Therapies

Many patients with serious primary immune deficiencies such as SCID, WAS, or CGD require a blood and marrow transplant (BMT) for cure of their disease. BMT is also known as a hematopoietic stem cell transplant (HSCT) and the terms BMT and HSCT are often used interchangeably. BMT is a form of stem cell therapy and is life-saving for many infants and children with serious primary immune deficiencies. Bone marrow stem cells used for transplant come from another person (ie, not the person with the primary immune deficiency). Stem cells will grow and form a new and normal immune system in the person affected by the primary immune deficiency. Stem cells come from one of three sources: (1) Bone Marrow – this is what is most commonly known as a “bone marrow transplant”; (2) Peripheral Blood (bone marrow stem cells found in the blood); or (3) Umbilical cord from a newborn baby (contains a large number of bone marrow stem cells).

In general, the best stem cell donor is a sibling to the patient who is both (1) a match (also called an HLA-match, or human leukocyte antigen match), and (2) NOT affected by the same disease. For each sibling, these criteria only occur about 20% of the time. Your doctor will want to take blood from each sibling to determine if they would be a suitable donor.

If a sibling is not available or is not a suitable match, other possible donors may include (1) a parent or sibling who is not a match (sometimes called a “haploidentical” donor) (2) an unrelated person found on a stem cell registry, or (3) an unrelated umbilical cord blood donor. There are many factors that go in to deciding who the best donor is when a matched sibling is not available. Speak to your doctor about these decisions.

Your doctor may recommend that certain medications be given to your child before the stem cells are infused. This is referred to as a conditioning regimen and usually consists of various combinations of chemotherapy (drugs that open up space in the bone marrow to accept the new stem cells, and that suppress the patient’s immune system so that it does not reject the new stem cells) and possibly other immune suppressing medications. These drugs will usually be administered intravenously in the days or weeks before BMT. Many different conditioning regimens are available. Some forms of SCID may not require a conditioning regimen. There are many factors that go in to deciding a conditioning regimen. As a result, it is impossible to make general recommendations on this website about what is the best conditioning regimen, or whether a conditioning regimen is needed or not. Your doctor will be able to discuss with you the recommendations regarding the conditioning regimen.

One common question asked by patients and parents is, “How do the new stem cells get into the body?” The answer is, the stem cells go right into the blood stream! Stem cells do not need to be injected directly into the bone marrow with large needles. Patients do not need to be brought to an operating room for a major surgery to receive the stem cells. In fact, the stem cell infusion is actually a minor procedure, usually done in the patient’s hospital room. The procedure is in fact very similar to getting a blood transfusion. Patients will usually have a central line inserted before BMT. A surgeon or other doctor will insert the central line in a minor surgery. A central line is a type of longer intravenous line (of which there are various types in use) that goes in through the skin (often on the chest, but they can be other places) and ends in the large veins inside the chest. The stem cells are infused through the central line and into the blood stream. The infusion takes anywhere between 15 minutes and four hours, depending upon the type of product and the volume. Once in the blood stream, the stem cells eventually “home” to the bone marrow (which is continuous with the blood) – where they will make new blood and a new immune system over time for the patient.

BMT can be a difficult process for patients and their families. Patients need to be treated at specialized hospitals that are used to treating young infants and children with primary immune deficiencies (many of these hospitals are members of the PIDTC). Patients and their families may need to be away from their home for months at a time. Patients may spend weeks or months in a hospital after the transplant. Patients can become very sick – both before the transplant and after. Infections are a major problem for BMT patients, particularly those with primary immune deficiencies. Please see the section on “What are the complications of blood and marrow transplant?” for further information. Follow up occurs for years after BMT and probably will be life-long.

There are many potential complications of BMT. Some of these complications occur early after the transplant (in the first weeks to months) and some occur later after transplant (in the months to years after BMT). The following is a list of the more common complications, but the list is not inclusive. Your doctor will spend more time with you discussing these risks in detail.

1. Infection – Many patients with primary immune deficiency will have had serious infections before BMT. New infections can occur after BMT as well (particularly in the first weeks to months after the transplant). Infections can make the patient very sick. There are too many infections to list, but bacterial, viral, and fungal infections all remain significant risks after BMT. Antibiotics, antifungals, and antivirals are the usual treatments. There are times, however, where even these treatments may not be successful. The goal of BMT is that, over time, the risk of infections (in particular, life threatening ones) goes down to the point where infections do not become a problem for patients with primary immune deficiency anymore. One of the major goals of the PIDTC research studies is to try to understand better how the new immune system works after BMT, and how this relates to the infections that are seen (or not seen).
2. Graft Versus Host Disease – The new immune system (found in the “graft,” or the BMT product) that develops after the transplant sometimes attacks the patient (the “host”) who receives the transplant. This is called graft-versus-host disease (GVHD). GVHD can be acute or chronic. Acute GVHD tends to occur in the first weeks to months after the transplant. Acute GVHD often shows up as a skin rash (similar to a sunburn), persistent nausea (feeling sick), vomiting, not wanting to eat, diarrhea, and less often as jaundice (yellowing of the skin and eyes) due to the liver being affected. Acute GVHD can range from minor to severe and potentially life threatening. More serious acute GVHD may require increasing the immune suppression after BMT, placing the patient at higher risk for developing infections.
3. Chronic GVHD tends to start months after BMT and can affect many different body systems. Chronic GVHD can also vary from fairly minor to very severe. Chronic GVHD can affect a patient in many different ways. Some patients complain of skin tightening, decreased joint mobility, mouth sores, difficulty breathing, sore eyes (sometimes dry and gritty), not wanting to eat, weight loss, vomiting, and just generally feeling unwell. This can go on for months to years.
   
   The last PIDTC study (6901) demonstrated that 8% of patients with SCID developed severe acute GVHD (grade 3-4), although it is likely that the risk of more mild forms of acute GVHD are probably higher (30-40%). Chronic GVHD was seen in 17% of patients who had received a transplant.

In its current available form, gene therapy (GT) is an experimental therapy that aims to replace the defective gene with a copy of the healthy gene. This allows the cell to start producing normal protein in hopes of curing the disease. Scientists have found that one of the most efficient ways to introduce the corrected gene into the cell is to use modified viruses. Scientists first inactivate the virus so that it cannot produce disease and then "load" it with the "normal gene" (for example, the WASP Gene in the case of WAS). These "loaded" viruses, referred to as "vectors", are then used to introduce the normal gene into the patient.

Because gene therapy is experimental, it only occurs at a few hospitals in the world. Patients are required to be enrolled on a research study to receive this treatment. Your doctor can help you in determining if you/your child are eligible for a research study. All research studies, including those involving gene therapy, are required to be registered before they begin on a publicly accessible website. The most common website is ClinicalTrials.gov. You can go to this website and search the name of your/your child’s condition along with gene therapy to see what trials may be available. Gene therapy trials for Wiskott-Aldrich syndrome, chronic granulomatous disease, ADA SCID and XSCID are ongoing.

The following are the four basic steps of gene therapy.

1. The vector is prepared and loaded with the normal gene, in preparation for introduction into the patient.
2. Doctors collect blood-forming stem cells from the patient's bone marrow or the blood. These cells are then grown in large numbers outside the body. Next, these cells are mixed with the vector. The virus infects these cells, converting them to repaired cells.
3. The patient is then given chemotherapy, in preparation for GT. This helps make space in the marrow for the repaired cells to multiply and to make sure that the patient’s body does not reject the repaired cells.
4. The repaired cells are now introduced into the patient in a process similar to blood transfusion.

These repaired cells then continue to multiply, forming more numbers of normal cells. Over time, the repaired cells should produce enough to cure the patient.

One particular kind of SCID, called adenosine deaminase deficiency (ADA)-SCID, is caused by lack of an enzyme (a protein in the body that helps break down other chemicals). Patients with ADA-SCID typically have very low T-cells, B-cells, and NK-cells because toxic byproducts build up as result of lack of the ADA enzyme. Patients with ADA-SCID present with similar infections as seen with the other forms of SCID.

ADA-SCID is the only type of SCID where patients can receive enzyme replacement. The enzyme has been made into a drug known as SC-PEG-rADA (elapegademase; Revcovi ®). SC-PEG-rADA is a recombinant form of the bovine ADA that does not come from animals and replaces the formerly available bovine PEG-ADA (Adagen ®). SC-PEG-rADA is given by a needle into the muscle (intramuscularly). Patients / parents learn to inject it themselves. Usually it is given once per week, although dose changes (both in terms of total dose and the frequency with which SC-PEG-rADA is administered) may need to occur based upon ADA levels that are monitored in the blood.

Patients with ADA-SCID can take SC-PEG-rADA for their entire lifetime. In some situations it is used as a “bridge” to transplant (i.e. used to improve the immune system temporarily while a patient is awaiting more definitive therapy). It is controversial which approach is better. One of the goals of the PIDTC 6901 and 6902 studies is to understand long-term outcomes for both SC-PEG-rADA and transplant for ADA-SCID.

Company-sponsored clinical trials assessing whether patients develop antibodies recognizing SC-PEG-rADA have found that patients who previously received PEG-ADA (Adagen) may present a transient immunologic response to SC-PEG-rADA. Since PEG-ADA is the same class of ERT used in the treatment of ADA-SCID, the following adverse reactions may also be seen with SC-PEG-rADA treatment: hemolytic anemia, auto-immune hemolytic anemia, thrombocythemia, thrombocytopenia, injection site erythema/urticaria, and lymphomas.