18 replies to this topic

[Dad'sAdvocate]

http://community.lls.org/message/57417#57417  Hi, It appears I had posted my Question in the wrong forum the above is a link to the original ? and replies, any input would be greatly appreciated!  Thank you!   Long story short....My father had normal blood work done just over 2 months ago and 5 days later before he could make it to the Onc to confirm suspicion of CML he suffered paralysis and had a chloroma removed from his spine.  I know this is not normally attributed with CML.  He was dx with Blast Phase CML PH+ and also has an additional triple chromosomal transformation 9,22,12.  He had emergency radiation and a round of cladribine, cytarabine  and  escalating doses of Gleevac.  He went through neutropenia fine.  Unfortunately, he did not go into remission.  His counts starting rising and the Dr. didn't even need to do the BMB at the follow up appt. after hospital discharge, so no Transplant as planned.  He has been in rehab since leaving the hospital to try to regain the use of his legs and functions. They put him on Gleevac again 600 mg. and his WBC's have went down now at 28,000 compared to 31,900 3 days ago and blast are ok but his platelets are continuing to rise.  They are now at 989,000.  They have been treating him as having AML since he had the chloroma (chemo wise) but what I'm wondering is the platelet rise a sign of the CML transitioning into AML?  If so he'd be PH+ AML?  And Gleevac isn't supposed to help AML much, correct?  I suppose we're in the watch and wait period to see how he responds to the Gleevac and that they would need to see a few CBC's to make an informed decision as to what plan of attack to take next.  ???  The onc said if the Gleevac kept him stable he'd be satisfied for now.  The next step will be to have him over to Moffitt in Tampa to consult with the Dr. who his Onc has been consulting with for treatment plan.  One good thing, his MRI's showed no more chloroma's have formed and no further damage to the spinal cord!   What are normal ranges in AML? I had read that Accelerated phase of CML is Platelet count >1,000,000, unresponsive to therapy. Would a platelet count > 1,000,000 be considered "stable?"  Does anyone have any experience in a case like this?  Thank you!  Kelly

[Trey]

Kelly,

We hope your Dad will do well.  He obviously has some tough challenges ahead of him, since his case is unusual.  He is putting up a good fight.

Of course, CML is caused by a chromosome translocation when a piece  of chromosome 9 swaps places with a piece of chromosome 22 and it is  designated t(9,22).  When another gene becomes involved in the translocation, it may or may  not be significant.  Involvement of chromosome 12 in CML is very rare, and does  not usually create a three-way t(9,12,22) but rather two separate  translocations t(9,22) and t(9,12) at the same time.  You might want to ask the Onc whether it is a 3-way or two separate translocations.  If separate translocations, here are some  references for your Onc:

http://www.ncbi.nlm.nih.gov/pubmed/7805037?dopt=Citation

http://atlasgeneticsoncology.org/Anomalies/t912ID1080.html

http://atlasgeneticsoncology.org/Anomalies/t0912q22p12ID1226.html

Essentially, translocations involving either chromosome 9 or 12 can cause over-production of blood cells, so when combined the effect can be magnified.  Whether it is a 3-way or two separate translocations, the involvement of 12 is not a good sign.

A chloroma can occur in CML on rare occasions with a blast crisis diagnosis, but can occur in Ph+ AML in late stage, or with certain myelodysplastic syndromes (MDS).

When CML transitions into the last stages it will normally mimic either AML or ALL.  If the lymph cells are not overly involved, then it would be acting like AML but with the Ph+.  I assume that in your Dad's case it mimics AML.

You also mentioned in the link you referenced that "I do remember off hand it did show abnormal male karotypes in all genes".  I assume you mean deletion of the Y chromosome.  So he also has deletion of the Y chromosome in all karyotyped cells in addition to the 9, 12, and 22 issues.

So the options could be: 1) CML, 2) CML + MDS, 3) Ph+ AML, or 4) Ph+ AML + MDS.

http://en.wikipedia.org/wiki/Myeloid_sarcoma

The platelets going up over 1 million is not a good sign.  It is certainly not a sign of stability.

On the better news side, his WBC count is not so bad right now.  That is some level of encouragement.  The hope would be for that to remain stable.

Overall your Dad is facing quite a challenge.  From what you have said, he does not appear to be in good enough shape for a BMT.  The involvement of chromosome 12, plus the deletion of  chromosome Y, plus the very high platelets, plus the blast crisis diagnosis puts him in a very high  risk category.  The CML drugs can sometimes (rarely) work under this type of scenario, but often not well,  and often not for very long.  But there are always exceptions.  Given  the lack of response to chemotherapy, there are not many alternatives.   But if it were me, I would rather be on Sprycel than Gleevec for late  stage CML.  Tasigna is not approved for blast crisis CML, so it is not an option.

Your Dad should only be treated by a very good leukemia specialist.  Local Oncs cannot handle this type of situation.

I might be able to help more if I could see the BMB report.  If you want to send it to me, contact me using the LLS email (click on my name, then under "Actions" click on "Send private message").

We hope your Dad will do well.

[mamawarrior]

Kelly, i am so sorry about your dad. I will be the first to admit that i know nothing about cml nor do i know if cml folks run platelets that high. My son had aml, diagnosed at 18, went through chemo for 8 mos, relapsed 14 mos. later, went through chemo again, then to transplant with chemo/total body irradiation and double umblical cord stem cell transplant.

Your post caught my eye and i just wanted to mention that after my sons very first induction chemotherapy, when he recovered his platelet count was high, in the 600,000 range. Certainly not as high as your dads but i was concerned and questioned the oncologist about it and he told me it was a "rebound or reactive thrombocytosis", his marrow responding to being slammed. His platelet counts did return to the low end of normal, which is normal for alot of aml folks. I have never heard of aml folks running high platelet counts, in most cases they are constanty requiring platelet transfusions because in aml the leukemia grows so rapidly that it crowds out the marrow and prevents the marrow from making red cells, normal white cells, and platelets. Generally on diagnosis, active disease or relapse of aml the platelets are very low.

Again, i know nothing of cml, how it transforms to aml, and i certainly would be concerned with a platelet count that high. I hesitated to even post here because of my lack of knowledge in this area  but thought i would respond to your aml question.  If by any chance this is aml, that is the only scenario i can think of, since that is an awfully high white count, to have a platelet count that high in aml. I hope that his next blood draw shows improvement.

[Dad'sAdvocate]

Thank you both for your replies.  I was mistaken about the chromosomal translocation.  It is a triple translocation between 7,11,12 in addition to the 9,22.

Trey, I sent the cytogenic report and went back and read in your blog that you too experienced a very high platelet count with CML as well so was reassured to know that someone else with CML  had a platelet spike so high.  Wow, Trey got your email THANK YOU!!!

Mama Warrior thank you for your reply!  I know no one here is a doctor or an expert but being new to this I would like to be informed as possible and reading others experiences is very helpful in at least knowing what to look for or good questions to ask.  That makes perfect sense that marrow would respond to being slammed.  My Dad does have CML but the chemo combo was actually for AML and Hairy Cell patients.  Reading your profile story you are indeed a Mama Warrior!  You've been through quite a journey, your son is a fighter and I wish you both the best!  Thank you for not hesitating to reply because everyone's replies and experiences answer questions.

Blood Work to be done again tomorrow, I'll update.

Thanks to all!

[Trey]

Kelly -- as we discussed by email, we both thought that posting my email to you, after I had reviewed the BMB report, might help others who might encounter this issue in the future:

As you have seen, the report states that there are 2 separate  translocations, namely, t(7,12,11)(p21q13p11) and t(9,22)(q34;q11).   These two translocations were seen in all 20 cells (white blood cells)  analyzed as shown by the "[20]" after the listed translocations, so he  is 100% positive in his marrow cells for these translocations.  The  report talks about how the t(9,22) causes CML, but it is silent about  what the t(7,12,11) might mean, except that under "Indications for  Study" it says "CML, AML".  So the lab is leaving the interpretation up  to the Oncs but suggesting the Oncs look into both CML and AML.

The t(9,22)(q34;q11) is the expected translocation in "normal" CML.   The t(7,12,11)(p21q13p11) is a very rare one, and I did not find any  exact reference in literature.  But we can extrapolate some things about  it.  As FYI, the translocations are listed with the first parenthesis  containing the specific chromosomes involved t(7,12,11), and the second  parenthesis shows where the chromosomes broke off from their original  locations (p21q13p11).  Both can be meaningful.

But first, there is no deletion of the "Y" chromosome.  Although  that can happen in CML, the report only says "abnormal male karyotype",  which simply means he is a male with some type of chromosome  abnormality.  So we can eliminate the Y chromosome issue.

But back to the t(7,12,11)(p21q13p11) issue, we would like to know  what these chromosomes cause when they come together.  And we know that  the various mixes of these chromosomes when combined can cause Acute  Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL).
We know that a t(7,11) causes AML (possibly some M2 or M4 subtypes, or  maybe just "unknown" subtype).
http://www.nature.co...ng0296-159.html
http://atlasgenetics...s/t0711p15.html
We  also know that t(7,12) causes AML (several subtypes) and also ALL.
http://atlasgenetics...0712ID1177.html
We know that t(11,12) can cause Acute Megakaryoblastic Leukemia, which  is associated with AML but primarily affects the platelets, since the  Megakaryocyte cells become the platelets.
http://atlasgenetics...5p13ID1428.html

So all three 7, 11, and 12 chromosomes can be involved in leukemia.   In this t(7,12,11) it is the t(7,11) which would be the expected type  of AML 2-way, with chromosome 12 entering as the third chromosome into  this 3-way translocation.  That helps narrow the field of possibilities  regarding the disease type and prognosis, but since the chromosome 12 is  thrown in, it could either help, or hurt, or do nothing.  When pieces  of chromosomes touch each other they create signals to the body, so if  chromosome 12 is keeping pieces from touching in certain ways, it could  make the outcome better or worse or be neutral.  There is no real way to  know.  So if you want hope, you can find it there, but it also offers  the opposite.

Since t(7,11) is AML, it becomes clear that your Dad has a form of  AML.  And since he also has t(9,22) he also has CML.  So I would  conjecture that this is Ph+ AML.  That is because the AML seemed to be  there from the beginning, not the CML first that then transitioned to  mimic AML.  So that is why I would call this primarily AML with the CML  added (Ph+ AML), especially with the chloroma.  With the entrance of  chromosome 12 into the 3-way mix on the AML side, anything can happen,  either helping or hurting, but seems to be unknown.  We only know what  these translocations cause by looking at what they have done in people  in the past.  With no history, the answer is unclear.

Additional information would come from the other reports.  If you  have others to send, I can take a look at them.  The additional  information needed would include Flow Cytometry Report, CBC, FISH, PCR,  Complete Metabolic Panel.  These would show valuable additional info as  follows:
Blast count
Make-up of blasts (cell types)
Marrow "morphology"  (non-chromosome abnormalities found in marrow)
High/Low cell counts  (esp platelets)
Is the leukemia in the spinal fluid? (Normally does  not enter it).
Any other risk factors found in the reports?

Regarding the  specialist issue, for cases like this, only a very accomplished  specialist can sort it out, if at all.  If it were me, I would go to MD  Anderson, but Tampa is closer for him.  On the other hand, your local  Onc knows he cannot handle this, so is only ordering tests and relaying  info.  That is OK, as long as nothing is missed.  It depends on how  comfortable you and your Dad are with the current process, need to  travel several times, etc.  But it would be a good idea to go to a  specialist at least one time when enough tests have been done to provide  a complete picture.

As far as your Dad's prognosis, I think it would be hard to say for  most Oncs.  Unusual cases create significant unknowns.  Your Dad is  certainly in a high risk category.  But even high risk patients can beat  the odds.  Regarding treatment, every Onc would tell him to have a BMT  if he can physically withstand it.  But the failure to respond to  chemo/radiation is an issue.  At some point a person needs to assess the  risks/benefits of drug therapy vs BMT, and quality of life for a  certain time period, whatever the time period might be.  A BMT if  unsuccessful is the worst of both worlds.  But there are sub-options  such as mini-transplant.  Drug therapy might be viewed as a long-shot  that would allow a better quality of life in the meantime.  I do not  know the right answer for him.

Hope this helps. This is a tough issue for you, and I am trying to be as factual  as possible.  I emphasize that with unique cases can come unique  outcomes.

[scuba]

Trey - Some clarification ...

How does CML cause high platelet count?  And why would the count go up if Gleevec is bringing the other counts down?

Is this because of the translocations you described above or something else? How do they measure for the various translocations apart from T(9,22)

[Dad'sAdvocate]

Thank you Trey!

To update from last blood counts...

WBC down from 28,900 to 22,800

Platelets down from 989,000 to 800's

Metamyelocyte's up (not sure what these are?) from 1 now at 4

also SGPT up

These reports were 6 days apart.

[Trey]

Michael,

First, I can assure you that your platelets rising has nothing to do with the scenario described above.

In CML (and also AML) the original leukemic cell is far up the chain in the blood stem cell hierarchy.  This is not true of other leukemias such as ALL and CLL, where the original leukemic stem cell is lower in the hierarchy.  So the higher the originating leukemic cell is in the stem cell hierarchy, the more different types of blood cells it produces.  So for CML and AML, the original leukemic stem cell produces all types of blood cells, including all types of white blood cells (both myeloid and lymphoid) plus red blood cells, and also megakaryocytes (which become the platelets as they break apart).  So this first item to note is that in CML, the WBCs, RBCs, and platelets are all fully involved in the leukemia problem.

When Gleevec starts working, killing off the leukemic cells (including a certain portion of the leukemic stem cell hierarchy), several things start to happen.  One is that not all types of cells are equally affected at first.  Megakaryocytes (which form platelets) live longer than the WBCs, so the WBC levels drop the fastest.  Then after the Megakaryocytes break apart into platelets, those platelets stay in the body for 8 - 10 days.  So the cycle for clearing the leukemic megakaryocytes/platelets is longer than for the WBCs. (As FYI, then end-state platelets and RBCs do not have a nucleus, so cannot truly be called "leukemic", but they can have reduced functionality)

Another factor is that platelets do not simply float around the body at will.  The spleen sequesters most platelets, and only releases them as it deems appropriate.  So the platelet count can bounce around quite a bit based on the whims of the spleen.

When the leukemic WBCs start dying off quickly and in huge quantities, the body says "Oh Sharts -- we need more WBCs!!!"  The good stem cells (non-leukemic ones) had been shut down because there were already too many WBCs.  Now they need to ramp up production.  So the start-up process can work inefficiently, with maybe more Megakaryocytes being produced than other cells, or maybe some other cell type, or maybe they are just slow to start, like Tedsey and others. Somehow the body is trying to respond to all the wierd signals, and sometimes odd things happen.

So for these reasons and others that are not completely understood, the platelet counts will often be the last to come back into normal range after starting drug therapy.  Often there will be an intial slow drop in platelets, followed by a spike higher, then a slow settling back into normal, and then maybe going too low, and then return slowly to normal.  That is what I saw, and what many experience.  That is also why an Onc will often declare a CHR while the platelets are  still in the high (or low) range.  There are also variations in experience, and some people have a completely different platelet experience for several reasons.  But I have described the "CML-normal" scenario.

[Trey]

Kelly,

That is encouraging.  There is a long road ahead, but any good news is wonderful.

A Metamyelocyte is a "teenager" white blood cell.  If Metamyelocyte counts are rising, then there is some level of maturing going on in the blood cells.  Mature WBCs work better than immature ones (WBC blasts).  Hopefully this means that the cells are maturing more normally.  But it is somewhat hard to tell without looking at the trends of all the WBCs over time.

SGPT (also called ALT) is a liver enzyme.  With all your Dad has been through, rising ALT is not unusual.

http://www.medicinenet.com/liver_blood_tests/page2.htm

[Dad'sAdvocate]

Thank you so much Trey!

We'll take any good news we can get!

And to quote my sister (I've been forwarding all information)

I'm sure you already have, but please be sure to thank him on behalf on the entire family.  Knowledge is power and he is the best source we've found so far!!!

We so appreciate you taking the time to explain the things we don't understand and we have more questions than the Oncologist has time.

This forum has been such a blessing!

[scuba]

Thanks Trey!  I have a better understanding now.

Also - this article fleshed out your comments as well:

http://clincancerres.aacrjournals.org/content/12/2/340.full

Getting at the stem cells that have become leukemic - seems to be the key (hence my interest in Dr. Li's work at U.Mass).

I wonder if there is something about middle age (50's) that provides an environment for translocation (in the case of CML).  So Even if drugs are developed that completely eradicates every Leukemic stem cell - is there something in our "older bodies" that cause normal blood stem cells to translocate the chromosomes and re-start the disease?

[Gayle]

I have CML and responded well to the Gleevec, however, my platelets never did respond.  When they reached 1.3 million doctor admitted me for pheresis.  This lowered my platelets, I remained on Gleevec while in the hospital, however they spiked a week later to 2.3 million and I did have a siezure as they placed the pheresis cath.  I was then put back on hydrea and switched to Tasigna.   Tasigna caused heart problems and I am now on hydrea and Sprycel.  Praying that all stays in check, however the hydrea is what is keeping my platelets in check!!  I have 100% confidence in my doc since I came to Pittsburgh, I have to trust him because no matter how hard I try, I can't grasp all the CML lingo.  My prayers to you and your family!

[scuba]

Hi Gayle - I am confused - why would the platelets jump like that?  I thought Gleevec would reduce platelet count if it is working?

I am only 3.5 weeks into Gleevec and my platelets also went up (590k) while my WBC's decreased to normal.  I wonder if something else is triggering this ...

[Tedsey]

Michael,

Re-reading and just had to comment.  I will rejoice if I am so lucky to make it to 50.  Will probably throw a block party and advertise in the paper.  Since CML is relatively rare, if it were just middle age that causes the translocation (and I think about 1/3 of our population is in their 20s & 30s and about 2% are children), CML would not be so rare.  If you are more susceptible to it, perhaps middle age is a factor.  But what factors have to be present to be susceptible?  And how long?  Thus, your musing about middle-age.  In the news lately, as you mentioned, there has been some controversy about Americans getting too much radiation through unnecessary medical tests.  I read it too.  Of course there are other sources of radiation.  For some of us CMLers, it may be that we have gotten too much.  So far, the best supported thing that may cause CML in many individuals is ionizing radiation (i.e. Hiroshima and getting CML as a secondary cancer after radiation therapy).  I have had tons of xrays, a few CT scans, an MRI (but I am not sure about the radiation there).  However, not all people who are exposed to radiation get CML.  I am keeping a log of how many xrays, etc. my kids get and will question if some future tests are needed.  Doctors do not track this.  My 3 yr old and 1 yr old each have had one xray.  My 1 yr old has had a couple of ultrasounds after her birth.  And I had many with my 1st child (did not know I was pregnant, funny, at the time, I thought I had cancer, so there was a lot of catching up to do to see how far along I was).  

I wonder if there is a way to test how much radiation a person has had or how radioactive they are.  I know most of my adult life, I have always caused interferrence whenever I passed a radio or other type of machine.

[scuba]

Hi Tedsey,

The point on medical equipment radiation is that many of the machines - especially machines located in specialized "imaging" labs are not calibrated properly and emit 100's of times more radiation than needed to get the diagnostic image.

This was reported in the news not too long ago and may be a surprise to many - it was for my Oncologist.  One CT-scan machine they tested provided enough radiation equivalent to 60,000 dental X-rays.  We just don't know.

Any way that's my thinking on why I have CML.  I had 3 CT-scans around my hips (hmmm - right where my bone makes blood cells) - all done at an imaging center rather than a hospital.  An MRI does not emit ionizing radiation.  It's just a strong magnet.

On platelets - Trey described earlier in this thread what is likely going on, but I am still puzzled - why both very high and very low platelets can be caused by CML (during Gleevec treatment).

The more we learn about CML the more complex it becomes.  No real surprise.  Proteins are as vairied as there are people.  Think about it:  We all have the 'same' basic protein make-up for our skin - yet we all look different from one another.  Just one tweak here and one tweak there makes my protein different than yours even though similar enough to be called skin.  At the cell level, the same is undoubtedly going on.  We all have "leukemic" stem and projenitor cells.  But each has a slightly different protein expressed.  That's why for some, Imatinib works and for others it doesn't (and everything in between).  It is my belief that true success in cancer will come from creating antibodies unique to each individual.  They take YOUR cancer cells and create the cure.  I don't know how pharamceutical companies make money doing that - customized drugs??

[Tedsey]

Michael,

If I could predict the future and I hope we are both around when it happens, from what I have already read, right now I believe what you say to be true. "It is my belief that true success in cancer will come from creating antibodies unique to each individual.  They take YOUR cancer cells and create the cure."  If it can be done with a pill or shot, then there is much reason for big pharma to go after this.  If still 1 out of 3 people come down with cancer in the future, there is a market.  Once scientists finish mapping the human genome (maybe less than 10 years if we are fast), it may be possible to see more.  As it is believed we differ genetically by 4%, which seems small philosophically, (i.e. what is race?  ex. some people who look like they have African heritage do not), but 4% is likely more of a significant number scientifically.  Perhaps it is possible to find pathways that lead to cures in most people or all.  I am afraid personalized medicine may come around a little late for us.  But if new drugs and therapies can keep this monster at bay until we very grow old and gray, it is all good--even if we cannot understand all the intricacies.

As for the original hematopoitic stem cell, how long do they live?  I am under the impression that there are ones as old as I am still hiding out in my body.  So, now I need to study what makes up a stem cell and how it behaves.   Is a projenitor and hematopoietic stem cell the same thing?  Or is there a hierachy?  Little confused.  

[scuba]

Trey will sort us out on the hierarchy ...

but training T-cells to attack the membrane proteins "unique" to Leukemic stem cells and unique to each one of us is where the answer lies.

I am making a bold statement:  That approach will work 100% of the time.  Until then - combinations might get us there for the vast majority, but not all (for example, interferon first, then Gleevec second seems to cause cure in some).  It's always the "some", not all.  All requires exact protein match.  And each of us have slightly different proteins.  Most are close enough for the Gleevec's, the Tasigna's, & Sprycell's to give excellent response, but not "Cure".  Some have Platelets go up, some go down. Why?  because our proteins are slightly different - close enough that skin is skin, not close enough that my skin looks different than yours.  It's that slight difference that at the molecular level makes all the difference.

Attack the damn thing at its roots with the exact protein inhibitor matched to your body to shut it down and blow it up.  What a breakthrough that would be.

[Trey]

Leukemic stem cells look very much like non-leukemic ones to the immune system (T-cells, ect).  As a crude example, if a normal cell has a PR1 antigen that is a certain height on the normal cell, the leukemic cell will have a PR1 that looks just like it, except it is 10% taller.  That is not a lot for the T-cell to use to recognize it as "non-self" and kill it.  So teaching the immune system to recognize and kill leukemic cells (vaccine) is not an easy task.  They are still looking for the one perfect antigen to use.

[scuba]

"They are still looking for the one perfect antigen to use"

That was my point Trey - finding the one perfect antigen.