Trey's CML Leukemia Blog

Making CML Leukemia Understandable

Trey's CML Blog

INTRODUCTION

This Blog is an attempt to compile several years of my postings from the Leukemia Lymphoma Society (LLS) CML Bulletin Board website. A number of people have said they found the posts to be useful for reference information.  For the current CML Support Group on the LLS website, click here and join in on the discussions with fellow CML patients and family members:
I am NOT a doctor. If this information is of any value, it is only for use in developing questions for your own Oncologist. If you want actual medical advice, always ask your Oncologist. I am just a fellow CML survivor helping where I can, and have no medical training whatsoever. This is not advice, just compiled postings from several years of CML survivors talking with each other. That is all this is -- nothing more.
This Blog starts with some general information I have written for those recently diagnosed with CML leukemia, then topics are arranged in alphabetical order. So it is likely more interesting to pick topics instead of reading in alphabetical order.

I have also written papers on CML special subjects which can be seen at this link:
http://community.lls.org/people/Trey/content?filterID=contentstatus[published]

Information for the CML Newly Diagnosed

We all remember how helpless we felt when newly diagnosed with CML. The information below covers a variety of subjects, starting with general information, and going to more specific information about CML. When getting started it helps to know where to find just a very few of the more useful CML resources. This information may also help avoid the numerous out-of-date (and needlessly scary) websites that would only cause undue anxiety, which is what most people find when initially searching the internet for information about CML leukemia, especially related to survival, prognosis, life span, and other important issues. This information is also useful to help family and friends understand what the newly diagnosed CML patient is facing. And the news is generally positive, since the outlook for CML has greatly improved over the past decade.
In general, the outlook for CML has changed significantly for the better since 2001 when Gleevec was approved for treatment. This drug changed CML from a deadly disease into one that has been highly survivable for most people, with less impact on our quality of life than prior to 2001. Additional CML drugs (Sprycel, Tasigna, Bosutinib, and Iclusig) have also been approved, and more are being developed. As a result of these extraordinary new drugs, the overall probability of surviving CML is now close to 95%. This compares with numbers that were very low prior to the introduction of Gleevec and the other drugs.
After reading this initial information I encourage you to visit the Leukemia & Lymphoma Society (LLS) CML Support Group where those with CML share our collective information about living with CML leukemia. We are a group of CML patients, caregivers, family & friends who help each other, but we are not doctors. Here is our home page if you wish to join us:
http://community.lls.org/community/bloodcancer/livingwith/cml
 
To start with some good news, here is a summary article that shows the dramatic changes in treating and surviving CML as a result of the drugs which have been approved since 2001. The article says that “In a study of patients with chronic myeloid leukemia, some 95 percent have survived the cancer after five years due to treatment with Gleevec...”
http://www.sciencedaily.com/releases/2006/12/061207160526.htm

News articles about how CML has become a very survivable disease:
http://jnci.oxfordjournals.org/content/early/2011/03/23/jnci.djr127.full
http://www.nytimes.com/2010/01/19/health/19brod.html?partner=rss&emc=rss
Dr Brian Druker, a leading CML specialist who was instrumental in the development of Gleevec, said that most CML patients could expect to live at least 30 years after diagnosis just based on current CML drugs even if nothing else comes along; but since much more is coming in the future, 30 years is likely just the beginning. Because Gleevec was only approved just over a decade ago, CML experts had previously hesitated to put a time-frame on expected survival due to lack of data, even though they often said it could be significant. So hearing Dr Druker say this shows the continually rising expectations for long term survival of CML. This should be very encouraging, and especially encouraging to young people with CML.
It is important for patients, family, and friends to know the following: 1) CML has changed from a poor prognosis to a very good prognosis due to the multiple available drugs – the survival rate is around 95%; much internet information is very out-of-date on this issue because of the recent advances in CML drug therapy; 2) bone marrow transplant has become a very rare event for those with CML, where in the past it was a primary therapy; 3) CML is probably the most likely leukemia to have a cure discovered in the reasonable future, according to CML experts. This information does not mean every person will respond the same way to drug therapy, and there is still a small percentage chance of not surviving CML, but the overall news is very positive.
The Leukemia & Lymphoma Society (LLS) Online Pamphlet and L&LS CML Overview provide excellent information for the newly diagnosed:http://www.lls.org//attachments/National/br_1169054588.pdf#/resourcecenter/freeeducationmaterials/leukemia/cml
Information from leading CML specialist Dr Brian Druker:
http://www.cancereducation.com/medclips2/abbz/transcripts.pdf
Animation showing the chromosome translocation that creates the BCR-ABL gene that causes CML and also how CML TKI drugs work: 
 http://www.youtube.com/watch?v=7ZMVQ1Vbb7Y
Video Presentations on CML and Treatment:http://www.leukemia-lymphoma.org/all_page?item_id=161418http://www.lls.org/#/resourcecenter/pastprograms/leukemia/
See “Archived Education Programs” and click on “MP3” for each video

Time Magazine article from 2001 when Gleevec was first approved:

The Leukemia & Lymphoma Society has a live person help line available to answer questions about CML:
1-800-955-4572
If you wish, before you call the L&LS CML Helpline, you can also search our support group website using the search button in the upper right part of the web page. You can search for discussions we have had regarding many subjects such as drug side effects, understanding test results, and many other subjects. Or just join our support group and start posting questions. For instance, here is a previous discussion that might be useful right away regarding CML testing and language your doctor might be using that sounds very foreign to you such as PCR, FISH, cytogenetics, bone marrow biopsy, and so forth:
http://community.lls.org/people/Trey/content?filterID=contentstatus[published]

This information is trying to fill a need to help the CML newbie get started, and to help eliminate the unnecessary shock of sorting through outdated information about CML on the internet that will needlessly scare you, your family, and friends. So much has changed in such a short time due to the new CML drugs. As a result, you will very likely live a long and mostly normal life, and without requiring a marrow transplant. A very small number will still not be so fortunate, but research continues to make advances, and new drugs are coming along to help those who are not currently doing as well. There is much to be hopeful about, and much to be grateful for. We are here if you need us, so please join in and learn along with us about living with CML leukemia.
http://community.lls.org/community/bloodcancer/livingwith/cml

Things To Do When Newly Diagnosed With CML Leukemia:
1) Assure the proper tests were performed.  Your Oncologist should have performed the following tests at diagnosis:  Complete Blood Count, Bone Marrow Biopsy (BMB), BCR-ABL FISH, BCR-ABL PCR
If any of these were not performed ask the Onc to perform them.

2) Get copies of all test reports, now and always.  Especially get a copy of the BMB report.  The doc must give test result reports to you if you ask.

3) Find out which CML Phase you are in at diagnosis (Chronic, Accelerated, or Blast).  If Accelerated or Blast, ask what defined that diagnosis

4) Ask what drug you will start with.  Traditionally Gleevec is the starting drug, but there are several options.  There is no right answer, but if in Accelerated or Blast Phase it should NOT be Gleevec.  

5) Ask if you will also take Allopurinol during the first couple weeks of starting the drug therapy.  Ask how long to take the Allopurinol (only a couple weeks normally)

6) If your Onc wants to start you on Hydroxyurea (HU) I would be reluctant unless the White Blood Count is extremely high (maybe over 500K).  The CML TKI drugs do the work HU can do but with less risk.  Read more about Hydroxyurea below.

7) Ask your Onc what your Treatment Plan will be.  For most patients diagnosed in Chronic Phase it will be TKI drug therapy only (Gleevec, Sprycel, Tasigna, Bosutinib, or Iclusig) and Allopurinol during the first couple weeks, and periodic testing.  At first there should be weekly Complete Blood Count (CBC) tests for a couple months.  At no later than 3 months a FISH and/or PCR test should be done.  At 6 months another Bone Marrow Biopsy (BMB) should be done unless the drug response has been very rapid and deep.  After that the periodic testing schedule should suit the level of response.

8) If diagnosed in Blast Phase it would be wise to pursue bone marrow transplant options in case a transplant is required.  Siblings should be tested first to see if they are a suitable marrow donor match.  

9) Read about specific issues such as CML testing and other CML subjects:
http://community.lls.org/people/Trey/content?filterID=contentstatus[published]

10) Join us on the Leukemia & Lymphoma Society Support Discussion Board:
http://community.lls.org/community/bloodcancer/livingwith/cml



ALPHABETICAL SECTIONS:

Adjusting to CML TKI Drugs (Gleevec, Sprycel, Tasigna, Bosutinib, Iclusig)

The body needs to adjust to CML drugs, and it can take some time. Generally, the side effects are worse during the first few weeks and months, and then generally improve as time goes by. So some side effects lessen in severity or even go away. Each drug has its own side effects. (See “Side Effects”). I found that after a few months some of the worst side effects lessened, and about the 1 year point most side effects became less of an issue, although some remained. The body can find ways to overcome many side effects, but some will likely continue. If they are debilitating, a switch to another drug can help, although sometimes it may trade one side effect for another.  People who start Sprycel seem to have an issue with headaches for a week or so after starting the drug.  Tasigna has an issue with skin rash and itching scalp.  So sticking with a drug for a couple months is normally required to overcome initial side effects.  After a few months you will know which side effect will remain.

Advanced CML Stages/Phases (Accelerated Phase, and Blast Phase)

The 3 phases/stages CML can be diagnosed during are Chronic Phase, Accelerated Phase, and Blast Phase (also called Blast Crisis).  It is important to know which stage you are in when diagnosed. For most people, CML drugs stop the advancement or progression of the disease. It turns CML into what might be called a “permanent, low-level chronic phase”. This is the basic goal of CML drug therapy. So the CML does not advance if the drugs do their job. If diagnosed in Chronic Phase the drugs will most often be the only therapy required. If diagnosed in Accelerated Phase the drugs will usually return the patient to Chronic Phase, and often for the long term. If diagnosed in Blast Phase the drugs have less chance to work, and transplant may become a requirement. Sprycel (Dasatinib) and Tasigna (Nilotinib) have been shown to be more effective than Gleevec for Accelerated Phase CML. Sprycel would be my personal first choice for accelerated CML. http://content.nejm.org/cgi/content/full/354/24/2531
(Read especially the section labeled "Discussion" in link above and the first several paragraphs)
The later the CML is diagnosed, the drugs can have a harder time working (especially Gleevec). Generally, if the CML is allowed to progress into the Blast Phase without drug therapy it becomes more unstable, and can mutate further and outsmart the drugs. Sprycel and Tasigna have advantages over Gleevec in the Accelerated Phase. I would ask the Onc for a clear game plan for treatment of advanced CML.
A CML Blast Crisis (BC) diagnosis makes treatment decisions less clear, since the CML drugs can be less effective at this stage. You will likely need to make decisions based on less information than you would like to have, and also based on statistical odds.
For Blast Phase patients, it could be wise to pursue the HLA typing, donor search, and other transplant preparatory actions while you are making treatment decisions (See “Transplant”):
http://www.marrow.org/PATIENT/Plan_for_Tx/index.html
http://www.marrow.org/PATIENT/Donor_Select_Tx_Process/index.html
http://www.marrow.org/PATIENT/Plan_for_Tx/Choosing_a_TC/US_NMDP_Transplant_Centers/US_NMDP_TC_Advanced_Search/search_return.pl
There are clinical trials for people with blast crisis CML:
http://clinicaltrials.gov/ct/search?term=cml+blast+crisis&submit=Search
You will want to ensure a proper diagnosis of BC, and make sure you understand whether it is myeloid BC or lymphoid BC. I recommend getting copies of all lab reports to ensure your results line up with the diagnosis. Blast count is important, but it is not the only factor in diagnosing Blast Phase CML.  It is useful to know if there are other complications or chromosome anomalies. The BMB report and Flow Cytometry Report would provide the required information.
The definition of CML blast phase has changed in the past few years. The World Health Organization (WHO) reclassified CML blast phase as 20% or higher, rather than the previous standard of 30%. So people are now being classified as blast phase when they formerly would have been only accelerated phase. That can be a source of confusion.
Some CML patients in BC have done well on CML drugs for a considerable period of time, others do well for a while but then the drugs stop working, and others do not respond at all to the drugs. There is no magic answer. But remember that most statistics you will see are from data accumulated before Sprycel and Tasigna were approved (although Tasigna is not currently approved for BC treatment). Most Oncs would suggest that if you have an excellent donor match, then BMT is recommended. And the best time to have a BMT is when you are in the best health. If you lose response to drug therapy then the BMT becomes tougher. But it is easy for docs to recommend a BMT, since they are not the one committed to the outcome. It’s like bacon and eggs -- the chicken is somewhat involved, but the pig is fully committed to the process. Docs are “involved”, like the chicken…
The following information is likely the most optimistic, and offers some hope that you could possibly do well on Sprycel, even though the odds are not as high as one would like to see:
http://www.cancer.gov/clinicaltrials/results/dasatinib0507
http://ctr.bms.com/pdf//CA180006ST.pdf
http://www.ncbi.nlm.nih.gov/pubmed/17185463?dopt=Abstract
Here are some other good articles you may find useful:
Dr Radich wrote the following, and is considered to be one of the best BMT docs -- he could be a great choice for an opinion:
http://asheducationbook.hematologylibrary.org/cgi/content/full/2007/1/384
Remember that the CML drugs generally stop the advancement of the CML, so CML advancement will usually be stopped and controlled for the long term (lifetime) for most CML patients. After approximately 2 years of drug treatment the odds of the CML advancing become very low.

Allopurinol

Allopurinol is generally prescribed when first starting the CML drugs. It is used for the first few weeks while the drug is killing off the billions of leukemic cells. Allopurinol helps prevent gout by helping the body excrete the lactic acid caused by all those dead cells in the bloodstream. If blood counts stabilize quickly, as shown by the white blood cell count returning to normal, the Allopurinol should not be necessary beyond the first 2 - 3 weeks. So the Onc should prescribe Allopurinol during the first couple weeks of CML taking the CML drug. I would add here that during initial drug therapy the body is under severe stress and vitamin supplements are advisable (a good multi-vitamin with folic acid and extra Vit C).

Anemia

CML drugs do a good job suppressing leukemic cells, but for most of us our blood cell counts can go too low, especially after a month or so on the drug. That causes many of us to live on the low end of normal or below normal for WBCs, RBCs, hemaglobin (HGB), hematocrit (HCT) and sometimes platelets (PLT). The result is a type of drug induced anemia, with less oxygen carrying capacity in the blood, and therefore we can become tired faster. As the body gets used to the drug over time, these counts can tend to creep back up a little, but for many of us they do not quite get back to the mid-normal range for several years.  Although anemia can be from low iron, low folic acid, or low B-12, CML drugs can induce an anemia that is unrelated to these deficiencies, called "chronic disease anemia". Have the doc test to see what type of anemia and to see if you are low on any particular minerals. You can ask your doc to run a Comprehensive Metabolic Panel (CMP) Test to see if you have a chemical deficiency such as iron. These should be done regularly, preferably quarterly. See link below to see what it tests for:
Generally, most of our low counts and low energy levels are not due to low levels of iron, folic acid, other minerals, etc. But I still believe in taking a daily multi-vitamin. The other hard news is that exercise is good for the low energy levels. Seems contradictory, but my Onc pushed me to exercise, and it certainly worked for me. Deep breathing every so often also helps when anemic.
If low blood counts are not due to a deficiency, then you will need to work through it, and hopefully it will improve over time. My energy levels have improved considerably over the years since diagnosis. Exercise can help, even when too tired – but hard to do.
The cause of low hemaglobin (HGB) count for many of us with CML is not normally lack of iron, but rather lack of a sufficient number of red blood cells (RBC). HGB (made mostly of iron) is contained in the red cells, and it is what carries oxygen throughout the body. If you have low RBC, then you have low HGB; and you cannot cram more HGB (iron) into the small number of red cells to fix the problem. This low RBC is why many of us suffer from fatigue. Look at your RBC count on your CBC Report and you will likely see that it is low. If not low, then iron deficiency is one of several possible causes of anemia, and lack of folate (folic acid) is another. Internal bleeding should be checked out, but it is less likely to be the problem.
http://www.anemia.org/patients/faq/
http://www.healthsystem.virginia.edu/uvahealth/adult_blood/folate.cfm
Before starting an iron supplement, folks with CML should have a Serum Iron Test. Too much iron is not a good thing. By the way, you are taking an iron supplement every time you take your Gleevec pill. The rust colored coating on Gleevec is...well...rust. Iron oxide.
Although our CML drugs are targeted drugs, they are not perfectly targeted at only the leukemic cells.
At first I was very tired and thought about CML every day. After a couple years I was able to exercise vigorously and lead a very normal life. I am over 50, but 30 year olds now have trouble keeping up with me now. I am as normal as the people I pass on the street each day, except that I appreciate what I have more than most of them.
Here is a good presentation about anemia (targeted for women, but helpful to guys, also):
http://chhs.georgiasouthern.edu/nursing/resources/pdfs/women_and_anemia_handout.pdf
Here is a good summary regarding why CML drugs tends to cause anemia as a side effect, and some helpful information about what to do. (Note that these websites were put together to help people with gastro-intestinal stromal tumors (GIST), which Gleevec is also used to treat, but the side effects are the same):
More about other Gleevec side effects:
I found the following website where someone said they tried Provigil and Ritalin but they did not help them with energy levels:
But we are all different, so you could discuss trying these or other drugs with your doc if the lack of energy is debilitating.

Basics of Understanding CML

To learn some of the basics about CML, here are some links to useful information in order from easier to understand to more advanced information.
The Leukemia & Lymphoma Society (LLS) Online Overview provide information for the newly diagnosed:
http://www.lls.org//attachments/National/br_1169054588.pdf#/resourcecenter/freeeducationmaterials/leukemia/cml
Information from leading CML specialist Dr Brian Druker:
http://www.ohsu.edu/edcomm/flash/flash_player.php?movie=adm/OHSU%20Knight.flv&width=320&height=240&title=The%20End%20of%20Cancer%20Is%20Within%20Reach
(NOTE: In link above start about 1/4 way through to skip the intro stuff)
Animation showing the chromosome translocation that creates the BCR-ABL gene that causes CML, and also how CML TKI drugs work:
http://www.youtube.com/watch?v=7ZMVQ1Vbb7Y
Video Presentations on CML and Treatment:
http://www.leukemia-lymphoma.org/all_page?item_id=161418http://www.lls.org/#/resourcecenter/pastprograms/leukemia/
Video Presentations on CML:
Managing the Disease:
http://cmlinfo.org/CMLmonitoring.html
http://bloodjournal.hematologylibrary.org/cgi/content/full/110/8/2828
/cml/content?filterID=content~objecttype~objecttype[thread]
The Leukemia & Lymphoma Society has an education lecture series, and they post the audio and transcripts on their website:
http://cml.leukemia-lymphoma.org/CMLApp/Controller?action=loadContent&itemid=191248&ln=7

Bone Health & CML Drugs

Here is a discussion on the subject of TKI drugs and bone health:
http://bloodjournal.hematologylibrary.org/cgi/reprint/107/11/4334.pdf
There has not been much mention of the issue since that initial article in May 2006. Overall, it seems that the higher the dosage, the more likely that bone health could be affected, but the sample size for the study was small. The articles indicate that it is a good idea to monitor phosphate levels in the blood, and also vitamin D.
Here are some interesting links discussing the issue:
There is some reason to believe that Gleevec could actually make bones stronger (but not proven):

Children taking CML drugs have sometimes seen reduced bone growth, which has caused some concerns about achievement of normal height.
http://www.springerlink.com/content/q220870864835077/
As with many side effects issues, CML drugs do not affect all of us in the same way. There is much more to learn about this issue. CML drugs have some impact on phosphorus and magnesium levels in the body, and to a lesser extent on calcium levels, which are important in bone and cartilage health.
Here are some interesting links discussing the issue:
There is some reason to believe that CML drugs could actually make bones stronger (but not proven):
Bone cells are normally very slow to turn over, but can apparently go into a hyperactive mode with CML drugs
Here is an illustration of bone marrow locations in the adult body, which shows that the shoulders definitely have marrow:
http://catalog.nucleusinc.com/generateexhibit.php?ID=9325

Blood Counts

(See also “Low Blood Counts”)
CML is primarily a disease of the white blood cells, but affects all blood cells. At diagnosis the white blood count (WBC) is high. Roughly speaking, the WBC at diagnosis will be between 50K and 250K, but can be higher or lower. The highest I have seen is around 700K. Other counts such as platelets are often high, but for some it can be low. Red Blood Count (RBC) can sometimes be low at diagnosis.
Our CML drugs do a great job reducing the high WBC. Often the newly diagnosed CML patient’s WBC can go too low within a couple months of starting drug therapy. This is called myelosuppression (supression of the marrow). See “Low Blood Counts” section.
If the Absolute Neutrophil Count (ANC) goes down below 1000 (also written on some reports as 1.0), many Oncs will recommend a drug therapy break of a couple weeks. This can often “reset” the body’s response and allow drug therapy to continue. The platelets are often the last blood count to get under control, which was the case for me.
When my platelets were close to 1 million my Onc made me stay well hydrated to help thin my blood. It took a while for my platelets to drop to normal, even though other counts dropped more quickly.
I started at approx 900K platelets before being diagnosed, fell to under 500K soon after starting 400mg Gleevec, then went back to nearly 1 million for no reason at all at three weeks after starting Gleevec (I did not take a break from Gleevec or change doseage).  The platelet spike can be due to the spleen's attempts to regulate platelet counts in the blood, since that is one of its tasks, so it can release platelets as it tries to reduce its bloated size.
Sometimes these tests are not as accurate due to temporary conditions such as nervous hyperventilating before the lab test, or a recent illness, or lab errors or contamination.
Megakaryocytes are the large pre-platelets before they break into many smaller pieces and become the platelets that clot blood. Some of us had a persistant cough prior to diagnosis, and that was due to the excessive number of Megakaryocytes caused by the leukemia, because the Megakaryocytes go to the lungs to break apart into the smaller platelets.
Since CML is a disease of the white blood cells (WBCs), and EOS, BAS, MON, & NEU are all WBCs, these will be out of whack at diagnosis and for some time afterward. Unless your doc thinks something else is going on (infection, parasite, severe allergies, etc) then it will simply take a couple months to stabilize. Then you may even have these WBC counts going too low for a while.
http://www.labtestsonline.org/understanding/analytes/cbc/test.html
When these WBCs are leukemic cells, they are even more unstable. After they are replaced with good WBCs, things should stabilize a bit more, although may remain low due to the impact of CML drug therapy.

BMB

A bone marrow biopsy (BMB) takes a sample of bone marrow (normally from the hip) and is necessary to properly diagnose CML since it checks for things that other tests cannot check for. After diagnosis it can monitor for advancing disease if there appears to be a loss of response to drug therapy. So a BMB is normally done at diagnosis, at 6 months post diagnosis, and maybe afterward as necessary until Complete Cytogenetic Response (zero BMB or zero FISH) is achieved, or after  that if drug response is lost.  (See "Testing" section)
There are generally three options for BMB “survival”:
1) Local anesthetic only (I also add "iPod" to this option). If you have the right attitude, it is not that bad. It is not so much "pain" as it is the thought of what is being done to you. The "iPod" (or TV) can distract you so you don't lie there concentrating on the procedure. This is the option I have used for all three of mine, with three different doctors, and works fine for me. But I have a high tolerance for such things, and just don't like extra medications. Plus I can drive myself home after a short wait.
2) Local anesthetic plus Vallium or equivalent (plus iPod). For the somewhat squeamish. Calming the nerves can help many get through this. With this option the doc should allow you to drive yourself home after a waiting period.
3) Local anesthetic plus a "twilight" sedation -- still conscious but out of it. For the very squeamish. No iPod needed -- you will hear music anyway. With this option you must have someone else drive you home.
With the local anesthetic, you will feel little actual pain, but you will feel the procedure being done (pressure, movement, noises, etc). Like having a tooth drilled. 
4)  Total unconscious sedation. 
Take a realistic view of what you can tolerate. If you are worried about it, take a conservative approach. It is a personal decision each must make based on knowing their own limitations.
BMBs look for issues such as secondary chromosome abnormalities, too few or too many cells (hypo- or hyper- cellular), bone cell status, blast count, presence of fibrous tissue, etc.

Bone Marrow Transplant
Bone Marrow Transplant (BMT) has become a last resort for adults, but for young people and children the issue of long term drug therapy vs. BMT is more of an emotional one.
The main positive issue for BMT is the possibility of a cure. That is a powerful motivator for some. But the negatives for BMT are a rather long list, including potentially not surviving the transplant, possible transplant failure (sometimes the transplant does not take, so no cure), the body fighting the transplanted cells and vice versa (painful and possibly debilitating graft vs host disease), potential sterility, increased risk of causing a secondary cancer, and so on. I am not anti-transplant. It is just that there are good points and bad points to consider.
Part of the choice depends on whether there is a "highly matched" marrow donor based oning human leukocyte antigen (HLA) match. The highest liklihood is from a sibling, whereby there is a 1 in 4 chance of a perfect match. Otherwise the odds get slim, although not impossible to match an unrelated donor somewhere in the world. Parents are not normally matches since they each have only 1/2 of the required genetic make-up. There is also the possibility of using cord blood stem cells donated at childbirth (left over blood from the placenta).
http://community.lls.org/docs/DOC-1375
Blasts and Blast Count

Blasts (immature WBCs) are an issue in CML because they can show disease progression under certain conditions.  A blast count at diagnosis which is over 30% is considered to show significant progression (Blast Phase CML) if combined with other high risk factors, and over 15% may show Accelerated Phase.  But blast count should not be viewed as the only factor in determining disease state since it can change significantly for short periods of time. 
There is an important issue that many do not understand about blast count and TKI drugs.  When the patient has severe low blood counts (myelosuppression) the blast count can become unusually high due to the body trying desperately to recover from the anemia.  So a high blast count, including after TKI drugs have been started and have caused anemia, should be treated as a different category, and not necessarily a sign of disease progression in isolation.  So beware of using high blast count as a sign of leukemia progression when severe anemia is present.
You can read more about blasts at this link:

Calcium

Calcium supplements and CML drugs should not be taken within several hours of each other.  When taken together, the calcium can absorb some of the drug preventing absorption into the body, which is like decreasing your dosage of CML drugs. Taking calcium is that in a concentrated supplement form it absorbs and holds onto whatever it comes into contact with in the digestive system, and then less than 30% of that calcium is taken into the body for use.
Some take calcium to counter diarrhea. It should be taken several hours apart from the CML drugs.
Here is an interesting article about how magnesium helps with calcium absorption, which is why they are often combined into one pill. But since CML drugs can cause the runs, and so can magnesium (as in Milk of Magnesia), you will want to see how the extra magnesium affects you.

Children With CML

We are all touched by any child who has to face this issue. But there is good reason to be very hopeful about the long term future of children with CML leukemia.
The treatment for children is the same as for adults except that if the child is very small they might reduce the dosage below 400mg. In general, teens respond very well to drug treatment -- often better than adults. The most difficult part is for parents to struggle with the issue of staying with drug treatment instead of marrow transplant. That is a tough one for parents.
CML is rare in children. There are approximatley 50 children diagnosed with CML in the US each year, and many more around the world. Approximately 3800 children are diagnosed with all types of leukemia each year in the United States, and many more around the world.
Here is a link to some information about other children with CML:
http://www.newcmldrug.com/Children/Default.asp
Sometimes it helps young people to understand that they are not alone. You can find other children with CML and other forms of leukemia, read their stories, and talk with them at the following websites:
One issue regarding CML drugs for children is that some have growth reduced by the drug.  But this appears to happen less often than originally thought.  There are some children on high dosage CML drugs that have grown normally, including a teenage girl who has been on high dose 800mg Gleevec for years (she is awe-inspiring).

You will find that you will not have all the information you want or need to find that one completely right answer for treatment, especially related to a transplant decision. So your goal becomes making a choice that, upon reflection and looking backward in the future with 20/20 hindsight, you will not be able to criticize the process you went through to make the best decision possible given a lack of perfect information.
You will want to explore the variation in levels of BMT risk between 11 years old and 25 years old, which may not be as significant as you think. If it were my child, I would not allow doctors to rush a me to decision. The window for BMT will not close quickly if no decision is made right away, so there is no reason to feel pressure to make a decision right away. Maybe this allows the child to eventually help make the decision during future years. That would be something to consider if you decided to allow time for the child to make its own informed decision, if you thought that was an appropriate consideration. There could also be other significant medical advances in that period of time.
There are, unfortunately, other unknowns to consider. The chemotherapy and radiation required to kill off all existing marrow stem cells (both good and leukemic ones) could possibly increase the risk of other future cancers, could damage organs and bones, cause sterility, and have other side effects (see links provided below).
Smaller dose chemotherapy BMT, mini-transplants, and transplants using unrelated donors are options, but most do not have the highest cure rates and have more potential side effects.
You may find that you do not need to make a decision in the next couple years. But other issues may come into play, such as how well your child deals emotionally with having CML, vs how well they would deal with the issues involved in the BMT process.
This is all just to try in some small way to help, but certainly falls short in many ways. None of us have enough information, nor are we qualified to adequately help you make this difficult decision. Research as much as you can, and consult the expert Oncologists in the CML specialty. Oddly, the fact that CML is now so treatable has created this dilemma for parents of children with CML, and for all younger people with CML, which is overall a good problem to have, since there are now choices.
Some additional information to consider:


Clinical Trials

There are numerous clinical trials in process at any given time that are either directly or indirectly related to CML. Here is a link to the U.S. clinical trials related to CML:
http://clinicaltrials.gov/ct/gui/action/SearchAction;jsessionid=9CFF057A706074D5F758EEC9744AFEBF?term=%22chronic+myelogenous+leukemia%22
Clinical trials test new CML drugs, and test other advances in medical science. Participating in a clinical trial can help advance the understranding of CML and help make new treatments available. If anyone wants to volunteer for the clinical trial, be sure to get your Onc's approval.
Leukemia vaccine trials are being done around the world using a number of approaches. Some well known CML experts are very exited about the possibilities, although there is much work to be done.
If currently approved CML drugs do not work, then a clinical trial for developmental drugs that are being tested could be a good option. But there are risks, so make sure your Onc approves of the therapy.
The National Institutes of Health (NIH) and others are constantly researching better stem cell transplantation techniques. They have improved transplantation processes over the years, and have a number of active clinical trials regarding stem cell transplantation to improve the processes even more:
http://patientrecruitment.nhlbi.nih.gov/BloodDiseases.aspx

CML WITH OTHER ABNORMALITIES and "ATYPICAL CML"

Typical CML is caused when two chromosomes (9 and 22) switch broken pieces with each other (translocation). This causes a Philadelphia Chromosome to be created out of the former chromosome 22. The translocation is shown as t(9;22)(q34;q11).
There are several variations from "normal" CML which occur in possibly 10% of cases.  These variations often include alternative Philadelphia Chromosome splicings or translocations.  This link is a tutorial on the various CML breakpoints and fusion genes. It suggests that a Multiplex PCR is required to properly identify the "exotic" breakpoints, such as the one you are looking for. 
Here is a graphic showing the various breakpoints in CML:
http://www.bioscience.org/2006/v11/af/1791/figures.htm
B3a2 and b2a2 are the most prevalent forms of BCR-ABL. These are found in p210 type CML. Some people have both b3a2 and b2a2 at the same time (that is the b3a3-b2a2 that confused you). Then there is the e1a2 BCR-ABL in p190 CML, which is somewhat rare. And the c3a2 p230 type CML is very rare. So people with CML can have various forms of BCR-ABL because the chromosomes can break off and fuse at different points.

Rare translocations (meaning other than the 3 main CML translocations -- see "Genetics of CML" section) may or may not respond differently to CML drugs as the 3 main translocations:
Sometimes the chromosome rearrangement includes deletions of genetic material:
http://www.nature.com/leu/journal/v14/n6/full/2401718a.html
The Onc may refer to partial deletion of chromosome 9 as part of the variant form of the Philadelphia Chromosome (may be at the argininosuccinate synthetapse (ASS) gene, which is found on chromosome 9, when there is a partial deletion). This is also called der(9) deletions.  It is not necessarily associated with poor response to CML drugs: "In conclusion, der(9) deletions occur in a significant fraction of patients with CML. These patients have clinical characteristics similar to those of patients without the abnormality. In contrast to previous literature reports, there was no difference in response to [Gleevec] or in overall outcome among patients treated with [Gleevec] by the presence or absence of der(9) deletions. Although a larger number of patients with longer follow-up might be necessary for definitive conclusions, our data suggest that treatment with imatinib mesylate may overcome the adverse prognostic impact of der(9) deletions in patients with CML. Still, until the significance of this phenomenon is clearly established in a prospective analysis, it is important to continue monitoring patients for this abnormality."
http://bloodjournal.hematologylibrary.org/cgi/reprint/105/6/2281
See also page 2282, paragraph titled "FISH"
Also, an unusual translocation t(9;22;22) means that you have an extra copy of chromosome 22 involved in the Philadelphia Chromosome (most of us have one copy of chromosome 22 in each Philadelphia Chromosome). Fewer than 1% CML patients have this doubled form of the Philadelphia Chromosome. But there are quite a few patients with some type of unusual variant of the Philadelphia Chromosome who are doing very well on drug therapy. But little is known about how such patients will respond to drug therapy. So it will likely need to be a "wait and see" approach, and your Onc will likely want to monitor you closely and be prepared to switch drugs quickly, if needed.
For people with CML, trisomy 8 is the most prevalent genetic change that can occur in addition to the Ph+ chromosome. It is having an extra chromosome 8 in the non-leukemic cells, and can come and go, so it is not always a bad predictor. I have seen other CML discussion sites where one person on 400mg Gleevec said she had trisomy 8 show up in a BMB, and the Onc increased the dosage to 600mg, and the next BMB showed no trisomy 8. It is not great news, and it is not dire news. It does warrant discussions with your Onc about increased dosage or other options.
So Trisomy 8 is having an extra chromosome 8, and Monosomy 7 is partial deletion of chromosome 7. As stated above, Trisomy 8 is the most common second chromosomal abnormality for people with CML. Monosomy 7 is seen occasionally. These can come and go, or they can remain. Hopefully they will go away by themselves, but it will take some time to see what they do. From what I have seen, the Trisomy 8 and Monosomy 7 seem to be less important than how you are responding to the drug treatment. These two chromosome abnormalities are not well understood regarding their impact on the course of CML.
Here is some info I have found:
http://www.nature.com/leu/journal/v18/n5/full/2403345a.html
(see also the footnoted articles 2 - 8)
The term "mutation" can be confusing. There are Tyrosine Kinase mutations (the spot where the CML drugs attach to the signaling Tyrosine Kinase and shut down the leukemic process) that can cause drugs to stop working. Then there are chromosome mutations such as Trisomy 8 and Monosomy 7 (mutations in chromosome numbers 7 and 8 out of the total 46 chromosomes, which are in 23 pairs). CML is caused by a chromosome mutation (Philadelphia Chromosome).
There are occasionally 3-way translocations in CML, and 4-way is even more rare. It does not necessarily mean anything, but this is a case where I would recommend seeking a second opinion from a specialist. Dr Druker at OHSU comes to mind, but there are others well qualified, especially at MD Anderson, maybe Dr H. Kantarjian or Dr Jorge Cortes. Unusual cases always should involve a highly specialized Onc.
CML is usually characterized by the reciprocal translocation of chromosomes 9 and 22, identified as t(9;22)(q34;q11), with the (q34;q11) showing the breakpoint regions of the two chromosomes in the order listed.
Here is a recent link on the subject of CML and some forms of secondary translocations. But unless you can find something that addresses the very specific translocation (which I could not) then it does not help much except to know that it is not unheard of:
Philadelphia Chromosome Negative CML (Ph- CML) is close in characteristics to another type of leukemia called CMML. Key information would be the results of a bone marrow biopsy (any chromosome abnormalities), PCR, WBC count from the CBC test, or other test results used in the diagnosis. Also, how the Onc is measuring progress from Gleevec since there is no bcr-abl to measure, and whether your WBC is dropping since starting Gleevec. The overall assumption is that Gleevec and other CML drugs do not work for Ph- CML.
Leukemia is generally characterized by an excess of abnormal white blood cells in the blood. However, there is a very rare form of leukemia called Hairy Cell Leukemia (HCL) that has low WBC, RBC, and PLT. It includes left side pain (spleen) and general fatigue, maybe a persistent cough. A BMB would confirm HCL. But there are other possible and less rare diagnoses.
http://health.nytimes.com/health/guides/disease/hairy-cell-leukemia/overview.html
CML-N is defined by a rare form of the BCR-ABL gene. When the pieces of chromosomes 9 and 22 break off and switch places (translocation) turning chromosome 22 into the leukemic Philadelphia chromosome, those pieces can break off at one on several locations along both the 9 and 22 chromosomes. The locations are called a, b, c, e etc. Most of us with CML have either b2a2 or b3a2 BCR-ABL. If you have CML-N, then you could have the c3a2 (also called e19a2, which is the same thing) variant of BCR-ABL.
Here is a quote about c3a2/e19a2 type CML-N:
"In the vast majority of CML cases the breakpoint on chromosome 22 falls in the so-called major breakpoint cluster region of the BCR gene (M-bcr), leading to a hybrid BCR/ABL mRNA with a b2a2 and/or b3a2 junction....To date, only a few cases of CML with the breakpoint in the minor (m-bcr) and micro (mu-bcr) bcr region have been described, and were associated with peculiar CML phenotypes. Indeed, the m-bcr breakpoint has been associated with classical CML with a prominent monocytic component, while the mu-bcr breakpoint which gives origin to the e19a2 transcript corresponding to the p230 fusion protein, has been associated with a mild CML phenotype. Pane et al1 proposed classifying these latter cases as neutrophilic-chronic myeloid leukemia (CML-N), a rare disease characterized by moderate and persistent neutrophilia without precursors in the peripheral smear, absent or minimal splenomegaly, normal or raised leukocyte alkaline phosphatase (LAP) score, and a benign clinical course."
http://www.nature.com/leu/journal/v15/n12/full/2402292a.html
Here is some reading about CML-N:
http://bloodjournal.hematologylibrary.org/cgi/reprint/88/7/2375?ijkey=7d8d5340737745223e64bb489fc2503db7f6d26f&keytype2=tf_ipsecsha


The BMB is the most definitive test to properly diagnose CML. Other tests (PCR and FISH) can detect the Philadelphia Chromosome and narrow the options down to 3 possibilities, but cannot absolutely say it is CML. Statisically, it is most likely CML. So your Onc was giving a preliminary diagnosis by saying it is CML based on either a FISH or PCR that showed you have the Philadelphia Chromosome, then a BMB was being done to completely confirm the diagnosis.
There are 2 parts to the BMB procedure. The inability to obtain aspirate fluid (a dry tap) does not mean the BMB test cannot be done. The BMB cytogenetics test for diagnosis can be done on the bone and marrow sample taken by the core sample needle. So the BMB diagnosis should still be able to be done, but the PCR or FISH on the aspirate fluid cannot be done for you, but these tests can be done on circulating blood.
Some things you might want to ask your Onc as a minimum are:
1) What was the CML Phase at diagnosis?
2) What did your BMB reveal at diagnosis regarding abnormalities other than the Philadelphia Chromosome? What was the marrow blast count at diagnosis?
There are several reasons why a BMB is important at diagnosis. The #1 issue is that there are 2 other forms of leukemia that can be Philadelphia Chromosome positive (Ph+), namely, certain types of ALL and AML leukemia. Your PCR report which says "final diagnosis" is misleading, because everything in that report could also be Ph+ ALL or Ph+ AML leukemia, even though they are more rare. If a person has Ph+ ALL or Ph+ AML instead of CML, they need to know that right away. Also, both PCR and FISH are looking for specific issues (BCR-ABL), but a BMB looks at the broader health of the marrow and its blood forming system. You mentioned checking for marrow fibrosis, which is significant. BMB also checks marrow blast count, which is needed to confirm CML stage (chronic, accelerated, or blast). BMB also looks for secondary chromosome abnormalities or translocations, which is important information. Other marrow health checks are also performed, which can guide treatment decisions. The NCCN CML Treatment Guidelines and every CML expert recommends a BMB at diagnosis. Having said that, most patients who test positive for the Philadelphia Chromosome will have "normal" CML without other complications. So statistically speaking, you could say that skipping the BMB is low risk. But when dealing with such extremely important issues, low risk is not good enough.
Ph+ ALL or Ph+ AML would have other chromosome translocations or abnormalities, and only the BMB would identify them. Your BMB says that you are human, male, 100% of the 20 marrow cells analyzed were Ph+, and there were no other abnormalities noted. You do not need to question your CML diagnosis, but curiosity about these details is a healthy thing. Good questions.
Myelodysplastic Syndrome can have low blood counts:
Myelofibrosis can have low blood counts. Diagnosing myelofibrosis along with CML is not easy, since it is hard to separate the symptoms. It is important to ask questions of the doctors and make sure they are specialists, not just standard Oncologists. Most Oncologists do not understand CML, and even fewer understand myelofibrosis.
Here is some information on the myelofibrosis issue to help you form some questions:
There are also some autoimmune possibilities that can act like MPD diseases.
CNL (as opposed to CML) is sometimes what an Onc will classify what looks like CML, but without the Philadelphia Chromosome (Ph+). It is sometimes called Ph negative (Ph-) CML or Atypical CML. Some consider it to be a type of CML, but there is debate about that. Some also suggest it might not be a separate disease, but maybe just an early form of another disease, such as Myelofibrosis with myeloid (marrow) metaplasia (cancer).
Our CML drugs do not work against CNL. You will need to consult with highly trained specialists. This is not something to trust to a standard Oncologist for a proper diagnosis.
http://jjco.oxfordjournals.org/cgi/content/full/30/8/362
http://www.ncbi.nlm.nih.gov/pubmed/8148416
If you have a rare Ph+ translocation called e1a2 you might have been mis-diagnosed as having CML, when you could actually have Philadelphia Chromosome Positive ALL (Ph+ ALL). Ph+ ALL must be watched very carefully, since Gleevec does not have as good a track record in fighting Ph+ ALL as it does for CML. So I would ask the Onc the following:
1) Do I have CML or Ph+ ALL? 2) If I have Ph+ ALL instead of CML, how would the treatment approach differ from this point on? 3) What is the recommended treatment approach?
Here is an extract on atypical CML:
"...a chronic myeloproliferative disorder with a clinical and hematologiacl picture similar to chronic myelogenous leukemia (CML) but lacking
Philadelphia chromosome and BCR-ABL rearrangement....By definition aCML cases lack in Philadelphia chromosome."
If you are Ph- and have no indication of bcr-abl, and truly have CML, that is a very rare form of CML, but there is still debate about what it might actually be. It could be an extremely rare translocation that testing systems (BMB, PCR, FISH) are not able to identify.

COST ISSUES

The Novartis full retail price for Gleevec in the U.S. is approx $130 per 400mg pill. But most pharmacies in the U.S. negotiate a lower price with Novartis, and pass some of that on to patients. So the full price at pharmacies can be from approx $80 up to the $130 per pill. Like most things, prices are negotiated. Some countries negotiate lower pricing with Novartis. Canada usually gets the lowest prices, from what I have seen.

Cramping

Cramping of muscles is a common Gleevec side effect. The cramping should get better over several months, but it could continue at a decreased intensity. It is one of the most persistent side effects of Gleevec. Try taking Gleevec at different times and see what works. As for me, I split my 400mg dosage and take half at breakfast and the other half at lunch or dinner (Onc approved). That has minimized side effects for me. I do not go along with the full glass of water with my meal. For me that promotes indigestion since it dilutes the digestive juices. I drink my water a half hour before and after meals. We are all different, so trying different approaches will lead you to find what works for you. The body takes time to adjust, but it finds a way in time.

CURE PROGRESS

There will be a cure for CML. It is the most well understood of all leukemias and even of all cancers. When it comes right down to it, CML is a dumb cancer. Powerful, but dumb. It generally only knows how to do one thing. It is a one-trick pony, although with a couple small head-fakes. Therein lies its weakness. Knowledge is power against this disease. It WILL be defeated. So how is it going?
As with any important progress, it is like building a brick wall. How do you do that? One brick at a time. Earlier bricks support later bricks. At some point, it becomes a wall. At this point there are a lot of bricks. And there are several good stone masons.
Our CML drugs generally target the offspring leukemic cells, and only some of the elder stem cells. But the originating CML stem cell and its main lieutenants evade the TKIs. This prevents the TKI drugs from curing CML. So the goal of our TKI drugs is to kill the offspring and reach a stalemate with the disease. This is far better than 15 years ago, but the real goal is to cure CML.
There are currently 4 FDA-approved TKI drugs available to keep CML under control. There are more drugs coming, and some of these will fix the problems with the existing drugs, overcoming kinase mutations that prevent the current drugs from working. Very helpful, but still not a cure.
The search for a method to kill the "eldest" CML stem cells is getting interesting. Most of the ideas will fail. Maybe all the existing ideas will fail. But they will advance the cause. Here are some (not nearly all) of the interesting recent developments:
http://www.sciencedaily.com/releases/2010/05/100517132842.htm
http://www.plosone.org/article/info:doi%2F10.1371%2Fjournal.pone.0006257
http://www.signaling-gateway.org/update/updates/200903/su-0903-1.html
http://ash.confex.com/ash/2009/webprogram/Paper21592.html
http://molpharm.aspetjournals.org/content/72/3/788.full
http://asheducationbook.hematologylibrary.org/cgi/content/full/2008/1/427
http://www.jci.org/articles/view/35660/files/pdf
These references merely provide a sense that the noose is tightening on CML. Its days are numbered. That number of days may still be large, or it may be small. But it is indeed finite.
CML is generally well understood as a disease, which makes it more likely that a cure could be found. There is increasing optimism about a cure in the reasonable future. Dr Druker said recently that most CML patients could expect to live at least 30 years after diagnosis just based on current CML drugs if nothing else comes along, but much more is coming in the future, so 30 years is just the beginning. Because Gleevec was only approved in 2001, CML experts have previously hesitated to put a time-frame on expected survival due to lack of data, even though they often said it could be significant. So hearing Dr Druker say this shows the continually rising expectations for long term survival of CML. This should be encouraging, and especially encouraging to young people with CML.
Here is an article about Nike founder Phil Knight giving $100M to the OHSU Cancer Center, with nearly all of it ($98M) going to Dr Brian Druker's research. Of course, we know Dr Druker as the researcher who was the driving force behind the clinical trials for Gleevec:
Here is a good example of the research being done at OHSU by Dr Druker's group:
The "queen bee" analogy in the article is actually referring to the originating leukemic stem cell that started the whole CML process. The analogy used is that our CML drugs kill off the "worker bees" (leukemic WBCs), but cannot kill the "queen bee" (originating leukemic stem cell), so the CML can keep going until the queen is eliminated, because she is the source of the worker bees. The article says that we need a way to kill the queen bee so we can eliminate the entire bee colony (cure).
Some people have taken Gleevec for years, then stopped and did not relapse over the next couple years. There is at least some possibility that they could be cured. The problem is that you don't know whether 100% of the leukemic stem cells are gone. Can Gleevec allow the person to outlive those originating CML stem cells, even if it cannot kill those leukemic stem cells directly? The general belief has been that Gleevec does not directly cure CML because it does not kill the original leukemic stem cell, and maybe some of its initial offspring as well. This has been shown in the lab, so it is assumed to be true in the body. Gleevec appears to only work against the "younger" leukemic cells, causing them to die off. It is suspected that the "oldest" leukemic stem cells have redundant survival systems that allow them to outsmart Gleevec. But a French study was conducted where a few stopped Gleevec after being PCRU for over 2 years, and some have not relapsed after several years off Gleevec. Here is a summary report:
http://abstracts.hematologylibrary.org/cgi/gca?allch=&SEARCHID=1&FULLTEXT=STIM&VOLUME=112&ISSUE=11&FIRSTINDEX=0&hits=10&RESULTFORMAT=&gca=ashmtg%3B112%2F11%2F187
The report shows that 15 CML patients who had been PCRU for 2 years or longer stopped taking Gleevec. Of those, 8 had not relapsed after 3 years off Gleevec. A follow-up French study started in 2007 is now being done, and started with 50 patients. There were 15 who had not relapsed after the first year.
This may seem like a cure for the 8 people in the older study, but some stem cell transplant patients have relapsed after much longer periods. But maybe they are actually cured. Is the 5-year wait for a cancer cure applicable to CML? Some transplant patients have relapsed after as much as 14 years post-transplant
So can Gleevec cure CML? Maybe, but maybe not directly. As I said earlier, the originating CML stem cells do not seem to be affected directly by Gleevec in the lab, and generally that seems true in the body since relapse is likely after stopping drug therapy. But Gleevec might create an environment where those original stem cells die after some period of time, naturally or otherwise. Or maybe those who respond very deeply to Gleevec have some innate ability that others do not have. Or maybe it is something else. Until this issue is better understood, it is best to stick with conventional treatment guidelines.
There are drugs like AP24534 (Dr Druker is working on this one) and other drugs that show promise in overcoming the very difficult T315i mutation:
http://www.ariad.com/wt/tertiarypage/AP24534
There are drugs that would work in a very different way than current drugs, targeting other kinases, CML cell "switches", or other cell signaling proteins.
There are CML "vaccines" being researched that are trying to make the CML patient's own immune defenses recognize CML cells as the enemy and destroy them:
http://ash.confex.com/ash/2008/webprogram/Paper11549.html
Vaccine Issue:see later discussion under "Vaccine".

DIAGNOSIS

A Bone Marrow Biopsy (BMB) is required to correctly diagnose CML and determine if there are high risk factors that only the marrow can show.  These can include secondary chromosome abnormalities, unusual cell types/sizes/shapes, fibrosis, or other abnormal issues, or even Philadelphia Chromosome positive ALL Leukemia. 
There is no way to diagnose CML or even any kind of leukemia based on that blood count alone. The WBC average at diagnosis is probably somewhere between 75,000 - 250,000. If the WBC is above 30,000, then it is likely to be leukemia (CML or AML).  The highest I have seen at approx 750,000. The earliest sign of CML can be high platelet levels with no other abnormal counts or symptoms, but other diseases have the same indicator. There are other diseases that often look like early stage CML, especially Essential Thrombocythaemia and Polycythemia Vera, which both have high platelet counts. A BMB should be done 100% of the time when trying to diagnose CML. It is important to evaluate the total chromosome picture at diagnosis, and periodically after that.
Things you will want to know at diagnosis:
1) Do I have CML, and does the BMB show the Philadelphia Chromosome? 2) What CML Phase am I in? Do I have any high risk factors? 3) When do I start drug therapy? What drug and dosage? 4) Did you perform a PCR test? A FISH test? What were the results? 5) Get a copy of all test reports

Diarrhea

Those of us with CML call the Gleevec diarrhea the "sharts". It is definitely an issue, especially during the early months after starting Gleevec. Many find that it improves over time.
My experimenting has shown that drinking those huge glasses of water or juice all at one time, especially when taking Gleevec, causes severe diarrhea. This makes sense in view of diarrhea being mostly water. I drink water in moderation throughout the day and now have very few issues. Gleevec with a meal is better than with a large glass of water in my opinion.
Some people have found that taking a large calcium pill daily will help, especially with a large meal. The reason is that dry calcium carbonate acts to absorb water in the intestines. People with IBS use this as a treatment.
http://www.ibstales.com/ibs_diarrhea.htm
But I would not take the calcium pill within several hours of taking Gleevec or Sprycel since it can reduce absorption of the drugs.
The other item is to ignore advice that we should drink huge quantities of water. That is like pushing the commode lever on the intestines -- FLUSH. Moderate intake of fluids spread throughout the day works well for me.
Since we are all friends here, there is also a useful practice to stuff TP in close and personal as a first line of defense. I call this the "poor man's Depends". It can buy time....I think I'll just leave it at that.
Here are my rules for beating the "Big D":
1) First, forget what the docs say about drinking huge amounts of water. It just comes out any opening it can find in greater volume. Drink only moderate amounts of liquid and space it out through the day. In fact, test this by greatly reducing fluid intake at first and see what happens. I do not find that drinking a large amount of water when taking Gleevec helps, as long as I take it with a meal. I also do not drink much fluid with any meals.
2) Stay on a consistent diet and regimen. Gleevec does not like sudden changes or variations in routine. This applies to eating, sleeping, and all habitual activities.
3) Apparently Dr Druker suggests taking Gleevec after lunch so there is food from breakfast and lunch already in the intestines to slow down any rapid movement through the bowels. I might also add that splitting the dosage in half (ask your Onc) and taking half after lunch and half after dinner could help.
4) Avoid most fruits. I had to avoid fruit early on, even though I love them all. I ate an occasional apple or some blueberries. No raisins, plums, prunes, cherries, apricots, etc. etc. After a year or so I could eat fruit again.
5) If the Big D comes on, it will want to stay for several days -- like a bad relative. And it must be brought back under control by eating and drinking less until it subsides, and by taking Immodium or whatever. Extra calcium can also help, but don't take it near the time you take Gleevec, since it can block absorption. People with IBS take calcium to help:
http://www.ibstales.com/ibs_diarrhea.htm
Overall, less water, less food intake, and more consistency in all activities can help. Immodium and calcium can help. But no real miracle cures. But I do think that it generally gets better over time as the body adjusts, even if it takes a couple or three years. That has been my experience. But if I ignore my own rules, I get a reminder.
Regarding water intake, I am not talking about severe dehydration, which is actually hard to do. Adequate creatinine clearance can occur with lower intake of fluids. The docs tell us to guzzle large amounts of fluids. That just makes more diarrhea.

DOSAGE

I take 400mg daily, and I split it 200mg at breakfast and dinner. Seems to help reduce side effects. It has helped me to split my 400mg dosage and take half in morning and half in evening. That way the body is not shocked by taking it all at once. Just after diagnosis my Onc told me to take a multivitamin and also folic acid to help rebuild good cells. I also took an iron supplement every few days, but not every day.
Increases in dosage are not "free" -- there are almost always side effects and cell count disruptions. I was doing well on 400mg and went to 600mg for a while, but it was quite a shock to my cell counts, so I went back to 400mg.
Some people can't handle anything higher than 400mg. I tried 600mg for a while and it negatively affected my counts, just not as severely as your husband's results, then I went back to 400mg and have stayed there. At this point the Onc will want to see his platelets stabilize above at least 50, and preferably above 75, before restarting Gleevec. After that happens, you might want to ask the Onc if he can restart at 300mg and work back to 400mg. I would avoid 600mg for quite a while. Since his blood counts were OK before he started 600mg, he should be able to work back to that level again, so I would not be overly concerned. When blood counts get severely depressed it just takes a little time to get them back on track.
Your Onc is probably just trying to give an extra push to get you into PCR undetectable by the next PCR. You already have a 3 log reduction, so this may not be necessary, but there is no harm as long as you can handle any increased side effects. Even with 400mg it seems you were on track to achieve PCRU next time, but both dosages are within recommendations.
During my first year on 400mg I was doing great, but I asked my Onc to up the dosage to 600mg to achieve results faster. I did achieve PCRU quickly, but going from 400mg to 600mg drove my CBC counts crazy (WBC and RBC went low, anemia, other weird counts), so I was glad to go back to 400mg a few months later, where I still remain.
One thing to consider is asking your Onc if you can split the dosage, and take 300mg twice a day. That is what I did to reduce side effects on 600mg. Even now, I still split my 400mg dosage and take 200mg twice per day. I think it helps reduce side effects for me.
There is not much data available on reducing dosage after Complete Molecular Response (CMR, or PCRU). And there is no consensus of opinion on the issue of reducing dosage over time. Most Oncs are reluctant to change dosage if the current one is working. But since 400mg is the "standard" dosage, it is not unreasonable to reduce the dosage, especially if side effects are an issue. Since you were on 600mg from the start, you do not know whether 400mg would have worked just as well. For those who started on 400mg and needed to increase to get the required response, dose reduction would be discouraged. If it were me, I would reduce the dosage as suggested by your Onc.
Below is an article that mentions the issue of dosage reduction over time, but it draws no conclusion.
How long should IM be continued in the responding patient?
Probably until a cure is discovered. Our CML drugs are designed to stop the progression of the CML and put us into a continuous low level of residual disease. There is preliminary evidence that the incidence of disease progression in responders diminishes with each successive year on IM. Moreover, there is no suggestion that the incidence of toxicity increases with duration of treatment. Anecdotal evidence suggests that most patients who stop taking IM lose within weeks or months the response they did achieve. These facts taken together suggest that the best advice for individual patients responding to IM is that the drug should be continued indefinitely, although whether this should be at full dose (400 mg daily) or at reduced dose is not yet established.
The Gleevec Blood Level Test (BLT) is a good idea after you have been on the 200mg for a few weeks. This test will show how much Gleevec is getting into your cells. Gleevec in the bloodstream plasma must go through the leukemic white blood cell walls in order to work. Different people have varying ability to get Gleevec into the cells, which is one reason why different doses are required for individuals. If you get enough Gleevec into the cells with 200mg then it might be enough for you, although it is not enough for most people. Here is info on the test from Novartis, which is I understand is providing free BLT testing:
http://www.cmlalliance.com/health-care-professional/cml-blood-level-tests.jsp
I do not believe there is a Tasigna Blood Level Test available yet.
Regarding the weight of a person and drug requirements, although it is logical that a smaller person would need less drug, the drug makers say the recommended dosage is independent of body weight. Personally, I would like to see a study done on that issue.
But it is interesting to note that when Gleevec was in early clinical trials, nearly all of the chronic phase CML patients taking just 200mg Gleevec achieved Complete Hematological Response, and some much deeper responses, showing that such a dosage certainly can have an impact, and that certain individuals need less Gleevec than others:
http://www.pslgroup.com/dg/1eccd2.htm
There are a few references to the subject that say it might be possible to reduce to 200 - 300mg after CMR (PCRU), but come to no real conclusions:
http://www.ingentaconnect.com/content/klu/277/2007/00000086/00000010/00000326?crawler=true
Dr John Goldman, a leading CML expert, says the following about patients in CMR:
http://bloodjournal.hematologylibrary.org/cgi/content/full/110/8/2828
"How long should IM be continued in the responding patient?
There is preliminary evidence that the incidence of disease progression in responders diminishes with each successive year on IM. Moreover, there is no suggestion that the incidence of toxicity increases with duration of treatment. Anecdotal evidence suggests that most patients who stop taking IM lose within weeks or months the response they did achieve. These facts taken together suggest that the best advice for individual patients responding to IM is that the drug should be continued indefinitely, although whether this should be at full dose (400 mg daily) or at reduced dose is not yet established."
There is not much data available on reducing dosage after Complete Molecular Response (CMR, or PCRU).
But it is interesting to note that when Gleevec was in early clinical trials, nearly all of the chronic phase CML patients taking just 200mg Gleevec achieved Complete Hematological Response, and some much deeper responses, showing that such a dosage certainly can have an impact, and that certain individuals need less Gleevec than others:
http://www.pslgroup.com/dg/1eccd2.htm
There are a few references to the subject that say it might be possible to reduce to 200 - 300mg after CMR, but come to no real conclusions:
http://www.ingentaconnect.com/content/klu/277/2007/00000086/00000010/00000326?crawler=true
So there is no current recommendation that encourages reduced dosage after CMR. But the main reason for that is it is not a big concern for researchers because it is viewed as only a residual issue for a few patients.
I started on 400mg when diagnosed in Oct 2005. I tolerated it very well, and had excellent initial results. After about 3 months I asked my Onc to step that up to 600mg for faster results, so we did. I was PCRU by 6 months post diagnosis. However, the 600mg sent my blood counts on a wild ride. I went back to 400mg after PCRU, where I am now. My recommendation is that, if you are tolerating 400mg very well, you might want to step it up to 600mg, not 800mg, and see how it goes. For most people 800mg suppresses the WBC and other counts severely. Even 600mg can be tough. And the additional benefit from 800mg over 600mg is not as significant as the increased benefit going from from 400mg to 600mg.
Going to higher dosages can bring on other issues. I was doing well on 400mg, and asked to raise it to 600mg. It really messed up by blood counts. I went back to 400mg, which is much friendlier to my counts, and I am PCRU at that level. But we all respond differently.
Also, the causes of resistance are not well understood, but there is certainly nothing that suggests that a 400mg dosage makes one vulnerable to Gleevec resistance, so you can cross that off your worry list. Docs would only be concerned about small dosages.
Gleevec Blood Level testing is sponsored by Novartis under a program they call CML Alliance:
The testing is free, but the doctor apparently must use a specific lab listed on the website. I have not tried to use this, so it needs to be checked out carefully.
There is not much information on reducing dosage after PCRU, so Oncs are reluctant to reduce dosage. But some patients have retained PCRU on a reduced dosage of Gleevec, even at 200mg - 300mg per day:
http://www.jstage.jst.go.jp/article/tjem/210/4/210_355/_article
Using a logical approach, if a certain dosage works well when we have many billions of extra leukemic white blood cells in our body absorbing the Gleevec, then wouldn't we be able to use less Gleevec when we achieve PCRU and have many billions fewer white blood cells? But logic does not always prove the point in medicine, so we must admit that we do not know for certain.
Another issue is that there are various levels of PCRU. Some are just barely undetectable, and others may be deeply undetectable. There is no way to know which you are, except that after years of PCRU you might assume you are more deeply PCRU than when you had the first negative PCR report.
Some remain concerned that taking too little Gleevec could cause drug resistance. This seems to be based more on uncertainty than any actual evidence, from what I see. Many researchers believe that resistance is probably caused by other factors, and most likely to occur in the first two years if it is going to occur at all. But that is still something to consider, since we really do not know for certain.
If it were me, and I was PCRU on anything higher than 400mg per day, and side effects were an issue, I would be inclined to reduce it to 400mg. But I would want my Onc to monitor me closely.

DRINKING

There is no known interaction between Gleevec and alcohol. But since all drugs (including Gleevec) and alcohol are processed by the liver, the liver will work harder. As with most things, moderation is the key.
See reference below:
http://www.cmlsupport.com/
Alcohol is not necessarily off limits if you are taking Gleevec. However, you should check with your doctor before consuming alcohol because both it and Gleevec are processed by the liver. Too much alcohol alone will harm the liver, so adding drugs that are processed by the liver makes the situation worse.
Let him have his margueritas -- at least they have a measurable and positive effect. I have seen nothing to say that very moderate drinking poses a significant risk of harm. Too bad the lab mice don't drink, otherwise we would know what happens. Bottom's up!
Gleevec is just approaching its 9th anniversary, so there are still many things we don't know with certainty due to a lack of data. But we know enough to understand that different people can do well on different levels of Gleevec. For some it is 800mg, and for others, much lower levels have the desired result. On this Board we have people with an undetectable PCR who are taking from 800mg down to 200mg (even though 400mg is the lowest officially recommended dosage).
So possibly plenty of Gleevec is getting into the blood plasma. I use the term "plasma" because this test checks levels in the blood plasma (serum), not inside the white blood cells. In fact, the cells are removed from the sample before being shipped to the lab. Gleevec only works inside the cells, not in the plasma. So there is a second level that Gleevec must go through, which is absorption into the cells. Cells have tiny "pumps" for intake and outflow, and for some people they work better than for others. There is no way to test for cellular level Gleevec. So this adds an unknown to the equation.
So it comes down to how well an individual is doing, and whether the patient, in consultation with the Onc, believes that lowering the dosage is in the overall best interests of the patient. That would consider a combination of PCR results and side effects. Most of us find that Oncs do not care much about side effects -- they think we should just be happy to be alive. We tend to believe in a balance.
I can only tell you what I would do in this case, which is that I would wait until I reached PCR undetectable, possibly two cycles, and then lower the dosage under very strict monitoring to see what happens.

Drug Development Info (New Drugs)

The ASH papers show that many new CML drugs are under development -- I counted at least 17 new CML drugs in development. As we know, there are currently 3 primary drugs approved by the FDA for CML. 
There are drugs like Ponatinib (Dr Druker is working on this one) and other drugs that show promise in overcoming the very difficult T315i mutation:
There are drugs that would work in a very different way than current drugs, targeting other kinases, CML cell "switches", or other cell signaling proteins.
There are CML "vaccines" being researched that are trying to make the CML patient's own immune defenses recognize CML cells as the enemy and destroy them.
There are drugs being investigated (with much more work required) that could potentially eliminate residual (quiescent) CML stem cells that could potentially cure CML, if successfully developed. Remember, I said much more work required.
Overall, the main point is that there is a lot of activity in the area of drug development for CML that could lead to better drugs, and solutions to current issues. Most new drug developments do not make it through the process to FDA approval. But with all the work being done there is reason to be even more optimistic about the future.

DRUG INTERACTIONS

The following websites provide info on drug interactions:
http://www.drugs.com/gleevec.html
The Novartis website says:
"Gleevec and Other Medications:
The body metabolizes, or breaks down, many drugs in the liver with a specific group of proteins known as enzymes. When Gleevec is taken at the same time as other drugs, these enzymes may be forced to put the other drugs aside while they break down Gleevec. This can result in higher- or lower-than-expected levels of the other drugs in the bloodstream. Similarly, certain drugs may force the enzymes to put Gleevec aside, which can result in higher- or lower-than-expected levels of Gleevec in the bloodstream. These effects are known as drug-drug interactions. In particular, Tylenol® (acetaminophen)*, birth control pills (oral contraceptives), blood thinners (especially warfarin, Coumadin®+), herbal products (e.g.,
St. John's Wort), erythromycin, phenytoin (e.g., Dilantin®‡, and anticonvulsants, are all broken down by the same enzymes that metabolize Gleevec. Drug-drug interactions may therefore occur with these medications."
http://www.gleevec.com/info/cml/howgleevecworks/sideandsafety.jsp
Here is some info on ibuprofen that can help with fever:
http://www.medicinenet.com/ibuprofen/article.htm
From what I can find, the issue about antibiotics is that some can cause the liver to remove drugs (such as Gleevec) very quickly from the bloodstream and reduce the effectiveness of the drugs, which essentially reduces the dosage of Gleevec in the body:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14605865&dopt=Abstract

Drug Manufacturer Info


DRUG RESISTANCE

Most people on Gleevec do not become resistent to it, only a small percentage. Recent published reports say that "Imatinib has resulted in excellent and sustained clinical response in most patients with CML. For a few patients, a treatment limitation has been the development of imatinib resistance, frequently the result of kinase domain mutations. The cause of increased susceptibility to mutation development remains unknown."
The key phrase is that "a few" become resistent. Information compiled on patients that have used Gleevec since it was first available show that the deeper the level of response the greater the liklihood of remaining in remission. Even if someone only achieves the minimum level of response/remission the probablity of remaining at that level or even better has been shown to be 75%, and if someone achieves the deepest levels of response/remission the probability of staying in remission is close to 100%. So the odds of doing very well over a long period on Gleevec are quite high as long as some level of response/remission is achieved. And the better the response, the higher the long terms odds that Gleevec will continue to work well for that person.
You might also want to look at another online forum where Sprycel is the main topic of discussion, and there are postings about folks having bone pain while on Sprycel:
http://www.newcmldrug.com/bms_discuss/default.asp

Exercise

It is likely that you will experience fatigue for a while, possibly extreme, which will slow you down. You might want to take it easy for the first couple weeks, then start exercising again, building up to full exercise over a few months. That is what I did, and my Oncologist (Onc) encouraged exercise. After a few months I felt much better, and after a year or so I felt as fit as before. Not everyone shares this experience, and we are all different.

Eye Issues

Eye bleeding associated with Gleevec is called a subconjunctival hemorrhage. The tiny veins in the eye are fragile and can break easily, but it is not clear exactly why Gleevec makes them break more often. In a sense, Gleevec can act as a "blood thinner", which may partially explain the cause. Taking other medications along with Gleevec can increase the incidents, such as antibiotics, coumadin, nonsteroidal anti-inflammatory drugs, aspirin, steroids, contraceptives, and others, since they are known to increase the occurrence of sub-conjunctival hemorrhages. This could be from a combination of factors along with Gleevec. It can be made worse by high blood pressure or low platelets. There could also be other issues, such as Gleevec interfering with normal body processes that is not well understood.
Dr Druker's clinical nurse has discussed this and other side effects of Gleevec:
http://www.cancereducation.com/cancersyspagesnb/transcripts/lls/35/aawe.pdf
I also have experienced a blind spot on one occasion. It was just off center in one eye, and it was a blank space (somewhat rectangular). I was able to look at things and position my eye so they simply disappeared. It lasted about 10 minutes. Gleevec can cause capillary breaks in the back of the eye causing a blind spot for a short time.
More rare is effects on the eye’s Juxtacanalicular tissue (JXT). It is part of the eye that helps drain excess fluid from the eyeball. Swelling (edema) in the eyes can block drainage and cause fluid build-up and pressure. This could be related Gleevec. If it is bad enough, you might ask your doc about whether a Canaloplasty might help.http://en.wikipedia.org/wiki/Trabecular_meshwork
Here is some info about Gleevec and eye problems:
Here is an article where Dr Druker's nurse, Carolyn Blasdel, talks about dealing with this and other side effects:
http://74.125.47.132/search?q=cache:T3rcDK_Fnj0J:www.cancereducation.com/cancersyspagesnb/transcripts/lls/35/aawe.pdf+reason+Gleevec+eye+conjunctival+hemorrhage&cd=11&hl=en&ct=clnk &gl=us

Fibrosis (Marrow)

If a person has marrow fibrosis at diagnosis for CML, Gleevec often reverses it. A return of marrow fibrosis during therapy could possibly be an indicator that Gleevec is not working as well. The BMB should show whether this is actually the case, but other tests might also be required (possibly a BCR-ABL Mutation Test)

Financial

Call the Leukemia & Lymphoma Society, Information Resource Center at (800)955-4572 and ask about potential financial help. Drug makers also provide free drugs under some conditions for patients who cannot affors the medications (See Novartis or Bristol Myers Squibb websites).

Gamma Globulin

Gamma globulin (also called antibodies) is a protein in the body that binds to viruses and bacteria in the body, and marks them for destruction by the immune system. So if your gamma globulin is low, and you already have a virus or infection, you may not have enough to adequately fight the virus/infection. You can get a shot of gamma globulin for a temporary boost to help fight the current problem if caused by a virus or bacteria.
The second issue to address is why your gamma globulin is low. Low intake of protein can be one cause. Here are a couple links for more information:
http://www.webmd.com/a-to-z-guides/Serum-Protein-Electrophoresis-SPE
I found an article that discusses Gleevec suppressing gamma globulin levels:
Haematologica 2003;88:762-768. "Chronic myeloid leukemia patients ... treated with Imatinib show reduced immunoglobulin levels and hypogammaglobulinemia". Other references say 25% of CML patients may have this side effect.

GENETICS OF CML

CML is caused by formation of the Philadelphia Chromosome.
http://atlasgeneticsoncology.org/Anomalies/t0922CML.html
People with CML can have various forms of BCR-ABL because the chromosomes can break off and fuse at different points. There are different types of BCR-ABL because when the pieces of chromosomes 9 and 22 break off and switch places (translocation) turning chromosome 22 into the leukemic Philadelphia chromosome, those pieces can break off at one on several locations along both the 9 and 22 chromosomes, which means they also fuse at different points. The locations are called a, b, c, e etc. Most CML is either b3a2 or b2a2 BCR-ABL and sometimes e1a2. In these the "b" is the BCR, and the "a" is the ABL. So your #22 chromosome broke off at BCR exon #3 (b3), and your #9 chromosome broke off at ABL exon #2 (a2) then they combined to form BCR-ABL form b3a2. The b3a2 and b2a2 are the most prevalent forms of BCR-ABL and are found in p210 type CML. Some people have both b3a2 and b2a2 at the same time. Then there is the e1a2 BCR-ABL in p190 CML, which is more rare. So people with CML can have various forms of BCR-ABL because the chromosomes can break off and fuse at different points. The CML drugs work well for all three types of BCR-ABL.Some have multiple types of these three. There are also other more rare types such as c3a2/e19a2 or e8a2 and other variants of BCR-ABL, and these probably require very close monitoring since less is known about them. Here is a chart on the various CML breakpoints:
http://jmd.amjpathol.org/cgi/content/full/6/4/343/F1
Here is another graphic showing the various breakpoints in CML:
http://www.bioscience.org/2006/v11/af/1791/figures.htm
Multiple breakpoints occurs in a small percentage of people with CML, and seems to have no real significance in terms of drug response.
But when determining your level of Ph+ chromosomes, you must add the PCR values for both variants together, so ask for the b2a2 and b3a2 values to be added together on each PCR. Here is some "light reading" on the subject of junction or breakpoint variants:
http://www.bloodjournal.org/cgi/content/abstract/92/9/3362
http://www.funpecrp.com.br/GMR/year2005/vol4-4/gmr0158_full_text.htm
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=441382
Here is a chart on the various CML breakpoints:
http://jmd.amjpathol.org/cgi/content/full/6/4/343/F1

GLEEVEC: GENERAL

CML is a disease primarily of the white blood cells where the body is flooded with large numbers of immature (therefore poorly functioning) white blood cells. Platelets also get into the act and often get out of control. Simply stated, Gleevec shuts down the leukemic cells (and then they die off) and allows the good cells to take over again. The goal is to put the patient into a continual state of low level chronic disease.
Our drugs have changed the nature of CML over a rather short time. More drugs are being developed. Therefore, much literature on the Internet is out of date, and things may sound more dire than they really are. CML has now become a highly treatable disease for the vast majority of people (approximately 95% survivable).
Here is what the FDA says about Gleevec:
http://www.fda.gov/medwatch/safety/2007/Sep_PI/Gleevec_PI.pdf
It will take some time for your body to adjust to Gleevec. Everyone is different, but it takes several months to normalize -- even then some counts will probably be high or low. For me, I take Gleevec halfway through a meal. I will usually drink water both 1/2 hour before and 1/2 hour after a meal, but I am not a big fan of drinking a lot of water during a meal since that dilutes the various digestive fluids that need to break down the food. Using this method I have no nausea or indigestion with Gleevec. I also split the dosage and take half at breakfast and half at dinner. I do not take Gleevec with just water. Taking it with food will help buffer the side effects on the stomach.
I started on 400mg, then after a couple months went to 600mg (at my own request) to ensure a fast response. The 600mg for me caused my WBC counts to drop and other blood counts to go off track, and caused Gleevec-induced anemia. So you will want to watch your blood counts carefully. I did achieve a 3 log reduction very quickly, then went back to 400mg after a couple months on 600mg. Some of my blood counts got out of control, for instance, my RDW went very high to 21.9, then slowly went back to normal. I have some counts that continue to be high and others low, but I am PCRU. My Onc calls my counts "CML normal".
With 600mg I split the dosage and took 300mg at breakfast and 300mg at dinner. That seemed to help with side effects.
Take Gleevec during or after a large meal to reduce stomach upset. It also helps to minimize activity for an hour after taking Gleevec until it leaves the stomach.
Imatinib Mesylate is not a generic version of Gleevec, they are the same thing. Gleevec is a brand name, and Imatinib Mesylate is the scientific name for it. Novartis has a patent making it the only authorized producer of Gleevec/Imatinib Mesylate through 2015. Generics are only allowed after a drug patent expires. But a company in India produces a so-called "generic" form of Gleevec and calls it Imatinib Mesylate, but it is not allowed in the since it violates US patent law, so it cannot be imported into the US. Canadians get a break on medicines for reasons not worth pursuing here, and US residents are also not allowed to bring Gleevec in from Canada.
Gleevec is called a "biologically targeted therapy", not a chemotherapy. The term "chemotherapy" means literally "chemical therapy", but the usage of the term is reserved for potent agents that are not targeted. Gleevec is like a bullet, and chemo is like a shotgun. If someone took chemotherapy every day, they would not survive very long. Also, you will never hear Dr Druker, Dr Shah, Dr Goldman or any of the most notable CML experts call these CML drugs "chemotherapy". Dr Druker's bio makes a point to distinguish Gleevec from chemotherapy:
http://www.hhmi.org/research/investigators/druker_bio.html
(See para 3)
Chemotherapy is generally used to describe a non-targeted approach to killing cancer cells in a brute-force manner. Our drugs are targeted, do not directly kill leukemia cells (even though the leukemic cells eventually die as an indirect result), and they do not kill the original leukemic stems cell(or cells). The problem is that "chemotherapy" is a very poorly defined term, which enables people to call our drugs chemo or chemo-like drugs. My simple approach to this is that I would rather be taking our drugs than having traditional chemotherapy, since I view them as very different.
Here is a quote about Gleevec vs. chemotherapy, showing that they are different:
“It is conceivable that biologically targeted therapies will ultimately replace current standard chemotherapy, but it will be a process of evolution, not a revolution,” says Louis Weiner, MD, director of the
Lombardi Comprehensive Cancer Center at Georgetown University.
http://www.curetoday.com/index.cfm/fuseaction/article.show/id/2/article_id/449
Some people seem to need less Gleevec than others to achieve treatment milestones. Whether this is a difference in absorption, a difference in body responses, or other differences is not well understood. But if you achieved a Complete Hematological Response in those first two months on 400mg Gleevec, then 400mg is likely doing the job for you. If you tolerate the 600mg well, then all is fine. If you have severe side effects that persist, or your blood counts crash, you might want to ask your Onc about going back to 400mg. Some people absorb more Gleevec than others, so some need higher doses to have the same impact. Here is an excerpt from the link below:
"The investigators concluded that maintaining imatinib plasma trough levels above 1000 ng/mL is an independent prognostic factor that may be important for achieving CCyR and MMR."
https://www.bloodleveltesting.com/Public/ImportanceBloodLevelTesting.aspx
The issue of body weight and Gleevec dosage requirement is an interesting one. The Japanese have done some work on this issue because of their smaller average size and weight. They have gathered information that they believe shows some correlation, mainly because people with lower body weight tend to have increased side effects, especially myelosuppression (low blood counts). But there is more work that needs to be done on this.
Here also is an article that says smaller people "clear" Gleevec more slowly from their system than larger people. If the body clears the drug more slowly, the build-up is greater due to the long half-life (roughly 18 hours) of Gleevec in the body.
The issue might be a combination of lower amount of blood and tissue by weight and lower liver weight. Also, a smaller liver would presumably clear the drug more slowly from the body than a larger liver. This is mainly conjecture. Again, more work needs to be done to confirm a correlation between body weight and dosage.
There is evidence that Gleevec has reduced cholesterol for some people. Gleevec affects platelet-derived growth factor (PDGF), which has a role in cholesterol formation.

Glucose Levels

Gleevec does impact blood glucose levels. This was noticed by tests done on diabetic CML patients, where data showed that Gleevec reduced glucose levels and helped control their diabetes to some degree. So for them it had a positive impact by lowering blood glucose levels. See article for details:
http://jco.ascopubs.org/cgi/content/full/22/22/4653
Of course, for someone who has low blood sugar, the Gleevec impact on lowering blood sugar levels is negative. This also makes me wonder if some of the extreme tiredness experienced by CML patients is not just anemia, but also combined with low blood sugar. Some of those with extreme fatigue might want to ask their doc to order a Blood Glucose Test to check on this issue (must not eat anything for 12 hours prior to this test).
Gleevec is not harming your pancreas. The effects are on the signaling mechanisms, not on the pancreas itself. Gleevec seems to actually help prevent pancreas islet damage (see article):
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WCB-4KT6GW4-1&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5 =0d447cb0cb18c98b164ba01176e50080

GOOD NEWS ABOUT CML

Gleevec and other medications help approximately 95% of us with CML live an otherwise fairly normal life.
Data accumulated from the patients from the Gleevec clinical IRIS trial through present day shows that those who attain a 3 log reduction (or better) have very little chance of relapse. No one would say "no" chance, but close enough.
Quote from the link below:
"The probability of progression free survival is tightly correlated with the level of response, approaching 100% in those patients who achieve a reduction of BCR-ABL mRNA by at least 3-log at 12 months."
It is also good news that the underlying mechanism of the CML Philadelphia Chromosome mutation and bcr-abl signaling are relatively well understood compared to how other leukemias and cancers operate. That allows CML research to focus on advanced issues that can improve our quality of life, and even trying to find a cure, while research into other leukemias and cancers are still focused on trying to just keep someone alive. So there is good reason to hope that Gleevec and other drugs will serve us well while better approaches are developed, and possibly a cure is found.

Heart Issues

Early reports of Gleevec causing heart problems have generally been dismissed as an over-reaction, but there are many things that remain unknown.

Tasigna has a warning about heart QT interval, so QT testing should be done before starting Tasigna.  Sprycel generally has the same issue, but does not have the FDA warning, but the manufacturer (BMS) discusses the QT issue on its website.  For those with normal QT intervals, these drugs have not shown themselves to be a significant risk among the population of TKI drug users.

But if heart region pain occurs (an emergency), a Comprehensive Blood Panel test done within 3 days of any chest pain can show whether it was a serious heart issue because the marker enzymes disappear quickly. You want to rule such issues out right away, and quick action is important.
http://www.revolutionhealth.com/conditions/heart/heart-attack/blood-tests/enzyme-protein
But there is a pocket of bone marrow in the sternum that can be over-crowded with cells due to CML at diagnosis and for a while afterward, and that over-crowding of a bone cavity can cause pressure and pain.
The only negative statement I have personally seen on this issue was from Dr Neil Shaw. See question 17 and the two answers:
http://www.leukemia-lymphoma.org/graphics/National/LLS0705transcriptwithslidesv3final.pdf

Herbal Supplements

You will have a difficult time finding information on Gleevec and herbal medicines. Here is a drug interaction checker, but it does not do very well for herbals.
http://www.medscape.com/druginfo/druginterchecker
See also Gleevec drug interactions at bottom of this link (not very useful for herbals):
http://www.rxlist.com/cgi/generic/gleevec_ad.htm
In general, Gleevec does not have a serious interaction problem with herbals with a few exceptions like St Johns Wort. But that doesn't mean you won't find another one if you experiment.

ILLNESS

Most CML patients do not need to be overly concerned about viruses and infections since our immune system can still respond effectively when required. CML can reduce resistance to such diseases/infections, but once Gleevec starts to work and the good white blood cells return to normal the body can once again fight disease and infections in a fairly normal manner. There is possibly one exception just after starting drug therapy when the leukemic WBCs are being killed off in large numbers and the good (non-leukemic) WBCs have not yet ramped up production. In this status, additional caution is required. Also, some with very low WBC counts, and those in blast phase must be more careful. Any high fever should always result in a visit to the doctor for anyone.
Our defense against viruses, bacteria, etc is multi-layered, including the lymph blood cells (T-cells, B-cells) and also non-lymph blood cells (neutrophils, basophils, eosinophils, etc). Both of these fight viruses, bacteria, and other invaders. CML does not affect the lymph cells as much as it affects the non-lymph cells. And even though the non-lymph cells may be somewhat suppressed by CML and/or our drugs, they are still adequate for most of us, and the body makes more when needed. As long as we have a reasonable WBC count, even if it is a bit low, our defenses are still very good.
If I feel a cold or sinus infection coming on, at the first sign I gargle several times a day and rinse my sinuses out with salt water several times a day (this procedure was previously provided to me by my regular doc years ago, and it is very effective, especially if I do it at first sign of cold/sinus symptoms.)
Swollen lymph nodes should always be checked out. But the only way to know the cause is to have testing performed. Lymph node swelling is normally due to infection or viruses, and less often due to other reasons.
There have been cases of dormant hepatitis B re-emergence while using Gleevec, so this is not an isolated case. Before Gleevec, the treatment for CML included interferon and/or hydroxyurea.

Interferon

Interferon was often used to treat CML before Gleevec was approved. It can help keep CML in check, but does not work nearly as well as Gleevec. Gleevec is recommended as the front line therapy for CML. Interferon does not create a lasting remission.
Interferon can also have significant side effects. Some people cannot tolerate it for very long since it can cause deep fatigue and continual flu-like symptoms.

SECTIONS "L" THRU "S"

Leukemia & Lymphoma Society (L&LS)

The LLS which runs this website has a call line where you can talk with a CML specialist at their Information Resource Center -- you can call (800)955-4572. They may also be able to help those who cannot afford the cost of the prescriptions and testing.

Life Expectancy

Here is an article that discusses the 95% CML survival rate due to Gleevec:
Since the time this article was written in 2006, two more drugs -- Sprycel and Tasigna -- have been introduced, which has extended the survival rates even further.
Dr Druker has said that the average lifespan for someone with CML on the current drugs is estimated to be approximately 30 years, and maybe longer since we just don't have the data to support longer term estimates. Also, that 30 year figure averages older and younger people, so statistically speaking, you would say that younger people have a longer life expectancy, and that older people will succumb to something other than the CML most of the time. He has also said that with the expected continued advances in new drugs, that 30 years could turn into a normal lifespan. He has also expressed his belief that a cure for CML can be found, and in the reasonable future.
The CML drugs have made most CML website information irrelevant and out of date. This should be an embarrassment to these so-called informational websites. So things are far better than you have seen on these irrelevant and out-of-date websites. The most knowledgeable researchers are becoming comfortable with the idea that our CML drugs can give most people with CML a normal life expectancy.
I would tell your family and friends that CML is the most treatable form of leukemia, since we now have three "miracle drugs" that work extremely well, and that there is a very high probability that you will live a long and mostly normal life. There is also reason to believe that CML leukemia can be cured in your lifetime, since researchers have made so much progress toward understanding CML. Overall, there is a very bright future
Unfortunately, Gleevec, Sprycel and Tasigna are not a cure. But the good news is that we are far better off than those who were diagnosed with CML just 10 years ago.
The reality is that Gleevec and other CML drugs have made CML a 95%+ survivable disease. CML is also the most likely leukemia to be cured some day.
We very rarely lose a member of this website to CML. Mostly we complain about other things, and often lose sight of how fortunate we are.

Liver Issues

Unless you have a reason to be concerned about your liver from a Liver Function Test (LFT), this should not be a big concern to you. My Onc does regular Comprehensive metabolic Panel (CMP) tests, which include LFTs, to watch for issues.
The ALT is the better indicator of liver issues since ALT is only produced by the liver. Sometimes it can be high on one test, then normal on the next. It is best to look for 2 consectutive ALT readings before becoming overly concerned. The other indicator, AST, can be affected by other issues such as muscle damage (pulls, strains, heart issues, etc), besides showing liver issues, so it is not the best indicator of liver issues. These two tests are best used to show trends rather than as single test values. Also, unless the ALT or AST is far above normal, it is not usually considered to be a serious issue.
Some people can have liver enzymes increase after starting Tasigna. This can go away as the body adjusts, but watch it carefully.
Also, try to avoid taking other medications, especially Tylenol, and avoid excessive alcohol. Most drugs are processed by the liver, and alcohol as well. The liver gets overworked when there are too many medications and such floating around.
I think the occasional drink is fine unless the liver enzymes are high. But if they are high I would stop until they return to normal. The liver can just need to "rest" for a while. I would suggest that anyone should not drink alcohol too close to the time they take their CML drugs.

Low Blood Counts (Myelosuppression)

Approx 25% of CML patients have this issue with Gleevec during the first few months. Oncs call this hematologic toxicity, myelosuppression, or cytopenia. The normal blood cell production system just takes a while to get going again. In the meantime, Gleevec is killing off the leukemic cells faster than they can be replaced with good ones. A Gleevec break (generally 2 weeks) is the recommended approach, and that often helps, but sometime a drug (Neulasta or Neupogen) is needed to boost cell production. One thing that my Onc told me was to take a folic acid supplement, which is important for cell production. Whether patient size matters is a subject of debate, but anecdotal evidence says it could be in some cases -- more study is needed.
In general, low counts (myelosuppression) occur soon after starting drug therapy more because of a lack of good stem cells than because of the drugs suppressing them, although it could be some of both. When the leukemic stem cells are out of control prior to diagnosis, the body signals to stop the over-production, because there are too many cells in the blood. But the only stem cells that listen are the good (non-leukemic) stem cells, so they cut way back on production, and even reduce the number of stem cells. The leukemic stem cells don't listen, and they keep proliferating like rabbits. When Gleevec or any CML drug quickly kills off the leukemic cells, it takes the body some time to recognize that more WBCs are needed, which takes some time before the good stem cells can produce enough new cells to raise the counts. In fact, the body needs to first produce more stem cells, then produce new WBCs. And since the stem cells involved in CML produce WBCs, RBCs, and platelet precursor cells, all three can be affected. That is why WBCs, RBCs, and platelets often are low at the same time. So this is why a change in drugs may not help. If it were me, I would give the low dose Gleevec a chance to work back up to full dose. But it is important to stay on the drug therapy, even if cell booster drugs are needed, and not give the CML a chance to advance.
If you can't keep the CBC counts up, you should ask about a WBC booster. Both Neupogen and Neulasta can be used for CML patients:
http://professional.cancerconsultants.com/oncology_leukemia_news.aspx?id=30738
http://patient.cancerconsultants.com/leukemia_cancer_news.aspx?id=32878
Neulasta has some characteristics that Neupogen does not have. Neupogen requires daily injections, but a Neulasta injection works in the bloodstream for over a week. That is why Neulasta is generally recommended.
Some Oncs would first try Neulasta (or Neupogen) and keep you on Gleevec. Your body needs to get used to the Gleevec and then the WBC count should improve over time. My WBC bottomed out at the 6 week timeframe, then got better, although slowly.
For others who might be interested in more details, here is some recent info from leading CML experts, and each covers the low counts issue, among other CML subjects:
Getting counts under control and getting faster response do not usually go together. So the Onc trying to do both at the same time is not a reasonable approach. Raising dosage to 600mg or 800mg Gleevec can suppress CBC blood counts. The normal response would be to take a two week drug holiday and start again, maybe at a lower dose. But to switch drugs starts the process over again, and CBC counts can be suppressed again until the body gets used to the new drug.
Most Oncs will not take someone off Gleevec until their absolute neutrophil count (ANC, which is NEU# on the CBC report) goes below 1.0; the total WBC is not as important as the ANC count. The critical level for hemoglobin (HGB) is 8.0
If platelets go below 50 you may need to talk to your Onc about options, such as a Gleevec break or taking a drug called Neumega. Below 30 they might consider a platelet transfusion. Bruising easily and tiny red dots on the skin (petechia) can be a sign of low platelets.
A LAP test can be used to try to evaluate people with slightly high WBC count to determine whether they have a leukemoid (leukemia-like) reaction, polycythemia vera, or myelofibrosis instead of CML. If LAP is high, it is very unlikely that you have CML, since people with CML have low LAP scores. Smoking can cause high WBC and LAP counts, but read about these issues below. If you ever wanted a motivation to stop smoking, this would be a good one to see if the levels drop to normal.
If WBC booster drugs or platelet infusions and others drugs do not help, then I would ask the Onc about switching to Sprycel to see if it works better.
Platelet counts can bounce around as the body tries to adjust to what it thinks is needed. The spleen sequesters about 1/3 of the platelets that are produced until blood signals are received that a wound has occurred, then they are quickly released. Disease can throw off the signaling processes, both for production and for release. And a sudden release (due to wound or just mixed signals) can spike the platelet counts. Your body can have a tough time figuring out what to do for a while.
You should be aware that the FDA issued a warning on cell booster drugs in 2008:
http://www.fda.gov/medwAtch/safety/2008/epo_DHCP_03102008.pdf
But since most people who use them are on chemotherapy, the data has mostly come from that population. That could possibly skew the results. You should discuss the risks and benefits with your Onc.
Procrit can be injected at longer intervals, if desired, since the HGB may just be a little lower on this lower dosage. That may not be entirely bad given the FDA warnings. Weekly doses are recommended. It seems to be a toss-up on which is better. It could take up to 3 weeks to see a difference:
http://health.lifestyle.yahoo.ca/drug_info_details.asp?brand_name_id=2028
"Darbepoetin alfa [Aranesp] does not act immediately and it may take several weeks before there is a noticeable response to the medication. The amount of time it takes for the red blood cell level to reach target is different for each person."
Many of us will continue to have relatively low WBC and RBC counts for quite a while. Often this gets better over time, but it may take a year or longer. Gleevec suppresses the leukemic white cells very quickly.
In CML, the leukemic cells take over the blood production system and overproduce leukemic white blood cells. This causes the body to try to reduce the huge number of blood cells in the body, and does it the only way it can, which is by suppressing normal (non-leukemic) cell production. The normal cells are the only ones that will heed the commands to slow down, and they do. When we start taking Gleevec, it rapidly kills off the leukemic cells and then we are often left with a deficit of good cells, because they need to ramp up production again. So in the first months after starting Gleevec we are vulnerable to low cell counts as the good cells get busy and start reproducing again, which can take some time. Although leukemia is mainly a disease of the white blood cells, the originating CML leukemic stem cells are those that make all myeloid blood cells -- white cells, red cells, and platelet precursors. That is why CML can cause all of our blood cell counts to get out of whack, including red cells and platelets.
You might ask "But doesn't Gleevec suppress good cell production, and cause the low cell counts?" Good question. While suppression of good cell production could possibly be a side effect for some people with CML, it is interesting to note that people who take Gleevec to control their GIST intestinal tumors do not suffer from blood cell count suppression. That has caused researchers to speculate that in CML, the good cell production might have been suppressed for a long time by the body in an attempt to try to reduce the out-of-control blood cell counts, and it might take normal blood cell production a while to recover once the leukemic cell production is brought under control.
As a side issue, it is not entirely clear that Gleevec directly causes the immune suppression (low WBC count). There is evidence of this because Gleevec is also used for another form of cancer, called GIST (an intestinal tumor), and GIST patients on Gleevec do not experience low WBC blood counts (see reference below, under paragraph titled "Adverse effects of IM").
Dr John Goldman, a leader in CML research, has the following to say about this issue:
"A significant proportion of patients sustains some degree of hematologic toxicity after starting treatment with IM [Gleevec] at 400 mg daily, and the proportion is higher in those who receive 800 mg daily. The toxicity may take the form of reduced cell numbers in a single lineage or pancytopenia. The cause of this myelosuppression is not entirely clear. It unlikely to be due to a direct effect of IM on residual normal hematopoiesis because it is rare in patients treated with IM for gastrointestinal stromal tumors (GISTs). It may be due to inadequate reserve of normal stem cells in some patients, but if so the basis for this heterogeneity is unknown. Neutropenia can often be managed by administration of granulocyte colony-stimulating factor (G-CSF)."
http://bloodjournal.hematologylibrary.org/cgi/content/full/110/8/2828

So it is more likely that a CML patient's low WBC counts are due to having too few good white cells due to the CML itself, while at the same time the leukemic WBC's have been killed off in large numbers. This causes a low WBC count, especially a few weeks after starting Gleevec since it takes a while for the good WBCs to rise again.
Each person has a different tolerance level for Gleevec, and for many of us, the higher the dosage the worse the side effects. The standard starting dose is 400mg, and there is something to be said for starting there and working up if needed. I started on 400mg, then asked to go to 600mg, then went back to 400mg after several months. The difference in side effects for me was significant. Now, after 3 years, I have very few side effects and all are mild. Some have a tough time tolerating 400mg, while others do fine on 800mg. Proper dosage within the range of 400-800mg is unique to each of us.
Staying with Gleevec to work through the worst part of the side effects is generally a good idea. Otherwise we would never know if we would be close to adjusting and having the side effects lessen. Most of us have side effects, and many of us have found that they get much better over time. After a while we know which ones will continue with us as our companions.
It is important to try to keep taking the drugs, but we know that can be a problem early in treatment because CBC counts can go too low. The leukemia treatment guidelines used by oncologists in the US is the National Comprehensive Cancer Network (NCCN) Guideline. It recommends that if the CML patient cannot stay on 400mg of Gleevec, then 300mg can be used. See link below, page CML-3:
http://www.nccn.org/professionals/physician_gls/PDF/cml.pdf
Many of us with CML have what is called Anemia of Chronic Disease, which shows up as low hemoglobin (HGB) and low RBCs, but most of us do not have low amounts of iron in the body. Docs will often look at a person with low HGB, especially women, and jump to the conclusion that they need more iron. For most of us with CML that is not the case, and too much iron can be harmful (which is why multivitamins with iron must be kept away from small children due to iron overdose concerns). And although it may seem odd, fatigue can be a symptom of too much iron:
http://www.irondisorders.org/Disorders/TooMuchIron.asp
The reason that our HGB is low is often because our red blood count (RBC) tends to be low. Red blood cells can only hold a certain amount of iron (HGB), so adding more iron to the body will not make the HGB rise under these conditions. A quick way to check this for yourself is to look at your RBC, and if it is low, your HGB will likely be low as well. Also, we take an iron supplement every time we take Gleevec, since the rust colored coating is indeed rust (iron oxide).
So the need for more iron for those of us with CML should be determined by more than HGB levels. If it were me, I would ask the doc to perform a Serum Transferrin Receptor test (also called Serum Iron test) for body iron levels before proceeding with an IV iron infusion. This is because iron can be toxic at high levels, so I am just urging a bit of extra caution. I realize it is difficult to try to tell a doc how to treat us, but they are only human.
Here is some additional info on this issue to discuss with your doc, if you wish:
"ACD [Anemia of Chronic Disease] is seen in a wide range of chronic malignant, autoimmune, leukemic, inflammatory, and infectious disease conditions ... Supplementation with iron for those with ACD is not warranted until the underlying cause of disease is cured. Harmful pathogen are nourished by iron and cancer cells require iron to grow and proliferate."
http://www.irondisorders.org/Disorders/Anemia.asp
http://www.irondisorders.org/Disorders/Iron-Deficiency.asp
http://adam.about.com/reports/000057_6.htm
[Note warnings about who should receive iron infusion injections.]
Overview of low iron causes:
http://en.wikipedia.org/wiki/Human_iron_metabolism

Low iron uptake: Some people do not uptake certain minerals, drugs, etc as well as others (can be heredity). This is why bleeding is not the only cause of low iron; bleeding is loss of iron, but the uptake side of the equation could mean it is not getting into the body in the first place. Your lack of any response to oral iron supplements could possibly indicate this low uptake problem.
Interactions: Taking calcium supplements with iron supplements can impede absorption of the iron.
The liver also plays a key role in iron regulation, so liver function should be monitored.
http://en.wikipedia.org/wiki/Hepcidin
If a person actually has very low iron, thyroid function should also be monitored since it is highly dependent on iron. Gleevec also can affect thyroid function in some people, which could make any such thyroid issues worse.
Also, the IV iron infusion process is a long one, and will take about 6 - 7 hours.

MISC
 
Many oncologists do not understand CML very well, so you should make sure you have one that does.
CML does take time to develop the 100K+ WBC counts. Based on relapse data from those with CML who have stopped taking Gleevec (during pregnancy, etc), it is probably in the six to twelve month range from normal WBC count to 100K (rough estimate). But some CML transplant patients have relapsed as much as 14 years after transplant. I have talked to people who had a CML relapse at 5 years, 8 years and 11 years after their transplants.
A 12K WBC can be a result of a low level infection or even hurrying up the stairs just before your blood is drawn for a CBC.
In my case, the first indication of CML was a CBC done in an emergency room due to an injury one year before my CML diagnosis. My platelet count was almost a million, but my WBC count was normal. By the way, the ER doc did not look at the CBC report, so did not see the high platelet count, and the early diagnosis was missed. One year later my WBC count was 100K and I was diagnosed after severe pain in my left side and hip bone. My doc looked back at the previous CBC report and saw the missed opportunity, and said high platelets can be one of the early indicators of CML.
Anyone who has pre-CML CBCs and can look back for clues could provide interesting data.
Here is a related article about how the pre-leukemic phase can be quite long for some people:
I had a minor pulled muscle earlier this year and my creatinine count went way high. So it doesn't always indicate kidney problems. It can often indicate muscle issues (injury, pulls, strains etc)
I found one reference on the LLS "Sprycel Talk" website (below) where a guy complained about sore nipples.
Gleevec has been shown to cause low levels of immunoglobulin in some people:
"In one study, 25% of patients with CML on 400 mg imatinib daily developed mild lymphopenia and a gradual reduction in serum immunoglobulin levels over 3 to 12 months of therapy"
http://bloodjournal.hematologylibrary.org/cgi/content/full/105/6/2473
Medical marijuana: If in U.S., check first to see if it is legal in your state; Effectiveness is said to be generally no better than other available drugs:http://www.medicalmarijuanaprocon.org/pop/StatePrograms.htm

Mutations in BCR-ABL

Mutations in the BCR-ABL (kinase mutation) can prevent CML drugs from working. This is different than chromosome mutations.
Resistence due to kinase mutations is most likely in the first year or so after diagnosis, then the probability of having one occur decreases significantly, although it can still happen. Those failing Gleevec generally do so within a year or so of starting drug therapy. Current thinking suggests that the mutation may be there from the beginning, and that it shows up over time (first year or so). The stats on Gleevec effectiveness are still very impressive. And either Tasigna or Sprycel work against most kinase mutations. There are currently over 100 forms of kinase mutations. And lab tests for kinase mutations are not as accurate as one would hope.
If a person stops responding to Gleevec, a BCR-ABL Kinase Mutation test should be done to see if there is a resistance to CML. Kinase mutations (not the same as chromosome mutations) are a leading cause of loss of drug therapy response, especially for Gleevec. This test can be done by Genzyme, MolecularMD, ARUP and others:
http://www.molecularmd.com/clinTestsBCRABLMutat.php
Here is a good (but difficult to read) article on mutations:
http://www.pubmedcentral.nih.gov/articlerender.fcgi?&pubmedid=17164333
If you have the T315i mutation, there are clinical trials of drugs that show promise:
T315I is one of many CML mutation subtypes. If you have the T315I mutation, neither Gleevec or Sprycel will be effective against it. A clinical trial of a drug under development might be a good option.
Not all Gleevec resistence is due to kinase mutations. Recent studies show that some resistence is caused by over-expression or LYN:

NEWLY DIAGNOSED

See the first paragraph of this blog posting

Normality

With CML, normal is generally “new normal”.
Generally, you can live a rather normal life, which includes exercising, dieting, taking vitamins, planning a future and doing what people without CML do. Hard as it might be to believe right now, in 18 months or so you will feel fairly normal about living with CML. It will not consume your life and your thoughts as it does now. You will get into a routine that works through trial and error, and only the daily pill will remind you of the CML.
The article below talks about a five year timeline to return to normal. But there would certainly be some fairly significant impact in a much shorter time frame.

Origins of CML

No one knows why any given person develops CML, except in extremely rare cases, so 99.9% of us will never know the answer to the questions "Why?" or "What?".  So attempts to find the cause are generally a waste of time.  And benzene and other chemicals that are known causes of other leukemias have not been linked to CML.  As for the "odds", CML is very rare, and it is even more rare to have more than one case in a family. Genetics within a family are very different due to the random combining of genes from the parents. This is why BMT donor matches are almost never found between parents and their children. This is not something worth getting concerned about since the odds are so very low.
There were questions on other postings about how long it takes for CML to develop. I have a little information about the development of my CML due to some odd circumstances. Exactly one year before my diagnosis I ended up in a hospital emergency room for a minor injury. A CBC was done by the ER doctor, but it was apparently not read. A year later I was diagnosed with CML, and my Onc reviewed old records and saw that my platelets were nearly 1 million on that ER CBC report from a year earlier, and the WBC count was normal, although on the higher side of normal (8.5K). At diagnosis my WBC count was 101K, and platelets were high, but lower than the ER CBC showed one year earlier. So the development of my CML started with very high platelets, and the WBC count went from 8.5K to 101K in exactly 12 months. So the average increase of white blood cells was approx 8K per month over that year.
My symptoms developed over that year, starting approx 6 months before diagnosis, with a mild cough that would not go away. (The cough is due to platelet formation, when large pre-platelet cells called megakaryocytes go to the lungs to be broken apart into smaller pieces to act as blood clotting platelets.) A couple months before diagnosis I had severe pain in my hips due to pressure in the marrow cavity from cell over-production. And finally spleen pain led to a doctor visit and a CBC that led to diagnosis.
So looking at the platelet issue, which was the first indicator of CML for me, it probably took many months for my platelets to reach nearly 1 million. Then it was another year for the WBC to reach 101K. So I would estimate at least 18 months, and maybe longer, for the CML to develop.
CML does not always start with high platelets for every person, so this would not be the same story for everyone. But this might provide some insight into the CML development timeline issue.
There is no documented link between a parent with leukemia and the child developing leukemia (unless both are exposed to the same carcinogen, such as benzene, in the same household). But since sibling genetics are more similar, the odds of a sibling of a leukemia patient developing leukemia, especially for identical twins, is slightly increased, but that risk is still very low.

Other Myeloproliferative Diseases

Normally, a WBC over 30,000 is where an MPD is nearly certain. CML is one of the MPDs, but there are others. Your doctor will determine if you have the Philadelphia Chromosome, which causes CML, in order to provide a proper diagnosis. When you go to the Hematologist you can expect them to take a bone marrow sample from your hip bone (bone marrow biopsy).
An normal infection will not cause the WBC to go up nearly that high, maybe 12,000 - 15,000. A massive whole-body infection could go near 25,000. Anything above 30,000 is likely related to the leukemia or another MPD.


PAIN MANAGEMENT
Naproxen (Aleve) seems to be the best overall pain releiver to use while taking CML TKI drugs.  Tylenol is too hard on the liver when used in conjuction with TKI drugs, and Motrin (Ibuprofen) has some suspected interference with TKI drug uptake into the cells. 

PCR

[NOTE: SEE ALSO THE “TESTING” PARAGRAPH]
PCR ("polymerase chain reaction" aka "real-time reverse transcription-polymerase chain reaction RT-PCR") is the testing method used to monitor leukia levels in the CML patient. Smaller PCR numbers are better numbers, because it means fewer leukemic cells in the body. So for instance, .01 is better than .1 Ask your Onc to tell you what the log reduction is, with 3 log reduction being the major goal in CML treatment. A log reduction is movement of the decimal point by one place, such as 10.0/1.0/.1/.01 -- each of these is a one log change from one number to the next number.
First, PCR results do fluctuate. A PCR test could be done twice on the same tube of blood and two different results would occur, although the numbers should be somewhat close. Some labs say that a PCR is only accurate to within approximately 1/3 of a log, which means that 3 PCR done at the same time on the same sample could yield results something like this example: .05%, .025%, .075% -- so you can see that there is a rather significant margin of error in the PCR testing. Although the PCR results are expressed in multiple decimal points, they are not all that precise. There are many variables, the most significant one being time from blood draw to actual PCR testing. If a PCR is done immediately after blood draw it will be higher than if the test is done 24 hours after the draw. If it is done 48 hours after the blood draw (the time limit for most labs), then the PCR number will likely be at least 1 log too low. If the tests are consistently done the same number of hours after the draw, and by the same lab, that would provide a good comparison from one result to the next. PCR results are best used when viewed over time, although if there is ever a 1 log or more jump then a re-test should be done immediately. An Onc will normally only become concerned if there is at least a 1 log increase. So although you would prefer to see continually smaller numbers, some people just take longer for their PCR numbers to drop. But if you wanted to ask the Onc about how to achieve faster results, you could discuss increasing the dosage.
PCR results can vary for several reasons. There could have been a change in either the lab or lab equipment. Just because your Onc uses the same lab, does not mean that lab didn't buy a new PCR machine or use different chemical reagents. Your PCRU could have been "barely undetectable", so another PCR could have a detectable result. PCRs are not as precise as the five decimal places they show. Longer term trends are more important than an individual PCR result.
PCR undetectable (PCRU) is equated to at least a 5 log reduction, well beyond the goal of a 3 log reduction.
If you use a hospital or an HMO, they often have contracts with a specific lab and send all their tests to one place to get discounts on the lab work. With a PCR, the sample should be processed within 24 hours for best results, since the sample degrades rapidly, which affects results (the longer the time, the "better" the PCR result appears to be). The sample can sometimes be frozen, but that is not the normal procedure because the unfreezing process is time consuming. Overnight mail in a cold-pack should be fine in most locations. Shipping to a local lab can sometimes take just as long as overnight mail. The best approach is to use a hospital that does its own PCRs, but many of us do not have that available to us. You could ask your doc if the local lab could be used, because sometimes they just don't know what the options are.
Many labs that standardize the PCR log reduction will use a starting PCR value of 10.0 for a standard CML patient at diagnosis. Other labs use average PCR values calculated on numerous patients over time, and some do not provide a methodology at all. Some labs are starting to use the "Intermational Scale" that uses 100% as the average starting point at diagnosis. So it is better to have your Onc provide your log reduction than use raw numbers. If the Onc cannot provide the log reduction, then using the 10.0 standardized PCR starting point for calculating log reductions, a 1 log drop would be 1.0 , 2 logs .1 , and 3 logs .01 I suppose the lab did not include its calculations of log reductions along with your results?
Many chronic stage CML patients will show 100% leukemic cells in the BMB, but the PCR number is almost always much lower. In my own case, at diagnosis my BMB showed 100% and my PCR was 7%. These numbers differ because PCR does not measure the ratio of leukemic cells to good cells in the blood, but rather amplified bcr-abl to a control gene using a complicated amplification process.
It is far more complicated than that because the sample is put through approx 40 rounds of DNA amplification, and a complex formula is used to calculate the result. You can read the following article for more info:
http://www.ambion.com/techlib/basics/rtpcr/
As for the PCR International scale standard of using 100% as the starting point for determining log reductions, the 100% number cannot be used without each lab using their own specific conversion factor, which most do not have. Below is a very informative discussion of recommendations to standardize CML PCR testing and results, because it is so hard to figure out due to differing methodologies. And after all, we just want to know how well we are doing.
http://bloodjournal.hematologylibrary.org/cgi/reprint/108/1/28?ijkey=9ce77cca9de720f445e9d1396b2fc4ff6a62038f
FISH cannot be used for 3 log reduction calculations.
All PCRUs are not equal. Some people in PCRU are "barely PCRU", others are in "deep PCRU", and others are somewhere in between. Any PCRU is extremely good, so we should not over-think this issue, since even a "barely PCRU" is approx a 5 or 6 log reduction. But to answer your question, someone who is "barely PCRU" can occasionally show positive on a PCR, since their leukemic cell count is somewhere around 1 in a million, which is the limit of PCR sensitivity. Those in deeper levels of PCRU will normally not show positive, because their leukemic cell count could be 1 in ten million or better. Occasionally a PCR can also find that needle in a haystack and register positive. This is why it is necessary to watch trends and not focus so much on individual test results.
Average BCR-ABL:ABL ratio in "previously untreated CML patients":
Quest Diagnostics 4.1325; MDACC: 50%; OHSU: 5%
There are only about eight major makers of PCR equipment, and the two most widely used are Applied Biosystems and Roche. Most US labs use one of these two. The manufacturers all seem to advertise quantitative RT-PCR detection levels at a minimum of 1 in 100,000, and most are assumed to be actually closer to 1 in a million. Lawyers only allow companies to advertise the conservative minimum capabilties so they won't be sued for false advertising. There does not seem to be much difference among the sensitivities of the various machines.
So why isn't the result from one lab comparable to another since the sensitivities are equivalent? Good question. Some variation comes from using different reagents and different control genes. Some comes from patent lawsuits by machine makers that limit flexibility in procedures and methods. Here is a paper on the attempt to standardize PCR testing:
http://bloodjournal.hematologylibrary.org/cgi/reprint/2006-01-0092v1.pdf
I see that the Univ of Washington Medical Center research lab uses both Applied Biosystems and Roche machines, so maybe the Cancer Center does also:
http://depts.washington.edu/hmcrt/realtimepcr.htm
OHSU has their own lab and does the PCRs on site. Here is a link to their CML PCR lab website:
http://www.ohsuhealth.com/consult/labs/results.cfm?labtestid=ECDE35BE-E1DD-DFA3-369C229909F8F5EB
Just as a point of academic discussion, it is the PCR lab equipment that makes the difference in a PCR, since the testing is all automated. So you would seek to find the lab with the best equipment. I don't know how to compare them, but there are not that many manufacturers of PCR machines. The point is that it is probably not worth much effort to have your testing done in any particular lab, as long as it is done at the same lab each time, and they process it quickly after the sample is taken.
This brings up a point that I learned the hard way -- do not have a PCR done (especially on bone marrow aspirant) late in the week if the sample will be sent to an outside testing lab. They do not work weekends, so your sample will spoil before they can do the test. I only schedule my PCRs on Monday - Wednesday. I only schedule mine for Monday or Tuesday, since most labs are closed on the weekend. If you have a sample taken on Thursday or especially Friday, it could easily spoil before the lab gets to it on Monday. OHSU has an excellent write-up regarding proper procedures for PCR sample collection, handling, storage, and shipment (I would show it to your Onc):
http://www.ohsu.edu/pathology/wardman/forms/bcrablspecrequire.pdf
Most labs say they do not allow freezing samples. But I think that is just a logistics issue so they do not have to take time to properly unfreeze them (a slow process). I was in a clinical trial where the US National Institutes of Health (a very prestigious institution) froze all my samples over several weeks for PCRs at a later date, all at the same time. They did not think the results would be altered, especially since they were looking for very minute traces of BCR-ABL (I am now and was then PCR undetectable). So as long as the lab will allow it, freezing samples for PCR is acceptable.
The 3 log reduction is only truly accurate if someone has a baseline PCR when first diagnosed, and before starting Gleevec/Sprycel or having other treatments. That does not normally happen. Most of us had a cytogenetics (microscopic look at approx 20 cells) and/or FISH (test on approx 200 cells) done at diagnosis, and a PCR only after we had been on therapy for a while. At the time of a first PCR several months after start of therapy, we could have already experienced a 1/2 to 1 log reduction. So it is not a good comparison to start with a 3 or 6 month PCR and say you will need another 3 log reduction from there, and worry because it is only 2 or 2.5, because it might actually be over 3 from diagnosis levels. This 3 log stuff is all very unscientific, and is only a rough indicator, and it can cause people to be concerned when it is not necessary. Also, unless every PCR is done on the same machine at the same lab each time, the results can vary.
Generally a first PCR is useful to set a baseline from which you want to see continual progress over time on a lowering trend (maybe not every PCR will show a reduction) until it reaches a relatively low level.
As for determining CCR (which is determined by either cytogenetics or FISH being zero), if the Onc stops doing these and uses PCR instead, you need to assume that you reach CCR at some point. That point is not the same for every PCR testing machine, but as a very rough indicator of CCR, if the PCR is less than .1% you could likely assume that is comparable to CCR, and maybe even before that.
There is work being done to standardize the PCR tests so that all PCRs will tell the same story.
PCR reports list the ratio of BCR-ABL (the RNA, not the DNA) to a control gene. It will also tell you the specific type of BCR-ABL you have, such as b3a2, b2a2, e1a3.
The b3a2 and b2a2 types of BCR-ABL are the most prevalent forms of BCR-ABL. These two are found in p210 type CML. Some people have both b3a2 and b2a2 at the same time (I have both). Then there is the e1a2 BCR-ABL in p190 CML, which is somewhat rare, which your husband also apparently has. So according to the PCR results you listed, he predominately has the b3a2 BCR-ABL, and has barely detectable b2a2 and e1a2, so he has all three types of BCR-ABL. There is also some possibility that the test incorrectly identified either the b2a2 or e1a2, since they are at extremely low levels. Gleevec and Sprycel both work for all three of these types of BCR-ABL. Reports say that there is no known prognostic significance to having multiple types of BCR-ABL.
To determine the overall PCR result when there are multiple BCR-ABL types involved, you must add all together.
For anyone who was confused about the negative log reduction on your first PCR at diagnosis your lab is obviously standardized on a 3 log measurement starting point of 10.0%, so since your initial PCR was higher than 10.0, the report said you had a negative log reduction of about 1/2 of 1 log.
Going from PCR undetectable to barely positive is not a big jump. These PCRs, even though measured out to several decimal points, are not all that accurate. Sometimes the same sample measured twice would show such a difference. And sometimes it depends on whether the PCR was done within 24 hours of the blood draw, or within 36 hours. If your next PCR is much higher, then that might be an occasion to do something. Increasing dosage would be a very conservative approach, but the PCR results do not really require such action. The downside impact of side effects should not be minimized. The Onc doesn't need to live with that, but you would. It is really a personal choice for you in consultation with your Onc.
Here is the OHSU (Dr Druker's lab) requirements for PCR specimen collection and processing:
http://www.ohsu.edu/pathology/wardman/forms/bcrablspecrequire.pdf
Tips for PCR sample draws:
1) Always have the PCR sample drawn on Monday through Wednesday, or early Thursday at the very latest. Never have a Friday PCR sample drawn. It will almost certainly sit around until Monday morning in the lab in-box.
2) Find out where your Onc's lab is. If it is across the country, see if there is another option. Overnight mail helps, but closer is better.
3) Watch the lab techs. If the sample used for the vial does not have a lavender top, tell them they have the wrong vial.
The PCR test should be done as soon as possible after the blood sample is drawn. Seems like the most recent one was done within 24 hours or so, which is good. But the MD Anderson one says it was 4 days -- that is not good, unless it was frozen, which few labs do. That is curious, but it was a while ago, so no worries now. Maybe the sample was taken on a Friday, and the PCR done the following week. This is why we should only have PCR blood drawn on Monday - Thursday, if possible, so it won't sit around during a weekend. Generally, the older the sample, the lower the PCR number, which can be misleading. Many labs set 48 hours as the time limit.
PCR results are normally expressed as a percentage, since a PCR is a ratio of bcr-abl to a control gene. If a lab is converting these to non-percentage scientific notation numbers, that is not a standard practice. I would ask the lab to clarify this issue.
However, there is a type of PCR that can be done that actually expresses the results in absolute terms instead of as a ratio to a control gene. But if this is done, you must NOT convert it back to a percentage. Most CML PCRs should be done using "Relative quantitation", which compares bcr-abl to an internal control gene (such as abl or b2m). Results are expressed as ratios of the amplified bcr-abl to the control gene which must then be converted in a percentage value (this can be confusing, so make sure your Onc provides the percentage, not the ratio since they are 2 decimal places different). There is also a lesser used "Absolute quantitation" of results when using competitive RT-PCR, which measures the absolute amount of a specific mRNA (such as bcr-abl) in a sample. So if somehow this was done, you must not convert the result to a percentage, but use it as it is given. Again, I would ask the lab guys to provide a clear explanation of your results. Most Oncs do not understand this issue very well.
The log reduction should be calculated from the lab standard, if one exists. Quest labs says: "Our data shows that, in our laboratory, the median of BCR-ABL:ABL ratio in previously untreated CML patients is 4.1325 in peripheral blood samples (N=120) and 5.09 in bone marrow samples (N=109).") So for Quest, a 5 log reduction from their baseline is .00004, which is likely below their detection capability (PCRU). Your actual 5 log reduction from your diagnosis PCR would be .0000194, which would certainly be undetectable.
A 1 log increase is the standard for concern over a PCR trend line. Mutations are very rare for patients with 3+ log reductions, and will occur more often for poorer responders, but one cannot say "never". PCRs can bounce around without causing concern. Sometimes the docs change labs, or the lab changes equipment, or one PCR is done on a "fresher" sample, and so on. Also, the Onc will want to ensure that he is taking the prescribed Gleevec dosage every day.
The IRIS reference just says that one commonly used average PCR baseline at diagnosis is 4.1325, so they are saying you could use that for determining your log reductions. Other labs use 7.0, 10.0, and other numbers. Interesting, but not very useful.
Leumeta is a Quest Diagnostics Lab name for their PCR:
http://www.questdiagnostics.com/hcp/topics/hem_onc/leumeta.html
There is a more sensitive PCR (nested PCR) that tests for approx 1 in 10 million, but it is more expensive and not normally done. It is also questionable what you would do with such additional information. Would knowing that you have a 6 log reduction help in some way? For most, the standard PCR (which is very sensitive) is just fine. A Nested PCR is essentially two back-to-back PCRs on the same sample using two sets of chemical primers to look at different parts of the DNA. It can be thought of as a PCR of a PCR result. It can potentially increase the sensitivity of a PCR from 1 in a million to approx 1 in 10 million. It is a very labor intensive process, so it is not used very often in regular CML monitoring.
This site has a good overall explanation of a PCR:
Here is a further definition of a Nested PCR
- Nested PCR is a conventional PCR with a second round of amplification using a different set of primers. This second set of primers is specific to a sequence found within the DNA of the initial conventional PCR amplicon. The use of a second amplification step with the "nested" primer set results in a reduced background from products amplified during the initial PCR due to the nested primers’ additional specificity to the region. The amount of amplicon produced is increased as a result of the second round of amplification and due to a reduction in any inhibitor concentrations.
Definition from:
Quality Assurance/Quality Control Guidance for Laboratories Performing PCR Analyses on Environmental Samples
- A very sensitive method for amplfication of DNA, which takes part of the product of a single PCR reaction (after 30-35 cycles), and subjects it to a new round of PCR using a different set of PCR primers which are nested within the region flanked by the original primer pair
Definition from:
http://www.med.unc.edu/wrkunits/3ctrpgm/pmbb/mbt/GLOS.htm
- A second PCR is performed on the product of an earlier PCR using primers which are internal to the originals. This improves sensitivity without impairing specificity
Definition from:
http://www.lshtm.ac.uk/pmbu/staff/rmcnerney/homepage/glossary.html
- The second round amplification of an already PCR-amplified sequence using a new pair of primers which are internal to the original primers. Typically done when a single PCR reaction generates insufficient amounts of product.
Definition from:
Bioinformatics Glossary
So the question for people with CML is: What is the usefulness of a Nested PCR in CML monitoring? It is only useful if someone with CML is negative by conventional PCR. The purpose would be to see if the leukemia can be detected by using a more sensitive method. Then you need to ask: "so what?" For those of us on Gleevec or Sprycel therapy, we know that we still have leukemia, so if the levels are less than 1 in 10 million as opposed to less than 1 in a million, the only benefit is making someone feel better about that, which can have emotional value for that person. But the best use of nested PCR is for someone who has had a stem cell transplant, to monitor them for the earliest signs of any return of the disease, so intervention can occur at the earliest possible time.
Additionally, since nested PCR is labor intensive, it is more susceptible to error and false reports. This can be due to contamination from handling, human error on primer usage, etc. Also, since a PCR is essentially an estimate of disease levels and not an actual measure, these estimates get less precise as the process becomes more detailed, as in a nested PCR.
A false negative PCR is normally due to a spoiled sample, when the PCR is not done soon enough after the sample is taken, and the cells become degraded. 48 hours is the standard cut-off for many labs, but even then the sample will have degraded by possibly 50%. A PCR requires viable cells to work. If the leukemic WBCs in the sample become degraded, the PCR will report low or zero. A false negative could also occur if the PCR was done improperly (less likely, but still possible due to human error).

Pain Management

Tylenol is harder on the liver than most pain medications, which is why I personally never take it. That is the reason why docs say do not take it with Gleevec, and the same logic also applies to Tasigna and Sprycel. The liver is a very important organ to protect for our long term effective drug therapy. For people who are not taking other drugs, Tylenol is probably just fine, but when taking other drugs that depend on processing by the liver, it should generally be avoided. I use aspirin or Motrin, but even those only rarely.
There are two main causes of joint pain for those with CML. First, joint pain at diagnosis is often due to a high number of cells packed into the marrow, found mainly in the hip bone, sternum, and near the joints. This overcrowding of cells causes internal pressure resulting in pain. This type of joint pain usually gets better over time. But that does not seem to be your issue. You seem to be describing the second type of joint pain which is as a side effect of Gleevec, which in your case is severe. As we all know, side effects are different for each of us. There are two recommendations I have found. First is pain medication, which you have tried. The second is movement, including very light exercise of the joint. The pain would likely be worse at first (I know, I know..) but the movement could make it better. Sorry -- no easy answer. Let us know what your Onc says.
It is extremely unlikely that your shoulder pain is connected to a change in CML status. A kinase mutation is not felt in that way, and is also not connected with bone necrosis. I would suggest that you view the shoulder pain as separate, although quite possibly a side effect from Gleevec. You have done what you need to do for now, which is have a 3 month PCR test. The Onc's lack of organization regarding the last PCR test does not mean that it is bad news. You said you had a 4 log drop in the first 12 months, which is very good, so there is only a low chance that such a good initial result turned around.
Unless the thigh pain is up at the hip socket, it is unlikely a marrow issue since there is no marrow in the femur mid-bone for adults. So the pain could be a side effect or related to some other issue.
http://catalog.nucleusinc.com/enlargeexhibit.php?ID=9325

Patents

Novartis has several patents on Gleevec, but generally the main U.S. patent expires in 2015 (it was extended from the original expiration date of 2013). The patent for Gleevec in Canada expires April 1, 2013. Gleevec was granted "orphan drug" status, meaning that it has a somewhat small population that benefits. U.S. patent law is favorable to companies which develop new drugs to fight rare diseases, granting extended patents. In this case, the original patent was 17 years, and another 1.6 years was later added (now Jan 4, 2015 in the U.S.).

There is a "method of use" patent on Gleevec covering treatment of GIST tumors that expires in June 2022. The implications for GIST patients through 2022 is somewhat unclear.
http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6958335.PN.&OS=PN/6958335&RS=PN/6958335

Novartis has a program to help those who cannot afford the drug that might be a fallback position, if needed. Just so you know, it is illegal to import any "generic Gleevec" into the
US.
There is no such thing as "generic Gleevec" in the U.S. since Gleevec has a U.S. patent through 2015. No generic Gleevec is allowed in the U.S. until the patent expires without FDA approval. A generic form of Gleevec/Imatinib is produced in India, but it cannot be imported. A company from India has petitioned the US FDA to allow their "generic imatinib" to be sold in the U.S. as soon as the Novartis patent expires in 2015.

Ph+ ALL & AML

There have been some discussions about Philadelphia Chromosome positive Acute Lymphoblastic Leukemia (Ph+ ALL) lately. There is also a Philadelphia Chromosome positive Acute Myeloid Leukemia (Ph+ AML). So it is natural to wonder how these relate to CML.
Ph+ ALL and Ph+ AML are related to CML in that all three of these forms of leukemia have the Philadelphia Chromosome that creates the BCR-ABL cycle, which leads to uncontrolled growth of leukemic white blood cells. The current three CML drugs can also inhibit the Ph+ ALL and Ph+ AML BCR-ABL, but there are some significant differences. In addition, both Ph+ ALL and Ph+ AML have other features that distinguish them from CML, although they can be difficult to see in the routine test reports and often require additional testing.
As the names imply, CML and AML are both diseases of the myeloid line (neutrophils, etc) of white blood cells (WBCs) and ALL is a disease of the lymphoid (T-cells, etc) WBCs. So the generalized distinction is which type of WBCs are more out of control, the myeloid or lymphoid cells. Beyond that, the “chronic” is generally a less aggressive form than the “acute” form.
Both Ph+ AML and Ph+ ALL are generally more aggressive forms of leukemia than CML. This especially applies to Ph+ AML, which is very aggressive. Patients with Ph+ AML and Ph+ ALL have many of the same Gleevec/Sprycel issues that we CMLers have, so they participate in this CML site to learn from our experiences. But we don’t generally hear about Ph+ AML because it rarely responds to CML drugs for very long, if at all, so Ph+ AML almost always results in the need for a stem cell transplant. And Ph+ ALL is more likely to become resistant to the drugs than CML, so with Ph+ ALL, drug response can sometimes be short-lived. Statistics are hard to find on Ph+ ALL response rates, but indicate that response to the CML drugs for more than a year is significantly less than for CML patients. So for Ph+ ALL a transplant is also more likely to be required, although the drugs can continue to work for a smaller number, possibly for a long time.
CML will generally have the b2a2 or b3a2 type of BCR-ABL (sometimes both), and rarely will include the e1a2 type. Ph+ ALL will more often have the e1a2 BCR-ABL, often along with b2a2 or b3a2 (or both). There are also other more rare BCR-ABL types. But BCR-ABL type alone is not sufficient to differentiate Ph+ ALL from CML. More testing is required to determine some subtle differences that can lead to a proper diagnosis. Recall that Ph+ ALL will show more activity in the lymphoid cell line than the myeloid cell line.
Treatment for Ph+ ALL usually involves a combination of Gleevec and chemotherapy, and substitutes Sprycel along with chemotherapy if necessary. Results are better than just TKI drugs alone. Stem cell transplant is also often used to treat Ph+ ALL due to the significant potential for relapse.
If CML progresses to the final (blast) phase, the CML can either turn into AML or ALL, or probably more accurately can look like one of them. At that point there are a number of additional chromosome mutations and other significant issues, which makes distinguishing among them difficult. But since the only remaining option is likely a stem cell transplant, trying to differentiate among them becomes a moot point since the treatment would probably not change.
Here are some online resources.
Phases of CML
Here is an excerpt on what defines transition to the accelerated phase of CML:
"The most objective findings are a blood blast percentage greater than 10, a platelet count less than 100,000/l (100 x 109/liter), blood basophils greater than 20 percent, and new clonal cytogenetic abnormalities accompanying the Philadelphia chromosome."
Some put the blast cut-off at 15%. It is not an absolute.
Generally, people with CML usually respond better to treatment if they are diagnosed and treated early. But everyone is different.
Here is a paper on treating Advanced Phase CML:
http://www.ufscc.ufl.edu/Patient/content.aspx?section=ufscc&id=765
Also, some patients are mis-diagnosed as in accelerated phase because of higher white blood cell counts, which is not appropriate. The most reliable indicators of accelerated phase are a blood blast percentage higher than 10% and additional chromosome abnormalities accompanying the Philadelphia chromosome. Ask the Onc why the diagnosis is accelerated phase.
There are a number of accelerated phase patients on this site, and doing well. We have options, which is the "good news" about CML.
That might be called "low end accelerated phase". These things are not so concrete as they might seem. Also, Gleevec could bring her back into chronic phase. The good news is no additional chromosome abnormalities, so things are probably not so bad. If the Gleevec works and stabilizes her cell counts, then most Oncs would not rush into a SCT.
PREGNANCY
The harsh reality is that CML requires some level of respect for its power if we are to control it and ultimately defeat it in our lives. So before considring stopping drug therapy to become pregnant, consider whether your CML is stable at low level disease (probably 3 log reduction or even PCR undetectable (PCRU). Focusing on the WBC is not the best indicator of CML stability. The PCR should be used to determine stability and CML status. WBC may not merely rise on a straight line, but will accelerate the longer you are off medication. Most Oncs would want to see a very low PCR that has been stable for a considerable period of time before suggesting pregnancy.
So why is it such a bad thing to stop taking drugs for 9 months to have a baby? First, the practical reality is that it will be more like 10 - 12 months considering all factors. If you start with very low PCRs, you might have time to go through the pregnancy without drugs, as some have done. But if you are not at very low PCR levels when you stop taking the drug, the CML has a "running start" and can run away quickly. The most significant problem with stopping drug therapy is that it could allow the CML to advance into more aggressive stages, and this is the worst scenario. When CML advances, it can possibly change into a more aggressive form. When that happens, more risk enters into the equation. When the CML drugs are working for someone, they are not only killing off leukemic cells, but even more importantly they are keeping the CML from advancing. That is why we can live long lives on drug therapy, because the CML does not advance for most of us who take the drugs. In fact, the most significant aspect of the CML drugs is not driving the leukemic cells to low or even undetectable levels, but rather that they stop the advancement of the disease itself. This keeps most of us in a "perpetual chronic stage" of CML, which is very survivable. When the drugs are taken away, that protection is no longer there.
There are other drugs such as Interferon or Hydroxyurea (HU) that have been used during the early part of pregnancy, but use of HU is discouraged by some due to possible impact on the fetus:
http://www.nature.com/leu/journal/v15/n8/full/2402168a.html
If you look at the planned pregnancies among women with CML they have generally started with very low PCR levels.
Another CML group has an interesting posting on this subject. Note that the woman had a very deep response to Gleevec (PCR Undetectable), then stopped Gleevec to have a baby. This particular woman remained PCRU throughout the pregnancy and had a normal child. An interesting story:
http://groups.google.com/group/CMLHope/browse_thread/thread/994434f9e8f9e747?hl=en
If a woman becomes pregnant while taking Gleevec, there is not enough data to clearly know what to do. There are developmental risks to the fetus according to researchers. You will need to look at all sides of the issue and make the best choice you can given the limited information. I would suggest that you look at your own health first. CML demands respect for its power. If you are PCR undetectable/negative (PCRU), then you have more options. If you are struggling against the CML, then you have fewer options. So the first item is to determine how well you could withstand another 6 months without drug therapy. I do not know anyone who would suggest that you continue taking Gleevec. Some Oncs use Hydroxyurea, but I will discuss later some warnings about using it during pregnancy. Interferon may be an option for you.
Regarding the fetus, you should first understand the negative side of this issue so you can make an informed decision. Novartis (Gleevec manufacturer) warns against mixing Gleevec and pregnancy:
(See Section: "Who should not take Gleevec")
You will need to decide if the lawyers are being overly cautious here, but they do have some data that caused them to say this, and they must take a cautious approach.
The most comprehensive information on this subject is in the following article:
"Of 180 women exposed to imatinib [Gleevec] during pregnancy, outcome data are available for 125 (69%). Of those with known outcomes, 50% delivered normal infants and 28% underwent elective terminations, 3 following the identification of abnormalities. There were a total of 12 infants in whom abnormalities were identified, 3 of which had strikingly similar complex malformations that are clearly a cause for concern. It appears that although most pregnancies exposed to imatinib are likely to have a successful outcome, there remains a risk that exposure may result in serious fetal malformations."
This article provides actual data that express the percentage issues. It also suggests that some have been able to identify abnormailities during pregnancy, and then potentially take action to terminate. Apparently there were others who did not identify abnormalities during pregnancy, or else did not take action to terminate.
"Women of childbearing age should avoid becoming pregnant if they are on Gleevec, and Gleevec should not be used during pregnancy due to the harm it can cause to an unborn fetus. There are no well-controlled studies in pregnancy, and the risk to the unborn child is not known. However, Gleevec has been shown to cause fetal deformity in animals, so Gleevec should not be taken by pregnant women unless it is clearly necessary. If you are of childbearing age, it is important that you use effective birth control during the course of your treatment. Additionally, women taking Gleevec should not breastfeed."
But then you will also find reports such as the following in articles that mention pregnancy while taking Gleevec:
"What can we do in the event of inadvertent conception on imatinib therapy? Although it is difficult to answer these questions, in light of reported cases, we conclude that patients who are under treatment of imatinib at the moment of conception may have normal pregnancies. We think that each case should be examined individually in terms of the aggressiveness of the disease, and decisions should to be individualized. In conclusion, in the face of complicated pregnancy with imatinib, both social and humanitarian factors should be considered, and the main aim should be to ensuer a healthy mother and a healthy infant in both the short- and long-term."
http://annonc.oxfordjournals.org/cgi/content/full/17/1/178
"The limited published literature suggests that imatinib is safe in pregnancy. However, animal experiments suggest it is unsafe."
"If pregnancy is to be continued, it is still unknown if it adversely affects the developing fetus."
Here is the transcript of a Leukemia & Lymphoma Society (L&LS) education series. In the question & answer section (pages 35 - 37) there is discussion about CML & pregnancy.
The most consistently found recommendation is that a woman should stop Gleevec before becoming pregnant, and then the chances for successful birth are very high:
Novartis, the maker of both Gleevec and Tasigna, has started a registry to gather data on women who have conceived after exposure to either of these drugs. Sprycel is made by Bristol Myers Squibb and is not included. This registry could potentially help determine if the recommendation to avoid conception during use of the drugs might be able to change, which could benefit future users of these drugs. Here is the website:
There is less known about issues with fathering a child while on Gleevec. There is a growing number of healthy babies born to Gleevec fathers. See the link to a transcript from a Leukemia & Lymphoma Society seminar (below), where the question & answer section (pages 35 - 37) discusses CML & pregnancy for both men and women with CML.
Some other info that may help men with CML:
Sprycel has the same warnings against pregnancy while taking it:
A small study of Sprycel and pregnacy shows that out of 8 women who took Sprycel while pregnant, 3 aborted by election, 2 aborted spontaneously, 1 baby was underweight, 1 had not yet been born, and 1 was born totally healthy. So for Sprycel it would be accurate to say that given this very small amount of data, that data is inconclusive.
QUESTIONS FOR ONC
At diagnosis it is important to know several things: 1) Do I have CML? (How was it diagnosed -- a BMB should show the Philadelphia Chromosome) 2) Do I have any high risk factors? 3) What CML Phase am I in (Chronic, Accelerated, or Blast Phase)? 4) Was a PCR done at diagnosis? What was the result? 5) When will I start drug therapy, and what drug(s) will I take, and what dosages?
For follow-up appointments, always go to an appointment with a written list of questions. At a minimum I would ensure that the following issues are discussed at every visit:
1) What do my test results show? What is out of range, if anything, even if you do not think it is important? What does each one mean? 2)
What tests are being ordered this time? (should normally be a CBC, CMP Panel, and PCR or FISH) 3) Am I making good progress relative to your expectations? 4) What is my treatment plan for the future? 5) Always get copies of all lab reports before leaving
RDW
RDW is one of those "other counts" that can get out of whack, especially on the high side. Mine got as high as 22 before going back down to normal, but that whole process took almost a year. My Onc was never concerned about it.
RDW shows the range of red blood cell sizes in the blood. So a high RDW means that you have some small RBCs and some large RBCs. So the range of cell sizes is greater than normal. This larger than average distribution of cell sizes is called anisocytosis. It also goes along with CML/Gleevec induced anemia (which you indicate you have). The iron won't likely help much unless testing has shown that you are truly iron deficient. I generally prefer taking folic acid supplements to help the body produce better quality cells. High RDW will need to resolve itself over time as the body adjusts.
I assume it is your RDW that is rising. Normal RDW is approx 12 -16. Mine went to 22 at the 6 month point after starting Gleevec, then returned to normal. My folic acid and iron levels were fine the entire time. Generally, high RDW means you have more variation in the size of the red blood cells than normal. You have been on Gleevec several years, so it is hard to say what is happening. If your doc has not done tests for anemia, that would be a good idea. Sometimes Gleevec just causes weird blood counts, for no particular reason.
Here is more info about RDW:
http://www.drkaslow.com/html/blood_cell_counts.html
The RDW stands for Random Distribution of RBC Weight. It tells how consistent are the size of the red blood cells. Newly made cells (reticulocytes), B12 and folic acid deficient cells are larger than iron deficient cells. This is an electronic index that may help clarify if an anemia has multiple components. The high RDW helps determine if there is only a B12 and/or folic acid deficiency (with normal RDW showing the red cells are mostly the same size) or with concomitant iron deficiency (a high RDW due to small and large red blood cells).
Optimal Range: 13
The RDW is often increased in:
* B12 and Pernicious anemia
* Folic acid anemia
* Iron deficiency anemia combined with other anemia
* Hemolytic anemia
* Transfusions
* Sideroblastic anemia
* Alcohol abuse
* Various less common and hereditary anemias
The RDW is often decreased in:
* Iron deficiency anemia (blood loss, parasites, poor iron absorption, etc.)
* Vitamin B6 anemia
* Rheumatoid arthritis
Neulasta or Neupogen are standard therapy for low WBC counts, including for those on Gleevec. If Gleevec is killing off the leukemic WBCs, then Neulasta or Neupogen generally promote growth of good WBCs, so the "gasoline on the fire" analogy is incorrect.
Regarding the question about what defines the cross-over from chronic to accelerated phase, and accelerated to blast crisis phase, it is mostly defined by higher blast counts. Blasts are very immature and abnormal WBCs that will never mature.
Resistence and Relapse
If resistence (drug therapy failure) is going to happen, it is most likely in the first 2 years or so after diagnosis. Resistance is failure for that particular drug, but there are currently 3 approved TKI drugs for CML, and usually one of them will work, with rare exceptions. The stats on Gleevec effectiveness are still very impressive, so it is not an "outdated" drug.
Mutations in the BCR-ABL structure (called a "kinase mutation") can prevent CML drugs from working. This is different than chromosome mutations. CML starts with a chromosome mutation (more specifically a translocation) when chromosomes 9 and 22 swap pieces. But a kinase mutation occurs in the leukemic cell's BCR-ABL signalling material called messenger RNA (mRNA), which is the location where the TKI drugs do their work. The drugs "park" in a slot in the mRNA and shut it down, stopping the leukemic cell from reproducing, and also causing it to self-destruct.
The probability of resistance decreases significantly after the first 2 years. Current thinking suggests that the roots of kinase mutations may actually be there from the beginning of the CML, and that they simply show up over time as the TKI drug kills off the non-mutated BCR-ABL cells. This is opposed to the theory that the kinase mutations are caused by the TKI drugs somewhere along the way. There are currently over 100 forms of kinase mutations. And lab tests for kinase mutations are not as accurate as one would hope. Kinase mutations are discovered by doing a kinase mutation test. They are not discovered by the other standard CML tests such as PCR, FISH, CBC, BMB, etc. The mutation must also be present in a fairly large number of leukemic cells to be discovered. In rough terms, kinase mutation tests do not work very well if the patient in CCyR or better.
If a person stops responding to Gleevec or another TKI drug, a BCR-ABL Kinase Mutation test should be done to see if there is a resistance to CML. Kinase mutations are a significant cause of loss of drug therapy response, especially for Gleevec. This kinase mutation test can be done by Genzyme, MolecularMD, ARUP and other labs:
http://www.molecularmd.com/clinTestsBCRABLMutat.php
It is important to continue to show progress in reduction of leukemic cells. Data shows that CML patients who have achieved at least CCR (cytogenetics and/or FISH are zero) have a high probability of no resistence or relapse. See the following information from the link below:
Here is an article on drug resistance and new CML Drugs:
http://www.cmlsupport.org.uk/?q=system/files/Mechanisms+of+Resistance+-+Imatinib.pdf

BCR-ABL kinase mutations are not the only reason for loss of response to drug therapy. Other reasons for loss of response are LYN Kinase over-expression by leukemic cells, and also BCR-ABL amplification (a stronger form of signalling process). Sprycel seems to be best equipped to handle loss of response to drug therapy due to LYN and BCR-ABL amplification, but the data is still inconclusive.
Here is some info about the success of using Sprycel after Gleevec resistance:
http://ash.confex.com/ash/2008/webprogram/Paper12511.html
Signs of possible disease progression may include increased PCR number (1 log or greater increase), blast count, increased basophils and/or monocytes, marrow fibrosis, and maybe additional chromosome changes. You might want to ask your Onc if any of the other issues are showing up. The BMB will be helpful.
T315i is a kinase mutation in BCR-ABL, which is the leukemic protein that causes out-of-control leukemic cell proliferation. Our CML drugs can block the BCR-ABL and shut it down (which also leads to leukemic cell death), except when mutations occur in the BCR-ABL. Gleevec is most susceptible to mutation blocking, and Sprycel and Tasigna overcome most of those mutation blocks. But none of the 3 can overcome the T315i mutation block, so they cannot work against it. Several new drugs are in development that show promise in working against T315i, so a clinical trial might be an option to look into.
There is no evidence that taking drug breaks will increase the potential for Gleevec resistance. The roots of resistance seem most likely determined from the beginning of the CML and how the original leukemia forms
Regarding the Kinase Mutation test, the results should tell you if you have a mutation that is interfering with the TKI drug effectiveness, and if so, you would need to switch drugs; and make sure the Onc tells you the actual mutation nomenclature since there are many of them (such as Y253, E255, etc). Some are better targeted by Sprycel, and others by Tasigna.
RESPONSE TO THERAPY 

Note that CML patients on TKI drug therapy have "response", rather than “remission”. The term used by the leading CML specialists is "response", not "remission", since remission implies a cure. This is more than just a technical difference, since other types of curable cancer have remission, but we have response to drug therapy. The exception is a bone marrow transplant where remission (cure) is the goal. The goal of our drug therapy is to gain maximum response to the drug therapy which halts disease progression and put the disease into a continuous state of very low level chronic stage CML. So the answer to your question is that we have various levels of response to treatment, not remission. But if family and friends don't understand that, then using the term "remission" is certainly understandable. But then "remission" would be hard to categorize, since one would need to assign an arbitrary point where "remission" occurs.
Stages of CML "Response":
- Diagnosis: A zero response baseline from which to measure response to therapy
- Complete Hematological Response (CHR): The WBC and platelets return to normal ranges and the spleen shrinks back to normal size
- Complete Cytogenetic Response (CCR): Either a BMB or a FISH is negative, or 2 log reduction in PCR from diagnosis or lab baseline average
- Major Molecular Response (MMR): PCR shows a 3 log (1000-fold) reduction in leukemia from diagnosis levels or lab baseline average
Complete Molecular Response (CMR): PCR is negative/undetectable (PCRU), so BCR-ABL transcripts are undetectable by PCR testing (leukemia levels too low to detect)
- Cure: 5 years of continuous PCRU with no therapy -- rare today without a BM transplant, but research looks promising and could change that some day soon.
It is most important to see the WBC count drop quickly. The red counts/HGB/HCT and maybe others will be unstable for a while, probably for months. The body must get used to Gleevec and figure out how to establish a "new normal" blood system, because the good cells are being put back in control instead of having the leukemic cells in control. The anemia will likely persist for a while. Many of us struggle with that issue, but it often improves over time.
Here is recent data regarding Gleevec. It shows that it has been effective for 95% of CML cases in this large sample of early users of Gleevec:
Other data shows that for those who initially respond well to Gleevec for several years, it is 99% likely that they will continue to respond well.
Here is an interesting paper on response to CML treatments.
http://bloodjournal.hematologylibrary.org/cgi/reprint/108/6/1809.pdf
If a person with CML responds well to drug therapy, then disease progression is halted. This is generally shown by declining BMB, FISH and PCR numbers. In the current era of drug therapy, if a person responds well and quickly to drug therapy, there is only a small chance of progression to later stages. When reading literature on CML, statistics such as disease progression, are out of date, which can be confusing.
A 2 log reduction on the PCR is considered to be a Complete Cytogenetic Response (CCR), even without a negative FISH or BMB.
Only 5% of CML patients reach PCRU, and approx 70% achieve 3 log reduction over a period of 5 years, but 95% do very well over the longer term. That should show you that PCRU is certainly not a requirement. Even a 3 log reduction is not a requirement. But it appears to be an accurate statement - from what we know - that the deeper responses are generally highly likely to be stable over the longer term, even though lesser responses are often stable as well. Remember that Gleevec may not work for everyone, but the other drugs often will work. Further, there will be more and better drugs in the future.
NCCN guidelines say that if a CCR is not attained in 12 months, an increased dosage or switch in drugs should be considered:
http://www.nccn.org/professionals/physician_gls/PDF/cml.pdf
(See page CML-4)
In CML monitoring there are two levels where doctors use the term zero. The first is CCR where either BMB or FISH (cytogenetics testing) shows zero. But that is not a deep response. Then there is a negative/undetectable/zero PCR (CMR or PCRU), which is a deep response. The following discussion applies only if we are discussing a zero PCR.
It is not necessarily the value of the FISH or PCR at diagnosis that shows a correlation to later outcome. Generally, being diagnosed in the Chronic Phase is better than diagnosis in later phases. Also, speed of response to Gleevec seems to have some correlation to longer term response, but the data is based on a fairly short time period that Gleevec has been in use.
Regarding how many achieve CCR, here is a quote from the link provided below:
"At the 42-month follow-up, 98% of newly diagnosed patients treated with Gleevec had achieved complete hematologic response (CHR), while 91% had achieved a major cytogenetic response (MCR) and 84% had achieved a complete cytogenetic response (CCR).
For patients who had achieved CCR and a thousand-fold (3 log) or greater reduction in Bcr/Abl transcript level – a molecular response – at 12 months, the probability of remaining progression-free was 98% at 42 months, compared with 90% for patients with CCR and less than a thousand-fold reduction in Bcr-Abl transcript level and 75% for patients who had not achieved CCR.
Responses to Gleevec were found to be durable at the 42-month follow-up, with an estimated 91% of patients maintaining CHR, 91% of patients maintaining MCR and 87% of patients maintaining CCR."
The deeper the level of response the greater the liklihood of continuing such response. Even if someone only achieves the minimum level of response the probablity of remaining at that level or even better has been shown to be 75%, and if someone achieves the deepest levels of response the probability of staying there is 98%. This data was over 3.5 years, and generally the data shows that the probabilities remain fairly constant over time. So the odds of doing very well over a long period on Gleevec are quite high as long as some level of response is achieved. And the better the response, the higher the long terms odds.
Most Oncs will say that if you continue to see lower PCR results, even if somewhat slowly, then you should stay on Gleevec. If your PCR results go up for a couple PCRs in a row, you will probably need to switch. If your PCR results are flat, there is no agreed-to recommendation, but most will recommend staying with Gleevec until the trend changes direction.
If PCR results rise unexpectedly and significantly, there are several issues to consider. A re-test is a good idea to validate the result, since sometimes the tests can produce inaccurate results due to contamination, errors, or other issues. Personally I would ask that the re-test be done right away instead of waiting a month, since if you have become resistant to Gleevec, then you are essentially having no therapy at all currently. Or if you are going to wait, I would request to increase Gleevec dosage now. If the PCR is shown to be accurate, then you will want to have the Onc order a bone marrow biopsy (BMB) and also a Gleevec resistance test (also called a Kinase Mutation Test).
Here is one lab's description of the resistance test:
http://www.aruplab.com/TestDirectory/resources/TechnicalBulletins/BCR-ABL1%20Kinase%20Domain%20Mutation%20Jan%202007.pdf
If tests show you are not resistant to Gleevec, then increasing the dosage could be an option. Otherwise, a switch to Sprycel or Tasigna would be needed. If the resistance test shows a T315 mutation (rare), then these other drugs will not work and other options would be needed.
The leukemia treatment guidelines used by oncologists in the US is the National Comprehensive Cancer Network (NCCN) Guideline. It recommends that if the CML patient achieves CCR within 12 - 18 months, then continue with same dosage of Gleevec unless there is loss of response (1 log increase in PCR). See link below, pages CML-4, CML-5, and CML-A:
http://www.nccn.org/professionals/physician_gls/PDF/cml.pdf
The other things you could ask the Onc to do would be to perform a Kinase Domain Mutation Test to test for possible Gleevec resistance (which would be a very conservative approach). Also, some leading Oncs are becoming more likely to switch to other drugs faster than in the past, including Dr Neil Shah who discussed this at the L&LS CML Education Series session in December. But that is not the prevailing recommended approach, and increasing Gleevec dosage is a reasonable approach.
There are 3 approved CML drugs: Gleevec, Sprycel (Dasatinib), and Tasigna (Nilotinib).
There are clinical trials on other experimental drugs that are not yet approved for prescription. Your Onc could possibly suggest a clinical trial, if current drugs do not work.
Here is a more complete listing of CML levels of response:
Complete hematologic response (CHR): Normal full blood count and white cell differential count
Minimal cytogenetic response: 66%–95% Ph-positive metaphases*
Minor cytogenetic response: 36%–65% Ph-positive metaphases*
Major cytogenetic response (MCR): 1%–35% Ph-positive metaphases*
Complete cytogenetic response (CCR): 0% Ph-positive metaphases*
Major molecular response (MMR): 3-log reduction of BCR-ABL by PCR
Complete molecular response (CMR): Negativity by PCR
*Measured by BMB Cytogenetics or FISH testing
There are more reasons than just kinase mutations for losing response:
Here are several good lectures by Dr Druker and others (see CML section and click on "text" button):
http://www.leukemia-lymphoma.org/all_page?item_id=161418#CML
The issue of how long Gleevec is keeping CML patients in a status of good response is being studied right now by the European Leukemia Network (ELN). Their work started July 2008:
http://www.leukemia-net.org/content/leukemias/cml/registry/imatinib_failure/
From what has been seen, the rate of Gleevec failure is highest in the first year or two. After that the rate of failure appears to drop to a low level. The IRIS Trials (the first large Gleevec study) showed that the risk of CML progression among those patients dropped to nearly zero after the first few years. So from what has been seen, Gleevec failure after several years is fairly rare. And the deeper the response, the more rare it becomes. I realize that if someone is one of the small number who fail Gleevec after several years, the statistics don't make it seem any better.
Sometimes Gleevec resistance is not associated with a kinase mutation. But Sprycel or Tasigna can still work most of the time.
Here is information showing how the second line drugs usually work well even if Gleevec stops working:
http://www.ufscc.ufl.edu/Patient/cancernews.aspx?section=cancernews&id=37344
http://professional.cancerconsultants.com/news.aspx?id=41090
It is believed that quick response indicates that resistance is unlikely to occur. But no one can say "never" occurs.
A zero PCR (PCRU, or CMR) does not mean zero leukemia. Some people with PCRU/CMR are barely undetectable, while others are deeply undetectable. But there is no way to know which is which. If someone is barely undetectable, it is more likely that they could be detectable again on future PCRs.
(See also "Resistence and Relapse")
Searching for Information on CML
The annual meeting of the American Society of Hematologists (ASH) was held in early December. These meetings provide the latest updates on CML and other hematological diseases from researchers from around the world.
A search for abstracts related to CML for ASH yields over 300 research papers, and the link is provided below (best way to use them is to look at titles for items of interest or use the word search):
http://ash.confex.com/ash/2008/htsearch.cgi?words=CML&action=search&formaction=http%3A%2F%2Fash.confex.com%2Fash%2F2008%2Fhtsearch.cgi&meetingid=1000&dir=webprogram&override=&exclu de=&config=&method=and&format=builtin-long&sort=score
SIDE EFFECTS
Side effects will often change when you change drugs. They are usually at their worst for a couple months after starting the drug, and often diminish over time. But some hang on, and those are different for each of us. Hope they subside soon for you.
You could consider taking Gleevec at night so you will sleep through the short term side effects you are having. As for me, I split my 400mg dosage and take 200mg twice a day, which helps with side effects. You could also ask your Onc about doing that. Most of us have found that some side effects diminish over the first several months. Hope you have the same experience.
The muscle pain caused by Gleevec as a side effect can be a real nuisance. I especially had it in the quadriceps of both legs shortly after starting Gleevec. It lasted for a month or so, then went away. The body must get used to Gleevec. I like to exercise, and I believe that has helped minimize side effects for me, which are now nearly non-existent. In the short term you will have more side effects to work through, but most will subside after the first few months. Then you will know which ones will remain as your companions.
Bone and joint pain can be associated with both fibromyalgia and CML. Because CML results in uncontrolled growth of cells in the marrow, the bone cavities where marrow is located (especially hips and upper legs) can have pain caused by the "pressure" from cell crowding that builds up inside those bone cavities. But if you have had the fibromyalgia for years, it is unlikely they are associated except that the combined effect could be even more painful now.
Fatigue and even exhaustion can often be present at CML diagnosis because the person is usually anemic. CML upsets the red blood cell production and oxygen carrying capacity. I was very anemic at diagnosis. The anemia will likely take time to subside. Your doctor should check your iron and folic acid levels. Even if both are fine, extra folic acid is needed by the CML patient, especially in the first few months. Folic acid plays a key role in cell production.
For most of us, Gleevec suppresses the red blood cell counts and hemaglobin levels. This causes loss of energy, because we do not have as much oxygen carrying capacity as we should have. Overall, vitamins are a good idea and can help, but will not solve the problem. My Onc tells me to exercise regularly, because it gets the blood pumping and oxygen flowing. This is hard to do at first when you feel tired. I found that I had to work through the first week of exercise making me feel worse, and then I started feeling much better. This does not solve the root problem, but I find that it helps. ...forgot to mention, I also do deep breathing several times a day, especially when feeling tired, to boost oxygen levels. The more you sit around, the less you breathe, which further reduces oxygen levels. So a mixture of exercise and deep breathing can boost oxygen levels.
Timing is a personal choice, and we all do different things based on what seems to work best for each one. And there is nothing wrong with taking Gleevec before sleeping, and many do that to sleep through side effects. Probably taking it with food is the one universal good idea. Taking it with lots of water is not -- it causes GI problems for many. I drink fluids a little through the day, and have few GI episodes as a result, and take very little fluid with Gleevec. Some of us split the dosage and take it twice a day. When it comes to how to take our meds, it is a "whatever works" proposition based on individual choice developed through trial and error, since we are all different.
Just as information, the battle against cancer and leukemia is often a battle against fast growing cells. Cancer and leukemia cells are fast growing cells. While traditional chemotherapy attacks all fast growing cells, Gleevec is more targeted than chemo. That is why I do not believe in calling Gleevec a chemotherapy. But Gleevec can still have an impact on some fast growing cells, such as hair and fingernails. The hair issue has to do with how Gleevec works. Although Gleevec is a highly targeted drug, it is not perfectly targeted. Gleevec works against fast growing cells, primarily the fast growing leukemic WBCs. It also works against some other fast growing cells, among which are hair follicles. The side effects of Gleeevc's impact on the follicles can be loss of hair for some (maybe temporary), making hair darker for some, making hair strands thicker or more curly for some, making hair grow in unusual places for some, and follicle itch for some (why the head itches). Some have found the hair loss to be temporary.
Hair can become course, or fall out, become darker, or otherwise be disrupted. Fingernails can become dull or otherwise change appearance. Gleevec interferes with some of their functions, but is generally a small price to pay.
Drug companies often do not know many of the side effects until people like you report them to the doctor, and data is collected over time. Sorry to say that with new drugs like Tasigna, combined side effects when taken with other drugs is generally not well understood. But it would be safe to say that combining these might make you more tired than either one by itself. In general, certain side effects when mixing drugs can compound those effects.
There have been a number of postings dealing with Gleevec, Spycel & Tasigna side effects, questions regarding which drug is better, and so on. Here is a good head-to-head comparison of these drugs:
http://www.hemonctoday.com/article.aspx?rid=30195
This shows that Sprycel does not cause the muscle cramping or rash problems that Gleevec has as side effects. But Sprycel can be harder on the liver, can cause lower phosphate levels (necessary for electrolyte balance and good bone health), and has worse fluid retention issues (including possible fluid build-up in the lungs) compared to Gleevec. Gleevec can cause worse bone and muscle pain than the others. Tasigna seems to have the lowest overall side effects unless a person has some specific heart related issues. These side effects can vary from person to person.
Regarding weakness and dizziness, if these side effects are going to resolve themselves -- at least to some degree -- it could take a year or so as the body tries to adjust, and you are about 6 months into this. Some people can't seem to shake some of the side effects even over time, and it will just take a while to see which ones remain. But generally, things often get better over time. I think that has been the experience for most of us regarding the side effects, and it has certainly been that way for me.
Severe side effects should subside over the coming months, and after a year or so we will know which ones will continue to be his companions. Things most often get better over time as the body adjusts.
I would encourage fighting fatigue by being as active as possible, slowly at first and then increasing activity. It is tough, and requires fighting, but I found that exercise got me back to a sense of normalcy and has allowed me to regain my energy levels.
Generally, the side effects for these drugs have some standard ones, and then there are some that only a few people have. Sometimes the side effects are from the drug, and sometimes from the CML, and it is not always possible to tell which is which. The good news is that sometimes the side effects are only temporary. I would think that in your case, if this is caused by the switch to Sprycel, that it could likely be only a temporary condition that will resolve itself as your body adjusts to the drug.
There is a problem associated with reduced immunoglobulin levels in some CML patients treated with Gleevec, and since Tasigna is so much like Gleevec, it could possibly have the same impact. Low immunoglobulin can be a factor in mouth sores, so testing for that might be a good idea:
http://www.haematologica.org/cgi/reprint/haematol.12642v1.pdf
I had a persistent cough for a number of weeks recently. Just when I was starting to get concerned about it, it went away and has not returned. I think I have become more sensitive to allergies in the past couple years, but I really don't know why the cough hung on for so long. But a persistent cough is not something that should be ignored, even if we might think it is a side effect.
Here is info on Gleevec side effects, including cough:
http://www.drugs.com/sfx/gleevec-side-effects.html
"Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Gleevec:
Anxiety; constipation; cough...."
Regarding the persistent cough some of us had prior to diagnosis that Alexandra mentioned, that was due to the very large number of Megakaryocytes in the blood caused by the leukemia. This was shown by a high platelet count at diagnosis. Megakaryocytes are the large pre-platelet cells that eventually break into smaller pieces and become the platelets that clot blood. Megakaryocytes go to the lungs to be broken apart into the smaller pieces (platelets) by the compression from the breathing action. The cough at diagnosis was due to the excessive number of these Megakaryocytes crowding into the lung area, which causes a cough. After the drugs get cell counts back to normal, this cough goes away.
Unusual bruising after exercise is not normal, so ask your Onc about it very soon. Bruising should not occur in areas where exercise did not include some physical impact to the area (trauma). One possibility is that it could be a sign of low platelets or platelets that are misshapen, because bruising is simply internal bleeding. But there are other possibilities, so you will want to check with your Onc or regular doctor.
Here is some information from a GIST support group where they discuss cramps from Gleevec. Recall that Gleevec is also approved to treat GIST intestinal tumors:
There are certain side effects of Gleevec, mixed with the effects of the CML itself, that could be involved in causing the chills. If you look at the main causes of unusual chills, they are anemia and hypoglycemia (low blood sugar). Both of these can be associated with CML and Gleevec. We understand how anemia is a problem for those taking Gleevec due to the low red blood counts and low hemoglobin. But a little known side effect from Gleevec is that it can cause some people to make more insulin, resulting in faster processing of sugar that can lead to sugar lows, and these sugar lows can cause chills. If you mix the two issues, it can be worse. Women are more susceptible to both of these issues. There is also a rare Gleevec side effect of low thyroid function, which can cause chills:
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/notices-avis/conditions/gleevec_fs_fd_ 107659-eng.php
See Section: "What are the side effects and how serious are they?")
This is not a prescription for "chocolate as medicine" to cure the chills. I'm just offering some "food for thought". I think it would be interesting if some of you with chills would have a glucose tolerance test to check for hypoglycemia. It could add to the knowledge base and help shed some light this issue.
Gleevec can negatively affect bone density in some people, and in others it improves it. So who knows what that means. There is evidence that the combination of CVML and Gleevec cause rapid turnover of bone cells in the marrow producing centers. Some believe that this quick turnover leads to the chronic pain that some have. Some have apparently had good experience using Fosamax, an osteoporosis drug.
Skin Problems
Those "weird red freckles" are called petechia, and are just dried blood caused by the CML. They can be dealt with by laser cosmetics if desired, but are not harmful.
http://en.wikipedia.org/wiki/Petechia
Any strange skin lump should be investigated by a doctor, but many are just regular skin issues, and Gleevec can cause rashes. CML and skin cancers are not connected. In the meantime you can look at this link:
http://www.webmd.com/content/tools/1/slide_spot_skincancer
What does it look like? Scaly or bumpy?
Hard to figure these things out sometimes. Sounds more like allergic reaction than a Gleevec rash, but no real way to know. If it were me, I'd try a simple antihistimine to see if that would help. If not, I'd go to a cortisone cream.
http://www.getridofthings.com/get-rid-of-a-rash.htm
Here are some photos of severe Gleevec rash:
http://www.cmlsupport.com/cmlphotos.htm
There are two issues we face that cause us to become pale. One is that Gleevec causes loss of skin pigment (hypopigmentation):
"Skin hypopigmentation is a benign side effect from imatinib mesylate treatment that appears to be reversible upon discontinuation or dose reduction. Several lines of evidence have previously reported that KIT and its ligand stem cell factor (SCF) have a regulatory role in melanocyte development and survival, suggesting a rational mechanism of action for imatinib mesylate in the pathogenesis of hypopigmentation. The signal transduction mechanism currently is believed to involve SCF ligand binding of KIT and downstream activation of MAP kinase (Erk-2). Microphthalmia (Mi), a basic helix-loop-helix leucine zipper (bHLHZip) transcription factor, is phosphorylated by MAP kinase at a serine residue (S73). Once phosphorylated, Mi transactivates the tyrosine pigmentation gene promoter and affects pigment production."
http://www3.interscience.wiley.com/cgi-bin/abstract/106556990/ABSTRACT?CRETRY=1&SRETRY=0
"Paleness (medical symptom): Several severe illnesses lead to general pallor of the body ranging from anemia to leukemia...."
http://www.wrongdiagnosis.com/symptom/pallor.htm
So if you have loss of pigment and anemia at the same time, the paleness will be pretty obvious.
SPECIALIST
If a person has a very "standard" form of CML without complicating factors, and responds well to Gleevec or other drugs as the first line therapy, there is not much, if anything at all, that a specialist could do for them. Most of the treatment is by a checklist that even we have access to (NCCN CML Treatment Guidelines):
http://www.nccn.org/professionals/physician_gls/PDF/cml.pdf
If a second opinion is truly needed for some reason, I would prefer to go to Dr Druker in Oregon (OHSU) or Dr Cortes at MD Anderson in Houston.
Dr Cortes at M.D. Anderson is an outstanding Oncologist, and people come from all over the world to be treated at M.D. Anderson due to its first class reputation.
If it were me, I would chose the closest good center, unless I had a confirmed serious setback in treatment that required specific consultation. If that happens, someone can always go see Dr Druker for a consultation. Otherwise, there is a lot to be said for minimizing the logistics hassles associated with doctor visits. What you seem to want right away is a quantitative PCR, which Vanderbilt could easily handle.
I assume your PCRs have dropped steadily. If so, then there is little that a specialist could do for you. If drug therapy is working, they will almost certainly tell you to keep doing what you are doing. If things change, and your Onc does not seem to understand what to do, a switch or specialist is certainly needed. Since you seem to be doing very well, the monthly labs and 3 month PCRs is the recommended schedule.
Before I would go to an expert, I would ask myself what I hoped to gain from it. You can learn a lot from internet sources, and read what Dr Smith, Dr Goldman, Dr Druker, Dr Shah, and others are saying about it. Most of what they would tell you in person you can read about.
Generally a CML expert will tell you that if you are dong well on your current therapy (generally Gleevec or Sprycel), that is all they will want to do for you. They will not take much time to talk with you about your condition beyond that. The good news about CML is that we have drug therapy that works well for most people, and if you are doing well, a local Onc who checks your blood counts and does routine exams is just fine.
Here are some thoughts on the issue of specialists, and others can add to it, since it will not cover all the issues.
1. CML Phase at diagnosis: If someone is diagnosed with CML in the Chronic Phase without other complicating factors, there is little a specialist would do for you until drug therapy has time to show whether it will work. There is a greater than 95% chance that drug therapy will work for Chronic Phase patients. You should be getting weekly CBCs in the first couple months after diagnosis, and they will provide critical information about response to drug therapy. If diagnosed in the Accelerated Phase a specialist could be a good idea depending on what the additional complications are. If diagnosed in the Blast Phase seeing a specialist very is important.
2. Lack of confidence in current Onc: The issue here is that most Oncs rarely or never see CML (until you came along). The good news is that as long as they performed a bone marrow biopsy (BMB), properly diagnosed the CML, prescribed Gleevec, and ordered weekly CBC tests then there is not much else that can be done but wait and see how it works. If the Onc seems uninformed or unprofessional, get another one, whether you go to a specialist or just another Onc on your insurance provider list after doing some research. Most of us get linked with an Onc because of circumstances beyond our control, so there is something to be said for picking your own Onc after doing some research. Make sure they are certified as both an Oncologist and Hematologist.
3. After being on drug therapy for a while: If Gleevec does not work, works only poorly, cannot be tolerated, or significant complications show up, a specialist could be required. Even then, it is fairly standardized what to do next, such as switch to Sprycel or Tasigna. But if the Onc does not do adequate testing to determine why Gleevec failed (Gleevec Resistance Test, Gleevec Blood Level Test, another BMB, etc), then a change in Oncs or a specialist could be a good idea.
4. If you are told you need a Bone Marrow Transplant, or you want to look into a BMT, see a specialist. Be careful that most BMT specialists are inclined to think that BMTs are a good idea. A CML specialist that takes an unbiased view would be a better choice.
5. If you want to participate in a clinical trial, see an independent specialist. The clinical trial Onc obviously thinks the clinical trial is a good idea, so get an unbiased view.
6. What is a CML Specialist anyway? There are probably only a handful of true CML specialists that know CML in the required detail to be called a real specialst. Otherwise there are a number of very good CML Oncs, and then there are Oncs who only know a little bit but just follow the checklist about what to do. Most of us end up with the last category, but as long as we were properly diagnosed and respond well to drug therapy there is generally not much else a specialist would do for us. See #2 above about picking your own Onc after doing some research.
This is not an exhaustive list on this issue, and it just my opinion. Regardless, if you believe that seeing a specialist is in your best interests, or that you just need a better Onc, then do it just to reduce your anxiety levels.
Here is an article Dr. Kantarjian wrote that deals somewhat with your situation:
http://content.nejm.org/cgi/content/full/354/24/2542
If it were me, and I wanted another opinion, I would go to MD Anderson (Dr Kantarjian) for a more neutral opinion, or Seattle Cancer Care Alliance (Dr Radich) to meet a BMT specialist.
http://www.mdanderson.org/departments/leukemia/display.cfm?id=c646ee15-d121-11d4-80fd00508b603a14&method=displayfull&pn=0f815fdc-c623-11d4-80fb00508b603a14
Two well known CML Oncs in NY are:
Dr. Steve D. Nimer, Hematologist-Oncologist Memorial Sloan-Kettering Cancer Center
http://www.mskcc.org/prg/prg/bios/134.cfm
Dr. Eric Feldman at The New York Hospital-Cornell Medical Center
http://nyp.org/FPHTML/1168360068786.html
Sprycel
Here are a couple detailed data sheets on Sprycel, for those taking it. They provide a lot of information about the drug:
https://www.sprycel.com/pdf/patient_info.pdf
http://www.emea.europa.eu/humandocs/PDFs/EPAR/sprycel/H-709-en6.pdf
Here is some information about Sprycel for those with sub-optimal responses to Gleevec:
Here are some useful links on Sprycel:
Here is a support group forum called "Sprycel Talk":
For those on Sprycel, here is the result of a study of pleural effusion (fluid build-up in the lung region) that included 138 Sprycel patients:
Summary: Pleural effusion occurred in 48 of 138 Sprycel patients (35%); 17% of those were grade 3 or 4. It is more likely to occur in accelerated phase and blast phase. Management included temporary interruption, diuretics, pulse steroids, and thoracentesis (using a needle to draw out fluid). A twice-daily dosage schedule may result in a higher incidence of pleural effusion.
Severe side effects that interfere with quality of life are a good reason to switch to another drug.
Tasigna side effects are listed at this website, but there are usually others that pop up.
http://www.drugs.com/tasigna.html
The best drug is the one that helps most with least side effects. That is different for each person.
Remember that Gleevec only works against the inactive configuration of BCR-ABL. Tasigna works the same way, but binds more tightly than Gleevec (in simplified terms). Sprycel works against both the active and inactive configurations of BCR-ABL, which has advantages.
Tasigna is not exactly like Gleevec in how it works and what it impacts. It can be thought of as a stronger Gleevec because it binds in the same location as Gleevec (unlike Sprycel, which binds differently), but otherwise it is different in some ways.
Tasigna. There is no generic version, and there will not be one until after 2020 when the patent expires. An overly simplified description of Tasigna is that it is a stronger form of Gleevec. Both Tasigna and Sprycel are recommended for Gleevec resistance. As I understand it, the cost is about 25% higher than Gleevec.
Regarding Sprycel and Tasigna. Generally, and over-simplifying the issue, Tasigna is a stronger form of Gleevec in that it works like Gleevec, but binds tighter. Sprycel works very differently, and shuts down BCR-ABL in both active and inactive configurations, unlike the other two that only work on the inactive form of BCR-ABL. Tasigna is approved for Chronic and Accelerated phases, but not Blast phase. Sprycel is approved for all 3 phases. That is why, if I were in the situation, I would personally prefer Sprycel for any advanced CML, but more real data is needed on this issue. If I were trying to reduce side effects, I would likely choose Tasigna. I don't know if Sprycel would work better for you than Tasigna, but if it were me, I would likely try Sprycel or a clinical trial for another drug before the mini-transplant. You might want to ask the MD Anderson Oncs about new drug clinical trials.
Two recent papers cited below provide updates on large groups of CML patients who failed Gleevec, and how they have responded to both Sprycel and Tasigna. The data continues to be very encouraging for those who fail Gleevec, even when mutations occur.
The following paper provides a 2 year update on Sprycel (Dasatinib) effectiveness from the START-C group (387 CML patients) for those who failed Gleevec for intolerance or resistance (including mutations):
http://gyncancers.asco.org/ASCO/Abstracts+%26+Virtu al+Meeting/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=35464
The following paper provides an update on Tasigna (Nilotinib) effectiveness from a group of 321 CML patients for those who failed Gleevec for intolerance or resistance (including mutations).
http://gyncancers.asco.org/ASCO/Abstracts+%26+Virtu al+Meeting/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=36186
The drug interaction checker says for both those drugs "generally avoid" combining these with Tasigna. The rationale is as follows:
"Theoretically, coadministration with other agents that can prolong the QT interval may increase the risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction."
http://www.drugs.com/drug_interactions.php
However, if you have no history of heart issues (esp. QT interval issues) that could possibly be overly conservative. The doc obviously believes you need to treat the pneumonia, so what else can you do? But you should ask your Onc about it.
Here is a group that discusses Tasigna, and you might want to post a question there also:
http://www.newcmldrug.com/amn_Discuss/default.asp
A recent paper cited below provide updates on large groups of CML patients who failed Gleevec, and how they have responded to both Sprycel and Tasigna. The data continues to be very encouraging for those who fail Gleevec, even when mutations occur. The paper provides a 2 year update on Sprycel (Dasatinib) effectiveness from 387 CML patients who failed Gleevec for intolerance or resistance (including mutations):
http://gyncancers.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=35464
The following paper provides an update on Tasigna (Nilotinib) effectiveness from a group of 321 CML patients for those who failed Gleevec for intolerance or resistance (including mutations).
http://gyncancers.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=36186
Here is some info about the Sprycel (Dasatinib) drug reimbursement program:
http://www.destinationaccess.com/index.aspx?bmscontentpg=sprycel
Some Oncs such as Dr Neil Shah would say switch to Sprycel at any sign that Gleevec is not working well. You could either go to 400mg Gleevec or switch to Sprycel. If it were me, I would switch to Sprycel.
STEM CELLS & CML
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NOTE: This is meant to provide a basic understanding of stem cells related to leukemia. I wrote this myself since I could not find references to cite that were easily understandable for most people, and also since the information is scattered across many sources of information. I find the subject very interesting, especially since it is the key to an eventual cure for leukemia and other blood cancers.
The term “stem cell” is not a single entity, but rather there are many types and levels of stem cells that form a hierarchy in the human body. A human starts as a single stem cell. The offspring of this original stem cell will eventually become every type of cell the body needs: bone, organ, brain, skin, blood, etc, etc. Because this first cell can make any type of cell in the body, it is called an “omnipotent” stem cell. During the first several divisions, the resulting cells are still omnipotent stem cells. But after these first few divisions, the stem cells begin to specialize. The first level of specialized stem cells are called “pluripotent” stem cells, which can make several types of cells, but no longer every type of cell in the body. The pluripotent stem cells can be brain but not blood cells, bone but not skin cells, etc. So the specialization of stem cells has started, but they are still all stem cells, just more specialized ones. The pluripotent stem cells go through a number of divisions until, at some point, the pluripotent stem cells further specialize and become an even more specific type of tissue, such as a blood stem cell (called a “hematopoetic” stem cell – Greek Hema means blood, and Poetic means it makes things). So from that very first cell until the first hematopoetic (blood) stem cell is made, every cell so far has been a stem cell. And these stem cells have become increasingly specialized along the way. For instance, the mother cell that made the hematopoetic stem cell is also capable of making blood vessel cells, and possibly other related cells. But now the hematopoetic stem cell can only make blood cells, although it can make any and every type of blood cell it wants (red blood cells, white blood cells, etc).
The hematopoetic (blood making) system is made up of a hierarchy of blood cell types, and becomes increasingly specialized top to bottom. The top cells in the blood making system hierarchy are called Long Term Hematopoetic Stem Cells (LT-HSC), which can live for many years, possibly decades. But each of its successive offspring (children, grandchildren, great-grandchildren) each have shorter lives, down to the final “working” cells (white blood cells, red blood cells, & platelets) which only stay in the body for days (WBCs) or a few months (RBCs). So the blood making process starts with the Long Term Hematopoetic Stem Cells (many millions of them), which divide and make daughter cells. But this division does not change the hematopoetic stem cell; as it divides it remains a hematopoetic stem cell (self renewal), but also makes a more specialized daughter stem cell at the same time. So the main feature of a stem cell is that it does not change itself by dividing. But the daughter cells become increasingly specialized as subsequent divisions occur. The offspring of the Long Term Hematopoetic Stem Cells are also stem cells, and they are called (wait for it…wait for it….) Short Term Hematopoetic Stem Cells. In reality, within the Long and Short Term Hematopoetic Stem Cell compartments are possibly as many as 16 sub-classes of Long and Short Term Hematopoetic Stem Cells.
Long Term Hematopoetic Stem Cells have the ability to make any type of blood cell, but they each have a built-in bias to produce either myeloid cells (marrow type – neutrophils, basophils, eosinophils, along with red blood cells and platelets, and some others) or lymphoid cells (T-Cells, B-Cells, NK-Cells, etc). So there are two co-existing sets of Long Term Hematopoetic Stem Cells, one set making mostly myeloid cells, and the other set making mostly lymphoid cells. These stem cells can change bias if injury requires more of the other type of cell, but otherwise they generally stick with their bias toward one of the two main blood cell lines. The Short Term Hematopoetic Stem Cells are even more biased toward the myeloid or lymphoid line than the Long Term Hematopoetic Stem Cells, so we see the specialization process continuing. They can still make any type of blood cell, but it is harder for them to switch back and forth from myeloid to lymphoid, and vice versa.
The Short Term Hematopoetic Stem Cell is the last of the true stem cells in the blood making hierarchy. After several divisions they eventually make a more committed cell, called a Multipotent Progenitor Cell. The Multipotent Progenitor Cell can still make all types of blood cells (red, white, etc). But since it has lost stem cell status, when it divides it makes two daughter cells, not a clone of itself and a daughter. So the key to progenitor cells is that they can divide and make two new cells, but cannot self renew. While the Multipotent Progenitor Cell is not truly a stem cell, it is believed to be capable of taking on stem cell qualities when required to do so, such as injury to the marrow. (This “going backward” theory has possible application to some types of leukemia.) So potentially the Multipotent Progenitor Cell can regain stem cell status under certain conditions. Recall that a stem cell can “self renew” when it divides, rather than merely make two daughters; but a progenitor cell can cannot self renew. This progenitor level of the hierarchy has a number of sub-levels of types of progenitor cells, which become successively more specialized. It is the progenitor cells that do most of the real work in making blood cells. Another big difference between stem cells and progenitor cells is that stem cells can divide with no apparent limit on the number of divisions, but progenitor cells only get a set number of divisions and then they die. This is why true progenitor cells cannot be the originating leukemic cell, because the disease would go away by itself as the progenitor cell divides itself into oblivion. But if a progenitor cell regains stem cell properties, as the Multipotent Progenitor Cell can, that restriction on number of cell divisions would disappear.
After several divisions, the Multipotent Progenitor Cells become more committed, producing the next level of progenitor cells called Oligolineage (single line) Progenitor Cells, still capable of division (making new cells) and like their parent they are not stem cells. But unlike their parent cell, they have most likely lost the ability to take on stem cell characteristics, even during a severe injury to the marrow. At this point the Oligolineage Progenitor Cells can only make one line of cells, white-myeloid (plus red cells and pre-platelets) or white-lymphoid cells. These Oligolineage Progenitor Cells divide another several times, becoming even more committed to one specific type of end-stage cell, and eventually they make the end stage blood cells – neutrophils, T-Cells, red blood cells, etc, etc. These end stage cells are no longer capable of dividing. They do their work for a few days (WBCs), weeks (platelets), or months (RBCs), and then are expelled from the body. A normal adult produces many billions of new blood cells each day. The final stage white blood cells are the only blood cells with a nucleus (so they are live cells). Red cells have no nucleus. And platelets are merely cell fragments, so are not cells at all.
Picture of the Hematopoetic (blood cell) hierarchy:
It is important to understand that the higher the cell is in the hierarchy, the longer it lives. The original stem cells that were made during the first few divisions from the single original human cell live for the lifetime of the person. The top level hematopoetic stem cell may live for many years, or even decades. No one knows. The progenitor blood cells may live for months, or maybe a couple years. The end stage white blood cells live for only a few days. As discussed, the red cells and platelets are not even technically live cells, since they have no nucleus, and platelets are not even whole cells. So the white blood cells are the live cells, and that is where the leukemia is located. Red cells and platelets are not truly leukemic as such, although their ancestors are, so the process may cause them to be deformed and have reduced efficiency. We have also noted that the blood making process is a hierarchy of cells, starting with levels of stems cells, followed by progenitor cells, followed by end stage cells. Each stage is increasingly specific in its function. Stem cells can clone themselves and also make a daughter at the same time. Progenitor cells can only make daughters. End stage cells cannot reproduce.
So where does a blood cancer begin? That answer is likely different for the various types of leukemias, lymphomas, and myelodysplastic syndromes. CML leukemia is a disease originating with a single Long Term Hematopoetic Stem Cell that makes a genetic mistake during division, resulting in a mutant (leukemic) blood cell. This mutant cell is called a Leukemic Stem Cell (LSC). Since it is both a stem cell and also is very high in the blood making hierarchy, it has great powers to perpetuate itself, and can also make every type of blood cell (myeloid-white, lymphoid-white, red, platelets, etc). This allows for much mischief.
Another important issue is that high level stem cells live most of their lives in seclusion, hiding and resting in a state of near dormancy, coming out very rarely to divide. After that, they assume the “hide and rest” mode (quiescence). They do this in protected areas of the marrow, deep in crevasses, where they are very difficult to reach by drugs, chemotherapy, T-Cells, and other hazards. They do not “come out and fight like a man”. They skulk and quiesce and….well you get the picture -- they are darn hard to reach or kill. And there is some evidence that TKI drugs and even Interferon can cause the leukemic stem cells to be more prone to go into hiding for long periods (quiescence). This adds to the problem of trying to kill them.
I previously said that CML is a disease originating with a single Long Term Hematopoetic Stem Cell. The stem cell origin is different for various types of leukemia (and myelodysplastic syndromes, lymphomas, etc). So CML leukemia starts very high in the hierarchy, at the Long Term Hematopoetic Stem Cell level. AML leukemia probably starts at the same level. But lymphoid leukemias (ALL and CLL) start lower in the hierarchy. How do we know? Because the lymphoid leukemias only affect the lymphoid cells, unlike CML and AML which affect all blood cell lines, including the lymphoid cells. So the lymphoid leukemias possibly start with a mutation at the committed progenitor line. But wait, the astute reader says -- the committed progenitor is not even a true stem cell. Very observant – but recall that I said the Multipotent Progenitor Cells can regain stem cell qualities. Possibly the lymphoid leukemias start at that level and then revert to stem cell capabilities, although they remain committed to producing only lymphoid white blood cells. But the myeloid leukemias start at a higher level, as shown by the impact on more blood cell lines, including all types of white blood cells (WBC), red blood cells (RBC), and megakaryocytes (pre-platelet cells). This is also why myeloid leukemias have more issues with anemia, platelets going too high or too low, etc. And stem cell transplants can more easily cure the lymphoid leukemias than the myeloid leukemias, since the lower the original leukemic cell is in the hierarchy, the more susceptible to chemotherapy, other drugs, and even to attack from normal T-Cells and NK-cells. The bad news for CML and AML is that their leukemic stem cell is harder to kill, so a BMT requires a harsher chemotherapy regimen and total body irradiation to attempt to kill the quiescent leukemic stem cells. But even so, relapse is more likely to occur in CML or AML because of the level of the originating stem cell in the hierarchy.
It is also important to understand that there is no test or other mechanism to determine if a specific blood cell is a leukemic hematopoetic stem cell. These higher level cells may “give off” (express) signals showing they are either higher or lower in the hierarchy, but no one can pinpoint the original leukemic mutant cell. The original leukemic cell could come up to a researcher and say “Hi, I’m the original leukemic cell” and no one would recognize it as such. Leukemic cells are probably not very truthful anyway. But research is homing in on being able to identify these cells more accurately. They generally are identified by “cluster designation” (CD numbers). A leukemic blood stem cell will be CD34+CD38- but requires more definition than that to identify it. Some research shows they could also have Thy1+, Lin-, IL1RAP+, and various other cell surface expressions.
So as we have seen, CML leukemia begins when a single hematopoetic stem cell (very high in the blood hierarchy) divides. It forms a clone of itself, and also forms a daughter cell that is slightly more differentiated than itself. So which one mutated – the clone or the daughter? No one knows. But it is during a division process where the first leukemic mutation occurs. During the division process the DNA is replicated, producing two separate strands, one for each of the two new cells (technically the clone has “self renewed”, and the daughter is new). One of the two cells ends up with damaged DNA, whereby the chromosomes 9 and 22 switch pieces of the chromosomes (for CML). Often this would be detected and the cell would go into self destruct mode, and it would not be a problem. Mistakes happen all the time, and the body takes care of it. But this one is missed, and whoever was on quality control duty that day messed up. Then the T-Cells look at the mutant cell and say “you look familiar, although not from around here…so I’ll let you go”. So the T-Cells do not kill the mutant, since it looks “close enough” to normal. But the leukemic cells have slight variations that could make them a target under the right conditions, which makes a potential leukemia vaccine interesting (maybe some day). But the mutant stem cell survives, and because it is so high in the hierarchy, over time (possibly a year or several years) it produces a whole lineage of leukemic cells that have survival advantages over the normal cells. As the body sends signals to stop the over-production, only the normal cells obey. So the body ends up with mostly leukemic blood cells.
TKI drugs work mainly on the mutant BCR-ABL messenger system found only in leukemic cells. While BCR-ABL is found in leukemic cells at all levels of the hierarchy, the cells most reliant on BCR-ABL for proliferation and even survival are the progenitor leukemic cells. Gleevec, Tasigna, Sprycel and clinical trial TKI drugs work quickly and effectively to shut down leukemic progenitor cells. When the TKI drugs block the BCR-ABL process, the leukemic cells become confused and self destruct (“Hooray, die you suckers” the crowd cheers with glee). But the high level leukemic stem cells are not so easily affected. This is because they have more options for survival, including multiple signaling pathways that can possibly evade or ignore the BCR-ABL shutdown by TKI drugs. (“Booooo” the crowd moans). And the highest level leukemic stem cells (the hematopoetic stem cells) can hide for long periods of time in a dormant state, where they apparently do not absorb fluids that might contain drugs, so the TKI drugs cannot reach them in this dormant state (and also chemotherapy cannot reach it, which makes CML and AML more difficult to eradicate prior to a bone marrow transplant). Sprycel seems to reach higher in the stem cell hierarchy to kill off some additional levels of leukemic stem cells because it also inhibits something called SRC, which some leukemic stem cells (lower level stem cells) need for survival. Tasigna and Gleevec do not inhibit SRC. But the big question is whether any TKI drug can kill the top level leukemic stem cells when they come out of hiding. And they may hide for years in some cases, so the opportunities are limited. Research in the lab is inconclusive on this point, but there is skepticism that current TKI drugs would kill these highest level leukemic stem cells under any scenario. But things can work differently in the body, and there are more factors, such as T-Cells and other issues that could possibly come into play, so no one knows the answer.
There are many other topics that could be covered in this discussion, but this is simply meant to be an overview of stems cells and leukemia. Leukemia was the first cancer shown to be caused by mutant stem cells. There is much more that needs to be learned about this subject. It is the key to the cure.
Additional reading:


Other stem cell related info:
There were some questions in other postings about whether someone with CML should consider having their own stem cells harvested after PCR shows they are undetectable for BCR-ABL. The purpose would be to transplant those harvested stem cells back into the same person some day if they ever lost remission and had no other options, either drugs or a suitable transplant donor. Another higher level goal for the future would be as a potential cure. Here is a link to someone who had the harvest done, and her story of the harvesting (but she has not used the harvested stem cells):
http://www.cmlsupport.com/cmlmystemcellharvest0402.htm
First, when Gleevec or Sprycel lead to PCRU, the person will almost always still have leukemic stem cells, so both good and bad cells would probably be collected during a stem cell harvest. Currently, processes to remove the bad ones from the harvest are not very effective, so the harvest could still contain cells that would perpetuate the CML if used later for transplant. So this procedure does not have much support for now, and is waiting for better techniques that can eliminate all leukemic cells from the harvest. And insurance companies consider it experimental, so you would pay for it yourself.
The possibility exists that some day a procedure could be developed to eliminate the leukemic stem cells from the stem cell harvest. Progress is being made on this issue. And since one's own cells are a truly perfect donor match, rejection/GVHD would not be an issue for transplant. But the stem cell transplant back into your own body first requires intensive chemotherapy and radiation to destroy all existing blood and marrow stem cells inside the body, which has significant risks and a long recovery period, and it also is not always effective in eliminating all leukemic cells in the body.
As for current technology, if a person had their own stem cells harvested, then lost remission and had no other options, this procedure could be used to possibly restore partial remission, assuming they survive the pre-transplant chemo/radiation in their weakened state of late-stage CML. It might buy the person some amount of time before the disease returned. For the potential future, if the technology is developed to eliminate the leukemic cells from the stem cell harvest, then it could become a better option for transplant than using donor cells from another person, and could be something more of us might consider doing (and insurance would pay for it, once it is proven effective).
The "quiescent leukemic cell" issue relates to the original stem cell (or cells) that had the first translocation of chromosome material that started the whole CML chain of events. All other leukemic cells in the body come from that original leukemic stem cell. That leukemic stem cell reproduces and creates leukemic progenitor cells, which in turn reproduce to create all the final leukemic WBCs in the body. Those final WBCs cannot reproduce, and they also die within a few days, so they are constantly being replaced. The leukemic progenitor cells live for quite a while, possibly for months, but eventually die also. But the stem cells live on and keep the leukemia going.
The theory is that the original leukemic stem cell or cells reproduce then go into a resting state (quiescent) and hide for long periods in the bone marrow close to the bone where they will not be disturbed. They become active occasionally to create new leukemic progenitor cells to keep the leukemia cycle going, then they go quiescent again. So they spend most of their time "hiding" in this quiescent state, which gives them increased survivability. This is all theory and not proven, but is generally accepted as the likely scenario.
The stem cells can live as long as the person does, which is why the leukemia does not go away. Gleevec cannot work against leukemic stem cells for a couple reasons. First, Gleevec and Sprycel do not seem to bind to leukemic stem cells or progenitor cells. Secondly, the leukemic stem cells go quiescent for long periods, and they are more protected in that state.
The PCR does not measure quiescent leukemic cells. For one reason, there may only be one or a few of them in the entire body. For a PCR to detect CML, there must be many leukemic cells in the sample (probably thousands or millions in a vial of blood, depending on the level of disease). So PCRs mostly measure the ultimate leukemic WBCs (the ones that cannot reproduce).
Stopping Gleevec

Going off drug therapy will most likely result in relapse for the majority of folks with CML. But a few have done it and have remained free of CML, some of them for years. The reason is not clear. There was a clinical trial in 2005 that took 12 people off Gleevec who had been PCR undetectable for over 2 years to see how many would relapse. They had monthly PCRs to carefully watch for signs of relapse. Half relapsed within a few months, but the other six did not relapse at all. Here is the article:
http://bloodjournal.hematologylibrary.org/cgi/reprint/blood-2006-03-011239v1
Dr John Goldman, one of the most respected CML experts, says about this subject:
"How long should IM [Gleevec] be continued in the responding [CML] patient? There is preliminary evidence that the incidence of disease progression in responders diminishes with each successive year on IM. Moreover, there is no suggestion that the incidence of toxicity increases with duration of treatment. Anecdotal evidence suggests that most patients who stop taking IM lose within weeks or months the response they did achieve. These facts taken together suggest that the best advice for individual patients responding to IM is that the drug should be continued indefinitely, although whether this should be at full dose (400 mg daily) or at reduced dose is not yet established. A small number of patients in whom BCR-ABL transcripts have been undetectable for more than 1 or 2 years have stopped taking IM for various reasons. In the largest series published thus far, 6 of 12 patients showed evidence of relapse at the molecular level within 5 months of stopping IM, but the other 6 remained in "complete molecular remission" at a median follow-up of 15 months. This observation does raise the intriguing possibility that IM continued for long enough might eradicate residual leukemia in selected patients, perhaps particularly in those who have previously been treated with interferon-alfa. In vitro studies however suggest that "quiescent" leukemia stem cells are highly resistant to IM, and thus some at least are likely to survive long term even in patients who achieve a complete molecular remission, a conclusion supported by mathematic modeling of changes in BCR-ABL transcript numbers in responding patients. Whether this is clinically relevant remains to be seen. In summary, responding patients should continue IM indefinitely until such time as the results of prospective studies suggest otherwise."
As for your case, Jeff, you did not mention PCR results, and only discussed BMBs. It seems that you have only had one negative BMB 6 months ago, and a positive one 16 months ago. BMB status is not the important indicator for considering stopping Gleevec. Negative PCRs for over 2 years is the criteria used for the study discussed above. I would not even consider it without 2 years of negative PCRs. Even then it is risky. The patients that did not relapse in the study had taken Interferon-alfa, and most of us did not have that treatment. It is unknown whether that had anything to do with it, but there is no way to know right now.
As I see it, there will be more clinical trials that include stopping drug therapy, and these will provide the necessary information that will allow an informed decision to stop treatment. Until then, the recommended approach is to continue, and especially if a person is not PCR undetectable for at least 2 years. If you stop too soon, you might need to start all over on your two years.
But this information is one more reason to have hope that we might not need to stay on drug therapy for the rest of our lives, because a cure might be possible.
Here is an excellent article published very recently by Dr John Goldman regarding treating CML in the Gleevec era. It covers a lot of issues and is certainly worth reading.
Your question: "So can CML come back if I stop it for only 2 weeks..?" It is not a question of whether CML will come back, because it is always there, but rather how many new leukemic cells will build up while not taking Gleevec. Gleevec is continually killing off new leukemic cells and preventing progenitor leukemic cells from making new leukemic offspring -- this is a daily process. So our therapy is a matter of driving the leukemic cell count to as few remaining leukemic stem cells as possible, maybe even back to the one remaining original cell that started the whole process with the Ph+ translocation. Whether that is possible is unknown, but that is the ultimate goal for Gleevec. Since Gleevec is presumably unable to kill leukemic stem cells, the CML will still be there as long as there are any remaining leukemic stem cells. So we need to get to a very low count and stay there. Even folks who are PCRU must continually keep this process going. If you stop Gleevec for 2 weeks, you will certainly be set back by some amount. Would you get back on track after re-starting? Probably so. But this is a war, and you do not give the enemy any advantage. Also, there is no guarantee that your energy levels will pop up as soon as you stop. Having said all that, you could ask your Onc about taking lower dosage for the 2 weeks and see what the answer is. Not recommended, but an in-between alternative if you are intent on doing this.
SWITCHING DRUGS
I would not be so reluctant to switch drugs. Dr Neil Shah said in the last L&LS Seminar that he believes Oncs should be switching their patients to other drugs more quickly when there is any suboptimal response to one of the drugs.
There is no reason why you could not go back to Gleevec at 800mg if Sprycel does not work for you, or even go to Tasigna. Seems like a reasonable thing to switch at this point. Both Gleevec and Sprycel can cause spaciness issues in some folks, but each person has a unique set of side effects. I would not let that deter you. The issue is a lack of good information. Oncs like to think in terms of progression: Gleevec first, and then Sprycel or Tasigna if needed. It also lines up with the old adage "if it ain't broke, don't fix it". But is there a problem with going the other way, and returning to Gleevec if Tasigna or Sprycel have bad side effects, or somehow do not work as well? Probably not, if Gleevec was working in the first place. So trying Tasigna chould be a reasonable choice, if desired, but since you are doing well, it is not a critical issue to switch. Remember that the short history of our drugs is showing that someone who achieves a 3 log reduction is approx 99% likely to continue doing well. But we all want to achieve better and better results. It is really a personal choice.
Generally, Gleevec is used as the first drug treatment for CML. Sprycel or Tasigna are used after that if Gleevec quits working (resistance), does not provide good results (suboptimal performance), or the side effects are unbearable. Since you were just diagnosed last month, Gleevec is the accepted way to start treatment. You will need to give it time to work, and also allow time to let your body adjust so the side effects will be reduced. Several months are needed for these to occur.
Technically speaking, Gleevec only works against the inactive configuration of the leukemic gene BCR-ABL (gene turned off). Sprycel works against both the active and inactive configurations of BCR-ABL, which has advantages. Tasigna works the same way as Gleevec, but binds more tightly than Gleevec (in overly simplified terms).
Here is a good head-to-head comparison of Gleevec, Sprycel & Tasigna:
http://www.hemonctoday.com/article.aspx?rid=30195
This shows that Sprycel does not cause the muscle cramping or rash problems that Gleevec has as side effects. But Sprycel can be harder on the liver, can cause lower phosphate levels (necessary for electrolyte balance and good bone health), and has worse fluid retention issues (including possible fluid build-up in the lungs) compared to Gleevec. Gleevec can cause worse bone and muscle pain than the others. Tasigna seems to have the lowest overall side effects unless a person has some specific heart related issues. These side effects can vary from person to person.
These drugs have changed CML from a very deadly disease into a very survivable one. It is good news that we have 3 options, and more drugs are being developed.
After a switch in drugs it is probably better to give it a few weeks to see how your body adjusts. Some of the side effects could lessen or hopefully even go away. But it sounds like the switch was harder on you than most, so I understand how difficult it is to live with that pain even for a few weeks.
First, there is no reason to believe that switching to Sprycel and back again to Gleevec would have any negative effects such as drug resistence. The two drugs work in very different ways. So you should put that concern to rest. And the fact that your WBC counts went up a little does not necessarily mean anything by itself. You did not say how high -- are they above the upper limit of normal (10), or just higher than before? WBC fluctuations can occur at any time, especially during the drug changeover.
You did not say what your Gleevec dosage was, or whether your Onc raised the Gleevec dosage up to 800mg before trying Sprycel. That is the recommended process. See web link below on recommended treatment processes. But your Onc has not done anything wrong, it just does not follow the conservative treatment course that is generally recommended. Since Sprycel is new, Oncs don't know when to switch their patients over, unless they fail Gleevec. If you had tolerated Sprycel well, you would likely think the Onc was doing the right thing for you.
But trying Sprycel again in a couple months before trying 800mg Gleevec (if you had not done that already) seems a bit unusual in view of your side effects. But those side effects can decrease in severity after the first few weeks, so that is also something to consider.
So I would just chill a bit. We are all in one big experiment that is working way better than the alternatives available just a few short years ago.
SYMPTOMS
I had an enlarged spleen at diagnosis, and very painful. But it has been normal size since shortly after starting Gleevec. But my spleen seems to regularly let me know that it is still there with occasional twinges of discomfort (not quite pain). I'm not sure, but I think the spleen is just responding somehow to either Gleevec or the continued minimal residual disease.
I never have right side pain, but if it is liver pain, the liver is in two lobes and is on both sides of the middle abdomen, larger lobe on the right, smaller lobe on the left. See photo of liver:
http://images.google.com/imgres?imgurl=http://www.liver-cancer.info/liverpic.jpg&imgrefurl=http://www.liver-cancer.info/&h=400&w=400&sz=18&tbnid=SRfKwAuGwd5KjM:&tbnh=124&tbnw=124&p rev=/images%3Fq%3Dliver&start=2&sa=X&oi=images&ct=image&cd=2
SECTIONS "T" THRU "Z"

Tasigna side effects are listed at this website, but there are usually others that pop up.
http://www.drugs.com/tasigna.html
The best drug is the one that helps most with least side effects. That is different for each person.
Remember that Gleevec only works against the inactive configuration of BCR-ABL. Tasigna works the same way, but binds more tightly than Gleevec (in simplified terms). Sprycel works against both the active and inactive configurations of BCR-ABL, which has advantages.
Tasigna is not exactly like Gleevec in how it works and what it impacts. It can be thought of as a stronger Gleevec because it binds in the same location as Gleevec (unlike Sprycel, which binds differently), but otherwise it is different in some ways.
Tasigna. There is no generic version, and there will not be one until after 2020 when the patent expires. An overly simplified description of Tasigna is that it is a stronger form of Gleevec. Both Tasigna and Sprycel are recommended for Gleevec resistance. As I understand it, the cost is about 25% higher than Gleevec.
Regarding Sprycel and Tasigna. Generally, and over-simplifying the issue, Tasigna is a stronger form of Gleevec in that it works like Gleevec, but binds tighter. Sprycel works very differently, and shuts down BCR-ABL in both active and inactive configurations, unlike the other two that only work on the inactive form of BCR-ABL. Tasigna is approved for Chronic and Accelerated phases, but not Blast phase. Sprycel is approved for all 3 phases. That is why, if I were in the situation, I would personally prefer Sprycel for any advanced CML, but more real data is needed on this issue. If I were trying to reduce side effects, I would likely choose Tasigna. I don't know if Sprycel would work better for you than Tasigna, but if it were me, I would likely try Sprycel or a clinical trial for another drug before the mini-transplant. You might want to ask the MD Anderson Oncs about new drug clinical trials.
Two recent papers cited below provide updates on large groups of CML patients who failed Gleevec, and how they have responded to both Sprycel and Tasigna. The data continues to be very encouraging for those who fail Gleevec, even when mutations occur.
The following paper provides a 2 year update on Sprycel (Dasatinib) effectiveness from the START-C group (387 CML patients) for those who failed Gleevec for intolerance or resistance (including mutations):
http://gyncancers.asco.org/ASCO/Abstracts+%26+Virtu al+Meeting/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=35464
The following paper provides an update on Tasigna (Nilotinib) effectiveness from a group of 321 CML patients for those who failed Gleevec for intolerance or resistance (including mutations).
http://gyncancers.asco.org/ASCO/Abstracts+%26+Virtu al+Meeting/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=36186
The drug interaction checker says for both those drugs "generally avoid" combining these with Tasigna. The rationale is as follows:
"Theoretically, coadministration with other agents that can prolong the QT interval may increase the risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction."
http://www.drugs.com/drug_interactions.php
However, if you have no history of heart issues (esp. QT interval issues) that could possibly be overly conservative. The doc obviously believes you need to treat the pneumonia, so what else can you do? But you should ask your Onc about it.
Here is a group that discusses Tasigna, and you might want to post a question there also:
http://www.newcmldrug.com/amn_Discuss/default.asp
A recent paper cited below provide updates on large groups of CML patients who failed Gleevec, and how they have responded to both Sprycel and Tasigna. The data continues to be very encouraging for those who fail Gleevec, even when mutations occur. The paper provides a 2 year update on Sprycel (Dasatinib) effectiveness from 387 CML patients who failed Gleevec for intolerance or resistance (including mutations):
http://gyncancers.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=35464
The following paper provides an update on Tasigna (Nilotinib) effectiveness from a group of 321 CML patients for those who failed Gleevec for intolerance or resistance (including mutations).
http://gyncancers.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=36186
Here is some info about the Sprycel (Dasatinib) drug reimbursement program:
http://www.destinationaccess.com/index.aspx?bmscontentpg=sprycel
Some Oncs such as Dr Neil Shah would say switch to Sprycel at any sign that Gleevec is not working well. You could either go to 400mg Gleevec or switch to Sprycel. If it were me, I would switch to Sprycel.
TESTING
This is designed as a general overview to provide a basic layman's understanding of testing and CML. I will avoid the jargon and keep this somewhat short, so this will not cover everything in detail. For more details, Google the phrase and also ask your doctor/Oncologist.
There are tests to diagnose CML, evaluate response to drug therapy, assess the levels of the disease, and to check for specific problems. Among these are Complete Blood Count (CBC), Bone Marrow Biopsy (BMB), Bone Marrow Aspiration (BMA), Cytogenetics Testing, Fluorescence In Situ Hybridization (FISH) testing, Polymerase Chain Reaction (PCR) testing, Comprehensive Metabolic Panel (CMP) testing, Kinase Domain Mutation testing, Gleevec Blood Level testing, and miscellaneous other tests.

When a person is suspected of having CML, testing is done to confirm the diagnosis. A Complete Blood Count (CBC) test will usually show a very high white blood cell (WBC) count, and may also show high platelets (PLT) and other abnormalities. But this does not confirm that a person has CML. The confirmation of CML is usually done by Cytogenetics Testing (cell testing) on white blood cells taken during a Bone Marrow Biopsy (BMB) process. During a BMB, a core sample is taken from the hip bone using a hollow needle, and marrow cells are collected that cling to that bone sample. While that hole is open in the hip bone, fluid from the hip marrow is also taken out by a syringe, and this second part is called a Bone Marrow Aspiration (BMA). So the BMA aspirate or fluid is extracted through the hole created during the BMB. Cytogenetics Testing is done on the core sample and aspirate fluid. Approximately 20 marrow cells are thoroughly examined in the lab for the leukemic Philadelphia Chromosome (Ph chromosome), which is the indicator of CML, and a diagnosis can be made. The sample is also checked for other abnormalities, including secondary chromosome mutations and other abnormalities. The aspirate fluid may also be tested by FISH or PCR testing (see later explanations). A follow-up BMB might be done again at six months post-diagnosis, and then every 12-18 months after that, or sooner if other tests show a suspected problem such as loss of response to drug therapy. When therapy reduces the levels of CML disease to where the Cytogenetics Testing (BMB or FISH) can no longer detect any Ph chromosome cells, that person has achieved a Complete Cytogenetic Response (CCR).
After diagnosis, it is important to continually monitor response to therapy with regular tests. The most basic of these tests is the Complete Blood Count test, which assesses overall blood health. When a CBC test shows that blood counts have returned to normal levels, and especially the WBC and platelet counts, the person has achieved a Complete Hematological Response (CHR). After that, the CBCs should still be continued, but the frequency is often reduced. CML patients can often have certain blood counts become too low, especially white and red blood cell levels and platelet levels, so continued monitoring is important. Also, a rapidly rising WBC count could indicate the need for more testing and possibly a change in drug therapy.
The BMA fluid taken during the BMB process can also be used to perform a FISH or PCR test. (FISH is fluorescence in situ hybridization and PCR is polymerase chain reaction). Or circulating (peripheral) blood can also be used to perform a FISH or PCR. Both FISH and PCR show the levels of CML disease, and are used to monitor progress, or detect setbacks or loss of response to therapy. A FISH test checks approximately 200 – 500 WBC cells, and counts the number of cells that have the Ph chromosome (technically it looks for the BCR-ABL gene in the WBC cells, which is produced by the Ph chromosome). FISH is done by a machine which uses a dye process, isolates approx 200 - 500 cells, and counts the leukemic WBC cells. The result is given as a percentage of leukemic cells to good cells, so the person can say that X% of their WBC cells are leukemic. The limitation of FISH is that it can only count a small sample of cells, so if the level of disease is only a few percent, the FISH report will likely be zero (a zero FISH is also CCR, same as a zero Cytogenetics Test). So FISH is generally not used once the level of leukemia drops below approximately 5%. At that point PCR testing is used to monitor CML patients in this Minimal Residual Disease (MRD) status, since PCR is far more sensitive than FISH. A trend among Oncologists is to start doing PCRs early instead of FISH, since PCRs are more sensitive and can be used to track log reductions in disease levels, and FISH cannot track log reductions (discussed later).
There are two types of PCR tests. One is called a Qualitative PCR, which is a simple “yes/no” test that says it either detected BCR-ABL (leukemic cells) or did not detect them, but no number is provided – this is generally only useful to help diagnose CML since it helps distinguish between CML and other types of leukemia. The other type of PCR, the Quantitative PCR, counts the number of BCR-ABL (Ph chromosome cells) and reports it as a percentage number, so this is the type of PCR that is useful to track treatment progress, especially in Minimal Residual Disease (MRD) status where the levels of Ph chromosome cells are low and harder to detect. Some Oncologists will do a baseline Quantitative PCR at or near diagnosis to establish a baseline from which to evaluate progress, especially toward a 3 log reduction in disease levels.
PCR tests a sample of blood or marrow fluid, and can detect approximately 1 leukemic cell out of 1 million cells in the sample, so the test is very useful for long term monitoring of disease levels and showing treatment progress. PCR testing can be done using either blood or BMA fluid. During a PCR test, the BCR-ABL in leukemic cells is counted and the result of the test is given as a percentage ratio of BCR-ABL (leukemic cells) to another gene in the cells (called a control gene). So PCR results are not a ratio of leukemic cells to good cells as we might think, which technically means that a PCR result is not actually a total percentage of leukemic cells in the body. This is one reason why PCR results from one person to another, and one lab to another, are not equivalent, due to lack of standardization among labs regarding equipment and which control genes are used (there are several different control genes used for CML PCRs). That is a reason for sticking with the same lab, so the results will be directly comparable for each PCR done, and trends can be watched. It is important when switching labs that the first PCR from the new lab be used to set a new baseline, since it may not directly compare to the previous PCRs from the other lab.
PCR results are very useful for showing trends, whether progress or retrogression. The hope for PCR results is to see progress toward a 3 logarithmic (3 log) reduction from the level of disease that existed at the time of diagnosis. This 3 log reduction is called a Major Molecular Response (MMR). A recent advance in PCR testing is that many (but not all) labs now give the log reduction along with the percentage number. So if your lab provides the log number, then use that to track log reduction progress. But if the lab does not provide this information, it makes the 3 log reduction goal more difficult to track, since many do not know where they started at diagnosis. There is some attempt to standardize PCR results, but it requires more effort. Because Gleevec, Tasigna and Sprycel can rapidly reduce the levels of leukemic cells, if the first PCR is not done before starting drug therapy, the individual baseline for calculating a 3 log reduction will not be available. Otherwise, the lab may provide your log reduction number based on average results for that lab. Or a very rough estimate will sometimes use .01% as the 3 log reduction goal. If someone has a baseline PCR value done at diagnosis, progress toward the 3 log goal can be calculated by taking the baseline PCR number and moving the decimal point 3 places to the left. For example, if the PCR at diagnosis was 10.0%, then moving the decimal point one place to the left is 1.0% (1 log), two decimal places is .1% (2 log), and three decimal places is .01%, which is a 3 log reduction. So 3 log/MMR for that person at that lab would be .01%.
If a 3 log reduction is achieved, the next goal becomes maintaining the 3 log reduction or even continued reduction toward a negative/undetectable PCR (PCRU). PCRU is the point where the PCR is not sensitive enough to detect any leukemic cells in the sample. This PCRU is called Complete Molecular Response (CMR), which is the deepest level of response currently measurable. In PCRU status, the leukemic cells are most likely still there, although fewer than 1 in a million. PCRU is roughly equivalent to a 5 – 6 log reduction in leukemic cells, depending on the lab. There is no test to determine if a person with CML is actually cured (usually associated with a stem cell/marrow transplant). The current indicator is 5 years without therapy coupled with continuous PCRU. Normally, the goal of CML drug therapy is to drive the number of leukemic cells to the lowest level possible, with the combined effect of stopping the advance of the disease.
FISH numbers do not correlate to log reductions, so only PCR can be used for log reduction measurements. Also, FISH percentages do not relate to PCR percentage numbers. For instance, at diagnosis I had both a FISH and PCR done. The FISH was 100% and the PCR was 7%.
It is not true that a low FISH means a low PCR. A FISH is like measuring the weight of something with your hand, and a PCR is like measuring with a surgical scale. Also, the FISH has an error rate of approx 5%, so your FISH could read 5% but actually be zero. When the FISH result gets below approx 5 - 10%, you should rely on PCRs from then on. A recent trend is to only perform PCRs from the start and not use FISH.
If any of the tests, such as CBC, Cytogenetics, FISH or PCR, show the patient may be losing response to drug therapy, additional tests may be ordered. A Kinase Domain Mutation Test is one test that may show whether a certain drug, especially Gleevec, can no longer work. The results will show if a mutation in the BCR-ABL has occurred that prevents the drug from working, and an alternate drug can usually be used. Sprycel and Tasigna work against most mutations, but both do not work equally well against certain mutations, so this test can also help with alternative drug selection. (Just an added note on the word mutation, a kinase domain mutation is not the same as a secondary chromosome mutation such as Trisomy 8, Monosomy 7, etc). Below is one lab’s description of this test:
http://www.aruplab.com/Testing-Information/resources/TechnicalBulletins/BCR-ABL1%20Kinase%20Domain%20Mutation%20Jan%202007.pdf
Another CML related test is the Gleevec Blood Level Test. This test can show how much Gleevec is being absorbed into the bloodstream, since we all absorb and process drugs at different rates. So this test can show whether a person needs to take a higher dosage of Gleevec to ensure adequate levels of drug in the bloodstream. This test is currently available free through Novartis (maker of Gleevec) under a program they call CML Alliance:
http://www.cmlalliance.com/health-care-professional/cml-blood-level-tests.jsp?site=google&irmasrc=none&source=01030&campaign=CML-900127
There are other tests that are used for monitoring CML patients. A Comprehensive Metabolic Panel (CMP) test should be performed regularly (probably at the same time PCR is done). This checks a range of issues such as liver function, kidney function, metabolite levels, etc.
http://www.labtestsonline.org/understanding/analytes/cmp/glance.html
Examples of some other relevant tests: CAT Scans or physical checks for enlarged spleen (left side pain), physical checks for enlarged lymph nodes, complete or partial physical exams. There are also other tests to check for other specific problems when suspected, such as thyroid function, heart issues, colonoscopy, bone density, skin problems, etc.
A sample CML testing schedule might look like the following (assuming no complications) -- your Onc should determine your specific schedule:
Diagnosis: BMB/BMA, FISH and/or PCR; CMP; abdominal (spleen) CAT scan; physical
First several months: CBC weekly
3 months: FISH and/or PCR; CMP
CBC now every 2 weeks
6 months: BMB/BMA; FISH and/or PCR; CMP
CBC now every 2 – 4 weeks
9 months: PCR; CMP
12 months: BMB/BMA, PCR; CMP
After 1 year: PCR and CMP every 3 months, CBC every 4 – 6 weeks; BMB every 18 months (some Oncs now eliminate BMBs after PCRU)
Your Onc should be following the National Comprehensive Cancer Network Guidelines for CML monitoring and treatment – you can read what your Onc should be reading:
http://www.nccn.org/professionals/physician_gls/PDF/cml.pdf
(See page CML-A for monitoring discussion)
Other thoughts: Get copies of every lab report – you will need them for reference. Also, your Onc will not normally take time to cover every issue with you during your office visit. Read all of your lab reports thoroughly. You must be your own health care advocate.
The trend seems to be no BMB after continuous PCRU for several cycles. But most Oncs will still want a PCR every 3 months. The risks are less after PCRU, but continued monitoring is still considered to be a requirement. If the Onc is comfortable with longer periods between PCRs, that is not unreasonable, but it is not standard protocol. Also, do not forget other tests.
If loss of Gleevec response occurs, a Kinase Mutation Test would be used to check for mutations that interfere with Gleevec's functioning. Here is one lab's description of the test:
http://www.aruplab.com/TestDirectory/resources/TechnicalBulletins/BCR-ABL1%20Kinase%20Domain%20Mutation%20Jan%202007.pdf
Other testing info:
The color of the stopper on the specimen tube the blood or marrow fluid is drawn into: Green top is for BMB and FISH. Lavender top is PCR. See the link below, page two (all labs use the same color coding):
http://www.genzymegenetics.com/pdf/CML_physician_brochure.pdf
If your Onc is very color conscious, for the next test, make sure he orders a "lavender top" (PCR).
PCRs for CML must use a lavender top tube, which uses a chemical called EDTA as an anticoagulant. The green top tube uses Heparin as an anticoagulant, and is used for other lab purposes. When a PCR is done, it is a good idea to watch the lab technician to make sure they use the lavender top tube for a PCR. We would like to think people will always do their job properly, but some times they do not.
The CBC can provide early indications of issues, such as rising WBC, too low WBC, etc. Statistics show that if someone is going to become resistant to Gleevec or other CML drugs, it will most likely occur in the first year or two after diagnosis, and a rising WBC can provide an early alert to perform more testing and possibly change treatment. The drug resistance issue is one reason why it is important to have very close monitoring during the first year or so.
FISH tests have a 1% - 5% error rate (depending on which FISH is used). It is a color based test, and the colors sometimes give a false reading when two signal colors line up one behind the other. The mixture of colors gives a false reading since the color looks odd to the computer. See the following picture to get an idea what I mean:
http://home.comcast.net/~john.kimball1/BiologyPages/C/CML.html
The conservative approach is yearly BMBs for all CML patients. Some Oncs will recommend 18 months for those with negative PCRs. See the following on page 1646, paragraph labeled "Chronic Phase CML":
http://www.cmlsupport.com/practicalmanagementjourclinonc0303.pdf
If everything is stable in the blood, then regular BMBs can be extended. But a BMB is a good idea if the blood starts showing unexplained changes.
Here are some links to help:
You should have regular CBCs, and also Comprehensive Metabolic Panel (CMP) tests to watch for mineral deficiencies, kidney and liver function, etc.
http://www.webmd.com/a-to-z-guides/comprehensive-metabolic-panel-topic-overview
It is standard to have weekly CBC blood tests for the first few months. For instance, my Onc did a BMB, FISH, and PCR at diagnosis. Then ordered weekly CBCs for the first three months. At three months another PCR and CMP, and changed the CBCs to every 2 weeks until the 6 month point. At 6 months another PCR and CMP, and every three months after that another PCR. At 6 months the CBCs were stretched out to monthly because I was responding well. My Onc was following standard procedures.
The weekly CBCs are important for two reasons. One is to show whether the WBC is dropping (hematologic response), which will show that Gleevec is actually working. If it does not start to work quickly, another course of action would be required. Without the weekly CBCs, you would not know. The second reason is that the blood counts must be monitored in case the WBC (especially neutrophils) goes too low, which can be a problem early in CML treatment. If the WBC goes too low, then a break from Gleevec could be required to get things back on track.
In the following paper co-authored by Dr Druker and others, on the third page it discusses starting with weekly CBCs until CHR, then CBCs every 2 weeks, then the interval can be lengthened to monthly after 3 months if there is a good cytogenetic response:
If a PCR test suddenly shows a sharp rise in the result:
1) Reaccomplish the PCR right away to assure it is accurate (sometimes things go wrong, such as contamination, lab errors, etc). We would hope that this is the problem, but you cannot count on that.
2) If the PCR result is confirmed, or at the same time as the PCR if you wish, have both a Bone Marrow Biopsy and a Kinase Domain Mutation test done. The latter tests for drug resistance, which is a primary cause of lack of response -- see link below for one lab's explanation of the test:
http://www.aruplab.com/TestDirectory/resources_testDirectory/Technica...
3) Depending on what the drug resistance test shows, possibly increase Gleevec dosage if not resistant, or switch to another drug if you are Gleevec resistant.
Here is some info on Gleevec resistance:
http://jci.org/articles/view/30890
4) Kinase Domain mutations are not the only reason for drug resistence. Researchers have found that an over-expression of the LYN Kinase can also cause drug resistence:
5) If in the meantime you wanted to increase Gleevec dosage, I would discuss that with your Onc. If the PCR increases by 1 or 2 logs, it likely would mean Gleevec has stopped working and a drug change would be required. But an interim increase in dosage is an option.
You might want to ask the doc to perform a Liver Function Test on an occasional basis to monitor for any issues. It is a recommended regular test for those taking Gleevec.
I have been PCRU for more than 2 years, and I am not as concerned about my quarterly PCRs, but I want the quarterly Complete Panel Test that includes liver function and other testing. Test links:
http://www.aruplab.com/Testing-Information/resources/TechnicalBulletins/BCR-ABL1%20Kinase%20Domain%20Mutation%20Jan%202007.pdf
I would have a Comprehensive Metabolic Panel (CMP) test done to check basic kidney function, or a more in depth kidney test if your doc thinks it is needed.
Regarding the BMB, although the practice has been to have a BMB at diagnosis, 6 months, 12 months and then every 18 months, some leading Oncs are suggesting that for those who are PCRU or even 3 log (MMR) it is not necessary, so your Onc is reflecting current trends in testing.
There is some disagreement about which control genes are best for CML, but generally I would not be concerned about it. If you want some more info you can read this article:
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1867593
Other less frequent tests:
Reticulocyte count is a test looking for small (i.e., immature) RBCs. RDW already told you that you had them, but this test tells you the percentage of them in the blood. As with anything that is immature, small/immature RBCs do not function as well as mature ones. Hence, another part of the anemia problem. Those of us with CML struggle with anemia. It generally gets better over time.
TRANSPLANT
Here is a wide range of website info on the transplant issue:
BMT donor typing is not normally done for CML because of both the high probability of success of drug therapy and issues relating to the donor typing process. It is easy enough to test siblings since they are a small number, and the probability of matching is reasonable (25% chance per sibling), although the process is not cheap and most insurance normally will not cover it unless a transplant decision has been made. So if any matching is done, it will start with siblings (parents are not likely donor matches). HLA tested to see if they would be a perfect match for you (25% chance per sibling). Otherwise, the docs can perform a free internet search to see if there are unrelated donors who match you on the first 6 out of 10 HLA factors.
If a person is not ready to proceed with a transplant now, the search for an unrelated donor is not very useful. The reason is that the preliminary search, although free, only searches for matches on 6 of the 10 HLA markers, because potential donors are only tested for 6 HLAs due to cost considerations. But before an actual BMT, a transplant center will require a search for a match of 10 HLA markers, which requires having the potential donors who matched at least 6 HLAs perform additional testing. This is not done unless the transplant decision has been made. So the donor search is not very useful unless a person is headed for a transplant.
You could do your own search for potential donors that match up to 6 of your 10 HLA markers (same as your doc would do) if you know your HLA markers, but that requires an HLA typing on yourself:
http://www.marrow.org/PATIENT/Donor_Select_Tx_Process/The_Search_Process/View_Potential_Matches_for_Your_HLA_Type/index.html
Regarding transplantation, I would ask the Onc the following questions: 1) What leads to this recommendation? 2) Do you think I am in Accelerated or Blast Phase? 3) Are there any clinical trials that might be an option? 4) What else can we do?
Transplants seem to follow what I call the "1/3 Rule": 1/3 of transplant patients have no serious problems and do well; 1/3 of transplant patients do not survive one year; 1/3 develop severe Graft vs Host Disease (GVHD) or relapse to the same disease
Many patients who have a transplant will still take the CML drugs after transplant. Some Oncs will want the patients to stay on the drugs.
Having a Matched Unrelated Donor (MUD) transplant is an option, and you will want to see a transplant specialist to find out if you believe it is the right option. It is difficult, but there are many examples of success. Here is a link to stories written by people who have experienced a transplant:
Here are some links to information about transplants that might be helpful:
Have they done a recent bone marrow biopsy to determine your current status? Have they considered putting you into a clinical trial for new drugs in development? Did you try all CML drugs? long enough to allow them to work? Are potential donors a very high match, or just somewhat matched? These might be some things to ask the docs. It is also important to have a CML specialist
If the other options are explored and a BMT is the only way, then you should look at it as the only real option that exists for a cure right now.
Transplant can cure, but not always. It also has significant risks. It requires careful thought and a good understanding of the issues involved. Here is a good overview on CML treatment (should probably show it to your Onc):
http://www.cmlsupport.com/practicalmanagementjourclinonc0303.
A decision on a BMT cannot be made until a suitable donor is found. If siblings are not a match, then a BMT match less likely. Most non-sibling donors do not match as well as one would hope, so the decision is not an easy one.
Regarding harvesting your own stem cells, cleaning them, and re-inserting as an autologous transplant:
There is no current method to remove all CML progenitor cells from a bone marrow stem cell harvest. The currently intended purpose for a harvest is for people with very low levels of CML disease (3 log or better), the stem cells can be frozen in storage in case the CML drugs stop working and the person goes into the accelerated and blast crisis phases of CML. Then the person can have chemotherapy to destroy all blood stem cells and then the harvest would be inserted as a transplant to re-populate the blood cells. There would be no issue with rejection, since it is one's own cells. The expectation is that the leukemia will still return, but this will buy time for other options by putting the person back into chronic phase CML.
Can have a bone marrow transplant (BMT) and still not be cured of CML (still have the Philadelphia chromosome) -- the answer is yes, some people are cured, and others are not.
The problem is that the BMT patient must first have chemotherapy and maybe also radiation to kill the blood stem cells that cause the CML. Since chemo does not differentiate between good cells and leukemic cells, it must try to kill them all. But often the chemo is not fully successful, and some leukemic stem cells can sometimes survive. After transplant, they can perpetuate the CML, sometimes showing up a year or more later. But chemo is very hard on the body. Chemo is a tricky procedure, since it is essentially a poison. There must be enough to kill all leukemic stem cells, but not enough to seriously harm the patient. So sometimes the leukemic stem cells can survive. This is especially true since they can "hide" in the lining of the marrow close to the bone where they are less susceptible to the chemo. More recent trends in Mini-BMTs do not use as much chemo, but rather depend on the new donor cells attacking and destroying the person's own cells in a battle for control inside the blood. This is called Graft Versus Leukemia (GVL) Effect. So the new blood cells from the donor attack and destroy the person's own blood cells (including the leukemic ones) and the person can be cured by this battle between new cells and old cells when the new ones win and take over production of the blood cells.
Mini transplants are those that do not wipe out the patient's immune system prior to the transplant. It can use either donor stem cells or the patient's own stem cells. This procedure is being used more often when transplants are needed for those who are older and/or have not responded very well to drug therapy. Because the patient's marrow is not wiped out prior to the transplant, the donor cells will wage a war against them and wipe them out, and hopefully the leukemic cells also. I will try to find some comparisons of effectiveness for you.
A mini-transplant is the same as a regular BMT except that the patient's own marrow system is not completely wiped out prior to transplanting the donor cells. Instead, there is a reduced level of chemotherapy and possibly radiation that partially suppresses the patient's immune system, then donor cells are transfused. This sets the stage for a battle between the donor cells and the patient's own blood cells (graft vs host and graft vs leukemia). The hope is that during this battle the leukemic cells will be wiped out by the donor cells. The donor can be a marrow donor or a cord blood donor.
Mini-transplants are being used generally for older patients who require a BMT because older patients are less able to withstand the intense chemotherapy and radiation required to completely wipe out the immune system prior to BMT. The fact that they may be less risky on the chemo/radiation part does not mean that they are less risky in other ways. However, an advantage is that the patient never loses their immune system during this mini-transplant process, unlike regular BMTs.
More info on mini-transplants:
It is interesting to note that a mini-transplant does not require a matched donor:
http://www.sciencedaily.com/releases/2007/12/071203103355.htm
Matching HLA donors is apparently not as important with these mini-transplants as with regular BMTs:
http://www.medicalnewstoday.com/articles/90629.php
There are also Cord Blood BMTs, and these do not require a perfect match. Generally the patient would receive cord blood from two separate donors. Cord blood does not have as many stem cells as a regluar BMT.
Be aware that transplant docs think that transplants are a good idea. Otherwise, they would have a different job.
I am not anti-BMT, but the mortality rate for any type of transplant is something that cannot be ignored. Here is the MD Anderson marrow transplant information:
http://www.marrow.org/PATIENT/Plan_for_Tx/Choosing_a_TC/US_NMDP_Transplant_Centers/Detailed_Center_Information/tc_idx.pl?ctr_id=535&p_src=state
It says that they performed 33 transplants for CML during that timeframe, and 20 lived at least one year (40% did not survive at least one year). Generally, of those who survive, the relapse rate (CML re-appears) is about 30%. Also, the long term "rejection" effects can be an issue. I am not anti-BMT, but just believe in being well informed. If you were told that there is only a 5% chance of not surviving a BMT, you might want to do some more research.
The data on their chart shows that for CML patients over age 50, MD Anderson transplanted 6 CML patients (unrelated donors only) during 2002-2006, and 3 lived at least one year. That is a small sample size, but also not very encouraging.
You might want to search for blogs by BMT paients. We lost one of our young CML members, Dawn, to transplant related issues. Her blog is instructive:
www.goshdawnit.com
I would suggest you also look at the L&LS BMT Support Group:
http://community.lls.org/community/bloodcancer/transplantation
As an issue of trivia, a successful BMT also changes the DNA signature of the person's blood, so the new sample will not match the old sample after BMT. The person's blood DNA will change to match the donor's DNA. Could be useful in writing a crime novel. But I digress...
And after a BMT the same tests are used to determine if the Philadelphia chromosome is still present, mainly bone marrow biopsy and PCR.
Here are some good references to learn more about BMT:
I would also suggest you read some personal diaries of those who have gone through a transplant to get an understanding of what is is like.
http://www.google.com/search?hl=en&q=diary+cml+transplant&btnG=Search
The only way that CML can increase risk of other cancers is if a person has a transplant, and the chemotherapy used to wipe out the existing blood stem cells can increase the risks of other cancers by some amount, although not well quantified.
Speed may seem like the best course, but it is not necessarily so for CML. Most Oncs will want to see if the drugs work well, which they do in many cases, including accelerated phase. That will take some time (months and maybe even years). Rushing into BMT before seeing if drug therapy works is usually discouraged. The BMT window is not likely to change much at this point, so time is not your enemy. Allowing drug therapy time to work could be the best approach.
This will not be an easy decision. The decision must be made based on far less information than she would like to have. Since she is responding well, Gleevec has, at a minimum, bought her time to look at all the available information and make a decision. The Onc is certainly correct to caution that a BMT works best when the patient is in the best condition, and therefore certainly should be done prior to going into blast phase. But if it were me, I would see a recognized leader in the field of CML oncology for a second opinion.
I do not try to talk you out of anything, just to give you information to help with a decision.
There are a number of blogs that have been done by CML transplant patients. Here are a few I found on a random search:
After BMT there are essentially three possibilities: 1) the Philadelphia Chromosome cells could could have been totally eradicated, 2) it could still be eradicated in the future by ongoing donor WBC action (since the SCT is still fairly recent), or 3) a low level of leukemic cells may still exist and could possibly cause relapse in the future. There is no current way to test except to have ongoing PCRs, and if possible, nested PCRs (which can be as sensitive as potentially 1 in 10 million).
The statistics are hard to pin down, but generally the odds of total cure by SCT/BMT, if one survives it, are between 60-80% depending on a lot of variables, and assuming the patient was in chronic phase when starting the process.
One interesting data point you should ask the doctors about is whether you end up with 100% donor white blood cells, your own WBCs, or a mixture (mixed chimerism). If 100% donor WBCs, there is a higher chance of total cure since all her WBCs would have theoretically been wiped out.
Doing the HLA matching with siblings is not a bad idea for a fallback position
As for whether I would have a BMT at my age (over 50) -- No, unless every other treatment option failed me first, including all drugs, clinical trials, etc.
Please remember that I am not anti-transplant. I am simply interested in people getting good information and making informed decisions.
Treatment
Here is the NCCN guide that many Oncs use for management of CML when there are issues:
The NCCN Guidelines are kept up to date, and they seem to purge the old ones. But you might be able to search and find the annual NCCN updates, such as this one for 2008:
http://www.nccn.org/professionals/meetings/13thannual/highlights/1351.html
Here is the NCCN Guideline used by US oncologists when dealing with CML:
http://www.nccn.org/professionals/physician_gls/PDF/cml.pdf
(See "Workup" page, note b)
Vaccine Issue
I participated in a vaccine clinical trial in 2006, and wanted to share my results and thoughts. This was a Phase I trial, which essentially checks to see if the substance is safe enough to try on a larger number of people in Phase II. So the data is very preliminary, since the trial was shorter than needed to demonstrate that this vaccine actually works. Phase II will start later this year when FDA approval is given.
The term “vaccine” can be confusing when used in this context, since a vaccine is normally used to prevent a disease from occurring, such as a flu vaccine. A leukemia vaccine would be given to someone who already has the disease, to control or possibly even eliminate the disease. If a vaccine is proven to be successful, it would presumably work on various types of leukemias, MDS, and possibly other malignancies.
Generally, the vaccine trials are trying to stimulate the body’s own immune system T-Cells to mount a battle against cells that have a larger than normal amount of a certain substance in them. Leukemic cells look close enough to normal to the body’s immune system, so they are left alone. But leukemic cells are actually different than normal cells in some important ways. So a vaccine would teach the immune system to recognize that the leukemic cells are different, since they have greater amounts of certain substances in the cells (such as PR1, WT1, etc). The theory is that if you can teach the body’s T-Cells to recognize the leukemic cells as abnormal, including the leukemic stem cells, the immune system would see them as a target and kill them. And since the leukemic stem cells are the source of all other leukemic cells in the body, killing them would be like cutting the head off the snake. But even if it did not kill the stem cells, a vaccine could be used to control the disease much as Gleevec and Sprycel kill the leukemic offspring cells, but not the stem cells that produce them. Remember that this is mostly theory and not yet proven as actually possible, although there is some evidence so far that the theory works to some degree on some people.
There are various types of vaccine trials ongoing around the country. Most involve a peptide called PR1. Others include a peptide called WT1. Some use other potential vaccine candidates, such as a person’s own leukemia cells that have been irradiated. The trial that I participated in included both PR1 and WT1 combined. You can read more about the details of this and other vaccines in the links below, but in short, PR1 and WT1 are present in normal cells, but they are present in much larger quantities in leukemic WBCs and especially in leukemic stem cells. So theoretically, the leukemic cells are different enough that the body’s immune system could be taught to recognize those differences and respond.
As previously discussed, leukemic cells look much like regular cells, so they are not attacked by the immune system’s T-Cells. Each type of T-Cell is specific to certain invaders. A polio vaccine teaches the body to make T-Cells to fight anything that looks like a polio virus, and the effects last for a lifetime. That is the theory of a leukemia vaccine, except that it is given to someone who already has leukemia to control or eliminate it. So a leukemia vaccine could be a cure, not just a prevention. The best use of a vaccine would be to eliminate the minimal residual disease levels (the leukemic stem cells) that remain after drug therapy reduces the leukemia levels in the body. Dr Cortes of MD Anderson has said: "If we are able to stimulate an immune reaction against leukemia cells while there is minimal disease, it could offer us a curative strategy." Again, this is theory, not yet proven fact.
So my experience in the clinical trial included getting a baseline PCR, BMB, and blood tests, followed the next week by several shots at the same time. This trial was a combination trial of PR1 and WT1 vaccines, so I (and 7 other participants with various leukemias or MDS) received shots including one PR1 vaccine, one WT1 vaccine, and a shot of Leukine to boost the immune system. Then we returned each week and provided blood samples for the next five weeks, and PCRs and other tests were done each week. Since I am PCR undetectable, they were not monitoring me for reduction of BCR-ABL, but rather looking to see if my immune system mounted a response by making T-Cells that would attack PR1 and WT1, which would assume the T-Cells would then attack leukemic cells. Most of the participants involved had a PR1 response, but fewer had a WT1 response. We learned after the trial that Gleevec actually inhibits WT1 levels in the body, so that could have interfered with my WT1 response. So the trial showed it was safe to use, and can now proceed to Phase II. In Phase II the shots will be given every three weeks for several months, and will show more about how effective the vaccine actually is.
So far the study looks like it has merit. But there is much work to do. And to prove that it eliminates CML stem cells is difficult since no PCR is sensitive enough, so how would anyone know if they are cured unless they stopped drug therapy? They are not ready to have anyone stop drug therapy yet, but some day it would require people with CML who are PCR undetectable to take part in a clinical trial where they stop taking Gleevec or Sprycel and only have the shots, to see if the person maintains or loses molecular response. That is not likely to be approved until much more basic research is completed.
Another interesting item was that I gave blood each week for 5 weeks, and 3 separate PCRs were done on same the blood sample each week. That was 15 PCRs in 5 weeks. One showed a faint BCR-ABL positive during the second week, but the other 14 were negative. I found that interesting, that 14 PCRs would be negative but one faintly positive. And the one that was faintly positive was also negative twice on separate PCRs from the same tube of blood. The docs said PCRs can be random like that, and that the one positive PCR was like finding a needle in a haystack. This further confirms why trend data is more important than one single PCR test.
Here are some links to additional leukemia vaccine information:
I volunteered for the trial because the National Institutes of Health was having trouble finding folks with CML who have a specific type of HLA (what they use to match donors for transplants). Mine matched, and I live in the DC area where NIH is located. The shots were no big deal -- just like any other only it seemed like they were injecting a large volume into me. I felt fine before and felt fine after. I am PCRU, so the shots could not show a drop in bcr-abl, but I did register a response, as I mentioned. I think you will hear a lot about vaccines during the next couple years. There are many trials using several different vaccine approaches. There is a lot of excitement about the possibilities. Most likely scenario is that vaccines can some day control CML like Gleevec does. Whether it can destroy the leukemic stem cells and cure CML is the real story that we must wait and see.
The Phase II for the clinical trial that I described above is now open. It is at the following link:
Pika asked above if I would participate in Phase II. The clinical trial lead, Dr Katy Rezvani, said that she would like to be able to measure a BCR-ABL response. Since I am PCRU, that is not possible in me. If she changes her mind, which is possible because it can be a challenge to find volunteers with exact HLA-A0201 matches (found in certain European descendants), I will volunteer again.
I participated in the Phase I clinical trial for the vaccine, which has ended. Participants in Phase I only received one set of shots. I continue to take Gleevec, so do not know if there was any long term impact. I was PCRU before the shots, and still am.
If one of the versions of a CML vaccine is proven to work (still not a certainty), there are two possibilities for response. One possibility is that instead of Gleevec or other drugs, someone with CML would get a series of initial shots and then booster shots every so often (once a month? once every several months? longer? -- no one knows.) The second possibility is a cure, where a series of shots would either eliminate all disease (including the original leukemic stem cells), or the body's T-cells would learn to kill all the offspring of the leukemic stem cells, so the disease would cease to be a problem and no drugs would be needed.
I want to continue to stress that there is much work to be done, and that a vaccine that actually works against CML has not yet been proven. Even though some levels of disease reduction have been noted in some individuals under certain conditions after receiving vaccine shots, others have shown little or no response.
Regarding whether anyone qualifies for the study, look at the following link for the Phase II trial:
http://clinicaltrial.gov/ct/show/NCT00488592;jsessionid=D972531406943C1B8C6A6512C99450EB?order=50
I can tell you that they can only use people who are in the HLA-A0201 type match. This is found in persons of European descent, and generally northern region, but not exclusively. They also want people with disease levels that can be monitored by PCR for measuring responses by bcr-abl reductions.
It will be several months before the report on the Phase II vaccine trial is ready for release.
For those in Great Britain, the clinical trial doctor who led the NIH vaccine trial I participated in has moved to Imperial College at Hammersmith Hospital in London, and is planning to conduct a CML vaccine trial using PR1 and WT1 +/- interferon-alpha in CML patients who have achieved cytogenetic remission but not PCRU. Timing is unknown. Anyone interested can email me directly.
There are a number of different approaches to leukemia vaccines being pursued. The NIH lists 6 leukemia vaccine clinical trials that are in process right now in the U.S.:
http://www.cancer.gov/search/ResultsClinicalTrialsAdvanced.aspx?protocolsearchid=4944001
Other vaccine research is being conducted in Italy and elsewhere. Some private companies are also experimenting with their own potential vaccines.
The vaccine clinical trial that I participated in during Phase I is now in Phase II, and is estimated to complete Phase II in Dec 2008:
http://clinicaltrials.gov/ct/show/NCT00499772
There is much work to be done, but the research shows that the concept is worth pursuing.
YOUNG PERSON
The following website has a "CML Child Talk" chat section:
http://www.newcmldrug.com/Children/Default.asp
The toughest part about CML for a fairly young person is the uncertainty over what the future holds. A CML diagnosis strips away the feeling of invulnerability, and it requires work to deal with it and stay positive about the future. Although Gleevec has made living with CML much easier, CML is still a serious disease that has a significant impact on anyone who has it, and also impacts their families.


Gleevec and other CML drugs have been shown to work well in children. This has changed the nature of treatment for children with CML from an immediate decision to do a transplant to a much more difficult decision. Generally, children will start on Gleevec and the family will discuss the pros and cons of transplant. There is a growing list of children who have stuck with Gleevec and have grown into young adults who are doing very well. The transplant issue for children has become more of a "lifestyle" issue than which treatment will work better. The choice will continue to be a difficult one for families as they struggle to decide, but fortunately the issue is less about survival than about other issues.





ZZZZ…Random Musings
We would like to return to completely normal, but the reality is that many of us will need to adjust to a "new normal". But the good news is that because of the CML drugs, approx 90% of us will live a long and fairly normal life.
When I was diagnosed, I told my immediate family, but none of my friends or co-workers. I asked my family to tell no one, which at first they did not understand. My rationale was that I did not want to have every conversation start with "so how are you doing?" That is why my closest friends and co-workers have no idea that I have CML. I would not presume to tell anyone to do the same, but I am so glad I did that, and am surprised I was able to think that clearly at the time. So even my close friends and work associates do not know. That was a personal decision to prevent having every conversation start with discussing my health. We are all different, but that was a good decision for me.
For the short term, your friend will need you to be very interested in her progress. But after a while, you may want to slowly start focusing on the routine stuff of life, and less on the CML, to help her return to a sense of normalcy. After all, the good news about CML is that we can treat it and live a normal, long life thanks to the wonder drugs we have available.
Most of you will feel much better over time. I think one year was a turning point, now that I look back on it. Most of us find that the first 3 months are the toughest, and that issues such as bone pain and other side effects either decrease or go away over time. I was diagnosed 3 years ago and the initial extreme tiredness for me has gone away, along with most side effects. I am as active now as prior to diagnosis. Most likely you will start feeling better in a couple months.
The Veterans Administration did an Agent Orange study and issued a report in 2003. It found a link to CLL leukemia, but not to the others, including CML: http://www1.va.gov/agentorange/docs/AgentOrangeNuJuly03.pdf (See page 5)
At the first sign of a sore throat I gargle several times a day with mouthwash as deeply in the throat as possible to kill the germs. This works well for me to limit the progression of the cold.
Carolyn Blasdel is Dr Druker's nurse. Her email is blasdelc@ohsu.edu
I don't drink any more water than I ever did. I think that is unnecessary and even counter-productive. Drinking extra water causes bloating and makes diarrhea much worse. If you want to make an easy change, just drink water in a normal manner, a little at a time throughout the day.
There is no Sears rating for "good, better, best" PCR results. The only "poor" result would be a 1 log or greater increase.
The leg sweats are common -- I get them and I am PCRU. I often sleep with a small pillow between the knees to keep the legs dry.
I have determined that slow stretching and muscle/joint warm-up is required prior to any physical activity. I am constantly pulling, straining, or injuring some ligament or muscle with only minor activity, and they heal slowly.
If you feel well, and your CBC counts are generally good, then that is a lot to be thankful for.
As for internet info on CML, anything prior to 2005 is highly suspect due to the fairly recent accumulation of data on how well our drugs work for the majority of us. The changes brought about by Gleevec have been so dramatic that the information exchange has not kept pace.
In CML, we are not actually in "remission", since that implies progress toward a cure. We are in various stages of "response", which is various degrees of reduced numbers of leukemic cells in the body. The "R" in CHR, MCR, CCR, CMR is always "response". I believe this is an important point, not just semantics. So for an Onc to say that someone with CML is in "remission" is neither accurate nor useful.
When it comes to CML, most Oncs have very little knowledge, and the nurses have far less. Trust, but verify.
Researchers are finding that we all absorb Gleevec at different rates, and it is a cellular issue. Possibly size and weight can be a factor, but not really known for certain, and seems more cell structure dependent. Some need 600mg to get the same amount of Gleevec into the cells as others do with only 400mg. Maybe 600mg will work better.
A person could have two PCRs done on the same exact sample of blood and the result could vary by ½ log.
Overall, steady wins the race
Just as an additional comment, Zavie's Zeroes are earned by achieving a zero BMB or FISH (Complete Cytogenetic Response -- CCR). If Zavie had a second program for PCRU, he would likely call it "Zavie's Double Zeroes". Not trying to start anything...
CML is also an exercise in learning lots of new and fun terminology.
There are many possible "reduced clearance" interactions with Gleevec, such as grapefruit juice. These are called moderate, and often are theoretical. Generally, if you are not at maximum Gleevec dosage, your Onc will normally not consider it an issue, but be sure to ask. On a related note, one could ask that if Gleevec would stay in our bloodstream longer if we just drank grapefruit juice (since it reduces Gleevec clearance), would taking a lower Gleevec dosage and drinking grapefruit juice have the same benefit as a higher dosage? Instead, we are told to avoid grapefruit juice. Just wondering out loud...
THAT'S ALL, FOLKS.

I am NOT a doctor. If this information is of any value, it is only for developing questions to ask your Onc. I am just a fellow CML survivor helping where I can, and have no medical training whatsoever. This is not advice, just compiled postings from over 3 years of CML survivors talking with each other. That is all this is -- nothing more.