“Stem Cells Cure Sickle Cell”
Shalini Shenoy, MD
Shalini Shenoy, MD, Professor of Pediatrics, Medical Director, Pediatric Stem Cell
Transplant Program, Washington University School of Medicine, St. Louis Children's
Hospital, talks about a possible new treatment for sickle cell disease.
Has treatment for sickle cell in the past few years been a bone marrow transplant
from a relative?
Dr. Shenoy: Sickle cell symptoms can be controlled with either blood transfusions or
hydroxyurea or medications that are supportive in general. However, they just help
control symptoms of the disease and sometimes they are unable to do that even if given
adequately. Then despite the best of transfusions or hydroxyurea, the disease
progresses and the blood vessel damage continues. Transplantation is considered a
cure because you’re replacing their blood cells completely with blood cells from a donor
who does not have the disease. Thus, you are replacing their sickle red cells with
normal red cells - something that will leave them cured of their disease.
Isn’t it amazing for a doctor to be able to say I’ve cured this disease?
Dr. Shenoy: Absolutely. This is a chronic disorder and they have to live with it for a
lifetime. It is hard when they encounter complications from the disease; these actually
increase as they grow older.
What kind of complications?
Dr. Shenoy: It is progressive blood vessel damage that then begins to hurt vital organs.
In the central nervous system it’s overt stroke or a silent stroke where brain changes
from blood vessel damage leads to difficulties with their studies and in maintaining their
IQ. An overt stroke could leave them partially paralyzed or have other neurologic deficits.
If it affects the lung, then it causes what’s called acute chest syndrome especially when
their younger. They have respiratory failure, and will often end up in the intensive care
unit ( ICU), or as they grow older pulmonary hypertension is a big risk for mortality.
Pulmonary hypertension can cause sudden death in patients with sickle cell disease.
Other organs that are damaged include the bones, kidneys, eyes, etc.
What’s the life expectancy?
Dr. Shenoy: The median time of survival for sickle cell disease is still 40 years for both
men and women. That doesn’t mean that some people won’t survive for longer, but that
is the survival period for the majority - the average lifespan they’re looking at, and this is
despite all the care we are able to give them. This also doesn’t take into account those
patients that survive longer but are left with a chronic disorder and are consistently in the
hospital and have a poor quality of life. Often they are in chronic pain, and have multiple
hospital admissions for all the complications that come with the disease. Yes, they
survive the disease but at what cost? If you put all that together, the morbidity with this
disease is quite high, not just the mortality.
Have you been curing it with a bone marrow transplant?
Dr. Shenoy: You can cure patients with a successful bone marrow transplant and this
was first proven in the late 1990s.
For yours, has it only been from a relative?
Dr. Shenoy: Transplant from a suitable relative or sibling is ideal because that’s the
probably the safest with the best outcomes. That’s because if you have a relative that’s
tissue matched like a brother or a sister, then it’s easy to get their cells to engraft in a
patient. They have a low incidence and severity of a complication called graft versus
host disease; this is due to donor immune cells coming into the transplant recipient (the
patient_ and causing trouble because they are foreign to the patient. We started off
studying transplants from brothers and sisters for this reason. It was shown that it was
effective, and it cured the disease. It not only cured it, but improved previous organ
damage in many cases.
Would it reverse the damage?
Dr. Shenoy: Yes, It could. It stabilized the damage first and then actually reversed it
and made things better. It suggested that you could actually cure the disease and give
potentially a normal lifespan without the morbidity of the disease. Then it was up to us to
make transplant available to more people and try to get over the toxicities that the
transplant came with.
If you didn’t have a matching relative you’d have to transplant from a unrelated
donor, that meant really harsh chemo and radiation?
Dr. Shenoy: That meant that your risks during the transplant were higher and one would
have to find perhaps safer ways of transplanting them which is giving them something
that they could tolerate and get the graft in. The way the first transplants were done was
with what is called myeloablative chemotherapy, and that is using high doses of
chemotherapy to ablate the marrow. The person who was getting the transplant got this
chemotherapy and the marrow completely was emptied. Then the new cells were given
they went in, they settled down, and they successfully made for a cure. But, when we did
that we exposed them to a lot of chemotherapy and then as we followed them along the
way there were a couple of things that were potential problems such as sterility, if they
were in the age range where they were getting a growth spurt there was potential growth
inhibition, etc. Not to mention the toxicities on their organs. If they had sickle cell disease
related damage to the liver for example, or the lungs then the chemotherapy actually
added to that toxicity and there was concern for liver dysfunction, veno-occlusive
disease as it’s called in the liver. There were specific toxicities to the kidney, to the lung
and so on, all potential problems. Thus, you had to be very careful about who you could
take to transplant because you didn’t want to make transplant cause more organ
damage. We tried to move on from there and give them conditioning therapy or a
preparative regimen that was not necessarily myeloablative chemotherapy based - it
was called a reduced intensity regimen, which could potentially be tolerated by even
those people that had organ damage from their disease. There was a potential to
maintain fertility as well. That was really important to some - because if you think about
it, it’s a parent giving us permission to go ahead and transplant a young child who would
probably be sterile as he/she grew up. This regimen was designed to reduce the toxicity
during transplant and also potentially decrease some of the late effects that came with
the myeloablative regimen that we were using.
How did you do that?
Dr. Shenoy: We did that by backing off on the amount of chemotherapy we gave them
and we used immunosuppressive medications like antibodies. What they did was
suppress the patient’s immune system significantly to allow the new donor cells to come
in and didn’t necessarily empty their marrow with chemotherapy. We backed off on the
chemotherapy we gave them, we didn’t use any radiation and we used more monoclonal
antibody type immunosuppressives to get the graft in. Now there are various protocols
looking at reducing the intensity of conditioning and still getting engraftment. As soon as
you reduce intensity what happens is the cells that are coming in are rejected by the
patient. If you go too low then you get more graft rejection and so that leaves you back
at baseline, you’re not curing the disease. There has to be a fine balance where you
reduce the intensity just enough to be able to get the graft in but you don’t reduce it way
too much where they get too much graft rejection. That’s one of the advances that’s
happened since the first sibling donor transplant.
Now you’ve advanced on that, right?
Dr. Shenoy: We are testing a reduced intensity approach that became a protocol for
unrelated donor transplant. We found that it was tolerated quite well by patients that
were even in their late teens. The older your patient the more the toxicity of the
transplant because they’ve had sickle related damage quite a bit. If you back off on the
intensity we found that you could give it to older patients and they tolerated it quite well.
As I said, there are now several protocols that took up the same idea and continue to
improve upon it. The other question is how do we offer this treatment to more patients?
What if you didn’t have a brother or sister that was a match? 10 years ago we just told
them, sorry you have no family member we can’t transplant you. Now, if they have a
suitable donor in the registry, and are eligible based on organ function and disease
severity, they are able to go to transplant on this study. It is looking to define outcomes
of unrelated donor transplants for sickle cell disease. When we first started that protocol
we said cord bloods that were eligible (suitably matched) could be used for transplant.
The criteria for matching cord blood are a little more lax than the criteria for matching
bone marrow because the risks of graph versus host disease are lower with cord blood
than they are marrow.
Are there any downsides?
Dr. Shenoy: The downside was increased graft rejection. If you go too low on the
intensity of your conditioning cord will tend to be rejected faster than marrow would be.
When we started the reduced intensity trial we took both marrows and cords and found
along the way that the marrows engrafted but the cords didn't, so the protocol then was
closed to cords and just left open for marrows. We went on to a more modified approach
with cords and are now testing this. We had a baseline reduced intensity regimen that
worked for bone marrow; we tweaked it a little bit more and now have a separate trial for
cord blood transplants. We started off first with a transplant trial for thalassemia using
this modified regimen. Thalassemia is another hemoglobinopathy which requires chronic
transfusion therapy so it was sort of comparable to what sickle cell disease needed. For
thalassemia, this turned out to be successful in getting engraftment even with cords.
We’ve opened that now to sickle cell disease as well such that we are now doing
reduced intensity transplants with cord blood as well, as a study.
Why wouldn’t you give this to everybody that has sickle cell?
Dr. Shenoy: First, finding a donor is the issue. If you didn’t have someone that was
reasonably matched for the cord or very well matched for the bone marrow then there
was no suitable donor available. Only 14% of patients will have a suitably matched
sibling donor. Another 30-40% can potentially find marrow or cord products. Others may
consider transplant on newer protocols looking at transplanting patients from family
members that are half-matched. Most of these transplants now are being performed in
reduced intensity fashion. Given the risks of transplant such as infections when the
immune system is suppressed, the risk of graft versus host disease, or organ damage
and a risk of death of any of these complications, we should be careful about choosing
our transplant candidates carefully – only those with severe disease – especially if they
have no matched sibling donors.
So there’s still 40% that aren’t eligible for transplant. Why is that?
Dr. Shenoy: If they don’t have a good donor, we just can’t take someone to transplant.
You’re taking non-relatives, but they’re still a match?
Dr. Shenoy: Correct. So it’s not a blood type match, there’s something called an HLA
match which is a tissue match. It is a tissue protein and there are a group of these
proteins that are important from the transplant perspective. We know what the important
ones are and those need to be matched for someone to be a good donor for a patient.
That’s what the registries do for us. These are voluntary donors registries that have
millions of donors saying if I can help somebody I will, please access me, so they sign-
up to be on the registry. The registry maintains this huge database of who’s in there and
who would like to donate. When we have a patient we contact the registry and say,
here’s the HLA type of our patient and the disease. We ask who they have in the
registry that could be a potential match. The majority of people on the registry are
Caucasian and it is not a very diverse. Efforts are being made to increase the diversity
because these HLA types often run true to race. If I have a Caucasian patient the
likelihood of my finding a donor is much higher than if I have a minority patient. This is
why we are trying to expand the registries to increase the pool of both marrow donors
and cord blood products - to try to increase the number of people that can benefit from
the registries.
Part of this talks about bone marrow transplants and then some of it talks about
stem cells. Is that the stem cells from the bone marrow?
Dr. Shenoy: Right. Stem cell is any cell that can go in, settle in the bone marrow, and
make new blood cells. Those can come from the bone marrow, peripheral blood, or cord
blood. We don’t use peripheral blood too much currently because the risk of graft versus
host disease is higher. Our preference is to use bone marrow or cord blood. The donor
cells need to be suitably HLA matched and then we can access the donor. This is all
done anonymously by the registry. Say we have a patient who has sickle cell disease
that could use your product, “would you be willing to donate and would you be willing to
donate bone marrow?” Most donors are nice enough to say I will do whichever the
center would prefer because I joined the registry to help. So we ask for morrow
preferentially.
Are you going to fight for that bone marrow because every disease is now using
stem cells in bone marrow? Is it really hard to get enough?
Dr. Shenoy: If we access a donor, say the donor was identified as being a good one for
this patient, that person is taken off the registry and is no longer available to others.
Multiple people won’t be accessing a single donor. It happens once and is very
systematically handled. The registry is lists all the other people that haven’t donated yet
so that’s how it works. We never come into contact with the donor to keep this free of
bias; this is all very voluntary. The registry contacts the donor, we don’t even know
where the donor is or who it is, it’s all anonymous. The donor donates and the product is
shipped over to us, it comes on a flight to us and then we infuse it. The donor and
recipient can arrange to meet at the end of 1 year after transplant if they wish.
Is this exciting to you?
Dr. Shenoy: Absolutely. When I first meet a patient our conversation is more about the
transplant as a possibility. Our second meeting is usually after that search has been
done and then we can sit down and talk more specifics.
For these people they’re done with sickle cell then right, will these people who
have spent half their life in the hospital have to come back to the hospital again?
Dr. Shenoy: The cure doesn’t happen overnight. Once the transplant is done it takes a
while. The blood cells come up pretty quickly but it takes a while for the immune system
to recover. We have to wait for the immune system and that takes the better part of that
first year. There are a lot of restrictions, lot of hospital visits, and a lot of care,
requirement for compliance, and a lot of medications. It’s not like, “I got my transplant
and now I’m home free”. We are very careful to make sure they understand how the
process goes.
Is it just like for an organ donor, do they have to stay on transplant drugs for the
rest of their life?
Dr. Shenoy: Not for the rest of their lives, only until they are at risk for graft versus host
disease. That’s the advantage we have over the organ transplant folks. This is not for life
you don’t have to keep taking these medications for life to keep the organ in. It is taken
to prevent graft versus host disease - until that risk is not there anymore.
How long is that usually?
Dr. Shenoy: Generally about a year to a year and a half. Some of them will have longer
need for immunosuppression because they have ongoing graft versus host disease, but
the majority of them come off their medications generally between one and two years
post-transplant.
Now just a short description, do you inject the transplant, how do you get it into
the body?
Dr. Shenoy: It’s given through a IV. They have a central line, it’s given like a blood
transfusion. It’s an anti-climax because that’s the day of transplant and everybody is
here, the family is here, everybody is watching. It’s basically a bag that looks like blood.
How long does it take?
Dr. Shenoy: It depends on the volume, it could take an hour or two but it just flows in.
The fascinating part is that these cells know where to go. You’re just giving them in a
blood vessel but they go directly to the bone marrow, settle there and make new cells. It
will change the blood type of the patient, so the patient thought they were O or
something but the donor was an AB, that’s what they’re going to be. They’re going to be
typing as an AB for the future. Their whole blood picture changes over to what the donor
looked like.
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If you would like more information, please contact:
Jackie Ferman
Manager, Media Relations
St. Louis Children's Hospital
(314) 286-0304
slchmedia@bjc.org
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