This overview is designed to be a layman's approach to help leukemia patients get started in understanding the difficult issues involved with a Bone Marrow Transplant (BMT), also known as a Stem Cell Transplant (SCT). Of course, only your Oncologist can assess individual needs, requirements, and treatment approach, but it helps to have some basic information so you can understand the Oncologist's language, and to help formulate questions.
A BMT replaces the blood making system of a person who has a serious blood disease. It is much the same as an organ transplant, with many similar issues. So in this regard the blood may be viewed as a "fluid organ". As with any transplant, the old must be taken out before the new is put in. But a BMT cannot remove the diseased blood, so the blood cells must be destroyed - all of them, both good and bad ones, and then the new blood cells can start with a clean slate. The blood making (hematopoietic) system is a very complex system made up of many layers of blood-making cells, starting with blood stem cells and ending with "worker bee" blood cells (white cells, red cells, platelets). The higher level stem cells survive for long periods, possibly a lifetime, and the worker bee cells may only live for several days. So the blood is constantly renewing itself, making billions of new cells every single day during the life of the person. http://en.wikipedia....transplantation
Before considering a BMT, other acceptable options should be ruled out. A BMT is often a "last resort" option. Determine that there is no other reasonable option except a BMT. A BMT will be neither fun nor risk-free, and it can sometimes shorten your life, or make your life miserable. It needs to be very carefully considered, and other options must be ruled out, including clinical trials for experimental drugs and treatments. Get second opinions. Do what it takes to become committed to the process. That does not mean that preliminary preparation cannot continue at the same time, which is often a reasonable approach. But make the final decision carefully.
A BMT can only be accomplished with "starter cells" from a donor, and these cells must be blood stem cells, because only stem cells can continually renew the blood over long periods of time. There are no "artificial hearts" when it comes to the blood, so a donor must provide the starter blood stem cells. The goal is to use these starter cells to form a new blood making system which is free of disease. And once the new blood making system is in place, it must be self-perpetuating. Sounds easy, but it is not. Mainly because the body is very protective of what it allows inside, and that is especially true of the blood. Anything inside the blood that looks "foreign" will be attacked. So when "foreign" blood is introduced into the body, it must be done in a very careful manner, and the new blood cells must be a suitable match to prevent rejection and serious side effects.
Highly matched donor blood cells are certainly preferred for two reasons: 1) poorly matched donor cells are more likely to be rejected by the body (failure to engraft the new blood cells), so the new blood cells do not take hold, which would leave the patient without any blood cells at all; and 2) poorly matched donor cells can cause significant graft vs host disease (GVHD) whereby the body continually attacks the new blood cells which are seen as "foreign", causing side effects that can range from discomfort to life threatening. So matching of donor blood cells to the recipient is likely the most important and time consuming part of the transplant process.
When discussing donor matching, it is not as simple as matching blood types such as O, A, B, or AB. The blood cells have markers on them called antigens which show they belong in the body. If the cell does not have the appropriate antigens, the body will seek to destroy it. This is how the body fights disease and infections, but it could also lead to rejection of the donor blood cells since they could be viewed as invaders. Matching is about selecting blood cells that the recipient's body will find reasonably acceptable. The human body, and especially the blood, is a high security zone, meaning the body does not tolerate intruders. So the body is constantly doing cell identification to make sure only approved cells are in the body. It does this by looking at the surface of a cell, which in high magnification can look like a spaceship from Star Wars - all kinds of bumps and protrusions hanging out. Among these on the white blood cell surface are "human leukocyte antigens" (HLAs) which are important for identification purposes. The body will attack cells that do not have the proper HLA "bumps" in the right places and the right sizes, so the key to matching blood cells are to find cells that have very similar HLAs on the cell surface. This allows the recipient's body to look at the new cells and deem them acceptable. If they are not deemed acceptable, they will be attacked as invaders, and the attacks can vary in intensity.
There are various degrees of acceptable matching, for which there is no magic formula, but there are established guidelines. And by the way, regardless of what anyone tells you about finding a "perfect match", there are only two truly perfect matches to your blood cells - yourself, and an identical twin. All other blood matches are imperfect -- period. So a main issue involved is that donor blood cells must be from a "compatible" donor, not a perfect donor, since compatibility of blood cells is a relative term unless the donor is an identical twin (and even then not always perfectly matched).
So when doing this HLA matching, you may hear people talk about 6 out of 6 HLA match (6/6), or 8/8, or 10/10, or 12/12. You may also hear people say that some of these are a "perfect match", but they are not, since there are hundreds of minor HLAs, not just 10 or 12. A so-called "perfect match" using the 10/10 or 12/12 or any higher matching scale is actually mismatched in many ways, but hopefully in less significant ways. So HLA matching is always some degree of non-matching, including siblings (except for an identical twin). The gold standard HLA match for a BMT is 10/10, and is often called a "perfect match", but it is not perfect at all since there are hundreds of antigens, not just 10. But we cannot change the whole world at once, so we will simply move on.
Matching a donor to a recipient is extremely important since an "acceptable match" is important to both survival and reducing graft vs host disease (GVHD). So a 10/10 match does not account for numerous minor HLAs, but fortunately these are usually not as important. But even a 10/10 match can sometimes result in GVHD, which shows that a somewhat significant mis-match has occurred among secondary antigens. The science is not very good at determining when secondary HLA mis-matches might become an issue, but they are normally not a significant issue.
A person receives half of their HLA type from each parent. So, for example, when a 10 out of 10 match is discussed, it means 2 sets of 5 antigen types, 5 received from each parent. So a person has one set of these 5 from their father and one set of the 5 from their mother, making up the 10 which should be matched when possible. So HLAs come in pairs, just as chromosomes do (23 chromosomes from each parent make up the 46 chromosomes in each cell of the child).
Transplant centers vary in how they describe HLA matching. The numbers are derived as follows. There are six "major" HLAs called HLA-A, HLA-B, HLA-C, HLA-DR, HLA-DQ, and HLA-DP, and a person has two of each of them - one of each passed down from each parent. So that is a total of twelve "major" HLAs, six from each parent. This is where the 12 out of 12 matching (12/12) comes from. But since HLA-DP is generally not considered as important as the others, it is often ignored, so the generally accepted "optimal match" if HLA-DP is ignored is 10/10. And although matching HLA-DP might be preferable, it is difficult to match 10/10 let alone 12/12. Most transplant centers attempt to achieve a 10/10 match. So if you have a 10/10 match, this should provide acceptable (not perfect) outcome, 9/10 should provide a very good outcome, and 8/10 can sometimes provide an acceptable outcome assuming it is as good as can be found. The caveat with playing the numbers game is that some HLAs are more important than others, so an 8/10 could be a bad match if the most important HLAs are unmatched -- this issue is often overlooked, so be careful here. Since some HLAs are more important than others, if the match is 9/10 and especially 8/10 but lacking one or more of the most important HLAs, the match is not as good as a 9/10 or 8/10 that includes the more important HLAs. In such cases, the match may not be acceptable at all. The most important HLAs are generally consided to be HLA-A, HLA-B, HLA-DRb1. Recall that cells have two of each of these HLAs, so when these three pairs all match the donor cells it is called a 6/6 match (also called a "clinical match"). The bone marrow Donor Registry only tests for "clinical matches", which is why a true match cannot be found simply by looking at the Donor Registry information. So additional testing of the 6/6 matching potential donors is required before an acceptable match can be found.
Many transplant centers believe that HLA-C should also be in the list of the most important HLAs when matching. This is why they will require an 8/8 match using the 4 "most important" HLAs, and every person has 2 of each HLA, one set from Mom and one set from Dad. The 10/10 matching adds HLA-DQ. And as we have noted, the 12/12 adds HLA-DP to the list.
So what is the process leading up to a BMT, and what are the timelines? They are different for each person, but in general they are as follows:
1) Determine that there is no other reasonable option except a BMT. A BMT will be neither fun nor risk-free. It needs to be very carefully considered, and other options must be ruled out, including clinical trials for experimental drugs and treatments. Get second opinions. Do what it takes to become committed to the process. But any patient can start the preliminaries for a BMT to shorten the timeline for later use, if desired. This is mainly looking for a suitable donor by testing siblings, which are more likely to match the recipient (25% chance per sibling). One caveat about most blood cancers - doctors are way too optimistic about what chemotherapy can do. Few are cured by the induction/consolidation strategy. Get the real story and decide.
2) Find a donor that is the best match possible, or determine that there is not a good match for you. If you have a matched sibling (probability is 25% for each sibling), then all is well. If not, this can be very time consuming, taking possibly months, so getting started before completing step 1 above is not a bad idea. See www.marrow.org
A side note here is that not everyone in the donor registry would actually commit to the procedure when the time comes to do so. Reality is tougher than the concept for some people. The percentage is small, but it does happen. A match is not a match until the cells are actually donated.
3) Look at the options for various BMT techniques based on donor matching results. Donor availability will drive the type of BMT used. If a good match is found, then a typical allogeneic (donor) BMT will likely be done. Otherwise, there are other options, even for those without a good match (see later).
4) Close in sequence, or possibly simultaneous to 3 above, is selection of a transplant facility. Not all are equal. BMT is a risky procedure with many variables. There are degrees of quality among various centers. You need to select wisely. Above all use a certified transplant center in the National Marrow Donor Program (NMDP) Network:
The best facility for you may be far away from home. But then there is also something to be said for using a competent one that is closest to home (family & support groups, your own home, logistics of getting follow-up check-ups and care, etc). But local is not always the best choice. This could take some time - do your research well. Ask tough questions about the Center's history and results.
5) Set the timing for the BMT and work toward it with purpose. There is a lot to do.
6) Get yourself in better physical condition. Walk, bike, work out, whatever. Eat better. You will need stamina. Get up and get moving.
7) Get your life in order -- well, to some degree at least. Off-load responsibilities, assign roles, assume you will be out of commission for quite a while. Maybe you won't be, but plan for the longer and hope for the shorter. Get any dental cleaning and work done now, and other medical procedures which might be required within the next year or so.
8) Thoroughly clean your home environment. When you come back after BMT you will be susceptible to viruses, bacteria, etc. Clean with a purpose. And make everyone keep it clean. It cannot be too clean. And that goes for people, too. Especially the people. Think clean, be clean, require clean.
9) Depending on personality, if you want to know what is coming, read the blogs of those who have gone before you. If you prefer to live in the present, stay away from them.
Once the BMT process begins, it usually has three main steps (with many sub-steps). These main steps are: 1) Attempt to destroy the existing diseased blood making system, generally with chemotherapy and radiation, 2) Transfuse compatible non-diseased donor blood stem cells into the patient to form a new blood making system, and 3) Monitor and treat the patient while waiting for donor cell engraftment. This sounds simple, but it is not. There are a number of issues that come into play which will be discussed later. And the process will take several weeks at a minimum, but possibly months if complications occur.
Once the diseased blood making system (and the immunity along with it) is destroyed, the new blood stem cells must be infused immediately. This "in-between" period after the old blood has been destroyed, and the new blood cells have not yet taken hold (engraftment) leaves the patient defenseless against even routine ailments, bacterial infections, and so forth. These now become life-threatening events that require medications in place of the immune system. After the new cells are transplanted into the blood, the waiting begins as the new cells engraft to start up a new blood making system. This can take a couple weeks, or longer, depending on the type of transplant. Hopefully the new immune system will begin to become functional within a month or so, but there will still be a long way to go. Don't let your guard down.
What are some of the variables involved in a BMT? First, the blood making system is hard to kill. The body protects the blood cells in a number of sophisticated ways that enable survival under extreme conditions. And the most difficult blood cells to kill are the stem cells. So killing all the diseased blood stem cells without killing the entire patient is a difficult and even tricky task. And this is very important since any diseased stem cells that escape could potentially reconstitute the entire disease over time (disease relapse). Chemotherapy and total body irradiation are used to attempt to eliminate the existing blood making system. Often this is successful, but sometimes it is not, since blood stem cells can hide deep in bone marrow niches where it is difficult for chemo to reach them, and radiation might miss them due to bone mass.
Another variable is the type of BMT that will be used. As discussed previously, this often depends on availability of a suitable donor. If a good match is found, the standard matched donor (either related to you or unrelated to you) will likely be used. If no suitable donor exists, there are several other options. These are nicely summarized in the following tutorial:
So if no suitable donor exists, a BMT can use mis-matched blood cells under certain conditions. Remember as you read these that there are reasons why they are not the primary method for a BMT, since each has its own issues. So these are generally not used if a good HLA match can be found since they are considered generally higher risk procedures. Those risks can be risk of transplant failure, disease relapse, suseptibility to infection or virus, significant graft vs host disease, or other risks to the patient. Other types of BMT can be quickly summarized as follows:
Cord Blood Transplant:
Blood collected during childbirth from unrelated women (usually) can be used for a BMT. HLA matching is not as important since these very young blood stem cells have not fully developed their antigens, so they can often adapt to the recipient even though clinically mis-matched. But since the number of stem cells in a unit of cord blood is small, the transplant will usually involve two separate units from separate people, and one of the two cell types will hopefully engraft. Timeline for engrafting is often longer, and rejection rates are higher.
This is a misnomer, but "mini" means less chemotherapy and no radiation during the preparation phase. This is often used in much older patients who cannot withstand the harsh chemo and radiation. The patient's blood cells are only "stunned", not fully destroyed, then the mis-matched donor cells start a "war" in the blood and take over control, killing the old blood cells. So HLA matching is not required. There are a number of risks, as one might imagine.
This uses significantly mis-matched parents, children, or siblings as donors. As discussed earlier, a person receives half of their HLA type from each parent. So when a 10 out of 10 match is discussed, it means 2 sets of 5 antigen types, 5 received from each parent. These 5 generally more important antigen types are called A, B, C, DRB1, and DQB1. So a person has one set of these 5 from their father and one set of the 5 from their mother, making up the 10 which should be matched when possible. Since one of the two HLA-A, HLA-B, and HLA-DRb are often a match for these related persons, these partial (often 3/6) matches combined with other techniques can make this an option when there is not an acceptable HLA match otherwise. Delayed engraftment is an issue, keeping the patient at risk due to lack of immunity for an extended period. There are also issues related to whether the techniques used will work in each case, including T-cell depletion, and other techniques that seek to prevent graft failure and GVHD due to the high mis-match. This is still considered experimental in many ways, but has made progress over the years.
One's own blood stem cells are harvested, sorted to attempt elimination of diseased cells, the existing blood system is either destroyed by chemo/radiation or not, and the supposedly non-diseased cells are put back in to re-start the blood production. Since these are the patient's own cells, the HLA matching is not an issue. But since the "cell sorting" process is not entirely effective, relapse rates are high. This is normally only used when no better option exists, or to buy time for some reason, but can sometimes be a reasonable option for certain sub-types of blood diseases.
Earlier we discussed that diseased blood stem cells might evade attempts to destroy them using chemo and radiation. But a second line of defense is "graft vs leukemia effect" (GVLE) which is similar to graft vs host disease (GVHD). If any diseased blood cells survive the chemo/rad treatment, then they may be killed off when the new blood cells take over, see the old (diseased) blood cells as foreign, and attack and destroy them. This odd turnabout, where the old blood cells that belong to the body are now seen as foreign is poetic justice that can sometimes help permanently eliminate the disease. This does not mean that an identical twin should not be used as a donor, but it is one advantage in having a good but imperfect match. (Recall that the only perfect donor match is an identical twin). As a related issue, if the original BMT begins to fail at some point, a second infusion of donor stem cells (without the chemo/rad pre-treatment) can sometimes salvage the engraftment process. This procedure is called a "Donor Leukocyte Infusion".
There are other issues involved with BMTs. Although HLA typing is the most important part of matching a donor to a patient, there are also other issues. Survival rates increase when the donor has the following characteristics:
Negative for cytomegalovirus (CMV), male, younger age, same blood type (i.e., A, B, O, AB), larger body weight, and matched race. However, these issues can only rarely be controlled.
BMT Outcomes -- Survival, Quality of Life, and Non-Survival:
BMT outcomes are "variable". The statistics are not great, but are not unacceptable. It is also difficult to summarize all types of blood diseases and their associated statistics. But the theory is that a BMT is used only when the patient would not otherwise survive without it. Outcome is affected by the overall health of the patient going into the BMT, age, donor matching, and other factors. You should go into a BMT expecting that the probability of long term survival is about 50/50 in rough numbers, although positive factors can increase that number, and negative factors can decrease it. There is also an old 30/30/30 "rule" which says that 30% are cured and live a great life, 30% relapse or live a poor quality life (GVHD), and 30% don't survive the BMT process (one year). And survival is not the only issue. Relapse is also a problem, since these blood cancers are hard to wipe out before starting over with the new blood system. And GVHD can certainly reduce the quality of life after the BMT, or it can also kill - which is why so much time was spent discussing HLA matching. These are hard things to discuss, but they must be considered. But if a person truly needs a BMT, then stats are irrelevant, and the person is a statistic of one. If you must have a BMT, do everything you can to increase your odds of survival. You have more control than you know. If you are asking "How?", the re-read everything before this paragraph. Optimal HLA matching, getting into better shape, choosing the best timing, keeping your surroundings ultra-clean, keeping well meaning people away from you during low immunity, telling nurses and others to re-wash their hands - it all adds up. Be paranoid - it is about survival.
Here is some information about BMT survival, and shows the impact of timing, disease stage, and HLA matching on survival:
Here is a chart of one-year survival rates for the top rated transplant centers using www.marrow.org data:
Some BMT trivia related to Matched Unrelated Donor BMTs:
1) The new blood will have a different DNA than your old blood (maybe you could fool the CSI detectives). But your other body tissue DNA is unchanged.
2) Your previous vaccinations are generally wiped out - new ones will be needed. The donor's blood will have immunities built up, but they will not be the same ones you had with your old blood.
There is much, much more information that could be added. Likewise, each individual will have a strong opinion about this difficult issue, and will argue about certain points. This has been kept concise (sort of) and is only meant to help people get started who find themselves in this difficult situation. There are many blood diseases that can result in a BMT, and they have individual issues, treatment options, and variable outcomes. But hopefully this puts some of the basic issues into a more understandable format so you can begin to make sense of this difficult subject, and provide a basis for discussing personalized treatment options with your Hematologist/Oncologist.