Research, Education and Family support for WAS families worldwide

Hematopoietc Cell Transplant

- Hematopoietic Cell Transplant
  - Currently, a Hematopoietic Cell Transplant (HCT) is the only proven curative treatment available for Wiskott-Aldrich Syndrome. The cells in the bone marrow (stem cells) are abnormal in patients with WAS and need to be replaced with healthy, donor stem cells in order to to cure the disease. The process by which these abnormal cells in the patient are replaced with healthy donor cells is referred to as a HCT or transplant. On this site, the word "transplant" and HCT are used interchangeably. During a transplant for WAS, at least three major things happen:
- The patients blood forming stem cells are destroyed using medicines. This helps to make place for the donor cells in the marrow. It also destroys the patients immune system, allowing the patient's body to accept the donor cells.
- The donor cells are given to the patient.
- The donor cells grow and multiply, curing the patient.

Stem cells can be obtained from three different sources:

- The bone marrow of the donor.
- Small numbers of stem cells exit from the bone marrow and are found in the blood and are called peripheral blood stem cells (PBSC). These cells can be stimulated to move to the peripheral blood in large numbers so that they can be harvested from the blood of the donor.
- Cord blood, which is the blood that is collected from the placenta and the umbilical cord after the baby is born, is a rich source of stem cells.

The Transplant Process

Once a patient is identified to be eligible for a transplant, the best possible donor is identified for him. The patient's body is more likely to accept cells that are from a donor that are most similar to his own cells (just as a patient with O+ blood type accepts blood transfusions from another patient who is O+, but will destroy all others). A patient's immune system identifies and destroys cells that are not from his own body as "foreign". Therefore, the donor is selected very carefully to minimize the two types of negative reactions: Graft Rejection and Graft versus Host Disease (GvHD). Graft rejection occurs when the donor cells are not accepted by the body of the patient. The opposite reaction is called Graft Versus Host Disease. GvHD occurs when the donors white blood cells view the patient’s body as foreign and attack the patients organs.

The process by which the best possible donor is obtained is called HLA matching. The donors could be one of the following three people:

Matched Sibling Donor (MSD): They are perfectly matched donors and the best possible donors. Each sibling has a 25% chance of being a perfect match. Occasionally other family members may be perfect matches.
Matched Unrelated Donor (MUD): If a matched sibling is not available, then a search is made of databases around the world for the best possible match. In most, but not all cases, acceptable donors are found for every patient. This is the second choice for donors in patients with WAS.
MisMatched Related Donor (MMRD): If no match is found and the patient needs to have a transplant, then one of the parents or other relatives may be selected as donors. They partially match the patients HLA type and are not the ideal donors for transplant. There are times however, when they are the best available match for the patient.

Pre Transplant Evaluation: Once the best donor is identified the pre-transplant evaluation begins. During the pre-transplant evaluation several tests are done to evaluate the function of the kidneys, heart, lungs etc to determine that the patient will be able to withstand the rigors of the transplant process and to have a baseline recording for further evaluation. Financial planning is done at this point and measures are set in place for the emotional support of the parents during the process. Going through a transplant is challenging and emotionally exhausting. Having a local support group through family, friends and religious affiliations can help to ease the process. The hospital transplant team will be there to guide you through the process physically and emotionally. Once all the evaluations and support systems are in place, the patient is hospitalized for the transplant.

In the Hospital: Most often the patient is hospitalized the day before the medications are started. Some children may have to be hospitalized earlier to get them ready for the transplant. Several medications are given while the child is in the hospital and lab work is done frequently, up to every day at times. To prevent the child from having numerous pokes every day, sturdier, temporary IV lines (referred to as a Broviac or a Hickman Catheter) are implanted in a vein in the child's chest.

Medications (chemotherapy) are then given to destroy the patient’s blood forming cells and to make place in the bone marrow for the donor cells. These medications help to destroy the patient’s immune system so that it does not reject the donor cells. The process is called myeloablation or conditioning. Commonly used chemotherapy drugs for transplant are given over 8 days. For this reason the day that chemotherapy is started is referred to as Day -9. Chemotherapy is continued until day -1. This is a "rest day" when no chemotherapy is given. On Day "0" the donor cells are infused into the patient. The donor cells are infused into the blood in a simple process similar to a regular blood transfusion. The days after this are counted up as day +1, +2 etc.

Blood samples are taken very frequently, even every day, to check for normal functioning of the body and to check if the donor cells are growing. Due to the chemotherapy, the patient will have a lower number of red blood cells, white blood cells and platelets in the blood. Over time the donor cells will grow and make new blood cells. This is called "engraftment" and is an important milestone in the transplant journey. "Engraftment" usually happens between Day +10 to Day + 28. Until such time that the donor cells grow and make enough cells, the patients are given transfusions of red blood cells and platelets as needed. IVIG is given as a replacement on a regular basis, until such time that the donor's white blood cells are functioning well.

During this process, the patients are on several different medications. Medications may be given to prevent the donor cells from attacking the patients organs (GvHD). Because the patients have no immune system until the donor cells are well established, they are highly prone to infections. Antibiotics, antivirals and antifungals are given for the prevention of infection and aggressive treatments are started if the patient develops a fever. Visitors are restricted to reduce the exposure to potential infections. To decrease the chance of infection, patients are put in rooms with special air filters. They may also be in a room with a positive pressure air system to make sure that the air from the outside does not enter the room. These methods to reduce infection are referred to as "protective or reverse isolation". It is important to follow the reverse isolation procedures outlined by the BMT team hospital scrupulously as infections can be serious and cause significant setbacks in the transplant path.

After Discharge: Patients are usually in the hospital for 25-45 days, until after engraftment happens and the doctors determine that they are ready to be discharged. Until 100 days have passed after the transplant, if possible patients stay within a 20 minute reach of the hospital in case an emergency were to arise. During this time labs are done very frequently, up to everyday. After the 100 day milestone, patients may be able to return to their homes, if all is stable. Labs and visits to the hospital are done on a weekly basis until the blood counts have stabilized and their immune system is better. Because they are at high risk for infections, patients movement outside the home is restricted and visitors to the home are limited. With all going well, patients have a normally functioning immune system (full immune reconstitution) by 2 years after transplant and can lead a normal life. These numbers are just averages and it may vary significantly from patient to patient, depending on the circumstances and the complications that may arise.

Transplant Data

The first successful bone marrow transplant for WAS took place in 1968. Significant advances in the field of HCT in the last two decades has improved the success rate for transplants. 5 year survivals for children transplanted under the age of 5 years with a perfect sibling match approaches 90%. When the transplant is done at experienced centers, a closely matched unrelated transplant is almost as successful as a MSD transplant1 in patients under 5. However, the management of MUD transplants in children is significantly more complicated2 and prolonged than an MSD.

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The long term outcome following BMT was studied by Ozsahin et al in 20083. An analysis of significant events was done on 96 WAS patients who received transplants between 1979 and 2001 who survived at least 2 years following transplant. Significant events include chronic graft-versus-host disease (cGVHD), autoimmunity, infections, and pre and post transplant complications.

The 7-year EFS was significantly influenced by donor group:

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Courtesy: Blood Journal

The Transplant Process Transplant data Decision Making

Event-free survival in transplanted Wiskott-Aldrich syndrome patients according to donor group (P = .01).

— indicates the MSD group; ... URD group; and , MMRD group.

Influence of various factors on 7-year event-free survival after hematopoietic stem cell transplantation (univariate analyses):

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— indicates not applicable.

* All P values are 2-sided and considered to be statistically significant for P < .05.

Courtesy: Blood Journal

This study confirms that despite these significant adverse events, for most patients transplant resolves and prevents long term, life threatening complications that are associated with WAS. This is true regardless of donor matching, although the outcome is more likely to be better in patients receiving MSD or MUD transplants.

Transplant patients under 2 years, including those who receive a MMRD have an improved long-term survival with a better quality of life.

Influence of factors on 7-year event-free survival (EFS) after HSCT in all patients (univariate analyses):

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— indicates not applicable.

Courtesy: Blood Journal

There is a significant incidence of the development of autoimmunity in up to 20% of patients after transplant. It was found to be related to mixed chimerism. Full engraftment or full chimerism is when all of the blood cells come from the donor after transplant and mixed chimerism is when the patient has a mixture of blood cells from the donor and some of his own blood cells which. This study found that:

the incidence of autoimmunity was 8% in patients with full chimerism whereas it was 72% in patients with mixed chimerism.

Relationship between chimerism and autoimmunity after HSCT:

[add table]

— indicates not applicable.

Courtesy: Blood Journal

Serious and sometimes fatal infections were noted in splenectomised patients, even 2 years after transplant and continues to remain a long term risk. Splenectomy should therefore be considered with caution in patients who are candidates for transplant.

Decision Making

Classic WAS: Specific indications have not been established, but the consensus from experts is that HCT is the treatment of choice when a patient has symptoms of Classic WAS or has a genotype that is consistent with Classic WAS. Transplant is ideally done at the earliest possible time because younger patients have better outcomes. In most, but not in all cases, transplant centers are able to find a good marrow or cord blood match. Historically, the success rate of HCT is lower in patients over the age of 5 years. Therefore, in patients who are over the age of 5 years, a careful analysis of the risks and benefits of HCT and other options should be evaluated with an experienced team of physicians prior to making a decision. Taking the time to discuss the various options with the specialists can help the parents understand the implications of the decisions, both, in the short term and in the long run. With the availability of gene therapy as an alternative, some parents may choose this as their option.

XLT with an MSD: With the excellent success rates of a matched sibling transplant, some experts feel that that HCT is indicated in patients with XLT who have a matched sibling donor4,particularly if the patient is under 5 years of age. This avoids the patient and the family having to deal with the uncertainity of the disease i.e. the potential for the development of malignancies and autoimmune disorders and dealing with bleeding issues. Once again, in patients who are over the age of 5 years, a careful analysis of the risks and benefits of HCT and other options should be evaluated with an experienced team of physicians prior to making a decision.

XLT without an MSD: With improvements in the field of transplantation medicine, the success rates of MUD transplants closely approximate those of a sibling donor. Patients under the age of 5 years have an excellent success rate, with the best success rates3 and least complications noted in children who are transplanted before the age of 2 years. Although, success rates are similar between sibling transplants and MUD transplants, the management of children receiving MUD transplants is considerably more complicated and prolonged2. In the case of patients with XLT without a matched sibling, it is ideal to discuss the various options with a team of experienced physicians prior to decision making. This is one of the several gray areas in WAS, where experts vary in their opinion, making it difficult for parents to decide on what is best for their child. There is no consensus on whether to transplant these patients, even if there is a 6/6 matched cord or an 8/8 matched marrow4. Some parents may choose to use pre implantation genetic diagnosis to have a matched sibling for a transplant. If the decision is made to transplant, it is optimal to transplant these children at an experienced center.

Meetings with the immunologists and transplant physicians is a valuable source of information inunderstanding treatment options and making the decisions that best suits each family. It helps to prepare for these meetings, by having a set of all labs and tests of your child and a list of questions that you might have as the discussion progresses. It is best to have two people during discussions with physicians to provide support, and to be another set of eyes and ears. A wealth of information is usually presented and it is difficult to absorb all the information provided. It may be helpful to have some form of recording of the conversation (with the permission of the physicians) to review at a later time. The thought of your child undergoing a transplant is scary and this is a good time to voice your fears and concerns and have them addressed. Statistics on success rates, mortality are discussed at these meetings. It is a good time to talk about any concerns that you may have about long term issues such as GvHD, infection, infertility, damage to various organs etc.

Making the decision to transplant or not is one of the most difficult decisions that is faced by these parents, particularly in patients with the milder forms of the disease. There are no guarantees either way and both are difficult paths. Parents need support during these times and it is best to avail the support of one’s family, friends, church, network groups etc. It may be helpful to join a support group or discussion forum and talk with parents who have gone through similar decisions. There are several patient blogs who have undergone transplants and it might be a good idea to peruse a few of them. It is important to remember that patients and parents have their biases and most patients ultimately look to the physicians to help them make the choice that is right for their family.

As parents, it is daunting to be faced with making life and death decisions for our children. After going through all the talking and listening, it is important to take a step back and realize that in some cases there is no perfect answer to the problem. There are risks involved no matter what. In some cases, the problems are immediate, in some cases it may be down the road. It is impossible to predict which child is going to have a good outcome and which child is not. Statistics are meaningful up to a point. After that, the chances of survival, infection, lymphoma, autoimmune diseases, GvHD etc is either 100% or 0% for each child. For some families it is a onetime decision and for some it might take several rounds of meetings to help the parents to arrive at a decision that they are comfortable with. Given that the experts themselves have no consensus in many cases, it is important that the wishes of each family is respected and that they are given adequate support to help them care of their child. A web site that allows parents to personalize some of the data and find outcomes based on the the particulars for their child isUS Patient Survival Outcomes Report.

Further Resources:

Citations:

1. Filipovich AH, Stone JV, Tomany SC, Ireland M, Kollman C, Pelz CJ, Casper JT, Cowan MJ, Edwards JR, Fasth A, Gale RP, Junker A, Kamani NR, Loechelt BJ, Pietryga DW, Ringdén O, Vowels M, Hegland J, Williams AV, Klein JP, Sobocinski KA, Rowlings PA, Horowitz MM. Impact of donor type on outcome of bone marrow transplantation for Wiskott-Aldrich Syndrome: collaborative study of the International Bone Marrow Transplant Registry and the National Marrow Donor Program. Blood. 2001 Mar 15;97(6):1598-603.

2. Filipovich A. Hematopoietic cell transplantation for correction of primary immunodeficiencies Filipovich. Bone Marrow Transplant. 2008 Aug;42 Suppl 1:S49-S52.

3. Ozsahin H, Cavazzana-Calvo M, Notarangelo LD, Schulz A, Thrasher AJ, Mazzolari E, Slatter MA, Le Deist F, Blanche S, Veys P, Fasth A, Bredius R, Sedlacek P, Wulffraat N, Ortega J, Heilmann C, O'Meara A, Wachowiak J, Kalwak K, Matthes-Martin S, Gungor T, Ikinciogullari A, Landais P, Cant AJ, Friedrich W, Fischer A. Long-term outcome following hematopoietic stem-cell transplantation in Wiskott-Aldrich syndrome: collaborative study of the European Society for Immunodeficiencies and European Group for Blood and Marrow Transplantation. Blood. 2008 Jan 1;111(1):439-45.

4. Ochs HD, Filipovich AH, Veys P, Cowan MJ, Kapoor N. Wiskott-Aldrich Syndrome: diagnosis, clinical and laboratory manifestations, and treatment. Biol Blood Marrow Transplant. 2008 Jan;15(1 Suppl):84-90.

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