Jump to content


Photo

Bone Marrow Transplant -- Introduction and Basics


  • Please log in to reply
22 replies to this topic

#1 Trey

Trey

    Advanced Member

  • PS Beta Group
  • PipPipPip
  • 1,705 posts
  • LocationSan Antonio, Texas

Posted 26 April 2011 - 09:07 PM

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.

http://www.marrow.or..._HTC/index.html

http://www.marrow.or...ping/index.html

http://www.bbmt.org/...0274-7/fulltext

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:

http://www.marrow.or...ist_by_state.pl

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:
http://www.cancer.go.../allpages/print

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.

Mini-Transplant:

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.

Haplo-Identical Transplant:

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.

Autologous Transplant:

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:

http://www.marrow.or..._HCT/index.html

Here is a chart of one-year survival rates for the top rated transplant centers using www.marrow.org data:

http://www.northside...ated_Charts.pdf

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.



#2 lala

lala

    New Member

  • Members
  • Pip
  • 0 posts

Posted 26 April 2011 - 09:37 PM

After reading this, I feel even more grateful for Gleevec----i guess i need to quit complaining about my fatigue at 54 years old!  WOW-this would be a tough journey.....

~lala



#3 warrior

warrior

    Advanced Member

  • Members
  • PipPipPip
  • 112 posts

Posted 27 April 2011 - 04:19 AM

I am  a caregiver of an auto-sct and do not  hang out on this board but saw the title of your post. In general it is a pretty good discription of alot of information. I do take acception to your  discription of auto SCT and mini transplants. For certain molecular variants of AML an auto sct is as effective as an allo I refer you to fig 3 of N Engl J Med. 2008 May 1;358(18):1909-18. Patients stem cells or cd34+ cells are not "cleaned" . They can be screened for the AML mutation by pcr and the current  hypothesis is that when there is a relapse after an auto it is because there were some remaining leukemic stem cells left after the myeoblative chemo.  I do not know about cml but an auto-sct is a viable option for certain AML varients and if you check out the bone marrow sct  board there are several success stories with this treatment part of clinical trial CALGB10503-02. As for mini - allo it depends on the protocol and the donor cells are HLA matched and patients  get  some chemo and some TBI. They are  designed for patients who can not tolerate harsh chemo and TBI usually older patients.



#4 hannibellemo

hannibellemo

    Advanced Member

  • Members
  • PipPipPip
  • 728 posts
  • LocationNorth Central Iowa

Posted 27 April 2011 - 06:29 AM

Warrior,

I agree with you that an auto-sct can be used successfully for AML. I have a friend that has done that, twice. The first was 20 years ago and she relapsed 10 years after, it is now 10 years after the second and she is very nervous waiting for the other shoe to drop. AML is, unfortunately, the least of her worries now because of all of the damage to her heart from the radiation and chemotherapy all those years ago.

Pat


Pat

 

"You can't change the direction of the wind but you can adjust your sails."

DX 12/08; Gleevec 400mg; liver toxicity; Sprycel 100mg.; CCyR 4/10; MMR 8/10; Pleural Effusion 2/12; Sprycel 50mg. Maintaining MMR; 2/15 PCRU; 8/16 drifting in and out of undetected like a wave meeting the shore. Retired 12/23/2016! 18 months of PCRU, most recent at Mayo on 7/25/17 was negative at their new sensitivity reporting of 0.003.<p>


#5 WoofWoof

WoofWoof

    New Member

  • Members
  • Pip
  • 1 posts

Posted 27 April 2011 - 07:59 AM

Thanks Trey, very informative and timely for me.


I have cancer but it doesn't have me


#6 HeatherZ

HeatherZ

    New Member

  • Members
  • Pip
  • 0 posts

Posted 27 April 2011 - 09:10 AM

Here is a blog for a girl in the midst of this right now: http://www.heatherwa...e.blogspot.com/

I 'met' her in the CML group on Facebook - She was dx with CML when she was pregnant.  Shortly after her baby was born (in Oct/Nov 2010) she found out she had AML (or possibly ALL, I can't remember) and she started the blog during her first extended stay for chemo.  Her cancer center is Emory and she has nothing but good things to say about them.  She is now a few weeks post transplant and doing pretty well.



#7 Trey

Trey

    Advanced Member

  • PS Beta Group
  • PipPipPip
  • 1,705 posts
  • LocationSan Antonio, Texas

Posted 27 April 2011 - 09:17 AM

Thank you.  I clarified a couple minor points to account for you inputs.  I included auto BMT because it is an option to consider for a limited number of people.  But in general the relapse rates are indeed very high for auto transplants, generally 60% - 80%, but of course it depends on disease type, stage, etc, etc.

Just to clarify, you mentoned that PCR can screen for leukemic cells in the sorted blood that would be used for the transplant, but PCR is not sensitive enough to declare the sample clear of leukemic cells.  It can only reliably detect about 1 in a million, and a BMT requires many millions of starter cells, so there is no way to determine that the transplant cells are disease-free.

BTW, I read your NEJM reference, but it does not appear to discuss the issue from what I read:

http://www.nejm.org/...ticleBackground

It only compares auto transplant to chemo alone (no transplant), where both have high relapse rates, unless I missed something?

We hope your family member continues to do well.



#8 LivingWellWithCML

LivingWellWithCML

    Advanced Member

  • Members
  • PipPipPip
  • 60 posts
  • LocationAtlanta, GA

Posted 27 April 2011 - 11:52 AM

Wow, her story is so incredible!  It's also reassuring to see that she had her transplant done at Emory in Atlanta - that's where my CML is being treated as well.  Here's to her continued recovery...

Dan


Dan - Atlanta, GA

CML CP Diagnosed March 2011

Gleevec 400mg


#9 HeatherZ

HeatherZ

    New Member

  • Members
  • Pip
  • 0 posts

Posted 27 April 2011 - 12:13 PM

I think seeing her pictures from her beginning chemo and then the picture of her getting the transplant is just so telling - You can definitly see the toll this process takes.



#10 warrior

warrior

    Advanced Member

  • Members
  • PipPipPip
  • 112 posts

Posted 27 April 2011 - 12:38 PM

Here is the reference of the article :

N Engl J Med. 2008 May 1;358(18):1909-18.

Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia.

Schlenk RF, Döhner K, Krauter J, Fröhling S, Corbacioglu A, Bullinger L, Habdank M, Späth D, Morgan M, Benner A, Schlegelberger B, Heil G, Ganser A, Döhner H; German-Austrian Acute Myeloid Leukemia Study Group. If you look at fig 3 a normal karyotype with NPM1+ FLT3- there is no increase in out come with an allo-sct.   Where did you get the 60-80% figure for relapse for it truly misleading. Is this for CML? AML is caused by over 52 different mutaions and lumping all the data together  is really not usefull. Treatment needs to risk adapted for the specific mutation associated with the disease. I agree that the PCR does not guarentee that the cd34 + stem cells are disease free. In my own laboratory studying completely other things the sensitivity of the pcr reaction is much more sensitive than 1 in a million. We can get a positive band from 1-2 cells with the correct primers.


#11 Happycat

Happycat

    New Member

  • Members
  • Pip
  • 5 posts

Posted 27 April 2011 - 03:29 PM

Trey,

Thanks for the info.  I'm surprised your fingers haven't fallen off typing all that!  It's a good basic guide.

Question for you and perhaps Warrior since it sounds like she does PCR work -

This might be a totally dumb question, but if PCR is used to make millions of copies of a gene (think that's right), why can't they just take a few good stem cells from a patient, amplify those good genes, then go in to the bad stem cells, extract the bad genes and replace it with good genes??  Just thinking there ought to be some way to use microbiology (molecular biology?) techniques to repair defective stem cells.

Traci



#12 Trey

Trey

    Advanced Member

  • PS Beta Group
  • PipPipPip
  • 1,705 posts
  • LocationSan Antonio, Texas

Posted 27 April 2011 - 03:29 PM

Here are partial comparative relapse rates.  Relapse rate for AML by itself (all sub-types) for autologous BMT is 35 - 70%.  Other blood cancers are even higher, such as MDS.

http://books.google....epage&q&f=false

See page 220 chart

Individual sub-types can certainly have differing outcomes, such as your family's case where there is normal karyotype (no chromosome translocation) and certain other specific mutations. My point remains to educate  those who might be facing a BMT in their future, so they will understand that while auto is an option in some cases, they should know that there is a very good reason why auto BMTs are rarely done -- high relapse rate.  Where there are exceptions, their own Onc will point that out.



#13 Trey

Trey

    Advanced Member

  • PS Beta Group
  • PipPipPip
  • 1,705 posts
  • LocationSan Antonio, Texas

Posted 27 April 2011 - 03:34 PM

Bad chromosomes in a cancerous cell cannot be "fixed" to cure the disease.  The cancerous cells must be eliminated in some manner to allow good cells to take control and maintain control over the long term.



#14 warrior

warrior

    Advanced Member

  • Members
  • PipPipPip
  • 112 posts

Posted 27 April 2011 - 03:48 PM

replacing a mutant gene in  human is not an easy task and is probably not a reasonable approach for leukemia however genetic repalcement of defective genes in humans has actually been accomplished (see

Ophthalmic Genet. 2008 Sep;29(3):89-91.Successful RPE65 gene replacement and improved visual function in humans)


#15 Happycat

Happycat

    New Member

  • Members
  • Pip
  • 5 posts

Posted 27 April 2011 - 06:37 PM

There are new technologies to edit genes (zinc fingers among them), that have shown good efficacy in early clinical trials.  There's a company called Sangamo (SGMO) that uses zinc fingers to selectively edit/modify genes.  Read the investing article below.  It's really fascinating technology.  My company licenses the technology from Sangamo, and it is way cool.  

They have actually been able to modify the CCR5 gene sequence for HIV patients, produce an autologous T-cell, then infuse that into the patients.  Five of the 6 patients treated had durable improvements in their T-cells.  It could actually end up being a cure for HIV - early days, so might not pan out, but quite exciting technology!

http://seekingalpha....logy?source=msn

Anyway, if they can modify T-cells of HIV patients, I figure it's got to be possible to modify those leukemic stem cells.  Maybe not today, but 10-15 yrs??

Traci



#16 CallMeLucky

CallMeLucky

    Advanced Member

  • Members
  • PipPipPip
  • 216 posts
  • LocationCT

Posted 27 April 2011 - 07:51 PM

"I figure it's got to be possible to modify those leukemic stem cells."

Is there a way to flag the leukemic stem cells?  I thought part of the issue was that they could hide and you can't always detect them at low levels?


Date  -  Lab  -  Scale  -  Drug  -  Dosage MG  - PCR
2010/Jul -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 1.2%
2010/Oct -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0.25%
2010/Dec -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0.367%
2011/Mar -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0.0081%
2011/Jun -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0%
2011/Sep -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0.00084%
2011/Dec -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0%
2012/Mar -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0.004%
2012/Jun -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0%
2012/Sep -  MSKCC  -  Non-IS  -  Gleevec  - 400 - 0%
2012/Dec -  MSKCC  -  Non-IS  -  Sprycel  - 100 - 0%
2013/Jan -  Quest  -  IS  -  Sprycel  -  50-60-70  - 0%
2013/Mar -  Quest  -  IS  -  Sprycel  -  60-70  - 0%
2013/Apr -  CUMC  -  Non-IS  -  Sprycel  - 50 - 0.036%
2013/May -  CUMC  -  Non-IS  -  Sprycel  - 50 - 0.046%
2013/Jun -  Genoptix  -  IS  -  Sprycel  - 50 - 0.0239%
2013/Jul -  Genoptix  -  IS  -  Sprycel  - 70 - 0.0192%
2013/Jul -  Genoptix  -  IS  -  Sprycel  - 70 - 0.0034%
2013/Oct -  Genoptix  -  IS  -  Sprycel  - 70 - 0.0054%
2014/Jan -  Genoptix  -  IS  -  Sprycel  - 70 - 0.0093%
2014/Mar -  Genoptix  -  IS  -  Sprycel  - 100 - 0.013%
2014/Apr -  Genoptix  -  IS  -  Sprycel  - 100 - 0.0048%
2014/Jul -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2014/Nov -  Genoptix  -  IS  -  Sprycel  - 100 - 0.047%
2014/Dec -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2015/Mar -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2015/Jun -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2015/Sep -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2015/Dec -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2016/Mar -  Genoptix  -  IS  -  Sprycel  - 100 - 0.0228%
2016/Jun -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2016/Sep -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2016/Dec -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2017/Mar -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2017/Jun -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2017/Sep -  Genoptix  -  IS  -  Sprycel  - 100 - 0%
2017/Dec - Genoptix  -  IS  -  Sprycel  -  100 - 0%
 

 


#17 Tedsey

Tedsey

    Advanced Member

  • Members
  • PipPipPip
  • 85 posts

Posted 27 April 2011 - 08:01 PM

I think the trouble is that they don't really know what they look like.  It appears cancer cells look very similar to normal cells.  I would love it if someone would write and tell me I am wrong and LSC can be definitively identified.  And I think there are only very educated guesses as to what the markers are on healthy stem cells too.     



#18 Trey

Trey

    Advanced Member

  • PS Beta Group
  • PipPipPip
  • 1,705 posts
  • LocationSan Antonio, Texas

Posted 27 April 2011 - 08:58 PM

Tedsey,

You are correct that no one knows exactly what a leukemic stem cell looks like.  It may be CD34+CD38-LYN- , but then does it have one or all of the following:

CD45RA+

CD123loCD45RA+

Or is it

CD34+CD38lowCD19+

When cells are sorted, they are sorted at a level that cannot filter out the leukemic stem cells, since they are not precisely identifiable.



#19 warrior

warrior

    Advanced Member

  • Members
  • PipPipPip
  • 112 posts

Posted 27 April 2011 - 09:15 PM

There is a recent paper in PNAS MArch 22, 2011 (5009-5014)  entitled Prospective separation of normal and leukemic stem
cells based on differential expression of TIM3, a human acute myeloid leukemia stem cell marker by
Jana et al. that suggests that TIM3 maybe an important marker



#20 valiantchong

valiantchong

    New Member

  • Members
  • Pip
  • 0 posts

Posted 27 April 2011 - 10:21 PM

Identifying and targeting leukemic stem cells

To identify CML stem cells, we tested whether BCR-ABL-expressing HSCs function as the stem cells. We first sorted HSCs (Lin-c-kit+Sca-1+) were sorted out from C57BL/6 BM cells and then transduced with BCR-ABL retrovirus, followed by transferring into recipient mice. The mice developed and died of CML. To definitively confirm that BCR-ABL-expressing HSCs are CML stem cells, we isolated bone marrow cells from primary CML mice, and sorted out the BCR-ABL-expressing HSCs (GFP+Lin-c-Kit+Sca-1+) by FACS. The sorted cells were transferred into recipient mice, and the mice developed and died of CML, indicating that BCR-ABL expressing HSCs function as CML stem cells.

One of major focuses in the lab is to understand the biology of leukemia stem cells (LSCs), and to identify selective and effective target genes that play key roles in survival and self-renewal of these LSCs. Based on our DNA microarray data and genetic validation of candidate genes in our leukemia mouse models, we have identified a group of genes that are essential for the functions of LSCs, shedding light on developing an anti-stem cell therapy for CML.


http://www.umassmed....fm?faculty=1323






1 user(s) are reading this topic

0 members, 1 guests, 0 anonymous users