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May 23, 2019  
MEDTECH1 HERO

Michael E. Trigg, MD: Making Strides in Pediatric Transplantation


January 16, 2001

Michael E. Trigg, MD, has worked tirelessly as a pediatric transplant surgeon with a specialty in high-risk patients. As Chief of the Division of Blood and Bone Marrow Transplantation (BBMT) at the Alfred I. duPont Hospital for Children and Professor of Pediatrics at Jefferson Medical College, he has worked with children with leukemia and solid tumors, as well as those with genetic diseases and resistant connective tissue diseases.

Prior to his work at the Alfred I. duPont Hospital, Dr. Trigg was the Director of Pediatric Bone Marrow Transplantation at The University of Iowa Hospitals and Clinics as well as Professor of Pediatrics at the University of Iowa for 11 years. The focus of his 20 current research studies, for which he is the principal investigator, is curing children with acute lymphoblastic leukemia (ALL). Dr. Trigg has also been listed in The Best Doctors in America and Who’s Who in Science and Technology. In his more than 20-year career, he has published more than 100 articles in the peer-reviewed literature and written numerous book chapters and abstracts.

Dr. Trigg performed Joel Doub’s 1988 bone marrow transplant (BMT). Joel was featured recently on MedTech1’s feature “Progress, One Patient at a Time.” When he first consulted with Dr. Trigg, Joel’s leukemia was in relapse and he was considered a high-risk candidate. Dr. Trigg, who was then with the University of Iowa, was willing to take the chance on Joel. His assertiveness was rewarded—Joel is now 27 years old and cured of his leukemia.







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MedTech1: How did you choose oncology, and specifically pediatric oncology, as your specialty?

Dr. Trigg: During medical school, most of us as students faced the task of deciding what specialty we wanted to go into. I had already made a decision before going to medical school that I wanted to work in pediatrics. I had done work during my summers as a camp counselor at two different camps for severely handicapped children, children who maybe now might not even be born. In those days, when there were fewer detection methods, there were a lot more children born with devastating physical and mental handicaps. I enjoyed working with those children during my undergraduate years of college. I also spent a summer working near my home in Connecticut, where there was a general hospital with a wing that was similar to a nursing home. The extraordinary amount of care that these children and young adults required, however, was beyond what a nursing home could give. The children received physical and occupational therapy every day. I was the head of activities there for three months and was the entertainer on service to dream up all kinds of activities for those kids. So I already knew before I went to medical school that pediatrics was what I wanted. That was a pretty easy choice.

It was during the first year of my pediatrics training that I made the decision to go into oncology. Then I applied for (required) fellowship training at this point, but I also went ahead and locked in a position at the National Cancer Institute (NCI) so that when I finished my three years of pediatric training I then could go on to pediatric oncology.

MedTech1: Has your work in oncology mainly been focused on bone marrow transplant?

Dr. Trigg: Initially, when I was starting out in oncology, it was more generalized. However, at the NCI in Bethesda, MD, we didn’t see children with all different types of cancer there. The only kids we would see would be those for whom we had a research interest or a study interest. The NCI, even though part of it looks like a hospital and people can just walk in, only treats people who are of research interest to the investigators there. For example, if you had some malignancy of your colon and researchers were not interested in studying that area, you would not be admitted. It is not a general hospital; it is a research hospital. When I was at the NCI receiving my training back in the late 1970s, BMT was still in its infancy. It was a hot area of research, so we had a tremendous amount of research going on in pediatric oncology there. BMT was available at half a dozen sites at most in the United States. It was a big interest of ours. Therefore, it was not unusual that someone like myself might be exposed to a lot of training and experience in that area just because of where I was and the research interests of the investigators who were there.

MedTech1: BMTs were first conceived to allow patients to receive high doses of chemotherapy, and then later they began to be used as therapy. Did you see that happen during your career? When did that shift occur?

Dr. Trigg: It depends on the disease. We saw initially that BMT, and the use of high dose therapy [followed by] rescuing someone’s bone marrow with new bone marrow, was only applied in the 1970s in people with relapsed disease or recurrent disease. It was used as a salvage technique or a last ditch effort. Things began to progress in the late 1970s with select diseases where we knew we weren’t making great progress with chemotherapy alone. We began using marrow transplantation as primary therapy for people. Soon after diagnosis, they would receive incredibly high doses of therapy that would, unfortunately, harm their bone marrow. Then, we would go ahead and give them new marrow at that point.

It was kind of an evolving process. With some diseases it happened not until the late 1980s or into the 1990s, and with others we were already doing that in the late 1970s.

MedTech1: You have been distinguished for your ability and willingness to treat high-risk patients. Do you find yourself seeing patients today who are fighting against as immense odds as children a dozen years ago?

Dr. Trigg: In some ways yes, and in others no. Let me explain that. The no part is that we understand a lot more now how to utilize these high-dose chemotherapy protocols. We understand better which patients will respond well to this and which ones will not and which ones could be treated with more conventional approaches. We have a better understanding now of how to utilize this therapeutic tool that is giving high doses of therapy and then rescuing the bone marrow with new marrow or new cells.

On the other hand, substantial progress has been made in treating, for example, children with ALL. I can tell a newly-diagnosed child who sees me in the clinic today that there is at least an 80 percent chance that that child will be cured with conventional therapy, whereas back in the late 1970s we would be talking about 55 or 60 percent.

As we keep improving the numbers and we have a larger number of children who can be cured, the kids who are remaining represent a more stubborn group, a group that’s harder to treat. If they’re harder to treat with conventional therapies, then they’re less likely to respond to these very high-dose therapies.

One of the advances that has been made in our treating kids with, for example, leukemia, is that we have more drugs available than we had 20 years ago. And we know how to use the drugs that we had 20 years ago a little bit better. We often treat them rather intensively. So those who fail the therapy have become resistant to a lot more drugs than we had 20 years ago. They have a leukemia that is very resistant, like an infection that is resistant to antibiotics, and we want to offer them a marrow transplant when they have already developed all of this resistance to commonly used chemotherapy drugs. It makes it more likely that they are going to fail with the transplant, and it makes it more likely that our subsequent therapies are going to result in incomplete eradication of their underlying disease. The disease will come back again because they have developed an incredibly resistant leukemia.

Obviously, we are curing more children now, because we went from 55 or 60 percent to 80 percent. So the additional therapies we gave were beneficial for a large number of children, but it left those who failed the therapies more prone to failure in the future because they have developed a variant of their original leukemia that is highly resistant to chemotherapy.

MedTech1: How do these children develop a resistant leukemia?

Dr. Trigg: Many of the leukemias that start out are heterogeneous, meaning that not all the cells are the same in someone’s leukemia. We end up killing off the sensitive cells, and the resistant cells then live on. Also, sometimes we can bring out or cause to develop a resistance that wasn’t there before. Bacteria do this all the time: an antibiotic that is useful for someone’s infection today might not be useful for it tomorrow because the bacteria learned how to metabolize the antibiotics and make them useless. The same thing can happen in cancer cells, where we end up selecting out those cells which are resistant. Or we induce certain enzymes within a cell to make it now resistant to that particular drug.

MedTech1: Is BMT ever used as a first-line therapy?

Dr. Trigg: Yes. We have a better understanding of this tool, so sometimes it is a first-line treatment. There are children, for example, with a certain kind of leukemia where soon after they present we’re not wasting their time with conventional therapy anymore because we know it’s doomed to failure. We go ahead right away, before there’s any resistance developing, and subject these kids to marrow transplantation.

MedTech1: You work with several diseases, not just leukemia. Is there one disease in particular that reacts especially well to BMT?

Dr. Trigg: The success rates in BMT are higher in certain diseases, particularly when we’re dealing with non-malignant diseases. Take, for example, a child with a congenital immune deficiency. There are several hundred children born in the United States every year who are lacking a complete or almost complete immune system. They’re protected by things transmitted from their mothers for the first few months of life. Then all of a sudden they fall apart—they start coming down with terrible diarrhea, pneumonias, and infections all over.

In fact, I have a picture here of a child about 10 years after a transplant for a severe immune deficiency. He was well until about six months of age when all of the immune mechanisms, which were passed through his mother to him, faded away. He was on his own then and he became deathly ill. He was probably a day or two away from death in the hospital for different serious infections that he had going on. I got involved. We were able to tide him over for the first week until we had all the tissue typing back on his family. It turned out that he had a sister who was a perfect tissue match. Because he had no immune system, he had no ability to recognize anything as foreign. So we simply took marrow from her and gave it to him. Within a month, he was out of the hospital and cured of all his infections. Now he’s about 10 years old.

These stories are very common in children with immune deficiencies, where upwards of 80 or 90 percent of kids will be cured with a marrow transplant. And the same will be true with kids and some adults who develop aplastic anemia. The condition is sometimes due to an infection or a chemical exposure, whereby their bone marrow loses the ability to make blood-forming cells. We have to replace it with new marrow. Usually we get it from a brother or sister who is perfectly matched.

Those diseases are very satisfying to treat because the cure rates are so high. Unfortunately, there are other diseases with less satisfaction, because, even under the best of circumstances, many of the people with malignancies will have their malignancy recur after a transplant, meaning that the therapy failed or their disease was highly resistant. Or they die of complications of the procedure, because it’s not like taking baby aspirin. It’s a potent therapy with lots of potential side effects.

MedTech1: A moment ago, you spoke about allogeneic transplants, which use donated bone marrow. Could you explain the difference between allogeneic and autologous transplants?

Dr. Trigg: Autologous means “from self” and allogeneic means “from someone else.” The complication of using someone else is that that person is really different. If I were getting bone marrow from someone else—it might be my brother or sister, a relative, or an unrelated person who decided to donate marrow—first of all, my body is going to look at that new marrow and say, “that’s not the same marrow” and may try to reject it. The same thing could happen if I was getting a kidney or a heart or a lung from somebody. I need to make sure that my immune system has been suppressed so that it doesn’t recognize that the new marrow is foreign and reject it.

Once the new marrow is growing in me, it is making its own immune system. It’s making the immune system from the person from whom it came. So that immune system is going to look around inside me and say, “what is this we’re seeing? We’re seeing the wrong person here.” They’re trained to attack foreign things, so those cells growing in me—which aren’t my cells really—start to attack me from the inside. It’s kind of like having an autoimmune disease like lupus or rheumatoid arthritis. Now I’ve got cells growing in me that are donor cells and they start to recognize me as foreign and attack me. Those attacks against vital organs can be serious and life threatening, so that I need to take drugs to tone down my new immune system. I need to tell it not to be so active and stop attacking me. But, of course, if I tone down my new immune system, it predisposes me to infections because now those cells don’t have the ability to fight off infections that I may develop.

Many complications exist when a person receives marrow or stem cells from another person, whereas if I get them from myself, they are my cells. They will know me, they will not fight against me, and they will grow very nicely in me. Potentially, I will have fewer complications. However, let’s say I’m getting a transplant for leukemia. My immune system already was not very good—it let me develop leukemia. It did not destroy the leukemia cells. Now, if I get my own cells back again and there were leftover leukemia cells in my body, my new immune system is the same as my old immune system and it’s not likely to recognize any leftover leukemia cells in me. However, if I had some leftover leukemia cells in me and I got marrow from another person who does not have leukemia, maybe that would give me a new immune system that is juiced up, that looks around and says, “there are some leukemia cells here. We ought to get rid of them because those aren’t nice things to have. They are kind of nasty.” And we know that those reactions occur in people who get marrow from another person. A new immune system from another person sometimes can be very helpful and protective in getting rid of leftover or residual leukemic cells.

A tremendous amount of work has gone on in the past 10 years in terms of defining what is the best allogeneic source. For many patients, particularly those who do not have a brother or sister in the family who is perfectly matched, we have various sources. It depends on the underlying disease that dictates what source might be best. We might have someone in the family who is incompletely matched who can donate marrow. We have now over 4 million people in the National Marrow Donor Program registry who have signed up to donate marrow, so we might have individuals out there who are very closely matched, but completely unknown to the individual, needing a transplant who would be willing to donate marrow.

We have thousands of umbilical cord blood specimens that have been saved. When a woman delivers a baby, there is a tremendous amount of blood that is left behind in the placenta or afterbirth that is thrown in the garbage. Because the baby is growing so quickly, and the organs are growing so fast, the baby needs a very large supply of blood. There are many blood-forming cells in the bone marrow and the blood stream of a newborn baby. We used to throw all those cells in the garbage; now we save them in select places and freeze them away. When there are individuals who need a stem cell transplant or marrow transplant, we can go to a computer bank and see if someone has an umbilical cord specimen that has been saved that is a match. Of course, that is in the freezer already, so you do not have to subject someone to the operating room for donation. It is already there; it is donated. We can just thaw it out and give it to somebody.

MedTech1: Are the success rates equal for allogeneic and autologous transplants?

Dr. Trigg: That is an interesting question. The answer is probably not. But there are some diseases where we have actually studied it. If you take, for instance, Hodgkin’s disease, which is a kind of lymph gland cancer, usually transplantation is not offered to these people until they have a recurrence of their disease because the primary treatment is so good. There have been studies whereby those who had a matched brother or sister in the family and had recurrent Hodgkin’s disease had an allogeneic transplant. Those who had recurrent disease but did not have a donor in the family got their own cells back. And those who got their own cells back had better survival. Part of the reason was that they did not have all the complications that come about from getting someone else’s immune system growing in them. They didn’t have the reactions of those new stem cells against their body. They didn’t have to take drugs to stop the immune system from being so active. Those drugs suppress the immune system and predispose the person to infection, so they didn’t have that risk.

So there are a few diseases where [doctors] have studied whether it makes a difference if you used an autologous source of stem cells versus allogeneic. In some cases, it makes no difference. In some cases, it is very clear that autologous would be better. There are some cases where it is clear autologous is worse, and that is with leukemia. Let’s say I had leukemia and I’m donating my own marrow for myself. Where does leukemia start? In the bone marrow. So I might end up getting back some of my own leukemic cells when I get back my own marrow, so that’s probably not a very good thing to do.

MedTech1: You also serve a Professor of Pediatrics at Jefferson Medical College. Tell me about that position.

Dr. Trigg: Most medical school professors do their teaching at the bedside. We have, rotating through our hospital here, residents in pediatrics or residents in orthopedics or cardiovascular surgery or cardiology or neurology or whatever. They participate in the day-to-day care of inpatients and outpatients, and then I provide a lot of their teaching at the bedside or in the clinic. It’s very rare that I get called upon to go up to Philadelphia and give a didactic lecture to a group of medical students or other allied health professionals. But that does happen a couple times a year. I do give a number of talks—depending on the year it may be five, ten, or fifteen—to various departments and groups of people in our hospital to help in their educational process so they can better take care of the patients I look after.

MedTech1: What has been the most satisfying aspect of your career?

Dr. Trigg: Clearly the most satisfying aspect is that I have been referred patients for whom there was no alternative therapy, or who may have been turned down from a variety of other transplant centers. Because of my aggressive nature and my willingness to apply things that are not necessarily proven, I have been able to either extend the lives of certain children, or, in some cases, provide them the hope for a very long life.

We don’t always know for sure how long people will live after these therapies. The first marrow transplants were done in 1968 and some of those children with immune deficiencies are alive today. However, they are only in their 30s. Whether or not they will live to be 70 or 80 or 90, of course, is completely unknown. Likewise, for anyone you know who has had a marrow transplant, they may be doing well five, 10, or 15 years later, but we have no idea if they are going to live a normal life span or not. At least we have given them hope and we have given them an opportunity to become a fully functional member of society and to begin to fulfill their own personal destiny. I think that is what it is all about. That is what gives me a lot of satisfaction.

Obviously, there are a lot of times I fail in this area and that is devastating. On the other hand, we also have to think of our successes, and that helps get us through the days and the weeks.

MedTech1: Would you say there has been one consistently frustrating aspect to your job? Is it seeing some of these transplantations fail?

Dr. Trigg: Well, that is always very frustrating. It is also very frustrating that we have made great strides over the past 20 years in being able to prevent or treat a number of unusual infections that occur, but there still are infections and processes that occur that I cannot conquer or treat effectively yet. Maybe 10 or 15 years from now that will happen. For example, there is a particular type of viral infection that can be absolutely devastating in a transplant patient. I have had about a dozen patients over many years who have died of that particular viral infection because, although I have published on treatments, my treatments are not very good. But recently, in the past year, I had another one of my marrow transplant patients develop the same infection and I gave one dose of a new drug that recently became available. The child is now six months from the time of that infection and cured. That’s the kind of progress that has been made in terms of fighting infections and supportive care, and will continue to be made in the years ahead. There are a lot of tools that I have available now that I did not have available five or 10 years ago. Ten years from now I’m going to look back and say, “Boy, it was medieval times back then. We did not have this, that, and the other thing available.”

MedTech1: Where do you see the field of BMT going in the next 10, 20, 50 years?

Dr. Trigg: On the one hand, there will be a number of children with particular diseases for whom we will not offer marrow transplantation because we will have discovered alternative therapies that are less risky. But I think that we will learn to use this tool to treat a number of other diseases that we haven’t yet applied it to in any great way.

To give an example, there are more people in the year 2000 receiving marrow transplants for treating rheumatoid arthritis and lupus than all the previous years that marrow transplant was offered combined. Even though it is a small number, our knowledge base is increasing. There are select individuals who should not be exposed to a lot of other toxic therapies, but marrow transplantation may be a relatively easy way of curing them of their underlying disease.

We have newer applications that have come about, and I think we are still going to see those in the years ahead. I think also, for some diseases for which we offer transplantation, what we really want is to give (patients) a new immune system that will recognize leftover malignant cells and destroy them. So we might be able to do transplants in an easier way, where we get parts of an immune system from another person—not a complete immune system, just parts of it—to grow. That may be enough to prevent recurrence of an underlying disease and spare the person getting that type of transplant all the toxicity of being exposed to intensive chemotherapy and radiation. I think there will be some ways that are under study now, and will get better and better in the years ahead, on how to manipulate the immune system and get things to grow a little better.

Also, I think we are going to see in the years ahead our ability to take samples of rare bone marrow and we will be able to grow it up into huge quantities in the laboratory and freeze it in many different containers so that many different individuals with that rare type would have access to it. I think that we will see now, and in the future, a variety of sources of marrow or stem cells from those who need to get it from someone else. Sometimes, the patient’s underlying disease will dictate what source they are going to get, or the availability of a particular source will determine what they are going to get. Again, this is a very big area of research as we compare one type of allogeneic transplant with another.

Editor's Note: The Alfred I. duPont Hospital for Children is part of Nemours. Visit the Nemours Web site at www.nemours.org.

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Last updated: 16-Jan-01

   
 
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