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.
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numerous out-of-date (and needlessly scary) websites that would only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:
https://communityview.lls.org/groups/chronic-myeloid-leukemia
https://communityview.lls.org/groups/chronic-myeloid-leukemia
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://www.nytimes.com/2010/01/19/health/19brod.html?partner=rss&emc=rss
http://www.sciencedaily.com/releases/2006/12/061207160526.htm
News articles about how CML has become a very survivable disease:
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 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; 4) 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:
https://www.lls.org/resource-center/download-or-order-free-publications
https://www.lls.org/resource-center/download-or-order-free-publications
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
http://www.youtube.com/watch?v=7ZMVQ1Vbb7Y
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
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 LLS support group
and start posting questions.
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.
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 was the starting drug, and it is still a good drug, but starting with Sprycel or Tasigna are also good options. There is no right answer, and other medical conditions should be considered. But if in Accelerated or Blast Phase Gleevec should NOT be the starting drug unless there is no other option.
5) Ask if you will also take Allopurinol during the first couple weeks of starting 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 regular (weekly) Complete Blood Count (CBC) tests for a couple months. At no later than 3 months another FISH and/or PCR test should be done. At 6 months another Bone Marrow Biopsy (BMB) can 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 while starting drug therapy (usually Sprycel) in case a transplant is required. Siblings should be tested first to see if they are a suitable marrow donor match. But some diagnosed in Blast Phase can continue drug therapy and do fine without transplant. Also, Blast Phase can be mis-diagnosed, so seek a second opinion.
9) Read about specific issues such as CML testing and other CML subjects. I have also written papers on CML special subjects including 1) Genetics of CML Leukemia: An Overview, 2) CML Testing Explained: Introduction and Basics of CML Leukemia Testing, and 3) Bone Marrow Transplant Overview which can be seen at this link:
http://treyscml.blogspot.com/p/special-topics-on-cml.html
10) Join us on the Leukemia & Lymphoma Society Support Discussion Board:https://communityview.lls.org/groups/chronic-myeloid-leukemia
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.
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”):
There
are clinical trials for people with blast crisis
CML:
http://clinicaltrials.gov
http://clinicaltrials.gov
You
will want to ensure a proper diagnosis of BC, so a second opinion from a CML Specialist is advisable. 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. Make sure you
understand whether it is myeloid BC or lymphoid BC. 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.
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. This may continue for years before leveling out. 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 and fatigue can result (see "Fatigue" section for other reasons).
Many
of us with CML have for the longer term 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).
The
reason that our hemaglobin (HGB) is low is often because our red blood count (RBC)
tends to be low. The
cause of low (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.
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. Also, Gleevec is coated in a rust colored coating which is indeed rust (iron oxide).
So
the need for more iron should be determined by 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.
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):
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
I have written special topics providing an overview of CML Leukemia:The Leukemia & Lymphoma Society (LLS) Online Overview provide information for the newly diagnosed:
http://www.lls.org
http://treyscml.blogspot.com/p/special-topics-on-cml.html
My intro at the start of the blog also provides an overview.
Bone
Health & CML Drugs
TKI
drugs and especially Gleevec cause what is called "accelerated
bone remodeling" which simply means the bones turn over minerals
more quickly (losing and gaining). Bones are not fixed entities but rather
constantly move minerals in and out. Bone
cells are normally very slow to turn over, but can apparently go into
a hyperactive mode with CML drugs. This faster bone remodeling does not
mean they are less healthy, but that they change over faster. This
can result in bone pain especially in the legs. Blood tests may show
elevated ALP (Alkaline phosphatase) as a result and may also show higher calcium and other minerals in the blood since the bones release the minerals more quickly. Generally bone pain
decreases over time.
Here is a discussion on the subject of TKI drugs and bone health:
http://bloodjournal.hematologylibrary.org/cgi/reprint/107/11/4334.pdf
Here is a discussion on the subject of TKI drugs and bone health:
http://bloodjournal.hematologylibrary.org/cgi/reprint/107/11/4334.pdf
Overall,
it seems that the higher the dosage, the more likely that bones 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. Children have been advised to take extra Vitamin D.
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):
Joint pain is also an issue for some patients. See "Joint Pain" section.
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. I have heard of a few over 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 because the tki drugs are killing off the leukemic WBCs, and the body has not yet ramped up production of the normal WBCs. The body tries to slow down WBC production during CML but only the normal ones respond. That is why our WBCs are nearly 100% leukemic at diagnosis.This myelosuppression (supression
of the marrow) takes time to reverse. 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.
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.
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 at least 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
http://www.labtestsonline.org/understanding/analytes/cbc/test.html
When
these leukemic cells are replaced with good WBCs, things should stabilize a bit more,
although may remain low due to the impact of CML drug therapy.
Bone
Marrow Biopsy
A
bone marrow biopsy (BMB) is necessary to properly diagnose CML since
it checks for things other tests cannot determine such as secondary
chromosome mutations, marrow blast count, overall marrow health
including maturation of cells, fibrosis of the marrow, and so on. The
NCCN CML Treatment Guidelines and every CML expert recommends a BMB
at diagnosis, so if your Onc wants to skip it he is not following
proper procedure. 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. After diagnosis it can monitor
for advancing disease if there appears to be a loss of response to
drug therapy (loss of CCyR). So a BMB is normally done at diagnosis,
possibly at 6 months post diagnosis if drug respnse is slow, and only afterward if Complete Cytogenetic Response (zero BMB or zero FISH) is not attained or if CCyR is lost. Tests run on BMB fluids are cytogenetics
test (chromosome analysis), FISH, and PCR (See "Testing"
section).
There
are generally three options for BMB:
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.
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 -- only if absolutely necessary
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.
4) Total unconscious sedation -- only if absolutely necessary
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.
http://www.answers.com/topic/bone-marrow-aspiration-and-biopsy
BCR-ABL
CML is caused by two genes being put together in an unnatural state in the chromosomes of the white blood cells. These two genes are BCR from chromosome 22 and ABL from chromosome 9. When the translocation of genetic material between chromosome 9 and chromosome 22 occurs it forms the Philadelphia Chromosome (the "new" chromosome 22). This leukemic BCR-ABL gene causes hyper-proliferation of white blood cells and the other abnormalities of CML.
http://www.cclocator.com/en/video/?v=zxXY19fQxf8&lang=e
BCR-ABL
CML is caused by two genes being put together in an unnatural state in the chromosomes of the white blood cells. These two genes are BCR from chromosome 22 and ABL from chromosome 9. When the translocation of genetic material between chromosome 9 and chromosome 22 occurs it forms the Philadelphia Chromosome (the "new" chromosome 22). This leukemic BCR-ABL gene causes hyper-proliferation of white blood cells and the other abnormalities of CML.
http://www.cclocator.com/en/video/?v=zxXY19fQxf8&lang=e
Bone Marrow Transplant
Bone
Marrow Transplant (BMT) has become a last resort for adults diagnosed with CML. For
young people and children the issue of long term drug therapy vs. BMT
is more difficult and often an emotional issue. The
main positive issue for BMT is that drug therapy works so well and is low risk, and also 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 on 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).
I have written a Bone Marrow Transplant paper which may help with understanding the various issues involved:
http://treyscml.blogspot.com/p/special-topics-on-cml.html
I have written a Bone Marrow Transplant paper which may help with understanding the various issues involved:
http://treyscml.blogspot.com/p/special-topics-on-cml.html
Blasts
and Blast Count
Blasts
(immature WBCs) are an issue in CML because they can show disease
progression under certain conditions. A bone marrow 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 be higher 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
Mineral
supplements are a good idea when taking TKI drugs. 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. Additional vitamin D should also be considered.
***Chemotherapy for CML
Chemotherapy was the primary form of treatment prior to TKI drugs, but it had minimal success. Now it is rarely used. Generally, chemotherapy should only be used for CML as a short term measure to gain time while preparing for a transplant. The chemo induces what might be viewed as a "false response" (my term -- trying to communicate clearly). TKI drugs attack the problem. Chemo attacks the symptoms. The chemo can knock back the leukemic cells very well the first time it is used. Each subsequent time it becomes less effective, in general terms. The chemo will eventually quit working altogether. Timeframe differs per individual, but months, not years. So bloodwork which improves after chemo is a false reading of disease status. Do not trust it. It will not last.
CML is different than the other forms of leukemia because the originating chromosome translocation for CML happens very high in the blood making (hematopoietic) chain, higher than most other leukemias including many AML subtypes. Some forms of AML can be cured or put into long term response by chemotherapy, while for CML it almost never happens. For those leukemias where chemo can cure the patient, the originating leukemic cells are rather low in the stem cell hierarchy, maybe even down in the progenitor cell level. So it is much harder to use chemo to wipe out the originating CML leukemic cell(s) due to their superior survival skills, which is why prior to TKI drugs CML was the worst type of leukemia in terms of survival.
A transplant can work because the chemo used then is much stronger (along with radiation and graft vs leukemia effect) which wipes out the entire existing blood making system, including the very high level stem cells where the CML originates. But then this stronger chemo regimen requires replacing the blood making system with donor cells which can start over.
CESSATION
(Stopping Drug Therapy) and CURE PROGRESS
Cessation means stopping all drug therapy. Some people have been able to do this, but there is no long term data. We also do not know why it is possible for some people and not for others. Drug reduction after deep response is often a better option for the majority of patients.
I can certainly understand why patients get excited about stopping therapy, but I want to insert a caution about the statistics. Success discussions assume a patient can go long term at MMR levels of the disease. That is not a level I would personally be comfortable with. So I don't think any discussion of achieving MMR and staying there is reasonable. Statistics for long term maintenance of PCRU after cessation are not available, but short term data shows the odds of this are not very high (maybe 35% but no long term data). Those who are in clinical trials for cessation are advancing the knowledge base, and that is a good thing, so I support that. But the excitement level over TKI cessation is not supported by the data.
For those who attain PCRU of 4.5 log reduction or deeper, and also maintain it for no less than 2 years, cessation is more reasonable, but odds of long term success are not high. Drug dosage reduction is probably a better option with a significantly higher chance of success and can provide relief from many side effects.
I have urged caution about this issue because the excitement levels do not match the reality of what has been demonstrated. There is far too little data, especially long term data. So most of us should expect to take the drug over the long term, but hopefully at reduced dosages. Also, other drugs are coming along such as ABL001 which could have a much better side effects profile if it works out.
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 generally only knows how to do one thing which is to use BCR-ABL to cause uncontrolled cell growth. So it is a one-trick pony, and 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, at least directly. So the primary 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 ultimate goal is to cure
CML.
There
are currently 5 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
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:
I
use the "queen bee" analogy when referring to the
originating leukemic stem cell that started the whole CML process.
The analogy 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.
So our TKI drug 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 TKI drugs. Since they are 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. But this is a war, and you do not give the enemy any advantage.
So our TKI drug 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 TKI drugs. Since they are 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. But this is a war, and you do not give the enemy any advantage.
I
take Gleevec, and my approach is to stay on the drug at half dosage
for an extended time (at least 10 years post-PCRU) under my own
theory that a cure may be possible from TKI drugs alone. I believe it
may be, but only after many years of chasing after every last
leukemic stem cell with TKI drugs until all leukemic stem cells burn
themselves out and die off from over-producing. This assumes the TKI
drugs do not attack the highest level leukemic stem cells directly,
but drive them into exhaustion since cells only get a certain number
of divisions and then they die. If cure by TKI drugs is possible,
then drug cessation would interrupt the drive toward that cure and
allow leukemic stem cells to remain in the body even if held in check
to some degree. Can TKI drugs 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. But I
proposed a theory that taking TKI drugs for many years may drive the
leukemic stem cells to divide themselves until they exhaust their
allowed number of divisions, since cells only get so many and then
they die. TKI drugs might create an environment where those original
stem cells die after some period of time, naturally or otherwise. Can
TKI drugs exhaust CML? Maybe.
Some people have taken Gleevec or other TKIs for years, then stopped and did not relapse over the next couple years. The success rate has been approximately 40% in several studies. The definition of "success" in those studies is not always continued PCRU status. There is at least some possibility that a few could be functionally cured (disease controlled by the body in a way which is not yet understood). But the time period monitored so far has only been a few years. Here is one 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
Some people have taken Gleevec or other TKIs for years, then stopped and did not relapse over the next couple years. The success rate has been approximately 40% in several studies. The definition of "success" in those studies is not always continued PCRU status. There is at least some possibility that a few could be functionally cured (disease controlled by the body in a way which is not yet understood). But the time period monitored so far has only been a few years. Here is one 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
This
may seem like a cure for the 8 people in the study, but some stem
cell transplant patients have relapsed after much longer periods. But
maybe these few are in a state of controlled disease apart from
drugs, or best case 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. No one knows, and more research
is required. Maybe those who respond very deeply to TKI drugs 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, and only try drug cessation in a
clinical trial and after a minimum of 4 years of drug therapy of
which the past 2 years were continuously PCR undetectable. At initial
PCRU there are still over 1 million leukemic cells in the body, so
the drug therapy needs to go far beyond that to give the body a
chance to handle the residual low level disease. Some might also
suggest that only those who responded quickly and deeply should
participate until more is understood.
There is often a TKI drug withdrawal which occurs after TKI drugs are stopped. It makes sense that because our body needed to adjust to them at the beginning, that it would also need to adjust to not having them. That is because the body adjusts to having the off-target kinase inhibitions. Those adjustments must be unwound after stopping. That is why it is better to reduce dosage before going into a TKI cessation program.
Let me be clear that those who are part of clinical trials are advancing the understanding of the disease, and this cessation issue is no exception, so I do not oppose such research. But understand it is research, not standard protocol.
There is often a TKI drug withdrawal which occurs after TKI drugs are stopped. It makes sense that because our body needed to adjust to them at the beginning, that it would also need to adjust to not having them. That is because the body adjusts to having the off-target kinase inhibitions. Those adjustments must be unwound after stopping. That is why it is better to reduce dosage before going into a TKI cessation program.
Let me be clear that those who are part of clinical trials are advancing the understanding of the disease, and this cessation issue is no exception, so I do not oppose such research. But understand it is research, not standard protocol.
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. 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.
The
treatment for children is the same as for adults except that if the
child is very small they might reduce the TKI drug dosage. 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. But the drugs have proven themselves in children over
more than 15 years now, and the liklihood of children living a normal
lifespan with CML are very high. And since there is mounting
information that the drugs may not be required for an entire
lifetime, this is even more reason to be optimistic about long term
prospects.
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:
http://www.newcmldrug.com/Children/Default.asp
http://www.childrenwithcml.org.uk/forum.asp?slevel=0z81&parent_id=81
http://www.cancercompass.com/message-board/message/all,3049,0.htm
http://www.kidscancernetwork.org/yourstory.html
http://www.acor.org/leukemia/sites2.html
http://cmlblog.spaces.live.com/default.aspx
http://www.childrenshospital.org/az/Site2170/mainpageS2170P0.html
https://www.teenagecancertrust.org/health-info/resources.php http://www.childrenwithcml.org.uk/home.asp?parent_id=1
http://www.childrenwithcml.org.uk/forum.asp?slevel=0z81&parent_id=81
http://www.cancercompass.com/message-board/message/all,3049,0.htm
http://www.kidscancernetwork.org/yourstory.html
http://www.acor.org/leukemia/sites2.html
http://cmlblog.spaces.live.com/default.aspx
http://www.childrenshospital.org/az/Site2170/mainpageS2170P0.html
https://www.teenagecancertrust.org/health-info/resources.php http://www.childrenwithcml.org.uk/home.asp?parent_id=1
One
issue regarding CML drugs for children is that some may 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).
Most Oncs view the CML TKI drugs as the proper therapy for children, although the issue of a bone marrow transplant may come up. 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.
Most Oncs view the CML TKI drugs as the proper therapy for children, although the issue of a bone marrow transplant may come up. 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.
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.
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
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
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).
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."
"...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.
Here
is some info on the subject of Ph- bcr/abl-
CML:
http://www.medscape.com/viewarticle/408451_6
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&uid=1643155&cmd=showdetailview&indexed=google
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2082654
http://www.medscape.com/viewarticle/408451_6
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&uid=1643155&cmd=showdetailview&indexed=google
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2082654
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
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
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
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)
http://www.nature.com/leu/journal/v18/n5/full/2403345a.html
(see also the footnoted articles 2 - 8)
Additional
info:
http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&list_uids=15510836&dopt=AbstractPlus
http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&list_uids=15510836&dopt=AbstractPlus
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
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
"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://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=8839830
COST
ISSUES
TKI
drugs are expensive. Those without adequate insurance can
contact the L&LS about some level of monetary support, and also
contact the drug manufacturers for support for low income patients.
Cramping
Cramping
of muscles is a common TKI drug side effect, especially for Gleevec.
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.
Deep Molecular Response (DMR) -- See also CMR and PCRU
Deep Molecular Response (DMR) is the same as CMR and PCR Undetectable (PCRU). It is the cut-off where any given lab stops reporting the PCR result. The PCR would provide results out to maybe 6 or 7 logs if allowed, but most labs cut off the results at 4.5 log to avoid false positives.
One person would be straining for years to achieve the 5 log DMR while all the MDA patients did their happy dances years ago when they met their paltry DMR of only 4 log. That is an entire log difference in definition of something called "Deep". So then it becomes a deep philosophical discussion about how deep deep is. Can there be a deeper than deep? I have used the term "deeply PCRU" contrasted with "barely PCRU" when discussing who can most likely succeed at TKI cessation. The real problem is CML patients measure PCRU to the .001's but the entire thing is cut with the meat-axe of lab variations of PCR cut-off, which can be a log different. Defining DMR to the nanometer when it doesn't even have any rules makes it imprecise, at the very least. PCRU is self defining as a negative PCR for that lab. DMR is undefined yet it sounds like it is something clear and precise. CMR was no better, but is DMR good enough?
If a patient is well served by having a term they can say to their family to explain their response level, that is useful. I just don't see DMR as that term. The family will not understand the "deep" or the "molecular" or the "response" -- they will continue to ask: "Well, are you cured?" Back to square one.
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 TKI 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.
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.
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
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 fruit 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
took 400mg Gleevec daily for the first several years, and I split it
200mg at breakfast and dinner. Seems to help reduce side effects.
Tasigna is alwatys split dosage, and Sprycel is not generally not
split. It has helped me to split my dosage and take half in morning
and half in evening. That way the body is not shocked by taking it
all at once.
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 higher
dosages.
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.But I went
to low (half) dosage after several years PCRU and have remained PCRU
for over 5 years since.
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? The answer may
vary based on the individual. Some may need to take the drugs
until a cure is discovered. Others can go to half or lower dosage,
and others may be able to stop (see Cessation discussion). Our CML
drugs are designed to stop the progression of the CML and put us into
a continuous low level of residual disease.
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
http://www.pslgroup.com/dg/1eccd2.htm
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."
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
http://www.pslgroup.com/dg/1eccd2.htm
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.
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.
Too much alcohol alone will harm the liver, so adding drugs that are
processed by the liver makes the situation worse. But moderation in
alcohol consumption appears to be fine. The TKI drugs alone may cause
blood markers ALT/AST to rise. These are not specific for the liver,
so this does not automatically mean the liver is the issue.
Drug
Development Info (New Drugs)
The
annual American Society of Hematologists (ASH) meeting is probably
the best resource for keeping up on new drug developments. ASH papers
show many new CML drugs are under development -- I counted at least
17 new CML drugs in development. As we know, there are currently 5
primary drugs approved by the FDA for CML.
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
http://www.drugs.com/gleevec.html
http://www.medscape.com/druginfo/druginterchecker
http://www.drugdigest.org/DD/Interaction/ChooseDrugs/1,4109,,00.html
http://www.drugs.com/drug_interactions.html
http://www.drugdigest.org/DD/Interaction/ChooseDrugs/1,4109,,00.html
http://www.drugs.com/drug_interactions.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
"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
Some
antibiotics may 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
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14605865&dopt=Abstract
Drug
Manufacturer Info
Drug companies participate in programs designed to help those who cannot afford their medications. Visit the manufacturer websites for information:
Example:
Novartis free drugs program (see link below):
http://www.pharma.us.novartis.com/about-us/our-patient-caregiver-resources/pap-enrollment.jsp
Novartis free drugs program (see link below):
http://www.pharma.us.novartis.com/about-us/our-patient-caregiver-resources/pap-enrollment.jsp
Check
also Bristol Myers Squibb (Sprycel), ARIAD (Iclusig)
DRUG
RESISTANCE
Most
people on Gleevec do not become resistent to it, but some do. More
become intolerant, meaning the side effects are too disruptive to
quality of life. For some patients, a treatment limitation has been
the development of imatinib resistance, frequently the result of
kinase domain mutations. For some the drug uptake from the alimentary
canal and from the blood plasma into the leukemic cells is a limiting
factor (the drugs only do their work inside a leukemic cell).
For others, there are cellular differences which can limit
effectiveness. In many cases the cause is simply not
understood. In any event, when a person becomes resistent or
intolerant to a certain TKI drug, the best choice is usually to move
on to another. There are 5 TKI drugs approved, so we should not
become overly attached to any specific drug unless it both works well
and has limited side effects. That is different for each
person. Moving on quickly to a new drug is often the best
choice.
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
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
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
Fatigue
The TKI drugs can cause fatigue, which can be one of the most debilitating side effects. This occurs especially during the first few months. After that the fatigue is often reduced, but this varies with the individual. Changing drugs may help, but I would wait for quite a while before changing if this is the main reason to see if the issue reduces over time.
Generally,
fatigue can be caused by 1) low blood counts which decrease oxygen flow in the blood, 2) thyroid dysfunction which can be a result of tki drugs, especially Gleevec. Most of our 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.
My energy
levels have improved considerably over the years since diagnosis. 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 60, 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.
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, Bristol Myers Squibb, ARIAD, or
Pfizer 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
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.
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
Here is an introductory tutorial I wrote about CML genetics:
http://community.lls.org/topic/1970-genetics-of-cml-leukemia-an-overview/?hl=%2Bgenetics+%2Bcml
http://atlasgeneticsoncology.org/Anomalies/t0922CML.html
Here is an introductory tutorial I wrote about CML genetics:
http://community.lls.org/topic/1970-genetics-of-cml-leukemia-an-overview/?hl=%2Bgenetics+%2Bcml
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
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.
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
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.
http://www.fda.gov/medwatch/safety/2007/Sep_PI/Gleevec_PI.pdf
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.
Gleevec
Generics
Imatinib
Mesylate is the active ingredient in Gleevec. In some parts of the
world a generic Imatinib has been available for several years due to
both patent infringements and earlier expiration of patent rights.
The remainder (including U.S.) will see generics starting in 2016.
Gleevec is a brand name, and Imatinib Mesylate is the scientific name
for the active ingredient. Novartis (Gleevec manufacturer) will be
sponsoring a generic through another company so the quality should be
the same for this generic when available.
Glucose
Levels
TKI
drugs can 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
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).
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."
"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 TKI drugs
will serve us well while better approaches are developed, and
possibly a cure is found.
Hair
Loss (Faster Hair Turnover)
TKI drug side effects include impact on some fast growing cells other than blood cells. Hair is one such fast growing set of cells, so some experience hair "loss", which is not actually loss but faster turnover of hair. So the hair falls out faster but is also replaced faster. But the hair will feel thinner as the shorter hairs re-grow. This is caused by off-target inhibition of cell processes (i.e., other than simply impacting the BCR-ABL leukemic process). Overall it should be remembered that this is not permanent hair loss but a faster turnover in hair. The net effect may be thinner hair at the longer parts, so it is especially noticable for those with longer hair due to the faster replacement cycle. But over time the body adjusts and sorts out this issue for most, although it may take over a year. An odd side effect for some has been re-pigmentation of graying hair, but generally only to a small degree.
Itchy scalp goes along with the hair loss. For me personally this has been one of the few long term side effects. The hair turnover ended for me after a year or so, but the itchy scalp has remained my "friend" for all these years. I am careful to only rub my head with the flat palm of my hand (do NOT use the fingernails) to avoid damage to the scalp which starts a bad cycle itself.
Prescription shampoos such as Ketoconazole and Ciclopirox are not intended to stop hair loss. In fact they can have the opposite effect in some people. These two shampoos are for scalp fungal infections and seborrheic dermatitis. The shampoos are also intended for infrequent usage (about twice a week and only for a couple months).
Heart Issues
TKI drug side effects include impact on some fast growing cells other than blood cells. Hair is one such fast growing set of cells, so some experience hair "loss", which is not actually loss but faster turnover of hair. So the hair falls out faster but is also replaced faster. But the hair will feel thinner as the shorter hairs re-grow. This is caused by off-target inhibition of cell processes (i.e., other than simply impacting the BCR-ABL leukemic process). Overall it should be remembered that this is not permanent hair loss but a faster turnover in hair. The net effect may be thinner hair at the longer parts, so it is especially noticable for those with longer hair due to the faster replacement cycle. But over time the body adjusts and sorts out this issue for most, although it may take over a year. An odd side effect for some has been re-pigmentation of graying hair, but generally only to a small degree.
Itchy scalp goes along with the hair loss. For me personally this has been one of the few long term side effects. The hair turnover ended for me after a year or so, but the itchy scalp has remained my "friend" for all these years. I am careful to only rub my head with the flat palm of my hand (do NOT use the fingernails) to avoid damage to the scalp which starts a bad cycle itself.
Prescription shampoos such as Ketoconazole and Ciclopirox are not intended to stop hair loss. In fact they can have the opposite effect in some people. These two shampoos are for scalp fungal infections and seborrheic dermatitis. The shampoos are also intended for infrequent usage (about twice a week and only for a couple months).
Heart Issues
TKI
drugs have side effects, and potential issues related to the heart
are not well understood, although some issues have been noted
especially in those who already have heart related problems.
Primarily, heart palpitations have been reported as an issue. The
cause is not known but since the TKI drugs deplete minerals such as
potassium and magnesium which are important for heart electrical
signalling, increasing mineral intake is a good idea. But early
reports of Gleevec causing heart problems have generally been
dismissed as an over-reaction, although 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.
Sprycel can especially cause fluid retention (edema) around the lungs and also around the heart. This increased pressure on the heart causes additional workload and could cause long term injury if it is not resolved. So beware of shortness of breath, heaviness in the chest, breathing difficulties, etc.
Sprycel can especially cause fluid retention (edema) around the lungs and also around the heart. This increased pressure on the heart causes additional workload and could cause long term injury if it is not resolved. So beware of shortness of breath, heaviness in the chest, breathing difficulties, etc.
If
you suspect heart issues are happening you should consider at 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
http://www.revolutionhealth.com/conditions/heart/heart-attack/blood-tests/enzyme-protein
Herbal
Supplements
You
will have a difficult time finding information on TKI and herbal
medicines except for St Johns Wort which is discouraged. Here is a
drug interaction checker, but it does not do very well for
herbals.
http://www.medscape.com/druginfo/druginterchecker
http://www.medscape.com/druginfo/druginterchecker
In
general, TKI drugs do not have a serious interaction problem with
herbals in moderation with a few exceptions like St Johns Wort. But
that doesn't mean you won't find another one if you experiment. Most
herbals are fine, but moderation is usually a good idea. I have seen
some discourage even green tea but I view that as nonsense.
Hydroxyurea (HU)
After seeing so many CML patients suffer from the use of Hydroxyurea as initial CML treatment, I am compelled to explain why this very poor practice should end.
Hydroxyurea (HU) also called Hydrea should NOT be used for initial CML leukemia treatment under almost any circumstance. Even if the initial WBC is well over 300K, TKI drugs are still preferred for initial CML treatment instead of Hydroxyurea. TKI drugs selectively target the leukemic blood cells, resulting in an effective, orderly and controlled decline in leukemic blood cells while sparing and preserving the good blood cells necessary for recovery from CML. Maybe if the patient is diagnosed in Blast Phase with high levels of blasts HU could be useful, but that is less than 1% of CML patients.
Hydroxyurea is a chemotherapy drug which indiscriminately kills off blood cells, both leukemic cells and good blood cells. At CML diagnosis the good blood cells are already struggling due to the body's attempts to limit blood cell production, since only good blood cells respond to signals to slow down blood cell production. Using Hydroxyurea kills off these already struggling normal blood cells, and when the TKI drugs bring down overall WBC by eliminating vast numbers of leukemic blood cells, a crash landing of blood counts results. This leads to critically low blood counts with which the patient will struggle for a long time. This actually sets back CML treatment as drug breaks are often required due to the low blood counts. Long term myelosuppression (low blood counts) can result.
Hydroxyurea also causes a yo-yo effect with blood counts, masking the true nature of patient response to TKI drugs. Hydroxyurea can result in enhancing leukemic cell rebound after the initial steep drop in blood counts.
I cannot stress strongly enough that HYDROXYUREA SHOULD NOT BE USED FOR INITIAL CML TREATMENT. Let the TKI drug bring down blood counts in a controlled manner to prevent a crash landing into severe myelosuppression, and to prevent killing off the already struggling normal blood cells. Recovery from CML is highly dependent on having an adequate pool of normal blood cells to repopulate the blood with normal cells.
Illness (Other Than CML)
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 may initially reduce resistance to such
diseases/infections in some patients, but once the TKI drug starts to
work and the good white blood cells return to normal the body can
once again fight disease and infections in a 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 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.
See
following info:
http://www.essortment.com/all/whatcausesswol_rgmg.htm
http://www.essortment.com/all/whatcausesswol_rgmg.htm
There
have been cases of dormant hepatitis B re-emergence while using
Gleevec.
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 TKI drugs and
often causes severe nausea. Interferon does not create a lasting
remission.
http://x.medscape.com/viewarticle/446651
There are some studies showing combination TKI drug and Interferon may be useful for overcoming some types of drug resistance. Interferon is sometimes used during pregnancy instead of TKI drugs.
Iron
There are some studies showing combination TKI drug and Interferon may be useful for overcoming some types of drug resistance. Interferon is sometimes used during pregnancy instead of TKI drugs.
Iron
The
reason 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. And although
it may seem odd, fatigue can be a symptom of too much
iron:
http://www.irondisorders.org/Disorders/TooMuchIron.asp
http://www.irondisorders.org/Disorders/TooMuchIron.asp
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.]
"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.
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
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.
,
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:
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.
SECTIONS
"L" THRU "S"
Leukemia
& Lymphoma Society (L&LS)
The
LLS has many educational resources available such as pamplets, a Chat
Board, and also has a call line where patients can talk with a CML
"specialist" at their Information Resource Center -- (800)
955-4572. They may also be able to provide some amount of help for
those who cannot afford the cost of the prescriptions and
testing.
L&LS Website:
L&LS Website:
http://www.lls.org/
LLS CML Discussion (Chat) Board
http://community.lls.org/forum/27-chronic-myeloid-leukemia/
LLS CML Discussion (Chat) Board
http://community.lls.org/forum/27-chronic-myeloid-leukemia/
Life
Expectancy
Most
CML patients, especially those diagnosed in chronic phase, will live
a normal lifespan thanks to the TKI drugs.
Here is an article that discusses the 95% CML survival rate due to Gleevec:
Here is an article that discusses the 95% CML survival rate due to Gleevec:
Since
the time this article was written in 2006, four more drugs --
Sprycel, Tasigna, Iclusig, and Bosutinib -- 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,
TKI drugs do not appear to be a cure. But the good news is that we
are far better off than those who were diagnosed with CML just 15
years ago.
CML
is also the most likely leukemia to be cured some day.
Liver
Issues
Unless
you have a reason to be concerned about your liver, this should not
be a big issue, but liver test markers can be increased by the TKI
drugs. Patients should have regular Comprehensive metabolic Panel
(CMP) tests, which include liver function tests, to watch for issues.
The ALT/AST markers can be increased due to many things beyond the
liver, so they are not necessarily signs of a liver issue. They
are also generally not viewed as an issue unless they more than
double, and even then this does not appear to be actual liver
"damage" but is often related to other things which affect
the ALT/AST results. It is best to look for 2 consectutive
ALT/AST readings before becoming overly concerned. So unless the ALT
or AST remain 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 monitor it.
Also,
try to avoid taking some 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.
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.
Women appear to have low counts more often than men.
Some Oncs start the newly diagnosed CML patient on Hydroxyurea (HU) instead of just the TKI drug. I view this as an error. So often we have seen patients who started on Hydroxyurea and then start the TKI drug have severe low blood counts. In this way the Hydroxyurea does more harm than good. The TKI drugs will bring down the WBC in an orderly manner, so let them do their work. Hopefully Oncs will get the message to stop using Hydroxyurea for initial CML treatment. It very often starts a cycle of myelosuppression which can be hard to emerge from.
Some Oncs start the newly diagnosed CML patient on Hydroxyurea (HU) instead of just the TKI drug. I view this as an error. So often we have seen patients who started on Hydroxyurea and then start the TKI drug have severe low blood counts. In this way the Hydroxyurea does more harm than good. The TKI drugs will bring down the WBC in an orderly manner, so let them do their work. Hopefully Oncs will get the message to stop using Hydroxyurea for initial CML treatment. It very often starts a cycle of myelosuppression which can be hard to emerge from.
In
general, low counts (myelosuppression) occur soon after starting drug
therapy because of a lack of good stem cells, and this takes time to
overcome as the body ramps up good cell production. When the leukemic
stem cells are out of control prior to diagnosis, the body signals to
stop the over-production of blood cells because there are too many.
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. 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. A drug break may become
necessary, but overall it is important to stay on the drug therapy,
even at lower dosage, 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
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 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.
Platelet
counts are usually the last blood cell type to normalize and 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.
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."
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. Usually this gets better over time, but it may take a
year or longer.
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
"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
Each
person has a different tolerance level for TKI drugs, and for many of
us the higher the dosage the worse the side effects.Forme, 600mg
Gleevec was too much. But I know of young girl taking 800mg Gleevec.
MINERAL DEPLETION BY TKI DRUGS AND SUPPLEMENTS
Overall, potassium shortage may be the most significant mineral issue with TKI drugs. Other mineral shortages can occur including potassium, magnesium, phosphorous, & calcium.
For muscle cramps potassium helps me better than any other minerals, but magnesium may also be useful (small dosage -- it has laxative effects).
For heart palpitation issues (Tasigna especially) I would try adding several minerals: potassium, magnesium, phosphorous, & calcium. All may not be the issue, but nothing wrong with a little extra of these. Potassium has a large role in heart electrical signals.
http://www.webmd.com...-and-your-heart
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
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
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
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, especially Sprycel. 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.
Pain side effects from the TKI drug are often muscle and koint related. When starting Sprycel expect headaches for a couple weeks. 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. Side effects are different
for each of us. There are two recommendations I have found useful for loint and muscle pain. First is
pain medication, 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 over the longer term.
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/
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
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 4.5 to 5 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
http://bloodjournal.hematologylibrary.org/cgi/reprint/2006-01-0092v1.pdf
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.
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. But this is rarely done due to cost.
The
3 log reduction (MMR) milestone is now determined by using International Standard numbers, which are standardized based on averages at each lab. A personal (vs International Standard) 3 log reduction can be used if someone has a baseline PCR
when first diagnosed, and before starting TKI therapy or having
other treatments. 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. This 3 log stuff 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 CCyR (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 CCyR at some point. That point is
not the same for every PCR testing machine, but as a very rough
indicator of CCyR, if the PCR is less than .1% you could likely assume
that is comparable to CCyR, 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
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.
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
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
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
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
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
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).
PCRU (PCR Undetectable)
Negative PCR, also called Complete Molecualr Response (CMR) and Deep Molecualr Response (DMR). The issue is various labs report PCRU at different levels. MD Anderson reports PCRU at 4.0 log reduction, which seems imprecise. Most labs report PCRU at 4.5 log reduction. Some go out to 5.0 log reduction. So there is an entire log difference in what most labs report as PCRU, causing patients to view their disease status differently.
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 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
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.
Plateaus in Drug Response
Sometimes a patient may have a quick initial response to TKI drugs and then experience a slow-down in the response where the PCR remains in a narrow range for quite a while. These TKI response plateaus (my terminology) usually occur starting at about the 12 - 18 month point but there are variations. Not everyone experiences them. Tasigna seems to be the drug most likely to have plateaus. The explanation would appear to be that the TKI drugs kill off the mid-tier progenitor leukemic cells fairly easily, then the higher level ones can be harder to kill and take longer. This can result in a response curve which appears to stall out, although it is likely just a change in which leukemic cells are being killed off, since killing off the higher order leukemic cells can be a slower process. Of course, the very highest level leukemic cells may not be killed off by the TKI drugs. The plateaus in drug response may last for quite a while, and then the PCR usually turns downward again.
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 (PCR undetectable - PCRU). A woman can easily lose MMR response in
less than 9 months, and some have lost CCyR during pregnancy which is a
real hazard to her. That is why starting a pregnancy while having CML
should be very carefully pondered. After the pregnancy Oncs will also discourage breast feeding.
The data about taking TKI drugs during pregnancy is limited. Most Oncs would recommend against it. There is risk, but it is hard to quantify due to lack of data. A fetus is made of fast growing cells, and these TKI drugs target fast growers. There is much that is not known about the issue. Using TKI drugs during pregnancy would probably only be done if the mother loses response very quickly and interferon does not work well enough. These can be hard choices.
The data about taking TKI drugs during pregnancy is limited. Most Oncs would recommend against it. There is risk, but it is hard to quantify due to lack of data. A fetus is made of fast growing cells, and these TKI drugs target fast growers. There is much that is not known about the issue. Using TKI drugs during pregnancy would probably only be done if the mother loses response very quickly and interferon does not work well enough. These can be hard choices.
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
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 after several years of sustained PCRU.
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 but very rare:
http://groups.google.com/group/CMLHope/browse_thread/thread/994434f9e8f9e747?hl=en
http://groups.google.com/group/CMLHope/browse_thread/thread/994434f9e8f9e747?hl=en
If
a woman becomes pregnant while taking TKI drugs 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.
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")
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
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 TKI drugs 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 TKI drugs.
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 The Oncologist
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
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).
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
* 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
* 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
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.
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
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 DRUG 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
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)
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).
"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
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
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
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:
http://mct.aacrjournals.org/cgi/content/full/2/3/225
http://asheducationbook.hematologylibrary.org/cgi/content/full/2006/1/219
http://esciencenews.com/articles/2008/06/25/activation.lyn.kinase.associated.with.imatinib.resistance.cml.patients
http://asheducationbook.hematologylibrary.org/cgi/content/full/2006/1/219
http://esciencenews.com/articles/2008/06/25/activation.lyn.kinase.associated.with.imatinib.resistance.cml.patients
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
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/
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
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
CML TKI drugs were introduced starting in 2001, but many websites
contain outdated information about life expectancy and many other
issues. That is why I wrote this informational "blog".
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. Side effects can sometimes be serious enough that a
change in drugs is necessary.
There have been a number of discussion about unusual side effects of TKI drugs over the years. Information is coming together which may shed some light on the issues involved. It is possible that numerous unusual side effects from TKI drugs are related interference with hypothalamus, pituitary, adrenal, thyroid gland function. These are the glands which are at the center of controlling many body functions. One study found that more than half of Gleevec patients experienced glucocorticoid deficiency, meaning the adrenal glands are not producing enough cortisol, and this has downstream impact on the thyroid. See link below.
This imbalance in the hypothalamus-pituitary-adrenal-thyroid axis (meaning these glands are tied together in function) can lead to a host of side effects we have complained about, including brain fog, fatigue, how the body deals with internal temperature (both feeling cold and night sweats, which are opposite extremes), and even sunken eyes or puffy face, just to name a few of the side effects. A cortisol (glucocorticoid) deficiency and resulting hypothyroidism (low thyroid function) is an under-appreciated side effect which more than half of TKI drug patients have experienced according to the study cited below. Since the production of cortisol is stimulated by the hypothalamus and pituitary, it is difficult to know where this imbalance originates. The feedback loop among these glands means that a dysfunction at one point can upset the entire system.
There has been little appreciation for this issue among Oncs and GP doctors. Maybe more of us should have an ACTH Stimulation Test, which tests pituitary stimulation of the adrenals, along with the more common thyroid test. It is possible that the dysfunction in both the hypothalamus or pituitary can be causing the downstream effects of low cortisol and low thyroid function, which in turn result in a host of side effects.
http://www.ncbi.nlm.nih.gov/pubmed/20089016
To help understand the interaction among the glands:
http://endocrine.niddk.nih.gov/pubs/addison/addison.aspx
There have been a number of discussion about unusual side effects of TKI drugs over the years. Information is coming together which may shed some light on the issues involved. It is possible that numerous unusual side effects from TKI drugs are related interference with hypothalamus, pituitary, adrenal, thyroid gland function. These are the glands which are at the center of controlling many body functions. One study found that more than half of Gleevec patients experienced glucocorticoid deficiency, meaning the adrenal glands are not producing enough cortisol, and this has downstream impact on the thyroid. See link below.
This imbalance in the hypothalamus-pituitary-adrenal-thyroid axis (meaning these glands are tied together in function) can lead to a host of side effects we have complained about, including brain fog, fatigue, how the body deals with internal temperature (both feeling cold and night sweats, which are opposite extremes), and even sunken eyes or puffy face, just to name a few of the side effects. A cortisol (glucocorticoid) deficiency and resulting hypothyroidism (low thyroid function) is an under-appreciated side effect which more than half of TKI drug patients have experienced according to the study cited below. Since the production of cortisol is stimulated by the hypothalamus and pituitary, it is difficult to know where this imbalance originates. The feedback loop among these glands means that a dysfunction at one point can upset the entire system.
There has been little appreciation for this issue among Oncs and GP doctors. Maybe more of us should have an ACTH Stimulation Test, which tests pituitary stimulation of the adrenals, along with the more common thyroid test. It is possible that the dysfunction in both the hypothalamus or pituitary can be causing the downstream effects of low cortisol and low thyroid function, which in turn result in a host of side effects.
http://www.ncbi.nlm.nih.gov/pubmed/20089016
To help understand the interaction among the glands:
http://endocrine.niddk.nih.gov/pubs/addison/addison.aspx
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.
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
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...."
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?")
See Section: "What are the side effects and how serious are they?")
http://209.85.173.132/search?q=cache:HkXWmczSJKYJ:www.liferaftgroup.org/docs/training_presentations/gleevec_managing_side_effects.pps+gleevec+thyroid&hl=en&ct=clnk&cd=2&gl=us
(See Section: "Less Common Side Effects")
(See Section: "Less Common Side Effects")
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 or TKI drug. 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
http://www.webmd.com/content/tools/1/slide_spot_skincancer
What
does it look like? Scaly or bumpy?
Take
a look at this to try to narrow the discussion
further:
http://www.healthline.com/adamcontent/rashes?utm_source=no_health_channel&utm_medium=google&utm_campaign=adam&utm_term=body%20itchy%20rash
http://www.healthline.com/adamcontent/rashes?utm_source=no_health_channel&utm_medium=google&utm_campaign=adam&utm_term=body%20itchy%20rash
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
http://www.getridofthings.com/get-rid-of-a-rash.htm
Here
are some photos of severe Gleevec
rash:
http://www.cmlsupport.com/cmlphotos.htm
http://www.cmlsupport.com/cmlphotos.htm
Here
is some more
info:
http://www.cmlsupport.com/cmlgleevecsideeffectsguide.htm
http://www.cmlsupport.com/cmlgleevecsideeffectsguide.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
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
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
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.
http://www.ohsucancer.com/index.asp?fuseaction=cancerClinics.doc
http://www.mdanderson.org/diseases/adultleukema/
http://www.mdanderson.org/diseases/adultleukema/
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.
Dr.
Kantarjian is a highly respected CML expert. Here is his MDA
info:
http://www.mdanderson.org/departments/leukemia/display.cfm?id=c646ee15-d121-11d4-80fd00508b603a14&method=displayfull&pn=0f815fdc-c623-11d4-80fb00508b603a14
http://www.mdanderson.org/departments/leukemia/display.cfm?id=c646ee15-d121-11d4-80fd00508b603a14&method=displayfull&pn=0f815fdc-c623-11d4-80fb00508b603a14
Here
is an article Dr. Kantarjian wrote that deals somewhat with your
situation:
http://content.nejm.org/cgi/content/full/354/24/2542
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
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
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
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
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
http://www.drugs.com/tasigna.html
Here
is some other
info:
http://www.medicalnewstoday.com/articles/58993.php
http://www.medicalnewstoday.com/articles/58993.php
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
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
http://gyncancers.asco.org/ASCO/Abstracts+%26+Virtu al+Meeting/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=36186
A
fact sheet on
Tasigna:
http://www.medsafe.govt.nz/profs/Datasheet/t/Tasignacap.htm
http://www.medsafe.govt.nz/profs/Datasheet/t/Tasignacap.htm
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
"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
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
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
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
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
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
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 TKI DRUG THERAPY
(See "Cessation" above)
SWITCHING DRUGS
I
would not be so reluctant to switch drugs. Dr Neil Shah has said 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.
Oncs
like to think in terms of progression: Gleevec first, and then
Sprycel or Tasigna if needed, then others as needed. 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? 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 has been used as the first drug treatment for CML.
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). But all are
good drugs.
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.
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.
Recommended
Treatment
Links:
http://www.haematologica.org/journal/2006/2/152.html
http://www.asheducationbook.org/cgi/content/full/2005/1/174
http://www.haematologica.org/journal/2006/2/152.html
http://www.asheducationbook.org/cgi/content/full/2005/1/174
SPLEEN PAIN
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
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
(Nilotinib)
Here is some overview info on Tasigna:
http://www.medicalnewstoday.com/articles/58993.php
Here are links to some detailed data on Tasigna, for those taking it. They provide a lot of information about the drug:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/022068lbl.pdf
http://www.medsafe.govt.nz/profs/Datasheet/t/Tasignacap.htm
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/notices-avis/conditions/tasigna_fs_fd_110305-eng.php
http://www.us.tasigna.com/index.jsp?source=01030&irmasrc=AM7WB0014&campaign=AM7-900104&site=google&HBX_PK=www.koreatimes.co.kr&HBX_OU=50&usertrack.filter_applied=true&NovaId=7852773831525391078
Here is some overview info on Tasigna:
http://www.medicalnewstoday.com/articles/58993.php
Here are links to some detailed data on Tasigna, for those taking it. They provide a lot of information about the drug:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/022068lbl.pdf
http://www.medsafe.govt.nz/profs/Datasheet/t/Tasignacap.htm
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/notices-avis/conditions/tasigna_fs_fd_110305-eng.php
http://www.us.tasigna.com/index.jsp?source=01030&irmasrc=AM7WB0014&campaign=AM7-900104&site=google&HBX_PK=www.koreatimes.co.kr&HBX_OU=50&usertrack.filter_applied=true&NovaId=7852773831525391078
Tasigna
side effects are listed at this website, but there are usually others
that pop up.
http://www.drugs.com/tasigna.html
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.
Tasigna has a "no food" requirement when taking the drug. That is because Tasigna had some bad luck during clinical trials, and ended up with this burdensome, and usually unnecessary, requirement. The "no food" requirement was put in place for the 1% of people with QT heart issues. For everyone else it is probably unnecessary. The issue is that if someone eats a triple Big Mac with double cheese, extra large fries, and a double milkshake with a slice of whale blubber, all that fat can cause the liver to focus only on the fat and ignore taking the drug out of the bloodstream. The net result is like taking double dosage. So everyone suffers from a 1% issue. If it were me, I would eat some crackers and drink some soda with it.
Tasigna has a "no food" requirement when taking the drug. That is because Tasigna had some bad luck during clinical trials, and ended up with this burdensome, and usually unnecessary, requirement. The "no food" requirement was put in place for the 1% of people with QT heart issues. For everyone else it is probably unnecessary. The issue is that if someone eats a triple Big Mac with double cheese, extra large fries, and a double milkshake with a slice of whale blubber, all that fat can cause the liver to focus only on the fat and ignore taking the drug out of the bloodstream. The net result is like taking double dosage. So everyone suffers from a 1% issue. If it were me, I would eat some crackers and drink some soda with it.
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
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
http://gyncancers.asco.org/ASCO/Abstracts+%26+Virtu al+Meeting/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=36186
A
fact sheet on
Tasigna:
http://www.medsafe.govt.nz/profs/Datasheet/t/Tasignacap.htm
http://www.medsafe.govt.nz/profs/Datasheet/t/Tasignacap.htm
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
"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
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
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
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
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).
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
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
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
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)
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)
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
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
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
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
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:
Dr
Druker article:
http://hep.uchicago.edu/~seturner/druk.pdf
http://hep.uchicago.edu/~seturner/druk.pdf
BMB
article:
http://www.forpath.org/0011/introduction.htm
http://www.forpath.org/0011/introduction.htm
Here
is a CBC
overview:
http://www.labtestsonline.org/understanding/analytes/cbc/test.html
http://www.labtestsonline.org/understanding/analytes/cbc/test.html
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
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.
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
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.
http://www.gleevec.com/info/cml/faq.jsp?usertrack.filter_applied=true&NovaId=3350119541883896361
(See section: "How should I be monitored during treatment?")
(See section: "How should I be monitored during treatment?")
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
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
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
I
put together a layman's guide to bone marrow transplant issues which
may be
helpful:
http://community.lls.org/topic/8367-bone-marrow-transplant-introduction-and-basics/?hl=%2Bbasics+%2Btransplant
Here is some general information on the CML transplant issue:
http://www.ufscc.ufl.edu/patient/content.aspx?section=ufscc&id=966
http://www.cmlinfo.org/sct.html
Here is a wide range of website info on the transplant issue:
http://community.lls.org/topic/8367-bone-marrow-transplant-introduction-and-basics/?hl=%2Bbasics+%2Btransplant
Here is some general information on the CML transplant issue:
http://www.ufscc.ufl.edu/patient/content.aspx?section=ufscc&id=966
http://www.cmlinfo.org/sct.html
Here is a wide range of website info on the transplant issue:
A transplant can work because the chemo used is much stronger (along
with radiation and graft vs leukemia effect) which wipes out the entire
existing blood making system, including the very high level stem cells
where the CML originates. But then this stronger chemo regimen requires
replacing the blood making system with donor cells which can start
over.
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.
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
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.
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. But odds of relapse is much higher.
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
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
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
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
www.goshdawnit.com
I
would suggest you also look at the L&LS BMT Support
Group:
http://community.lls.org/community/bloodcancer/transplantation
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:
http://www.medscape.com/viewarticle/408451_8
http://en.wikipedia.org/wiki/Bone_marrow_transplant
http://www.bmtinfonet.org/newsletters/issue47/mini.html
http://www.lymphomation.org/bmt-mini.htm
http://en.wikipedia.org/wiki/Bone_marrow_transplant
http://www.bmtinfonet.org/newsletters/issue47/mini.html
http://www.lymphomation.org/bmt-mini.htm
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
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
of proceeding with a transplant 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:
http://www.cmlsupport.org.uk/?q=frontpagediaries
http://cml.davidrobertcox.com/
http://caringbridge.org/visit/leamorrison
http://www.pj-plog.blogspot.com/
http://www.caringbridge.org/ct/warner/history.htm
http://cml.davidrobertcox.com/
http://caringbridge.org/visit/leamorrison
http://www.pj-plog.blogspot.com/
http://www.caringbridge.org/ct/warner/history.htm
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, assuming the patient survives the process, are between 60-80% depending on a lot
of variables, and assuming the patient was in chronic phase when
starting the process. If the patient is in the latter stages, success rates are lower.
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 CML patients diagnosed in Accelerated Phase, and is a necessity for those diagnosed in Blast Phase.
Please
remember that I am not anti-transplant. I am simply interested in
people getting good information and making informed decisions. The risks are significant, there is often long term damage to the body, and there can be relapse. It is a difficult decision.
Treatment Guidelines
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
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)
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:
http://www2.mdanderson.org/depts/oncolog/articles/05/4-apr/4-05-1.html
http://www.medicalnewstoday.com/medicalnews.php?newsid=48990
http://www.cancer.gov/clinicaltrials/MDA-DM-97325#Outcomes_CDR0000067600
http://www.medicalnewstoday.com/medicalnews.php?newsid=48990
http://www.cancer.gov/clinicaltrials/MDA-DM-97325#Outcomes_CDR0000067600
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
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
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
http://clinicaltrials.gov/ct/show/NCT00499772
Here
are some other interesting recent
articles:
http://www.cancerwise.org/march_2008/display.cfm?id=07ec8eb6-0636-464f-8c6431df0eac67e3&method=displayfull&color=red
http://www.sciencedaily.com/releases/2007/12/071210094351.htm
http://bloodjournal.hematologylibrary.org/cgi/content/abstract/blood-2008-04-150045v1
http://health.yahoo.com/leukemia-treatment/vaccine-produces-leukemia-remissions/mdanderson--1C235AB9-0AA1-4772-960101B61BA1DCAB.html
http://www.cancernetwork.com/leukemia/article/10165/1161889
http://www.cancerwise.org/march_2008/display.cfm?id=07ec8eb6-0636-464f-8c6431df0eac67e3&method=displayfull&color=red
http://www.sciencedaily.com/releases/2007/12/071210094351.htm
http://bloodjournal.hematologylibrary.org/cgi/content/abstract/blood-2008-04-150045v1
http://health.yahoo.com/leukemia-treatment/vaccine-produces-leukemia-remissions/mdanderson--1C235AB9-0AA1-4772-960101B61BA1DCAB.html
http://www.cancernetwork.com/leukemia/article/10165/1161889
There
is much work to be done, but the research shows that the concept is
worth pursuing.
YOUNG PEOPLE WITH CML
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 and other CML drugs have 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, but 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 choice" (sorry, that is very much inadequate) issue rather than which treatment will work better. Transplant may (but not always) result in a cure, but it has serious potential side effects such as sterility, autoimmune issues, susceptibility to secondary cancers in the future, and so on, as well as the risks of the transplant itself. The choice will continue to be a difficult one for families as they struggle to decide, but fortunately with CML the issue is less about survival than about other issues
For a bone marrow transplant introductory paper see here:
http://treyscml.blogspot.com/p/special-topics-on-cml.htm
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 and other CML drugs have 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, but 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 choice" (sorry, that is very much inadequate) issue rather than which treatment will work better. Transplant may (but not always) result in a cure, but it has serious potential side effects such as sterility, autoimmune issues, susceptibility to secondary cancers in the future, and so on, as well as the risks of the transplant itself. The choice will continue to be a difficult one for families as they struggle to decide, but fortunately with CML the issue is less about survival than about other issues
For a bone marrow transplant introductory paper see here:
http://treyscml.blogspot.com/p/special-topics-on-cml.htm
RANDOM
MUSINGS......
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.
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.
Most of us feel much better over time as drug treatment progresses and we adjust to the CML drug. 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, headaches, and other side effects either decrease or go away over time. I was diagnosed in 2005 and the initial extreme tiredness for me went away after a year or so, along with most side effects. Muscle cramps have held on but are significantly decreased. I am as active now as prior to diagnosis.
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.
I
have determined that slow stretching and muscle/joint warm-up is
required prior to any physical activity. I am more susceptible to
muscle pulling, straining, or injuring some ligament or muscle with
only minor activity, and they heal more slowly.
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 TKI drugs at different rates, and it
is both a GI tract uptake issue and also a cellular uptake issue.
Possibly size and weight can be a factor, but that is not 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.
A
person could have two PCRs done on the same exact sample of blood and
the result could vary by ½ log. PCRs are estimates, not actual
measurement.
CML
is an exercise in learning lots of new and fun terminology you never
wanted to know.
Overall, steady wins the race.
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 years of CML survivors talking with each other. That is all this is -- nothing more.