we're doing a bone marrow transplant, the sooner we do a bone marrow transplant after diagnosis, the better the outcomes, and that needs to be balanced with the side effects with the transplant. So when one is doing a second course of immune suppression, the question is how well is one going to respond vis-à-vis what are the other options? I always view that as a very individualized decision that a doctor, the patient, and the parents need to sit down and really spend time thinking about different scenarios and what the goals are and what the concerns are.

INTERVIEWER: Are there long-term effects of treatment with ATG and cyclosporine?

DR. MARGOLIS: ATG, cyclosporine, and prednisone, in general, are very well tolerated with probably less late side effects compared to maybe a transplant. That said, cyclosporine does affect the kidneys and one needs to really watch kidney function over a long period of time. That's probably the biggest one that I worry about. We do worry about relapse, that the aplastic anemia can come back. We also worry that the bone marrow can switch on us, and instead of having aplastic anemia, it evolves into what we call clonal evolution, having monosomy-7 MDS, or something like PNH.

INTERVIEWER: When a child is diagnosed with both aplastic anemia and PNH, which disease do you treat?

DR. MARGOLIS: It really depends on what the presenting features of the disorder are. The aplastic anemia and PNH sort of fit in on a Venn diagram and most kids with aplastic anemia will have a very small percentage of PNH type cells, and what they really have is aplastic anemia, and I would treat them as aplastic anemia. There are some other people who present with very minor bone marrow failure but very much the symptoms of PNH, the hemolysis, the unrelenting high LDH, the anemia; those people I would treat as PNH and really individualize the therapy based on what we think the natural history is more due to.

INTERVIEWER: How do parents decide when a child is well enough to participate in normal childhood activities like school, sports, childcare, etc.?

DR. MARGOLIS: We try to encourage our patients to go to school. I think that every family is going to have their own view of risks and benefits. The biggest problem with school is that schools are breeding grounds for viruses, and as we all know, viruses can cause bone marrow to slow down. So, if we are trying to get bone marrow recovery, if there is a set of viruses running through school, that scares people, so we try to work that out. Other normal activities, riding a bike – understand what your platelet count is and wear a helmet. Riding a horse – you need a bit of a higher platelet count. Playing football –those are all individual decisions that a doctor, the child, and the family will make. I think that the higher the counts, the more normal one's activity can be. Our goal is to try to have as little of a bubble as humanly possible, but we recognize that many families like that bubble and so we will work with the family to try to do what's best for the kid.

INTERVIEWER: What special precautions should be taken when getting a child vaccinated?

DR. MARGOLIS: With vaccines and aplastic anemia you need to know whether you are dealing with a killed vaccine or a live vaccine? The vaccines that are killed probably are of very little danger to a child with aplastic anemia. If they're on immune suppression, the vaccine may not make the response that we want it to. If we use the flu as the best example, I would encourage children with aplastic anemia to get a flu vaccine. I do not think that it will do them any harm, and if they have an immune response to it, it will help prevent them from getting the flu. Live-virus vaccines are a little bit trickier--the chickenpox vaccine, the measles vaccine--and that's when I would talk to your doctor about how much immune suppression you are on and try to make that decision.

INTERVIEWER: Is it okay for a child with aplastic anemia to go swimming, especially in a lake?

DR. MARGOLIS: That's a great question. Individual risks/benefits. Some families will let their kids swim in a lake, others won't. To me, it's what's the neutrophil count? If their neutrophil count is normal, I probably would let the kid swim in a lake. I think that there's a lot of mental health that goes along with that. Some parents may think I'm crazy, but you want to shower afterwards. I think that the lower the neutrophil count, the more concerned I am with getting infected with a weird bug. So once again, it sounds like a common theme here, talk to your doctor. There's probably no right or wrong answer. Tell your doctor your concerns and let's look at the neutrophil count and try to make a data-based decision as best we can.

INTERVIEWER: How do parents decide when their child needs to go to the emergency room or to see a doctor?

DR. MARGOLIS: The first question is, what are the blood counts? The lower the blood counts, the quicker the trigger to go to the emergency room. If your neutrophil count is under 500, my strong recommendation is to go to the emergency room right away if you have a fever. The higher the neutrophil count, the less we worry, and it may be a phone call to the clinic. I think that's one where you and your treating doctor really need to set out a game plan for when to call. With trauma, it depends on your platelet count. I've seen kids get very sick from minor trauma with a platelet count that was 20 or 30. So it's one of those things where make a game plan with your doctor. Any trauma, though, that leads to loss of consciousness, well of course that needs to necessitate a trip to the ER if your platelet count is low.

INTERVIEWER: Can aplastic anemia or its treatment affect a child's ability to have their own children in the future?

DR. MARGOLIS: I don't know of any data that aplastic anemia, by itself, can cause infertility. That said, the treatment for aplastic anemia may cause infertility. ATG treatment, by itself, I know of no data that would suggest that it would cause infertility, nor would cyclosporine. However, a bone marrow transplant, depending on the intensity of the medications utilized, may cause infertility. The good news is there is excellent data out of Seattle that Cytoxan and ATG together with a matched sibling transplant does preserve fertility, meaning that men have fathered children and women have borne children that are healthy after that type of therapy. With the older, more intensive transplants for aplastic anemia using an unrelated donor, those transplant regimens did cause infertility. With the newer approaches to transplant for aplastic anemia, we don't think that those treatment plans will cause infertility. However, we have only honestly been using them for 5 to maybe 10 years, and so the true data is just starting to mature. When I always talk to families about that, we like to think that these doses of very low dose radiation and low doses of chemotherapy will not be associated with infertility, but the jury is still out because we just haven't been doing them for 10, 20, 30 years.

INTERVIEWER: Is aplastic anemia hereditary?

DR. MARGOLIS: Aplastic anemia may be inherited if it is an inherited bone marrow failure syndrome. So I think, once again, to differentiate acquired aplastic anemia versus an inherited bone marrow failure syndrome is job #1 at the beginning of the diagnosis. If it's acquired aplastic anemia, we don't like to think of that as inherited; there may be a genetic predisposition to having an autoimmune disease, like there is with many other autoimmune diseases. It's not unusual to take a family history and find lupus or thyroid disease or arthritis in the family of a child who has aplastic anemia. There may be a genetic predisposition to develop an autoimmune disease like aplastic anemia, but that is not an "inherited" genetic defect where we can actually find the gene at this point.

INTERVIEWER: Will life-long follow-up or monitoring be required for a child who has aplastic anemia?

DR. MARGOLIS: It depends. It depends on how they respond. I think the yellow wristband or the red and white wristbands are a reminder that one has had a disease. Most of our patients that are, for lack of a better word, cured of their disease, probably don't need monitoring on a day-by-day basis. But when they go to the doctor for their annual physical exam, I think that it's important to bring up that history and to monitor for side effects of the treatment, whether that treatment had been a bone marrow transplant or that treatment was ATG and cyclosporine.