Sickle Cell Disease: Symptoms and Benefits of Bone Marrow Transplant

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Sickle Cell Disease: Symptoms and Benefits of Bone Marrow Transplant




Guest:  Dr. Michelle Hudspeth – Pediatrics - Hematology/Oncology

Host:  Dr. Linda Austin – Psychiatry


Dr. Linda Austin:  I’m Dr. Linda Austin.  I’m talking, today, with Dr. Michelle Hudspeth who is Director of the Pediatric Blood and Marrow Transplant program at the Children’s Hospital here at MUSC.  Dr. Hudspeth, one of your areas of interest is the treatment of children with sickle cell disease.  Just what is sickle cell disease?


Dr. Michelle Hudspeth:  Sickle cell disease is really a devastating disease for a number of African-American patients in the United States.  What happens in sickle cell disease is there’s actually just one small mutation change, but that change is significant enough that it changes the makeup of hemoglobin.  And hemoglobin, as you may know, is a major component of red blood cells.  That’s what allows us to carry the oxygen in the body and have energy.  Unfortunately, in these patients, this abnormal hemoglobin causes an abnormal shape of the red blood cell. 


We used to think that the was the main problem of the disease, you had an abnormal shape of the red blood cell and it sort of jammed up in the blood vessels and that’s what caused all the problems.  We now have learned so much more about sickle cell disease.  It’s not simply just the shape of this red blood cell but, really, this abnormal hemoglobin induces so many changes throughout the body that there are just a lot of abnormal interactions between the hemoglobin and the white blood cells in the blood vessels.  It’s a very complex disease and, unfortunately, really, has major complications for a number of patients.  For instance, this was shown by the Cooperative Study of Sickle Cell Disease (CSSCD), these patients, unfortunately, have a greatly shortened life expectancy of around only 42 to 48 years. 


Dr. Linda Austin:  And they go into crises from time to time which are quite painful.


Dr. Michelle Hudspeth:  That’s right.  There are a number of different problems, and that’s the issue.  This abnormal hemoglobin causes the red blood cells to turn over very quickly and break down.  So, not only are the patients anemic, they have kind of chronic problems with not delivering enough oxygen and other needs to other tissues, so they really experience damage to many other organs.  They have lung damage, kidney damage.  Ten percent of pediatric sickle cell patients will go on to have a stroke.  It can be devastating.  And what we’re also learning now is up to 20 percent of patients will have what we call a silent stroke, meaning, we don’t see a change in their ability to talk and walk, but if you check their brain MRIs, they most definitely have had an abnormality there.  And if you do special testing, like you would for school, they’re certainly being impaired in their ability to learn.  So, really, this disease has consequences throughout the body.  And for many patients, they’re frequently in the hospital with pain and other issues.


Dr. Linda Austin:  So, let’s talk about the treatment.  What do you do for these patients?


Dr. Michelle Hudspeth:  Well, a lot has been learned over the years in terms of supportive care, very simple things, such as starting penicillin, because we know these patients are prone to getting life-threatening infections.  So, simple things, like starting penicillin when they’re babies, can make a big impact.  We’ve learned other things over the years.  If somebody is at a high risk for stroke, we can predict that to some degree by using ultrasounds to look at their blood flow.  We can start them on transfusions, and that can decrease their risk.  However, even with all these things that we’ve learned over the years, there’s still a seven percent chance of dying by the age of 18 for patients with sickle cell disease.  That’s quite significant.


The other counterpart is we certainly see a lot variability in patients and we haven’t really learned that yet, why some patients with sickle cell disease seem to have to be in the hospital all the time and have a very severe course as children while other children may only be in the hospital every so often.  But what our adult colleagues are coming back and telling us, even those kids who seem to have a mild course of disease as children, by the time they come to us as adults, they still have organ damage, and we’re seeing all the results of that.  So, it’s quite a devastating disease.


Dr. Linda Austin:  You mentioned in another podcast that some of these patients actually get bone marrow transplants, correct?


Dr. Michelle Hudspeth:  That is correct.  And that’s an area I feel quite passionate about because I think that, unfortunately, there’s a bit of a health disparity here and that, probably, they’re not being referred for transplant consultation as often as they should be.  We’ve learned a lot about bone marrow transplant for sickle cell disease.  In the setting where they have a matched brother or sister, who’s the donor, these patients do quite well.  They have anywhere from an 85 to a 95 percent chance of overall survival, of being cured for sickle cell disease.  So, at this point in time, bone marrow transplantation offers the only cure for sickle cell disease.


I think people have often been scared about the risk of bone marrow transplant and the things related to that.  The most current data tells us that the risk of dying from the transplant procedure itself is only seven percent.  And, as I just told you, the chance of dying from sickle cell disease by age 18 is also seven percent.  So, really, we’re not increasing the chance of a patient dying here, but what we are doing is offering the chance for cure, for a lifetime, and making a significant difference.


Dr. Linda Austin:  So, walk us through the procedure of doing a bone marrow transplant for these patients.  What age, for example, would you begin to think about this?


Dr. Michelle Hudspeth:  Typically, patients with sickle cell disease don’t tend to have, really, manifestations until after a year of age, and that’s because they have a high proportion of this fetal hemoglobin that’s still in their bodies as infants.  Typically, we would look at a patient who’s had some marker of a severe disease course, such as having a stroke, having had silent stroke on MRI, some other concerning complication.  In general, we know it’s much better to transplant these patients when they’re younger rather than when they’re older.  It seems to be, from the transplants done across the world, that age 15 is an important age.  Over the age of 15, you seem to increase your chances of having complications related to the transplant.  So, we certainly prefer to have children who are young. 


What typically would happen, we would have a patient who’s had some marker of having a severe disease course referred to us.  Then we would need to do what’s called HLA (human leukocyte antigen) typing.  This is different than blood typing.  We actually don’t look at all to see what blood type someone is to be a bone marrow match.  This is more complicated typing than that.  So, we would want to look at full siblings.  Any full sibling has a 25 percent chance of being a match with the patient that we’re looking at, so that’s important testing that we would need to do.  If you look overall at sickle cell patients, close to 20 percent of sickle cell patients will have a full match.


Dr. Linda Austin:  Does the candidate donor have to be a full match?


Dr. Michelle Hudspeth:  At this point in time, that is recommended.  We know that you certainly increase your transplant-related mortality the more mismatched the donor is.  And, right now, that would not be considered an indication for transplant in sickle cell disease, so we would recommend, and really require, that you have a matched sibling donor.


Dr. Linda Austin:  Now, if there is not a matched sibling donor, might you look outside the family?


Dr. Michelle Hudspeth:  That is a possibility.  In the United States, and actually throughout the world, there’s a registry of bone marrow donors that can be searched.  Unrelated donor transplantation for sickle cell disease has a higher rate of complications and morbidities and, right now, is mainly being looked at in the context of clinical trials.


Dr. Linda Austin:  So let’s assume, then, that there is a sibling and there is a perfect HLA match, what happens then?


Dr. Michelle Hudspeth:  Then we get the patient prepared for transplant.  For any of our patients that go through transplant, we do a number of tests ahead of time to make sure that they have adequate organ function to tolerate what’s needed for transplant.  So, they would undergo a series of tests, including an echocardiogram, to look at their heart, lung function test, kidney function test, a number of different blood tests, all to make sure that they would be suitable to handle the complications and the treatment related to bone marrow transplant.  Then begins, really, a long period of conversation with the family to make sure that they fully understand what’s involved and what’s required for transplant.  If everyone is in agreement to move forward then we schedule a date for transplant.


What transplant involves, for sickle cell disease, we use a combination of three drugs ahead of time as part of what we call the preparative regimen.  This is really to prepare the body to accept the new bone marrow.  We give a drug called Busulfan for four days.  That’s a drug that we monitor very closely and target the dose, especially for each person’s individualized metabolism.  The other drug is called Cyclophosomide.  That’s also administered once a day for four days.  And then we give another drug called ATG (anti- thymocyte globulin) and that’s just an immune suppressive agent that helps prepare that body to receive the new bone marrow, and that’s given over three days.


Then, on what we call day 0, we sort of count down the negative days, the days that they get chemotherapy, and on day 0, actually, we tell the patients it’s their new birthday.  That’s the day that they receive the bone marrow.  We would do a bone marrow harvest on their sibling, and we could talk more about that in a few minutes.  Then the bone marrow comes to them in a bag that looks, simply, like a bag of blood and they receive that through a special IV line.  And, again, if you walked in the room, you wouldn’t think anything special was going on that day other than a blood transfusion.  Then, from that time, they would need to be in the hospital generally for about a month.  They’re very immunosuppressed at that time.  We have to wait for that new bone marrow to grow.


Dr. Linda Austin:  Immunosuppressed means?


Dr. Michelle Hudspeth:  They’re immune system is weakened, so they’re at a high risk for having an infection or other complications.  We have them in our special bone marrow transplant rooms designed to filter out infections and other concerns and we put them on special medicines to try to prevent infections and watch them very closely.


Dr. Linda Austin:  Am I right in guessing that they are pretty sick puppies during this, that they’re not feeling too well?


Dr. Michelle Hudspeth:  During the time that they receive the chemotherapy itself, it’s generally not so bad.  It’s generally that week afterwards, when the side effects of all the chemotherapy catches up with them.  We certainly treat the nausea.  If they have any pain, we treat that.  If they have enough nausea and something we call mucositis, which is mouth sores, that they can’t eat, we can give them nutrition through their IV line.  So, we do a lot of supportive care in that time.  And, it is variable.  The majority of patients are able to stay on our unit, in our specialized bone marrow transplant rooms, and we’re able to support them quite well.


Dr. Linda Austin:  So they stay in the hospital for?


Dr. Michelle Hudspeth:  Generally about a month.  And then it’s important because, really, they’re resetting their whole immune system as this bone marrow is growing and recovering.  It’s very standard, across the country, that we require them to be within close distance of the transplant center for the first 100 days after transplant.  We know that, in particular, that first 100 days, you need to be watched very carefully for complications or other concerns.  We have special transplant housing here at our Ronald McDonald House for patients that don’t live locally.  Then, once they’re discharged from the hospital, which is generally after about a month’s time, we generally see them two to three times in clinic each week and take care of any needs that they might have.


Dr. Linda Austin:  You mentioned that you’re observing for complications, what might those be?


Dr. Michelle Hudspeth:  There are a number of complications.  You can imagine, it’s sort of a balancing act.  We have the immune system of the recipient and the immune system of the new bone marrow.  As I mentioned, we do something called HLA typing to see that they’re matched.  However, we’re able to test for many things, but we, obviously, can’t test for every possible difference between people.  We know that even if you’re a perfect match on paper, there are still going to be some small differences.  Those are the small differences that can sometimes create a problem.


One problem is rejection.  That’s what happens when the new bone marrow comes in and the person receiving it, the sickle cell patient, their bone marrow sees that bone marrow and says, hey, how’re you doing, you know, we’re a lot alike, aren’t we?  But then says, wait a minute, we’re not completely alike, you’re a little different over here.  So, sometimes the recipient’s immune system can mount a reaction to the new bone marrow coming in because they see those small differences and can reject the bone marrow.  In sickle cell disease, that can happen up to 10 percent of the time.  But, thankfully, most of the time, their own bone marrow actually comes back and the patients survive and do fine.  Unfortunately, we haven’t cured their sickle cell disease, but many of those patients go on to have a successful second transplant. 


So, rejection is one of the major complications.  The flip side of that, in thinking about this balancing of immune systems, is something called graft-versus-host disease.  Graft is a funny word that we use to refer to this new bone marrow coming in.  It’s called a graft.  And this is sort of the flip side.  Host is the patient receiving the bone marrow graft.  As this bone marrow graft comes in, it’s typed for all the things we can type for.  But it can come in and see that recipient and say, oh, we’re a lot alike, but wait a minute, there are still some small differences between us.  And, the immune system in the new bone marrow can start attacking the recipient and that can cause the graft-versus-host disease.  We give medications to prevent this, but we’re not always successful.  So, we generally see graft-versus-host disease in this setting about 15 to 20 percent of the time. 


Dr. Linda Austin:  Now, at what point are you able to say, it worked, you’re fine, no more problems?


Dr. Michelle Hudspeth:  We do testing along the way to see how much of that bone marrow is the recipient and how much is the donor.  If by 100 days we’ve seen very steady, what we call ingraftments, we have close to 100 percent of donor cells in there, we feel quite comfortable, and we’ll have a huge party at one year.  If we’ve made it to 100 days, we’ve made it past the major point of rejection.


Dr. Linda Austin:  That must be so thrilling.


Dr. Michelle Hudspeth:  Oh, it is thrilling.  And what’s clear is, we’ve looked at these sickle cell disease patients over time, one of the problems of sickle cell disease is that their spleen, which is an organ that filters the blood, doesn’t work well.  And this is the basis of their risk for infections.  And after transplant, a number of patients actually regain complete function of their spleen, which is very exciting.  Another problem in sickle cell patients is they don’t grow very well because of this chronic disease they have.  After transplant, what we’ve seen is that teenagers have improved growth.


Dr. Linda Austin:  Now, you started to talk about the process of harvesting the bone marrow from the sibling.  What does that process consist of?


Dr. Michelle Hudspeth:  That day is a little bit harder for the sibling than the person receiving the bone marrow.  The sibling undergoes general anesthesia so they don’t feel anything during the procedure.  We then remove bone marrow from their hip bones.  The hip bones are where most of the bone marrow in the body lives.  While the patient is asleep, we insert needles and pull out the bone marrow.  The bone, really, just kind of looks like blood when it comes out.  And the pediatric oncologist doing the procedure has the ability to check the bone marrow as it’s coming out.  We need a certain number of cells in order for it to be successful.  We’re able to monitor that number of cells during the procedure such that we don’t take more than we need from the donor, but we want to make sure we have enough for the recipient.


It’s and outpatient procedure.  They, generally, are discharged that same day.  They’re generally a little bit sore afterwards.  We usually tell them to take it easy for a couple of days.  It’s very rare for them to need a blood transfusion or any other support.  I’m constantly amazed that the children actually bounce back very quickly.  I had one donor who actually did cheerleading tryout two days later.  So, the children actually recover quite well.


Dr. Linda Austin: Something to cheer about.


Dr. Michelle Hudspeth:  Absolutely.


Dr. Linda Austin:  How many transplants do we do a year for sickle cell?


Dr. Michelle Hudspeth:  It varies greatly.  So far, this year, we’ll be up to two transplants.


Dr. Linda Austin:  In the first three months of 2008?


Dr. Michelle Hudspeth:  That’s right.


Dr. Linda Austin:  So, maybe, roughly, one per month, or so?


Dr. Michelle Hudspeth:  It really was increased for a time and has sort of dropped off.  And this is sort of an area of interest for me because I think that, again, with this being the only curative therapy for the disease and with the overall complication rate being very low, I think we simply aren’t having enough patients referred to us that could really benefit from this therapy.


Dr. Linda Austin:  Important to get the word out.


Dr. Michelle Hudspeth:  Absolutely.


Dr. Linda Austin:  Dr. Hudspeth, thank you so much for talking with us.


Dr. Michelle Hudspeth:  Thank you.


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