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When primary immunodeficiency is likely to cause significant harm or death, an allogeneic hematopoietic stem cell transplant (HSCT), more commonly known as a bone marrow transplant (BMT), may be the best treatment option.
Primary immunodeficiency (PI) causes a wide spectrum of symptoms with varying severity. Some forms of PI are mild and don't cause significant harm, or may be effectively treated with agents like immunoglobulin (Ig) replacement therapy. Other forms of PI are so severe that individuals have a very poor quality of life or can die as a result of their disease. When PI is likely to cause significant harm or death to someone, an allogeneic hematopoietic stem cell transplant (HSCT), more commonly known as a bone marrow transplant (BMT), may be the best treatment option.
Some common indications for allogeneic HSCT include severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome (WAS), chronic granulomatous disease (CGD), leukocyte adhesion deficiency (LAD), immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, X-linked lymphoproliferative disease (XLP), hyper IgM syndrome, combined immune deficiency (CID), and hemophagocytic lymphohistiocytosis (HLH). Allogeneic HSCT can also be considered for other forms of PI.
Immune system cells develop from special cells that live in the bone marrow called hematopoietic stem cells. Hematopoietic stem cells produce all blood cells including red blood cells, platelet-producing cells, and immune system cells such as neutrophils, T cells, B cells, and natural killer (NK) cells. People with PI essentially have broken pieces in their immune systems. Immune system cells may be missing or just not work properly. An allogeneic HSCT can replace an individual’s own hematopoietic stem cells with stem cells that will produce functioning immune system cells. In this way, a person's immune system can be fixed.
Hematopoietic stem cells can be transferred from one person to another person. The person who receives the stem cells is called a recipient of HSCT. The term, allogeneic, indicates that the stem cells given to the recipient came from someone else, the hematopoietic stem cell donor. If an allogeneic HSCT is successful, the donor's hematopoietic stem cells will replace the recipient's own cells. The donor cells will live in the recipient’s bone marrow and make blood and immune system cells.
Allogeneic HSCT also fixes any problems with other blood cells. For example, platelets will be fixed in those with WAS who have a successful allogeneic HSCT. Unfortunately, problems outside of the blood or immune system will not be fixed. For instance, if an individual with IPEX has diabetes before transplant, they will still have diabetes after transplant, because the cells in the pancreas that make insulin have been destroyed by this disease, and HSCT cannot replace pancreatic cells.
Hematopoietic stem cells may be collected from the bone marrow, the peripheral blood, or from umbilical cord blood, so HSCT procedures may be called bone marrow transplants (BMT), peripheral blood stem cell transplants, or cord blood transplants depending on the source of the stem cells. The transplant itself does not require surgery for the recipient, as the hematopoietic stem cells are typically infused into a large vein in the same way that a patient receives a blood transfusion.
The first step in HSCT is finding a suitable donor. Finding a donor can take several weeks or months. Donors can be family members or unrelated to the person undergoing HSCT. Unrelated donors are usually found through bone marrow registries or umbilical cord blood banks.
Whether related or not, the donor has to have the same or almost the same human leukocyte antigen (HLA) typing results, which are obtained from a blood test, as the HSCT recipient. The immune system uses HLA proteins on cells to help determine which cells belong to the body and which don't. HLA-matched donors are the best donors because when HLA proteins are the same between a donor and recipient, the chances of complications, such as graft rejection and graft versus host disease (GVHD), are low.
Everyone has two sets of HLA genes. One set is inherited from a person's mother, and the other set is inherited from a person's father. Transplant doctors typically look at 8-12 HLA genes when trying to find a matched donor. A fully matched donor would be an 8/8, 10/10, or 12/12 (depending on the testing lab) HLA-matched donor.
The best stem cell donor for an individual with PI is an HLA-matched sibling. The sibling must have the same mother and father as the recipient. Full biological siblings of the individual with PI have a 25% chance of being a perfect match, so families may need to look elsewhere for a donor. Note that it is important that potential sibling donors are evaluated for PI before being used as donors.
See if you are eligible for clinical trials evaluating new approaches and protocols for treating PI with a hematopoietic stem cell transplant (HSCT).
Some individuals with PI may be fortunate enough to have a transplant center at their nearby hospital, but many will have to travel to specialized centers for transplantation. This can be difficult for families and can be emotionally and financially challenging. Individuals with PI and their families may or may not have options when it comes to choosing a transplant center. Sometimes insurance requires individuals to use certain specialists or certain facilities. Under other insurances, individuals can research facilities and doctors and choose what they think is best. Two resources for finding transplant specialists include the Primary Immune Deficiency Treatment Consortium (PIDTC) and The National Marrow Donor Program.
Individuals with PI and their families usually meet members of the transplant team, which can include physicians, nurse practitioners, social workers, psychologists, nurses, and financial counselors. These team members help prepare recipients and their families for the impact the transplant will have on family life, and they provide support and assistance with all aspects of the transplant.
Regardless, individuals and their families should ask key questions of the transplantation specialists. Points to keep in mind include the length of time the center has provided HSCTs, the number of HSCTs the center has performed on persons with the individual's specific PI, and the number of HSCT specialists on staff.
Here is a list of questions to ask a healthcare team before choosing them to perform the HSCT.
Individuals with PI and their families should learn as much as they can about the HSCT procedure before it occurs. The following questions can be used to both educate caregivers and evaluate the hospital's experience.
Staff at the hospital, in collaboration with the family, will often work with insurance companies to get approval for the transplant. The time spent at a transplant center can vary from center to center, and it also varies from person to person. However, recipients and families can generally expect to stay at or near the transplant center for at least 3-6 months before returning home. Allogeneic HSCTs are generally performed in the hospital, but once recipients are healthy enough, they are discharged from the hospital and return to the transplant clinic several times a week.
HSCT recipients typically have a large battery of tests and procedures done before transplant to make sure they are healthy enough to have a transplant. Healthcare providers may find hidden problems that need to be addressed prior to transplant, such as infections or organ function problems. Immunologists and transplant providers typically order many blood tests, as well as imaging studies, such as computerized tomography (CT) scans, ultrasounds, and/or magnetic resonance imaging (MRI). Special tests of kidney function are also done. The heart is evaluated with an echocardiogram (ECG, EKG), which is an ultrasound of the heart. If recipients are old enough, pulmonary function testing will be done. Some may need procedures such as a bone marrow biopsy, lumbar puncture, bronchoalveolar lavage, or gastrointestinal endoscopy prior to allogeneic HSCT. All of these tests usually take a few weeks to complete.
Before having a transplant, a recipient and/or family must give consent to proceed with the transplant. Members of the transplant team will meet with the recipient and/or family to go over the process and the risks and benefits in detail. Recipients and families should ask questions and be sure that they understand the proposed treatment before proceeding.
HSCT is different than organ transplants (e.g., liver, lung, or kidney) in several ways. The transplant itself is not a surgery, because the stem cells are given in a vein similar to a transfusion. Also, HSCT recipients need special preparation to receive the stem cells that solid organ patients don’t need. The process of replacing the stem cells in the bone marrow requires an inpatient stay of about six to eight weeks. This inpatient stay is what most people think of as 'the transplant.'
After discharge, full recovery of the immune system to a functioning immune system occurs as an outpatient and is a process that takes many months, up to a year. Unlike solid organ transplant recipients, HSCT recipients are able to wean off of immune suppressive medications if all goes well because the new immune system becomes accustomed or tolerant to the patient's body.
If the HSCT recipient is healthy enough to proceed with the transplant, they will receive a long-term (but ultimately temporary) IV line in a large vein in the chest or neck. This line is called a central line. The recipient will go under general anesthesia in order for the central line to be put in.
The central line helps doctors take blood from the recipient to monitor the progress of the new immune system. Doctors also use the line throughout the transplant process to administer chemotherapy, the donor cell infusion, antibiotic, antiviral, and antifungal medications to prevent infection, and IV fluids. It avoids the need for repeated IV placement and venipuncture. The recipient or a caregiver will need to learn to take care of the central line.
What happens during conditioning is similar to what happens before replanting a garden. If the HSCT recipient's immune system is a garden filled with weeds, the weeds may need to be cleared out before healthy plants can grow. For stem cell transplant, the conditioning regimen acts as weed killer. It is a combination of medications that destroy the recipient's own immune and stem cells to prepare for receiving the donor stem cells.
The goal of conditioning is to increase the chances of complete replacement of the recipient's immune system with donor cells and reduce the chance of treatment complications, such as failure to engraft and GVHD. On the other hand, the use of conditioning comes with side effects and the potential for serious risks of its own. Together, the recipient, their family, and their doctors should review the options available and decide whether to use conditioning based on the balance of benefits and risks.
In general, conditioning may be recommended when the recipient has some immune function or when the stem cell donor is not related to the recipient. In general, conditioning may not be recommended when the donor is a fully matched sibling or the recipient has an active infection, is very young (under 2 months of age), or is small (e.g., was born prematurely). Conditioning is also not recommended when treating certain types of SCID that amplify the toxicity of conditioning drugs. However, when conditioning is not used, the chances of the recipient achieving a fully functioning immune system are generally lower. The recipient may need additional treatment, have more infections post-transplant, or even need another HSCT later in life.
A doctor may strongly recommend that conditioning be used or not used based on his or her best judgment and current research guidelines, the recipient’s specific situation, and sometimes the hospital’s standard practice. If conditioning is recommended, questions to ask the doctor include:
If conditioning is not recommended, questions to ask the doctor include:
There are two major categories of conditioning, drugs that target stem cells and drugs that target immune cells. They have different goals. HSCT recipients may have one or both types of conditioning before treatment.
Conditioning targeting stem cells uses chemotherapy drugs to reduce the number of stem cells in the recipient's bone marrow. Doctors call this myelosuppression. The goal is to make space in the recipient's bone marrow for the donor stem cells to engraft. There are several intensities of myelosuppressive conditioning. They use the same drugs, such as busulfan or melphalan, but vary in the dose and number of drugs used. The three categories of myelosuppressive conditioning include:
Conditioning targeting immune cells uses drugs to reduce the T and B cells in the recipient’s immune system. Doctors call this immunosuppression. The goal is to protect the donor stem cells from being attacked by the recipient’s immune cells. There are two categories of immunosuppressive drugs:
Conditioning can have short-term side effects and long-term risks. Short-term side effects are temporary and usually subside when the treatment starts working. Long-term side effects may appear months or years after conditioning. In addition, some short-term side effects may become chronic and last a long time.
Short-term side effects may be mild to severe:
Any one of these long-term complications is infrequent, but recipients and their families should know that they do sometimes occur:
Once a donor is found, the timing of the transplant must be arranged so that the donor cells are ready when the recipient has completed conditioning and is ready to receive them. The planned day of stem cell infusion is called Day 0. Stem cells are given through the central line like a blood transfusion. Similar to a blood transfusion, the stem cell transplant is a minor procedure that can take as short as 30 minutes or as long as a few hours. General anesthesia is not necessary and caregivers may be present during the procedure.
After Day 0, recipients typically remain in the hospital for several weeks while doctors wait for the new stem cells to grow. In the garden analogy, once the weeds are gone and the seeds are planted, there is a period of time when the garden is empty because it takes time for the healthy plants to grow. During this time, there are no blood cells being produced by the bone marrow, so it is common for the recipient to need blood and/or platelet transfusions.
Recipients are watched closely for any signs of infection, and they may need pain medicines, medicines for nausea, and fluid and nutrition support. Frequent blood tests are performed to monitor for any signs of organ dysfunction. Most recipients also receive medications that suppress the immune system in order to help prevent GVHD. Common examples include cyclosporine or tacrolimus.
After an HSCT, doctors expect engraftment to occur. Engraftment is when the donor's hematopoietic stem cells grow in the recipient and start making healthy blood cells. Transplant teams monitor the recipient with a blood test called a complete blood count (CBC). When the stem cells start to work, the numbers of particular blood cells will start to rise.
The anticipated time it takes for different cell types to recover to a safe level varies. Until doctors are sure that there is good engraftment, the recipient will be monitored very closely. Sometimes the recipient is given medication to jumpstart white blood cell production specifically.
Once there are signs of engraftment, a special blood test will be done to determine what percentage of blood cells are from the donor, called an engraftment or chimerism study. Chimerism refers to having cells in the body with different genes, in this case, hematopoietic stem cells and blood cells with the donor's genes and all other cells with the recipient’s genes. The higher the percentage of blood cells with the donor’s genes, the better the HSCT has worked.
Once the blood counts recover to a safe level, recipients may be able to transition to outpatient care at the transplant center. Recipients will have a lot of oral medications, and many need some IV medications, IV fluids, or IV nutrition during the early outpatient treatment phase. Home healthcare services, depending upon an individual's insurance coverage, may help with these needs.
The recovery process for a recipient after an HSCT takes at least several months, and will vary according to conditioning, the type of donor, any complications, and the individual hospital or transplant center’s criteria for discharge. Typically, once a recipient's donor cells are producing enough neutrophils and platelets to keep the patient safe, they are ready for discharge. Recipients must not have fevers or bleeding, and they need to be able to take their medications as prescribed. Recipients and/ or caregivers must be comfortable taking care of the central line, and they may also need to learn to give IV fluids, IV nutrition, and even some IV medications.
Once a recipient is discharged, they usually come back to the transplant clinic several times a week for lab work, examinations, and infusions. Often recipients are discharged to housing that is close to the transplant center, particularly if their own homes are some distance away. Recipients can still develop complications after discharge, including infections, organ toxicities from medications, and GVHD.
Once engraftment occurs, and the frequency of blood draws goes down, the central line may be taken out.
By Day +100, some recipients are ready to return to their own homes and can continue to follow up just with their local healthcare providers. Recipients often still need to take several medications for the first year after transplant, including immune-suppressive medications to prevent GVHD. Until they have a full recovery of immune cell numbers and are successfully weaned off of immune suppressive medications, recipients should remain isolated. In isolation at home, visitors should remain restricted, and the recipient will not be allowed outside, or in public places, for several months. Neutrophils recover just a few weeks after transplant, but T cells require many months and B cells may take 1-2 years.
Healthcare providers can do blood tests to see how an individual’s immune system is recovering and make recommendations about when it is safe to stop isolation. Once the immune system is fully recovered, recipients should receive routine re-vaccination following the transplant.
Once a family's time in the hospital or in a temporary apartment comes to an end, the family must consider how to prepare their home for the arrival of the newly transplanted individual.
The patient must stay at home, and should not go out into public places until the doctor gives permission. The recipient is still very vulnerable to infection, and germs must be controlled as much as possible.
Families must consider guidelines for travel, visitors, food preparation, home cleaning, and mold remediation. All families are different and suggested ideas on visitors and cleaning will vary with doctor recommendations and family lifestyle.
Travel: When the recipient rides in the car, keep the vehicle windows up and set the heat or air conditioning to recirculate the inside air instead of pulling in outside air. This is particularly important when driving past construction sites, which can throw fungal spores into the air.
Visitors: Limit visitors to those who live in the house and any regular caretakers of the patient, such as nurses.
Food preparation: Keep these food-related recommendations in mind.
For infants on formula, consider following these recommendations:
Home cleaning
Mold remediation: If mold is discovered in walls or carpets before the recipient comes home, have it professionally removed and complete all other cleaning several weeks before the recipient arrives home. If mold is discovered after the recipient is home, it is best not to disturb it. Have the severity of the mold problem evaluated by a professional. Consult with your immunologist. Relocation may be necessary.
By 1-2 years post-transplant, most recipients have good immune system recovery and do not need frequent follow-up. It is generally recommended that an individual return for follow-up yearly or every other year, as this long-term follow-up is important to monitor them for late complications of transplant. These late complications are mostly related to the conditioning medications given to prepare the recipient for transplant, but they may also be related to organ damage caused by infection or immune dysregulation before the transplant.
The severity and likelihood of late complications related to allogeneic HSCT is variable. Possible long-term complications from chemotherapy drugs include harm to vital organs such as the brain, lungs, kidneys, and liver. Sometimes, these complications are reversible with medication.
Other complications include endocrine problems such as thyroid function, growth, or puberty issues, reduced fertility, and increased risk of cancer.
Individuals who develop chronic GVHD need special long-term follow-up. The transplant team can tell recipients and caregivers more about what long-term monitoring may be needed.
This page contains general medical and/or legal information that cannot be applied safely to any individual case. Medical and/or legal knowledge and practice can change rapidly. Therefore, this page should not be used as a substitute for professional medical and/or legal advice. Additionally, links to other resources and websites are shared for informational purposes only and should not be considered an endorsement by the Immune Deficiency Foundation.
Adapted from the IDF Patient & Family Handbook for Primary Immunodeficiency Diseases, Sixth Edition.
Copyright ©2019 by Immune Deficiency Foundation, USA
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