Chronic Granulomatous Disease (CGD) can be cured by bone marrow transplantation, but this is complex and not universally available for every patient with CGD. Patients may lack a fully matched normal sibling or may be doing well enough with normal treatment that they do not want a transplant. Decisions regarding bone marrow transplants need to be weighed carefully. However, some patients with CGD have good transplant options and may want to explore this.
Both myeloablative (traditional conditioning of chemotherapy and radiation) and non-myeloablative (lower-dose conditioning regimen of chemotherapy and radiation) regimens have been successful.6,7,8,9 Non- myeloablative transplants have reduced the risk of regimen-related toxicity and allow for transplantation in the setting of active infection.
Although bone marrow transplants are an option to cure patients with CGD, it is important to note that the overwhelming majority of patients with CGD survive without a transplant. Survival in CGD has improved greatly over the last several decades, primarily due to improved antibiotic therapy, and is approximately 90 percent at 10 years.10,11,12
Types of Stem Cell Transplantation
Traditionally, hematopoietic (“blood-forming”) stem cells (HSC) were obtained from the bone marrow. This process was called “bone marrow transplantation.” However, new methods now obtain HSC from peripheral blood, or blood taken from the placenta at birth (“cord blood”). Cord blood provides an alternative source of HSC for the immune and blood systems. The process of taking HSCs from one person and transfusing them into another is called hematopoietic stem cell transplantation, or HSCT. Unlike transplantation of a solid organ (such as a kidney or liver), HSCT does not involve surgery. It is more similar to a blood transfusion, but instead of just blood, the transfusion also contains HSCs.
The transplantation of HSCs from a “normal” individual to an individual with CGD has the potential to replace the deficient immune system of the patient with a normal immune system and, thereby, affect a cure.
There are two potential obstacles that must be overcome for HSCT to be successful. The first obstacle is that the patient (known as the recipient or host) may recognize the transplanted stem cells as something foreign. The immune system is programmed to react against things perceived as foreign and tries to reject them. This is called graft rejection. In order to prevent rejection, the donors for CGD patients should be a close a match as possible. Even with a close match, patients with CGD require either full or reduced intensity conditioning to weaken their own immune system so as to prevent it from rejecting the transplanted HSCs. Conditioning also reduces the number of defective HSC in the recipient’s bone marrow in order to “make room” for the new HSC to engraft.
Although the conditioning regimens prevent the host from rejecting the transplanted HSCs, they may cause serious side effects. These include transient loss of all of the cells of the bone marrow so the patient is very susceptible infections, anemia (low RBC) and bleeding problems due to low platelets. They also may cause severe blistering of the mouth or other mucous membranes that makes getting adequate hydration and nutrition very difficult. And they can cause sterility.
The second obstacle that must be overcome for the transplant to be successful is Graft versus Host Disease (GVHD). This occurs when the mature T-cells in the donor cell suspension perceive the host’s tissues as foreign and attack these tissues. To prevent GVHD, medications to suppress the inflammation caused by the donor T-cells are used. These medications may include steroids, cyclosporine and other drugs.
In order to prevent some of these potential obstacles, it is important to try to identify a “matched” donor. A matched donor is one who’s Human Leukocyte Antigens (HLA) are the same as those of the recipient.
Selecting a Donor
HLA are tissue types. Each of us has our own collection of HLA antigens on our cells including the cells of our immune system and bone marrow, as well as on cells in most other tissues and organs. The exact structure of these HLA antigens is determined by a series of genes clustered on the sixth (6th) human chromosome. Compatibility of HLA is very important to determine the chance of successful engraftment while keeping the risk of GVHD low.
There are many different variants for each of these HLA genes in humans. The combination of HLA alleles of each individual is relatively unique. However, since the HLA genes are closely clustered on chromosome 6, they are usually inherited as a single unit. Therefore, the chance that an individual’s brother or sister shares the same HLA alleles is relatively high.
There is a 1 in 4 chance that any sibling could be a perfect match for the patient. Unfortunately, due to the laws of probability and the fact that most families have a limited number of children, fewer than 25% of patients have a sibling who is a “match.” Therefore, there has been a major effort to develop alternative methods to offer the possibility of a transplant to patients who do not have a matched donor in their own family.
One alternative is to try to find a suitable matched donor through one of the worldwide computer-based registries of individuals who have volunteered to serve as bone marrow donors. The National Marrow Donor Program in the U.S. has listings of hundreds of thousands of individuals who have provided a blood sample to have their HLA type measured. Similar registries are present in many countries around the world.
Information on the combination of HLA alleles of more than 19 million volunteer donors is collected in Bone Marrow Donors Worldwide (BMDW). This database can be easily accessed by authorized healthcare professionals to explore the possibility that there is a matched unrelated donor (MUD) available for a patient who needs HSCT and does not have an HLA-matched donor in the family.
Another source of HSC used for transplantation in patients with CGD is umbilical cord blood. In the growing fetus, HSC frequently leave the marrow and are found circulating in high numbers in the blood. At the time of birth, the placenta can be recovered, the blood that is remaining removed and the HSC isolated and banked. These cord blood HSC may then be HLA typed and used for transplantation. Since cord blood contains fewer mature T-lymphocytes than the marrow or blood of adult donors, sometimes cord blood transplants have been successful even though the degree of match between donor and patient was not very good. One limitation of cord blood HSC transplantation is that, because of the limited volume of umbilical cord blood, there may not be a sufficient numbers of HSC to treat a larger child or adult successfully.
Donating Bone Marrow
HSC are “harvested” from the donor by removing bone marrow from the pelvic bones. Bone marrow is removed by drawing the marrow up through a needle that is about 1/8 of an inch in diameter. Only two teaspoons are taken from each puncture site because, if more is taken, the sample is diluted with the blood that flows through the bone marrow space. Bringing blood with the bone marrow increases the risk of the sample carrying the mature T-cells that have the potential to cause GVHD.
Usually, two teaspoons are taken for each two pounds of the recipient’s body weight. The average donor might have only a few punctures performed to get enough stem cells for a baby, but more than 100 punctures may be required to get enough stem cells for a teen or full sized adult. The procedure may be performed under general anesthesia or under spinal anesthesia. The discomfort after the procedure varies from donor to donor.
Almost all donors will require some type of pain control medication for two to three days after the procedure, but most donors are not required to stay in the hospital overnight and are able to return to full activity shortly afterwards. The donor’s immune system is not compromised because HSC and marrow quickly regenerate.
Once it has been harvested, the bone marrow is passed through a fine sieve to remove any small particles of bone and processed further, if necessary, to remove incompatible red blood cells, or to remove T-cells. It is then placed into a sterile plastic bag and infused into the host intravenously just like a blood transfusion.
As an alternative to bone marrow harvesting, HSC can be obtained from peripheral blood and then purified via a process known as apheresis. Typically, in order to enrich the amount of HSC in peripheral blood, the donor receives subcutaneous injections of granulocyte-colony stimulating factor (G-CSF) or of plerixafor in the days that precede the blood collection. Both G-CSF and plerixafor mobilize the HSC from the bone marrow, transferring them into peripheral blood, so that a large number of HSC are present in the peripheral blood before the apheresis procedure.The donor’s blood is collected from an arm vein, using a needle that is connected with a machine that removes the white blood cells. After white blood cells are removed from the blood, the remaining red blood cells are then returned to the donor via a vein in the opposite arm. The HSC are then purified from the other white blood cells.
Again, however, HSCT is not indicated for all patients with CGD, as many of these patients do well on medical management. The risks and benefits of the procedure must always be carefully weighed.
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8 Seger RA, Gungor T, Belohradsky BH, et al. Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft: a survey of the European experience, 1985-2000. Blood 2002;100:4344-50.
9 Soncini E, Slatter MA, Jones LB, et al. Unrelated donor and HLA-identical sibling haematopoietic stem cell transplantation cure chronic granulomatous disease with good long-term outcome and growth. Br J Haematol 2009;145:73-83.
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Source: Immune Deficiency Foundation Patient & Family Handbook for Primary Immunodeficiency Diseases FIFTH EDITION Copyright 2013 by Immune Deficiency Foundation, USA. This page contains general medical information which cannot be applied safely to any individual case. Medical knowledge and practice can change rapidly. Therefore, this page should not be used as a substitute for professional medical advice