ST. LOUIS, Mo. (Ivanhoe Newswire) -- Sickle cell is a serious disease that causes pain, anemia, infection, organ damage, and even stroke. It’s the most common inherited blood disorder in the U.S. The good news is bone marrow transplants can be a cure. The bad news is not every patient has a matching donor. Now, researchers are looking at a new way to offer more patients transplants.
Madisyn Travis is like any other nine-year-old, but there’s something that sets Madisyn apart. She has sickle cell, an inherited red blood cell disease.
“It makes me feel bad and sometimes I have to go to the hospital,” Madisyn told Ivanhoe.
“It’s really hard to see her life interrupted,” Denise Travis, Madisyn’s mom, told Ivanhoe.
However, soon Madisyn will get a bone marrow transplant to cure her disease. Her little brother or sister are both matches and one will be the donor.
Madisyn is one of the lucky ones. Only 14 percent of patients have a matching sibling.
“Ten years ago, we’d just tell them, ‘sorry you have no family member. We can’t transplant you,’” Shalini Shenoy, MD, Professor of Pediatrics, Medical Director, Pediatric Stem Cell Transplant Program, Washington University School of Medicine, St. Louis Children's Hospital, told Ivanhoe.
Dr. Shalini Shenoy is studying a new option for patients without related donors. Stem cells from a baby’s umbilical cord can be infused in the arm. They travel to the bone marrow, settle there, and make new cells.
“Now, with this, we can take another 30 percent or 40 percent to transplant,” Dr. Shenoy said.
Madisyn is excited about a cure and even though they annoy her at times, she’ll have her brother and sister to thank for it.
Sickle cell is more common in minorities, occurring in about one in every 500 African Americans and about one in every one-thousand Hispanic Americans.
So far, just three patients have been treated with the umbilical cord blood transplant using unrelated donor cord blood. Ten research centers across the country are participating in Dr. Shenoy’s study.
TOPIC: STEM CELLS TO CURE SICKLE CELL
REPORT: MB #3717
BACKGROUND: Sickle cell disease is a disorder that has an effect on how red blood cells carry oxygen to the body. Normal red blood cells are rounded, but when a person has sickle cell disease, their red blood cells look like a crescent moon. The name “sickle cell” comes from the crescent shape of the cells. Sickled cells have a hard time moving through the blood vessels. They can get stuck and block blood vessels, which stops the oxygen from getting through. This is a painful disorder that may also cause harm to certain bones, organs, and muscles. Having the disease means a lifelong battle against the health problems it can cause, like pain, anemia, stroke, and infections. However, people are able to have a good quality of life by learning how to manage the disease. (Source: www.webmd.com)
CAUSES: Sickle cell disease does not just develop; it is inherited from a parent. However, a child has to inherit two sickle cell genes, one from each parent. If a child carries the gene from only one parent, then they do not have sickle cell disease, just the sickle cell trait that they could pass on. (Source: www.webmd.com)
TREATMENT: Early treatment includes daily antibiotics from two months to five years of age in order to prevent infections. Managing pain is a big part of treatment for sickle cell disease. Parents can plan for a painful event ahead of time by creating a pain management plan with the child’s doctor. Some people may need regular blood transfusions to lower the risk of stroke and treat anemia. (Source: www.webmd.com)
NEW TREATMENT: Bone marrow transplants are usually used as a last-line of defense against cancer, especially leukemia. However, in the past ten years, non-cancerous diseases have gone from making up about 15 percent of all pediatric bone marrow transplants to 35 percent. In the mid-90s, transplants were found to be successful for patients suffering from severe sickle cell disease, but only if their tissue matched a sibling donor. Transplants from unrelated donors were found to be too toxic, requiring an excessive amount of chemotherapy and radiation. Researchers tried to use smaller doses of the chemicals, called “reduced intensity,” which resulted in patient’s bodies rejecting the transplants. Dr. Shenoy and colleagues continued testing the “reduced intensity” theory. Dr. Shenoy’s approach involved using antibodies that target proteins in the immune system and finding the amount of toxic chemicals that wipe out just enough of the body’s immunity to allow the graft to take over. Her approach was proved successful in treating sickle cell patients and other life-threatening metabolic and bone marrow failure disorders. About five years ago, it was adopted as the protocol for using transplants from unrelated donors to treat non-cancerous disorders. However, finding a match is still difficult. Dr. Shenoy says that you have a better chance at finding a cord match rather than a marrow. Adding one more immune-suppression drug to the mix, holds promise. Dr. Shenoy was granted approval to lead a cord-blood transplant study involving 10 research centers across the country. However, the study has a safety restriction: three patients must have successful transplant before moving on to the next three. (Source: http://www.stltoday.com/lifestyles)
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 curedoesn’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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