Lakshmanan Krishnamurti, M.D., a pediatric hematologist at the Children’s Hospital of Pittsburgh of UPMC, talks about a less toxic form of bone marrow transplantation for sickle cell disease.
What is sickle cell disease?
Dr. Lakshmanan Krishnamurti: Sickle cell disease is an inherited disorder of the red blood cell, so people are born with it. Your red blood cell is typically the shape of a donut filled in – we call that a bi-concave disc. It turns out that this is a perfect shape for the red blood cell to smoothly flow through blood vessels. It’s also very compressible and deformable, so it can squeeze and cut through nooks and crannies. The molecule called hemoglobin which is inside the red blood cell which actually carries oxygen, is normally dissolved in the water inside the red blood cell, like salt and water. When you have this inherited disorder, the hemoglobin becomes a big polymer, or a crystal. This distorts the shape of the red blood cell. The red blood cell becomes rigid and not deformable, and it also becomes the shape of a sickle, or a half moon. This is not an advantageous shape – the red blood cells get stuck and cause blockages of blood vessels, so the parts of the body that are then dependent on getting blood are not going to get blood. The other thing that happens is because this red blood cell is rigid, it can bend and squeeze, so it breaks. The red blood cells don’t live the usual life of three months. They’re gone in 20 days, so you’re lacking in red blood cells. In Latin, we call that anemia, so that’s why it’s also called sickle cell anemia. Because of this obstruction, various parts of your body are suffering due to lack of oxygen, so the most commonpresentation of this is pain in a limb, your back, chest, or anywhere. Also, 10 percent of the patients have a stroke and loss of body function because of that, and that occurs, unfortunately, in very young children – those between the ages of two and six have the biggest risk for stroke.
When do patients start to manifest symptoms of sickle cell disease?
Dr. Krishnamurti: Because in the United States every baby born is screened for sickle cell disease, we’re not waiting to find out later when it’s presenting. I typically see babies with sickle cell disease when they’re about a week old, much before they might actually develop any symptoms. The earliest symptom might be in infancy when they might get painful swelling of their hands and feet. There’s also a big danger for a child with sickle cell disease – one of the first organs to be affected is the spleen. The spleen is the organ that lives under the left side of your rib cage and it’s important for fighting infections when you’re too young to have built a repertoire of antibodies. It’s got a lot of blood vessels going through it, so the sickle red cells obstruct the blood flow and the spleen stops working, sometimes after the first six months of life. That puts this young child at a huge risk for infections, and by some particular organisms called pneumococcus – it’s a kind of bacteria that causes serious pneumonia. A child with sickle cell disease might never be diagnosed and might actually die in infancy which is the reason every baby is screened to see if they have sickle cell disease, so we can start them on penicillin and give them vaccines against pneumococcus.
What is the treatment for children with sickle cell?
Dr. Krishnamurti: I think the most important major part of the treatment is to give preventive treatment against these bacterial infections, pneumococcus, which is giving them the regular vaccines and then some additional vaccines that they have to get. They get on penicillin and stay on it for many, many years, and then you really enroll them in what’s called comprehensive care. This care is not episodic – we find this in newborns and we start taking care of them. We educate the families, prepare them for emergencies, and focus on the child developing to be a full member of society. Here at Children’s, we take care of them from the time that they are born until age 21, and we’re taking care of the whole child and the whole family.
Is there a cure for the disease?
Dr. Krishnamurti: There is a cure for sickle cell disease. Let’s not forget that you can improve the lives of children with sickle cell disease. You can see that they have as normal a life as possible. There are children going to college every year who have sickle cell disease, who come from elsewhere to go to school here, and there are several adults that are leading normal lives. There are treatments that we can do to decrease complications, such as blood transfusion. For some of the patients, if they’ve had a stroke, we can prevent recurrence of stroke by putting them on blood transfusions once a month. That’s a very involved treatment that has its own set of complications. There is a medication that is approved by the FDA called hydroxyurea for the treatment of sickle cell disease, and that can cut down complications by 50 percent and it can improve survival in patients with sickle cell disease. It’s very important to know that these treatments are available. For patients who have severe disease, there is another treatment available that’s bone marrow transplantation.
Which patients are candidates for bone marrow transplantation?
Dr. Krishnamurti: In medicine you’re always making a risk benefit ratio, so if somebody is doing really well and is not having a lot of problems, then you wouldn’t offer them a risky procedure. If they’re having more problems, then the risk from the disease outweighs the risk from the treatment. Bone marrow transplants for sickle cell disease have been done now for more than 20 years. Originally, even bone marrow transplantation was designed as a treatment for somebody who accidentally had exposure to a nuclear weapon. That’s how the research started in what became bone marrow transplants. Once we learned that you can do this safely, we used it to treat cancer, like really bad leukemia. The first sickle cell patients to get a transplant did not get a transplant for sickle cell disease – they got it because they incidentally also had leukemia. When we realized that you could cure sickle cell disease along with curing leukemia, we started treating patients with sickle cell disease with a transplant. Because transplant traditionally has been a serious treatment of last resort, we have to offer it only to patients with severe disease. As the outcomes with transplant get better, as our ability to take people through transplant improves, as we make transplant less toxic, the kind of patient that we offer transplant to also changes, so who we offer transplant to is a moving target.
What are you doing here at Children’s to make transplantation less toxic?
Dr. Krishnamurti: Since transplant really started off as a treatment for an accidental exposure to a nuclear weapon, there was always that concept that the marrow gets wiped out like with a nuclear weapon and you give the patient the new marrow. When they took this on to treat cancers, they gave high doses of chemotherapy and/or radiation to get rid of the old marrow. This is particularly important in patients with leukemia, because you wanted to get rid of the leukemia completely – every last cell of it. That’s what caused the toxicity – the major part of the toxicity was a conditioning regimen.
In sickle cell disease, you don’t have to get rid of every last cell. We’re not worried about a chance of sickle cell relapsing in the same way, so if a way could be found where you could achieve the same thing – getting the new bone marrow cells to come in and work without getting rid of all of the old bone marrow with heavy duty chemotherapy – then you can achieve the same thing at less cost to the patient’s good health. That was the challenge on how to do this. It turned out that when they first did transplants for patients with cancer that if you got a transplant from an identical twin, you did worse than if you got a transplant from a non-identical twin. This would appear counter-intuitive, because all we’re trying to do in transplant is match as closely as possible. This led to the concept that there is some benefit to the differentness of the bone marrow because when you give a bone marrow transplant, the donor’s bone marrow comes with its immune system. What people realized is that a donor’s bone marrow could do some of the work for you in clearing the abnormal host bone marrow, so you can do this in a less toxic way than by giving a whole bunch of chemotherapy, so you can cut down the chemotherapy and rely instead on some of the donor’s immune system.
What do you call this procedure?
Dr. Krishnamurti: We call it reduced intensity bone marrow transplantation. We’re not trying to oblate or destroy the bone marrow; we do try to reduce the amount of original bone marrow because we need to create some space. We also give very immuno-suppressive medications so that the patient does not reject the donor’s bone marrow, and then allow the donor’s bone marrow to gradually replace the patient’s bone marrow, and in some cases, they’re actually mixed –it’s a mix of patient and donor. The interesting part of it is that there are multiple types of cells in the bone marrow – the cells that make white blood cells, the ones that make platelets, and the cells that make red blood cells. In a patient with sickle cell disease, their white blood cells are fine, their platelets are fine. All we care is about changing their red blood cells, and that’s exactly what happens. They are a mix for the white blood cells, they’re a mix for the platelets, but they’re almost all donor normal red cells in the bone marrow.
How does the body adapt to the transplant?
Dr. Krishnamurti: The way the bone marrow transplant works is sort of like a marriage. You put two people together, you have all these friends and family saying okay, everything’s going okay for a few months and then they get used to each other, and then, of course, everybody backs off – nobody is asking how things are going. What happens is that you have the patient’s immune system, you have the donor’s immune system, and all of them are together. For three to six months, you keep them on immuno-suppression and then they become mutually tolerant, and then you withdraw the immuno-suppression. If everything works, the patient is no longer on any medicine. This is how it’s different from organ transplant, because the transplanted organ doesn’t come with the immune system and there’s no possibility of getting mutual tolerance, and patients have to do years and years of immunosuppressive medications, but a child with sickle cell disease and has had a transplant that worked is basically a regular kid.
What kind of success have you had with this transplantation?
Dr. Krishnamurti: We’ve transplanted seven patients so far, and actually, they’re all alive and doing well. One patient, unfortunately, stopped taking her immuno-suppressive medications during that critical period, so she has her sickle cell disease back. The other six patients are off immuno-suppression – The longest has been about 10 years now, and they’re basically on no medications. One of the organs which stops working in patients with sickle cell disease, the spleen, actually grows back, so an organ actually comes back from the dead, so they don’t need to be on any medications at all. We’ve also done this type of transplant in some very high risk patients who would not typically be transplanted. When they were first started, the conventional transplant for sickle cell disease was offered to children under the age of 16 and then adults. The first few adults who were transplanted did not do well, because their disease is much more advanced and they didn’t tolerate the transplant regimen, so transplant for adults has not been an option. There is an irony and sort of a tragedy in this because children with sickle cell disease often do well, so we tell them that they’re okay and we don’t really need to do anything more for them, and then they’re over 20 and suddenly things start showing up, and then we tell them, ‘Sorry, it’s too late to do anything.’ We’ve actually transplanted, three people who are older than 16 and who actually all tolerated it well. One patient had multiple complications – she had had a stroke, had clots in her blood vessels, and was allergic to blood, so every time she needed blood, it had to be flown in from Chicago. She had ion overload from too many blood transfusions, so her liver ion levels were very high. She had lung problems because of sickle cell disease. This is not the kind of person who could have had a conventional transplant, especially as a young adult. She’s now five years out from transplant and is in nursing school. The important thing about reduced intensity transplant is that it could be a treatment option for patients with advanced sickle cell disease, for whom conventional transplants were not an option.
What’s the quality of life like for patients with advanced sickle cell disease?
Dr. Krishnamurti: The quality of life is variable in patients with sickle cell disease. Some people have a lot of problems; others have fewer problems, so there’s a lot of variability, but for people with advanced disease, even moderate exercise, like walking down to the neighborhood store to pick up their prescriptions, could be a problem. They could have hip problems – you have young patients who need hip replacements. Stroke, again, is a major, major complication.
Even patients who are doing well as children, when they reach young adulthood, the complications that have been slowly building up start becoming manifest, so the third decade of life onwards can be quite a serious situation, even for patients who have been doing well. The other thing is that we’re really not able to predict who is actually going to do badly as an adult.
At what point should patients have tests to see if transplant is an option?
Dr. Krishnamurti: While transplant is a serious treatment, the testing to see whether a transplant is an option should really happen even if someone is not committed to transplant. For instance, what we do is if there is a full sibling, then we will type them -- it’s a simple blood test. If you delay transplant and you’re already very sick, then it becomes a self-fulfilling prophecy, so if you want to consider transplant, you should really consider it early. The conversation about transplant needs to happen early.
Is a sibling your best bet for transplant?
Dr. Krishnamurti: Yes, a sibling is the best match, but unfortunately, only 14 to 20 percent of the time are you going to have a white blood cell matched sibling, so then you’re ruling out 85 percent of the patients. There are seven million people who signed up to be volunteer donors so you could possibly find a match – they’re matched on the white blood cells, but they’re not your flesh and blood for all the other cells, so even though you can do it, there is more risk for complications. The research now is to do reduced intensity transplants from unrelated donors, so that’s the exciting part of where things are going forward. I think as we do that, you’ll see that the application of transplants or treatment for sickle cell disease will become much wider, and this is why this research is important – to reduce the toxicity of transplant, so you can improve the applicability of it and acceptability.