Frans Smiers (59) is a pediatrician-hematologist at the LUMC hospital in Leiden. He specialises in the diagnosis and treatment of children with hemoglobinopathy such as sickle cell disease and beta thalassemia

What is a stem cell transplant?

Your bone marrow contains stem cells. They’re the parent cells of all blood cells and they work like a blood factory in your body. These stem cells may contain a manufacturing 'error' that leads to sickle cell disease or beta thalassemia. If you replace the stem cells, you eliminate the 'error' that causes the disease and the patient is cured. That, in a nutshell, is what a stem cell transplant is.

How often are stem cell transplants performed in the Netherlands for these two disorders?

It’s about ten per year, but the numbers are rising rapidly. This is thanks to the availability of donors of stem cells, the new blood factory.

When do you opt for a stem cell transplant?

A stem cell transplant is a complex treatment that involves risks and disadvantages but to date, it is the only way to cure the disease. You need to make a very careful consideration. We opt for a transplant if the disease causes so many symptoms and damage to the body that the quality of life is severely affected or if the outlook is that it will be, or that a patient’s life expectancy is limited and the effect of alternative therapies is inadequate. It must be physically feasible, the patient’s condition must be good enough to undergo the complex treatment. Preferably at the earliest possible age, before the disease causes any irreversible damage.

The younger the better?

For sickle cell patients, yes, because organ damage is still non-existent or very limited. And for beta thalassemia patients because the many blood transfusions cause an increased risk of rejection of the graft, combined with an iron overload in the body that can cause damage to organs.

What are the alternatives for a transplant?

Well, they’re limited. In the case of beta thalassemia, you remain dependent on blood transfusions, with the risk of iron overload, which causes complications in the medium and long term. This is somewhat more complicated in sickle cell disease. Due to the organ damage that occurs, the patient’s condition is in a downward spiral. In the long term, alternative treatments are no longer sufficient to prevent this ongoing damage. Alternative treatment is an option, it is a choice that parents sometimes make, yet the outcome with these patients is not always positive, unfortunately.

Can anyone receive a stem cell transplant?

Anyone can undergo a transplant, provided their physical and mental condition is good enough. First, you receive pre-treatment involving chemotherapy which shuts down your own blood factory. The new stem cells are subsequently administered to the patient via a drip. Then it’s a waiting game ... a long period during which you have to be nursed in isolation due to the risk of infections. The patient also suffers side effects that affect organs such as the liver, kidneys and lungs. As the new stem cells start to grow, a new immune system is created. Then there is the risk of rejection, graft-versus-host disease: the new immune cells see the patient’s body as the enemy. This can make the patient very ill. The body is put under severe strain. If your condition is not good enough, a transplant isn't possible. On top of all that, there’s the psychological and emotional strain. Not only for the patient, but also for the family and other people within the patient’s network. You need to assess in advance whether that network can withstand that strain. This is also because a large part of the post-treatment of the bone marrow transplant takes place at home and the role that parents and caregivers play during that period is very important.

What determines the chances of success in the event of a stem cell transplant?

That’s determined by two things; first of all, the pre-treatment condition of the patient. Someone with sickle cell disease who’s already suffered a lot of organ damage will suffer more from the side effects and adverse impact of the transplant. A patient with beta thalassemia who has had many transfusions resulting in iron overload in the organs has a smaller chance of success than a patient who has had few transfusions. Second, the availability of a donor is important. There are different types of donors for the stem cells of the new blood factory and each group of donors has its own risk profile in terms of side effects or the acceptance of the graft.

What are the success rates for the different disorders?

In order to properly understand success rates, you first have to define success. We split the definition into two: you can define success as a successful stem cell transplant, after which the disease disappears in its entirety but there’s also another outcome, which is that you die as a result of the complications. It’s a rather undesired outcome, but an important one to mention, nonetheless.
Looking at percentages in the different disorders, chances of you surviving a transplant in the event of sickle cell disease are high, more than 90-95%. Some centres claim a success rate of 99% but on average it’s 95%. The chance of the disease having disappeared after the transplant is slightly lower, around 90%. This is because the transplanted cells can still be pushed out by the remaining own original stem cells. In the case of beta thalassemia, survival rates are about the same as those for sickle cell disease, around 90 to 95% but the chance of you actually getting rid of the disease is slightly lower, between 85 and 90%. This has to do with the fact that it’s an altogether different disease and the often large amount of blood transfusions that a patient with beta thalassemia has received. The more transfusions, the higher the risk of the graft not growing properly or that it will be rejected.

What steps are involved in stem cell transplants?

First, you need to find a donor. If there are parents, brothers or sisters, there’s always a suitable donor available. The most favourable donor would be a brother or sister with the same HLA code (human leukocyte antigen code) as the patient. If it’s not, we can check the donor database outside the family to see if there’s a donor available with a similar HLA type. Nowadays, we can also select one of the parents if half the HLA type is the same. That’s normally always the case and, therefore, with the help of new techniques, we can also use them as a donor, so there’s always a donor available.

What’s the next step?

Next, the donor’s health is examined. When you collect the stem cells it’s important that the donor is in good health. The donor shouldn’t be exposed to any risk. Blood is taken a number of times to check the HLA code and to see whether the donor has had viruses that the patient has not had. The patient is checked to see if there are no antibodies against the HLA of the parents, should they be the donor. If everything checks out, bone marrow will be taken from the donor. A needle is used to penetrate the bone and suck up bone marrow (usually the bony parts above the buttocks). This is done under anaesthetic.

How are the donor stem cells inserted?

The bone marrow that is collected, which looks like blood, is processed in the laboratory. The red blood cells are removed, leaving a whitish liquid that is transferred into the blood via a drip or central line. The new stem cells find their way through the blood into the bone marrow, where they will settle and grow.

How is the patient prepared?

The transplant distinguishes three major steps. Before the new blood factory can be installed, the old factory needs to be demolished and removed. This is done through chemotherapy that consists of a number of steps, depending on the donor. There are chemotherapy sessions that destroy the immune system in the patient, whereas other sessions break down the bone marrow itself and clear it up. They are slightly more aggressive. Another step follows after the transplant, when the new blood factory has been installed. That’s when the aggressive immune cells of the patient, that could attack the body, are disabled or subdued.

What’s all this like for a patient?

It varies considerably, depending on age and how well you can explain it to the patient. The impact on the parents also varies, yet the fear factor for the disease you want to rid through a transplant is such that the willingness to accept a patient becoming sick from the treatment is also slightly higher. The difficult part is explaining how sick being sick really is. The chemotherapy makes your hair fall out, while damage to the mucous membrane causes pain in the mouth and the abdomen. The patient lives in an isolated room because of the risk of infections which can be very upsetting and sometimes also harmful. It’s very difficult to predict whether that will play a role. That differs from patient to patient. You could, perhaps unceremoniously, compare it to a Tour de France where you don’t know which mountainous stages are included and how long the remaining distance to Paris is.

Why do you have to remain in an isolated room?

When the old blood factory has been shut down and the new one hasn’t yet fully grown, you have a limited defence against bacteria, viruses and fungi, making you extremely susceptible to infections. You must be protected from the outside world. Hence the isolation.

And how long do you have to be in isolation for?

On average, it amounts to two months. That’s from the beginning of the transplant, the chemotherapy, up to when the new blood factory starts to grow. This growth process comprises a number of phases. The initial immune cells, the granulocytes (a type of white blood cells), don’t make the immune system strong enough yet to handle the entire outside world. They need the least time to grow from a stem cell into granulocyte.

After the granulocytes, which cells are up next?

It varies, usually, it's the red blood cells. The thrombocytes, the platelets, normally follow a little later. The return of the lymphocytes is important. They form an important part of the immune system. However, there’s a risk that these T-cells attack the patient, an expression of rejection. When those cells start to emerge, we try to keep them calm so that they can get used to the new environment, allowing us to make a selection between aggressive and non-aggressive T-cells. It can take months before the immune system is strong enough to handle the entire outside world. During that time, you must take isolation measures, even if the patient is back home. That’s a tough regime. The patient can’t go to school, can’t travel with public transport and is not allowed to go into any shops. You can play outside and receive visitors, but contact in confined spaces with people you don’t know isn’t possible.

What’s a T-cell attack on the body like?

Well, there are various scenarios. Very acute, when the T-cells become aggressive and suddenly attack the body. This can cause skin symptoms, as well as organ damage to the intestines or the liver. However, this can also occur stealthily, many months later when the patient is already at home for example, in a scenario where the lungs are chronically attacked and become damaged. That’s an insidious process, as are the skin problems that slowly grow worse. Different phases of rejection diseases can be distinguished in the process. You need to be vigilant for that.

What would the response be?

If T-cells become aggressive and attack, you have to administer immunosuppressive drugs, which in their turn raises the risk of infection. However, allowing the T-cells to continue their attack is more dangerous. You need to find a balance in that. Most patients respond well to the medication, but a certain group does not and needs additional medication. Yet a small group doesn’t respond to this either, so the T-cells continue their attack and cause damage. The patient can, ultimately, die as a result.

Can that treatment be completed at home?

Sometimes, you have to be admitted if the attack of the T-cells is too intense, thus requiring a strong response in terms of suppressing the immune system. That’s when the patient needs a lot of support and would, therefore, need to be admitted. Still, you can often be treated with medication at home, combined with frequent check-ups in the hospital.

Can you still revert back to your own blood factory if things go wrong?

Before we start disabling your own blood factory, we collect bone marrow as a backup. In case the new blood factory doesn’t want to grow, we still have your own blood factory that we can reinstate. We would also do this if the T-cells of the new blood factory become so aggressive that the patient’s life is threatened. We would have to shut down the new blood factory and reinstall the old one. However, this reinstatement process often doesn’t work because the treatment would put too much of a strain on the patient at that time.

What’s the psychological impact of the treatment?

As the transplant grows closer, tension rises. Yet the moment the chemotherapy starts, tension melts away. The first side effects of the chemotherapy, hair loss, for example, are often emotional as well. The waiting time between disabling your own bone marrow and the growing of the new bone marrow is a tough period. You feel as if you’re not making any process And if infections occur, tensions run higher than when they do not. And even after being discharged from the hospital, there’ll be another tense period of waiting, as you don’t know yet whether the cells that are growing are from the donor or if they’re remaining indigenous cells. There are quite a few tense periods and patients and parents deal with this in very different ways.

Is psychological support provided?

The support base of the parents and the family as a whole is assessed in advance. This is strengthened, where necessary. Albeit rare, the support base can be so weak that allowing the patient to undergo a transplant would be irresponsible. However, we usually try to strengthen and support the family as a whole in such a way that the transplant can still go ahead.

How long do these difficult phases last?

On average, between six and twelve months, but if you’re unlucky, you may still be undergoing treatment for the adverse side effects of the transplant after two years.

What are the differences in terms of the transplant procedure for sickle cell disease and beta thalassemia?

They’re different diseases. Sickle cell disease is characterised by painful crises and the blockage of blood vessels causing organs to break down. These are symptoms not seen in beta thalassemia. Instead, when suffering from beta thalassemia, you’re confronted with hyperactive bone marrow, although the net production of red blood cells is very limited. The immune system in beta thalassemia is much more alert and active, so patients run a higher risk of the transplanted cells being rejected. This is less so in sickle cell patients, but organ damage can have an adverse effect on the transplant. They are the main differences.

How high is the mortality risk?

Approximately 5% of patients who undergo a transplant, both with beta thalassemia and sickle cell disease, are at risk of dying. This is because they have to deal with infections, rejections or complications, such as the acute side effects of chemotherapy.

What are those side effects?

The chemotherapy affects all cells that divide quickly. These are cells of the hair follicles (which will grow back later), of the mucous membranes, such as the intestinal membrane but also the cells in the ovaries and the testicles.

Does that affect a patient’s fertility?

It does, even though the combination chemotherapy we use today is slightly milder, we can never exclude a patient becoming infertile. In older boys who already produce sperm cells, we can freeze sperm cells in advance. In girls who are mature enough, we can have one of the ovaries removed and frozen before chemotherapy starts. But that’s not an option for small children. So that’s a risk you have to take.

What are the side effects of anti-rejection drugs?

Virus infections that you have had can become active again, such as shingles, as well as the side effects of high blood pressure. Some medications can cause high blood pressure, intensified hair growth, also in places where you don’t want it, or trembling hands. Sometimes, these side effects are so intense that we have to switch to a different type of medication but they are of an altogether different category than the side effects of chemotherapy.

And what about gene therapy?

Gene therapy (inserting a piece of DNA to replace the part of DNA that is broken in a patient) is a treatment option in the near future. It can cause harmful side effects and also fail but the major advantage is that you don’t develop rejection diseases. Other disadvantages are the same as seen in the transplant option; you still need chemotherapy and isolation. And there’s the risk that it doesn’t work but I expect that between now and ten years, gene therapy for beta thalassemia and sickle cell disease is a real treatment option. This time is not given to everyone and it would be dangerous to postpone treatment such as a stem cell transplant in favour of gene therapy treatment that is not yet available. If ultimately, it doesn’t become available, you may have suffered a lot of damage in the meantime, not to mention the time you will have lost as a patient.