Overview of Hematopoietic Stem Cell Transplantation in Sickle Cell Disease
Sickle cell disease (SCD) is a common blood disorder in the United States, affecting around 100,000 people, predominantly of African heritage. Globally, the disease impacts roughly 20 million individuals. At first, the nature of SCD wasn’t clear when it was described around the 1900s. It was only in 1949 that Dr. Linus Pauling discovered the cause: an abnormal form of a component in our blood, hemoglobin, which adopts a “sickle” shape when in a low-oxygen environment. This abnormality is due to a small genetic change in the particular component of hemoglobin, specifically in the beta-globin gene, and is referred to as hemoglobin S.
Here’s something important about sickle cell disease: it’s a type of genetic disorder that you can only get if you received the faulty gene from both your parents, a type of disorder known as an autosomal recessive disorder. When you receive just one faulty gene instead of two, you get what’s called a sickle cell trait. This trait is usually harmless, but the shape of the cells can become irregular if there’s very little oxygen present.
Significant progress in understanding SCD has been made over the years, though it took until around two decades ago for a potential cure to be discovered. SCD research was generally underfunded and overlooked, possibly due to the predominant impact on the African community. Thanks to important legislation like the Sickle Cell Anemia Act of 1972 and the creation of the Sickle Cell Disease Association of America, awareness and research funding have gradually increased. This has led to significant advancements, like the first bone marrow stem cell transplant for SCD.
The mentioned act also helped improve the way we detect SCD. In most parts of the United States today, newborns are screened for SCD even before they leave the hospital. Early detection means that treatment can be started sooner, which greatly reduces the disease’s impact on these individuals. Current treatments include giving antibiotics like penicillin to children under five, using a medication called hydroxyurea to increase the levels of a type of hemoglobin present in fetuses, performing preventive blood transfusions, and prescribing pain relievers, including opioids. Unfortunately, these treatments mostly just help manage symptoms and SCD patients still struggle with recurrent pain, organ damage, and a shorter lifespan. This emphasizes the urgent need to find a definitive cure for SCD.
As recent as September 2018, the National Heart, Lung, and Blood Institute (NHLBI) launched the Cure Sickle Cell Initiative, which is focused on using new genetic techniques to potentially cure SCD. Progress in gene therapy techniques is showing very promising results, though authorization from the United States Food and Drug Administration (FDA) is still pending.
Anatomy and Physiology of Hematopoietic Stem Cell Transplantation in Sickle Cell Disease
Sickle cell disease is a condition you get from your parents, meaning you inherit it through genes. It occurs due to a small change in one of the building blocks (amino acids) of hemoglobin, which is what allows red blood cells to carry oxygen. Normally, this building block is called glutamate, but in sickle cell disease it gets replaced by another one called valine.
When the body is low on oxygen, this change causes the hemoglobin to stick together inside the red blood cells. This makes the red cells change from their normal round shape to a sickle shape, hence the name “sickle cell disease”. These deformed cells can clog tiny blood vessels, stopping the normal flow of blood and oxygen to body organs. This lack of oxygen can damage the organs and cause the problems usually seen in sickle cell disease.
Why do People Need Hematopoietic Stem Cell Transplantation in Sickle Cell Disease
Hematopoietic stem cell transplantation (HSCT), also known as a bone marrow transplant, is a medical procedure that can potentially cure sickle cell disease (SCD). However, not everyone with the disease is suitable for the treatment due to the severe side effects it can cause. People with a severe form of the disease typically experience complications like strokes, lung problems, constant pain, kidney disease, eye damage, bone disease in multiple joints, and persistent, painful erections (priapism). These people may be considered for HSCT.
Choosing to go ahead with HSCT is a big decision. Doctors have to carefully compare the benefits of the treatment with the risks before recommending it. Some of the risks include infections, a reaction where the donor cells attack the patient’s body (graft-versus-host disease), and injury to organs from the intense medical treatment used to prepare the body for the transplantation. Also, if a person already has heart, lung, or kidney disease, HSCT can affect these conditions unpredictably. Ultimately, HSCT should only be recommended when the benefits are greater than these risks.
Ideally, HSCT should be done on children with a high risk of severe SCD before they start to experience complications. However, it’s hard to predict when complications might develop without a reliable biological marker. The development of other medical treatments for SCD also complicates the decision to recommend HSCT since there are no studies comparing HSCT directly with these treatments. Therefore, HSCT is more likely to be recommended to people who prefer not to use long-term medical therapies. This challenge with HSCT is acknowledged in the 2014 guidelines issued by the National Heart, Lung, and Blood Institute (NHLBI). They agreed that more research was needed for selecting patients and donors and deciding on the best transplantation method before HSCT could become widely available as a cure for SCD.
Doctors generally agree that HSCT should be suggested for children with worsening heart, kidneys, and lungs, repeated strokes, and persistent painful erections, even after the best medical treatment. HSCT can also be considered for older adolescents and young adults who can understand the risks and benefits of the procedure. However, regardless of the patient’s age, it’s important to have a suitable donor, such as a fully matched sibling. Alternate donors, including partially matched and unrelated matched donors, might be considered in some cases.
The best age to receive HSCT hasn’t been determined yet, however, studies have shown that children, particularly those under 10, survive the procedure better than adults. The best source of donor stem cells is also yet to be established. The stem cells can come from umbilical cord blood, bone marrow, or circulating blood. Of these options, umbilical cord blood and bone marrow are thought to be better because they are less likely to cause graft-versus-host disease than circulating blood. Nonetheless, a study on HSCT in SCD did not show a lower occurrence of graft-versus-host disease with cord blood and bone marrow stem cells. However, survival was better with these sources compared to circulating blood stem cells.
Preparing for Hematopoietic Stem Cell Transplantation in Sickle Cell Disease
Undergoing a stem cell transplant is quite a complex process. It requires a lot of checks and a thorough preparation. Initial tests involve a basic blood count test to count the number of different types of blood cells, a comprehensive metabolic profile to examine various chemicals in your blood, and testing urine for 24 hours to check the health of your kidneys.
Furthermore, a type of scan called an MRI (or magnetic resonance imaging) brain test is carried out to look for any unusual changes, including blood vessel abnormalities in the brain. Doctors also need to do a heart test (called an echocardiogram) to estimate the pressure in your lung arteries. A dental check-up and tests to see how well your lungs are working are also part of this pre-transplant examination.
The most crucial part is finding the right match of ‘HLA-typing’ – a kind of genetic match – to find the best possible donor. To avoid complications of the blood’s red cells, doctors check the particular form of red blood cells of both the patient and the donor. Doctors also check for any ‘donor-directed’ antibodies, as these can cause risks after the transplant.
Moreover, the patient needs to stop taking a specific drug called Hydroxyurea before the transplant. To further reduce the risk of complications, a procedure called an ‘exchange transfusion,’ often takes place. It’s also important to talk to the patients and their families about the risk of becoming infertile after the transplant, and potential fertility preservation methods should be discussed before starting the stem cell transplant process.
How is Hematopoietic Stem Cell Transplantation in Sickle Cell Disease performed
Bone marrow transplant is also known as hematopoietic stem cell transplantation (HSCT). Basically, it’s a procedure where we take special cells, called stem cells, from another person (the donor) and put them into you (the recipient). There are two main types of this procedure: autologous, where you receive your own stem cells, and allogeneic, where you receive cells from another person. The autologous method doesn’t work well for sickle cell disease unless the stem cells have been modified with special techniques to fix the genetic issue causing the disease. The allogeneic method is more common. The donor, who could be a sibling or unrelated, must be matched to you. This matching is based on something called human leukocyte antigen (HLA). If all 8 HLA locations match, then the donor and recipient are considered fully matched.
The HSCT procedures have been continuously improved and refined since the first one was done in 1984. The process involves using chemotherapy, a cancer treatment, to remove the recipient’s stem cells. New, healthy stem cells from the donor then replace these. The very first HSCT procedure involved a high dose of a drug called cyclophosphamide and something called total body radiation. Since then, the process of preparing the patient for the transplant has been significantly improved, including treatments that are less intense and don’t completely get rid of the marrow.
For sickle cell disease, treatments that combine strong chemotherapy and total body radiation are typically used. Some examples include busulfan and cyclophosphamide or busulfan and fludarabine. Once the treatment has been given and the stem cells from the donor have been transferred, we look to see how well the patient’s body has accepted the new cells, something we call engraftment. We measure this by looking at the donor chimerism, which is the proportion of blood cells that come from the donor. We need at least 20% of blood cells to be from the donor to make sure the patient will not experience sickling, which is what causes issues in sickle cell disease.
After the transplant, we have to be careful not to use a drug called granulocyte-colony stimulating factor because it has caused sickle cell crises in some cases. We also need to ensure the recipient gets vaccinations and preventive treatment against GVHD (a condition where the new cells attack the recipient’s body) and infections that can happen after a transplant, following the usual procedures for bone marrow transplantation.
Possible Complications of Hematopoietic Stem Cell Transplantation in Sickle Cell Disease
Since 1984, over 1200 bone marrow transplants – a procedure also known as Hematopoietic Stem Cell Transplantation (HSCT) – have been performed. However, this procedure can have several complications. These can be related to the preparatory treatment for the transplant, the transplant operation itself, the drugs taken post-operatively to prevent rejection, or the high financial cost.
Before the transplant, you’d typically undergo a “conditioning regimen”, which prepares your body for the new cells. This treatment can potentially cause injury to organs and long-term effects like infertility and an increased chance of getting another form of cancer later in life. The transplant operation carries its own risks, and these get bigger when the donor and recipient aren’t a good match. While finding a matching donor is ideal, it’s often hard to do. Even with a well-matched donor, around 9% of patients still experience rejection of the new cells. Additionally, 15% of patients develop a condition called chronic GVHD (Graft-versus-host disease), an immune reaction where the new cells fight the body’s own tissues.
The medicines taken to keep GVHD under control can lower the body’s natural defenses, paving the way for infections. Some patients might also have wounds on their legs that take a long time to heal, raising the risk of infection further. Another issue is the significant cost of all the medical procedures and medications involved, which can be especially hard for people without strong financial resources.
Now, all these potential complications need to be thought about very carefully when considering a bone marrow transplant for Sickle Cell Disease. It’s important to discuss these complications with your doctor and your close family or friends. By knowing what might lie ahead, you’ll be better prepared to face any complications and have a successful outcome. The strategies used to manage these complications depend on your personal situation.
Immediate post-operative complications like infections or organ injury typically fall to the transplant team to manage. Similarly, acute GVHD is typically managed by the transplant team. Late developing complications like secondary cancers, however, usually also involve a broader medical team. Infertility is addressed by providing counseling about preserving fertility options even before the transplant happens.
What Else Should I Know About Hematopoietic Stem Cell Transplantation in Sickle Cell Disease?
Sickle Cell Disease (SCD) is a life-long illness with no known cure that can affect multiple organs in the body, lead to a lower quality of life and reduce life expectancy. One treatment that currently offers hope of a cure is Hematopoietic Stem Cell Transplantation (HSCT), but it’s important to know that this treatment can also have severe side effects. This makes it suitable mainly for younger patients with a strong ability to tolerate such side effects.
There’s also a need to find a matching donor for this treatment, typically a sibling who shares similar genetic characteristics. Due to these requirements, the chances that every sickle cell patient would find a suitable person to donate are quite slim.
Another promising option comes from Autologous Stem Cell Transplantation, which uses the person’s own cells that have been genetically modified, eliminating the need for a donor. This treatment is not yet commercially available though, with several related treatments still in the process of gaining approval from the Food and Drug Administration (FDA), the US agency that regulates medical products.
